key: cord- - yuznrdv authors: hübener, p.; braun, g.; fuhrmann, v. title: das akut-auf-chronische leberversagen als diagnostische und therapeutische herausforderung der intensivmedizin date: - - journal: med klin intensivmed notfmed doi: . /s - - - sha: doc_id: cord_uid: yuznrdv acute-on-chronic liver failure (aclf) is an emerging clinical syndrome in patients with underlying liver disease that is usually triggered by one or multiple insults and characterized by progressive hepatic and nonhepatic organ failure, a significant risk of infections, and high short-term mortality rates. despite our incomplete understanding of the underlying pathophysiology, aclf requires timely diagnostic and therapeutic measures aiming at the identification and elimination of causative factors as well as the prevention of complications to improve the prognosis of affected patients. das akut-auf-chronische leberversagen (aclf) wird im zusammenschluss der european association for the study of the liver (easl) und der american association for the study of liver diseases (aasld) als "akute verschlechterung einer vorbestehenden chronischen lebererkrankung, die üblicherweise im zusammenhang mit einem auslösenden ereignis steht und aufgrund eines multiorganversagens mit erhöhter -monats-letalität verbunden ist" definiert [ ] . der fokus der definition liegt dabei eindeutig auf dem organversagen, das zumeist extrahepatische organe betrifft (. abb. ) und die prognose betroffener patienten am stärksten beeinflusst [ , ] . zur identifizierung, risikostratifizierung sowie definition in abhängigkeit von klinisch relevanten outcomeparametern wurden in großen prospektiven multizentrischen untersuchungen -davon eine in europa (chronic liver failure consortium acute on chronic liver failure in cirrhosis, canonic) und eine in kanada/den usa (north american consortium for the study of end stage liver disease, nacseld) -risikogruppen p. hübener, g. braun und v. fuhrmann repräsentieren die sektion gastroenterologie der deutsche gesellschaft für internistische intensivmedizin und notfallmedizin (dgiin). mit hoher kurzfristiger mortalität identifiziert. gleichzeitig wurde die prognostische wertigkeit klinischer scores für das aclf evaluiert [ , ] . hierbei zeigte sich ein in der tendenz erwarteter, in der tatsächlichen ausprägung jedoch alarmierender anstieg der kurzzeitletalität bis hin zu über % [ ] . klar abzugrenzen ist das aclf daher vom akuten leberversagen (alv), das durch den funktionsausfall einer zuvor gesunden leber definiert ist und bei dem durch intensivmedizinische und supportive maßnahmen in über % der fälle ein Überleben ohne organtransplantation erreicht werden kann [ , ] . die identifikation spezifischer auslöser des aclf ist für die diagnosestellung nicht zwingend erforderlich (. tab. ). die häufigsten auslöser des aclf sind geographisch unterschiedlich verteilt und oft für den krankheitsverlauf relevant [ ) . die häufigsten auslöser des aclf sind geographisch unterschiedlich verteilt und oft für den krankheitsverlauf relevant [ , ] . sie beinhalten lokale und generalisierte infektionen, neue oder fortgesetzte leberschädigung durch alkohol und/oder andere hepatotoxische substanzen, operationen, zirkulationsstörungen sowie seltenere ursachen wie beispielsweise einen schub einer autoimmunen hepatitis (. tab. ). während die varizenblutung traditionell eher als dekompensation einer vorbestehenden leberzirrhose gewertet und ihre mortalität in den letzten jahren durch moderne evidenzbasierte behandlungsstrategien (einschließlich endoskopischer blutstillung, medikamentöser und interventioneller senkung des portosystemischen druckgradienten und vermeidung infektiöser komplikationen) gesenkt werden konnte, können sowohl hämorrhagischer als auch septischer schock nach einer blutung ein aclf auslösen. in bis zu % der fälle kann kein auslösendes ereignis identifiziert werden. in diesen fällen liegen möglicherweise subklinische infektionen, passagere störungenderintestinalen barriere oder unerkannte hepatotoxische effekte als mögliche auslöser zugrunde [ ] . unabhängig davon, ob das aclf durch direkte oder indirekte schädigung der leber ausgelöst wird, scheinen faktoren im zentrum der pathophysiologie der erkrankung zu stehen: ) hämodynamische veränderungen und ) systemische inflammationsreaktionen ("systemic inflammatory response syndrome", sirs; [ , ] [ ] . zudem wurden auch andere pro-und antiinflammatorische zytokine (stnf-α r , il- , il- , il- , ifn-γ) in stark erhöhten plasmatischen konzentrationen bei patienten mit aclf nachgewiesen [ ] . auch routinelaborparameter, wie leukozyten und crp, sind bei patienten mit aclf erhöht und korrelieren in ihrer höhe mit der anzahl von organausfällen und dem aclf-grad [ ] . bei patienten, die eine erste immunaktivierung im rahmen des auslösenden stimulus überleben, wird, ähnlich wie bei der sepsis ohne lebererkrankung, ein Übergang in einen immunsupprimierten bzw. immundysregulierten zustand ("immune paralysis"; [ ] ) beobachtet, der das risiko für weitere infektionen signifikant erhöht. angesichts der hohen letalität hospitalisierter zirrhotiker bei infektionen (etwa %) bzw. bei schweren bakteriellen infektionen mit septischem schock ( - %; [ ] [ ] [ ] ) erscheint eine aggressive antiinfektive präventions-und therapiestrategie bei aclf-patienten von zentraler bedeutung. die canonic-studie ging der frage nach, welcher anteil von -zunächst meist auf einer normalstation -hospitalisierten zirrhosepatienten ein aclf aufweisen oder im verlauf entwickeln und welche prognostischen parameter sich in dieser patientengruppe ausmachen lassen, um besonders gefährdete subgruppen frühzeitig zu erkennen. das aclf wurde dabei als häufigste indikation für eine aufnahme von zirrhosepatienten auf eine intensivstation identifiziert. die anzahl und das jeweilige ausmaß von organversagen wurden mittels eines modifizierten sequentialorgan-failure-assessment(sofa)-scores erfasst, da sich dieses system in der vergangenheit zuverlässiger in der mortalitätsabschätzung von kritisch kranken zirrhosepatienten erwiesen hatte als die meld-oder child-pugh-klassifikation. der sofa-score wurde für die studie modifiziert (. tab. ) und schließlich in eine vereinfachte form ("clif consortium organ failure score", clif-c-ofs) mit identischen organparametern und ähnlichem prognostischem wert modifiziert. der schweregrad des aclf wurde anhand der anzahl der organausfälle (of) stratifiziert: aclf : of, aclf : of, aclf : - of. in die außerordentlich hohe dynamik des krankheitsbilds aclf spiegelt sich auch in der tatsache wider, dass während der hospitalisierung in etwa % eine besserung und in % eine verschlechterung auftrat [ ] . die heilungsrate sank mit dem aclf-grad von % (aclf ) über % (aclf ) bis auf % (aclf ). da sich der aclf-grad zumeist in den ersten beiden bis maximal tagen änderte, wird hier ein "goldenes zeitfenster" für therapeutische interventionen vermutet (. abb. ). für eine risikoabschätzung von patienten mit akuter dekompensation einer leberzirrhose mit oder ohne aclf wurden klinische und laborchemische parameter identifiziert, die mit erhöhter mortalität assoziiert waren. hier wurden ) die anzahl von organversagen (nach clif-kriterien), ) das patientenalter sowie ) die konzentration zirkulierender leukozyten als unabhängige variablen identifiziert. diese resultate gingen wiederum in eine erweiterung des clif-c-ofs ein ("clif consortium aclf score", clif-c aclfs), der einen punktwert von - annehmen kann und eine deutlich bessere vorhersagekraft hinsichtlich der -, -, -und -tages-mortalität besitzt als meld-, meld-na-und child-pugh-score [ ] . nachteilig ist hierbei, dass der score (verglichen zum ursprünglichen sofa-oder auch clif-sofa-score) nicht ohne eine komplexe formel berechnet werden kann; die kalkulation kann jedoch beispielsweise durch einen onlinerechner des "clif consortium" erfolgen [ ] . in der weiteren aufarbeitung der canonic-kohorte zeigte sich eine %ige letalität von patienten mit ≥ organversagen und/oder einem "clif-aclfs score" ≥ nach - tagen therapie, sofern keine lebertransplantation erfolgte [ ] . die zahlen unterstreichen den stellenwert eines frühen und raschen -insbesondere intensivmedizinischen -therapiebeginns, um das fortschreiten des multiorganversagens zu durchbrechen. ob eine frühzeitige lebertransplantation bei patienten mit aclf zielführend ist, ist derzeit thema kontroverser debatten und wird erst durch zukünftige studien geklärt werden können. zusätzlich kann die wiederholte risikostratifizierung mittels scores bei patienten mit aclf in dem schwierigen entscheidungsprozess hinsichtlich der art des weiteren therapeutischen vorgehens (kurativer oder palliativer therapieansatz) helfen. wir möchten jedoch betonen, dass derartige entscheidungen definitiv ärztliche entscheidungen sind, die niemals von einem score übernommen werden dürfen. im rahmen dieses ärztlichen entscheidungsprozesses müssen neben der unmittelbaren schwere der erkrankung beispielsweise auch der mutmaßliche patientenwunsch, jeweilige lokale und nationale Überlebensraten, eine potenzielle reversibilität der or-das akut-auf-chronische leberversagen als diagnostische und therapeutische herausforderung der intensivmedizin zusammenfassung das akut-auf-chronische leberversagen ("acute-on-chronic liver failure", aclf) ist ein emergentes krankheitssyndrom, das durch einen oder mehrere akute trigger bei vorgeschädigter leber ausgelöst wird und vom progressiven hepatalen und nichthepatalen organversagen, einem gravierenden risiko infektiöser komplikationen sowie hoher kurzfristiger letalität gekennzeichnet ist. wenngleich pathophysiologisch noch weitgehend unverstanden erfordert das aclf frühzeitige diagnostische und therapeutische maßnahmen, die sich auf zugrunde liegende ursachen sowie das verhindern von komplikationen richten, um die prognose betroffener patienten zu verbessern. leberversagen · zirrhose · infektion · organversagen · transplantation acute-on-chronic liver failure: a diagnostic and therapeutic challenge for intensive care abstract acute-on-chronic liver failure (aclf) is an emerging clinical syndrome in patients with underlying liver disease that is usually triggered by one or multiple insults and characterized by progressive hepatic and nonhepatic organ failure, a significant risk of infections, and high short-term mortality rates. despite our incomplete understanding of the underlying pathophysiology, aclf requires timely diagnostic and therapeutic measures aiming at the identification and elimination of causative factors as well as the prevention of complications to improve the prognosis of affected patients. liver failure · cirrhosis · infection · organ failure · transplantation acute-on chronic liver failure acute-on-chronic liver failure toward an improved definition of acute-on-chronic liver failure survival in infectionrelated acute-on-chronic liver failure is defined by extrahepatic organ failures acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis lessons from look-back in acute liver failure? a single centre experience of patients acute liver failure the pathogenesis of aclf: the inflammatory response and immune function acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis tumor necrosis factor alpha and interleukin plasma levels in infected cirrhotic patients pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study patients with acute on chronic liver failure display "sepsis-like" immune paralysis short-term prognosis of community-acquired bacteremia in patients with liver cirrhosis or alcoholism: a population-based cohort study bacterial infection in patients with advanced cirrhosis: a multicentre prospective study infections in patients with cirrhosis increase mortality fourfold and should be used in determining prognosis clinicalcourseofacuteon-chronic liver failure syndrome and effects on prognosis development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure acute-on-chronic liver failure: consensus recommendations of the asian pacific association for the study of the liver (apasl) glucocorticoids plus n-acetylcysteine in severe alcoholic hepatitis prednisolone or pentoxifylline for alcoholic hepatitis management of critically-ill cirrhotic patients intensive care of the patient with cirrhosis acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes acute-onchronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list acute-on-chronic liver failure: terminology, mechanisms and management bacterialinfectionsincirrhosis: a position statement based on the easl special conference management of acute-on-chronic liver failure transfusion strategies for acute upper gastrointestinal bleeding albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. a randomized, controlled study deleterious effects of betablockers on survival in patients with cirrhosis and refractory ascites nonselective beta blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis lack of consensus for usage of beta-blockers in end-stage liver disease treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-onchronic liver failure intensive care unit admissions with cirrhosis: risk-stratifying patient groups and predicting individual survival prognostic importance of the cause of renal failure in patients with cirrhosis acutekidneyinjuryandacute-onchronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the international club of ascites albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study randomized controlledstudyofextracorporealalbumindialysis for hepatic encephalopathy in advanced cirrhosis extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the relief trial prometheus versus molecular adsorbents recirculating system: comparison of efficiency in two different liver detoxification devices effect of the molecular adsorbent recirculating system and prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-onchronic alcoholic liver failure effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure high-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial extracorporeal liver support and liver transplant for patients with acute-on-chronic liver failure international liver transplant society practice guidelines: diagnosis and management of hepatopulmonary syndrome and portopulmonary hypertension pulmonary complications in liver diseases therapeutic options in pulmonary hepatic vascular diseases hepatocardiac disorders : interactions between two organ systems hepatic encephalopathy in patients with acute decompensationofcirrhosisandacute-on-chronic liver failure coagulation parameters and major bleeding in critically ill patients with cirrhosis management of acute-on-chronic liver failure: rotational thromboelastometry may reduce substitution of coagulation factors in liver cirrhosis nutrition for the liver transplant patient nutritional management of acute and chronic liver disease the nutritional management of hepatic encephalopathy in patients with cirrhosis: international society for hepatic encephalopathy and nitrogen metabolism consensus the safety of intubation in patients with esophageal varices granulocyte colony-stimulating factor mobilizes cd (+) cells and improves survival of patients with acute-on-chronic liver failure key: cord- - po xe g authors: streetz, k.l.; tacke, f.; koch, a.; trautwein, c. title: akutes leberversagen: Übersicht zur aktuellen diagnostik und therapie date: - - journal: med klin intensivmed notfmed doi: . /s - - - sha: doc_id: cord_uid: po xe g although acute liver failure is a rare disease with a prevalence of per million people, it has a considerablely high mortality rate of %. the main causes in western civilizations are drug overdose (acetaminophen) and viral hepatitis. patients are affected by the loss of liver synthesis function and are at risk of developing hepatic encephalopathy and possible multiorgan failure. specific therapies consisting of the administration of n-acetylcysteine (acetaminophen) or of nucleotide/nucleoside analogs (hepatitis b) are possible, but are often not adequate. orthotopic liver transplantation is, therefore, frequently the only remaining effective therapy for severe acute liver failure. due to organ shortage, new prognostic tools, e.g., the acute liver failure study group (alfsg) score, have been developed to improve patient selection using sufficiently stringent selection criteria. das alv ist als eine potenziell reversible leberfunktionsstörung (ikterus, koagulopathie "international normalized ratio", inr, > , ) mit rascher entwicklung einer hepatischen enzephalopathie ohne vorliegen eines chronischen leberschadens definiert. die amerikanische "acute liver failure study group" unterscheidet in bezug auf die zeit zwischen dem auftreten von koagulopathie und beginnender hepatischer enzephalopathie weiterhin zwischen dem hyperakuten (< tage), dem akuten ( - tage) und dem subakuten ( tage - monate) leberversagen [ ] . in deutschland geht man aktuell von etwa - fällen eines alv aus [ ] . insgesamt liegt die prävalenz bei etwa pro mio. einwohner. epidemiologische daten zur genese des alv zeigen bezüglich der zugrunde liegenden ursachen ein diversifiziertes bild. eine kürzliche erhebung an patienten einer deutschen kohorte zeigte, dass die ursache in % nicht durch acetaminophen (paracetamol) induziert medikamentös toxisch, in % viral und in % durch acetaminophen bedingt war. in % der fälle konnte sie sogar nicht genau bestimmt werden [ ] . eine lebertransplantation erfolgte hier in % der schweren fälle mit begleitender enzephalopathie. in nordamerika und mitteleuropa dominieren intoxikationen (hauptsächlich paracetamol, antibiotika u. a.) vor viralen hepatitiden und selteneren ursachen (. tab. ). in etwa % der fälle bleibt die ursache noch unklar, wie durch eine große aktuelle auswertung des eurotransplant-registers (. abb. ) verdeutlicht wird [ ] . die dem alv zugrunde liegende pathogenese ist abhängig von der auslösenden ursache vielfältig. getriggert durch zytotoxische botenstoffe (tumornekrosefaktor-α, tnf-α) und mediatoren (reaktive sauerstoffradikale) kommt es zum hauptsächlich periportalen zelluntergang, der durch nekrotischen und apoptotischen zelltod von hepatozyten bedingt ist. begleitet wird dies von einer variablen entzündungsreaktion. bei unkontrolliertem untergang von hepatozyten kommt es zu einer progredienten organdysfunktion mit entwicklung einer koagulopathie. durch die verringerte synthese von gerinnungsfaktoren und deren inhibitoren verlängert sich die prothrombinzeit. eine begleitende plättchendysfunktion und thrombopenie führt dann zu klinisch vermehrter blutungsneigung. der ausfall der hepatischen entgiftungsfunktion geht mit einem messbaren anstieg des bilirubins und des ammoniaks einher. es kommt weiterhin zu einer erhöhung des splanchnischen druckgra- ausreichend effektiv. die durchführung einer lebertransplantation ist hier oft die einzige verbleibende therapieoption. neue prognosescores, wie der acute-liver-failure-studygroup(alfsg)-score, ermöglichen eine verbesserte patientenselektion, um dem organmangel durch eine ausreichend stringente indikationsstellung gerecht zu werden. paracetamol · transplantation · hepatische enzephalopathie · multiples organversagen · organdysfunktionsscore acute liver failure. diagnosis and therapy abstract although acute liver failure is a rare disease with a prevalence of per million people, it has a considerablely high mortality rate of %. the main causes in western civilizations are drug overdose (acetaminophen) and viral hepatitis. patients are affected by the loss of liver synthesis function and are at risk of developing hepatic encephalopathy and possible multiorgan failure. specific therapies consisting of the administration of n-acetylcysteine (acetaminophen) or of nucleotide/nucleoside analogs (hepatitis b) are possible, but are often not adequate. orthotopic liv-er transplantation is, therefore, frequently the only remaining effective therapy for severe acute liver failure. due to organ shortage, new prognostic tools, e.g., the acute liver failure study group (alfsg) score, have been developed to improve patient selection using sufficiently stringent selection criteria. acetaminophen · transplantation · hepatic encephalopathy · multiple organ failure · organ dysfunction scores problemen) und ggf. rekombinanter faktor viia sowie kryopräzipitat (fibrinogen, faktor viii, xiii, von willebrandfaktor; bei hypofibrinogenämie < mg/dl) verwendet. zur prävention der statistisch häufigen oberen gastrointestinalen blutung wird die durchführung einer säuresuppression mittels protonenpumpenhemmern oder h -blockern empfohlen. die behandlung des alv sollte bei entsprechender schwere der erkrankung (anhaltende leberfunktionseinschränkung, beginnende enzephalopathie) nach möglichkeit in einem zentrum mit transplantationsmöglichkeit erfolgen. sofern möglich sollte natürlich unverzüglich eine kausale therapie eingeleitet werden (. tab. ). die etablierte therapie des häufigen paracetamolinduzierten alv besteht in der intravenösen gabe von n-acetylcystein (nac) in form eines -stündigen reduktionsschemas (nac: mg/kg/h für h, dann , mg/kg/h für h und , mg/kg/h für h). interessanterweise wurde in einer prospektiven multizentrischen studie gezeigt, dass es beim nicht durch paracetamol bedingtem alv unter gabe von nac zumindest bei patienten mit niedriggradiger hepatischer enzephalopathie (°i-ii) ebenfalls zu einer verbesserung des transplantatfreien Überlebens kommt [ ] . daher empfiehlt sich das nebenwirkungsarme nac-schema generell auch bei allen anderen entitäten des alv. eine spezifische behandlung sollte bei der akuten hepatitis-b-infektion eingeleitet werden. sinnvoll erscheint aktuell die einleitung einer behandlung mittels hochpotenter antiviraler medikamente, wie entecavir und tenofovir [ ] . bei sicherung der diagnose einer autoimmunen hepatitis ist eine steroidtherapie indiziert [ ] . im rahmen eines herpes-simplex-virus(hsv)-induzierten alv wurde die wirksamkeit von aciclovir gezeigt. die wenigsten therapien sind jedoch durch gute randomisierte studien abgesichert, da aufgrund der niedrigen fallzah-len oft nicht ausreichend patienten rekrutiert werden können. da der verlauf des alv in seiner geschwindigkeit kaum vorhersagbar ist, empfiehlt sich die frühzeitige verlegung in ein transplantationszentrum. kontraindikationen für eine lebertransplantation, wie aktiver alkoholabusus, drogenkonsum, schwere systemische und maligne erkrankungen sowie eine fehlende soziale einbindung, die für die komplexe anschließende nachbetreuung notwendig ist, müssen ausgeschlossen werden. lebertransplantation sollte rasch und unverzüglich erfolgen die listung für eine lebertransplantation sollte rasch und unverzüglich erfolgen, um auf den möglicherweise rapiden verlauf des alv entsprechend reagieren zu können. durch alv bedingte lebertransplantationen machen etwa % aller lebertransplantationen aus, wie aktuelle daten des europäischen lebertransplantationsregisters zeigen [ ] . diese rate blieb über die letzten jahre ungefähr konstant. daten einer prospektiven amerikanischen studie belegen die effektivität und notwendigkeit dieser therapieoption [ ] . hier wurde gezeigt, dass % der patienten mit alv nach erhalt einer frühen transplantation überlebten, während die Überlebensrate ohne lebertransplantation bei nur % lag. in der regel beeinflussen faktoren den erfolg einer notfalllebertransplantation im rahmen einer high-urgency(hu)-listung eines patienten mit alv: das alter des empfängers, die schwere der lebererkrankung und die qualität des spenderorgans. je schlechter der klinische zustand des patienten ist, umso schwieriger sind die allgemeinen transplantationsbedingungen. patienten mit paracetamolinduziertem alv sind hierbei am meisten beeinträchtigt. ebenso zeigen patienten über jahre eine -fach erhöhte morta- koch geben an, dass kein interessenkonflikt besteht. f. tacke erhielt vortragshonorare von den firmen gilead trautwein erhielt vortragshonorare von den firmen gilead dieser beitrag beinhaltet keine studien an menschen oder tieren evolution of indications and results of liver transplantation in europe. a report from the european liver transplant registry (eltr) extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-onchronic liver failure: the relief trial population-based surveillance for acute liver failure acute liver failure: a life-threatening disease liver transplantation for acute liver failure in europe: outcomes over years from the eltr database etiologies and outcomes of acute liver failure in germany usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure acute liver failure: summary of a workshop intravenous n-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure extracorporeal detoxification using the molecular adsorbent recirculating system for critically ill patients with liver failure results of a prospective study of acute liver failure at tertiary care centers in the united states development of an accurate index for predicting outcomes of patients with acute liver failure keratin variants predispose to acute liver failure and adverse outcome: race and ethnic associations management of severe acute to fulminant hepatitis b: to treat or not to treat or when to treat? key: cord- - iisb jw authors: khurana, aman; nelson, leslie w; myers, charles b; akisik, fatih; jeffrey, brooke r.; miller, frank h.; mittal, pardeep; morgan, desiree; mortele, koenraad; poullos, peter; sahani, dushyant; sandrasegaran, kumar; tirkes, temel; zaheer, atif; patel, bhavik n. title: reporting of acute pancreatitis by radiologists-time for a systematic change with structured reporting template date: - - journal: abdom radiol (ny) doi: . /s - - - sha: doc_id: cord_uid: iisb jw acute pancreatitis has a wide array of imaging presentations. various classifications have been used in the past to standardize the terminology and reduce confusing and redundant terms. we aim to review the historical and current classifications of acute pancreatitis and propose a new reporting template which can improve communication between various medical teams by use of appropriate terminology and structured radiology template. the standardized reporting template not only conveys the most important imaging findings in a simplified yet comprehensive way but also allows structured data collection for future research and teaching purposes. acute pancreatitis (ap) is a common inflammatory process affecting the pancreas with variable disease severity, ranging from a mild course treated with conservative management to severe progressive disease resulting in major morbidity and mortality [ ] . the majority of acute pancreatitis episodes are secondary to gallstones ( . %) and alcohol use ( . %) [ , ] . another relative prevalent etiology is hypertriglyceridemia ( . %), while fourty-eight percent of cases have no known etiology [ ] . iatrogenic injury, infections, neoplasia, structural abnormalities, inflammatory bowel disease, toxins, trauma and drugs are less common etiologies of acute pancreatitis [ ] . per the revised atlanta classification, the diagnosis of acute pancreatitis is defined by at least out of the following features: epigastric pain often radiating to the back, biochemical findings of serum amylase and lipase at least three times the normal limit or radiologic imaging features suggestive of acute pancreatitis [ ] . the revised atlanta classification also differentiates between an early and late phase of acute pancreatitis [ ] . the early phase occurs within the first week of disease onset with pathology caused by early inflammation secondary to peripancreatic edema and ischemia. the severity of this early phase is based on patient's clinical presentation as the imaging findings sometimes may not correlate well [ ] . this is a dynamic phase where the patient will either resolve or continue to progress to a more severe presentation. the late phase begins within the second week of onset and can last weeks to months and is characterized by the presence of local complications and systemic inflammation. the various complications are able to be characterized by radiological imaging while organ failure continues to be a clinical diagnosis [ ] . the prevalence of pancreatitis has increased by a total of % from to . when divided by age groups, the incidence of acute pancreatitis in emergency department visits showed an increase of . % (ages - ) and . % (ages - ) from to . this is in contrast to older patients which demonstrated a decrease in incidence − . % (ages - ) and − . % (greater than years old) [ ] . the obesity pandemic appears to have increased the incidence and severity of acute pancreatitis secondary to the risk of gallstones, diabetes mellitus, hypertriglyceridemia, incretin based medication and endoscopic interventions for management [ ] . in , there were approximately , annual emergency department visits for the diagnosis of acute pancreatitis and , visits for chronic pancreatitis. of these visits, % of acute and . % of chronic pancreatitis were admitted to the hospital with a median length of stay of days. there were ( . %) and ( . %) hospital deaths related to acute and chronic pancreatitis, respectively. the aggregate charges for the pancreatitis treatment in was $ , , , and aggregate costs were $ , , , [ ] . the atlanta classification system for acute pancreatitis was the first standardized system proposed to create a standardized communication for gastroenterologists, pathologists, radiologists and surgeons with common terms of acute pancreatitis and associated complications [ ] (table ). at the time of its creation, the classification made great strides by attempting to standardize the diagnosis of acute pancreatitis and provide a framework to consistently and reliable define its severity and categorize its complications. as a greater understanding of the pathogenesis and natural evolution of the disease occurred, shortcomings of the original atlanta classification schema were uncovered. as an example, one major limitation was its lack of specific radiologic criteria for defining complications associated with ap, especially when describing pancreatic and peripancreatic fluid collections. the classification defined the following four complications: acute fluid collection, acute pseudocyst, pancreatic abscess, and pancreatic necrosis (table ) [ ] . these definitions were vague and failed to adequately describe isolated peripancreatic collections as well as collections that contained both solid and fluid components. ultimately, this contributed to the widespread misuse and incontinency in applying the terms. this limitation was highlighted in a study that demonstrated poor interobserver agreement between radiologists using the original classification for characterizing peripancreatic collections on ct [ ] . the original classification did not differentiate pancreatic and peripancreatic necrosis nor did it delineate sterile vs infected necrosis. properly describing and differentiating these entities is crucial because there is a profound impact on prognosis and management. in the revised atlanta classification sought to resolve these limitations by updating terminology, types of ap, definitions of complications, and separating the disease temporally into two distinct phases. previously, there have been several terms within the nomenclature for describing complications of acute pancreatitis that have been ambiguous and/or improperly used leading to much clinical confusion. one such example was the term "pancreatic abscess" that had been defined as "a circumscribed intra-abdominal collection of pus, usually in proximity to the pancreas, containing little or no pancreatic necrosis, which arises as a consequence of acute pancreatitis or pancreatic trauma" [ ] . infected necrotic collections are far more common than true pancreatic abscesses and the distinction between the two entities is important because of a profound impact on morbidity and mortality as well as management [ ] . in order to truly differentiate the two entities, positive fluid cultures were required in the absence of necrosis to accurately define a collection as a pancreatic abscess. this was impractical and only contributed to delayed or inappropriate care. ultimately, due to its ubiquitous misuse the term pancreatic abscess was removed from the nomenclature in the revised atlanta classification in and has been replaced by infected or sterile necrosis as described below. the revised atlanta classification (rac) of ap published in to address the growing limitations of the original ac schema (table. ). greater understanding of the pathophysiology and natural evolution of the disease resulted in defining two distinct phases of ap: early (< week after onset) and late (> week after onset). severity and management during the early phase are solely based on clinical parameters, whereas in the late phase clinical and radiographic findings influence management and severity. an important change in the rac was the development of a three-tiered system for grading ap severity as mild, moderately severe, or severe based on the presence and duration of organ failure. mild pancreatitis is defined by lack of organ failure, lack of local or systemic complications and self-resolving course [ ] . moderately severe acute pancreatitis defined by transient organ failure (< h) or local or systemic complications with absence of persistent organ failure. moderately severe acute pancreatitis may require treatment and does have slightly increased mortality (approximately %) [ ] . severe ap is characterized by organ failure greater than h, often accompanied by local and systemic complications or death. approximately - % of acute pancreatitis will advance to severe acute pancreatitis [ ] . the duration of organ failure is a marker of poor outcome and associated with higher morality, therefore requires more aggressive management [ ] . to facilitate prompt and appropriate management in patients with ap, the rac eliminated and outdated ambiguous terms such as infected pseudocyst, phlegmon, hemorrhagic pancreatitis and persistent acute pancreatitis, that lead to confusion and often delayed or inappropriate treatment. perhaps the greatest improvement of the rac was its development of specific criteria for categorizing complications of ap. this was a significant limitation of the original classification that contributed to poor interobserver agreement in defining pancreatic and peripancreatic fluid collections. the rac distinguishes complications as either acute (< weeks after onset) or delayed (> weeks after onset) and further subcategorizes based on necrotic vs interstitial types of pancreatitis [ ] (table ) . it should be noted that it takes approximately weeks to form a well-defined capsule and therefore the revised classification emphasizes on this point. some collections may form capsules before or after this time interval, in those cases the imaging characteristics are given preference over this time interval. acute complications are categorized as either acute peripancreatic fluid collection (apfc) or acute necrotic collection (anc) and delayed complications are defined as either pancreatic table differences between types of acute pancreatitis (a) and fluid collections (b) in the and atlanta classifications for acute pancreatitis please note that it takes approximately weeks to form a well-defined capsule and therefore the revised classification emphasizes on this point. some collections may form capsules before or after this time interval, in those cases the imaging characteristics are given preference over this time interval pseudocyst (pc) or walled-off necrosis (won). any of these collections can develop a superimposed infection, therefore they are referred to as either sterile or infected. each type of collection is managed uniquely, and thus, it was essential to standardize definitions so that complications can be accurately and consistently reported to surgeons, endoscopists, interventionalists, and clinicians with greater clarity. imaging is typically not indicated in the early course of ap because the diagnosis can be made on clinical and biochemical data and early imaging (< h) can often be misleading because of underestimation of the true degree of parenchymal involvement as well as the inability to reliably assess complications in the early course of the disease [ ] . furthermore, early imaging has not been found to improve clinical outcomes and in some studies, it has been suggested that it may prolong hospitalization [ ] . iap/apa guidelines state that initial imaging is indicated in the following circumstances: ( ) diagnosis is unclear ( ) confirm the clinical prediction of severe pancreatitis ( ) clinical deterioration or failure to respond to conservative measures [ ] . imaging still plays a monumental role in the characterization and management of complications of ap. contrast-enhanced ct is the modality of choice in the initial assessment of patients with ap to determine the etiology, define the severity and identify complications and early signs of necrosis [ ] . defined by the current revised atlanta classification there are currently two main morphologic subtypes of ap based on radiographic findings: interstitial edematous pancreatitis (iep; % of cases) and necrotizing pancreatitis (np; % of cases) [ ] . the characteristic radiographic findings of iep include: focal or diffuse pancreatic edema, diffuse pancreatic enhancement, peripancreatic fat stranding and/or haziness (fig. ). np demonstrates a relatively more diverse array of morphologies dependent on the location of necrosis. the location of necrosis differentiates the three patterns of np: pancreatic ( %), peripancreatic ( %) or combined ( %) (fig. ) . in pancreatic np, the key radiographic finding is focal or diffuse non-enhancement of the pancreatic parenchyma without the presence of a peripancreatic necrotic collection (fig. ) . peripancreatic np usually demonstrates diffuse pancreatic enhancement, but will have mixed solid/fluid necrotic collection(s) in the peripancreatic tissues (figs. , ) . combined np will show diffuse or focal areas of pancreatic non-enhancement in addition to adjacent necrotic peripancreatic solid/fluid collections (figs. , ) [ ] . imaging within the first h of symptom onset may fail to demonstrate necrosis as interstitial edema and early necrosis can look identical (heterogeneous enhancement). if present, the region(s) of necrosis will evolve over time and develop a characteristic non-enhancement pattern which is best evaluated by contrast enhanced ct. for these reasons, h after the onset of symptoms is considered the ideal time for imaging patients in order to confidently identify acute complications of ap [ ] . in a clinical setting, determining necrotic versus interstitial edematous pancreatitis is critically important as it has a profound impact on prognosis. patients diagnosed with iep have a mortality rate of approximately % compared to patients with np, which have a mortality rate of % and up to % if superimposed infection is present [ ] . abdominal ct has contributed significantly to the assessment of acute pancreatitis by determining the degree of severity, extent of necrosis, fluid collections, pseudocysts, abscess and prognosis [ ] . according to the working group of the international association of pancreatology (iap) and american pancreatic association (apa) iap/apa acute pancreatitis guidelines when a patient presents with diagnostic uncertainty of acute pancreatitis there is a strong recommendation to complete initial ct assessment [ ] . however, optimal timing of initial ct imaging is at least - h after the onset of symptom presentation. performing a ct scan earlier than this has been shown to have low yield and no clinical management implantations [ ] . further indications for ct imaging include confirmation of severity based on clinical course, failure to respond to conservative treatment and clinical deterioration. follow up imaging with ct is indicated when there is a lack of clinical improvement, especially when there is consideration for an invasive intervention [ ] . mr with fluid sensitive sequences helps better fig. axial cect images of a pancreatic parenchymal necrosis alone with heterogeneous nonenhancement of the pancreas (arrow) b peripancreatic necrosis alone with heterogeneous area of non-enhancement with non-liquified components in the peripancreatic fat (arrow) but with normally enhancing pancreas parenchyma (arrowhead) and c pancreatic and peripancreatic necrosis with peripancreatic necrotic collection (arrow) and heterogeneous non-enhancement of the pancreas indicating necrosis (arrowhead) fig. axial cect image of diffuse necrotizing pancreatitis and the proposed template demonstrating non-enhancing pancreatic parenchyma (demarcated by arrows) and surrounding inflammatory changes assess the presence of debris within a fluid collection and the presence of ductal disruption [ ] . the management of acute pancreatitis is mostly supportive care, however, the challenge of treatment occurs when the patient presents with severe disease and complications [ ] . therefore a multidisciplinary approach is utilized when there is an indication for intervention. determining the amount of necrosis (less than %, - % or greater than %) and the location of necrosis (head, body or tail) assists in the determination of the patient's potential need for operative intervention [ ] . a patient with presence of pancreatic necrosis is ten times more likely to have surgical intervention [ ] . another example of the role of imaging in altering the management is the diagnosis of infected necrosis, which is made when the patient experiences fever, develops increasing inflammatory markers and demonstrates gas in the peripancreatic collection on imaging, at which point percutaneous fine needle aspiration of the collection is not required to confirm the diagnosis as the clinical and radiological findings are sufficient for a diagnosis [ ] . radiological modalities not only assist with the patient's diagnosis, but can also help reveal the cause of acute pancreatitis. visualization of the gallbladder and biliary tract can further evaluate pathology as biliary or non-biliary etiology, as gallstones are the most common cause of acute pancreatitis accounting for at least - % of cases [ , ] . management of ap is largely influenced by two main factors: severity and complications. one of the most crucial steps in initial management of a patient presenting with ap is determining the etiology of pancreatitis so that any reversible cause can be addressed promptly. once the etiology has been addressed, the severity of the disease needs to be determined in order to appropriately triage patients to ensure that the critically ill receive the appropriate level of care. the iap/apa evidence-based guidelines for the management of acute pancreatitis state that the best predictor of ap severity/prognosis at the time of admission and at hr is the presence of systemic inflammatory response syndrome (sirs) [ ] . any patient that is classified as severe should be admitted or transferred to the icu for close surveillance as mortality in this population has been reported to be as high as - % [ ] . patients classified with mild disease often have a self-limited course that requires supportive care only. patients classified with moderately severe or severe disease will require more aggressive care and possibly open or minimally-invasive interventions. patients with morphologic iep on imaging often have a mild and self-limited course that typically only requires supportive care. if present, concomitant apfcs often will either regress or mature to pseudocysts, of which the majority of will resolve without requiring intervention. approximately % of patients with pseudocysts develop symptoms or superimposed infection that in turn requires intervention [ ] . percutaneous or endoscopic catheter drainage are the treatment modalities of choice in the management of infected or symptomatic pseudocysts. patients with morphologic np on imaging have increased morbidity and mortality requiring intervention far more often than ap patients without concomitant necrosis. surgeons, endoscopists, interventionalists and radiologists must be able to work together and communicate openly and effectively so that the best treatment plan can be tailored to each individual case of infected np. at the center of this multidisciplinary approach is the role of the radiologist in communicating the appropriate information that is needed in order to tailor management. therefore a more comprehensive yet structured reporting template is imperative for clear and concise communication of the most relevant information to the members of the multidisciplinary team. while the revised atlanta classification system has made improvements in the diagnosis and classification of acute pancreatitis, there are still areas for further improvement. for example in one prospective study by talukdar et al., patients who were originally classified into moderately severe acute pancreatitis with primary infected necrosis had outcomes similar to severe acute pancreatitis, therefore the former disease course should be treated more aggressively [ ] . also, with the current classification, there remains variability among subspecialty and general radiologists as shown by sternby et al. who demonstrated only fair agreement between the local radiologists and the central expert in diagnosis of non-homogeneous collections and extra-pancreatic necrosis resulting in inconsistent reporting [ ] . further establishment of widespread terminology use and simple identification of complications could continue to improve pancreatitis templates [ ] . until now, however, no radiology reporting templates have been proposed for standardized reporting of acute pancreatitis and its complications. the rsna's radiology reporting initiative has been a widely recognized effort to improve reporting practices by creating and managing a library of clear and consistent report templates [ ] . greater standardization could result in more comprehensive reports, better communication and fewer misdiagnoses [ ] . consistent radiologic reports are of paramount importance in assessment of the degree of disease severity and response to therapy in both clinical practice and clinical trials. a prior study compared content, clarity and clinical usefulness of conventional (free text) and structured radiology of body ct scans and found that mean content and clarity satisfaction ratings were significantly higher for standardized reporting when compared to conventional reports [ ] . structured reporting has been introduced in other abdominal imaging pathologies, particularly pancreatic cancer where newer reporting styles have shown superior evaluation of pancreatic cancer and resultant improvement in surgical planning, with increased confidence of surgeons regarding decisions about tumor resectability when structured reports were utilized [ ] . safety checklists are frequently used in surgery as a quality assurance tool to effectively reduce complication rates and mortality in adults undergoing noncardiac surgery [ ] . beyond improved clinical communication, the implementation of checklists in radiology has been demonstrated to reduce variability and error rates [ , ] . another key role of structured reporting is its role in facilitating learning among trainees by providing them with a standardized and systematic approach to recognize the key features needed in radiologic reports of patients with specific diseases. even though implementation of department-wide standardized structured reporting can be problematic, prior work has shown excellent adoption rate (approaching %) by focusing on automatic population of examination specific reports and more efficient report monitoring for quality assurance and research [ ] . overall, structured reporting aims to provide the benefits of standardization such as clearer communication, comprehensive details and increased accessibility of data for research without compromising radiologists' ability to communicate qualitative findings and opinions. the proposed reporting template is for acute pancreatitis and is meant to be used with contrast enhanced ct imaging to ensure a complete evaluation of the pancreatic parenchyma and associated vasculature. the template was constructed from a group of expert radiologists who are members of society of abdominal radiology, pancreatitis disease focussed panel over multiple sessions. the entire reporting template is summarized in appendix table . the primary goal of standardized reporting is to ensure proper communication between all sub-specialists involved in the care of the patient. this template incorporates revised atlanta classification scheme and terminology while maintaining flexibility to add free text for the qualitative aspects of the report. the four broad categories of this template are . pancreas, . peripancreatic collections, . upper abdominal vasculature and . other. these categories allow comprehensive reporting of pancreatic parenchymal enlargement and enhancement, patency of the pancreatic duct, location and type of peripancreatic collection, presence of gas/infection within and around the pancreas and assessment of peripancreatic vasculature for thrombosis, aneurysm etc. the first and the most important category of this template is centered around findings related to the pancreas itself. pancreatic enlargement is classified as focal or diffuse and its enhancement is classified as homogenous or heterogenous (figs. , ) . this is most helpful in describing interstitial edematous pancreatitis. pancreatic necrosis is subclassified by the anatomical region of the organ and percentage of the non-enhancing pancreatic parenchyma, for example %, < %, - % and > % subcategories (fig. ) . these subcategories are clinically important because amount of gland necrosis is predictive of development of superimposed infection, organ failure, and morbidity and mortality, and need for necrosectomy [ ] . evaluation of the pancreatic duct is often not reported in free text reports but in this template we focus on the contiguity of the pancreatic duct in efforts to identify and correctly diagnose disconnected duct syndrome (fig. ) . in these patients, the disease can be centered about the ductal epithelium and persistent inflammatory collections and fistulae are usually seen. the diagnosis of disconnected duct syndrome is suggested when following findings are encountered, > cm area of necrosis, viable upstream tissue and extravasation of contrast on ercp [ ] . dpds can be suggested on cross-sectional imaging, cect or mrcp, however, pancreatography remains the gold standard for confirmation and ductal characterization [ ] . secretin-enhanced mrcp is an emerging technique that utilizes the physiologic properties of secretin to induce pancreatic exocrine function, which in turn produces optimal ductal morphologic features that can be appreciated on mrcp. the administration of secretin during mrcp results in increased sensitivity for detecting chronic pancreatitis, ipmns and ductal injuries or variants compared to mrcp without secretin administration [ ] . for this reason secretin-enhanced mrcp has been postulated to be a reliable noninvasive alternative for diagnosing dpds. however, secretin-enhanced mrcp has not yet been proven to have greater sensitivity than ercp in determining the site of ductal disconnection, therefore it currently assumes a complementary role to traditional endoscopy in diagnosing dpds [ ] . additional findings related to pancreatic duct include presence of dilation, strictures and calculi. intrapancreatic collections can be seen with pancreatic parenchymal necrosis and disconnected duct syndrome. lastly, other ancillary findings related to pancreas are reported such as presence of pancreatic divisum or solid/cystic mass. the second most important category in the reporting template is peripancreatic fluid collections. they are subcategorized as . acute peripancreatic fluid collections which are associated with interstitial edematous pancreatitis or . acute necrotic collections associated with necrotizing pancreatitis provided if the retroperitoneal findings are visualized less than weeks from symptom onset. acute peripancreatic fluid collection should be homogenous density and adjacent to the pancreas, intrapancreatic fluid collections and collections with variable attenuation should be considered as necrosis [ ] . acute necrotic collections may reside within the pancreatic parenchyma and may be associated with pancreatic duct disruption (fig. ) . similarly, pseudocyst and walled off necrosis categories are used when encapsulated collections associated with interstitial and necrotizing pancreatitis, respectively, are more than weeks old respectively (figs. , ) . all of these collections can be sterile or infected. unlike pseudocysts, walled off necrosis collections commonly involve pancreatic parenchyma. the location fig. a proposed template with axial cect image of focal area of intraparenchymal pancreatic necrosis (arrow) which is suspicious for a disconnected pancreatic duct and b coronal mrcp confirming disconnected duct syndrome as no connection between the pancreatic ductal segments (arrowheads) is visualized and the intraparenchymal fluid collection is again seen (arrow) of the peripancreatic collection is crucial for gastroenterologists and interventional radiologists to plan the drainage route and feasibility. it may be subclassified as within transverse mesocolon, mesenteric root, and right or left anterior pararenal spaces. presence of gas and hemorrhage within the collection are other important findings which predict higher morbidity and mortality and thus deserve attention in this template. the determination of an infectious process is important for diagnosis as there is a higher likelihood for treatment and intervention if it is present [ ] . thus it is critical to have appropriate communication with the patient's primary care team. collections that demonstrate non-liquified material are more likely to be infected or secondary to fat necrosis. however, the best indicator for infection fig. a proposed template and axial cect image of an acute peripancreatic collection with non-encapsulated fluid within the transverse mesocolon (arrow) and left anterior pararenal space b proposed template and axial cect image of a peripancreatic pseudocyst with mass effect (arrows) in a patient with an episode of acute pancreatitis more than weeks prior to imaging fig. a proposed template and axial cect showing necrotizing pancreatitis with adjacent heterogeneous encapsulated walled off necrosis with internal fat components (arrow) in the transverse mesocolon in a patient with an episode of acute pancreatitis more than weeks prior to imaging and b proposed template and axial cect showing necrotizing pancreatitis with adjacent walled off necrosis with foci of gas (arrow) in the transverse mesocolon and left anterior pararenal space fig. a proposed template and axial cect showing a large peripancreatic pseudocyst with non-dependent gas (arrow) b proposed template and axial unenhanced ct showing a heterogeneously attenuating pseudocyst with adherent blood products (arrow) fig. a proposed template and axial cect showing extensive upper abdominal varices (arrow) secondary to splenic vein thrombosis due to infected necrosis b proposed template and curved planar reformation of ct angiogram showing a splenic artery pseudoaneurysm (arrow) secondary to infected necrosis on ct imaging is the presence of gas in the fluid collections although often not seen [ ] (figs. , ) . of note, it is important to thoroughly evaluate for gas caused by fistula, spontaneous drainage into the gastrointestinal tract and/or prior intervention to avoid false positive findings [ ] . if there is no gas present in the collection and there remains a high suspicion, diagnostic proof may be obtained by performing fine need aspiration for gram stain and culture of fluid [ ] . lastly, the presence of pancreatic stent and its positioning are included to aid clinicians in deciding further patient management. a brief yet important category in this proposed template is focused on upper abdominal vasculature. the pancreas is surrounded by crucial mesenteric and splenic vasculature which are commonly involved in acute or resolving pancreatitis. the splenic, superior mesenteric and portal veins can be thrombosed based on the location of parenchymal inflammation and/or necrosis. perigastric varices can be a subtle indicator of underlying splenic vein thrombosis in patients with severe inflammation or intrapancreatic fluid collections which could make direct vascular evaluation difficult (fig. ). pseudoaneurysms occur from erosion of acute necrotic collections, walled off necrosis and pseudocysts into adjacent vasculature (fig. ). these take time to occur and therefore do not present in early disease but are associated with high mortality rates (~ %). typical clinical presentations include hemorrhage within the gastrointestinal tract or within intraperitoneal spaces. last but not the least, the proposed template includes a section for adding free text in the midst of a very templated report. this will allow the radiologists to comment on ancillary findings such as gastric or left colonic wall thickening, duodenal narrowing and edema, presence of gallstones, biliary ductal dilation etc. this section also provides space to explain any of the above findings or complications in further detail. comparisons to prior studies can also be described at length in this section. acute pancreatitis is a dynamic disease with various imaging presentations leading to important clinical management decisions. imaging can aid in stratification of patients, particularly in identifying pancreatic and peripancreatic necrosis. in this paper, we tried to comprehensively discuss the historic and current classifications of acute pancreatitis and propose a new reporting template which fosters communication between different medical teams by use of appropriate terminology and structured radiology template. the standardized reporting template reduces ambiguity in radiologist's reports while allowing creation of a structured data repository for future research and teaching purposes. the revised atlanta classification has been adopted by various academic and private practice centers all over the world but still differences exist between the reports of a general radiologist and an expert when describing various components of acute pancreatitis. we aim to bridge those differences by offering a structured radiology report which provides a comprehensive step-by-step approach in reporting cases of acute pancreatitis and allows radiologists to add important information as free-text at the end of the template. needless to say, specific larger studies are needed to validate improved outcomes in patients with acute pancreatitis for which standardized reporting template is used. acute pancreatitis: international classification and nomenclature updated imaging nomenclature for acute pancreatitis trends and outcomes of hospitalizations related to acute pancreatitis: epidemiology from to in the united states drug-induced pancreatitis: incidence, management and prevention acute pancreatitis: revised atlanta classification and the role of cross-sectional imaging the revised atlanta classification for acute pancreatitis: updates in imaging terminology and guidelines revised atlanta classification for acute pancreatitis: a pictorial essay classification of acute pancreatitis- : revision of the atlanta classification and definitions by international consensus incidence, admission rates, and predictors, and economic burden of adult emergency visits for acute pancreatitis: data from the national emergency department sample obesity and pancreatitis burden and cost of gastrointestinal, liver, and pancreatic diseases in the united states: update a clinically based classification system for 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of clinical, biochemical, and imaging parameters in predicting the severity of acute pancreatitis practice and yield of early ct scan in acute pancreatitis: a dutch observational multicenter study ct and mri assessment of symptomatic organized pancreatic fluid collections and pancreatic duct disruption: an interreader variability study using the revised atlanta classification management and outcomes of acute pancreatitis patients over the last decade: a us tertiary-center experience computed tomographic prognostic factors for predicting local complications in patients with pancreatic necrosis computed tomography severity index is a predictor of outcomes for severe pancreatitis computed tomography severity index vs. other indices in the prediction of severity and mortality in acute pancreatitis: a predictive accuracy metaanalysis treatment of severe acute pancreatitis and its complications the revised atlanta classification of acute pancreatitis: its importance for the radiologist and its effect on treatment clinical utility of the revised atlanta classification of acute pancreatitis in a prospective cohort: have all loose ends been tied significant interobserver variation in the diagnosis of extrapancreatic necrosis and type of pancreatic collections in acute pancreatitis -an international multicenter evaluation of the revised atlanta classification rsna radiology reporting initiative -reporting wiki electronic synoptic operative reporting: assessing the reliability and completeness of synoptic reports for pancreatic resection improving communication of diagnostic radiology findings through structured reporting structured reporting of multiphasic ct for pancreatic cancer: potential effect on staging and surgical planning effect of a -item surgical safety checklist during urgent operations in a global patient population checklists: from the cockpit to the radiology department quality initiatives: lean approach to improving performance and efficiency in a radiology department improving consistency in radiology reporting through the use of department-wide standardized structured reporting necrotizing pancreatitis: a review of multidisciplinary management disconnection of the pancreatic duct: an important but overlooked complication of severe acute pancreatitis endoscopic transpapillary drainage in disconnected pancreatic duct syndrome after acute pancreatitis and trauma: long-term outcomes in patients peripancreatic collections in acute pancreatitis: correlation between computerized tomography and operative findings necrotizing pancreatitis: contemporary analysis of consecutive cases the authors had control of the data and the information submitted for publication. bhavik patel receives research support from ge healthcare and is on its speaker's bureau. temel tirkes is supported by national cancer institute and national institute of diabetes and digestive and kidney diseases of the national institutes of health under award numbers r dk and u dk (consortium for the study of chronic pancreatitis, diabetes, and pancreatic cancer). the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health. all other authors are not employees of or consultants for industry and had control of inclusion of any data and information that might present a conflict of interest. there was no industry support specifically for this study. see table . key: cord- -uzxaey k authors: lehner, g.f.; pechlaner, c.; graziadei, i.w.; joannidis, m. title: monitoring von organfunktionen: dysfunktion von niere, leber, gastrointestinaltrakt und gerinnung date: - - journal: med klin intensivmed notfmed doi: . /s - - - sha: doc_id: cord_uid: uzxaey k monitoring of organ function is one of the core tasks of intensive care medicine. although various monitoring devices and parameters have already been established for some organs, there are no or only few conditionally useful parameters or scores available for the kidneys, liver, gastrointestinal tract, and blood coagulation. therefore, specific biomarkers and scores as well as combinations of both are currently investigated for better monitoring of these organs. this article gives a critical overview of currently used as well as investigational biomarkers, tests and scores in general, and shows some examples of the implications for common diseases, clinical situations and constellations in the intensive care unit. aufgrund der fixen algorithmischen wertung einzelner parameter in scoringsystemen ist die individuelle einschätzung von patienten oft erschwert. bei einigen spezifischen krankheitsbildern können einzelne laborparameter oder ein charakteristisches muster mehrerer laborwerte aussagekräftiger sein als ein score, wobei gängige routinelaborwerte häufig spezifität vermissen lassen. zunehmend stellt sich daher auch die forderung nach organspezifischen biomarkern zur besseren einschätzung von organfunktionen bzw. funktionsänderungen. der vorliegende artikel versucht eine integration verschiedener scores unter einschluss von bekannten und neuen biomarkern für das monitoring der organfunktion für niere, leber, gastrointestinaltrakt und gerinnung. akute beeinträchtigungen der nierenfunktion können unterschiedliche schweregrade aufweisen. das spektrum reicht von einer verminderten urinausscheidung über einen anstieg der renalen retentionsparameter (kreatinin, harnstoff) bis hin zur notwendigkeit einer nierenersatztherapie. die bislang übliche subsumierung all dieser zustandsbilder unter dem begriff akutes nierenversagen erscheint unter dem aspekt der je nach schweregrad der nierenfunktionsbeeinträchtigung stark divergierenden mortalität und morbidität ungeeignet. als eine alternative terminologie wurde der weiter gefasste begriff der akuten nieren schädigung ("acute kidney injury"; aki) eingeführt, zu dem bereits kleinere veränderungen der nierenfunktion gerechnet werden [ , ] . im klinikalltag beruht die beurteilung der nierenfunktion im wesentlichen auf parametern wie der harnproduktion oder der ausscheidung von wasserlöslichen stoffwechselendprodukten, welche beide im starken ausmaß von der glomerulären filtrationsrate (gfr) abhängig sind. eine abnahme der gfr stellt die pathophysiologische gemeinsamkeit der vielfältigen ursachen von akuten nierenschädigungen dar [ ] . als eine näherungsweise abschätzung der gfr gelten die serumkrea tininwerte (s cr ), da eine lineare beziehung zwischen /s cr und der gfr besteht und eine verdoppelung des serumkreatinins einer reduktion der gfr um etwa % entspricht [ ] . ein wesentliches problem des serumkreatinins besteht jedoch darin, dass dieser parameter unter nicht-steady-state-bedingungen (also gerade bei akuter nierenschädigung) keine zuverlässige aussage über die filtrationsleistung darstellt und diese zumeist überschätzt. dementsprechend ist auch die errechnete glomeruläre filtrationsrate (egfr) in dieser situation, im gegensatz zur chronischen nierenschädigung, nicht aussagekräftig. in dieser situation scheint die dynamik der veränderung des serumkreatinins eine verlässlichere aussage über die akute nierenfunktionsstörung zu geben als statische grenzwerte. im jahr wurden von der acute dialysis quality initiative (adqi) die sog. rifle-kriterien, ein akronym der beinhalteten klassen, entwickelt und drei schwergrade der nierenschädigung definiert [ ] . diese klassifizierung beruht zum einem auf der bestimmung von serumkreatinin oder der berechnung der gfr, zum anderen auf der aufzeichnung der harnausscheidung als sensitiver parameter für nierenfunktionsstörungen. auf basis dieser beiden werte erfolgt eine einteilung des schweregrades in die klassen f "risk", "injury" und "failure". zwei weitere klassen werden durch die dauer der abhängigkeit von einer nierenersatztherapie bestimmt (> wochen bzw. > monate) und sind somit outcome-kriterien, nämlich f "loss" und "end stage renal disease". [ ] . obwohl beispielsweise in einer klinischen studie gezeigt werden konnte, dass in einer hochrisikopopulation eine akut eingeschränkte nierenfunktion mittels cystatin c im serum bereits h vor einem anstieg des serumkreatinins festgestellt werden kann [ ] , konnte in einer allgemeinen, heterogenen icu-population weder der serum-noch der urinspiegel dieses markers befriedigend ein aki oder die notwendigkeit einer nieren ersatztherapie voraussagen [ ] . einschränkungen für den breiten einsatz von cystatin c ergeben sich außerdem aus f der fehlenden standardisierung, f dem hohem preis und f der potenziellen beeinflussbarkeit durch entzündung und hormon- intensivmedizin · score · biomarker · prognosebeurteilung · blutgerinnung monitoring of organ function is one of the core tasks of intensive care medicine. although various monitoring devices and parameters have already been established for some organs, there are no or only few conditionally useful parameters or scores available for the kidneys, liver, gastrointestinal tract, and blood coagulation. therefore, specific biomarkers and scores as well as combinations of both are currently investigated for better monitoring of these organs. this article gives a critical overview of currently used as well as investigational biomarkers, tests and scores in general, and shows some examples of the implications for common diseases, clinical situations and constellations in the intensive care unit. intensive care · score · biomarker · prognosis · blood coagulation störungen sowie durch einige medikamente (z. b. hydrocortison, cyclosporin a). darüber hinaus scheint die renale exkretion von niedermolekularen proteinen wie cystatin c oder ngal wesentlich durch proteinurien (z. b. albuminurie) beeinflusst zu werden [ ] . somit bleibt die forderung nach einem zuverlässigen gfr-monitoring beim kritisch kranken patienten offen. erste tierexperimentelle daten z. b. zur bestimmung der gfr mittels endovaskulärer fiberoptischer messung der elimination von fluoreszenzmarkiertem inulin und dextran lassen auf neue "bedside"-methoden hoffen [ ] . zusammenfassung wa stunden früher als die rifle-kriterien aufzeigen [ , ] . es stellt sich aber berechtigterweise die frage, ob ein anstieg des serum-ngal, das ebenfalls glomerulär filtriert wird, nicht eher eine Änderung der gfr als eine tubuläre schädigung reflektiert. eine metaanalyse bestätigt die effektivität von ngal [ ] , allerdings mit geringerer aussagekraft bei erwachsenen verglichen mit kindern. bei schwerer sepsis scheint serum-ngal als frühmarker kaum geeignet, zumal die produktion von ngal durch leukozyten bei diesem krankheitsbild auch ohne aki erhöht ist [ ] . trotz der viel versprechenden ersten studien kann aufgrund der oben erwähnten einschränkungen der generelle einsatz von ngal in der täglichen klinischen praxis noch nicht empfohlen werden [ ] . kim ist ein oberflächenprotein, welches in proximalen tubuluszellen bei ischämie exprimiert wird. für die ausscheidung von kim- im harn konnte einerseits eine hohe spezifität für "akute tubuläre nekrose", andererseits eine gute korrelation mit der letalität bei aki nachgewiesen werden [ ] . weitere biomarker wie nhe , ein membrangebundenes protein, waren ebenfalls im harn von patienten mit ischämischem nierenversagen nachweisbar. das zytokin il scheint ein vielversprechender marker für eine akute nierenschädigung im rahmen von systemischen inflammationsprozessen zu sein. bei patienten mit ali / ards und aki war erhöhtes il- im harn mit erhöhter sterblichkeit assoziiert [ ] . der einsatz der genannten biomarker bei der klinischen diagnose und der klassifizierung der akuten nierenschädigung könnte in zukunft sowohl das frühere erkennen einer nierenfunktionsbeeinträchtigung ermöglichen und durch den dar-aus resultierenden früheren behandlungsbeginn die therapie optimieren als auch die sensitivität und spezifität der existierenden systeme (rifle, akin) wesentlich verbessern sowie möglicherweise sogar verlässliche aussagen über das outcome der patienten ermöglichen. dabei sind noch zahlreiche offene fragen zu beantworten, wie beispielsweise die bedeutung einer stratifizierung der patienten nach der basalen nierenfunktion und/ oder dauer der nierenschädigung vor der anwendung dieser neuen biomarker [ ] . auch die richtige auswahl der bezugsgröße für biomarker im harn scheint erheblichen einfluss auf deren performance zu haben [ ] . abnormitäten der leberparameter sind bei patienten an der intensivstation (icu) oftmals weniger als ausgeprägter hepatozellulärer schaden zu interpretieren, sondern eher als kollateralschaden eines schweren krankheitsbildes (sepsis, infektion) und medikamentös-toxischer kofaktoren. für eine umfassende bewertung von auffälligkeiten bei leberparametern sollten auch testungen auf folgende mögliche ursachen erfolgen: (apache) ii, sofa] eine höhere wertigkeit [ ] . eine prognostische bedeutung des meld-scores konnte sowohl bei patienten ohne hinweis auf eine vorbestehende lebererkrankung, mit nicht-paracetamol-induziertem leberversagen [ ] als auch bei zirrhotischen patienten mit sepsis [ ] gefunden werden. um die prognose bei leberzirrhotischen patienten mit hepatorenalem syndrom (hrs) abzuschätzen, bietet sich die kombination aus meld-score und hrs-subtyp an [ ] . zusammenfassend beziehen leberspezifische scores, vermutlich aufgrund ihrer fokussierung auf leberparameter, andere wichtige mortalitätsdeterminanten nicht mit ein und sind daher für eine verlässliche beurteilung der Überlebensprognose bei icu-patienten nur bedingt nützlich. die an einer icu verwendeten parameter zum monitoring der leber sind im grunde leberfunktionstests sowie gängige labortests, die üblicherweise in synthese-, entgiftungs-, cholestase-und leberzerfallsparameter unterteilt werden (. tab. ). dynamische leberfunktionstest sind, abgesehen von der indocyanine green plasma disappearance rate (icgpdr) und des maximal liver function capacity based on c-methacetin kinetics ( limax™) tests, für routineuntersuchungen wegen der teilweise anspruchsvollen technischen voraussetzungen nur bedingt praktikabel. die icg-pdr kann nichtinvasiv relativ schnell gemessen werden und hat, wenn bei icu-aufnahme gemessen, einen hohen prognostischen wert, welcher mit üblichen scoringsystemen wie saps ii oder apache ii vergleichbar ist [ ] . da nicht nur die parenchymale funktion die icg-pdr beeinflusst, sondern auch die leberperfusion und die biliäre exkretion, sind insbesondere kurzfristige Änderungen dieses parameters nicht spezifisch für leberfunktionseinschränkungen. vielmehr scheinen kurzfristige Änderungen durch variationen der splanchnikusfunktion bzw. leberperfusion bedingt zu sein. im rahmen von leberresektionen oder lebertransplantationen könnte künf-tig der limax™-test helfen, die restkapazität der leber bzw. die initiale leberfunktion nach transplantation zu bestimmen [ ] . dieser "bedside"-test misst zur beurteilung einer akuten leberfunktionsstörung sind wegen ihrer kurzen halbwertszeiten (von h bei faktor vii bis tage bei fibrinogen) die von der leber produzierten gerinnungsfaktoren geeignet. die testung der prothrombinzeit (pt) integriert die faktoren ii, v, vii, x und fibrinogen, also auch vitamin-k-abhängige faktoren. zusammenfassend bietet sich zur erfassung sowohl chronischer als auch akuter einschränkungen der leberfunktion v. a. die kombination aus serumalbumin und pt an. eine isolierte erhöhung des konjugierten bilirubins im serum ist meist mit einer erkrankung der leber und/oder der gallenwege assoziiert. bei icu-patienten mit zirrhose ist die höhe des bilirubins bei aufnahme ein unabhängiger prädiktor für icu-mortalität [ ] . ein weiterer wert, der die entgiftungsfunktion der leber widerspiegelt, ist das serumammoniak. obwohl die höhe dieses parameters wenig mit dem schweregrad der hepatischen enzephalopathie und der leberfunktion korreliert und ebenso bei portovenösen shunts trotz relativ normaler leberfunktion erhöht sein kann, besteht eine gute korrelation zwischen arteriellem ammoniak und intra kraniellem druck bei alv [ ] . zwei enzyme, die einen hepatozellulären schaden anzeigen, sind die in zahlreichen organen vorkommende aspartatamino transferase (ast) und die relativ leberspezifische alaninaminotransferase (alt). erhöhungen bis etwa u/l sind häufig unspezifisch und können bei vielen entitäten von lebererkrankungen auftreten (häufig schwere fettlebererkrankung). das beispielsweise für eine ischämische hepatitis typische muster ist eine plötzliche, mehr als -fache erhöhung der transaminasen mit einem verhältnis von ast / alt > und eine erhöhung der leberspezifischen laktatdehydrogenase (ldh), welche etwa bis tage andauert. ein gutes prognostisches zeichen und indikator für hepatologische regeneration nach akutem leberversagen ist eine hypophosphatämie [ ] . hohe werte von afp (α-fetoprotein), neben seiner bedeutung bei neoplasien vermutlich ebenso ein marker für leberregeneration, stellen bei paracetamolinduziertem alv ein gutes prognostisches kriterium dar [ ] . als funktionelles monitoring des gastrointestinaltrakts gilt im wesentlichen die darmfunktion, bestehend aus toleranz der enteralen ernährung, darmtätigkeit und stuhlentleerungsfrequenz. zum gastrointestinalen monitoring im weiteren sinne können auch werte wie der hämatokrit, hämoglobin, gerinnung, herzfrequenz, blutdruck und andere eine gastrointestinale blutung anzeigende parameter hilfreich sein. spezielle krankheitsbilder wie eine mesenteriale durchblutungsstörung präsentieren sich oft unspezifisch durch leukozytose, ldh-und laktaterhöhung. vorläufige ergebnisse lassen auf neue wertvolle biomarker wie das ischämiemodifizierte albumin hoffen [ ] . obwohl der funktion des gastrointestinaltrakts große bedeutung bei kritisch kranken patienten zugeschrieben werden kann, gibt es derzeit noch keinen allgemein akzeptierten und gut validierten score für dieses organsystem. einige klinische konstellationen wurden bereits bezüglich ihrer prognostischen relevanz getestet. reintam et al. [ ] beispielsweise fanden bei einem kollektiv von icu-patienten eine prognostische wertigkeit bezüglich icu-mortalität des mittleren gastrointestinal failure (gif) scores, bestehend aus den relativ allgemeinen parametern intraabdominelle hypertension und nahrungsmittelintoleranz. eine intensivmedizinisch bedeutende erkrankung des pankreas ist insbesondere die akute pankreatitis. für deren initiale diagnose sind eine mindestens -fach erhöhte amylase oder eine erhöhung der spezifischeren lipase im serum wegweisend [ ] . bei durch gallensteine verursachten pankreatitiden und in den ersten stunden nach symptombeginn ist v. a. die amylase hilfreich, für eine spätere diagnose einer pankreatitis anderer genese eher die lipase [ ] . im klinischen alltag ist für die beurteilung des schweregrads und der prognose einer akuten pankreatitis besonders das c-reaktive protein stunden nach beginn der symptome hilfreich [ ] . künftig potenziell nützliche prognostische parameter könnten inflammatorische marker wie interleukin- und interleukin- sein [ ] . für das krankheitsbild der akuten pankreatitis, werden sowohl organspezifische (ranson-score, modifizierte glasgow-kriterien) als auch allgemeine scores (apache-ii-score, oder ein den body-mass-index einbeziehender apache-o-score) zur prognosebeurteilung und zur abgrenzung einer schweren verlaufsform verwendet. der ranson-score und die modifizierten glasgow-kriterien basieren auf parametern der ersten stunden, der apache-score kann hingegen sowohl bei aufnahme als auch darauf folgend wiederholt bestimmt werden. das laufende monitoring des pankreas besteht bei pankreatitis somit im wesentlichen aus der amylase und lipase. stuhl elastase und pankreolauryltest finden derzeit ihre anwendung als monitoringparameter für die exokrine pankreasfunktion. es gibt keinen einzelnen labortest, der im einzelfall die frage beantworten könnte: "funktioniert die gerinnung in diesem patienten normal?", wie dies auch für andere komplexe systeme nicht möglich ist, z. b. entzündung. die kombination von pt mit partieller thromboplastinzeit (ptt) und plättchenkonzentration ist der übliche mindeststandard zumindest jener intensivstationen, die gerinnung überwachen, üblicherweise als teil des laborroutinemonitorings. die schwelle zur bestimmung dürfte allgemein relativ niedrig liegen, weil das benötigte blutvolumen rela-tiv klein ist, die tests allgemein verfügbar und relativ billig sind. die standardkombination erfasst wohl einzelne wesentliche aspekte der blutgerinnung, aber einige andere wichtige aspekte nicht (. tab. ) . für korrekte interpretationen und treffsichere rückschlüsse sind ihre lücken und grenzen hinderlich. von den drei hauptkomponenten der hämostase (plättchen, plasmatische faktoren, gefäße) ist das komplexe system der plasmatischen faktoren am besten zugänglich, eben durch die globaltests (pt und ptt). die beiden tests messen in erster linie die geschwindigkeit bis zur plasmagelierung. im gegensatz zur geschwindigkeit der fibrinbildung ist die aussagekraft von pt und ptt für die einschätzung der anderen beiden aspekte -regulation/begrenzung und gerinnselqualität -undefiniert, und bestenfalls schwach. diese einschränkungen können wohl am besten erklärt werden durch die biologisch-biochemische komplexität und die unvermeidlichen artefakte der in-vitro-untersuchungen (blutabnahme, transport, zitrat, rekalzifizierung, unphysiologische aktivierung und milieu, fehlen von fluss und endothel). beide, komplexität und artefakte, tragen zu zwei aspekten bei, die für die korrekte interpretation von gerinnungsuntersuchungen besonders relevant sind: . relativ hohe anfälligkeit gegenüber technischen störfaktoren (präanalytik), und . relativ eingeschränkte standardisierbarkeit und damit vergleichbarkeit von tests [ ] . dementsprechend sind z. b. sensitivität und cutoffs unscharf und relativ willkür-lich definiert, z. b. wie empfindlich die tests für klinisch relevante defekte sind oder ab welcher auslenkung eine spezifische therapie veranlasst werden soll. für wichtige aspekte der blutgerinnung fehlen aussagekräftige praktikable labormethoden, insbesondere für die fibrinolyse, die plättchenfunktion, die globale balance der gerinnung (eu-, prooder antikoagulant), und für die gefäßfunktion (pro-bzw. antikoagulant). zur beurteilung der gerinnselqualität, zumindest seiner festigkeit, könnten thrombelastogramme (teg) beitragen, durch den teg-parameter maximalamplitude ("clot firmness" zur plättchenfunktion sind in den letzten jahren zunehmend mehr praktikable, automatisierbare methoden entwickelt worden, v. a. zur einschätzung von plättchenfunktionshemmern in der kardiologie. diese tests ergeben im vergleich untereinander bemerkenswert diskrepante ergebnisse, auch bei den bisher überwiegend sehr eng gestellten fragen (z. b. clopidogrel-resistenz). bislang bleibt die klinische aussagekraft vage, widersprüchlich und dementsprechend unübersichtlich [ ] . für die einfache umfassende frage, ob die globale plättchenfunktion eines konkreten patienten in klinisch relevantem maße eingeschränkt oder gesteigert ist, fehlen aussagekräftige methoden und daten, auch für das pfa-system [ ] . für hyperkoagulabilität oder throm boserisiko fehlt bislang ein aussagekräftiger globaltest (sozusagen eine "thrombose-ptt"). störungen der blutgefäße können im gerinnungslabor nicht erfasst werden, ja generell nicht mit labormethoden; die gerinnungsexperten beiziehen. wir empfehlen, bei unklarheiten im gerinnungsmonitoring eher frühzeitig gerinnungsexpertise einzuholen. dies begründen wir mit der auch für gerinnungsexperten nicht leicht zu überschauenden komplexität der gerinnung -pathophysiologie, testdetails, testinterpretation -, dem nutzen einer möglichst effizienten und zeitnahen klärung von differenzialdiagnosen, und -last but not least -mit den relativ aufwändigen und nicht ungefährlichen therapieoptionen. die neue, geriatrische cme-fortbildung ist keine klassische, auf ein bestimmtes organsystem bezogene fortbildungsserie, sondern sie beinhaltet die interdisziplinäre und funktionelle herangehensweise mit blick auf den älteren patienten, so wie er sich dem arzt gegenüber präsentiert. dies schließt vor allem die diagnostischen und therapeutischen fallstricke mit ein, die in praxis und klinik immer wieder probleme bereiten. nicht nur das "kennen" altersassoziierter störungen, sondern das "können", sprich das "beherrschen" der spezifischen probleme der alterspatienten im ärztlichen alltag ist ziel dieser cme-fortbildung. in Österreich und in deutschland befinden sich geriatrie-curricula für hausärzte, dem additiv-fach (in Österreich) und dem facharzt innere medizin und geriatrie (im rahmen der Überarbeitung der musterweiterbildungsordnung der bundesärztekammer in deutschland) in vorbereitung. die cme-beiträge in der zeitschrift für gerontologie und geriatrie (zgg) werden sich daran orientieren. im laufe der nächsten jahre sollen alle wichtigen inhalte der einschlägigen curricula behandelt, vertieft und prüfungsrelevant gestaltet werden. die cme-fortbildung in der zgg ist immer leitlinienkonform und aktuell auf die inhalte neu herausgegebener oder überarbeiteter leitlinien abgestimmt. der erste beitrag wird frei zugänglich sein. www.cme.springer.de meld score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation pharmacology and management of the vitamin k antagonists: american college of chest physicians evidence-based clinical practice guidelines phosphorus as an early predictive factor in patients with acute liver failure defining acute renal failure: physiological principles. intensive care med acute renal failure -definition, outcome measures, animal models, fluid therapy and information technology needs blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study biomarkers and acute kidney injury: dining with the fisher king? prognostic models in cirrhotics admitted to intensive care units better predict outcome when assessed at h after admission plasma neutrophil gelatinase-associated lipocalin is an early biomarker for acute kidney injury in an adult icu population diagnosis, objective assessment of severity, and management of acute pancreatitis. santorini consensus conference the influence of clinical characteristics, laboratory and inflammatory markers on ‚high ontreatment platelet reactivity' as measured with different platelet function tests clearance and beyond: the complementary roles of gfr measurement and injury biomarkers in acute kidney injury (aki) improved performance of urinary biomarkers of acute kidney injury in the critically ill by stratification for injury duration and baseline renal function the link between vascular features and thrombosis timedependent variations in ischemia-modified albumin levels in mesenteric ischemia accuracy of neutrophil gelatinase-associated lipocalin (ngal) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis the role of pfa- testing in the investigation and management of haemostatic defects in children and adults early detection of acute renal failure by serum cystatin c acute kidney injury in critically ill patients classified by akin versus rifle using the saps database meld score as a predictor of pretransplant and posttransplant survival in optn/unos status patients prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit the definiton, classification, and prognosis of chronic kidney disease: a kdigo controversies conference report urinary n-acetyl-beta-(d)-glucosaminidase activity and kidney injury molecule- level are associated with adverse outcomes in acute renal failure test characteristics of urinary biomarkers depend on quantitation method in acute kidney injury acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury neutrophil gelatinase-associated lipocalin (ngal) as a biomarker for acute renal injury after cardiac surgery albuminuria increases cystatin c excretion: implications for urinary biomarkers sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury diagnostic value of plasma cystatin c as a glomerular filtration marker in decompensated liver cirrhosis urine il- is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit serum interleukin- , interleukin- , and beta -microglobulin in early assessment of severity of acute pancreatitis. comparison with serum c-reactive protein comparison of local international sensitivity index calibration and ‚direct inr' methods in correction of locally reported international normalized ratios: an international study gastrointestinal failure score in critically ill patients: a prospective observational study serum and urine cystatin c are poor biomarkers for acute kidney injury and renal replacement therapy prognostic value of the indocyanine green plasma disappearance rate in critically ill patients alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury the limax test: a new liver function test for predicting postoperative outcome in liver surgery renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of meld score persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure a portable fiberoptic ratiometric fluorescence analyzer provides rapid point-of-care determination of glomerular filtration rate in large animals serum neutrophil gelatinase-associated lipocalin (ngal) as a marker of acute kidney injury in critically ill children with septic shock a critical evaluation of laboratory tests in acute pancreatitis key: cord- - lhrkmrv authors: roden, anja c.; tazelaar, henry d. title: lung date: - - journal: pathology of solid organ transplantation doi: . / - - - - _ sha: doc_id: cord_uid: lhrkmrv experiments with animals in the and s demonstrated that lung transplantation was technically possible [ ]. in , dr. james hardy performed the first human lung transplantation. the recipient survived days, ultimately succumbing to renal failure and malnutrition [ ]. from through , multiple attempts at lung transplantation failed because of rejection and complications at the bronchial anastomosis. in the s, improvements in immunosuppression, especially the introduction of cyclosporin a, and enhanced surgical techniques led to renewed interest in organ transplantation. in , a -year-old-woman received the first successful heart–lung transplantation for idiopathic pulmonary arterial hypertension (ipah) [ ]. she survived years after the procedure. two years later the first successful single lung transplantation for idiopathic pulmonary fibrosis (ipf) [ ] was reported, and in the first double lung transplantation for emphysema [ ] was performed. experiments with animals in the and s demonstrated that lung transplantation was technically possible [ ] . in , dr. james hardy performed the first human lung transplantation. the recipient survived days, ultimately succumbing to renal failure and malnutrition [ ] . from through , multiple attempts at lung transplantation failed because of rejection and complications at the bronchial anastomosis. in the s, improvements in immunosuppression, especially the introduction of cyclosporin a, and enhanced surgical techniques led to renewed interest in organ transplantation. in , a -year-old-woman received the first successful heart-lung transplantation for idiopathic pulmonary arterial hypertension (ipah) [ ] . she survived years after the procedure. two years later the first successful single lung transplantation for idiopathic pulmonary fibrosis (ipf) [ ] was reported, and in the first double lung transplantation for emphysema [ ] was performed. over the following years, the number of lung transplants rapidly increased, and the operation became an accepted treatment for an end-stage lung disease. today, there are four major surgical approaches to lung transplantation: single and bilateral lung transplantation (blt), heart-lung transplantation, and transplantation of lobes of lungs from living donors. in , , lung transplantation procedures were reported worldwide to the registry of the international society for heart and lung transplantation (ishlt) in adults, the highest number for any year until then [ ] . in the same year, lung transplantations were reported in children, the majority in adolescents ( - years old) [ ] . although the number of single lung transplantations has been relatively stable, blts have continuously increased within the past years. in fact, in , blt was the most common lung transplantation procedure performed with % of all lung transplantation procedures, largely due to transplantation for cystic fibrosis and chronic obstructive lung disease/ emphysema which made up for . and . % of all blts between and [ ] . the mean age of transplant recipients has consistently increased since rising to an all time high of . years in [ ] . the most common indications for lung transplantation in adults are chronic obstructive pulmonary disease (copd)/emphysema, ipf, cystic fibrosis and alpha- antitrypsin deficiency emphysema (aat) (see table . ) [ ] . indications for pediatric lung transplantation vary by age (see table . ). in children over years old, cystic fibrosis is the most common indication [ ] , followed by ipah. in contrast, in infants and preschool children, lung transplantations are usually performed for ipah, congenital heart disease, idiopathic interstitial pneumonitis, and surfactant protein deficiency. well-selected patients with systemic diseases such as sarcoidosis, lymphangioleiomyomatosis, and pulmonary langerhans' cell histiocytosis have also had satisfactory results after lung transplantation [ , , , , ] as have selected patients with scleroderma [ , , ] . multiple cases of incidental t n m or even stage iiia non-small cell carcinoma in the excised native lungs of transplant recipients have been reported [ , , ] . although one patient with stage iiia poorly differentiated squamous cell carcinoma died months after transplantation of a neoplastic thromboembolus, patients with t n m carcinoma are generally free of recurrence. currently, only patients with near end-stage lung disease and a limited life expectancy should be considered for lung transplantation [ ] . however, since lung transplantation is a rapidly evolving field, there are no hard and fast rules about who may be transplanted. when choosing a transplantation procedure, several issues are considered including the shortage of organ donors, the original disease, and the center's experience with graft and patient survival. general guidelines for the selection of the procedure have been proposed [ ] and are based on the nature of the underlying lung disease. while blts are mandatory for cystic fibrosis [ , ] ipf idiopathic pulmonary fibrosis; aat alpha -antitrypsin deficiency; ipah idiopathic pulmonary arterial hypertension; lam lymphangioleiomyomatosis; ob obliterative bronchiolitis [ ] , this procedure has also become more popular for indications such as aat, copd, ipf, and ipah. singlelung transplantation is usually performed in patients with restrictive fibrotic lung disease, eisenmenger syndrome with reparable cardiac anomaly, and older patients with copd. heart-lung transplantation is considered in patients with eisenmenger syndrome with irreparable cardiac defect, pulmonary hypertension with cor pulmonale, or end-stage lung disease with concurrent severe cardiac disease [ , ] . transplantation of lobes from living donors is a recently developed technique involving bilateral implantation of the lower lobes usually from two blood group-compatible living donors. the procedure has been performed in patients with cystic fibrosis, although the indications have been recently broadened. the functional and survival outcomes are similar to those achieved with conventional transplantation of cadaveric lungs. donation of a lobe decreases the donor's lung volume by an average of approximately %, which is not associated with long-term functional limitation. other factors of the recipient that must be taken into consideration on an individual basis include ventilator dependence, previous cardiothoracic surgery, and preexisting medical conditions (e.g., hypertension, diabetes mellitus, osteoporosis) since posttransplantation medical regimen can worsen these illnesses. severe coronary artery disease is a contraindication to lung transplantation. however, coronary artery bypass grafting at the same time as lung transplantation has been performed with a reasonably good outcome in some centers, although less invasive preoperative interventions, such as percutaneous transluminal coronary angioplasty and stenting, are preferred. although the donor selection criteria may vary amongst centers, generally acceptable donor criteria include age of donor < years for lung transplantation and < years for heart-lung transplantation. in , the average donor age was . years [ ] . other donor criteria include the absence of severe chest trauma or infection, no prolonged cardiac arrest (heart-lung transplantation only), minimal pulmonary secretions, negative screens for hiv, hepatitis c, and hepatitis b and blood type (abo) compatibility. a close match of lung size between donor and recipient, pao > mmhg on % fraction of inspired oxygen (fio ), clear chest radiograph and no history of malignant neoplasms are also required. most transplant centers will use lungs from a cytomegalovirus (cmv)-positive donor for transplantation into a cmv-negative donor given an adequate postoperative cmv prophylaxis. with the current techniques, satisfactory graft function can be obtained after an ischemic interval of as long as - h. for pulmonary preservation, systemic heparinization of the donor and hypothermic flush perfusion of the allograft are most commonly used in clinical practice. most flush solutions are administered at a temperature of °c, while topical cooling is carried out by filling the pleural cavity with iced crystalloid solution. the harvested lungs are then immersed in crystalloid solution, packed in ice, and transported at a temperature of - °c. the infusion and transport is performed during active ventilation and static inflation with o , respectively. acute and chronic alloreactive injury to the donor lung affects both the vasculature and the airways [ ] . usually, rejection is evaluated on transbronchial biopsies (see below sect. . ). on only rare occasions, wedge biopsies are performed. other specimens might include explants for retransplant or autopsy specimens. acute rejection is characterized by perivascular mononuclear cell infiltrates, which may be accompanied by sub-endothelial chronic inflammation (e.g., endotheliitis or intimitis), and also by lymphocytic bronchiolitis. in contrast, chronic rejection is manifest by fibrous scarring, involving the bronchioles and sometimes associated with accelerated fibrointimal changes affecting pulmonary arteries and veins. the presence of presumed irreversible dense eosinophilic hyaline fibrosis in airways and vessels remains the key histologic discriminator between acute and chronic rejection of lung. the histologic changes are divided into grades based on intensity of the cellular infiltrate, and the presence and absence of fibrosis. hyperacute rejection occurs within minutes to a few hours after the newly transplanted organ begins to be perfused. it is a type ii hypersensitivity reaction, mediated by preexisting antibodies to abo blood groups, human leukocyte antigens (hla) class i, or other antigens on graft vascular endothelial cells. preexisting antibodies can result from previous pregnancies, blood transfusions, or a previous transplant. antibody binding provokes complement and cytokine activation leading to endothelial cell damage and platelet activation with subsequent vascular thrombosis and graft destruction. the outcome is usually fatal. in the lungs, hyperacute rejection grossly presents by edema and cyanosis of the graft. histologically, platelet thrombi, neutrophilic infiltration, fibrin thrombi, necrosis of vessel wall, and morphologic features of diffuse alveolar damage (dad) are observed [ ] . although hyperacute rejection is a well-known complication in kidney and heart transplantations, in lung transplantation it appears to be rather rare with only five cases reported. one patient reported presented with severe hypoxia, high fever, hemodynamic instability and developing acute renal failure h after completion of the anastomoses [ ] . chest radiograph displayed a completely opacified left lung, with homogenous infiltrates. bronchoscopy revealed abundant pink frothy fluid draining from the allograft. mean pulmonary artery pressure increased to mmhg. the patient died h later. at autopsy, the vascular and bronchial anastomoses appeared patent without signs of injury. the transplanted lung showed red hepatization and a firm consistency. microscopically, signs of acute lung injury were evident. although a pretransplant panel-reactive antibody (pra) was negative, flowcytometry revealed and % reactivity against hla class i and ii, respectively with anti-a detected among the preformed antibodies. three other reported patients with hyperacute rejection died within h to days after transplantation [ , , , ] . although in three of the five reported patients pretransplant pras were negative, crossmatch was positive in all cases with anti-a the most common identified antibody. collectively, although hyperacute rejection is rare after lung transplantation, one should keep this reaction in mind given that false-negative pras may occur and pretransplantation cross match is not often possible [ ] . acute rejection is the host's response to the recognition of the graft as foreign. most patients develop at least one episode of acute rejection within the first weeks following transplantation, typically in the first - days, with % of patients experiencing at least one episode in the first year [ ] . obliterative bronchiolitis (ob) is the most common late cause of mortality and morbidity after lung transplantation occurring in % by . years and % by years in patients who survive at least days [ ] . it also has a significant negative impact on quality of life parameters. risks for acute rejection include hla mismatching, type of immunosuppression, infection, and recipient factors. it is generally thought that the intensity of host alloimmune response is related to recipient recognition of differences with the donor hla antigens and that this process drives acute lung allograft rejection. a higher degree of mismatch increases the risk of acute rejection [ , , ] . however, this effect is not consistent across all hla loci or studies. mismatches at the hla-dr, hla-b [ ] , and hla-a [ ] loci, as well as a combination of all three loci [ ] , appear important. in addition, the ishlt registry has not found a correlation between hla mismatching and survival [ ] . thus, while hla mismatching between donor and recipient likely contributes to the immunologic basis for acute rejection, it is difficult to discern if a mismatch at a particular locus or if different degrees of mismatch significantly alter the overall risk for acute rejection. viral infections have been thought to modulate the immune system and heighten alloreactivity. indeed, a high incidence of acute rejection has been found in lung transplant recipients after community-acquired respiratory tract infections with human influenza virus, respiratory syncytial virus (rsv), rhinovirus, coronavirus, and parainfluenzavirus [ , , ] . although cmv is considered a potential risk factor for ob, studies directly linking cmv infections or cmv prophylaxis strategies with acute rejection have been inconsistent [ ] . in one study, chlamydia pneumoniae infection was linked to the development of acute rejection and ob [ ] . several host genetic characteristics have been suggested to modulate acute lung rejection. for instance a genotype leading to increased il -production may protect against acute rejection [ ] and a multidrug-resistant genotype (mdr c t) appears to predispose to persistent acute rejection resistant to immunosuppressive treatment [ ] . the effect of age on acute rejection appears to be bimodal, with the lowest incidence of acute rejection in infancy (<age ) [ ] and increased risk during childhood as compared with adulthood [ ] . the incidence of acute rejection in older lung transplant recipients (age and higher) does not seem to change [ ] ; in fact, an increased rate of infections in older lung transplant recipients is thought to contribute to an increased mortality detected at one center arguing for reduced immunosuppression in these patients [ ] . the clinical course of acute rejection can be variable. patients with acute rejection might present with dyspnea, fever, leukocytosis, and a widened alveolararterial oxygen gradient. higher-grade rejection appears to cause more severe symptoms and can lead to acute respiratory distress [ ] . in patients with rejection, pulmonary function testing may show a decrease in forced expiratory volume in s (fev ) and vital capacity (vc). although spirometry has a sensitivity of greater than % for detecting infection or rejection grade a and higher, it cannot differentiate between the two [ ] . the usefulness of spirometry is diminished in single lung transplant recipients, as the contralateral native lung dysfunction confounds the pulmonary function test results [ ] . pulmonary function testing should therefore be used only as an adjunct to clinical evaluation. although in approximately half of the cases of acute rejection, the findings on chest radiograph are normal, chest radiographs may reveal ill-defined perihilar and lower lobe opacities, along with septal lines and pleural effusions. findings on ct scan might include ground-glass opacities, septal thickening, volume loss, nodules and consolidations, and pleural effusions. infiltrates observed on imaging studies during the first week after lung transplantation usually are caused by reimplantation response (i.e., reperfusion edema). persistent infiltrates beyond the first week suggest acute rejection or infection. however, although early small studies attempted to demonstrate the usefulness of chest x-rays and chest ct scans in the diagnosis of rejection, more recent data show very low sensitivity for acute rejection (as low as %) and no discriminatory value between rejection and other processes [ ] . exhaled nitric oxide (no) is also an attractive marker of lung injury; it has been correlated with lymphocytic bronchiolitis [ ] and acute rejection [ ] . furthermore, in a study of inert gas single breath washout, the slope of alveolar plateau for helium had a sensitivity of % for acute rejection [ ] . although lung transplantation has come of age, the development of ob remains the biggest hurdle preventing long-term survival in many patients [ ] . because of its low sensitivity ( %) and specificity ( %), ob remains difficult to prove pathologically with transbronchial biopsy [ , ] . as a consequence, a clinical definition, called bronchiolitis obliterans syndrome (bos) was proposed [ ] . this is based on pulmonary function criteria, initially fev evolution, and more recently, mid-expiratory flow rate (fef ) [ ] . the onset of bos-symptoms is usually insidious, with progressive exertional dyspnea, often accompanied by cough, which may be dry or productive. the incidence of bos is highest after the first year following lung transplantation. however, the risk of bos increases to - % - years after the lung transplantation procedure. it remains the leading cause of morbidity and death after lung transplantation, accounting for about - % late mortality and some % of patients affected by the condition years after transplantation [ ] . as discussed above, an acute immunologic event (acute rejection) may trigger the onset of ob [ ] . however, nonalloimmune injury such as a respiratory tract infection (cmv or non-cmv viral infection) is increasingly recognized as also having an important impact on the development of ob [ , ] . in fact, cmv pneumonitis affects over % of lung transplant recipients. despite treatment, it increases the risk for ob and death. early detection of ob in a preclinical stage is ideal so that aggressive attempts can be made to prevent a fully developed syndrome. however, to date, no particular marker to indicate ob, either from the peripheral blood or bronchoalveolar lavage (bal) fluid, has predicted a risk for this disease. an association between chronic aspiration and ob after heart-lung transplantation has also been observed [ ] , and there is a high frequency of gastroesophageal reflux with resultant aspiration following lung transplantation [ , , , , , ] . for instance, one study described gastrointestinal complications including gastroesophageal reflux in % of patients who underwent lung transplantation [ ] . other than leading to an increase in acute rejection by exacerbating the alloimmune response, aspiration of gastric contents might act independently of the alloimmune response to promote allograft injury and the development of ob. experiments in rats have further substantiated the association between chronic aspiration and ob [ ] . despite the common clinical impression that lymphocytic pleural effusions are a hallmark of acute rejection, published data are inconclusive [ ] . collectively, although the presentation of the patient and several ancillary studies might suggest a transplant rejection process, tissue diagnosis is necessary for definitive diagnosis. in , the ishlt sponsored the lung rejection study group (lrsg), a workshop to develop a "working formulation" for the diagnosis of lung rejection by transbronchial biopsy [ ] . the proposed grading scheme found wide acceptance. due to developments in the field and experience with its use, lrsg has remet twice since to assess the merits of the grading scheme. the revisions were published in [ ] and [ ] , respectively. the grading scheme is strictly pathologic and does not consider any clinical parameters. due to overlapping histologic features between acute rejection and infection, the grading scheme relies on the absence of concurrent infection. the most recent classification of lung allograft biopsies is the ishlt revised consensus classification of allograft rejection [ ] (see table . ). this classification was revised from the ishlt consensus classification. there were no significant changes in the grading of acute rejection in the latest classification, but it was acknowledged that minimal acute rejection is not solely a high power diagnosis but can also be recognized at low power in an adequately alveolated biopsy. in the grading system, small airways rejection was graded in a four-tiered system, b through b , respectively (see table . ). the classification consolidated those into low grade and high grade small airways inflammation to make the evaluation easier. the "r" behind b and b denotes the revised classification. chronic airways rejection is not divided into active and inactive anymore but only into present and not present. there are no differences in the classification of chronic vascular rejection between the and classification. r denotes revised an attempt should be made to accurately distinguish the grade of rejection since treatment is largely dependent on the histologic grade. furthermore, an effort should be made to review the report of the previous biopsy and to comment on whether rejection is ongoing or resolving. although in general, patients with grade a biopsies will not receive increased immunosuppression, surveillance might be intensified and the time to the next biopsy shortened. in contrast, a biopsy patients will receive an increase in immunosuppression. grade a and a patients will be treated similar and receive more immunosuppression. inter-and intraobserver variability in grading can impact treatment and outcome [ , ] . studies have evaluated the inter-and intraobserver variability of the grading scheme. two studies found relatively good interobserver agreements for the a-grades (kappa of . and . ) [ , ] , but this could not be replicated in another study in which the kappa was . in spite of dichotomization of the a-grades to a /a vs. a - [ ] . intraobserver agreement for acute rejection has been found to be good: kappa values of . and . [ , ] . infection can complicate the diagnosis of acute rejection. viral infection in particular can cause mononuclear inflammation [ ] . in addition, alveolar damage with macrophage and fibrin accumulation was found to be present in % of transbronchial biopsies in the first months after transplantation, further increasing interobserver pathologist discordance. therefore, in general, the lrsg recommends grading rejection only after the exclusion of infection. in contrast to the a-grade, the interobserver variability for grading airways inflammation (b-grades) was only fair with kappas of app . [ , ] . for this reason, the lrsg has now simplified b-grading to two possible grades. this nomenclature is to be used for grading of noncartilagenous small airways only after rigorous exclusion of infection [ ] . eosinophils can accompany acute lung rejection and are recognized in the ishlt classification in high grade rejection (grades a /a ) [ ] . the presence of eosinophils has been suggested as a risk factor for bos in small single-center studies [ ] . furthermore, high proportions of b cells have been shown to accompany steroid-resistant rejection in lung transplant patients [ ] . the mechanisms by which b cells contribute to refractory rejection are not entirely clear, although they may reflect ongoing humoral rejection, perhaps explaining the diminished responsiveness to standard immunosuppression. mast cells have been identified in acute rejection biopsies of increasing a-grade but their role has not been elucidated [ ] . rejection and chronic airways inflammation should be distinguished from bronchiolar associated lymphoid tissue (balt). balt is found in the vicinity of airways, usually contains black anthracotic pigment and presents as a rather nodular collection of chronic inflammatory cells which does not surround a vessel. acute rejection is defined by the presence of perivascular mononuclear cell infiltrates with or without endotheliitis. with progression, this infiltrate becomes more widespread and extends into the alveolar septa and, subsequently, into the alveoli. the majority of the mononuclear cells in acute rejection are t cells, although a few studies have described increased populations of b cells or eosinophils [ , , ] . in grade a normal pulmonary parenchyma is present. scattered infrequent blood vessels, particularly venules, in the alveolated lung parenchyma are surrounded by a relatively thin chronic mononuclear infiltrate (see fig. . ). the lymphocytic rim is rather small and does not spill into the adjacent interstitium. endotheliitis and eosinophils are absent. although previous classification systems commented on a certain number of lymphocyte layers, the current ishlt classification only requires a complete rim of vessels by lymphocytes. in adequately alveolated and artifact-free specimens, the lymphocytic infiltrates might be detected at low magnification. although in mild acute rejection the perivascular infiltrate of lymphocytes is essentially confined to the perivascular adventitia without infiltrating the interstitium, there are more layers of lymphocytes surrounding the vessel and lymphocytes might focally, minimally spill into the adjacent interstitium (see fig. . ). more frequent perivascular mononuclear infiltrates are seen surrounding venules and arterioles. they are readily recognizable at low magnification. these infiltrates usually consist of a mixture of small round lymphocytes, activated lymphocytes, plasmacytoid lymphocytes, macrophages, and eosinophils. there is frequently subendothelial infiltration by mononuclear cells which may be associated with hyperplastic or regenerative changes in the endothelium, i.e., endotheliitis. concurrent lymphocytic bronchiolitis may be seen in association with mild acute rejection. grade a acute rejection shows easily recognizable cuffs of venules and arterioles by dense perivascular mononuclear cell infiltrates which are commonly associated with endotheliitis (see fig. . ). eosino phils a b and even occasional neutrophils are common. this grade is defined by the extension of the inflammatory cell infiltrate into perivascular and peribronchiolar alveolar septa which broadens the interalveolar septa and airspaces are associated with collections of intraalveolar macrophages in the zones of septal infiltration. type ii pneumocyte hyperplasia and histologic features of acute lung injury may become apparent. in severe rejection there are diffuse perivascular, interstitial, and air space infiltrates of mononuclear cells with prominent alveolar pneumocyte damage and endotheliitis (see fig. . ). this may be associated with intra-alveolar necrotic epithelial cells, macrophages, eosinophils, hemorrhage, and neutrophils and usually some evidence of acute lung injury in form of organizing pneumonia or hyaline membranes. parenchymal necrosis, infarction, or necrotizing vasculitis might be identified; however, these features are more evident on surgical rather than transbronchial lung biopsies. it should be noted that a paradoxical diminution of perivascular infiltrates can occur as cells extend into alveolar septa and spaces where they are admixed with macrophages. this grade can sometimes be difficult to distinguish from an infectious process, harvest/reperfusion injury, or drug toxicity, however, the presence of perivascular inflammation is helpful in establishing the diagnosis. this grade applies only to small airways such as terminal or respiratory bronchioles. bronchi, if present, should be described separately. it is important to mention in the pathology report whether or not small airways are present. the r behind grades and denotes the revised version. the small airways appear unremarkable without evidence of bronchiolar inflammation. low grade inflammation is characterized by lymphocytes within the submucosa of the bronchioles (see fig. . ). the lymphocytic infiltrates can be infrequent and scattered or forming a circumferential band, however, intra-epithelial lymphocytic infiltration is not present. although occasional eosinophils may be seen within the submucosa, there is no evidence of epithelial damage, neutrophils, necrosis, ulceration, or significant amount of nuclear debris. this grade combines and replaces the working formulation b and b grades. in high grade small airways inflammation there is marked lymphocytic infiltrate of the airway epithelium and airway wall. the mononuclear cells in the submucosa appear larger and activated with greater numbers of eosinophils and plasmacytoid cells. in addition, there is evidence of epithelial damage including necrosis, metaplasia, and marked intra-epithelial lymphocytic infiltration. in its most severe form, high grade airways inflammation is associated with epithelial ulceration, fibrino-purulent exudate, cellular debris, and neutrophils. it is important to exclude an infectious process. in this grade the changes are ungradeable due to sampling problems, infection, tangential cutting, artifact etc. the working formulation for pulmonary rejection has equated ob with one type of chronic rejection, the c-grade. the term as used in the consensus classification is restricted to submucosal and intraluminal scarring of membranous and respiratory bronchioles. when large tissue sections of lung are examined, the process of ob is pan-lobar but patchy. the small airways appear similar in size to the accompanying artery with a ragged inner surface. fibrosis is not present. narrowing of the airways due to fibrosis in the airway wall is seen. the fibrosis is usually eccentric (see fig. . ). ob may be manifest by a histopathologic spectrum of changes depending on the acuteness of the process, the degree of organization and the amount of accompanying inflammation. in the acute phase there is usually loose myxoid granulation tissue with variable numbers of inflammatory cells filling or partially obstructing the airway lumen, resembling "organizing pneumonia." in later phases, ob may consist of eccentric, occasionally confluent plaques of dense hyalinized collagen applied to the wall of bronchioles. metaplastic squamous or cuboidal epithelium may cover these bronchiolar scars. in other airways a slit-like lumen may remain as a result of a confluent submucosal scar or intraluminal polyps of scar tissue. capillaries supplying these intraluminal masses of collagen are occasionally prominent. in the most severe cases the bronchiolar lumen can be entirely occluded by dense scar tissue and be recognizable only with the aid of an elastic stain, its location adjacent to an artery, and by the presence of residual circumferential smooth muscle. in the later phases, inflammation may be minimal. usually, the scarring process is confined exclusively to respiratory bronchioles and terminal bronchioles, although it may occasionally involve adjacent alveoli. the pulmonary arteries appear of a similar size as the accompanying airway. the intima is slender, the media not thickened. chronic vascular rejection rarely is identified on biopsies since they usually lack vessels of sufficient size. wedge biopsies, explants, or autopsy material may reveal it. in the typical case, pulmonary arteries and more often veins are thickened by fibrointimal connective tissue (see fig. . ) . also, thickening is usually concentric. chronic vascular rejection may be patchy and typically involves smaller vascular arteries and veins. in the early stages of chronic vascular rejection, the intimal proliferation occurs on the luminal aspect of an intact elastic lamella. subsequently, the internal elastica may become fragmented and discontinuous. occasionally the underlying muscular wall becomes thinned. in approximately half of the reported cases a concurrent endovasculitis has been observed. the process is similar in pulmonary veins, although the intimal deposits may be less cellular and more waxy, eosinophilic, and sclerotic. chronic vascular rejection should be distinguished from recanalizing thrombi. unlike the situation with heart transplant recipients, chronic vascular rejection in lung transplants has not resulted in graft loss; however, some patients develop pulmonary hypertension particularly those with bos [ , ] . mimickers of severe acute rejection include conditions that might present with acute lung injury or dad. these conditions include infection, drug toxicity, antibody mediated rejection (amr), or harvest/reperfusion injury. therefore, careful slide review for perivascular inflammation should be performed, stains for microorganisms including gomori-grocott methenamine silver stain (gms) and acid fast bacilli (afb) might be added and careful search for viral inclusions should be undertaken. although perivascular mononuclear infiltrates are helpful to identify rejection, these are not entirely specific for acute rejection and many other conditions may simulate or mimic alloreactive lung injury [ ] . differential diagnostic considerations include cmv pneumonitis, pneumocystis jiroveci pneumonia and posttransplantation lymphoproliferative disease (ptld). further differential diagnosis of perivascular and interstitial infiltrates include recurrent primary diseases. amr or humoral rejection is well established in other solid organ transplantation. it was originally recognized in kidney transplant patients who presented with acute allograft rejection, antidonor antibodies, and poor prognosis [ ] . amr is thought to be due to circulating antibodies that are either preformed because of pregnancy, blood transfusion, or previous organ transplantation or arise de novo after transplantation due to hla-mismatch. although amr is an increasingly recognized entity in lung transplantation, it is still under investigation. early observations were based on the phenomenon of hyperacute rejection, where preexisting donor-specific antibodies lead to complement activation and rapid graft loss. later it has been recognized that lung transplant recipients also can develop antibodies after transplantation to the allograft that might lead to amr. evidence suggests that amr occurs to donor major histocompatibility (mhc) antigens, although other endothelial and epithelial antigens expressed in the lung may become antibody targets as well. the recent development of very sensitive and specific solid phase flowcytometry and luminex-based methodologies has allowed for accurate detection of antibody specificities in sensitized recipients and it has become clear that more patients than previously expected present with preformed anti-hla antibodies. immune stimulation by prior infections or autoimmunity might contribute to the development of antibodies to allomhc in those patients with no identifiable risk factors. these preexisting antibodies can react with donor antigens, leading to immediate graft loss (hyperacute rejection) or accelerated humoral rejection and bos [ ] . furthermore, recent studies have consistently demonstrated an increased incidence of acute rejection (a threefold increase in one study) [ ] , persistent rejection, increased bos [ ] or worse overall survival [ ] in patients with anti-hla antibodies. this effect is apparent both with pretransplant hla sensitization and with the development of de novo anti-hla donorspecific antibodies after transplantation [ ] . about - % of lung transplant recipients are presensitized to hla antigens [ ] . even though "unacceptable antigens" are avoided during the virtual crossmatch, patients with positive pretransplant pra are at higher risk for posttransplant complications. their posttransplant pra can stay stable or increase via generation of either donor-specific or nondonor-specific anti-hla antibodies. similarly, patients that had negative pra screening tests before transplantation can develop de novo nondonor-specific or donor-specific anti-hla antibodies after transplantation. the mechanisms by which antibody promotes lung allograft injury remain poorly understood. antibody binding to allomhc or other endothelial or epithelial targets in the lung could lead to activation of the complement cascade with complement deposits leading to endothelial cell injury, production of proinflammmatory molecules, and recruitment of inflammatory cells. com plement independent antibody-mediated mechanisms can also induce endothelial cell activation without cell injury, leading to increased gene expression and subsequent proliferation [ ] . as demonstrated by in vitro studies, anti-hla antibodies can cause proliferation of airway epithelial cells as well, producing fibroblast-stimulating growth factors [ ] , potentially contributing to the generation of obliterative airway lesions. recent studies have attempted to evaluate immunoglobulins (ig) and complement deposits in the subendothelial space. septal capillary deposits of igs and complement products such as c q, c d, c d, and c b- have been described in association with anti-hla antibodies [ , ] as well as allograft dysfunction and bos [ , ] . the concept of specific histopathologic features associated with humoral rejection remains controversial in lung transplantation. recent studies question the relation between complement or ig staining and allograft rejection [ , ] . others demonstrate that c d and c d staining can occur in lung transplant recipients with nonalloimmune lung injury such as infection and primary graft dysfunction (pgd) with no evidence of anti-hla antibodies [ ] . differences in staining techniques between different laboratories may further explain some of the inconsistencies in the published data. the ishlt revised consensus classification did not agree upon any histopathologic features that might be specific for amr in lung [ ] . although capillary injury/small vessel intimitis might raise the suspicion of amr, these are nonspecific findings that can also occur in severe acute rejection, infection, or harvest/reperfusion injury. furthermore, although often the term "capillaritis" is mentioned, ishlt recommends to use the term "capillary injury" which allows for a broader spectrum of morphological changes of the vessels including intimitis, whole wall thickness inflammation, neutrophilic infiltration (which should be distinguished from neutrophilic margination), thrombosis, and necrosis. furthermore, signs of dad and intra-alveolar hemorrhage can occur with amr although again, they are not specific. given the lack of specific histologic findings of amr in lung transplantation, a multidisciplinary approach to diagnosis is recommended that includes the following: ( ) the presence of circulating antibodies (hla antibodies, antiendothelial and antiepithelial antibodies), ( ) focal or diffuse c d deposition (see fig. . ), ( ) histologic features of acute lung injury or hemorrhage (dad, capillary injury with neutrophils and nuclear debris) and ( ) clinical signs of graft dysfunction. if amr is clinically, immunopathologically, or histologically suspected, one might perform immunostains for c d, c d, cd , and cd . however, these stains are extrapolates from kidney and heart transplantation and although there have been several studies advocating their use [ , , , ] , there are no large scale studies validating their use. c d has been studied extensively in kidney and heart transplant and has been identified as a useful adjunct in the diagnosis of amr in these organs. however, in lung that is not the case. one of the reasons for the difficulties in lung is the relatively high background that is encountered in immunohistochemistry (ihc) as well as immunofluorescence (if). often, c d binds to elastic laminas or shows other nonspecific binding. staining is commonly only focal and therefore sensitivity and specificity have not been established yet given the limited sample size of transbronchial biopsies. only linear, continuous subendothelial staining of capillaries, arterioles, and/or venules count as positive by ihc. also, c d is not specific to amr but also can be seen in infection, harvest/ reperfusion injury, or even in severe acute rejection, basically in any process that is associated with complement activation. there is no ihslt recommendation at this time regarding to the coexistence of amr and acute rejection. although clinical evaluation of the patient may suggest the possibility of rejection, tissue evaluation is necessary for a definitive diagnosis. initially, investigators were hesitant to routinely utilize transbronchial biopsy to monitor the graft as it was thought that the amount of tissue obtained would be too small to make a definitive diagnosis. there was also concern about passing a bronchoscope over the anastomosis. however, transbronchial biopsy is now a routine procedure and has become the gold standard to evaluate the graft for acute and chronic rejection, infection, and possible recurrent disease since currently, no surrogate markers have been sufficiently validated as means to reproducibly identify patients with acute rejection. specifically, there is no serological marker to indicate rejection is occurring. after lung transplantation the total bal fluid cell count is constantly increased even in periods with no evidence of infection or rejection [ ] . in the early posttransplantation period (first weeks), there is a dominance of neutrophils in the bal fluid (up to - % of total cell count) until about months later when the cell count normalizes [ ] . acute rejection has been associated with elevated cd + t cells, activated cd + t cells, a trend toward increased nk t cells, increased b cells, and decreased nk cells in the bal [ ] . nevertheless, no study has proven the bal cellular composition to be adequately sensitive or specific in the discrimination of rejection from infection [ ] . small studies have found a correlation between acute rejection and elevation of il [ ] , il [ ] , and ifn gamma in the bal [ ] . recent advantages in genomics offer the potential for more specific means of diagnosing rejection in lung transplantation. a pilot study of gene expression in the bal of lung transplant recipients found that gene expression signatures related to t-lymphocyte function, cytotoxic cd activity, and neutrophil degranulation correlate with acute rejection [ ] . however, these studies have no clinical use at the present time. recently published studies in heart transplantation describe the use of peripheral blood gene expression profiling to identify future risk of cardiac allograft rejection [ ] . a similar study is now underway in lung transplantation, known as the lung allograft rejection gene expression observational (largo) study. preliminary data from almost patients, similar to the cargo results, show differential gene expression in the lymphocyte priming and neutrophil homeostasis pathways for a vs. ³a acute lung rejection [ ] . such testing may hold promise for a noninvasive technique to monitor the status of the transplanted organs. another study described marked serum elevations of hepatocyte growth factor (hgf) in lung transplant . the high power view shows capillaritis in a case of amr characterized by focally thickened interstitium due to neutrophils and nuclear debris with capillary destruction. the insert reveals c d immunoperoxidase stain (see arrow) focally lining the endothelium of capillaries and small vessels (magnification × , insert × ) recipients with acute rejection. however, smaller elevations in hgf also occurred with lung infection, and additional studies are needed to validate specificity and sensitivity of hgf for acute rejection [ ] . in conclusion, although there are a few promising noninvasive techniques, these are early studies that need to be confirmed in larger studies before being considered for widespread clinical use. therefore, microscopic tissue evaluation remains the gold standard for diagnosing rejection. bronchoscopy and biopsy postlung transplantation are generally performed if there is any clinical suspicion of rejection, infection, recurrent disease, or ptld. in addition, many transplant centers now follow protocol biopsies. however, the pros and cons of surveillance bronchoscopies with biopsy are still debated and therefore, there are no guidelines established in regards to the timing of postlung transplantation surveillance bronchoscopy and biopsy. one institution reports surveillance biopsies in pediatric lung transplant recipients at week and , , , and months posttransplantation [ ] . the rational for surveillance biopsies includes the occurrence of clinically silent acute rejection, inadequate surrogate markers for acute rejection, and the relatively low risk of the bronchoscopy procedure. the yield for acute rejection by transbronchial biopsies was reported . - % and % or greater in studies performing surveillance transbronchial biopsies [ , ] , clinically indicated and follow-up bronchoscopies [ ] . grade a and higher acute rejection has been found in a relatively high percentage of asymptomatic patients, ranging from to % [ , ] . silent acute rejection appears most common within the first months of transplantation ( . % at - months; . % at - months; . % after year) [ ] . the rate of unsuspected but clinically significant infection was highest between and months posttransplantation but a relatively high rate ( . %) was also detected after year. one small study questioned the benefits of performing surveillance bronchoscopy with biopsy, suggesting that the benefits do not outweigh the procedural risks [ ] . in this study, changes in management based on transbronchial biopsy and bal results were significantly higher in the clinically indicated group ( %) compared with the surveillance group ( %) and were mostly related to infection. interestingly, no silent acute rejection episode requiring treatment was detected in the surveillance group of this study. collectively, these findings may reflect differences in programs and operators. although it has been shown that transbronchial biopsy is often the only mean to reveal silent acute rejection of the allograft, definitive evidence that treatment of such episodes have a positive impact on survival or prevention of bos has yet to be demonstrated. however, based on the link between acute rejection and development of bos, surveillance transbronchial biopsies in asymptomatic lung transplant recipients has become common practice in many large lung transplantation centers because evidence suggests that patients who have multiple episodes of low grade (a ) lesions within the first months posttransplantation develop early onset bos. however, there were no differences in overall survival in patients with and without a acute rejection [ ] . there is also evidence that a rejection increases the risk of higher-grade subsequent rejections (³a ) [ , ] . the finding of a solitary perivascular monocytic infiltrate was followed by worsening acute rejection in four untreated patients in one study, while the treatment of such a solitary infiltrate in nine patients resulted in improvement of the rejection score [ ] . the presence of severe lymphocytic bronchiolitis also has been associated with increased risk of bos and death after lung transplantation, independent of the presence of acute rejection [ ] . a study [ ] in which surveillance transbronchial biopsies were performed at , , , and weeks posttransplantation, at the time of symptoms, and for follow-up of acute rejection or cmv pneumonia showed that patients who develop acute small airways rejection within the first year after transplantation are at risk of development of bos at . , . , and . years after detection of b / b lesion (by ishlt criteria, see table . ), b lesion or b /b lesion, respectively. this study strongly suggests that the main utility of surveillance biopsies may be to use lymphocytic bronchiolitis as a surrogate predictor of long-term outcome. however, the impact of therapy for lymphocytic bronchiolitis has yet to be assessed. although complications related to bronchoscopy occur, including a small risk of severe complications, the majority of cases have a favorable outcome. adverse events reported with bronchoscopy in lung transplant recipients include transient hypoxemia, bleeding, pneumothorax, arrhythmia, and anesthesia related complications [ , ] . bronchoscopy may have contributed to faster deterioration of one patient's already critical condition; however, in the posttransplantation setting, -bronchoscopy has no reported mortality [ , ] , although there are anecdotal reports of death related to transbronchial biopsy. the ishlt revised consensus classification of acute allograft rejection [ ] requires the evaluation of at least five pieces of well-expanded alveolated parenchyma. however, the bronchoscopist may need to submit more than five pieces to provide this minimum number. further biopsies may improve the detection of ob, although there is no specific number of small airways required by the ishlt consensus classification to exclude this diagnosis. gentle agitation in formalin to open up the alveoli may improve the histologic appearance of the fragments. histologic examination should include three levels from the paraffin block for hematoxylin and eosin (h&e) staining [ ] . connective tissue stains such as trichrome or verhoeff-van gieson (vvg) stain to evaluate airways for the presence of submucosal fibrosis are essential for the diagnosis of ob, and atherosclerosis. silver stains such as gms can be performed for fungi, including pneumocystis, but have not been routinely mandated by the ishlt revised consensus classification, given the numerous microbiologic, serologic, and molecular techniques available for the diagnosis of opportunistic infections. bal may be performed at the time of biopsy and is useful for the exclusion of infection, but currently has no clinical role in the diagnosis of acute rejection (see above). infection is the leading cause of death in lung transplant recipients. factors that increase a patient's susceptibility to infection after transplantation include immunosuppression, reduced mucociliary clearance, decreased cough reflex resulting from denervation, and interruption of lymphatic drainage. bacterial pneumonias are the most common infections following lung transplantation [ ] and occur in more than % of patients during the first year after transplantation (highest incidence is during the first month posttransplantation) (see fig. . ). furthermore, bacterial pneumonia remains a major infectious complication throughout the patient's life. the donor lung is affected most often. gram-negative organisms are most common, especially enterobacter and pseudomonas. bronchitis secondary to pseudomonas species or staphylococcus aureus infection also is observed. bacterial pneumonia typically manifests radiographically as a lobar or multilobar consolidation. viral pneumonias develop in approximately % of patients who have undergone lung transplantation. they occur at any time following transplantation. cmv is the second most common cause of pneumonia in patients who have received lung transplants, and it is the most common opportunistic infection ( - % of opportunistic infection) [ ] . it represents the most significant viral infection, and usually occurs - months after transplantation. primary infection is the most serious form and is observed in - % of seronegative patients who received a graft from a seropositive donor. in patients who are seropositive, secondary cmv infection develops from reactivation of latent disease following the institution of immunosuppressive therapy or from infection with a different strain of cmv. infected patients may be asymptomatic or may develop a fulminant pneumonia, possibly with extrathoracic findings such as retinitis, hepatitis, and gastritis. presenting symptoms include dyspnea, fever, and cough. the most common finding on chest radiographs in patients with cmv infection is diffuse parenchymal haziness. ct scan findings include areas of ground-glass attenuation; reticulation; multiple, small, ill-defined -to -mm nodules; and, even less commonly, areas of dense consolidation. the diagnosis of cmv pneumonia can be made by bronchoscopy with lavage and biopsy. cytopathic changes associated with cmv infection include cytomegaly, multiple small basophilic cytoplasmic inclusions, and a large nuclear inclusion surrounded by a halo with thickened nuclear membrane (see fig. . ). prophylactic therapy with acyclovir and immune globulin has not reduced the incidence of cmv infections in patients who have undergone transplant procedures. a less common cause of viral infection includes the herpes simplex virus (hsv) infection. patients with hsv infection present with fever, cough, and dyspnea, but they demonstrate symptomatic improvement after therapy with intravenous acyclovir. radiographic findings may be absent or may demonstrate diffuse groundglass opacities. histopathologically, the classic hsv inclusion consists of a dense, eosinophilic mass within the nucleus that is surrounded by a clear halo and peripherally marginated, beaded nuclear chromatin. hsv may form multinucleated cells. opportunistic fungal infections are less common than viral infections, but they are associated with higher mortality. fungal pneumonias usually occur - days following transplantation and more commonly involve the transplanted lung. however, they also can involve the native lung in single lung transplantation cases, especially in patients with copd. ct imaging studies most commonly reveal a combination of nodules (multiple, variable sizes, irregular margins), consolidation, and ground-glass opacification. pleural effusions are also common ( % of cases). gms will help to identify fungal organisms. however, even in the absence of identifiable organisms on gms, infection might be considered and cultures and serology should be attempted. locally invasive or disseminated aspergillus infection accounts for - % of posttransplantation infections and - % of deaths in patients who undergo lung transplantation. aspergillus infection most commonly is characterized by local invasion of a necrotic bronchial anastomosis (i.e., ulcerative aspergillus infection, when involving the lung parenchyma, tends to cavitate and has an upper-lobe predominance. histopathologically, the hyphae of aspergillus sp are septated and branching. they appear uniform and grow in parallel fashion with septae at regular intervals. the branching is dichotomous and usually at °angle. inhaled amphotericin b is often used in the immediate posttransplantation period to help eliminate this complication [ ] . patients are also discharged on voriconazole as daily prophylaxis for the first year. patients who have undergone lung transplant procedures have an increased susceptibility to p jiroveci infection, but prophylaxis with trimethoprim-sulfamethoxazole is effective in preventing the infection (incidence is nearly %). without prophylaxis, the incidence of p jiroveci infection approaches %. histologically, cysts of p jiroveci are round to oval, measure - mm in diameter, and often have very prominent grooves or folds. p jiroveci pneumonia classically consists of an intra-alveolar foamy exudate in which the organisms appear as small "bubbles" in a background of proteinaceous exudate, although a variety of other reactions can occur as well [ ] . the incidence of ptld is significantly higher after thoracic organ transplantation compared with any other solid-organ transplant [ ] . they develop in - % of lung transplant recipients, as opposed to an approximate % incidence in other solid organ recipients, with % of the ptlds presenting in the allograft. in adults, ptlds are the most common neoplasms at year posttransplantation (peak, - months posttransplantation) [ ] . in children [ ] , lymphomas are by far the most common posttransplantation malignancy at any time. in fact, ptld is a major cause of morbidity and mortality in pediatric lung transplant recipients [ ] . risk factors for ptld after solid organ transplantation include patient's age, type of organ transplanted, ebv infection status of host before transplantation, and the immunosuppressive regimen [ , , , ] . ptlds are a clinically, morphologically, and molecularly heterogeneous spectrum of lymphoproliferative disorders, ranging from early, ebv-driven, polyclonal, polymorphic proliferations (infectious, "mononucleosis-like") to ebv-positive or ebv-negative monomorphic tumors [ , , , ] . ptlds most commonly are associated with ebv infection of b-cells either by reactivation of latent virus or primary ebv, most commonly acquired from donor organs [ ] . a recent study showed [ ] that five of seven lung-transplanted children who developed ptld were ebv-negative recipients who received ebv-positive lungs. in a series [ ] of heart and/or lung transplant recipients, ptlds were identified. amongst the ptld cases, there were two b-cell monoclonal polymorphic ptlds and b-cell monomorphic ptlds (see fig. . ) ( diffuse large b-cell lymphomas (dlbcl) and two burkitt lymphomas). ebv was detected in of the patients. all cases showed monoclonal igv gene rearrangements; igv somatic hypermutation was found in % of cases, indicating a prevalent origin from germinal center-experienced b cells. given the association between ebv infection and ptld, elevation in ebv viral load measured in peripheral blood has been proposed as a marker for the development of ptld [ ] . in addition, monitoring the degree of immunosuppression after diagnosis of ptld with immune function assays and immunosuppressive drug levels may aid clinicians in assessing the risk for ptld and monitoring treatment after diagnosis [ ] . t-cell ptlds tend to occur later and tend not to be associated with ebv infection. t-cell ptlds are associated with a worse prognosis than b-cell ptld. patients with ptlds may be asymptomatic, or they may have nonspecific complaints such as fever, weight loss, dyspnea, and lethargy. solitary or multiple pulmonary nodules ranging in size from . to cm are the most common pulmonary manifestation of patients with ptlds. mediastinal and hilar adenopathy also can be observed in - % of cases. patients who present with a solitary pulmonary nodule have a better overall prognosis. however, most ptlds have a rapid onset, a predilection for extranodal sites, and an aggressive clinical behavior with poor outcome [ , , , , ] . as a result of the high mortality associated with ptld, treatment often poses a challenge. the most common treatment of ptld has included decreasing immunosuppression in combination with surgical resection, antiviral agents, radiation, and chemotherapy [ , , ] . the reduction or withdrawal of immunosuppressive therapy may result in a partial or complete regression of the ptld [ ] . a higher risk of graft rejection associated with ptld treatment is one reason for the need for early detection of the disease [ , , , ] . in adults, malignancy remains a common complication after lung transplantation [ ] . among lung transplantation survivors, . , . , and . % have a malignancy at , , and years posttransplantation, respectively. although lymphoproliferative disorders are most common at year posttransplantation, nonmelanoma skin malignancy is the leading malignancy at and years posttransplantation. in children [ ] , the incidence of posttransplantation malignancy is higher than in adults early after transplantation with . % of children developing them within the first year after transplantation. at years posttransplantation, . % were found to have a malignancy. at any time posttransplantation, lymphomas are by far the most common posttransplantation malignancy in children. the risk for cancer is higher following lung transplantation than after kidney transplantation [ , ] . lung transplant patients have unique characteristics, as their baseline genetic and environmental background, and immunosuppressive regimens are different from patients receiving kidney transplant, all of which may contribute to the increased risk [ ] . besides nonmelanoma skin cancer and lymphoproliferative disorders, other malignancies repor ted to be associated with solid organ transplantation include: kaposi's sarcoma, anogenital cancers, oral cavity malignancies, esophageal and urinary bladder cancer, hepatocellular carcinoma, and sarcomas [ , ] . acute graft vs. host disease (gvhd) is an uncommon and usually fatal complication of lung transplantation for which no effective therapy exists. among the ten reported patients, eight had grade to acute gvhd and died within days. there is one recent case report [ ] of a patient with grade to acute gvhd after blt who was successfully treated with highdose corticosteroids after basiliximab and extracorporeal photopheresis were unsuccessful. after days the patient had developed low grade fever, chills, and pruritic maculopapular rash on the chest that spread to the proximal extremities in the next days. liver function tests were elevated. a skin biopsy showed dermal inflammation, patchy loss of basal layer with vacuolar degeneration, apoptosis, and cell necrosis suggesting gvhd. a few days later, profuse, green, watery diarrhea developed with abdominal pain and paralytic ileus. colonoscopy showed ulceration of mucosa and destruction of intestinal crypts, features compatible with gvhd. there was leucopenia, severe anemia, and deterioration of liver function. the diagnosis was confirmed by chimerism study that revealed a recipient/donor lymphocyte ratio of : . a second case of acute gvhd after lung transplantation was successfully treated with corticosteroids [ ] . this patient presented with mild symptoms (pruritic rash and blurry vision) suggesting low-grade gvhd. the diagnosis was confirmed when a small dose of prednisone resulted in the resolution of gvhd within weeks. lung harvest/reperfusion (ischemia/reperfusion, i/r) injury after transplantation remains the most common cause of early posttransplantation respiratory failure and manifests typically during the first h after transplant [ ] . reported rates are as great as % [ ] . the -day mortality of patients with i/r injury is about %, compared with % in patients without i/r injury [ ] . the clinical equivalent to i/r injury is pgd. the ishlt working group on pgd proposed a four-tiered grading scheme of pgd based on pao /fio (p/f) ratio and radiological chest infiltrates assessed at time points up to h: t ( -within h of reperfusion, , , and h) [ ] . i/r injury usually presents with the immediate impairment in lung function after transplantation accompanied by rapid development of pulmonary edema, increased pulmonary vascular resistance, and decreased airway compliance. patients with i/r injury require prolonged mechanical ventilation with greater hospital stays and are at an increased risk of multiorgan failure. lung i/r injury has long-term consequences and is a risk factor for late graft failure (ob) [ , ] . i/r injury can occur due to prolonged ischemia during transplantation. ischemic injury to the pulmonary vascular endothelium increases permeability and results in pulmonary edema. histologically, i/r injury presents as acute lung injury pattern including dad (see fig. . ). perivascular infiltrates are usually not present and distinguish it from acute rejection. however, infection can present similarly and needs to be excluded with stains, cultures, and serology. the pathophysiology of lung i/r injury remains incompletely understood. the lungs are particularly susceptible to i/r injury, likely owing to the rich vascularity and relatively large surface area over which blood-borne components interact with the endothelium. the mechanisms of i/r injury are diverse and include generation of reactive oxygen species (ros), leukocyte activation/recruitment, complement and platelet activation, abnormalities in pulmonary vascular tone, and increased procoagulant activity. the production of proinflammatory cytokines is increased considerably in the lung after i/r. expression of cytokines in the lung after i/r may not only cause immediate tissue injury, but may predispose the lung allograft to rejection. several studies suggest that lung i/r injury is biphasic, with a distinct, acute injury characterized by macrophage activation followed by a later, neutrophildependent injury [ ] . although recurrent disease in the allograft has been reported in some of the transplantation cases, in general, this has not been clinically significant. diseases for which recurrences in the allograft have been reported include giant cell interstitial pneumonia, sarcoidosis, lymphangioleiomyomatosis, langerhans' cell histiocytosis, allergic bronchopulmonary aspergillosis, desquamative interstitial pneumonia, bronchioloalveolar carcinoma, alveolar proteinosis, and diffuse pan bronchiolitis. morphological features are identical to the disease in nontransplanted lung. bronchial dehiscence is the most common anastomotic airway complication in the early postoperative period. it occurs in - % of cases. ischemia at the anastomotic site is the major factor in the development of this complication. dehiscence probably is best assessed by bronchoscopy; however, ct scans typically demonstrate the presence of extraluminal gas, which is % sensitive and % specific for dehiscence. patients with telescoping anastomoses also may develop small anastomotic diverticula, which appear as smooth rounded air collections at the inferior-medial aspect of the anastomosis. anastomotic stricture occurs in approximately % of cases, and the risk for stenosis may be increased with a telescoping anastomosis. stenoses often manifest with progressive airflow obstruction that can be difficult to differentiate from other causes, such as acute rejection or bos. stricture probably is best evaluated by bronchoscopy; however, ct scans often demonstrate the area of narrowing. treatment is stenting, typically with an expandable metallic stent. more recently, balloon dilatation has obviated the need for stents in some centers. app % of lung transplantations between and were single lung transplants (slt) [ ] . copd, aat, and ipf accounted for app % of the indications for slts [ ] . advantages of slt over blt include a technically easier procedure, shorter surgery time, and the ability to transplant two patients from one donor. however, there are disadvantages to slt. for instance, survival rates for slt and blt recipients are different, diverging most obviously in later years after transplantation. -year survival for slt was % compared with % for blt [ ] . other disadvantages of slt include less pulmonary reserve, and the propensity for complications related to the residual native lung. native lung complications have previously been reported in . - % of patients. they may be associated with significant morbidity and mortality [ , ] and may partly explain why outcomes with slt are inferior to those of blt. a recent study [ ] reported the occurrence of pneumothoraces, malignancy, aspergilloma, pneumonia, bronchopleural fistulas, and pulmonary embolism. some forms of advanced lung disease, including copd and ipf, are associated with increased risk for lung cancer, a complication that can arise in the native lung after transplantation [ , ] . patients also often have structural damage to the native lung from their underlying disease process, which can increase the risk of other complications such as aspergilloma and pneumothoraces. the median time from transplantation to major native lung complication was . years (range, . - . years). in one study [ ] , of patients with native lung complications died thereof. median posttransplant survival was lower in slt recipient with significant native lung complications ( . vs. . years, p = . ). native lung pneumonectomy was performed in patients. in patients with native lung complications there was a trend toward improved posttransplant survival in patients who underwent native lung pneumonectomy compared with those who did not undergo pneumonectomy. however, there was no difference in survival between patients who underwent native lung pneumonectomy to those who had no native lung complication. the majority of patients with ob also have severe bronchiectasis. by specimen bronchograms, the bronchial tree shows alternating areas of dilatation and constriction. microscopically, the bronchiectasis may be associated with areas of mucous plugging, goblet cell hyperplasia, squamous metaplasia, denudation of the bronchial epithelium, submucosal scarring, and acute and chronic inflammation of the bronchial wall. occasionally foreign body giant cells are present, probably representing a manifestation of aspiration. obliteration of the terminal respiratory bronchioles is often observed distal to these areas. the bronchiectasis of lung allografts is probably the result of several factors including immune-related injury, infection, mucostasis, aspiration, and loss of innervation. despite advances in operative management, lung preservation, critical care, and immunosuppression, longterm survival in lung transplantation remains limited. in fact, outcomes for lung transplantation are the worst of any solid organ transplant [ ] . the main obstacles to present day lung transplantation involve: ( ) lack of donor organs, ( ) i/r injury, ( ) acute rejection, and ( ) development of ob. the increased susceptibility of the lung to injury, infection, and constant environmental exposure with local innate immune activation likely contributes to the high rates of rejection. the ishlt registry reports a -year survival rate of % and -year survival rate of % [ ] . mortality is highest in the first year, which consistently decreases across subsequent time periods (see table . ). in the first days, graft failure, non-cmv infections, cardiovascular complications, and technical problems account for most of the mortality. after the first year, bos and non-cmv infections were the predominant causes of death. by years, malignancies and cardiovascular causes account for almost % of reported causes of death. however, compared with data beginning in , overall survival has consistently improved by era. the improvement in survival is largely due to improvement in the year survival. long term survival has improved as well, although to a seemingly lesser degree. evidence suggests that age, pretransplant diagnosis, and donor cmv status play important prognostic roles. for instance, the survival half-life for patients older than years of age was . years compared with . years for those aged - . overall survival rates at months after transplantation are lowest for ipf ( %) and ipah ( %) and highest for cf ( %) and copd ( %), most likely due to differences in early complications, including pgd [ ] . cmv seropositivity of the donor is associated with worse survival; however, the underlying reasons for this association are not entirely clear. inducing a state of immune suppression is the key to successful clinical lung transplantation. the immunosuppressive regimens used for lung transplantation are based on successful protocols that have evolved for renal and heart transplantation. posttransplantation morbidities (see table . ) present at years are those commonly caused or exacerbated by immunosuppressive medicines, including hypertension, renal dysfunction, and dyslipidemia. bos and malignancies are other common posttransplantation morbidities. for instance, bos had developed in % of patients by . years after transplantation and in % by years. however, most surviving patients reported no activity limitations at , , , and years (> % at each time point). furthermore, % of survivors reported at least one malignancy at years after transplantation, and % were affected by malignancies at years. survival after pediatric lung transplantation is similar to that reported in adults with a median survival of . years for the period -june . but, results are clearly improving [ ] . one and -year survival rates for pediatric recipients transplanted in the most ob obliterative bronchiolitis recent era ( - / ) are and %, respectively, compared with and % for recipients transplanted between and . graft failure, technical issues, cardiovascular failure, and infection are the most common causes of pediatric death in the early posttransplant period whereas infection, graft failure and bos are the most common causes of late death. the prevalence of bos steadily increases with time posttransplantation. as expected, the cumulative incidence of malignancy also increases with time after transplantation, with lymphoproliferative disorders making up the great majority of reported malignancies in children. despite the complications, the functional status of the great majority of long-term pediatric survivors is very good, with % of -year survivors reporting no limitations in activity. a total of pediatric retransplant procedures were reported between january and june . the majority of these procedure were performed > months after the initial transplantation. survival over this period was slightly poorer than for primary transplantations, being % at years. prediction of lung-transplant rejection by hepatocyte growth factor development of malignancy following lung 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human leukocyte antigen matching on long-term outcome after lung transplantation alpha -antitrypsin deficiency carriers, tobacco smoke, chronic obstructive pulmonary disease, and lung cancer risk lung transplantation exacerbates gastroesophageal reflux disease the potential role of mast cells in lung allograft rejection revision of the working formulation for the classification of pulmonary allograft rejection: lung rejection study group can immunohistological analysis of transbronchial biopsy specimens predict responder status in early acute rejection of lung allografts? interleukin- production genotype protects against acute persistent rejection after lung transplantation the impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients key: cord- - s g wvd authors: zheng, guoping; huang, lanfang; tong, haijiang; shu, qiang; hu, yaoqin; ge, menghua; deng, keqin; zhang, liuya; zou, bin; cheng, baoli; xu, jianguo title: treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study date: - - journal: respir res doi: . / - - - sha: doc_id: cord_uid: s g wvd background: recent studies have demonstrated that mesenchymal stem cells (mscs) modulate the immune response and reduce lung injury in animal models. currently, no clinical studies of the effects of mscs in acute respiratory distress syndrome (ards) exist. the objectives of this study were first to examine the possible adverse events after systemic administration of allogeneic adipose-derived mscs in ards patients and second to determine potential efficacy of mscs on ards. methods: twelve adult patients meeting the berlin definition of acute respiratory distress syndrome with a pao( )/fio( ) ratio of < were randomized to receive allogeneic adipose-derived mscs or placebo in a : fashion. patients received one intravenous dose of × ( ) cells/kg of body weight or saline. possible side effects were monitored after treatment. acute lung injury biomarkers, including il- , il- and surfactant protein d (sp-d), were examined to determine the effects of mscs on lung injury and inflammation. results: there were no infusion toxicities or serious adverse events related to mscs administration and there were no significant differences in the overall number of adverse events between the two groups. length of hospital stay, ventilator-free days and icu-free days at day after treatment were similar. there were no changes in biomarkers examined in the placebo group. in the mscs group, serum sp-d levels at day were significantly lower than those at day (p = . ) while the changes in il- levels were not significant. the il- levels at day showed a trend towards lower levels as compared with day , but this trend was not statistically significant (p = . ). conclusions: administration of allogeneic adipose-derived mscs appears to be safe and feasible in the treatment of ards. however, the clinical effect with the doses of mscs used is weak, and further optimization of this strategy will probably be required to reach the goal of reduced alveolar epithelial injury in ards. trial registration: clinical trials.gov, nct acute respiratory distress syndrome (ards) is a major cause of acute respiratory failure and is often associated with multiple organ failure. clinical disorders such as pneumonia, sepsis, aspiration of gastric contents, and major trauma can precipitate ards. the pathogenesis of ards involves lung endothelial injury, alveolar epithelial injury, and the accumulation of protein-rich fluid and cellular debris in the alveolar space [ ] . even with the current advances in lung-protective ventilation and fluid management, patient mortality rate remains high. a clinical diagnosis of ards is associated with large financial burdens due to long hospitalization and icu stays, a poor survival rate, and an increased use of health services after hospital discharge. most patients who survive an episode of ards will sustain some degree of permanent physical disability as well as reduction in their quality of life. in addition, survivors often have long-term neuromuscular, cognitive, and psychological symptoms [ ] . to decrease the occurrence of these life-changing consequences, alternative therapeutic options are needed that can reduce lung injury while facilitating and enhancing lung repair. in the past decade, the preclinical and clinical studies of mscs have boosted the expectations of both patients and physicians for mscs as a treatment modality. unlike embryonic stem cells, the procurement and use of mscs is less controversial. there are multiple mechanisms responsible for the protective effects of mscs, including the secretion of multiple paracrine factors capable of modulating the immune response and restoring epithelial and endothelial integrity [ ] . moreover, their immunomodulatory capacity, coupled with low immunogenicity, have opened up possibilities for their allogeneic use, consequently broadening the possibilities for their application. allogeneic mscs have been applied to treat graft-versus-host diseases [ ] , myocardial infarction [ ] , autoimmune diseases [ ] , and inflammatory bowel diseases [ ] . in may , canadian health regulators approved prochymal tm , the first allogeneic mscs-based drug, for acute graft-versus-host diseases in children who have failed to respond to steroid treatment. bone marrow (bm)-mscs are the most widely used mscs in clinical trials. unfortunately, the harvest of bm is a highly invasive procedure. furthermore, the number, differentiation potential, and maximal life span of mscs from bm decline with increasing age [ , ] . due to their ease of procurement and cell banking, the adipose-derived mscs have received significant attention over the past few years [ ] . many studies, including publications from our group [ , ] , have demonstrated compelling evidence of the benefits of mscs from both bone marrow [ ] [ ] [ ] and adipose tissues [ ] [ ] [ ] in animal models for lung injury and ards. we hypothesized that allogeneic adipose-derived mscs serve as a potential therapeutic agent for the treatment of ards. in this randomized, placebo-controlled phase i clinical trial, the primary goal was to evaluate the safety and feasibility of systemic administration of allogeneic adipose-derived mscs in ards patients. secondary goals were to determine potential efficacy and the effect of mscs on biomarkers for ards. this was a single-center, randomized, double-blind, and placebo-controlled study. the study protocol complied with the declaration of helsinki and was approved by the research ethics committee at shaoxing second hospital (clinical trials.gov identifier: nct ). written informed consent was obtained from the patient or legally authorized representative before enrolling each patient. study enrollment occurred between january and april . ards was defined and classified according to the berlin definition [ ] . in the new berlin definition, diagnostic criteria for ards rely on categories: ( ) timing: within week of a known clinical insult or new or worsening respiratory symptoms; ( ) radiography: bilateral opacitiesnot fully explained by effusions, lobar/lung collapse or nodule; ( ) origin of lung edema: respiratory failure not fully explained by cardiac failure or fluid overload, and ( ) oxygenation impairment: subdivided into categories according to the degree of hypoxemia severity (mild, moderate and severe). the berlin definition eliminated the concept of acute lung injury, which now falls in the category of mild ards. eligible patients were at least years of age and diagnosed within hours with a pao /fio ratio of < . exclusion criteria included pre-existing severe disease of any major organs, pregnancy, pulmonary hypertension, malignant disease, human immunodeficiency virus (hiv) infection or if informed consent could not be obtained. patients were randomized upon study enrollment. for all patients, a negative fluid balance was maintained by diuretics and fluid restriction. ards network low tidal volume protocol was adopted for standardized ventilator management, targeting a tidal volume of ml/kg of the patient's ideal body weight and a plateau pressure less than mmhg [ ] . per the requirement of research ethics committee at shaoxing second hospital, frozen mscs with dmso and fetal bovine serum were not allowed to be infused to patients directly. for the mscs group, frozen cells were immediately thawed, cultured with patient's own serum and harvested in - hours. freshly harvested mscs, at a dose of × cells/kg body weight, were suspended in ml normal saline for peripheral intravenous infusion and administered over hour within hours of enrollment. for the placebo group, a bag of ml normal saline was infused at similar time point. after administration of the mscs or placebo at day , patients were assessed daily at days , , , , , and (or until hospital discharge or death, whichever occurred first). patients who were discharged from the hospital before day were asked to return to the study site for assessment. all other aspects of the therapeutic management of the patients were left to the discretion of the clinical team. the primary endpoint was the occurrence of adverse events. secondary efficacy endpoints included the following: pao /fio ratio, hospital indices (length of hospital stay, ventilator-free days and icu-free days at day ), and serum biomarkers of ards including il- , il- and sp-d. normal human adipose-derived mscs were purchased from atcc (cat # pcs- - , lot , passage , manassas, va). the donor of the mscs was a year-old female of hispanic origin. mscs were certified to be negative for hiv, hbv, hcv, bacteria, yeast and mycoplasma. after purchase, sterility, viral, and endotoxin tests of the mscs were performed at the pathology lab of shaoxing second hospital to confirm the certificate of analysis. cells were then resuspended in expansion media containing dulbecco's modified eagle's medium (dmem) -low glucose supplemented with penicillin and streptomycin and % fetal bovine serum (fbs) (life technologies, grand island, ny) plus egf and fgf (r&d systems, minneapolis, mn) at a density of cells/cm . cultures were maintained at °c in a humidified atmosphere containing % co in mm dishes (life technologies, grand island, ny). when the cultures reached near confluence (> %), the cells were detached by treatment with trypsin/edta and replated at a density of cells/cm . mscs were passaged up to a maximum of four times. after sufficient mscs were expanded, cells were harvested and cryopreserved in % culture media, % fetal bovine serum and % dmso. sterility, viral, and endotoxin tests were carried out again after the expansion. right after each enrollment, ml of peripheral blood was collected and serum harvested from the patients. if a patient was randomized to mscs treatment, cryopreserved mscs were immediately thawed, washed with phosphatebuffered saline (pbs), and cultured with the same expansion media above except supplemented with % of the patient's own serum at a density of cells/cm for - hours. cells were harvested with trypsin/edta and quantitated with a hemocytometer. viral and endotoxin tests were performed prior to the infusion. all cell culture procedures were carried out in good manufacturing practice (gmp) conditions by personnel who had received formal training in gmp within a facility with highly controlled temperature, room air, pressure, etc. morphology was monitored twice a week throughout the culture period by light microscopy. immunophenotyping of cultured mscs was performed using flow cytometry. the following markers were analyzed: cd , cd , cd , cd , cd , and human leukocyte antigen (hla)-dr (bd biosciences, franklin lakes, new jersey). the samples were analyzed on a facscalibur using cellquest pro software (bd biosciences). for osteogenic differentiation of the expanded mscs, cells were further cultured with osteogenic medium containing % fbs, . mm l-ascorbic acid -phosphate and . m β-glycerophosphate in dmem. after - weeks, the cultures were stained for alkaline phosphatase (alp) a b sixteen c bl/ male mice aged - week-old were randomized into study groups: short term mscs ( days), short term placebo, long term mscs ( days), and long term placebo. animal studies were approved by the institutional animal care and use committee at zhejiang university. mice received one high dose of intravenous infusion of × expanded cells/kg of body weight or normal saline at day . mice were sacrificed at day or day . at the sacrifice, serum was harvested for monitoring renal function, liver function, cardiac enzymes, and pancreatic enzymes. kidney, liver and lung samples were paraffin-fixed for histopathological analysis. five milliliters (ml) of peripheral blood were collected from patients immediately before mscs or saline treatment (day ) and day after treatment. serum samples were collected by centrifugation at , g for minutes and stored at - °c until assay at the end of the trial. il- , il- and sp-d levels were determined by commercial enzyme-linked immunosorbent assays (elisa) (r&d systems, minneapolis, mn). continuous variables were expressed as mean ± standard deviation (sd). comparisons of continuous variables between two groups were performed by using unpaired student's t-test. comparisons within groups were performed by using paired t-test. differences were deemed statistically significant at p < . . kidney liver lung figure histology of kidneys, liver and lungs after mscs treatment. mice were administered intravenously with one dose of × mscs/kg of body weight or placebo. after days, kidney, liver and lung samples were harvested for h&e staining. adipose-derived mscs were spindle-shaped with a fibroblast-like morphology and were attached to the plate during cell culture. these characteristics were well preserved during subculture for a total of passages before harvest. for phenotypic characterization of mscs, surface protein expression at the end of expansion was examined by flow cytometry. the mscs were positive for cd ( . %), cd ( . %), and cd ( . %), but were negative for cd ( . %), cd ( . %), and hla-dr ( . %). the expanded mscs preserved the abilities of osteogenesis as determined by alkaline phosphatase staining ( figure a ) and adipogenesis as assayed by oil red o staining ( figure b ). after administering one high dose of × mscs/kg or normal saline at day via intravenous infusion, no mouse death was observed during the -day study period. there were no significant differences in liver (alanine aminotransferase and total bilirubin) and kidney (creatinine and blood urea nitrogen) function between the two groups on both day and day (table ) . mscs treatment did not alter cardiac enzymes, pancreatic enzymes and body weight (data not shown). mice treated with mscs did not show any histopathological changes in the liver, lungs, or kidneys at both day ( figure ) and day (data not shown). a total of ards patients were screened for enrollment in the study. of this number, patients were not enrolled because of the exclusion criteria or refusal to participate the study. the study population is comprised of patients randomized to the mscs group and patients to the placebo group. baseline demographics with no statistically significant differences between the study groups are summarized in table . within hours of randomization, patients received one dose of × cells/kg body weight or saline as a single intravenous infusion over minutes. study drugs were well tolerated. no adverse events were recorded during infusions. one patient from each group presented with diarrhea one day after study drug treatment and resolved within hours. one patient in the mscs group developed rash in the chest area after the infusion and resolved spontaneously over hours. during the study period, one patient in the mscs group died of multiple organ failure. deaths occurred in two patients in the placebo group with one multiple organ failure and the other sepsis. none of the deaths were considered to be related to the study drugs by the clinical investigators and were consistent with the patients' existing disease processes. all the remaining patients completed the -day follow-up period. there were no other adverse events or serious adverse events. as part of the safety and efficacy assessment, an evaluation of the oxygenation index and patient outcomes was conducted. significant improvements in oxygenation index (pao /fio ) from baseline were observed in all data points in the mscs group. in the placebo group, there were no significant improvements at days (p = . ) and (p = . ) as compared to baseline. the pao /fio did not differ significantly between mscs and placebo groups at all time points (figure ). assessment of hospital indices did not reveal significant differences in length of hospital stay, ventilator-free days and icu-free days at day between the two study groups (table ) . there were no statistically significant differences in serum sp-d, il- or il- levels between the mscs and placebo groups at both day and day (table ). in the placebo group, sp-d, il- or il- levels were similar between day and day ( figure b, d, f) . these findings are in agreement with those reported in other ards studies which showed no changes in biomarkers during the first week of ards development [ , ] . in the mscs group, serum sp-d levels at day were significantly lower than those at day (p = . ) ( figure a ). the il- levels at day showed a trend towards lower levels as compared with day , but this trend was not statistically significant (p = . ) ( figure e ). although the mean value for il- at day was much lower than that of day (table ) , the difference was not statistically significant due to the variation of the data (p = . ) ( figure c ). animal studies from our research group and others have showed that mscs from both bone marrow [ ] [ ] [ ] [ ] [ ] and adipose tissues [ ] [ ] [ ] the anti-inflammatory/immunomodulatory effect of mscs provides a therapeutic rationale for ards. it has been reported that the pathogenesis of ards involves procoagulant and inflammatory mechanisms as well as damage to the epithelial and endothelial compartments [ ] . biomarkers that reflect inflammation (il- , il- ) [ ] , coagulation (plasminogen activator inhibitor- , protein c, thrombomodulin) [ ] , endothelial cell injury (von willebrand factor) [ ] , and epithelial cell injury [sp-d and receptor for advanced glycosylation end products (rage)] [ ] , have all been linked to increased disease severity and poorer clinical outcomes in patients with ards. our results suggest that the mscs may be effective in decreasing epithelial cell injury as evidenced by reduced sp-d levels at day after mscs treatment. the levels for pro-inflammatory cytokine il- were decreased with only marginal significance (p = . ) in mscs group. therefore, the present data are not sufficient to support a conclusion that mscs exert their effects through alleviating lung inflammation. in the present study, mscs were administered through peripheral intravenous infusion. intravenous delivery of mscs is especially advantageous to lung diseases. other studies showed that the majority of administered stem cells were initially trapped in the lungs. infrared imaging revealed stem cells evenly distributed over all lung fields ventilator-free days at study day . ± . . ± . . data are presented as mean ± sd. p values were calculated using student's t-test. [ ] . systemic administration of mscs was recently reported in chronic obstructive pulmonary disease (copd). there were no significant differences in the overall number of adverse events, frequency of copd exacerbations, or worsening of disease in mscs-treated patients. pulmonary function testing and quality of life indicators remained the same after mscs treatment. for patients who had elevated c-reactive protein levels at study entry, an early significant decrease in the levels of circulating c-reactive protein was demonstrated in mscs-treated group [ ] . adipogenic precursors were first isolated from human adipose tissue by plastic adherence [ ] . adipose-derived mscs were identified and characterized in human fat tissue by zuk et al. in [ ] , and this led to the recognition of adipose tissue as an alternative to bm for mscs. bm-mscs reside in the bone marrow stroma in relatively small quantities. it has been estimated that they comprise about . %- . % of the total marrow nucleated cells [ ] , whereas the proportion of adipose-derived mscs is approximately % of all nucleated cells of adipose tissue [ ] . this difference is particularly relevant for making adipose-derived mscs more suited for clinical applications due to their ease of accessibility. adipose-derived mscs have other advantages as compared with bm-mscs. it was initially shown that both bm-mscs and adipose-derived mscs exhibit immunosuppressive properties in vitro [ ] . adipose-derived mscs can be more effective suppressors of immune response. they were significantly better than bm-mscs in inhibiting both the differentiation of blood monocytes into dendritic cells as defined by cd expression and the expression of co-stimulatory molecules (cd , cd ) on the surface of mature monocyte-derived dendritic cells. adipose-derived mscs were more powerful than bm-mscs at stimulating data are presented as mean ± sd. sp-d = surfactant protein d (ng/ml); il- = interleukin (pg/ml). il- = interleukin (pg/ml). p values were calculated using unpaired student's t-test. the secretion of immunosuppressive cytokine il- by dendritic cells [ ] . it has been demonstrated that adipose-derived mscs show a significantly greater angiogenic potential compared with bm-mscs [ ] , and may be more effective in cardiovascular pathologies associated with ischemia. allogeneic bm-mscs, prochymal tm , has been approved in canada and new zealand for acute graft-versus-host diseases in children who have failed to respond to steroid treatment. allogenic adipose-derived mscs have been tested to treat several diseases. an open-label, singlearm clinical trial was conducted for crohn's disease. twenty-four patients were administered intralesionally with million adipose-derived mscs in each draining fistula tract. a subsequent administration of million adipose-derived mscs was followed if fistula closure was incomplete at week . no safety concerns were revealed at months follow-up. at week , . % of the patients showed a reduction in the number of draining fistulas with . % of the patients achieving complete closure of the treated fistula [ ] . vanikar et al. administered allogeneic adipose-derived mscs along with hematopoietic stem cells intraportally in patients with insulin-dependent diabetes and followed the patients for months. clinical parameters improved significantly as evidenced by a decreased exogenous insulin requirement, reduced levels of glycosylated hemoglobin, elevated serum c-peptide levels, and resolved diabetic ketoacidosis events [ ] . allogenic adipose-derived mscs have been explored as a salvage therapy of patients with severe steroid-resistant acute graft-versus-host diseases [ ] . complete response was achieved in patients, of them were still alive after a median follow-up of months. all survivors were in good clinical condition and in remission of hematological malignancy [ ] . with the application of mscs in the clinical setting, there is no standard protocol regarding how to expand these cells with gmp. most existing expansion protocols use dmem supplemented with fbs. however, fbs is a source of xenogeneic antigens and carries the risk of transmitting animal viruses and prions [ ] . immunological reactions and anti-fbs antibodies have been observed after transplantation in allogeneic hematopoietic stem cell recipients [ ] . as an alternative for fbs, platelet lysate [ ] , both autologous [ ] and allogeneic human serum [ ] , and serum-free medium have been tested for mscs expansion [ ] . to mitigate the allergic reactions in seriously ill ards patients and meet the requirements of the research ethics committee at shaoxing second hospital, mscs were cultured in autologous human serum for - hours after enrollment in the present study. this delay in mscs administration may have reduced the effect of mscs in ards. our pilot study is limited primarily by the small sample size. the current sample size limits the statistical rigor and power of our findings and, thus, our conclusions regarding safety and efficacy. another limitation is that the follow-up period was only days. longer follow-up periods are essential in evaluating the long-term effects of the cells. finally, our study lacked data regarding the time-response relationship and the dose-response relationship for mscs. what remains unknown is how often or how many mscs should be administered in ards. due to the small sample size, only limited effects can be observed in this preliminary study. nevertheless, the findings demonstrated that infusion of allogeneic adipose-derived mscs was safe and there were no significant adverse events related to the mscs in ards. the change in ards biomarker, sp-d, after treatment may suggest the protective effect of mscs. additional large studies with a long follow-up period are necessary to confirm the safety and efficacy profile of mscs in ards and to establish the best strategy for their administration, including concomitant medication and dosage. 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available for redistribution the authors declare that they have no competing interests. we would like to give special thanks to dr. mauricio rojas, university of pittsburgh school of medicine, for his very helpful comments and suggestions. we would also like to thank tingting li, wei wang, xiaojiao yang, and xuezhi ye from shanghai biomed union for their support in gmp production of mscs. this work was supported by the national natural science foundation of china ( ) and shaoxing plan to jx, and the national natural science foundation of china ( ) and the zhejiang province science and technology program ( c ) to qs. key: cord- -ndmf ekp authors: akins, paul taylor; belko, john; uyeki, timothy m.; axelrod, yekaterina; lee, kenneth k.; silverthorn, james title: h n encephalitis with malignant edema and review of neurologic complications from influenza date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: ndmf ekp background: influenza virus infection of the respiratory tract is associated with a range of neurologic complications. the emergence of pandemic influenza a (h n ) virus has been linked to neurological complications, including encephalopathy and encephalitis. methods: case report and literature review. results: we reviewed case management of a -year old hispanic male who developed febrile upper respiratory tract signs and symptoms followed by a confusional state. he had rapid neurologic decline and his clinical course was complicated by refractory seizures and malignant brain edema. he was managed with oseltamavir and peramavir, corticosteroids, intravenous gamma globulin treatment, anticonvulsants, intracranial pressure management with external ventricular drain placement, hyperosmolar therapy, sedation, and mechanical ventilation. reverse transcriptase polymerase chain reaction analysis of nasal secretions confirmed h n virus infection; cerebrospinal fluid (csf) was negative for h n viral rna. follow-up imaging demonstrated improvement in brain edema but restricted diffusion in the basal ganglia. we provide a review of the clinical spectrum of neurologic complications of seasonal influenza and h n , and current approaches towards managing these complications. conclusions: h n -associated acute encephalitis and encephalopathy appear to be variable in severity, including a subset of patients with a malignant clinical course complicated by high morbidity and mortality. since the h n influenza virus has not been detected in the csf or brain tissue in patients with this diagnosis, the emerging view is that the host immune response plays a key role in pathogenesis. the current pandemic of influenza a (h n ) ( h n ) virus has presented challenges for clinicians the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the centers for disease control and prevention. worldwide. neurologic complications of seasonal influenza are likely under-recognized by neurologists and the frequency of acute or post-infectious neurologic complications with h n virus infection is unknown. it is worth noting the historical relationship between h n and neurology. following the - h n pandemic, an increase was observed in encephalitis lethargica cases [ ] . what have neurologists learned about complications of h n virus infections worldwide? we present a case report of h n -associated encephalopathy and review neurologic complications associated with seasonal influenza and h n virus infection. the kaiser permanente inpatient neurosurgery service maintains ongoing institutional review board approval for a prospective database registry for clinical research purposes. we identified a case of acute encephalopathy associated with h n virus infection of the upper respiratory tract referred from an outside kaiser community hospital for management. we conducted a detailed review of the electronic medical records. we also conducted a literature review using pubmed. mesh search terms included influenza, encephalitis, encephalopathy, h n , acute necrotizing encephalopathy, and meningitis. a previously healthy -year old male college student had days of non-productive cough, rhinorrhea, myalgias, and fever but no headaches or neck stiffness. on the th illness day, he presented to the emergency department of a community hospital with lethargy and confusion. he was electively intubated for airway protection. his chest x-ray (cxr) was normal. routine admission laboratory tests including hepatic transaminases were within normal range. a non-contrast head computed tomography (ct) did not reveal any abnormalities (fig. , top row) , and he underwent lumbar puncture. cerebrospinal fluid (csf) analysis showed wbc/ll with % lymphocytes, rbc/ll, protein mg/dl, and glucose mg/dl. he was diagnosed with meningoencephalitis and started on vancomycin, ceftriaxone, acyclovir, and oseltamivir ( mg twice daily per nasogastric tube). on the morning of the third-day of hospitalization, he experienced tonic-clonic seizures and remained comatose with extensor posturing afterwards. repeat head ct (fig. , bottom row) demonstrated diffuse brain edema and effaced basal cisterns. he received fosphenytoin, mannitol, and propofol. the treating physicians contacted the neuro-intensive care unit at kaiser sacramento for additional assistance. he was emergently transferred to the kaiser permanente sacramento neuro-intensive care facility (nicu). on arrival, his initial examination demonstrated a glasgow coma scale of (e v m ). his repeat cxr did not demonstrate on the bottom row, the small arrow points to effacement of basal cisterns (left) and subcortical brain edema (larger arrows, bottom row, left and right). this subcortical edema is confirmed on mr imaging (fig. ) any infiltrates or signs of acute respiratory distress syndrome (ards). an external ventricular drain was placed by the neurosurgeon at the bedside. he reported that the csf pressure noted at the time of initial catheter placement was elevated. the first recorded intracranial pressure (icp) was mm hg, and this reading was taken after the expected loss of csf during the procedure. on the second day of nicu hospitalization, his glasgow coma scale (gcs) score was (e v m ) and average icp was mm hg. throughout the remainder of the hospitalization, the recorded icp remained below mm hg. initial icp was maintained with external ventricular drainage at cm relative to the external auditory canal and a midazolam infusion ( mg/h). electroencephalogram (eeg) monitoring demonstrated diffuse, severe slowing in the delta range and no electrographic seizures. on hospital day , mri of the brain was obtained (see fig. ). he received days of dual neuraminidase inhibitor treatment (oseltamivir mg twice daily per nasogastric tube, peramavir mg iv daily); intravenous gamma globulin ( gm/ kg days); dexamethasone ( mg iv load, mg iv every h with taper over weeks); icp monitoring and management; ventilator support; and anticonvulsants (fosphenytoin, levetiracetam). his weekly glasgow scale scores showed delayed improvement ( , e v m , admission): (e v m , week ), (e v m , week ), (e v m , week ), (e v m , week ). the midazolam infusion was discontinued on hospital day , after clinical observation and eeg confirmation that he was not having electrographic seizures. thereafter he received intermittent doses of lorazepam as needed for sedation while on the ventilator. over weeks, neuroimaging demonstrated improvement in his brain edema with restoration of his basal cisterns, and the external ventricular drain was successfully weaned and removed. more rapid weaning of his external ventricular drain was not attempted due to severe neurologic impairments with gcs less than eight and radiographic appearance of diffuse brain edema and effaced basal cisterns. his nicu course was complicated by ventilatorassociated klebsiella pneumoniae and spontaneous pneumomediastinum on day of intensive care. chest ct demonstrated subcutaneous emphysema, mediastinal emphysema, bilateral lower lobe atelectasis, and no pulmonary interstitial emphysema, or pneumothorax. he did not develop adult respiratory distress syndrome or suffer periods of hypoxemia. rt-pcr of an admission nasopharyngeal swab was positive for h n virus at the california department of public health virology laboratory. rt-pcr analysis of csf samples was negative for influenza a and b viruses, herpes virus type , , and , varicella, enterovirus, and epstein barr virus. nasopharyngeal samples were negative for enterovirus and mycoplasma pcr. bacterial and viral cultures of csf were negative. test results from clinical specimens (blood, endotracheal aspirate, serum, and csf) sent to the california encephalitis project did not reveal an alternative cause. follow-up mri brain imaging (fig. b, d) was repeated at month. after weeks, he transitioned to acute rehabilitation, and month later returned home. because he had improved upper extremity use without recovery in his legs, the physiatry staff performed spine mr imaging and no specific cause was identified. at the time of this case report, the patient has returned home with his family. he is talking and interacting with his family normally. he has not returned to college. his gastromy tube has been removed. he has generalized rigidity without tremor or dyskinesia. he is ambulatory but requires a walker due to reduced endurance and leg weakness. fig. magnetic resonance imaging was done at the time of patient transfer a, c to the neuro-intensive care center and at month of treatment b, d with influenza-specific antiviral therapy, corticosteroids, and intravenous gamma globulin therapy. a coronal flair image shows diffuse brain edema with sulcal effacement and symmetric hyperintensities selectively affecting the white matter and sparing cortex and subcortical nuclei such as basal ganglia and thalami. b coronal flair image at month shows resolution of sulcal effacement, marked reduction in white matter hyperintensity, and relative brain atrophy ( year old patient). c diffusion-weighted imaging on admission showed some increased signal in the periventricular zones that were also bright on t and flair sequences consistent with t shine-through. d diffusionweighted imaging at month revealed hyperintensity in the caudate and putamen with corresponding decreased signal in adc map and lack of hyperintensities on t and flair sequences (see fig b) we present a case of a patient with acute encephalitis associated with febrile upper respiratory tract illness due to h n complicated by seizures and malignant cerebral edema. few adult cases of h n influenzaassociated acute encephalitis or encephalopathy have been reported to date. descriptions of h n -associated neurologic complications are limited to case reports and small case series, and have been more commonly reported among young children. given the current influenza pandemic, we provide an overview of neurologic complications associated with seasonal influenza and h n (fig. ) and review clinical management and rationale. influenza virus infections can cause human respiratory disease and have been associated with a variety of central nervous system disorders [ ] . influenza virus has been rarely detected in csf of patients that developed acute encephalitis/encephalopathy [ ] [ ] [ ] . the systemic inflammatory response syndrome (sirs) to influenza virus infection of the upper respiratory tract is hypothesized to play a prominent role in the more severe stages leading to cytokine dysregulation (''cytokine storm'') in influenzaassociated encephalopathy or encephalitis (iae) patients [ ] . elevated cytokines in serum and csf have been reported in patients with seasonal influenza-associated encephalopathy [ , [ ] [ ] [ ] [ ] . elevated csf to plasma ratios suggest activation of cytokine production within the cns may have occurred along with the respiratory tract and systemic cytokines [ , , ] . microglia and astrocytes are capable of producing cytokines in the cns [ , ] . it is known that influenza virus infects and replicates at the nasopharyngeal epithelium leading to extensive damage during infection. below the mucosa, the free nerve endings of the olfactory nerves may also become infected. as seen with herpes simplex viruses, some postulate that influenza virus could penetrate and replicate at the olfactory mucosa and the free nerve endings with resultant axonal transport of virions to the olfactory bulbs, to the olfactory tract, and finally to the brain [ ] . there is some literature to support this mechanism when one looks at h n , or avian influenza, where mice inoculated intranasally with h n developed cns lesions in the pons, medulla oblongata, and cerebellar nuclei. astrocytes and glial cells were positive for viral antigen but viral replication ceased before days [ , ] . further study is needed to elucidate the pathogenesis of cns disease complicating influenza a infection. neurologic symptoms associated with influenza can arise at different intervals after the initial influenza illness (fig. , table ). when assessing patients clinically, it is important to determine if the patient has active or recent symptoms (within days) of influenza or if the neurologic symptoms have appeared in a subacute manner. we will first discuss neurologic complications in the setting of recent influenza virus infection and then proceed to complications that present in a delayed manner the development of a confusional state in the setting of influenza illness symptoms and fever raises the possibility of influenza-associated encephalitis or encephalopathy. the degree of encephalopathy varies from a confusional state to obtundation. it is important to recognize that a small portion of cases can rapidly deteriorate to coma and subsequent brain death due to diffuse, malignant cerebral edema. focal and generalized seizures often occur and can be present with either mild or severe cases. the presence of fever and altered mental state should prompt clinicians to pursue csf analysis unless neuroimaging or laboratory studies reveal a contraindication. influenza illness may include upper respiratory symptoms, pneumonia, or diarrhea (more commonly in young children with seasonal influenza). a thorough medical assessment to exclude other causes such as sepsis, metabolic or toxic disorders, structural cns diseases, and other cns infections is warranted. we define encephalitis by the presence of inflammation in the csf or demonstration of viral infection in brain biopsy or autopsy specimens. we define encephalopathy when csf is acellular and brain biopsy or autopsy specimens have failed to demonstrate viral infection. in some cases, this distinction is arbitrary and the case has borderline csf pleocytosis or csf analysis was not performed due to malignant brain edema. a consistent observation is that patients with seasonal influenza-associated encephalopathy rarely ever have evidence of influenza viral rna in csf based on rt-pcr analysis of csf. furthermore, there is no evidence of seasonal influenza virus infection of brain specimens. in one case series, only one out of patients with acute seasonal influenza-associated encephalitis had influenza viral rna detected [ ] . terminology for post-infectious encephalitis can be confusing. for example, the international pediatric multiple chronic condition * sometimes classified as adem [ ] sclerosis study group [ ] listed ten terms that have been used to describe acute disseminated encephalomyelitis (adem). some terms focus on the triggering event, such as post-infectious encephalomyelitis; others on pathologic or pathophysiologic features such as acute demyelinating encephalomyelitis or hyperergic encephalomyelitis. these authors also classify acute hemorrhagic leukoencephalitis, acute necrotizing hemorrhagic leucoencephalitis (also known as acute necrotizing encephalitis, (ane)), and acute hemorrhagic encephalomyelitis as hyperacute forms of adem. these diagnostic terms are of great historical interest. they generally preceded modern neuroimaging and relied more on the clinical and pathologic details. the study group also lumps a diversity of neuroimaging findings under the diagnosis of adem including: ring-enhancing lesions; diffuse and multi-focal regions of t hyperintensity with and without associated hemorrhage; multi-focal lesions with associated mass effect (tumefactive lesions); and images with symmetric, bithalamic edema. while we prefer one term (adem) rather than ten terms to describe post-infectious encephalitis, we are concerned that the pathophysiology and outcome of a process leading to the formation of ring-enhancing lesions (demyelinating, for example, acute demyelinating encephalomyelitis) must be radically different than that causing bithalamic edema (necrotizing, for example, ane). in reality, iae presents along a spectrum ranging from milder cases with normal neuroimaging to more malignant cases with abnormal neuroimaging and less favorable outcomes. for the sake of discussion and literature review, we present a simplified classification scheme based on clinical and imaging findings. the iae benign variant can present with fever, confusional state, and seizures but neuroimaging with ct brain or mri brain does not demonstrate any acute abnormalities. csf analysis is within normal limits or has borderline findings. rt-pcr testing for h n influenza viral rna is positive in upper respiratory secretions but negative when csf is tested [ ] [ ] [ ] . these patients typically recover within week, and most cases have received oseltamavir and anticonvulsants. the initial reports of pediatric cases of h n encephalopathy in the us were not severe [ ] . similarly, other reported adult cases of h n iae without ards have not been severe with complete recovery [ , ] . a more recent pediatric case series of h n iae reported that / patients had imaging abnormalities and neurologic sequelae [ ] , so the treating physicians need to be aware that full recovery is not a certainty. the iae with splenial sign presents with acute febrile respiratory illness and additional neurologic symptoms with a characteristic mri abnormality. we found case reports associated with seasonal influenza but not with h n . it has been reported in children, but rarely in adults [ ] [ ] [ ] [ ] [ ] [ ] . encephalopathy is always present and can be severe. seizures are often present. mri imaging demonstrates increased t and flair signal and restricted diffusion in the splenium of the corpus callosum. this finding is reversible. the mri finding is not specific and has been reported with other infections, high-altitude brain edema, and certain metabolic states such as hypernatremia [ ] . csf analysis is unremarkable. these patients have been treated with oseltamavir and anticonvulsants, and typically recover within month. the iae with posterior reversible leucoencephalopathy syndrome (pres) presents as moderate to severe febrile encephalopathy. this subtype has been reported with seasonal influenza but not specifically with h n . the mri imaging appears radiographically identical to pres caused by more typical causes such as pregnancy or malignant hypertension [ , ] . vascular caliber changes have been observed in these cases; this is non-specific and can be related to infectious vasculitis or pres. given the diverse causes of pres including malignant hypertension, pregnancy, metabolic disorders, and certain medications such as chemotherapeutics and immunosuppressants; it is often difficult to distinguish the pathophysiology of iae in this clinical setting. therapy is focused upon antiviral treatment, corticosteroid administration, and supportive care. iae with malignant brain edema is one of the most challenging subtypes to diagnose and treat. both seasonal influenza and h n can be complicated by severe forms of acute encephalopathy and malignant brain edema [ ] [ ] [ ] [ ] . survival in some cases has been achieved with aggressive neuro-intensive case management with other therapies, including administration of antivirals, corticosteroids, immunoglobulin ( gm/kg in adult patients), hyperosmolar therapy, plasmapheresis, and hypothermia in some cases. one of the goals of treatment is to reduce viral expression with early antiviral treatment and thereby to reduce stimulation of the host inflammatory response. our case presentation illustrates the rapid time course for this complication (see fig. ) and neurocritical care treatment approaches. because of diffuse brain edema, a broad treatment approach using hyperosmolar therapy, intubation, fever control, and sedation were important. to the best of our knowledge, this is the only case description of iae in which an external ventricular drain was utilized, probably because it is difficult to place a catheter into the small, compressed ventricles of patients with diffuse brain edema associated with influenza. another adult case of h n encephalitis has been reported with radiographic findings similar to ours. fugate et al. [ ] described an adult with h n influenza-associated acute hemorrhagic leukoencephalitis. like our patient, their case also showed confluent areas of increased t signal in the periventricular white matter and centrum semiovale. because of the additional finding of microhemorrhages demonstrated on gradient echo mri sequences, they diagnosed acute hemorrhagic leukoencephalitis or hurst disease. their patient also had restricted diffusion in the basal ganglia (see fig. ). because their patient had severe adult respiratory distress syndrome (ards) with oxygen saturation readings in the range of - %, the authors attributed the basal ganglia findings to hypoxic brain injury. our patient did not have advanced pulmonary disease, hypoxia, or hypotension. care should be taken to distinguish iae with malignant edema from reyes' syndrome in which patients may present with lethargy, confusion, seizures, or coma accompanied by brain edema. reyes' syndrome most commonly occurs in children but has been reported in adults following influenza and aspirin ingestion [ ] . it can be distinguished based on the accompanying hepatic abnormalities, hyperammonemia, and hypoglycemia. caution should be taken with any neurosurgical procedures in reyes' syndrome due to increased risk of perioperative bleeding. one of the most devastating complications of seasonal and pandemic influenza is ane [ ] [ ] [ ] . patients develop rapid neurologic deterioration to coma. seizures are often present. initial brain ct may show decreased density in the thalami, and mri of brain demonstrates the characteristic bilateral thalami lesions. this finding may be initially mistaken for ischemic strokes (top-of-basilar syndrome) or venous infarction secondary to thrombosed internal cerebral veins, vein of galen, or straight sinus. it is interesting that there have been case reports for recurrent ane and also familial ane. this suggests that there may be a genetic susceptibility and a gene associated with familial seasonal influenza ane cases has been reported (nuclear pore gene, ranbp ; [ ] ). this condition is often fatal or accompanied by permanent neurologic sequelae in surviving cases. it is intriguing that the neuroanatomical changes found in the thalami, midbrain, and cerebellum on neuroimaging correlated with the clinical symptoms reported for encephalitis lethargica, specifically ''sleeping sickness'', ophthalmoparesis, quadriparesis, and delayed parkinsonism (see below). it is conceivable that survivors with less fulminant involvement could manifest a clinical syndrome with symptoms and signs that localize to brainstem structures. a pediatric case of h n -associated ane with bilateral thalamic imaging findings without associated malignant brain edema has been published [ ] , but detailed clinical follow-up was not reported. during the subacute period, additional classic neurologic syndromes associated with influenza have been described. post-influenzal cerebellitis is quite uncommon and has been reported rarely in adults [ ] [ ] [ ] . this syndrome was diagnosed in a -year old woman who developed ataxia, dysarthria, and truncal titubation month after influenza b virus infection, with neurologic symptoms that resolved gradually after an additional month. ct and mri brain imaging were unrevealing. csf studies detected evidence of the persistence of the np gene of influenza b virus in the csf from samples taken and weeks after the onset of initial influenza illness. a -year old woman gradually developed gait and speech problems after influenza a illness that was treated with oseltamavir. csf showed pleocytosis. the cerebellar cortex had increased t signal which resolved over an day period. she received pulse intravenous corticosteroid therapy. her symptoms resolved [ ] . plasmapheresis [ ] and ivig [ ] have also been used for this condition. some cases of cerebellitis following viral and mycoplasma illness have developed fulminant cerebellar swelling with secondary brainstem compression, obstructive hydrocephalus, with fatal outcome [ ] . interventions with posterior fossa decompression and external ventricular drain placement may lead to a favorable outcome in a child with this severe condition. antibodies to the glutamate receptor have been reported in patients with post-infectious influenza viral cerebellitis [ ] . guillain-barre syndrome (gbs) is a subacute, immunemediated disease predominantly affecting the peripheral nervous system. the diagnosis and treatment are wellknown to most neurologists and this condition has been extensively described and reviewed. gbs has been rarely reported in association with seasonal influenza virus infection [ ] , but it should be noted that influenza testing is rarely pursued in gbs cases and may be unrevealing. treatment for influenza-related gbs is identical to treatment for other gbs due to other associated causes. monitoring for respiratory compromise due to neuromuscular weakness with timely respiratory support if needed is critical. plasmapheresis or gammaglobulin treatments are also helpful. the precise pathophysiology is uncertain, but molecular mimicry of the infectious agent is presumed to stimulate autoimmune responses. this has been demonstrated to occur in campylobacter jejuni-associated gbs [ ] . influenza-associated myositis has been reported with seasonal influenza [ ] and h n variant [ ] . myalgias are a common symptom of influenza, but some patients develop frank weakness and have elevated serum levels of creatine phosphokinase (cpk). it is more common in children but has been seen in all age groups. the calf muscles are most suspectible, and patients may walk with a stiff gait or toe walk. onset is usually within the first week of infection and spontaneous improvement typically occurs within weeks in most cases. rarely, severe cases can result in myoglobinuria-associated renal failure and compartment syndromes requiring fasciotomies. influenza can also selectively attack specific muscle groups such as the heart (myocarditis). muscle biopsy shows necrosis, regenerating fibers, and occasionally inflammation. post-viral parkinsonism has been reported after an assortment of infections including influenza virus [ ] . an outbreak of these cases was temporally noted following the great influenza (h n ) pandemic of - [ ] . patients with this condition respond poorly to medical therapy, and it has an unfavorable prognosis. encephalitis lethargica is also known as von economo encephalitis and sleeping sickness [ ] . a wave of such cases was reported following the - influenza a (h n ) virus pandemic. the cardinal features of this condition are altered consciousness with prolonged somnolence and ophthalmoplegia. after intervals of months to years, survivors are at risk of developing parkinsonism. pathological findings include nerve cell destruction primarily in the midbrain, subthalamus, and hypothalamus [ , ] . using modern laboratory techniques, formalin-preserved autopsy brain specimens of encephalitis lethargica cases analysed for influenza viral rna were negative [ ] . scientists have proposed a ''hit-and-run'' model of early viral-mediated injury with late sequelae [ ] . the neurologist oliver sacks [ ] drew attention to this mysterious disorder and the discovery of l-dopa, in his book, awakenings later converted to a feature-length movie. the delayed appearance of restricted diffusion in the basal ganglia in our patient and others [ ] is concerning for this condition (fig. ) . we do not know if this indicates that our patient with h n is at risk of developing postviral parkinsonism, but long-term clinical follow-up will be important. a delayed diffusion neuroimaging abnormality was also reported in the dentate nucleus of a patient with seasonal influenza encephalopathy/splenial sign [ ] . we present a case of acute encephalitis associated with pandemic influenza a (h n ) virus infection, complicated by malignant brain edema. the emerging hypothesis about acute neurologic complications of seasonal influenza is that the immune response triggered by influenza virus infection of the respiratory tract plays a prominent role in the pathogenesis of neurological manifestations. this hypothesis regarding the development of acute encephalopathy and brain edema is analogous to current theories about the role of the immune system and cytokines in the development of ards with h n virus infection. we have also provided an overview of the spectrum of acute and post-infectious neurologic complications reported in association with seasonal and pandemic influenza virus infection of the upper respiratory tract. neurologists should be aware of the potential for a wide range of neurologic complications in association with the current h n pandemic and seasonal influenza. influenza, encephalitis lethargica, parkinsonism neuropathogenesis of influenza virus infection in mice pcr on cerebrospinal fluid to show influenza associated acute encephalopathy or encephalitis detection of influenza virus rna by reverse-transcription-pcr and proinflammatory cytokines in influenza-associated encephalopathy acute encephalopathy associated with influenza a virus infection th and th hypercytokinemia as early host response signature in severe pandemic influenza acute encephalopathy associated with influenza a infection in adults systemic cytokine responses in patients with influenza-associated encephalopathy cytokine profiles induced by the novel swine origin influenza a/h n virus: implications for treatment strategies tumor necrosis factor-a, interleukin- b, and interleukin- in cerebrospinal fluid from children with prolonged febrile seizures. comparison with acute encephalitis/encephalopathy sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism microglia in health and disease microglia in diseases of the central nervous system astrocytes are active players in cerebral innate immunity 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cerebellitis induced by epstein-barr virus brain spect imaging and treatment with ivig in acute post-infectious cerebellar ataxia: case report acute near-fatal parainfectious cerebellar swelling with favourable outcome guillain barre syndrome and influenza virus infection carbohydrate mimicry between human ganglioside gm and campylobacter jejuni lipooligosaccharide causes guillain-barre syndrome benign acute childhood myositis: laboratory and clinical features melting muscles: novel h n influenza a associated rhabdomyolysis viral parkinsonism lack of detection of influenza genes in archived formalin-fixed, paraffin waxembedded brain samples of encephalitis lethargica patients from to new york: random house, inc key: cord- -xez zso authors: stephens, r. scott title: icu complications of hematopoietic stem cell transplant, including graft vs host disease date: - - journal: evidence-based critical care doi: . / - - - - _ sha: doc_id: cord_uid: xez zso hematopoietic stem cell transplant (hsct) is an essential treatment modality for many malignant and non-malignant hematologic diseases. advances in hsct techniques have dramatically decreased peri-transplant morbidity and mortality, but it remains a high-risk procedure, and a significant number of patients will require critical care during the transplant process. complications of hsct are both infectious and non-infectious, and the intensivist must be familiar with common infections, the management of neutropenic sepsis and septic shock, the management of respiratory failure in the immunocompromised host, and a plethora of hsct-specific complications. survival from critical illness after hsct is improving, but the mortality rate remains unacceptably high. continued research and optimization of critical care provision in this population should continue to improve outcomes. non-infectious complications of hsct. respiratory failure is the most frequent cause of intensive care unit (icu) admission after hsct, most frequently from an infectious cause. the patient was placed on high-flow nasal cannula (hfnc) for oxygenation support and started on a norepinephrine infusion for hemodynamic support. antibacterial coverage was changed to meropenem, levofloxacin, and vancomycin, and voriconazole was added for antifungal coverage. her central line was removed. her respiratory status continued to decline, and endotracheal intubation and mechanical ventilation were required h after admission. she was placed on volume assist-control with a tidal volume of ml/kg predicted body weight, and bronchoscopy with bronchoalveolar lavage (bal) was performed. the bal fluid was initially bloody, but cleared with sequential aliquots. microbiologic studies of the bal fluid were positive for respiratory syncytial virus and pseudomonas aeruginosa. she was maintained on low tidal-volume ventilation and vasopressors were weaned off. her white blood cell count slowly began to recover, and her respiratory status began to improve. she was extubated on hospital day and was discharged from the icu on hospital day . hematopoietic stem cell transplant (hsct) has become an essential therapeutic modality in the treatment of malignant and non-malignant hematologic disease. in , more than , hscts were performed in the united states, including approximately , autologous hscts and more than allogeneic transplants [ ] . allogeneic transplants are associated with more morbidity and mortality than autologous transplants, and are further categorized based on conditioning regimen (myeloablative [ma] vs non-myeloablative [nma]), donor-recipient relation (related vs unrelated), hla matching (full match vs haploidentical vs mismatched), and stem cell source (bone marrow, peripheral blood, umbilical cord blood). in general, nma regimens are associated with less peri-transplant morbidity and mortality than fully ablative transplants. in both ma and nma transplants, the cytotoxic conditioning regimen required in hsct rapidly induces neutropenia by injuring hematopoietic precursor cells within the bone marrow [ , ] . neutropenia persists until donor cell engraftment or bone marrow recovery. the period of aplasia and neutropenia places the hsct patient at high risk for infectious complications. in addition to the lack of immune cells, the mucosal barrier of the intestinal tract is disrupted by chemotherapy, creating portals through which enteric pathogens can enter the bloodstream [ ] [ ] [ ] . the respiratory system is also more susceptible to infection, with qualitative and quantitative dysfunction of alveolar macrophages, lymphocytes, and neutrophils [ ] [ ] [ ] . even after the marrow and mucosal surfaces have recovered, the immunological consequences of hsct can cause further complications requiring critical care. refinement of transplant techniques over the last decades has dramatically decreased transplant-related mortality, but approximately % of hsct patients require critical care [ ] and earlier icu admission has been associated with improved survival rates [ , ] . still, icu mortality in allogeneic hsct patients remains approximately % [ ] . the early complications of hsct (day - ) are predominantly infectious in nature, and patients typically present to the icu with septic shock or respiratory failure. the latter is the most common reason for icu admission after hsct [ ] . non-infectious complications also occur, and can involve nearly any organ system. neutropenic fever, defined as any fever higher than . °c or a sustained fever greater than . °c for more than h with an absolute neutrophil count (anc) less than cells/ mm , occurs in more than % of patients undergoing hsct [ , ] . no organism is identified in about % of neutropenic fevers [ , ] . bacteremia is documented in up to % of patients. gram-positive bacteria are most commonly isolated [ , ] (table . ), while gram-negative infections confer a higher mortality risk [ ] . fungal infections, particularly candida and aspergillus species, are frequent, especially in prolonged or profound neutropenia [ ] . approximately % of allogeneic hsct patients will develop severe sepsis during the engraftment period [ ] , and mortality is approximately % in those who go on to develop septic shock [ , , ] . mortality predictors include concomitant graft-vshost disease (gvhd), respiratory failure, positive blood cultures, and multi-organ failure [ , ] . neutropenic fever and sepsis are medical emergencies, and appropriate empiric antibiotics must be started without delay: ideally within min of presentation [ , , ] and potentially within min [ ] . empiric antibiotics must cover common organisms and should be tailored to patientspecific culture data and institutional epidemiology [ , ] . appropriate empiric antibiotics include an anti-pseudomonal penicillin or cephalosporin (e.g. piperacillin/tazobactam or cefepime, respectively), or a carbapenem [ , ] . vancomycin is not routinely indicated but should be added in the presence of a suspected catheter-related infection, soft tissue infection, oral mucositis, pneumonia, known colonization with resistant gram-positive organisms, or hemodynamic instability [ , , ] . aminoglycosides should not be added to an anti-pseudomonal beta-lactam unless required by allergies, resistant organisms, or refractory hemodynamic instability [ , , [ ] [ ] [ ] . fluoroquinolones, which are frequently used as prophylaxis in hsct patients, should not be used as empiric monotherapy due to the likelihood of resistance. in hemodynamically unstable patients, anti-pseudomonal beta-lactams should be escalated to a carbapenem and consideration should be given to the addition of an aminoglycoside or aztreonam [ , , , ] . vancomycin should be added if not already part of the regimen, and anti-fungals with activity against yeasts and molds (e.g. liposomal amphotericin, caspofungin, or voriconazole) should be strongly considered in all unstable patients [ , , , ] . identification of infectious organisms and control of infectious sources are essential to optimize outcomes but the infectious workup should not delay antibiotic administration. blood cultures and respiratory cultures should be obtained and sinus, head, chest, and abdominal imaging performed as indicated [ , ] . abdominal pain or diarrhea associated with fever suggests neutropenic enterocolitis (typhlitis) which can lead to intestinal necrosis [ , ] . in the hemodynamically unstable patient with a central venous catheter, early catheter removal is associated with improved survival [ ] ; infected or potentially infected catheters should be removed without delay. acute respiratory failure and acute respiratory distress syndrome (ards) are major problems after hsct [ , ] . data from the s indicated that - % of patients undergoing hsct experience a respiratory complication [ ] . more recent data suggest that more than % of patients undergoing allogeneic transplant develop ards with a mortality rate of - % [ , ] . most cases of respiratory failure and ards after hsct are related to infection, either a primary pulmonary infection or sepsis [ ] . common pulmonary infections and associated risk factors are shown in table . hsct [ , ] , and is associated with significant mortality, especially with progression to lower respiratory tract infection [ ] [ ] [ ] . in some cases, antiviral therapy with agents such as oseltamivir (influenza) or ribavirin (respiratory syncytial virus) is indicated [ ] . bacterial pneumonias are also common and may occur as a co-infection or secondary infection with a respiratory virus. fungal and other opportunistic infections such as pneumocystis jirovecii must also be considered [ ] . as in immunocompetent patients, treatment of ards centers on treatment of the underlying cause while providing supportive care with low tidal volume mechanical ventilation. neuromuscular blockade and prone positioning should be considered in patients with an arterial po : fio ≤ mmhg [ ] [ ] [ ] . non-invasive ventilation (niv) is frequently used as firstline respiratory support in hsct patients [ ] . however, early studies which showed a mortality benefit in immunosuppressed patients with using niv compared to invasive mechanical ventilation were limited by relatively few numbers of hsct patients and extremely high mortality in the control groups [ , ] . it is nearly impossible to control delivered tidal volume with niv and high delivered noninvasive tidal volumes are linked to higher rates of niv failure [ ] . more recent data suggest that niv may not be beneficial in hsct patients and heated humidified high-flow oxygen may be a better option [ , [ ] [ ] [ ] [ ] [ ] . chest computed tomography (ct) scanning should be performed in all patients with respiratory symptoms [ ] . the presence of respiratory failure, respiratory symptoms, or abnormalities on chest imaging should prompt evaluation for a respiratory infection. in many cases a non-invasive evaluation is appropriate, but bronchoscopy may be indicated in some patients [ , , ] , and bronchoscopic findings that lead to a change in management are associated with improved outcomes [ ] . two specific forms of respiratory failure after hsct warrant special mention: diffuse alveolar hemorrhage and idiopathic pneumonia syndrome. diffuse alveolar hemorrhage (dah) occurs in up to % of patients and is associate with poor outcomes [ , ] . diagnosis is most commonly made by observation of progressively bloody aliquots of bronchoalveolar lavage. steroids are the mainstay of treatment of dah, with some evidence that efficacy is greatest at doses < mg/day of methylprednisolone equivalent [ ] . idiopathic pneumonia syndrome (ips) is a form of noninfectious lung injury after hsct and is clinically defined by diffuse alveolar injury when infection, cardiac dysfunction, renal failure, and volume overload have been excluded [ ] . ips can have many manifestations, including ards, pulmonary capillary leak, dah, or cryptogenic organizing pneumonia. ips is thought to affect up to % of patients after myeloablative allogeneic hsct, and only ~ % of patients after non-myeloablative hsct. median time of onset of ips [ , ] is days after hsct and mortality ranges from - % in all patients, with nearly % mortality if mechanical ventilation is required [ ] . though the pathophysiology of ips is incompletely understood, research indicating a pathogenic role for tnf-α has led to the use of the anti-tnf-α antibody etanercept to treat ips, with mixed clinical results [ ] [ ] [ ] [ ] . the single randomized placebo-controlled trial in adults included only patients and showed no benefit to etanercept when added to steroids (methylprednisolone mg/kg/ day) [ ] . neurologic complications are frequently encountered after hsct [ ] . intracerebral hemorrhages are a constant threat in thrombocytopenic patients. infections of the central nervous system (cns), including viral, bacterial, and fungal, can occur, and may require modification of antibiotic regimens to ensure cns penetration. seizures and generalized encephalopathy can occur, often with cryptic causes. posterior reversible encephalopathy syndrome (pres) is increasingly recognized, especially in patients receiving tacrolimus-based gvhd prophylaxis. any of these complications may be life-threatening, and close collaboration with neurology and neurocritical care specialists may be required. acute kidney injury (aki) is common after hsct and affects up to % of patients, with higher incidence after allogeneic transplant than autologous transplant [ , ] . in addition to the usual icu causes of aki such as septic shock, there are many specific contributors to the risk of aki in hsct, including preparative chemotherapeutic regimens, nephrotoxins (e.g. tacrolimus, cyclosporine, antimicrobials), elevated cytokine levels, gvhd, and hepatic sinusoidal obstruction [ ] . hemorrhagic cystitis arising from chemotherapy toxicity or viral infection can cause significant blood loss and obstructive nephropathy due to blood clots. management of aki primarily consists of limiting exposure to nephrotoxins (if able) and maintaining adequate hemodynamics. if hemorrhagic cystitis is present, continuous bladder irrigation with a three-way catheter should be considered. the requirement for renal replacement therapy is ominous and portends a high mortality rate [ ] . hepatic veno-occlusive disease (vod), also known as sinusoidal obstruction syndrome, primarily occurs after myeloablative hsct, but can occur after a non-myeloablative transplant [ ] . vod is thought to be caused by damage to the hepatic endothelium and leads to obliteration of hepatic sinusoids and hepatocyte necrosis. incidence of vod is thought to be approximately %, though estimates vary. diagnosis is based on clinical findings (table) including hepatomegaly, elevated bilirubin ascites, and weight gain [ ] . there are limited therapeutic options for vod, and the prognosis is poor. a major complication of allogeneic hsct is graft-versushost disease (gvhd), which is divided into acute and chronic forms. acute gvhd is a major contributor to peritransplant morbidity and mortality, and is caused by donororigin t-cells recognizing recipient tissues as foreign and instigating an immune response against the transplant recipient [ ] . acute gvhd generally occurs within the first days after transplant and can affect the skin, mucosa, intestinal tract, and liver. grading is based on severity of clinical manifestations, which include skin erythema or maculopapular rash; nausea, emesis, or diarrhea, and elevated bilirubin levels ( fig. . , table . ) [ ] [ ] [ ] [ ] . acute gvhd can progress to frank epidermal desquamation, massive diarrhea and hematochezia, and fulminant liver failure, respectively. severe skin acute gvhd behaves much like a burn injury, and the expertise of a burn center may be required. corticosteroids are the mainstay of treatment for acute gvhd, and the prognosis of steroid-refractory disease is poor [ , ] . prophylaxis against gvhd is an essential part of allogeneic transplant regimens and includes a variety of modalities, including calcinuerin inhibitors, anti-metabolites, and post-transplant cyclophosphamide [ ] . as gvhd prophylaxis has improved, more patients are presenting with grade ii or grade iii acute gvhd (and fewer are presenting with grade iv acute gvhd), the incidence of hepatic acute gvhd is decreasing, and overall mortality from acute gvhd is decreasing in patients treated with tacrolimusbased gvhd prophylaxis [ ] . chronic gvhd is the major cause of non-relapse-related mortality after hsct [ ] . despite its name, chronic gvhd is defined clinically, rather than by time after transplant, and can present at any time during the transplant course. by years after transplant, up to - % of patients will have some manifestation of chronic gvhd [ ] [ ] [ ] . though the biology of chronic gvhd is complex and incompletely understood, clinically it mimics autoimmune disease [ ] . while diagnostic criteria include effects on the skin, oral mucosa, eyes, liver, gi tract, joints, genitals, and lungs, chronic gvhd can affect almost any organ system and is staged according to severity of organ involvement [ ] . selected manifestations and diagnostic criteria are in table . . of the manifestations of chronic gvhd, the most relevant to the icu physician is pulmonary chronic gvhd. the only recognized manifestation of chronic pulmonary gvhd is bronchiolitis obliterans syndrome (bos), which is diagnosed by documentation of the new onset of an obstructive ventilator defect (fev : fvc < . and fev < % predicted) and air trapping (documented by expiratory ct scan or pulmonary function tests) in the absence of an explanatory pulmonary infection [ ] . bos results from a b c d peribronchiolar fibrosis and obliteration of small airways resulting in the characteristic obstructive physiology [ ] . interstitial and subpleural fibrosis may also occur, resulting in concomitant restrictive physiology. bos occurs in approximately - % of all patients after allogeneic hsct, and % of those with chronic gvhd, but is likely underdiagnosed [ , , ] . inhaled corticosteroids appear efficacious in improving fev in established bos [ ] . systemic steroids are also commonly used to treat bos and most patients are maintained on anti-gvhd immunosuppression with tacrolimus, sirolimus, or a calcineurin inhibitor [ ] . the combination of inhaled fluticasone, azithromycin, and montelukast (fam) appears to slow the decline in lung function with bos [ ] but has not yet been proven in a randomized controlled trial. while fam is standard therapy for established bos, recent data argue strongly against using azithromycin as prophylaxis against bos due to decreased survival due to a higher rate of hematologic relapse [ ] . though fam has been shown to decrease the progression of bos, mortality due to progressive lung disease remains high, and patients typically present to the icu with respiratory failure. unfortunately, with end-stage bos, there are no effective therapeutic options. a select few patients may be eligible for consideration for lung transplantation, but this is unusual, hsct is increasing in volume and importance as a therapeutic modality, and the volumes of hsct patients requiring critical care is accordingly continuing to increase. there is good reason to think that the pathogenesis of critical illness is substantially different in the immunosuppressed hsct patient. yet our understanding of critical illness in this population is limited, and many practices are extrapolated from the general critical care population without direct evidence in the hsct population. in response to this, research agendas for critically ill hematology and oncology patients have been proposed [ ] . neutropenic sepsis is typically thought of as an uncontrolled variant of non-neutropenic sepsis. however, the real picture is likely much more complicated, and neutropenic sepsis and respiratory failure may be very different from their nonneutropenic counterparts. even the phrase "neutropenic sepsis" is a misnomer, as the hsct myelopreparative regimens also result in pancytopenia. leukopenia, including neutropenia, lymphopenia, and monocytopenia, dramatically changes not only the acute response to infection, but the regulation of the adaptive immune response and the resolution and repair of injury [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . platelets are increasingly recognized to play a vital role in the defense against bacterial, viral, and fungal infections, and like leukocytes, are integral to the development and resolution of organ failure [ ] [ ] [ ] [ ] [ ] . not surprisingly, thrombocytopenia is associated with poor outcomes in critical illness [ ] . taken together, these data strongly support the notion that common critical care conditions, such as sepsis and respiratory failure, may differ dramatically in hsct patients compared to "normal" patients. encouragingly, survival in neutropenic sepsis appears to be improving, but still lags that of non-neutropenic patients [ , , ] , and more research is needed. drug-resistant and multi-drug resistant (mdr) organisms are an increasing problem in hsct patients, and the situation shows no sign of improving [ , , ] . vancomycinresistant enterococcus (vre) bacteremia affects up to % of patients after hsct and is associated with poor outcomes [ ] [ ] [ ] . similarly, mdr gram negative infections, particularly carbapenem-resistant enterobacteriaceae (cre), are associated with high mortality rates in allogeneic hsct patients [ ] . successful treatment cre infections is challenging, and requires early use of multi-drug antibiotic regimens, typically including aminoglycosides, carbepenems, and polymyxins. however, none of the available regimens are particularly effective, and new antimicrobials are desperately needed. an increasingly recognized complication of hsct is hsctassociated thrombotic microangiopathy (hsct-tma) [ ] , which has some features in common with betterknown microangiopathic processes such as thrombotic patients can present to the icu with acute kidney injury and neurologic changes in addition to hemolytic anemia and thrombocytopenia [ , ] . management is predominantly supportive, with blood pressure control, cessation of any possible pharmacologic instigators (tacrolimus or cyclosporine), and renal replacement therapy playing major roles. recent case reports have suggested a possible role in some patients for the anti-cd antibody rituximab or the anti-complement antibody eculizumab, though neither of these agents has been definitively proven effective [ ] . as noted above, advances in transplant techniques have allowed the increased use of alternative donors, including related haploidentical donors [ ] [ ] [ ] . similarly, peripheral blood stem cells (pbsc) are increasingly used for transplant instead of bone marrow stem cells [ ] . however, the use of peripheral blood results in a larger number of donor t-cells included in the transplanted stem cells. this higher t-cell dose can result in a profound syndrome of fevers, vascular permeability, hemodynamic instability, acute kidney injury, and respiratory failure. this constellation of findings is associated with elevated levels of inflammatory cytokines and has accordingly been labeled as cytokine release syndrome (crs). while most associated with chimeric antigen receptor (car) t-cell therapy [ ] , crs is increasing recognized after pbsc transplant and is associated with poor outcomes [ ] . emerging data suggest that anti-il- therapy with tocilizumab may improve outcomes, but more research is needed [ ] . hsct continues to grow as a therapeutic modality and the pool of both potential donors and recipients continues to increase. as hsct volumes increase and the complexity and potential toxicity of hsct regimens expands, the number of critically ill hsct patients will increase [ ] . in response to this growing icu volume, some centers continue to admit hsct patients to general icus, but many high-volume transplant centers have developed specialty hsct icus. while specialty hsct icus have a number of potential benefits, there are few data to support (or dissuade) their development. development of best practices for the provision of critical care to hsct patients, including the optimum icu organization is an important area for study [ ] . great progress in the critical care of hsct patients has been made, but with continued basic and clinical research and further development of the sub-specialty of oncologic critical care, outcomes for critically ill hsct patients should continue to improve. current uses and outcomes of hematopoietic cell transplantation (hct): cibmtr summary slides hematopoietic stem cell compartment: acute and late effects of radiation therapy and 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hla-haploidentical allogeneic blood or marrow transplantation for peripheral t cell lymphoma outcomes of nonmyeloablative hlahaploidentical blood or marrow transplantation with high-dose post-transplantation cyclophosphamide in older adults hla-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide peripheral-blood stem cells versus bone marrow from unrelated donors management of the critically ill adult chimeric antigen receptor-t cell therapy patient: a critical care perspective severe cytokine-release syndrome after t cell-replete peripheral blood haploidentical donor transplantation is associated with poor survival and anti-il- therapy is safe and well tolerated key: cord- - yu di g authors: fujishima, seitaro title: pathophysiology and biomarkers of acute respiratory distress syndrome date: - - journal: j intensive care doi: . / - - - sha: doc_id: cord_uid: yu di g acute respiratory distress syndrome (ards) is defined as an acute-onset, progressive, hypoxic condition with radiographic bilateral lung infiltration, which develops after several diseases or injuries, and is not derived from hydrostatic pulmonary edema. one specific pathological finding of ards is diffuse alveolar damage. in , in an effort to increase diagnostic specificity, a revised definition of ards was published in jama. however, no new parameters or biomarkers were adopted by the revised definition. discriminating between ards and other similar diseases is critically important; however, only a few biomarkers are currently available for diagnostic purposes. furthermore, predicting the severity, response to therapy, or outcome of the illness is also important for developing treatment strategies for each patient. however, the pao( )/fio( ) ratio is currently the sole clinical parameter used for this purpose. in parallel with progress in understanding the pathophysiology of ards, various humoral factors induced by inflammation and molecules derived from activated cells or injured tissues have been shown as potential biomarkers that may be applied in clinical practice. in this review, the current understanding of the basic pathophysiology of ards and associated candidate biomarkers will be discussed. acute respiratory distress syndrome (ards) is defined as an acute-onset, progressive, hypoxic condition characterized by bilateral lung infiltration on chest x-ray or computed tomography [ ] . ards develops quickly after several conditions, traumas, or insults. however, it needs to be confirmed that the condition does not result from heart or renal failure or overhydration. diffuse alveolar damage (dad) is designated as a specific pathological finding for ards. for more than two decades, the definition set forth by the american-european consensus conference (aecc) has been used for the clinical diagnosis of ards [ ] , and a newer definition with better specificity has long been awaited. in , a draft of a revised definition was presented at the th annual congress of the european society of intensive care medicine in berlin, and its final version was published in jama in may [ ] . in the revised berlin definition, the term ards was redefined as a broader concept including a milder condition of lung injury; therefore, it became equivalent to acute lung injury (ali), which was the previous aecc definition. the revised ards definition was significantly improved by the inclusion of timing, underlying conditions, and the mandated determination of the pao /fio ratio under positive airway pressure. however, no new parameters or biomarkers were adopted. in this review, the current understanding of the basic ards pathophysiology and associated candidate biomarkers will be discussed. the essential pathophysiology of ards includes increased pulmonary microvascular permeability. the process of water passage from the capillaries to the alveoli is presented with several physical barriers, including endothelial and epithelial cell layers, the basement membrane, and the extracellular matrix. among these barriers, water passage (permeability) across endothelial and epithelial cell layers is actively regulated. increased vascular permeability in ards is the result of several independent mechanisms. first, tissue injury and the resultant destruction of the pulmonary microvascular architecture contribute to a direct leak of blood components from the capillaries to the alveoli. in addition, endothelial and epithelial permeability is dynamically regulated by a set of inter-and intracellular molecules, the dysregulation of which may also induce increased vascular permeability. in order to protect the lungs from pulmonary edema, the pulmonary lymphatic system and epithelial water channels play important roles in pumping water out of extravascular space. however, when vascular leakage surpasses the capacity of these compensating systems, clinical pulmonary edema develops. there are multiple mechanisms by which vascular permeability is regulated. sphingosine- phosphate (s p) binds to its receptor, s p , and regulates vascular permeability through non-muscle myosin light chain kinase (nmmlck) and the rho family gtpase pathway [ ] . in addition, angiopoietin- (ang- ) binds to its receptor, tie- , to stabilize the vasculature through the activation of syx and rho a [ ] . in contrast, angiopoietin- (ang- ) is produced by activated endothelial cells and competes with ang for tie binding to destabilize vascular junctional formation [ ] . the dysregulation of any of these mechanisms may lead to a change in vascular permeability; therefore, these factors may represent potential biomarkers for ards. acute inflammation of and neutrophil accumulation in the lungs are commonly observed in both patients with ards and animal models of the disease. extensive research has revealed the pathogenic roles of neutrophilmediated acute inflammation in ards development [ ] . neutrophils release cytotoxic molecules, including granular enzymes, reactive oxygen metabolites, bioactive lipids, and cytokines, and induce the formation of neutrophil extracellular traps (nets) [ ] . in addition to causing tissue necrosis, these cytotoxic molecules induce apoptosis and autophagy, each of which causes tissue injury and cell death, which are characteristic of ards [ ] . numerous proinflammatory cytokines play major roles in acute inflammation and the development of inflammatory lung diseases, including ards. among these, tumor necrosis factor alpha (tnfα) and interleukin beta (il- β) can induce ali when administered to animals, and their levels are also elevated in the lungs of ards patients. therefore, they are thought to be key pathogenic cytokines in ards. in addition, a neutrophil chemotactic chemokine, interleukin (il- , cxcl ), is important because its neutralizing antibody was protective against the development of ali in animal models, and il- levels are elevated in the lungs of ards patients [ ] . additional cytokines and chemokines are involved in the development of ards, including il- and il- , both of which, like il- β, are regulated by the inflammasome/caspase- pathway [ , ] . these cytokines may represent good targets for antimediator therapy for ards as well as become potential biomarkers of ards. recently, pattern recognition receptors (prrs) were demonstrated to play a key role in innate immunity [ ] . prrs are cell-surface or cytosolic proteins expressed by innate immune cells, and each is activated by a specific molecule (s). prr ligands are divided into two categories, namely, pathogen-associated molecular patterns (pamps) and damage (danger)-associated molecular patterns (damps). pamps are extrinsic molecules derived from various microorganisms, while damps are intrinsic molecules derived from injured cells or extracellular molecules. when these prrs are activated, nuclear factor (nf)-κb translocates to the nucleus, predominantly through a myeloid differentiation primary response gene (myd )-dependent mechanism. activation of prrs also leads to the transcription of proinflammatory cytokines such as tnfα, il- β, and il- . table lists the major prrs and their counterpart pamps and damps. infection, including severe sepsis and pneumonia, is the leading predisposing factor for ards. in this regard, the pathogenic roles of lipopolysaccharide (lps) have been thoroughly examined. because other pamps can induce proinflammatory reactions, it is reasonable to speculate that they also play important roles in the development and progression of ards. in addition, because tissue destruction (i.e., multiple trauma and burn injuries) is a major predisposing factor for ards, we can speculate that damps play critical roles in its onset and/ or progression. the high-mobility group box protein (hmgb ) was one of the earliest discovered nuclear binding proteins demonstrated to function as a damp [ ] . this protein not only leaks from damaged cells, but its production is also induced in activated dendritic cells and macrophages. hmgb can potently induce inflammation through its interaction with multiple receptors, including the receptor for advanced glycation end products (rage), toll-like receptor (tlr ), and toll-like receptor (tlr ). initially, a pathogenic role of hmgb was reported in association with sepsis; subsequently, its involvement in ards was also revealed [ , ] . histone, another nuclear binding protein, is released into the circulation after trauma and can induce inflammation and ali in animal models [ ] . further, mitochondrial dna can induce the production of il- and thus may play a role in ards as a damp [ ] . at present, however, little is known of the pathogenic roles of prrs, pamps, and damps in ards, and their involvement needs to be clarified in future studies. differentiating similar diseases or conditions from ards remains to be a matter of great importance. currently, only a few biomarkers are clinically available for this purpose. for example, brain natriuretic peptide (bnp) is used for differentiation between ards and hydrostatic pulmonary edema, although its usefulness remains controversial [ , ] . procalcitonin is increased in bacterial infection, but not in viral or fungal infection; it may be useful for discriminating between bacterial pneumonia and ards. however, because the sensitivity of procalcitonin is as high as % for bacterial pneumonia and because bacterial pneumonia and sepsis are common predisposing conditions for ards, its utility is limited [ ] . predicting the severity of illness is also important to develop a specific diagnostic strategy for each patient with ards, but the pao /fio ratio is the sole clinical parameter used for this purpose. the importance of biomarkers is underscored by the fact that they can also be utilized to predict response to therapy and prognosis. however, no ards-specific biomarkers are currently available for these purposes. as discussed above, various humoral factors have been identified as candidate biomarkers of ards (table ) . among the proinflammatory cytokines, tnfα, il- β, interleukin (il- ), and il- are elevated in the bronchoalveolar lavage fluid (balf) of ards patients, and their levels were reportedly higher in non-survivors than in survivors [ ] . we previously showed that il- levels in balf were higher in patients with ards and inhalation injury [ , ] . these levels were also able to predict the degree of lung oxygenation impairment in inhalation injury. recent secondary analysis of the ards clinical network's (ardsnet) activated protein c study, where various candidate biomarkers of ards were assessed, showed that plasma plasminogen activator inhibitor (pai- ) and il- were correlated with the oxygenation index (mean airway pressure × fio /pao ). furthermore, ventilator-free days were significantly shorter in patients with higher levels of il- , il- , and thrombomodulin, which were associated with poor patient outcomes [ ] . among these three molecules, the usefulness of il- in predicting the outcome of ards was confirmed by several additional studies [ , ] . a recent report from harvard demonstrated that il- is a new ards biomarker [ ] . this study was independently performed by three affiliated hospitals and showed a consistent increase in plasma il- levels in ards patients, while mortality was increased in direct proportion to plasma il- levels. several growth factors have been determined to be candidate biomarkers of ards. in this regard, the lung levels of vascular endothelial growth factor (vegf) and keratinocyte growth factor (kgf) were shown to correlate with the severity of illness and reflect patient outcome [ , ] . furthermore, secondary analysis of the ardsnet's fluid and catheter treatment (fact) study revealed that plasma levels of growth differentiation factor- (gdf- ) were increased in proportion to -day mortality [ ] . another recent study showed that ang- , a competitor of ang- and a regulator of vascular permeability (as mentioned earlier), could predict the prognosis of ards [ ] . as described, among inflammatory cells, neutrophils play dominant roles in inducing ards through the release of various cytotoxic substances and mediators, including granular enzymes, reactive oxygen species, bioactive lipids, cytokines, and nets. therefore, these neutrophil-derived molecules can be candidate biomarkers of ards. neutrophil elastase, a major granular enzyme with potent nonspecific tissue destruction activity, forms a complex with alpha -antitrypsin (ne-at) soon after release from activated neutrophils. we have previously shown that the levels of the ne-at complex were increased in ards patients and were significantly higher in a subgroup of patients with clinical deterioration after admission than in a subgroup without deterioration [ ] . leptin, a hormone involved in the regulation of energy intake and expenditure, was also shown to contribute to ards development. epidemiological data demonstrated the low incidence of ards among patients with diabetes mellitus; however, the reason for this is unknown [ , ] . recently, a decrease in leptin levels in these patients was shown as a potential key mechanism underlying this epidemiological finding. in an animal experiment, leptin induced the expression of transforming growth factor beta (tgf-β) and the production of collagen types i and ii in the presence of tgf-β, and leptin-deficient mice were resistant to the development of ali [ ] . furthermore, in non-obese patients with ards, leptin levels in balf correlated with tgf-β levels. the duration of artificial ventilation and icu stay was significantly longer in a subgroup of ards patients with higher leptin levels in balf than in those with lower leptin levels in balf [ ] . these results suggest that leptin can be a candidate biomarker of ards. substances derived from activated cells or injured tissues can also reflect the degree of inflammation or tissue injury and, consequently, the severity of ards. in addition to the earlier discussed pathogenic role of hmgb in ards, it was shown to be a candidate biomarker of ards, along with soluble rage [ ] . excessive formation and ineffective clearance of neutrophil extracellular trap in alveolar space would be responsible for the pathogenesis of ards. the increase in dna decorated with proteases and histone in balf was observed in cystic fibrosis [ ] and acute inhalation injuries [ ] . thus, dna in balf could also become the candidate as biomarker for ards. similarly, histone may be useful as an ards biomarker in patients with lungs subjected to multiple trauma [ ] . as the roles of damps in the pathophysiology of ards are revealed, their utility as biomarkers will also be clarified. among endothelial cell-derived molecules, plasma levels of soluble p-selectin and soluble intercellular adhesion molecule (sicam- ) were reported as candidate biomarkers. the potential of sicam- was demonstrated by multicenter studies [ , ] . additional epithelial cellderived molecules that represent candidate ards biomarkers include sialylated carbohydrate antigen krebs von den lungen- (kl- , a fragment of muc mucin), surfactant protein b (sp-b) [ ] , surfactant protein d (sp-d) [ , , ] , clara cell protein cc- [ ] , and the gamma- chain of laminin- (an extracellular matrix protein with cell adhesive properties) [ ] . in , an article that focused on a new meta-analysis of plasma biomarkers for ards was published [ ] . the authors analyzed studies and found that kl- , lactate dehydrogenase, soluble rage, and von willebrand factor are strongly associated with ards diagnosis in the at-risk population. for outcome prediction, they found that il- , il- , ang- , and kl- were most strongly associated with mortality from ards. in parallel with progress in the understanding of ards pathophysiology, several molecules have been shown to be candidate biomarkers of this disease, with the clinical usefulness of some being confirmed by large-scale or multicenter studies. however, none of these candidates have been clinically applied for diagnosis or prediction of disease severity, response to therapy, and prognosis in patients with ards. future studies, along with a search for new biomarker candidates, need to determine the potential application(s) of each candidate discussed here. this will lead to improved diagnosis and treatment strategies for patients with ards. update in acute respiratory distress syndrome definitions, mechanisms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome: the berlin definition concepts in microvascular endothelial barrier regulation in health and disease regulation of vascular permeability by sphingosine -phosphate angiopoietin signaling in the vasculature neutrophil-mediated tissue injury and its modulation excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis interactions between mechanical and biological processes in acute lung injury a prominent role of il- in inflammatory lung diseases and multiple organ dysfunction syndrome human mesenchymal stem cells overexpressing the il- antagonist soluble il- receptor-like- attenuate endotoxin-induced acute lung injury inflammasome-regulated cytokines are critical mediators of acute lung injury innate immune recognition in infectious and noninfectious diseases of the lung hmg- as a late mediator of endotoxin lethality in mice increased levels of soluble receptor for advanced glycation end products (srage) and high mobility group box (hmgb ) are associated with death in patients with acute respiratory distress syndrome contributions of high mobility group box protein in experimental and clinical acute lung injury circulating histones are mediators of trauma-associated lung injury circulating mitochondrial damps cause inflammatory responses to injury diagnostic utility of b-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study b-type natriuretic peptide in the assessment of acute lung injury and cardiogenic pulmonary edema usefulness of procalcitonin for the diagnosis of ventilator-associated pneumonia inflammatory cytokines in the bal of patients with ards. persistent elevation over time predicts poor outcome pathogenetic and predictive value of biomarkers in patients with ali and lower severity of illness: results from two clinical trials national heart blood, and lung institute acute respiratory distress syndrome network: use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury prognostic and pathogenetic value of combining clinical and biochemical indices in patients with acute lung injury vascular endothelial growth factor in epithelial lining fluid of patients with acute respiratory distress syndrome keratinocyte growth factor and hepatocyte growth factor in bronchoalveolar lavage fluid in acute respiratory distress syndrome patients growth differentiation factor- and prognosis in acute respiratory distress syndrome: a retrospective cohort study plasma angiopoietin- predicts the onset of acute lung injury in critically ill patients neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients role of diabetes in the development of acute respiratory distress syndrome* diabetes, insulin, and development of acute lung injury leptin promotes fibroproliferative acute respiratory distress syndrome by inhibiting peroxisome proliferatoractivated receptor-{gamma} hartl d: cxcr mediates nadph oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation dna and inflammatory mediators in bronchoalveolar lavage fluid from children with acute inhalational injuries soluble intercellular adhesion molecule- and clinical outcomes in patients with acute lung injury soluble form of p-selectin in plasma is elevated in acute lung injury elevated plasma surfactant protein-b predicts development of acute respiratory distress syndrome in patients with acute respiratory failure acute respiratory distress syndrome network: plasma surfactant protein levels and clinical outcomes in patients with acute lung injury critical care research group of the quebec respiratory health network: outcome value of clara cell protein in serum of patients with acute respiratory distress syndrome laminin gamma fragments are increased in the circulation of patients with early phase acute lung injury plasma biomarkers for acute respiratory distress syndrome: a systematic review and meta-analysis cite this article as: fujishima: pathophysiology and biomarkers of acute respiratory distress syndrome the author declares that he has no competing interest. key: cord- -vimq qs authors: casillas, javier; sleeman, danny; ahualli, jorge; ruiz-cordero, roberto; echenique, ana title: acute pancreatitis (ap) date: - - journal: multidisciplinary teaching atlas of the pancreas doi: . / - - - - _ sha: doc_id: cord_uid: vimq qs all of these conditions can be associated with acute pancreatitis, except ? acute pancreatitis defi nition: • acute infl ammatory process of the pancreas with a wide range of manifestations and clinical variation, ranging from local infl ammation to systemic manifestations such as organ failure. • the frequency of acute pancreatitis varies among different countries. • in the usa, the frequency of pancreatitis is higher in patients older than years. • the rate of pancreatitis in black americans is times higher than in white americans. • the frequency of pancreatitis is approximately equal in men and women. acute pancreatitis is classifi ed into two types. • acute edematous interstitial pancreatitis total score : points are given on a scale from to to determine the grade of pancreatitis and treatment - mild, - moderate, - severe • computed tomography (ct) and magnetic resonance imaging (mri) are the preferred imaging modalities. • contrast-enhanced ct (cect) is currently the gold standard for evaluating patients with suspected acute pancreatitis. • the role of this modality is to confirm or exclude the clinical diagnosis, to establish the cause, to determinate the severity, to detect complications of the acute pancreatitis, and to provide guidance for therapy. • very useful to predict clinical outcome. • mr imaging is particularly useful in pregnant patients and in patients who cannot receive iodinated contrast material due to allergic reactions or renal insuffi ciency. • abdominal ultrasound is an inexpensive, convenient imaging modality helpful to evaluate the presence of gallbladder and/or common duct stones in acute pancreatitis. • many scoring systems have been reported, but none has proven to be perfect. • they are superior to clinical judgment for triaging patients to more intensive and aggressive therapy. • acute interstitial pancreatitis (aip) (figs. . - . ) -homogeneous or heterogeneous pancreatic parenchymal enhancement (diffuse or focal due to interstitial parenchymal edema) -normal or mild to severe peripancreatic and retroperitoneal infl ammatory changes (fatty stranding) depending on the severity of the acute pancreatitis -varying amounts of peripancreatic fl uid -thickening of the retroperitoneal fascia • interstitial pancreatitis (figs. . - . ) -diffuse or focal enlargement of the pancreas. -pancreatic boundaries are blurred. -normal or hypointense signal intensity of the pancreas relative to the liver on t -weighted images and hyperintense on t -weighted images. -threadlike, interlobular, hyperintense structures (interlobular septal infl ammation). -peripancreatic and/or pancreatic edema or fl uid collections. • pancreatic necrosis (figs. . - . ) -focal pancreatic necrosis is characterized by spotted, patchy, non-enhancing pancreatic parenchyma on contrast-enhanced mr images. -diffuse pancreatic necrosis is characterized by non-enhancing pancreatic parenchyma on dynamic contrast-enhanced mri. • infected pancreatic necrosis findings -focal or diffuse, non-enhancing segments in the pancreatic parenchyma of low signal intensity associated with signal void areas (pockets of air in the pancreatic parenchyma) • patients with organ failure at admission have a higher mortality. • the highest mortality is among those patients with multisystem organ failure and sustained organ failure for > hours. • patients with signs of organ failure require admission in an intensive care unit or stepdown unit. • organ failure (acute pancreatitis) -approximately % of patients. mostly transient with very low mortality. -median prevalence of organ failure in necrotizing pancreatitis is % (more common in infected necrosis). • vital signs, oxygen saturation, and fl uid balance should be carefully monitored. -aggressive iv fl uid replacement is the cornerstone of therapy. - - ml/h × - hours, with frequent reevaluations during that time. • patients should have the head of the bed elevated. • lactate ringer's solution reduces the incidence of sirs compared to saline solution. • nutritional support -in mild pancreatitis , oral intake is restored within - days, when patient is hungry and does not have nausea or vomiting and pain is controlled without medications -low-fat diet is recommended to start. -in severe pancreatitis , nutritional support should be initiated when it becomes clear that the patient will not be able to consume nourishment by mouth for several weeks. -enteral feeding is preferable to total parenteral nutrition (stabilizes gut barrier function, is safer and less expensive than tpn). ○ nasogastric (ng), nasoduodenal (nd), or nasojejunal (nj) tube feedings are equivalent. ○ unless patient is retching and vomiting in which case nj is more reasonable. • organ dysfunction (management) -pressor agents for sustained hypotension -intubation and assisted ventilation for respiratory failure -renal dialysis for intractable renal failure • respiratory failure is the most common form of organ dysfunction. • there is evidence that early aggressive fl uid resuscitation prevents or minimizes pancreatic necrosis and improves survival. • lactate ringer's solution is associated with positive effects on acid-base homeostasis. • enteral feeding is associated with a reduction in mortality, systemic infection, and multiorgan dysfunction. • most patients with infected necrosis have systemic toxicity, fever, and leukocytosis. -ct-guided percutaneous aspiration with gram stain and culture is indicated when infected necrosis is suspected. -if gram-negative organisms are isolated, the antibiotics recommended are: ○ carbapenem, a fl uoroquinolone plus metronidazole, or a third-generation cephalosporin plus metronidazole pending results of culture sensitivity. • percutaneous external lavage of infected necrosis has signifi cantly lower morbidity and mortality than surgical necrosectomy. • best suited for the stable patient. • its success depends on the close interdisciplinary approach between the surgeon and the interventional radiologist. • retained common bile duct stone could lead to organ failure. -absence of fl ow in the vein(s) involved -partial or complete venous intraluminal fi lling defect in vein(s) involved (partial thrombosis) -lack of identifi cation of the splenic vein associated with multiple local venous collaterals is diagnostic of splenic vein thrombosis. -conservative -the use of anticoagulants is controversial. mild peripancreatic infl ammatory changes in the rest of the pancreas. note the prominence of the short gastric veins, multiple venous collateral in the territory of the left gastric vein ( arrowheads ), and the lack of identifi cation of the splenic vein . . pseudoaneurysms (figs. . - . ) • rare complication of acute pancreatitis • more common in chronic pancreatitis. • most frequently associated with pseudocysts. • rupture of pseudoaneurysm is rare; however, the mortality rate is high when it occurs. • autodigestion of the arterial walls by the pancreatic enzymes • direct damage from severe infl ammation • vascular wall erosion from pancreatic enzymes within the pseudocyst or direct vascular compression or ischemia • in those rare patients where it is diffi cult to catheterize the artery involved, the alternative is to access the artery percutaneously for treatment with vascular coils or direct thrombin injection. or bowel obstruction • rare complication of acute pancreatitis • secondary to the compression of the stomach, small bowel, or colon by a pancreatic fl uid collection acute pancreatitis: assessment of severity with clinical and ct evaluation classifi cation of acute pancreatitis- : revision of the atlanta classifi cation and defi nitions by international consensus mr imaging of the pancreas: a pictorial tour imaging of acute pancreatitis and its complications a modifi ed ct severity index for evaluating acute pancreatitis: improved correlation with patient outcome predicting the severity of acute pancreatitis disconnection of the pancreatic duct: an important but overlooked complication of severe acute pancreatitis percutaneous lavage as primary treatment for infected pancreatic necrosis the revised atlanta classifi cation of acute pancreatitis: its importance for the radiologist and its effect on treatment tailored helical ct evaluation of acute abdomen clinical management of patients with acute pancreatitis • dilatation of the biliary system secondary to a compression of the common bile duct by pancreatic collection or by a pseudocyst • percutaneous or endoscopic decompression of the pancreatic fl uid collection or pseudocyst. patient went to an outside facility with increased abdominal pain and was found to have evidence of hemorrhage into the pseudocyst. patient was referred to the interventional radiology service for diagnostic visceral angiogram and possible embolization of splenic artery. axial image ( a ) from cect initially done at outside institution reveals a small area of low attenuation in the tail of the pancreas ( arrow ) associated with mild peripancreatic infl ammatory changes. in the follow-up cect ( bc ) performed weeks later, axial images reveal a large collection with high density in the tail of the pancreas extending into the lesser sac ( arrows ). finding suggestive of acute hemorrhage into the known pancreatic pseudocyst. a selective angiogram of the splenic artery performed the same day ( d ) shows a small pseudoaneurysm of the splenic artery in the body of the pancreas ( arrow ). this pseudoaneurysm was successfully treated with multiple endovascular coils ( e ) ( arrow ) key: cord- -pva xy authors: mannem, hannah c.; donahoe, michael p. title: transfusion and acute respiratory distress syndrome: clinical epidemiology, diagnosis, management, and outcomes date: - - journal: hematologic abnormalities and acute lung syndromes doi: . / - - - - _ sha: doc_id: cord_uid: pva xy transfusion related acute lung injury (trali) is a life-threatening complication of blood product transfusion. it is the leading cause of blood product transfusion related death in the usa. the syndrome is defined by hypoxemic respiratory failure with bilateral infiltrates on chest x-ray in the setting of a blood transfusion and absence of cardiac failure. the exact incidence of trali is unknown, but the incidence is higher in the critically ill patient population. multiple patient and donor related risk factors for trali exist, including critically illness, alcohol use, and receiving transfusions with high plasma volumes. practitioners should have a low index of suspicion for the diagnosis of trali, and blood bank reporting is vital to aid in diagnosis and future prevention. management is primarily supportive care, with supplemental oxygen as the mainstay for therapy. despite the transient course of trali, its morbidity is severe with the majority of patients requiring mechanical ventilation and treatment in the intensive care unit. for patients that survive trali, outcomes are promising without residual pulmonary deficits. prevention strategies over the past years have helped to decrease the incidence of trali and have led to increased awareness of this condition in the medical field. the association was made into a distinct clinical entity with specifi c clinical criteria in by popovsky and colleagues and redefi ned by the national heart, lung, and blood institute (nhlbi) , as well as the canadian consensus conference (ccc) in [ - ] . two key points were highlighted in the revision of the defi nition. the fi rst was emphasizing an acute and new presentation of respiratory distress. the second focus was to eliminate other temporally associated, alternative risk factors to explain the new lung injury (table . ). two other terms were also defi ned-possible trali and delayed trali . possible trali occurs when the acute respiratory distress takes place in the setting of a blood transfusion, as well as other co-existing risk factors for development of acute respiratory distress syndrome (ards) , including: trauma, sepsis, pancreatitis, aspiration, inhalation, drug overdose, or burns. delayed trali is defi ned as trali which occurs after h but within h of a blood transfusion (table . ). these distinctions between trali, possible trali, and delayed trali help to further elucidate incidence, pathophysiology, and treatment of this condition by clarifying the disease for future research investigations. two pathophysiologic mechanisms of trali have been recognized, immunemediated trali and non-antibody mediated trali . anywhere from to % of reported cases are found to be immune-mediated trali, which occurs when leukoagglutinating antibodies from the donor blood bind to conjugate recipient antigens [ ] . by defi nition, evidence of antibodies from the blood donor are present; most commonly anti-hla and anti-hna antibodies, with anti-hna a associated with worse clinical outcomes [ , ] . the second mechanism for development of trali is classifi ed as non-antibody mediated trali and stems from an antibody independent mechanism. approximately % of trali falls into this category, in which no antibodies are found in the donor blood product. silliman and colleagues have described the non-antibody mediated mechanism as a two-hit model. the fi rst hit involves neutrophil priming and sequestration secondary to a preexisting condition in the recipient. in the second hit, biologic modifi ers such as lipids in the blood product activate neutrophils and lead to capillary leak in the lung endothelium [ , ] (see chap. ). risk factors for the development of trali can be broken into two categories, recipient and donor related risks. the recipient of the blood product may have underlying disease states and clinical conditions, which put them at increased risk (table . ). also the donor profi le and blood components being transfused may also put the recipient at higher risk for development of trali. multiple recipient related risk factors are noted in the literature. most of these studies are retrospective and small. however, it is evident from clinical data that the critically ill population is at the highest risk for the development of trali [ ] . in one multicenter, prospective trial, history of liver transplant, chronic alcohol use, active tobacco use, shock, increased il- levels in serum, increased peak airway pressures of > cm h o on the ventilator, and an overall positive fl uid balance were all signifi cant risk factors for trali [ ] . multiple studies reveal sepsis and shock as major risk factors. not only being critically ill, but also being on mechanical ventilation at the time of transfusion may increase risk independently. a prospective cohort study showed % of patients on mechanical ventilation at the time of transfusion developed acute lung injury [ ] . multiple other studies have also shown recipient risk factors such as: major surgery within h of blood transfusion, hematologic malignancy, higher apache ii scores, and active liver disease [ ] . the risk for development of trali also increases with the number of transfusions, as seen commonly in the trauma population where patients are receiving massive transfusions [ ] . not only critically ill patients, but cardiac and orthopedic surgery patients are also at higher risk for trali development [ ] . the time on cardiac bypass appears to be correlated as well, with longer bypass times leading to higher risk of trali development [ ] . despite the multitude of recipient risk factors reported, most of which are seen in the critically ill population, trali is also reported in otherwise healthy individuals at the time of transfusion [ ] . the development of trali in this healthy patient population supports the realization that the risk of trali is not dependent on the recipient alone. all forms of blood products have been reported to cause trali, including: whole blood, packed red blood cells, apheresis platelets, fresh frozen plasma, cryoglobulin, intravenous immunoglobulin, granulocytes, and allogeneic stem cells [ ] . however, blood products with higher plasma volume are at the greatest risk, specifically fresh frozen plasma, apheresis platelets, and whole blood. in the fda reported cases of death due to trali, fresh frozen plasma was the most implicated [ ] . in one retrospective cohort study from , fresh frozen plasma and platelet transfusions led to a higher incidence of trali versus red blood cell transfusion in the icu population [ ] . it remains unknown the exact amount of plasma which must be transfused in order for trali to develop. reports of as little as - ml of plasma transfused before trali development are in the literature; however, plasma volumes greater than - ml are thought to be the threshold which puts patients at a higher risk [ ] . another important risk factor is the gender of the donor, and preventive strategies in the past years have focused on gender related donor deferral . female, multiparous donors have allo-immunization from pregnancy. blood from this particular group of donors has a much higher risk of trali development in the recipient secondary to the anti-hla and anti-hna antibodies, which bind to recipient antigens and lead to immune-mediated trali. the prevalence of antibodies in this population increases with parity. a % approximate frequency of anti-hla antibodies exist if a female has had more than three pregnancies [ ] . another potential risk factor where studies have shown controversial data is blood product storage time. experts in the fi eld hypothesize that longer storage times of red blood cells may lead to a higher incidence of trali. experimental models in preclinical trials show a positive correlation between longer blood storage times and trali; however, there remains no overt clinical evidence to support the fi nding [ ] . studies done in the preemie population showed no difference in the incidence of trali based on blood storage time. an ongoing study in the adult intensive care unit population is underway that hopefully will help to clarify the importance of blood storage time as a potential risk factor [ ] . the true incidence of trali is unknown secondary to prior lack of a concise definition, the inconspicuousness of the diagnosis, and lack of a structured reporting system. it occurs in all age groups, including children and the geriatric population. it occurs at the same frequency in women and men. reported trali incidence varies between . and % of patients transfused and . - . % per product transfused, with the higher incidence in the critically ill patient population [ ] . up to - % of patients in an intensive care unit receive some form of blood product transfusion, and more independent patient risk factors exist in the critically ill population, which may account for this increase in incidence (see section "risk factors"). even though the overall reported incidence of trali remains low, it is almost certainty an under-recognized and underdiagnosed condition. in the setting of no gold standard for diagnostic testing, a passive reporting system, and an array of mild cases which do not meet the consensus defi nition of the disease, trali remains under-reported [ ] . despite the underestimated incidence of trali, the overall frequency has decreased since the mid- s secondary to preventative strategies for plasma and platelet transfusions (see section "prevention"). as stated before, all blood products have been implicated in trali development, and the incidence of trali varies based on blood product components. products with higher plasma volume have higher incidence of trali. reports reveal incidences at approximately / whole blood products vs. / fresh frozen plasma vs. / , red blood cells [ , ] . however, the incidence of trali in plasma products has decreased in the past decade secondary to risk mitigation strategies, leaving the incidence of red blood cell transfusions at a higher rate in the more recent years [ ] . trali can present with a large variation in disease severity. by nhlbi and ccc defi nition % of patients with trali have hypoxemic respiratory failure and bilateral pulmonary infi ltrates on chest x-ray. clinically, the most common complaint of patients is dyspnea. however, a large number of patients are critically ill and on mechanical ventilation at the time of blood transfusions leading symptoms to be unhelpful. despite patients being unable to report symptoms, clinical signs of respiratory distress and failure are present, typically within one to h of a blood transfusion in the majority of patients. predominately, patients are tachypneic, and in approximately one-third of patients, fever and/or hypotension may develop. rarely patients may develop new onset hypertension. most notably in the vital signs, spo should be decreased compared to before the transfusion. patients on mechanical ventilation may experience a change in pulmonary compliance with an increase in peak and plateau pressures. pink, frothy secretions from the mouth or endotracheal tube occur in roughly half of patients who develop trali. physical exam should help rule out other etiologies of respiratory distress and should be thorough including a complete lung, heart, and skin exam. lung auscultation reveals bilateral crackles. exam fi ndings suggestive of cardiac failure should not be present, such as jugular venous distention and an s on cardiac auscultation. it is important to keep in mind that very mild cases of trali do exist, which may not fall into the nhlbi and ccc defi nitions. mild cases may go unrecognized or present with a similar presentation to the underlying disease process, albeit in a less severe form . practitioners should have a high index of suspicion for trali when administering blood products, especially in the critically ill population. diagnosis can be diffi cult as there is no gold standard diagnostic test for trali. any person who develops even the least amount of dyspnea or respiratory distress in temporal association with a blood product transfusion should have further clinical and diagnostic evaluation for trali. patients who meet the nhlbi and ccc defi nition (table . ) including, new hypoxemic respiratory failure with a pao /fio ratio < and bilateral pulmonary infi ltrates within a h time frame from blood product transfusion, deserve further workup to confi rm the diagnosis. one of the goals of the diagnostic workup should be to rule out other possible etiologies for the new development of ards, which would then classify the patient as possible trali. no diagnostic lab tests are available that confi rm the diagnosis of trali. an arterial blood gas can be helpful to quantify the degree of hypoxemia. the most common laboratory fi nding is acute and transient leukopenia, which is thought to be secondary to neutrophil sequestration into the pulmonary vasculature and can be seen in - % of patients [ ] . thrombocytopenia has also been reported in trali. other laboratory tests, although not diagnostic may also be helpful. in other etiologies of ards such as sepsis, a leukocytosis may be present. an elevated brain naturitic peptide can be seen in transfusion associated circulatory overload (taco) and should not be elevated in trali alone. as stated before, a chest x-ray revealing bilateral pulmonary infi ltrates is a ubiquitous fi nding in trali, and should be performed for any patient with suspicion of the diagnosis. historically the pulmonary infi ltrates in trali were described as "white out lungs." this may be the scenario in extreme cases; however, both alveolar and interstitial infi ltrates have been described in a spectrum from bilateral and patchy to diffuse territories of the lung fi elds. despite the fi ndings being nonspecifi c, the presence of bilateral infi ltrates should reach % in this patient population. the chest x-ray is also helpful to eliminate other etiologies of acute respiratory failure, such as pneumothorax . for any suspected trali reaction, it is of vital importance the associated blood bank be contacted. typically a transfusion reaction lab panel is sent, which is directed by the blood bank or transfusion medicine director. the panel includes a complete blood count, haptoglobin, bilirubin, direct coombs test, and most importantly hla and hna antibody testing in the donor blood sample. anti-hla and anti-hna antibodies strongly support the diagnosis of trali but are not essential for diagnosis. - % of trali reactions are found to be non-antibody mediated [ ] . however, positive antibody results can guide future trali prevention if found in the donor blood product (see section "prevention"). antibody testing may take days to weeks for results, and therefore no acute treatment decisions should be made based on antibody testing alone. in distinguishing trali from other disease states it is important to consider other causes of ali/ards, as well as other transfusion reactions. in , new terminology was instituted as part of the trali defi nition, termed, possible trali . this defi nition takes into account other etiologies of ali/ards, which the patient may be at risk for at the time of blood transfusion (table . ). since no gold standard diagnostic test exist for trali, and it occurs most commonly in the critically ill population with multiple other comorbidities, possible trali remains a very relevant diagnosis. if any of these other conditions exist or are suspected, a defi nitive diagnosis of trali cannot be made. further diagnostic workup should be done in order to eliminate the additional etiologies. fever can occur as part of trali; however, pneumonia, pancreatitis, and sepsis should be suspected as well as an etiology of the acute lung injury. cbc, blood cultures, and chest x-ray can all help to further delineate other disease states. other conditions such as inhalation, drowning, cardiac bypass, drug overdose , and trauma may be more obvious from history alone. various other blood transfusion reactions exist, all of which can overlap with aspects of the clinical presentation of trali. each blood transfusion reaction is managed differently, therefore it is vital to establish the correct diagnosis. the transfusion reaction that mimics trali the most is taco (see chap. ). taco may coexist with trali and distinguishing between these two diagnoses may be diffi cult (table . ). both conditions present acutely during or after blood product transfusion. also, both lead to acute respiratory distress and hypoxemia with bilateral infi ltrates on chest x-ray. while trali's clinical presentation stems from non-hydrostatic pulmonary edema with capillary leak, taco is secondary to hydrostatic pulmonary edema. the two conditions are both transient but managed differently. diuretics are the mainstay of treatment for taco, but may be detrimental in the treatment of trali (see section "medications"). a positive fl uid balance is a risk factor for development of trali, and if the positive fl uid balance is secondary to compromised cardiac function a higher awareness for taco should exist. while no defi nitive test exists to distinguish between the two, diagnostic tools such as elevated jugular venous pressure, an s on cardiac auscultation, a transthoracic echo showing depressed cardiac function, and/or an elevated bnp may suggest taco vs. trali. if the patient has a pulmonary artery catheter in place, an elevated pulmonary capillary wedge pressure and/or central venous pressure also favors the diagnosis of taco. as stated before, chest x-ray is unhelpful in distinguishing between the two diagnoses. other transfusion reactions may also overlap in clinical presentation with trali; however, they are usually more obvious to diagnose. like trali, an anaphylactic reaction from a blood product transfusion may also lead to hypoxia and hypotension. conversely, the clinical presentation of patients undergoing an anaphylactic reaction may demonstrate signs of airway compromise, such as stridor, bronchospasm, laryngeal edema, and/or wheezing, as well as an associated rash, urticaria, and/or diarrhea, all of which are not seen in trali alone. in septicemia from blood product transfusion, which can occur in the setting of contaminated blood products, microbiology is usually positive. patients may also have a leukocytosis , which is very uncommon in trali. platelets are most commonly associated with septicemia from a transfusion. lastly, hemolytic transfusion reactions develop acutely with blood product transfusion, but hypoxia and acute respiratory distress are not the mainstay. fever and hypotension occur in almost all patients with hemolytic reactions and less often in trali. laboratory tests will also reveal a hemolytic pattern, such as a low haptoglobin , elevated unconjugated bilirubin and an elevated lactate dehydrogenase. similar to the diagnosis, the management of trali is also nonspecifi c. no exact therapy for trali exists, and supportive therapy is the mainstay for treatment. if trali is suspected while a blood product is actively being transfused, it should be stopped immediately. all subsequent blood product transfusions should also be held in the acute setting until the diagnosis is made and treatment ensued. as mentioned before, the blood bank or transfusion medicine physician should be notifi ed with any suspicion of trali in order to potentially identify and exclude involved donors if relevant antibodies are present. oxygen supplementation is the primary management in trali. although mild cases are reported where little to no oxygen is necessary, almost all patients require some form of oxygen. studies show up to - % of patients develop severe enough hypoxemia to require mechanical ventilation [ , ] . there are no specifi c studies looking at mechanical ventilation strategies in trali specifi cally; however, it is reasonable to adopt the ventilation strategies from the ards network trial [ ] . the restrictive tidal volume approach with tidal volumes set at ml/kg of predictive body weight vs. ml/kg has been shown to improve mortality in ards, and therefore should be the mainstay ventilation approach in the trali patient population. maintaining plateau pressures < cm h o has also been shown to improve mortality and the incidence of barotrauma in the ards population [ ] . in severe cases where mechanical ventilation fails to support the patient's physiologic demands, the use of extracorporeal membrane oxygenation (ecmo) has been described in case reports [ , ] . however, no randomized control studies exist to support the use of ecmo for trali specifi cally . the volume status of patients who develop suspected trali should be examined carefully, as management decisions are dependent on this judgement. as mentioned above, in the patient who appears to be volume overloaded with depressed cardiac function the diagnosis of taco should be strongly considered, and diuretics should be administered. commonly patients who develop trali are found to be hypovolemic [ ] . trali in the hypovolemic patient may lead to hypotension and shock. intravenous fl uids should be given in this setting, as well as pressors if needed, to support end organ perfusion during the acute episode. while steroids have been studied extensively in ards, no randomized control trials looking at the use of steroids in patients with trali have been completed. the use of steroids in the ards population remains controversial, but data suggest use after days may be harmful [ ] . in patients with trali, case reports with intravenous corticosteroids do exist [ ] . however, in the setting of no true prospective clinical trials, the negative side effects, and the transient clinical course of trali, the use of corticosteroids is not routinely recommended in the treatment of trali. evidence from the factt trial supports the use of a conservative fl uid strategy in the ards population [ ] . however, as stated before patients who develop trali are at risk for hypotension and shock, especially in the setting of hypovolemia. intravenous fl uids are the mainstay of therapy for hemodynamic support early on in trali, especially without evidence of coexisting taco. diuretic therapy should be used judiciously in this patient population, as it may worsen outcomes early on. based on evidence from the ards population, if patients are still requiring high levels of oxygen supplementation once they are hemodynamically stable and volume resuscitated, a role for diuretic use in trali may still exist [ , ] . with no specifi c management strategies for trali exist, prevention measures are of the utmost importance. over the past years policies have been put into place at blood product donation centers in order to guide risk mitigation. the largest risk mitigation strategies so far have focused on plasma donation. no practical risk reduction measures are established for red blood cell transfusion prevention from a donation perspective. some experimental models suggest washing of stored red blood cell products to prevent trali, but it is yet to be determined if this strategy makes a difference and can be feasible in a clinical setting. however, strategies exist to assist in the prevention of all adverse transfusion reactions, most importantly being the use of conservative transfusion practices. an overall judicious approach to blood product transfusion is the simplest and most effective strategy for trali prevention. evidence from a randomized, doubleblinded control trial shows the incidence of ards is decreased with a conservative red blood cell transfusion strategy vs. a liberal one [ ] . other studies suggest ffp is still over utilized at times by physicians with no clear indications for its use [ ] . with electronic medical records in the forefront of today's health care, data suggest that electronic decision support to further guide the ordering of blood product transfusions not only decreased the amount of blood transfusions given but also decreased the incidence of acute lung injury [ ] . blood utilization guidelines and blood conservation programs should be established in health care centers to help minimize unnecessary transfusions. a patient tailored approach should be taken for patients who do need non-emergent blood product transfusions. patient related risk factors for trali should be considered, and an attempt to minimize these risk factors prior to transfusion is an important component of primary trali prevention . as mentioned above, the reporting of any suspected or confi rmed trali episode is vital to secondary prevention. the american association of blood banks (aabb) advocates that implicated donors abstain from any type of blood product donation until leukocyte antibody testing has been complete. in the donors who are found to have leukocyte antibodies which match or are likely to match recipient leukocyte antigens, deferral from at least plasma and platelet apheresis donation is mandatory. if the donor is found to have anti-hna a antibodies, which have been shown to lead to an increase severity of trali, they are deferred from all types of blood donation [ ] . in the mid- s, risk mitigation strategies for trali were instilled in order to exclude "at risk" donors from certain types of blood product donation. an observational study, leukocyte antibody prevalence study (laps) looked at antibody levels in volunteers for blood donation using fl ow cytometry. only - % of anti-hla and anti-hna antibodies were present in the male, never-pregnant female, and prior blood product recipient populations compared to multiparous female donors with approximately % of antibodies present [ ] . other studies report higher frequency of antibodies in the multiparous, female population as well, putting patients who receive blood products from this population at an increased risk for immune-mediated trali [ , ] . in the aabb published the recommendation, "…blood collecting facilities should implement interventions to minimize the preparation of high plasma-volume components from donors known to be leukocyte-allo-immunized or who are at increased risk of leukocyte alloimmunization ." based on this recommendation, the deferral of multiparous, female donors from plasma donations was implicated. the policy to use solely male donors for plasma donation led to a two-thirds decreased incidence in trali [ ] . data also shows since the deferral of multiparous females from plasma donation, the reported cases of deaths to the fda from plasma associated trali decreased from % before to % from to [ ] . the multiparous, female donor deferral strategy also has been used in platelet apheresis donation; however, with the shortage of donors available to meet the demanding needs of platelets, it is not completely feasible to implement complete deferral of high risk donors. another option for primary prevention of trali is the concept of leukocyte reduced blood. reduction of leukocyte antibodies in high volume plasma products has been shown to reduce trali incidence [ ] . however, patients still may be at risk for the non-immune mediated form of trali. pooled solvent detergent plasma was approved by the fda in as an alternative to ffp. in observational data, there was no reports of trali in ten million units of solvent detergent plasma [ ] . multiple studies from other countries as well have confi rmed the lack of trali in transfusions with solvent detergent products [ , , ] . the pooling and dilution of anti-hla antibodies is thought to play a large role in this decreased incidence. potential risks of pooling high volume plasma products also exist including, exposure to multiple donors and increased transmission of viruses . the majority of patients who develop trali require close monitoring in an intensive care setting. the degree of hypoxemia and lung injury is variable but commonly can be very severe. however, a subset of patients who develop trali will only require minimal supportive care and may even go undiagnosed. no studies have shown clinical severity correlating to the type of blood product or the amount of plasma transfused. worse clinical outcomes have been shown in patients who are positive for hna- a and hla-a antigens [ ] . despite the potential severity of trali, the timeframe is short-lived. studies show that even when patients require mechanical ventilation, the respiratory distress from trali resolves on average within h. in the patient population who is already critically ill, the time course may extend up to - days [ , ] . one report found that % of trali cases resolved within - h [ , ] . unlike ards from other etiologies where mortality rates can range from to %, trali has signifi cantly lower rates of death. studies show that mortality rates from trali alone range from to %, with higher percentages quoted from the icu population [ , ] . reports as high as % mortality have been shown in trali patients who were critically ill at the time of trali diagnosis; however, the cohorts utilized in these studies included some " possible trali " cases as well [ , , ] . despite a very similar clinical presentation as ards, trali also differs in the fact that it has minimal to no physical or pulmonary sequelae. in ards, patients are known to have decreased exercise capacity and decreased lung function on pulmonary function tests for up to years after initial pulmonary insult [ ] . in patients who recover from trali there are no residual pulmonary complications. this population of patients returns back to baseline pulmonary function and does not have complications of pulmonary fi brosis. permanent lung damage is rare [ , ] . based on limited evidence, it also appears patients who develop trali are not at increased risk for recurrent episodes of blood transfusion reactions from other donors. caution should be taken with blood transfusions from previously implicated donors; however, overall patients should not be restricted from receiving blood products in the future [ , , ] . current risks of transfusion-transmitted agents: a review fatalities caused by trali giving trali the one-two punch indiscriminate transfusion: a critique of case reports illustrating hypersensitivity reactions toward an understanding of transfusion-related acute lung injury: statement of a consensus panel transfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies proceedings of a consensus conference: towards an understanding of trali transfusion-related acute lung injury: a dangerous and underdiagnosed noncardiogenic pulmonary edema the role of neutrophils in the pathogenesis of transfusion-related acute lung injury the effect of previous pregnancy and transfusion on hla alloimmunization in blood donors: implications for a transfusion-related acute lung injury risk reduction strategy donor antibodies to hna- a implicated in trali reactions prime neutrophils and cause pmn-mediated damage to human pulmonary microvascular endothelial cells in a two-event in vitro model transfusion-related acute lung injury: current concepts for the clinician transfusion-related acute lung injury: incidence and risk factors transfusion-related acute lung injury in the critically ill: prospective nested case-control study transfusionrelated acute lung injury and pulmonary edema in critically ill patients: a retrospective study risk factors and outcome of transfusion-related acute lung injury in the critically ill: a nested case-control study transfusion-related acute lung injury: a case-control pilot study of risk factors the incidence, risk factors, and outcome of transfusion-related acute lung injury in a cohort of cardiac surgery patients: a prospective nested case-control study transfusion-related acute lung injury (trali) fresh-frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients transfusion-related acute lung injury transfusion-related acute lung injury; clinical perspectives effects of storage on effi cacy of red cell transfusion: when is it not safe? transfusion-related acute lung injury: a clinical review transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors white blood cell-reactive antibodies are undetectable in solvent/detergent plasma transfusion-related acute lung injury: a review transfusion-related acute lung injury: a preventable syndrome? diagnostic and pathogenetic considerations in transfusion-related acute lung injury the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome management of transfusion-related acute lung injury with extracorporeal cardiopulmonary support in a four-year-old child single hospital experience of trali transfusion-related acute lung injury (trali): presentation, epidemiology and treatment corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ards) in adults: meta-analysis comparison of two fl uid-management strategies in acute lung injury transfusion-related acute lung injury (trali): current clinical and pathophysiologic considerations a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. transfusion requirements in critical care investigators, canadian critical care trials group toward the prevention of acute lung injury: protocol-guided limitation of large tidal volume ventilation and inappropriate transfusion transfusion reactions: newer concepts on the pathophysiology, incidence, treatment, and prevention of transfusion-related acute lung injury prevalence of hla antibodies in remotely transfused or alloexposed volunteer blood donors measures to prevent transfusion-related acute lung injury (trali) cost-effectiveness of solvent/detergenttreated fresh-frozen plasma transfusion-related acute lung injury: reports to the french hemovigilance network transfusion-related acute lung injury: a rare and lifethreatening complication of a common procedure transfusion-related acute lung injury (trali): clinical presentation, treatment, and prognosis functional disability years after acute respiratory distress syndrome case report: transfusion-related acute lung injury (trali)-a clear and present danger transfusion-related acute lung injury transfusion-related acute lung injury recurrent transfusion-related acute lung injury key: cord- -i e uj s authors: heffner, john e; highland, kristin b title: chronic obstructive pulmonary disease in geriatric critical care date: - - journal: crit care clin doi: . /s - ( ) -x sha: doc_id: cord_uid: i e uj s copd is a progressive disorder that is punctuated in its later stages with acute exacerbations that present a risk for respiratory failure. copd has a disproportionate impact on older patients. in the icu, therapy is directed toward unloading fatigued respiratory muscles, treating airway infection, and prescribing bronchodilatory drugs. most patients survive hospitalization in the icu for an episode of respiratory failure. the severity of the underlying lung disease, however, underlies the poor outcomes of patients in terms of postdischarge survival and quality of life. worldwide impact, predicted to become the fifth leading burden to world health by [ ] . copd now causes million deaths worldwide each year [ ] . the elderly are especially subject to the health effects of copd. copd is the primary or contributing diagnosis for more than % of hospitalizations of patients years of age [ ] . medicare health care expenditures are . times higher for elderly patients with copd compared with age-matched persons without this condition ($ , versus $ , ) [ ] . the mean per-person direct medical expenditures among persons with copd years of age is $ , in dollars [ ] . results from two large epidemiologic studies-the third national health and nutrition examination survey and the estudio epidemiolólico de la epoc en españa survey-note the highest copd occurrence rates in the elderly [ , ] . between % to % of current smokers in older age groups were noted to have symptomatic copd in these large population-based surveys [ , ] . because of recent trends in smoking habits, the prevalence of copd is higher in women than in men. the prevalence and societal impact of copd are predicted to increase. feenstra et al [ ] projected with a dynamic life-table model that loss of life years due to copd in the netherlands will increase by % in compared with the baseline year of . health care costs due to copd are predicted to increase by % over the same -year period. elderly patients with moderate to severe copd experience acute exacerbations of their airway disease, each of which presents a risk for acute respiratory failure. although definitions of acute exacerbations vary, recent consensus statements define exacerbations by the presence of one or more of the cardinal symptoms of increased dyspnea, increased sputum volume, and increased sputum purulence [ ] . using this definition, the severity of acute exacerbations is graded by the winnepeg criteria (box ) [ ] . an international working group of pulmonary physicians has recommended a more comprehensive definition of acute exacerbations. this group contends that the requirement for symptoms of bronchitis (cough and purulent sputum) underidentifies patients with acute exacerbations. their proposed definition of an exacerbation is ''a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying copd'' [ ] . the severity of acute exacerbations using this definition are graded by the level of health care used (see box ) [ ] . regardless of the definition used, elderly patients with advanced copd experience on average two to three acute exacerbations each year, with each episode lasting days [ ] . the pathophysiology of acute exacerbations of copd is incompletely understood, but increased concentrations of proinflammatory mediators and inflammatory cells in expectorated sputum, broncho-alveolar lavage samples, and tissue biopsied from the lung during exacerbations demonstrate the presence of inflammation within and surrounding airways [ - ] . during an acute exacerbation, this inflammation assumes characteristics of an allergic response increased eosinophils and upregulation of rantes (regulated upon activation, normal t-cell expressed and secreted) in the epithelium and subepithelium [ ] . common triggers for acute exacerbations of copd include airway infections [ ] , particulate air pollution [ ] , and environmental temperature changes [ ] , although up to % of patients have no clinically apparent etiologic factor [ ] . patients with acute exacerbations commonly have associated conditions such as congestive heart failure, pulmonary emboli, and extrapulmonary infections. bronchial infections are important causes of acute exacerbations with bacterial, atypical bacterial, and viral pathogens being the most commonly identified microbes (box ) [ ] . although the lower airway of patients with copd harbors a mixed flora of bacteria, airway inflammation and bacterial load increases during an acute exacerbation [ , ] these observations suggest that new or more virulent bacterial strains introduced into the airway population of colonized bacteria promote an inflammatory response that triggers acute exacerbations of box . criteria for grading the severity of an acute exacerbation of chronic bronchitis american college of chest physicians-american college of physicians/american society of internal medicine guidelines [ ] mild exacerbation: presence of any one of the cardinal symptoms of increased dyspnea, increased sputum volume, or increased sputum purulence with the addition of an upper respiratory infection within the past days, fever with no other cause, increased wheezing or cough, or a % rise over baseline in respiratory rate or heart rate. moderate exacerbation: presence of any two of the three cardinal symptoms of an exacerbation. severe exacerbation: presence of all three of the cardinal symptoms of an exacerbation. international consensus group [ ] mild exacerbation: patient has an increased need for medicaiton, which can be managed in the patient's normal environment. moderate exacerbation: patient has an increased need for medication and feels the need to seek additional medical assistance. severe exacerbation: patient/caregiver recognizes obvious and/ or rapid deterioration in condition, requiring hospitalization. copd [ ] . ten to % of patients with acute exacerbations have infections with two or more pathogens. among atypical pathogens, chlamydia pneumoniae has been estimated to account for % to % of acute exacerbations but up to % of exacerbations that result in admission to the icu [ , ] . viral bronchitis is found in % to % of patients with acute exacerbations but only % of those who require icu admission [ - ] . one recent study indicates that exacerbations due to viral bronchitis are more severe compared with nonviral exacerbations, and are associated with a longer time to recovery [ ] . viral particles have also been shown to produce latent infections, which can augment the inflammatory response to a subsequent stimulant of airway reactivity [ ] . elderly patients with an acute exacerbation of airway disease experience increased resistance to expiratory airflow and increased work of breathing, which can cause respiratory muscle fatigue. as shown by the spirometric flow-volume loops in fig. , normal individuals breathe at rest with expiratory air flows that are well within the limits of their maximal flow rate capacity. healthy persons, therefore, do not reach their maximal flow rates even with vigorous exercise. in contrast, patients with moderate to severe copd have tidal volume flow rates [ ] . during an acute exacerbation, patients' attempts to increase minute ventilation by increasing tidal volume are limited by the low maximal flow rates. patients respond with an increased respiratory rate, which decreases the time available for expiratory emptying of alveoli through narrowed airways. patients experience progressive trapping of air within the lung (''dynamic hyperinflation''), which increases work of breathing [ ] . eventually, increasing fatigue prevents patients from meeting their ventilatory demands and causes hypercapnic respiratory failure [ ] . based on this pathophysiology of respiratory failure in copd, management centers on decreasing airway resistance and decreasing work of breathing by ''unloading'' ventilatory demands on respiratory muscles to treat or prevent respiratory muscle fatigue. most therapeutic recommendations for managing elderly patients in the icu with acute exacerbations of copd derive from expert consensus because of the paucity of large prospective randomized trials [ ] . initial management includes supplemental oxygen by nasal cannulae or through a face mask that controls oxygen flow. oxygen flows are titrated with goals of achieving oxygen saturation between % and % and a partial pressure of arterial oxygen between to mm hg. oxygen flow is monitored to prevent hypercapnia, which can result from the effects of supplemental oxygen on increasing dead-space ventilation and ventilation-perfusion mismatching. inhaled bronchodilators promote bronchodilation that can achieve a % to % increase in fev and fvc within to hours [ ] . fourteen randomized trials support the conclusion that short-acting b-agonists (albuterol, levalbuterol, pirbuterol, bitolterol, fenoterol, metaproterenol, terbutaline) and anticholinergictype inhaled bronchodilators (ipratropium bromide) have similar efficacy for managing acute exacerbations, and both are more effective than parenteral bronchodilators [ ] . the faster onset of action of b-agonists and the lower frequency of adverse effects with anticholinergic drugs determine drug selection for individual patients. no differences exist between the administration of inhaled bronchodilators by meter dose inhalers with a spacer or a jet nebulizer [ ] . initial therapy is usually started with a nebulizer, however, because critically ill patients with acute respiratory distress may experience difficulties using meter dose inhalers [ ] . patients are switched to metered dose inhaler (mdi) therapy as soon as they regain an ability to synchronize their breathing with the mdi device. although clinicians often combine inhaled short-acting b-agonists with ipratropium bromide for patients with acute exacerbations, existing data demonstrate only marginal benefits with combined therapy. the recent evidence-based consensus statement by the american college of chest physicians and the american college of physicians/american society of internal medicine recommends initial treatment with ipratropium bromide with the addition of a shortacting b-adrenergic agonist if patients do not respond to a maximal dose of the anticholinergic drug [ ] . other experts recommend the reverse approach beginning with a b-agonist drug [ ] . the ideal dosing schedule for short-acting b-agonists and ipratropium bromide has not been established. high doses of b-agonists may cause tachyarrythmias, tremor, idiosyncratic bronchoconstriction, and tachyphylaxis [ , ] . data do not support the use of parenteral aminophylline for critically ill elderly patients hospitalized in the icu with acute exacerbations of copd. in emergency department settings, short-term use of aminophylline demonstrates either no change in measurable outcomes [ ] or a decreased risk of subsequent hospitalization [ ] . the high rates of adverse effects in patients treated with aminophylline combined with its questionable benefit have markedly decreased the use of this drug in the icu. recent guidelines do not recommend the use of aminophylline for acute exacerbations of copd [ ] . the role of bacterial infections in causing exacerbations of airway disease support the use of antibiotics, although no studies have been performed in critically ill patients [ ] . cumulative findings from several studies, however, demonstrate benefit for patients with acute exacerbations who have severe exacerbations as marked by the presence of purulent sputum [ , , ] . because most studies of antibiotic efficacy for acute exacerbations were performed before the era of multidrug resistant bacteria, the appropriate selection of antibiotics for critically ill patients remains unclear. ''first-line'' antibiotics (doxycycline, trimethoprimsulfamethoxazole, amoxacillin) have been recommended for general ambulatory patients with acute exacerbations [ ] . many clinicians, however, use newer classes of more broad-spectrum antibiotics for hospitalized patients. demonstration of superiority of these newer drugs awaits randomized controlled trials. pending the results of these studies, it is reasonable to recommend newer macrolides (azithromycin or clarithromycin), newer cephalosporins (cefpodoxime, cefprozil), amoxicillin/clavulanate, or doxycycline for hospitalized patients. critically ill patients and patients with risk factors for poor outcomes (baseline fev < % predicted, comorbid conditions, three or more exacerbations during the last months) benefit from newer fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin) because of the risk of gram-negative organisms. if pseudomonas aeruginosa is suspected (baseline fev < % predicted, underlying bronchiectasis, multiple courses of antibiotics), ciprofloxacin is the preferred antibiotic [ ] . prospective, randomized controlled trials demonstrate that systemic corticosteroids improve outcome for patients with acute exacerbations, as demonstrated by more rapid improvement in measured airflow, gas exchange, and respiratory symptoms with decreased treatment failure rates and relapse rates [ ] . existing studies have used different treatment regimens so the optimal dose and duration of corticosteroids are unknown. the largest study to date of hospitalized patients, however, used methylprednisolone, mg iv every hours for days followed by a corticosteroid tapering schedule using oral prednisone [ ] . patients treated for weeks with corticosteroids did as well as patients treated for weeks. hyperglycemia is the major complication of corticosteroid therapy for hospitalized patients with acute exacerbations [ ] . no studies support the use of expectorants, mucolytic agents, or mucokinetic drugs in managing critically ill patients with copd [ ] . physical therapy with postural drainage and chest clappage may acutely worsen respiratory function without providing any measurable benefit. positive pressure ventilation unloads respiratory muscles and prevents or treats respiratory muscle fatigue. ventilatory support can be provided by a tight-fitting face mask in the form of noninvasive positive pressure ventilation (nippv) or by tracheal intubation with mechanical ventilation. nippv has been shown in randomized controlled trials to provide benefits to subsets of patients with acute respiratory failure by decreasing the need for intubation, shortening hospital stay, and increasing survival [ - ] . many of these benefits occur because of the lower risk for pneumonia with nippv compared with intubation and mechanical ventilation [ ] . the rationale for nippv derives from the respiratory muscle unloading that occurs during ventilatory support that allows patients to maintain adequate breathing until the underlying airway problems reverse [ ] . all hospitalized elderly patients who present with respiratory distress from acute exacerbations should be evaluated for nippv. patients admitted with even mild respiratory acidosis may benefit from nippv [ ] . unfortunately, only % of hospitalized patients are candidates for nippv [ ] . poor candidates for nippv include patients with cardiovascular instability, respiratory arrest, limited ability to clear increased airway secretions, poor airway control, agitation or severe encephalopathy (glascow coma scale < ), uncooperability, upper gastrointestinal bleeding, upper airway obstruction, high risk for aspiration, and facial features that interfere with proper fitting of a face mask [ ] . recent studies demonstrate that the use of nippv does not require more nursing or respiratory therapist time compared with intubation and mechanical ventilation [ ] . basic principles for initiating nippv are listed in (box ). the key to successful application of nippv for patients with copd is thoughtful individualization of care and cautious titration of the positive pressure support. patients with severe respiratory failure who are not candidates for nippv require intubation and mechanical ventilation. ventilatory support provides an increased minute ventilation to correct abnormalities in gas exchange, and unloads respiratory muscles to allow recovery from respiratory muscle fatigue. identify appropriate patient review the equipment with the patient and explain care fit an appropriate-sized mask adjust ventilator initially at a low pressure ( - cm h o inspiration; - cm h o expiration) with the patient holding the mask in place. ask the patient to report comfort level and adjust ventilator pressures accordingly adjust oxygen flow rates to meet target oxygen saturation levels adjust the mask to avoid leaks monitor patient frequently and coach breathing patterns gradually increase inspiratory pressures for maximal relief of dyspnea although the specific techniques of mechanical ventilation are beyond the scope of the present article, general principles center on the avoidance of dynamic hyperinflation. patients with acute respiratory failure have increased airflow limitation, which slows expiratory airflow and delays alveolar empyting. mechanical ventilation with large tidal volumes and rapid respiratory rates produce dynamic hyperinflation and raised alveolar pressures at end expiration, which is termed autopositive end expiratory pressure (auto-peep). auto-peep interferes with patients' abilities to spontaneously trigger the ventilator, creates discomfort that may require heavy sedation, and compromises cardiac function. strategies to avoid dynamic hyperinflation include use of lower tidal volumes, increased inspiratory flow rates, and moderate respiratory rates. use of applied-peep at a lower level than measured auto-peep may enhance ventilator triggering and promote patient comfort. more detailed reviews of ventilator strategies for patients with copd are reviewed elsewhere [ ] . most patients intubated for respiratory failure due to copd improve within the first hours of care and undergo successful weaning and early extubation. goals for these patients are to reverse bronchospasm, rest fatigued ventilatory muscles, prevent dynamic hyperinflation, and avoid oversedation, which is associated with increased risks for nosocomial pneumonia and delayed weaning. patients who require mechanical ventilation for longer than hours are at increased risk of death and long-term mechanical ventilation [ ] . although no prospective, randomized data support the role of early tracheotomy for ventilator-dependent patients with copd [ ] , we have found tracheotomy valuable in promoting patient comfort with decreased need for analgesics and sedatives, improved nutrition, articulated speech, and patient mobility [ ] . these factors combined with the improved access to the lower airways for pulmonary toilet and decreased airway resistance during weaning trials promote successful weaning. we evaluate patients for tracheotomy after days of intubation. if successful extubation appears unlikely during the next several days, we proceed to tracheotomy to promote patient comfort and an early weaning from ventilatory support [ ] . copd is a progressive disease characterized by a long preclinical phase and a gradual decline in lung function over years after patients become symptomatic. some patients experience an abrupt and permanent loss of lung function during acute exacerbations. it is not possible to predict the clinical course of individual patients with copd because of the variability of the disease and limitations of studies that examine clinical predictors. studies have observed, however, accelerated decline in lung function in heavy and current smokers and in patients with mucus hypersecretion, low functional status, airway hyperreactivity, polymorphism in the tnf-a gene promoter region, and elevated levels of fibrinogen [ - ] . the prognosis for patients hospitalized with an acute exacerbation associated with hypercapnia is poor in terms of survival and postdischarge health-related quality of life. prognosis is determined more by the severity of the underlying copd than by factors associated with the hospitalization. more than % of patients admitted with an acute exacerbation require rehospitalization within months [ , ] . the mortality of patients hospitalized for an acute exacerbation is % to % [ ] , but mortality climbs to % to % for patients who require icu admission [ , ] . the -day, -day, -year, and -year mortality for patients discharged after an acute exacerbation is %, %, %, and %, respectively [ , ] . six months after discharge, only % of patients are alive and able to report a good, very good, or excellent quality of life [ ] . disabling symptoms of dyspnea are the most important factors decreasing quality of life [ ] . in view of this poor long-term prognosis both in terms of survival and quality of life, risk stratification models to identify patients at high risk of inpatient death or a poor postdischarge outcome would assist patient selection for intubation. niewoehner et al observed that the fev at admission and over the first several days of hospitalization is highly associated with clinical outcome [ ] . for patients who require intubation and mechanical ventilation, comorbidities, and acute illness severity scores are predictive of survival [ ] . requirements for mechanical ventilation beyond hours and extubation followed by reintubation are associated with a high mortality [ ] . connors et al reported data from the study to understand prognoses and preferences for outcomes and risks of treatments that found an independent association of severity of illness scores, body mass index, older age, prior functional status, severity of hypoxia, congestive heart failure, serum albumin, and the presence of cor pulmonale with survival [ ] . almagro et al [ ] recently reported that quality of life, marital status, depressive symptoms, comorbidity, and prior hospital admission identified hospitalized patients with a poor postdischarge survival [ ] . unfortunately, none of these models successfully identifies individual patients who have greater than % likelihood of dying [ ] . moreover, most of these prediction models have not been validated in an independent cohort. consequently, no existing system for predicting inpatient mortality or postdischarge functional capacity is suitable for selecting patients for instituting, continuing, or withdrawing life-sustaining therapies [ , ] . palliative and end-of-life care in the icu most patients with advanced copd want to make their own decisions regarding life-supportive care either by communicating with their physicians directly or through an appointed surrogate or instrument of advance care planning [ ] . to make informed decisions, however, patients need to understand the nature of life-supportive interventions and the probability of different outcomes if life interventions are used for respiratory failure. unfortunately, most elderly patients with moderate to severe copd have not discussed with their primary care physicians the appropriateness of life-supportive care or the nature of intubation and mechanical ventilation [ ] . if advance care planning has not occurred in the outpatient setting, discussions regarding the appropriateness of life-sustaining care should take place during the hospitalization for an acute exacerbation. ideally, the primary physician who knows the patient most intimately should initiate these discussions, which has been termed ''captaincy'' [ ] . often, however, the primary care physician is not available to discuss end-of-life care during hospitalization in the icu, which requires the critical care physician to serve this role. in discussing end-of-life care, critical care physicians need to inform patients and families about the anticipated value of life-supportive care. they should adopt, however, a broader approach to advance care planning that incorporates the patient's perspective. physicians in the icu often over focus on discussions regarding the life-sustaining interventions that should be applied in various clinical circumstances. patients and families, however, have more overarching goals that pertain to preparing for death, achieving a sense of control, and securing personal relationships with friends and families. patients with terminal copd are oriented toward their psychologic, emotional, and spiritual needs. discussions may shift from patient -physician discussions on the use of lifesupportive interventions to patient -family -friend communications to fortify relationships and share decisions about life-supportive care through mutual support [ ] . patients with acute exacerbations who choose to forego life-supportive care or have it withdrawn need relief of pain and suffering and expert management of their end-of-life care [ ] . they also benefit from reassurance that their physicians and nurses will not back away from their care. disabling symptoms of cough, dyspnea, anxiety, and depression typically complicate the terminal course of patients dying with copd [ ] . most patients at the terminal stage of copd choose not to use ventilator support, or to use it only for a time-limited span, if they can be sure of competent relief of terrifying dyspnea. copd is a progressive disorder that is punctuated in its later stages with acute exacerbations that present a risk for respiratory failure. copd has a disproportionate impact on older patients. in the icu, therapy is directed toward unloading fatigued respiratory muscles, treating airway infection, and prescribing bronchodilatory drugs. most patients survive hospitalization in the icu for an episode of respiratory failure. the severity of the underlying lung disease, however, under-lies the poor 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management of acute exacerbations of copd: a summary and appraisal of published evidence relationship between flora in sputum and functional impairment in patients with acute exacerbations of copd. study group of bacterial infection in copd effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. department of veterans affairs cooperative study group comparison of the acute effects on gas exchange of nasal ventilation and doxapram in exacerbations of chronic obstructive pulmonary disease noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure international consensus conferences in intensive care medicine. noninvasive positive pressure ventilation in acute respiratory failure noninvasive positive pressure ventilation in the setting of severe, acute exacerbations of chronic obstructive pulmonary disease: more effective and less expensive early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial one year period prevalence study of respiratory acidosis in acute exacerbations of copd: implications for the provision of non-invasive ventilation and oxygen administration mechanical ventilation in chronic obstructive lung disease predictors of outcome for patients with copd requiring invasive mechanical ventilation the role of tracheotomy in weaning tracheostomy management in the chronically ventilated patient timing of tracheotomy in mechanically ventilated patients effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of fev . the lung health study methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. the lung health study research group association of chronic mucus hypersecretion with fev decline and chronic obstructive pulmonary disease morbidity. copenhagen city heart study group chronic mucus hypersecretion in copd and death from pulmonary infection functional status and survival following pulmonary rehabilitation outcomes following acute exacerbation of severe chronic obstructive lung disease does increased access to primary care reduce hospital readmissions? veterans affairs cooperative study group on primary care and hospital readmission the necessary length of hospital stay for chronic pulmonary disease dying with lung cancer or chronic obstructive pulmonary disease: insights from support. study to understand prognoses and preferences for outcomes and risks of treatments living and dying with chronic obstructive pulmonary disease relation of fev( ) to clinical outcomes during exacerbations of chronic obstructive pulmonary disease. department of veterans affairs cooperative study group mortality after hospitalization for copd evaluation of prognostic criteria for determining hospice eligibility in patients with advanced lung, heart, or liver disease. support investigators. study to understand prognoses and preferences for outcomes and risks of treatments chronic obstructive pulmonary disease-ethical considerations of care attitudes regarding advance directives among patients in pulmonary rehabilitation advance end-of-life treatment planning. a research review ethical issues in the chronically critically ill patient advanced lung disease: palliation and terminal care key: cord- -obph gup authors: degnan, tina h.; skolnik, neil s. title: appropriate antibiotic use for treatment of nonspecific upper respiratory infections, rhinosinusitis, and acute bronchitis in adults date: journal: essential practice guidelines in primary care doi: . / - - - - _ sha: doc_id: cord_uid: obph gup acute sinusitis, bronchitis, pharyngitis, and nonspecific upper respiratory tract infections (uris) account for the majority of antibiotics prescribed by primary care physicians in the united states. the emergence of antibiotic-resistant bacteria in the community setting is now an issue for individual patients as well as society at large, and it is the responsibility of all clinicians to limit antibiotic treatment to those patients who are most likely to benefit from it. the vast majority of acute respiratory infections are caused by viruses. antibiotic treatment of patients with these infections selects for resistant nasopharyngeal bacteria, acutely increasing the spread of resistant pathogens through secretions and predisposing the treated patient to more serious bacterial infections in the future. the guidelines summarized in this chapter were designed by a panel of physicians representing family medicine, internal medicine, emergency medicine, and infectious diseases to provide a practical approach to the appropriate diagnosis and treatment of previously healthy adults with nonspecific uri, acute sinusitis, or acute bronchitis in the ambulatory care setting. recommendations for the diagnosis and treatment of pharyngitis are provided in a separate chapter. approach to the appropriate diagnosis and treatment of previously healthy adults with nonspecific uri, acute sinusitis, or acute bronchitis in the ambulatory care setting. recommendations for the diagnosis and treatment of pharyngitis are provided in a separate chapter. the diagnosis of nonspecific uri should be applied to a patient with an acute infection involving sinus, pharyngeal, and upper airway symptoms without a prominent symptom with which to make a more specific diagnosis of sinusitis, pharyngitis, or bronchitis. antibiotics are ineffective in treating nonspecific uris because most often, a virus is the causative agent. mild cases are most frequently caused by rhinoviruses. patients with more severe symptoms, especially when accompanied by myalgia and fatigue, are likely to be infected with influenza or parainfluenza viruses. other sources of uri symptoms include adenovirus and respiratory syncytial virus (rsv). multiple studies have failed to show a benefit for antibiotic treatment in adults with uri. purulent secretions and prevention of complications are two common justifications for antibiotic treatment of uri. the clinical finding of purulent sputum or rhinorrhea in a patient with uri symptoms is not a reliable indicator of bacterial infection and should not be used to justify treatment of the uri with antibiotics. bacterial complication of a viral uri is rare, and antibiotics have not been shown to prevent complications such as pneumonia or hasten the resolution of uri in previously healthy adults. on the contrary, unnecessary antibiotic use predisposes patients to carriage of antibiotic-resistant streptococcus pneumoniae and to invasive infection with this bacterium in the future. acute rhinosinusitis (acute sinusitis) is a common primary care diagnosis and physicians prescribe an antibiotic to - % of patients with this illness. although primary care physicians tend to think of rhinosinusitis as an acute bacterial infection, the majority of cases are caused by a virus. the lack of straightforward diagnostic criteria or available testing with which to distinguish a bacterial sinusitis that might benefit from antibiotic therapy from a viral infection has led to the clinical overdiagnosis of bacterial sinus infections and the overprescription of antibiotics. symptom duration is one criterion that has been used to diagnose acute bacterial sinusitis. by definition, acute rhinosinusitis symptoms last less than wk, but patients and physicians begin to suspect bacterial rather than viral infection when symptoms last longer than a few days. studies of rhinovirus infection describe duration of symptoms from to d, with an average illness lasting about - d. an estimated . - % of viral uris are complicated by sinus ostia obstruction leading to bacterial infection. although studies have shown that few patients with symptoms lasting less than d will have bacterial infections, the small percentage of bacterial compared with viral sinus infections and the underestimation of the duration of viral symptoms suggest that the majority of illnesses lasting longer than d are caused by viruses and will not benefit from antibiotic treatment. the gold standard method for diagnosis of bacterial sinusitis is sinus puncture, with s. pneumoniae and haemophilus influenzae being the most commonly isolated organisms. this invasive test is clearly impractical for routine use in the primary care office. sinus radiography is another test that has limited value for routine diagnosis of bacterial infection. just as the symptoms of viral and bacterial rhinosinusitis overlap, so do the radiographic changes they produce. most patients with viral sinusitis will have abnormal sinus radiographs, and determination of the degree of mucosal thickening and sinus obstruction becomes a judgment call with predictive value similar to that of clinical findings alone. a further similarity of viral and bacterial rhinosinusitis is that all infections with mild to moderate symptoms are likely to resolve with symptomatic treatment alone. therefore, rather than assigning treatment based on the difficult distinction of acute viral vs bacterial rhinosinusitis, antibiotic treatment should be prescribed for those patients with severe symptoms regardless of duration or patients with moderate symptoms that persist beyond d. patients who experience severe symptoms of purulent nasal discharge accompanied by maxillary tooth or facial pain, especially when unilateral, unilateral sinus tenderness, and worsening of symptoms after initial improvement should be treated with narrow-spectrum antibiotics such as amoxicillin, doxycycline, or trimethoprim-sulfamethoxazole in addition to the symptomatic treatments recommended for all patients with acute rhinosinusitis. patients with mild symptoms or moderate symptoms persisting for less than d should be treated with appropriate doses of analgesics, antipyretics, and decongestants and educated about their diagnosis and the chosen treatment strategy. recently published, updated guidelines from the american academy of allergy, asthma and immunology support the use of narrow-spectrum antibiotic therapy, specifically amoxicillin, as the first choice in the treatment of uncomplicated sinusitis in children and adults. depending on the local prevalence of β-lactamase-producing strains of bacteria, it might be reasonable to add potassium clavulanate, in the form of amoxicillin-potassium clavulanate, which is usually effective against β-lactamase-producing h. influenzae, m. catarrhalis, s. aureus, and anaerobic bacteria. these guidelines indicate that in certain areas there are high rates of resistance to sulfamethoxazole-trimethoprim present in s. pneumoniae, h. influenzae, and m. catarrhalis, so that sulfamethoxazoletrimethoprim would not be an ideal first choice. acute bronchitis is a clinical diagnosis defined as an acute respiratory infection in which cough is a predominant symptom. cough may be dry or productive of sputum but by definition lasts less than wk. cough illness lasting longer than wk should be categorized as chronic or persistent cough illness and evaluated as such. assessment of patients with chronic cough often begins with chest radiography and is beyond the scope of this chapter. as with the uri and sinusitis guidelines, the recommendations for acute bronchitis summarized here apply only to healthy adults without underlying lung disease. the majority ( %) of previously healthy adults presenting to the primary care office with a chief complaint of cough will have acute bronchitis associated with uri. the next most common diagnoses are asthma ( %) and pneumonia ( %). previously undiagnosed asthma in a patient with acute cough is an important consideration, but it is difficult to distinguish asthma from transient bronchial hyperresponsiveness and abnormal spirometry associated with uncomplicated acute bronchitis. pneumonia is potentially the most serious diagnosis associated with acute cough illness and can be fairly accurately distinguished from acute bronchitis based on clinical examination findings. therefore, the primary objective of the office visit for acute cough should be to exclude a diagnosis of pneumonia. non-elderly adult patients with normal vital signs (heart rate ≤ , respiratory rate ≤ , and oral temperature ≤ °c) and chest examination (absence of signs of focal consolidation such as asymmetric breath sounds, rales, egophony, or fremitus) are unlikely to have pneumonia. a patient with cough for less than wk, whose clinical examination is not suspicious for pneumonia may be considered to have acute bronchitis, which is likely because of infection with a respiratory virus. chest radiography or other diagnostic tests are rarely warranted in a previously healthy adult in whom pneumonia has been excluded based on clinical presentation. acute bronchitis is caused by both upper and lower respiratory tract viruses. lower respiratory tract viruses such as influenza a and b, parainfluenza , and rsv are the most common causes of acute bronchitis, but upper tract viruses such as coronavirus, adenovirus, and rhinovirus may also cause acute cough illness. bordetella pertussis, mycoplasma pneumoniae, and chlamydia pneumoniae (strain twar) are the only nonviral causes of uncomplicated acute bronchitis in previously healthy adults, accounting for - % of cases. gram stain and culture of sputum does not reliably identify these agents and, therefore, it is not recommended for evaluation of acute bronchitis in adults without underlying lung disease. randomized controlled trials have shown that antibiotic treatment of acute bronchitis in previously healthy adults is not beneficial. the two uncommon exceptions to this rule include cases of bacterial superinfection as evidenced by infiltrate on chest x-ray and cases of suspected pertussis. because previously immunized adults often do not present with the characteristic whooping cough of pertussis, it is difficult to distinguish this disease in this patient population from other causes of acute bronchitis. it is recommended that antibiotic treatment for pertussis should be limited to those adults with a high probability of exposure to the disease, such as during documented outbreaks. treatment is largely beneficial as it decreases shedding of the organism. as pertussis is rarely suspected prior to - d of illness it is too late to speed resolution of symptoms. influenza infection is one other circumstance in which antimicrobial treatment of acute bronchitis may be warranted. influenza viruses are the most common causes of uncomplicated acute bronchitis. it has been shown that during documented influenza outbreaks, clinical judgment can be as accurate as rapid diagnostic tests, which have a sensitivity of - %. however, judgment must also be used in weighing the high cost of the newer neuraminidase inhibitors, which are active against both influenza a and b, against their rather limited benefit of d of less illness in addition to the requirement that they be taken within h of symptom onset and may contribute to the emergence of resistant viral strains. in summary, a previously healthy adult patient with acute cough illness without signs of pneumonia or exposure to pertussis will not benefit from antibiotic treatment. chest radiography should be limited to those cases in which pneumonia is suspected or cough has persisted for more than wk in the absence of other known causes. some patients with acute bronchitis will expect antibiotic treatment for uncomplicated acute bronchitis based on past experience. when antibiotic treatment is not warranted, all patients will benefit from the explanation that they have acute bronchitis, a self-limiting viral infection that may be thought of as a "chest cold," and discussion about why antibiotics are not being prescribed. patients should be prepared for the possibility that cough could last an average of - d. analgesics, antipyretics, antitussives, β-agonist inhalers, and vaporizers should be offered, with the explanation that they will not shorten the course of illness but will provide symptomatic relief. principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: background, specific aims, and methods principles of appropriate antibiotic use for treatment of nonspecific respiratory tract infections in adults principles of appropriate antibiotic use for acute sinusitis in adults principles of appropriate antibiotic use for treatment of acute bronchitis in adults the diagnosis and management of sinusitis: a practice parameter update key: cord- -jwm s gm authors: mishra, ajay kumar title: acute pancreatitis date: - - journal: clinical pathways in emergency medicine doi: . / - - - - _ sha: doc_id: cord_uid: jwm s gm early diagnosis and treatment are crucial in the management of acute pancreatitis to prevent complications and to reduce morbidity and mortality. • acute pancreatitis (ap) is an acute infl ammatory process in which there is autodigestion of pancreas by its own enzyme. • annual incidence of ap varies between . and . cases per , worldwide with an increasing trend in the annual incidence [ , ] . even though the case fatality rate for ap has decreased over time, the overall population mortality rate for ap has remained unchanged [ ] . • aetiological variation has been seen depending upon the lifestyle in different population. • early diagnosis and treatment are crucial in the management of acute pancreatitis to prevent complications and to reduce morbidity and mortality. • other life-threatening conditions which mimic acute pancreatitis should also be considered and ruled out simultaneously while managing the patient. • prophylactic antibiotics are not indicated in sterile pancreatic necrosis. • consider early admission in intensive care unit after initial resuscitation in the emergency department. • generally, acute pancreatitis is more common in males than females. in males, the aetiology is more often related to alcohol; in females, it is more often related to biliary tract disease. • the overall mortality in patients with acute pancreatitis is - %. mortality due to biliary pancreatitis is high as compared to alcoholic pancreatitis. twenty percent of patients present with severe disease (organ failure) in whom, mortality is approximately % [ ] . pathophysiology ( fig. . ) • the causes of acute pancreatitis have been listed in table . [ - ] . • cholelithiasis is the most common cause of acute pancreatitis ( - %), whereas alcohol is the second most common cause ( - %) [ - ] . • revised atlanta criteria (table . ) defi nes severity of acute pancreatitis into three categories -mild acute pancreatitis, moderately severe acute pancreatitis and severe acute pancreatitis [ ] . • local complications include peripancreatic fl uid collections and pancreatic/peripancreatic necrosis (sterile or infected). • organ failure is defi ned as a score of or more using the modifi ed marshall scoring system (table . ) [ , ] . • phases of severe pancreatitis [ , ] : -early -usually last for the fi rst week in which patient may present with systemic infl ammatory response syndrome (sirs). -late -follows the early phase and lasts from weeks to months, usually characterised by local complications and/or persistent organ failure. • most patients with severe pancreatitis present to emergency department during the early phase without any signs of organ failure and local complications, thus leading to errors in clinical management of this disease [ ] . activation of zymogen activation cascade & release of inflammatory mediators (tnf-α, il- , il- ) • -cullen sign -bluish discolouration around the umbilicus due to haemoperitoneum -grey turner's sign -reddish-brown discolouration along the fl anks resulting from retroperitoneal haemorrhage (fig. . ) any acute abdomen or sometimes cardiac as well as pulmonary conditions can mimic ap. some of the common differentials are enlisted in the box below. • the diagnosis of ap should be considered in presence of two of the following three criteria: i. typical abdominal pain suggestive of ap ii. serum amylase and/or serum lipase more than three times the upper limit of normal value iii. characteristic feature of ap in abdominal imaging • detailed history should be taken to fi nd out the cause of ap, including history of alcohol consumption, hyperlipidaemia, similar episodes in the past, abdominal trauma and past history of gallstones or ercp. medication history should be asked to rule out drug induced ap. • apart from serum amylase and lipase, complete blood count including haematocrit, liver function test, serum triglyceride levels, serum calcium, blood urea nitrogen (bun) and serum electrolytes should be checked to look for aetiology as well as to assess severity of ap. • serum triglyceride level of > mg/dl is considered signifi cant as a cause of ap in absence of gallstones and history of alcohol abuse. • ecg -to rule out acute coronary syndrome. • chest x-ray erect view to look for air under diaphragm in case of intestinal perforation and also to aid to diagnosis of any pulmonary pathology, e.g. ards. • in female patients under reproductive age group, bedside urine pregnancy card test should be done to rule out ectopic pregnancy. • transabdominal ultrasound should be done in all patients of ap to look for possible causes [ ] . • in patients > years of age without any identifi able cause of ap, pancreatic tumours should be suspected as a probable cause [ , ] . • acute mesenteric ischaemia • perforated gastric or duodenal ulcer • dissecting aortic aneurysm • biliary colic • acute myocardial ischaemia • ectopic pregnancy • intestinal obstruction • ards • contrast-enhanced computed tomography (cect) and/or magnetic resonance imaging (mri) of the abdomen should be done only in patients in whom diagnosis is not certain or in those patients who do not show any signs of improvement within - h of hospital admission [ ] . • assess and stabilise airway, breathing and circulation. • early aggressive intravenous hydration [ ] with isotonic crystalloids to be started for all patients to correct hypovolaemia due to third spacing of fl uids, vomiting, reduced oral intake, increased respiratory loses and/or diaphoresis. special precaution to be taken in patients with renal and/or cardiac disease. • lactated ringer's solution is the preferred crystalloid over . % normal saline for fl uid replacement [ ] . • adequate analgesia should be given at the earliest. inj. morphine at a loading dose of . mg/kg body wt. followed by . mg/kg body wt. every min can be administered until the pain is relieved [ ] . • nasogastric (ng) tube to be inserted and patient to be kept nil per orally (npo) to give rest to the infl amed pancreas; however prolonged fasting should be avoided. early oral feeding in acute pancreatitis is benefi cial in terms of shorter hospital stay, decreased infectious complications and decreased morbidity and mortality [ ] . • prophylactic antibiotics should not be given for severe ap and sterile necrosis [ ] . antibiotics should be given only if there is evidence of infected necrosis, extrapancreatic infection, cholangitis, bacteraemia, catheter-acquired infections, urinary tract infection and/or pneumonia. • ercp should be done within h of admission in patients with concurrent acute pancreatitis and acute cholangitis [ ] . • patients with moderately severe or severe acute pancreatitis should be admitted to an intensive care unit. (fig. . ) acute pancreatitis is associated with emotional, physical, as well as fi nancial burden on the society [ ] with signifi cant morbidity and mortality. early diagnosis and early aggressive intravenous hydration can reduce morbidity and mortality as well as prevent complications. contrast-enhanced computed tomography (cect) and/or magnetic resonance imaging (mri) should be reserved for patients who fail to improve clinically or in whom diagnosis is not confi rmed. patients with moderately severe or severe acute pancreatitis should be admitted to intensive care unit whenever possible. it is important to rule out other lifethreatening differential diagnosis of acute pancreatitis before shifting the patients from the emergency department. clinically stable clinically unstable/not improving • early aggressive iv hydration. • adequate analgesia. • npo, ng tube with continuous dependent drainage. • assess airway, breathing & circulation. • insert large bore iv cannula. • collect blood sample & send for cbc, rft, lft, serum electrolytes, serum amylase & lipase, serum calcium, serum triglyceride level. • urine pregnancy test in female patients. • obtain lead ecg & chest x-ray erect position pa/ap view. rule out life threatening differential diagnosis & manage accordingly. usg abdomen to look for aetiology & possible differential diagnosis. plan to shift patient early to icu. increasing united states hospital admissions for acute pancreatitis trends in the epidemiology of the fi rst attack of acute pancreatitis: a systematic review burden of gastrointestinal disease in the united states: update clinical practice. acute pancreatitis classifi cation and pathogenesis of pancreatitis erythromycin-induced pancreatitis drug-induced pancreatitis: a critical review acute pancreatitis: does gender matter? acute pancreatitis in fi ve european countries: etiology and mortality the changing character of acute pancreatitis: epidemiology, etiology, and prognosis acute pancreatitis classifi cation working group. classifi cation of acute pancreatitis - : revision of the atlanta classifi cation and defi nitions by international consensus multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome the continuing challenge of early mortality in acute pancreatitis fatal outcome in acute pancreatitis: its occurrence and early prediction initial management of acute pancreatitis: critical issues during the fi rst hours detection of gallstones in acute pancreatitis: when and how? clinical considerations and clues to diagnosis epidemiology, natural history, and predictors of disease outcome in acute and chronic pancreatitis the revised atlanta classifi cation for acute pancreatitis: updates in imaging terminology and guidelines decreased mortality in acute pancreatitis related to early aggressive hydration lactated ringer's solution reduces systemic infl ammation compared with saline in patients with acute pancreatitis emergency sedation and pain management meta-analysis: total parenteral nutrition versus total enteral nutrition in predicted severe acute pancreatitis present and future of prophylactic antibiotics for severe acute pancreatitis is early endoscopic retrograde cholangiopancreatography useful in the management of acute biliary pancreatitis? a meta-analysis of randomized controlled trials. dig liver dis key: cord- -h omskec authors: uber, amanda m.; sutherland, scott m. title: acute kidney injury in hospitalized children: consequences and outcomes date: - - journal: pediatr nephrol doi: . /s - - - sha: doc_id: cord_uid: h omskec over the past decade, the nephrology and critical care communities have adopted a consensus approach to diagnosing acute kidney injury (aki) and, as a result, we have seen transformative changes in our understanding of pediatric aki epidemiology. the data regarding outcomes among neonates and children who develop aki have become far more robust and aki has been clearly linked with an increased need for mechanical ventilation, longer inpatient stays, and higher mortality. though aki was historically thought to be self-limited, we now know that renal recovery is far from universal, particularly when aki is severe; the absence of recovery from aki also carries longitudinal prognostic implications. aki survivors, especially those without full recovery, are at risk for chronic renal sequelae including proteinuria, hypertension, and chronic kidney disease. this review comprehensively describes aki-related outcomes across the entire pediatric age spectrum, using the most rigorous studies to identify the independent effects of aki events. acute kidney injury (aki) describes a phenomenon marked by a rapid decline in renal function, reduced elimination of waste products, dysregulated electrolyte and acid-base balance, and impaired fluid homeostasis [ ] . it has become a common complication among hospitalized children and we are fortunate that recent advances in the diagnostic approach have improved our understanding of pediatric aki epidemiology [ ] [ ] [ ] [ ] . acute kidney injury is now clearly associated with poorer early outcomes and those who develop aki frequently experience adverse consequences while hospitalized ( fig. ) [ , [ ] [ ] [ ] . additionally, a connection between aki and long-term sequelae has been established (fig. ) ; persistent renal morbidity and chronic kidney dysfunction are highly prevalent among aki survivors [ ] [ ] [ ] [ ] [ ] [ ] [ ] . our epidemiologic progress has extended to neonatal aki as well which is significant given the unique diagnostic challenges in this population. we know that a neonate's serum creatinine at birth is a reflection of maternal renal function and, depending on gestational age, can take days or weeks to achieve true steady state. additionally, neonates have impaired urinary concentrating ability which can mask oliguria [ ] [ ] [ ] [ ] . however, the last few years have seen tremendous advances in our ability to accurately diagnose and study neonatal aki. in this context, the goal of our review is to comprehensively describe aki-related outcomes across the entire pediatric age spectrum while focusing on studies which have employed a standard, consensus aki definition. when reviewing aki outcome studies, it is essential to interpret the data within the context of several general concepts. understanding these concepts allows one to more effectively compare analyses and extrapolate findings. first, it is important to identify how aki is diagnosed; this has a significant impact on the type of aki events identified and the resultant outcomes. historically, the absence of a standard aki definition hampered our ability to understand aki epidemiology and fully explore aki-related outcomes. in , the acute dialysis quality initiative (adqi) group created the risk, injury, failure, loss, esrd (rifle) criteria, establishing the first consensus approach to aki identification and ushering in the modern era of aki outcomes research [ ] . since then, however, several iterations of rifle have been developed and employed; these include the acute kidney injury network (akin), the pediatric risk, injury, failure, loss, esrd (prifle), and the kidney disease: improving global outcomes (kdigo) classification systems [ ] [ ] [ ] [ ] . although all these definitions have the same foundation, the subtle differences which exist between them can lead to significantly different epidemiologic findings. for example, prifle has been described as more sensitive and akin as more specific, suggesting that the severity of aki identified by the two definitions will be less and more severe, respectively [ ] [ ] [ ] ] . indeed, when the two definitions were applied to the same population, the mortality risk of stage akin defined aki (or . , th ci . - . ) was significantly higher than stage prifle defined aki (or . , th ci = - . ) [ ] . given that kdigo is the most current evolutionary form of the consensus approach, we hope that studies will move towards employing it preferentially as this will allow outcomes to be compared between adults and children, across diseases, and within different patient populations. second, outcomes among children with aki are dependent on the population examined. as an example, one study examined mortality rates among children with stage aki who were and were not receiving critical care; patients who developed aki while in the intensive care unit (icu) had an increased risk of death (likelihood ratio . , th ci . - . ) whereas those on acute care wards did not (likelihood ratio . , th ci . - . ) [ ] . third, aki outcomes tend to be associated with severity of illness. for example, among neonates who experienced encephalopathy, aki was associated with increased length of stay [ ] . however, that effect was mitigated when severity of illness parameters was included in the model, and it is common for those who are most ill to have the poorest aki-related outcomes [ , ] . indeed, one of the most important aspects of aki outcomes research is determining the independent effect attributable to aki itself. the best available data demonstrate that in hospitalized children, aki is associated with increased need for mechanical ventilatory support, longer hospital and icu stays, and higher mortality (fig. ) . despite the aforementioned relationship between disease complexity, severity of illness, and aki, multivariate analysis continues to find that aki is associated with poorer in-hospital outcomes, even after adjusting for disease outcomes among children who develop acute kidney injury (aki). children who develop aki while hospitalized are at risk for poorer short-and mid/long-term outcomes. across both acute and critical care populations, aki is associated with longer lengths of stay, non-recovery of baseline renal function, and chronic renal disease including proteinuria, hypertension, and chronic kidney disease (ckd). children receiving critical care who develop aki are more likely to require prolonged mechanical ventilation support and experienced higher mortality. egfr estimated glomerular filtration rate, los length of stay severity and confounders. this is true not only in children and adolescents, but neonates as well; the independent effects of aki on outcomes have been found across the entire pediatric age spectrum. across nearly all critically ill populations, aki has been associated with an increased need for mechanical ventilation as well as longer a longer duration of support [ , , [ ] [ ] [ ] [ ] [ ] [ ] . for example, the development of aki was associated with . additional days of ventilator support (p < . ) across a general critical care population; notably, those with kdigo stage aki received mechanical ventilation for . additional days (p < . ), suggesting a dose dependent effect [ ] . within a similar population, a single center study found that the development of aki more than doubled the length of mechanical ventilation ( . vs. . days, p < . ) [ ] . the multicenter, prospective assessment of worldwide aki, renal angina, and epidemiology (aware) study, which is the largest such study performed to date, was able to demonstrate a stepwise increase in mechanical ventilation use which correlated with aki severity (table ) ; patients with stage , stage , and stage aki required mechanical ventilation . %, . %, and . % of the time, respectively (vs. no aki at . %) [ ] . the same effect has been seen in neonates; selewski and colleagues demonstrated that neonates who develop aki after experiencing perinatal asphyxia require mechanical ventilation for more days (p < . ) than those who do not develop aki [ ] . aki has also been linked with longer hospital and icu lengths of stay (los). in the original prifle (pediatric rifle or pediatric risk, injury, failure, loss, esrd) study, patients who experienced aki had longer hospital los ( . ± . days vs. . ± . days, p = . ) than those without aki [ ] . this finding is highly relevant since, as previously discussed, prifle is a more sensitive aki definition which identifies milder aki events, underscoring the strength of the association [ , ] . aware corroborated this finding as patients with aki (increase of . - . days, p < . ) and severe aki (increase of . - days, p < . ) had longer icu los even after adjusting for severity of illness (table ) [ ] . this association is also seen in neonates across all gestational ages. two single center reports found that aki increased hospital los among neonates by . days (p = . ) and . days ( th ci . - . ), respectively [ , ] . the first study was performed in term infants experiencing asphyxia (mean gestational age ± . weeks, mean birth weight ± g) [ ] . the second study, which found the larger impact on los, examined aki in very low birth weight (vlbw) neonates (mean gestational age . ± weeks, mean birth weight ± g) [ ] . these two studies not only demonstrate the significance of aki among newborns, they also highlight the influence that the patient population and severity of illness can have on aki related outcomes. importantly, the association between aki and los is evident even in studies focused on non-critically ill children. for example, zappitelli and colleagues examined children receiving acute care who were administered aminoglycosides [ ] . even after adjusting for confounders, children with aki had longer los. this effect was more pronounced for children who experienced more severe aki (stage and ), which again suggests a dose-dependent effect. rheault et al. investigated aki in children admitted with nephrotic syndrome [ ] . they too found that aki was independently associated with prolonged hospitalization. thus, the association between aki and longer los can be found across all pediatric age groups and in both intensive and non-intensive care settings. [ ] . chawla et al. found that aki events were associated with a mortality rate more than double that of myocardial infarctions [ ] . in children, aki has also been independently associated with reduced survival. in a two-center, retrospective study, alkandari et al. found that children admitted to the intensive care unit who developed aki were - times more likely to die than those who did not; those with severe aki (kdigo stage / ) experienced mortality rates that were - times higher, even after adjusting for severity of illness and intergroup differences. [ ] . these findings were corroborated by aware, the aforementioned multicenter, prospective study, which found that kdigo stage / aki was associated with higher mortality even after adjusting for covariates (table ) [ ] . these findings have been extended to neonates by a number of analyses [ , , , [ ] [ ] [ ] . for example, in vlbw infants, aki was associated with a nearly two-fold increased risk of death after adjusting for confounders [ ] ; similar results have been found in term and near term infants [ ] . perhaps, the best illustration of the mortality impact of aki among neonates is the assessment of worldwide acute kidney injury epidemiology in neonates (awaken) study which evaluated the incidence of and outcomes following aki across newborns from pediatric institutions (table ) [ ] . after adjusting for relevant confounders and intergroup differences, aki was associated with a . -fold increased risk for death ( th ci . - . , p < . ) [ ] . it is important to note that in children, the impact of aki on morality has been confined to critically ill patients. in one representative study, aki was significantly associated with higher mortality in the pediatric icu; however, this was not the case in patients receiving acute care (fig. ) [ ] . while the best available data are not yet able to demonstrate a causative effect of aki on survival, it certainly demonstrates that critically ill children who develop aki experience higher mortality independent of underlying disease severity. the data available to date demonstrate that aki is associated with significant adverse short-term consequences. more recently, however, data regarding mid-and long-term outcomes have begun to emerge. we now know that chronic renal dysfunction is common following aki events and proteinuria, hypertension, and chronic kidney disease (ckd) are more highly prevalent among aki survivors than in the general population (fig. ) . moreover, renal recovery, or the lack thereof, seems to play an important prognostic role in children who develop aki in the hospital. renal recovery is a newer concept which remains inconsistently defined, and over the past to years, studies have used different approaches to characterize recovery [ ] [ ] [ ] . indeed, renal recovery has been described as a post-aki nadir serum creatinine of less than mg/dl, a nadir serum creatinine that is less than . x, . x, or . x baseline, a creatinine that is within . mg/dl of baseline, no longer requiring renal replacement therapy (rrt), or no longer meeting any aki criteria [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this has created heterogeneity among the data and complicated our interpretation; however, the data which are available clearly demonstrate the prognostic importance of this outcome concept. given the paucity of data regarding renal recovery in children, it is helpful to examine the relevant adult findings. one french multicenter study found that among , adults with dialysis requiring aki, renal recovery occurred . % of the time [ ]. this is a relatively high rate of recovery, likely reflecting the fact that they defined recovery as no longer needing rrt. long et al. evaluated , adults who experienced aki while receiving either acute or critical care [ ] . overall renal recovery, when defined as a serum creatinine < . x baseline (no longer meeting stage aki criteria), was %. not surprisingly, the study found a dose-dependent effect and recovery was less common as aki severity increased; renal recovery occurred in %, %, and % of adults with stage , stage , and stage aki, respectively. finally, a study of adults undergoing transcatheter aortic valve replacement found that renal recovery, or a lack thereof, carries prognostic implications. of those with aki, % experienced full renal recovery, defined as no longer meeting any stage aki criteria at discharge [ ] . while those with full recovery experienced greater -year mortality (adjusted hr . , th ci . - . ) than those without aki at all, patients with only partial recovery (discharge creatinine > . x baseline but not requiring rrt) experienced even higher -year mortality (adjusted hr . , th ci . - . ). not surprisingly, those who continued to require rrt at discharge had the highest -year mortality risk of all (hr . , rth ci . - . ). pediatric data, though not as extensive, are consistent with the adult findings described above. for example, basu et al. described the post aki course of children who developed aki and required rrt [ ] . when defined as non-dialysis dependence month after aki, renal recovery occurred in % of patients. however, only % of patients had an estimated glomerular filtration rate (egfr) > ml/min/ . m by that time, suggesting that even though many patients may not need rrt indefinitely following aki, a far smaller proportion experience complete recovery. hessey et al. examined pediatric icu admissions and found that the likelihood of recovery was highly dependent on how it was defined [ ] . for example, . % of patients with aki recovered function when it was defined as a discharge creatinine < . x baseline, but recovery only occurred in . % when it was defined as discharge creatinine < . x baseline. hollander et al. examined children who underwent cardiac transplantation and found that % experienced renal recovery (creatinine < . x baseline months after the aki event) [ ] . notably, recovery was more common in the setting of mild aki (stage recovery % vs. stage / recovery %, p < . ), echoing the dose-dependent effect of the adult findings described above. perhaps most interestingly, this study found that non-recovery was a risk factor for the subsequent development of ckd. while none of the patients who survived aki and recovered developed ckd, % of those who did not recover from aki developed ckd (defined as egfr < ml/min/ . m , p = . ). the concept of renal recovery is relatively new and few adult studies and fewer pediatric studies have been performed. in fact, no studies examining recovery in neonates exist at all. however, the data we do have clearly underscore the prognostic relevance of renal recovery and the importance of standardizing the definition. the association between aki and long-term renal sequelae in children has been described for over a decade. one of the earliest studies performed in hospitalized children examined patients with aki (based upon diagnostic coding) and found that proteinuria ( %), hypertension ( %), and an estimated gfr of less than ml/min/ . m ( . %) were common following aki [ ] . buysse and colleagues studied children who developed aki (defined as creatinine x normal value) in the setting of septic shock and found nearly identical rates of hypertension and proteinuria years after the aki event [ ] . hingorani et al. found that aki (defined as a serum creatinine x baseline) increased the risk for ckd (egfr < ml/min/ . m ) by % in children undergoing stem cell transplantation [ ] . mammen et al. reviewed aki survivors (akin stage or greater) - years after icu discharge. they found only moderate rates of hypertension ( . %) and proteinuria ( . %); however, nearly % of these children had an egfr < ml/min/ . m [ ] . although these data are compelling, the studies are plagued by several issues which were well illustrated by a meta-analysis performed in [ ] . this analysis found that the studies performed up to that point had widely variable follow-up timeframes, diagnosed aki in different ways, defined outcomes dissimilarly, and almost universally failed to include a non-aki comparator group. since then, the majority of studies have used a consensus definition for aki, improving our ability to compare findings. additionally, many have compared outcomes between aki and non-aki cohorts. as an example, one such study examined hypertension among children undergoing stem cell transplantation. they found that high blood pressure was common across the entire population; however, aki (defined as doubling of serum creatinine, equivalent to kdigo stage or greater) was associated with a . -fold increased risk for the [ ] . in acute care environments, mortality among children with and without aki was similar regardless of aki severity (p > . ). in children receiving critical care, mortality was higher among children who experienced aki than those who did not. there was a dose-dependent effect as mortality was higher at each successive severity stage. the increases at stage and stage were statistically significant when compared with the prior stage (p < . ). all stages had significantly higher mortality than patients without aki (p < . ) development of hypertension [ ] . menon et al. examined children who developed nephrotoxic aki and found impressively high rates of proteinuria ( . %), hypertension ( . %), and an egfr < ml/min/ . m ( . %) [ ] . when compared with matched non-aki controls, those who experienced aki had significantly lower egfr, more proteinuria, and a higher incidence of hypertension [ ] . there have been two prospective studies performed specifically in the setting of congenital heart disease. the first is a -year follow-up of the translational research investigating biomarker endpoints in aki (tribe-aki) study; the authors found that hypertension ( %), proteinuria ( %), and a egfr < ml/ min/ . ( %) were common following cardiac surgery; however, these sequelae were not more common among the children who experienced perioperative aki [ ] . the second, entitled bfollow-up renal assessment of injury longterm after aki (frail-aki),^compared renal findings in children years after undergoing cardiopulmonary bypass. the aki and non-aki patients had similar rates of proteinuria and hypertension as well as comparable egfrs [ ] . they did note that those with aki had higher urinary levels of il- and liver-type fatty acid binding protein (l-fabp) than non-aki patients and healthy controls; this suggests that patients who experience aki may have subtle evidence of chronic renal injury even in the absence of overt ckd. interestingly, a subsequently published study did find that cardiac surgery-associated aki was associated with a greater risk for ckd stage or greater [ ] . the -year cumulative incidence of ckd for patients with cardiac surgeryassociated aki was %, higher than the % seen in those without aki (adjusted hr . , th ci . - . ). while this study was retrospective in nature, it was large, used a consensus definition for aki, and a rigorous definition of ckd. the data in neonates suffer from similar issues to those described above. namely, the studies describing the relationship between aki and the subsequent development of ckd have been observational, small, focused on specific patient cohorts, and often use disparate diagnostic criteria for both aki and chronic renal dysfunction [ ] . however, chaturvedi et al. examined eight observational studies and noted rates of ckd up to % in various populations; furthermore, proteinuria was seen in - % of patients and hypertension was seen in > % of patients in six of the eight studies analyzed [ ] . one of these studies is particularly relevant because they used a consensus definition for aki (rifle), applied an appropriate definition for ckd, and included a non-aki comparator group [ ] . this analysis, performed by zwiers and colleagues, examined children who underwent extracorporeal membrane oxygenation (ecmo) during the neonatal period; they found that aki was associated with increased risk for the subsequent development of ckd (or . , th ci . - . , p = . ) [ ] . in summary, although we are in need of more rigorous and larger analyses, the studies performed to date clearly suggest that, across the entire pediatric age spectrum, the development of aki puts children at risk for chronic renal disease. over the past decade, we have seen an increase in the quality and generalizability of aki research primarily due to the development of a consensus aki definition. the creation of a standard approach to aki identification has given us a more detailed and accurate understanding of the manner in which aki affects short-and long-term outcomes in children. the best available data now suggest that neonates, infants, children and adolescents with aki will require mechanical ventilation for longer durations, remain in the hospital for greater periods of time, and experience higher mortality. though some work remains to fully develop a consensus definition around renal recovery, we now know that recovery is far from universal, less likely when aki is more severe, and has prognostic implications for long-term renal function. the studies performed to date demonstrate that proteinuria, hypertension, and reduced excretory function are highly prevalent following aki and greatly exceed the rates seen in the general pediatric population. additionally, there seems to be a dose-dependent association between aki and ckd risk. thus, children who develop aki are at risk for long-term renal sequelae and these children warrant long-term observation and monitoring. review questions (answers are provided following the reference list) . true or false? studies which include a more severe phenotype of aki are likely to find a stronger association with poor outcomes? . aki is associated with higher mortality in children who are receiving a. intensive care b. acute care c. both intensive and acute care d. neither intensive or acute care . aki has been associated with a greater risk for chronic renal disease in children who are receiving a. intensive care b. acute care c. both intensive and acute care d. neither intensive or acute care . renal recovery is a. a concept in need of a unifying diagnosis b. less common with more severe aki c. potentially associated with chronic kidney disease d. all of the above conflict of interest the authors declare that they have no conflicts of interest. aki in hospitalized children: comparing the prifle, akin, and kdigo definitions improving global outcomes (kdigo) acute kidney injury work group. kdigo clinical practice guideline for acute kidney injury modified rifle criteria in critically ill children with acute kidney injury acute dialysis quality initiative w ( ) acute renal failure -definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (adqi) group acute kidney injury network ( ) acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury epidemiology of acute kidney injury in critically ill children and young adults aki in hospitalized children: epidemiology and clinical associations in a national cohort acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study acute kidney injury and chronic kidney disease as interconnected syndromes the severity of acute kidney injury predicts progression to chronic kidney disease chronic kidney disease after acute kidney injury: a systematic review and meta-analysis elevated bp after aki long-term risk of ckd in children surviving episodes of acute kidney injury in the intensive care unit: a prospective cohort study - year longitudinal follow-up of pediatric patients after acute renal failure acute kidney injury associated with high nephrotoxic medication exposure leads to chronic kidney disease after months neonatal acute kidney injury update on acute kidney injury in the neonate acute kidney injury in the neonate incidence and outcomes of neonatal acute kidney injury (awaken): a multicentre, multinational, observational cohort study a comparison of the systems for the identification of postoperative acute kidney injury in pediatric cardiac patients acute kidney injury in neonatal encephalopathy: an evaluation of the awaken database acute kidney injury in children incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery: a prospective multicenter study western canadian complex pediatric therapies follow-up g ( ) acute kidney injury after heart transplant in young children: risk factors and outcomes fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry congenital heart surgery in infants: effects of acute kidney injury on outcomes sepsis prevalence o, therapies study i, pediatric acute lung i, sepsis investigators n ( ) acute kidney injury in pediatric severe sepsis: an independent risk factor for death and new disability validation of the kdigo acute kidney injury criteria in a pediatric critical care population acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia recognition and reporting of aki in very low birth weight infants acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: a retrospective cohort study midwest pediatric nephrology c ( ) aki in children hospitalized with nephrotic syndrome acute kidney injury after cardiac surgery according to risk/injury/failure/loss/end-stage, acute kidney injury network, and kidney disease: improving global outcomes classifications association between aki and long-term renal and cardiovascular outcomes in united states veterans epidemiology of acute kidney injury in critically ill patients: the multinational aki-epi study acute kidney injury reduces survival in very low birth weight infants fluid overload and mortality are associated with acute kidney injury in sick near-term/term neonate acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case-control analysis acute kidney disease and renal recovery: consensus report of the acute disease quality initiative (adqi) workgroup renal recovery at different ages renal recovery renal recovery and long-term survival following acute kidney injury after coronary artery surgery: a nationwide study acute kidney injury recovery pattern and subsequent risk of ckd: an analysis of veterans health administration data predicting renal recovery after liver transplant with severe pretransplant subacute kidney injury: the impact of warm ischemia time efficacy and outcomes of continuous peritoneal dialysis versus daily intermittent hemodialysis in pediatric acute kidney injury recovery from acute kidney injury and ckd following heart transplantation in children, adolescents, and young adults: a retrospective cohort study improved long-term survival and renal recovery after acute kidney injury in hospitalized patients: a year experience the association between renal recovery after acute kidney injury and long-term mortality after transcatheter aortic valve replacement renal function follow-up and renal recovery after acute kidney injury in critically ill children long-term health status in childhood survivors of meningococcal septic shock chronic kidney disease in long-term survivors of hematopoietic cell transplant long-term risk of chronic kidney disease and mortality in children after acute kidney injury: a systematic review hypertension in long-term survivors of pediatric hematopoietic cell transplantation kidney outcomes years after pediatric cardiac surgery: the tribe-aki study follow-up renal assessment of injury long-term after acute kidney injury (frail-aki) cardiac surgery in patients with congenital heart disease is associated with acute kidney injury and the risk of chronic kidney disease the path to chronic kidney disease following acute kidney injury: a neonatal perspective ckd and hypertension during long-term followup in children and adolescents previously treated with extracorporeal membrane oxygenation answers: .true; studies which include a more severe phenotype of aki are likely to find a stronger association with poor outcomes? .a key: cord- -bz ui a authors: hans-peter, kapfhammer title: posttraumatic stress disorder in survivors of acute respiratory distress syndrome (ards) and septic shock date: - - journal: psychosom konsiliarpsychiatr doi: . /s - - -x sha: doc_id: cord_uid: bz ui a acute lung injury (ali) and acute respiratory distress syndrome (ards) define medical conditions of acute respiratory insufficiency deriving from direct and indirect damage of the alveolar parenchyma and often associated with multiorgan dysfunction (mods). as a rule, intensive care is based on mechanical ventilation often requiring high doses of sedatives and narcotics. despite major progress in intensive care medicine the rate of mortality is still very high. whereas in the past the level of medical progress has been rated based on the mortality rate alone, the many negative somatic and psychological sequelae in long-term-survivors of ards are only now being appreciated. from a perspective of c/l psychiatry persisting cognitive dysfunctions, anxiety and mood disorders, posttraumatic stress disorders (ptsd) in their negative impact on health-related quality of life are intensively investigated. in the etiopathogenesis of ptsd associated with ali/ards, many influences have to be discussed, e.g., increases in co( ) triggering panic affects, a mismatch of norepinephric overstimulation and cortisol insufficiency, negative effects of high doses of benzodiazepines resulting in oversedation, prolonged phases of weaning and more frequent states of delirium. consolidation and retrieval of traumatic memories of the icu stay are influenced by complex factors. from a clinical point of view prophylactic stress doses of hydrocortisone may reduce the major risk of ptsd associated with ali / ards. abstract acute lung injury (ali) and acute respiratory distress syndrome (ards) define medical conditions of acute respiratory insufficiency deriving from direct and indirect damage of the alveolar parenchyma and often associated with multiorgan dysfunction (mods). as a rule, intensive care is based on mechanical ventilation often requiring high doses of sedatives and narcotics. despite major progress in intensive care medicine the rate of mortality is still very high. whereas in the past the level of medical progress has been rated based on the mortality rate alone, the many negative somatic and psychological sequelae in long-term-survivors of ards are only now being appreciated. from a perspective of c/l psychiatry persisting cognitive dysfunctions, anxiety and mood disorders, posttraumatic stress disorders (ptsd) in their negative impact on health- in the etiopathogenesis of ptsd associated with ali/ ards, many influences have to be discussed, e.g., increases in co triggering panic affects, a mismatch of norepinephric overstimulation and cortisol insufficiency, negative effects of high doses of benzodiazepines resulting in oversedation, prolonged phases of weaning and more frequent states of delirium. consolidation and retrieval of traumatic memories of the icu stay are influenced by complex factors. from a clinical point of view prophylactic stress doses of hydrocortisone may reduce the major risk of ptsd associated with ali / ards. [ ] . in den letzen bis jahren gab es geradezu einen explosionsartigen wissenszuwachs zur pathophysiologie und differenzialtherapie von mods bis hin zur aufdeckung molekularer mechanismen. neben untersuchungen zu akuten krankheitsstadien von ali und ards zeichnen sich die mittel-und langfristigen probleme eines Überlebens aber ebenfalls immer deutlicher ab. auf einer somatischen ebene sind vor allem ein reduziertes körpergewicht, eine eingeschränkte körperliche belastungsfähigkeit, persistierende schmerzsyndrome, neuropathien, heterotrophe ossifikationen, kosmetisch störende narben von tracheostomien, fixierte deformationen an fingern und schulter hervorzuheben [ ] . hiermit assoziierte bedeutsame einbußen in der gesundheitsbezogenen lebensqualität sind im langzeitverlauf zu beachten [ ] . in einer konsiliarpsychiatrischen perspektive sind die vielfältigen psychopathologischen komplikationen, die eine schwerwiegende somatische erkrankung wie ards oder septischer schock sowie deren intensivmedizinische therapiemodalitäten während des aufenthalts auf einer intensivstation begleiten können, seit langem bekannt [ ] . die langfristigen psychosozialen und psychologischen probleme als konsequenzen aus dieser erkrankung und dem notwendigen intensivmedizinischen behandlungskontext werden in studien erst in den letzten jahren zunehmend stärker beachtet. diskutiert wird vor allem eine erhöhte psychiatrische komorbidität hinsichtlich neurokognitiver dysfunktionen, angst-und stimmungsstörungen und speziell posttraumatischer belastungsstörungen. negative interferenzen sowohl mit der gesundheitsbezogenen lebensqualität als auch mit der somatischen morbidität werden erkennbar. einflussfaktoren auf diese komplexen somatopsychischen und psychosomatischen zusammenhänge zeichnen sich erst allmählich ab. dies gilt auch für die erprobung therapeutischer und präventiver interventionsstrategien. Überlebende einer akuten respiratorischen insuffizienz im rahmen eines ali oder ards weisen ein signifikant erhöhtes risiko für anhaltende neurokognitive dysfunktionen im langzeitverlauf auf. hierauf machte bereits eine frühere neuropsychologische studie aufmerksam [ ] . mittlerweile existieren mehrere untersuchungen von unterschiedlichen arbeitsgruppen zu diesem thema. sie bestätigen, dass eine subgruppe von früheren ards-patienten in der tat persistierende kognitive leistungseinbußen zeigt [ ] . die prävalenzzahlen schwanken zwischen einem drittel und ca. drei viertel der Überlebenden eines ards. zahlreiche methodologische probleme erschweren aber die interpretation dieser stark divergierenden häufigkeitsangaben. nicht selten ist die unterscheidung von daten zur prävalenz und zur inzidenz unmöglich, da in den studien nur ausnahmsweise informationen zur prämorbiden kognitiven performanz enthalten sind. dies ist von bedeutung, da in einigen bedingungskonstellationen wie z. b. einer vorbestehenden alkoholabhängigkeit nicht nur ein erhöhtes risiko zu einem ards selbst besteht, sondern auch eigenständig kognitive dysfunktionen assoziiert sein können. ebenso bleibt unklar, ob eher spezifische kognitive leistungsdomänen wie aufmerksamkeit, merkfähigkeit oder exekutivfunktionen oder überwiegend das globale kognitive leistungsvermögen diffus durch den somatischen krankheitsprozess und/oder interferierende therapiemaßnahmen negativ beeinflusst werden. auch wenn zahlreiche variable wie hypoxie, delir, glukosedysregulation, metabolische entgleisung, inflammation, medikamenteneffekte von sedativa und narkotika mögliche und auch wahrscheinliche mechanismen einer vermittlung dieser kognitiven beeinträchtigungen andeuten, ist eine differenzielle ätiopathogenetische bewertung noch nicht möglich. der sich in einigen studien andeutende spezielle zusammenhang von deliranten zuständen während der intensivmedizinischen behandlung und kognitiven defiziten in der langzeitperspektive stellt sich wiederum in anderen untersuchungen nicht so klar dar [ ] . von großer klinischer relevanz allerdings erscheint, dass diese dauerhaften neurokognitiven defizite mit signifikanten einschränkungen der gesundheitsbezogenen lebensqualität, der beruflichen rehabilitation sowie mit beachtlichen ökonomischen kosten einhergehen [ , , ] . nach intensivmedizinischen behandlungen wegen eines ards liegt die inzidenz einer neu auftretenden major depression bei ca. % [ ] , nach sars (severe acute respiratory syndrome im kontext einer infektion mit dem sars-coronavirus) in einem ähnlich hohen umfang [ , ] . die rate an angststörungen, vor allem an panikstörungen ist ebenfalls deutlich erhöht und bewegt sich zwischen bis % [ , ] . in einer konsiliarpsychiatrischen perspektive überwiegen angststörungen eher schon während der unmittelbaren intensivmedizinischen behandlung, während depressive störungen sich erst allmählich gegen ende des aufenthalts auf intensivstation und in der weiteren folge darstellen. nicht selten kann bei letzteren auch bereits prämorbid eine depressive vulnerabilität nachgewiesen werden [ ] . in einer allgemeinen ätiopathogenetischen betrachtung darf nicht allein auf die bedingungen von ali/ ards und intensivmedizinische interventionen fokussiert werden, sondern ist eine multifaktorielle betrachtungsweise zu fordern. somatische folgezustände nach überlebtem ali/ards bedeuten für viele patienten erhebliche funktionsbehinderungen (s. oben). sie können pessimismus, resignation und demoralisierung fördern. sowohl angst als auch depression bewirken im verlauf sehr häufig eine subjektive befundverschlimmerung, ohne dass hiermit auch objektivierbare verschlechterungen der lungenfunktionsparameter einhergehen müssen. sie führen zu einer erhöhten inanspruchnahme von medizinischen einrichtungen und zu einer unnötig intensivierten medikamentösen therapie. die gesundheitsbezogene lebensqualität ist oft gerade infolge persistierender angst und depressivität dramatisch reduziert [ ] . im kontext einer betrachtung von affektiven und vor allem von angst-und panikstörungen nach ali und ards ist in den letzten jahren eine klinische und wissenschaftliche diskussion auch um ein erhöhtes risiko einer posttraumatischen belastungsstörung als möglicher langzeitfolge entstanden. in einer ersten retrospektiven untersuchung wiesen schelling et al. [ ] bei insgesamt patienten ( patienten nach ards und nach septischem schock) ca. jahre nach der erkrankung auf eine prävalenz von ca. % an schweren posttraumatischen stresssyndromen hin. prävalenz und schweregrad der in einem selbstfragebogen (ptss- ) erfassten posttraumatischen stresssymptome korrelierten in dieser studie nicht mit dem schweregrad von ards/septischem schock oder dem ausmaß der assoziierten organdysfunktionen sondern mit der von den patienten nach intensivbehandlung jeweils erinnerten anzahl traumatischer erlebnisse (definiert als angst / panikreaktionen, atemnot, schmerz und alpträume / halluzinationen). patienten mit multiplen (> ) traumatischen erfahrungen während der intensivmedizinischen behandlung zeigten eine signifikant schlechtere gesundheitsbezogene lebensqualität, wobei insbesondere die psychosoziale, weniger die körperliche funktionsfähigkeit der patienten eingeschränkt war. kapfhammer et al. [ ] bestätigten an derselben patientenpopulation in einer nachfolgenden konsiliarpsychiatrischen studie, die sich methodisch auf ein standardisiertes klinisches interview mittels scid sowie auf verschiedene psychometrische tests stützte, im wesentlichen diese zusammenhänge. zum zeitpunkt der entlassung von der intensivstation hatten , % dieser patienten das vollbild einer ptsd, , % wiesen eine sub-ptsd auf. zum follow-up termin acht jahre später zeigte sich bei noch , % das vollbild eines ptsd und bei , % ein sub-ptsd. kein patient ohne posttraumatische symptome bei der entlassung hatte eine ptsd mit verzögerter manifestation entwickelt. bei patienten mit ptsd-vollbild zum zeitpunkt der entlassung persistierte diese störung über die gesamte follow-up zeit und schwächte sich im günstigeren fall in richtung eines sub-ptsd ab. in der psychometrischen testung erzielten die patienten mit dem vollbild einer ptsd durchwegs ungünstigere resultate. die deutlichsten einbussen zeigten sich in der gesundheitsbezogenen lebensqualität (sf- ), der situationsangst (stai-x ) sowie der somatisierung (soms). das ausmaß an koexistenter depressivität (madrs) erschien in dieser gruppe vergleichsweise nur moderat auffällig. kognitive dysfunktionen (skt) waren zwar in einer subgruppe nachweisbar, diskriminierten aber nicht hinsichtlich des ptsd-status. als risikofaktoren für die entwicklung eines ptsd konnten nicht die schwere der somatischen erkrankung (apa-che ii score, lung injury score), aber die anzahl der tage der intensivmedizinischen therapie sowie multiple subjektive traumatische erinnerungen (> alpträume, angst/panik, respiratorischer distress, erstickungsgefühle oder unzureichend behandelte schmerzen) auf intensivstation identifiziert werden. mittlerweile existiert eine reihe weiterer studien aus unterschiedlichen arbeitsgruppen, deren ergebnisse in mehreren systematischen reviews detailliert dargestellt sind [ , , ] . in einer zusammenfassenden beurteilung scheint wenig zweifel daran zu bestehen, dass persistierende symptome eines ptsd mögliche langzeitfolgen nach ali/ards sein können und hiermit erhebliche einschränkungen in der gesundheitsbezogenen lebens-qualität einhergehen. ebenso klar muss aber festgehalten werden, dass große unterschiede in den designs der einzelnen studien, ihr überwiegend retrospektiver charakter, meist nur sehr kleine sample-größen, heterogene messzeitpunkte im hinblick auf den zeitabstand zur intensivmedizinischen behandlung, ein erheblicher verlust von patienten in der perspektive des follow up und damit fragliche generalisierbarkeit der gefundenen ergebnisse hinsichtlich der definierten ausgangsstichprobe, eine häufig unzureichende psychiatrische diagnostik, eine nichtbeachtung von zwischenzeitlichen einflussfaktoren eine realistische einschätzung des ausmaßes eines ptsd nach ali/ ards etwa im vergleich nach exposition gegenüber anderen traumatischen ereignissen noch nicht erlauben. diese zurückhaltung ist auch im hinblick auf diskutierte risikovariablen wie länge des aufenthalts auf intensivstation und krankenhaus, beatmungsdauer, sedierungsgrad, weibliches geschlecht, lebensalter, prämorbide psychopathologie, anzahl traumatischer erinnerungen, verfügbare psychosoziale unterstützung angezeigt [ , ] . Über neurobiologische mechanismen der traumatisierung und der entwicklung eines ptsd jenseits der oft beeindruckenden subjektiven berichte von patienten, an welche traumatische erfahrungen sie sich während einer intensivmedizinischen behandlung erinnern und sowohl in intrusiven tagesbildern als auch in wiederkehrenden alpträumen oft über viele jahre wiedererleben, kann vorläufig nur in ersten ansätzen diskutiert werden. einige aspekte sollen aufgenommen werden. nach der prominenten hypothese von klein [ ] ist das auftreten von panik pathophysiologisch auf einen falschen erstickungsalarm zu beziehen. panikattacken resultieren demnach aus einer abnorm sensitiven reagibilität des medullären chemorezeptorensystems, dem entscheidenden atmungskontrollsystem im hirnstamm auf ein ansteigendes arterielles carbondioxid (co health-related quality of life stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double-blind, single center study indications and practical use of replacement dose of corticoids in critical illness epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study a randomized trial of intermittent lorazepam versus propfol with daily interruption mechanically ventilated patients lung disease. in: levenson jl (ed) textbook of psychosomatic medicine psychiatric morbidity in survivors of the acute respiratory distress syndrome: a systematic review glucocorticoidinduced reduction of traumatic memories: implications for the treatment of ptsd social support during intensive care unit stay might improve mental impairment and consequently health-related quality of life in survivors of severe acute respiratory distress syndrome the pharmacology of oversedation in mechanically ventilated adults connors af ( ) outcomes up to years after severe, acute respiratory failure risk factors for post-traumatic stress disorder symptoms following critical illness requiring mechanical ventilation: a prospective cohort study the prevalence of post traumatic stress disorder in survivors of idu treatment: a systematic review delirium, cognitive dysfunction and posttraumatic stress disorder one-year outcomes in survivors of the acute respiratory distress syndrome quality of life, emotional abnormalities, and cognitive dysfunction in survivors of acute lung injury/acute respiratory distress syndrome longterm neurocognitive function after critical illness neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome post-traumatic stress disorder and posttraumatic stress symptoms following critical illness in medical intensive care unit patients: assessing the magnitude of the problem memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care anpassungsstörung, akute und posttraumatische belastungsstörung posttraumatic stress disorder in long-term survivors of ards: results of a psychiatric follow-up study and psychological tests false suffocation alarms, spontaneous panics, and related conditions: an integrative hypothesis the long-term psychological effects of daily sedative interruption on critically ill patients daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation quality of life and psychological status in survivors of severe acute respiratory syndrome at months postdischarge acute respiratory distress syndrome ahl ström g ( ) severely ill icu patients recall events and unreal experiences of hospital admission and icu stay -- and months after discharge intensive care unit drug use and subsequent quality of life in acute lung injury patients controlled sedation with alphaxolonealphadolone factual memories of icu: recall at two years postdischarge and comparison with delirium status during icu admission --a multicentre cohort study the relationship between cognitive performance and employment and health status in long-term survivors of the acute respiratory distress syndrome: results of an exploratory study psychiatric and psychosocial outcome of cardiac surgery with cardiopulmonary bypass: a prospective -month follow-up study epidemiology and outcomes of acute lung injury short-and long-term followup of intensive care unit patients after sedation with isoflurane and midazolam -a pilot study stressful memories and psychological distress in adult mechanically ventilated intensive care patients -a -month follow-up study post-traumatic stress disorder in somatic disease: lessons from critically ill patients the effect of stress doses of hydrocortisone during septic shock on post-traumatic stress disorder in survivors stress doses of hydrocortisone, traumatic stress, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized trial health-related quality of life and posttrauamtic stress disorder in survivors of the acute respiratory distress syndrome the effect of stress doses of hydrocortisone during septic shock on post-traumatic stress disorder and health-related quality of in life in survivors (eds) handbook of liaison psychiatry epidemiology and treatment of psychiatric conditions that develop after critical illness epidemiology of depression and antidepressant therapy after acute respiratory failure medical post-traumatic stress disorder. catching up with the cutting edge in stress research post-icu consequences of patient wakefulness and sedative exposure during mechanical ventilation stress doses of hydrocortisone reduce chronic stress symptoms and improve healthrelated quality of life in high-risk patients after cardiac surgery: a randomized study posttraumatic stress, anxiety, and depression in survivors of severe acute respiratory syndrome (sars) post-traumatic stress disorder key: cord- -vzn ub authors: thompson, b. taylor; ranieri, v. marco title: steroids are part of rescue therapy in ards patients with refractory hypoxemia: no date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: vzn ub nan rescue therapies for acute respiratory distress syndrome (ards) usually target patients with severe hypoxia and/ or hypercarbia refractory to conventional therapies and are considered when rapid deterioration in the patient's condition over a period of hours suggests an increased risk of death. under these circumstances conventional mechanical ventilation will almost certainly cause additional lung injury if "rescue therapies" are not implemented. inhaled nitric oxide, inhaled epoprostanol, high-frequency ventilation, prone positioning, or immediate cannulation for extracorporeal membrane oxygenation (ecmo) or extracorporeal carbon dioxide removal (ecco r) are often considerations in this setting. three thoughtful views on the value, if any, of rescue therapies were published in intensive care medicine last year [ ] [ ] [ ] . none of these expert commentaries recommended corticosteroids as a rescue option. should they have? are the known effects of corticosteroids on the injured lung likely to reverse or stabilize lung injury in these catastrophically ill patients in a timely way? when confronted with such dramatic cases clinicians should first ensure that the underlying cause of ards has been identified and effectively treatment started, such as appropriate antibiotics and source control for patients with sepsis and prompt management of volume overload for hypervolemic patients. because rescue therapies are, in essence, life support or lung protective measures that do not treat the underlying disease processes leading to these catastrophic cases, intensivists must consider specific causes of ards or ards mimics that may benefit from specific therapies, including corticosteroids. ards mimics should be suspected when no identifiable risk factors for ards are apparent [ ] . examples include severe ards from pneumocystis jiroveci pneumonia presenting as an aids-defining illness, diffuse alveolar hemorrhage from vasculitis, acute hypersensitivity pneumonitis, cryptogenic organizing pneumonia, or acute eosinophilic pneumonia. these uncommon diseases may rarely present with fulminate ards and have specific treatments, including corticosteroids (table ) [ ] [ ] [ ] [ ] . corticosteroids have not been systematically studied as rescue therapy for acute ards, so much of the evidence that bears on this question is indirect. four randomized trials of high-dose steroids for prevention of ards (methyprednisolone at, for example, mg/kg every h for h, or equivalent doses dexamethazone) showed no effect or harm of this therapeutic strategy and were the subject of a contemporary bayesean meta-analysis [ ] . this analysis determined that the probability for an odds ratio of ≥ for developing ards and for death was and %, respectively. these probabilities suggest steroids are ineffective for prevention and probably harmful-although the credible intervals both include . accordingly, treatment with high doses of corticosteroids for short periods early in the course of critical illness has largely been abandoned. recent meta-analyses and a systematic review of studies of lower dose corticosteroids for established ards show substantial heterogeneity of the pooled trials along with short-term improvement in lung physiology and outcomes, including earlier achievement of unassisted breathing [ , , reviewed in ] . additional studies of corticosteroids for patients with ards and sepsis are ongoing and needed (clinical trials.gov identifiers nct and nct ). do these short-term improvements in lung physiology with corticosteroids support their use as rescue therapies? to do so, a relevant improvement of physiological variables would need to be observed in a matter of minutes or hours to "rescue" a patient from fulminant ards. in a recently published study, meduri et al. carefully observed the patterns of response to corticosteroids in patients with established and presumed fibroproliferative ards [ ] . of the patients enrolled in their study, demonstrated a "rapid" response to corticosteroids. unfortunately "rapid" meant that in these responders the partial pressure of arterial oxygen/ fraction of inspired oxygen (pao /fio ) had improved on day following initiation of steroid therapy and that static respiratory system compliance had improved on day . one-third of the patients did not improve at all. similarly, the ards network noted improvement in pao /fio and plateau airway pressure after and days, respectively, of steroid therapy and more rapid liberation from mechanical ventilation [ ] . recent studies of steroids for community acquired pneumonia (cap) also document beneficial acute responses, but the time course is relatively slow for the purposes of immediate rescue. for example, in one study of patients with severe cap the median time to clinical stability was shorter in the steroid group [ . days, interquartile range (iqr) . - . days] than in the placebo group ( . days, iqr . - . days) [ ] , and in a second study of patients with cap, time to treatment failure was reduced but the difference appeared after days [ ] . these encouraging data suggest corticosteroids at lower doses early in the course of pneumonia or ards improve lung function but that the onset of action is too slow and inconsistent and the magnitude of the effect too small to be recommended as a reliable life-saving rescue therapy. furthermore, corticosteroids have been associated with late complications, such as secondary infections and new shock [ , ] . because of the modest, delayed, and inconsistent physiologic improvement observed with the use of corticosteroids for ards and cap and the concern for late complications, we do not recommend the use of corticosteroids as rescue therapy for patients with immediately life-threatening early ards. clinicians should remain vigilant for steroid-responsive diseases that may masquerade as ards, especially in patients without identifiable risk factors for the syndrome of ards. some of these patients will require corticosteroids and other diseasespecific treatments for optimal outcomes. table steroid-responsive conditions which may present with severe acute respiratory distress syndrome some diseases, such as granulomatosis with polyangiitis leading to diffuse alveolar hemorrhage, require additional immunosupressive treatment with cyclophosphamide or rituximab [ ] . other conditions require removal of the offending antigen [heat shock proteins (hsp); asparagine endopeptidase (aep)]. acute interstial pneumonia (hamman rich) is often treated with corticosteroids but efficacy has not been established ards acute respiratory distress syndrome acute eosinophilic pneumonia (aep) diffuse alveolar hemorrhage from vasculitis crytogenic organizing pneumonia acute hypersensitivity pneumonitis (hsp) pneumocystis jiroveci pneumonia complicating human immunodeficiency virus (hiv) nonspecific interstitial pneumonitis and pneumonitis associated with connective tissue disease rescue therapy for refractory ards should be offered early: yes rescue therapy for refractory ards should be offered early: no rescue therapy for refractory ards should be offered early: we are not sure acute respiratory distress syndrome mimickers lacking common risk factors of the berlin definition acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure corticosteroids as adjunctive therapy for severe pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome pathogenesis and treatment of anca-associated vasculitides corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ards) in adults: meta-analysis prolonged glucocorticoid treatment is associated with improved ards outcomes: analysis of individual patients' data from four randomized trials and trial-level meta-analysis of the updated literature steroids for acute respiratory distress syndrome? corticosteroid rescue treatment of progressive fibroproliferation in late ards. patterns of corticosteroid rescue treatment of progressive efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome adjunct prednisone therapy for patients with community acquired pneumonia: a multicentre, doubleblind, randomised, placebo-controlled trial effect of corticosteroids on treatment failure among hospitalized patients with severe communityacquired pneumonia and high inflammatory response: a randomized clinical trial hydrocortisone therapy for patients with septic shock key: cord- -vs yondw authors: dere, willard h. title: acute bronchitis: results of u.s. and european trials of antibiotic therapy date: - - journal: am j med doi: . / - ( ) -e sha: doc_id: cord_uid: vs yondw acute bronchitis, an illness frequently encountered by primary-care physicians, is an inflammation of the tracheobronchial tree that results from a respiratory tract infection. it is characterized by persistent cough and sputum production and is occasionally accompanied by fever and/or chest pain. acute bronchitis may have a viral or bacterial origin and is often treated with antibiotics. four clinical trials were conducted to compare high and low doses of loracarbef, a new oral β-lactam antibiotic, with three agents commonly used to treat acute bronchitis: amoxicillin/clavulanate, cefaclor, and amoxicillin. results of these studies indicated that loracarbef, and mg twice daily, had clinical and bacteriologic efficacy against the common respiratory pathogens streptococcus pneumoniae, haemophilus influenzae, and moraxella (branhamella) catarrhalis that was comparable with that of the comparative agents. loracabef was as well tolerated as cefaclor and amoxicillin; moreover, it produced a significantly lower incidence of diarrhea than did amoxicillin/clavulanate. loracarbef may be considered a safe and effective alternative agent for the treatment of patients with acute bronchitis. a cute bronchitis, an illness frequently encountered by primary-care physicians [ ] , is an inflammation of the tracheobronchial tree that results from respiratory tract infection [ ] . viruses as well as bacterial respiratory pathogens have been implicated in the etiology of acute bronchitis. unfortunately, however, the identification of specific causative agents has been hampered by difficulties in obtaining reliable sputum samples for culture [ , ] ; as a result, there is considerable controversy regarding the best course of treatment for this condition. patients with acute bronchitis that is suspected to be of viral origin are often treated with acetaminophen [ ] and cough suppressants [ ] for symptomatic relief. when bacterial origin is either suspected or documented, antibiotics are routinely used for treatment [ , ] . newer antibiotics are currently being tested to determine their efficacy against such illnesses as acute bronchitis. this article reviews the etiology and treatment of acute bronchitis as well as the safety and efficacy results of four clinical trials designed to compare a new fllactam antibiotic, loracarbef, with agents currently used as therapy for patients with this condition. patients with acute bronchitis generally have a persistent cough that is usually accompanied by sputum production and occasionally by fever, chest pain, or both. these symptoms develop quickly and are usually preceded by an upper respiratory tract infection [ ] [ ] [ ] [ ] [ ] . such factors as the age and general health of the patient, climate, exposure to air pollutants, and cigarette smoke contribute to the onset and severity of the illness [ , , ] . the etiologic agents most likely to cause bronchitis vary with the age of the patient. viral pathogens include respiratory syncytial virus, parainfluenza virus, rhinovirus, and influenza virus [ ] [ ] [ ] as well as adenovirus [ , ] , coronavirus [ , ] , and rubeola virus [ ] . the extent to which bacterial infection is implicated in the development of acute bronchitis is controversial, in part because it is difficult to obtain sputum samples that are not contaminated with bacteria normally present in the nasopharyngeal tracts of healthy persons. nevertheless, it is generally agreed that bacterial invasion may cause or prolong the illness. it is now recognized that mycoplasma pneumoniae [ , ] and bordetella pertussis [ ] are potential primary etiologic agents of acute bacterial bronchitis. common respiratory bacteria, such as streptococcus pneumoniae, haemophilus influenzae, and staphylococcus aureus may be responsible for secondary bacterial infections. additional bacterial pathogens, such as moraxella (branhamella) catarrhalis and chlamydia psittaci, may also play a role in the development of acute bronchitis. to date, there have been only five randomized, placebo-controlled trials conducted to assess the efficacy of antibiotic therapy in acute bronchitis [ ] [ ] [ ] [ ] [ ] . results of these trials were mixed. in addition, their significance is unclear because rigorous diagnostic criteria for sputum purulence, pathogen isolation, and pathogen susceptibility testing were not applied, and four of the five studies had small sample sizes. nevertheless, two of the studies [ , ] demonstrated a benefit for patients who received treatment: in both, symptoms improved and sputum production decreased, and in one, days lost from work also decreased [ ] . results of another study suggest that patients with chronic obstructive pulmonary disease and the associated risk factors of dyspnea, increased sputum production, and sputum purulence constitute a subgroup of patients with acute bronchitis who derive the greatest benefit from antibiotic therapy [ ] . it has been estimated that > % of patients with acute bronchitis are treated with antibiotics [ ] . historically, the most commonly used antibiotics have included erythromycin, tetracycline, and amoxicillin as well as ampicillin, trimethoprim/ sulfamethoxazole, and cefaclor [ ] . additional drugs are currently being developed to enhance the efficacy and improve the safety of treatment of these patients. loracarbef, a member of the carbacephem class of fi-lactam antibiotics, is a new oral agent that can be administered twice daily. the carbacephems are chemically similar to the cephalosporins except that a sulfur atom has been replaced by a methylene group, which changes the dihydrothiazine ring of the cephalosporin nucleus to the tetrahydropyridine ring of the carbacephem nucleus. this substitution confers greater stability to the carbacephems [ , ] . loracarbef has activity against a wide range of gram-positive and gram-negative bacterial pathogens [ , ] , including those thought to play a role in acute bronchitis. four clinical trials (two in the united states, two in europe) were initiated to study the relative effectiveness of loracarbef in treating acute bronchitis. each trial was designed as a two-arm, randomized, parallel study comparing the efficacy of loracarbef with that of another antibiotic frequently used for treating acute bronchitis. the first study compared high-dose loracarbef ( mg twice daily) with amoxicillin ( mg three times daily) (dere wh, unpublished data, ) . the second trial compared low-dose loracarbef ( mg twice daily) with amoxicillin ( mg three times daily) [dere wh, unpublished data, ] . of the remaining two trials, one compared low-dose loracarbef with the standard dose of cefaclor ( mg three times daily) [ ] , and the other compared high-dose loracarbef with the standard dose of amoxicillin/clavulanate ( / mg three times daily) [ ] . all regimens were administered for days. to be enrolled in any of these four studies, patients were required to have a diagnosis of acute, purulent bacterial bronchitis. all of the patients had a cough that was productive of purulent sputum as confirmed by microscopic examination (>- white blood cells and < epithelial cells per highpower field). furthermore, to ensure that the infection was acute, patients were required to have experienced a rapid onset of symptoms within days of enrollment in the study. patients who were diagnosed as having chronic bronchitis or who had an infiltrate on chest radiograph, renal impairment, or hypersensitivity to fi-lactams were excluded from these trials. pregnant and nursing women were also not eligible. more than , patients were enrolled in the four studies: a total of received high-dose loracarbef, received low-dose loracarbef, received amoxiciuin/clavulanate, received cefaclor, and received amoxicillin [ , ; dere wh, unpublished data, ] . many of the patients enrolled in these clinical trials did not qualify for clinical and bacteriologic evaluation; disqualification in most cases occurred because pretherapy evaluation of sputum cultures did not yield a known respiratory pathogen. of patients who were considered evaluable, % had pure or mixed cultures positive for one of the following four organisms: h. influenzae, s. pneumoniae, m. catarrhalis, and haemophilus parainfluenzae ( table |) . resistance of respiratory pathogens to the antibiotics used was uncommon in both treatment groups in all four studies (table ii) [ , ; dere wh, unpublished data, ] . these low rates of resistance to loracarbef, amoxicillin/clavulanate, and cefaclor were not unexpected; surprisingly, however, the level of resistance to amoxicillin, particularly of h. influenzae, although higher than for the other agents, was also relatively low. the explanation may likely be that the studies involving the amoxicillin treatment groups took place in europe, where the prevalence ofh. influenzae resistance to amoxicillin is generally lower than it is in the united states [ ] . to determine the clinical and bacteriologic responses to antibiotic therapy, patients were evaluated within days (posttherapy) and then - days (late-posttherapy) after the drugs were discontinued. the results of these studies are shown in table ii ] [ , ; dere wh, unpublished data, ] . from these data, it is clear that clinical and bacterial responses to both high-dose and low-dose loracarbef were virtually identical. in addition, loracarbef had comparable clinical and bacteriologic efficacy to each of the comparative agents. the relative safety of loracarbef in comparison with the other antibiotics was also addressed in these studies. in the study comparing loracarbef with amoxicillin/clavulanate, a similar proportion of patients in each group reported experiencing nausea, vomiting, or both as well as rash or other cutaneous manifestations of hypersensitivity (table iv) [ ] ; the proportions of patients who discontinued therapy were also comparable. however, a significantly greater number of patients in the amoxi- cephalothin disk was used to test susceptibility to cefaclor. mpicillin was used to test susceptibility to amoxicillin. data from [ , ; dere wh, unpublished data, ] . cillin/clavulanate group reported experiencing diarrhea. in the study in which loracarbef was compared with cefaclor, the safety profiles of the two drugs were similar for all event categories ( table v) [ ] . this was also true for adverse reactions reported by patients who received treatment with high-dose loracarbef, low-dose loracarbef, or amoxicillin (table vi) [dere wh, unpublished data, ] . in summary, recent clinical trials designed to evaluate the use of loracarbef in treating acute bronchitis have shown that loracarbef had clinical as well as bacteriologic efficacy similar to that of the comparative drugs against such major respiratory pathogens as h. influenzae, m. catarrhalis, ; posttherapy evaluation occurred days after therapy was discontinued; late posttherapy, - days after therapy was discontinued. "clinical success" refers to elimination of or improvement in symptoms. ~b'bacteriologic success" refers to documented elimination or presumed elimination (in patients who had clinical success and a repeat culture was not possible or indicated--sputum production resolved) of the pathogen. §high-dose ioracarbef = mg twice daily; low-dose ioracarbef = mg twice daily. data from [ , ; dere wh, unpublished data, ] . . * . nausea and/or vomiting . * . rash and related terms . patients discontinuing . due to an adverse event *one patient who reported experiencing nausea, vomiting, and diarrhea is recorded in both the categories "diarrhea" and "nausea and/or vomiting." adapted with permission from [ ] . most common adverse events emerging during therapy with amoxicillin vs. high-dose and low.dose loracarbef acute bronchitis: aetiology, symptoms and treatment respiratory infections in ambulatory adults. choosing the best treatment pleuropulmonary and bronchial infections gooch wm bronchitis and pneumonia in ambulatory patients management of acute and chronic respiratory tract infections rapid noninvasive techniques for determining etiology of bronchitis and pneumonia in infants and children the treatment of acute bronchitis with trimethoprim and sulfamethoxazole a placebo-controlled, double-blind trial of erythromyein in adults with acute bronchitis randomised controlled trial of antibiotics in patients with cough and purulent sputum a randomized, controlled trial of doxycycline in the treatment of acute bronchitis erythromycin in the treatment of acute bronchitis in a community practice antibiotic therapy in exacerbations of chronic obstructive pulmonary disease -sulfonyi-l-carba-l-dethiacephems -quaternary ammonium -carba- -dethiacephems loracarbef (ly ) versus cefaelor in the treatment of acute bacterial bronchitis loracarbef (ly ) versus amoxicillin/clavulanate in the treatment of acute purulent bacterial bronchitis antimicrobial resistance in haemophilus influenzae: a global perspective and s. pneumoniae. the clinical and bacteriologic efficacy rates of both low-dose and high-dose loracarbef were virtually identical. loracarbef had an excellent safety profile comparable with that of cefaclor or amoxicillin; in comparison with amoxicillin/clavulanate, a significantly lower incidence of diarrhea occurred with loracarbef. therefore, loracarbef may be considered a safe and effective alternative agent for the treatment of patients with acute bacterial bronchitis. key: cord- -lrzzak l authors: marres, h. a. m. title: keel-, neus-, oorziekten date: - - journal: codex medicus doi: . / - - - - _ sha: doc_id: cord_uid: lrzzak l hypertrofie van het lymfoïde weefsel in de nasofarynx. een van de meest voorkomende aandoeningen op de kleuterleeftijd. vanaf de schoolleeftijd minder frequent door involutie van het adenoïd. aet. recidiverende infectie. sympt. . neussymptomen a. belemmerde neusademhaling, waardoor open mond, snurken, onrustig slapen, kwijlen, vaak slechte eetlust en gesloten neusspraak. stemverlies. daarnaast onder suggestieve beïnvloeding 'stem teruggeven'. de stemplooien 'recht zetten' door vanuit hoesten met stem in e en ononderbroken zitting de patiënt weer tot foneren en daarna tot spreken met stem te brengen. het is van belang de behandeling snel in te zetten, omdat anders fixatie in het gedrag plaatsvindt. soms is psychotherapie noodzakelijk. allergologisch onderzoek bij rinitis . anamnese vragen naar klachten, zoals niezen, jeuk in de neus, waterige secretie en verstopping, naar verband hiervan met expositie aan allergenen (o.a. invloed van behuizing en werk, contact met dieren, seizoengebondenheid), naar andere manifestaties (conjunctivitis, astma, constitutioneel eczeem) en familie. bij inspectie van de neusholte wordt meestal een livide en gezwollen mucosa aangetroffen. . intracutane huidproeven bepaling van huiddrempelwaarden met verdunningsreeksen van extracten met atopische inhalatie-allergenen zoals huisstofmijten, pollen en dierlijke epidermale producten. . bepaling van specifieke ige-titers in het serum (rast, zie hoofdstuk : allergeenspecifieke ige-antistofbepaling). . neusprovocatie er wordt verschillend geoordeeld over de betekenis van deze proef. behalve bepaling van de allergeendrempel is ook histaminebepaling (hyperreactiviteit) nodig. . onderzoek van neusslijm en bloed op eosinofilie alleen aanwezig bij voldoende expositie aan allergeen. niet specifiek voor atopie. angiofibroom, zie *neus-keelfibroom. anosmie en hyposmie uitval c.q. vermindering van de reuk. twee vormen. . geleidingsanosmie verlies van reuk doordat de reukprikkel het in de bovenste neusgang gelegen reukepitheel niet kan bereiken als gevolg van afwijkingen in de neus. aet. rinitis, neuspoliepen, allergische rinopathie, vasomotore rinopathie, septumdeformatie, eventueel neustumor. diagn. na afslinken (bijv. met lidocaïne- % en adrenaline- %) is de reuk beter. th. causale behandeling. . perceptieanosmie verlies van reuk doordat het reukzintuig en/of de centrale reukbanen en reukcentra zijn aangedaan. aet. a. reukzintuig: virusinfectie (bijv. influenza) , trauma, eventueel operatie. b. fila olfact: trauma (verscheuring fila, fractuur van de l. cribrosa), meningeoom. c. centraal: tumor van de frontaalkwab. diagn. reuktest, mri-scan. th. meestal niet mogelijk. progn. bij infectieuze anosmie kan gedeeltelijk of geheel herstel optreden. articulatiestoornissen, zie *spreekstoornissen. dislocatie van het arytenoïd. aet. onjuiste intubatie, uitwendig trauma. sympt. heesheid, pijn, soms slikstoornissen. th. repositie. meestal blijvende heesheid. spreekstoornis waarbij spraakklanken, lettergrepen en woorden niet of gedeeltelijk worden gearticuleerd. aet. slechte articulatiemotoriek en akoestische controle. taalzwakte. sympt. slechte articulatie, overhaast spreken, vaak herhalingen, slechte woordkeus. diff. differentiatie met stotteren kan moeilijk zijn. th. spraak-taalonderwijs. bijholteonderzoek . kloppijn sinus maxillaris en sinus frontalis. . drukpijn op uittreedplaats van nn. infraorbitales en supraorbitales. vooral l-r-verschil belangrijk. . doorlichting (diafanoscopie) a. sinus maxillaris: lampje in de mond (bovenprothese verwijderen!) en het oplichten van wang en oog beoordelen en uitdrukken in cijfers, bijv. van t/m . b. sinus frontalis: lampje onder tegen de supraorbitaalrand. . sinusscan. . r€ ontgenfoto a. volgens tschebull: beoordeling van sinus maxillaris, etmoïd en sfenoïd. b. volgens steenhuis: beoordeling van sinus frontalis en etmoïd. c. zijdelings: beoordeling van sinus frontalis en sfenoïd. . ct-scan (coronaal, axiaal). . proefpunctie en spoeling sinus maxillaris via onderste neusgang. . antroscopie met koudlichtoptieken via onderste neusgang of fossa canina. . exploratie bij verdenking op een maligne proces. te verdelen in carcinoom van mobiele tong, van de mondbodem en van de wangmucosa. aet. chronische prikkeling (tabak, alcohol) , soms leukoplakie als voorstadium. hist. plaveiselcelcarcinoom. sympt. pijnlijk, nietgenezend ulcus. vroege metastasering naar regionale klieren (kaakhoek en jugulair). halitose (zie ook hoofdstuk : halitose), vermagering. th. bij beperkter proces operatie (ruime excisie, hemiglossectomie). vaak is ook homolaterale halsklierresectie noodzakelijk. bij grote uitbreiding combinatietherapie van chirurgie en postoperatieve radiotherapie. progn. bij vroegtijdige ontdekking - % vijfjaarsoverleving, bij gevorderde stadia - % vijfjaarsoverleving. carcinoom van de hypofarynx en postcricoïd carcinoom voork. hypofarynxcarcinoom: meestal bij mannen van middelbare en oudere leeftijd. voorkeurslokalisatie is de sinus piriformis. postcricoïd carcinoom: meer bij vrouwen. aet. bekende factoren zijn: alcohol, roken, gebruik van prikkelende spijzen en dranken, vroegere r€ ontgenbestraling in het halsgebied (wegens tuberculeuze halslymfomen); bij vrouwen soms plummervinsonsyndroom als voorstadium. sympt. slikklachten, pijn (uitstralend naar het oor), vooral bij eten en drinken van zure en prikkelende spijzen, progressieve vermagering, halskliermetastasen (jugulair), heesheid door ingroei in larynx of stilstaande larynxhelft. diagn. laryngo-oesofagoscopie met biopsie. r€ ontgenonderzoek. diff. globusgevoel, dyskinesie van de oesofagus; oesofagusdivertikel. th. radiotherapie al of niet met chemotherapie. resectie van hypofarynx c.q. cervicale oesofagus meestal met laryngectomie in uitgebreide gevallen. progn. tot % vijfjaarsoverleving. freq. meest frequente maligne tumor in het hoofd-halsgebied, ca. % van alle maligne tumoren. sterke voorkeur voor het mannelijk geslacht (verhouding man:vrouw is : ), het frequentst tussen en jaar. aet. vooral roken. soms leukoplakie als voorstadium. hist. in meer dan % van de gevallen is sprake van een plaveiselcelcarcinoom. meestal goed of matig gedifferentieerd. zelden anaplastisch carcinoom of sarcoom. indeling (tnm-classificatie) . naar lokalisatie: a. glottisch carcinoom, frequentst ( %), b. supraglottisch carcinoom, (ca. %), c. subglottisch carcinoom (ca. %). . naar uitbreiding. carcinoom van de larynx, glottisch carcinoom, uitgaande van de ware stemplooi. sympt. heesheid: zeer vroeg optredend verschijnsel dat gedurende zeer lange tijd het enige symptoom kan blijven. bij uitbreiding stridor, dyspnoe en slikklachten. regionale kliermetastasen (jugulair); de metastasen treden relatief laat op doordat plicae vocales geen lymfevaten bevatten, ook metastasen op afstand pas in een laat stadium. diagn. indirecte en directe laryngoscopie, beoordeling van uitbreiding van de tumor en beweeglijkheid van de aangedane larynxhelft, biopsie, r€ ontgenonderzoek (ct-scan, mri), algemeen onderzoek. t : beperkte tumor, normaal bewegende stemplooi, geen metastasen. t : tumor uitgebreid in omgeving (andere stemplooi, andere etage, stemplooi minder beweeglijk). t : stilstand stemplooi maar de tumor blijft tot de larynx beperkt. t : doorgroei in larynxskelet. th. en progn. curatief stadium : bij beperkte tumoren chirurgische excisie (meestal door laserchirurgie), anders bestraling; prognose goed ( % vijfjaarsoverleving). zie ook hoofdstuk : bestralingen hoofd-halsregio. t en t : bestraling; indien dit onvoldoende resultaat geeft operatie, meestal laryngectomie. soms is partiële laryngectomie mogelijk. t : operatie in combinatie met bestraling. regionale kliermetastasen (groter dan cm) vereisen radicale halsklierextirpatie (resectie en block van m. sternocleido, m. sternocleidomastoideus, vena jugularis interna en supraclaviculair, jugulair en submandibulair klier-en vetweefsel). indien aan beide zijden nodig, dan ten minste een interval van enige weken aanhouden of aan een zijde de vena jugularis sparen. palliatief bestraling, tracheotomie, voedingssonde. carcinoom van de larynx, supraglottisch carcinoom, uitgaande van de valse stemplooien, de arytenoïden, de plica aryepiglottica of de laryngeale zijde van de epiglottis. sympt. pijn is het frequentste eerste verschijnsel (spontane pijn en slikpijn, vaak uitstralend naar het oor); slikstoornissen, heesheid, regionale kliermetastasen (jugulair) treden relatief vroeg op. diagn. als bij glottisch carcinoom. th. en progn. curatief kleine tumor: bestraling ( - gy) of operatie (partiële laryngectomie). grote tumoren met invasie in het larynxskelet: laryngectomie of supraglottische hemilaryngectomie, in combinatie met bestraling. vaak ook radicale halsklierextirpatie nodig. progn. gunstig voor de kleine vroeg ontdekte tumoren. vaak echter late diagnose, daardoor in het algemeen matig (ca. % vijfjaarsoverleving). palliatief als bij glottisch carcinoom. carcinoom van de neusbijholten . sinus maxillaris tumoren van: a. infrastructuur (bodem, processus alveolaris), b. mesostructuur, c. suprastructuur. . etmoïd. . sinus frontalis en sfenoïd (zeldzaam). aet. onbekend. chronische prikkeling speelt waarschijnlijk een rol (bij houtbewerkers veel adenocarcinoom). hist. plaveiselcelcarcinoom, adenocarcinoom, anaplastisch carcinoom, sarcoom (fibro-, chondro-) nonhodgkinlymfoom. voork. veelal op middelbare leeftijd, echter ook bij jonge kinderen (dan veelal sarcoom, rabdomyosarcoom); vaker bij mannen dan bij vrouwen. sympt. pijn is het frequentste eerste verschijnsel, vaak van neuralgisch karakter. zwelling, afhankelijk van de lokalisatie: processus alveolaris, palatum, wang, mediane ooghoek, oogbolverplaatsing (vaak eerste symptoom van etmoïdproces). eenzijdige purulente neussecretie als gevolg van secundaire infectie, vaak gemengd met wat bloed, soms fetide. metastasering zowel in regionale klieren als op afstand treedt relatief laat op. diagn. biopsie, eventueel via proefexploratie van de bijholte; ct-scan en mri-scan. th. operatie (extirpatie via laterale rinotomie of bovenkaakresectie) in combinatie met bestraling. evt. lokale applicatie van cytostatica (volgens sato). bij nonhodgkinlymfoom cytostatica, evt. ook alleen bestraling. progn. tot % vijfjaarsoverleving. neuralgie in het gebied van neuswortel en nasale ooghoek; eventueel rinitisverschijnselen en tranend oog. aet. prikkeling van n. nasociliaris door afwijking etmoïd, concha-mediacompressie. sympt. pijn mediane. ooghoek, neuswortel. vasomotore rinopathie en (kerato)conjunctivitis. diagn. vermindering van de pijn na anesthesie van de homolaterale neusholte. th. zo mogelijk causaal; septumcorrectie, concha-mediacorrectie, etmoïdchirurgie. afsluiting van de achterste neusopening. de afsluiting kan benig of vliezig zijn en komt zowel aan e en als aan beide zijden voor. aet. meestal congenitaal, in % als onderdeel van een syndroom, zoals het charge-syndroom en het treacher-collinssyndroom. incidentie: op de - geborenen. soms later ontstaan als gevolg van operatie of ontsteking. sympt. volledig opgeheven neuspassage aan e en of beide zijden (bij pasgeborenen leidt dit tot grote problemen bij de voeding omdat voor het drinken neusademhaling vereist is), ophoping van mucopurulent neussecreet. deze specifieke bevindingen zijn zeer suggestief voor een choanaalatresie. diagn. sonderen, r€ ontgenfoto's met contrastmiddel in liggende houding, ct-scan. th. operatie: . endonasaal, een opening maken, waarin gedurende weken een siliconrubberen buis wordt achtergelaten; . transpalatinaal benaderen van de choane en de afsluiting reseceren. solitaire, meestal uit de sinus maxillaris afkomstige, grote poliep die zich uitbreidt in de choane en soms tot in de orofarynx. vooral bij volwassenen. corpus alienum in de (hypo)farynx graten, splinters, spelden e.d. blijven gemakkelijk in farynx en hypofarynx steken; vooral in tonsil, zijstrengen en sinus piriformis. de anamnese is meestal duidelijk: tijdens of aansluitend op maaltijd wordt een pijnlijke steek ervaren waarna het slikken moeilijker is of zelfs onmogelijk. sympt. pijn, spontaan en bij slikken, vaak uitstralend naar het oor, speekselvloed. bij lokalisatie in de sinus piriformis vaak pijn bij draaien van het hoofd. soms blijft het voorwerp niet steken, maar veroorzaakt het bij doorslikken een laesie. de klachten zijn dan dezelfde doch nemen geleidelijk af. diagn. faryngoscopie. eventueel r€ ontgenfoto. th. verwijdering in direct beeld, spiegelbeeld of per endoscopie. verwijdert men het voorwerp niet, dan ontstaat meestal een ontstekingsreactie. deze kan leiden tot spontane uitstoting door ontsteking en necrose van het omgevende weefsel of tot uitgebreide flegmone van hals en mondbodem. vreemd voorwerp waardoor ontsteking, ulceratie en granulatie van het neusslijmvlies ontstaan. meestal bij kinderen. indien langdurig bestaand kan zich door afzetting van zouten rondom het corpus alienum een zgn. rinoliet vormen. sympt. indien niet opgemerkt ontwikkelt zich geleidelijk het beeld van purulente eventueel fetide neussecretie (soms met wat bloed gemengd) aan e en zijde, en neusverstopping; soms bloeding vanuit granulaties. th. de techniek van verwijding is afhankelijk van patiënt (leeftijd) en aard van het voorwerp. een vers corpus alienum kan meestal na lokale anesthesie met een speciaal instrument (niet met pincet!) worden verwijderd. zo nodig onder narcose. deformatie benig neusskelet . scheefstand van het benige neusskelet scheefstand van de benige neuspiramide. aet. vrijwel altijd het gevolg van recent of oud trauma. sympt. behalve scheefstand ook meestal kanteling van de ossa nasalia. het bot aan de zijde waarnaar de scheefstand is gericht is naar binnen gekanteld (geïnfracteerd). vrijwel altijd gecombineerd met septumdeformatie. diagn. vooral palpatoir. r€ ontgenfoto's zijn bij acute fractuur zelden zinvol. th. chirurgische correctie door osteotomieën, waarna repositie, in combinatie met septumcorrectie. . benige zadelneus inzakking van het benige neusdorsum, meestal met septumdeformatie. aet. ernstig neustrauma, septumabces in de jeugd, congenitaal, lues iii. sympt. cosmetische bezwaren, verminderde neuspassage. aanwezige afwijkingen van septum en ostium internum. th. chirurgische reconstructie van septum en subcutane transplantatie van eigen of donorkraakbeen of -bot. . benige knobbel benige verhevenheid van het benige neusdorsum, meestal in de mediaanlijn. aet. hereditair; excessieve botvorming na vroeger trauma. sympt. cosmetische bezwaren, verminderde neuspassage. th. chirurgische correctie. deformatie kraakbenig neusskelet . scheefstand van het kraakbenige dorsum deviatie van de kraakbenige neusrug, gewoonlijk door septumdeformatie. vaak gecombineerd met misvorming van de triangulaire kraakbeentjes. aet. vrijwel altijd trauma; vaak klein trauma in de jeugd waardoor geleidelijke groeimisvorming. sympt. verminderde neuspassage (septum, klep); cosmetische. soms ook deviatie van het benige dorsum (in dezelfde of in tegenovergestelde richting, c-vorm of omgekeerde c-vorm). th. chirurgische correctie met correctie van het septum en eventueel van de benige piramide indien ( e enzijdige) neusobstructie aanwezig is of er sprake is van scheefstand. . kraakbenige zadelneus inzakking van het kraakbenige neusdorsum. aet. septumabces, cocaïnegebruik, septumcorrectie waarbij te veel van het kraakbenig septum is gereseceerd, trauma. sympt. cosmetische; gestoorde neuspassage (septumdeformatie, klep). th. septumreconstructie; met transplantatie van eigen of donorkraakbeen in neusdorsum. . neuspuntdeformatie misvorming en/of asymmetrie van de neusvleugelkraakbeentjes door aanlegstoornis (bij labioschisis en mediane neusfusiestoornis) of door trauma in de jeugd, waardoor uitgroeistoornis. th. chirurgische correcties. ontstaan van een dubbele toon bij foneren. aet. organische afwijking waardoor de stemplooi in twee gedeelten wordt gedeeld die afzonderlijk trillen. bijv. noduli vocales, stemplooipoliep. gestoorde stemgeving door onregelmatige stemplooitrillingen of gestoorde stemplooisluiting. het door de glottis geproduceerde basisgeluid heeft niet het karakter van een heldere toon, maar meer dat van een ruis of een toon met een ruw of korrelig aspect. overweegt de ruis, dan spreekt men wel van heesheid (veelal sluitingsdefect); overwegen de lage, onregelmatige frequenties, dan spreekt men van schorheid (veelal onregelmatige stemplooitrillingen). aet. organisch afwijkingen van de stemplooien: . laryngitis waardoor zwelling, . tumoren, poliepen waardoor massatoename en soms onregelmatige oorziekten epistaxis, zie *neusbloeding. aet. infectie acuut of chronisch, viraal en bacterieel. bij bovensteluchtweginfecties, rinitis, sinusitis. irritatie overmatig roken, alcoholgebruik, reflux, overmatig gebruik van prikkelende gargarismata of 'ontsmettende' zuigtabletten, overmatig stemgebruik, mondademhaling. atrofische faryngitis-(pharyngitis sicca) atrofie van het farynxslijmvlies als onderdeel van het plummer-vinsonsyndroom en bij atrofische rinitis. sympt. acute faryngitis: keelpijn, prikkelend gevoel in de keel, slikpijn, schraapneiging. chronische faryngitis: prikkelend gevoel, schraapneiging, soms globusgevoel. bij onderzoek diffuus rood slijmvlies, soms met secreet; soms roodheid en zwelling van eilandjes lymfoïde weefsel. bij atrofische faryngitis glad, soms gelakt uiterlijk van het slijmvlies en korstvorming. th. zoveel mogelijk causaal, in casu bestrijding van infecten van neus, sinus of bronchi, rook-en alcoholverbod, stemrust, herstel van de neusademhaling. irritaties vermijden. alleen wanneer genoemde factoren geen rol spelen symptomatische therapie. fonatie, ventriculaire ('valsestemplooispraak') stemgeving door het in trilling brengen van de valse stemplooien (plicae ventriculares). twee vormen. vorm van hyperkinetische dysfonie door overmatige spieractiviteit worden de plicae ventriculares tegen elkaar gebracht, waardoor het basisgeluid niet met de plicae vocales wordt geproduceerd. de stem is rauw, schor en geknepen (zie *dysfonie, hyperkinetische). als compensatie ontwikkeld in die gevallen waar glottissluiting onmogelijk is, kan geluid worden geproduceerd door de valse stemplooien (na stemplooiextirpatie, recurrensparalyse en andere). atrofie van het tongslijmvlies; onderdeel van plummer-vinsonsyndroom, bij hyperchrome anemie (chronische glossitis). oorziekten hypofarynxdivertikel, zie *oesofagusdivertikel. waarneming van een onaangename geur die niet overeenkomt met de reukprikkel of zonder dat een reukprikkel aanwezig is. een vorm van parosmie. aet. als bij *parosmie. bij psychosen als hallucinatie. combinatie van bronchiëctasieën, dextrocardie, chronische sinusitis en polyposis nasi (zie hoofdstuk : primaire ciliaire dyskinesie). laryngitis (algemeen) acute of chronische ontsteking van de larynx. banale laryngitis acute en chronische vorm, irritatie: roken, stemmisbruik. specifieke laryngitis . laryngitis tuberculosa (secundair aan longtuberculose), lupuslaryngitis (primaire vorm van tuberculose). . laryngitis diphtherica, laryngitis subglottica (kinderen), epiglottitis (kinderen), laryngotracheobronchitis (kinderen), atrofische laryngitis, in combinatie met atrofische rinofaryngitis (ozaena). laryngitis, acute banale aet. . infectieus: a. respiratoire virussen; b. bacterieel, secundair aan respiratoire virus of secundair bij bronchitis of sinusitis. . acute stemoverbelasting. . inhalatie-irritantia. sympt. heesheid tot afonie. prikkelhoest, gevoel van droogheid in de keel. bij kinderen stridor en dyspnoe door subglottische zwelling (zie *laryngitis subglottica). diagn. zwelling en roodheid van de larynx, vooral van de plicae vocales. soms wat mucopurulent secreet of beslag. kleine erosies en submuceuze bloedinkjes zijn mogelijk. th. meestal spontane genezing. symptomen kunnen bestreden worden met keelpastilles of hoestdrank. stemrust, rookverbod. inhalaties (mentholkamferspiritus op heet water). eventueel vasoconstrictieve neusdruppels als aerosol. in ernstige of langdurige gevallen een breedspectrumantibioticum. laryngitis, chronische banale aet. vanuit acute laryngitis; secundair aan chronische bronchitis of chronische rinosinusitis; irritatie (roken); stemmisbruik. sympt. heesheid, prikkelhoest, schrapen. diagn. hyperemie en zwelling van de gehele larynx of alleen van de stemplooien. soms vorming van granulaties of poliepen. lokale epitheelmetaplasie, waardoor leukoplakie. diff. stemplooicarcinoom; specifieke laryngitis. th. irritatieve factoren wegnemen: stemrust, rookverbod. infectie bestrijden: antibiotica algemeen, eventueel in een aerosol, vasoconstrictor (neusdruppels) als aerosol. poliepweefsel, leukoplakie verwijderen (larynxmicrochirurgie). eventueel de oorzaak op afstand behandelen. stemlessen indien foutief stemgebruik de oorzakelijke factor is. ontsteking van de larynx met zwelling van slijmvlies en bindweefsel van het subglottische gebied, waardoor stridor op de voorgrond staat. daarom wel pseudokroep genoemd (kroep = difterie). voork. bij kinderen van tot jaar. begin in de vroege avonduren, vaak onder invloed van bepaalde klimatologische factoren. aet. virale infectie waarna bacteriële superinfectie. tevens allergische en andere constitutionele factoren. vaak bij meer kinderen in hetzelfde gezin. sympt. in de avonduren beginnende, inspiratoire stridor met intrekkingen (jugulair en in epigastrio), heesheid met blafhoest (typische metalige klank) en lichte temperatuurverhoging ( c). vaak spontaan herstel in enkele uren. soms progressie met toeneming van stridor en dyspnoe. in zeldzame gevallen blauwe asfyxie, waarna witte asfyxie en exitus. het beeld kan verraderlijk snel veranderen. diagn. typische anamnese en klinisch beeld. directe laryngoscopie: laryngitis met sterke, rode subglottische zwelling. diff. epiglottitis, tracheolaryngobronchitis, bronchopneumonie, corpus alienum. th. lichte gevallen (meest voorkomend.) zorgen voor vochtige lucht, lichte sedering (suppositorium), de larynx sprayen met vasoconstrictor. ernstige gevallen behalve de genoemde therapie ook corticosteroïden, eerste dosis intramusculair. breedspectrumantibioticum kan men overwegen wanneer de klachten aanhouden (secundair infect). croupette (met waterdamp verzadigde lucht, extra o ). bij ernstige of langdurige dyspnoe nasotracheale intubatie, eventueel tracheotomie. ontsteking van de larynx door tuberkelbacillen, meestal secundair aan longtuberculose. infectie geschiedt door het ophoesten van sputum met tuberkelbacillen. zeldzaam geworden, maar komt door migratie van en naar gebieden waar tuberculose endemisch is, in ons land toch nog voor. sympt. als bij chronische banale laryngitis, vaak ook pijn. diagn. zwelling met infiltratie van stemplooi (vaak e en zijde) en interarytenoïdeaal. ulceratie met beslag. op grond van het histologische beeld (biopsie), actief longproces met positief sputum. diff. maligne tumoren. th. algemene tuberculosetherapie. slap larynxskelet, waardoor vernauwd lumen met aanzuigen van de slappe supraglottische structuren (epiglottis) bij inspiratie (zie ook *tracheomalacie). oorziekten aet. het jonge kraakbeen is slapper dan normaal. relatie met gastro-oesofageale reflux wordt gesuggereerd. soms beperkte laryngofissuur. sympt. typische inspiratoire stridor (kakelen), vooral bij huilen. th. geen. protonpompremmers (antacida). progn. gunstig. inspectie van larynx en hypofarynx: a. met een spiegel (indirecte laryngoscopie); b. starre optiek; c. flexibele fiberoptiek via de neus; voordelen: geringe belasting, goed uitvoerbaar bij hoge reflexen; nadeel: minder goed beeld dan bij starre optiek (b en c worden directe laryngoscopie genoemd); d. met behulp van endoscopen, veelal in narcose, waardoor biopteren mogelijk is; bij deze vorm van laryngoscopie is het mogelijk de stemplooien met de microscoop te inspecteren en onder de microscoop te opereren (suspensielaryngoscopie). nasaliteit (rhinolalia) groep spraakstoornissen met overmatige (hypernasaliteit) of te geringe (hyponasaliteit) bijdrage van de neusresonantie. hypernasaliteit (*rhinolalia aperta) klinkers krijgen nasale bijklank en medeklinkers gaan vergezeld van door de neus ontsnappend luchtgeruis. aet. congenitaal te kort verhemelte, schisis, (bulbaire) verlamming. hyponasaliteit (*rhinolalia clausa) verminderde neusklank en verkorte uitspraak van de nasale medeklinkers m, n, ng: 'warme limonade' klinkt als 'warbe libodade'. bij een gering te kort verhemelte wordt gedurende het spreken, ter voorkoming van hypernasaliteit, het verhemelte voortdurend gesloten gehouden (rinitis, allergie, neuspoliepen, septumafwijking). th. bij verkort verhemelte faryngoplastiek ter verbetering van de velofaryngeale afsluiting. nb geen adenotomie bij congenitaal te kort verhemelte, omdat anders de nasofarynx niet meer afgesloten kan worden tijdens spraak of slikken. acute of chronische ontsteking van de nasofarynx. acute vorm meestal onderdeel van een acute bovensteluchtweginfectie. aet. verkoudheidsvirus, adenovirus en andere. chronische vorm secundair aan chronische purulente rinitis en/of sinusitis, waardoor voortdurende secreetafvoer via de nasofarynx, ook wel 'postnasal drip' genoemd. chronische irritatie vooral door roken. atrofische nasofaryngitis als onderdeel van atrofische rinitis of *ozaena. sympt. vage pijn, gevoel van dikte hoog in de keel. neiging tot schrapen. soms onaangename smaaksensaties. diagn. bij rhinitis posterior geïnjecteerd slijmvlies, soms met secreet of crustae. kweek, eventueel biopsie. th. indien mogelijk causaal, anders symptomatisch; fysiologisch zout, neusdruppels of zout waterspoeling. nasofarynxtumor, maligne voork. op alle leeftijden mogelijk, ook bij kinderen (dan meestal sarcoom). in zuidoost-azië zeer veel voorkomend ( % van alle maligne tumoren!). ook in gebieden waar op jonge leeftijd infectie met het epstein-barrvirus endemisch is. hist. plaveiselcelcarcinoom, anaplastisch carcinoom, lymfepithelioom, sarcoom, (non)hodgkinlymfoom. sympt. oorverschijnselen door tuba-afsluiting (vaak enkelzijdig) geleidingsverlies en vocht in het middenoor. metastasen in de regionale lymfeklieren, meestal in de spinale keten (voorrand van de trapezius). neusverschijnselen belemmerde neuspassage, rhinolalia clausa, epistaxis. neurologische verschijnselen door doorgroei in de schedelbasis (achtereenvolgens n. vi-, n. iii-en n. iv-uitval). diagn. proefexcisie; r€ ontgenonderzoek, ct-scan en mri-scan. th. bij carcinoom bestraling van het primaire proces en hals. combinatie met chemotherapie vergroot het therapeutisch effect. eventueel halsklierdissectie als primaire tumor na bestraling is verdwenen en kliermetastasen resteren. progn. afhankelijk van de pathologische anatomie: ongedifferentieerd carcinoom, lymfepithelioom gunstig ( % vijfjaarsoverleving). neusbloeding (epistaxis) bloedverlies uit de neus. aet. lokale oorzaken trauma (peuteren, snuiten, ongeval), infectie (banaal of specifiek, vaak in het eindstadium van banale rinitis), tumor (vaak eerst streepjes bloed in het neussecreet), hereditaire teleangiëctasieën (m. rendu-osler). algemene oorzaken hypertensie, bloedafwijkingen (vnl. hemorragische diathese), algemene infectieziekten, graviditeit, premenstrueel. neusverstopping e en zijde septumdeformatie, rinosinusitis aan e en zijde, benigne of maligne tumor, corpus alienum, choanaalatresie. beide zijden septumdeformatie, allergische rinitis, vasomotore rinopathie, polyposis nasi, rinosinusitis aan beide zijden, vergroot adenoïd (kind), nasofarynxtumor, slijmvlieszwelling onder invloed van medicamenten, choanaalatresie. inspectie van de slokdarm. . door middel van een starre buis (verschillende diameters en lengten) met proximaal koud licht. eventueel lucht inblazen. voordelen: goed overzicht, vooral van postcricoïd gebied en oesofagusingang (cervicale oesofagus). grote biopsie is mogelijk, verwijderen van corpus alienum. nadelen: algemene anesthesie is gewenst, er bestaat gevaar voor perforatie van de wand. . door middel van een flexibele oesofagoscoop: technisch eenvoudiger, minder belastend, superieur voor inspectie distale oesofagus en oesofagus-maag-overgang. uitstulping van de oesofaguswand. twee vormen: pulsiedivertikel (hoge = cervicale; lage = thoracale) en tractiedivertikel. . pulsiedivertikel (zenkerdivertikel), eigenlijk is het juister dit te beschouwen als hypofarynxdivertikel, frequentste vorm, cervicaal gelokaliseerd; voornamelijk bij ouderen. aet. ontstaat door herniatie van de hypofarynxwand tussen overlangse en dwarse oesofagofaryngeale spiervezels (in de zgn. driehoek van killian). sympt. stadium : vage slikklachten, globusgevoel. stadium : idem doch met regurgitatie enige tijd na de maaltijd. stadium : verdere toeneming van de bestaande klachten. vermagering, halitose, eventueel ontsteking. soms is de zak in de hals palpabel. diagn. slikfoto met contrast. zeer voorzichtig met oesofagoscopie. diff. met oesofaguscarcinoom. th. endoscopisch: trachten het divertikel bij de oesofagus in te lijven door klieven van de tussenwand, bij voorkeur met een stapler of met laser. uitwendig: resectie van het divertikel en myotomie van de musculus cricopharyngeus via laterale halsincisie. . tractiedivertikel meestal thoracaal in de voorwand. aet. congenitaal; schrompeling van de hilusklieren (tuberculose e.a.). sympt. meestal geen of weinig klachten. diagn. slikfoto met contrast. driehoekige tentvormige uitstulping van de oesofagus met de punt behalve naar caudaal ook vaak naar lateraal of craniaal. th. zelden noodzakelijk. oesofagusstenose, zie *verbranding van oesofagus en hypofarynx. zeer langzaam groeiende tumor, meestal bestaande uit compact bot, uitgaande van de wand van een van de bijholten, gewoonlijk sinus frontalis of etmoïd. sympt. zeer vaak geen klachten; toevalsbevinding op r€ ontgenfoto's van de bijholten. soms hoofdpijn, vooral als het osteoom druk gaat uitoefenen op de omgeving. dan ook verdringing van het oog. diagn. r€ ontgenfoto. th. chirurgische verwijdering. ozaena (stinkneus, rhinitis atrophicans cum foetore) degeneratieve aandoening van mucosa en submucosa van de neus, met vorming van fetide korsten. aet. onbekend, hereditaire en welvaartsfactoren (o.a. voeding) spelen een rol. vrijwel altijd klebsiella ozaenae aanwezig als superinfectie. secundaire vorm na conchachirurgie. voork. vooral vrouwen, begin rond puberteit. sympt. sterke foetor, verwijding van de neusholte met ophoping van groengrijze korsten. soms ook nasofarynx, orofarynx en larynx aangedaan. soms atrofie uitwendige neus. diff. atrofische rinitis, zelfde beeld doch geen foetor, in het algemeen geen klebsiella. th. vernauwing van de neusholte door submuceuze implantatie van bot of kraakbeen. symptomatisch neusspoelen met fysiologisch zout, indifferente neuszalf. goedaardige tumor van het larynxepitheel, vaak multipel. voork. vooral bij kinderen (dan meestal spontaan verdwijnend in de puberteit). bij volwassenen meer solitair. aet. virusinfectie (hpv ). sympt. heesheid, progressief tot afonie; inspiratoire stridor en benauwdheid. diagn. bij indirecte of directe scopie multipele, grijsrode, wratachtige tumoren, uitgaande van stemplooien, valse stemplooien, arytenoïden en plicae aryepiglotticae. th. verwijderen via directe laryngoscopie, (microchirurgie, laserchirurgie, shaver). in het algemeen ontstaat na enige tijd een recidief; daarom zeer conservatief te werk gaan, te meer omdat in de puberteit spontane involutie verwacht mag worden. antivirale middelen kunnen ook intralaesionaal worden gespoten. de resultaten zijn bemoedigend. progn. goed. zelden maligne degeneratie. paralyse van de stemplooi stoornis in de beweeglijkheid van e en of van beide larynxhelften. indeling op grond van de stand waarin de stilstaande stemplooi zich bevindt. . paramediaan; ook wel abductieparalyse ('posticusparalyse') genoemd. . intermediair; ook wel adductieparalyse ('recurrensparalyse') genoemd. aet. . iatrogeen (schildklieroperatie). . schildklierafwijkingen (struma, schildkliercarcinoom). . maligne lymfomen van het mediastinum (n. recurrens links). . virale infecties. . halstumor. . aneurysma aortae. verder: cerebrale stoornissen, bulbaire laesies, foramenjugularesyndroom, larynxtrauma. naar lokalisatie . supranucleair (vasculair accident, tumor). . nucleair (progressieve bulbairparalyse, tumoren, vasculair accident, syringobulbie). . foramen jugulare (glomustumor, nasofarynxtumoren). . cervicaal (schildklier, lymfomen, trauma, larynx-, oesofagus-mondcarcinoom). . thoracaal (maligne lymfomen van linker mediastinum, aortaboog, pleuratop). sympt. afhankelijk van de stand van de stemplooi en of de paralyse een of beide zijden betreft. . paramediane stilstand: a. e en zijde, lichte heesheid als gevolg van het niet geheel sluiten van de glottis en hypotonie van de verlamde stemplooi, b. beide zijden, benauwdheid met inspiratoire stridor. de stridor heeft een karakteristiek gierend karakter, vooral in de slaap. . intermediaire stilstand: heesheid, bij paralyse aan beide zijden meestal afonie. diagn. indirecte laryngoscopie is gewoonlijk voldoende voor de diagnose. men vindt stilstand in bepaalde positie, vaak met hypotonie van de stemplooi. later vaak strakke plica door atrofie en soms binnenwaartse kanteling van het arytenoïd. soms is directe laryngoscopie zinvol om een oorzaak ter plaatse uit te sluiten. stemonderzoek. onderzoek naar de oorzaak (mediastinum-ct, neurologisch onderzoek). diff. met functionele dysfonie van psychogene aard of door stemoverbelasting; ankylose van het cricoarytenoïdegewricht (reumatoïde artritis). th. oorzakelijk symptomatisch. bij paramediane stilstand aan beide zijden: tracheotomie. spreekcanule (inspiratie via canule, expiratie via de larynx, zodat normaal gesproken kan worden). bij blijvende paralyse: fixatie van e en stemplooi naar lateraal door arytenoïdresectie. bij stilstand in intermediaire stand aan e en zijde stemlessen (glottissluitingsoefeningen) om de andere stemplooi te leren door overcompensatie de glottis te sluiten. eventueel injectie van e en stemplooi met autoloog vet om de glottisopening te verkleinen of chirurgische medianisatie (techniek vlg. isshiki). geassocieerde stemplooiparalyse stemplooiparalyse komt vaak voor als onderdeel van een uitgebreider syndroom van uitvalsverschijnselen. syndroom van de bulbaire zenuwen: uitval van ix, x, xi en xii. foramenjugularesyndroom en spatiumparapharyngeumsyndroom: uitval van ix, x, xi en sympathicus. aortaboogsyndroom: uitval van x (n. laryngeus superior intact), n. phrenicus en sympathicus. reukgewaarwording die niet met de prikkel overeenkomt. aet. zintuiglaesie (infectie), hormonaal (graviditeit), na trauma, bij cerebrale afwijkingen (epileptisch aura). acute of chronische ontsteking van het larynxskelet. aet. tijdens of na irradiatie wegens maligne tumor van het larynx-hypofarynxgebied waarop superpositie van banale infecties. sympt. heesheid, slikklachten, stridor eventueel dyspnoe, pijn in de hals, uitstralend naar boven, soms koorts. diagn. bij laryngoscopie roodheid en zwelling van de larynx of een gedeelte daarvan (vooral arytenoideus), pijnlijk bij palpatie van larynx. th. antibiotica, corticosteroïden, bij benauwdheid tracheotomie, bij necrotisering of abcedering chirurgische therapie (drainage, verwijdering van sekwesters). ontsteking c.q. abcedering van het peritonsillaire weefsel, gewoonlijk aan e en zijde. aet. uitbreiding van banale tonsillitis. sympt. in principe als bij acute tonsillitis, doch meestal heviger. sterker algemeen ziek zijn, slikken en ook spreken ('hete aardappel' in de keel) gaat zeer moeilijk. gewoonlijk trismus (onvermogen om mond geheel te openen). speekselvloed. compl. als bij acute tonsillitis. kans op complicaties duidelijk groter. diagn. enkelzijdige rode zwelling van het palatum molle boven de tonsil. verplaatsing uvula. trismus. th. bij verdenking op abcedering punctie (kweek). antibiotica (breedspectrum), bij belaste anamnese tonsillectomie à chaud of à froid. pharyngitis, zie *faryngitis. min of meer gesteelde, glanzende, lichtgrijze, weke zwellingen, uitgaande van slijmvlies van neus en bijholten. aet. chronische prikkeling en/of infectie, hyperplasie van het slijmvlies, ten slotte leidend tot poliepvorming, vooral bij *rhinopathia chronica infectiosa. hist. zeer losmazig bindweefsel, waarin eiwithoudend vocht, bloedvaten, klieren, eventueel cysten, eosinofielen, veel mestcellen. bekleed met cilinderepitheel. lokalisatie neus: vrijwel altijd uitgaande van het slijmvlies van concha media en middelste neusgang. bijholten: het frequentst is lokalisatie in het etmoïd, daarna in de sinus maxillaris. choane: zie *choanaalpoliep. sympt. neuspoliepen neusverstopping; verschijnselen van recidiverende infectie, chronische rinosinusitis, anosmie. sinuspoliepen als bij sinusitis chronica. diagn. neus inspectie. sinus r€ ontgenfoto, antroscopie, ct-scan. diff. maligne tumor. nb soms secundaire poliepvorming rondom een maligne tumor(!), papilloma inversum, meningok ele (mediaal van de concha media). th. verwijdering van de poliepen uit neus, c.q. etmoïd (etmoïdectomie) en sinus maxillaris (meestal endonasaal). onderhoudsdosis corticosteroïden lokaal (spray). bij ernstige, recidiverende gevallen systemisch. antibacteriële therapie bij infecties. acute abcederende ontsteking van de lymfeklieren in het spatium retropharyngeum. voork. bij kleine kinderen. op latere leeftijd verdwijnen de desbetreffende lymfeklieren. aet. adenoïditis, rinitis. sympt. bemoeilijkte ademhaling, moeilijk slikken, soms dwangstand van het hoofd naar achteren. algemeen ziek zijn, koorts. diagn. gladde, fluctuerende rode zwelling van de farynxachterwand. ct-scan. diff. met peritonsillaire flegmone en abces. th. punctie (kweek), waarna drainage transoraal of via de hals. cave aspiratie van pus en luchtwegobstructie. antibiotica parenteraal. bepaling van de perceptie en identificatiedrempel van geuren. in vergelijking met het onderzoek van andere zintuigen, zoals oog en oor, is het reukonderzoek sterk in ontwikkeling achtergebleven. men onderscheidt twee belangrijke oorzaken. . het werkingsmechanisme is nog onbekend. men neemt aan dat er geurgroepen zijn, o.a. kamferachtig, muskusachtig, etherachtig, scherp en rottend. de fysische en/of chemische basis hiervan is echter onzeker. . toedienen van een gestandaardiseerde prikkel aan het reukepitheel is moeilijk. diverse factoren (o.a. anatomische, slijmvlieszwelling, inspiratiediepte) beïnvloeden de uitkomsten. bij het standaardonderzoek wordt gebruik gemaakt van flesjes met de zeven basisgeuren in afnemende verdunning of de gestandaardiseerde upsit-reuktest ( verschillende geuren). de drempel wordt zowel voor als na ontzwellen van het neusslijmvlies bepaald ten einde zo mogelijk perceptie en geleidingsanosmie te onderscheiden. rhinitis acuta (coryza, neusverkoudheid ) acute ontsteking van het slijmvlies van neus en nasofarynx en soms ook van orofarynx en larynx. in nederland en belgië de meest voorkomende ziekte. aet. virusinfectie (rinovirus, adenovirus, coronavirus e.a.) regelmatig na enige dagen bacteriële superinfectie. bijkomende oorzakelijke factoren: plotselinge afkoeling van het lichaam, anatomische afwijkingen in de neus, verminderde algemene weerstand. sympt. roodheid en zwelling van het neusslijmvlies met veel waterig secreet. neusverstopping, waardoor hyposmie en gesloten neusspraak. soms niesbuien. later meer mucopurulente secretie, soms epistaxis. algemeen: lichte malaise, soms hoofdpijn en lichte koorts. compl. sinusitis, laryngitis, bronchitis. th. geen specifieke therapie. door het grote aantal virusvarianten geen vaccinatie. symptomatisch: neusdruppels (decongestiva) om de neuspassage te verbeteren en secreetafvloed te bevorderen. algemeen salicylpreparaten; algemeen antibiotica alleen geïndiceerd bij complicaties of geprotraheerd verloop bij patiënten met allergie (zie *rhinopathia allergica). overmatige neusresonantie bij het spreken. doordat het palatum molle de nasofarynx onvoldoende kan afsluiten wordt de lucht in nasofarynx en neusholte bij bepaalde spraakklanken te sterk (c.q. mede) in trilling gebracht. het duidelijkst waarneembaar is dit bij explosieve consonanten (k, p, t) en bij alle vocalen. aet. organisch palatoschisis. congenitaal te kort palatum molle bij submuceuze gehemeltespleet (benige spleet of incisuur mediaan in het achterste gedeelte van het palatum durum). verworven bewegingsbeperking van het palatum molle (verlittekening na te). te wijde nasofarynx. paralyse van het palatum molle (n. ix, difterie, bulbairparalyse, foramenjugularesyndroom). functioneel gewoontevorming. pijn (tonsillitis, na te). bij perceptieslechthorendheid (om de eigen spraak via beengeleiding beter te kunnen waarnemen). sympt. karakteristieke spraak, in het bijzonder verandering van spraakklanken die normaal geen neusresonantie bezitten, zoals k, p en t. bij ernstiger vormen ontstaat ook vervorming van klinkers. nasale souffle; bij het spreken ontsnapt lucht via de neus. vloeistof in de neus bij drinken. compensatoir overmatig gebruik van de neusvleugels ten einde een afsluiting voor in de neus te verkrijgen. diagn. articulatie-onderzoek, in het bijzonder van woorden met de consonanten k, p en t: 'piet de koekenbakker koopt twee prachtige kaketoes'. aa-ie-fenomeen: afwisselend aa en ie laten zeggen met open en met dichtgeknepen neus. bij rhinitis aperta is een geringer verschil in neusresonantie tussen aa en ie hoorbaar dan normaal. mobiliteit en afsluitmogelijkheid van het palatum molle beoordelen door inspectie tijdens vocaalstoten (kort en krachtig aa laten zeggen) en door meten van de blaaskracht. een koud spiegeltje dat tijdens het uitspreken van orale spraakklanken onder de neusopening wordt gehouden beslaat. th. chirurgisch (sluiten van het palatumdefect, push-backoperatie, velofaryngeale plastiek, implantatie in de nasofarynx). obturator in ernstige gevallen waar operatieve correctie onvoldoende mogelijk is. spraakles. zogenaamde stootoefeningen om de functie van palatum molle en zijstrengen te verbeteren, bij functionele oorzaak en na chirurgische correctie. zie ook *nasaliteit. abnormaal geringe neusresonantie bij het spreken. doordat neus en/of neus-keelholte geheel of gedeeltelijk zijn geobstrueerd is de normale neusresonantie sterk verminderd. vooral opvallend bij de zgn. nasalen m, n en ng. aet. organisch . obstructie in de neus door: slijmvlieszwelling, conchahypertrofie door rinitis, rhinitis vasomotorica, poliepen, septumdeformatie, tumoren. . obstructie van de nasofarynx, adenoïdhypertrofie, tumoren, choanaalpoliepen. functioneel gewoontevorming. sympt. karakteristieke spraak, vooral bij woorden met nasale consonanten. in-en expiratoir belemmerde neuspassage. diagn. articulatie-onderzoek. woorden met nasale consonanten laten nazeggen: 'warme limonade' wordt 'warbe libodade'. th. bij organische oorzaak causale therapie. zie ook *nasaliteit. rhinopathia (algemeen) min of meer chronische aandoening van neusslijmvlies, niet door acute of specifieke infectie, nieuwvorming of anatomische afwijkingen bepaald. drie vormen: *rhinopathia allergica (atopica), *rhinopathia vasomotorica (non-atopica) en *rhinopathia chronica infectiosa. overlapping van ziektebeelden is mogelijk. soms vindt men in andere organen eenzelfde ziekteproces (bijv. atopie: ogen, longen). rhinopathia allergica (rhinopathia atopica, rhinitis allergica) ziektebeeld in de neus, bepaald door contact van atopische inhalatieallergenen met specifieke ige-antistoffen op mestcellen in het slijmvlies, waarbij mediatoren vrijkomen die de verschijnselen veroorzaken. gemiddeld e en tot enkele jaren contact met allergeen is nodig voor sensibilisatie bij een waarschijnlijk erfelijk bepaalde constitutie. meestal vindt men atopie voor verscheidene allergenen tegelijk. de aandoening komt vooral voor tussen het vijfde en veertigste levensjaar, bij mannen eerder en vaker dan bij vrouwen. veelal familiair. belangrijkste allergenen: graspollen (typische hooikoorts, voornamelijk van half mei tot half juli), huisstofmijten (vooral in oude en vochtige huizen, het hele jaar aanwezig met als top de periode augustus-december), huidschilfers van kat, cavia enz. (incidentele of chronische expositie). aspecifieke prikkeling (hyperreactiviteit), infecties en soms stress kunnen voorkomen. sympt. niezen, jeuk in de neus en van palatum, waterige secretie, verstopping (bij expositie aan allergeen; dan ook jeuk in de ogen en/of astma mogelijk aandoening van het neusslijmvlies door aspecifieke overprikkelbaarheid van het slijmvlies door autonome disbalans (relatieve overheersing van de oorziekten parasympathicus in het neusslijmvlies). prikkels: temperatuurovergang, geuren en dampen zoals sprays, alcohol, tabaksrook, uitlaatgassen. komt vooral voor vanaf het vijfendertigste levensjaar, bij vrouwen ook wel vanaf het twintigste levensjaar. de aandoening verergert door infecties en stress (overvoerd leefpatroon). diff. met prikkeling door ammonia, traangas, peper en dergelijke, overprikkelbaarheid onder invloed van anatomische afwijkingen zoals spina septi, *sludersyndroom of hormonale factoren, overprikkelbaarheid zoals bij rhinopathia allergica (atopica) en rhinopathia chronica infectiosa. sympt. niezen, prikkelend gevoel in de neus, waterige secretie, verstopping, soms tranende ogen. diagn. . blauw-rode natte neusslijmvliezen met sterke zwelling van de conchae, vooral inferiores. . uitsluiten van allergie (atopie) door *allergologisch onderzoek. . soms lokale en bloedeosinofilie. th. . vermijden van aspecifieke prikkels. . symptomatisch antihistaminica en/of beclometasonneusspray, zo nodig tijdelijk ook een lage dosering prednison oraal. . antibiotica en neusdruppels bij bacteriële infecties. . verwijderen hyperplastisch slijmvlies, conchareductie. inspectie van de inwendige neus van voren met behulp van speculum. beoordeling van septum, vestibulum, ostium internum (klep), conchae, slijmvlies, aanwezigheid van secreet en abnormaal weefsel. bij onvoldoende overzicht, ook na slinken van het slijmvlies, uitvoeriger onderzoek met behulp van dunne starre optieken (zgn. nasendoscopie). inspectie van choanen en nasofarynx via de mond met behulp van een kleine spiegel. beoordeling van choanen, conchastaarten, uitmonding van de tuba eustachii, nasofarynxachterwand en nasofarynxdak. uitvoeriger onderzoek met behulp van starre optiek na naar voren trekken van het palatum molle ('teugelen'). rinitis, idiopathische, zie *hyperreactiviteit neusslijmvlies. zeer langzaam voortschrijdende infectieuze aandoening van het slijmvlies van de neus, later ook van de lagere luchtwegen. haardgewijs voorkomen (centraalen oost-europa, india, indonesië, zuid-amerika). aet. besmetting met klebsiella rhinoscleromatis. sympt. vaste, gladde, knobbelige zwellingen van het slijmvlies die tot afsluiting kunnen leiden, littekenvorming en stenose. diff. met lues, tuberculose, tumoren, keloïd, leishmaniasis. th. antibiotica (penicilline, streptomycine), radiotherapie (meestal weinig effect). schorheid, zie *dysfonie. ophoping van pus onder het mucoperichondrium c.q. mucoperiosteum van het septum. aet. vrijwel altijd een geïnfecteerd hematoom, ontstaan door neustrauma of na septumoperatie. sympt. algemeen ziek zijn met koorts, soms septisch beeld, pijn; belemmerde neuspassage. bij onderzoek sterk rode, indrukbare zwelling van het septum, meestal aan beide zijden, die de neus afsluit. compl. als resttoestand kraakbenige zadelneus. diagn. punctie of incisie. th. na punctie (voor diagnose en kweek) ruime incisie en verwijdering van necrotisch kraakbeen en bot, waarna primaire reconstructie van het gedestrueerde septumskelet met kraakbeen of bot om de kans op littekenretractie en kraakbenige zadelneus te voorkomen. antibiotica op geleide van grampreparaat en kweek. richel van het septum, meestal bestaand uit bot en kraakbeen en gelokaliseerd in de onderste neusgang. vaak uitlopend in een spina en met septumdeviatie die vaak naar de andere kant is gericht. aet. vrijwel altijd trauma. dislocatie van het kraakbenige septum en vomer van de crista maxillae en palatinae, waardoor excessieve en gestoorde groei van septumonderdelen op deze plaats. sympt. soms geen, soms verschijnselen zoals bij septumdeviatie en/of spina septi. th. septumcorrectie. scheefstand van het kraakbenige en/of benige neustussenschot. vaak in combinatie met crista en/of spina aan de contralaterale zijde. aet. vrijwel altijd na trauma. vaak zeer gering trauma in de vroege jeugd waardoor geringe dislocatie en geleidelijke groeimisvorming. sympt. belemmerde neuspassage aan e en of aan beide zijden; gestoorde secreetafvoer waardoor vaker sinusitis en tubotympanitis; hoofdpijn. diagn. inspectie en palpatie. indelen naar niveau: hoog (middelste-bovenste neusgang) en laag (onderste neusgang), voorachterwaarts: ostium ext., ostium int. (klep), voorste helft van de neusholte, achterste helft van de neusholte. th. septumcorrectie door submuceuze resectie, repositie en re-implantatie van septumgedeelten. kan in principe op iedere leeftijd worden uitgevoerd. wel zal op jonge leeftijd de indicatie sterker moeten zijn en de operatie behoudender moeten worden uitgevoerd. ophoping van bloed onder het mucoperichondrium van het septum, gewoonlijk aan beide zijden. aet. trauma, soms als complicatie van septumoperatie. sympt. gehele of gedeeltelijke obstructie van de neus. soms pijn. groot gevaar voor abcedering. diagn. punctie. diff. abces. th. incisie van het septumslijmvlies langs de neusbodem, zo nodig aan beide zijden, waarna tamponnade ter voorkoming van recidief. antibiotica ter voorkoming van abcedering. opening in het neustussenschot. aet. na septumoperatie waarbij tegenover elkaar liggende laesies in het slijmvlies zijn ontstaan, ten gevolge van chronisch neuspeuteren, cocaïne snuiven, granulomatosis van wegener en maligne processen. sympt. vaak geen. in sommige gevallen korstvorming in de perforatie; recidiverende epistaxis. bij kleine perforaties vaak fluitende geluiden bij inspiratie. diagn. bij twijfel over de oorzaak biopsie uit de rand van de perforatie. th. . zalf tegen korstvorming. . prothese ('septumbutton'). . chirurgische sluiting door mobilisatie naburig slijmvlies of met labiogingivale zwaailappen. puntig uitsteeksel van het benige septum, meestal van het vomer, basaal en achter in de neus gelokaliseerd. vaak gecombineerd met crista. aet. groeistoornis na trauma. sympt. vaak geen klachten. soms verschijnselen van het zogenoemde *sludersyndroom (rhinitis-vasomotorica-beeld, hoofdpijn). th. septumcorrectie. sinusitis ethmoidalis (etmoïditis) . acute vorm acute ontsteking van het slijmvlies van de zeefbeencellen, meestal bij kinderen. ook gecombineerd met acute sinusitis maxillaris of als onderdeel van acute pansinusitis. aet. acute rinitis (pneumokokken, h. influenzae, moraxella catarrhalis). sympt. pijn in de neuswortel, achter het oog en in het voorhoofd. purulent secreet uit de neus en in de nasofarynx. neusverstopping. algemeen ziek zijn. compl. uitbreiding naar de orbita (vooral bij jonge kinderen). begint met ooglidoedeem, bij progressie protrusie en verplaatsing van het oog naar lateraal, sterke chemosis. bij onvoldoende therapie abcedering met restverschijnselen in de vorm van oogbewegingsstoornissen en verlies van visus. acute meningitis. diagn. pus in de middelste neusgang, ct-scan. diff. bij orbitale flegmone differentiëring met sinuscavernosustrombose (ct-scan, oogfundus). th. acute sinusitis: antibiotica algemeen, drainage bevorderen door neusdruppels (neusspray) en medianiseren van de concha media. bij onvoldoende succes eventueel endonasaal openen van het etmoïd. bij orbitaal abces openen en draineren hiervan via paranasale incisie. . chronische vorm eveneens vaak gecombineerd met chronische sinusitis maxillaris of onderdeel van chronische pansinusitis. meestal aan beide zijden. sympt. als bij de acute vorm, doch minder hevig. vooral pijn rondom de neuswortel en achter het oog. zeer vaak poliepvorming, waardoor afvloedbelemmering en onderhouden van het ontstekingsproces, anosmie. diagn. r€ ontgenfoto, ct-scan. diff. adenocarcinoom, plaveiselcelcarcinoom van het etmoïd. th. conservatieve therapie als bij chronische sinusitis maxillaris. bij polypose verwijdering van de poliepen, met endonasale etmoïdectomie. sinusitis frontalis (voorhoofdsholte-ontsteking) ontsteking van het slijmvlies van de voorhoofdsholte. . acute vorm vanuit acute rinitis. sympt. pijn in het voorhoofd, vaak zeer hevig. soms licht oedeem van het voorhoofd en het bovenooglid. symptomen van acute rinitis. algemeen ziek zijn, meestal hoge koorts. compl. acute meningitis, hersenabces. orbitaflegmone: protrusie met naar beneden verplaatsen van het oog, sterk ooglidoedeem. diagn. sterke druk-en kloppijn boven de aangedane holte. slechte doorlichting (bij sinusitis frontalis een niet zeer betrouwbaar symptoom vanwege een individueel verschil in grootte en asymmetrie), r€ ontgenfoto's, ctscan. th. algemeen antibiotica, secreetafvoer via ductus nasofrontalis bevorderen door luxatie concha media en intensief afslinken met neusdruppels, liever nog neusspray. indien onvoldoende effect, de sinus openen via een wenkbrauwincisie en een drain achterlaten. niet spoelen via de ductus vanwege kans op laedering hiervan, waardoor recidief. . chronische vorm met frontale hoofdpijn, wisselend karakter, vaak in de loop van de dag opkomend. compl. doorbraak door de achterwand waardoor meningitis, epiduraal abces. doorbraak door de bodem waardoor oogverdringing. osteomyelitis os frontale. diagn. r€ ontgenfoto's, voorachterwaarts en zijdelings, ct-scan. th. indien kort bestaand: beginnen met conservatieve therapie zoals bij de acute vorm, anders drainage via incisie in de wenkbrauw. verwijdering van irreversibel gedegenereerd weefsel en achterlaten van een drain. antibiotica algemeen en lokaal. bij recidieven operatief verwijden van de ductus nasofrontalis (langdurig drain in de ductus) of obliteratie van de holte. sinusitis maxillaris . acute vorm acute ontsteking van het slijmvlies van de bovenkaakholte. aet. secundair aan acute rinitis (pneumokokken, h. influenzae, moraxella catarrhalis, streptokokken). bijkomende etiologische factoren zijn bestaande neusslijmvliesallergie en septumafwijkingen; dentogeen vanuit wortelontsteking (pre)molaren of na extractie hiervan. secundair aan nasale intubatie. sympt. pijn in de bovenkaak, soms zeer hevig, kloppend, borend. uitstraling vaak naar oog en voorhoofd. purulente neussecretie, bij dentogene sinusitis meestal fetide, neusverstopping. algemeen ziek zijn met koorts. compl. acute meningitis, orbitaflegmone. diagn. druk-en kloppijnlijke bovenkaak. niet-oplichten van de holte bij diafanoscopie. sluiering op r€ ontgenfoto, ct-scan, antroscopie. th. in aanvang symptomatisch: pijnstilling, neusspoelingen met fysiologisch zout, neusdruppels (decongestiva). bij langdurige klachten (> - dagen) of heftige klachten en/of algemeen ziek zijn: algemeen antibiotica (amoxicilline, tetracycline). indien empyeem is ontstaan: kaakpunctie (punctie via de onderste neusgang). bij dentogene oorzaak direct na het begin van de therapie ook tandheelkundige behandeling. . chronische vorm niet-genezen van acute sinusitis maxillaris, op basis van anatomische variaties (klein fysiologisch ostium), allergie, chronische etmoïditis, secundair aan een tumor, dentogeen. sympt. als bij acute sinusitis, doch minder hevig. de pijn is vaak wisselend en komt in de loop van de ochtend op. soms geen neussecretie als gevolg van retentie. aangezien slijm uit neus en bijholten normaal naar de farynx wordt afgevoerd soms klachten hierover, faryngitis en onaangename smaak. compl. hyperplasie van het slijmvlies van kaakholte en neus met poliepvorming. diagn. als bij de acute vorm. diff. met maligne tumor van sinus maxillaris of etmoïd; sinuscyste. th. kaakspoeling, herhaling (afhankelijk van pusproductie) een tot drie maal per week, neusdruppels, algemeen antibiotica. indien onvoldoende resultaat: infundibulotomie en vergroten fysiologisch ostium, nasoantrostomie (volgens claou e) in onderste neusgang of operatie via neus of buccogingivale incisie (volgens caldwell-luc), irreversibel gedegenereerd weefsel verwijderen en drainage verzorgen. ontsteking van het slijmvlies van e en of van beide wiggenbeensholten. vrijwel altijd gecombineerd met ontsteking andere bijholten. aet. vanuit acute rinitis. sympt. hoofdpijn, vaak op de kruin of in het achterhoofd gelokaliseerd. vage malaiseverschijnselen. secreet in nasofarynx en keel. diagn. secreet uit nasofarynxdak bij rhinitis posterior. r€ ontgenfoto's, ct-scan. compl. osteomyelitis, trigeminusneuralgie, neuritis retrobulbaris. diff. tumoren. th. conservatief: antibiotica algemeen en neusdruppelen. chirurgisch: openen van het sfenoïd via het septum of (endoscopisch) vergroten van het fysiologisch ostium. sinusitis van alle bijholten (pansinusitis) . acute vorm acute ontsteking van sinus ethmoidalis, sinus frontalis en sinus maxillaris, meestal eenzijdig. sympt. vooral pijn en algemeen ziekzijn; meningitis, orbitaflegmone, hersenabces. diagn. r€ ontgenfoto's. th. zie onderscheiden aandoeningen. . chronische vorm chronische ontsteking, meestal met poliepvorming, van sinus ethmoidalis, frontalis en maxillaris. frequent op basis van allergisch neusslijmvlies, vaak aan beide zijden. sympt. en diagn. zie onderscheiden aandoeningen. th. in het algemeen chirurgisch. verwijderen van het gedegenereerde weefsel met caldwell-luc-operatie, etmoïdectomie en uitwendige sinus-frontalisoperatie. na sanering zorgen voor drainage. nabehandeling met antibiotica algemeen en eventueel met corticosteroïden. dunwandige, met heldergeel vocht gevulde zak in de sinus maxillaris. slijmvliescyste niet-secernerende cyste (ophoping vocht in submucosa). retentiecyste (retentie in afgesloten slijmvlies). dentogene cyste radiculaire of tandwortelcyste (cysteuze degeneratie van een wortelgranuloom), meestal bij volwassenen. folliculaire of coronaire cyste (uitgaande van het embryonale tandzakje, soms tandkroon in de cyste), meestal bij jongeren. sympt. slijmvliescysten geven vaak geen klachten. soms echter hoofdpijn. wanneer zij de sinus geheel opvullen ontstaat geleidelijke zwelling van de wang met indrukbare sinusvoorwand (zgn. pingpongbalfenomeen). in dit stadium pijnklachten. soms spontane lediging van de cyste: afvloed van dunne heldergele vloeistof. dentogene cysten dezelfde verschijnselen met tandheelkundige symptomen. diagn. r€ ontgenfoto, antroscopie. dentogene cysten bevinden zich op de sinusbodem. slijmvliescysten kunnen ook in laterale wand of dak optreden. doorlichting geeft vaak een normaal beeld! diff. met sinusitis, tumor. bij twijfel antroscopie. th. slijmvliescysten alleen verwijderen bij klachten. dentogene cysten altijd opereren, tevens tandheelkundige therapie of operatie volgens caldwell-luc of marsupialisatie van de cyste naar de mond. sinus-maxillarisfistel (dentogeen) open verbinding van mondholte naar sinus maxillaris via het extractiekanaal van een bovenkaakelement. aet. extractie premolaar of molaar. sympt. secundaire unilaterale sinusitis, maxillaris gewoonlijk met fetide secretie, waardoor vieze smaak in mond. soms pijn. diagn. bij persen met gesloten neus ontsnapt lucht en soms ook secreet uit de fistelgang. de fistel is meestal te sonderen. th. de verse fistel zo spoedig mogelijk sluiten met behulp van trapeziumvormige, buccale slijmvlies-periostlap (zgn. rehrmanplastiek). indien sinusitis is ontstaan deze eerst genezen door frequente spoeling van de kaakholte (via neus of fistel) en antibiotica algemeen. met slijm gevulde, afgesloten en gedilateerde bijholte. aet. afsluiting van het ostium van de sinus door trauma (meestal operatie) of ontsteking. meestal in sinus frontalis. sympt. lokale pijn, hoofdpijn. lokale zwelling die uitwendig zichtbaar kan zijn. oogverschijnselen door verdringing van de oogbol naar beneden en lateraal: dubbelbeelden, visusvermindering. bij lokalisatie in de sinus maxillaris indrukbare zwelling van de maxilla. bij infectie zgn. pyok ele met meer ontstekingsverschijnselen. diagn. vooral op grond van r€ ontgenfoto's, ct-scan. diff. tumoren kunnen eenzelfde beeld geven. bij twijfel daarom exploratie en pathologisch-anatomisch onderzoek. th. altijd operatie. hoofdpijn aan e en zijde (eventueel met rhinitis-vasomotorica-beeld als gevolg van prikkeling van het ganglion pterygopalatinum). aet. spina septi die contact maakt met c. inferior en daardoor het ganglion pterygopalatinum prikkelt. sympt. eenzijdige hoofdpijn, die gelokaliseerd is in neuswortel, oog en bovenkaak. rhinitis-vasomotorica-beeld: tranende ogen, eventueel waterige neussecretie en -verstopping aan e en zijde. diagn. inspectie na afslinken van het slijmvlies. indien afslinken de hoofdpijn doet verdwijnen is de diagnose vrijwel zeker. th. spinaresectie. ontstaat meestal door trillen van het palatum molle, vooral bij inspiratie. snurken kan ook ontstaan door trillen van farynxwand of epiglottis. veel voorkomende aandoening, meestal bij ouderen, vooral mannen. soms onderdeel van het obstructief slaapapnoesyndroom (osas, zie hoofdstuk : slaapapnoesyndroom). aet. factoren: obesitas, verslapping van de farynxof palatummusculatuur, mondademhaling, op de rug slapen, alcoholgebruik of slaapmedicatie voor het slapengaan. th. de behandeling hangt af van de plaats(en) waar het snurkgeluid ontstaat. bij heftig palatumsnurken is inkorten van het palatum molle (uvulo-palatoplastiek) een mogelijkheid. soms is afvallen, matigen met alcohol en/of herstel van de neusademhaling voldoende. slapen in zij-of buikligging en het 's nachts inhouden van de gebitsprothese zijn praktische maatregelen met wisselend resultaat. spraak, spreken en taal spraak gesproken taal; het typisch menselijke vermogen tot verbale communicatie. met spraakvermogen wordt zowel het expressieve als het receptieve aspect van de gesproken taal bedoeld. spreken het voortbrengen van spraakklanken door middel van ademstroom, stemspleet, aanzetstuk (mond-en keelholte), verhemelte, tong en lippen (de belangrijkste articulatieorganen). taal het vermogen spraak te decoderen naar haar betekenis en betekenis om te zetten in spraak en/of schrift. non-verbale communicatie omvat de betekenisexpressie door houding, beweging, gebaar, gelaatsmimiek en stemtoon. spraak-en taalontwikkeling, vertraagde achterstand van spraak-en taalontwikkeling in vergelijking tot die van het gemiddelde kind. veel voorkomend, vaker bij jongens dan bij meisjes. aet. psychische en pedagogische oorzaken diverse factoren, soms combinaties: stoornissen in het gevoels-en wilsleven, emotionele conflicten, pedagogische fouten, tweetaligheid in het gezin, psychotrauma, langdurige ziekte e.d. organische oorzaken slechthorendheid, oligofrenie, geboortetrauma, encefalitis. sympt. het kind spreekt nog niet of slecht in vergelijking met kinderen van dezelfde leeftijd. mogelijkheden: . alleen klinkerspraak (vocaalspraak), . vervanging van alle medeklinkers en medeklinkercombinaties door e en bepaalde medeklinker (t of k; zgn. kakuminale spraak), . vervanging van medeklinkers door enkele medeklinkers (d, t of p; zgn. hottentottisme). daarbij: grammaticale en syntaxisfouten, beperkte taalschat. diagn. routine-kno-onderzoek en audiometrie. spraak-taalanalyse, articulatieonderzoek. psychologisch en intelligentieonderzoek. eventueel neurologisch, pediatrisch en psychiatrisch onderzoek. th. afhankelijk van de oorzaak. zo mogelijk causaal. voorts op de stoornis gerichte therapie: spraakles, eventueel buitengewoon onderwijs. stoornissen in de productie van de spraakklanken. articulatiestoornissen rhinolalia (rhinolalia aperta, rhinolalia clausa), sigmatisme, rotacisme, labdasisme en andere. dysartrie-anartrie spreek-en stemafwijking door innervatiestoornis van de spraakorganen, gekenmerkt door stoornissen in ritme, tempo, modulatie, articulatie en intonatie. zie ook *broddelen en *stotteren. stemstoornissen *dysfonie (heesheid, schorheid), *afonie (fluisteren), *diplofonie (dubbeltonig stemgeluid), ventriculaire *fonatie (valsestemplooispraak). aet. . functioneel (frequentst), te onderscheiden in psychogeen (emotionele gespannenheid of conversieverschijnsel) en habitueel (verkeerd stemgebruik door te weinig spanning, hypokinese, of juist te veel, hyperkinese). . primair organische oorzaken zijn onder meer verlamming, larynxtumoren en hormonale veranderingen (zie *stemstoornissen, hormonale). . secundair organische stemplooiafwijkingen kunnen ontstaan als gevolg van habitueel verkeerd stemgebruik: reinkeoedeem, nodulaire laryngitis, chronische hyperplastische laryngitis. th. bij primair organische oorzaken: waar mogelijk, bij secundair organische oorzaken: stemtherapie in combinatie met stemplooimicrochirurgie. bij functionele dysfonie reëducatie van stemgebruik en veranderen van stemgewoonten alleen. dysfonie, ontstaan onder invloed van hormonale veranderingen. . hypogonadisme 'castratenstem'; bij hypogonadisme blijft de normale mannelijke larynxgroei uit zodat de hoge kinderstem blijft bestaan. diff. met de mutatiefalsetstem die een andere oorzaak heeft en bij normale larynxgroei optreedt. . hypothyreoïdie gaat gepaard met monotone, lage stem en trage, slecht gearticuleerde spraak. bij hyperthyreoïdie kunnen omgekeerde verschijnselen bestaan. . stemverandering in de graviditeit onder invloed van oestrogeenproductie kan de stem in de graviditeit door lichte zwelling van de stemplooien iets lager en enigszins schor worden. . virilisatie van de vrouwenstem a. door 'therapie' met androgene hormonen of anabole stoffen met androgene bijwerking. b. ovariumtumoren, adrenogenitaal syndroom. sympt. de stem is subjectief veranderd en wordt als 'vreemd' ervaren. hij is onvast geworden en slaat snel over. diagn. stemlabiliteit; verschuiving van de stemomvang naar beneden met extra daling van de laagst bruikbare toon. soms onvoldoende glottissluiting en lichte stemplooizwelling. th. de ontstane verandering is irreversibel. de stemtherapie moet gericht zijn op functionele aanpassing aan de verandering. stomatitis, zie hoofdstuk : stomatitis. stotteren (balbuties, dysfemie) ontwikkelingsstoornis van het spreken, gekenmerkt door herhaling van beginklanken, gespannen pauzes (blokkades) en vermijdingsverschijnselen (omredigeren, zwijgzaamheid). ook komen vegetatieve reacties voor (pupilverwijding, transpireren, hartkloppingen). aet. het stotteren ontwikkelt zich als een neurotische reactievorm, op basis van een genetische aanleg (jongens drie maal meer dan meisjes). derde tot vierde jaar: het zgn. spraakontwikkelingsstotteren, meestal voorbijgaand. begin basisschool: kritieke fase als gevolg van spanning door het nieuwe milieu met losraken uit de vertrouwde omgeving. diff. verhoogde aandacht voor spreken doet broddelen afnemen en stotteren toenemen. th. preventie door voorlichting ouders: beginnend stotteren is een signaal dat het kind zich onveilig voelt of zich onder druk voelt staan, of op abnormale wijze aandacht zoekt. latere stadia: versterken van eigen identiteit, desensibiliseren voor het stotteren, werken aan meer ontspannen, meer verbonden, minder gehaaste spreekwijze. op afstand hoorbare ademhaling, afhankelijk van de fase van de ademhaling gedurende welke deze het sterkst is in te delen in inspiratoire en expiratoire stridor, naar de plaats van ontstaan in . palatum molle, . tongbasis, . larynx, . trachea, . bronchi. inspiratoire stridor bij hoog gelokaliseerde stenosen, doordat het lumen van dit gedeelte van de ademweg het kleinst is tijdens de inademing. door onderdruk in het lumen wordt de wand tijdens de inspiratie aangezogen, wordt bij uitademing het lumen door overdruk vergroot. aet. tongbasis bij zuigelingen mandibulahypoplasie. mondbodemflegmone, carcinoom. larynx epiglottitis, laryngitis subglottica, larynxoedeem, larynxtumoren, stilstand van de beide stemplooien (in paramediane stand). trachea tumoren (schildklier, trachea), littekenstenose. expiratoire stridor bij bronchiale vernauwing; het bronchuslumen is het nauwste tijdens expiratie doordat de bronchi door de positieve intrathoracale druk gecomprimeerd worden. beoordeling van de stemplooitrilling door belichting met lichtflitsen, waarvan de frequentie enkele trillingen per seconde kleiner is dan die van de stemplooitrilling zelf. wanneer deze bijv. hz bedraagt en men een flikkerfrequentie van trillingen per seconde spiegelt, ziet men de stemplooi een schijnbare trilling van maal per seconde uitvoeren. tonsil, maligne aandoeningen van . maligne tonsiltumor plaveiselcelcarcinoom, soms eerste lokalisatie van een non-hodgkinlymfoom. sympt. keelpijn, uitstralend naar oor en hals, slikklachten, halitose; vroege metastasering van het plaveiselcelcarcinoom naar de regionale lymfeklieren (kaakhoek, jugulair). th. bestraling (soms in combinatie met chemotherapie), operatie of combinatie van beide. wegens de grote kans op occulte metastasering wordt de klinisch niet voor metastase verdachte halslymfeklierketen electief medebehandeld. progn. door veelal late diagnose vrij slecht: vijfjaarsoverleving %. . maligne tonsiltumor als onderdeel van een systeemziekte de keelamandelen zijn vaak (eenzijdig) aangedaan als onderdeel van acute of chronische leukemie of een (non)hodgkinlymfoom. soms is de tonsilaandoening het eerste verschijnsel. bij de acute lymfatische leukemie ontstaat het beeld van acute tonsillitis met necrose, bij de chronische vorm wordt hypertrofie met ontsteking gevonden. tonsillitis (algemeen) acute of chronische ontsteking van de keelamandelen. tonsillitis agranulocytotica ulcererende tonsillitis als begeleidende ziekte bij agranulocytose. banale tonsillitis acute of chronische tonsillitis, meestal door hemolytische streptokokken veroorzaakt (zgn. tonsillitis lacunaris). tonsillitis bij acute leukemie. tonsillitis luetica zeldzame vorm van lues i. tonsillitis bij m. pfeiffer tonsillitis als onderdeel van een algemene infectie met epsteinbarrvirus. tonsillitis van plaut-vincent acute tonsillitis aan e en zijde met necrose, veroorzaakt door fusiforme bacteriën en spirillen. tonsillitis tuberculosa boviene tuberculose waarvoor de tonsillen een porte d'entr ee vormen. verder vindt men tonsillitis bij difterie, roodvonk en maligne tonsiltumoren (zie afzonderlijk besproken vormen). voork. vooral bij kinderen en jeugdige volwassenen. sympt. keelpijn, vaak angina genoemd, vooral bij slikken, uitstralend naar het oor. algemeen ziek zijn met koorts (soms hoog). halitose. pijnlijke hals door regionale lymfadenitis (kaakhoek, hoog jugulair). diagn. de tonsillen zijn rood en gezwollen met witgele proppen in de crypten. rode zwelling van farynxbogen en farynxachterwand. compl. peritonsillaire flegmone en abces. acute reuma met endocarditis, acute glomerulonefritis. lymfadenitis colli, eventueel halsklierabces. sepsis. diff. met alle andere vormen van tonsillitis. th. zacht dieet, zo nodig analgetica. een ijskraag helpt soms tegen de pijn. geen plaatselijke therapie. penicilline is effectief doch niet altijd nodig; wel steeds bij patiënten met hart-en nierafwijkingen. bij recidivering (meer dan - tonsillitiden per jaar) tonsillectomie in een rustige periode. acuut of chronisch verlopende tonsillitis aan beide zijden met necrose en ulceratie bij agranulocytose. aet. agranulocytose, onafhankelijk van de oorzaak. secundaire banale infectie. hist. beeld van ulcus zonder ontstekingsreactie in de randen. sympt. als bij banale tonsillitis, vaak ook stomatitis, algemene verschijnselen. diagn. op grond van bloedafwijkingen. th. agranulocytose: zie hoofdstuk : agranulocytose. tonsillitis-stomatitis: antibiotica, gargarisma. acute tonsillitis door epstein-barrvirusinfectie aan beide zijden met sterke vergroting en roodheid van de tonsillen. vaak secundair aan bacteriële infectie gesuperponeerd; dan meer het beeld van tonsillitis lacunaris. onderdeel van een algemene ziekte van het reticulo-endotheliale systeem. sympt. behalve algemeen ziek zijn: koorts, klieren, leverfunctiestoornissen, miltvergroting, keelpijn met slikpijn, halitose. ontsteking van de halsklieren, vooral van de spinale keten (voor m. trapezius). soms sterke halszwelling. diagn. bloedbeeld; reactie van paul-bunnel. th. zie hoofdstuk : mononucleosis infectiosa. tonsillectomie in acute stadium indien er sprake is van dreigende faryngeale obstructie. tonsillitis chronica (banaal) chronische irritatie van de keelamandelen. voork. kinderen en jeugdige volwassenen. aet. bacteriële infectie van (door vorige infecties) minder valide tonsillen. sympt. lichte wisselende keelpijn met vage slikklachten, soms echter geen pijn. algemene klachten, lichte malaise. halitose, vieze smaak in de mond (multipele), jugulaire halslymfomen. diagn. geïnjiceerde, crypteuze tonsillen. in de crypten retentie van detritus dat bij druk met de spatel op de voorste palatumboog naar buiten gedrukt kan worden. de tonsillen zijn vaak hypertrofisch, vooral bij kinderen. zij kunnen echter ook normaal van grootte zijn of zelfs atrofisch. vaak vergroeiing met de omgeving door de recidiverende chronische infectie. vergrote halslymfeklieren, vooral hoogjugulair. bij tonsilkweek streptococcus haemolyticus, h. influenzae en andere. th. tonsillectomie indien de recidiverende ziekteperiodes duidelijk gerelateerd zijn aan de tonsilinfecties. acute ontsteking aan e en zijde met ulceratie van de tonsil, veroorzaakt door fusiforme bacteriën en spirillen. voork. vooral bij adolescenten, vaker bij mannen dan bij vrouwen. aet. slechte mondhygiëne en verminderde algemene weerstand zouden een rol spelen. sympt. keelpijn met slikklachten aan e en of beide zijden. halitose. slechts weinig algemeen ziek zijn, in tegenstelling tot bij acute banale tonsillitis. geringe temperatuurverhoging. lichte ontsteking van de regionale klieren. diagn. tonsillitis aan e en zijde met ulceratie zonder algemeen ziekzijn. uitstrijk uit ulcus. in methyleenblauw of een grampreparaat zijn fusiformen en spirillen zichtbaar. eventueel kweek. diff. maligne tumor, acute leukemie. th. penicilline. gargarisma. tracheastenose, zie *larynx-tracheastenose. slap tracheaskelet waardoor vernauwd lumen door aanzuigen van de wand bij inspiratie. bij kinderen vaak met *laryngomalacie. aet. primair bij algemene ziekten van het bindweefsel. secundair als gevolg van druk door tumoren of grote vaten. operaties en/of ontsteking van trachea of omgeving. een relatie met gastro-oesofageale reflux wordt verondersteld. sympt. inspiratoire stridor. th. bij beperkte aandoening geen. eventueel decompressie door bijvoorbeeld aortopexie, anders tracheostomie. verbranding van oesofagus en hypofarynx kan het gevolg zijn van het drinken van zuren, logen of zeer hete dranken. zuren veroorzaken diepe caustische necrose, logen progressieve colliquatienecrose. laesies als gevolg van hete dranken zijn meestal oppervlakkige slijmvliesverbrandingen. voork. vooral bij jonge kinderen, verder als suïcidepoging. sympt. acuut beeld pijn, spontaan en bij slikken, sialorroe, soms benauwdheid en heesheid door larynxoedeem, braken (hemorragisch), koorts, in ernstige gevallen shock. compl. oesofagusperforatie met mediastinitis, hemorragische gastritis, maagperforatie, intoxicatie. late verschijnselen oesofagusstenose: passagestoornissen, vooral bij eten van vast voedsel. regurgitatie. oesofagitisverschijnselen. maagschrompeling, zelden oesofaguscarcinoom. diagn. inspectie van mond en keel. afwezigheid van roodheid, blaren of beslag zegt niets over het al of niet bestaan van laesies verderop. flexibele oesofagoscopie: ook al brengt dit perforatiegevaar met zich mee, toch is endoscopie vereist om de ernst van de laesies vast te stellen ter bepaling van de therapie; men beëindige de scopie zodra hieraan voldaan is. r€ ontgenfoto thorax. th. zie ook hoofdstuk : logen en *zuren. acute fase maagspoelen via sonde (alleen bij verse gevallen). antidotum. in het algemeen: melk, norit Ò . bij logen: verdund citroenzuur of azijnzuur. bij zuren: magnesium usta, bicarbon. natr. voedingssonde via de neus. breedspectrumantibioticum. zo nodig shockbehandeling, parenterale voeding, tracheotomie. late verschijnselen het voorschrijven van corticosteroïd om stricturen te voorkomen staat ter discussie. mocht toch een stenose (zijn) ontstaan, dan regelmatig oprekken via oesofagoscopie door middel van halfvaste bougies. eventueel maagfistel en 'draad zonder eind' aanleggen. bij irreversibele stenose chirurgie (oesofagoplastiek, coloninterpositie). vestibulitis nasi (eczema narium) diffuse ontsteking van huid en subcutis van neusingang en vestibulum nasi. aet. bacteriële infectie (meestal stafylokokken), vaak ook mechanische factor (neuspeuteren). soms secundair aan purulente rinosinusitis. sympt. rode, geëxcorieerde huid rond de nares en in het vestibulum. in het acute stadium vochtig en pijnlijk. bij het meer chronische beeld: vorming van korstjes en jeuk waardoor peuteren en kans op onderhouden van de infectie. th. zalf of cr eme met antibiotica en corticosteroïden. eventueel indifferente therapie met lanoline-vaseline-glycerine-anesthesinezalf, boorzalf of zinkzalf. zingknobbeltjes (noduli vocales) tegenover elkaar zittende, grijswitte knobbeltjes op de grens van het voorste en middelste derde gedeelte van de vrije rand van beide stemplooien. voork. schoolkinderen, vooral jongens van tot jaar; onvoldoende geschoolde zangers en sprekers. aet. stemoverbelasting: veel schreeuwen, onjuiste zangtechniek, zingen in verkeerd register. hist. in eerste instantie epitheelverdikking, oedeem en fibrose van de submucosa. later hyaliene degeneratie. sympt. heesheid, snelle 'vermoeidheid' en overslaan van de stem; soms diplofonie. diagn. karakteristiek beeld bij spiegelen. stemanalyse. th. stemrust. het beste is een spreekverbod gedurende bijv. e en week. daarna intensieve stemlessen. aanleren van goede steminzet, vermijden van 'wilde lucht' bij foneren door adembeheersing en glottissluiting. eventueel zeer conservatieve microchirurgische verwijdering van knobbeltjes. progn. op den duur gunstig. bij verdwijnen van de oorzaak meestal geleidelijk spontane genezing. adaptatie-onderzoek zie ook *audiometrie, specieel-diagnostische. adaptatie afnemen van de reactie van een zintuig op een prikkel; normaal fysiologisch verschijnsel. habituatie afnemen van de reactie bij een zeer langdurig aangeboden prikkel. bij retrocochleaire laesies vindt men vaak een pathologisch toegenomen adaptatie (engels: 'tone decay'). dit verschijnsel is van belang voor het onderscheid tussen cochleaire en retrocochleaire perceptiedoofheid. toongenerator waarmee zuivere tonen (sinus), met variabele frequentie en intensiteit worden aangeboden. dit kan gebeuren via een hoofdtelefoon ter bepaling van de luchtgeleidingsdrempel en via een beentriller op het mastoïd ter bepaling van de beengeleidingsdrempel. octaafaudiometer audiometer waarmee frequenties vast ingesteld worden en de drempel wordt gemeten door variëren van de intensiteit. gemeten wordt bij de octaven , , , . , . , . , . hz, soms ook bij tussenfrequenties. continue audiometer hiermee wordt de intensiteit vast ingesteld en de drempel bepaald door (continu) variëren van de frequentie van hoog naar laag en omgekeerd. vooral geschikt voor nauwkeurige bepaling van hogetonenverlies, zoals bij lawaaitrauma. screeningaudiometer eenvoudige audiometer waarmee alleen geluid via een hoofdtelefoon (luchtgeleiding) toegediend kan worden met een beperkt aantal frequenties (meestal , . , . , . hz) en een beperkt aantal intensiteiten. geschikt voor oriënterend onderzoek door huis-of schoolarts. hoge tonen audiometer hiermee kunnen ook zeer hoge frequenties tot . hz worden onderzocht, bijv. bij controle op beginnende ototoxische beschadiging. b ek esy-audiometer audiometer waarbij de frequentieschaal automatisch wordt doorlopen en de patiënt zelf zijn drempel aangeeft door het drukken van een knop. geschikt voor aanvullende diagnostiek van perceptieslechthorendheid. audiometrie bij kinderen verschillende methoden; de keuze is afhankelijk van leeftijd, ontwikkeling en intelligentie van het kind. . auropalpebrale reflex bij zuigelingen tot ongeveer weken. op geluiden met een sterkte van db of meer ontstaat knipperen van de oogleden. . reactie-audiometrie kan worden toegepast vanaf de de- de maand. onderzoek in het vrije veld naar de reactie (omkijken) op bepaalde prikkels waarvan intensiteit en frequentiespectrum bekend zijn (rammelen, belletjes, claxon enz.). in eenvoudige vorm als screeningtest in gebruik op zuigelingenbureaus (zgn. ewing-test). . spelaudiometrie bij kinderen vanaf het derde jaar toe te passen. het kind wordt geleerd dat het een bepaalde handeling mag uitvoeren zodra het een toon hoort, bijv. een knopje indrukken zodat een plaatje verschijnt of in eenvoudige vorm blokjes stapelen (bloktest). bij kleine kinderen wordt vrije-veldstimulatie toegepast, bij oudere kinderen worden koptelefoons gebruikt zodat beide oren afzonderlijk onderzocht kunnen worden. behalve de genoemde subjectieve methoden kunnen de objectieve methoden worden gebruikt: . tympanometrie objectieve methode om luchthoudendheid en luchtdruk van het middenoor te bepalen (zie *tympanometrie). . *elektroaudiometrie. . meting *otoakoestische emissie. audiometrie, objectieve, zie *impedantiemetrie en *elektroaudiometrie en *oto-akoestische emissie. audiometrie, specieel-diagnostische naast toondrempel-en spraakaudiometrie is een aantal diagnostische tests ontwikkeld; vooral van betekenis voor bepaling van aard en lokalisatie van gehoorstoornissen. . tympanometrie, zie *tympanometrie. . hersenstamaudiometrie (bera), zie *elektroaudiometrie. . elektrocochleografie (ecog), zie *elektroaudiometrie. . stapediusreflexmeting bij stimulatie van ipsi-of contralaterale oor treedt met à db boven de drempel aantrekking van m. stapedius op. dit geeft verandering van de impedantie, die gemeten kan worden met de impedantiemeter. ind. topodiagnostiek van n. facialislaesie, ketenafwijkingen (bijv. stapesfixatie door otosclerose) eventueel als onderdeel van objectieve audiometrie. . balanstest interaurale vergelijking van de luidheidsfunctie van het oor. bij abnormale toeneming van de luidheid ten opzichte van de intensiteit wordt gesproken van regressie of recruitment. dit verschijnsel is specifiek voor cochleaire perceptieslechthorendheid. test alleen uitvoerbaar wanneer e en oor normaal is. . toonvervaltest (tonedecaytest) test waarbij de perstimulatoire adaptatie aan een continue geluidsprikkel wordt gemeten. normaal is een intensiteit van db boven de drempel voldoende om een toon permanent te kunnen horen. dient de geluidsintensiteit opgevoerd te worden, dan spreekt men van toonverval. dit verschijnsel is vrij specifiek voor perceptieslechthorendheid als gevolg van een retrocochleaire laesie (bijv. brughoektumor). . b ek esy-audiometrie (zie ook *audiometer) hiermee wordt behalve de drempel ook het kleinst waarneembare intensiteitsverschil en langs indirecte weg ook de perstimulatoire adaptatie bepaald. audiometrie, toondrempel-(drempelaudiometrie) bepaling van de gehoordrempel voor zuivere tonen (sinus). met behulp van een audiometer wordt de nog juist waarneembare intensiteit voor de diverse frequenties van het normaal hoorbare frequentiegebied bepaald. men kan twee werkwijzen volgen. octaafaudiometrie hierbij wordt bij een aantal vaste frequenties de drempel bepaald. continue audiometrie hierbij wordt in plaats van de frequentie de intensiteit op een aantal vaste niveaus ingesteld waarbij wordt nagegaan welke frequenties worden gehoord. achtereenvolgens wordt aan beide oren eerst de drempel bepaald voor luchtgeleiding (m.b.v. koptelefoons) en daarna voor beengeleiding (m.b.v. een beengeleider op het mastoïd). bij het onderzoek wordt het oor dat niet getest wordt uitgeschakeld door het te maskeren met behulp van een ruis. bij beengeleidingsonderzoek is dit altijd noodzakelijk, omdat anders het andere oor 'mee kan horen' (zgn. overhoren). met het bepalen van de drempel voor luchtgeleiding onderzoekt men het gehele akoestische systeem, met die van de beengeleiding alleen het cochleaire en het centrale gedeelte. door lucht-en beengeleidingsaudiogram te vergelijken kan worden vastgesteld of de stoornis in geleidingsapparaat, perceptieapparaat of beide gelegen is. uit lucht-en beengeleidingsaudiogram kan worden geconcludeerd (zie ook *slechthorendheid): . grootte van het gehoorverlies, i.c. het drempelverlies; . soort van gehoorverlies, a. geleidingsslechthorendheid (afb. . ), luchtgeleiding gestoord, beengeleiding normaal, b. perceptieslechthorendheid (afb. . ), lucht-en beengeleiding in gelijke mate gestoord, c. gemengde slechthorendheid, verlies voor de luchtgeleiding groter dan voor beengeleiding; . frequentieverloop van het gehoorverlies. men kent de volgende belangrijke audiogramcurven, die meer of minder karakteristiek zijn voor bepaalde vormen van doofheid. . oplopend: in lagere frequenties groter verlies dan in hogere. veel bij geleidingsdoofheid, soms bij perceptiedoofheid, vooral beginnende m. m eni ere. . vlak: het verlies is voor alle frequenties even groot (afb. . ); zowel bij geleidingsdoofheid (vooral de ernstiger vormen) als bij perceptiedoofheid. . aflopend: het verlies is het grootst in de hoge frequenties (afb. . ); komt voor bij de meeste vormen van perceptiedoofheid. de curven lopen meestal geleidelijk af (zoals bij presbyacusis, toxische beschadiging), soms zeer steil en abrupt (bij hereditaire doofheid, ernstige lawaaibeschadiging). . 'dip' vorm: circumscript gehoorverlies, meestal tussen . en . hz; komt in het algemeen voor bij geringe lawaaibeschadiging. baha, zie *hoortoestel. in korte tijd ontstane onderdruk in het middenoor, gepaard gaande met hemorragische effusie. aet. snelle stijging van de luchtdruk, bijv. door snelle daling in een vliegtuig, waarbij de tubafunctie onvoldoende is om de ontstane onderdruk in het middenoor te equaliseren. klap op het oor. sympt. felle oorpijn, slechthorendheid en oorsuizen. diagn. ingetrokken trommelvlies, sterk geïnjiceerd, soms met hemorragieën; hemorragisch vocht in trommelholte. bij audiometrie geleidings-of gemengd verlies (binnenoor kan ook beschadigd zijn). bij tympanometrie onderdruk-of vochtcurve (zie afb. . ). trommelvliesperforatie. th. trommelvliespunctie of paracentese om de druk te equaliseren en het transsudaat af te zuigen. neusdruppels. eventueel antibiotica bij infectie. zie ook hoofdstuk : barotrauma. cerumen (oorsmeer) product van kliertjes in de huid van het kraakbenige gedeelte van de gehoorgang. de kleur varieert van donkergeel tot donkerbruin, de consistentie van dik vloeibaar tot halfvast. de productie is individueel zeer verschillend. cerumen bevat veel vetten en is licht zuur. het heeft een beschermende functie. men reinige zelf zijn gehoorgang niet van cerumen, behalve voor zover dit in de gehoorgangingang zichtbaar is. schoonmaakpogingen met wattenstokjes, lucifers, haakjes e.d. zijn sterk af te raden. zij leiden vaak tot afsluiting en tot otitis externa als gevolg van beschadiging van de huid. afsluiting van de gehoorgang door cerumen. aet. productie van veel oorsmeer, vaak samen met pogingen van de patiënt zelf de gehoorgang schoon te maken. sympt. afsluiting treedt meestal acuut op onder invloed van water. klachten van drukgevoel, slechthorendheid, vaak oorsuizen, soms duizeligheid. th. uitspuiten (wanneer althans geen trommelvliesperforatie bestaat) met water op lichaamstemperatuur. opzetstuk van de spuit goed vastschroeven. uiteinde van de spuit met de hand fixeren ten opzichte van het hoofd. na uitspuiten de gehoorgang met een wattenstokje nadrogen, eventueel eenmalig antibiotica-corticosteroïdzalf inbrengen. zo nodig kan de oorprop te voren week gemaakt worden door indruppelen van ol. ijfolie of %-nahco -oplossing (geen slaolie gebruiken vanwege het indikken/stollen van deze olie). proppen met vaste consistentie kunnen soms gemakkelijker met een zgn. cerumenlisje of -haakje worden verwijderd, onder microscopisch zicht. een uit afgestoten epidermislagen bestaande massa met cholesterolkristallen en vet. breidt zich expansief uit door appositie van steeds nieuwe lagen, afkomstig van een buitenste levende epitheellaag, de 'matrix' genaamd. hierdoor typische opbouw in concentrische lagen. karakteristiek witglanzend aspect. gedraagt zich als een benigne, expansieve tumor die de omgeving arrodeert. sympt. conductief gehoorverlies, chronische otorroe, vertigo. aet. congenitaal ontstaat uit epidermiscellen, die door een ontwikkelingsstoornis in het middenoor of mastoïd worden aangetroffen. verworven ontstaat bij chronische otitis media door ingroei van epitheel van de gehoorgang via een shrapnell-perforatie, soms via een randstandige trommelvliesperforatie en leidt tot destructie van de gehoorbeentjesketen en kan tot ernstige complicaties leiden (zie *otitis media purulenta chronica). diagn. otoscopisch onderzoek en ct-scan van het rotsbeen. th. operatieve verwijdering. bleek knobbeltje op de rand van de helix, vooral bij oudere mannen. aet. onbekend. sympt. zeer pijnlijk bij aanraking, de patiënt kan niet op het oor liggen. diff. carcinoom, hyperkeratosis senilis. th. excisie. cochleair implant, zie *hoortoestel. snel progressieve, tweezijdige labyrintitis met ernstige cochleaire perceptiedoofheid, duizeligheid en interstitiële keratitis. voork. hoofdzakelijk bij jongeren. aet. auto-immuunziekte door onbekende oorzaak. sympt. ernstig gehoorverlies, oorsuizen en duizeligheid; vaak ook afwijkingen aan andere organen. th. corticosteroïden, immuunsuppressiva. vooral bij kinderen en geestelijk gestoorden. bij volwassenen soms watjes. soms insecten. sympt. soms geen (toevallige vondst). bij inklemming: pijn, gehoorverlies, suizen en otitis externa. th. uitspuiten. niet met een pincet proberen. de oorarts gebruikt speciale haakjes of oogjes. doofheid, zie *slechthorendheid, *geleidingsslechthorendheid, *perceptieslechthorendheid. in ruime zin wordt met duizeligheid bedoeld: iedere sensatie van een gestoorde relatie tussen individu en zijn omgeving. vele indelingen zijn mogelijk. duizeligheid bij multipele sclerose vooral in het begin van de ziekte en bij opflikkeringen kunnen evenwichtsstoornissen optreden. sympt. (draai)duizeligheid met statische en loopstoornissen. soms gehoorstoornissen. diagn. complexe beelden waarvan de centrale origine duidelijk is: de statische loop-en wijsproeven zijn veelal gestoord, er is nystagmus, behalve horizontale ook verticale en rotatoire; soms positie-en plaatsingsnystagmus. de calorische prikkelbaarheid is meestal ongestoord. zie ook *perceptieslechthorendheid/doofheid bij multipele sclerose en hoofdstuk : multipele sclerose. kortdurende duizeligheid met voorbijgaande overwegend rotatoire *nystagmus na verandering van de hoofd-en lichaamsstand. vaak geleidelijk spontaan herstel. aet. laesie van het evenwichtszintuig, losgeraakte otolietresten in posterieure halfcirkelvormige kanaal, soms posttraumatisch; soms vasculaire stoornis (arteriosclerose). sympt. korte periode van duizeligheid na draaien van het hoofd en gaan liggen. diagn. het beeld is op te wekken door de patiënt uit zittende houding met naar links of rechts gedraaid hoofd snel achterover te leggen; de hierdoor ontstane duizeligheid en vaak rotatoire nystagmus zijn na ongeveer , à minuut verdwenen. geen andere afwijkingen bij het onderzoek. diff. plaatsings-en positienystagmus van andere, niet-'benigne' oorsprong, zoals bij cerebellumtumor, ponstumor enz. deze zijn niet uitputbaar doch constant. th. epley manouvre. eventueel fysiotherapie. duizeligheid na commotio cerebri is vaak onderdeel van een syndroom, bestaande uit hoofdpijn, concentratiezwakte, slaapstoornissen en vegetatieve verschijnselen. geen duidelijke relatie met de ernst van het trauma. psychische factoren spelen vaak een rol. bij onderzoek geen of weinig afwijkingen. soms is bij elektronystagmografie een spontane of plaatsingsnystagmus aantoonbaar. vervormd waarnemen van geluid. verschillende mogelijkheden: 'vals' waarnemen van bepaalde geluiden, metalige bijklank; dubbelhoren (een bepaalde toon wordt met het ene oor hoger of lager gepercipieerd dan met het andere oor, zgn. diplacusis binauralis). komt vaak voor bij m. m eni ere. dysostosis craniofacialis (m. crouzon) combinatie van brachycefalie, hypertelorisme, exophthalmos met visusverlies, onderontwikkelde bovenkaak, neusmisvorming en dysplasie middenoor, gehoorgang (atresie) en oorschelp. th. behandeling afhankelijk aard en ernst (schedel, aangezicht, oor). zie ook hoofdstuk : craniosynostose. dysostosis mandibulofacialis (treacher-collinssyndroom) ontwikkelingsstoornis van de eerste kieuwboog, meestal op genetische basis, bestaande uit: hypoplasie van boven-en onderkaak, antimongoloïde stand van de oogspleet en atresiesyndroom bestaande uit microtie, gehoorgangatresie en middenoordysplasie. diagn. genetisch onderzoek. th. afhankelijk aard en ernst (aangezicht, oogspleet, oren). congenitale dysplasie van trommelholte, trommelvlies, gehoorbeentjesketen en tuba. ernstige vorm in combinatie met dysplasie gehoorgang (atresie) en oorschelp (microtie). aet. hereditair of exogene noxe tijdens embryonale ontwikkeling (bijv. thalidomide). het frequentst zijn anomalieën van lange incusbeen en stapes, waardoor de gehoorbeentjesketen niet functioneert. sympt. geleidingsslechthorendheid van à db voor alle frequenties. soms zijn geen afwijkingen aan het trommelvlies zichtbaar. kan zowel aan e en als aan beide zijden voorkomen. diagn. audiometrie, ct-scan. diff. met otosclerose, onderbroken keten als gevolg van otitis media (meestal afwijkingen van het trommelvlies) of na trauma (anamnese). th. exploratie en indien mogelijk reconstructie gehoorbeentjesketen en trommelvlies. vorm van objectieve audiometrie waarbij de door geluidsstimulatie optredende potentialen van de haarcellen, n. cochlearis en de auditieve kernen en banen in de hersenstam worden geregistreerd. ind. a. indien niet op conventionele wijze een betrouwbaar drempelaudiogram kan worden verkregen (kleine kinderen, simulanten). b. voor de diagnostiek van retrocochleair gelokaliseerde gehoorstoornissen, vooral brughoek-en ponsprocessen vanwege de hierbij optredende latentietoenemingen tussen de verschillende toppen. c. gehoorscreening bij (jonge) kinderen en neonaten. . hersenstamaudiometrie (bera) hierbij bevindt zich de actieve elektrode op de kruin, de referentie-elektrode op het mastoïd. geregistreerd worden toppen: n -n. cochlearis, n -nucleus cochlearis, n -olivacomplex, n -en n -hogere centra. drempelbepaling op grond van amplitude-intensiteitscurve, latentiebepaling van de verschillende toppen op grond van intensiteits-latentiecurve. bij bera is top de duidelijkste. latentieverschuiving van n aan het te onderzoeken oor ten opzichte van die aan het normale oor pleit voor een retrocochleaire laesie. ind. a. drempelbepaling bij jonge kinderen, eventueel volwassenen. b. diagnostiek van retrocochleaire perceptieslechthorendheid. . elektrocochleografie (ecog) hierbij wordt de actieve elektrode (diameter , mm) via het trommelvlies op het promontorium geplaatst. op deze wijze wordt o.a. de samengestelde actiepotentiaal van de n. cochlearis geregistreerd. bij kinderen is narcose noodzakelijk, bij volwassenen soms lokaal anesthesie. ind. bij kinderen indien met bera geen responsies worden verkregen. bij volwassenen voor differentiële diagnostiek van cochleaire stoornissen. evenwichtsonderzoek statische en bewegingsproeven (vestibulospinale reflexen) a. proef van romberg (gesloten ogen, voeten tegen elkaar), eventueel door middel van een stabilometer (platform waarop wordt gestaan die de variaties van voetbelasting registreert), met het hoofd recht en naar links en rechts gedraaid. b. loopproef (ogen dicht). c. pas-op-de-plaatsproef. d. eventueel wijsproeven (ogen dicht) in drie vlakken. . nystagmusonderzoek onderzoek naar spontane, fixatie-, blikrichtings-, positie-(hoofd rechts, hoofd links, hoofd achterover, rechter zijligging, linker zijligging), plaatsings-en optokinetische *nystagmus. met bril van frenzel of door middel van de veel gevoeliger elektronystagmograaf met actieve elektroden bitemporaal en indifferente elektrode frontaal. onderzoek naar labyrintprikkelbaarheid en nystagmusvoorkeur calorisch onderzoek door spoelen van de gehoorgang met water van en van c ( cc in s). bepaling van maximale snelheid van de langzame nystagmus. links-rechtsverschillen en nystagmusrichtingverschillen van meer dan % zijn pathologisch. . pendelstoelonderzoek of draaistoelonderzoek registratie van de nystagmus als reactie op een afwisselend links-en rechtsomdraaiing met verschillende hoeksnelheid van de stoel. plotseling functieverlies van het evenwichtsorgaan, geïsoleerd of in combinatie met cochleaire uitval. meestal aan e en zijde. aet. labyrintitis (viraal of bacterieel); trauma (commotio, contusio, fractuur, bloeding); vasculair accident (trombose of embolie van de eindarteriën); acute intoxicatie; neur(on)itis vestibularis. sympt. hevige draaiduizeligheid met nausea, braken, zweten; valneiging, loopafwijkingen, miswijzen naar de zieke kant; slechthorendheid en oorsuizen als de cochlea mede getroffen is (zie *slechthorendheid). diagn. vestibulair statische proeven, loop-en wijsproeven tonen sterke afwijking in de richting van de aangedane kant. horizontale nystagmus, meestal derdegraads naar de gezonde kant. de langzame fase, de vestibulaire component van de nystagmus, is naar de zieke kant. zgn. harmonie vestibulaire. calorisch onderzoek (in de acute fase gecontraindiceerd) toont verminderde of onprikkelbaarheid. audiometrie en mri (ctscan). diff. aanval van m. m eni ere, cerebrovasculair accident. th. causaal (zie desbetreffende aandoeningen). facialisparalyse ( perifere type) uitval van de motorische functies van e en gelaatshelft met, afhankelijk van de plaats van de laesie, homolaterale uitval van traansecretie, m. stapedius en smaak op het voorste gedeelte van de tong. aet. paralyse volgens bell (waarschijnlijk herpetiforme etiologie), chronische otitis media met cholesteatoom, acute otitis media, fractuur van het os temporale, ooroperatie, herpes zoster oticus, lyme disease (borrelia burgdorferi), maligne parotistumor, aangezichtsverwonding. sympt. uitval van motoriek van de gehele gelaatshelft: de patiënt kan: het voorhoofd niet rimpelen en fronsen (voorhoofdstak), het oog niet sluiten (oogtak), de tanden niet laten zien, niet fluiten, de wangen opblazen en p zeggen (mondtak). in het begin ook hypotonie, speciaal van de mondtak, waardoor deze hangt en het drinken en spreken gestoord is. bij poging tot sluiten van het oog treedt de reflectoir opwaartse draaiing van de oogbol wel normaal op, waardoor uitsluitend sclera zichtbaar is, zgn. symptoom van bell. compl. keratitis door uitval van oogknipperen. als resttoestand contractuur, vooral van de mondhoek, en synkinesieën. diagn. beoordeling van de motoriek van iedere tak afzonderlijk en uitdrukken hiervan in een schaal (bijv. house i-vi). letten op hypotonie, contractuur en synkinesieën. kno-onderzoek, bestaande uit routineonderzoek, audiometrie en ct-scan. elektromyografie en elektroneuronografie: onderzoek op denervatieverschijnselen, prikkelbaarheidsdrempel. topodiagnostiek van de laesie op grond van functie van de voorhoofdstak, traansecretie, stapediusreflex en smaak. diff. centrale facialisparalyse (dan voorhoofdstak intact). th. causaal. *facialisparalyse volgens bell. chronische otitis media met cholesteatoom: zo snel mogelijk operatie. acute otitis media: antibiotica, indien geen verbetering sanerende ooroperatie. fractuur van het os temporale: . indien direct na het ongeval aanwezig betekent dit dat de zenuw doorsneden of ingeklemd is; daarom zodra de algemene toestand dit toelaat exploratie met vrijleggen van de zenuw, eventueel plastiek. . indien enige tijd na het ongeval ontstaan dan vermoedelijk compressie door oedeem; expectatieve houding, eventueel corticosteroïden. tumoren, afhankelijk van de omstandigheden: . facialisplastiek. . n. xii-n. vii-anastomosering. . cosmetische chirurgie in later stadium. zie ook hoofdstuk : facialisparalyse. facialisuitval van het perifere type aan e en zijde, meestal acuut ontstaan zonder duidelijke oorzaak: idiopathische perifere aangezichtsverlamming. aet. waarschijnlijk herpessimplexvirus. sympt. acuut (in enkele uren) optredende parese of paralyse van de spieren van e en gelaatshelft, hyperacusis (uitval van n. stapedius), smaakverlies op de voorste helft van de tong (uitval van de chorda tympani), intacte traansecretie (soms hypersecretie door corneaprikkeling), soms pijn in de mastoïdpunt. diagn. zie *facialisparalyse (perifere type). th. expectatief. bij ernstige parese of paralyse corticosteroïden en antivirale medicatie. spontaan herstel treedt bij % op. bij parese vrijwel altijd volledig herstel, bij paralyse correlatie met aanvang en snelheid van functieverbetering. chirurgische decompressie van de zenuw heeft geen aantoonbaar effect. onwillekeurige contracties van spieren, verzorgd door e en of meer facialistakken. aet. kernlaesie, abnormaal verloop arterie, beginverschijnsel van een op de zenuw drukkend proces. sympt. onwillekeurige, kortdurende, irregulaire contracties, meestal van de oog-en/of mondtak van e en kant. verergering onder invloed van emoties. soms langdurige kramptoestand. nauwkeurig kno-(oor, parotis) en neurologisch onderzoek (mri, angiografie) is nodig voordat tot symptoombestrijding mag worden besloten. th. symptomatisch. lichte sedering. partiële uitschakeling van n. facialis (botulinetoxine). contracties van een gedeelte van de aangezichtsmusculatuur op basis van gewoontevorming. betreft meestal m. orbicularis oculi, soms m. caninus. in principe willekeurige contracties. aet. onder invloed van emoties. diff. fluisterspraakonderzoek methode van gehooronderzoek waarbij men bepaalt tot op welke afstand gefluisterde woorden nog juist goed worden verstaan. normaal (in stilte) is dit m voor woorden met lage frequenties, toenemend tot m voor woorden met hoge frequenties. bij het fluisterspraakonderzoek kieze men daarom zowel woorden met voornamelijk lage frequenties (boom, doen) als hoge (sissen, fiets), liefst e enlettergrepige. steeds zorgen voor goede afsluiting van het niet-onderzochte oor. de methode is simpel, doch kwantitatief onbetrouwbaar (invloed van woordkeuze en omgevingslawaai, intensiteit van het fluisteren). niet-aangelegde gehoorgang. deze kan geheel ontbreken of na enkele mm tot cm blind eindigen. meestal in combinatie met een oorschelpmisvorming (microtie of anotie, zie *oorschelpdysplasie) en vaak ook met een *dysplasie van het middenoor. allerlei combinaties zijn mogelijk. komt zowel aan e en als aan beide zijden voor. aet. . hereditair. . exogene noxe in de eerste maanden van graviditeit (bijv. thalidomide). . onderdeel syndroom (m. crouzon, zie *dysostosis craniofacialis; treacher-collinssyndroom, zie *dysostosis mandibulofacialis). sympt. behalve de uitwendig zichtbare misvorming, geleidingsslechthorendheid van à db door volledig uitvallen van het geleidingsapparaat. de cochlea is vrijwel altijd normaal. th. e en zijde bij lichte afwijking geen therapie of operatieve correctie op schoolleeftijd of daarna. beide zijden eerst hoortoestel; soms is het nodig een gehoorgang te formeren voor het oorstukje. op schoolleeftijd operatieve correctie (gehoorgang formeren, tympanoplastiek met ketenreconstructie). een of meer gladde, witgele knobbeltjes, uitgaande van de benige gehoorgang. aet. chronische prikkeling, vooral bekend als gevolg van herhaalde inwerking van koud water (zwemmen, koud douchen). sympt. geen, tenzij retentie van cerumen optreedt. dan slechthorendheid, vaak met suizen, soms ook secundaire otitis externa. th. operatieve verwijdering bij recidiverende cerumenretentie of otitis externa. gehoorgangfurunkel, zie *otitis externa circumscripta. gehoorverlies door afwijking in gehoorgang en/of middenoor. bij *audiometrie verhoogde luchtgeleidings-en normale beengeleidingsdrempel. aet.*otitis media en resttoestanden, *otitis media met effusie en resttoestanden, *otosclerose, congenitale middenoordysplasie. zie ook *slechthorendheid. glomustumor (paraganglioma, chemodectoma) tumor, uitgaande van niet-chroomaffien paraganglionair weefsel, op verschillende plaatsen in het lichaam voorkomend in de vorm van zgn. glomera. de bekendste zijn: glomus caroticum (in carotisbifurcatie), glomus jugulare (langs v. jugularis interna); glomus tympanicum (diverse glomera langs het verloop van n. tympanicus), glomus vagale. glomustumor is de frequentste tumor van het middenoor, meestal glomusjugularetumor. de tumor is gewoonlijk benigne en groeit langzaam expansief met arrosie van de omgeving. metastasering is echter mogelijk. aet. erfelijk met wisselende penetrantie. voork. meestal op middelbare leeftijd, vaak familiaal voorkomend en soms bij dezelfde patiënt multifocaal. hist. groepen epitheloïde cellen in sterk gevasculariseerd stroma. geen mitosen. sympt. glomus jugulare of tympanicum: vaak eerst oorsuizen met pulserend karakter, spoedig gevolgd door geleidingsslechthorendheid. later facialisparalyse en labyrintuitval; soms hevige oorbloeding. bij lokalisatie in het foramen jugulare uitval van n. ix, x en xi (foramenjugularesyndroom). diagn. in het beginstadium vindt men een door het trommelvlies rood doorschemerende kleine tumor, later een grote, rode, gladde tumor die bij laedering zeer hevig bloedt. mri, mra of angiografie. th. voorkeursbehandeling bij progressieve klachten: chirurgische extirpatie, voorafgegaan door pre-embolisatie. indien niet operabel radiotherapie. glomustumoren zijn echter weinig stralengevoelig. bloedophoping in c. tympani, meestal na trauma (vooral lengtefractuur van het os petrosum). sympt. geleidingsverlies, meestal na tot weken herstel. th. in het algemeen niet nodig. punctie is niet zinvol. hemifaciale microsomie (goldenharsyndroom) congenitale onderontwikkeling van bovenkaak, onderkaak, uitwendig oor en middenoor aan e en zijde, nervusfacialisparese of -paralyse. ontwikkelingsstoornis van het eerste en tweede kieuwbooggebied. sporadisch voorkomend. voor oorsymptomatologie zie *dysplasie van het middenoor en *gehoorgangatresie, gehoorgangdysplasie. infectie door herpeszostervirus met blaasjes in de oorschelp, soms gepaard gaande met uitval van een of meer hersenzenuwen, vooral n. facialis en n. cochlearis en n. vestibularis (dan *ramsay-huntsyndroom genoemd). vaak op oudere leeftijd. aet. opflikkering van latent aanwezige varicellavirus. hist. lymfocytaire infiltratie van ganglion en zenuw. sympt. roodheid met blaasjes, vooral in het cavum conchae, die snel indrogen. neuralgie die soms maanden kan blijven bestaan. perceptieslechthorendheid, vooral voor de hoge frequenties. nystagmus (meestal uitvalsnystagmus), gestoorde statische proeven in de acute fase, verminderde calorische prikkelbaarheid van het labyrint. diff. met herpes simplex (geen pijn, geen uitval van de hersenzenuwen). diagn. klinisch beeld. direct microscopisch onderzoek van inhoud van de blaasjes (tzanck-test). eventueel serologisch onderzoek. th. antivirale medicatie in combinatie met corticosteroïden zo snel mogelijk starten. blaasjes droog behandelen. progn. de prognose ten aanzien van de uitvalsverschijnselen is matig. vorm van osteogenesis imperfecta (zie hoofdstuk : osteogenesis imperfecta). combinatie van blauwe sclerae, fragilitas ossium en geleidingsslechthorendheid. afwijkingen aan de stapes, soms van de voetplaat gelijkend op die bij otosclerose, soms atrofie van de crura. aet. hereditaire aandoening; stoornis van mesenchymale weefsels. th. eventueel stapeschirurgie. hoortoestel (hoorapparaat) elektrisch apparaat, bestaande uit microfoon, versterker en luidspreker, dat geluid versterkt. als spanningsbron batterijtje of oplaadbare accu. voorzien van aanuitschakelaar, volumeregelaar, telefoonschakelaar (aan te zetten bij telefoneren en bij gebruikmaking van ringleiding in theater, kerk enz.), instelbare frequentiegevoeligheid en in sommige gevallen instelbare versterkingsregeling (zgn. peakclipping of automatische versterkingscontrole). sommige toestellen bieden keuze uit verschillende programma's en hebben infrarood-afstandsbediening. er bestaan luchtgeleidingstoestellen (de meest gebruikte) en beengeleidingstoestellen (o.a. voorgeschreven bij otitis media met secretie en bij tweezijdige gehoorgangatresie). de volgende typen worden onderscheiden: in-het-oor-toestel (iho) ind. lichte en matige slechthorendheid. achter-het-oor-toestel ind. matige tot ernstige slechthorendheid. voordeel: natuurlijke geluidsopvang; nadeel: windgeruis. kasttoestel ind. zeer ernstige slechthorendheid. wordt onder de kleding gedragen, heeft grootste vermogen en grote instelmogelijkheden. bezwaren: geluidsopvang op onnatuurlijke plaats, kledinggeruis, zichtbaarheid. hoorbril in principe gelijk aan achter-het-oor-toestel, wordt echter verwerkt in brillenpoot. beengeleidingshoorbril bril met hoortoestel in brillenpoot met directe geluidsoverdracht op het mastoïd. verder zijn de volgende aanpassingen mogelijk: monauraal een van beide oren wordt met een toestel uitgerust. bij lichte slechthorendheid meestal het slechtst-, bij matige tot ernstige slechthorendheid het best horende oor. binauraal toestel in beide oren. cros (contra-routing-of-signal) achter-het-oor-toestel, waarbij het geluid wordt opgevangen aan het ene oor en via een los elektrisch snoertje achter het hoofd om c.q. door een brillenpoot wordt geleid naar een toestel met versterker en telefoon aan het andere oor. ind. eenzijdige doofheid. bi-cros als cros, doch aan ontvangend oor een volwaardig toestel. ind. eenzijdige doofheid met gelijktijdig slechthorendheid aan het andere oor. baha (bone anchored hearing aid) hoortoestel (beentriller) dat op een in het os temporale aangebrachte titaniumschroef wordt gefixeerd waardoor stimulatie van het binnenoor via botgeleiding mogelijk is. in principe vergelijkbaar met beengeleidingshoortoestel (zie hiervóór). biedt echter grotere mogelijkheden door het betere contact met het schedelbot. ind. geleidingsslechthorendheid en gemengde slechthorendheid (met redelijke binnenoorfunctie) indien aanpassing van een gewoon (luchtgeleidings)toestel niet mogelijk is (bijv. door congenitale afwijkingen) of gecontra-ïndiceerd is (bijv. chronisch loopoor). cochleair implant (elektrische binnenoorprothese) elektrische apparatuur bestaande uit een microfoon, spraakprocessor, uitwendige spoel, inwendige spoel en elektroden die via het ronde venster in de cochlea worden gebracht waarmee bij (sub)totaal doven de resterende vezels van de gehoorzenuw kunnen worden gestimuleerd. ind. (sub) totaal dove volwassenen en kinderen die met een gewoon hoortoestel niet in staat zijn spraak te verstaan. de inwendige spoel wordt langs chirurgische weg in het os temporale geïmplanteerd. de elektroden worden via het mastoïd en het ronde venster in de cochlea gebracht. de uitwendige spoel wordt tegenover de inwendige op de huid gebracht en magnetisch gefixeerd. de spraakprocessor wordt samen met de microfoon achter het oor geplaatst (oorhanger). de spraakprocessor kan ook als kastje in de kleding worden gedragen. de resultaten zijn zeer bevredigend, maar intensieve en langdurige training is vereist. oorstukje individueel uit kunststof gegoten stukje dat past in de gehoorgang en het cavum conchae om het geluid van het toestel aan het oor toe te dienen. het oorstukje dient goed passend te zijn, anders ontstaat rondzingen (fluiten). soms wordt naast het geluidtoevoerend kanaal in het oorstukje een tweede kanaal geboord ter beluchting van de gehoorgang en/of wijziging van de frequentiekarakteristiek van het toestel. abnormaal luid waarnemen van geluid, soms met pijnsensaties. bij cochleaire laesies met sterke recruitment, zoals m. m eni ere en lawaaitrauma. verder tijdelijk bij uitval van m. stapedius door facialisparalyse. de impedantie van het middenoor (trommelvlies en gehoorbeentjes) is de weerstand die het middenoor biedt bij akoestische stimulatie. de impedantie (c.q. meegevendheid of compliantie) wordt gemeten door te bepalen welk deel van de geluidsgolf door het trommelvlies wordt teruggekaatst. tympanometrie, zie *tympanometrie. stapediusreflexmeting, zie *audiometrie, specieeldiagnostische. kinetosen (luchtziekte, wagenziekte, zeeziekte) prikkelingsbeeld met sterke vegetatieve en algemene verschijnselen onder invloed van voortdurende bewegingen en versnellingen. aet. diverse factoren spelen een rol: voortdurende, overmatige belasting van het evenwichtssysteem, individuele gevoeligheid, psychische factoren, training. sympt. vegetatieve verschijnselen staan op de voorgrond, waaronder nausea, braken, zweten, bleekheid, versterkte darmfunctie. voorts lichte duizeligheid. th. labyrintdemping (cinnarizine), parasympathicolytica, lichte sedering. beschadiging van het evenwichtssysteem door inwerking van toxische stoffen (acuut of chronisch). aet. medicamenten aminoglycoside-antibiotica (streptomycine, neomycine, kanamycine, gentamicine, amikacine, tobramycine), fenothiazine, kinine en zijn derivaten. industrieel koolmonoxide. genotmiddelen nicotine, alcohol, narcotica. sympt. duizeligheid, soms draaisensaties, vaker onzekerheid, statische en loopstoornissen, nystagmus, gehoorverlies en oorsuizen door gelijktijdige beschadiging van het akoestische systeem. diagn. gestoorde statische en loopproeven (vooral bij acute beschadiging; bij chronische intoxicatie compensatie hiervan), spontane nystagmus, positie-en plaatsingsnystagmus, verminderde calorische prikkelbaarheid. diff. evenwichtsstoornissen van infectieuze en vasculaire origine. th. labyrintdempers alleen in het acute stadium. . oorsuizen (*tinnitus) vaak zeer hevig, vooral tijdens de aanval. meestal dreunend, in latere stadia een meer hoog karakter. . vaak drukgevoel in het oor. diagn. de diagnose berust op typische anamnese, audiometrie, vestibulaire bevindingen en uitsluiting van andere, bekende afwijkingen met gelijkende symptomen. audiometrie zuiver perceptieverlies, in het begin meestal alleen lagere frequenties, later alle frequenties. sterke regressie. in latere stadia bij spraakaudiometrie groot discriminatieverlies. vestibulair spontane nystagmus, vaak afhankelijk van positie en positieverandering. verminderde tot afwezige prikkelbaarheid van het labyrint bij calorisch onderzoek. m. m eni ere kan evenzeer tot de stoornissen van het evenwichtssysteem als tot die van het akoestische systeem worden gerekend. in de acute fase van de ziekte staan de vestibulaire verschijnselen op de voorgrond, vooral tijdens een aanval. tussen de aanvallen door, in latere stadia en bij resttoestanden overwegen de klachten van slechthorendheid en oorsuizen. th. conservatieve behandeling leefregels en eventueel sedativa, betahistine ter verbetering van microcirculatie en op indicatie endolymfe-pomp remmende middelen en calcium-entryblokkers. chirurgisch decompressie saccus endolymphaticus. behandeling niet bewezen succesvol, wellicht zelfs schadelijk. destructieve ingrepen n. vestibularis-doorsnijding, labyrintdestructie en transtympanale aminoglycosiden-toediening. terughoudendheid in verband met mogelijke betrokkenheid contralaterale oor. meningitis als complicatie van acute of chronische otitis media. . meningitis bij acute otitis media meestal gelijktijdig met of kort na ontstaan van otitis. gewoonlijk bij zuigelingen of jonge kinderen. diagn. otologisch: trommelvliesinspectie en punctie (kweek). ct-scan-onderzoek rotsbeen. th. algemene therapie en gerichte antibiotica. chirurgische sanering van het mastoïd. . meningitis bij chronische otitis media uitbreiding van chronische otitis media, meestal met cholesteatoom, naar de dura van de middelste (evt. achterste) schedelgroeve. soms gecombineerd met epiduraal abces. aet. bacterie van chronische otitis media. diagn. otologisch: trommelvliesinspectie, kweek, ct-scan. th. zo spoedig mogelijk drainage en sanering van mastoïd en epitympanum. algemene therapie, gerichte antibiotica. zie ook hoofdstuk : meningitis purulenta. microtie, zie *oorschelpdysplasie. ontsteking van het trommelvlies met vorming van blaasjes, gevuld met sereus of serosanguinolent vocht tussen epitheel-en bindweefsellaag van het trommelvlies. aet. virusinfectie. sympt. pijn, soms enig gehoorverlies. th. symptomatisch. lokale (otalgan Ò -druppels) of algemene pijnbestrijding. indien ook otitis media: antibiotica. degeneratieve verandering van het trommelvlies, meestal als gevolg van (chronische) ontsteking, soms na trommelvliestrauma. fibrosering van de elastische vezellaag van het trommelvlies met kalkafzettingen. deze manifesteren zich meestal als grillige scherp begrensde wittige plaques in het trommelvlies. zie ook *tympanosclerose. uitval van het perifere evenwichtssysteem, meestal eenzijdig, berustend op ontsteking van het eerste neuron c.q. de n. vestibularis. aet. waarschijnlijk virusinfectie, meestal blijvende evenwichtsuitval. diagn. volledig kno-, vestibulair, audiometrisch, r€ ontgenologisch (ct-scan), neurologisch en intern onderzoek (virustiters voor neurotrope virussen). bij evenwichtsonderzoek spontane horizontale nystagmus naar het niet aangedane oor, verminderde calorische prikkelbaarheid van aangedane zijde. normaal gehoor. de diagnose is vaak per exclusionem. th. symptomatisch, in de aanvang (bij heftige duizeligheid) antivertiginosa, na de acute fase fysiotherapie voor centrale compensatie. plaatsingsduizeligheid blijft nog vaak lang aanwezig. onwillekeurige oogbeweging met langzame (vestibulaire) en snelle (centrale) component. richting horizontaal, verticaal of rotatoir. graad eerstegraads: indien alleen aanwezig bij kijken in nystagmusrichting. tweedegraads: indien aanwezig bij kijken in nystagmusrichting en bij vooruit kijken. derdegraads: indien aanwezig bij kijken in alle richtingen. . oculaire nystagmus, zie hoofdstuk : nystagmus. . vestibulaire nystagmus (perifeer en/of centraal). a. positienystagmus nystagmus of verandering in nystagmus, optredend in een bepaalde hoofd-of lichaamsstand (hoofd rechts, hoofd links, hoofd achterover, rugligging, linker zijligging, rechter zijligging). kan uitputbaar en niet uitputbaar zijn en wisselende of constante richting bezitten. b. plaatsingsnystagmus nystagmus of verandering in nystagmus bij overgang (plaatsing) in een andere positie. zie ook *duizeligheid bij positieverandering. . nystagmus door neurologische aandoeningen. oorfistel/sinus, congenitale congenitale sinus of fistelgang, meestal pre-auriculair gelokaliseerd. op zichzelf onbelangrijke anomalie, meestal van hereditaire origine. kan onderdeel zijn van het branchio-oto-renaalsyndroom en dan gecombineerd met congenitale afwijkingen van gehoorgang en/of middenoor (zie *dysplasie van het middenoor en *gehoorgangatresie). dominant-erfelijk. de pre-auriculaire sinus is een overblijfsel van de eerste kieuwspleet. th. operatieve excisie in geval van recidiverende ontsteking. oorschelpmisvormingen komen geïsoleerd voor, doch vaak in allerlei combinaties met (syndromale) gehoorgang-en middenoormisvormingen (zie *gehoorgangatresie, gehoorgangdysplasie en *dysplasie van het middenoor). aet. hereditair of door exogene factoren (bijv. thalidomide) tijdens de embryonale ontwikkeling. . lichte anomalieën grootte, vorm of configuratie is afwijkend: a. de oorschelp of een gedeelte ervan is te groot (macrotie), b. oorschelp met sterk naar binnen gerolde helix, c. oorschelp met ontrolde helix, d. afstaand oor, de inplantingshoek ten opzichte van de schedel is te groot. . microtie, te kleine, rudimentair aangelegde oorschelp. ernstige anomalieën tot anotie zijn mogelijk. meestal gecombineerd met gehoorgangatresie en middenoordysplasie. soms bevindt het rudiment zich voor en onder de normale plaats van de oorschelp, zgn. wangoor of melotus. th. afhankelijk van de instelling van de patiënt. eventueel operatieve reconstructie of een kunstoorschelp. oorsuizen, zie *tinnitus. otalgie (oorpijn) kan optreden bij zeer uiteenlopende aandoeningen. . oor acute otitis media (heftig stekend, vaak bonzend), otitis externa (meestal met jeuk), myringitis bullosa, chronische otitis media (zelden, wijst op secreet of cholesteatoom onder spanning), herpes zoster oticus (heftige neuralgie), middenoorcarcinoom, acute facialisparalyse (bell). . gebit aandoeningen van de achterste molaren van de bovenkaak (uitstralende pijn). . temporo-mandibulaire disfunctie malocclusie, waardoor asymmetrische belasting. . keel bij tonsillitis, na tonsillectomie en bij tumoren uitstralende pijn naar het oor (prikkeling van n. glossopharyngeus n. tympanicus). . hypofarynx-larynxingang bij maligne tumor, eventueel bij ontsteking, uitstralende pijn in hals en oor (prikkeling van n. vagus -n. auricularis vagi). . cardiagebied hernia diaphragmatica (oorpijn links via n. auricularis vagi). blauwrode zwelling van de oorschelp als gevolg van een bloeduitstorting tussen kraakbeen en perichondrium, meestal in de bovenste helft en aan de voorzijde van de oorschelp. aet. trauma. sympt. fluctuerende zwelling met blauwrode verkleuring van de huid. gevaar van infectie waardoor *perichondritis, abcedering en oorschelpmisvorming door bindweefselretractie (zgn. bloemkooloor, vaak bij boksers!). th. punctie en aspiratie of chirurgische verwijdering. daarna adequaat drukverband. antibiotische bescherming. otitis externa circumscripta (gehoorgangfurunkel) ontsteking van huid en subcutis van het buitenste gedeelte van de uitwendige gehoorgang. gaat uit van haarfollikel of talgklier. aet. s. aureus. vaak speelt mechanische beschadiging (peuteren) een oorzakelijke rol. sympt. zeer pijnlijke lokale roodheid met zwelling van het perifere gedeelte van de gehoorgang. diff. otitis ext. diffusa (geen punctum maximum van de pijn). th. tampon met zure oordruppels of nat houden en vaak verversen. antibiotica bij algemeen ziek zijn. furunkel pas openen als deze rijp is. otitis externa diffusa . droge vorm (eczemateuze vorm) aet. infectie door bacteriën (staphylococcus, pseudomonas) of schimmel (aspergillus niger en aspergillus flavus), mechanische factoren (peuteren, overmatig reinigen) en water (wassen, zwemmen) spelen hierbij meestal een rol; als onderdeel van een huidziekte (eczeem enz.), allergisch (voor oordruppels, haarspray enz.) of mechanisch (peuteren, oorstukje). sympt. jeuk (pathognomonisch voor otitis externa), soms pijn, gehoorverlies bij d ebris op trommelvlies. men ziet geïnjiceerde meatus, schilfers en ander d ebris. soms doet ook de oorschelp mee. th. reiniging! indifferente therapie met zure oordruppels. lokale applicatie van antibiotica/ corticosteroïden in druppelvorm of cr eme, later zalf, eventueel in het begin op tampons indien de eerste therapie niet helpt. soms alleen corticosteroïden en/of antiseptica (clioquinol). bij schimmels antimycotica. de therapie lang voortzetten en zeer geleidelijk verminderen. oorzaak trachten te elimineren (factor peuteren, zwemmen, oorstukje van hoortoestel, haarspray e.d.). . vochtige vorm lokale infectie, meestal bacterieel; mechanische factoren (peuteren) en water (zwemmen) spelen vaak een rol. secundair aan otitis media purulenta. sympt. jeuk, pijn, vaak gehoorverlies als gevolg van secreetophoping, soms oorsuizen. de meatus is rood gezwollen en bevat waterig of vochtig secreet. soms uitbreiding op oorschelp en onmiddellijke omgeving van het oor. th. reiniging: eventueel door uitspuiten. lokaal antibiotica (corticosteroïden in cr eme-of druppelvorm), in het acute stadium bij voorkeur met tampons. bij hevige acute ontsteking met veel zwelling zijn b€ urowtampons in eerste instantie te verkiezen. otitis externa necroticans (maligne otitis externa) vorm van diffuse chronische otitis externa met klinisch maligne beloop. bij patiënten met afweerstoornissen, diabetes mellitus of slechte algemene conditie. aet. infectie door pseudomonas aeruginosa. sympt. oorsecretie, pijn, geleidingsslechthorendheid, granulaties en necrose van huid en secundair van benige gehoorgang, middenoor en mastoïd. compl. facialisparalyse, labyrintitis, uitval andere hersenzenuwen (n. xii, n. v) kan letaal verlopen. diff. carcinoom, gewone otitis externa. diagn. ct-scan laat botdestructie zien. th. gerichte antibiotica (hoog gedoseerd, langdurig) lokaal en systemisch, (operatieve) reiniging. otitis media (algemeen) ontsteking van het slijmvlies (en evt. bot) van het middenoor (trommelholte, tuba, trommelvlies en gehoorbeentjesketen). aet. viraal, bacterieel, evt. schimmel (secundair). vormen: . otitis media purulenta, acuut (oma), chronisch, resttoestand; zie hierna. . otitis media met effusie (ome), acuut, chronisch, resttoestand; zie hierna. . specifiek: a. tuberculose, b. granulomateuze aandoeningen (bijv. m. wegener, zie *granulomatosis van wegener). otitis media met effusie (algemeen) (ome, tubotympanitis, tubaircatarre) verzamelnaam voor aandoeningen met vochtophoping in het middenoor bij intact trommelvlies; otitis media serosa, seromucosa, mucosa ('glue ear', lijmoor). aet. tuba-insufficiëntie met subchronische infectie. otitis media met effusie, acuut (ome ) ontsteking van het slijmvlies van tuba en trommelholte, waardoor onderdruk en vochtophoping ontstaan in het middenoor bij een intact trommelvlies. ome bij kinderen freq. zeer hoge incidentie op de kleuterleeftijd, vooral in winterseizoen en vroege voorjaar. meestal tweezijdig. aet. ontsteking van neus en nasofarynx, meestal primair van virale oorsprong, doch secundair bacterieel (verwekkers zie *otitis media purulenta acuta). frequente complicatie van de gewone verkoudheid. sympt. meestal weinig. belangrijk is de slechthorendheid, die soms lang onopgemerkt blijft en na langere tijd consequenties kan hebben (leerprestaties, pedagogisch). diagn. trommelvlies licht geïnjiceerd (roze-geel) en verdikt door ophoping taaie mucus c.q. mucopus in middenoor. tympanogram: vlakke curve. audiogram: geleidingsverlies in de orde van - db, meestal voor alle frequenties. th. in het begin kan een afwachtende houding worden aangenomen, omdat de uiteindelijke negatieve invloed op de taal-spraakontwikkeling gering is. eventueel worden neusdruppels (matig effectief) en/of antibiotica (effectief) gegeven. indien geen verbetering binnen circa drie maanden: trommelvliesbuisje en adenotomie overwegen. ome bij volwassenen aet. virale infectie (verkoudheid) of barotrauma. indien enkelzijdig dient *nasofarynxcarcinoom te worden uitgesloten. sympt. verstopt gevoel in het oor met druksensatie, slechthorendheid soms met oorsuizen, soms wisselend afhankelijk van hoofdstand, soms borrelen in het oor bij neussnuiten, soms pijn, soms autofonie. diagn.*trommelvlies ingetrokken, eventueel vocht zichtbaar (vochtspiegel, belletjes lucht in het vocht). tuba afgesloten (*valsalvaproef, *politzer-manoeuvre). audiogram: licht tot matig geleidingsverlies. th. neusdruppels, eventueel antibiotica (breedspectrum), trommelvliespunctie (heldergeel, dun, vloeibaar, steriel vocht), politzeren en de patiënt de proef van valsalva laten doen. indien aanwezig oorzakelijke factoren behandelen, vooral septumdeformaties en bijholteontstekingen. otitis media met effusie, chronisch en resttoestand chronische en herhaalde ome wordt gekenmerkt door permanente tubadisfunctie en daardoor atelectase van het middenoor met vergroeiing, atrofie, fibrose, intrekking van het trommelvlies, adhesies in de trommelholte en ketenfixatie. geleidingsverlies, vooral in de lage frequenties. th. zeer beperkt. trommelvliesafwijkingen, middenooradhesies en ketenfixatie zijn zeer moeilijk operatief op te heffen. vaak ontstaan na het losmaken van vergroeiingen en fixaties nieuwe adhesies. otitis media purulenta acuta (oma) acute ontsteking van het middenoorslijmvlies met vorming van purulent secreet. zeer frequente ziekte, vooral bij kinderen tussen en jaar. in dat geval zeer vaak aan beide zijden, bij ouderen meestal aan e en zijde. aet. in volgorde van frequentie: streptococcus pneumomoniae, h. influenzae, moraxella catarrhalis, streptococcus haemolyticus. na herhaalde recidieven wordt vaker h. influenzae gekweekt. de infectie bereikt het middenoor via de tuba (tenzij sprake is van een infectie via een bestaande trommelvliesperforatie). meestal gaan acute rinitis en adenoïditis vooraf. vaak ook als complicatie bij een andere infectieziekte. sympt. oorpijn, vaak zeer hevig, soms met bonzend karakter. algemeen ziekzijn, vooral bij kleine kinderen op de voorgrond tredend. koorts, soms dyspepsie en braken. volwassenen klagen meestal ook over pulserend oorsuizen en soms over duizeligheid. trommelvliesbeeld: eerst 'vaatinjectie', vooral langs hamersteel en in achterbovenkwadrant; daarna 'rood-bomberend', het trommelvlies is sterk rood en staat vooral achter-boven bol, de normale contouren zijn verdwenen, de hamersteel is niet meer zichtbaar; ten slotte 'bleek-bomberend', onder invloed van de druk ontstaat plaatselijk ischemie, een voorstadium van perforatie. compl. acute mastoïditis (drukpijn op mastoïd, sluiering van de mastoïdcellen op r€ ontgenfoto's), intracraniële en intratemporale complicaties (zie *otitis media purulenta chronica: compl.) th. afhankelijk van de ernst (onder meer gerelateerd aan het stadium), leeftijd en risicofactoren. 'watchful waiting' bij begin stadia en bij gezond kind zonder belaste anamnese. alleen symptomatisch: pijnstilling aangevuld met neusdruppels. bij ernstig ziek zijn, herhaalde recidieven, risicogroepen en kinderen beneden , jaar oud worden antibiotica voorgeschreven. paracentese is geïndiceerd bij heftige, slecht op medicatie reagerende pijn, otitis media met abnormaal beloop en als sparende ingreep voor het trommelvlies bij dreigende perforatie. de paracentese is 'sparend' voor het trommelvlies in tegenstelling tot 'spontane' perforatie, die alleen mogelijk is na necrose van een gedeelte van het trommelvlies. otitis media purulenta chronica (ompc ) chronische ontsteking van slijmvlies (en bot) van trommelholte en gehoorbeentjesketen. vaak met chronische mastoïditis. men onderscheidt twee vormen: met cholesteatoom en zonder cholesteatoom. aet. niet-genezen acute otitis media. verwekkers: s. aureus, pseudomonas, proteus mirabilis, e. coli, anaeroben. sympt. loopoor, purulente vaak fetide secretie, slechthorendheid, soms oorsuizen. zelden pijn; dit wijst op secreet of cholesteatoom onder spanning. diagn. bevindingen . secretie, meestal geelbruin/geelgroen gekleurd, vaak fetide, wat een teken is van weefselafbraak. . trommelvliesperforatie. van belang hierbij is a. lokalisatie: pars tensa (frequentst) of pars flaccida (membraan van shrapnell): shrapnell-perforaties zijn berucht omdat ze meestal gepaard gaan met cholesteatoom, b. randstandige of niet-randstandige perforatie. . granulatie-en poliepvorming als gevolg van chronische slijmvliesontsteking. audiometrie geleidingsslechthorendheid. soms ook enig hogetonenperceptieverlies als gevolg van secundaire cochleabeschadiging. in beginstadia is het geleidingsverlies gering en betreft vooral de lage tonen. wordt de keten onderbroken, dan vindt men à db verlies voor alle frequenties. r€ ontgenfoto's (sch€ uller, ct-scan) sluiering van het mastoïd, sclerosering en soms holtevorming bij cholesteatoom. compl. . intratemporale complicaties: bezold-abces (abces m. sternocleidomastoideus); citelli-abces (abces m. digastricus); facialisparalyse; petrositis (syndroom van gradenigo: eenzijdige abducensuitval en trigeminusprikkeling); labyrintitis (acuut perceptief gehoorvlies en evenwichtsstoornissen). . intracraniële complicaties: meningitis; sinus sigmoideus-trombose; extraduraal of subduraal empyeem; hersenabces; otogene hydrocefalus (intracraniële drukverhoging met visusstoornissen en dubbelbeelden alsmede misselijkheid en braken). th. . conservatief regelmatige, goede reiniging, granulaties en poliepen verwijderen, lokale toepassing van breedspectrumantibiotica en corticosteroïden in druppelvorm door de perforatieopening. . operatief a. bij cholesteatoom, indien zichtbaar of bij vermoeden hierop (ct-scan, shrapnell-perforatie). b. indien het chronische ontstekingsproces ondanks adequate conservatieve therapie niet tot rust komt of telkens weer recidiveert. c. intracraniële en intratemporale complicaties dienen te worden beschouwd als medical emergency en dien men zo spoedig mogelijk te behandelen door middel van chirurgische sanering van het ziekteproces en breedspectrumantibiotica, later gevolgd door specifieke antibioticumbehandeling. van de uitbreiding hangt af welke operatie verricht zal worden: . mastoïdectomie en atticoantrotomie (saneren van mastoïd, antrum en epitympanum), . posterieure tympanotomie met middenoorsanering, . conservatieve radicaaloperatie (idem, maar nu met wegnemen van de gehoorgangachterwand en -bovenwand, zodat gehoorgang, mastoïd en epitympanum e en holte worden) of . radicaaloperatie (als het voorgaande, doch met uitruiming van het middenoor). waar mogelijk vindt na de sanering in dezelfde zitting reconstructie plaats (trommelvliessluiting en ketenreconstructie, eventueel gehoorgangachterwandreconstructie). na een sanerende operatie wegens cholesteatoom waarbij de gehoorgang intact is gelaten, vindt na / - jaar revisie op restcholesteatoom plaats (second look). oorsuizen. soms verergering door graviditeit. beter horen in lawaai (paracusis willisi). soms perioden van duizeligheid. diagn. normaal trommelvliesbeeld. udiometrie: klassiek is een zuivere geleidingsdoofheid die geleidelijk toeneemt en ten slotte bij volledige stapesfixatie tot à db verlies voor alle frequenties leidt, meestal inzinking in middenfrequenties (carhart notch). bij stapediusreflexmeting wordt geen reactie verkregen. wordt ook de cochlea aangedaan, dan treedt bovendien perceptieverlies op en ontstaat een gemengde slechthorendheid. de waarschijnlijkheidsdiagnose wordt gesteld op anamnese, familiaal voorkomen, normaal trommelvlies en audiometrie. th. stapeschirurgie. verwijderen van de stapesbovenbouw, maken van een opening in de gefixeerde voetplaat, plaatsen van een prothese (teflonstaaldraad, piston of anderszins). de resultaten zijn bij goede techniek zeer goed. hoortoestel indien operatie gecontra-indiceerd is. ook hiermee worden goede resultaten bereikt. bij aantasting van het binnenoor wordt wel nafluoride voorgeschreven. inspectie van gehoorgang en trommelvlies via een trechter. het trommelvlies wordt beoordeeld op aanwezigheid en plaats van lichtreflex, stand van hamersteel, kleur, perforaties, toestand van de membraan van shrapnell (pars flaccida), atrofische plekken en kalkafzettingen. perceptiedoofheid, unilaterale hereditaire (cochleadysplasie) dysplasie van de cochlea aan e en zijde. dominant-erfelijk met wisselende expressie. het vestibulaire apparaat is normaal. th. geen indien het gehoor aan de andere zijde normaal is. perceptieslechthorendheid/doofheid (algemeen) slechthorendheid c.q. doofheid door afwijkingen in de cochlea, n. cochlearis of centraal-auditief systeem. bij *audiometrie wordt eenzelfde verlies voor luchtgeleiding als beengeleiding gemeten. meest voorkomende oorzaken: presbyacusis, lawaaibeschadiging, hereditair, infecties, toxische beschadigingen, m eni ere en trauma. th. zo mogelijk causaal, cochleair-implant bij doofheid (zie *hoortoestel). zie ook *slechthorendheid. perceptieslechthorendheid, acute (plotselinge doofheid ) plotseling optredende ernstige slechthorendheid of doofheid, meestal eenzijdig, vaak gepaard gaand met oorsuizen, soms ook met duizeligheid. voork. in nederland worden - patiënten per jaar getroffen door plotselinge doofheid aan een of beide oren. aet. plotselinge slechthorendheid kent vele oorzaken, waaronder infecties of ontstekingen, vasculaire, hematologische, metabole oorzaken, auto-immuunprocessen, neurologische stoornissen en psychogene oorzaak. in een overgrote meerderheid van de gevallen kan echter geen oorzaak gevonden worden, de idiopathische plotselinge perceptieve slechthorendheid of plotsdoofheid. in recent onderzoek wordt reactivatie van een herpetiforme infectie van het binnenoor als oorzaak aannemelijk gemaakt. sympt. plotselinge sterke vermindering of uitval van de gehoorfunctie, vaak geassocieerd met oorsuizen. aanvalsgewijs optredende duizeligheid kan eveneens optreden. diagn. screening met stemvorkproeven van weber en rinne. subjectief audiometrisch onderzoek toont een perceptief gehoorverlies, evenwichtsonderzoek soms aanwijzingen voor een verminderd prikkelbaar labyrint. door middel van aanvullend audiovestibulair, laboratorium-, beeldvormend, neurologisch en intern onderzoek kan een eventuele onderliggende oorzaak worden vastgesteld of uitgesloten. th. bij aangetoonde oorzaak afhankelijk van het onderliggend lijden. bij de idiopathische vorm is alleen van corticosteroïden slechts een beperkt therapeutisch effect aangetoond. progn. in - % van de gevallen treedt gedeeltelijk herstel van de gehoorfunctie op, in een kleine minderheid wordt een functioneel gehoor bereikt. perceptieslechthorendheid/doofheid bij het jonge kind zonder speciale hulp komt bij aangeboren en vroeg verworven ernstige slechthorendheid of doofheid de spraakontwikkeling niet op gang. dit is het geval wanneer het gehoorverlies groter is dan gemiddeld à db. bij tijdige opsporing en goede diagnostiek kan dank zij hoorprothesen en speciaal onderwijs stomheid, afhankelijk van de ernst van de slechthorendheid, in belangrijke mate worden voorkomen. aet. . hereditair (ca. %) a. nietsyndromaal. b. cochleaire dysplasie. c. zeldzame vormen: cretinisme, syndroom van waardenburg en andere. . prenataal ontstaan (ca. %) a. rubella van de moeder, indien opgetreden in de eerste tot vierde maand van de graviditeit. b. andere (infectie)ziekten of intoxicatie (aminoglycosiden) in het begin van de graviditeit. . perinataal ontstaan (ca. %) a. kernicterus, ophoping van bloedafbraakproducten in akoestische kernen. b. geboortetrauma/ asfyxie/prematuritas, waardoor centrale en/of cochleaire laesies. . vroegverworven (ca. %) a. meningitis/encefalitis. b. infectieziekten (bof, influenza). c. recidiverende otitiden. sympt. geen reactie op normale huiselijke geluiden en op roepen en dergelijke; achterblijven of uitblijven van eigen geluidsproductie (het zgn. tateren of keuvelen zoals de iets oudere normaal horende zuigeling doet), uitblijven of achterblijven van de spraakontwikkeling, pseudodebiliteit en pseudo-autisme zijn mogelijk als gevolg van doofheid en niet-spreken. diagn. zo vroeg mogelijk gehooronderzoek. methode afhankelijk van leeftijd en ontwikkeling (zie *audiometrie bij kinderen), spraaktaalonderzoek, psychologisch en intelligentieonderzoek, soms neurologisch onderzoek. th. zo vroeg mogelijk hoortoestel in e en of op beide oren (dit ook afhankelijk van de sociale omstandigheden). hoortraining; tot jaar: hoortraining thuis onder leiding van de akoepedist van een dovenschool, - jaar: kleuterklas van doven-of slechthorendenschool, vanaf jaar: doven-of slechthorendenschool. bij subtotale doofheid elektrische binnenoorprothese (zie *hoortoestel: cochleair implant). in het verloop van de ziekte treedt soms slechthorendheid op. vaak spontaan herstel in korte tijd. perceptieverlies, sterk gestoord spraakverstaan, geen regressie, meestal sterk pathologische adaptatie. vrijwel altijd ook afwijkingen van het vestibulaire systeem, zie *duizeligheid bij multipele sclerose. beschadiging van cochlea en het centraalakoestische systeem door o -tekort. vooral bekend als gevolg van vlak voor, tijdens of direct na de geboorte optredende asfyxie. ook bekend op latere leeftijd, bijv. stoornis bij narcose (vooral ouderen met verminderde cerebrale doorbloeding). cochlea en centrale zenuwstelsel zijn zeer gevoelig voor zuurstofgebrek. hist. laesies van orgaan van corti en centraalakoestische systeem. sympt. slechthorendheid aan beide zijden, vaak asymmetrisch, vooral voor de hoge frequenties; vaak ook motorische stoornissen (spasticiteit) en intelligentiedefecten. th. zie *perceptieslechthorendheid/doofheid bij het jonge kind. perceptieverlies door aandoening van n. cochlearis, vestibularis en cochlea en vestibulair orgaan. zie *herpes zoster oticus. bij perceptiedoofheid lateralisatie in het beste oor, bij geleidingsdoofheid in het slechtste oor. zeer gevoelige proef, doch bij gemengde doofheden moeilijk te interpreteren. stemvorkonderzoek heeft als voordeel dat het eenvoudig is. het is echter niet kwantitatief (inconstante prikkel, invloed omgevingslawaai). als oriënterend onderzoek en als controle van een audiogram kan het echter goede diensten bewijzen. men realisere zich verder dat de verkregen uitkomsten alleen gelden voor de gebruikte frequentie. voor een kort oriënterend onderzoek kieze men de stemvork van hz. ontsteking met trombosering van de achter het mastoïd verlopende sinus sigmoideus. als gevolg van mastoïditis. sympt. ernstig ziekzijn met septisch beeld: intermitterend hoge temperatuur, koude rillingen, hoofdpijn. diagn. mri-onderzoek, mra-onderzoek cerebrale vaten. th. zo spoedig mogelijk sanerende ooroperatie met blootleggen van de sinus. antibacteriële therapie. geen antistollingstherapie. subjectief oorsuizen waarnemen van geluid zonder dat hieraan een geluidsprikkel ten grondslag ligt (het meest voorkomend). objectief oorsuizen horen van in het eigen lichaam geproduceerde geluiden (somatosounds) die ook voor een ander waarneembaar zijn te maken. oorsuizen kan zeer hinderlijk zijn, vooral in stilte. het karakter is zeer uiteenlopend. het kan continu of onderbroken zijn en al of niet pulserend. het kan sissend of ruisend zijn, dreunend of zoemend. een complex geluid (geruis) komt vaker voor dan een toon. aet. subjectief oorsuizen . uitwendig oor: cerumen, otitis externa. . middenoor: otosclerose, acute otitis media, acute otitis media met effusie, resttoestand otitis. . binnenoor: lawaaitrauma, intoxicaties, m. m eni ere, infecties, presbyacusis (weinig), bloed(vat)stoornissen. . retrocochleair: tumoren. . reflectoir: door afwijkingen van neus, hals of gebit. objectief oorsuizen vaatafwijkingen (arterioveneuze aneurysmata, arteriosclerose), glomustumor, spiercontracties (middenoorspieren, palatumspieren), kaakgewrichtafwijkingen. diff. zeer belangrijk. volledig kno-onderzoek met audiometrie is noodzakelijk. indien men geen otologische oorzaak vindt, moet men neurologisch, intern, oogheelkundig en tandheelkundig onderzoek overwegen. th. zoveel mogelijk causaal. in vele gevallen, m.n. bij oorsuizen door binnenoorlaesies of czs, is dit niet mogelijk. men heeft dan de volgende mogelijkheden: uitleggen van de oorzaak van het suizen of cognitieve of behaviour therapie, psychofarmaca, labyrintdempers, hoortoestel (maskeert het suizen), lidocaïne- % intraveneus in opklimmende dosis ( tot ml) doet het suizen soms tijdelijk verdwijnen. de vele andere gebruikte medicijnen hebben geen bewezen effect. trauma, zie *binnenoortrauma, *lawaaibeschadiging, *trommelvliestrauma, middenoortrauma, *othematoom. prominerende processus brevis, korter schijnende, meer horizontaal staande hamersteel (doordat vooral de umbo intrekt), verscherping van voorste en achterste plooi, putje in de membraan van shrapnell, onderbroken of verplaatste lichtreflex. als gevolg van onderdruk in het middenoor (ome, tubadisfunctie). trommelvliestrauma, middenoortrauma . trommelvliesperforatie perforatie of scheur als gevolg van luchtdrukverhoging zoals bij explosie, klap of zoen op het oor, of penetrerende verwonding (bij schoonmaken van de gehoorgang of een lasvonk). sympt. oorpijn, slechthorendheid, meestal met suizen, bloeding. diagn. vaak typische anamnese van klap op oor, pijn, gehoorverlies, oorsuizen. perforatie, onregelmatig van vorm met bloederige, rafelige randen. audiometrie geleidingsslechthorendheid. indien alleen trommelvliesperforatie meestal gering verlies, bij ketenlaesie - db. soms ontstaat secundair otitis media. th. meestal spontaan herstel. tympanoplastiek in vers stadium bij subtotale perforatie (gemakkelijker, verse wondranden). eventueel ketenreconstructie. antibiotica ter voorkoming c.q. genezing van secundaire ontsteking. . *hematotympanon bloed in het middenoor als gevolg van fractuur van het os temporale. . luxatie van gehoorbeentjes gevolg van schedeltrauma; breken van de keten gebeurt meestal door luxatie van de incus. vaak ook hematotympanon. sympt. geleidingsverlies van tot db. th. ketenreconstructie. bepaling van de compliantie (impedantie) van het oor tijdens variatie van de luchtdruk in de uitwendige gehoorgang. betrekkelijk eenvoudige en snel uitvoerbare onderzoekmethode waarmee kan worden bepaald: a. of zich lucht of vocht achter het trommelvlies bevindt, b. de druk van de lucht in het middenoor ten opzichte van de buitenwereld. de test is niet uitvoerbaar bij ophoping van cerumen of andere belangrijke afwijkingen in de gehoorgang. bij trommelvliesperforatie en onbeweeglijkheid van het trommelvlies (bijv. atelectase van het middenoor) geeft de test geen informatie. ind. belangrijk onderzoek voor het vaststellen van tubaircatarre, vocht in het middenoor (ome). ook bij jonge kinderen uitvoerbaar en daarom geschikt als screeningsmethode voor het vaststellen van otitis media met effusie. diff. differentiële diagnose bij geleidingsverliezen. techn. in de gehoorgang brengt men het afsluitend buisje met drie kanalen aan. via kanaal wordt een laagfrequente testtoon met constante intensiteit aangeboden. via kanaal meet men hoeveel van het aangeboden geluid wordt teruggekaatst. de mate waarin dit geschiedt, geeft informatie over de meegevendheid (compliantie) van het middenoorsysteem. via kanaal wordt de luchtdruk in de gehoorgang automatisch gevarieerd. de meegevendheid wordt geregistreerd als functie van de luchtdruk. indien het middenoor luchthoudend is, treedt een piek op in de curve wanneer de luchtdruk in het middenoor en die in de gehoorgang gelijk zijn. is vocht in het middenoor aanwezig, dan vertoont de curve geen piek, maar heeft een vlak karakter (zie afb. . ). veranderingen (onregelmatige witte plaques) van trommelvlies en middenoorslijmvlies als gevolg van chronische en recidiverende otitis media. vaak ook ketenfixatie (stapesvoetplaat en hamer en incus in het epitympanum). geleidingsslechthorendheid. resttoestand na otitis media. hist. fibrose, hyaliene en kalkachtige degeneratie. sympt. geleidingsverlies. th. chirurgisch. persen bij gesloten neus en mond, waardoor als gevolg van de verhoogde druk in de nasofarynx lucht in het middenoor wordt geperst. het doorgaan van de lucht is hoorbaar als een korte klik. de onderzoeker kan dit waarnemen via een afluisterslang in de gehoorgang of door inspectie van het trommelvlies (verandering lichtreflex) tijdens de manoeuvre. normaal is een overdruk van à cm water voldoende om de tuba te openen. bij trommelperforatie en goede tubafunctie is vaak geruis hoorbaar in plaats van een knapje. bij vocht in het middenoor kan een borrelend geluid ontstaan. vestibulaire verschijnselen door ischemie van evenwichtszintuig, vestibulaire kernen en cerebellum als gevolg van vertebralis-basilaris-insufficiëntie. hierbij doen zich de volgende mogelijkheden voor die in combinatie voorkomen: . trommelvliesafwijkingen (perforatie, fibrose, kalkafzetting, atrofie), . ketenafwijkingen (onderbreking of fixatie), . degeneratie van het middenoorslijmvlies (*tympanosclerose), . adhesies in de trommelholte en . tubadisfunctie waardoor onderdruk en intrekking van het trommelvlies indien dit intact is. sympt. slechthorendheid, eventueel re-infecties via trommelvliesperforatie. diagn. trommelvliesbeeld . perforatie. . kalk en fibrosering in de middelste trommelvlieslaag. . atrofie (gedekte perforatie). . intrekking. audiogram geleidingsverlies, afhankelijk van de ernst van de afwijking. het verlies is het grootste in lage tonen (oplopende curve). bij onderbreking van de keten en bij volledige fixatie à db geleidingsverlies voor alle frequenties trommelvliessluiting (myringoplastiek) ter verbetering van het gehoor en om een exogene re-infectie te voorkomen met behulp van autogene of allogene fascie of andere membraneuze structuur. . ketenreconstructie met behulp van autogene of allogene gehoorbeentjes en van prothesen van niet-biologisch materiaal. . opheffen van adhesies, klieven van strengen, losmaken van trommelvlies van promontorium vergroeid of van gefixeerde ketendelen biopt van granulatieweefsel met typisch pathologisch beeld. kweek. meestal bestaat ook banale superinfectie. onderzoek op tuberculose elders in het lichaam door de uitwendige haarcellen geproduceerde trillingen, die in de gehoorgang meetbaar zijn. men onderscheidt: spontane en door geluid opgewekte emissies (echo) zeldzaam bij het negroïde en mongoloïde ras. frequenter bij vrouwen dan bij mannen ( op ). aet. hereditaire aandoening met onregelmatige dominante wijze van overerving. grote endocriene verschuivingen (puberteit, graviditeit) kunnen het proces versnellen perceptieslechthorendheid/doofheid door immuunstoornissen cochlea en evenwichtsorgaan kunnen worden aangetast bij auto-immuunziekten. hetzij als onderdeel van een op verschillende plaatsen optredende stoornis, hetzij als geïsoleerde manifestatie perceptieslechthorendheid/doofheid door kernicterus perinataal ontstane perceptiedoofheid aan beide zijden ten gevolge van toxische beschadiging van de akoestische kernen door bloedafbraakproducten (zgn. kernicterus). vaak ook beschadiging van motorische kernen waardoor spasticiteit grens waarboven beschadiging: ca. mg bilirubine per liter. hist. degeneratie van zenuwcellen in nucleï cochleares, vooral de dorsale kern (hoge tonen). sympt. ernstige doofheid aan beide zijden, waardoor achterblijven van spraak-en taalontwikkeling, vaak ook spasticiteit; de intelligentie is meestal ongestoord. diagn. perceptiedoofheid aan beide zijden, meestal symmetrisch, met het grootste verlies voor de hoge frequenties perceptieslechthorendheid/doofheid door toxische beschadiging beschadiging van cochlea en e neuron door inwerking van toxische stoffen antibiotica uit de aminoglycosidenreeks, zoals streptomycine, neomycine vestibulair nystagmus (spontane, positie-invloed), gestoorde statische proeven in de beginstadia. verminderde prikkelbaarheid tot totale uitval van het vestibulaire apparaat bij calorisch onderzoek. th. hoortoestel geeft meestal matig resultaat. progn. vestibulaire verschijnselen: gunstig, uitval wordt op den duur gecompenseerd. gehoor: afhankelijk van het type intoxicatie, gunstig bij diuretica en salicyl. sombere prognose bij antibiotica. geen herstel, soms zelfs nog enige tijd progressie na het staken van de therapie (vooral van antibiotica bekend). prev. scherpe controle indien een ototoxisch medicament wordt gegeven gedurende lange tijd, in hoge dosis, of bij gestoorde nierfunctie met eventueel direct aanpassen van dosis of zelfs staken om verdere schade te voorkomen. audiometrie (hoge tonen, zie hoge tonen *audiometer) voor de aan algemeen perceptieslechthorendheid/doofheid op erfelijke basis; meestal een afwijking in de cochlea. . aanlegstoornis/degeneratie a. aanlegstoornis, dysplasie of aplasie van het labyrint, b. degeneratie van bij de geboorte normaal gehoor op jeugdige of op latere leeftijd. . syndromaal/niet-syndromaal hereditaire perceptiedoofheid komt alleenstaand voor en in combinatie met afwijkingen aan andere organen: a. oog, b. centraal zenuwstelsel, c. bindweefsel overerving: recessief geslachtsgebonden. vormen: . totale aplasie van het labyrint, zeldzaam, . dysplasie van de benige cochlea (mondini), . cochleosacculaire type: gestoorde vliezige cochlea en sacculus; de meest frequente vorm. sympt. ernstige slechthorendheid vanaf de geboorte, waardoor uitblijven van de spraakontwikkeling en algemene retardatie. audiogram: meestal symmetrische perceptieslechthorendheid hoortoestel, hoortraining, slechthorendenof dovenschool (zie *perceptieslechthorendheid/doofheid bij het jonge kind) gewoonlijk dominante, niet-geslachtsgebonden overerving met volledige penetrantie. hist. degeneratie van orgaan van corti en eerste neuron. sympt. progressieve slechthorendheid voor beide oren in dezelfde mate. begin op de schoolleeftijd. de spraak is normaal ontwikkeld. soms oorsuizen, geen vestibulaire verschijnselen. audiometrie: symmetrisch perceptieverlies, meestal eerst voor de hogere, later voor alle frequenties. sterk verminderde spraakverstaanvaardigheid. regressie. th. hoortoestel proberen wanneer het gehoorverlies zodanig is geworden dat het spraakverstaan ernstig is gestoord. vaak teleurstellend resultaat (recruitment, vaak steil aflopend audiogram). slechthorenden-of dovenschool. congenitale hereditaire perceptiedoofheid als onderdeel van een syndroom syndroom van usher congenitale perceptiedoofheid syndroom van alport progressieve perceptieslechthorendheid met progressieve glomerulonefritis. perichondritis auricularis ontsteking van het perichondrium van de oorschelp eventueel subperichondrale abcedering met necrose van kraakbeen. bij chronisch verloop onregelmatige verharding hiervan. gevaar voor misvorming van de oorschelp door bindweefselretractie, zgn. bloemkooloor. th. algemeen antibiotica met breed spectrum uitbreiding van acute otitis media en mastoïditis of chronische otitis media en mastoïditis, gewoonlijk met cholesteatoom. sympt. soms volledig of onvolledig syndroom van gradenigo: abducensparalyse, pijn in het trigeminusgebied en verlaagde corneareflex. soms piekende temperatuur in acute gevallen. diagn. klinisch beeld en ct-scan van het rotsbeen om drukverhoging in de nasofarynx mogelijk te maken moet deze door het palatum naar de keel toe worden afgesloten. dit tracht men te bereiken door de patiënt tijdens het blazen een slok water te laten slikken of woorden met veel gutturalen te laten zeggen (hik-hak-hok, koekoek) andere factoren zoals lichte lawaaibeschadigingen, intoxicaties, infecties, vasculaire afwijkingen enz. kunnen mede een rol spelen. hist. degeneratie van het orgaan van corti (verlies van haarcellen, degeneratieve veranderingen in de basilaire membraan), verdwijnen van zenuwcellen van het ganglion spirale en verlies van neuronen van het centraalakoestische systeem. sympt. slecht verstaan van spraak het tweegesprek gaat veel beter. soms licht oorsuizen. diagn. trommelvlies soms lichte degeneratieve verschijnselen zoals kalkafzetting het spraakaudiogram is soms veel slechter dan men op grond van het drempelaudiogram zou vermoeden, meestal groot discriminatieverlies. th. hoortoestel, eventueel met hoortraining. succes hangt af van vele factoren: grootte van het discriminatieverlies, algemene cerebrale en fysieke conditie en houding van de omgeving (langzaam combinatie van uitval van n. cochlearis (eventueel ook n. vestibularis), n. facialis en blaasjes in de oorschelp als gevolg van herpeszosterinfectie (zie *herpes zoster oticus en *perceptieslechthorendheid/doofheid door herpes zoster) recruitment (regressie) recruitment is een verschijnsel dat zich alleen voordoet bij perceptieslechthorendheid van cochleaire oorsprong ten gevolge van uitval buitenste haarcellen bij intacte binnenste haarcellen. ontbreekt bij retrocochleaire laesies (brughoektumor, centraal proces). kan bijdragen tot de differentiële diagnostiek. voorts leidt het tot verslechtering van de spraakverstaanvaardigheid doordat het de onderlinge luidheidsverhouding van diverse spraakklanken verstoort. daarom moet hiermee rekening worden gehouden bij het aanpassen van een hoortoestel de meest informatieve zijn: het transversale, het semilongitudinale en het semi-axiale vlak. . mri a. labyrint met inspuiting gadolineum. door middel van speciale technieken zijn de inhoud (vloeistof) van cochlea en evenwichtsorgaan zichtbaar te maken van boven afgesloten door een loep en aan de zijkant voorzien van een slangetje met ballon. door de trechter goed sluitend in de gehoorgang te plaatsen is het mogelijk door middel van de ballon de luchtdruk in de gehoorgang te variëren en het trommelvlies te bewegen doofheid: het gehoorverlies is zo groot dat de patiënt akoestisch van de wereld is afgesloten. men kan slechthorendheid op verschillende wijzen nader indelen. . naar grootte van het drempelverlies licht slechthorend: tot db verlies. matig slechthorend: à db verlies. zwaar slechthorend: à db verlies. gehoorresten/doof: meer dan db verlies. . naar lokalisatie van de stoornis a oorzaken: otosclerose met cochleaire aantasting, gelijktijdig voorkomen van geleidings-en perceptieslechthorendheid. . naar frequentieverloop van het drempelverlies zie ook audiogramcurven. a. hogetonenverlies, het verlies betreft vooral de hogere frequenties, het meest bij perceptiedoofheden. b. lagetonenverlies (ook wel basdoofheid genoemd), het verlies betreft vooral de lagere frequenties niet te verwarren met bewuste simulatie en aggravatie van slechthorendheid (meestal bij keuringen, verzekeringskwesties en dergelijke). aet. psychische conflictsituatie. vooral bij meisjes op de schoolleeftijd. sympt. patiënt klaagt over slecht horen, terwijl communicatie ongestoord is. diagn. bij gehooronderzoek wisselende en vaak ongewone uitkomsten. geen overeenstemming tussen de resultaten van verschillende methoden van onderzoek (bijv. groot verlies in toonaudiogram bij subnormaal spraakaudiogram) normaal en bij perceptiedoofheid wordt de stemvork het luidst c.q. het langst gehoord via luchtgeleiding (rinne-positief) meestal arteriosclerose; soms druk op a. vestibularis (zie *duizeligheid, *duizeligheid bij halswervelkolomafwijkingen). sympt. korte aanval van duizeligheid, al of niet met valneiging, loopstoornissen en vegetatieve verschijnselen. de aanvallen recidiveren waar mogelijk causaal; fysiotherapie. vertigo duizeligheid met draaisensaties (vaak in het horizontale vlak): de patiënt voelt zichzelf draaien of ziet de omgeving draaien key: cord- - gi xrci authors: chow, anthony w.; hall, caroline b.; klein, jerome o.; kammer, robert b.; meyer, richard d.; remington, jack s. title: evaluation of new anti-infective drugs for the treatment of respiratory tract infections date: - - journal: clin infect dis doi: . /clind/ .supplement_ .s sha: doc_id: cord_uid: gi xrci these guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. a wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. microbiologic evaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. alternatively, surrogate markers may be used to identify the etiologic agent. the efficacy of new drugs is evaluated with reference to anticipated response rates. establishment of the microbial etiology of respiratory tract infections is hampered by the presence of “normal flora” of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. this issue is addressed for each category of infection described. for example, it is suggested that for initial phase trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collect exudate for culture. acute exacerbations of chronic bronchitis also present difficulties in the establishment of microbial etiology. these guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. for pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. for each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. clinical improvement is not acceptable unless quantitative response measures can be applied. these guidelines deal with the evaluation of anti-infective drugs for the treatment of respiratory tract infections. five clinical entities are described: streptococcal pharyngitis and tonsillitis, otitis media, sinusitis, bronchitis, and pneumonia. a wide variety of microorganisms are potentially pathogenetic in these diseases; these guidelines focus on the bacterial infections. inclusion of a patient in a trial of a new drug is based on the clinical entity, with the requirement that a reasonable attempt will be made to establish a specific microbial etiology. microbiologicevaluation of efficacy requires isolation of the pathogen and testing for in vitro susceptibility. alternatively, surrogate markers may be used to identify the etiologic agent. the efficacy of new drugs is evaluated with reference to anticipated response rates. establishment of the microbial etiology of respiratory tract infections is hampered by the presence of "normal flora" of the nose, mouth, and pharynx, which may include asymptomatic carriage of potential pathogens. this issue is addressed for each category of infection described. for example, it is suggested that for initial phase trials of acute otitis media and acute sinusitis tympanocentesis or direct sinus puncture be used to collectexudate for culture. acute exacerbationsof chronic bronchitis also present difficulties in the establishment of microbial etiology. these guidelines suggest that clinical trials employ an active control drug but leave open the possibility of a placebo-controlled trial. for pneumonia, the guidelines suggest the identification and enrollment of patients by the clinical type of pneumonia, e.g., atypical pneumonia or acute bacterial pneumonia, rather than by etiologic organism or according to whether it was community or hospital acquired. for each respiratory infection, the clinical response is judged as cure, failure, or indeterminate. clinical improvement is not acceptable unless quantitative response measures can be applied. this is one of a series of disease-specific guidelines that have been prepared to assist sponsors and investigators in the development, conduct, and analysis of studies of new antiinfective drugs. these guidelines deal with the conduct of phase through phase clinical trials and are subsets of the general guidelines for the clinical evaluation of anti-infective drug products, which should be consulted for prerequisites to conducting studies in humans. these guidelines for the evaluation of drugs for the treatment of respiratory tract infections include acute streptococcal pharyngitis and tonsillitis, acute otitis media, acute and chronic sinusitis, acute exacerbations of chronic bronchitis, and acute infectious pneumonia (table ). the focus is primarily on infections of bacterial etiology, especially those due to respiratory pathogens such as streptococcus pyogenes, streptococcus pneumoniae, haemophilus irfiuenzae, and moraxella (branhamella) catarrhalis and respiratory anaerobes (e.g., bacteroides species, fusobacterium nucleatum, and peptostreptococcus species). readers should consult the specific guidelines for the evaluation of new anti-infective drugs for mycobacterial and fungal infections. the guidelines for clinical microbiology provide important background information and should be used in concert with the current guidelines. the respiratory tract infections considered in these guidelines are among the most frequent disease entities encountered in both children and adults. they are associated with potentially serious morbidity if unattended or treated subop-timally. they also are infections in which evaluation of specific anti-infective therapy may be difficult. the reasons for the difficulties include: ( ) routine noninvasive collection of specimens and culture techniques are often inadequate, and specimens are regularly contaminated by the indigenous microflora of the oropharynx and the upper airways; ( ) the microbial etiology is often complex and polymicrobial; and ( ) newly recognized etiologic agents continue to emerge (e.g. , legionella species, chlamydia pneumoniae, and coxiella burnettii). even with the use of sophisticated sampling and microbiologic techniques, the causative agents can be identified only for a small proportion ( %- % at best) of patients. furthermore, good clinical practice requires empiric initiation of anti-infective therapy for these conditions (with the possible exception of group a streptococcal pharyngitis) on the basis of a presumptive initial diagnosis before confirmatory microbiologic data are available. frequently, the microbiologic response to therapy cannot be definitively evaluated, even when the etiologic agent has been identified. this is often the case in otitis media, sinusitis, and pneumonia, when the use of invasive procedures such as tympanocentesis, sinus puncture, or transtracheal aspiration to confirm microbial eradication in the patient who is improving clinically generally is considered unjustified. thus, whereas microbiologic failure can be documented by repeat cultures, microbiologic eradication can only be assessed presumptively on the basis of clinical response. the current standards of anti-infective therapy for the respiratory tract infections encompassed in these guidelines are summarized in table . in addition to the changing trends in microbial etiology, several controversial areas exist: ( ) the clinical significance of ,b-iactamaseproduction among respiratory pathogens and the respiratory tract infections under study should be categorized according to the ageof the patient, chronicity of the disease, and anyunderlying or concomitant disease(s) in the patient. theinvestigational drugshould have in vitroactivity against the specific respiratory tract pathogen to be evaluated in a pathogen-specific studyandactivity against the vastmajority ofstrains ofthemost likely encountered pathogens in a diseasespecific study. evaluation oftheinfluence ofcombination therapy is desirable, as is assessment of the emergence of resistance in vitro. information obtained from studies in animals maybe of assistancein identifying preliminary dosage schedules for humans. evaluations of efficacy in standardized animalmodels of infection may be performed. determination of drug levels in respiratorytract secretions (suchas sinus, middle-ear, or endotracheal aspirates) or in tissue (such as pulmonary parenchyma) is not required because at present the clinical significance of these concentrations is uncertain. institutions should be capable of performing the following studies relevant to the management of respiratorytract infections when appropriate to a specific protocol: nucleic acid probeanalysis foridentification ofselected respiratory pathogens, radiography andcomputerized tomography (ct) and/or magnetic resonance imaging of the head and neck, sinuses, and chest; arterialblood gasdeterminations; tympanocente-sis; sinus puncture; thoracentesis; and bronchoscopy. these studies should be done in addition to routine diagnostic microbiologic testing. alternatively, special studies may be performed at a reference laboratory skilled in these procedures and approved by the appropriate authorities. the preferred design is the randomassignment of patients to the investigational-drug and active-control-drug groups. therandomization schedule shouldbe maintained bya study monitor. patients should be stratified according to age, severity of infection, presence of underlying disease, and concomitant non-antibacterial therapy. blinding of both subjects and investigators to treatment group(double-blind design) is encouraged whenever feasible. in all cases, the inclusion and exclusion criteria should be clearly identified prior to initiation of the study. all patients enrolled in the study should be assessed on the basis of "intention to treat." a uniform approach to clinical and microbiologic assessment duringand after therapy shouldbe implemented. endpointsforbothclinicaland microbiologic evaluation should be clearly stated, and whenever possible a quantitative scoring system should be devised. patient compliance shouldbe verified (e.g., by pill counts or by appropriate assays of drug concentrations in serum or other body fluids). the clinical entity addressed in this guideline is group a j -hemolytic streptococcalpharyngitis and tonsillitis. not included are clinical cases of pharyngitis due to other agents or cases in which streptococcihavebeen isolated in cultures of throatspecimens but have notbeen documented to be group a j -hemolytic streptococci. groupa j -hemolytic streptococcal pharyngitis remains one of the most frequentacute infections seen in ambulatory patients, especially school children between and years of age [ ] [ ] [ ] [ ] [ ] [ ] . antibiotic therapy for streptococcalpharyngitis is aimed not only at symptomatic improvement of the acute infection [ ] [ ] [ ] [ ] [ ] [ ] and the prevention of suppurative complications but also, and most importantly, at the prevention of the subsequent occurrenceof acute rheumatic fever [ , ] . the incidence of acute rheumatic fever in the united states has declined dramatically overthe past severaldecades, suchthat by the sit wasa rare sequelaof streptococcal pharyngitis [ , , ] . however, between and fourmajor outbreaks of acute rheumatic fever in three states resulted in a heightened concern for optimal treatment of streptococcal pharyngitis [ ] [ ] [ ] . penicillin, given orally or intramuscularly, has generally beenconsidered the drug of choiceand the drugagainst which other regimens havemost often been judged. a full days of oral therapy or a single injection of benzathine penicillin is required [ ] [ ] [ ] [ ] . shortening a course of penicillin by even a few days has been shown to resultin an appreciable increase in the rate of treatment failure. however, even withthe recommended days of oral therapy, the failure rate may still be high [ ] [ ] [ ] [ ] . in recent studies, penicillintherapy, givenorally or intramuscularly, has been associated withratesof microbiologic failure as high as %- %, in contrast to the rates of %- % seen years ago. the reasons for this increase are not clear,although the presenceof j -lactamase-producing organisms in the throat flora and an increasein the tolerance of streptococci to penicillin havebeen suggested as contributing causes. resistanceto erythromycin, a frequently used al- group a j -hemolytic streptococcalpharyngitiscan not be diagnosed accuratelyon clinical grounds alone because it is frequently difficult to differentiate this entity from pharyngitis caused by other organisms. therefore, diagnosis requires a positiveculture for group a j -hemolytic streptococcifrom a throatswab specimen in a patientwith symptomatic pharyngitis. alternatively, the diagnosismaybe made by use of one of therapiddiagnostic kitsthatcandetectgroupa j -hemolytic streptococcal antigen directly from a throat swab specimen [ ] [ ] [ ] [ ] . for the purposeof the evaluation of newdrugs, however, the diagnosis shouldbe confirmedwith a throat culture, since the sensitivity ( %- %, most %- %) and specificity ( %- %, most > %) of the rapid detection kits are quite variable [ ] [ ] [ ] [ ] . drugsused for the treatmentof group a j -hemolytic streptococcalpharyngitis shouldhavebeen shown to havebactericidal activity against group a j -hemolytic streptococci and to haveundergone relevant phase studiesprior to the initiation of clinical investigations. the drug under consideration shouldhave a lowindex of toxicity in bothchildrenandadults, sincea numberof otheragents existthat offer acceptabletherapyfor group a j -hemolytic streptococciand since streptococcal pharyngitis is usually a minor disease. furthermore, the drug shouldresult in clinical improvement within - hoursoftheinitiation oftherapy, withresolution offever within hours in uncomplicated streptococcalpharyngitis, as can be expected withpenicillin andother antimicrobial agents currentlyapproved for treatmentof streptococcalpharyngitis [ , [ ] [ ] [ ] [ ] [ ] [ ] . the drug under considerationalso should provide an acceptably low rate of microbiologic failure associated with recurrence or persistent carriage and a rate no greater than that associatedwith current standard therapy with penicillin ( %- %) [ ] [ ] [ ] [ ] . the drug shouldbe capableof preventing the suppurative complications of group a streptococcal pharyngitis and, ideally, of preventing rheumatic fever. it would be desirable to have data indicating that the drug is capable ofpreventing rheumatic fever, but it is recognized that this goal may not be achievable. a current concern in the treatment of acute streptococcal pharyngitis is whether the failure rate for penicillin therapy will continue to climb and whether penicillin should still be considered the standard therapy. in addition, there is controversy about when antimicrobial therapy should be initiated. clinical differentiation of group a streptococcal pharyngitis from other causes of sore throat is not alwayspossible, a problem that raises the question of whether antibiotic therapy should be initiated before bacteriologic confirmation is available. furthermore, prompt treatment of group a ( -hemolytic streptococcal pharyngitis has been shown to interfere with the antibody response and possibly to result in a higher rate of recurrence than that seen in patients whose therapy is delayed for a few days [ ] . last, controversy exists concerning whether post-treatment cultures should be obtained to detect bacteriologic failures and whether asymptomatic carriage necessitates treatment [ ] . patients eligible for study entrance are children or adults with symptomatic pharyngitis or tonsillitis of acute onset clinically consistent with infection with group a i -hemolytic streptococci and from whom group a ( -hemolytic streptococci have been isolated in cultures of throat -swab specimen or for whom a rapid screening test has indicated the presence of streptococci. to be evaluable for efficacy, the screening test results must be confirmed by culture. the guideline generally applies to ambulatory patients. signs and symptoms of acute pharyngitis or tonsillitis of acute onset include sore throat and evidence on physical examination of inflammation of the uvula and pharynx or tonsils, including erythema, often with edema of the tissues, with or without exudate. fever mayor may not be present. a single culture specimen should be obtained from the posterior pharynx prior to initiation of anti-infective therapy. at least colonies of group a i -hemolytic streptococci should be present on the culture plate. a throat specimen for culture is obtained with use of a throat swab that is passed over both sides of the posterior pharynx and the uvula [ ] . the preferred culture medium is sheep's-blood agar. all cultures negative at hours should be reincubated for another hours. reduced oxygen tension may enhance identification of group a ( -hemolytic streptococci. such a reduction may be achieved in a simple manner by stabbing the agar after the sample is streaked or by using a coverglass pressed onto the primary zone of inoculation [ ] . group a streptococci are identified by the bacitracin method or by an-other method of at least equal sensitivity and specificity [ , , ] . if a rapid diagnostic test is used for identification of group a streptococci, the findings must be confirmed by culture [ ] [ ] [ ] . the streptococci obtained on culture should be saved for subsequent typing when possible. the drug under consideration should be active in vitro against group a ( -hemolytic streptococci. the institution or the investigator should have access to a clinical microbiology laboratory where the following tests can be performed: culture of throat swabs on sheep's-blood agar and identification of group a ( -hemolytic streptococci. alternatively, a single laboratory may process samples referred from participating centers. clinical studies should include patients of different age groups, since the clinical manifestations of group a streptococcal pharyngitis and tonsillitis may vary with age of the patient. streptococcal pharyngitis is uncommon in children < years of age. classic exudative pharyngitis is most frequently observed in school-aged children. group a streptococcal pharyngitis in teenagers and adults is often atypical. children, adolescents, and adults of both sexes should be included. for other considerations, see general guidelines, section ix. it is not considered ethical to use a placebo control. an active control drug should be used. the control agent should be selected on the basis of previous experience demonstrating that it is among the most effective agents for the treatment of group a ( -hemolytic streptococcal pharyngitis at standardized and well-tolerated doses. the study should compare the trial drug with the active control drug. the treatment regimens should be randomized and of a double-blind design whenever possible. phase studies shouldprovide adequateinformation concerning dose, dosage interval, andotherpharmacokinetic characteristics. the usefulness of monitoring concentrations in serumor other bodyfluids or tissuesshouldhave been determined. the form of the drug (liquid, tablet, capsule)should be acceptable for patients of any age included in the study and should be an accurate dose (e.g., no cutting of tablets required). theusualtreatment coursewithstandard regimens (e.g., penicillin or erythromycin) is days. the optimalduration of therapy with the study drug maybe determined by additional studies. the initiation of therapy should be standardized, i.e., at the time of clinical diagnosis or at the time of culture confirmation. ifit proves necessary to add a seconddrug or to substitute a newantimicrobial drug, treatment is considered to have failed clinically. in the eventof allergy to or failure of either drug being evaluated, the patient shouldbe treated with an alternative, standard active drug. response should be evaluated by both clinical and bacteriologic assessment. clinical assessment should include history andphysical examination. documentation of the clinical response with regard to symptoms and signs, including fever, shouldbe obtainedat - days after initiation of therapy and at weekly intervals (± days) thereafteruntil the patient is asymptomatic. the -to -day assessment may take the form of a telephone call. patients should be observed posttherapy for a sufficient time to permit detection ofrelapse of disease and/orpost-streptococcal nephritisor carditis. the periodof post-treatment evaluation will varywithknowledge of the durationof anti-infective activitysubsequent to terminationof administration of the test drugs. asa generalguide, patients shouldbe followed-up for - weeks after termination of therapy. evaluation of thebacteriologic response requires a repeated throatcultureat the firstfollow-up visit, within - days after the end of therapy, and at any time clinical symptoms recur. additional posttreatment throatculturesmaybe necessary for patients treatedwith drugs known to remain in serum or tissue for intervals beyond the initial -to -day evaluation. all organisms recovered should be saved for typing if possible. groupa streptococci recovered duringtherapy or at the time of the follow-up visit should be evaluated for their in vitro susceptibility to the study drug. theserologic response to groupa~hemolytic streptococci may be evaluated in acute-and convalescent-phase sera for titersofantibody to streptolysin-o (aso) or otherstreptococcal antigens. serologic evaluation, however, is not required for evaluation of drug efficacy. compliance shouldbe evaluated by the return of all medicationcontainers andof anyremaining drugat the endoftherapy. documentation of drug in the urine or blood may also be used to assess compliance. ( ) definition ofclincial response. clinical cureis defined as complete disappearance of signs and symptoms without recurrence; clinical cure with recurrence is defined as the development of symptomatic pharyngitis documented to be causedbygroupa~hemolytic streptococci beforeor during follow-up in patients who were asymptomatic at the initial follow-up assessment; and clinical failure is defined as lack of any response to therapy. ( ) definition of microbiologic response. microbiologic eradication is defined as eradication of group a , -hemolytic streptococci at the initialand subsequent follow-up examinations; microbiologicpersistence is defined as failure to eradicate group a , -hemolytic streptococci at the time of initial follow-up; andmicrobiologic relapse is defined as initialsuppression of groupa~hemolytic streptococci withsubsequent positive cultures for group a , -hemolytic streptococci. thefinal assessment of efficacy maybe categorized according to both clinical and microbiologic criteria as in table . otitis media is the most frequent diagnosis recorded for infants and children who visit physicians because of illness [ ] . before years of age more than two-thirds of children have had one or more episodes of acute otitis media (aom) and more than one-third have had three or more episodes [ ] . the highest incidence of aom is in children - months of age. the incidence declines with age except for a limited reversal of the downward trend at the time of entry into day care or school. although middle-ear infection is considered uncommon in adults, a recent survey identified almost million visits to physicians by adults each year for this problem [ ] . males have a significantly increased risk for aom, and native americans and canadian and alaskan eskimos have high rates and severe disease. incomplete data suggest that american blacks have fewer episodes of ear infection than do members of other racial groups in the united states. early occurrence of the first episode of aom, sibling history of recurrent aom, not being breast fed, and attendance in day care are all associated with increased risk for recurrent aom [ , ] . since aom and secretory otitis media (som) are defined by the presence of middle-ear effusion (mee), techniques to determine the presence of air or fluid in the middle ear are critical to diagnosis. three methods are available: the standard technique of pneumatic otoscopy, typanometry, and acoustic reflectrometry. tympanometry uses an electroacoustic impedance bridge to record compliance of the tympanic membrane (tm) and provides objective evidence of the status of the middle ear and the presence or absence of fluid. technical difficulties limit the use of tympanometry in children during the first months of life. the acoustic otoscope or reflectometer is a hand-held instrument that utilizes principles of reflected sound waves to diagnose the presence of air or fluid in the middle ear. the microbiology of aom has been documented by appropriate cultures of mee obtained by needle aspiration. many studies have been performed in the united states, scandinavia, and japan. the bacteriologic results are consistent in demonstrating the importance of s. pneumoniae, h. influenzae ( % nontypable, % type b), and m. catarrhalis [ ] . s. pneumoniae is the most important bacterial cause of otitis media and is defined in mee of about one-third of children with aom. otitis media due to h. irfiuenzae has been associated with %- % of cases of aom, and rv %- % ofthese strains produce j -lactamase. m. catarrhalis has been isolated from mee in %- % of cases of aom, and a majority of these strains produce j -lactamase. virologic and epidemiologic data suggest that viral infection frequently is associated with aom. mycoplasma pneumoniae does not appear to playa role in aom, although some patients with lower respiratory tract disease due to m. pneumoniae may have con-comitantaom. c. trachomatis is a cause of aom but almost exclusively in infants < months of age. the microbiologic diagnosis of aom can be made only by aspiration of mee. this procedure should be done only by persons skilled in the technique. cultures of throat and nasopharyngeal swab specimens are of no value because they are neither sensitive nor specific when compared with culturs of isolates from the middle ear. the results of cultures of middle-ear fluids from the two ears are disparate in rv % of cases of aom (e.g., effusion from one ear may be sterile while the effusion from the other yields a bacterial pathogen, or different bacterial pathogens are isolated from the two ears). therefore, for evaluation of new drugs or vaccines, it is important that each diseased ear be aspirated for a complete microbiologic assessment and that outcome for each ear be evaluated separately [ ] . suppurative sequelae such as mastoiditis and other infratemporal and intracranial complications occur but are uncommon in developed countries. hearing loss is the most important complication of aom and mee. patients with mee suffer from hearing loss of variable severity. on average, a patient with fluid in the middle ear has a -decibel hearing loss. since intellectual development is dynamic during infancy, when the incidence of aom is highest, there is concern that any impediment to reception or interpretation of auditory stimuli might have an adverse effecton development of speech, language, and cognitive abilities. some studies suggest that children with histories of recurrent aom have lower scores in tests of linguistic and cognitive abilities than do their diseasefree peers [ ] . the clinical entity discussed in this guideline is limited to aom (synonyms include acute suppurative om and acute purulent om). the microorganisms considered are s. pneumoniae, h. infiuenzae, and m. catarrhalis. not included in this guideline are secretory otitis media and chronic suppurative otitis media. som is defined as the presence of mee behind an intact tm without acute signs or symptoms (synonyms include chronic om with effusion, persistent mee, om with effusion, and serous om). chronic suppurative om is defined as chronic discharge from the middle ear through a perforation of the tm (synonym includes chronic om). tympanocentesis and culture of mee is required for microbiologic diagnosis of aom. nose and throat cultures are of no value. tympanocentesis is a safe procedure when performed by skilled and experienced persons. the procedure provides not only specific microbiologic diagnosis but also symptomatic relief of acute pain by decompressing the em ; (suppl ) middle-earabscess. there is transientpain during the few seconds of the procedure. rare untoward events may occur, including bleeding, tearing of the tympanic membrane, and ossicular dislocation. approximately one-third of children with aom caused by a bacterial pathogen improve without treatment with antibacterial drugs. clinical resolution may occur because the contents of the middle ear are spontaneously discharged, either through the eustachian tube or by means of a spontaneous perforation of the tm. with appropriate antimicrobial therapy, however, signs and symptoms of aomimprovewithin - hours. mee maypersist (even though sterile) for weeks to months after onset of aom. the goals of antimicrobial therapy for aom are the rapid resolution of signs and symptoms of disease; sterilization of the mee; prevention of suppurative sequelae; reduction of the occurrence of relapse and recurrences; and decrease in time spent with mee. the preferredantimicrobialagent for the patient with aom must be active againsts. pneumoniae, h. irfluenzae, and m. catarrhalis. group a streptococci, staphylococcus aureus, gram-negative enteric bacilli, and anaerobic bacteria are infrequent causes of aomand need not be considered in initial therapeutic decisions. amoxicillin or an equivalenthas been the standard regimenfor aomsinceit is effective againstmost strains of the three major pathogens and is well tolerated, producing limited adverse effects. however, since at present %- % of h. irfluenzae strainsand %- % of m. catarrhalis strains in the united states produce~-lactamase, ã -lactamase-stable agent (such as amoxicillinplus a~-lacta mase inhibitor, a second-or third-generation cephalosporin) or a combination such as trimethoprim-sulfamethoxazole or erythromycin/sulfisoxazole may also be used. clinical trials with these agents indicate that all regimens are of approximately equal clinical efficacy when the bacterial pathogens are susceptible [ ] . the control drug chosen for a clinical trial should be among the most effective and safe agentsavailable for treatment. it is expected that an effective agent will sterilize the middle-ear fluid of bacterial pathogens in > % of infected ears within hours. a second aspiration of middle-earfluidshouldbe consideredfor anypatientfor whom the outcome at hours is clinical failure. chemoprophylaxis has been shown to be of value in the prevention of acute illness in children who have had recurrent aom [ ] . more than studies in which a penicillin, a sulfonamide, or erythromycinwas used haveidentifiedprotective efficacy against new episodes of aom in %- % of cases in comparisons with a placebo control group. the changing susceptibilitypatterns of bacterial pathogens associatedwith aomwarrant considerationof new and effectivedrugs with activityagainstall major pathogens. newdrugs should have advantages over currently available agents, including ( ) ease of administration to ensure compliance and greater conveniencefor the patient (e.g., once-a-day dosing, drug stabilityat room temperature, prolongeddrug shelf-life); ( ) reduced incidence of relapse and recurrence; and ( ) reduced duration of mee after resolution of acute signs and symptoms. newdiagnostic instrumentswith improvedcapacity for examinationof the middle ear (of most importance is diagnosis of the presence of fluid in the middle ear) also are needed. even the most experienced otoscopists are accurate in diagnosing the presence of mee in only rv % of cases. tympanometryand acoustic reflectometry are of value in assisting the otoscopist but are insufficiently sensitive and specific to assure accuracy of diagnosis for all children enrolled in clinical trials. a noninvasive technique for determining the organisms present in mee is needed for the facilitation of appropriate microbiologic diagnosis and optimal use of approved drugs. currently, only needle aspiration of the fluid from both middle ears assures definition of the etiologicagentsof aom. patients eligible for inclusion in studies will be children or adults with symptomsand signs clinicallycompatiblewith aom. ( ) clinical criteria. aom is defined as inflammation of the middle ear evidencedby the presence of fluid and accompanied by specific signs or symptoms such as ear pain, ear drainage, hearing loss, or nonspecific findings such as fever, lethargy, irritability, anorexia, vomiting, or diarrhea. thepresence ofmee is definedby pneumatic otoscopy with or without use of tympanometry or acoustic reflectometry. ( ) microbiologic criteria. specific microbiologic diagnoses of aom can be determinedonly by aspirationof mee. both ears should be aspirated when the patient has bilateral aom. tympanocentesis is a standard procedure and is described in various texts on otolaryngology [ ] . the procedure should be performed only by qualified personnel with previous experience. nose and throat cultures are of no value in the microbiologic diagnosis of aom since they are neither sensitive nor specific for predicting bacteria present in mee. specimens for such cultures may be obtained from selected patients for monitoring change in susceptibility patterns of nasopharyngeal or oropharyngeal isolates during the course of antimicrobial therapy. the drug under consideration should have proven in vitro activity against s. pneumoniae, h. injluenzae, and m. catarrhalis. group a streptococci, s. aureus, gram-negative enteric bacilli, and anaerobic bacteria are infrequent causes of adm and need not be considered in initial therapeutic decisions. in vivo evidence of sterilization of bacterial pathogens should be obtained with use of an appropriate dosage schedule in an animal model of adm. the chinchilla has been used most frequently in assessments of pathogenesis and therapy and should be considered for such in vivo studies. the investigator or the institution should have access to a clinical microbiologic laboratory where personnel can perform the following tests: culture of mee for the isolation and identification of common pathogens in adm and in vitro susceptibility testing, including tests for ,b-iactamase production. the institution should have appropriate facilities and investigators experienced in middle-ear examination and aspiration of mee. clinical studies should be conducted with patients of different age groups and racial backgrounds. in newborns and infants up to weeks of age, the bacterial pathogens in adm differ from those in older children and include organisms acquired during delivery. in addition, pharmacologic considerations are different for older infants and children. the incidence of adm is highest between the ages of and months. the risk for adm is significantly increased in males, native americans, and canadian and alaskan eskimos, and the risk may be lower for black americans than for white americans. children, adolescents, and adults of both sexes should be included in studies. phase evaluations may include singledose administration before tympanocentesis to assess the penetration of drug into middle-ear fluids. initial clinical studies should not include children with focal anatomic, physiologic, or systemic immune defects; children who had received a systemic antimicrobial agent within the past days for treatment of an illness other than adm; and neonates or infants < weeks of age. the control agent should be selected on the basis of expected patterns of in vitro susceptibility of the most common pathogens (s. pneumoniae, h. injluenzae, and m. catarrhalis) in the community. because of the difficulties in obtaining reliable cultural information in adm even under protocol conditions, it may be appropriate to adopt a sequential study strategy: ( ) a small (r'-ji patients) phase trial can be conducted in which mee aspiration and culture is performed for all patients to document the unique microbiology of the population to be studied. in vitro antimicrobial susceptibility testing should be performed for all mee isolates, and both clinical and presumed microbiologic outcome should be assessed (see definitions below). repeat aspiration ofmee is required only if there is evidence of clinical failure. in the phase trial, an "open" uncontrolled study may be conducted. because the number of centers that perform tympanocenteses is presently limited and a second aspiration of mee cannot be recommended for children who are clinically cured or improved, the microbiologic response is correctly termed presumptive eradication. clinical and presumed microbiologic efficacyfor a minimum of patients with documented adm, with cases each due to the three major bacterial pathogens (s. pneumoniae, h. injiuenzae, and m. catarrhalis, respectively) should be sufficient to determine whether the drug is effective on an organism-specific basis. both organism-specific and disease-specific responses should be evaluated. for the purpose of organism-specific evaluation, a minimum of isolates from~ patients is required for evaluation. ( ) if the preliminary assessment is favorable (i.e., a clinical and presumed microbiologic response rate of~ %), a larger, comparative phase trial with an active control should be conducted. a double-blind study design is desirable whenever feasible; in any event, the evaluator should be blinded. aspiration of mee for microbiologic diagnosis before treatment is desirable but not required, but aspirates from those patients who fail to respond clinically are required. all drugs will be provided to the patient by the investigator or his or her designee. for young children unable to swallow tablets or for those with a small body mass, the use of a suspension or other acceptable formulation is necessary for accurate dosing. it is not anticipated that addition of a new antimicrobial agent will be required. if there is clinical failure (see definition below) after hours of therapy, tympanocentesis should be performed; modification of antimicrobial therapy will be based on the data obtained from culture and from susceptibility testing. both clinical and presumed microbiologic responses should be assessed. after enrollment, observations should be made - daysafter initiation of therapy and at least and - weeks later. the precise period of posttreatment evaluation will vary according to knowledge of the anticipated duration of antiinfective activity subsequent to termination of administration of the test drugs. at each visit an interval medical history should be obtained and otoscopic examination, including tympanometry or acoustic reflectometry, should be performed to determine the status of the middle ear. during reexaminations, children should be assessed for other foci of infection and for adverse effects of the test drug. the treatment outcomes for the study and control groups should be compared according to the proportion of patients in the following outcome categories: ( ) clinical cure with presumed microbiologic eradication; ( ) clinical failure with microbiologic persistence; and ( ) clinical relapse or recurrence. ( ) definition of clinical response. clincal cureis defined as resolution of signs and symptoms (e.g., pain, fever, vomiting), exclusive of mee, within hours in a child who remains well throughout the course of therapy and follow-up. clinical failure is defined as lack of resolution of signs and symptoms, exclusive of mee, within hours of onset of therapy. relapse is defined as reappearance of signs and symptoms of adm after initial response during or within days of conclusion of therapy. recurrence is defined as reappearance of signs and symptoms of adm~ days after the conclusion of therapy. ( ) definition ofmicrobiologic response. it is recognized that whereas the microbiologic response can be accurately assessedonly by repeat aspirationsof mee during or after com-pletion of antimicrobial therapy, repeat tympanocentesis in a patient who is clinically improving is generally not warranted. all patients for whom outcome is classified as clinical failure, relapse, or recurrence should undergo repeated aspiration of mee before their antimicrobial regimens are toms of acute sinusitis are often difficult to distinguish from those of the common cold or from allergic (vasomotor) rhinitis. the most common complaints are cough ( %) and nasal discharge ( %). parents often notice a malodorous breath among preschoolers ( % of cases) who have neither signs of pharyngitis nor poor dental hygiene [ , ] . in adults, postnatal purulent discharge and facial pain over the affected sinus that worsens with movement or percussion are the cardinal symptoms [ , ] . fever occurs in < % of cases. hyposmia, jaw pain with mastication, nasal congestion, and a history of recent upper respiratory infection are other manifestations. in patients with nosocomial sinusitis secondary to prolonged nasotracheal intubation, the clinical features, except for unexplained fever, may be relatively silent. symptoms associated with chronic sinusitis are usually less intense but more protracted than those in acute sinusitis. fever is uncommon. fatigue, general malaise, and an ill-defined feeling of unwellness and irritability can be more prominent than local symptoms of nasal congestion, facial pain, or postnasal drip [ ] . the precise microbial etiology of sinusitis can be determined only by direct aspiration of the sinus, since nasopharyngeal secretions are regularly contaminated by the indigenous flora and culture results correlate poorly with results for sinus aspirates [ , ] . this difficulty may limit the ability to make a definitive assessment of the microbiologic response to anti-infective therapy. s. pneumoniae and unencapsulated h. influenzae are responsible for > % of cases of acute sinusitis in adults, while m. catarrhalis in addition to s. pneumoniae and h. influenzae account for two-thirds of cases in children [ , , ] (table ). s. aureus is a common nasal contaminant and an infrequent cause of acute sinusitis. obligate anaerobes are uncommonly isolated in acute sinusitis. in contrast, the microbiology of chronic sinusitis is usually logic persistence, emergence of resistance, or superinfection and optional determinations of drug concentrations in mee for such patients; ( ) repeated hematologic, hepatic, and renal function studies as appropriate; ( ) monitoring of change in susceptibility patterns of bacterial isolates in nasoor oropharyngeal culture specimens for selected patients; and ( ) recording of allergic or toxic reactions or important adverse effects, which will be grounds for terminating the use of either the study drug or the standard drug. patients should be followed up clinically and by otoscopy biweekly until mee has completely resolved. repeated aspiration of mee should be performed for patients with clinical relapse or recurrence. the time to resolution of mee should be recorded. laboratory studies to monitor resolution of infection and adverse reactions should be repeated according to the protocol. c. sinusitis sinusitis is a common disorder both in children and adults. approximately . % of upper respiratory infections in children are complicated by acute sinusitis, and . % of adults have chronic sinusitis. because of the location and rich vascular supply of the sinuses, these infections are potentially life-threatening in that intracranial suppurative complications may result, including epidural or subdural empyema, brain abscess, or cavernous sinus thrombosis. early diagnosis and effective antimicrobial therapy are critical for the prevention of such complications as well as chronic sequelae. the paranasal sinuses are lined with ciliated pseudo-columnar epithelium and are connected to each other through small tubular openings, the sinus ostia, which drain into various regions of the nasal cavity. the paranasal sinuses are generally considered to be sterile, although transient colonization by the resident upper respiratory flora does occur [ ] . conditions that affect the patency of the sinus ostia, .the normal mucociliary function of the sinus epithelium, or immune defenses of the upper airways or events that facilitate direct introduction of microorganisms into the paranasal sinuses are the key predisposing factors to sinus infection [ ] . such conditions include viral upper respiratory tract infections, respiratory allergies, alterations in mucus (e.g., cystic fibrosis), and selective deficiencies in immunoglobulins. dental extraction or periapical infections of the maxillary molar teeth are a particularly important cause of maxillary and chronic sinusitis. the clinical manifestations of sinusitis vary greatly depending on the duration of infection (i.e., acute or chronic) and the age of the patient (i.e., child or adult). in children, symp- [ , ] . viridans streptococci and nonencapsulated h. infiuenzae are the major aerobic isolates. nosocomially acquired sinusitis secondary to head trauma or prolonged nasotrachea intubation is commonly causedbypolymicrobial gram-negative bacilli and s. aureus as well as by anaerobes [ ] . fungal sinusitis is rare, but aspergillus, mucor, candida, pseudoallescheria boydii (scedosporium spiospermum) and other saprophytic fungi can cause invasive diseaseusually in the debilitated host. although antecedent viral upper respiratory infection is an important cause of acute sinusitis, viruses (e.g., rhinovirus, influenza, parainfluenza, and adenovirus) are isolated only in %of antralaspirates [ ] . the clinical entities included in this guideline are acute sinusitis (symptoms present for~ weeks) and chronic sinusitis (symptoms present for~ months). not included in this guideline are subacute cases (symptoms lasting - months), whichhave a variable naturalhistory and in which the bacterial etiology is poorly defined. the goals of antimicrobial therapy for acute sinusitis are ( ) the eradication of the causative pathogens; ( ) the provision of symptomatic relief; ( ) the restoration and improvementof sinusfunction; and ( ) the prevention of intracranial complications and chronic sequelae. although many management options are available, antimicrobial agents are the mainstay of therapy for acute sinusitis. the therapeutic efficacy of anti-infective agents for acute sinusitis hasbeenestablished by placebo-controlled clinical trials [ ] and in studies that employed sinus aspiration before and after treatment [ , ] . standardtherapy is usuallyselected on anempiricbasisanddirected against themost likely pathogens, including h. infiuenzae, s. pneumoniae, and m. catarrhalis (see table ). oral therapy with a j -lactam agent suchas ampicillin for - days is generally prescribed and is considered the standardregimenfor acute sinusitis in bothchildren and adults. a favorable rate ofclinical response of %- % canbe expected withthisregimen. in penicillinallergic patients, a second-generation cephalosporin (e.g., cefaclor), a macrolide/sulfonamide (e.g., erythromycin/sulfisoxazole) or trimethoprim/sulfonamide (such as trimethoprimsulfamethoxazole) combinations have yielded comparable results. penicillins (such as amoxicillin plus a j -lactamase inhibitor) or cephalosporins thathavea more-extended spectrum have not yielded superior results in controlled trials [ ] [ ] [ ] even though theprevalence ofj -lactamase-producing strains among respiratory pathogens appears to be increasing(upto % ofh. influenzae strains, %- % ofm. catarrhalis strains,and %- % of respiratoryanaerobes) [ ] . in 'patients with chronic sinusitis, surgical procedures to facilitate sinus drainage through the creationof an artificial ostium and submucosal resection of diseased tissue appear to be the mainstays of treatment. the role of anti-infective agents in chronic sinusitis is not as clear as that in acute sinusitis. conservative therapy with anti-infective agents or sinusirrigationwithout surgical intervention is successful in onlyone-thirdof cases [ , ] . withcombined medicaland surgical treatment, the curerate forchronicmaxillary sinusitis is > % after years of follow-up [ ] . anti-infective agents useful forchronic sinusitis should have broad-spectrum activity against respiratory anaerobes as well as against viridansstreptococci, s. pneumoniae, h. influenzae, and m. catarrhalis. several issuesin the management of acute and chronic sinusitis remain controversial. these include: ( ) the optimal duration of therapy for acute and chronic sinusitis; ( ) the clinicalrelevance of the increasing prevalence of in vitro resistanceto j -lactam agents among upper respiratorypathogens; ( )the roleofrespiratory allergy in recurrent or chronic sinusitis; ( ) the value of adjunctive measures such as oral or topical decongestants, antihistamines, and intranasal steroids in the treatment of acuteand chronic sinusitis (such measures must be standardized in both study and control groups during initialassessment of new antibiotic regimens for both acute and chronic sinusitis); ( ) the optimal mode of surgical management in chronic sinusitis (i.e., preservation of sinus epithelium vs. radical mucosal resection); ( ) avoidance of the need for sinus puncture by the use of endoscopic sinoscopy for performing quantitative cultures. patients eligible for study will be children or adults with symptoms and signs clinically compatible with acute or chronic sinusitis. (i) clinical criteria. acute sinusitis is defined as inflammation of the sinuses associated with symptoms lasting~ weeks. clinical findings suchas fever, headache, malartenderness, andnasal discharge (which are often nonspecific) should be supported by objective localizing studies such as radiography, ultrasonography, or ct. transillumination of the s sinuseshas a relatively low sensitively ( %) and specificity ( %) for acute sinusitis [ ] and should not be used as the solediagnostic criterion. transillumination is alsoless informativein children< years of age ( % concordanceand % discordance compared with radiographic findings) because of either poor cooperationof the child in performingthe test or thedevelopmental variations of the sinuses in this agegroup [ ] . anterior rhinoscopy mayrevealhyperemicand edematous nasal turbinates, often with purulent dischargefrom the middle meatus where the orifices of the maxillary, frontal, andanteriorethmoidal sinusesenterthe intranasal cavity [ ] . imaging studies (roentgenography, ultrasonography, or ct) should be performed in all cases. other laboratory studies suchas neutrophil count, erythrocyte sedimentation rate, and c-reactive protein should also be performed. chronic sinusitis is definedas inflammation of the sinuses associated with symptoms lasting > months that are compatiblewithradiographic abnormalities (determined byroentgenography, ultrasonography, or ct). if possible, chronic sinusitis should be confirmedby endoscopic sinoscopy with direct visualization of the sinusmucosa, appropriatemicrobiologic sampling, and histopathologic evaluation [ , ] . ( ) microbiologic criteria. the precise microbial etiology of sinusitis can be determined only by direct aspiration or injection wash of the sinus cavity. cultures of the surface of the nasal vestibule or the nasopharynx are unreliable becauseof their regularcontamination bythe residentmicroflora and should not be used for assessment of microbiologic efficacy of study regimens. access to the maxillary sinus can be obtainedintranasally througha puncturebelow the inferior turbinate and to the frontal sinus through a puncture below the infraorbital rim oftheeye. thorough cleansing of thepuncture site with an appropriate antiseptic is important to minimize contamination of the specimen with surface bacteria. if no fluid is obtained, ml of sterile normal saline without bactericidalpreservativeshouldbe instilledand the washings reaspirated. specimens should be sent to the laboratory for leukocytecounting, gram staining, and culture for aerobes, anaerobes, fungi, and mycobacteria. viral cultures are of investigational interest. withthe appropriate technique, > % of such specimenswill yield positivecultures in acute maxillary sinusitis [ ] . furthermore, if organisms are seen on gram-stained preparations of antral secretions, a presumptive diagnosis can be made by assessing the bacterial morphotype in up to % of cases [ ] . quantitative cultures (~ cfu/ml of aspirate) are usefulin distinguishing true infection from colonization or contamination [ , ] , but such studies are labor-intensive and are not required for microbiologic diagnosis in clinical trials. in chronic sinusitis, microbiologic diagnosis can be confirmedby cultureof diseasedmucosaobtainedby biopsyduring endoscopicsinoscopy or surgery. in such cases, the culture results should be correlated with the histopathologic findings to exclude the possibility of specimen contamination. for a pathogen-specific evaluation, the drug under consideration should haveprovenin vitro activity against the specific bacteriaprevalent in sinusitis, and for a disease-specific evaluation (i.e., acute vs. chronic, pediatric vs. adult), the drug should havea broad range of activity against the most prevalent pathogens. the investigator or subinvestigator should have the necessary skillsto perform sinuspuncturefor microbiologic evaluationsof acuteandchronicsinusitis and endoscopic sinoscopy for studies of chronic sinusitis. the institution should have the facilities and personnel with expertise to perform and interpret radiographs, ultrasonography, or ct and microbiologic studies of the paranasal sinuses. clinical evaluation of new treatment regimens should be conducted with patients grouped by specified age, underlying disease, duration of symptoms, and presence or absence of respiratory allergy. since these factors appear important both in predictingthe microbial etiologyand in overallprognosis,their contribution to treatmentoutcomeshouldbe carefully controlledby appropriate randomizationduring patient enrollment or by stratification eitherprospectively or posthoc during analysis of results. children, adolescents, and adults of both sexesare eligible for inclusion. patientswho havereceivedother antimicrobial therapy within the preceding weeks, patients with hypersensitivity reactions to drugs of a similar class, and patients with other concurrent, acute infectious illnesses should be excluded. in acute sinusitis, an active control regimen with proven efficacy againsts. pneumoniae, h. injluenzae, and m. catarrhalis shouldbe used. in chronicsinusitis, a placebo-controlled trial is consideredjustified since the role of antimicrobial therapy for this condition remains unclear at this time. because of the difficulties in obtaining reliable cultural information about sinusitis even under protocol conditions, it may be appropriate to adopt the following sequential study strategy. ( ) conduct a small (rvloo patients) phase trial in which sinus puncture and culture is performed for all patients to document the unique microbiology of the intended study population, with at least cases of each of three major bacterial pathogens implicated (s. pneumoniae, h. irfiuenzae, m. catarrhalis). in vitro antimicrobial susceptibility testing of all sinus isolates should be performed. both clinical and presumed microbiologic outcomes are assessed (see definitions below). repeated aspiration of the sinus is required only if there is evidence of clinical failure. in the phase trial, an "open" uncontrolled study may be conducted, although a randomized comparative double-blind trial with an active control is still desirable despite the clearly inadequate size of the sample for meaningful comparisons of clinical response rates. a conrolled comparison provides additional information regardmg the expected response rate in a particular community. both organism-specific and disease-specific responses should be evaluated. for purposes of organism-specific evaluation a minimum of isolates from~ patients is required for evaluation. ( ) if the preliminary assessment is favorable (i.e., a clinial and presumed microbiologic response rate of~ %), it is reasonable to conduct a larger, comparative phase trial with at active control. sinus puncture for microbiologic diagnosis and sinus radiography before treatment are desirable but not required, but examination of aspirates and sinus radiographs is necessary for those patients who fail to respond clinically. in vitro antimicrobial susceptibility testing should be performed for all isolates from cultures. use of adjunctive medications such as oral or nasal decongestants, antihistamines, or intranasal steroids should be standardized such that hey~re used either in both the study and control groups or in neither of the groups. similarly, in studies of chronic sinusitis, the mode of concomitant surgical therapy (i.e., endoscopic sinuscopy with limited mucosal curettage vs. a more conventional approach of radial mucosal resections) should also be standardized or stratified. the projected sample size must include consideration of the expected difference in efficacy of the study and control regimens, the expected proportion of cases due to each of the major bacterial pathogens (and that one-fourth of all cases of acute sinusitis are due to nonbacterial causes that would not be affected by either antibacterial agent), and an anticipated rate of spontaneous clinical cure of rv %among children with acute sinusitis [ ] . the treatment course is usually - days for acute sinus-itis. si.nce the opt~mal duration of therapy has not been clearly estabhshed for either acute or chronic sinusitis, this could be the mainfocus of evaluationin phase trials. patients should be assigned randomly to the test or "control" group, and if p~e~reatment cultures of the sinuses are not performed, the chmcal and presumed microbiologic response should be evaluated by a blinded observer. for children unable to swallow tablets or whose body mass is small, either a suspension or an acceptable alternative formulation of the study drug or the control drug is necessary for precise dosing. modification of the study by the addition of a new antimicrobial agent may be necessary if the clinical response after - days of therapy is suboptimal. in such instances sinus aspiration for documentation of the microbiologic response is required before the therapeutic regimen is modified. addition of a new antimicrobial agent constitutes a clinical failure of the initial treatment regimen. both clinical and presumed microbiologic responses should be~s~:ss.ed. clinical evaluation should be made - days after imuation of therapy and weekly or biweekly thereafter until the resolution of all symptoms and signs. use of a scoring system, pa:ticularly a binomial (yes/no) objective scoring system, for signs and symptoms such as fever, pain, headache, tenderness, nasal discharge, and purulence is strongly encouraged. imaging studies (roentgenography, ultrasonography, or ct) should be repeated at least at the completion of antimicrobial therapy. patients with chronic sinusitis should be further assessed by repeated endoscopic sinoscopy before or after completion of therapy. information about concentrations ?f dru~in sinus aspirates or mucosal biopsies may be of value iii studies of chronic sinusitis, but they are not critical to studies of efficacyin acute sinusitis and are not required for final evaluation. since a repeat of sinus puncture is generally not justified in patients who have responded clinically to therapy, the microbiologic response in such patients can only be judged presumptively. comparisons of treatment outcomes in the study and control groups should be made according to the proportion of patients in the following outcome categories: ( ) clinical cure with presumed microbiologic eradication; ( ) clinical failure with microbiologic persistence; ( ) clinical and/or microbiologic relapse and recurrence; and ( ) indeterminate. ( ) definition ofclinical response. clinical cure is defined as complete resolution of signs and symptoms at the conclu-sio~of antimicrobial therapy and at follow-up. clinical failure is defined as lack of improvement in signs and symptoms within a defined period of therapy ( hours for acute sinusi-sn tis and weeksfor chronic sinusitis). earlyrelapse is defined as reappearane of signsand symptoms or newclinicalfindings of sinusitis within daysafter the conclusionof therapy. late relapse is definedas the reapearrance of signs and symptoms or new clinical findings of sinus infection after days but within month after the conclusion of therapy. ( ) definition of microbiologic reaponse. presumed microbiologic eradication is definedas cases in whichpretreatment cultures of sinus aspirates were positive, clinical signs and symptoms resolvecompletely, and posttreatmentculturesare not performed because clinical response is complete. confirmed microbiologic response is defined as cases in which the causativeorganismcannot be isolated in cultures of sinus aspirates performed after hours of antimicrobial therapy. such repeated cultures of sinus aspirates are likely to be performed only in the setting of clinical failure. a statement as to microbiologic eradication is not possible because of the influence ofconcomitantantimicrobial therapy. microbiologic persistence is defined as a positive culture of sinus aspirates after at least hours of antimicrobial therapy. if a pretreatment culture of sinus aspirate was performed and was positive, the isolation of the same organism after~ hours of therapy is considered confirmed microbiologic persistence. if no pretreatment culture of sinus aspirates was performed, isolation of a pathogen after~ hours of treatment is considered presumptive microbiologic persistence. superinfectionis defined as the emergenceof new or resistant organisms in cultures of sinus aspirates after~ hours of antimicrobial therapy. ( ) initial clinical evaluation and imaging (roentgenography, ultrasonography, or ct) of the paranasal sinuses; ( ) hematologic, hepatic, and renal function studies; ( ) sinus puncture and microbiologicstudies for phase trials and optionallyfor phase trials; and ( ) endoscopic sinoscopy, bacterial cultures,andoptionaltissuebiopsyfor studiesof chronic sinusitis. (b) assessment during the course of therapy should include: ( ) clinical evaluation at - and - days after initiation of antimicrobial therapy, and weekly or biweekly thereafter until resolution of all symptoms and signs; ( ) aspiration of sinuses for microbiologic studies for patients who fail to respond clinically after at least hours of antimicrobial therapy to define microbiologic persistence, emergence of resistance, or superinfection; and ( ) repeated imaging, hematologic. hepatic, and renal function studies as appropriate. patients should be followed up clinically and with imaging for at least weeksafter completionof antimicrobial therapy to assess relapse or recurrence, clinical complications, and adverseeffects of the antimicrobialregimen. sinus aspiration should be performed for those patients with clinical relapse or recurrence. bronchitis is an inflammatory conditionof the tracheobronchial tree. it is both acute and chronic and is caused by a variety of irritants and infectiousagents. productive cough is the commondenominator of this condition, and the sputum produced ranges from mucoid to frankly purulent. acute bronchitis is generally an infectious process. it occurs in all age groups and is most common in the winter months, when acuterespiratory infections are prevalent. most cases are thought to be due to respiratory viruses, including those associatedwith the common cold and other respiratory viruses involved in infections of the lower respiratory tract (e.g., adenovirus, rhinovirus, coronavirus, influenza, parainfluenza, respiratory syncytial virus, coxsackievirus). m. pneumoniae, c. pneumoniae, and legionella specieshave also been implicated in some cases. the frequency of infection due to these pathogens is not certain. chronic bronchitis generally is defined as a condition characterized by cough and excessive secretion of mucus in patients who have coughed up sputum on most days during consecutive months for > successive years. this disease is caused by prolonged exposure to pulmonary irritants, the mostprominentof whichis cigarette smoke.atmospheric pollution also playssome role, as do recurrent episodes of infection. chronic bronchitis results in widely ranging degrees of respiratoryembarrassment. in its most severe forms, obstructive pulmonary disease, emphysema, and respiratory failure occur. patientswith chronic bronchitis frequently experienceepisodes of acute disease superimposedon the chronic process. these exacerbationsare characterized by some combination of increasing cough, sputum volume and purulence, and respiratory distress. the role of infectionin these episodes has been difficult to define. the bacterial speciesmost oftenmentioned as potential etiologic pathogens include s. pneumoniae, typable(especially typeb)and nontypable h. irfiuenzae, and m. catarrhalis. however, the same organisms, particularly haemophilus species, can be isolated from the respiratory secretionsof patientswith chronic bronchitiswho do not present with evidence of acute exacerbation [ ] . gump et al. did report an association between purulence of sputum and an increase in the number of pneumococciin the sputum em ; (suppl ) of patients with acute exacerbations [ ] . haemophilus parainfluenzae, viridans streptococci, and strains of enterobacteriaceae also are isolated from patients with acute exacerbations of bronchitis, but their pathogenic role is even less welldefined. viruses, m. pneumoniae, c. pneumoniae, andperhapslegionella speciesplayan etiologic role in some cases of acute exacerbations. the only clinical entity included in this guidelineis acute exacerbation of chronic bronchitis. considerable controversy surrounds the use of antibacterial agents for patientswith acute exacerbations of chronic bronchitis [ , ] . tager and speizer [ ] reviewed the existing studies in and concluded that the role of antimicrobial agentsin the management of these patients needed reassessment and that respiratory infections appeared to contribute to worsening of episodesof coughand productionof sputum. a recent double-blind randomizedplacebo-controlled study by anthonisen et al. [ ] showed a significant clinicalbenefit in association withantibacterial therapy. the recovery of peak air flow wasmore rapid and the rate of clinicaldeteriorations requiring therapeutic intervention was lower in antibiotictreatedpatients. response to treatment wasevidenced by the trilogy of decreased dyspnea, sputum volume, and sputum purulence. treatment success wasdefined as resolution within days of all symptoms that accompanied the exacerbation. no attempt at microbiologic confirmation wasperformed in this study. antibacterial agentsutilizedin thetreatmentgroup included trimethoprim-sulfamethoxazole, amoxicillin, and doxycycline. althoughcontroversy aboutpossiblemicrobialpathogenesis persists, most clinicianselect to treat the acute exacerbations as infectious events and direct that therapy at s. pneumoniae andh. influenzae and, morerecently, at m. catarrhalis. the duration of therapy is generally - days. it should be recognized that up to %of strains of h. influenzae and %- % of m. catarrhalis strains produce ( -lactamase. the etiologicrole of viruses, m. pneumoniae, c. pneumoniae, and legionella in acute exacerbations of chronic bronchitis needs clarification. determination of their role will be facilitated by the application of more sensitive and specific microbiologic diagnostic techniques (e.g., nucleic acidprobes, polymerase chain reactions, antigen detection). patients eligible for study will primarily be adults with symptoms and signscompatible with acute exacerbations of chronic bronchitis. ( ) clinical criteria. patients must (a) havehad a chronic cough and sputumproduction for > consecutive years and on mostdaysfor consecutive monthsand (b) haveevidence of acute exacerbation as indicated by some combination of increasedcough and/or dyspnea, increased sputumvolume, or increased sputum purulence. ( ) microbiologic and other laboratory criteria. these criteria include (a) negative chest roentgenogram to rule out pneumonia; (b) productionof purulent sputumas defined by the presence on a gram-stainedpreparation of > polymorphonuclear leukocytes and < squamous epithelial cells per low-power magnification (x ) field(thepresenceofpredominant bacterialmorphology maybe noted); (c) documentation of the presence or absence of potential bacterial pathogens and monitoringof emergenceof resistant isolates during antimicrobial therapyby sputumcultureand susceptibility tests. the drug under consideration should have provenin vitro activityagainsts. pneumoniae, h. influenzae, and m. catarrhalis. dosage ofthe studydrugmustbe determined by means of pharmacokinetic and in vitro studies. the investigator or subinvestigator shouldhavethe necessary skills to assesspulmonary functionand interpret radiographicstudies. the institution shouldhave adequate facilities for performance of laboratorystudies, including hematologic, hepatic, andrenalfunction testsandstudies ofpulmonary function, especially arterial blood gas analysis, forced vital capacity, fev! (forcedexpiratory volumein sec), total lung capacity, and peak flow spirometry. . design and implementation of phase , , and clinical trials onlyadultpatients(~ years)with stablechronicpulmonary disease should be included. patients who are experiencing an acute exacerbation of chronic bronchitis are eligible. patients with cystic fibrosis, patients unable to give informed consent, and patients with a known history of hypersensitivity to the study or control drug should be excluded. steroid use is not necessarily a criterion for exclusion. even though the use of antibacterial agents for treatment of acute exacerbations of chronic bronchitis is controversial, the presence of s. pneumoniaeand other potential pathogens in some patients and the concomitant need for corticosteroids in some patients suggest the need for an active control drug. both control and study drugs should be active in vitro against s. pneumoniae, h. influenzae type b, and m. catarrhalis. placebo-controlled trials may be conducted. in phase studies, human pharmacologic and pharmacokinetic studies should demonstrate sufficient absorption and achievement of peak serum concentrations that exceed the mic for the major respiratory pathogens. in phase and trials, study patients should be stratified according to major host factors (e.g., history and duration of smoking). whenever feasible, studies should be prospective, randomized, and of double-blind design. no additional antimicrobial agent is permitted. concurrent medications (e.g., bronchodilators) should be administered in the same manner to study and control groups. the study patients may be stratified according to the use of concomitant steroid therapy. another strategy might be to design a four-arm randomized comparison: ( ) study drug with steroids; ( ) control drug with steroids; ( ) study drug with no steroids; and ( ) control drug with no steroids. in projecting a sample size, consideration must be given to the expected difference in efficacy of the study and control regimens and the desirability of undertaking poststudy subset analysis of pertinent patient variables. variables include ( ) the presence or absence of adjunctive treatment; ( ) the presence or absence of fever; ( ) status of pulmonary function; and ( ) characteristics of sputum. duration oftreatment is generally - days. however, the optimal duration of therapy could be a main focus of evaluation. in comparative studies, patients should be assigned randomly to the test or "control" group, and insofar as possible, the study should be blinded. for patients who do not demonstrate clinical improvement (i.e., decreased dyspnea, cough, and volume and purulence of sputum production) or whose clinical conditions worsen after - days of treatment, clinical failure will be declared and such patients will be removed from the study. the addition of an antimicrobial agent that is not a study drug will also result in a designation of clinical failure. clinical response and results of pulmonary function tests and/or arterial blood gas analyses can be used to assess efficacy. the effect of treatment on sputum microbiology will be monitored. failure to eradicate a potential pathogen in a patient with a complete clinical response is common in this disease. the bronchial secretions of many patients remain "colonized" after the acute episode resolves. all patients entered into the study should be assessed on the basis of intent to treat. the clinical response in both the study and control group will be classified as ( ) clinical cure, ( ) clinical improvement (which requires measurement of an objective end point, e.g., volume and/or purulence of sputum), ( ) clinical failure, and ( ) indeterminate. patients will be evaluated at - days after initiation of treatment, and weekly thereafter. ( ) definitions ofclinical response. clinical cureis the resolution of acute symptoms and signs to a baseline level of dyspnea, cough, sputum production, and, if elevated at enrollment, resolution of fever. clinical improvement is the subjective improvement in dyspnea, with reduction in cough, a quantified reduction in -hour volume or purulence of sputum, and a return of the temperature to normal if the patient is initially febrile. clinicalfailure is the lack of any resolution in the magnitude of the dyspnea, sputum purulence, or fever (if present) that prompted enrollment of the patient in the study. clinical response indeterminate should be substantitated by stated reasons. the clinical response definition may be supported by improvement or lack of improvement in sequential measurements of the patient's white blood cell count, oxygen saturation, and/or pulmonary function tests. ( ) definitions ofmicrobiologic response. the categories of microbiologic response commonly encountered include eradication, persistence, relapse, reinfection, and superinfection consult general guidelines, section xiii.c, for detailed definitions. ( ) initial history and physical examination should be performed just before enrollment. ( ) chest radiography should be performed to rule out pneumonia. ( ) hematologic, hepatic, renal, pulmonary function, and arterial blood gas studies (with room air) should be performed. ( ) gram stain and ern ; (suppl ) culture of sputum plus determintion of -hour sputum volume should be performed; nucleic acid probes and culture for mycoplasma and legionella may be included. ( ) at a minimum, patients should undergo clinical evaluation - days after initiation oftherapy and weekly thereafter until completion of therapy. ( ) for febrile patients the body temperature should be determined a minimum of four times daily. ( ) quantitation of the volume of sputum produced daily and/or daily assessments of the degree of sputum purulence may assist in assessment of the patient's clinical response. ( ) it is helpful to monitor patient's arterial blood gases and/or expiratory flow rates at periodic intervals. the precise frequency depends on the individual protocol (e.g., every - days for hospitalized patients and perhaps once during therapy for outpatients). ( ) repeated chest radiographic, hematologic, hepatic, and renal studies are appropriate at - days after treatment has begun and within hours after the end of treatment. ( ) a sputum culture during therapy is indicated if there is evidence of clinical failure. in individual patients, such cultural data may be useful in identifying the emergence of bacterial resistance or in documenting failure to eradicate a potential bacterial pathogen (e.g., s. pneumoniae). patients should undergo clinical and microbiologic assessment within hours, - days, and - days after completion of therapy. the clinical assessment should include assessment of cough, dyspnea, sputum volume, and sputum purulence. oximetry to determine oxygen saturation and spirometry should be performed. a chest radiograph is not required unless clinically indicated, since the presence of a pulmonary infiltrate precludes enrollment. sputum should be submitted for gram staining, culture, and sensitivity testing, or-in the case of mycoplasma or legionella infections -for nucleic acid probe tests. lower respiratory tract infections include bronchitis, bronchiolitis, and pneumonia and its complications. the relative frequency of isolation of various etiologic agents that cause community-acquired pneumonia differ according to age group, socioeconomic status, underlying disease, time of year, and possible concomitant viral illnesses. prospective studies of the causes of community-acquired pneumonia are often difficultto interpret because of imprecise methods of microbio-logic diagnosis, such as reliance on sputum culture and/or serologic testing. however, it is generally accepted that in north america viral agents (e.g., respiratory syncytial virus and parainfluenza virus type ) are most important for children < years of age. the inability to obtain sputum from infants and children is a major deterrent to microbiologic diagnosis of pneumonia in this population. m. pneumoniae is considered to be a major cause of community-acquired pneumonias in north americans - years of age. in older individuals, mycoplasmas and viruses are less common causes, while bacterial agents are more prevalent. a majority ( %- %) of cases of pyogenic pneumonia with acute onset in middle-aged or older adults are due to s. pneumoniae [ , ] . pneumonias due to h. injtuenzae (either ampicillin-susceptible or ampicillin-resistant), s. aureus, mixed aerobicanaerobic bacteria, and aerobic facultative gram-negative bacilli such as klebsiella pneumoniae, in rank order, are less common. legionella species, (determined primarily on the basis of serologic studies) account for a variable proportion of cases of community-acquired pneumonia in adults (e.g., in % of patients not requiring hospitalization and in %- % of those hospitalized). legionella species probably account for %- % of cases of so-called atypical pneumonia [ , ] . other agents that cause nonpyogenic, or atypical, pneumonia include m. pneumoniae, c. bumetii, c. pneumoniae, and, rarely, chlamydia psittaci. in classic pneumonias, the isolation of certain pathogens can often be linked to certain specific conditions of the host (e.g., infection with group a , -hemolytic s. pyogenes, s. aureus, h. irfiuenzae, or s. pneumoniae following influenza). both typable and nontypable strains of h. influenzae are pathogenic primarily among smokers, patients with chronic obstructive pulmonary disease (copd), and some patients with lymphoma or other malignancies. aspiration pneumonia in the community is believed to involve mostly the normal oropharyngeal aerobic and anaerobic flora. in the nursing home or nosocomial setting, infections with aerobic gramnegative bacilli and s. aureus are additional considerations in aspiration pneumonia. data for nosocomial pneumonias prior to from the centers for disease control (cdc) may not be completely reliable because they appear to be based primarily on results of sputum cultures and cultures of endotracheal suction specimens. nonetheless, the rank order of pathogens in the last reported cdc survey of nosocomial infections is pseudomonas aeruginosa ( . %), s. aureus ( . %), klebsiella species ( . %), and enterobacter species ( . %), followed by escherichia coli, serratia marcescens, and proteus species [ , ] . data based on the results of transtracheal aspiration performed on members of a high-risk population of elderly men in a veterans administration hospital and nursing home in the s give a different perspective on nosocomial pneumonia. bartlettet al. [ ] relied only on isolates from blood cultures, pleural fluid, andtranstracheal aspirates. they found gram-negative bacilliin about one-halfof patients studied, anaerobes (peptostreptococcus species were the most common isolates) in about one-third, and s. pneumoniae in about one-fourth. klebsiella species were the most commonly isolated gram-negative aerobic bacilli. the isolates were polymicrobial in about one-half of the patients. gram-negative bacilli are morelikely to be involved in nosocomial pneumonia in high-risk populations, such as those in intensive care units, than in other patients. outbreaks of nosocomial pneumonia dueto someorganisms, including aerobic gram-negative bacilli and organisms not usually appreciated as nosocomial pathogens, may present particular problems. thelattergroupincludes s. pneumoniae, ampicillin-resistant h. infiuenzae, and m. catarrhalis [ ] [ ] [ ] . the timely use of appropriate systemic antibacterial therapyshould eradicatethe pathogen in a largenumberof cases of pneumonia and lead to a reduction in morbidity as well as mortality. efficacy ofnewagents should at leastequalthose of established regimens when evaluated in prospective, randomized, controlled trials (active treatmentconcurrentcontrol) [ , ] . if l -lactamase-producing pathogens are suspected (e.g., h. influenzae), both the study and control drugs should have in vitro activity against such pathogens. theefficacy ratesfora newdrug for etiologic agents andclinicalsyndromes in which thereis noestablished therapy should at least equal those in recent historical controls. data from open studies may be useful in these instances. dataobtained frompartsoftheworldotherthanthe united states may be considered supporting evidence of efficacy. however, possible regional differences in resistance patterns mustbe notedandmay preclude directcomparison (e.g., appreciably higher resistance to penicillin g among s. pneumoniae strainsisolated in south africa and to erythromycin in spain than in north american isolates). the local antimicrobial susceptibility patterns will clearlybe the predominant influence on the choice of concurrentactive treatment control regimens. ( ) clinical entities to be included are common communityacquired or nosocomial bacterial pneumonias. clinical entities not included are bronchitis, bronchiolitis, lowerrespiratory tract infections in patients withcystic fibrosis, lowerrespiratory tract infections caused by infrequent and/or difficultto-diagnose entities (e.g., infections withanaerobic bacteria; psittacosis, qfever, tularemia, andplague; andinfections with mycobacteria, viruses, or fungi). ( ) microorganisms included in the guideline are s. pneumoniae (prototype), h. injluenzae, s. aureus, facultative aerobic gram-negative bacilli, pseudomonas species, m. pneumoniae, and legionella species. the diagnosis of infectious pneumonia combines clinical, laboratory, andmicrobiologic data. a compatible clinical picture (fever, cough, and/orauscultatoryfindings such as rales and/or evidence of pulmonary consolidation) together with confirmatory chestradiographic findings and isolationof the causative pathogen(s) from suitable respiratory specimens (e.g., expectorated sputum, transtracheal aspirate,bronchial washings or lavage, pleuralfluid) or bloodestablishes the diagnosis of bacterialpneumonia. pneumonia due to m. pneumoniae is identified by culture or nucleic acid probe and/or by documentation of a fourfold or greater rise in titer of complement-fixing antibody. detection of cold agglutinins does not establishthe diagnosis. the diagnosis of legionella pneumonia requires isolation of the organism from sputum, a bronchoalveolar lavage specimen, pleural fluid, or blood. alternatively, legionella antigen may be detected by immunofluorescence in respiratory secretions or byradioimmunoassay in urine. also, legionella maybe detected in respiratorysecretions withnucleic acidprobes. testing forantibody in acute-and convalescent-phase sera, except for antibody to l. pneumophila serogroup , is not specific enough for reliablediagnosis oflegionellosis, especially in areas of lowdisease prevalence. diagnostic methods for detection of c. pneumoniae are under development. the bacterialpathogens isolated shouldbe tested for susceptibility to antimicrobial agents by standardized methods. determinations of mbcs, postantibiotic effect, or effect of subinhibitory concentrations of antibiotics are notdone routinely andare notgenerally required forassessment of efficacy. when mycoplasma or legionella is isolated, antimicrobial susceptibility testing is not done routinely. selection of empiricantimicrobial therapy is based on the suspected pathogens and their anticipated susceptibility in vitro. penicillin g remainsthe drug of choice for almostall s. pneumoniae infections in the unitedstates [ ] . ampicillin or a cogeneris the drug of choice for pneumonia due to non-sdactamase-producing h. injluenzae. aspiration pneumonia acquired in the community is treated with penicillin g, usually without the benefit of culture results. a lincosamide or a combination of a penicillin and a -lactamase inhibitor are alternatives. a macrolide (e.g., erythromycin) or tetracycline is preferred forpneumonia dueto m. pneumoniae or c. pneumoniae, and erythromycin is the choice for legionella infections [ , ] . a semisynthetic penicillinaseresistantpenicillin is the treatment of choicefor pneumonia dueto methicillin-sensitive s. aureus. a combination ofa suitable cephalosporin or penicillin and an aminoglycoside is frequently employed for infections due to facultative gramnegative rods or to pseudomonas. in most other instances of community-acquired pneumonia, combination therapy is usually not required. oral preparations of the aforementioned parenteral compounds or oral drugs with comp~able in vi.tro activity can be used in milder cases. the optimal duration of therapy varies, but uncomplicated s. pneumoniae pneumonia is usually treated for - days [ ] . for treatment of nosocomial pneumonias (e.g., associatew ith ventilator use), combination therapy with an extendedspectrum penicillin or cephalosporin and an aminoglycoside is commonly employed. initial therapy must be directed at the suspected pathogens in a given hospital and their known susceptibility profile. determination of the concentration of antimicrobial agent(s) in serum, other bodily fluids, or tissues is not done routinely. most often, cure is defined by clinical criteria alone. with resolution of the inflammatory process, the patient is unable to provide secretions from the lower airway for documentation of eradication of the causative pathogen. patients requiring tracheostomy or endotrachĩ ntubation may have persistent, presumably tracheal, colomzation with an etiologic organism after the criteria for clinical cure of pneumonia are met. relief of endobronchial obstruction and/or drainage of empyema fluid remains a mainstay of therapy for lower respiratory tract infections. the probability of cure for s. pneumoniae pneumonia is variable and ranges from % in uncomplicated infection to (\) %- % with bacteremic disease [ ] . relapse is not a significant problem with s. pneumoniae. newer methods for more precise microbiologic diagnosis of pneumonia, such as the use of semiquantitative cultures of protected endoscopic brushings or bronchoalveolar lavage specimens, are promising.· the practice of changing parenteral therapy to therapy with an oral agent such as a fluoroquinolone after - days is gaining increasing acceptance, as is the use of intravenous antimicrobial therapy in the home for follow-up management. it is likely that the number and precision of diagnostic techniques that rely on antigen detection or nucleic acid detection will increase. patients eligible for study are adults and children of both sexes with confirmed or presumptive diagnosis of communityacquired or nosocomial pneumonia. these guidelines may be adapted to treatment of patients in either a hospitalized or ambulatory setting or for patients that progress from hospital to an outpatient setting. ( ) clinical criteria. patients must have signs and symptoms consistent with bacterial pneumonia (chest pain, cough, and/or ausculatory findings such as rales and/or evidence of pulmonary consolidation) with or without fever (oral temperature > °c [ . of]) or leukocytosis (blood leukocyte count > , /mm or > % band forms), and there must be radiographic or other laboratory evidence that supports the diagnosis (see below). ( ) microbiologic and otheretiologic (noncultural) criteria. specimens obtained by expectoration or by endotracheal aspiration should be screened microscopically for suitability of culture (presence of > polymorphonuclear leukocytes and < squamous epithelial cells/low-magnification field [x ]). suitable specimens should be cultured aerobically in appropriate media. blood specimens should be cultured for all patients, and pleural fluid, if present, should be aspirated, examined by microscopy, and cultured for both aerobes and anaerobes. the microbiologic diagnosis of infectious pneumonia is confirmed by the following criteria: (a) purulent expectorated sputum-identification of a predominant suspected pathogen by culture and/or microscopy (e.g., with s. pneumoniae by finding an average of > lancetshaped diplococci/oil-immersion field [x , ] for fields examined) (material from endotracheal suctioning may also be used, and slides should be saved and made available as part of the case record) or (b) transtracheal aspirate, bronchial brushings, or biopsy material (obtained under direct visualizationwith a fiberopticbronchoscope, preferablydoublesheathed) -gram stain reveals neutrophils and a predominant pathogen is suspected by smear or culture; quantitative cultures of endobronchial brushes from potentially infected ventilator-dependent patients may be of value; (c) pleuralfluid or direct lungaspirateidentification of a predominant pathogen on gram stain or by culture; (d) positiveblood cultureyields a pathogen in a patient with a compatible clinical syndrome of bacterial pneumonia in the absence of another source of bacteremia. ifan organism is isolated, it should be susceptible to both the study and the control drug. clinical improvement or stabilization must be documented by hours to permit retention in the study. (e) surrogate markersdetection of antigen or specific nucleic acid by non-culture methods may be used as a surrogate marker of infection. culture or other non-cultural methods for confirmation ofthe diagnosis of pneumonia must follow within - hours of starting therapy to retain the patient in the study. isolation by culture is not required for the diagnosis of pneumonia due to m. pneumoniae, legionella, or c. see general guidelines, section ii.d. use of accepted animal models for pneumoniacaused by specific pathogens is desirablefor evaluations of dosage, duration of therapy, achievable serum concentrations, and comparisons with other agents for efficacy and relative toxicity, as described in general guidelines, section ii.e. determinations of levels of antimicrobial agents in respiratory tract secretions and tissue are optionalsince there is a lack of accepted interpretation of results physicians should be available who are competent in the following procedures: bronchoscopy, endobronchial protectedbrush sampling, bronchoalveolar lavage, and thoracentesis. in addition to standard clinical microbiology, the laboratory should have access to nucleic acid probes for detection of legionella and mycoplasma, detectionof legionella species antigen, and determination of titers of specific antibody to mycoplasma and legionella. for most studies, adults ( - years of age) and elderly patients (~ years of age) will be the prototype groups to be studied. additional potential study populations are neonates, infants, children, and immunosuppressed patients. male andfemale patients willbe included. pregnantor lactating women will be excluded. patientswith severeunderlying diseases (e.g., aids, metastatic tumor, shock) will be excluded. patients are excluded if they have received prior therapy witha potentially effective anti-infective agentfor~ hours. see generalguidelines, sectionix, for additional details. it is notconsidered ethical to usea placebo control in studies evaluating the efficacy of a new anti-infective drug for treatment of pneumonia. active or historical controls are needed to assess the relative value ofthenewdrug. thehistoricalcure rate of uncomplicated (nonbacteremic) pneumonia due to s. pneumoniae in healthy hosts is '\j %. whenever feasible, the use of a control drug is desirable. the control anti-infective agent should be a drug, or one of several drugs, approved for pneumonia and still recognized by authoritative publications as "standard" treatment. other considerations are discussedin the general guidelines, section x. whenever possible, the study design shouldbe randomized, prospective, and double-blind. see general guidelines, sections x and xi, for details. the spectrumof organisms that causepneumoniais the result of the interplay of multiplehost factors and environmental factors. only somedeterminant factors in the host-parasite relationship are understood, e.g., the presenceor absence of oropharyngeal binding sites for microorganisms, patientage, immune status prior to infection, aspiration of oropharyngeal secretions, concomitant chronic diseases and/or organ failure, or damageto nonspecific or specific portions of the host defenses against microbial invasion. in a given patient, one or more factors may apply. ( ) community-acquired vs. hospital-acquired pneumonia. thetraditional distinction between community-acquired and hospital-acquired pneumonia has blurred. traditional community-acquired pathogens, such as s. pneumoniae or l. pneumophila, are now recognized as causes of hospitalacquired pneumonia. patients with chronic diseases, e.g., lung, heart, renal, and/or hepatic failure, are cared for with increasing frequency outside of the hospital. these disease statesincrease the likelihood of colonization ofthe oropharyngeal secretions with facultative gram-negative bacilli and, hence, increase the risk of pneumonia due to this class of organisms traditionally associated withnosocomial pneumonia. ( ) patient selection based on clinical category. because of this blurring between community-and hospital-acquired pneumonia, it is reasonable to select patients as trial candidateson thebasisofthe clinical picture. the greaterthehomogeneity of the randomized population of patients with pneumonia, the greaterthe likelihood thetrial results willhave clinicalimport. somepatientsmay fit in more than one category. suggested categories for patients with pneumoniaare presented in table . by necessity, the categories are arbitrary and will requireperiodic revision as new insights into pathogenesisemerge. in clinicaltrials ofpatientswhopresent with signsand symptoms of atypical pneumonia, mostpatients enrolled will be ambulatory. in trials of acute bacterial pneumonia, mostpatients willbehospitalized. atthetimeofpatient for statistical considerations, it is strongly recommended that patients be stratified into no more than three clinical categories of pneumonia. for example, in a comparative trial of two parenteral drugs with an appropriate spectrum of activity, patients could be categorized in one of three categories, i.e., acute bacterial pneumonia, aspiration pneumonia, or respirator-associated pneumonia, and then randomized. subsequent to the end of the study, patient response can be analyzed by type of infecting organism, presence of organ failure, severity of pneumonia, and other factors. alternatively, a trial may be designed to study the response of only those patients who meet the clinical criteria for atypical pneumonia. in this example, no stratification would occur prior to randomization. ( ) compromised host. pneumonia, and other infections in the compromised host, is discussed in detail in the guide-lines on infections in the febrile, neutropenic patient. the compromised host mayor may not be neutropenic, have inadequate immunoglobulins, or exhibit abnormal lymphocyte function. a wide variety of opportunistic pathogens cause pulmonary infection in the compromised patient. development of a pulmonary infiltrate in a patient with a hematologic malignancy (e.g., leukemia or lymphoma) is a grave prognostic sign and requires an urgent, aggressive, and carefully planned approach to diagnosis and management. for example, local signs of infection in patients who are neutropenic often are fewer and less severe than those in the non-neutropenic person. frequently, neutropenic patients have distant sites of infection from which organisms may have disseminated to the lungs. no symptoms, signs, or roentgenographic features are specific for a given opportunistic infection in the compromised patient. noninfectious pulmonary pathologic conditions are common in this population and may mimic infection. these include radiation pneumonitis, drug toxicity, involvement by the underlying malignancy, pulmonary hemorrhage, pulmo-nary infarction, and congestive heart failure. concurrentand sequential infections of the lung are commonin this population, making the relationship of disease manifestations to a single pathogen difficult to ascertain. early diagnosis is often critical for these patients. guidelines used for diagnosis by examination of pulmonary infiltrates in healthy patients maynot be applicable for diagnosisin patients whoare compromised. for example, severely neutropenic patients may not have neutrophils in their sputum despite having significant bacterial or fungal pneumonia, and for some pathogens the sputum culture may be negative despitethe presenceof invasive lung infection (e.g., aspergillus pneumonia) ..the diagnosis of pulmonary infection in the compromised host may require the performance of an invasive procedure, e.g., percutaneous needle aspirationof the lung, transtracheal aspiration, bronchial lavage and brushingfor quantitative bacteriology, transbronchial biopsy, or open lung biopsy. pneumonia in the compromised patient may be rapidly fatal-hence, the need for empiric antimicrobial therapy. in addition, it is oftennecessaryto reduce the dosageof the immunosuppressive therapeuticagent. thus, the combinedexpertise of all involved physicians is desirable. the duration of treatmentvaries with the clinical category of pneumonia, with the results of blood cultures, and with the status of host defenses. for acute bacterial pneumoniain noncompromised hosts, it maybe desirable to treat until the patient's temperature has returnedto and remained in the normal range for a specific period, e.g., - days. the possible routesof administration and conversion fromone routeof administration to another are discussed in the general guideline, section xii. see general guidelines, section xii.f. clinical evaluation is based on resolutionor improvement of clinicaland laboratory signsof infectionsuch as fever and leukocytosis, purulent sputumproduction, and radiographic lung infiltrates. hospitalized patients will be assessed every day during treatment and within - days after completion of treatment. bodytemperaturewill be measuredat least every hours during treatment, and the peak temperature for eachdaywillbe recorded. measurements ofvital signs(blood pressure, heart, and respiratory rates) will be obtained before enrollment and on each day at approximately the same time. the character of the sputum (color, consistency, volume, and number of neutrophils per low-magnification field [x d will be recorded when the patient enters the study and at regular intervals thereafter. arterial blood gas determinations will be performed as clinicallyindicated. a chest radiographwill be obtained days after initiationof therapy, within hours of completion of therapy, and at any other time the investigator deems necessary. the location and extent of pneumonic involvement (e.g., segmental, lobar) and the presenceof pleural effusion must be notedand recorded. whenever possible, the same radiologist (or a panel of radiologists) from the sameinstitutionshould interpret all radiographs. other special radiographic studies (e.g., ct scan) will be obtained as clinically indicated. repeated culturesof respiratory tract secretions,if obtainable, will be performed at - hoursafterinitiation oftherapy, within hours of the completion of therapy, and whenever clinically indicated. standardized susceptibility testing (disk diffusion or broth dilution) will be performed on all isolates considered potentially significant. blood cultures will be repeatedif initially positiveor if the patient fails to respond to treatment. collectionof specimens that require the use of semi-invasive techniques (e.g., collection of pleural fluid, transtracheal aspiration, bronchoscopy) should be repeated onlyif the clinicalresponseis suboptimal. tests for surrogate markers will be repeatedif these were originally used for diagnosis. for all patients a posttherapy evaluation is necessary for collecting information that will assist in makinga precise assessmentof the patient's clinical and microbiologic response to therapy. patients who have received at least days of therapy and at least % or more of prescribed medicationwill have an assessment of clinical response. ( ) clinical cure is defined as complete resolution of all signs and symptoms of pneumonia and improvement or lack of progression of all abnormalities on the chest radiograph. ( ) clinical failure is defined as anyof the following conditions: persistence or progression of all signs and symptoms after - days of therapy; development of new pulmonary or extrapulmonary clinical findings consistent with active infection; persistence or progression ofradiographic abnormalities; deathdue to pneumonia; or an inability to complete the study because of adverse effects. ( ) indeterminate indicates that extenuating circumstances preclude classification as cure or failure. ( ) definition of microbiologic response ( ) microbiologic eradication is defined as elimination of the original causative organism(s) from the same site (e.g., expectoratedsputumor normally sterile body fluids such as pleural fluidor blood)during or upon completion of therapy. ( ) presumed microbiologic eradication is defined as absence of appropriate material for culture (e.g., sputum or pleural fluid) for evaluation because the patient has improved clinically and does not produce sputum or because repeated aspiration of pleural fluid is not clinically justified. ( )microbiologic persistence is defined as failure to eradicate the original causative organism(s) from sites previously listed, whether or not signs or inflammation are present. ( ) microbiologic relapse is defined as recurrence of pulmonary infection with the same organism(s) within days after discontinuation of treatment or during treatment after two consecutive cultures have been negative. ( )superinfection is defined as development of a new lower respiratory tract infection (documented by fever, chest radiograph, and/or auscultatory findings) during treatment or within days after treatment has been completed that is due to a new or resistant pathogen not recognized as the original causative organism(s). ( ) colonization is defined as the development of a positive sputum culture that yields a bacterial strain other than the primary causative isolate that appears > hours after initiation of therapy, persists in at least two repeated cultures, and is not associated with fever, leukocytosis, persistence or progression of pneumonia, or evidence of infection at a distant site. ( ) eradication and reinfection is defined as elimination of the initial infecting pathogen followed by its replacement with a new species or with a new serotype or biotype of the same organism in sputum, pleural fluid, or blood in the presence of signs or symptoms of infection after completion of therapy. for new or additional antimicrobial therapy because of continued infection at the original site in the absence of microbiologic data. ( ) indeterminate is defined as circumstances in which it is not possible to categorize the microbiologic response because of death and the lack of opportunity to perform further cultures, the withdrawal of the subject from the study before follow-up cultures can be obtained, incomplete microbiologic data, or concurrent treatment of the patient with a potentially effective anti-infective agent that is not part of the study protocol. the name of the agent and the dose and duration of this therapy must be recorded. the duration of therapy will affect decisions about patient evaluability and outcome. ( ) otherconsiderations-when more than one pathogen is present, a separate analysis must be made for each organism. (a) baseline assessment ( ) blood for initial cultures, respiratory tract secretions (sputum), and/or pleural fluid, and/or surrogate markers of infection will be obtained. a complete history and physical examination will be performed. ( ) tests of hematologic, re-nal, hepatic, and pulmonary function will be performed. ( ) radiographic studies such as chest radiography or ct scanning will be performed. arterial blood gas determinations and other tests, such as a diagnostic bronchoscopy, will be done if clinically indicated. ( ) culture of sputum will be repeated at - hours if available; blood cultures will be repeated at - hours if initially positive. semi-invasive tests will be repeated only if there is a suboptimal clinical response. ( ) hematologic, renal, hepatic, and pulmonary function tests will be repeated on days - of therapy and at least every - days during therapy. ( ) antimicrobial concentrations in blood will be determined if possible, but pharmacokinetic studies of respiratory secretions and other body fluids are optional. ( ) if sputum is available, follow-up cultures should be done within hours after completion of therapy. ( ) hematologic, renal, hepatic, and pulmonary function tests will be repeated at hours after completion of therapy. ( ) chest radiography will be performed within hours of completion of therapy, but other imaging (e.g., ct) and semi-invasive studies (e.g., bronchoscopy) will be performed only if the clinical response is suboptimal. response to therapy will be judged by a combination of clinical and microbiologic criteria and analyzed by intention to treat. clinical response is paramount. comprehensive review of morbidity and mortality trends for rheumatic fever, streptococcal disease, and scarlet fever: the decline of rheumatic fever streptococcal disease world-wide: present studies and prospects beta-hemolytic streptococcal diseases streptococcal pharyngitis pharyngitis: management in an era of declining rheumatic fever streptococcal pharyngitis in the s effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis and pharyngitis comparative effects ofpenicillin, aureomycinand terramycin on streptococcal tonsillitis and pharyngitis effect of treatment on streptococcal pharyngitis: is the issue really settled does penicillin make johnny's strep throat better? streptococcal pharyngitis: placebo controlled double-blind evaluation of clinical response to penicillin therapy the effect of penicillin therapy on the symptoms and signs of streptococcal pharyngitis prevention of rheumatic fever acute rheumatic fever: the come-back of a disappearing disease the fall and rise of rheumatic fever in the united states resurgence of rheumatic fever in the intermountain area of the united states adverse and beneficial effectsof immediate treatment of group a beta-hemolytic streptococcal pharyngitis with penicillin the group a streptococcal carrier state. a reexamination suitability of throat culture procedures for detection of group a streptococci as reference standards for evaluation of streptococcal antigen kits specificity study of kits for detection of group a streptococci directly from throat swabs identification of streptococcal pharyngitis in office laboratory: reassessment of new technology rapid strep tests: making sense of a crowded market. contemporary office visits to pediatricians. national ambulatory medical care service greater boston otitis media study group. epidemiology of otitis media during the first seven years of life in children in greater boston: a prospective, cohort study middle ear disease in samples from the general population. ii. history of otitis media and otorrhea in relation to tympanic membrane pathology, the study of men born in and frequency and severity of infection in day care disparate cultures of middle ear fluids the greater boston otitis media study group. otitis media in infancy and intellectual ability, school achievement, speech, and language at age years otitis media in infants and children: management sulfisoxazole as chemoprophylaxis for recurrent otitis media -a double-blind crossover study in pediatric practice otitis media in infants and children: tympanocentesis bacteriology of the 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pivampicillin beta-lactamase producing bacteria in head and neck infection short and long-term treatment results in chronic maxillary sinusitis endoscopic paranasal sinus surgery headaches and sinus disease. the endoscopic approach macroscopic purulence, leukocyte counts and bacterial morphotypes in relation to culture findings for sinus secretions in acute maxillary sinusitis sinusitis of the maxillary antrum management of acute and chronic respiratory tract infections role of infection in chronic bronchitis erythromycin in the treatment of acute bronchitis in a community practice a placebo-controlled, double-blind trial of erythromycin in adults with acute bronchitis role of infection in chronic bronchitis antibiotictherapy in exacerbations of chronic obstructive pulmonary disease community-acquired pneumonia and acutebronchitis prospective study of the aetiology and outcome of pneumonia in the community howcommonis legionnaire's disease? nationalnosocomial infection studyreport. annual summary hospital-acquired pneumonia bacteriology of hospital-acquired pneumonia nosocomialpneumococcal bacteremia a nosocomial outbreak of ampicillinresistant haemophilus influenzae type b in a geriatric unit a nosocomial outbreak of branhamella catarrhalis confirmed by restriction endonuclease analysis theclinicalevaluation of antibacterial drugs guidelines for evaluating new antimicrobial agents principles and practice of infectious diseases acute pneumonia key: cord- -rje bnph authors: ballas, samir k. title: sickle cell anaemia: progress in pathogenesis and treatment date: - - journal: drugs doi: . / - - sha: doc_id: cord_uid: rje bnph the phenotypic expression of sickle cell anaemia varies greatly among patients and longitudinally in the same patient. it influences all aspects of the life of affected individuals including social interactions, intimate relationships, family relations, peer interactions, education, employment, spirituality and religiosity. the clinical manifestations of sickle cell anaemia are protean and fall into three major categories: (i) anaemia and its sequelae; (ii) pain and related issues; and (iii) organ failure including infection. recent studies on the pathogenesis of sickle cell anaemia have centred on the sequence of events that occur between polymerisation of deoxy haemoglobin (hb) s and vaso-occlusion. cellular dehydration, inflammatory response and reperfusion injury seem to be important pathophysiological mechanisms. management of sickle cell anaemia continues to be primarily palliative in nature, including supportive, symptomatic and preventative approaches to therapy. empowerment and education are the major aspects of supportive care. symptomatic management includes pain management, blood transfusion and treatment of organ failure. pain managment should follow certain priniciples that include assessment, individualisation of therapy and proper utilisation of opioid and non-opioid analgesics in order to acheive adequate pain relief. blood selected for transfusion should be leuko-reduced and phenotypically matched for the c, e and kell antigens. exchange transfusion is indicated in patients who are transfused chronically in order to prevent or delay the onset of iron-overload. acute chest syndrome is the most common form of organ failure and its management should be agressive, including adequate ventilation, multiple antibacterials and simple or exchange blood transfusion depending on its severity. preventitive therapy includes prophylactic penicillin in infants and children, blood transfusion (preferably exchange transfusion) in patients with stroke, and hydroxyurea in patients with frequent acute painful episodes. bone marrow and cord blood transplantation have been successful modalities of curative therapy in selected children with sickle cell anaemia. newer approaches to preventative therapy include cellular rehydration with agents that inhibit the gardos channel or the kcl co-transport channel. curative gene therapy continues to be investigational at the level of the test tube and transgenic mouse models. tomatic management includes pain management, blood transfusion and treatment of organ failure. pain managment should follow certain priniciples that include assessment, individualisation of therapy and proper utilisation of opioid and nonopioid analgesics in order to acheive adequate pain relief. blood selected for transfusion should be leuko-reduced and phenotypically matched for the c, e and kell antigens. exchange transfusion is indicated in patients who are transfused chronically in order to prevent or delay the onset of iron-overload. acute chest syndrome is the most common form of organ failure and its management should be agressive, including adequate ventilation, multiple antibacterials and simple or exchange blood transfusion depending on its severity. preventitive therapy includes prophylactic penicillin in infants and children, blood transfusion (preferably exchange transfusion) in patients with stroke, and hydroxyurea in patients with frequent acute painful episodes. bone marrow and cord blood transplantation have been successful modalities of curative therapy in selected children with sickle cell anaemia. newer approaches to preventative therapy include cellular rehydration with agents that inhibit the gardos channel or the kcl co-transport channel. curative gene therapy continues to be investigational at the level of the test tube and transgenic mouse models. although sickle cell anaemia has been referred to as the 'first molecular disease' [ ] and paved the way to modern molecular biology, its management has lagged behind other subsequently described molecular disorders. for decades the management of sickle cell pain, the hallmark of sickle cell anaemia, was limited to bed rest, hydration and inadequate analgesia. lack of understanding of the nature and pathophysiology of the pain associated with sickle cell anaemia hampered rational approaches of therapy and had an adverse effect on the quality of life of an already compromised health status of affected patients. fortunately, during the last decade, advances in the field ushered significant changes in the attitude of care providers towards sickle cell anaemia. most important among these has been the finding that treatment of patients with sickle cell anaemia with hydroxyurea [ ] [ ] [ ] had a significant salutary effect on the clinical picture as shown in table i. moreover, long-term follow-up of adult patients with sickle cell anaemia showed that hydroxyurea therapy is associated with reduced mortality. [ ] this fact rekindled interest in sickle cell anaemia and opened the gates for revitalised basic and clinical research on various aspects of sickle cell anaemia. we are amid a renaissance in the field where sickle cell anaemia is no longer regarded as an unmanageable disorder, and effective treatment and cure are achievable goals in the near future. this paper reviews recent advances in the pathogenesis and treatment of sickle cell anaemia. sickle cell anaemia is a hereditary disorder of haemoglobin (hb) where the sickle gene is inherited, homozygously, from both parents. the sickle mutation is the result of a single base change (gat → gtt) in the sixth codon of exon of the β-globin gene responsible for the synthesis of the β-globin polypeptide of the hb molecule (α β ). this change, in turn, results in replacement of the normal glutamic acid with valine at position of the β-globin chain and the formation of sickle hb. [ , ] in a sense, the mutation is akin to a typographical table i . beneficial effects of hydroxyurea in patients with sickle cell anaemia decreases the frequency of acute painful episodes decreases the incidence of acute chest syndrome decreases the blood transfusion requirement decreases morbidity and mortality error where a change of one letter of a keyword of a manuscript ('punctuation mutation') corrupts the meaning of the intended message. typographical errors in articles, however, are episodic and have a transient effect that is effaced with time. the sickle mutation, on the hand, is permanent and often afflicts a life with pain, disability and morbid existence. the most important pathophysiological event in sickle cell anaemia that explains most of its clinical manifestations is vascular occlusion which may involve both the micro-and macrovasculature. [ ] [ ] [ ] [ ] factors that culminate in vascular occlusion are listed in table ii. [ , [ ] [ ] [ ] [ ] the primary process that leads to vascular occlusion is the polymerisation of sickle hb upon deoxygenation which, in turn, results in distortion of the shape of red blood cells (rbcs), cellular dehydration, and decreased deformability and stickiness of rbc that promotes their adhesion to vascular endothelium. progress in the pathogenesis of vascular occlusion pertains to cellular dehydration and adhesion to endothelial cells described in sections . . and . . , respectively. cellular dehydration is secondary to loss of k + and water. two major transport mechanisms seem to play a significant role in cellular dehydration. the first mechanism is the kcl co-transport pathway activated by acidification and cell swelling. [ ] [ ] [ ] this pathway is most active in reticulocytes and is a feature of low-density sickle cells (reversibly sickled cells -rsc). reticulocyte dehydration appears to contribute to the generation of dense sickle cells directly without going through repetitive cycles of oxygenation-deoxygenation. [ ] the second transport system that mediates cellular dehydration is the ca + -activated potassium channel or the gardos pathway, which seems to be activated by ca + reflux-induced deoxygenation. [ ] [ ] [ ] [ ] [ ] [ ] although much of the intracellular ca + in sickle cells is sequestered in endocytic ves-icles, [ ] [ ] [ ] transient reflux of ca + during deoxygenation-induced sickling seems to be responsible for stimulating the gardos pathway. unlike the kcl co-transport, the gardos pathway seems to be most active in the dense fraction of sickle cell anaemia rbcs. however, in most patients both transport systems are operative. it should be noted, however, that the exact mechanism by which polymerisation of sickle hb leads to cellular dehydration is not fully delineated to date. further research in this area may refine current approaches to molecular therapy. adhesion of sickle rbc to vascular endothelium appears to be a pathophysiological contributor to vaso-occlusion. sickle rbc adhere to cultured endothelial cells in vitro under both static and dynamic conditions whereas normal cells do not. [ ] [ ] [ ] [ ] these findings suggest that sickle rbc have sticky surfaces that promote their attachment to monolayers of cultured endothelial cells. these in vitro observations have been documented to also occur in ex vivo perfusion studies in rats [ ] and transgenic mice. [ ] both cellular and plasma factors have been reported to affect adhesion of sickle rbc to vascular endothelium. thus, young deformable sickle rbc appear to be more adherent to vascular endothelium than are dense, rigid, irreversibly sickled cells. [ , , ] two receptors, α β and cd are present on sickle cell anaemia rbc. the former has been shown to play a role in the adherence of sickle rbc to endothelial cells via vascular cell adhesion molecule (vcam)- . [ , ] plasma factors that enhance adhesion include fibrinogen, factor viii, fibronectin, hyperosmolality, von willebrand factor, thrombospondin and microparticles from activated platelets. [ , , , [ ] [ ] [ ] [ ] thrombospondin released from activated platelets bridges the gap between endothelial cells and sickle rbc by binding to cd receptors on the former and cd receptor or sulfated glycan on the latter. [ , ] matsui et al., [ ] have recently reported that when endothelial cells are activated, p-selectin, a glue-like molecule, moves from their intracellular environment to their outer surface where it binds to sickle cells. this is a novel finding that sheds new light on the pathogenesis of vaso-occlusion. previous studies (vide infra) showed that activated p-selectin triggers clotting in platelets and helps leucocytes to adhere to endothelial cells, and they assumed that rbc did not bind directly to pselectin. matsui et al. [ ] presented the first evidence that p-selectin binds to normal rbc and, to a greater extent, to sickle rbc. this finding suggests that inhibition of p-selectin should be considered as a novel approach for the treatment of acute sickle cell painful episodes. adherence of sickle rbc to vascular endothelium results in intimal hyperplasia in larger vessels that may lead to vascular occlusion and tissue infarction. [ , ] hebbel et al. [ ] reported strong correlation between the degree of adhesion of sickle cell anaemia rbc to endothelial cells in vitro and the severity of the disease in patients with sickle cell anaemia or other variants of sickle cell disease. these interesting findings, however, await documentation by others. hypofibronectinaemia seems also to be related to disease severity, the lower the level of plasma fibronectin, the more severe the disease. [ ] recent in vivo studies in transgenic mice suggest that vascular occlusion results in the creation of an inflammatory state. [ , ] the sequence of events seems to be as follows: (i) reticulocytes carrying the α β receptor adhere to endothelial cells; (ii) this is followed by logjam where there is propagation of occlusion caused by the accumulation of rigid deoxygenated mature rbc proximal to the site of adhesion; (iii) the obstruction eventually clears leading to reperfusion and its associated injury; and (iv) a new cycle of adhesion starts thus creating a vicious cycle of occlusion and reperfusion. evidence of reperfusion injury includes: (i) inflammatory response in the vascular bed of the transgenic mouse with increased leucocyte rolling, adhesion and emigration after hours of mild hypoxia followed by reperfusion; (ii) local production of free radicals; and (iii) the complete inhibition of (i) and (ii) after the infusion of a monoclonal murine anti-p-selectin antibody, but not an anti-reselectin antibody, before reoxygenation. [ ] the implication of this sequence of events is that restoration of oxygen to ischaemic tissue results in the generation of free radicals associated with inflammatory endothelial and tissue injury. further evidence of the importance of adhesion in the pathogenesis of sickle cell anaemia was provided by kaul et al. [ ] who investigated the ability of two murine monoclonal antibodies (mab) to inhibit sickle rbc-endothelium interactions induced by platelet activity factor (paf). the mab used were e and lm- . the former mab ( e) inhibits both α v β and glycoprotein (gp) iib/iiia that bind primarily to fibrinogen and von willebrand factor. lm- , on the other hand, selectively inhibits α v β . infusion of washed sickle cell anaemia rbc in the ex vivo mesocecum of the rat, pretreated with paf, with or without a control antibody resulted in extensive adhesion of sickle rbc in venules associated with post-capillary blockage. pre-treatment of the vasculature with either e or lm- , but not with control antibody, inhibited the adhesion of sickle rbc in postcapillary venules. whether the same sequence of events occurs in patients with sickle cell anaemia or not awaits carefully designed clinical trials with antibodies that inhibit the interaction of sickle rbc and endothelial cells. major concerns of similar trials in humans were raised by hebbel. [ ] these include: (i) the risk associated with the inhibiting effect of mab e on platelet function with an unpredictable net clinical effect (i.e. thrombosis versus bleeding); and (ii) to be effective, these antibodies have to be administered before the rbc adhere to the vessel wall (i.e., pre-treatment before the onset of a vaso-occlusive event) a scenario that is unpredictable in patients with sickle cell anaemia. available data suggest that treatment with these mab after the onset of vaso-occlusion may not be effective. the abnormally high base-line leucocyte count both in patients with sickle cell anaemia and in the sickle transgenic mouse seems to be a marker of this proposed chronic inflammatory state of sickle cell anaemia. [ , ] other factors that influence vaso-occlusion in sickle cell anaemia pertain to the α-genotype, βhaplotype, total hb level and fetal hb (hb f) levels. sickle cell anaemia can be divided into subcategories depending on the α-genotypes and β-haplotypes. [ ] [ ] [ ] about % of patients with sickle cell anaemia have normal α-genotypes (β s /β s , αα/αα), % have one α gene deleted (β s /β s , -α/αα) and the remaining % have two α genes deleted (β s /β s , -α/-α). the effect of α gene deletion on the clinical picture of sickle cell syndromes is controversial. generally speaking, α gene deletion is associated with milder anaemia, [ ] and hence fewer complications associated with severe anaemia and less blood transfusion. the increased haemoglobin level associated with α gene deletion, however, increases the blood viscosity, which is often accompanied by increased frequency of painful crises [ , ] and vaso-occlusive episodes such as avascular necrosis. [ , ] the effect of α gene deletion on the clinical picture is best illustrated in patients with sickle cell anaemia with two α gene deletions (β s /β s , -α/-α). table iii lists the unique features of this type of sickle cell anaemia. [ ] [ ] [ ] [ ] noteworthy is that hemoglobin a (hb a ) is elevated in sickle cell anaemia with two α gene deletions, a finding that confuses this diagnosis with s-β-thalassemia that is typically also associated with elevated hb a levels. this clinical picture, family history, haematological data and molecular diagnostics can differentiate the two diagnoses. [ ] β-haplotypes refer to the nucleotide sequence ′ and ′ to the sickle gene. three major types have been described in africans and african-americans. [ ] these are the senegalese (sen), benin (ben) and central african republic (car) haplotypes. the significance of these haplotypes pertains to their effect on hb f production. it has been established that the higher the hb f level, the milder is the sickle cell anaemia. [ ] the sen haplotype, especially in the homozygous state, is associated with relatively high hb f levels and, hence, milder disease. [ , ] however, these conclusions are based on population data and may not apply to an individual patient. sickle rbc from patients with a high level of hb f seem to be less adherent to vascular endothe- [ ] found that paediatric sickle cell anaemia patients with high levels of f cells had a concomitant decrease in the number of cd +, very late antigen (vla) + and cd + erythrocytes, and hence, less adherent rbc. moreover, hb f seems to affect the exposure of phosphatidylserine on the surface of rbc and coagulation activation. in vivo cycles of sickling/ unsickling with resulting membrane changes and microvesicle formation are one factor responsible for phosphatidylserine exposure. [ ] phosphatidylserine-exposing rbc in the transgenic sickle mouse [ ] were found to have shortened red cell survival. children with sickle cell anaemia and high hb f levels were reported to have less phosphatidylserine-exposing rbc and, hence, milder haemolytic anaemia suggesting a possibly milder clinical picture. [ ] other factors that may effect the severity of sickle cell anaemia include gene modifiers (epistatic genes) that may affect the phenotypic expression of the sickle mutation. styles et al., [ ] reported that specific human leucocyte antigen (hla) alleles may influence the risk of stroke in sickle cell anaemia. adekile et al. [ ] found that the c→t mutation of the methyltetrahydrofolate reduction gene is relatively frequent among kuwaiti patients with sickle cell anaemia, but did not find any correlation with disease severity or prevalence of avascular necrosis. the role of epistatic genes in modifying the phenotypic expression is currently an active area of research. future research findings may enable us to decipher the intricate pathophysiology of sickle cell anaemia and its complications, and usher in newer therapeutic venues. in addition to the factors discussed in section . , there is growing evidence that psychosocial and environmental factors may precipitate vasoocclusion and affect the frequency and severity of painful episodes. physical stress, trauma, dehydration and infections are such known factors. the clinical management of the majority of patients with sickle cell anaemia is primarily palliative in nature. palliative care is the total comprehensive care of patients whose disease is not responsive to curative therapy. [ ] it targets the numerous complications of sickle cell anaemia during the life of a patient from childhood through adulthood. the major goal of palliative care is the achievement of the best quality of life of patients and their families. palliation in sickle cell anaemia includes: (i) general supportive care; and (ii) targeted symptomatic management of complications. supportive care pertains to empowering the patients to live with their disease and be authorities on its manifestations that apply to them individually. this includes the following: • education about sickle cell anaemia, its genetic basis, inheritance and family counselling • adherence to regular schedule of medical follow-up • avoidance of situations that exert an adverse effect on their disease and adoption of those activities of daily living that are beneficial to them • knowing their rights and responsibilities as patients with sickle cell anaemia when dealing with care providers, medical facilities and the workplace • whenever possible, participation in local support groups and communication with community leaders and advocates. sickle cell pain is unique and like other types of pain is a complex human experience that is strongly affected not only by pathophysiological factors, but also by psychological, social, cultural and spiritual factors. the pain is the result of tissue damage generated by the sickling process and occlusion of the microvasculature. tissue damage, in turn, releases several mediators of inflammation that ini-tiate a painful stimulus that is transmitted along a-δ and c peripheral nerve fibres to the dorsal horn of the spinal cord. from there the stimulus crosses to the contralateral side and ascends along the spinothalamic tracts to the thalamus, which in turn, sends the message to the brain where the stimulus is perceived as pain. other concurrent processes may affect pain perception. one process pertains to descending fibres from the midbrain to the dorsal horn that inhibits the transmission of painful stimuli via endogenous endorphins. another process pertains to communications between the thalamus, the reticular formation and the limbic system, which together modulate the emotional response to pain that may enhance or inhibit the intensity of pain perception. the unique features of sickle cell pain are listed in table iv. it is primarily a nociceptive type of pain, i.e. the result of tissue damage. however, it could be or could have a neuropathic component. [ ] the latter is characterised by burning sensation, tingling and numbness. thus, it is important to conduct a thorough history and physical examination to determine whether sickle cell pain is associated with a neuropathic component or not. this is an important aspect of the treatment because the management of neuropathic pain utilises special approaches as will be discussed in this section. rational and effective management of sickle cell pain includes: (i) thorough assessment; (ii) utilisation of both non-pharmacological and pharmacological agents; and (iii) a comprehensive plan for disposition and longitudinal follow-up. assessment is the most important initial step in effective pain management. it should be conducted before and periodically after the administration of analgesics. [ ] [ ] [ ] assessment relies heavily on patient self report. other factors in the process of assessment should include the presence or absence of other complications of the disease, family member reports and vital signs. the patient self report should include multidimensional scales describing the intensity, quality, location, distribution, onset, duration, mood, sedation, pain relief and factors that aggravate or relieve pain. the intensity of pain can be assessed by using any of several available scales such as the visual analogue scale, verbal, numerical or wong-baker faces scale for children. it is important, however, to stick to one scale and use it routinely so that both the patient and provider become familiar with it and its significance to a certain patient on an individual basis. nociceptive sickle cell pain, typically, is sharp and/or throbbing in nature. pain that is burning, shooting, lancinating or tingling in nature suggests the presence of a neuropathic component of pain that entails the utilisation of certain adjuvants as will be discussed in this section. [ , ] initial pain assessment establishes a baseline against which the effectiveness of analgesics in achieving pain relief can be compared. subsequent assessment allows increasing the dose of analgesics to achieve desirable pain relief, tapering the dose of analgesics as the painful episode resolves, identification of adverse effects of therapy or the emergence of complications of the disease which allow intervention to modify the treatment plan as needed. non-pharmacological management of pain includes cutaneous stimulation [transcutaneous electrical nerve stimulation (tens), heat, cold and vibration] distraction, relaxation, massage, music, topical agents: lidocaine/prilocaine; capsaicin tramadol corticosteroids guided imagery, self-hypnosis, self-motivation, acupuncture and biofeedback. although there are no well-controlled clinical trials on the efficacy of these modalities on the management of sickle cell pain, there are many anecdotal reports of their efficacy in pain management. pharmacological management of pain includes three major classes of compounds: non-opioids, opioids and adjuvants. [ , ] a major difference between non-opioids and opioids is that the former have a ceiling effect which refers to a dose above which there is no additive analgesic effect. [ ] nonopioids (table v) include paracetamol (acetaminophen), non-steroidal anti-inflammatories (nsaids), topical agents, tramadol and corticosteroids. paracetamol has analgesic and antipyretic effects, but no anti-inflammatory component. [ ] the daily total adult dose must not exceed g in to divided doses. [ ] high dosages damage the liver and could be fatal. the daily dose should be decreased in the presence of liver disease. the daily dose of combination medications (medications that contain paracetamol plus an opioid) must be controlled so that the g limit of paracetamol is met. nsaids (table vi) include non-selective cyclooxygenase (cox) inhibitors, and selective and partially selective cox- inhibitors. [ ] [ ] [ ] nsaids have an anti-inflammatory effect in addition to their analgesic and antipyretic potential. they act primarily at the level of nociceptors where pain impulses originate and, hence, are often referred to as peripherally acting analgesics. they exert their analgesic effect by decreasing the synthesis of prostaglandins by inhibiting cox enzymes, [ ] thus, decreasing or abolishing the sensitisation of nociceptors by prostanoids. the traditional non-selective nsaids inhibit both the housekeeping cox- and the inducible cox- enzymes. selective nsaids inhibit only the cox- enzyme and spare cox- , which is needed to produce physiological levels of prostaglandins. nsaids have potentially serious systemic adverse effects. they include gastropathy, nephropathy and haemostatic defects. they should not be administered to patients with renal disease or with history of peptic ulcer disease. it is advisable not to administer them continuously to patients with sickle cell disease for more than days. moreover, certain nsaids are associated with idiosyncratic (non-prostaglandin-mediated) reactions as shown in table vii. most recent among these is immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and paracetamol. [ ] the antibodies described were mostly specific for gp iib/iiia and less often to gp ib/ix/v. cox- inhibitors are associated with significantly less gastrointestinal and haemostatic adverse effects [ , ] than the non-selective nsaids, but their effect on renal function seems to be the same. [ , ] the concomitant administration of ketorolac with opioids was reported to exert an additional analgesic effect and decrease the amount of opioids consumed for the treatment of acute painful episodes. [ ] tramadol [ ] is a synthetic centrally acting analgesic not chemically related to opioids. it acts as a weak agonist with preferential affinity to the μ receptors. moreover, it inhibits neuronal re-uptake of both serotonin and norepinephrine, and stimulates the release of serotonin. thus, functionally, it has properties of an opioid and an antidepressant. the initial enthusiasm that this drug is not associated with clinically significant respiratory depression or addiction potential [ ] waned after reports indicating that seizures may be an adverse effect and an increasing abuse potential. currently, tramadol is not a scheduled drug and it seems to be as effective as paracetamol with mg codeine with the added advantage of a tricyclic antidepres-sant-like effect. tramadol may be administered by the oral or parenteral route, and it is available in slow-release form. only the oral form is approved for marketing in the us at the present. anecdotally, tramadol seems to be effective in the management of mild or moderately severe pain in some patients with sickle cell anaemia. opioid analgesics [ ] have fewer systemic adverse effects than nsaids but their use in sickle cell disease is often associated with many myths about drug-seeking behaviour and addiction. there are four major classes of opioids: agonists, partial agonists, mixed agonists-antagonists, and antagonists (table viii) . traditionally, opioid antagonists have been regarded as having no analgesic effect and their use is primarily limited to counteract the depressive effects of opioid agonists. recently, however, [ ] there have been reports showing that small doses of antagonists in combination with agonists seem to enhance the analgesic effect, and prevent or delay tolerance to opioid agonists. should this approach be proven by controlled trials, it would be a novel tool in the management of pain. opioid agonists are most often used in the management of sickle cell pain, especially in adults. they decrease or modify the perception of pain at the level of the central nervous system (cns). they exert their effect by binding to μ, κ, and to a lesser extent, δ receptors. [ ] opioid agonists can be administered via several routes (orally, subcutaneously, intramuscularly, intravenously, transdermally, etc.) and methods, including continuous intravenous drip, patient-controlled analgesia (pca) pump or intermittent injection. pethidine (meperidine), morphine and hydromorphone are the major opioid analgesics used in the treatment of severe pain in the emergency department (ed) and hospital. long-acting opioids, such as the oxycodone controlled-release (cr) formulation oxy-contin ® (oxycodone cr) and morphine cr, are useful in the management of chronic pain and in combination with short-acting opioids for breakthrough pain. adverse effects of opioid analgesics include itching, nausea, vomiting, sedation and respiratory depression. seizures may be associated with op-ioids, especially with the prolonged use of pethidine, in some patients. tolerance and physical dependence occur in some patients, but addiction is rare. [ ] as a group, opioid analgesics have no ceiling effect (with the possible exception of codeine) and hence, the only limiting factor for dosage is adverse effects. severe sedation and respiratory depression are the most important adverse effects. hospitalised patients receiving opioid analgesics on a regular basis should be monitored for their respiratory rate and sedation level. a respiratory rate less than per min and/or severe sedation justifies missing, decreasing or delaying the dose, or discontinuing the opioid in question until the depressive effects disappear. opioid analgesics should be used carefully in patients with impaired ventilation, asthma, increased intracranial pressure and liver failure. the dosage of pethidine and morphine should be adjusted in the presence of renal failure. they are also histaminergic and histamine release may trigger bronchospasm or initiate an allergic reaction. morphine is the most histaminergic of all opioids. [ ] the presence of paracetamol in combination with codeine or oxycodone limits the daily dose that can be safely used so that the maximum allowable dosage of paracetamol is not exceeded. the use of paracetamol in conjunction with monoamine oxidase inhibitors may cause a severe adverse reaction characterised by excitation, hyperpyrexia, convulsions and death. [ ] the co-administration of antipsychotics with pethidine may cause neuromuscular disorders including akathisia, dystonia, tardive dyskinesia and neuroleptic malignant syndrome. [ ] adjuvants include antihistamines, antidepressants, benzodiazepines and anti-convulsants. these are heterogeneous compounds that potentiate the analgesic effect of opioids, ameliorate their adverse effects and have their own mild analgesic effect. the most commonly used adjuvants in the management of sickle cell pain are listed in table ix. the role of selective serotonin reuptake inhibitors (ssri) in sickle cell anaemia is not clear at the present. adjuvants must be used with care and patients should be monitored carefully when receiving them. adjuvants also have adverse effects, some of which precipitate or worsen some of the manifestations of sickle cell anaemia as is discussed later in this section. [ ] acute painful episodes of mild or moderate severity are usually treated at home using a combination of non-pharmacological and pharmacological modalities. home treatment of pain usually follows the three step analgesic ladder proposed by the world health organisation (who). [ ] mild pain is treated with non-pharmacologic agents alone or in combination with a non-opioid. more severe pain entails the addition of an opioid ± an adjuvant. data from the multi-center study of hydroxyurea (msh) [ , ] in sickle cell anaemia showed that a oxycodone/paracetamol formulation was the opioid most often used for the home treatment of pain. [ ] however, this report was before the advent of the new formulations of opioids such as oxycodone cr. whether oxycodone/paracetamol continues to be the first in this scenario of pain management remains to be seen. severe acute sickle cell painful episodes are usually treated in a medical facility using paren-teral analgesics. progress in this area pertains to the advent of day hospitals where patients are promptly evaluated by a team of experts in the management of sickle cell pain without exposure to the delay that is common in hospital emergency rooms. [ ] available data in the literature show that management of patients with severe acute painful episodes in such facilities, especially those that operate on a -hour basis, reduce the frequency of hospital admissions. these findings should encourage other metropolitan hospitals in cities with a large population of african-americans to follow suit by establishing acute care facilities specifically designed for patients with sickle cell disease. the establishment of such facilities nationwide may, in turn, verify the cost-saving potential of this approach to healthcare. data from the msh showed that the parenteral opioid most often used in the management of acute sickle cell painful episodes in the ed or hospital was pethidine. [ ] again, this was in and since then, there have been many anecdotal reports from many hospitals of switching to other opioids than pethidine, but detailed studies to confirm this are not available to date. patients with chronic sickle cell pain and those with very frequent acute painful episodes are best managed with a combination of long-acting opioids and a short-acting opioid for breakthrough pain. again, there are anecdotal reports that this approach decreased the frequency of admissions to the ed and/or hospital, but data to confirm this are not available to date. oxycondone cr seems to be unique in that it has both an immediate analgesic effect and a delayed long-acting effect. these properties made oxycodone cr popular among drug abusers who learned to remove the mesh and release high-dose of pure oxycodone that has immediate 'euphoric' effect. [ ] care providers should exert caution in prescribing oxycodone cr as well as other opioids and keep records of assessment and plans of management of their patients. most patients usually tolerate the chronic anaemia of sickle cell disease. sickle hb has decreased promethazine oxygen affinity and, hence, is efficient in delivering oxygen to tissues. the two major objectives of blood transfusion in sickle cell anaemia are; (i) improvement of the oxygen carrying capacity of blood; and (ii) dilution of circulating sickled rbc in order to improve microvascular perfusion. specific indications for blood transfusion are listed in table x. [ ] [ ] [ ] the goal of exchange transfusion is to increase or maintain a hb level of about g% and to decrease the level of sickle hb to < %. [ , ] in patients with stroke undergoing exchange transfusion to prevent recurrence of a cerebrovascular accident, a level of sickle hb < % seems to be acceptable. [ , ] however, there are no controlled studies to show which target of sickle hb is better in relief of the acute symptoms and prevention of recurrence. more blood units may be needed to decrease sickle hb to < % and thus, more exposure of the patient to donor blood. on the other hand, decreasing sickle hb to < % only may increase the fre-quency of blood exchanges required to keep sickle hb at this level. blood selected for transfusion for patients with sickle cell anaemia should meet the criteria listed in table xi. because the majority of patients with sickle cell anaemia are africans or african-americans and because they receive blood given by caucasians, there is a high incidence of allo-immunisation in transfused patients with sickle cell anaemia. [ ] the most prevalent allo-antibodies in patients with sickle cell anaemia include anti-c, -e and -k. thus, the use of phenotypically matched blood, at least for these antigens, is highly recom- mended. [ ] some blood banks implemented programs to increase communication between the african-american community and medical facilities to ensure the presence of a blood supply from african-american donors directed for patients with sickle cell anaemia in order to reduce the incidence of allo-immunisation to those antigens that are prevalent in african-americans. however, there are no data to show the desirable outcome, if any, of this practice. one concern about this practice (designated donations from african-americans to patients with sickle cell anaemia) is that it may increase the incidence of transfusion-related graft versus host disease unless such blood is routinely irradiated. some of the complications seen in patients with sickle cell anaemia are secondary to therapeutic interventions. table xii lists some of these complications. patients transfused before , when a reliable second generation screening test for hepatitis c virus (hcv) was introduced in blood banks, are at a higher risk for transmission of hcv. approximately to % of adult patients who received a blood transfusion before are positive for hcv antibody. these patients should be followed-up regularly and the levels of hepatic enzymes monitored periodically. increase in the enzyme level beyond what is expected in sickle cell disease is an indication for a liver biopsy. if the latter shows evidence of hepatitis, specific therapy with a combination of interferon and ribavirin [ ] would be considered. patients with sickle cell anaemia taking ribavirin should be monitored carefully because ribavirin may worsen their haemolytic anaemia. [ ] the transfusion of leucocyte-reduced components decreases the chances for allo-immunisation and febrile transfusion reactions. the transfusion of phenotypically identical rbc also minimises the chances for allo-immunisation and haemolytic reactions. iron overload is best monitored by periodic determination of serum ferritin levels in frequently transfused patients. [ ] serum ferritin levels > μg/l in the steady state are suggestive of iron overload. to confirm the diagnosis of iron overload, a liver biopsy is indicated in order to quantitate the amount of iron per gram of tissue. hepatic iron concentration > mg/g liver dry weight is diagnostic of iron overload and is an indication for chelation therapy with deferoxamine. prophylaxis: prophylactic oral penicillin (or a macrolide if there is sensitivity to penicillin) should be given to infants and children with sickle cell disease for a minimum of years. [ ] all patients with sickle cell disease should receive the polyvalent ( -valent) pneumococcal polysaccharide ( ps) vaccine starting at age years and every to years thereafter. [ ] the heptavalent pneumococcal conjugate vaccine (pc v ) should be given to all children at , , and months of age. patients with sickle cell disease should also receive the pc v vaccine at age and years. other recommended vaccinations, in addition to routine childhood vaccines, include haemophilus influenza type b conjugate vaccine at ages , and months, influenza vaccine annually, and hepatitis b vaccine at birth or the first visit of children and adults who have no serological evidence of previous exposure to the hepatitis b virus. immunosuppression: sickle cell anaemia has an unusual relationship to certain infectious agents. individuals with sickle trait are resistant to infection by plasmodium faliciparum but patients with sickle cell anaemia are susceptible. individuals with fy(a-b-) red cells are resistant to infection by other types of malarial parasites. several acquired abnormalities render patients with sickle cell disease immunocompromised and hence susceptible to a number of infections that are a major cause of mortality and morbidity. these include immunomodulation secondary to blood transfusion and iron overload. [ ] the increased susceptibility of patients to infection with polysaccharide-encapsulated bacteria (streptococcus pneumoniae and h. influenzae) is secondary to absence of splenic function. cellular immunity may be compromised by transfusion-related iron overload and abnormalities in b cell immunity may explain antigen processing defects. infections due to escherichia coli are usually associated with urinary tract infection (uti) in adult patients. patients with sickle cell anaemia are susceptible to osteomyelitis secondary to salmonella typhimurium in addition to the usual causes of bacterial osteomyelitis such as staphylococcus aureus. [ ] the susceptibility to infection by salmonella may reflect the ability of this organism to flourish in partially necrotic bone. management: treatment options for infections include penicillin, cephalosporins, macrolides, tetracyclines, fluoroquinolones, aminoglycosides and cotrimoxazole (trimethoprim/sulfamethoxazole) [table xiii]. the choice of antibacterial depends on the possible pathogen, the possibility of resistance, the severity of the infection and the characteristics of the patient such as age, allergies and concomitant complications. bacterial resistance is a serious and rapidly increasing worldwide problem. pneumococci continue to be the most important organisms causing pneumonia (especially community acquired pneumonia) and also play a very important role in other infections such as sinusitis, otitis media and meningitis. [ ] approximately to % of s. pneumoniae strains are resistant to penicillin. highly penicillin-resistant strains of s. pneumoniae are also resistant to amoxicillin/clavulanic acid and cephalosporins. approximately % of these strains are resistant to macrolides and % to tetracyclines. resistance to fluoroquinolones is currently low. moreover, approximately to % of h. influenzae strains are resistant to penicillin. neurological complications occur in % of patients with sickle cell disease and are more common in sickle cell anaemia than in other sickle cell syndromes (hb sc disease, s-β thalassemia). cerebral infarction (figure ) is more frequent in children, whereas intracerebral haemorrhage is more prevalent in adults. microaneurysms (commonly referred to as moya moya) involving fragile dilated vessels that develop as compensatory collateral circulation around areas of infarction seem to be responsible for haemorrhage in adults (figure ). unlike other vascular beds, large vessels rather than microvessels seem to be the site of occlusion with consequent infarction. approximately twothirds of children with cerebral infarction (who are not transfused) may develop further ischaemic events within years [ , ] a major breakthrough in the management of cns complications in children has been the prevention of stroke in patients at risk for this complication. [ , ] specifically blood transfusion prevented the occurrence of stroke in children who had abnormal results on transcranial doppler ultra-sonography (tcd). blood velocity of cm/sec or more in either the internal carotid or middle cerebral artery is abnormal (normal < cm/sec) and is an indication for blood transfusion or exchange transfusion. the appropriate therapy for a child with cerebral infarction due to vaso-occlusion or an asymptomatic patient with abnormal transcranial doppler studies is exchange transfusion or hypertransfusion to maintain the sickle hb level below %. red cell transfusions are usually continued for a minimum of years after which transfusion therapy is individualised. whether chronic transfusion therapy for adults with cerebral infarction secondary to vaso-occlusion is indicated or not remains unknown. similarly, the appropriate treatment of an adult patient with cerebral haemorrhage has yet to be determined. a thorough search for aneurysms should be made and surgical intervention considered. ware et al. [ ] have recently suggested that some children with sickle cell disease and stroke may discontinue chronic transfusion and use hydroxyurea therapy to prevent stroke recurrence. this approach is desirable because it prevents or decreases the risks associated with blood transfusion mentioned above. more data, however, are needed to justify this modality of therapy. other risk factors for stroke in children include bacterial meningitis, family history of a sibling with stroke, severe acute chest syndrome, acute anaemic episodes, recurrent episodes of seizure, impaired cognitive skills, lack of α-gene deletion and the car β s -haplotype. one study suggested that high homocysteine levels may be a risk factor for cerebrovascular accidents in patients with sickle cell anaemia. [ ] seizures in sickle cell disease may be secondary to an epileptic focus as a result of infarction or to treatment with large doses of pethidine, or they may be idiopathic. antiepileptic therapy is recommended for patients with abnormal electroencephalograms. charache et al. [ ] introduced the term acute chest syndrome to define acute episodes of fever, chest pain, increased leukocytosis and pulmonary infiltrates in adult patients with sickle cell anaemia, most of whom probably had pulmonary infarction. with time, the definition of acute chest syndrome has expanded to include hypoxemia, cough, shortness of breath, wheezing, chills and worsening anaemia. [ ] moreover, the current definition of acute chest syndrome stresses that the infiltrates must be 'new'. the signs and symptoms of acute chest syndrome vary from very mild to very severe and even life-threatening. another feature of acute chest syndrome that is not included in the definition is the presence of blister cells in peripheral blood. [ ] acute chest syndrome is second to acute painful episodes as the most common cause of hospitalisation of patients with sickle cell disease and also the most common complication of surgery and anaesthesia. [ ] acute chest syndrome is the most common cause of death and is closely associated with acute painful episodes especially in adults. [ , ] although acute chest syndrome is usually self-limited and resolves with treatment, it can be associated with respiratory failure with a mortality rate of about . % in children and . % in adults. [ , ] risk factors for developing acute chest syndrome are listed in table xiv. [ ] the incidence of acute chest syndrome is highest in sickle cell anaemia, followed by s-β -thalassemia, hb sc disease and s-β + -thalassemia in decreasing order of frequency. the single most important preventive factor is a high level of hb f due either to endogenous genetic factors or to exogenous induction with drugs such as hydroxyurea. [ , [ ] [ ] [ ] [ ] the mean corpuscular volume (mcv) of rbcs, platelet count and α-thalassemia bear no relation to acute chest syndrome. [ ] aetiologies of acute chest syndrome include infection, especially communityacquired pneumonia, pulmonary infarction as a result of in situ sickling, fat-bone marrow embolism or pulmonary embolism. infection is commonly caused by chlamydia, mycoplasma, respiratory syncytial virus, coagulase-positive s. aureus, s. pneumoniae, mycoplasma hominis, parvovirus and rhinovirus in decreasing order of frequency. [ ] adhesion of sickled rbc to endothelial cells of small or medium-sized pulmonary vessels may result in occlusion of microvascular flow and consequent pulmonary infarction. [ , , ] this sequence of events is supported by dynamic imaging studies but confirmatory clinical data are not available. pulmonary thromboembolism is uncommon as a cause of acute chest syndrome despite the presence of a hypercoagulable state in sickle cell disease. [ ] it seems that this hypercoagulable state plays a more important role in stimulating cellular adhesion and activating the inflammatory system than in initiating the thrombotic cascade. [ , ] pulmonary fat-bone marrow embolism (figure ) in patients with sickle cell anaemia appears to be more common than previously thought. [ , ] the characteristic clinical picture is that of severe bone pain, usually in long bones, followed by dyspnea, hypoxia and fever. tissue infarction of the bone marrow within the long bones seems to generate a source of fat and necrotic tissue that has been demonstrated on autopsy. at the same time, serum levels of secretory phospholipase a , (spla ), an inflammatory mediator, increase in patients with acute chest syndrome [ ] and liberate free fatty acids from membrane phospholipids of damaged tissue that are believed to cause damage to pulmonary endothelium culminating in a leak syndrome which, if severe, may be similar to adult respiratory distress syndrome (ards). an elevated level of spla is both a marker and probably a predictor of acute chest syndrome. diagnostic work-up of acute chest syndrome should include serial chest radiographs, induced deep sputum and blood cultures, monitoring arterial blood gases, monitoring haemoglobin level, ventilation and perfusion scans, and ruling out thrombophlebitis in the pelvis or lower extremities. the diagnosis of fat embolism entails the identification of fat-laden macrophages in induced deep sputum, or better bronchoalveolar lavage fluid obtained by bronchoscopy. [ , ] blister cells have been described in the peripheral blood of patients with sickle cell disease and acute chest syndrome. [ ] management of acute chest syndrome includes oxygen, incentive spirometry, antibacterials, simple blood transfusion or exchange transfusion, judicious use of analgesics, careful hydration and possibly vasodilators. incentive spirometry prevents splinting and atelectasis, and may actually prevent acute chest syndrome in patients who have rib infarction. [ ] intravenous antibacterials are indicated since it is difficult to rule out pneumonia or infected lung infarcts. a combination of a third generation cephalosporin and a macrolide or a fluoroquinolone (table xiii) should be used to cover typical and atypical pathogens. simple transfusion or exchange transfusion is indicated in patients with worsening respiratory function. the beneficial effects of blood transfusion may not be due simply to decreasing the proportion of sickled rbc and other mechanisms may be involved. these include: (i) an immunomodulatory mechanism by which inflammatory cytokines [interleukin(il)- , in particular] bind to the duffy antigen present on transfused rbcs, but often absent on rbcs of african-americans; [ ] and (ii) the albumin that is present in transfused units or used in blood exchange may bind free fatty acids, thus neutralising their damaging effect on the pulmonary endothelium. although intravenous corticosteroids in children with acute chest syndrome may be beneficial, [ ] their use in adults with acute chest syndrome is controversial. huang et al. [ ] reported two adult patients with sickle cell disease whose clinical picture deteriorated and was complicated by worsening pain, fat embolism and coma after corticosteroid therapy. adults, unlike children, have more adipose tissue that may hypertrophy with corticosteroids, increasing the chances of fat embolisation. moreover, corticosteroids may induce or worsen avascular necrosis, which is more common in adults than in children. excessive use of opioid analgesics may precipitate acute chest syndrome because of the depres- sive effect on respiration. recent reports [ ] recommend the use of nsaids. this recommendation should be considered carefully. opioids have a few systemic adverse effects, and careful monitoring of their use ensures their safety. they should be discontinued if the respiratory rate is ≤ per minute and their adverse effects can be quickly reversed with opioid antagonists. nsaids, on the other hand, have considerable systemic adverse effects that may not be readily obvious. nsaids decrease the levels of prostaglandins and prostacyclin, prostanoids that are essential in modulating the vascular tone of smooth muscle and renal blood flow. thus, nsaids may worsen the clinical picture of acute chest syndrome as a result of vasocontrictive effects. preliminary reports on the use of nitric oxide (no), a vasodilator, in patients with sickle cell disease support a possible role of this agent in the management of acute chest syndrome in the future. [ ] other vasodilators such as prostacyclin and calcium channel antagonists have not been reported in the management of acute chest syndrome. another recent investigational approach to treat acute chest syndrome includes the use of purified poloxamer , which is a non-ionic surfactant. it is hypothesised that this agent reduces blood viscosity, prevents adhesion of rbcs to vascular endothelium and improves microvascular blood flow. [ , ] because acute chest syndrome is relatively frequent in patients with sickle cell anaemia, and in view of the need to monitor arterial blood gases in its management, it is important to establish baseline blood gases and pulmonary function tests for all patients. these determinations will be of value in evaluating patients who present with acute onset of pulmonary signs and symptoms. sickle cell anaemia is associated with numerous renal complications that span a spectrum from hyposthenuria to end-stage renal failure (table xv) . [ ] [ ] [ ] [ ] uti is usually caused by e. coli and is more common in females than in males. the increased frequency of uti in sickle cell anaemia may relate to renal infarction or to immunodeficiency. the hypoxic, acidotic and hypertonic environment of the renal medulla causes sickling of the rbc in the vasa recta and leads to infarction of the renal medulla, hyposthenuria and haematuria (gross or microscopic). inability to acidify the urine after an acid load can also occur. these renal tubular defects (haematuria, hyposthenuria) occur not only in patients homozygous for the sickle gene, but also in patients who are heterozygous (for example, as, sc, sd and so). management of haematuria in a patient with sickle cell anaemia follows conservative guidelines. strict bed rest alone results in spontaneous remission in most patients. in a few instances, gross haematuria may be severe enough to warrant blood transfusion or exchange transfusion. nephrectomy should be avoided. the use of aminocaproic acid and desmopressin may be effective in controlling haematuria. renal medullary carci- noma should be ruled out in all patients with gross haematuria. potassium excretion is also impaired and episodes of hyperchloraemic acidosis have been reported. in vitro haemolysis of collected blood samples kept in the lab at room temperature for some time before analysis may explain the spurious hyperkalaemia in some patients with sickle cell anaemia. occasionally, hyperkalaemia is reported in association with type renal tubular acidosis, but renal insufficiency is present in the majority of these patients. papillary necrosis may be more common in hb sc disease. [ ] hyperuricaemia in patients with sickle cell anaemia is the result of both increased bone marrow activity with consequent enhanced urate production secondary to purine metabolism and an acquired decreased renal tubular clearance of urate. gout has been described in a few patients. allopurinol may be indicated to lower serum urate levels. nephrotic syndrome, with or without hypertension, occurs frequently. microscopic haematuria, proteinuria, hypertension and the nephrotic syndrome are markers of incipient end-stage renal failure. proteinuria occurs in % of patients with sickle cell anaemia and elevated serum creatinine levels in approximately %. proteinuria causes congestion of tubular endothelium as a result of tubular uptake of protein. congestion induces growth factors which, in turn, lead to proliferation of fibroblasts that culminate in renal fibrosis and renal failure. the pathological lesion is usually glomerular enlargement and peripheral focal segmental glomerulosclerosis. treatment with enalapril (an angiotensin-converting enzyme inhibitor) seems to reduce the degree of proteinuria in patients with sickle cell anaemia suggesting that capillary hypertension may be a pathogenic factor in sickle cell nephropathy. once chronic renal failure sets in, patients require long-term haemodialysis and are candidates for kidney transplantation. [ , , ] priapism occurs when sickle cells congest the copora and prevent emptying of blood from the penis. it can result from tricorporal involvement (both of the corpora cavernosa and the corpus spongiosum) or bicorporal involvement (both corpora cavernosa). the latter is more common, especially in children, and is not regularly associated with impotence. there are two major clinical presentations of priapism: acute and chronic. [ ] the acute presentation is characterised by a prolonged painful erection that persists beyond several hours, responds poorly to exchange transfusion and frequently requires surgical intervention. acute priapism may be followed by complete or partial impotence. the chronic form of priapism is characterised by repetitive, reversible, painful erections called 'stuttering' priapism. it usually occurs after intercourse or it may awaken patients early in the morning. stuttering priapism responds well to diazepam or pseudoephedrine. patients who become impotent may benefit from psychological counselling and the insertion of penile implants. a practical and relatively simple approach to manage outpatients with priapism has been recently reported. [ ] specifically, aspiration of the corpora cavernosa followed by irrigation with a dilute epinephrine solution was effective in producing detumescence in most patients. patients who do not respond to this approach are potential candidates for exchange transfusion and/or surgery. [ ] leg ulcers leg ulceration is a painful and sometimes disabling complication of sickle cell anaemia that occurs in to % of adult patients. severe pain may necessitate the use of opioid analgesics. leg ulcers are more common in males and older patients, and less common in patients with α-gene deletion, high total hb level or high levels of hb f. [ ] leg ulcers seem to be more common in patients who are also carriers of the car β-gene cluster haplotype. [ ] treatment of leg ulcers includes wound care using wet to dry dressings soaked in saline or burrow's solution. with good localised treatment, many ulcers heal within a few months. leg ulcers that persist beyond months may require blood transfusion or skin grafting, although results of the latter treatment have been disappointing. because leg ulcers may recur after minimal trauma, protec-tive legging with non-elastic (special velcro) lower-extremity orthoses with ankle straps, to be worn during working hours, appears to be an effective preventive measure. [ ] principles of management of leg ulcers include education, protection, infection control, debridement and compression bandages. efficacy of blood transfusion/exchange transfusion, hyperbaric oxygen and skin grafting is anecdotal in nature. osteomyelitis may complicate chronic leg ulcers, especially those associated with deep wounds, and it is advisable to rule out this complication with a bone scan or magnetic resonance imaging (mri), with gadolinium as needed. to date, there has been no controlled trial of the treatment of sickle cell leg ulcers to identify the best approach to management. the relationship between leg ulcers in patients with sickle cell anaemia and hydroxyurea is not clear. early reports [ ] showed that hydroxyurea seems to have a salutary effect on leg ulcers. recent reports [ ] indicated that hydroxyurea used in the treatment of myeloproliferative disorders is associated with increased incidence of leg ulcers. to date, there is no evidence whether hydroxyurea is beneficial or harmful in the management of leg ulcers in patients with sickle cell anaemia. ferster and colleagues [ ] recently reported their experience with a group of children and young adults with sickle cell disease treated with hydroxyurea for a median follow-up of . years. leg ulcers did not complicate the clinical picture of these patients. recent advances in the management of leg ulcers include the topical application of a plateletderived growth factor prepared either autologously or by recombinant technology, and the use of cultured skin grafts. the use of newly described semipermeable polymeric membrane dressing may promote healing. [ ] to date, there are no data about these new modalities in the management of leg ulcers in patients with sickle cell anaemia. avascular necrosis (also called ischaemic necrosis or osteonecrosis) is the most commonly observed complication of sickle cell disease in adults. although it tends to be most severe and disabling in the hip area, it is a generalised bone disorder in that the femoral and humeral heads as well as the vertebral bodies may be equally affected. the limited terminal arterial blood supply and the paucity of collateral circulation make these three areas especially vulnerable to sickling and subsequent bone damage. patients with sickle cell anaemia and α-gene deletion have a higher incidence of avascular necrosis because the relatively high hematocrit increases blood viscosity and thus, enhances microvasculopathy in the aforementioned anatomic sites. [ , ] the mcv and serum aspartate aminotransferase (ast) levels are negatively correlated with avascular necrosis. [ ] medical treatment of avascular necrosis is symptomatic and includes providing non-opioid and/or opioid analgesics for pain relief, as well as minimal weight bearing. advanced forms of the disease require total bone replacement. core decompression (figure ) in the management of avascular necrosis appears to be effective if done in the early stages of avascular necrosis. [ ] results of hip arthroplasty in patients with sickle cell anaemia are not as encouraging as results of arthroplasty performed for an arthritic hip. [ ] placement of an internal prosthesis may be difficult owing to the presence of hard sclerotic bone in patients with sickle cell anaemia. other problems associated with hip arthroplasty in these patients include an increased incidence of infection, [ , ] a failure rate of about % and a high morbidity due to loosening of both cemented and uncemented prosthesis. recent techniques of arthroplasty may improve the life expectancy of hip prostheses. chronic hyperbilirubinaemia, cholelithiasis and gall bladder disease are common in patients with sickle cell anaemia. at least two-thirds of patients with sickle cell anaemia have hepatomegaly and % have cholelithiasis. about % of patients with cholelithiasis undergo cholecystectomy either prophylactically or after an episode of acute calculus cholecystitis. most cholecystectomies are currently performed by laparoscopy, a much simpler procedure than laparotomy, and are associated with less morbidity. [ , ] a genetic basis for the hyperbilirubinaemia pertains to mutations in udp-glucoronyl transferase (ugt a), the enzyme that catalyses bilirubin glucoronidation. it seems that genetic polymorphism of the ugt a enzyme affects the metabolism of bilirubin. the bilirubin level as well as gallstone formation appear to be significantly higher in patients with the / genotype compared with the / genotypes of the enzyme. [ ] similar findings were reported in patients with hb e-thalassemia. [ ] hepatic crisis (also called sickle cell intrahepatic cholestasis) is manifested by the sudden onset of right upper quadrant pain, progressive hepatomegaly, increasing bilirubin levels (mostly indirect), and prolongation of prothrombin and partial thromboplastin times. [ ] the levels of liver enzymes [γ-glutamyl transpeptidase (γgt) and alanine amino transferase(alt)] are also increased but not to those levels seen in acute viral hepatitis. hepatic crises vary in severity from mi-nor episodes to severe life-threatening situations. total blood exchange is a recommended form of therapy. blood exchange is indicated if the total bilirubin level increases progressively to values greater than g/l. at that level, the prothrombin time values are usually prolonged. blood exchanged should be total in nature, that is, remove whole blood and replace it with red cells and fresh frozen plasma in order to correct the coagulation abnormality. it is the hope of patients with sickle cell disease and their families that there will be, in the near future, therapy that will either cure or markedly alter the natural history of this disease. with better understanding of the pathology of sickle cell disease and co-ordination of multiple therapies that attack different pathological mechanisms of the disease, this goal seems likely. table xvi lists current approaches that have the potential to ameliorate or cure sickle cell disease. although the long term safety and efficacy of these novel therapies have not been well studied, there is good potential for them to reach phase iii clinical trials in the near future. allogeneric bone marrow transplantation (bmt) as a treatment for sickle cell anaemia was first used in europe for patients from africa on the assumption that the risks of disease in their countries of origin justified the hazards of transplantation. [ ] these patients did well and since then additional [ , ] children and adolescents younger than years of age who have severe complications (stroke, recurrent acute chest syndrome or refractory pain) and have an hla-matched donor available were the best candidates for transplantation. about % of patients with sickle cell anaemia met these requirements. about patients with sickle cell anaemia have undergone bmt compared with more than patients with β-thalassemia. more than % of the patients with sickle cell anaemia survived, to % had event-free survival and % graft rejection. neurological complications (seizures or intracranial bleeding) were common in the first transplant recipients. careful control of blood counts, blood pressure and anticonvulsantdrug prophylaxis may forestall these complications. follow-up is still short and the full extent of toxicity is unknown. whether transplantation can reverse established organ damage is also not known, but early reports from europe suggest some improvement in chronic lung, bone and cns disease. [ ] data from the us, however, showed that bmt does not reverse the progression of neurological events. successful umbilical cord blood transplantation from related and unrelated donors in children with sickle cell anaemia seems to be possible. [ ] [ ] [ ] a recent report of two patients with high risk sickle cell disease, publicised by the news media, achieved cure by using unrelated umbilical cord blood cell transplantation (ucbct). [ ] both patients were reported to be alive with donor haematopoietic engraftment and without new manifestations of sickle cell disease at . and . months, respectively, after ucbct. gene therapy, in simple terms, is the introduction of new genes into healthy or abnormal cells either in vitro or in vivo. gene therapy in sickle cell anaemia is limited at present to investigational laboratory procedures and the use of transgenic mouse models to determine the most effective and safest method of altering the genetic information in haematopoietic stem cells. research in this area has advanced at a faster rate than previously expected and gene therapy may be available for trial in selected patients with sickle cell disease in the near future. [ ] the goal of preventive therapy is to ameliorate the clinical picture of sickle cell disease in general, and to decrease the frequency and severity of acute painful episodes in particular. for many years the major goal of primary therapy for sickle cell disease was to identify an antisickling agent that would prevent or reverse the polymerisation of sickle hb in rbcs. although the search for beneficial antisickling compounds continues, the promising approach to prevent the polymerisation of sickle hb has been the use of compounds that increase the production of hb f. the status of these attempts is as follows. induction of hb f: high levels of hb f have a beneficial effect in patients with sickle cell anaemia. platt et al. [ ] has shown that there is a significant inverse correlation between the frequency of painful crises and hb f levels greater than %, i.e. the higher hb f, the milder the disease. hb f interferes with the polymerisation of sickle hb and, the higher (and the more pancellular) it is, the lower the intracellular concentration of sickle hb. however, there are exceptions to this rule in that there are patients with high hb f levels and severe disease and vice versa. agents that have been shown to increase the level of hb f in humans are listed in table xvii. among these, currently hydroxyurea as monotherapy seems to be the least toxic and most effective. [ ] [ ] [ ] moreover, the only drug studied for efficacy in a relatively large scale, placebo-controlled, randomised clinical trial is hydroxyurea. hydroxyurea: is a cell-cycle specific cytotoxic agent that inhibits ribonucleotide reductase. the molecular mechanism(s) by which hydroxyurea increases the production of hb f is(are) unknown. possible mechanisms include perturbations in cellular kinetics and/or recovery from cytotoxicity, recruitment of early erythroid progenitors and recruitment of primitive erythroid progenitors (bfu-e) that lead to production of hb f-containing reticulocytes (f-reticulocytes). long-term hydroxyurea therapy with the maximum tolerated dose (mean dose . ml/kg) with respect to myelosuppression, raises hb f by as much as to % (mean . %, range . to . %). in the randomised, placebo-controlled, doubleblind msh study, among adult patients with sickle cell anaemia with three or more painful crises per year, hydroxyurea resulted in a significant (p < . ) reduction in the incidence of painful crises, acute chest syndrome and transfusion requirement. [ , ] there was no difference between the placebo and hydroxyurea arms in the incidence of death, stroke and hepatic sequestration. maximum tolerated doses of hydroxyurea were not required to reduce the incidence of painful episodes. although an increase in hb f seems to be the obvious and logical explanation for the salutary effects of hydroxyurea, other reasons for its beneficial effects include changes in rbc volume, cellular hydration, the cell membrane and a direct effect on endothelial cells adverse effects of hydroxyurea are listed in table xii. toxic effects are dose-and time-dependent. careful monitoring of blood counts every weeks after starting hydroxyurea can prevent these. later the frequency of monitoring of blood counts and blood chemistries can be decreased to once every to months once the patient is in a stable condition and receiving an acceptable maintenance dose. anaemia is a rare toxic effect of hydroxyurea and, in fact in the msh study, most patients who took hydroxyurea experienced an increase in their hb levels. the idiosyncratic effects of hydroxyurea occur in some patients but not others. however, the incidence of these effects was similar between the placebo and hydroxyurea in the msh study. [ ] in animal studies, hydroxyurea had carcinogenic and teratogenic effects. [ ] [ ] [ ] to date, however, no carcinogenic effect has been reported in patients with polycythemia vera and erythrocytosis due to congenital heart disease treated with hydroxyurea. [ , ] the following limitations should be considered when using hydroxyurea to prevent painful crises in patients with sickle cell disease. firstly, hydroxyurea was approved in the us by the food and drug administration for the prevention of crises. secondly, the long-term effects of hydroxyurea in patients with sickle cell disease are not known, and finally, some patients do not respond to hydroxyurea. methods to identify these non-responders are being studied in order to improve the selection process for hydroxyurea therapy. in some patients combining hydroxyurea with other agents that augment hb f production may be indicated. short chain fatty acids: the role of butyrate analogues as potential inducers of hb f synthesis was based on the observation that infants who have high plasma levels of γ-aminobutyric acid (gaba) in the presence of maternal diabetes mellitus do not undergo the normal fetal-to-adult haemoglobin switch. this led to the discovery that butyric acid, sodium butyrate, and gaba inhibit the normal progress of haemoglobin switching in developing animal models and stimulate the production of hb f in adult animals. butyrate seems to exert its effect through sequences near the transcriptional start site to induce the activity of the human γ-globin gene promoter. a small phase i/ii study where three patients with sickle cell anaemia and three patients with β-thalassemia were treated with intravenous arginine butyrate showed significant and rapid increase in fetal globin synthesis to levels that can ameliorate the clinical picture of these disorders. [ ] the demonstration of specific neuropathological lesions in baboons receiving extended infusions of arginine butyrate at -fold the human dose, however, raised safety concerns about the use of butyrate in humans. [ ] the prolonged use of arginine butyrate is limited because it has to be given intravenously and because it is rapidly metabolised by the liver. this generated efforts to find oral butyrate analogues for the induction of hb f. isobutyramide, a butyrate derivative, has been produced as an oral alternative and has been shown to increase hb f production. [ ] sodium phenylbutyrate, an analogue of butyric acid, is an investigational drug currently undergoing investigation in a phase iii trial for the treatment of patients with inherited disorders of the urea cycle. non-anaemic patients receiving sodium phenylbutyrate were found to have high levels of hb f. [ ] because butyric acid and its analogues are short chain fatty acids, other compounds that belong to this category were considered as potential inducers of hb f. non-anaemic patients receiving valproic acid for epilepsy had increased levels of hb f. [ ] with the exception of arginine butyrate, the analogues mentioned in this section (isobutyramide, phenylbutyrate, phenylacetate and valproic acid) are available in oral form. together, available data suggest that short chain fatty acids may play a role in the primary treatment of sickle cell disease by increasing hb f production. however, their precise role, either alone or in combination with other agents, awaits controlled phase iii clinical trials. erythropoietin: hematopoietic growth factors such as il- , colony-stimulating factor (csf) and granulocyte-monocyte csf can augment hb f lev-els in erythroid cell cultures and in experimental animals. [ ] however, none of these have been reported for this purpose in clinical trials. recombinant human erythropoietin (rhuepo) has been shown to increase hb f levels in erythroid cell cultures, and in non-anaemic baboons and macaques. the molecular mechanism by which rhuepo augments hb f levels seems to be the result of recruitment of f positive progenitor cells, primarily cfu-e derived from an influx of the more primitive bfu-e compartment. [ ] clinical trials in which high doses of rhuepo along with iron supplementation were given to patients with sickle cell anaemia showed an increase in the percentage of freticulocytes and hb f. [ ] extreme caution must be exercised in giving growth factors to patients with sickle cell anaemia. the administration of g-csf to three patients with sickle cell disease caused severe pain and multiorgan failure with a fatal outcome in one. [ ] [ ] [ ] the administration of erythropoietin to patients with sickle cell disease on a regular basis without transfusion will increase the production of sickle hb and the hb level to g% or higher that, together, are associated with increased blood viscosity which, in turn, may accelerate vaso-occlusion. polymerisation of deoxy sickle hb results in cellular dehydration which, in turn, increases the intracellular concentration of sickle hb that leads to further polymerisation, thus, creating a vicious cycle. major mechanisms by which water is lost from sickle cells include the ca + -activated potassium channel (gardos channel) and the kcl cotransport channel. activation of these channels results in k + and water loss from sickle erythrocytes with consequent dehydration. a decrease in the intracellular concentration of sickle hb, even small decreases, can slow the polymerisation of sickle hb to a point where rbcs can exit from the capillaries (decreased transit time) before the sickle hb polymerises (increased delay time for polymerisation). hydroxyurea achieves this goal by decreasing the effective concentration of sickle hb and diluting it with hb f, which does not participate in polymerisation. another approach to inhibit polymerisation is to rehydrate sickle rbcs and restore their normal water content. [ , ] recently, a selective approach to specifically rehydrate sickle rbcs by inhibiting the gardos pathway has been tried by using oral clotrimazole. [ ] in five patients treated with mg/ kg/day of clotrimazole, the rbc gardos channel was inhibited, cell k + content increased, rbcs were rehydrated, and a very modest increase in haemoglobin levels was noted. the effects of clotrimazole on cellular rehydration, however, were very modest compared with those seen in hydroxyurea. nevertheless, the advent of clotrimazole offers a novel and different therapeutic approach for the treatment of sickle cell disease. it warrants a larger long-term clinical trial to determine its efficacy in the primary treatment of sickle cell disease. furthermore, a combination of hydroxyurea and clotrimazole may ensue in an additive beneficial effect in ameliorating the clinical picture of sickle cell disease. similar results were found by the use of oral magnesium, [ ] which inhibits the kcl co-transport channel. these include no, [ ] anti-adhesion molecules, [ ] the surfactant poloxamer- , [ ] levocarnitine, [ ] arginine, [ ] zileuton, a -lipoxygenase inhibitor, [ ] green tea, [ , ] aged garlic, [ , ] and herbal extracts. [ ] some of these agents are being used on an investigational basis. there are anecdotal reports of success in a few patients using some of these agents. the efficacy of any of these agents, however, awaits proof by phase iii doubleblind, placebo-controlled trials. in recent years, there have been considerable advances in understanding the pathogenesis of sickle cell anaemia. although management of sickle cell anaemia continues to be primarily palliative in nature, there have been promising preventative and curative approaches to therapy. pain management should be individualised and coupled with the proper utilisation of opioid and non-opioid analgesics in order to acheive adequate pain relief. early recognition and treatment of organ failure minimises morbidity and improves outcome. the use of hydroxyurea decreases the morbidity and mortality of sickle cell disease. cure is possible in selected children with bone marrow or cord blood transplantation. future research seems to focus on 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extract (pfaffia paniculata) in-vitro department of medicine, cardeza foundation for hematologic research supported in part by the sickle cell program of the commonwealth of pennsylvania, harrisburg, pennsylvania, usa. there are no potential conflicts of interest that are relevant to the contents of this manuscript. key: cord- -nhsn cru authors: cameli, matteo; pastore, maria concetta; soliman aboumarie, hatem; mandoli, giulia elena; d'ascenzi, flavio; cameli, paolo; bigio, elisa; franchi, federico; mondillo, sergio; valente, serafina title: usefulness of echocardiography to detect cardiac involvement in covid‐ patients date: - - journal: echocardiography doi: . /echo. sha: doc_id: cord_uid: nhsn cru coronavirus disease (covid‐ ) outbreak is a current global healthcare burden, leading to the life‐threatening severe acute respiratory syndrome coronavirus (sars‐cov‐ ). however, evidence showed that, even if the prevalence of covid‐ damage consists in pulmonary lesions and symptoms, it could also affect other organs, such as heart, liver, and spleen. particularly, some infected patients refer to the emergency department for cardiovascular symptoms, and around % of covid‐ victims had finally developed heart injury. therefore, the use of echocardiography, according to the safety local protocols and ensuring the use of personal protective equipment, could be useful firstly to discriminate between primary cardiac disease or covid‐ –related myocardial damage, and then for assessing and monitoring covid‐ cardiovascular complications: acute myocarditis and arrhythmias, acute heart failure, sepsis‐induced myocardial impairment, and right ventricular failure derived from treatment with high‐pressure mechanical ventilation. the present review aims to enlighten the applications of transthoracic echocardiography for the diagnostic and therapeutic management of myocardial damage in covid‐ patients. postmortem examination of covid- victims. in two studies by shi et al and guo et al, among and patients hospitalized for covid- , respectively, % and % had acute myocardial injury, which was associated with higher mortality and incidence of complications, such as acute respiratory distress syndrome (ards), malignant arrhythmias, acute renal injury, and coagulopathy. echocardiography is considered the first-choice diagnostic technique for the evaluation of myocardial structure and function, due to its high availability and cost-effectiveness. for this reason, a conscious inhospital application of transthoracic echocardiography (tte), using a focused and safe approach, according to the latest european association of cardiovascular imaging (eacvi) and american society of echocardiography (ase) recommendations, , could reduce the potential risks of covid- heart injury, providing early detection and treatment. these documents do not provide strict indications on whether to perform or reject an echocardiographic examination in this period of social distancing, since it should be tailored on the single patient, trying to avoid unnecessary exam- guidance for covid- suggests that patients demonstrating hf, arrhythmia, electrocardiographic (ecg) changes, or cardiomegaly should undergo echocardiography. as reported by the national health commission of china (nhc), some of the confirmed cases of sars-cov- patients first showed cardiovascular rather than respiratory symptoms. after the nasal or pharyngeal swab has done to test covid- patients' status before the admission , the first step of triaging usually comprises ecg and blood cardiac enzymes dosage; however, evidence has shown that troponin and brain natriuretic peptide (bnp) levels could increase due to covid- itself, proportionally to the severity of the disease. in fact, a meta-analysis showed that troponin i values were significantly higher in patients with severe compared to those with mild illness due to sars-cov- infection. he et al conducted a study in critical covid- patients dividing them into two groups according to the presence ( patients, . %) or absence ( patients, . %) of myocardial injury, revealing that the injury group presented significantly higher inhospital mortality ( . % [ / ] vs. . % [ / ] , p = . ), c-reactive protein (crp), and n-terminal pro-bnp (nt-pro-bnp, p < . ). chen chen et al also analyzed covid- subjects and found of them ( . %) having troponin elevation, which was independently correlated with covid- critical severity with multivariate regression analysis (odds ratio, or = . , % ci . - . , p = . ). accordingly, acc covid- clinical guidance pointed out that that classic symptoms and presentation of acute myocardial infarction may be unclear in the context of covid- , resulting in underdiagnosis. moreover, in a small italian report of covid- patients with st-elevation myocardial infarction (stemi), . % of them presented with acute chest pain, while . % had regional wall-motion abnormalities at tte. in fact, echocardiography could support diagnosis in this setting, revealing suggestive signs of acute myocardial infarction, new-onset or worsening congestive hf, pericardial effusion or tamponade, and rv overload due to pulmonary embolism or cor pulmonale (table ). this would lead to an accurate triaging, ensuring each patient the appropriate treatment. various degrees of myocardial injury (defined as raised troponin levels over the th percentile of reference range) have been recently shown in patients with covid- . , in a clinical study involving patients with covid- , patients ( . %) had acute myocardial injury and ( . %) had arrhythmia, the majority of them during hospitalization in intensive care unit (icu). there are many possible causes of acute myocardial injury in critically ill patients, including acute coronary syndrome, hf, myocarditis, hypotension or shock, sepsis, and infection. to date, the mechanism responsible of myocardial injury in covid- is uncertain; however, hypothesis has focused on local or systemic immune response, possibly causing cardiomyocytes degeneration and/or microvascular thrombosis. accordingly, current reports suggest that the majority of covid- patients with myocardial injury without evidence of epicardial coronary artery thrombosis, show imaging data supporting the diagnosis of acute myocarditis , ; also, cases of fulminant myocarditis and fatal arrhythmias have been described. , even if a direct cardiotropic localization sars-cov- into myocytes has never been demonstrated, some authors showed autoptic findings (eg, lymphocyte infiltrates and macrophagic response) compatible with viral myocarditis. [ ] [ ] [ ] moreover, in a retrospective study by ruan et al evaluating factors associated with mortality in covid- subjects, patients who died showed higher levels of troponin, myoglobin, c-reactive protein, serum ferritin, and interleukin- , suggesting a high inflammatory burden in covid- with a possible rise in myocarditis-related cardiac events. for acute myocarditis, a combination of cardiac magnetic resonance (cmr) and myocardial biopsy is the reference diagnostic method, preceded by coronary angiography to rule out acute coronary syndromes. this is also valid for covid- patients. accordingly, inciardi et al presented a case of a -year covid- woman who developed acute myocarditis diagnosed, after exclusion of coronary disease and tte findings consistent with acute myocarditis (increased wall thickness, diffuse echo-bright myocardial appearance and diffuse lv hypokinesis, with lvef %), by cmr as increased wall thickness with diffuse biventricular hypokinesis and signs of marked biventricular myocardial interstitial edema by t mapping sequences and late gadolinium enhancement. however, in critical patients and in this reduced healthcare services emergency status, cmr and myocardial biopsy could not be promptly available and coronary angiography would put unstable patients at higher risks. therefore, an echocardiographic study could be used as the first investigation tool to orient diagnosis with high-sensitive but less specific findings, that are listed in table . additionally, lv longitudinal strain proved to correlate with myocardial edema detected by cmr in patients with acute myocarditis and its bull's eye representation shows the localization of myocardial damage, with gls typically reducing from endocardial to epicardial layer ( figure ). in patients with covid- , cardiovascular involvement leading to cardiac dysfunction and failure is not uncommon, probably due to systemic inflammatory response, innate immune-related myocardial damage, or respiratory-induced hypoxemia during covid- progression. , this also affects patients without history of chronic hf, which could rapidly develop severe hf and die for sudden cardiac death after covid- infection. in fact, the most likely mechanism of hf in these patients is consequent to lung tance devices, such as intra-aortic balloon pump, could be necessary to assist hemodynamics and improve outcome. therefore, focused but thorough and, if necessary, repeat ultrasound examination is important in covid- patients with possible or overt hf not only for diagnosis and prognosis, but also to assess patients' clinical status and response to therapy ( figure ). in a recent study by zhou et al involving covid- subjects, a half of their patients finally developed sepsis at a median of days. in particular, sepsis was the most frequently observed complication, followed by respiratory failure, ards, hf, and septic shock. sepsis is caused by exaggerate host response to infection leading to life-threatening multiorgan failure (mof), recognized with altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities, or low blood pressure. this could lead to septic shock, that is persisting hypotension despite volume resuscitation and hemodynamic instability requiring vasopressor treatment. the first diagnostic approach could be done with sequential organ failure assessment (sofa) score, which is a good diagnostic marker for sepsis and septic shock, reflecting the degree of mof. however, several authors investigated the role of echocardiography for the study of septic shock, which could offer important information on cardiac loss of function due to sepsis. it has been shown that in these patients a certain grade of diastolic dysfunction could be detected by power and tissue doppler imaging (tdi): the most used parameter is transmitral e/e′ ratio, with a lack of defined cutoff value; however, a higher proportion of diastolic dysfunction with values of e′ < - cm/s was found to be independently associated with higher risk of death the use of echocardiography in this clinical setting could help clinicians in early recognizing myocardial damage due to covidderived sepsis. according to common ards management, patients, % of patients required mechanical ventilation, % of whom died. whether it was due to the end-stage disease or to ventilation-induced heart and/or lung complications is not known. however, further evidence on this topic is timely needed in order improve the therapeutic management of covid- patients. transesophageal echocardiography (toe) has been widely used for monitoring ventilated patients in the last years. in fact, in these patients tte is often challenging, due to the position of patients with lower mobility, and the poor acoustic window due to hyperinflated lungs. however, the development of new indices for the assessment of lv systolic/diastolic function and filling pressures by tdi, and of rv dimension and function, have led to reconsider the use of serial tte for noninvasive monitoring of ventilated patients. thanks to the widespread use of echocardiography in icu, rv dimension and function could be closely monitored in these patients. , as repessé et al suggested, a rv-driven adjustment of peep levels could help intensivists to find a balance between risks and benefits of this therapeutic approach (ie, lung recruitment and overdistension), thus preventing early mortality for ventilation-induced rv failure. lu could be an important ally also in this context. in addition, rv myocardial performance index (rv mpi), also known as "tei index" determined on trans-tricuspid velocities by pulsed wave or tissue doppler imaging, is a high-sensitive index for the diagnosis of rv dysfunction. due to the need of balancing between risks of contagion for and benefits for patients, the common indications and modalities to perform echocardiography should be reconsidered in covid- patients; therefore, the choices for the use of portable devices and transesophageal echocardiography should be tailored on the single patients depending on his clinical status and cardiovascular conditions. portable machines have the advantage to be easier to clean and to cover than common echocardiographic machines and could be preferred for a basic assessment of biventricular function, valvular disease, and pericardial effusion. however, in patients with suspected or known cardiac impairment or in uncertain clinical cases, the quality of the tte evaluation could be sacrificed using portable echocardiographers. as an alternative, we propose the use of a dedicated echocardiographic machine in covid units which should also be sanitized after use, thus combining safety and effectiveness. in addition, for difficult cases or severe cardiac dysfunction, we suggest performing a comprehensive image acquisition with offline measurement of complex and advanced parameters in a safe environment and at clinician time discretion, in order to obtain a complete echocardiographic examination reducing the time of exposure to sars-cov- . echocardiography is a precious tool in the hands of an expert operator to improve diagnostic procedures and therapeutic management who director-general's opening remarks at the media briefing on covid- - the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) -china report of the who-china joint mission on coronavirus disease cardiac manifestations of patients with covid- pneumonia and related treatment recommendations covid- and the cardiovascular system impact of complicated myocardial injury on the clinical outcome of severe or critically ill covid- patients a pathological report of three covid- cases by minimally invasive autopsies association of cardiac injury with mortality in hospitalized patients with 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to the failing left ventricle standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the eacvi/ase/industry task force to standardize deformation imaging acute hf score, a multiparametric prognostic tool for acute heart failure: a real-life study prognostic value of right ventricular longitudinal strain in patients with covid- echocardiography to guide fluid therapy in critically ill patients: check the heart and take a quick look at the lungs clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical management of severe acute respiratory infection (sari) when covid- disease is suspected serial evaluation of the sofa score to predict outcome in critically ill patients prognostic impact of left ventricular diastolic function in patients with septic shock early diastolic dysfunction is associated with intensive care unit mortality in cancer patients presenting with septic shock outcome prediction in sepsis: speckle tracking echocardiography based assessment of myocardial function left ventricular global longitudinal strain is independently associated with mortality in septic shock patients effect of lung recruitment and titrated positive end-expiratory pressure (peep) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial clinical management of severe acute respiratory infection when novel coronavirus ( -ncov) infection is suspected: interim guidance. world health organization reacquainting cardiology with mechanical ventilation in response to the covid- pandemic. jacc case rep oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. a secondary analysis of the lovs and express trials acute cor pulmonale in ards: rationale for protecting the right ventricle echocardiographic pattern of acute cor pulmonale prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome influence of positive end-expiratory pressure on myocardial strain assessed by speckle tracking echocardiography in mechanically ventilated patients prevalence and prognostic value of acute cor pulmonale and patent foramen ovale in ventilated patients with early acute respiratory distress syndrome: a multicenter study echo-doppler demonstration of acute cor pulmonale at the bedside in the medical intensive care unit hemodynamic monitoring by echocardiography in the icu: the role of the new echo techniques the prognostic role of speckle tracking echocardiography in clinical practice: evidence and reference values from the literature lung ultrasound for critically ill patients the relation between quantitative right ventricular ejection fraction and in dices of tricuspid annular motion and myocardial performance index myocardial function during low versus intermediate tidal volume ventilation in patients without acute respiratory distress dyndrome respiratory and haemodynamic changes during decremental open lung positive end-expiratory pressure titration in patients with acute respiratory distress syndrome acute pulmonary embolism and covid- pneumonia: a random association? covid- complicated by acute pulmonary embolism pathological evidence of pulmonary thrombotic phenomena in severe covid- esc guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the successful percutaneous thrombectomy in a patient with covid- pneumonia and acute pulmonary embolism supported by extracorporeal membrane oxygenation key: cord- -um qu xr authors: magnani, silvia; muser, daniele; carugo, stefano title: acute myocarditis: an overview on emerging evidence date: - - journal: trends cardiovasc med doi: . /j.tcm. . . sha: doc_id: cord_uid: um qu xr nan myocarditis is an inflammatory disease of the heart that may present with a wide spectrum of clinical manifestations, ranging from an asymptomatic state to infarct-like chest pain, severe heart failure, and lifethreatening ventricular arrhythmias. although endomyocardial biopsy still represents the gold standard, the diagnosis of acute myocarditis currently relies on several clinical and imaging criteria. at the present time, several aspects of this complex disease need to be clarified: which patients need a biopsy? what is the role of the cardiac magnetic resonance (cmr) regarding myocarditis assessment? what is the workflow that can drive to a correct diagnosis and treatment? the variability of clinical manifestation and the risks of a sudden hemodynamic deterioration make the delineation of this process extremely challenging. as previously reported, myocarditis can evolve toward three main different scenarios with different long-term implications: a benign self-limited form, a form characterized by an arrhythmic expressivity and a form characterized by heart failure (acute/chronic). in this issue of trends in cardiovascular medicine, ammirati et al. systematically review all the available evidence from observational registries on acute myocarditis with special attention to the areas in which we have a substantial lack of knowledge. combining retrospective data from multiple studies is gaining importance to create risk stratification models able to identify those patients at higher risk who may benefit from further investigation, close medical followup and evaluation for an implantable cardioverter defibrillator (icd). the authors have reported data from a large italian multicenter registry including patients with acute myocarditis confirmed by ebm. the authors found that a pool of variables including presentation with hemodynamic decompensation, left ventricular ejection fraction (lvef) < % and a qrs duration > msec characterize a subgroup of patients with "complicated" acute myocarditis whom may benefit from mechanical hemodynamic support. in this scenario, physicians need to be trained to quickly identify patients with hemodynamic instability and to promptly refer them to tertiary centers where mechanical support and cardiac surgery are available. interestingly, similar findings have been reported in the pediatric population. according to a german registry including children and young adults (median age -years) admitted to the hospital for acute myocarditis presenting with decompensated heart failure, the need for mechanical hemodynamic support was as high as % while in-hospital death/heart transplant rate was %, and the overall mortality rate was %. unfortunately, all these data come from relatively small retrospective studies with a substantial lack of large randomized trials. the pathophysiologic process behind acute myocarditis typically involves an abnormal immune-mediated response to various viral agents. recently, the covid- outbreak renewed attention to viral myocarditis. in the present work, the authors describe the viral role in different settings: passive bystander, causative agent able to directly damage myocytes or trigger of immune response against the myocytes. in a large european study of epidemiology and treatment of inflammatory heart disease, presence of viral genome was found in only % of symptomatic cases. when acute myocarditis is highly suspected based on a clinical evaluation, cmr is recommended to confirm the diagnosis thanks to its tissue-characterization capabilities. in particular, cmr has demonstrated an accuracy of % in identifying acute myocarditis when at least two out of three of the following criteria are present: ( ) edema visualized ast enhancement, ( ) scar or active inflammation visualized by late gadolinium enhancement (lge) imaging, usually in a regional subepicardial distribution. the use of ebm remains indicated to guide therapy in patients with high risks features while in uncomplicated cases cmr together with biomarkers like cardiac troponin may be sufficient. the aha/acc statement and the esc recommendations for emb were more strict regarding the use of ebm, recommending it only in unexplained, new-onset heart failure of < weeks duration associated with hemodynamic compromise, and in the setting of unexplained new-onset heart failure between weeks and months duration associated with a dilated lv and new bradyarrhythmia or new ventricular arrhythmias, or a failure to respond to standard care within to weeks of diagnosis. the statement expanded the indications relying more on the physician choice in every patient with suspected myocarditis. this position has been confirmed in since emb may be considered in patients with heart failure that is rapidly progressing. biopsy is also indicated in association with biomarkers and cardiac imaging in a new emerging entity: myocarditis associated with use of immune checkpoint inhibitors (ici). ici are antibodies that induce an immune-mediated attack on cancer cells by blocking tumor-driven inhibition of t-cell activation. their use is significantly increased and represents a new frontier for their disseminated use despite unpredictable side effects including myocarditis, colitis, dermatitis, pneumonitis and endocrinopathies. because of substantial lack of prospective data, treatment of ici-associated myocarditis remains empirical. in the oncoming years a substantial effort in determining accurate risk stratification tools is warranted. emerging cmr studies regarding scar assessment in term of extension and localization seem to help the clinician identify patients that need to be protected from life-threatening arrhythmias. moreover, recent studies have highlighted that myocarditis can be the first signs of an underlying cardiomyopathy. ; in conclusion, nowadays, despite great improvements in the diagnosis and treatment of myocarditis, its morbidity and mortality are still significant and further efforts are required for identification of short and long term prognosis predictors. myocarditis in clinical practice update on acute myocarditis fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction severe heart failure and the need for mechanical circulatory support and heart transplantation in pediatric patients with myocarditis: results from the prospective multicenter registry "mykke the european study of epidemiology and treatment of cardiac inflammatory diseases (esetcid). first epidemiological results international consensus group on cardiovascular magnetic resonance in myocarditis. cardiovascular magnetic resonance in myocarditis: a jacc white paper current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the european society of cardiology working group on myocardial and pericardial diseases immune checkpoint inhibitor myocarditis: pathophysiological characteristics lymphocytic myocarditis: a genetically predisposed disease? desmoplakin cardiomyopathy, a fibrotic and inflammatory form of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy key: cord- -fl dsu d authors: turnidge, john title: responsible prescribing for upper respiratory tract infections date: - - journal: drugs doi: . / - - sha: doc_id: cord_uid: fl dsu d upper respiratory tract infections (urtis) are responsible for a large amount of community antibacterial use worldwide. recent systematic reviews have demonstrated that most urtis resolve naturally, even when bacteria are the cause. the high consumer expectation for antibacterials in urtis requires intervention by the general practitioner and a number of useful strategies have been developed. generic strategies, including eliciting patient expectations, avoiding the term ‘just a virus’, providing a value-for-money consultation, providing verbal and written information, empowering patients, conditional prescribing, directed education campaigns, and emphasis on symptomatic treatments, should be used as well as discussion of alternative medicines when relevant. the various conditions have differing rates of bacterial infection and require different approaches. for acute rhinitis, laryngitis and tracheitis, viruses are the only cause and, therefore, antibacterials are never required. in acute sore throat (pharyngitis) streptococcus pyogenes is the only important bacterial cause. a scoring system can help to increase the likelihood of distinguishing a streptococcal as opposed to viral infection, or alternatively patients should be given antibacterials only if certain conditions are fulfilled. strategies for treating acute otitis media vary in different countries. most favour the strategy of prescribing antibacterials only when certain criteria are fulfilled, delaying antibacterial prescribing for at least hours. in otitis media with effusion, on the other hand, there is no primary role for antibacterials, as the condition resolves naturally in almost all patients aged > months. detailed strategies for acute sinusitis have not been worked out but restricting antibacterial prescribing to certain clinical complexes is currently recommended by several authorities because of the high natural resolution rate. worked out but restricting antibacterial prescribing to certain clinical complexes is currently recommended by several authorities because of the high natural resolution rate. respiratory tract infections are the most common reasons for prescribing antibacterial agents in developed countries, representing about % of all prescriptions in community practice. of these, upper respiratory tract infections (urtis) constitute more than half of all general practice attendances, and it is common for antibacterials to be prescribed for % or more of these. [ , ] furthermore, there has been a trend in some countries to the use of broader spectrum and more expensive agents. [ ] as viruses are the most frequent cause of urtis, high levels of antibacterial prescribing for urtis suggest that there is considerable unnecessary prescribing. resistance to antibacterials has recently been targeted by the world health organization for major international action, [ ] and reducing unnecessary prescribing is an essential component of this strategy. tackling prescribing/consuming for respiratory tract infection is likely to lead to the greatest reduction. given that resistance to antibacterials in the common bacterial respiratory pathogens, especially streptococcus pneumoniae, is increasing worldwide, [ ] it is time to critically review prescribing practices in patients with urti and find methods for not prescribing antibacterials to patients who are unlikely to benefit. [ ] the most important feature of urtis is that most resolve naturally and rapidly, whether the infection is viral or bacterial. it cannot be stressed enough that even bacterial urtis have a high rate of spontaneous resolution. this has two important implications: antibacterials will help only a small proportion of patients, even when the infection is known to be bacterial, and levels of resistance must be very high before there will be a noticeable effect on outcomes. [ ] this explains the apparently paradoxical recommendations by many authorities that the antibacterial of choice -when required -is a narrow spectrum drug, even if resistant bacteria are known to be common. estimated natural resolution rates without complications are as follows: acute otitis media to %; [ ] streptococcal pharyngitis > %; [ ] and acute sinusitis about %. [ ] because of high natural resolution rates, the default position for the treatment of urtis is not to prescribe an antibacterial. this is not the expectation of many patients who present to the general practitioner. indeed, many patients visit their doctor only because they or a relative believe they need an antibacterial, and in most developed countries antibacterials are not available over the counter. however, the combination of 'routine' antibacterial prescribing and belief that the patient expects to be prescribed an antibacterial has created a positive feedback loop whereby the prescriber may feel reluctant to discuss not using antibacterials with many patients. this feedback loop must be broken, and it requires the application of a general practitioner's professional integrity to take this step with each new consultation. the most important reason for inappropriate prescribing is fear of losing the patient's confidence. if the doctor has prescribed unnecessary antibacterials for the patient in the past for the same condition, it takes courage and finesse to tackle the patient with the 'new' idea that antibacterials are not needed. some general suggestions about how this might be done follow. make expectations explicit: a recent study of patients presenting with sore throats has shown that patients' expectations are not usually explicit. [ ] to make matters worse, doctors' ideas about what the patient expects are often incorrect for the simple reason that they make an assumption and do not expressly ask what the patient expected. a direct question to the patient will determine what the patient expects and whether they really expect to be given an antibacterial. if the patient does not expect an antibacterial and you do not feel they require one, the consultation can conclude to everyone's satisfaction. if the patient expects an antibacterial and you believe they do not need one, you have an opportunity to discuss with them why they don't need one. even if they insist, you have sown the seed of doubt for their next urti. avoid the term 'just a virus': the term 'just a virus' is widespread in community practice. when this term is used medically it implies that the infection resolves relatively quickly and without complications. however, in the lay mind the term is often interpreted as 'this is a trivial infection; why did you bother to consult me?'. as anyone knows who has had a 'streaming head cold' or influenza, viral infections can be quite debilitating. a sympathetic tone and an expression that viruses are just as troublesome as bacteria will make all the difference. provide value for money: another finding from the sore throat study [ ] was the importance placed by the patient on the doctor taking an active interest in their problem and giving them 'value for money'. value for money means different things to different people, but simple ingredients such as time, sympathy, being taken seriously and physical examination can make a significant difference. provide verbal information: each consultation is an opportunity for education. if the practitioner knows that the information they will be giving will be new, the opportunity should not be squandered. in this context, it is better to give information that is personalised ('we know now that antibiotics will not help you') than to quote from studies and metaanalyses and systematic reviews. one part of achieving this personalisation is to emphasise the personal risks of taking antibacterials: adverse reactions such as rash, and the risk of becoming colonised with a resistant bacterium that will be harder to treat when they really do need antibacterials. the practitioner may choose to stress the effect on normal flora in terms of thrush (candidia-sis), diarrhoea and selection of a resistant strain or creating a vacuum for a resistant strain to be picked up from someone else. of course, the practitioner must tailor the information to the education and skill level of the individual patient. some patients respond also to the 'green' message: that unnecessary antibacterials breed resistant bacteria (which are genetically modified organisms!) which can harm them or which they can spread to others, i.e. they are bad for public health and the planet. provide written information: a number of brochures are available which provide information about the usefulness of antibacterials or on the management of specific conditions. fact sheets on common infections can be found on the us centers for disease control and prevention website (http://www.cdc.gov). a number of useful information sheets directed at certain urtis are available on the worldwide web. these are listed in table i. you may choose to develop your own handouts. empower patients: there is considerable scope for empowering patients in the decision-making and therapeutic process. the current popularity of alternative medicines attests to the fact that patients are seeking more control over their illnesses. emphasising the positive effects of symptomatic treatments and providing more detailed prescriptions of how these could be used, as well as the value of antibacterials only when they are really necessary, can give the patient some sense of control. one method of achieving this is to write a 'symptomatic prescription' that contains instructions and useful information about the various symptom remedies; this offers the benefits of 'value for money' and 'written information' in the guise of a true script. an example can be found on the australian national prescribing service website (http://www.nps.org.au). consider conditional or deferred prescribing: a useful technique for patients who have a sustained belief in the need for antibacterials when they are not needed is conditional prescribing. this means writing a prescription and suggesting to the patient that they have it filled only if certain con-ditions develop, the most common being 'worse the next day' or 'no better after days' (these are fairly lenient conditions). one sore throat study in the uk used this technique as of arms of a prospective study and showed that more that twothirds of patients did not have their script filled. [ ] another study, in patients with otitis media, combined this strategy with a patient/parent handout and showed a significant reduction in prescribing compared with a control general practice. [ ] directed campaign: simple but deliberate education campaigns can be effective. [ ] one general practice study was able to show that simultaneous education of the prescribers in their practice, and their patients, led to a significant drop in the number of prescriptions (table ii) . patient information was provided through a poster in the waiting rooms, at the time of consultation and by a generic brochure handed to patients who did not require antibacterials for their respiratory tract infection. alternative medicines: herbal and other overthe-counter remedies have become popular in recent years and many are advocated by the manufacturers for the treatment of infections. in particular, echinacea, in various forms, has received some scientific scrutiny and has been the subject of systematic review in urtis. [ , ] there is some evidence to suggest that echinacea reduces the duration of symptoms in urtis, but insufficient to recommend which product or preparation may be best, as several studies have used multiple actives (i.e. that include echinacea along with other 'active' agents). there is evidence that echinacea is ineffective as prophylaxis for rhinovirus infections. [ ] sharing this information with patients who are interested in alternative medicines may assist the patient with positive alternatives to antibacterial therapy. undifferentiated urti is the most common category of urti presenting to general practitioners. this diagnosis is often made when symptoms suggest one or more of the urti-specific syndromes, but are sufficiently indistinct on history and examination to make a diagnosis. it is clear that this condition is viral and there is no indication for either microbiological investigations or antimicrobial treatment. the prescription for this condition is obviously symptomatic relief: whatever you think will most appeal to the patient. more importantly, follow-up of worsening symptoms will usually lead to a syndromic diagnosis. acute rhinitis, 'head cold' or the common cold, although more common in winter, is prevalent all year round and only a small proportion of patients seek medical help. they often do so as parents of children with purulent rhinitis, a very common problem in the young child. [ ] it is usually in the context of clear nasal discharge becoming purulent that medical help is sought, either with children, or with adults who assume that purulent discharge is a sign of sinusitis and that sinusitis must be treated with antibacterials. antibacterial prescribing is common for this condition [ , ] but is almost never required. all acute rhinitis is viral, even with purulent discharge. rhinoviruses are the most frequent, followed by coronaviruses and influenza viruses. culture of purulent nasal discharges often reveals what seem to be significant pathogens such as s. pneumoniae, haemophilus influenzae or staphylococcus aureus. however, these are opportunistic colonisers and should be ignored. there are no useful routine microbiological investigations for acute rhinitis. because purulent rhinitis suggests a component of bacterial overgrowth contributing to the illness, there have been placebo-controlled trials of antibacterials, conducted in urti, to both treat and prevent purulent rhinitis. [ ] none of these studies has demonstrated a benefit for antibacterials either as treatment or to prevent rhinitis becoming purulent. medications to control secretions are all that is required. antibacterials should never be prescribed unless the diagnosis is considered to be acute sinusitis, and then only when certain conditions are fulfilled (see section . ). topical or oral decongestants are the most widely used, and many topical agents are available over the counter. single doses have been shown to be quite effective in short term relief of symptoms but repeated use over days shows little extra benefit. [ ] nasal decongestants are not without their problems, and alternatives such as saline nasal sprays are recommended by some to prevent the rebound congestion associated with decongestant medications. steam inhalations, although still widely used, are probably of no greater benefit than saline nasal spray, both achieving the same aim of thinning secretions to facilitate their clearance. if decongestants are prescribed or recommended, their use should be restricted to days or less to reduce the risk of rebound congestion. zinc and high dose ascorbic acid (vitamin c) have also been examined critically in systematic reviews. whereas zinc shows no benefit and runs the risk of producing adverse effects, [ ] trials have shown that high dose ascorbic acid can reduce the duration of symptom days by to %. [ ] . sore throat (acute pharyngitis) the second most common general practice presentation after undifferentiated urti is sore throat. usually the patient presents because symptoms are sufficiently severe to affect eating and swallowing. if the sore throat is accompanied by rhinitis or cough, it is highly likely that the infection is viral. it is important to exclude epstein-barr virus infection in the appropriate age group. this virus tends to cause the most severe sore throats. it can be suspected when patients have lymphadenopathy apart from in the anterior cervical area, namely posterior cervical, axillary and inguinal, plus splenomegaly. viruses are the most common cause of sore throat. streptococcus pyogenes is the only important bacterial cause and is more common between the ages of and years. corynebacterium diphtheriae is very rare now. another bacterium that causes sore throat, arcanobacterium haemolyticum, is considered an uncommon cause of pharyngitis. there is a strong belief in the role of antibacterials for sore throat in both prescribers and the public. the former are keen on antibacterials because of the well documented difficulty in distinguishing streptococcal infection from viral infections. consequently, the medical profession often prescribes antibacterials and the public come to assume that antibacterials are necessary for sore throat. although is it possible to shorten symptom duration by antibacterial treatment of streptococcal pharyngitis, it is only by a matter of hours. the principal reason for treating streptococcal pharyngitis is to prevent the complications of rheumatic fever and acute glomerulonephritis. there is no doubt that antibacterials can prevent a significant proportion of rheumatic fever. however, rheumatogenic strains of s. pyogenes are now very rare in many populations in developed countries. a metaanalysis has shown no measurable effect on reducing rates of acute glomerulonephritis. [ ] the value of antibacterials in preventing suppurative complications such as quinsy, otitis media and sinusitis has also been examined. one systematic review concluded that antibacterials did reduce the rates of these complications but that, because the complications themselves are infrequent, a very large number of patients need to be treated to prevent suppurative complications in a few. [ ] thus, the need for antibacterials at all has been questioned, even in patients with proven streptococcal disease. [ ] a group from canada has recently developed a scoring method to improve the likelihood of distinguishing viral from streptococcal infection [ ] (fig. ). this simple method, which can be performed within a minute, is based on history and throat examination, and it offers the potential for the patient to participate, giving them some power to understand the decision-making process. this group has been able to show that antibacterial use can be reduced overall in sore throat prescribing, without prejudicing outcomes. culture of throat swabs is the gold standard for the diagnosis of s. pyogenes infection. in general, if antibacterials are going to be prescribed, it is sore throat or strep throat? is an antibacterial required? this practical tool will help primary care physicians decide on the management of patients presenting with upper respiratory tract infection and sore throat step determine the patient's total sore throat score by assigning points to the following criteria: step under the assumption that there is streptococcal infection. in us office practice it is common to test throat swabs with point-of-care antigen tests and manage the patient on the basis of the results. negative antigen tests are sent for culture because generally the specificity of these tests is high but the sensitivity is lower (≈ %). [ ] in other countries, antigen tests are not relied upon and culture is recommended. if the scoring method is used, the likelihood of streptococcal infection is not high, and thus a throat swab is still useful. if the results of throat swab culture are negative, the correct approach is to notify the patient to cease the antibacterial. alternatively, the conditional prescribing strategy could be used -a script written but filled only if the culture is positive. [ ] throat swab results are often available the next day (identification only). there is no evidence that this puts the patient at increased risk of suppurative or nonsuppurative complications. except possibly for group c streptococci, the findings of other types of β-haemolytic streptococci have no clinical significance, even if the laboratory elects to report it. symptomatic relief should be the primary concern. there are many over-the-counter antiinflammatory, antiseptic and anaesthetic remedies for sore throat (lozenges and gargles are the most popular). unfortunately, there is no useful scientific evidence for or against any of these. preparations that use topical antiseptics should probably be avoided, as they can sometimes co-select for antibacterial resistance. excellent self help and information can be found at the following website: http://www.ghc.org/web/health_info/disease/ flu_cold.jhtml. the current us recommendations are to diagnose an infection and treat those confirmed as positive on antigen testing or culture. in contrast, the current australian recommendations (table iii) suggest treatment for only a proportion of patients with presumptive or proven streptococcal infection. this is based on the rationale that in communities where rheumatic fever is rare, the benefit of antibacterial treatment for streptococcal sore throat is marginal. when antibacterials are needed, the drug of choice is phenoxymethylpenicillin (penicillin v). there is still a tendency to prescribe the broader spectrum amoxicillin for this condition, [ ] on the mistaken belief that because it is better absorbed it must be a better choice. however, s. pyogenes remains highly susceptible to penicillin, and phenoxymethylpenicillin is more than adequate to cover it. amoxicillin has a higher rate of adverse effects than phenoxymethylpenicillin and is, therefore, an inferior choice. for patients with penicillin allergy, roxithromycin or erythromycin should be used. cefalexin or cefaclor could be used but are broader spectrum and unnecessary unless the patient is also intolerant of macrolides. acute otitis media is an acute infection in the middle ear secondary to obstruction of the eustachian tube and trapping of potential pathogens resident in the nasopharynx. it is a difficult condition to diagnose clinically, yet clinical findings are the way to make a diagnosis. the condition is most common in young children, and the important symptoms, such as middle ear pain/ache and hearing impairment due to the accompanying effusion, cannot be articulated at this age. furthermore, visualising the tympanic membrane can be a challenge in this age group, but unless the tympanic membrane can be seen, the diagnosis is only patients aged to years with presumptive streptococcal sore throat in communities with a high incidence of acute rheumatic fever, e.g. some aboriginal communities in central and northern australia and in some underprivileged communities existing rheumatic heart disease at any age scarlet fever peritonsillar cellulitis or abscess (quinsy) presumptive. a useful additional feature is ear tugging in the younger age group. most importantly, reddening and/or dullness (loss of light reflex) of the tympanic membrane is common in urti and does not constitute acute otitis media, which can be diagnosed only when there is obvious middle ear effusion characterised by bulging and/or failure of movement on insufflation. tympanocentesis studies show that s. pneumoniae is responsible for to % of infections, h. influenzae to %, moraxella catarrhalis to %, other bacteria approximately % and viruses alone around %. [ ] there is a difference between the bacteriology of previously untreated acute otitis media and that of patients with persistent infection, [ ] resistant bacteria being more common in the latter. pain is the principal clinical problem in otitis media, and the main reason that medical help is sought. thus, pain relief is the main target of therapy. however, more than half of patients will be pain free within hours of presentation whether antibacterial therapy is used or not. [ ] meta-analyses have quantified the benefit of antibacterials. [ , ] the most widely cited metaanalysis concluded that the spontaneous cure rate without antibacterials or tympanocentesis was %, and that antibacterial therapy increased the cure rate by %, or patient in . [ ] there was no clear benefit of one antibacterial over another. other large studies have shown that without any antibacterial therapy the rates of complications such as meningitis and mastoiditis are less than . and . %, respectively. [ ] therefore, antibacterial therapy is aimed at earlier symptom relief for the % of patients known to benefit. unfortunately, there are no known features at the time of presentation that distinguish those who will benefit from the majority who will not benefit. were these able to be defined, the prescriber would be in a better position to prescribe only for those who needed antibacterials. in , there was considerable international variation in prescription rates of antibacterials for otitis media, ranging from % in the netherlands to % in australia. [ ] most countries examined in this study had prescribing rates above %. rates are likely to be lower now that the message about the marginal benefits of antibacterials has become disseminated. the ideal microbiological investigation for acute otitis media is tympanocentesis. it both relieves pressure, and therefore pain, and permits culture for bacterial pathogens (and viruses if so desired). understandably, this difficult procedure is not recommended routinely. instead, otoscopy findings are the key to the diagnosis, and recommendations about which antibacterials are best refer to the results of cultures from studies where tympanocentesis has been performed in all patients. if the tympanic membrane is already perforated, it is possible to culture any pus that may be present. however, the value of antibacterials after the infection has progressed to perforation is unclear, as the condition has already undergone selfdrainage and pain has been relieved. pain relief should be the main concern of therapy and patience an integral part of the management. authorities differ in their recommendations for the use of antibacterials. in the us, routine use of antibacterials is recommended for otoscopyproven acute otitis media (but not otitis media with effusion). [ ] the us rationale is that there is proven benefit in some patients and that at the time of presentation these cannot be distinguished from others who will not benefit. the dutch approach is quite different, with antibacterials being withheld for to hours, after which time patient contact is made to determine whether there are persistent symptoms [ ] (table iv) . australia has elected to follow the dutch guidelines in large part. [ ] it is widely agreed that amoxicillin is the drug of choice, even though resistance in the important bacteria is common. the rationale is that only a small proportion of patients benefit, that resistance in the main bacterial pathogen, s. pneumoniae, is mostly low level and the pathogen will respond to amoxicillin, and that coverage is superior to that of cefaclor, roxithromycin and cotrimoxazole. in the patients who is allergic to penicillin, choices are more restricted. second and third generation oral cephalosporins, such as cefaclor, cefuroxime axetil, cefixime, cefpodoxime proxetil, ceftibuten, cefdinir, cefprozil and loracarbef can be used, although all have less activity against strains of s. pneumoniae with reduced penicillin susceptibility than amoxicillin when pharmacodynamic factors are taken into account. [ ] intramuscular ceftriaxone can also be used. cephalosporins should be avoided if there is a history of anaphylaxis to penicillins. the rates of resistance to cotrimoxazole (> %) are now too high in most countries for this agent to be recommended. newer macrolides such as roxithromycin, clarithromycin or azithromycin can be used, but their activity against h. influenzae is limited, and rates of resistance in s. pneumoniae range from to % or more. the duration of therapy in the first instance should be days at most, as longer courses have been shown in meta-analyses not to be of additional value. [ , ] longer courses are recommended in children aged less than years [ ] or in patients with a history of recurrence, where there are data to support the use of longer courses of days. [ ] in patients who fail to respond to first-line treatment, the drug of choice is amoxicillin/clavulanic acid, as it is assumed that bacteria resistant to amoxicillin are still present. if the patient is penicillin allergic or reacted to amoxicillin in the previous course, all the currently available alternatives are suboptimal. the cephalosporins or macrolides noted in the previous paragraph or cotrimoxazole may be tried, but if failure is a result of penicillinresistant s. pneumoniae, there is a high likelihood of resistance to these agents as well. the new fluoroquinolones such as moxifloxacin or gatifloxacin may be used in adults, but their use in children is restricted by the current nonavailability of paediatric formulations and there is considerable controversy about whether these agents should be used at all in children because of resistance selection in pneumococci. [ ] . otitis media with effusion otitis media with effusion (ome) should not be confused clinically with acute otitis media. it is a subacute process manifest by persistent middle ear effusion following acute otitis media. therefore, it presents primarily as impaired hearing on the affected side, and examination shows dullness with or without some bulging of the tympanic membrane. there are no signs or symptoms of acute inflammation, i.e. no pain, fever or redness of the tympanic membrane. ome can either follow a documented occurrence of acute otitis media or present de novo. in either case it follows an episode of otitis media that has not drained either through the eustachian tube or the tympanic membrane. the role of bacteria in this condition is unclear. tympanocentesis cultures demonstrate bacteria in fewer than % of patients. [ ] the natural history of effusion is well documented. after acute otitis media, % still have an effusion after month, % after months and % after months. [ ] in other words, effusion is mostly asymptomatic and a common finding after table iv . dutch guidelines for the treatment of acute otitis media treat only symptoms for the first days [e.g. paracetamol (acetaminophen)] re-evaluate after days -prescriber discretion about giving antibacterials depending on persistence and severity of symptoms (pain, fever) no special treatment for tympanic membrane perforation, other than prescribe antibacterials if it persists for more than days treatment of symptoms only for first hours [e.g. paracetamol (acetaminophen)] telephone contact after hours -if symptoms persist, either wait a further hours or prescribe antibacterials, depending on severity acute otitis media, and it is likely resolve with the passage of time without intervention. two meta-analyses of antibacterial use have demonstrated a significant but small benefit for antibacterial use over placebo in the range of to % better outcomes. [ , ] patients without a preceding history of acute otitis media appear to experience greater benefit. there are no useful simple investigations for ome. the diagnosis is made on history and otoscopic examination. the benefits of antibacterial treatment in ome are small. as a result, all authorities agree that routine antibacterial treatment is not recommended. reassurance of the parents is the most useful first approach, provided that there is not a history of frequently recurrent acute otitis media. decongestants do not help and systemic corticosteroids, although they may provide some benefit, are not recommended because the risks are thought to outweigh the benefits. [ ] antibacterials should be considered as the first intervention when the effusion persists for longer than months. choices should be similar to those of failure of first-line treatment of acute otitis media. the duration is contentious but courses of as long as month would not be unreasonable. failure of antibacterial treatment or the presence of significant complications of ome warrant surgical intervention (tympanostomy tube). [ ] . acute sinusitis acute sinusitis is characterised by fever, headache and facial pain and/or tenderness over the maxillary or frontal sinus(es). it is principally an adult disease. these features are often present early in the course of acute rhinitis in the absence of bacterial infection. it is also tempting to diagnose sinusitis if nasal secretions become purulent. acute sinusitis, like acute otitis media, is usually a disease of obstruction and bacterial trapping. therefore, the presence of nasal pus suggests either inflammation in the nasal cavity itself or that sinuses are draining. meta-analyses have not shown a major benefit from the use of antibacterials in patients with acute sinusitis. [ , ] the natural resolution rate without antibacterials within week of presentation is about %. [ ] if antibacterials are prescribed for sinusitis-like symptoms without further investigation, at least study has confirmed that antibacterials are not superior to placebo. [ ] it is likely that the poor efficacy of antibacterials in this setting is because of the fact that sinusitis-like symptoms are common in viral rhinitis, and thus early in the course of illness most patients with such symptoms have a purely viral and self-resolving infection. for this reason, most authorities now do not recommend administering antibacterials to all patients with sinusitis-like symptoms. the bacteriology of acute sinusitis is similar to that of acute otitis media, being dominated by s. pneumoniae, h. influenzae and m. catarrhalis. [ ] as for acute otitis media, the ideal investigations, sinus tapping or washout for culture, are not general practice procedures. cultures of nasal secretions are not useful and can be quite misleading. plain radiography has moderate sensitivity and specificity, and is most beneficial in excluding the diagnosis (high negative predictive value). be wary, as minor degrees of sinus mucosal thickening are also common in viral urtis. more sensitive tests such as ct scan should be reserved for patients with a complicated disease course. authorities currently recommend withholding antimicrobials unless specific conditions have been met. us recommendations are to administer narrow spectrum antibacterials in the first instance if the clinical criteria for the diagnosis are met: prolonged rhinosinusitis signs and symptoms without improvement for > to days, or more se-vere rhinosinusitis symptoms such as fever ≥ °c, facial swelling and facial pain. [ ] the current australian guidelines are shown in table v. early in the course of illness the infection should be managed symptomatically with agents such as topical or systemic decongestants. because the bacteriology of acute sinusitis is similar to that of acute otitis media, the choices of antibacterial, when they are indicated, are similar, with the added benefit that doxycycline can be used as this is mainly an adult disease. the rationale of choices is explained in section . . , with amoxicillin as the drug of choice. in patients who are penicillin-allergic, oral second or third generation cephalosporins or doxycycline are the best alternatives, and failure to respond or relapses should be treated with amoxicillin/clavulanic acid. although they might be regarded as lower respiratory tract infections, acute laryngitis and tracheitis are often part of upper respiratory syndromes, especially the common cold. hoarseness or loss of voice is the hallmark of laryngitis, whereas the features of tracheitis are cough and retrosternal chest pain exacerbated by coughing. the presence of productive sputum implies bronchitis in addition, and the condition should be managed as such. one condition that can mimic laryngitis is acute epiglottitis, most often caused by the invasive h. influenzae type b. it is now a rare disease in children because of vaccination, but it must be emphasised that this condition can still occur in inadequately vaccinated children and also rarely in adults. acute epiglottitis is life-threatening as a result of sudden airway obstruction. in children, acute viral laryngitis and tracheitis can occasionally cause severe subglottic oedema, resulting in partial airway obstruction with a characteristic cough and inspiratory stridor, that is, croup. both acute epiglottitis and croup require urgent hospitalisation to manage the patient's airway. acute laryngitis and tracheitis are almost always viral in origin, with parainfluenza virus, rhinovirus, adenovirus and influenza viruses being the most common agents. two controlled trials with antibacterials have shown no useful symptomatic benefit from their use. [ , ] this is indirect evidence that bacterial superinfection does not play a role. no investigations are required for these conditions. symptomatic management is all that is required: voice rest and humidification are used most commonly. cough suppression may be tried if retrosternal pain on coughing is a problem but is not recommended as a routine. antibacterial therapy is never required. we have entered a new era in the management of upper respiratory tract infections: it is the era of minimal antibacterial prescribing. the general practitioner must take a leading role in winding back the high community expectation of a 'pill for every ill' when that pill is an antibacterial. even though we do not yet have the bedside tests to distinguish with certainty that patients might benefit from antibacterials at the time of consultation, there are now simple algorithms and lists for providing confidence. there is also a good deal of educational material to assist patients and parents in 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otitis media treatment of acute otitis media with shortened courses of antibiotics short course antibiotic therapy for respiratory infections: a review of the evidence management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the drug-resistant streptococcus pneumoniae therapeutic working group resistant bacteria in middle ear fluid at the time of tympanotomy tube surgery epidemiology of otitis media in children meta-analysis of antibiotics for the treatment of otitis media with effusion use of antibiotics in preventing recurrent otitis media and in treating otitis media with effusion. a meta-analytic attempt to resolve the brouhaha role of surgery for otitis media in the era of resistant bacteria antimicrobial treatment in acute maxillary sinusitis: a meta-analysis are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? a meta-analysis the end of antibiotic treatment in adults with sinusitis-like complaints in general practice? a placebo-controlled double-blind randomised doxycycline trial acute sinusitisprinciples of judicious use of antimicrobial agents inefficacy of penicillin v in acute laryngitis in adults. evaluation from results of double-blind study erythromycin in acute laryngitis in adults department of microbiology and infectious diseases, women's and children's hospital, king william rd, north adelaide sa inappropriate antibacterial use. every opportunity should be taken to re-educate the public about the minor role of antibacterials in urti. key: cord- - x j authors: vergison, anne title: microbiology of otitis media: a moving target date: - - journal: vaccine doi: . /j.vaccine. . . sha: doc_id: cord_uid: x j abstract the microbiology of acute otitis media (aom) is linked to the nasopharyngeal commensal flora. this respiratory ecosystem undergoes various selective pressures, such as antibiotic consumption and vaccine use. socio-economic conditions also influence the bacterial composition of the nasopharynx. streptococcus pneumoniae, non-encapsulated haemophilus influenzae, moraxella catarrhalis, and group a streptococcus are the leading causes of bacterial aom worldwide. this paper will discuss the causes and consequences of recent shifts in the underlying microbiology of aom. otitis media (om) is a very common childhood disease and a major concern for paediatricians. in a prospective, -year study performed in the usa, over three quarters ( %) of children who completed the investigation experienced at least one episode of acute om (aom) by the age of years and % had suffered from at least three episodes [ ] . the centers for disease control and prevention has estimated that om accounts for more than million physician visits per annum in the usa [ ] . furthermore, in a recent multinational survey, paediatricians reported that they saw at least one patient with om per day [ ] . aom is often preceded by a viral upper respiratory tract infection (urti) -the most common infectious illness in the general population [ ] , and a very common illness in children. in a prospective, -year study following children aged from months to years, a total of urtis were recorded, with aom reported in ( %) children in the course of the viral infection, i.e. . episodes of aom per child per year [ ] . the underlying microbiology of infectious diseases is known to change in response to environmental factors, such as vaccination and antibiotic consumption. for example, the epidemiology of bacterial meningitis has changed in countries where haemophilus influenzae type b [ ] , group c meningococcal, and pneumococcal conjugate vaccines have been introduced, with a dramatic reduction in the incidence of bacterial meningitis overall. however, non-vaccine serotypes of streptococcus pneumoniae now account for a more significant proportion of the disease in the countries * tel.: + ; fax: + . e-mail addresses: anne.vergison@ulb.ac.be, anne.vergison@huderf.be. where the seven-valent pneumococcal conjugate vaccine (pcv ; prevnar tm /prevenar tm ) is widely used [ , ] . furthermore, s. pneumoniae isolates with reduced susceptibility to penicillin were recovered from human infections in the late s in australia and new guinea [ ] . since then, penicillin non-susceptible s. pneumoniae strains have spread all over the world and their prevalence has dramatically increased in various countries [ ] . moreover, s. pneumoniae accumulated multiple resistance determinants in some strains and serotypes [ ] [ ] [ ] , and modified the epidemiological landscape in some regions, including the usa [ ] . although in most regions, penicillin remains active against s. pneumoniae despite increased minimal inhibitory concentrations and can be used safely to treat pneumococcal infections other than meningitis, some multiresistant strains have been described in infections such as aom [ ] . a recent report from the usa presented nine clinical failures in aom due to s. pneumoniae resistant to amoxicillin, oral cephalosporins, macrolides, clindamycin, and co-trimoxazole, and required tube placement for drainage and the use of levofloxacin, a drug which is not licensed for paediatric use [ ] . in another recent us study, an increased proportion of severe mastoiditis cases was observed, mostly due to multiresistant serotype a s. pneumoniae [ ] . at the beginning of the th century, group a streptococcus (gas) was the most common pathogen leading to complications in aom, but it is now rare in the western world. a 'new' triad of aom pathogens has emerged in the last century -s. pneumoniae, non-encapsulated h. influenzae (often called non-typable h. influenzae [nthi]), and moraxella catarrhalis -all of which are commensal bacteria found in the human nasopharynx. this review provides some insight into the microbiology of aom in an era of antibiotic resistance and pneumococcal conjugate vaccine use. aom is a multipathogen disease, and can be caused by a number of different viruses and bacteria. viruses alone are found in only % of cases, while co-infection with bacteria is seen in % of cases [ ] . among the viruses, coronavirus, respiratory syncytial virus, and adenovirus are most commonly associated with aom [ ] . s. pneumoniae and h. influenzae are by far the most common bacterial pathogens in aom, being recovered in up to % of cases. m. catarrhalis is usually the third most frequent bacterium isolated ( - %) and gas makes up - % of cases, although the incidence of gas infection differs between countries, depending on when the study was performed, and whether severe cases of aom were included ( fig. ) [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the diagnosis of aom is difficult as a number of symptoms, for example pain, fever, conjunctivitis, and headache, are shared with other infections of the upper respiratory tract. furthermore, diagnosis in young children is hampered by the child's inability to describe their symptoms and the likelihood that they will be distressed and experiencing pain. for a clinical diagnosis of aom, the key criteria that should be met are a history of acute onset of signs and symptoms (fever, distinct otalgia that precludes nor-mal activity, or sleep), with signs of middle ear infection (a cloudy, bulging, or clearly immobile eardrum with red colouration of the eardrum and the presence of fluid in the middle ear or otorrhoea) [ , ] . some clinical signs have been associated with particular otopathogens (e.g. conjunctivitis is associated with h. influenzae, while more severe cases of aom are more often caused by s. pneumoniae) [ ] [ ] [ ] . however, accurate identification of underlying pathogens is not possible purely on clinical grounds. in the large, prospective finnish trial, severe tympanic membrane findings (bulging tympanic membrane or spontaneous perforation) with concomitant high fever had a % positive predictive value and a % negative predictive value for a s. pneumoniae aetiology of the aom episode. the presence of a purulent conjunctivitis gave a positive predictive value for h. influenzae aom of % with an % negative predictive value. no useful predictors were found for m. catarrhalis aom [ ] . even in the absence of definitive clinical signs for the identification of the underlying otopathogen(s), most guidelines do not advocate the systematic use of tympanocentesis, in which fluid is collected from behind the eardrum and analysed to identify the infectious organisms involved and perform antibiotic susceptibility testing. if an antibiotic treatment was to be prescribed, it would be chosen on empirical grounds based on local epidemiological data. however, in selected cases (antibiotic treatment failure and complicated aom), it is essential to identify the causative otopathogen accurately and determine its antibiotic susceptibility. tympanocentesis will, therefore, be recommended in order to ensure the most effective treatment course [ , , ] . all-cause aom incidence peaks between the ages of and months, with one study reporting a peak incidence at months of . aom events/ child months (fig. ) [ ] . in this study, nthi showed a distinct pattern of incidence compared with s. pneumoniae and m. catarrhalis. there was an increase in the incidence of nthi aom after the age of months, peaking at months ( . aom events/ child months). moreover, h. influenzae was associated with recurrent aom. it was recovered in middle ear fluid (mef) in % of first aom episodes compared with % of all subsequent om episodes, and when only the first aom episodes were considered, no peak in the incidence of h. influenzae aom could be demonstrated in children over year of age. despite the use and availability of antibiotics and appropriate medical access, aom can often lead to recurrences and, in rare cases, severe intratemporal (facial paralysis, labyrinthitis, and acute petrosistis, which are extremely uncommon) and intracranial complications, such as mastoiditis, meningitis, intracranial abscesses, and sinus thrombosis. although mastoiditis has become infrequent in industrialized countries (incidences from . to / , childyear) [ ] [ ] [ ] , it is still a common belief that antibiotic treatment should be prescribed in aom to prevent its occurrence. the prevention of mastoiditis by systematic antibiotic treatment of aom has never been established [ , ] . many factors can account for variations in the incidence of mastoiditis in different countries: socio-economic and living conditions, antibiotic prescribing rates, exhaustiveness of the epidemiological surveillance systems, and differences in complication rates by pathogens [ , , ] . indeed, not all bacterial otopathogens have the same propensity to cause complications of aom. gas is associated with the most frequent and severe complications, such as mastoiditis (table ) , while severe complications of h. influenzae are uncommon and those of m. catarrhalis infection are rare [ ] . as previously discussed, evidence suggests that s. pneumoniae is more common in severe episodes of om [ ] , while nthi is more commonly associated with recurrent om (rom) (fig. ) [ , ] . one recent study assessed the underlying microbiology of rom (defined as three acute episodes in the previous months or four in the past months) and aom treatment failure (defined as persisting signs and symptoms of aom after ≥ h of antibiotic therapy or within days of completing an antibiotic treatment course) in us children following the widespread introduction of pcv in [ ] . although there was a slight increase in the proportion of s. pneumoniae isolates present during the - season, h. influenzae was the most frequently isolated pathogen ( % of all isolates across three respiratory seasons, [ ] [ ] [ ] [ ] in this difficult-to-treat patient group during a time of increasing and widespread use of pcv (fig. ). difficulties encountered in the treatment of om are not only due to the existence of antibiotic resistance in otopathogens, but are also attributable to the biofilm nature of bacterial om infections. table the risk for development of mastoiditis following aom caused by different bacterial otopathogens [ ] . in natural environments, the majority of bacteria exist as a biofilm (a structured community of microorganisms embedded within a polymeric matrix that is attached to an inert or living surface) rather than in a planktonic state. in contrast to planktonic bacteria, biofilm bacteria are characterized by slow rates of cell division and a tolerance to very high concentrations of antibiotics. biofilm infections are, therefore, difficult to treat effectively with currently available antibiotic agents, which rely on the rapid metabolic and divisional rates of planktonic bacteria for their mode of action. the presence of bacterial biofilms in om was first suspected owing to the persistence of infection despite treatment with antibiotics and the absence of positive cell culture specimens. definitive evidence for the biofilm nature of om has been provided by a number of studies. for example, one study used polymerase chain reaction techniques to detect h. influenzae dna and mrna in mef from children with chronic om with effusion. the presence of the short-lived mrna molecules, even in the absence of positive culture specimens, indicated the presence of viable bacteria in these specimens [ ] . additionally, the three major bacterial pathogens of om have been proven to form biofilms in vitro and in vivo [ ] [ ] [ ] [ ] [ ] , while one study has reported the direct detection of bacterial biofilms on middle ear mucosa biopsies from children with chronic om [ ] . antibiotic use results in the selection of strains resistant to antibiotics. this was demonstrated in vitro for s. pneumoniae by alexander fleming shortly after he discovered penicillin [ ] . more recently, the correlation between antibiotic consumption and resistance was demonstrated in a european study comprising countries. outpatient antibiotic use was correlated with resistance for all antibiotic-pathogen combinations, and more specifically for s. pneumoniae [ ] . the nasopharynx constitutes a wide reservoir where resistant bacteria (s. pneumoniae but also streptococcus viridans, h. influenzae, and m. catarrhalis) can easily be selected whenever antibiotic selective pressure is applied [ ] . antibiotic resistance in s. pneumoniae and h. influenzae has become a major public health issue and a european union priority for research and action. it is expected that the prevalence of chronic obstructive pulmonary disease will increase in the coming years in europe, and both s. pneumoniae and h. influenzae have major infectious roles for this condition [ ] . similarly, the world health organization (who) has set antimicrobial resistance contain-ment as a research priority, particularly regarding s. pneumoniae [ ] . all three major otopathogens cause antibiotic resistance concerns. penicillin and multidrug resistance in s. pneumoniae has already been described above. in europe, dual erythromycin and penicillin non-susceptibility varies widely between countries, from less than % to more than % [ ] . while amoxicillin resistance in m. catarrhalis is universally seen in approximately % of the strains, it is still a limited occurrence in nthi (a mean of % ␤-lactamase production in one international study) [ ] . however, some regions, such as france, the usa, japan, and other southern asian regions have high rates of amoxicillin resistance in nthi [ , ] . several mechanisms cause this resistance, the most common being ␤-lactamase production, which is detected in most laboratories. however, other resistance mechanisms are increasingly being described in france and japan, which confer additional resistance to amoxicillin-clavulanate, cefuroxime, and sometimes to third-generation cephalosporins, and which are usually not investigated in routine microbiology [ , ] . in a recent study conducted in japan, only % of the nthi strains isolated from children with urtis were amoxicillin susceptible and % were ␤-lactamase producers; the others were also resistant to amoxicillin-clavulanate and to a various degree to cephalosporins [ ] . the introduction of conjugate vaccines that impact on the commensal flora creates 'epidemiological niches' for alternative potential pathogens that are not included in the vaccine. the introduction of pcv in the usa resulted in rapid shifts in the microbiology of om [ , , , ] . pcv vaccination was followed by rapid replacement with non-vaccine s. pneumoniae serotypes in the nasopharynx of vaccinated children and their siblings and, as a result, the proportion of aom caused by vaccine serotypes has fallen and disease caused by non-vaccine serotypes and other pathogens, such as nthi, has risen. for example, in one us study, significant increases in the percentage of aom cases due to non-pcv pneumococcal serogroups occurred between and (from % to %, respectively; p < . ). however, no decline was observed in the penicillin non-susceptible s. pneumoniae strains [ ] . as mentioned previously, multidrug-resistant replacement serotypes may arise [ ] , stressing the need for reduced antibiotic prescribing in order to maximize the benefits of the vaccine in eliminating the most prevalent antibiotic-resistant serotypes. additionally, the trend for an increase in persistent aom and aom treatment failure attributable to h. influenzae observed from to in a single us study centre [ ] was also reported in three us centres for the period - [ ] . om is a common disease that affects approximately three quarters of children before their third birthday. currently, s. pneumoniae and nthi are responsible for approximately % of all bacterial aom cases, with s. pneumoniae generally causing more severe episodes, and nthi responsible for recurrent episodes. the underlying microbiology of om, which is inherently linked to the 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their susceptibility to antibiotics remarkably high prevalence of fts i gene mutations in haemophilus influenzae isolates from upper respiratory tract infections in children of the sapporo district changes in frequency and pathogens causing acute otitis media in - acute otitis media due to penicillin-nonsusceptible streptococcus pneumoniae before and after the introduction of the pneumococcal conjugate vaccine i would like to thank philippe lepage and pierre smeesters for the critical proofreading of this manuscript. a.v. has received speaker fees from glaxosmithkline, sanofi and wyeth, consultant fees from glaxosmithkline and wyeth, and research fees from wyeth. key: cord- -hxoyfh o authors: kaur, gagandeep; neekhra, aneesh; houghton, david; scarff, jonathan r.; lippmann, steven title: resolution of acute disseminated encephalomyelitis following termination of pregnancy date: - - journal: psychosomatics doi: . /j.psym. . . sha: doc_id: cord_uid: hxoyfh o nan a cute disseminated encephalomyelitis (adem) is a rare autoimmune illness characterized by inflammation of central nervous system myelin with resultant white matter damage. adem includes a wide variety of clinical presentations, thus contributing to a complex differential diagnosis. it most frequently occurs in children during winter or spring months following an upper respiratory infection by viruses, such as epstein barr, coxsackie, coronavirus, cytomegalovirus, hepatitis a, human immunodeficiency virus, influenza, measles, rubella, varicella, and west nile virus. [ ] [ ] [ ] alternatively, it may result from a variety of bacterial or parasitic infections. nearly % of cases are precipitated by immunization, with measles/mumps/rubella vaccine being the most frequent cause. common clinical features of adem include fever, altered mental status, hemiparesis, ataxia, cranial neuropathies, and spinal cord dysfunction. severe cases may be accompanied by seizures or coma, as neurological signs are referable to the location of the lesion burden. , , although the exact pathophysiology remains unclear, a hypersensitivity reaction with demyelination is implicated. the prognosis varies and the outcome may be fatal. surviving patients exhibit varying degrees of recovery and often do not return to their previous baseline functioning. ms. a, a -year-old african-american woman was brought to the emergency room by her parents because she was socially withdrawn and was exhibiting strange behavior (such as bizarre posturing and aimless staring) for the previous days. she was not speaking or responding to interviewer's questions, so history was obtained from relatives. they reported her as experiencing progressive difficulty in performing activities of daily living and not attending to personal hygiene. in addition, she was refusing oral intake. there was no recent history of fever, apparent infection, or vaccinations. she had become pregnant several weeks prior and had spoken to her family about planning to terminate the pregnancy. a previous pregnancy, labor, and delivery were uncomplicated. the medical history otherwise revealed no psychiatric diagnoses or medical illnesses, and her parents knew of no other current health concerns. she had no known allergies and was not taking any medications. the patient was a smoker and had been using marijuana and cocaine. there was a family history of schizophrenia in one relative. on examination in the emergency department, ms. a was ft in tall and weighed pounds. vital signs were within normal limits. she was awake but mute, did not respond to stimuli, had a flat affect, and appeared to be catatonic. incontinence of urine was noted. she did not follow commands or visually track movement about the room. cranial nerve examination was unremarkable, including a normal oculocephalic reflex with full nuclear eye movements. assessment of the motor system was normal without waxy flexibility. painful stimuli resulted in withdrawal of all extremities without focal weakness. deep tendon reflexes were symmetrical and plantar responses were flexor. a complete blood count and comprehensive metabolic panel were within normal ranges. her toxicology screen result was negative. an intrauterine pregnancy of weeks gestation was confirmed by abdominal ultrasound. the patient was considered nondecisional. after a medical ethics consultant opined that her parents were appropriate decision-makers for her, they were included in clinical discussions and treatment planning. the initial diagnosis was psychosis with catatonia, and she was admitted to the inpatient psychiatry unit. there, pharmacotherapy with olanzapine and lorazepam was initiated, but no improvement was noted. given the bizarre nature of her presentation and the acute onset of her illness, a magnetic resonance imaging (mri) scan of the brain was performed. it revealed several large, dense, deep white matter lesions in the frontal, parietal, and temporal lobes (figure) . these findings resulted in obstetrical and neurological consultations. the pregnancy was considered normal by the obstetrician, and a presumptive diagnosis of adem was made by the neurologist. the patient was transferred to the neurology service, and all aforementioned pharmacotherapies were discontinued. on the neurology service, a lumbar puncture was performed and it revealed unremarkable results for cerebrospinal fluid glucose, protein, red blood cells, white blood cells, albumin, and an igg synthesis rate. the evaluation of lyme igg and igm, cytomegalovirus igg, cryptococcus antibodies, jakob-creutzfeld virus, and oligoclonal bands showed negative results. epstein barr virus igg was positive and igm was negative; the herpes simplex virus igm was positive. serum herpes simplex virus and were negative, while igg was positive, as determined by polymerase chain reaction. an electroencephalogram revealed normal brain activity without evidence of ictal activity or slowing. intravenous (iv) steroids and iv immunoglobulins (ivig) were administered, a gastric tube was placed, and supportive care was initiated. without clinical progress over the next weeks, she received a second course of methylprednisolone, plasma exchanges, and iv acyclovir. despite these measures, no improvement in her neurological or mental status was observed. three mri scans over a -week period documented an increase in the size of the original lesions and central necrosis in frontal lesion, without edema, shift, or hemorrhage. her family reported that ms. a had told them that she did not want to remain pregnant and had planned to terminate this pregnancy. expressing concern for potential congenital anomalies given the patient's substance abuse, the parents asked to terminate the pregnancy. termination occurred case reports month after admission, with normal histopathology reported. over the next months, her condition gradually improved in modest proportions, as demonstrated by limited eye contact and facial gestures to family members. she began to visually track people in her room, but remained mute and unresponsive to commands. after months of hospitalization, ms. a was transferred to a long-term rehabilitation facility where she gradually recovered some language function and ambulation. a repeat mri revealed interval improvement of inflammatory lesions with evidence of some deep tissue loss. at follow-up in the neurology clinic, she was slowly improving but still exhibited considerable cognitive impairment and depression. referred to the psychiatry clinic, she showed some further improvement in speech and comprehension. her neurological and psychiatric status remained stable months later. she then declined future appointments and was lost to follow-up. our case emphasizes the variable presentations of adem and highlights diagnostic and treatment dilemmas in the setting of pregnancy. making a correct diagnosis and initiating proper treatment for adem are critical. brain imaging is recommended in most new presentations of neurological dysfunction or psychiatric conditions or both. mri and lumbar puncture may confirm the presence of demyelinating diseases, including adem. , more invasive procedures, such as a brain biopsy or cerebral angiogram, are rarely necessary and pose additional risk. vigorous treatment for a potential infectious process is recommended, whereas anti-inflammatory and immunemodulating pharmacotherapies are the primary interventions for adem. corticosteroids and ivig may shorten the duration and severity of illness or halt disease progression. plasmapheresis may be offered with or without immunosuppressive agents, but usually in cases resistant to steroids. supportive measures, including physical therapy and skin care, are provided on a routine basis. surviving patients may exhibit slow, partial recoveries over several months, whereas others might retain permanent neurological deficits, persistent psychiatric symptoms, and residual cognitive impairments. this case posed challenges to the usual treatment plan. morbidity to both mother and fetus could escalate if immunomodulatory therapy was withheld. alternatively, high-dose steroids can result in fetal hypoadrenalism, and methylprednisone is a category d pharmaceutical during the first trimester of pregnancy. in addition, there is a risk of stroke during ivig infusions, and this could theoretically be increased owing to the hypercoagulable state of pregnancy. conversely, there is some controversial evidence for ivig being protective against repeated miscarriages. ms. a's neurological status began to improve after the pregnancy was terminated. this poses questions about whether pregnancy could have precipitated the illness and whether termination attenuated the disease process. the relationship between adem and pregnancy is uncertain. , one case of adem in the third trimester responded favorably to plasmapheresis after treatment failure with high-dose corticosteroids. in contrast, other cases of fulminant demyelinating disease during pregnancy have resulted in coma. , another demyelinating illness, marburg's disease, is similarly rapid and fulminant, but less likely during pregnancy; case, resistant to steroids, ivig, and plasmapheresis, resulted in death. pregnancy is associated with a reduced inflammatory response due to increased levels of antiinflammatory and immunosuppressant cytokines which prevent fetal rejection and promote passive transfer of antibodies to the fetus. these hormonally-induced alterations are essential to support a successful full-term pregnancy. this may explain the decreased frequency of relapses in a related demyelinating disease, multiple sclerosis, during pregnancy. in a retrospective study of multiple sclerosis patients, higher parity was associated with a reduced risk of a first demyelinating event, with a % reduction in risk during each subsequent pregnancy. this stands in contrast to our case, in which a multiparous patient experienced her first demyelinating event. however, women with radiologically-identified, asymptomatic multiple sclerosis who then became pregnant were more likely to develop new mri-documented pathology. this suggests that pregnancy may activate disease in presymptomatic individuals. it is possible that our patient had asymptomatic pathology that became evident during and exacerbated by pregnancy, but it is impossible to conclude this without premorbid brain imaging for comparison. another explanation includes her compromised immunity while being pregnant, which can lead to increasing severity of infectious diseases. for example, morbidity from influenza can increase during pregnancy, which might have predisposed her to a possible virally-induced adem. alternatively, a direct immune-mediated response to the fetus may have triggered the adem; this is supported by the beginning of recovery after pregnancy termination in our vignette. determining whether a causal relationship exists is not possible, because the natural course of this disease and its potential response to immunotherapies tend toward recovery over a similar time period. this case emphasizes the variety of psychiatric and neurological signs and symptoms of adem as well as therapeutic options. whether a relationship between pregnancy and adem exists remains uncertain. research might discover why pregnant individuals with adem have demonstrated variable responses to steroids, plasmapheresis, and ivig. further investigation may determine whether an immune-mediated response to the fetus can precipitate adem. given ethical concerns and the rarity of this condition, it is impossible to determine whether a causal relationship exists between termination of pregnancy and resolution of treatment-resistant adem. acute disseminated encephalomyelitis and its place amongst other acute inflammatory demyelinating cns disorders acute disseminated encephalomyelitis the clinical course of acute disseminated encephalomyelitis neurological complications of immunization acute disseminated encephalomyelitis: a long-term prospective study and meta-analysis the pathological spectrum of cns inflammatory demyelinating diseases acute disseminated encephalomyelitis: an update when should brain imaging be performed?: a case report of caudate nucleus infarct role of mri in the differentiation of adem from ms in children acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features treatment of acute disseminated encephalomyelitis safety of intravenous immunoglobulin treatment intravenous immunoglobulin and idiopathic secondary recurrent miscarriage: a multicentered randomized placebo-controlled trial acute disseminated encephalomyelitis in a pregnant woman successfully treated with plasmapheresis the follow-up of acute disseminated encephalomyelitis in a comatose pregnant woman an autopsy case of acute multiple sclerosis (marburg's type) during pregnancy multiple sclerosis and pregnancy offspring number, pregnancy, and risk of a first clinical demyelinating event: the autoimmune study impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort pregnancy and pregnancyassociated hormones alter immune responses and disease pathogenesis the authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. key: cord- -rlwoy ms authors: tedeschi, delio; rizzi, andrea; biscaglia, simone; tumscitz, carlo title: acute myocardial infarction and large coronary thrombosis in a patient with covid‐ date: - - journal: catheter cardiovasc interv doi: . /ccd. sha: doc_id: cord_uid: rlwoy ms this is a case report of a ‐year‐old male, without any cardiovascular risk factor and no cardiac history admitted to hospital with a diagnosis of interstitial pneumonia caused by coronavirus disease (covid‐ ). after days, the blood tests showed a significant rise of inflammatory and procoagulant markers, along with a relevant elevation of high‐sensitivity troponin i. electrocardiogram and transthoracic echocardiogram (tte) were consistent with a diagnosis of infero‐posterolateral acute myocardial infarction and the patient was transferred to the isolated cath lab for primary percutaneous coronary intervention (pci). the angiography showed an acute massive thrombosis of a dominant right coronary artery without clear evidence of atherosclerosis. despite the optimal pharmacological therapies and different pci techniques, the final timi flow was / and after hr the clinical condition evolved in cardiac arrest for pulseless electric activity. acute coronary syndrome–st‐elevation myocardial infarction is a relevant complication of covid‐ . due to high levels of proinflammatory mediators, diffuse coronary thrombosis could occur even in patients without cardiac history or comorbidities. this clinical case suggests that coronary thrombosis in covid‐ patients may be unresponsive to optimal pharmacological (gp iib–iiia infusion) and mechanical treatment (pci). was transferred from another hospital to our institution. the patient claimed he had been previously in contact with a colleague positive to covid- . a nasopharyngeal swab for covid- detection was collected, and after hr the test result confirmed the active infection. the patient's symptoms started with low-grade fever, dry cough, asthenia, and muscle pain on march . after a couple of days, the fever became higher and unresponsive to paracetamol. the patient had no history of other preexisting pathological conditions except amoxicillin allergy. the results of physical examination on march revealed blood pressure of / mmhg, heart rate of bpm, body temperature of c, oxygen saturation (spo ) of % while breathing ambient air, respiratory rate of breath/min; the spo reached % after oxygen supplement by venturi mask at l/min, and fio of %. routine blood tests at admission revealed normal white blood cell count ( , μl) with % neutrophil and . % lymphocyte, normal platelet count ( × μl), normal hemoglobin concentration, high levels of c-reactive protein (pcr mg/l), and slight increase of lactate dehydrogenase (ldh u/l) normal levels of bnp (probnp pg/ml). the serum creatinine was . mg/dl and egfr at ml/ min ( table ) . the arterial gas analysis showed a ph of . , oxygen partial pressure of mmhg, carbon dioxide partial pressure of mmhg, and bicarbonate level of mmol/l. the chest x-ray revealed evidence of pneumonia with bilateral multiple interstitial ill-defined patchy opacities ( when admitted, the patient was treated with dexamethasone ( mg iv), hydroxychloroquine ( mg twice daily), antiviral drugs (lopinavir/ritonavir- tablets / mg twice daily), oxygen support (venturi mask fio %), antibiotic prophylaxis with ceftriaxone ( g iv), and venous thromboembolic (vte) prophylaxis with enoxaparin ( , u.i. sc). after hr, n-acetylcysteine ( mg twice daily) and furosemide ( mg iv twice daily) were administered. during the first days of the hospital stay, the clinical conditions and the vital signs of the patient were stable (afebrile, spo - % at l/min, and fio %). on the sixth day, the patient showed a significant worsening of the shortness of breath and oxygen saturation (spo %), indeed respiratory support by cpap machine was started (fio %, peep cmh o). on the seventh day (march ) the patient showed a significant psychomotor agitation along with slight chest discomfort. the daily blood tests showed a significant rise of pro-coagulant and inflammatory markers d-dimer ( , ng/ml), white blood count abbreviations: egfr, estimated glomerular filtration rate; ldh, lactate dehydrogenase; n/a, not applicable; pro bnp, pro-brain natriuretic peptide. f i g u r e chest radiography at presentation: bilateral multiple interstitial ill-defined patchy opacity ( , μl), pcr ( mg/l), ldh ( u/l), ferritin ( , ng/ml) along with a significant elevation of high sensitivity troponin i levels ( , ng/ml) ( table ) . angiography showed a high grade thrombus burden diffused in all rca extensions (figure c) . we decide to proceed with manual thrombus aspiration, as first strategy, using a fr eliminate aspiration catheter (terumo medical) without achieving any effective recanalization. images of diffuse intracoronary thrombosis with persistent timi - flow was documented. eptifibatide μg/kg iv bolus was given, followed by continuous infusion of μg/kg/min; the act value was s; after some minutes we administered a second eptifibatide μg/kg intracoronary bolus through the tip of eliminate aspiration catheter, placed in distal rca. in order to maximize the thrombectomy effect, we proceeded with a manual thrombus aspiration using a f guide extension catheter guideliner (teleflex medical) as described in previously published case series. the guideliner was carefully advanced to the distal part of rca, and aspiration with a cc syringe via a y connector through the side port was performed during slow retrieval of the catheter (figure d ). previous studies - have linked acute infections with an increased risk for acute myocardial infarction (ami). in fact, the host inflammatory response to the infection often results in the release of proinflammatory cytokines and activation of platelets, leukocytes, and endothelial cells that can activate procoagulant pathways with prothrombotic status and consequently higher risk of acute cardiovascular events such as ami. , many possible biological factors related to the covid- infection could be involved in the physiopathological cascade that could precipitate cardiovascular complications, especially acs : • high levels of systemic proinflammatory cytokine and mediators of atherosclerosis may determine the plaque rupture through local inflammation. • procoagulant effects of systemic inflammation may cause coronary thrombosis: plaque thrombosis, stent thrombosis, and spontaneous thrombosis. reports showed that patients with covid and severe respiratory distress often develop complications such as liver dysfunction or renal failure which can be related to procoagulant status. [ ] [ ] [ ] in our report, the years old male developed an ami-stemi just when blood tests showed an important elevation of proinflammatory and thrombotic activity mediators while these results were normal in the preceding days. the main angiographic finding was an acute massive thrombosis of a dominant rca without evidence of clear coronary stenosis or atherosclerotic plaques. considering the diffuse thrombosis was resistant to pharmacologic and mechanical therapy, this case supports the hypothesis that the proinflammatory and prothrombotic status related to covid- infection was the main factor that triggered the coronary thrombosis. as the intracoronary imaging test was not performed (oct-ivus), the limitations of this report is the lack of clear information about the pathogenetic mechanisms underlying the rca thrombosis. furthermore, as the autopsy was not performed, we assume that fatal outcome was due to a combination of severe oxygen desaturation, acute ischemic heart failure, and consequent severe acidosis. however, we cannot exclude concomitant pulmonary thromboembolism or thrombosis of other organs as precipitating factors of cardiac arrest. this case report highlights the clinical impact of acs-stemi in covid- patients. high levels of proinflammatory and hyperthrombotic activity could significantly affect the final outcome, even in young patients without cardiac past history or significant comorbidities. potential effects of coronaviruses on the cardiovascular system: a review forward and back aspiration during st-elevation myocardial infarction: a feasibility study role of acute infection in triggering acute coronary syndromes risk of myocardial infarction and stroke after acute infection or vaccination influenza infection and risk of acute myocardial infarction in england and wales: a cali-ber self-controlled case series study acute myocardial infarction after laboratory-confirmed influenza infection association of cardiac injury with mortality in hospitalized patients with covid- in wuhan, china cardiovascular implications of fatal outcomes of patients with coronavirus disease abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia attention should be paid to venous thromboembolism prophylaxis in the management of covid- coagulopathy and antiphospholipid antibodies in patients with covid- clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province key: cord- -zjrkfe b authors: popat, bhavesh; jones, andrew t. title: invasive and non-invasive mechanical ventilation date: - - journal: medicine (abingdon) doi: . /j.mpmed. . . sha: doc_id: cord_uid: zjrkfe b early recognition of patients who might potentially require ventilatory support is a key goal of critical care outreach programs and an important skill for all hospital medical staff. decisions about the initiation and timing of invasive ventilation can be difficult and early discussion with critical care colleagues is essential. appropriateness of invasive ventilatory support may also be an issue requiring advanced discussion with patients and their families. in the past – years, the role of non-invasive ventilation (niv) has expanded, not least in an attempt to minimize the complications inherent with invasive ventilation. as such, niv is now considered first-line therapy in some conditions (chronic obstructive pulmonary disease, pulmonary oedema, mild-to-moderate hypoxaemic respiratory failure in immunocompromised patients), and a ‘trial of niv’ is often considered in respiratory failure resulting from an increasingly wide range of causes. when using niv, the importance of the environment (setting, monitoring and experience of staff) and forward planning cannot be overemphasized. when used for other than the standard indications, niv should be employed in a high-dependency/intensive care setting only in patients for whom invasive ventilation would be considered. indications for ventilation early identification of critically ill patients, before the occurrence of significant cardio-respiratory decompensation, is one of the major goals of critical care outreach programmes. patients who require ventilatory support often develop a common pattern of physiological deterioration including: increasing respiratory rate asynchronous respiratory pattern a change in mentation and level of consciousness frequent oxygen desaturation despite increasing oxygen concentration hypercapnia and respiratory acidosis circulatory problems, including hypotension and atrial dysrhythmias. the modern ventilator is a complex computer-driven tool and a detailed description of its modes and use are beyond the scope of this article (see further reading). in simple terms, it mixes air under pressure with variable oxygen concentrations to provide inspiration and expiration, each 'breath' is characterized by three factors, which can be adjusted by the operator; trigger: the ventilator can deliver a breath according to a timer that defines a specific set rate (ventilator initiated/ mandatory breaths), or as a result of the patient's own breathing efforts effecting a change in the pressure or flow in the ventilator circuit (patient-initiated/spontaneous breaths). target: the flow of air into the lung can be to a specific target flow rate (volume control) or pressure (pressure control; pressure support; bi-level) termination: the signal for the ventilator to finish inspiration and allow expiration (passive) may be the achievement of a specific volume (volume-cycled: volume control), after a specific time (time-cycled: pressure control/bi-level) or following the reduction of inspiratory flow to a preset level (flow-cycled: pressure support) niv refers to the provision of respiratory support without direct tracheal intubation. as such, it aims to avoid some of the complications inherent with invasive ventilation, such as the need for sedation with risks of haemodynamic instability and subsequent risk of delirium, nosocomial infection, etc. in a recent worldwide survey, use of niv increased from % to % of all episodes of mechanical ventilation between and respectively, with even higher rates of use in some european countries. indeed, for some situations it is considered the first-choice mode of ventilatory support ( niv today consists almost exclusively of the delivery of positive pressure ventilation via an external interface. there are six broad types of interface available, each with its own particular benefits and drawbacks (see further reading): total face masks (enclose mouth, nose eyes) full face masks (enclose mouth and nose) nasal mask (covers nose but not mouth) mouthpieces (placed between lips and held in place by lip seal) nasal pillows or plugs (inserted into nostrils) helmet (covers the whole head/all or part of the neck e no contact with face). niv can be delivered using most modern 'intensive care' ventilators. for sicker patients this has several advantages (ability to deliver higher and precise concentrations of oxygen; separate inspiratory/expiratory limbs minimizing re-breathing of co ; better monitoring/alarm features; and rapid access to invasive ventilation). outside of the icu, niv is commonly applied using smaller, 'simpler' but increasingly sophisticated 'non-invasive' ventilators, which can provide a range of respiratory support modes. pressure-cycled modes are generally preferred (accommodation of leaks), and breaths can be either patient-triggered (pressure support or bi-level positive airway pressure (bipap)), or initiated and controlled by the ventilator (pressure control). indeed, both modes are often used synergistically to provide back up when triggering is poor or if patient respiratory rate is unreliable, and to cover potential apnoeic episodes. acute hypercapnic respiratory failure patients with acute hypercapnic respiratory acidosis secondary to an acute exacerbation of chronic obstructive pulmonary disease (copd), represent the most extensively studied group, and the greatest evidence for benefit exists in copd. e numerous studies and meta-analyses have confirmed that use of niv is associated with reduced risks of treatment failure (rr . ), lower intubation rates (rr . ) with lower incidence of nosocomial infections, and a reduction in mortality (rr . ) with subsequent reduced hospital length of stay and costs. these benefits have been shown predominantly in patients with mild-to-moderate hypercapnic respiratory failure (ph . e . ). as such, niv should be considered first-line therapy for this patient group, and can be safely used in appropriately staffed and monitored environments outside of the icu. this does not preclude the use of niv in patients with more severe respiratory failure, e and a ph as low as . may still be compatible with favourable outcomes. however, such patients should be managed in a high-dependency environment, to allow for rapid escalation to intubation and invasive ventilation if appropriate. the importance of an established structure for effective niv delivery cannot be overemphasized. early initiation by experienced and skilled staff, appropriate environments and monitoring, and protocols to aid patient selection and subsequent decision making are key to the successful and safe application of niv in all forms of respiratory failure ( figure ). although treatment failure is uncommon in mild-to-moderate respiratory failure, it becomes increasingly frequent in sicker (lower ph and/or significant hypoxaemia) patients (table ) . common causes of niv failure include interface leaks and patient asynchrony with the ventilator ( table ). in experienced hands, such issues can be recognized early and rapidly remedied; if this is not possible, intubation and invasive ventilation will need to be considered. , the appropriateness of invasive ventilation in patients with copd can be a contentious issue. however, recent evidence suggests more favourable outcomes than predicted, with stable or even improved quality of life in most patients. decisions about the extent of future intervention should be made by a senior physician, taking into account factors such as functional status, previous pulmonary function tests, existing comorbidities, body mass index, the need for long-term oxygen therapy and the patient's expressed wishes; ideally before the initiation of niv. the outcome should be documented in the medical record and communicated to the patient/family as appropriate. recommendations based on levels of evidence level evidence systematic reviews (with homogeneity) of rcts and individual rcts (with narrow cis) evidence of use (favourable) acute pulmonary oedema the use of niv (including continuous positive airway pressure (cpap)) to treat respiratory failure secondary to acute pulmonary oedema is widespread. e several meta-analyses have established benefit, including decreased intubation rate (cpap/ bi-level) and mortality (cpap) compared to standard medical therapy. however, these findings were not borne out in a recent randomized control trial, even though physiological improvements occurred earlier in the niv arms (cpap/bi-level). the low rate of intubation (< %), and the potential for crossover between the study arms may have limited the ability to document improvements with niv. the european cardiology task force for diagnosis and treatment of cardiogenic pulmonary oedema recommends niv/cpap as first-line treatments in addition to standard medical therapy when respiratory failure is present. there is conflicting evidence for the use of niv in hypoxaemic respiratory failure. e a recent meta-analysis where niv in addition to standard therapy was compared to standard therapy alone, in hypoxaemic respiratory failure not related to •diagnose need for niv ( fig. ; pulmonary oedema, reported improvements in intubation rate, mortality and hospital length of stay with the use of niv. however the literature in this area is hampered by marked heterogeneity between the study populations in both cause and severity of respiratory failure e in particular the frequency of pre-existing copd. therefore, although some studies suggest benefit, routine use of niv in severe pneumonia or acute respiratory distress syndrome (ards) cannot be recommended. however, in immunocompromised patients, studies have shown early niv use to be beneficial in the management of hypoxic respiratory failure, particular in patients with solid organ transplantation, haematological malignancies and hiv infection. e niv should be considered in such patients, preferably in a highdependency/icu environment with rapid access to invasive ventilation and multi-organ support. in an attempt to limit exposure to the risks of invasive mechanical ventilation, niv is being used increasingly to promote earlier extubation and prevent re-intubation. present evidence suggests it is most likely to be beneficial in copd patients, medical patients with multiple morbidities who are likely to fail on extubation and those with hypercapnia during spontaneous breathing trials. with increasing expertize in its use, it is not surprising that clinicians have been keen to exploit the potential benefits of niv over invasive ventilation in other , forms of respiratory compromise (table ) . it is important to recognize that in some conditions the literature represents small series from experienced centres and the importance of the environment and forward planning cannot be overemphasized. in these circumstances we would recommend that niv should be employed in an intensive care setting only if invasive ventilation would be considered for the patient. invasive mechanical ventilation requires access to the trachea, most commonly via an endotracheal tube, and represents the commonest reason for admission to the icu. large multinational surveys confirm the common indications for invasive ventilation to be: coma % copd % ards % heart failure % pneumonia % sepsis % trauma % postoperative complications % neuromuscular disorders %. decisions about the initiation and timing of invasive ventilation can be difficult and early discussion with critical care colleagues is essential. appropriateness of ventilatory support may also be an issue requiring advanced discussion with patients and families. once a decision to intubate has been made, the transition from an awake and self-ventilating patient to controlled invasive ventilation can be very difficult in the critically ill. most patients will have evidence of developing or established organ dysfunction, particularly cardiovascular dysfunction (ischaemic heart disease, sepsis), and commonly such patients are hypovolaemic. both anaesthetic induction agents and positive pressure ventilation (which decreases venous return) produce cardiovascular depression and peri-intubation hypotension is common. in addition, cessation of spontaneous ventilation can lead to very rapid desaturation in such patients, due to their marginal respiratory reserve and circulatory problems. such consequences need to be anticipated: large-volume cannulae should be in place; access to plasma expanders and inotropes should be immediately available; and following induction of anaesthesia the airway must be rapidly secured by an experienced member of the critical care team e ideally in an appropriately equipped area of the hospital. descriptions of individual ventilatory strategies are beyond the scope of this chapter. however, over the past e years there has been increasing recognition that invasive ventilation, although lifesaving, can be associated with significant complications, such as nosocomial pneumonia, critical illness neuromyopathy syndromes and barotrauma (pneumothoraces); and ventilation itself may be associated with propagation of underlying lung injury and subsequent worsening of multi-organ failure. , the landmark nih ards network trial confirmed that in patients with acute lung injury, the use of a reduced tidal volume ( ml/kg) and avoidance of high airway pressures (< cmh o) were associated with improved mortality ( % vs. . % (nntz )) when compared with a conventional ventilatory approach. although it is not without controversy, this and subsequent studies form the basis for management of patients with hypoxaemic respiratory failure. although individual patients differ, key concepts include: low tidal volume ( ml/kg ideal bodyweight) and avoidance of high inspiratory pressures (p plat < ) to minimize the risk of volutrauma reduced oxygenation targets (sao e %; po . e . ) e 'permissive hypoxia' acceptance of mildemoderate respiratory acidosis e 'permissive hypercapnia' greater use of positive end-expiratory pressure (peep), particularly in more severe hypoxaemia (nb: peep should be used cautiously and may be contraindicated in obstructive airways disease) early use of neuromuscular blockade in severe cases general strategies avoidance of excessive fluid administration minimizing sedation once acute insult has settled e daily sedation holds (interruption of sedation), use of sedation scores daily trials of spontaneous breathing and protocolized weaning once initial insult has resolved early and appropriate nutritional support deep vein thrombosis prophylaxis stress ulcer prophylaxis more recently, attention has turned to the use of extracorporeal support in patients with extreme gas exchange abnormalities. in the recent cesar study, transfer to a centre capable of delivering extracorporeal membrane oxygenation (ecmo) was associated with improved outcome (death or disability) at months. this study and the high-profile success of ecmo in the h n influenza pandemic has resulted in a resurgence of interest in this technique. simpler forms of extracorporeal support exist where hypercapnia is the predominant problem. the development of these and other specialist techniques, along with a recognized volumeeoutcome relationship for mechanical ventilation, has promoted the concept of advanced respiratory support centres to manage the sickest patients. longer term, there is an increased recognition that survivors of critical illness can be left with significant physical, mental and psychological sequelae and early rehabilitation and icu followup programmes have evolved to address these issues. principles and practice of mechanical ventilation evolution of mechanical ventilation in response to clinical research non-invasive ventilation in chronic obstructive pulmonary disease: management of acute type respiratory failure early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial clinical practice guideline for the use of noninvasive positive pressure ventilation in copd patients with acute respiratory failure non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: cochrane systematic review and meta-analysis non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease. cochrane database syst rev noninvasive vs. conventional mechanical ventilation in patients with chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease d nejm the use of noninvasive mechanical ventilation in copd with severe hypercapnic acidosis nippv e niv in acute respiratory failure guideline non-invasive ventilation in acute respiratory failure survival and quality of life for patients with copd or asthma admitted to intensive care in a uk multicentre cohort: the copd and asthma outcome study (caos) randomised controlled comparison of continuous positive airways pressure, bilevel non-invasive ventilation, and standard treatment in emergency department patients with acute cardiogenic pulmonary oedema noninvasive pressure support ventilation vs. continuous positive airway pressure in acute hypercapnic pulmonary edema non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema: a randomised trial noninvasive ventilation in patients with acute cardiogenic pulmonary edema effect of non-invasive positive pressure ventilation (nippv) on mortality in patients with acute cardiogenic pulmonary oedema: a meta-analysis noninvasive ventilation in acute cardiogenic pulmonary edema executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the task force on acute heart failure of the european society of cardiology the evidence for noninvasive positive-pressure ventilation in the care of patients in acute respiratory failure: a systematic review of the literature does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? a systematic review failure of non-invasive ventilation in patients with acute lung injury: observational cohort study noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial noninvasive ventilation for treatment undergoing solid organ transplantation noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure noninvasive ventilation for treating acute respiratory failure in aids patients with pneumocystis carinii pneumonia use of non-invasive ventilation to wean critically ill adults off invasive ventilation: metaanalysis and systematic review non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma the use of non-invasive ventilation for life-threatening asthma attacks: changes in the need for intubation overview of ventilator-induced lung injury mechanisms cellular responses to mechanical stress: invited review: mechanisms of ventilator-induced lung injury: a perspective ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. the acute respiratory distress syndrome network how best to ventilate? trial design and patient safety in studies of the acute respiratory distress syndrome higher vs lower positive endexpiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis neuromuscular blockers in early acute respiratory distress syndrome efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial use of weaning protocols for reducing duration of mechanical ventilation in critically ill adult patients: cochrane systematic review and meta-analysis efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial extracorporeal membrane oxygenation for influenza a(h n ) acute respiratory distress syndrome the novalung Ò ila membrane ventilator: technical aspects hospital volume and the outcomes of mechanical ventilation one-year outcomes in survivors of the acute respiratory distress syndrome key: cord- -c vu ako authors: sherk, peter a.; grossman, ronald f. title: the chronic obstructive pulmonary disease exacerbation date: - - journal: clin chest med doi: . /s - ( ) - sha: doc_id: cord_uid: c vu ako nan peter a. sherk, md, and ronald f. grossman, md, frcpc chronic obstructive pulmonary disease (copd) is characterized by the presence of airflow obstruction caused by chronic bronchitis or emphysema. this airflow obstruction is generally progressive, may be accompanied by airway hyperreactivity, and often is partially re~ersible.~ declining lung function is almost universally caused by decades of tobacco smoke exposure and develops insidiously so that patients often do not complain of exertional dyspnea until their -second forced expiratory volume (fev,) is between % and % of its predicted value. when the fev, falls below l, patients are disabled in the activities of daily living and have a -year survival of approximately ?! . forced expiratory volume in second declines by about ml/year in healthy nonsmokers, whereas the average decline is approximately ml/year in smokers. approximately % of smokers are susceptible to the airway effects of smoking and will develop copd. these patients show accelerated rates of decline in fev, of between and m l /~e a r .~~ in , approximately million americans suffered from copd, an estimated increase of % since .'j it ranks fourth among leading causes of death in north america and is the only leading cause of death that is rising in prevalence.'j, according to estimates made by the national heart lung and blood institute, the annual total cost arising from copd was nearly $ billion dollars. this amount includes almost $ billion in direct health care expenditures, nearly $ billion in indirect morbidity costs, and $ . billion in indirect mortality costs. periods of relative clinical stability during the course of copd are interrupted by recurrent exacerbations. the definition of an acute exacerbation of copd (aecopd) is imprecise but is generally considered clinically as an episode of increased dyspnea, sputum production, and sputum purulence in a patient with copd." when these symptoms are severe and accompanied by significant hypoxemia or hypercapnia, patients may require hospitalization. this article focuses primarily on the management of hospitalized patients with ae-copd outside of the intensive care unit and reviews the evidence supporting the available therapies for copd exacerbations. cigarette smoking is the most important cause of copd.lo smoking compromises local airway defense mechanisms by damaging ciliated airway epithelium, increasing mucus viscosity, and slowing mucociliary clearance. these conditions promote bacterial colonization of the lower respiratory tract. the three major bacterial pathogens isolated from patients with copd during periods of both clinical stability and exacerbation are nontypeable haemophilus influenzae, streptococcus pneumoniae, and moraxella cafar~halis.~~ when fev, is severely reduced, enterobacteriaceae and pseudomonas aeruginosa are also commonly detected. these organisms possess a wide array of virulence factors that allow them to evade clearance from the lower airways. although a detailed discussion of the bacterial mechanisms of colonization and infection is beyond the scope of this article, several concepts are noteworthy. smokers prone to acute episodes of bronchitis have a greater degree of bacterial adherence to oropharyngeal airway epithelial cells compared with nonsmokers.'o , iz after adhering to mucus or epithelial cells, pathogenic bacteria elaborate exoproducts that stimulate excess mucous production,' disorganize and slow ciliary beatingy damage epithelial and impair immune effectorcell function.= furthermore, bacterial proteases destroy local immunoglobulin^.^^ when these bacteria loiter in the airways, a host inflammatory response is stimulated. with the movement of large numbers of neutrophils and their subsequent release of proteases and toxic oxygen radicals, epithelial surface damage may be enhanced. after the inciting impact of smoking, bacterial colonization therefore begets airway damage which, in turn, begets further inflammation and bacterial colonization. this event is the vicious circle hypothesis that has been proposed to explain how the bacteria-host interaction establishes the insidious loss of lung function. , disordered pulmonary gas exchange is characteristic of acute exacerbations of copd. patients typically are found to have severe hypoxemia with or without hypercarbia. a variety of infectious and noninfectious insults result in inflammation, bronchospasm, and mucous hypersecretion. these lead to acute airway narrowing that aggravates ventilation-perfusion (v q) mismatching and, can worsen existing hyperinflation. although v q inequality is the most important determinant of hypoxemia, low mixed venous oxygen tension (pvo ) is ' a contributing factor.i during exacerbations, the work of breathing increases to overcome increased airway resistance and dynamic hyperinflation. oxygen utilization by the respiratory muscles therefore is markedly increased, resulting in lower pvo . fortunately, among patients with adequate cardiac reserve, increases in cardiac output partly compensate for diminished pvoz to defend arterial oxygenation. among the mechanisms leading to hypercarbia, v / q mismatch is probably more important than hypoventilation, at least among patients who recover from their exacerbations without needing mechanical ventilation. this concept is supported by the observation that, during exacerbations, patients are often hypercarbic despite increased minute ventilation.' , ' hypoventilation may be an additional mechanism of hypercarbia if respiratory muscle fatigue and acute respiratory failure ensue. the relationshp between bacterial infection and copd exacerbations is not precisely understood. several lines of evidence, however, have established an important role for bacterial infection in many exacerbations. high titers of antibody against nontypeable h. influenzaes , , and m . ~a t a r r h a l i s~~ are found following aecopd. although bacterial colonization of the distal airways is common in stable copd, patients with exacerbations often have higher numbers of organisms.", table summarizes studies using protected specimen brushes to define the microflora of the distal airways in copd exacerbations. mons et a found positive bacterial cultures in % of outpatients with aecopd. compared with stable patients, exacerbated patients were twice as likely to have positive cultures (i.e., cfu/ml) and five times as likely to have bacterial counts greater than , cfu/ml. likewise, s. pneumoniae is more likely to be found in sputum during exacerbations than remission. fagon+' et a found evidence of bacterial infection in % of patients who required mechanical ventilation. streptococcus pneumoniae, h. influenzae, m . cafarrhalis, and enteric gram-negative organisms collectively accounted for % of the isolates. the investigators did not attempt to identify m . pneumoniae, c. pneumoniae, or respiratory viruses. interestingly, gram-negative bacteria accounted for % of isolates, and nearly half of these were h. parainfluenzae. yet, similar studies employing protected brush specimens have not detected h. parainfluenzae among patients with copd exacerbations. * moreover, smith et a p were unable to demonstrate rises in antibody against h. parainfluenzae following copd-related acute respiratory illnesses. it seems justified therefore to consider h. parainfluenzae as generally nonpathogenic. in contrast to the findings of fagon et al,'i a more comprehensive microbiologic survey of patients with severe exacerbations found a higher incidence of potential pathogens. overall, % of patients had at least one positive bacterial culture or positive serology for c. pneumoniae or respiratory viruses. all cultures were obtained within hours of admission, thereby reducing the likelihood of nosocomial infection. streptococcus pneumoniae, h. influenzae, and m . cafarrhalis accounted for % of potential pathogens. strikingly, gramnegative enteric bacteria and pseudomonas or stenotrophomonas represented % of potential this study suggests that a broader profile of potential pathogens may be present among patients with copd with severe exacerbations. although these findings should be confirmed in a larger study, the choice of empiric antibiotics for patients with aecopd should be based in part on the degree of exacerbation severity, and broaderspectrum initial coverage may be warranted for patients with aecopd who present with respiratory failure and require mechanical ventilation. the source of bacterial infection during a copd exacerbation may be endogenous or exogenous. in a small group of patients followed for years, exacerbations coincided with reinfection by strains of h. influenzae having either the same (i.e., endogenous) or different (i.e., exogenous) dna fingerprint. strains of h. influenzae were shown to persist for several months and antibiotic treatment was not effective in eradicating the ba~teria. ~ estimates of the proportion of copd exacerbations associated with viral infection range from % to %. this large discrepancy is because of significant differences in study design. several studies lacked adequate control by failing to record the frequency of viral infection during exacerbation-free periods.@, others, such as those by sommerville and stenhouse,l , attempted to detect only selected pathogens. variability in the definition of an exacerbation is another factor that may affect the percentage of exacerbations caused by viral illness. finally, different serologic and isolation techniques account for some of the variety in study re~ults. ~ the three most rigorous studies are summarized in table . * * the proportion of exacerbations attributed to viral (or mycoplasma) illness ranges from % to %. influenza, parainfluenza, and coronavirus were the most frequent pathogens to be significantly associated with exacerbations. more recently, goh et a p performed a prospective etiologic study of inpatients with aecopd. they collected paired sera for influenza a, b, and parainfluenza viruses as well as legionella, mycoplasma, and chlamydia. positive serology was found in patients ( %), of whom patients ( %) had viral infections. the most common organism was influenza a, with patients demonstrating positive serology ( %). five patients had positive serology for legionella, whereas no evidence was found for infections caused by mycoplasma or chlamydia. gump et a observed patients every weeks for years and documented exacerbations. they derived a striking correlation of infection with exacerbations by interpreting their data in a time-weighted analysis. they found that the incidence of infection was l"/o per patient week of exacerbation but only . % ver patient week in remission. in their -year aniiysis, buscho et alz found that % of exacerbations were associated with viral infection. this rate was twice that of viral infections during remission detected as an asymptomatic fourfold rise in antiviral antibody titers. in the largest study, smith et ap followed patients over years and analyzed more than acute respiratory illnesses. they associated nonbacterial infections with approximately % of acute respiratory illnesses but only % of illnessfree periods. in contrast with the work by buscho and gump, smith et noted a high rate of rhinoviral infection. uncontrolled studies by mcnamara and eadie ,, also reported rhinoviral infections to be associated with copd exacerbations in % and % of cases, respectively. common colds may have a deleterious effect upon lung functionz and patients with copd are more likely to develop increased cough and lower respiratory tract symptoms during rhinoviral infections than healthy smith et apz performed a -year observational study of patients to assess potential interactions between viral, mycoplasmal, and bacterial infections in patients with copd. they calculated the ratio of number of observed exacerbations to number of expected viral or bacterial associations. haemophilus influenzae and s. pneumoniae were isolated more than twice as often as expected following influenza virus infection. marked rises in titers of antibodies against h. influenzae were associated with preceding viral or mycoplasma infections, suggesting that viral infection promotes increased invasiveness of h. influenzae and subsequent infection. there are no other rigorously performed clinical studies of the interaction between viral and bacterial infections in aecopd. although the concept that viruses promote secondary bacterial infection seems biologically plausible and is supported by animal research, it remains unknown how often bacterial infection in aecopd follows an inciting viral infection. suspended particulate matter less than pm in diameter @'mi ") is produced by vehicle exhaust and many industrial processes. several epidemiologic studies*, have associated elevated pm,, levels with a wide range of respiratory outcomes, including reduced pulmonary function and increased chronic respiratory symptoms, rates of hospitalization, and mortality. similar associations exist for other pollutants, notably sulfur dioxide (so,) and nitrogen dioxide. a -year study in bar-celona reported that small increases of so, and airborne particles produced adjusted increases of % in emergency room admissions for copd in winter and % in summer. similar rates of excess hospitalizations for copd have been reported from sydney, australia ( %); detroit, michigan ( %); and birmingham, alabama ( %).*', ' although small, these effects represent a significant public health concern, particularly because they are demonstrable at pollution levels below current air-quality standards. in summary, the foregoing studies imply that bacterial pathogens can be identified in approximately half of copd exacerbations. viral pathogens are identifiable in about % of such episodes. poor air quality may account for slightly more than % of episodes of aecopd. in many copd exacerbations, no obvious pathogen or precipitating cause is found. it is not known how frequently other potential factors, such as medication noncompliance or coincidental events such as pulmonary embolism and myocardial infarction, play an inciting role in aecopd. indeed, it is often difficult to distinguish clinically between exacerbations with and without an infectious cause. this distinction is discussed subsequently in the section on antibiotic therapy. smoking cessation is the most important intervention in the management of patients with copd. the landmark lung health study confirmed that smoking cessation greatly reduces the rate of fevl decline.'" the benefit of smoking cessation is seen even in patients over the age of years. chronic sputum production often clears within weeks of stopping although nicotine replacement therapy is an effective approach to smoking cessation, counseling by a physician has been shown to be the most potent inter-ver~tion.'~~ each year, influenza and its complications are responsible for hundreds of thousands of excess hospitalizations, tens of thousands of excess deaths, and billions of dollars in health care c o s~s .~~,~~ those with chronic lung disease are at especially high risk for the consequences of influenza. despite recommendations for annual influenza vaccination, recent studies have documented inadequate vaccination rates in this risk group. , among elderly persons, including those with chronic lung disease, nichol et alb overwhelmingly demonstrated the efficacy and cost effectiveness of influenza vaccination. in a serial cohort study of more than , patients,* vaccination was associated with a % to % reduction in the rate of hospitalization for all acute and chronic respiratory conditions. another study by the same authorsa found that influenza vaccination was associated with a % reduction in the risk for death from any cause (odds ratio [or] = . ; % confidence interval [ci] = . - . ). a recent metaanalysis of cohort studies concluded that the estimates of vaccine efficacy for preventing respiratory illness, hospitalization, and death were %, % and %, respe~tively.'~~ these data clearly affirm that influenza vaccination is an indispensable part of the care of all elderly persons, especially those with copd. the value of pneumococcal vaccination for elderly patients with copd has been controversial. two randomized controlled trials evaluating the vaccine's efficacy among patients with copd were unable to show statistically significant protective benefit. , a recent meta-analysis concluded that the vaccine provides partial protection against bacteremic pneumococcal pneumonia but not against other important outcomes, including bronchitis or mortality caused by pneumococcal infection. this protective benefit was seen only in low-risk groups and not among those with copd or other highrisk patients. nevertheless, pneumococcal vaccination continues to be strongly recommended for patients with copd because it is safe and has been found to provide significant benefit for patients in case-control and indirect cohort studiesz , , ln as well as in a more recent randomized populationbased several additional novel strategies for reducing acute exacerbations of copd are under investigation. for example, om- bv is an oral immunostimulating agent containing lyophylized fractions of the eight most common respiratory pathogens. its use was associated with a % reduction in the incidence of acute exacerbations of chronic bronchitis and a % decrease in antibiotic use among elderly institutionalized patients in one trial, and the same frequency of exacerbations but less than half as many days in hospital as those given placebo in another?,, n there was a trend toward fewer hospitalizations for respiratory reasons among those receiving the immunostimulating drug. although not available in north america, om- bv has been used for many years in europe. further trials are required to properly define its role. another approach has been the subcutaneous administration of hyaluronic acid (ha), a glycosaminoglycan with neutrophil-regulating functions, to patients with chronic bronchitis. fewer acute exacerbations of bronchtis and reduced antibiotic use were noted among ha-treated patients in a placebo-controlled crossover study. other investigators found that continous administration of carbocysteine lysine salt monohydrate during winter months was effective in preventing ae-copd and reducing antibiotic consumption in patients with chronic b r~n c h t i s .~ despite these recent intriguing data suggesting that immunomodulatory agents may attenuate the development of aecopd, randomized, controlled trials are needed to clarify their potential roles in the routine management of patients with copd. the following sections provide an overview of the merits (or lack thereof) of common therapeutic interventions for aecopd. controlled oxygen (o,), bronchodilators, antibiotics, corticosteroids, noninvasive ventilation, nutritional support, and chest physiotherapy are discussed. when available, evidence from randomized controlled trials is presented. hypoxemia is the most immediate threat to life for patients with aecopd. hypercapnia is a wellrecognized consequence of , therapy. in the past, the risk of hypoventilation or even apnea resulting from , administration has been vastly overestimated, and the notion that , commonly induces clinically important hypercarbia and acidosis has been discredited.'" , , lo the traditional concept is that correction of hypoxemia with supplemental oz removes the hypoxic drive to breathe and leads to a fall in minute ventilation and subsequent carbon dioxide (co,) retention. aubier et all found that although administration of supplemental oz does reduce minute ventilation and increase arterial partial pressure of carbon dioxide (paco,), mouth occlusion pressure (an indicator of central respiratory drive) was significantly higher during acute exacerbations than during stable conditions. the drive to breathe therefore remained very high in spite of oxygen treatment. in a later study by the same authors,i patients with copd and acute respiratory failure received % , for minutes to abolish hypoxic drive. minute ventilation fell by only % and could not account for the entire increase in paco,. the authors concluded that the rise in c was caused by increased vd/vt) (i.e., increased deadspace ventilation) and that the primary mechanism of oz-induced hypercarbia is v / q mismatching, perhaps through the loss of hypoxic vasoconstriction. more recent work by dunn et a and stradling has challenged aubier's conclusions and defended the traditional concept that hypoventilation, rather than v / q mismatching, is to blame for ,-induced hypercarbia. one further mechanism that appears to contribute, albeit to a minor extent, is the haldane effect, whereby co, is displaced from hemoglobin by , causing a rise in p~c o , .~~~ nevertheless, the risks for acute hypoxemia far outweigh the risks for severe hypercarbia. as such, supplemental , administration is recommended for hypoxemic patients with aecopd. oxygen initially should be given to any hypoxemic patient with aecopd by nasal cannulae or venturi mask. if nasal cannulae are used, flow rates of to l/minute generally suffice. the inspired concentration of oxygen (fio,) usually increases by % to % for each increase of l / minute in flow but varies according to the patient's own inspiratory flow rate. venturi masks are more precise and should initially be set to deliver a fio, of % to %. on average, the pao, increases by mm hg when the fio, is increased from room air to %, and by mm hg when the fio, is increased to %. the target pao, is between and mm hg, corresponding to the pao, at which there is near-complete saturation of hemoglobin with ,. rarely, overzealous , administration produces progressive hypercapnia and respiratory acidosis. o, , for this reason, response to , must be assessed according to arterial blood gas and ph measurements. these should be obtained at baseline and within minutes of starting or changing the , concentration. if pao, remains intractably low or the ph drops as a result of increasing paco, alternate strategies to improve hypoxemia and respiratory acidosis must be devised. these include maximizing bronchodilation and the use of assisted ventilation. the role of bronchodilators in the management of stable copd is discussed in the article by ferguson on pharmacologic therapy for copd. bronchodilator agents, specifically p,-agonists and ipratropium bromide (ib), also play a central role in the management of patients with aecopd, with and without respiratory failure. these agents are generally given by inhalation to reduce side-effects and, in the acute setting, nebulizers have been traditionally preferred over metered-dose inhalers (mdis) for ease of drug administration. , * although there are few data to support the choice of either p,-agonists or ib as first-line therapy for acute exacerbations, p,-agonists are usually given as the first step, perhaps because of the longer time to peak effect for ib. , when given in recommended doses (two puffs), ib generally produces greater bronchodilation than p,-agoni~ts.~~, ipratropium bromide and p,-agonists are often used together in the acute setting, despite a lack of evidence from randomized-controlled trials that they are more efficacious in tandem than either agent alone in that ~e t t i n g .~~,~~,~~ in a doubleblind, randomized study involving patients with aecopd, the effects of . mg of ib, . mg of fenoterol, or a combination of the two agents were compared. all three regimens resulted in improved spirometric function at and minutes post-treatment, but combination therapy was no better than either agent alone. similarly, odriscoll et alas compared nebulized salbutamol ( mg) with and without ib ( . mg) in patients with aecopd. one hour following treatment, peak expiratory flow rates were not significantly different between regimens. others have examined clinical, rather than spirometric, outcomes following combined therapy in aecopd. , patients randomly assigned to a combination of isoetharine and ib were discharged from the emergency department an average of minutes sooner than those who received only isoetharine. the authors attributed this time saving to approximately five puffs of ib. interestingly, mean discharge fev, was not different between the two groups. o because these studies followed patients for only to minutes, moayyedi et a recently attempted to capture longer-term benefits of combination therapy. comparing nebulized treatments of salbutamol with and without ib among inpatients with aecopd, they found no difference in duration of stay, subjective breathlessness, or spirometric values over a -day assessment period. considerable effort has been made to establish the most effective method for delivering bronchodilator drugs to patients with acute airflow obstruction. delivery methods include mdis with or without a spacer device, nebulizers (hand-held or attached to a face mask), and dry powder inhalers. a recent systematic review of randomized studies comparing mdis and nebulizers for administration of p,-agonists in acute exacerbations of asthma and copd found the two methods to be equivalent. a reasonable approach advocated by several workers is to begin with nebulized treatments among patients who are too dyspneic to use an mdi and spacer device ~o r r e c t l y .~~,~~~ as early as is feasible patients can then be switched to mdis, which can result in considerable cost savings.m, lzo theophylline theophylline has been used for decades to ameliorate symptoms in patients with airflow obstruction.lz the use of theophylline in the management of stable copd is discussed in the article by ferguson in this issue. theophylline has now been relegated to having a minor role in the acute setting because of the development of safer and more potent bronchodilators?l, the lack of convincing, well-designed trials showing its efficacy has further contributed to the decline in its use. o, , there are only two published studies that relate specifically to the role of theophylline in the treatment of copd exacerbations. the first, by rice et al, was a small, yet rigorously controlled trial in which patients were randomized to aminophylline infusion or placebo during hospitalization for ae-copd. the drug conferred no incremental benefit over standard care in either subjective (dyspnea scores) or objective (spirometry) outcome measures. gastrointestinal side effects were more common in the aminophylline group. an emergency department-based study randomized patients with acute bronchospasm to receive either aminophylline or p a~ebo.l~~ the trial included patients with asthma and copd but failed to report the number of each. unexpectedly, there was a threefold decrease in the hospital admission rate for patients treated with aminophylline ( p = . ). the authors argued that aminophylline should be considered in selected patients with acute exacerbations of copd and asthma because reduced hospitalizations would decrease costs. although their study illustrates a potentially important clinical benefit of theophylline, a cautious approach is necessary. the effect of theophylline on admission rates was not the primary outcome variable and the reduction in admission rates did not quite reach statistical significance after adjusting for multiple comparisons. even though the magnitude of the clinical benefit was large, theophylline produced no objective improvement in pulmonary function as measured by spirometry. despite these reservations, similar reports of clinical benefit in the absence of statistically significant spirometric improvement have been found in studies of corticosteroids in acute asthma and bronchodilator therapy in acute copd.ll bacterial infections' contribution to exacerbations of copd has been inferred from studies demonstrating clinical benefit as a result of antibiotic therapy. antibiotics have been employed for prophylaxis and acute treatment of aecopd. in the s and s, attention was given to preventing exacerbations with antibiotics. murphy and sethim reviewed nine prospective, placebocontrolled trials of antibiotic prophylaxis. of these, five failed to show any reduction in the frequency of exacerbations, although two demonstrated significantly less time lost from work among patients receiving antibiotics. in contrast, compared with placebo, antibiotic prophylaxis significantly reduced the frequency of exacerbations in four studies. in these investigations, prophylaxis seemed to benefit patients suffering the largest annual number of exacerbations. some authorities therefore have recently suggested that antibiotic prophylaxis may be appropriate for individuals prone to frequent exacerbation^,'^ although this practice is not recommended as part of the regular care of all patients with copd. the prescription of antibiotics to facilitate early recovery in aecopd has become routine despite unresolved questions about their true benefit.'" , , nicotra et ap randomized inpatients with aecopd to either tetracycline or placebo for week. at days, there was no difference between groups in terms of oxygenation or lung function. in a similar, but larger, study of outpatients with uncomplicated aecopd, jorgensedl also could not demonstrate a clinically important advantage of amoxicillin over placebo. these null trials notwithstanding, the highestquality clinical study to date, by anthonisen et al," concluded that antibiotics improved outcomes. they randomized outpatients to receive either placebo or broad-spectrum antibiotic (amoxicillin, trimethoprim-sulfamethoxazole, or doxycycline) during copd exacerbations. exacerbations were classified according to severity. type (the most severe) was defined as an increase in dyspnea, sputum volume, and sputum purulence. type involved the presence of only two of the three symptoms, and type was defined as the presence of one of the three symptoms in addition to one other finding (sore throat, rhinorrhea, fever, increased wheeze, or increased cough). compared with placebo, antibiotics shortened the duration of exacerbations by about days and accelerated recovery of peak expiratory flow rate ( p < . for both). treatment success, defined as resolution of symptoms within days, occurred in % of the placebo group and . % of patients receiving active treatment (p < . ). significantly, among patients presenting with type l exacerbations, clinical deterioration was more than twice as common with placebo as with antibiotic. a clinician therefore would need to treat roughly eight exacerbations with antibiotics to achieve one treatment success beyond chance, or two in order to avoid a single deterioration. the authors concluded that avoidance of deleterious outcomes is the strongest reason to offer antibiotics to patients with ae-copd. furthermore, they stated that antibiotics are clearly indicated in type exacerbations, of no benefit in type exacerbations, and probably justifiable for patients with type presentations." similar findings were reported in another largescale, randomized trial comparing amoxicillin / clavulanate to placebo? , saint and associate^'^^ systematically reviewed the clinical efficacy of antibiotics for aecopd. they identified nine randomized, placebo-controlled trials of antibiotics in copd exacerbations in which the patients were followed for at least days. because no outcome measure was common to all nine studies, the authors derived an overall effect size to quantify the efficacy of antibiotics and concluded that a small but statistically significant improvement could be expected among patients receiving antibiotics. from the six trials that reported peak expiratory flow rates, an overall improvement of . liters per minute favoring the antibiotic group was noted. although small, such an effect may be clinically important for patients with severely compromised baseline lung function by preventing respiratory failure and hospital or intensive care unit (icu) admission. l to reduce the risk for treatment failure, antibiotics should be selected according to pertinent clinical data and the potential for antimicrobial resistance. several schemes have been proposed to stratify the patient's risk and select the most appropriate therapy.'" , , the simplest, and most recent, classification system is presented in table . g r o s~m a n~~ has classified acute exacerbations into four groups. group patients have acute simple bronclutis, likely of viral origin, for which anti- antibiotic therapy is directed at l ? aeruginosa and other commonly drug-resistant gram-negative bacteria (see table ). as noted, approaches to antibiotic therapy based upon a rational appraisal of patient risk factors and likely pathogens reduce the risk for treatment failure and avoid unnecessary medical and economic expense. there are outcome data to suggest this approach leads to improved clinical outcomes, with reduced overall a retrospective study by destache and colleagues demonstrated that, compared with the usual first-line antibiotics in the treatment of acute exacerbations of chronic bronchitis, the use of newer antibiotics reduced both the hospitalization rate and failure rate. although the acquisition cost of newer antibiotics (cephalosporins, macrolides and fluoroquinolones) was higher, the overall costs of the treated patients given these drugs were lower. in particular, the group receiving amoxicillin/ clavulanate, azithromycin, or ciprofloxacin had the lowest hospitalization rate, clinical failure rate, and costs compared with cephalosporins or first-line therapy. the hypothesis that aggressive antibiotic therapy should be offered to high-risk patients was tested in a recent, prospective, health economic study.= patients with at least three treated exacerbations of chronic bronchitis in the past year were randomized to receive either ciprofloxacin or any nonquinolone-based therapy for their next acute exacerbation. clinical endpoints (days of illness, hospitalizations, time to next exacerbation) were blended with quality-of-life measurements (nottingham health profile, st. george's hospital respiratory questionnaire, health utility index), and total respiratory costs from a societal perspective. although the overall results indicated no advantage for either treatment arm, in patients with risk factors (severe underlying lung disease, more than four exacerbations per year, duration of bronchitis greater than years, elderly, significant comorbid illness) the use of ciprofloxacin led to improved clinical outcome, higher quality of life, and fewer costs. the results of this study would suggest that aggressive antimicrobial therapy directed especially toward resistant organisms in high-risk patients is a more effective strategy than no therapy or therapy with older antimicrobials that would not be effective against the usual target organisms, particularly p-lactamase-producing h. influenzae. further studies are needed to clarify the optimal antibiotic treatment regimens for subgroups of patients with aecopd. randomized, controlled trials of the efficacy of corticosteroids for acute exacerbations of copd are summarized in table . their role in outpatient exacerbations has been evaluated in only one small study.lz compared with placebo, oral prednisone ( mg tapered to mg over days) significantly improved airflow and oxygenation and resulted in fewer treatment failures. fev, improved on average by only ml per day among patients receiving prednis ne. ~ these findings support earlier retrospective data that suggest that, among patients with aecopd presenting to an emergency department (ed), the incidence of revisit to the ed within hours is significantly reduced if corticosteroids are prescribed. corticosteroids are often given initially by ed physicians and several trials have examined this practice. z, emerman et a studied the effect of a single dose of methylprednisolone ( mg intravenously [iv]) upon pulmonary function and hospitalization rates for patients in the ed with copd exacerbations. they failed to show any improvement in spirometry or decrease in the rate of hospitalization. patients were treated for approximately . hours and the single steroid dose and short period of observation, however, have been postulated to account for the apparent lack of effi-cacy of steroids in this study. more recently, bullard et al" demonstrated a beneficial effect of steroids upon flow rates as early as hours after initiation of treatment. in , alberp provided the initial justification for the routine use of systemic steroids in the care of hospitalized patients with copd exacerbations. forty-four patients with copd and acute respiratory insufficiency were randomized to placebo or methylprednisolone . mg / kg intravenously every hours for days. those treated with steroids were significantly more likely to achieve a % or greater increase in fev, over their baseline. this effect was observed by hours following the start of treatment and persisted for hours. corticosteroids improved postbronchodilator lung function more than placebo but had minimal effect upon total symptoms in another small trial in which hospitalized patients were randomized to receive placebo or mg of oral prednisolone for days.% although the studies described have established that corticosteroids significantly increase fev, over the short term, no study was explicitly designed to capture longer-term endpoints or the adverse consequences associated with steroid therapy!" lo rostomlo studied hospitalized patients with ae-copd given placebo or methylprednisolone ( mg tapered to mg over month) and followed for month after discharge. mean fev, and fvc values were no different between the treatment groups at the end of the study. more recently, niewoehner et alas published the important systemic corticosteroids in chronic obstructive pulmonary disease exacerbations trial. they performed a three-way randomization whereby patients received an -week course of glucocorticoids, received a -week course, and re- ceived placebo. steroids resulted in faster recovery of fev, and shortened hospital stay by day (p < . ). at both and days, steroid therapy reduced treatment failures (defined as death from any cause, need for intubation, readmission, or intensification of drug therapy) by approximately %. there was no difference between and weeks of treatment with respect to spirometry or treatment failure rates, however. the dose of methylprednisolone was high ( mg every hours for days) and resulted in significantly more hyperglycemia and, possibly, increased secondary infection rates.' in summary, the evidence from randomized, controlled trials supports the conclusion that among patients with acute exacerbations, oral or intravenous corticosteroids significantly increase the fev, for up to hours and likely reduce the risk for treatment failure. there is no proved benefit for treatment longer than weeks. hyperglycemia is the most common short-term complication of steroid treatment. as further studies become available, it will be possible to better understand the risk-benefit ratio for corticosteroids and, through meta-analysis, to better define the optimum dose and duration of therapy. it is also important to investigate the long-term risk for adverse effects of intermittent corticosteroids in patients who require them for recurrent exacerbations over many years time. noninvasive positive-pressure ventilation (nppv) is arguably the most significant recent advance in the care of patients with copd with acute respiratory failure. it avoids the complications of endotracheal intubation and preserves airway defense mechanisms while allowing patients to eat, speak, and expectorate secretions. acute respira-tory failure in copd is often characterized by a vicious circle wherein the respiratory muscles must meet ever-increasing ventilatory demands under conditions of worsening hypoxemia, hypercapnia, and acidosis. when the increased metabolic requirements of the respiratory muscles cannot be matched by a commensurate rise in the cardiac output, further acidosis and muscle fatigue ensue. by allowing the muscles to rest, nppv interrupts this process, thereby preventing respiratory arrest and death.n table summarizes the randomized, controlled trials of nppv in aecopd. bott et all randomized patients with copd and hypoxemic-hypercarbic respiratory failure to either conventional treatment or volume-cycled nasal nppv. patients in both groups had similar pretreatment blood gas and spirometric abnormalities. at hour, there was a significant rise in ph and drop in paco in the nppv group compared with conventional treatment. nppv also resulted in significantly less breathlessness by day . most importantly, however, intention-to-treat analysis revealed a trend toward lower -day mortality in the nppv group ( / versus / , relative risk = . , % ci . - . , p = ns). this effect became significant after excluding the four patients randomized to nppv who did not receive it (two were confused, one was unable to breathe through his nose, one had all active treatment withdrawn). none of the patients randomized to nppv required intubation and no serious complications of nppv were reported. the study has been criticized for the lack of standardized treatment in both groups and for the unusually high mortality in the control group. kramer et af investigated the impact of nppv on need for intubation among patients with severe hypercarbic respiratory failure, most with copd exacerbations. sixteen patients ( with copd) were randomized to pressure-limited nasal nppv in addition to standard care and patients ( with copd) received standard care alone. clear a priori indications for intubation were given. significantly, only five patients ( %) in the nppv group required intubation, compared with ( %) in the standard therapy arm. furthermore, maximal inspiratory pressures increased significantly in the nppv arm over hours, indicating a rapid reversal of diaphragmatic fatigue. in contrast to work by bott,is however, there were no significant differences in pam between the treatment groups at any time over the first hours. the study was underpowered to detect differences in mortality. a more recent european multicenter trialz randomized patients to standard therapy or pressure-limited nppv by face mask. all patients required admission to an intensive care unit and were followed until death or hospital discharge. noninvasive ventilation markedly reduced the need for intubation (controls % versus nppv %). compared with standard care, nppv also significantly reduced mortality ( % versus %), complication rates ( % versus %), and mean duration of hospital stay ( days versus days) (all p < . ). more recently, celikel et a compared pressurelimited nppv by face mask with usual care among patients with moderately severe hypercarbic acute respiratory failure and copd. noninvasive positive-pressure ventilation resulted in significantly fewer treatment failures, defined as need for intubation in the nppv group and need for nppv or intubation in the control group. hospital stays were significantly shorter in the nppv group. in contrast, barb et al,i however, were unable to demonstrate any statistically significant benefit of nasal nppv over conventional treatment in terms of duration of hospitalization, dyspnea scores, arterial blood gas measurements, or maximal inspiratory pressures. patients in this trial, however, were clearly not as ill as those in other studies. indeed, no patient in either group required intubation. randomized, controlled trials of nppv for the treatment of aecopd with hypercarbic respiratory failure recently were reviewed systematially.^^ the pooled odds ratio for intubation following nppv is . ( % ci, . - . ). more importantly, however, the trials that included mortality as an outcome collectively demonstrate a strong survival benefit for nppv. * , the pooled odds ratio for death is . ( % ci, . - . ). therefore, at worst, nppv increases the patient's chance of surviving by nearly %; at best, the chance of survival is % better than that of a similar patient not receiving nppv. improvements in ph and pacoz within hour of initiating nppv and good level of consciousness at the beginning of nppv are associated with successful responses to nppv in patients with aecopd and respiratory acido~is.~ malnutrition is common among patients with copd and increases the morbidity and mortality associated with the disease. the veterans administration cooperative study of pulmonary function showed that patients with fevl less than or equal to . l weighed less than % of their ideal body weight (ibw), compared with near normal body weight in less severely impaired patients. in another study, % of patients with emphysema were found to weigh less than % of their ibw. furthermore, reported that more than % of hospitalized patients with copd had evidence of weight loss. pingletongl found that, among ventilated patients, mortality was significantly higher in those who were poorly nourished than in those with better nutritional status. poorly nourished patients also had a significantly higher frequency of hypercapnia. the principal effects of malnutrition upon the respiratory system are thought to be worsened respiratory muscle function, impairment of ventilatory drive, and immune dysfunction. malnutrition impairs muscle function by reducing the availability of energy substrates such as glycogen and phosphate and by altering the structure of muscle fibers. when combined with intercurrent airway infection and the mechanical disadvantage of the diaphragm in copd, malnutrition may have a profound effect on respiratory muscle mechanics. experimental evidence for blunted hypoxic drive in response to semistarvation suggests another mechanism by which patients with copd may be predisposed to respiratory failure. , no randomized, controlled trial has demonstrated reduced morbidity and mortality as a result of nutritional support during acute respiratory failure. nevertheless, clinicians should be able to identify malnourished patients and understand the goals of nutritional therapy. particular attention should be paid to patients with hypercatabolic states that increase the risk for protein-calorie malnutrition. the subjective global assessment and the harris-benedict equation are two valid clinical instruments for assessing malnutrition and planning nutritional therapy. they are reviewed elsewhere?" in general, the goals of nutritional supplementation among patients with acute respiratory failure consist of maintaining body weight and preventing protein breakdown. the effects of malnutrition and nutritional supplementation in patients with copd are discussed in more detail in the article by schols and wouters in this issue. the value of chest physiotherapy (postural drainage with or without chest percussion) in aecopd has not been demonstrated. studies of patients with aecopd have failed to demonstrate a beneficial effect of chest physiotherapy upon sputum volume, gas exchange, or spirometry. one trialz documented a transient but significant decrease in fev, as a result of bronchoconstriction following chest percussion and vibration. some evidence suggests that patients with larger volumes of airway secretions (> ml/d), particularly those with bronchiectasis, may benefit. in some guidelines, therefore, chest physiotherapy has been advocated in this ~ituation.~ in general, however, it is not recommended in the routine management of aecopd. ° although outcome data are important, caution is required in their interpretation. because data are generated by observing large numbers of patients, typically in tertiary referral centers, the pertinence of these data to individual patients may be limited, especially outside of major centers where most copd exacerbations are studies of prognosis in patients with copd and acute respiratory failure performed during previous decades are less relevant by today's standards. current outcomes appear to be better than those of the past, in part because of the widespread use of controlled oz therapy, corticosteroids and ib, availability of better p,-agonists, reduced use of methylxanthines, and increased use of noninvasive ventilatory support.j indeed, there is evidence to support a trend toward improved survival for hypercapnic respiratory failure over the past years. the mortality rates in studies of survival of acute respiratory failure in copd conducted from to ranged from % to %, with an overall mortality of %. for similar studies between and , the range is % to %, with an overall mortality the most recent and comprehensive evaluation of outcomes following aecopd was published by connors et a as a component of the landmark study to understand prognoses for outcomes and risks of treatment (support) they prospectively studied more than patients admitted to five us tertiary care hospitals with severe hypercarbic copd exacerbations (initial paco,~ mm hg). baseline fev, was not available for most patients. half the patients required intensive care unit admission and % required mechanical ventilation. hospital mortality was %. more striking, however, was the finding that following discharge, one third of the patients died in within months and one half within years. not surprisingly, patients who survived hospitalization had a substantial risk of discharge to a facility other than their home ( %) and of readmission to acute care over the ensuing months ( %). higher acute physiology score (acute physiology and chronic health evaluation; apache ), older age, and poor functional status prior to admission independently increased risk of death. improved survival was of %. predicted by greater bmi and albumin level, higher paoz / fio, and, surprisingly, the presence of cor pulmonale and congestive heart failure as the cause of the exacerbation. the latter findings may be explained by the good response of these two disorders to acute therapy. also supports the finding that host factors are principal determinants of outcomes of aecopd. in their retrospective analysis of exacerbations in patients with copd, severity of airflow obstruction, use of home , frequency of exacerbation, history of previous pneumonia or sinusitis, and use of maintenance corticosteroids each were independently associated with treatment failure. surprisingly, age, choice of antibiotics, and presence of comorbid conditions did not affect the treatment outcome in that study. several investigators z , l oo, iw have evaluated the prognosis of patients with copd who require icu admission for acute exacerbations. the results have been somewhat contradictory. kaelin et a , z for example, using several easily obtainable indices, were unable to discriminate between patients surviving more or less than months following intubation. in their analysis of consecutive acute copd exacerbations, neither age nor spirometric, blood gas, or nutritional indices predicted survival. in contrast, menzies et a * reported that, among their patients, higher baseline fev, and serum albumin were significantly associated with improved -year survival following mechanical ventilation. these contradictory findings are especially curious given that both studies had similar inclusion and exclusion criteria and periods of observation. moreover, their populations both had a mean percent-predicted fev, of % and nearly identical baseline values for serum albumin. more recently, rieves et alloo tried to identify clinically useful variables that predict successful weaning from mechanical ventilation and shortterm survival in patients with copd with acute respiratory failure. they observed episodes of acute respiratory failure in and patients with baseline fev, of greater and less than l respectively. only % of the cohort with severe copd survived weaning and spontaneous breathing for hours. furthermore, in the same group, -year survival was only %. absence of infiltrates on chest radiograph was the most influential predictor of survival in patients with severe copd. pneumonia accounted for most of the infiltrates that were seen in this group. baseline fev, obtained during a period of clinical stability prior to the episode of acute respiratory failure was available for all patients. the extent of baseline obstruction alone was not statistically correlated with short-term survival in either group, but the combination of severe baseline obstruction and pulmonary infiltrates markedly increased the risk for death. outcomes following aecopd associated with icu admission and respiratory failure are a study by dewan and discussed further in the article by sethi and siege in this issue. seneff et allo recently refined the discussion over the relative prognostic value of different clinical variables following copd exacerbation. they analyzed admissions for acute copd exacerbation from the apache i database. hospital mortality was %. for patients aged and older, hospital and -year mortality rates were % and % respectively. their report emphasizes that individual clinical variables have different value for predicting short-and long-term survival. patient age, for example, was a statistically significant determinant of -month survival but not influential for hospital mortality after accounting for nonrespiratory organ dysfunction. similarly, the presence of hypercarbia was of no value in predicting hospital mortality but became important over the long term; -year mortality rates for patients with admission paco of less than mm hg versus greater than mm hg were % and % respectively. the most significant predictors of short and long-term mortality are development and severity of multiple organ dysfunction syndrome. respiratory dysfunction is more important over the longer term. as the authors state: "in most cases, the acute, life-threatening components of the exacerbations can be reversed and short-term death avoided by mechanical ventilation and other appropriate treatments. however, because abnormalities in respiratory physiology reflect underlying severity of lung disease, patients with greater abnormality who survive hospitalization are at greater risk of subsequent death."io chronic obstructive pulmonary disease is the only leading cause of death with a rising prevalence. the medical and economic costs arising from acute exacerbations of copd are therefore expected to increase over the coming years. although exacerbations may be initiated by multiple factors, the most common identifiable associations are with bacterial and viral infections. these are associated with approximately % to % and % to % of copd exacerbations, respectively. in addition to smoking cessation, annual influenza vaccination is the most important method for preventing exacerbations. controlled o is the most important intervention for patients with acute hypoxic respiratory failue. evidence from randomized, controlled trials justifies the use of corticosteroids, bronchodilators (but not theophylline), noninvasive positive-pressure ventilation (in selected patients), and antibiotics, particularly for severe exacerbations. antibiotics should be chosen according to the patient's risk for treatment failure and the potential for antibiotic resistance. in the acute setting, combined treatment with p-agonist and anticholinergic bronchodilators is reasonable but not supported by randomized controlled studies. physicians should identify and, when possible, correct malnutrition. chest physiotherapy has no proven role in the management of acute exacerbations. effect of non-invasive positive pressure ventilation on mortality in patients admitted with acute respiratory failure: a meta-analysis clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind population-based trial randomized, prospective trial of noninvasive positive-pressure ventilation in acute respiratory failure does chest physical therapy work? respiratory viral infections in hospital patients with chronic bronchitis bronchodilating effect and side effects of p adrenoreceptor stimulants by different modes of administration efficacy of pneumococcal vaccine in severe chronic obstructive pulmonary disease aminophylline treatment in severe acute asthma. a meta-analysis a controlled trial of methylprednisolone in the emergency treatment of acute asthma lode h respiratory tract infections: when is antibiotic therapy indicated? chronic obstructive pulmonary disease acute respiratory failure viral and mycoplasma pneumoniae infections in exacerbations of chronic lung disease noninvasive positive pressure ventilation in acute respiratory failure respir care clin north am . prevention and control of pneumoccocal disease: recommendations of the advisory committee on immunization practices (acip) the interaction of pneumolysin sufficient and deficient isogenic variants of streptococcus pneumoniae with human respiratory mucosa effect of pseudomonas aeruginosa rhamnolipids on mucociliary transport and ciliary beating nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room antibody responses to bacterial antigens during exacerbations of chronic bronchitis the veterans administration cooperative study of pulmonary function-mortality in relation to respiratory function in chronic obstructive pulmonary disease aminophylline for acute exacerbations of chronic obstructive pulmonary disease severe copd and acute respiratory failure. correlates for survival at the time of tracheal intubation bacterial adhesion to oropharyngeal and chronchial epithelial cells in smokers with chronic bronchitis and in healthy nonsmokers the long-term efficacy of methylprednisolone in the treatment of acute exacerbation of copd antibiotics in chronic obstructive pulmonary disease exacerbations. a meta-analysis acute on chronic respiratory failure-assessment and management of patients with copd in the emergent setting air pollution and hospital admissions for the elderly in detroit, michigan hospital and -year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease austrian r the protective efficacy of polyvalent pneumoccocal polysaccharide vaccine epidemiology of chronic obstructive pulmonary disease decreased duration of emergency department treatment of chronic obstructive pulmonary disease exacerba tions with the addition of ipratropium bromide to p-agonist therapy optimal pharmacologic treatment of the critically ill patient with obstructive airways disease interactions between viruses and bacteria in patients with chronic bronchitis association of viral and mycoplusma pneumoniae infections with acute respiratory illness in patients with chronic obstructive pulmonary disease haemophilus influenzae and haemophilus parainfluenzae in chronic obstructive pulmonary disease bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (copd) requiring mechanical ventilation stark je, heath re, curwen mp: infection with influenza and parainfluenza viruses in chronic bronchitis rhinovirus infection in acute exacerbations of chronic bronchitis: a controlled prospective study hypercapnia during oxygen therapy in airways obstruction: a reappraisal aerosol bronchodilator delivery methods: relative impact on pulmonary function and cost of respiratory care air pollution and emergency room admissions for chronic obstructive pulmonary disease: a -year study comparison of anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease: a -day multicentre study an alteration in the host-parasite relationship in subjects with chronic bronchitis prone to recurrent episodes of acute bronchitis the smoking cessation clinical practice guideline panel and staff: the agency for health care policy and research smoking cessation clinical practice guideline controlled trial of oral prednisone in outpatients with acute copd exacerbation predictors of mortality in chronic obstructive pulmonary disease: a -year follow-up study a review and economic evaluation of bronchodilator delivery methods in hospitalized patients tor delivery in acute airflow obstruction-a metaanalysis theophylline: recent advances in the understanding of its mode of action and uses in clinical practice subcutaneous administration of hyaluronan reduces the number of infectious exacerbations in patients with chronic bronchitis hypercapnia outcome from respiratory failure nutritional aspects of chronic obstructive pulmonary disease the biology of bacterial colonization and invasion of the respiratory mucosa the role of corticosteroids in acute exacerbations of chronic obstructive pulmonary disease (cochrane review). the cochrane library aminophylline therapy for acute bronchospastic disease in the emergency room a short-term follow-up study on ex-cigarette smokers: with special emphasis on persistent cough and weight gain key: cord- -lavcsqov authors: desforges, marc; le coupanec, alain; dubeau, philippe; bourgouin, andréanne; lajoie, louise; dubé, mathieu; talbot, pierre j. title: human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? date: - - journal: viruses doi: . /v sha: doc_id: cord_uid: lavcsqov respiratory viruses infect the human upper respiratory tract, mostly causing mild diseases. however, in vulnerable populations, such as newborns, infants, the elderly and immune-compromised individuals, these opportunistic pathogens can also affect the lower respiratory tract, causing a more severe disease (e.g., pneumonia). respiratory viruses can also exacerbate asthma and lead to various types of respiratory distress syndromes. furthermore, as they can adapt fast and cross the species barrier, some of these pathogens, like influenza a and sars-cov, have occasionally caused epidemics or pandemics, and were associated with more serious clinical diseases and even mortality. for a few decades now, data reported in the scientific literature has also demonstrated that several respiratory viruses have neuroinvasive capacities, since they can spread from the respiratory tract to the central nervous system (cns). viruses infecting human cns cells could then cause different types of encephalopathy, including encephalitis, and long-term neurological diseases. like other well-recognized neuroinvasive human viruses, respiratory viruses may damage the cns as a result of misdirected host immune responses that could be associated with autoimmunity in susceptible individuals (virus-induced neuro-immunopathology) and/or viral replication, which directly causes damage to cns cells (virus-induced neuropathology). the etiological agent of several neurological disorders remains unidentified. opportunistic human respiratory pathogens could be associated with the triggering or the exacerbation of these disorders whose etiology remains poorly understood. herein, we present a global portrait of some of the most prevalent or emerging human respiratory viruses that have been associated with possible pathogenic processes in cns infection, with a special emphasis on human coronaviruses. the central nervous system (cns), a marvel of intricate cellular and molecular interactions, maintains life and orchestrates homeostasis. unfortunately, the cns is not immune to alterations that lead to neurological disease, some resulting from acute, persistent or latent viral infections. several viruses have the ability to invade the cns, where they can infect resident cells, including the neurons [ ] . although rare, viral infections of the cns do occur [ ] . however, their incidence in clinical practice common virus, is associated with febrile illness, fever, cough and congestion [ , ] , as well as a characteristic rash and koplik's spots [ ] . in rare circumstances, significant long-term cns diseases, such as [ ] post-infectious encephalomyelitis (pie) or acute disseminated encephalomyelitis (adem), occur in children and adolescents. other examples of rare but devastating neurological disorders are measles inclusion body encephalitis (mibe), mostly observed in immune-compromised patients, and subacute sclerosing panencephalitis (sspe) that appears - years after infection [ ] . yet, with the exception of hiv, no specific virus has been constantly associated with specific human neurodegenerative disease. on the other hand, different human herpes viruses have been associated with alzheimer's disease (ad), multiple sclerosis (ms) and other types of long-term cns disorders [ ] [ ] [ ] . as accurately stated by majde [ ] , long-term neurodegenerative disorders may represent a "hit-and-run" type of pathology, since some symptoms are triggered by innate immunity associated with glial cell activation. different forms of long-term sequelae (cognitive deficits and behavior changes, decreased memory/learning, hearing loss, neuromuscular outcomes/muscular weakness) were also observed following arboviral infections [ , , [ ] [ ] [ ] . including the few examples listed above, more than one hundred infectious agents (much of them being viruses) have been described as potentially encephalitogenic and an increasing number of positive viral identifications are now made with the help of modern molecular diagnostic methods [ , , [ ] [ ] [ ] . however, even after almost two decades into the st century and despite tremendous advances in clinical microbiology, the precise cause of cns viral infections often remains unknown. indeed, even though very important technical improvements were made in the capacity to detect the etiological agent, identification is still not possible in at least half of the cases [ , ] . among all the reported cases of encephalitis and other encephalopathies and even neurodegenerative processes, respiratory viruses could represent an underestimated part of etiological agents [ ] . respiratory syncytial virus (rsv), a member of the orthopneumovirus genus [ ] , infects approximately % of infants before the age of and almost % by the age of years old [ ] , making it the most common pathogen to cause lower respiratory tract infection such as bronchiolitis and pneumonia in infants worldwide [ , ] . recent evidence also indicates that severe respiratory diseases related to rsv are also frequent in immunocompromised adult patients [ , ] and that the virus can also present neuroinvasive properties [ ] . over the last five decades, a number of clinical cases have potentially associated the virus with cns pathologies. rsv has been detected in the cerebrospinal fluid (csf) of patients (mainly infants) and was associated with convulsions, febrile seizures and different types of encephalopathy, including clinical signs of ataxia and hormonal problems [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . furthermore, rsv is now known to be able to infect sensory neurons in the lungs and to spread from the airways to the cns in mice after intranasal inoculation, and to induce long-term sequelae such as behavioral and cognitive impairments [ ] . an additional highly prevalent human respiratory pathogen with neuroinvasive and neurovirulent potential is the human metapneumovirus (hmpv). discovered at the beginning of the st century in the netherlands [ ] , it mainly causes respiratory diseases in newborns, infants and immunocompromised individuals [ ] . during the last two decades, sporadic cases of febrile seizures, encephalitis and encephalopathies (associated with epileptic symptoms) have been described. viral material was detected within the cns in some clinical cases of encephalitis/encephalopathy [ ] [ ] [ ] [ ] [ ] but, at present, no experimental data from any animal model exist that would help to understand the underlying mechanism associated with hmpv neuroinvasion and potential neurovirulence. hendra virus (hev) and nipah virus (niv) are both highly pathogenic zoonotic members of the henipavirus genus and represent important emerging viruses discovered in the late s in australia and southern asia. they are the etiological agents of acute and severe respiratory disease in humans, including pneumonia, pulmonary edema and necrotizing alveolitis with hemorrhage [ ] [ ] [ ] [ ] . although very similar at the genomic level, both viruses infect different intermediate animal reservoirs: the horse for hev and the pig for niv as a first step before crossing the barrier species towards humans [ ] . in humans, it can lead to different types of encephalitis, as several types of cns resident cells (including neurons) can be infected [ , ] . the neurological signs can include confusion, motor deficits, seizures, febrile encephalitic syndrome and a reduced level of consciousness. even neuropsychiatric sequelae have been reported but it remains unclear whether a post-infectious encephalo-myelitis occurs following infection [ ] [ ] [ ] . the use of animal models showed that the main route of entry into the cns is the olfactory nerve [ ] and that the nipah virus may persist in different regions of the brain of grivets/green monkeys [ ] , reminiscent of relapsing and late-onset encephalitis observed in humans [ ] . influenza viruses are classified in four types: a, b, c and d. all are endemic viruses with types a and b being the most prevalent and causing the flu syndrome, characterized by chills, fever, headache, sore throat and muscle pain. they are responsible for seasonal epidemics that affect to million humans, among which , to million cases are lethal each year [ , ] . associated with all major pandemics since the beginning of the th century, circulating influenza a presents the greatest threat to human health. most influenza virus infections remain confined to the upper respiratory tract, although some can lead to severe cases and may result in pneumonia, acute respiratory distress syndrome (ards) [ , ] and complications involving the cns [ ] [ ] [ ] . several studies have shown that influenza a can be associated with encephalitis, reye's syndrome, febrile seizure, guillain-barré syndrome, acute necrotizing encephalopathy and possibly acute disseminated encephalomyelitis (adem) [ ] [ ] [ ] [ ] [ ] [ ] . animal models have shown that, using either the olfactory route or vagus nerve, influenza a virus may have access to the cns and alter the hippocampus and the regulation of neurotransmission, while affecting cognition and behavior as long-term sequelae [ , , [ ] [ ] [ ] [ ] . the influenza a virus has also been associated with the risk of developing parkinson's disease (pd) [ ] and has recently been shown to exacerbate experimental autoimmune encephalomyelitis (eae), which is reminiscent of the observation that multiple sclerosis (ms) relapses have been associated with viral infections (including influenza a) of the upper respiratory tract [ ] [ ] [ ] . another source of concern when considering human respiratory pathogens associated with potential neuroinvasion and neurovirulence is the enterovirus genus, which comprises hundreds of different serotypes, including polioviruses (pv), coxsackieviruses (cv), echoviruses, human rhinoviruses (hrv) and enteroviruses (ev). this genus constitutes one of the most common cause of respiratory infections (going from common cold to more severe illnesses) and some members (pv, ev-a and -d , and to a lesser extent hrv) can invade and infect the cns, with detrimental consequences [ ] [ ] [ ] [ ] . even though extremely rare, hrv-induced meningitis and cerebellitis have been described [ ] . although ev infections are mostly asymptomatic, outbreaks of ev-a and d have also been reported in different parts of the world during the last decade. ev-a is an etiological agent of the hand-foot-mouth disease (hfmd) and has occasionally been associated with upper respiratory tract infections. ev-d causes different types of upper and lower respiratory tract infections, including severe respiratory syndromes [ ] . both serotypes have been associated with neurological disorders like acute flaccid paralysis (afp), myelitis (afm), meningitis and encephalitis [ , [ ] [ ] [ ] [ ] . last but not least, human coronaviruses (hcov) are another group of respiratory viruses that can naturally reach the cns in humans and could potentially be associated with neurological symptoms. these ubiquitous human pathogens are molecularly related in structure and mode of replication with neuroinvasive animal coronaviruses [ ] like phev (porcine hemagglutinating encephalitis virus) [ ] , fcov (feline coronavirus) [ , ] and the mhv (mouse hepatitis virus) strains of mucov [ ] , which can all reach the cns and induce different types of neuropathologies. mhv represents the best described coronavirus involved in short-and long-term neurological disorders (a model for demyelinating ms-like diseases) [ ] [ ] [ ] . taken together, all these data bring us to consider a plausible involvement of hcov in neurological diseases. the first strains of hcov were isolated in the mid- s from patients presenting an upper respiratory tract disease [ ] [ ] [ ] [ ] . before the severe acute respiratory syndrome (sars) appeared in and was associated with sars-cov [ ] [ ] [ ] , only two groups of hcov, namely hcov- e (previous group , now classified as alphacoronavirus) and hcov-oc (previous group , now classified as betacoronavirus) were known. several new coronaviruses have now been identified, including three that infect humans: alphacoronavirus hcov-nl [ ] and betacoronaviruses hcov-hku and mers-cov [ , ] . the hcov- e, -oc , -nl and -hku strains are endemic worldwide [ , , [ ] [ ] [ ] [ ] [ ] [ ] and exist in different genotypes [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in immunocompetent individuals they usually infect the upper respiratory tract, where they are mainly associated with - % of upper respiratory tract infections (uri): rhinitis, laryngitis/pharyngitis as well as otitis. being highly opportunistic pathogens [ ] , hcov can reach the lower respiratory tract and be associated with more severe illnesses, such as bronchitis, bronchiolitis, pneumonia, exacerbations of asthma and respiratory distress syndrome [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the - sars pandemic was caused by a coronavirus that emerged from bats (first reservoir) [ ] to infect palm civets (intermediary reservoir) and then humans [ ] . a total of probable cases were reported and almost % ( cases in more than countries) of these resulted in death [ ] [ ] [ ] . the clinical portrait was described as an initial flu-like syndrome, followed by a respiratory syndrome associated with cough and dyspnea, complicated with the "real" severe acute respiratory syndrome (sars) in about % of the patients [ , ]. in addition, multiple organ failure was observed in several sars-cov-infected patients [ ] . in the fall of , individuals travelling from the arabian peninsula to the united kingdom were affected by the middle-east respiratory syndrome (mers), a severe lower respiratory tract infection that resembled sars, leading also to gastrointestinal symptoms and renal failure among some patients [ ] . molecular sequencing rapidly showed that the new epidemic was caused by a new coronavirus: the mers-cov [ , , ] . mers-cov most probably originated from bats before infecting an intermediary reservoir (the dromedary camel), and also represented a zoonotic transmission to humans. phylogenetic analyses suggest that there have been multiple independent zoonotic introductions of the virus in the human population. moreover, nosocomial transmission was observed in multiple hospitals in saudi arabia [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . although possible, human-to-human mers-cov transmission appears inefficient as it requires extended close contact with an infected individual. consequently, most transmission have occurred among patients' families and healthcare workers (clusters of transmission). a more efficient human-to-human transmission was observed in south korea, during the outbreak of mers-cov [ , ] . even though it has propagated to a few thousand people and possesses a high degree of virulence, mers-cov seems mostly restricted to the arabic peninsula and is not currently considered an important pandemic threat. however, virus surveillance and better characterization are warranted, in order to be prompt to respond to any change in that matter [ , [ ] [ ] [ ] . as of october , , the world health organization (who) reported that mers-cov had spread to at least different countries, where laboratory-confirmed human cases have been identified with being fatal (https://www.who.int/emergencies/mers-cov/en/). as observed for the four circulating strains of hcov [ , ] , both sars-cov and mers-cov usually induce more [ , ] severe illnesses, and strike stronger in vulnerable populations such as the elderly, infants, immune-compromised individuals or patients with comorbidities [ , ]. over the years, like sars-and mers-cov, the four endemic hcov have also been identified as possible etiological agents for pathologies outside the respiratory tract. indeed, myocarditis, meningitis, severe diarrhea (and other gastrointestinal problems) and multi-organ failure [ , , [ ] [ ] [ ] [ ] have been reported, especially in children. recent investigations on hcov as enteric pathogens demonstrated that all hcov strains can be found in stool samples of children with acute gastroenteritis; however, no evidence of association could yet be clearly demonstrated with disease etiology [ , ] . different reports also presented a possible link between the presence of hcov within the human central nervous system (cns) and some neurological disorders among patients examined [ ] [ ] [ ] [ ] [ ] [ ] . like all viruses, hcov may enter the cns through the hematogenous or neuronal retrograde route. in the human airways, hcov infection may lead to the disruption of the nasal epithelium [ ] and, although they bud and are released mostly on the apical side of the epithelial cells, a significant amount of viruses is also released from the basolateral side [ ] . thus, although hcov infections are, most of the time, restricted to the airways, they may under poorly understood conditions pass through the epithelium barrier and reach the bloodstream or lymph and propagate towards other tissues, including the cns [ , , , ] ; this was also suggested for other respiratory viruses that can reach the human cns, namely, rsv [ , ] [ , ] . moreover, persistently-infected leukocytes [ ] may serve as a reservoir and vector for neuroinvasive hcov [ ] . therefore, neuroinvasive hcov could use the hematogenous route to penetrate into the cns. the second form of any viral spread towards the cns is through neuronal dissemination, where a given virus infects neurons in the periphery and uses the machinery of active transport within those cells in order to gain access to the cns [ , ] . although the olfactory bulb is highly efficient at controlling neuroinvasion, several viruses have been shown to enter cns through the olfactory route [ , ] . after an intranasal infection, both hcov-oc and sars-cov were shown to infect the respiratory tract in mice and to be neuroinvasive [ ] [ ] [ ] [ ] [ ] . over the years, we and others have gathered data showing that hcov-oc is naturally neuroinvasive in both mice and humans [ , , , , ] . experimental intranasal infections of susceptible mice also indicate that, once it has invaded the cns, the virus disseminated to several regions of the brain and the brainstem before it eventually reaches the spinal cord [ ] [ ] [ ] . furthermore, based on more recent work [ ] , figure illustrates the olfactory route, which is clearly the main route of neuroinvasion used by hcov-oc , as well as the early steps of subsequent neuropropagation within the cns in susceptible mice and recapitulates the suggested equivalent pathway in humans. nevertheless, our data suggest that hcov-oc may also invade the cns from the external environment through other pathways involving other cranial peripheral nerves [ ] , reminiscent of what was shown for other human respiratory viruses such as rsv and influenza virus [ ] . therefore, on the one hand, an apparently innocuous human respiratory pathogen such as the hcov may reach the cns by different routes and induce short-term illnesses, such as encephalitis. on the other hand, it may persist in resident cells of the human cns and may become a factor or co-factor of neuropathogenesis associated with long-term neurological sequelae in genetically or otherwise predisposed individuals. because of their natural neuroinvasive potential in humans and animals, a possible association between the presence of ubiquitous human coronaviruses in the triggering or exacerbation of neurological human pathologies has often been suggested over the years. it is now accepted that hcov are not always confined to the upper respiratory tract and that they can invade the cns [ , , , ] . as other viruses listed herein, hcov are neurotropic and potentially neurovirulent. even though no clear cause and effect link has ever been made with the onset of human neurological diseases, their neuropathogenicity is being increasingly recognized in humans, as several recent reports associated cases of encephalitis [ ] , acute flaccid paralysis [ ] and other neurological symptoms, including possible complications of hcov infection such as guillain-barré syndrome or adem [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the presence and persistence of hcov in human brains was proposed to cause long-term sequelae related to the development or aggravation of chronic neurological diseases [ ] [ ] [ ] [ ] [ ] [ ] [ ] . given their high prevalence [ , ] , long-term persistence and newly recognized neuropathogenesis, hcov disease burden could currently be underestimated. this suggest that better surveillance, diagnoses and deepened virus-host interactions studies are warranted in order to gather more knowledge that will make possible the development of therapeutic strategies to prevent or treat occurrences. potential short-term neuropathologies sars-cov, hcov-oc and - e are naturally neuroinvasive and neurotropic in humans and therefore potentially neurovirulent [ , , , , , ] . furthermore, animal models showed that sars-cov could invade the cns primarily through the olfactory route [ ] or even after an intra-peritoneal infection [ ] , and induce neuronal cell death [ , ] . to our knowledge, no reports on the presence of the three other coronaviruses that infect humans in the cns have been published. however, neurological symptoms have been described in patients infected by all three viruses [ , , ] . making use of our in vivo model of hcov neuropathogenesis, relying on the natural susceptibility of mice to hcov-oc -the most prevalent strain among endemic hcov [ , ] -encephalitis and transient flaccid paralysis associated with propagation towards the spinal cord and demyelination and long-term persistence in surviving mice were observed [ , [ ] [ ] [ ] [ ] [ ] [ ] ; thus, recapitulating the neurological afflictions reported in some patients infected by hcov [ , , , , [ ] [ ] [ ] ] . although we must interpret data obtained in rodents with all the caution dictated by the use of a non-human host, it is likely that the underlying mechanisms described will have relevance to the human situation or at least provide leads to investigate neurotropic hcov in humans. in susceptible mice, hcov-oc has a selective tropism for neurons in which it is able to use axonal transport as a way of neuron-to-neuron propagation [ ] . these results, together with data harvested with the use of microfluidic devices (xona microfluidic), helped to elaborate a putative model of propagation adapted from tomishima and enquist [ ] , in which infectious hcov-oc could either be assembled in the cell body or at different points along the axon using the anterograde axonal transport to propagate between neurons or from neurons to glial cells surrounding neurons in the cns (figure ). furthermore, based on previous data using different mutant recombinant viruses harboring mutation in the s protein [ , , ] and making use of a luciferase expressing recombinant hcov-oc [ ] [ ] [ ] , we are now showing that the rate and success of virus propagation towards the spinal cord, in part through the neuron-to-neuron pathway, correlates with the exacerbation of neurovirulence ( figure ). [ ] and adapted from tomishima and enquist [ ] . in this model, solid arrows represent fully assembled virus transport and dashed arrows represent subvirion assemblies [ ] . schematic representations were assembled with the motifolio neuroscience toolkit, . [ ] was injected intra-nasally (i.n.) into mice. virus spread was assessed by bioluminescence imaging (bli) with the xenogen vivo vision ivis imaging system (perkin-elmer) in infected anaesthetized mice placed in a light proof specimen chamber after intraperitoneal injection of d-luciferin. images were taken with a ccd camera mounted in a light-tight imaging chamber, using the acquisition software living image version . . (caliper-lifesciences). evaluation of associated clinical scores: (levels to : is asymptomatic; is mice with early hunched back; is mice presenting slight social isolation, weight loss and abnormal gait; is mice presenting total social isolation, ruffled fur, hunched back, weight loss and almost no movement; and is mice moribund or dead (presented elsewhere; [ ] ), indicate that only mice with a positive signal at both the level of the brain and spinal cord were evaluated to be at level to . hcov-oc structural and accessory proteins are important for infection and some clearly represent virulence factors [ , [ ] [ ] [ ] [ ] , , ] . using neuronal cell cultures and our murine model, we gathered data indicating that some of these proteins also play a significant role in viral dissemination [ , ] and now aim to exploit these promising leads to fully understand the course and determinants of propagation to and through the cns and complete the neurologic portrait of short term hcov neuropathogenesis. the presence of hcov rna in the human cns establishes the natural neuroinvasive properties of these respiratory viral agents. moreover, it also suggests that they persist in human cns [ ] as they do in human neural cells [ , ] and in the cns of mice that survive acute encephalitis. these surviving mice exhibited long-term sequelae associated with decreased activity in an open field test and a reduced hippocampus with neuronal loss in the ca and ca layers [ ] , reminiscent of what was observed after infection by the influenza a virus and rsv [ , ] and to the significant loss of synapses within the ca region after infection by wnv [ , ] . the precise and complete etiology of several long-term neurological pathologies still represent a conundrum. multiple sclerosis (ms) represents one such neurological disease for which an infectious agent or agents may play a triggering role, with viruses the most likely culprit in genetically predisposed individuals [ ] . it has been suggested that several neurotropic viruses could be involved in ms pathogenesis but that they may do so through similar direct and/or indirect mechanisms [ ] [ ] [ ] [ ] [ ] . however, although research has not yet led to a direct link to any specific virus, association of coronaviruses with ms has been suggested [ ] . even though hcov-oc and - e were detected in some control brains and in some brains coming from patients with different neurological diseases, there was a significantly higher prevalence of hcov-oc in brains of ms patients [ ] . moreover, autoreactive t cells were able to recognize both viral and myelin antigens in ms patients but not in controls during infection by hcov-oc and hcov- e [ , ] . thus, the immune response may participate in the induction or exacerbation of long-term neuropathologies such as ms in genetically or otherwise susceptible individuals. furthermore, it was shown that in recombination activation gene (rag) knock-out mice, hcov-oc -induced encephalitis could be partially mediated by the t-cell response to infection [ ] . this underlines the possibility that, like its murine counterpart mhv, long term infection of the cns by hcov [ ] may participate in the induction of demyelinating ms-like lesions. immune cell infiltration and cytokine production were observed in the mouse cns after infection by hcov-oc . this immune response was significantly increased after infection by viral variants, which harbor mutations in the viral glycoprotein (s) [ ] . these variants also induced glutamate excitotoxicity [ , ] , thus increasing damage to neurons [ ] and/or disturbing glutamate homeostasis [ ] and thereby contributing to neuronal degeneration and hind-limb paralysis and possible demyelination [ ] [ ] [ ] [ ] . the degeneration of neurons may eventually lead to death of these essential cells by directly generating a cytotoxic insult related to viral replication and/or to the induction of different regulated cell death (rcd) pathways [ ] [ ] [ ] . our results indicate that the underlying mechanisms appear to involve different cellular factors and pathways of rcd, described and reviewed elsewhere [ , ] . virus-cell interactions are always important in the regulation of cell response to infection. for hcov-oc , we clearly showed that the viral s and e proteins are important factors of neurovirulence, neuropropagation and neurodegeneration of infected cells [ ] [ ] [ ] , ] . we have also demonstrated that the he protein is important for the production of infectious hcov-oc and for efficient spreading between neuronal cells, suggesting an attenuation of the eventual spread into the cns of viruses made deficient in fully active he protein, potentially associated with a reduced neurovirulence [ , ] . coronavirus accessory proteins have been extensively studied and are now considered as important viral factors of virulence implicated in pathogenesis while counteracting innate immunity [ ] [ ] [ ] [ ] . two of these accessory proteins (ns and ns ) produced during infection by hcov-oc play a significant role in virulence and pathogenesis in the mouse cns [ ] . like for several other respiratory viruses, accumulating evidence now indicate that hcov are neuroinvasive in humans and we hypothesize that these recognized respiratory pathogens are potentially neurovirulent as well, as they could participate in short-and long-term neurological disorders either as a result of inadequate host immune responses and/or viral propagation in the cns, which directly induces damage to resident cells. with that in mind, one can envisage that, under the right circumstances, hcov may successfully reach and colonize the cns, an issue largely deserted and possibly underestimated by the scientific community that has impacted or will impact the life of several unknowing individuals. in acute encephalitis, viral replication occurs in the brain tissue itself, possibly causing destructive lesions of the nervous tissue with different outcomes depending on the infected regions [ ] . as previously mentioned, hcov may persist in the human cns as it does in mice [ , ] and potentially be associated with different types of long-term sequelae and chronic human neurological diseases. in their famous review on cns viral infection, published a few years ago, koyuncu et al. [ ] insisted that, under the right conditions, all viruses can have access to the cns. what "under the right conditions" means certainly represents a subject of debate among virologist and physicians. nevertheless, as stated in the introduction of this review, viral factors (mutations in specific virulence genes), host factors (immunodepression, age) or a mixture of both (underlining the importance of virus-host interactions), are all good candidates to refer to if one intends to find the beginning of an explanation. a fast and accurate diagnosis would certainly improve prognosis for patients with a suspected cns infection. identification of a specific virus provides relevant information on how to treat a patient; therefore, the development of modern technologies, such as high throughput sequencing (next generation sequencing) are warranted as it represents a potentially unbiased marvelous tool for rapid and robust diagnosis of unexplained encephalitis or other types of encephalopathies or neuronal manifestations, especially in the context where more traditional techniques have failed to identify the etiological agent [ , , , , , ] . therefore, although our attention is mainly on a few different viruses such as hsv, arboviruses and enteroviruses, it may now be the time to look at cns viral infection from another perspective. these viruses truly represent an important proportion of cns viral infection associated with encephalitis, meningitis, myelitis and long-term neurological disorders. nevertheless, accumulating evidence in the scientific literature strongly suggest that many other viral candidates could be underestimated in that matter. several human respiratory viruses are neuroinvasive and neurotropic, with potential neuropathological consequences in vulnerable populations. understanding the underpinning mechanisms of neuroinvasion and interaction of respiratory viruses (including hcov) with the nervous system is essential to evaluate potentially pathological short-and long-term consequences. however, viral infections related to diseases that are rare manifestations of an infection (like long term chronic neurological diseases), represent situations where koch's postulates [ ] need to be modified. a series of new criteria, adapted from sir austin bradford hill, for causation [ , ] was elaborated by giovannoni and collaborators concerning the plausible viral hypothesis in ms [ ] . these criteria certainly represent a pertinent tool to evaluate the involvement of human respiratory viruses as a factor that could influence long-term human neurological diseases. to continue the gathering of epidemiological data is justified to evaluate the clear cause and effect link between neuroinvasive respiratory viruses and short-and long-term human neurological diseases. understanding mechanisms of virus neuroinvasion and interactions with the central nervous system is essential for different reasons. first, to help better understand 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infectious agents clinical metagenomic sequencing for diagnosis of meningitis and encephalitis human virome in nasopharynx and tracheal secretion samples the aetiology of tuberculosis (translation of die aetiologie der tuberculose ( ) sequence-based identification of microbial pathogens: a reconsideration of koch's postulates the environment and disease: association or causation? infectious causes of multiple sclerosis this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license we thank jessy tremblay for his excellent work in confocal microscopy images. the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. key: cord- -ak pq authors: nan title: th european congress of intensive care medicine athens - greece, october – , abstracts date: journal: intensive care med doi: . /bf sha: doc_id: cord_uid: ak pq nan objectives: evaluate the levels of tnf, il- and pai-i in different moments of the ards and the possible relationships among them. methods: septic patients with ards were studied. also significant differences for: tnf, pai-i and il- in septic patients and both evaluations of ards with control gropup; pai- between septics and nd evaluation in ards, and between the ist and nd evaluation in ards; il- between septics and both evaluations in ards; and il-~ in both evaluations in ards patients in relation to mortality. conclusions: i) elevations of tnf, pai-i and il- , with clinical signs, are suggestive of infection; ) the persistent and progressive elevation of pai-i with any clinical criteria may suggest evolution to ards; ) due to its own kynetics, il- takes part later in the acute phase, its levels being related to the magnitude of the injury in the tissues. objectives: the influence of long-term volume therapy with different solutions on plasma levels of circulating adhesion molecules was studied. methods: according to a randomized sequence, patients with sepsis secondary to major surgery exclusively received either hydroxyethylstarch solution ( % hes, mean molecular weight (mw) , daltons, degree of substitution (ds) . ) or human albumin % (ha) for volume therapy for days. plasma levels of circulating (soluble) adhesion molecules (endothelial leukocyte adhesion melecule- [selam -i] , intercellular adhesion molecule- [sicam -i] , vascular cell adhesion molecule- [svcam -i] , and p-selectin ) were serially measured on the day of admission to the intensive care unit (='baseline ' value) and during the next days. results: selam-i, sicam-i, and svcam-i plasma levels were markedly higher than normal at baseline in both groups. in the hes-patients, selam-j decreased to normal range, whereas it further increased in the ha-group (from • to • during the study period, sicam-i and svcam-i plasma levels remained unchanged in the hes-patients, but further increased in the ha-group (from • to , • sgmp- increased significatly only in the ha-group ( • to • only pao /fio was significantly correlated to plasma levels of adhesion molecules. conclusions: sepsis is associated with markedly elevated plasma levels of adhesion molecules indicating endothelial activation or damage. by long-term volume therapy with hes, these levels remained unchanged or even decreased, whereas volume therapy with human albumin did not have any beneficial effects on soluble adhesion. central venous catheters are frequently used in the care of the critically ill patient. the incidence of catheter related sepsis varies in the literature. we investigated the occurrence of contamination and sepsis compared to results of the epic study as part of quality assesment in our intensive care unit. from january until august all removed central venous catheters were examined for microbiological culture. the patients who showed signs of sepsis were also registered. the results of the contaminated catheters and septic patients were compared with results from the epic study. during the month period , patients were hospitalized on our intensive care unit. central venous catheters were examined for microbiological culture. specimens appeared to be possitive ( %). patients showed clinical signs of sepsis. the incidence of sepsis due to contaminated central venous catheters was / ( %). the incidence of sepsis due to the presence of all central venous lines was / ( %). the microorganisms responsible for the sepsis syndrom were : stapylococcus aureus (n= ), escherichia colt (n= ), others (n= ). in the epic study the percentage for sepsis on the icu was . % for the netherlands and . % for europe. despite a high number of positive culture from removed intravascular lines, a low percentage of sepsis was seen compared to results of the epic study. we recommend routine bacteriological culture of all removed central venous lines and recommend to look at colonization and sepsis due to intravascular lines as a measure of quality control in the intensive care unit. objectives: prognostic assessment of simplified acute physiology score (saps) in granulocytopenie patients with septic shock (ss). methods: the medical records of admissions to an intensive care unit (icu) of granuloeytopenic patients with ss are reviewed. fiftytwo patients had haematological malignancies. seven patients had aplastie anaemia. patients were categorised as survivors (discharged from icl and non-survivors (died in the icu). saps index was calculated for patients daily during their stay in icu. all patients were severe granulocytopenic (total white cell count less than , ] ] ). results: five patients ( , %) were discharged from icu. fifty-four patients died in icu. non-survivors had saps on admission higher than survivors ( . + . and . + . , respectively, p< , , mann-whitney u test). no patient with a saps greater than survived. mortality among the patients with saps from to was , %o. the evolution of ss was rapid. the mean stay in icu among non-survivors was only hours. an analysis of the saps index on admission of non-survivors showed an inverse correlation with the duration of their stay in icu (r=- , , p= . ). all survivors recovered from granulocytopenia. they had normal white cell counts at the time of discharge from icu. there was inverse correlation in survivors between saps and white cell counts, when these parameters were evaluated daily. however, the saps index alone cannot be considered to be on individual predictor factor of mortality. patients who had failure of the malignancy to respond to chemotherapy and who had persistent granuloeytopenia died in icu despite saps index on admission and recovery from ss. conclusion: saps index greater than , failure of the malignancy to respond to chemotherapy and persistent leueopenia all point to a poor outcome of granulocytopenie patients with ss. introduction: antipyretics sometimes are used for fever control in febrile neutropenic patients with hematological malignancies(hm). we observed a dramatic fall of blood pressure(bp) and development of septic shock(ss) in some of the patients who received antipyretics. aim: to clarify can antipyretics provoke ss in neutropenic patients with infection. methods: retrospective review of medicat records of neutropenic(wbc < , / )patients with hm, admitted to the intensive care unit for ss, was performed. there was selected group of patients receiving antipyretics shortly before a fall of bp. results: there was a definite causal relationship between receiving antipyretics and fall of bp in from patients. all patients had fever due to infection and had normal level of bp before receiving antipyretics. hypotension developed within minutes up to , hours after administration of antipyretics. three patients received , g of metamisol and one , g ofparacetamol per os. in all cases we observed dramatic diaphoresis and the temperature fall to subnormal level ( . + . ~ accompanied'by hypotension. but in - hours the fever was coming back without blood pressure elevation. the fluid replacement was controlled by central venous or wedge pressures. there were required + ml colloid and cristalloid solutions for volume loading. in spite of fluid administration the hypotension persisted and all patients required inotropic therapy. only one patient survived and is alive now. conclusion: it seems to us that our data offer to state that antipyretics administration can initiate ss in febrile neutropeuic patients with infection. objectives: to assess the agreement between cardiac output (co) measured by odm t and by other methods used in icu patients. methods: we prospectively studied adu t patients requiring hemodynamic monitoring with a pulmonary artery catheter. an esophageal doppler monitor provided measurements of co (odm), stroke volume and flow time (ft) used as an indirect evaluation of patient's volume status. patient hemodynamic status was evaluated by a modified fast response pulmonary artery catheter (baxter health care corporation, santa ana, ca), allowing co measurements by thermodilution "d) and an evaluation of right ventricular ejection fraction and end diastolic volume (rvef and rv-edv). in the last six patients co was measured by transthoracic echocardiography (echo) and oxygen consumption was measured by a deltatrack ii metabolic monitor (datex) allowing co calculation according to the fick formula (fick). the agreement between methods measuring co and their reproducibility, were evaluated by bland and altman analysis. results: agreement between co measurements is expressed as bias (d) and % limits of agreement (l of a = d_+ sd . td-fick - . - . to . fick-echo . - . to . there was no correlation between ft and rv-edv. conclusions: although co measurements by odmil had the best reproducibility, the limits of agreement between the four methods tested were unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of co measurement in the icu. phd, a. paltzev, v.bajbikov, b.dobryakov d.sc., a.ostanin phd, o.leplifia phd, h.chernykh phd munieip. hosp. n l, n ; inst. of clin. immunol., novosibirsk, russia objectivies: efficiency of native cytokines used in the treatment of patients with severe surgical infections has been studied. methods: for two years patients were treated with cytokine mixture (ssp) obtained by arterio-venous perfusion of swine spleen and contained the following cytokines: il- , il- , il- , tnfa, ifny, gm-csf. results: ssp intravenous infusions were shown to accompany with mortality decrease from . % to . % in patients with abscessed pneumonia and lung abscesses and from % to % if disease course was complicated with sepsis. in patients with purulent peritonitis and sepsis efficiency of ssp was decreased due to endotoxieosis. thus, we used adoptive immunotherapy with mnc activated in vitro with ssp or recombinant il- . intravenous infusions of such cells resulted in transformation of a pathologic process from destructive into productive one. moreover, clinical manifestations of sepsis were controlled in % and mortality was decreased from % to %. conclusions: the use of eytokines themselves as well as cytokine-treated lymphoeytes permits to control the disease and leads to the mortnlity decrease owing to stimulation of host defence mechanisms. background: although red blood cell transfusions (rbct) are used to increase oxygen availability in septic patients, several lines of evidence suggest that rbct may actually worsen tissue hypoxia. thus, rbct may negatively influence outcome of septic patients. objectives: to determine the association of ) rbct ; ) number of units transfused; and ) mean age of the units transfused on the first day of transfusion with mortality of critically ill septic patients. methods: we prospectively identified patients who met strict criteria for sepsis syndrome (ss) seen in the icu of st. paul's hospital from to and excluded patients who died in the first days after the onset of sepsis. we recorded clinical characteristics, multiple system organ failure score, and apache ii at onset of sepsis. then, we retrospectively recorded the total number and age of rbc units transfused during the first days after onset of sepsis. overall -day mortality was %. results: the main results are shown in the table. the mortality of patients who received rbct was nearly double the mortality of those who did not receive rbct even after adjusting for severity of illness using apache ii. objectives: gastric mucosal acidosis is frequently observed in patients with sepsis. the aim of this study was to determine whether volume infusion using pentaspan| decreases abnormal gastric mucosal pco (pico ) in patients who have sepsis syndrome (ss) who have already been resuscitated using clinical endpoints. methods: we prospectively identified patients who met strict criteria for ss, had a pulmonary artery catheter and a gastric tonometer in place, and pico > mmhg. pentaspan| ( ml) was infused in rain. measurements of hemodynamics, hemoglobin, arterial lactate, blood gas analysis, and pico were performed before and repeated miff and hr after pentaspun| infusion. we calculated the pico -arterial pco' difference (pico -paco ) and phi (using henderson-hasselbach equation). anova was used to assess statistical significance. results: all patients werereceiving adrenergie drugs. map was : : mmhg and lactate . : : . mmol/l. pentaspan| increased ci by % (p< . ) but did not change pico ( and increase m oxygen o* wery were simimny achieved in both groups. nevertheless, epinephrine was associated with a lactic acidosis and increased laetate/pyruvatemia ratio (l/p) that evoke a dysoxia rather than a metabolic effect. an higher gastric mucosal pco in the ep group compared to nor-rob suggests the hypothesis of an anaerobic production of co in favor of a splanchnic hypoxia. in both group, arterial ketone body ratio that reflects hepatic mitochondrial redox state, compared to a control group without shock was decreased but increased between and hours after restoration of arterial pressure. the association norepinephrine-dobutamine seems to be better for splanehnic circulation than epinephrine and should be used for dopamine resistant septic shock. moreover, the increase in arterial pressure with nor-dob improved gastric mueosal ph and hepatic mitochondrial redox state and argue to reconsider arterial pressure as a significant goal for resuscitation in septic shock. conclusion: significantly higher malondialdehyde and ghitathione levels and glutathione-peroxidase activity in group ns at the end of icu stay were related to mortality these findings indicate an increased generation of free oxygen radicals together with increased anfioxidant activity in this group and sapport the employment of antioxidant interventions in critically ill patients. oblecfives: to determine the role of nitric oxide (no) in the mechanism of septic shock induced by isolated limb perfuslen with recombinant tnfcr methods: we have measured tnfr~ and metebo~ites of no in patients with signs ot septic shock following treatment with isolated limb perfusion for nonresectable soft tissue tumors and melanomas of a limb. perfuslen was carried out with melphalan (burroughs wellcome) and recombinant tnfcr (boehringer). tnfc~ was determined by specific radiometric assay (medgenix diagnostics), nitrate and nitrite were measured with a modification of the guess reaction ~. results: results are shown in the table. conclusions: during isolated limb pedusion with recombinant tnf~ very high levels of tnfcr were measured in arterial blood in patients. they all showed signs of severe sepsis syndrome with shock from vasodilafion, probably due to leak of recombinant tnft~ from the peduslen circuit to the systemic circulation. tnfc~-induced vasodilation was not accompanied by a rise in serum no-metsbolites. our findings do not confirm the widely accepted theory, mainly based on animal experiments, that genera• of no is the key pathogenefic mechanism in septic vasodilafion , nor that tnfrt invariably induces forreafion of no. the precise mechanism of shock in these patients remains to be elucidated. references: . moshage h, kok b, huizenga jr, jansen plm nitrite and nitrate determinaiions in plasma: a critical evaluation. clin chem : / . . moncada s, higgs a. the l-argioine-nitrio oxide pathway. n engl j med ; : - ec is a commonly used for prolonged, stable animal anesthesia. noting that the hypotension after iv lps was attenuated by ec, we hypothesized ec also protects against lps toxicity. sprague-dawley rats received ip saline (s), thiobutabarbita mg/kg (tb), or varied doses of ec, followed hours later by bolus mg/kg iv lps. -day survival is shown below: group: s tb ec( . gmikgi ec( .sgm/kg) ec(i. gm/kg) alive (n) t ~ total (n) s s "signiflcant;y different from all other groups, p< . s / rats given lps followed hours later by ec ( . gm/kg) also died. additional rats were treated with s (n= ) or gm/kg ec (n= ) followed by mg/kg lps, then sacrificed at hours. blood glucose (bg, mg/dl),.hematocrit (hct), leukocyte count (wsc/mm~ platelet count (pltxl ~/mm ), bicarbonate (hco, mg/dl), gross bowel hemorrhage (bh, - scale) and lung myeioperoxidase activity (mpo, ~vmirvgm wet lung) are shown below ( we conclude that ec reduces the lethality and multiple organ toxit;~ty of lps. its diverse effects suggest asite of activity upstream from the cytokine cascade. these results are important for studies of lps which may use ec anesthesia and may have potential in the therapy of septic shock. [zo = hz impedance (z; {dyn.sec.cm " }); zl = first harmonic z; zc = characteristic z; z ph. = t'trst harmonic phase angle {radians}; f, #, * at least p < . between fio . and . , fio . and fio . &no - . _+ . - . _+ . # - . + . m - . + . * - . + . * - . + . * - . _+ . * in hyperoxia, compared to dogs at the same q, minipigs had a higher ppa ( + rnmhg versus + mmhg; p < . ). hypoxia increased (ppa-ppao) at all levels of q by an average of mmi-ig in minipigs and mmhg in dogs. inhaled no inhibited hypoxia-induced (ppao-ppa)/q changes in both species. conclusions: we conclude ~ that the minipig is an animal model of elevated pulmonary vascular resistance and impedance, and ~ that hypoxia-induced alterations in pvz spectrum are due to changes of resistance in small arteries. objectives: ) to determine the toxicity of ng-monomethyi-larginine (nma) administered by intravenous bolus to patients with refractory septic shock. ) to investigate the biologic activity of nitric oxide synthase inhibitors in septic shock. methods: from august to january , thirteen patients with vasopressor refractory septic shock received nma intravenously in escalating doses from to mg/kg. results: no hepatic, renal, gastrointestinal, or hematologic toxicity was observed at doses of nma as high as mg/kg. significant biological activity was observed at all dose levels consisting of increased blood pressure (systolic blood pressure from . mm hg + . to . _+ . s.e.m., p= . , systemic vascular resistance ( + to + dyne.sec/ cm s, p=. ), and a decrease in vasopressor requirements. the magnitude and duration of these effect were dose dependent. decreased cardiac output ( . _+ . to . _+ . i/min p=. ) and increased pulmonary artery pressure ( . _+ . to . _+ . mm hg; p=. ) were also observed. no significant effects on heart rate, pulmonary capillary wedge pressure, or central venous pressure were observed. four of patients survived for more than days, patients died of cancer complications (all patients had maintained blood pressure for h on nma) and patients died of complication attributable to septic shock (mods, ards, dic, refractory hypotension), and patient was unevaluable. conclusions: no adverse clinical effects have been observed in patients receiving bolus doses of nma as high as mg/kg. the increased pulmonary artery pressures observed in septic shock patients is further augmented by nma and may limit the dose which can be administered by intravenous bolus. other schedules of drug dosing may attenuate this effect. glucose-insulin-potassium (gik) solutions have been shown to improve cardiac contractility and increase oxygen availability in experimental and clinical settings of septic shock. several mechanisms have been proposed to explain these effects including a direct improvemeut of the energy balance by glucose, a direct influence of insulin on cardiac performance or an increase in intravascular volume due to the hyperosmolarity of the solution. to explore the role of hyperosmolapity, we compared the effects of gik to those of a isoosmolar hypertonic saliue solutiou in endotoxin shock in dogs. methods : the study included mongrel dogs ( • pentobarbitalanesthetized aud mechanically ventilated with air. thirty minutes after the intravenotls administration of mg/kg of e. coli endotoxin, the dogs were randomized to receive a ml/kg infusion in rain of a hypertonic ( mosm]l) solution iucludiug either a mixture of glucose % with u insulin and meq kcl/l (glk-group ) or hydroxyethyl starch . % in naci . % (hes-group ). in each dog, a . % saline infi~sion was continued to maintain the puhnonary arlery occluded pressure at baseline level. hemodynamic, blood gas aualysis and laboratory data were collecled at baseline and miu, rain, rain, and nunutes later.. results : eudotoxin administration was followed by a fall in mean arterial pressure (map) aud cardiac index (ci) and a rise in blood lactate levels. resuscitation with either gik or hes hypertoaic solutions resulted in similm increases in map, ci, oxygen delivery and left ventricular stroke index (table ) . we conclude that during resuscitation from endotoxic shock the use of gik solutions is not superior to hypertouic hes solutions. the higher blood lactate levels observed in the dogs receiving gik can be attributed to the glucose metabolism. , for group , for group ) were drawn and immediately analysed at ~ using the abl radiometer for po , pco and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the ps at ph= . , pco = mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood, as was the ps "in vivo" (i.e. the ps at the patient's value of ph, pcoz and temperature), using siggaard-andersen's algorithm. the data were compared by the one-way anova test and by the t-test for paired and unpaired samples. results: the mean resulting values (in mmhg) with the statistical differences are shown in table i. in addition, the time series analysis shows the mean ps~st values as statistically below the psin vivo" in the septic patients while the opposite is shown for the cardiac patients. no differences in the time analysis are demonstrated for the second group. a possible clinical significance may be drawn from these different behaviours. objectives:toxemia degree and humoral immunity condition have been studied in patients aged from to with progressive course of sepsis and polyorganic insufficience. methods: such toxemia and humoral immunity findings as lencositlcindex of toxication (lii), level of oligopeptides of the middle molecular mass registered at the wave length of nm(mmi) & nm (mm ), distribution index (id), immunoglobulins a,m,g, concentration of circulating immunocomplexes (cici & cic ) and also some clinical and biochemical findings on the , , day after the operation serve as criteria for treatment effect. results: it was founded that in intensive therapy and detoxication, level of lii is successively decreased from . ~ . to . +. on the -th day after the operation. true decrease of the level mm from . ~. to . +. un & optimal density and increase of distribution index from . to . are argued. conclusions: in studlng the dynamics of the immunoglobulin's spectrum and the true increase of immunoglobulin g level from . +. g/i to i . +. g/i on the -th day after the operation simultaneously with the decrease of cic from . ~ to . ~ . (p . ) were founded. some stages of the investigation true increase of lymphocytes from . + . % to . + . % was noted and it appeared to be a favourable prognosis finding for disease outcome. high correlation dependence between bacillus-and segmentonuclear neutrophils and immunoglobullns g & m (r=. -. in p<. ) was discovered and it also showed positive dynamics of the course of the disease. a year old male patient was admitted to the icu with severe paraquat poisoning. treatment consisted of gastic lavage and oral administration of fullers earth. because of very high plasma levels hemodialysis together with charcoal hemoperfusion was started within one hour after admission. this treatment was further continued by continuous veno-venous hemofiltration in order to remove the circulating paraquat and also circulating cytokines. nevertheless patient s condition worsened necessitating artificial. ventilation and hemodynamic support. patient died hours after admission of acute multiple organ failure due to paraquat poisoning. serum levels of paraquat were determined by colorimetric method (table) . levels of interleukin (il ) and (il ), tumor necrosis factor (tnf-alpha), interleukin i receptor antagonist (il ra) were determined both in plasma and ultrafiltrate ( q~!ectives : evaluate in critically ill patients the effects of tow-dose dopamine on gastric mucosal blood flow (gmbf) using laser-doppler flowmetry, a continuous non invasive method of assessing microcirculation. methods : patients requiring both mechanical ventilation and pulmonary artery catheterization for multiple trauma (n= ), ards (n= ) and pancreatitis (n=l) were included. in each patient, the laser-doppler (ld) probe was inserted through a naso-gastric tube. the ld signal is proportional to the number of red blood cells moving in the measuring volume and the mean velocity of these cells. when the ld signal was satisfactory, an aspiration was created into a catheter which was fixed in parallel to the ld probe, to maintain the tip of the probe against the gastric wall at the site of measurement. data (systemic hemodynamic parameters and gmbf) were obtained at the end of a rain resting period (baseline), then min after dopamine ( mcg/kg/min) infusion, and finally rain after the end of dopamine infusion (recovery gmbf _+ (perfusion units) gmbf ~a% vs baseline) * p < . vs "baseline" and "recovery". conclusions : ) despite a slight increase in co (+ %), the dramatical increase in gmbf (+ %) with dopamine, strongly suggests a selective vasodilator effect of low-dose dopamine on gasaic mucosal perfusion. ) laser-doppler flowmetry appears a promising method to assess gastric microcircalation in critically ill patients. increasing evidence suggests that the activation of inos is the final common pathway for vasodilation in human sepsis associated with endotoxic shock. activation of the cellular immune system induces the excessive release of the pteridines neopterin (n) and , -dihydroneopterin (nh ) by human macrophages/monocytes. besides the well established diagnostic value of pteridines in several inflammatory diseases, it is speculated that these substances per se exhibit biochemical functions. thus we hypothesize that pteridines can modulate inos gene expression in vascular smooth muscle cells (vsmc) in vilro. cdtured rat aortic vsmc from female wistar kyoto rats were incubated with n ( pm), nh ( ilm), lipopolysaccharide (lps, ~g/ml), and interferone-~/(ifn-~/, u/ml) for h, respectively, inos gene expression was measured by competitive reverse transcription polymerase chain reaction. the results are summarized in the table. the present study demonstxates a neopterin induced increase in inos mrna expression at the transcriptional level in vsmc. while coincuhation of cells with n + lps resulted in an additive effect on inos gene expression, n + ifn- seem to have a more than additive effect nh did not alter inos mrna synthesis, but it suppresses the lps as well as the ifn-yinduced augmentation of inos gene expression. we speculate that this pteridine-mediated modulation of inos gene expression is involved in the regulation of the vascular tone in endotoxic septic shock. the relationship of sepsis and coagulation abnormalities is well known, mainly in severe sepsis and septic shock. still farther, the extreme expression of hemostasis abnormalities (disseminated intravascular coagulation) in sepsis, has been extensively described. we studied the changes in several coagulation and fibrinolysis markers in septic patients, trying to correlate them with the evolution of the sepsis phenomenon, with an emphasis in its early stages, where therapeutic intervention might be more drastic. in patients, with sepsis, with severe sepsis and with septic shock, as well as in healthy volunteers (control group) we measured : platelet (ptl), coagulation markers [fxii, fvii, fviii, fvw, fibrinogen (fibr) we conclude that all parts of the coagulation system are gradually changed during the evolution of sepsis phenomenon , even in the earliest stage of sepsis. the expression of an inducible nitric oxide (no) synthase (inos) plays a major role in the pathophysiology of septic shock (ss). inhibition of inos could therefore be of therapeutic value. however, such an inhibition has been shown to be detrimental, increasing tissue anoxia (and end-organ damage), possibly through the simultaneous blockade of constitutive nos (cnos). thus, selective inhibition of inos might be more suitable. we evaluated the effects of l-canavanine (can), a more potent inhibitor of inos than cnos, in an animal model of ss. method: in anesthetized rats, catheters were placed in the femoral vein and artery. rats were given an iv bolus of lipopolysaccharide (lps, mg/kg), at baseline (to). after h (t ), rats received at random an infusion of either can ( mg/kg/h; can group, n=l ) or an equivalent volume of . % naci ( cc/kg/h; nac group, n= ), giyen over h (t -t ). a third group (sham group, n= ) received . % nac in place of lps, and then was treated like the nac group. mean blood pressure (mbp), blood lactate and nitrates (no ) were measured each h. glucose, creatinine and asat were also measured in rats (n= in each group). the can _+ * + "t . + . "~ . +_ . "t + " + " *p< . can vs naci ?p< . vs sham can suppressed the hypotension, reduced the hypoglycemia and hyperlactatemia, and attenuated the biological signs of renal and hepatic dysfunction induced by endotoxemia. these effects were associated with a lesser elevation of blood no , confirming a partial inhibition of inos. conclusion: l-canavanine attenuates the hemodynamic and metabolic consequences of endotoxemia in the rat. these effects may be related to a partial inhibition of inos. they contrast with the deleterious effects described with non selective inhibitors of nos. l-canavanine could become a new tool for the treatment of septic shock. rocalc tonin :marker of sepsis, ii~flammaiiur% t~ boifi .cheval*~ jf.timsit*, m.assicot**, b.misset*,/.carlet*, c.bohuon** saint joseph heap, paris**biochemistry institut g roussy, villejuif, ce bi~)l~i~ttectives_: high serum levels of procalcitoaln (proct) have been shown to be ~ss-ocinted with bacterial infection. however, few data exist about the ability of proct to differenciate septic shock and shock from other origin in which an activation of intlmmamtory mediators has been also demonstrated. methods: thirteen patients with bacterial septic shock (ss), patients with non septic shock (nss), patients with bacterial infection without shock ( nf) and icu patients without shock and without infection (control) were compared for proct levels at dayl, , , , . patients were classified blindly and independently fi'om proct results. twelve patients were excluded because any classification was impossible due to mixed pathology. proct was measured with ebemoluminescenee (brahms diagnostica-berlin). results: dayl, proct levels are significantly different between the four groups. dayl proct levels are correlated with saps (p= . ), infection ( . +_ vs _+ ,p= . ), shock ( _+ vs +.- ,p= . ), death at day ( _+ vs _+ ,p= . ). when shock and infection are introduced in multifactor &nov& only infection remains correlated with day proct levels ( = . ) in patients with shock, dayl proct levels are correlated with saps, infection and death at day , but not with arterial lactate levels (p= . ), white blood calls (p= . ) or fever (p= . ). proct levels remain higher i~i septic shock patients at day , and ( figure) . i c edpsion: procalcitonin levels in the first three days of shock are differen[" between septic and non septic shock patients. in patients with diseases known to induce acute an inflammatory process, procaldtonin seems to be a marker o~ infection. obiectives-to evaluate the effect of endotoxic shock on the distribution of blood flow between the mucosal and the muscular layer of the intestinal wall. methods: in fasted pigs, mean aortic pressure (map, mm hg), cardiac output (co, ml/min-kg),superior mesenteric artery flow (q sma, ml/min.kg), and phi, where measured before (control) and after i.v. endotoxin ( gg/kg). the blood flow to the mucosal and the muscular layer was measured in regions (proximal jejunum (pj), mid-small intestine (mi) and terminal ileum (ti)) by colored microspheres, using adjacent samples in each region. the muscular layer was separated from the mucosa by blunt dissection, and the flow determined independently in each layer. results: endotoxin with fluid resuscitation induced the expected decrease in map ( . _+ . vs . -+ . , p< . ), and phi ( . !-_ . vs . _+ . , p< . ), with a constant co ( _+ vs _+ , p= . ) and qst, aa ( . _+ . vs . _+ . , p= . ). the results of regional pertusion are presented in the table. (flow in ml/rain g of tissue; mean _+ sem ; * p< . vs control by two-way anova) conclusions-these data indicate that the mucosal flow increased during septic shock. they suggest that a decrease in phi may be due to hypoper~usion of the muscular layer or to metabolic alterations within the mucosa, despite a % increase in flow. acute increase in wbc count (from a mean of lo.oo mm a to o /mm~), between the rd and the th day of therapy. there was a decline of the wbc count to an average of about . mm a after decreasing the daily dose of the medication to mcg there was no increase in tile absolute number of the eosinophils during the whole course of the medication. there was a slight decrease in the c complement between . to . g/i. normal values . to . g/i there was no change in c values. conclusions : an early increase in wbc count was observed ( rd day) without subsequent increase in the number of immature types from bone marrow, probably due to the mobilization of wbc from the periphery and this increase was dose dependent. there was a slight decrease in c fraction of complement, probably due to the consumption of this fraction in the process of opsonization. no adverse effects of the medication were observed, during the treatment with the above dose. these data sugest that cm csf may be a useful complement to tile main antimlcrobial treat,nent ~ of septic [cu patients. objectives: as part of a large multicentric, placebo-controlled, randomized clinical trial investigating the effects of interleukin- receptor antagonist (ii-lra) in the treatment of severe sepsis and septic shock, this substudy evaluated in dem.il the acute hemodynamic effects of ii-lra in patients who were invasively monitored. methods: in a total of evaluable patients in whom vasoactive support was little altered, hemodynamic measurements were performed at baseline (twice), and i hour, h, h, h, h, and h after the administration of mg/kg (n= ) or mg/kg (n= ) of i - ra or the corresponding placebo (n = ). / patients ( %) were treated with adrenergie agents and / ( %) with mechanical ventilation. data were analyzed by a kruskal-wallis test. results: during the study, there was no significant difference with time or between groups in arterial pressure, cardiac filling pressures, cardiac index or left ventricular stroke work (figure). burmester, "~ man and h. djonlagic medical university (internal medicine, "cardiology, *'microbiology) and "**southern city hospital, lfibeck, germany obiectives: evaluation of the incidence of bacteremia and sepsis in patients with nontyphoidal salmonella (s.) infections, specification of risk factors, need of icu treatment, clinical course, and mortality in the group of the patients who developed septic complications. methods: data of all patients with microbiologically proven s. infections hospitalized in the medical university of lobeck and in the southern city hospital of l beck from to . results: within the observation period s. was isolated from the stool cultures of patients. in patients (g m, f, median age yrs) s. could be detected in blood cultures ( s. enteritidis, s. typhimurium). in addition, in of these patients s. was also isolated from other specimens (urine, liquor, and tissue fluids derived from abscess punctures). in all patients with positive blood cultures the clinical course of s, infection was complicated: ? patients developed mof (acute renal failure, ards, hemodynamic instability, dic) and required icu treatment for at least up to days, of the patients died. the predisposing disorders in the patients with s. bacteremia were (n=): aids ( ), immunosuppressive drugs ( ), chronic alcoholism ( ), malignancies ( ), none ( ). septic complications in patients with nontyphoidal s, infections are relatively rare (in this study < % of all hospitalized patients with microbiologically proven salmonellosis) but severe (mortality of approx. %). patients at risk for a complicated clinical course are predominantly those with predisposing disorders but occasionally also patients without evidence for an underlying disease. age (yr) + + death (n) duration of shock (h) + + noradrenaline (rag/h) , _+ + temperature (~ , + , + pvr (dynxsecxcm - ) + + co (ljmin) , _+ , , + , lactate (mmol/l) + , , + interleukin- (pg/ml) _+ + interleukin- (pg/ml) , _+ , , + , tnf-alpha (pg/ml) , + , + neopterin (nmol/l) , + , + crp (rag/l) _+ +_ pro-ct (ng/ml) , + , , + there was no positive correlation between serum lactate levels, degree of shock, hypoxemia and pro-ct positivity. pts with septic shock of bacterial origin entirely developed hyperprocalcitoninemia, whereas pts with cardiogenic shock, who expired within h did not. however, in late cardiogenic shock (> h) all pts developed fever of unknown origin and consecutive hyperprocalcitoninemia. these data suggest bacterial inflammation and/or mucosal translocation of bacterial products in pts with prolonged cardiogenic shock. the use of a loading dose of quinine ( . mg/kg base in h) is recommended in previously untreated patients (pts) with sfm, particularly in multi-drug resistance areas. this protocol is difficult to validate, since the viability of microorganisms is not assessed routinely in parasitology laboratories. objectives: to examine the evolution of parasite viability during the early phase of therapy of sfm. methods: from / to / , pts with sfm (who ) treated with iv quinine for less than h were included prospectively. blood samples were collected at o, , , , , and h viability was assessed by culturing parasitized red blood cells in the presence of h-hypoxanthine, and radioactivity was determined at h by scintillation counting. viability was expressed as the percentage of radioactivity compared to the initial sample. plasma quinine was determined by liquid chromatography. tile ratio plasma quinine (pmol/ )xlo /icso for quinine (nmo]/]) was called the parasiticida/ index. results: pts were included, • saps . -+ . . the initial parasitemia was t. + . %. complications of malaria were coma ( pts), shock ( pts), renal failure ( pts) and acute lung injury ( pts). all strains were sensitive to quinine (icso -- nmol/ ). in pts who were not given a loading dose, parasite viability increased by and %, with concomitantly low quinine levels ( and #mow] at h); pt died. in pts that received a loading dose (serum quinine at h = . -- . ~mol/]) a marked decrease of parasite viability (by +_ % at h) was shown. viability was inversely correlated with plasma quinine (r=. , p-.o ) and parasiticidal index (r=. , p-.o ). conclusions: even with fully sensitive strains, the use of a loading dose of quinine seems warranted in severe falciparum malaria in order to reach rapidly adequate plasma quinine ]evels, necessary to inhibit significantly parasite viability. l nkka, e ruokonell j takala. critical care research program, department of intensive care, kuopio univ hospital, finland objective: to determine the incidence of positive blood cultures, their microbial subgroups and to evaluate the outcome of icu patients with different bacleremias. material and methods: we analysed all positive blood cultures in consecutive admission to a university hospital icu in - and the icu and hospital survival of the bacteremia patients. during these years patients had positive blood cultures that were considered as clinically relevant, excluding colonizations or contanfinations. results: patients with positive blood cultures had an icu survival of . % (vs. , % in all icu patients) and six month survival of . % (vs. . % in all icu patients). the most common bacteria were enterobacteriaceae ( , %), staphylococcus aureus ( , %) , coagulase negative staphylococci ( . %), pseudomonas ( . %) and slieptococci ( . %). obiectives: to evaluate prognostic factors and mortality in consecutive patients (pts) with hiv infection and septic shock. methods: from - to - , records of consecutivepts with septic shock (crit care med , : - ) admitted to the icu were reviewed retrospectively. results: among pts with septic shock admitted during the study period, had hiv infection- of whom had aids-(gr. i) and were hiv-negative (gr. ill. ten gr. ii pts ( %) were irnmunosuppressed because of neoplastic or immune dlsease. mechanica] ventilation was required in % gr. i and % gr. ii pts in gr . i pts ( %) a multivariate analysis demonstrated that hiv infection and sap i were independently predictive of death in pts with septic shock. ~onclusions: evidence of increased mortality, number of organ failures and higher severity scores (saps i does not take into account immunosuppression) is demonstrated in hi v-positive pts, infection with hiv appears to be an independent prognostic factor in pts with septic shock. the frequency of opportunistic infections (often responsible for delayed diagnosis and treatment) may contribute to the poor prognosis in this population. obiectives: to determine interleukin (il)-i levels in plasma of patients with sepsis and septic shock. to analyze the relationship between plasma il- and the proinflammatory mediators, tumor necrosis factor-aifa (tnf) and il- , the underlying severity of the disease and the evolution of patients with sepsis. methods: we studied critically ill patients ( men, women; - years old) in three diferents groups. group i: patients without evidence of infection, group i : patients with sepsis and with septic shock (group iii). we measured plasma il-lo, tnf and il- levels in the first hours of diagnosis. severity of illness was estimated with the acute physiology and chronic health evaluation (apache ii) scoring sytem. results: plasma levels of il- were higher in group iii (median, pg/ml; range, - pg/ml) than in group ii (median, pg/ml; range, - pg/ml; p <. ) and group i (median, pg/ml; range, - pg/ml; p <. ). median il- concentrations did not differ among patients who survived (median pg/ml; range, - pg/ml) and those who died during the overall follow-up period ( days) (median, ; range, - pg/ml); but patients who died in short-term (< hours) with catecholamine-refractory hypotension showed the highest concentrations of il-io (median, pg/ml; range, - pg/ml). in patients with bacteriemia ( %), levels of il- were higher (median, pg/ml; range, - pg/ml) than in those with negative blood culture (median, , pg/ml; range - . pg/ml; p< . ). there was a good correlation between plasma il-io concentration and levels of tnf (r= . ; p < . ) and il- (r= . ; p < . ). the correlation between levels of il- and the apache ii score was significant only in the septic shock group (r= . ; p <. ). conclusions: in septic shock, il-io and proinflammatory citokines are released in high concentrations. the significant correlation observed in patients with septic shock between il- levels and apache ii, short-term death and bacteriemia can possibly be explained by the massive inflammatory response in septic shock with fulminant course. intensive care department -calmette hospital - lille -france. in septic shock, inadequate splanchnic blood flow may play a prominent role in the pathogenesis of multiple organ failure. measurement of gastric phi has been propose to evaluate tissue oxygenation in splanchnic organs. objectives: to compare gastric phi values with hepatic icg clearance, an index of liver blood flow and function ; to determine if one of these two methods could be proposed to assess the entire splanctmic peffusion in septic shock. methods : patients (age : • years ; saps ii : • were prospectively investigated (septic shock : bone criteria). following parameters were collected during hours : systemic hemodynamic parameters (swan ganz catheter a h -ref computer -baxter lab.), calculated systemic oxygen transport (do ), oxygen consumption (vo ) by indirect calorimetry (deltatrac datex lab.), gastric intramucosal pco (pco ss) and phi (trip -ngs catheter -tonometrics lab.) and plasma disappearance rate of icg (pdr dye) (femoral artery fiberoptic/thermistor catheter , cold z computer -pulsian medizintechnik, germany). correlations were performed using a linear regression. elevated in all days with the highest value in second and third days of treatment. nonsurvivors had higher values of these parameters than survivors but differences did not reach statistical significance. another trend of changes were observed in selectin p (gmp- ) concentration. in all patients concentrations measured were elevated but in survivors after not significant decrease this parameter in second day another one had simmilar values. in patients who died we noted significant decrease in third day (p < . ) whereafter prominent increase, significant after seventh day, in comparison to third day value and value in survivors group. icam- concentrations in all patients reached high levels and in nonsurvivors after four day of treatment significant increase in comparison to survivors we found. conclusions: multiple trauma complicated with sepsis induce rapid elevation of concentrations of il- , il- and increased expressior of adhession molecules (selectin e, p, icam- ) measure of icam- and selectin p concentration determine lung injury severity and prognosis as to health and life. (clp) .pathophysiology of cip is unclear, but changes in regional bloodflow may be a ~ignificant factor. nerve blood flow (nbf)is reduced in rat models of hemorrhagic shock (g),but no information is available in sepsis. we studied the comparative effect of acute endotoxemic shock {etx)& h on perfusion of rat sciatic nerve. methods: male sprague-dawley rats were anesthetized with pentobarbital (ip), instrumented with a tracheostomy, carotid arterial & venous catheters and mechanically ventilated (fi = . ). the left sciatic nerve was surgically exposed. monitored variables included: a) mean arterial pressure (map,mmhg) ,b) nbf (ml/ o g/min) by laser doppler flow meter,c) nerve internal arterial diameter (id ~ m) by video image shearing and splitting method. after stable baseline measurements were obtained, acute hypotension was induced by randomly assigning the rats to etx ( . b , difco) in saline at mg/kg or h. both interventions produced % reduction in map within min., which recovered to baseline values spontaneously in etx group, & by reinfusion of heparinized withdrawn blood in m. data were analyzed by linear regression, two-way repeated measures analysis of variance followed by bonferroni-t method. experimental stages were:( )baseline, ( ) mid-point of map reduction; ( ) nadir of hypotension, ( )midpoint of map recovery, & ( ) after stable recovery of map. both etx & h induced shock result in similar reduction in nbf consistent with lack of autoregulation in peripheral nerve vessels independent of etiology. since cip is primarily associated with sepsis, it is not likely that acute reduction in nbf alone causes cip. direct & indirect neurotoxic effects of mediators of sepsis need to be evaluated. .':_.~::::o o:oc ., objectives : evaluate the relationship between il- , a cytokine which inhibits tnf, production and protects mice from endotoxin toxicity, and the other proinflammatory cylokines, tnf~, il and ils in severe sepsis and septic shock. methods : twenty-eight icu patients ( m, f, mean age + y) were studied as soon as they developped a severe sepsis (n = ) or a septic shock episode (n= ) as defined by a conference consensus in ( ). tnf~, il , il s and il- plasma levels were measured by immuno-radiometrie assays from medgenix (fleurus, belgium). lc mean and range. results : the comparisons between cytokine levels in severe sepsis versus septic shock were made using the logarithm of the value in order to normalize the distribution of data, and student test. il- plasma levels were higher in patients with septic shock than in patients in severe sepsis. there was a significant correlation (p < . ) between il- and tnf a (r= . ), il- and il~ (r = . ) and il- and il s (r = . ) as well as between il- and apache n score (r= . ). patients who died (n = ) had il- levels higher than patients who survived but this difference was not statistically significant ( pg/ml vs . pg/ml; p> . ). conclusions : during severe sepsis and sepsis shock, il- seems at least to follow the same evolution (increase in plasmatic level) with the severity of sepsis as the other cytokines. reference : ( ) crit care med ; : - . objectives: to evaluate the effects of steroids on hemodynamics and mortality in septic patients with konwn levels of cortisol concentration. methods: retrospectively we analyzed data ofpatients with documented septic shock who received steroids after assessment of adrenal function. in all patients hemodynamic parameters as well as the necessary vasoactive medication were assessed, before and hours after corticosteroid medication. immediately before administration of corticosteroids adrenal function was evaluated with cortisol levels before and after synthetic corticotropin ( . mg). finally we studied mortality. we defined a positive respons on corticosteroids as an elevation of map of at least mmhg and/or a decrease in the necessary vasoactive medication of at least % within hours. adrenal insufficiency was defined as a cortisol level after stimulation of less than nmol/l. results: of patients were found to respond to steroid medication, did not. mean cortisol levels before and after corticotropin were • and • nmol/l in the responder group (rg) and • and • nmol/l in the non responder group (nrg). in the rg out of ( %) were found to have an adrenal insufficiency, in the nrg out of ( %). in the rg -weeks mortality was . % (l out of ), the overall mortality % ( out of ). mortality in the nrg was % ( out of ) (p < . ) and % ( out of ) (p < . ) respectively. conclusions: in patients in septic shock there is a beneficial effect of steroids in case of adrenal insufficiency, but also in a subgroup with normal adrenal f{unction. obiectives: intercellular adhesion is a critical step in the accumulation of leukocytes. postischemic cardiac lymph has the capacity to stimulate icam-i. in the coronary microcirculation neutrophils can be trapped and in many cases obstruct capillaries, previously we found that troponin t (s-tnt) a marker for myocardial iechemia, was increased in septic patients. the aim of the study was to follow slcam- and s-tnt levels continuously starting at the beginning of sepsis. methods: patients were ingluded in this institutionally approved study after relatives had given their informed consent. all patients were included within hrs following the beginning of sepsis. blood was drawn every hrs in the first ;~ hrs, after hrs, followed once per day for days. s-tnt, icam- , elam (elisa's, boehringer mannheim inc, r&d systems ltd.) arterial and venous blood gases were determined, an ecg and a complete hemedynamir measurement including cardiac output were obtained. all patients received adequate volume and catecholamine therapy (norepinephrine, dopamine, dobutamine; median (range) . ( . - . ), . ( . - ), . ( . - . ) pg/kg/min, respectively). statistical analysis: wileoxon signed rank-sum test. . ( . - . ) . patients had s-tnt levels > . pg/l. of these died, whereas only of patients died with s-tnt values < . pg/l (p= . ). all patients that died had elevated sjcam- levels ( ilg/l:cut-off ) whereas in the survivor group only % had elevated icam- levels (p= , ). conclusions: increased slcam- and s-tnt levels were found during early sepsis in the majority of patients, a high sicam- and s-tnt value was associated with a higher mortality. the research of the noninvasive haemodynamic monitoring accelerated recently all over the world. the aim of our study was to test whether the changes of the haemodynamk parameters measured by impedance cardiography (icg) were corresponded to clinical changes in septic patients. investigations were performed on critically ill postoperative septic patients (their multiple organ failure score was - /with icg monitor. in cases the investigation~ were performed in septic shock. the measured parameters were: heart rate (hr), mean arterial pressure (map), cardiac output (co), peripherial resistance (svr),preejection period (pep), and ventricular ejection time (vet). these parameters were measured during - hours in every minutes, depending on the patients cl~tnical condition. results: at the septic patients the hr and the co ]~reased. in septic shock the co was significantly higher the svr lower than in the septic group. in the hr there was no difference between the two groups. in septic shock noradrenalin influenced more effectively the measured parameters than dobutamin. conclusion: the trend of the measured icg parameters correlated with the clinical changes of septic patient's state. the noninvasive haemodynamic monitoring by impedance cardiography helps the planning and leading the adequate intensive therapy of these critically ill septic patients. to evaluate the development of sirs, sepsis and septic shock in hospitalized patients with fever, a prospective study was performed on patients using previously defined criteria. methods: normotensive patients with fever (temperature > . ~ axillary), admitted to the department of internal medicine were evaluated for the existence of sirs during the first three days of the study and sepsis at inclusion. during a follow-up period of days the patients were daily evaluated for the development of sepsis or septic shock. results: most patients ( %) had or developed sirs within the first three days, patients ( %) did not. sepsis was present in % at inclusion. in patients with sirs, % did not progress to sepsis or septic shock, % progressed to sepsis (mean interval . • . days), and patient (< %) directly progressed from sirs to septic shock. in patients with sepsis, % progressed to septic shock (mean interval . • . days). sepsis was preceded by sirs in %. septic shock was preceded by sepsis in % and by sirs in %. conclusions: % of patients with fever in an internal medicine department develop sirs, or sepsis. furthermore, progression from sirs to sepsis or septic shock is poorly predicted by fever or sirs. nevertheless, all patients with septic shock were preceded bysirs or sepsis. taken together, this may indicate a severity hierarchy of the syndromes. however, fever, sirs and sepsis are relatively poor indicators of development of septic shock. this supports further research on additional predictors of septic shock. b. m.manuylov, v.b.skobelsky (moscow) in recent years sodium hypochlorite (sh) has been successfully used to eliminate pyo-septic complications. moreover, the mechanism of the sh effect on the immune system has not been sufficiently studied. the aim of the present investigation was to study the mechanism of sh effect in inflammatory pulmonary diseases. patients with double pneumonia were subjected to the evaluation. sh in the concentration of mg/l in the volume of - m / hours was administered by drop infusion into the central vein. to evaluate one of the defence systems the leukocytes activity by the chemoluminescence technique was studied. in all the patients baseline secondary immunodeficiency which was indicated by the decrease in the luminescence level was established. even hour after the sh administration the leukocytes activation exp-ressed by the enhancement of their chemoluminescence . - times was observed. this supports the available findings that accumulation and liberation of the oxygen active forms (ol'oh, ' , h ) are accompanied by the increased phagocytosis, i,e. the signs of "the oxydation explosion" testify to the favourable sh effect on the course of inflammation processes. the use of sh permitted to decrease the percentage of lethality in double pneumonia by % in the intensive care unit over the year. at the same time, excessive activation of free radical oxygen may be a damaging factor. therefore, precise individual control over the choice of concentration, dosage and the preparation administration rate is required. prospective, double-blind, placebo-controlled, trial of atiii substitution in sepsis r. a. balk objective: pilot study to evaluate the efficacy and safety of atiii substimtion therapy in patients with sepsis. efficacy assessed using change in mortality or organ failure/dysfunction. adult patients meeting a definition of sepsis and cared for in a tertiary care academic medical center in chicago were identified and prospectively randomied to receive either atiii (kybernin p) or placebo in a double-blind treatment protocol. all other therapy and patient management were under the direction of the patient's attending physician. all patient's were followed for days and the organ dysfunction/failure were scored using published scoring systems (jordan et al crit. care med. , goris et al arch. surg. , kuaus et al ann. surg. colldusions:wha~ we met the shomaeker objectiv% the mortality and the pro~os[s were i~ttc*. those criteria were obtained with file tradititmal t~ctor likr doht~mme, hut c.~vh ~,as ca in~aertam measure. they ac~s smxergically in the optimizatic~l of the fell vmtrictdar work index, tad fimdameatally cavh seox~s to have an impo.aat role in the better respiratory ev-altmtioa, leaving yet the possibility to coltrol the flui& r althou~l eomproved it's not aec~pt~xl file importmlce h* the diminution, of the sepsis modiat~lrs llke fnt and il- with h~wmotiltrafi(al, stopphlg the evolution to nmltiorganic failure mid de~easethe mortality. with ours clhlicals results, we could saythat cavii in multiol~atlie disfut~oa septic patieats, se~r~ to be an c xilna] supoa or troatmeat maesure. of anaesthesia and intensive therapy, medical university of prcs, p~csf hungary. objectives: since some biological effects of bacterial endotoxin require an interaction between the lps molecule and a serum factor(s), we hypothesized that lps-induced no production and cgmp accumulation in vascular smooth muscle cells (vsmc), a mechanism ~thought to underlie cardiovascular collapse associated with septic shock, is modulated by serum factor(s). methods: cultured vsmc from rat aorta were challenged with e. coli lps for - hours either in the presence or absence of fetal calf serum (fbs), and no production was monitored by radioimmunoassay determination of cgmp content of hci extracts. results: in the absence of serum, o ng/ml lps was required to increase cgmp levels, whereas the presence of % fbs shifted the lps concentration curve i times to the left. similarly to fbs, human serum also potentiated lps-induced cgmp accumulation. in contrast to lps, serum had no effect on cgmp accumulation elicited by sodium nitroprusside, a no releasing agent, suggesting that the sensitivity of vsmc to generate cgmp in response to exogenous no is not modulated by serum. heat inactivation (> ~ min) but not removal of small molecules (< , d) from the serum by dialysis, reduced the potentiation of cgmp accumulation by serum. time course studied indicated that serum is required within the first min of lps exposure to increase cgmp levels. to investigate whether the effect of serum is specific for lps, we treated the cells with increasing concentration of interleukin -~ (il-i). % fbs shifted the il-iinduced cgmp responses five times to the left. conclusions: our study suggests that lower concentrations of e. cell lps and il-i require a heat labile macromolecule in the serum in order to elicit no production. this factor is present in the human serum and it may play a potentially important role during no synthesis induction in vsmc. objective: to evaluate the factors of acquisition and the outcome of methicillin resistant staphylococcus aureus (mrsa) bacteremia in an intensive care unit (icu). methods: all patients in which bacterermia due to staphylococcus aureus developed > hours following admission to our icu, during a year period ( january through january ) were reviewed. patients (pts) were included, mean age , y (sd , ), saps , (sd , ), mac cabe ( and ) %, mortality directly due to sepsis %. pts had mrsa bacteremia and methicillin susceptible staph. aureus (mssa) . both groups were compared using the chi square (with correction of yates), fisher's exact, student's t or wilcoxon test. results: there was no statistically significant difference between mrssa and mssa regarding at age ( , + , vs , + , ) , saps ( , + , vs , + , ), use of vancomycin ( % vs %), mechanical ventilation ( % vs %), number of days (d) before the drawing of the first positive blood culture (median d, range - d vs median d, range - d). more mrsa than mssa pts had previous use of nonsteroidal anti-inflammatory drugs (nsaid) ( % vs % p< , ), central venous catheter infection due to staph.aureus ( , % vs % p< , ), but previous use of antibiotics was not significantly different ( , % vs %). the outcome of the bacteremic pts was not statistically different: saps at the first day of bacteremia ( , +_. , vs , + , ), severe sepsis and septic shock ( % vs %), persistence of the bacteremia ( % vs %), mortality directly due to bacteremia ( % vs %). conclusion: previous use of nsaid, infection of venous central catheter are more frequently associated with mrsa bacteremia. thus, similar to others studies (hershow infect control hosp epidemio ; : - ) , these results do not indicate that mrsa is associated with increased virulence. objectives: to closer definition of mosf formation mechanismes in nosocomial sepsis (ns) the complex clinicobiochemical, microbiological, immunological, functional exaroination of cases with ns had been done. methods: examination of cellular and humoral immunity, nonspecific immunologic reactivity, systemic and hepatic circulation, microbiological examination of blood,electro-and echocardiography, sonography and computer tomography of chest and abdomen organs were obligatory. autopsy findings of dead cases had been analized. results: in cases ( , %) opportunistic pathogen microscopic flora ( staphylococcus anreus,staphylococcus epidermidis, staphylococcus saprophyticus) had been found out in blood inoculations. in cases ( %) side by side with destructive process in lungs the bacterial endo-and myocarditis with blood circulation failure had been determined.in cases ( %) simultanious lesion of three organs (heart,lungs,liver) had been found. morphologic examinations of dead cases ( %) internal revealed involvement of them in mosf-syndrome.hyperplasia of adenohypophysis;sclerosis of adrenal glands cortical layer;perivascular brain oedema,paralysis of brain capillaries and plasmorrhagia, cerebral thrombosis and cerebral abscess,necrobiosis of epithelium tubules of the kidney,pletora of hepar, fatty and granular degeneration of hepatocytes had been found.atrophy of white pulp and hyperplasia of red pulp, supress of lymphoid tissue, plethora and formation of infarctious had been found in spleen. mentioned changes in spleen were indispensable in ns. conclusion: in ns spleen can not secure it functions to support and appropriate detoxication potencial of organism,elimination of microbes,toxines,antoallergenes. insolvency of immunological link of antimicrobic defence is the starting mechanism of mosf developmentin ns. %neviere, jl. chagnon, b. vallet, d. mathieu, n lebleu, f. wattel ] ept of intensive care, hop calmette, lille, france ~everal studies have described tiypoperfusion of intestine during sepsis. owever, it is unknow whether the mesenteric blood flow is associated with nucosal hypoperfusion. additionally, the effects of resuscitation on the ntestinal microcirculation remain controversial. bjectives : to describe the effects of endotoxin in a porcine model during ~hock and resuscitation. ~ethods : ten pigs ( kg) were anesthetized and instrumented for "neasurement of cardiovascular variables. gastric and gut oxygenation vere assessed by intra-mucosal ph and microvascular laser doppler lowmetry. after baseline data collection, a minute intravenous infusion )f escherichia colt (serotype h , sigma, st. louis, mo) was begun ~t a rate of pg/kg. an infusion of either saline at . ml/kg/min (group ; n= ) or saline and dobutamine at a rate of pg/kg/min (group ii; n= ) vas begun mn after the end of the endotoxin infusion. tesults : to td t ~ fl w fluid ioadin,q alone sfyras d, k perreas, e douzinas, k spanou, m pitaridis and c roussos critical care dpt, evangelismos hosp., athens univ, school of medicine. obiectives: much controversy exists concerning the beneficial effects of cvvh on sepsis. we studied the effects of cvvh application on septic patients with reference to the following parameters: i) survival rate ii) cytokines' removal and iii) timing of cwh onset. methods: patients with sepsis (criteria according to accp/sccm, ) underwent cvvh as soon as they developed renal failure or dysfunction (urinary output< ml/ h, cr> . mg/dl and bun> mgd'dl ). specimens were collected: blood samples before cvvh and therafter both blood and ultrafiltrate (uf) samples on , and hours. cytokines tnfa, i - and ii- were measured by the immunoassay method in all specimens (uf and plasma -p) and sieving coefficient ([uf]/[p]) and h solute mass transfer of tnf and i - were calculated (v h x [uf] ). the apache ii score before cvvh onset, the duration of icu stay and the timing of cwh application related to the sepsis onset in days (ta) were recorded.with respect the mortality two groups were formed, i.e. group a (survivors) and group b (non-survivors) . the morbidity period in days of those septic patients who died in the past year and were not subjected to cwh (group c) was compared to that of group b. results: group a included pts and group b pts with mean+sd age ( _+ vs _+ , ns) and apache scores( _+ vs -+ . , ns). the mean ta-+ sd was . + vs -+ , p< . . the mean_+se morbidity period of group b vs group c was _+ vs _+ . p< . . the mean values of cytokines are presented in the following figures. the sieving coefficient for tnf was . and for i - was . . the solute mass tranfer was -fold the actual plasma content at a given time. . o conclusions: i) early application of cvvh seems to favourably affect the outcome of septic patients, ii) cytokine plasma levels do not decrease although cytokine removal is substantial, iii) it seems that cwh application in sepsis of any stage helps to buy time for further treatment. the most commonly monitored variables in shock stages idclude : arterial pressure, heart rate, central venous pressure, pulmonary artery wedge pressure and cardiac index. with vigorous therapy it is possible to bring these values back into the normal range in both survivors and nonsurvivors. therapeutic goal in septic shock stages is to maximize the values of cardiac index, delivery (do ) and consumption (c ). objectives: the main purpose of this article is to determine the relationship betwee~ delivery an consumption as a sign of hypoxia. fifteen patitents with septic shock were treated with intention to maximize the value of ci,d and v . we compared the levels of these parameters between the survivors and nonsurvivors and found no significant differences after hours. high levels of do and v may not guarantee against tissue hypoxia in early stage of septic shock. zjar~iic, dj janjic, lj. gvozdenovic, a.komareevic. t.petrovic, &marjanovic, institute of surgery, novi sad, yugoslavia objectives: evaluation and mutual comparison of clinical signs, laboratory data and microbiological monitoring in the patients with burn sepsis. method: retrospective analysis of the recorded data of all burn patients treated in our department between january and december . specially attentions were given to data considering wound infection, positive haemocultures, positive urinocultures and characteristics of septic state. results: out of patient there were ( , ~) adults and ( , ( ~) children. almost two thirds of the patients ( - , ~) were males. the predominantly cause ( , ~) of children's burns was scalding b~y hot liquids and flame burns ~ , ~) in adult patients. the most frequdntly species isolated from surface swat~ were pseudomonas aeruginosa ( " in adult patients) and staphyloccocus epidermidis ( , % in children). in only five patients ( , ~ the haenmcultures were positive -pseudomonas aeruginosa was isolated in three and staphyloccocus aureus in two patients. urine infection was diagnosed in , % of all patients. the treatment protocol included use of imipenem and polyvalent pseudomonas vaccine again~ pseudomonas aeruginosa and vancomycin and aminoglycosides against staphylococcus aureus. total mortality rate in this group of burned patients was , ~, but the mortality rate caused of sepsis was low (i %) . conclusions: early detection of any signs of wound infection and symptoms of septic state is a foundation for prevention and treatment of burn sepsis. the burn sepsis could be reliable detected by continuously monitoring the patient's status and by systematic microbacteriological monitoring of the burned patients. hyperdynamic vasoplegic septic shock p.f. laterre, p. goffette, j. roeseler, j.p, fauville, a. poncelet, p. lonneux, m.s. l~eynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. splanchnic ischemia is described as a common feature of septic shock and could determine the development of msof. therapy such as noradrenaline (na) aiming at improving blood pressure is expected to worsen splanchnic ischemia by its vasoconstrictive effect and subsequent reduction in intestinal blood flow. ob[ective: evaluate the effect of na on splanchnic blood flow. material and method : in a patient admitted for variceal bleeding, ards and sepsis with positive blood culture, a fiberoptie catheter was positionned in the portal vein after recanalisation of its portosystemic stent shunt. blood pressure (bp-mmhg) , ci, svr, do (vigilance ~ baxter), v (indirect colorimetry), arterial, mixed venous and portal vein blood gases, phi were determined before (to) and during (t ) na infusion ( , to , hcg/kg/min.) . changes in splanchnic flow were assessed by changes in portal oxygen saturation (sp ) and arterio-portal oxygen saturation gradient (sao, -spoe laterre, ,lp. pedgrim, th. dugernier, v. delrue, ph. hantson, p. mahieu, m.s. reynaert. dept. of intensive care, st. luc univ. hospital, brussels, belgium. aim of the study : prospective determination of plasma levels of in patients with ss and their correlation with the type of microorganism and outcome. material and methods : in patients (pts) with ss and severe sepsis, plasma levels of tnfti, ill-b, il and il were determined every hours for days and on day after fulfilling the criteria of ss and severe sepsis. results : in pts, sepsis was caused by a gram (-) microorganism, in pts by a gram (+) and in pts no microorganism was identified. there were survivors ( %) (s) and non-survivors ( %) (ns) . cytokines profiles and levels were not different between gram (+) and gram (-) sepsis. ill-b levels were seldom elevated whatever the group studied. tnfot and il- were significantly higher in ns than in s ( objective: to evaluate the effects on the nitric oxide synthase inhibitor l-n~ hcl ( c ) on myocardial performance in human septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion >_ .i ]tg/kg/min with a map _< mmhg. cardiovascular support was limited to na _+ dobutamine (db), c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t = ); and at the end of treatment (t = ) with c . conclusions: c can restore systemic vascular tone in patients with septic shock enabling na therapy to be reduced and/or removed. the ci tends to fall whilst lv performance is sustained over time. c is a novel vasoacfive agent for the treatment of septic shock, which is undergoing further clinical evaluation. laterre, f. thys, e. danse, j.p. pelgrim, e. florence, z roeseler, m.s. r eynaert. dept, of intensive care, st. luc univ, hospital, brussels, belgium. therapy aiming at improving blood pressure and cardiac index in septic shock (ss) might have deleterious effects on regional blood flow. objectives : compare the influence of volume loading (vl), dobutamine (dobu) and noradrenaline (na) on sushepatic oxygen saturation (shoe) and svoe-sho, gradient in treated ss. material and methods : in patients with ss, ci (thermodilution) , doe, svo,. sho,, svoe-sho e gradient and lactate (l) were determined before (to) and after (t ); vl, dobu and na. results: in patients with treated ss, tests were performed (vl n= ; dobu n= ; na n= method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map< mmhg) or the requirement for a noradrenaline (na) infusion ~> . ~g/kg/min with a map _< mmhg. cardiovascular support was limited to na + dobutamine (db), c was administered for up to h at a fixed dose-rate of either i, . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at h from the start of treatment (t = ); and at the end of treatment (t - ) with c . conclusions: c is a novel vasoactive agent that can sustain map in patients with septic shock, enabling na support to he reduced and/or removed. there is a tendency for the ci to fall during treatment, which may be reflex in response to the increase in systemic vascular tone. c is a promising new therapy for septic shock, which will now be evaluated in a randomised, placebo-controlled safety and efficacy study. k. guntupalli objective: to evaluate the acute effects of the nitric oxide synthase inhibitor l-n~ hc ( c ) on selected indices of organ function in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . [xg/kg/ min with a map _< mmirlg. cardiovascular support was limited to na + dobutamine. c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. indices of organ function were assessed at baseline (t = ); at the end of treatment (t = ); and h after treatment (t = ) with c . results. -median values (* assessment made at h or when c discontinued). conclusions: there was no appareut dose-dependent adverse effect on these indices of organ function either during or after exposure to c . the plmelet count tended to fall whilst creadnine appeared to increase over time in all dose cohorts. this novel and promising therapy for septic shock will now be evaluated in a randomised, placebo-controlled safety and efficacy sludy. pharmacokinetics of c in patients with septic shock preliminary results z. hussein, b. jordan, c. fook-sheung, k. guntupalli objective: to evaluate the pharmacokinetics of the nitric oxide synthase inhibitor l-n~ hc ( cg ) given by continuous infusion for h in patients with septic shock. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion --> . ~tg/kg/min with a map _< mmhg. cardiovascular support was limited to na • dobutamine. c was administered for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. plasma was collected from each patient over a h period and analysed for c . pharmacokinetic parameters were derived from plasma concentration-time profiles using non-compartmental pharmacokinetic analysis. results: the (cm~ -maximum plasma concentration; auc -area under curve; cl -plasma clearance; v,, s -steady state volume of distribution; t'/ -plasma elimination halflife). conclusion: the pharmacokinetics of c in patients with septic shock are dose-independent at infusion rates up to . mg/kg/h. at higher rates, clearance of c decreases without any marked change in volume of distribution. c metabolism may be partially saturable at dose-rates above . mg/kg/h. obiectives: investigate the effect of the no synthase inhibitor, l-nt-methylarginine hc ( c ) on the haemodynamics and survival rate in a conscious mouse model of endotoxin shock. methods: female cd- mice ( - g) were instrumented under gaseous anaesthesia (isofluorane, %) and connected to a swivel tether system for continuous monitoring of blood pressure and drug administration. results: after h recovery, endotoxin administration (e. col• :b , - . mgkg - i.v.) elevated the plasma concentration of nitrite/nitrate (nox) and caused a progressive fall in mean arterial pressure (map) from + to + mmhg (n= , p< . ) at h, with a survival rate at h, h and h of %, % and % respectively. c administered as a h continuous infusion ( mgkg-th -t i.v., n= ), h after endotoxin, inhibited the elevation of plasma nox and attenuated the fall in map from + to + mmhg (n= ) at h, with an improved survival rate at h, h and h of %, % and % respectively. conclusions: this study suggests that overproduction of no is involved in the hypotension and mortality characteristic of septic shock. inhibition of no synthase using c represents a novel and promising treatment for septic shock. cultures of e.coli ( , %) and candida( , %) were olso received from autopsy material of children;p.aeruginosa,unspored anaerobes,proteus sp.,s.aureus,b.pneumonia were found in the few cases. in adults the spectrum of bacterioflora was mo~ re limited speaking about the number of species and cultures. in generalized forms of bacterial pyo-septic pathology a wider specific spectrum of causative agents was revealed usua fly with associations. e.coli and k.pneumonia played the leading role in children as well as in adults. in general,k.pneumonia ( , %cultures) and common e.coli( , %)prevailed according to the date of microbiological investigations of authopsy material in pyo-septfc pathology in . objectives: .in spite of all clinical exertion sepsis is still the reason for high clinica! lethality. this study is characterizing the group of patients which survived a septi~ shock. methods: during a period of months all surgical patients on icu were registrated prospectively, more than parameters for each of them were documented'daily in a paradox file. results (see table ): of patients fulfilled the criterion of a septic shock (r. bone, ) , of them died at the lth day, while the surviving group of patients stayed almost days at icu. obiectives: to compare the effects of and % pentastarch solutions to a human albumin solution on oxygen delivery (do ) in septic patients. methods: this stud}, included septic patients with fever (t > ~ tachycardia flqr > /rain), tachypnea (rr > /min) or mechanical ventilation, leukocytosis (wbc> /mm ) or leukopcnla (wbc< ()/mm ) and a clinical source of infection, who required a fluid challenge. in each patient the pulmonary arterial occlusion pressure (paop) was < mmhg. patients were randomized to receive ml of % albunun (n:i ), hydroxyethyl starch (hes -mw /d.s. . ) % (n: ) or t % (n=i ); patients were also treated with adrenergic agents. results cardiac index (c ) increased significantly only in % lies (table) hemoglobin (hb) decreased significantly at min in the same group. there was not significant change in oxygen delivery ( do ). baseline ci alb . :: . (l'min/m ) hes % . = . hes % . polyneuropathy of the critically ill (pci ) is a well recognized complication, acquired in the course of severe illness. we undertook a prospective study, to estimate the severity, extension and time of onset of pci in a selected group of patient with established septic shock ( bone's criteria ). all patients received inotropic circulatory support and were mechanically ventilated. none received relaxants or aminoglycosides. pci was diagnose<by clinical investigation and by emg, and repeated weekly ( axonal degeneration ). after days ( day = onset of septic shock ) in % of the patients pci was demonstrable. after days % of the patients had pci. there was a strong correlation between pci and other mof and between pci and encephalopathy ( eeg ). we conclude that i. pci is a common complication after septic shock. . pci develops early in the course of illness ( % after days ). . pci can be considered as a part of mof, suggesting a common pathogenesis. objectives: we addressed two questions: ) can serial measurements of vapco and avph also reflect the onset of tissue hypoxia during endotoxemia? ) are whole body changes in vapco and avph associated with parallel changes in regional circulation? methods: in anesthetized, mechanically ventilated dogs exhaled gases were sampled for determination of oxygen consumption (vo ). a catheter was positioned into the pericardial cavity to induce cardiac tamponade. ultrasonic flow probes were placed around superior mesenteric, left renal and left femoral arteries, and the corresponding veins were cannulated. group l served as control (n= ), group (n-- ) received mg/kg of endotoxin. thirty min later, tamponade was induced to gradually reduce do . results: systemic do crit was higher ( . _+ . vs . + . ml/kg.min, p < . ) and critical oxygen extraction ratio (o ererit) was lower ( . +_ . vs . +_ . %, p< . ) in the endotoxie than in the control group. meslenteric and femoral do crit were higher in the endotoxic than in the control group ( . _+ . vs . _+ . mlll g tissue.min and . _+ . vs . _+ . ml/min, respectively, both p< . ). regional o ercrit were lower in we endotoxic than in the control group (mesenteric: . _+ . vs .i_+ . %, renal: . + . vs . -+ . % and femorah . -+ . vs . _+ . %, all p< . ). vapco and avph followed a similar pattern in both groups, increasing slightly before do crit was reached, but dramatically wh,en do fell below do crit. in the presence like in the absence of endotoxin, systemic and regional do crit calculated from vo , from vapco , or from avph were similar; do crit was also significantly higher in the mesenteric and the femoral beds of the endotoxic than the control dogs. systemic and regional do crit could be calculated from the blood lactate levels only in the control group. conclusions: during an acute reduction in blood flow i) vapco and avph can reflect hypoxic threshold in the presence like in the absence of endotoxemia. ) alterations in organ oxygen extraction capabilities induced by endotoxin can be reflected by regional changes in vapco and avph. objectives: enhanced nitric oxide (no) release has been incriminated in the vasodilation and myocardial depression characterizing septic shock, but the administration of no blockers has yielded equivocal results. the present study explored the systemic and regional effects of a no donor linsidomine (sin-i) during endotoxic shock. methods: anesthetized dogs received endotoxin ( mg/kg iv), followed min later by a saline infusion to keep cardiac filling pressures constant. oxygen uptake (vo ) was derived from the expired gas analysis. regional blood flow was measured by an ultrasonic flowmeter (transonic). results: the control endotoxie group (n= ) maintained low arterial pressure and systemic vascular resistance. the dogs receiving a continuous infusion of , , ~ug/kg.min of sin- starting min following initial fluid resuscitation (each dose for h), had a higher cardiac index ( . -+ . vs . _+ . l/min.kg, p< . ) and lower systemic and pulmonary vascular resistance than the control group ( -+ vs -+ and -+ vs -+ dyne.sec/cm , respectively, both p< . ). arterial pressure and pulmonary artery pressure were not influenced. sin- significantly increased the mesenteric blood flow from -+ to + % of baseline levels and renal blood flow from -+ to -+ % (both p< . ) but did not influence femoral blood flow. the relative blood flow was increased in the mesenteric bed (at all doses), and reduced in the femoral bed (at highest dose). systemic oxygen delivery, vo , oxygen extraction and blood lactate levels had similar course in the two groups. conclusions: in fluid-resuscitated endotoxic shock dogs, the no donor sin- increased cardiac index without deleterious effects on arterial pressure, and increased splanchnic blood fl w. objectives: sepsis syndrome is associated with the release of a variety of inflammatory mediators, such as interleukins, tumor necrosis factor and platelet-activating factor (paf). administration of paf, a naturally occuring phospolipid, to laboratory animals has been demonstrated to resullt in pathological changes that closely resemble those found in sepsis. in addition, paf antagonists of various origins have been demonstrated to attenuate cardiovascular collaps and to protect against lethality in endotoxemia. in the present study the efficacy and safety of the paf-antagonist tcv- g was investigated in sepsis syndrome patients. in addition, the putative inflammatory parameters tumor necrosis factor (tnf), interleukin il) - il- , and soluble (s) e-selectin were measured in both tcv- and placebo treated patients. metho.~a randomized, double-biind, multi-center study was undertaken to compare the safety and efficacy of intravenously administered tcv versus placebo (takeda chemical industries ltd., osaka, japan). tcv- was used as add-on to conventional therapy in the treatment of patients with severe sepsis and septic shock ( . mg/kg body weight intravenously over hrs, twice a day for one week). day mortality was registered, as well as vital signs, laboratory parameters, hemodynamic parameters, apache ii score and mof score. plasma samples for the determination of inflammatory parameters were collected twice a day for one week. the study was approved by each institutional review board and written informed consent was obtained for each patient. results: a total of patients were included in the study. one patient had to be excluded as a result of protocol violation of the remaining patients patients were randomised to receive tcv- and to be treated with placebo. there were no significant differences between the treatment group with respect to age. gender, and apache i~ score on admission. however, admission levels of il- and il- , considered to reflect severity of disease, tended to be higher in tcv treated patients: . . vs . ng/ml for il- (p. ) and . vs . ng/ml for il- (p. ) in tcv- and placebo treated patients, respectively. a remarkable difference in survival, however not significant, was observed at day i.e. the end of tcv treatment (mortality: out of in the tcv group and out of patients in the placebo group). the inc;dence ui ~-,~verse events, 'n both treatment groups were comparable. plasma il- and plasma il- levels tended to decrease more rapidly in tcv treated patients compared to controls (p=. and p=. , for il- and /l- respectively) conclusions: tcv- is safe as add-on treatment in sepsis syndrome patients. the data presented indicate that tcv- may enhance survival of sepsis syndrome which will be assessed in a phase ill study. objective: oxidation of lipids by free oxygen radicals playes an important role in sepsis. an important source of oxygen radicals is the respiratory burst of phagocytic leukocytes, especially~ polymorphonuclear leukocytes. clinically the hallmark of sepsis is the capillary leak, which is mediated in part by oxyradicals. the adult respiratory distress syndrom (ands} represents the most studied capillary leak phenomenon in sepsis. methods: in ii patients (df,~m, aged - y.) with verified septicemia had been included in this study. beginning from day oxidisable lipidautoantibodies (club), ~opterin and crp were determined in the patients serum and compared against the apache ii score during the days - . patients, f and m died @u= ring their stay at the icu, of them in less than h~urs: after admission. at the begin surviving patients showed olab values between - %, non-survivors between - %, com= pared to neopterin values of - m~ol/l in survivors and - ~mol/l in non-survivors. apache ii score didn t show any difference. during the following days olab sbowed an in= crease in survivors, while in non-survivors olab stayed equal or showed a decrease. no difference between both groups was found in neopterin, crp and apache ii score. as result we conclude, tbat lipidperoxidation playes an important role during septicemia. olab as a marker of this process are predictive for the outcome of patients. obiectives : to evaluate the influence of cardiopulmonary bypass ongastrointestinal transit. meth~xls; gastrocoecal transit time (gtt) in consecutive children on day after uncomplicated open heart surgery was compared to gtt in children after closed heart thoracic surgery and to healthy controls. gtt was measured by hydrogen breath testing, using lactulose (o, g/kg in a % aequous solution) as nonabsorbable marker. exspiratory hydrogen content was measured using a electrochemical system (stimotron). patients in both groups had continuous infusion of morphine and midazolam and were comparable in respect to catecholamine dose. children with a history of toddler's diarrhoea and children with elevated central venous pressure were excluded. results: gastrocoecal transit was delayed in all patients after cpb, no transit was achieved within minutes in / . after closed heart surgery gtt was delayed (+- ) min vs. (+- ) compared to controls, but transit was achieved in all aptients within rain. mean dopamine dose was , mcg/kgmin after cpb and , meg after closed heart surgery.. conclusions: after uncomplicated cpb gastmcoecal transit is extremely delayed. the degree of delay is not explained neither by the use of analgetic and sedative drugs neither by the use of catecholamines. factors directly related to cpb (e.g. low flow perfusion, hypothe,mia) may be responsible. these findings are of limited clinical relevance in ancomplicated cases. in critically ill patients delayed enteral feeding may contribute to infectious complications. studies of therapentic measures to accelerate gastrointestinal transit therefore are warranted. neonatal ecmo -czech experience. nekvasil r., penkova z, vasek l., plier p., bobula a novotna e., pavlicek v., hnilicka m. nicu and ecmo center brno and dept. pediatric surge ', children's hospital brno, czech republic. introduction. in spite of the fact that neonatal ecmo has been gradually considered a standard method of solving uncontrollable respiratol t failure in newborns in most countries of the western europe, the introduction of this sophisticated method in countries of the former communist block meets a lot of problem. material methods. in the course of two years, only newborns, b.w. - g, were reffered to neonatal ecmo because of uncontrollable respiratow failure. at the admission the average values of oxygenation index were + , and aado , -+ , kpa. results. newborns ( %) died shortly alter" admission or during transport without possibity to further is newborns ( , %) were treated using high-frequency ventilation (hfo or hfjv), one for conspicuous airway resistance paradoxically with low-frequency ippb. all ventilated newborns survived. ecmo was applied in newborns ( , %) and of them survived the mortality rate of group mentioned was %. conclusion. the fact that in the czech republic ( mil. population with natality rate of about . newborns/year) only small part of patients was reffered to neonatal ecmo has a number of causes. the most important are: unacquaintance of prognostic and indication criteria at forwarding workplaces and the aversion of neonatologist to all new.therapeutic interventions. last but not least, a negative role is also played by current change of health service systems when, under the influence of health-service insurance companies a newborn in serious condition given only a standard intensive care in primary and secondary nicu is literally "the golden calf", and therefore these workplaces either do not send him or send him too iate ~o an ecmo center. stndy aim: urfactant, which is being applied into the lungs for treatment of respiratory distress syndrome, can reach the circulatory blood system by absorption. it refinances local fimctiun of macrophages and lymphocytes and increases the accumulation of nentrophils into the hmgs this eunld influence the local acute phase reactiml in the hmgs after surfactant application. "ilia aim of the stud), was to investigate the influence of oatural and artificial surfactaat onto the acute phase reaction and the blood elottiog system. material :and methods: a) measurement of tnf-a, - , ltb and thromboxane b release in whole blood: each of . ml hepariaised blood of healthy adult volunteers was iucubated lbr hears with eillier ill ug/ml lps, mg/ml b&,ine smfactant (alveulhct/themae), rag/nil artificial surfactant (exosurf/wellcome), og lps + i mg/ml bovine surfactant or i ug lps + i mghal artificial sorfactant, tleparinised bhx-,d without additions was used for controls. ' e concentration of e)lokines and eicosanoids ".van measured semiquantilatively by eijsa or eia (dimmva/hamburg) after ceatrifagalion, b) measurement of platelet aggregation: each of . ml haparinised hltxxl of healthy adult vohmteers was inculmled lbr hours with eilher aghnl i,ps, i mg/ml bovine surfactant (alveafact/thomae), i mg/ml artificial snrlhctant (exosurf/wellcotne), it} ug lps + i mghnl bovine snrfactant or ug lps + i mg/ml artificial surfaetant, tlepminised blood withont additions was nsed for controls. platelet aggregation in whole blood was measured by impedance in the aggregometer (g~nstaedt). c) measurement of the dotting activity: citrated bleed of healthy adult w~lunlccrs was mixed with difl'ereul couccalrations of imvine or artificial snrfactant fad then prolhrombiu tiaras and imrlial thrmnlx~plaslia filues were ineasnrcd. for measurement of the prokoagulatioo acfivily the reagent in the qnick test was replaced by surfaclant. results: dependmlt on the dose both surfactants stimulated the release of - but not or tnf-a io wlmle blood. "illere was no suppression of the lps-indaeed eytokine-release. both surfaclants did not directly influence the extrinsic blood coagulation system, while both activated the inniasie activity dependant on the dose. platelat aggregatiun was slightly stimulated by bovine snrfactunt and strongly inhibited by by artificial surthctant. in comhinafion with . ~ both factors showed no difft.'renca to lps ahme.'fhe reltu.tse of eiconasnid~." was stimolated more by artificial surfactant then by bovine surfilctant with regard to the cyehmxygelmse (thromboxsne b ) and the lipooxygenase (lencotrieae b ) pathways. conclusion: we cooclude: ) i:lovine as well as artificial surfaelant stimulate the cellular inmnn]e response. ) bovine as well as artificial surfnctant activate the intrinsic ctmgnlation cascade. ) bovine surlilctant stimulates platelet aggregation, artificial sar-fijctant inhibits platelet aggregation.. introduction: although the use of modem noninvasive methods like measurement of tope , tcpco or san leeds to an carly infonnation about pathologic alterations of the gas exdmage of ventilated patients, these methods cannot replace invasive bloodgas analysis. a new noninvasive method to monitor the capillary gas exchange is the reflection spectrophotometry. to record reflection spectra with a ldgh sensitivity on the surface of tissue we eonstnmted a special mierolightgnide photospectronmter (empito). this spectrometer enables the investigation of local helerogenities of llbo and lb content, capillary flow rate and oxygen uptake rate. aim of the study: ) to compare the sousitivity and specifity ofthe empilo with other non-invasive method~ of monitoring the gas exchange in neonatal intensive care patients. ) to investigate the possibility of obtainiug infonnations about the local nptake and the venous as well as arterial satnration. patients and methods:we investigaled non-selected patients of oar pediatric intensive care unit. for coulinnons monitoring we conslracted a special sappert to fix file end nf the microlightguide+ during the investigation tope , tcpco and san were measured by standard methods. "fo investigate the local tisslm oxygen uptake we recorded spectres within minutes by moving the lightgnide over an described area of the skin of the patient. 'lhe reselting i(gx) l ibo vahms were sorted by a software package. on the assumption that the low values correspond to the tibo value of the veaons ends of the capillaries and the high values to those of the arterial ends we ) it is possible to gel infonnations about the local o -uptake and arterial saturation ia the peripheral tissue by photoslg'ctroscopy. ) in combination with noninvasive pl i-measorement it seems possible to reduce withdrawal of blood for invasivn bhmd gas analysis. objectives:improve ventilation,tissue oxygenation and acid base balance among extremly low birth weightand premature infants. methods: fourteen cases were s~udied,their gestational age ranged from( - )ws.continnous positive air way pressure was applied to six cases at peep level from ( - )cm h o through nasal pronge,(group i),the other cases were managed as routine,(group ii).blood gases, tcpo ,tcco ,resp.rate,depth and pattern were monitored for assessment of tissue oxygenation and ventilation, results: our rasults showed that early application of cpap improve ventilation among ( . %)of cases,while ( . %)of cases need imv.the cases of group ii need imv among ( %)of the studied cases during the second or the third day of life. conclusions:-this preliminary study showed the import-............ ance of early application of cpap before the onset of respiratory distress syndrom to improve spontaneous ve ventilation,tissue oxygenation and to gecrease the risk of intubation. comparative assessment of pediatric intensive care; a national multicenfre siudy. reinoud j.b.j. gemkc, gouke j. bonsel , the dutch picasso (pediatric intensive care assessment of outcome) study group. twilbelmina children's hospital and utrecht university, utrecht department of clinical epidemiology, academic medical center, : amsterdam, the netherlands the performance of all ( ) pediatric intensive care units (icus) in the netherlands ( tertairy and non-tertiary) was analyzed in an open prospective muiticenter study. effectiveness of care was defined as the ratio of observed to prism-score derived expected mortality aenee, standardized mortality rate). efficiency was determined by objective criteria (mortality risk > % or administration of at least icu-dependent therapy)'. consecutive admissions aged < years old were included. overall, observed and expected mortality were in good agreement (p > . ). between hospitals, crude mortality showed wide variations (mean . %, range - %). however, in each center, observed and expected mortality were similar (mean ratio . , range . - . ). in tertiary care centres, severity of illness corrected mortality in high-risk patients was less than in non-tertiary care centres; paradoxically, in low-risk patients the opposite was found. probably the large proportion of low-risk tertiary care patients suffering from severe, incurable chronic disease, explains the higher mortality in this group. this indicates that simultaneous assessment of circumstances of dying and of long term morbidity in similar future studies is imperative. the average proportion of efficient icu days was %, however large variations between units were found (range: - %). in conclusion differences in mortality rates among pediatric icus were explained by differences in severity of illness. high efficiency rates in combination with adequate effectiveness, found in several centres suggest that admission and discharge decisions might be improved by a better selection of high risk patients requiring icu-dependent therapies, especially in less efficient centres. objectives: previously published studies showed that serum lactate levels correlated with outcome of severe ill adult, 'we hypothesized that critically ill newborns are often incurred hypopeffusion manifested by elevated lactate levels. these initial blood lactate levels should be related to nicu outcome. design: prospective study with ethical comfnittee approval. setting: the -bed neonatal intensive care unit of a university hospital material and method: a total of consecutive outbem newborns admitted to nlod from , . to ., . were enrolled to the study. babies who died or were discharged from the unit within hours of treatment were excluded from the study, mean birth weight was g (+/- r), mean gestatational age was weeks (+/- . wks), mean age at the admission was h (+/- hi. multiple (~_ j organ system failure occurred jn . % of babies at the admission./~tertal lactates were measure/at the admission, among - hour and - hour of n[c'lj therapy. outcome was defined as a mortality and length of nicu stay. results" survival rate was . %, mean length of nicu stay for survivors was . days (+/- . day). we found high lactate levels at the admission in . % babies (~ . % with levels above . retool/i). the mean arterial lactate concentrations for nonsurvivors were signiftcahtly higher than for survivors durin~ consecutive da~ as follows: objectives: the purpose of our research was to analyze the frequency of bronchial asthma (b.a.) exacerbations in pregnant women and health status of infants. methods: the research was based on the epidemiological investigation and prolonged observation of pregnant women with b.a. during the gestation period. remission of b.a. before the pregnancy in excess of years was recorded in patients ( . %), patients ( . %) reported a - year remission and patients ( . %) had a remission lasting less than months before they became pregnant. results: seven patients ( . %) developed medium attacks in the second half of pregnancy, four patients ( . %) experienced light attacks of b.a. asthma attacks were most frequently caused by acute respiratory diseases and stress factors. in two cases with grave manifestation of b.a., the pregnancy ended in abortion within the first - weeks due to the frequent and heavy choking attacks. to fight b.a. attacks, five patients used adrenomimetics (salbutamol, becotid) in sprays, six women were administered theophyllinum and salbutamol in the form of tablets during - weeks. a significant portion of pregnant women with b.a. ( %) exhibited frequent complications during pregnancy (toxemia, late gestosis, threat of miscarriage). our findings prove that babies born from women with b.a. of domestic and pollen origin had a low body weight ( - gr), functional immaturity and chronic antenatal and intranatal hypoxia twice as often as the infants born from healthy women without allergic background. conclusions: preventive treatment of women with b.a. prior to pregnancy is required to maintain a stable remission of the disease, which is a key to having healthy children delivered by mothers suffering from b.a. introduction. intracerebral hemorrhage (ich) is a common event in human prematudty, affecting about % of newborns weighing below g who are born before weeks of gestation, however, little is known about the pathogenesis of ich with exception of the prematurity of the brain itself, (birth) trauma, and asphyxia. the postischemic production of oxygen free radicals (ofr) dudng reoxygenation as a cause of brain damage has been demonstrated in animal research. since almost all preventive antioxidant activity of plasma is associated with ceruloplasmin and transferdn we investigated the association of such iron-oxidizing resp. iron-binding proteins and ich. we could demonstrate significantly reduced levels of both, iron-oxidizing and iron-binding proteins, in premature asphyxiated newboms pdor to development of ich. an increase of suparoxide after hypoxia in the presence of iron ions facilitates the formation ofthe highly reactive hydroxyl radicals. our data support the theory that ich may be caused by ofr, which can damage any sensitive tissue including growing endothelial cells. the estimation of transferrin-saturation and measurement of ceruleplesmin levels might help to identify an infant at dsk before the onset of ich. with the new medos | hia-vad | cardiac assist system the missing tool in the armamentarium of cardiac surgeons is available in two pediatric sizes: i -ml and -ml pump volume. the right sided pumps are % smaller for biventricular use. between february and may we implanted this assist system in children. the indications and demographics are indicated in the following table (left ventricular assist device-lvad, right vad-rvad univentricular vad-uvad, post cardiotomy cardiac failure-pcf, dilated cardiomyopathy-cmr bland white garland syndrome-bwg, tetralogy of fallot-tof, hypoplastic left heart syndrome-hlhs). objectives: evaluate tile effeci'of inhaled nitric oxide (no) as puhnona] t vasodilating agent ill tile posloperalivc period after correclion of congenital heart defects in infant. patient n.l: kg, lnonlhs, down syndrome undenvcnl rep~fir of atrioventricular septal defect (avsd). after surgery the puhnonary arlcry pressure (pap) slowly rose to tile syslemic dcspilc tnaximal eonvcnlional fllerapy (fentanyl mcg/kg/h, hypocapnia of mmhg and metabolic alcalinization). no was delivered into tile inspiratory branch of!be breathing circuit at ppm, and the gas aoalyser for no and no (polylron dmger) were situated at the espiratory branch, a rapid dccrcasc of pap io i/ of systemic was obtained with a dramalic improvement. no was continued at ppm for six days and the baby was exlnbated if! days after surgery and discharged from the icu days after. patient n. : . kg, monlhs, onderwen! repair of avsd. the day after surgery the systemic oxygen salnralion was % wilh a pap at % of systemic. two hours of c wenlional therapy failed o improve ihc patient and no administration was slarled at ppm. so dramatically incrcased to %, but the pap dropped only to % of syslemic. nevertheless ihe clinical conditions improved and the no administration could be reduced at ppm in the following days. she was extubaled days after surgery and discharged from the icu days after. patient n. : kg, 'ears. underwen| hearl tral~splantalion for congenital heart disease with moderate hypoplasia of pulmonary arlcrics. at the end of cardiopulmonary bypass the transpnlnlonary al~erio-venoas gradient yeas higher than mnfflg and we speculaled !hat w'ls due to a degree of puhnonary vasocostrictiont. the nsnal dose of no was otilised, however no significant modilicalion of pulmonary pressure or systemic oxygen saluralion was noled, and after h no was discontinned. tile palienl was carried io the icu with maximal inotropic support, extubated after d;b's and disclmrged from the icu after days. in all patient no major adverse effect relaled to no admilfistration ",','as holed. conclusion: in our experience no ms a pulmonary vasodilaling agent is effective and easily adjustable to tile palienls requiemenls, however its use remains limited ill those palienl ill whoin tile alnonll! of fixed inlllllojliify vascular resistance is predominanl. we report the use of ecmo support in two unusual cases of severe tracheal disruption in which it had become impossible to achieve adequate ventilation. case : severe tracheal laceration due to aspiration of a share forelan bodv: a previously healthy month old toddler was referred for ecmo following aspiration of a porcelain foreign body (with razor sharp edges) which had become embedded in the right mainstem bronchus with massive extrusion of air. this was removed on veno-arteda[ ecmo support, as the patient was unventilatable prior to bronchoscopy due to ongoing airieak. ecmg was continued after bronchoscopy to permit airway healing without the presence of an endotracheal tube. unfortunately, an extensive pulmonary haemorrhage on day of ecmo necessited re-exploration of the airway. this revealed a posterior tracheal tear from the cricoid to the middle of the right lower lobe. following repair the patient was left on ecmo support together with high frequency oscillation ventilation (hfov), the latter being used to minimise potential aideak and maximise alveoli recruitment. ecmo was weaned after days ( hours) -the patient was extubated weeks later. case : tracheal wound dehiscence due to seosls -tracheal transelant on ecmo: a month old infant with a c[inically significant congenital long segment tracheal stenosis and left pulmonary artery sling underwent resection of the stenosis, followed by primary reanastomosis. this was complicated, days later, by severe mediastinitis and complete dehiscence of the anastomosis. an autologous pericardial patch was used to repair this, however, the tracheal wound again dehisced days later making mechanical ventilation impossible. in view of ongoing sepsis and a severely disrupted trachea ecmo was the only possible form of support. following resolution of the local sepsis ( days) a definitive procedure in the form of a tracheal homograft (transplant) was undertaken on ecmo. the patient was managed on ecmo and hfov for a further days, the hfov being used to optimize rapid lung inflation. unfortunately this patient died months after weaning from ecmo due to complete disintegration of the homograft, which was not deemed reparable. conclusions: ) ecmo can be used in the acute management of oxygenation when there is major airway disruption making mechanical ventilation impossible. ) hfov was a useful adjunct in aiding recruitment of lung volume on ecmo in these two patients. backoreund: persistent pulmonary hypertension of the newborn (pphn) consists of a heterogenous group of diseases ranging from transient reversibte pulmonary hypertension to fixed primary malformations of the lung (primary pulmonary dyspfasia-ppd). inhaled nitric oxide (ino), a selective pulmonary vasodilator, has been proposed as a treatment for severe pphn. obiective and methods: ino was administered to near term neonates with severe persistent pphn, oxygenation index > and echocardiogrephic evidence of pulmonary hypertension, in order to further determine the clinical role of ino in the treatment of pphn. the response to ino was also analysed retrospectively to examine whether this could be of diagnostic value in differentiating at an early stage patients with reversible from fixed causes of pphn results: twenty one of the patients studied responded to the initial trial of no ( ppm x minutes), as defined by a greater than percent improvement in pad as well as a fall in the el to < . these patients were continued on ino therapy, with patterns of response emerging: pattern babies (n= ) continued to show a sustained response to ino and were successfully weaned from it within days -all survived. pattern babies (n= ) failed to sustain their response to ino over hours, as definded by a rise in the el > . six survived, five with ecmo. pattern babies (n= ) had a sustained dependence on ino for - weeks. all three died and lung histology revealed severe primary pulmonary dysplasia (ppd). patients with ppd (pattern ) not only required ino for longer periods of time than did the sustained responders (pattern ), but also required significantly higher doses of ino we report on the air transport of paediatric intensive care patients. these transports fall into three categories: ) retrieval of critically ill neonates and paediatdc patients referred for either ecmo or inhaled nitric oxide (ino) (n = ). one patient was transferred on ind. mean transfer time . hours (se + . hrs). ) long distance international transport using chartered aircraft (n = ). the indications for these transfers included both urgent retrievals for cardiac surgery and semi-elective transfer of stable patients back to their referring unit following treatment in tertiary centres. mean transfer time . hours (se + . hrs) ) long distance international transport using commercial aircraft (n = ). indications for transfer were either semi-elective retrieval for tertiary treatment or the return of stable chronically ventilated patients to their referring hospitals. mean transfer time hours (se _+ .fhrs, longest hrs). the transport team consisted of a paediatric intensive care doctor of at least registrar grade and a registered sick chidrens nurse with intensive care experience. the administrative components of the transfer (ambulances, airlines, customs) were managed in collaboration with companies specializing in air ambulance transfers. outcome: all the patients were safely transported to their destination without mortality or morbidity. complications durino transfer ir~lv~; ) patient complications -semielective endotracheal tube change and central access needed in the only patient brought to the commercial aircraft by the referring hospital (all others retrieved directly from referral hospital), seizure in patient with known encephalopathy, severe cyanotic spells in patient with fallots tetralogy who was retrieved for urgent surgery for this indication ) mechanical compfications -ventilator failure, incubator battery failure, oxygen regulator failure -all occurred with equipment sent from referral hospital, this was unfamiliar and unchecked by our transport team -it was not the decision of the transfer team to use this equipment on this single occassion. ) administrative complications -confiscation of incubator battery by airport security police, excessive delay by custom officials ( hours) in the airport. the incidence of such problems were felt to be low and unpredictable. in conclusion: mechanically ventilated paediatric patients can be safely transported on both chartered and commercial airlines. these transports are best accomplished by trained intensive care medical and nursing staff with the backing of an air ambulance organization competent in arranging the necessary administrative details. it is essential to use your own equipment and to retrieve the patient _directly from the referrin(] hospital to minimise ootential complications. our experience with anaesthesia for paediatric electromyography _w_._pla_ti_k_a_n_o_v, r.eousseff, k.pavlova, d.marinova dpts. of anaesthesiology and int. care and clinika] neurophysiology, med. university, pleven, bulgaria ~)_b_j#~ti_v~. to t~st a " heavv sedation " regimen of anaest-es~a for the purpose of paediatric electromyography d#s~gil~ non-randomized,non-blinded human trial in the seting of an uriiversity hospetal. _m_a_t_eri_a_is_a_nd_ m_e_th_od_s_. children,asa i-if,median age years,range - who undervent eleetrcmyography required anaesthesia. they recieved low-dose ketamine + i~iazepam or midazolam via musculary route( children,age - yrs,ketamine , mg/kg, diazepam - mg total dose ) or per os ( children,ketamine - mg/kg,diazepam , mg/kg or midazclam , - , mg/kg ) _resu_l_t_s. - minutes after medication a state of heavy sedation with weak spontaneos and stimuli-provoked movements was achieved in all children, that lasted - minutes and allowed adequate needle emg and nerve conduction investigation. children recieved additional , - , vol.% halothane during the placement of the needle. non -invasive blood pressure , breath and heart sounds and hb sad by pulse oxymetry were monitored.none of the older children disclosed memories of pain when asked after they regained adequate verbal contact.no complicationes were observed. antenatal maternal steroids reduce the risk of periventricular-intraventricular hemorrhage in very premature neonates treated with natural surfactants. i.apostolidou, c.papagaroufalis, g.touloumi, m.xanthou, n.kalpoyannis a' and b" neonatal icu "ag. sophia" children" s hosp. athens, greece. dept of hygiene and epidemiology, athens university, greece. obiectives: the aim of the study was to evaluate the association of periventricular-intraventricular hemorrhage (p-ivh) in surfactanl treated premature neonates with pre-and postnatal variables. methods: the population of the study was neonates admitted during the years to , with gestational age _< weeks and severe respiratory distress syndrome (rds) (mechanical ventilation and arterialalveolar oxygen tension ratio (ajapo ) < . ), who received rescue therapy of at least two doses of natural surfactants (alveofact or curosurf) and examined with ultrasound and/or autopsy for the presence of p-ivh (papile's classification). the examined factors in each neonate were the following: gestational age, birth weight, sex, multiple pregnancy, antenatal maternal steroids (complete and incomplete course of betamethasone), a/apo before the administration of the st dose of surfeclant, delivery, apgar score at min, type of surfactant, pneumothorax and patent ductus arteriosus. the statistical methods used were x and one-way analyses of variance followed by logistic regression medels, results: the incidence ot p-ivh was . %. three factors were found to have an independent relation to p-ivh (final logistic regression model): gestalional age, a/apo before surfactant administration, and antenatal administration of maternal steroids (complete and incomplete courses). for every weeks of lower gestational age the neonates had an almost doubled associated risk of p-ivh (or: . , % c : . , . ). for every . on average decrease of a/apo before surfactant administration the risk of p-ivh in the neonates was . times higher ( % ci: . , . ). the neonates whose mothers received antenatally steroids had only one tenth of the risk of p-ivh of the neonates whose mothers had not (or: . , % ci: . , . ). conclusions: our results suggest that the antenatal administration of maternal steroids, even less than hours before delivery, reduce the risk of pqvh in very premature neonates treated with natural surfactants, whereas the small gestational age and the lung immaturity still remain the main risk factors tor the development of p-ivh. we analysed retrospectively the management of ( boys, girls) accidental ingestions of foreign bodies in children (mean age : . years, range : months- years). no child had ingested more than foreign object. the majority of the ingested foreign bodies were : coins (n : ), toy parts (n : ), jewellery (n : ), batteries (n : ), "sharp" materials such as needles and pins (n : ), "large" amounts of food (n : ). impaction of food occurs more frequently in children after oesophageal reconstruction in cases of oesophageal atresia. although according to literature "coca-cola" is reported to be effective, this was not seen in our experience. / patients had minor transient symptoms at the moment of ingestion, such as retrosternal pain. only children experienced severe manifestations (cyanosis, dysphagia). in these children, endoscopy revealed oesophageal and gastric erosions. children were seen at the emergency ward within a few hours after the accident ( mean : hours, range min. - hours). chest and/or abdominal x-ray was performed as first-line investigation ( / objects were radio-opaque), and revealed an (unexpected) oeeophageal impaction in children. in / the foreign body was in the stomach. batteries, sharp objects and objects trapped in the oesophagus were removed, either by endoscopy or by magnet-extraction whenever possible. the outcome of the patients was excellent. no complications were observed. extraction is recommended in symptomatic patients, and whenever the foreign body is trapped in the oesophagus, or if the foreign object is "sharp" or a battery. objectives: two strategies were used for management of malignant diphtheria in children aged from . to years. methods: protocol n consisted of intravenous administration of diphtheria antitoxic serum, prednisolone ( mg/kg bw/day), plasmapheresis and supportive care. protocol n included the use of antitoxic serum against the background of high-dose dexasone ( - mg/kg bw/day), hemocarioperfusion and a preventive use (before the clinical manifestation of myocardial damage) of inotropic medications, inhibitors of angiotensin-converting enzyme and pentoxyphylline. each of protocols included the monitoring of serum toxin (diphtherin) levels. results: the group of patients treated according to the protocol n consisted of children with malignant diphtheria, of them with severe malignant diphtheria (grade and ). all patients exhibited the circulation of toxin during at least three days after the start of treatment. all patients with severe grade of disease demonstrated heavy cardiovascular disturbances associated with malignant diphtheria. of the children in the group died seven. the children of the second group were treated according to the protocol n . out of total of patients of this group. patients had severe malignant diphtheria. in all children a significant reduction in serum toxin level was revealed after hemocarboperfusion. in all but one case the satisfactory control of cardiovascular function on was achieved. of children admitted to the trial survived, one child with malignant diphtheria of grade and congenital filbroelastosys of the left ventriculum died. the severity of neurological complications was similar in each of groups. conclusions: the use of hemocarboperfusion, high-dose dexasone and early prevention of heart failure as a adjunct to the standart treatment has been shown to be of benefit in the management of malignant diphtheria. t. schaible, i. reiss, j. m er, l. gortner med. university of lqbeck, children's hospital, kahlhorststr. - , l~beck, germany surfactant therapy seems a promising approach for the treatment of the biochemical and biophysical abnormalities of the pulmonary surfactant system in severe ards. patients and methods: over a months period non-neonatal pediatric ards patients (age - months) in a "pre-ecmo"-situation (oi over h) were treated with bovine surfactant (alveofact| the underlying conditions-of ards were pneumonia ( ), sepsis ( ), immunosuppression ( ), near drowning ( ), neurogenous ards ( ). a total of - mg/kg b.w. was applied in several fractions. before surfactant therapy, we first tried different ventilation (best peep-finding, inversed i/e-ratio, hfo-ventilation) while monitoring the pulmonary mechanics. for hemodynamic stabilisation both norepinephrine and epoprostenol were used to optimize pulmonary perfusion for max. hrs. if there was no improvement of the oi by at least , further treatment with surfactant was initiated. in addition to surfactant all patients received a treatment with dexamethasone of mg/kg in doses. patients with no benefit (oi remained unchanged or increased within the max. - hrs) were taken on ecmo. results: nine patients improved within hours after surfactant therapy: the oi decreased from a level of (mean, range - ) before our treatment to a level of (mean, range - ) thereafter. in patients we were able to continue the positive effects of our treatment and they could be weaned of the respirator within - days. the other patients got worse despite respiratory improvement, they suffered of multiorgan failure of more than organ systems. the last patient did not benefit from surfactant, he had to be put on ecmo, but died because of a complication (hemopericard)after days. the autopsy of the ecmo-patient showed a pulmonary fibrosis, but the other death were not due to pulmonary failure. conclusion: a different sequential ards treatment integrating surfactant therapy can reduce the number of patients requiring ecmo. but ecmo as a therapeutic tool should be available in centers involved in ards treatment. l.blindl, t.p.le, h.weinzheimer, centre for paediatrics, university of bonn, germany selective reduction of elevated pulmonary vascular resistance by inhaled prostacycliu (pgi) has been reported in adults with acute lung injury, neonates with persistent pulmonary hypertension and in one infant with idiopathic pulmonary hypertension. we report on the effect of aerosolized prostacyclin in two children with secondary pulmonary hypertension. patient : in a boy with down's syndrome an avsd had been surgically corrected at month of age. at , yr of age a catheter examination revealed a pulmonary vascular resistance of % of systemic vascular resistance in room air and at an fin of . . prostacyclin ( . mcg/ml) was administered with a jet nebulizer at an fin of . . pvr declined to . systemic vascular resistance and returned to baseline after stopping pgi-inhalation. subsequent intravenous infusion ( ng/kg rain) had to be stopped after minutes because of systemic arterial hypotension. patient : a month old male infant with bronchopulmonary dysplasia developed suprasystemic right ventricular pressure inspire of therapy with oxygen and nifedipin. while he was spontaneously breathing % oxygen via face mask pao was mmhg, arterial ph was . . systolic arterial pressure was mmhg, a rv-ra gradient of mmhg was measured by cw-doppler. while fio was maintained aerosolized prostacyclin was administered over minutes. rv-ra gradient was mmhg, systemic blood pressure mmhg, pao mmhg. two hours later nitric oxide ( ppm) was inhaled at an fio of ( , . rv-ra gradient declined from to mmhg, systemic systolic blood pressure remained stable at mlnhg. discussion: sporadic experience shows that aerosolized prostacyclin selectively reduces elevated pulmonary vascular resistance in some patients. in patient the poor response to inhaled pgi compared to inhaled nitric oxide may be explained by the fact that the action of pgi is not independent from endothelial function, limiting it's effect in severe vascular disease. during the last two years ( - ), infants weighing less than gr. admitted to our referral unit. thirty four of them ( %) survived, ( % of infants weighing - g and % of infants weighing - gr survived) for the years - - the survival of these infants was % and for the years - - , % (p< . ). we analyzed the perinatal and neonatal factors influencing the outcome of these infants. the comparison among neonatal survivors ( ) to neonatal deaths ( ) shows: gestational age: . w ( ) to . w ( ) (s). birth weight: . g ( ) to . ( ) (s). apgar score: , ( ) to . ( ) (ns). presentation and mode of delivery: breech presentation is associated with higher incidence of neonatal deaths. i.v.h. (at the age of weeks): no one of the survival infants had evidence of i.v.h. respiratory problems: intubation, at the admittance of the infants . ",,( ) to % ( ) (s) use of surfactant: % ( ) to % ( ). bpd observed in % of the babies and only one was dependent on oxygen at home. antenatal betamethasone was given in % of the mothers. in conclusion: ) a great improvement in the survival rate observed in these infants the last years in our unit. ) factors with positive effect are increasing gestational age and birth weight, the absence of i.v.h. and the use of surfactant. the breech presentation and the severe respiratory problems increase the incidence of death. animal experiments demonstrated, that brain temperature determines the amount of neuronal damage caused by hypoxia and that mild hypothermia may have a protective effect. until now there is no method described and evaluated to measure brain temperature in neonatal intensive care units. we non-invasively measured brain temperature analogues, nasopharyngeal (tnasoph) and zero-heat-flux temperature (zht) at the temple whereby under zero heat flux surface temperature represents deep head and thus brain temperature. the aim of our study was to investigate the practicability of the method, the relationship of the two brain temperature analogues to rectal temperature (trect) and their dependence on insulation, thermal environment, body activity and time course. we investigated healthy preterms less then weeks postnatal age (gestational age +_ . wks; x + sd, weight +_ g) in an incubator. tnasoph was measured by a thermistor within a feeding tube, advanced to the nasopharynx, zht temple by a thermistor and a heat flux transducers both covered by an insulating pad, and trect thermal environment was characterised by operant temperature (tair . . + twall . ). body activity was video taped. measurements were performed during the following interventions: i/ insulation increased by turning the temple with sensors onto the mattress ( rain). ii) insulation increased by a cap ( min), iii) min after its removal, iiii) increased operant temperature by . + . ~ ( min). results: seven children with ea had a gasless abdomen, the endoscopic procedure excluded ( ) or diagnosticated an upper pouch fistula ( ). in patients who suspected "h" fistula ( ) broncoscopy has strong advocated method to make diagnosis and established cervical approach. from july newborns with ea and lower pouch tef received a selective transtracheal incannulation. we were not able to proceed just in case with congenital subglottie stenosis. in these patients we provided gastric drainage by radiopaque and flexible - french catheter. the knowledge of the precise anatomic position of tef consent to adjust the tip of the endotracheal tube in order to achieve best ventilation. the presence of the catheter through the fistula helps the surgeon to identify, it quickly. no complications were correlated to the procedure and no babies had early pneumonia. alimentary continuity was achieved in all patients ( primary anastomosis, resections of tef, oesophagocoloplasty and died with gastrooesofagostomy). the late mortality . % ( ) was only directly related to the severity of associated malformations. conclusion: the advantages of this technical approach are unquestionable for the anaesthesiologist and the surgeon. in our experienc e the procedure improves perioperative management of babies and appears to be safe. relation between cytokines, prethrombotic markers and endotelial injury markers in children with septic shock objectives: to establish the relationship between cytokines (tnf, il- , il- ) prethrombotic markers (d.d., pcam) and endothelial injury markers (tm, uwf) in pediatric patients with sepsis and bacteriemia without shock, and patients with septic shock. design and methods: prospective study, children ( months- years) were admitted in our picu in with the following diagnosis: bacteriemia ( ) sepsis ( ) and septic shock ( ) according to jacob's r f criteria. measurements: il- , il- , tnf, tm, vnf, d.d. pcam and routine laboratory data on admision, , , hours and on discharge. the prism (pediatric risk of mortality score) was also recorded. results and conclusions: two patients in the septic shock group died. significant differences were found between non-shock and septic shock patients in relation to tm, dd, pcam, il- , il- and tne high levels of tnf and il- are closely associated with the severity of septic shock with purpura in children. low levels of pcam on admission were associated with severe shock. who underwent open hea~nt surgery, hypervotaemia with or without oliguria was the most frequent reason to start pd ( %). in patients pd lasted less then one week and there were no complications; in patients it lasted - days (one child had a peritonitis). instillation of dialysis fluid into the peritoneal cavity was associated with a significant increase in central venous pressure. there were no significant changes in cardiac output or arterial oxygeu saturation. in all patients pd dhnjnished fluid overload or improved the metabolic status. patients ( %) survived the postoperative course and all had complete reintegration of renal function. conclusion: pd is a useful method to treat the fluid overload and acute renal failure in paediatric patients following open heart surgery with file effects of little importance on the cardiovascular fimction. obieetives: with the marketing of computerised systems for lung function testing in newborns, there has been an increasing interest in clinical approaches. percentile curves of pulmonary parameters permit an appropriate and clinically useful interpretation. however, the manual evaluation of the results using different curves is an impractical technique. therefoi'e a computer programme was developed. methods: the percentiles ( %, %, ~ %, %) of the most important pulmonary parameters were determined non-parametrically in weight-classes. for the calculation we have taken results of our own as well as other laboratories using a meta-analysis of reference studies. in all, individual data of - healthy newborns ageing between - days were collated. using these percentiles, for every parameter in relation to the body-weight the cumulative distribution was calculated approximately using piecewise linear and exponential functions. as shown in the figure the results of computing are represented numerically as well as graphically and can be included in the patient report. conelusions: clinic~d experiences with the programme have shown that representation of all measured parameters on standardised % scales allows an easy interpretation at first sight and improves the detection of pathologic patterns in the parameters. ")supported by bmft, fp "risikoneugeborene" prism (pediatric risk of mortality) score is a well known, already validated scoring system that quantifies severity of illness based on routinely clinical and laboratory variables measuring physiological instability. once computed the score by summing up the weights corresponding to the most abnormal value recorded during the first hours, the overall risk of mortality can be predicted by using the coefficients estimated by a logistic regression where prism score is the main independent variable. (pollack mm et al, -pediatric risk of mortality (prism) score. crit. care med. ; : - . to assess the applicability and validity of prism in the italian setting we launched out a prospective data collection in a sample of pediatric icus. measures of calibration (goodness of fit statistics) and discrimination (receiver operating characteristics and area under the roc curve) are planned to be adopted in the cohort of patients recruited during year period. as the validation study started on july , data collection is still on going and validation analyses will be carried out on july . up to now centers recruited cases. at present, characteristics of the sample recruited are the following: most of the patients were male ( %); the mean age is years with % of patiens having less than days; more than half were medical cases ( %) admitted from emergency room or from hospital floor ( %); % cases were admitted with an organ failure while % to be intensively monitored. icu-mortality was l %. the paper will present final results of calibration and discrimination analyses that will be carried out in the whole sample and across subgroups known to differ in terms of clinical relevance and prognosis. if calibration and discrimination assessment will produce not satisfactoty findings, a customization of the current coefficients will be made allowing a formal comparision of previous and new parameters. jf riera-faneao, m wells, j lipman. baragwanath intensive care unit, university of the witwatarsrand, south africa. [background the prism score is designed to assess the likelihood of death in ipaediatdc icu patients, using only acute physiological disturbances, age and [operative status to predict mortality. there is no evaluation of chronic health status, [including malnutrition. this may significantly affect its ability to accurately predict outcome in a population where malnutdtion is common. aim to determine the influence of nutritional insufficiency, as indicated by a low weight-for-age on outcome prediction by prism. patients & methods we analysed prism, weight and demographic data co ected prospectively from consecutive paediatdc icu admissions over a year pedod. a proportional weight (pwt) was calculated as a percentage from the th centile of the who weight-for-age growth charts. the pwt was compared for survivors and nonsurvivors, and mortality compared for pwt categodes nho wellcome classification). multivariate statistical techniques were used to identity associations with non-survival and to develop a modified logistic regression equation including a measure of i nutdtional status. receiver operating characteristic (roc) analysis was performed including and excluding patients with low pwt for the odginal and modified equations. results non-survivors had a lower weight than survivors ( . kg and . kg medians p = ) a lower pwt ( % and % medians p = . " . the incidence of malnutdtion , in our icu population was %. the mortality of manoudshed patients was' significantly increased (p = . ), with a good correlation with the degree of malnutrition. the accuracy of prism was significantly improved when malnourished patients were excluded from the analysis (roc value increased from . to . ). ! logistic regression and discriminant analysis identified a significant association between prism, pwt and outcome; age and operative status were not significantly related to mortality. the use of a modified equation including the raw prism score, pwt category and age can significantly improve the discriminatory power (az dm/elopmental sample . , az validation sample . ). the modified formula is: legit = - . + . *prism score - . *age + . *weight category, where the probability of mortality is exp(iog/t)/ + exp(iogio. discussion although we can improve the prediction of mortality by a modified or recelibrated formula, this still does not compare with the reference prism population. the need for validation of the score itself, in the association with outcome of the acute physiological variables themselves, is thus apparent. we conclude that while the odginal prism formula can be improved significantly, a modification of the basic variables in this and other third wodd populations may be essential. a high incidence of malnutrition is an independent risk factor of mortality, and an important cause of the poor discriminatory performance of prism. in order to improve the accuracy of prism, nutritional status should be taken into account. objectives: to assess the value of inhaled no to differentiate between pulmonary vascular constriction or fixed anatomical obstruction. methods: we assessed the response to ppm inhaled no in patients( m, f, median age . months, range day to years) with signs of increased pulmonary vascular resistance, there were pre and postoperative patients. patients were divided into responders(+) or non-responders(-). a positive response was defined as a % reduction in pulmonary arterial pressure and pulmonary vascular resistance(pvr) or in the presence of a left to right shunt, a fall in pvr accompanied by increasing pulmonary blood flow. left atrioventricular valve atresia + mustard pat: pulmonary atresia vsd: ventricular septal defect asd: atrial septal defect pda: patent ductus arteriosus tapvc: total anomalous pulmonary venous connection the responders( / ) were characterised by left to right shunts or pulmonary venous hypertension( / ). patient# was weaned from ecmo with inhaled no. patient# , without congenital heart disease, underwent a lung biopsy which confirmed reversible pulmonary vascular changes. patient# had a pulmonary hypertensive crisis which responded to no. all non-responders( / ) had evidence of anatomic obstruction to pulmonary blood flow (# , , )or a low pvr(# ) on subsequent cardiac catheterisation. in patient # , lung biopsy confirmed severe obliterative vascular disease. conclusions: inhaled no appears to be an effective pulmonary vasodilator. a failed response may be evidence of either irreversible pulmonary vascular disease or a residual anatomical obstruction which may be surgically remediable in the postoperative cardiac patient. therefore, inhalation of no may be a useful diagnostic test to differentiate between fixed anatomical obstruction and reversible vasoconstriction. results: during these years, the incidence of sdra was . % of the total of admissions. the most common etiology was meningococcic septic shock. since , there is a decrease of its incidence. (from % to %) and an increase of pneumonia and immtmodeficiencies. mean age of our patients was , years ( % males, % females), total mortality by sdra was % and there is an increase up to % since mean time of stay of the dead was , days and , days those who survived. although during the late years we offer in the picu a better attendance quality to the patients with sdra and the mean stay is longer, both for those who die and for those who survive, mortality of patients with sdra have increased. the incidence of sdra secondary to the septic shock of a meningococcic etiology have decreased. on the contrary, the sdra secondary to infections by opportunistic germs in patients with congenital inmmunodeficiencies or acquired immuodeficiencies have a tendency to increase. in our series, this change of aetiology is the responsible for the increase in mortality. hospital infantil unlversitario "virgen de roclo". sevilla. espalqa aims:to assess the incidence, etiology, clinical course, sequelae and mortality of the patients admitted to a paedfiatic intensive care unit with the diagnosis of severe traumatism. material and method: cases of severe traumatism in children admitted to our icu in the period from january to june were reviewed. age of patient ranged from months to years, % were males. in our series, % of cases suffered traumatism due to a traffic collision and % had a fall from a considerable height. only in one case was traumatism due to violence to the child. we assessed the first assistance received in % of cases: where was it performed, interval of time since the accident, and steps taken. these data were also studied in relation to the latter evolution. results: % of our patients suffered cranioencephalic traumadsm (ct); in % it was an isolated picture and in % of cases was associated to other lesions. there was participation of thoracic and/or abdominal organs in % of cases. % of cases presented important maxillofacial involvement. only one case presented serious cervical medullar lesion. mortality in our series was . %. in . % important sequelae remained. all of these patients presented tepas on admission equal or lower than . % of those with traumatises had slight sequelae. . % of the total evolve towards healing. a polytraumatized child is a patient that benefits considerably of it admission in a paedriatic !cu. the rapidity in receiving first aid and its quality are essential to avoid sequelae and to make mortality decrease. after unilateral lungtransplantation % of the patients develop a lung failure with decrease of perfusion and increase of pulmonary blood pressure in the transplantated lung. the improvement of perfusion is an importent task in the postoperative period. case report: a year old girl with idiopathic pulmonary fibrosis received a left sided single lung transplantation. during the early postoperative period occured a higtter demand of oxygen and an increasment of the pulmonary vascular resistence in the left lung. the pulmonary ventilation and perfusion scintigraphy indicated in comparison with the right lung a reduced perfusion of only % in spite of a ventilation of % of the transplanted lung. to improve the perfusion of the transplant we administrated per inhalation prostacyclin in a maximal dose of ng/kg/min. the arterial blood pressure decreased but the perfusion continued nearly at the same level. during the following administration of ppm no in the respiratory air we achieved a significant reduction of the respiration pressure f~m to nun h and of the pulmonary arterial pressure. the perfusion in the transplanted lung increased to ca/of the total pulmonary perfusion. after days of administration with no we were able to withdraw the axtifical respiration without any following complications. conclusions: the perfusion of transplanted lungs is a major proble_r~ in the postoperative period. this case demonstrated the advantage of no towards the inhalativ application of prostacyclin. no showed a significant improvement of perfusion in the transplanted lung of a year old girl. results: a total of children with ards were treated with bovine surfactant (alveofact| cases were evalable. the median age was . years (range weeks to , years). in six cases ards was associated with pneumonia, in two cases with lung hemorrhage; in one case isolated ards followed hemihepatectomy. the first surfactant application was performed with a median latency of clays (range - days) after first symptoms of ards witha median doseof mg/ kg (range - mg/kg). in patients doses of surfactant were applied. during the hour before therapy, the median pao / fio -ratio was - . within min. after application of exogenous surfactant the pao / fio -ratio increased to with successive decrease over a period of hours to . accordingly, an increase in pao and oxygen saturation and (less significant) a decrease in ventilation parameters could be observed. analysis of broncho-alveolar lavage before surfactant application in children receiving repeated doses revealed in most examined cases either clear surfactant deficiency or pathological function. of treated patients survived ( of the , respectively). of the surfactant doses were applied in the surviving patients.conclusions: the application of exogenous surfactant in children with ards caused a significant increase in oxygenation, which declined over a period of - hours. the effect often could repeatedly reproduced, in one case after applications. the increase in oxygenation often allowed the reduction of fio and/or the inspiratory pressure. no side effects were observed after exogenous surfactant application.in many cases the application of surfactant wag too late after first symptoms of disease (median latency days). ards mostly due to pneumonia seemed to respond to surfactant therapy less well or not at all. permanent junctional reciprocating tachycardia (pjrt) is the most common incesant supraventricular tachycardia (svt) in children. it is usually drug resistant and its onset in early life has been associated with dilated eardiomyopathy. we report our clinical experience with patients detected antenatally and another diagnosed at months of age. method.diagnosis: negative p waves were detected in leads ii,iii and f, p'r > rp" and there was not warm-up at tachycardia onset.clinical records, ekg,x-rays, echo and holter were reviewed. ep studies were undertaken only with therapeutic purposes. results. in a year period patients under y of age fullfilled diagnostic criteria; were detected prenatally ( - weeks) and one was diagnosed at age mo. the fetuses had intermitent svt during gestation. all of them had pjrt in the first month of life at rates between and bpm. they were admitted to the icu but did not develop signs of heart failure. they were controlled with digoxine (d); d and quinidine; d and propafenone in to days. one was in sinus rhytm until age y; he then showed persistent pjrt over % of the day on repeated holters and underwent successful radiofrecuency catheter ablation (rfca).the other two patients showed initially a lowering of tachycardia rate followed by sinus rhytm for over % of the day (follow-up ran and y). the mo. old infant was admitted to the icu in severe cardiac failure. echocardiogram showed marked systolic dysfunction (shortening fraction %) treatment with digoxine, amiodarone and propafenone were unsuccessful despite lowering heart rate to ; rfca was performed at m. of age with restoration of sinus rhytm and rapid recovery of contractility. all patients were given atp at admission with transient ( to see) recovery of sinus rhytm. ff,s clinical course of pjrt is variable. atp is useful only as a diagnostic tool. initial treatment with digoxine + amiodarone or propafenone is adviced. rfca is a very useful therapeutic modality and can also be performed in young infants twelve patients ( %) died. these were meningitis, head injury, sub-arachnoid bleeds, status epileptieus, leukaemie, drowning, and multiple trauma. calculated from the a admission day p edialric risk of mortality score (prism), the probability of death (p) ranged from - %. of the deaths, i were predicted by prism analysis except for the leukaemie patient (p i%) who died from haematological complications following chemotherapy. two children predicted to die (p % & %) survived. the median length of stay was days (range - days). patlents( %) received ventilatn~ support and patienta( %) were transferred to specialist units ( neurosciences, liver, cardiac, bums). this data supports the view that many paediatric patients are being adequately treated in a dgh icu. meningitis and other neurological illness caused the majority of deaths and respiratory problems caused most admissions. most deaths ( of ) occurred within a few hours of admission. ectopic junctional tachycardia (ejt) is one of the most dangerous arrhythmias in the postoperative setting of congenital heart defects since it does not respond to antiarrhythmics or defibrilation. the object of this presentation is to report on two patients who presented f_jt in the early postoperative period and developed intense congestive heart failure which could be controlled after treatment with moderate topical hypothermia. two patients, m and y, diagnosed of atdoventficular septal defect and tetralogy of fallot developed intense heart failure in the early postoperative period. taehyeardia rate was and bpm. medical drug therapy included weaning from vasoactive drugs, iv digitalization and iv amiodarone treatment. there was not response. they were both surfaced cooled by placing plastic bags filled with cold water over the patient's chest and abdomen. temperature was monitored to obtain a central temperature of ~ there was a gradual decrease in heart rate in the following hours ( - bpm) paralel to the degree of surface cooling and clinical course estabilized.both recovered normal sinus rhytm in to hours. there were not significant arrhytmias after the procedure and postop, was uneventful. conclusions. moderate hypothermia is a very useful manuever for the treatment of drug resistant ejt. since it lacks side effects of other antiarrthymics we beleave it should be the treatment of choice for the treatment of ejt in the postoperative patient. present understanding of the pathogenesis of sepsis, based on the theory of systemic inflammatory reaction, has risen new interest in the more invasive methods of treatment, like plasmapheresis, leucapheresis and exchange transfusion (et). obiectives: evaluate the effect of et in the treatment of neonatal sepsis. material and methods: from september to december , a prospective study was carried out, where the severest cases of bacteriologically proven neonatal sepsis (n= ) were treated with et. in total newborns were treated for culture positive sepsis in the intensive care unit during this study period. diagnosis of sepsis was based on the clinical criteria of suspected neonatal sepsis, used by mc harris et al., laboratory data and positive blood culture. newborns with severe congenital malformations were excluded. et was carried out with fresh (less than hours old) adsol-conserved erythrocytes, from which buffy coat had been removed, and same donors plasma, using a slow continuous two-site technique. the mean volume of et was . ml/kg. the effect of et was assessed as a change in the score for acute neonatal physiology (snap), general treatment results were compared with a historical control group of newborns, treated for culture-positive sepsis in the same icu during the first eight months in . students ttest and chi-square test were used in statistical analysis of the data. results: with the use of el a significant decrease in mortality was achieved: death of cases during the study period, compared to deaths among the controls (p< . ). no baby, receiving et, died. the incidence of severe complications did not differ in the two groups. the snap-score showed quick improvement by the first post-transfusion day (p<o. ) and the effect persisted during the five following days. conclusions: we conclude, that the use of et in the treatment of critical cases may help to lower the mortality of neonatal sepsis. it provides a quick improvement in the clinical condition of septic neonates. the granulocyte-colony stimulating factor (g-csf) is largely employed in granulocytopenic patients. experimental studies have' demonstrated the effectiveness and safety of the therapeutic use, nevertheless the human employ is reported almost exclusively in neoplastic patients submitted to chemotherapy and in patients with fungal or pseudomona~ spp infections. the authors report the data concerning three non granulocytopenic children: in the first, o girl years old, affected by pseudomomm aerug/n~a pyeionephritis, the antibiotic therapy was not tolerated in consequence of renal and hepatic failure. the second patient, an infant months old, has been treated with salbactam-ampiciilin, ceftriaxone and chioramphenicol because of haemepldlw iafluem~ meningitis; a late neurological aggravation required the antibiotic therapy recommencement the last, a years old insulin dependent diabetic boy, was affected by cared/do spp systemic infection; the antifungnl therapy w~ not practicable in consequence of renal and hepatic involvement in all the g-csf was administred subcutaneously at the'dose of $ u for days. a significant increase of granulocytes was ever noted already after the second administration until hours after the last dose. clinical signs, fever and biochemical values are promptly influenced positively and all patients are restored to health. no side affects were noted. the granulocyte colony stimulating factor, at indicated doses, can prove of great help in critical patients, in who the antibiotic or antifangal therapies can result toxye or cannot be tolerated. the ~reptococcas p~, among the gram pmltlve~ represents the main causative organism of bacterial meningitis in children, with the majority of deaths occurring within hours of admission, the third generation cepohlosporim were indicated as antibiotic of first choice, and some literature reports have demonstrated no significant dlffereuces in dinical course of patients treated with ce~rlaxoae and of those treated with ampieibin and chlornmphenicol. the authors report the ease of on infant, male, months old, submitted to a neurosurgical interventiol after days the infant became febrile and lethargic and a bacterial meningitis by ~trepmcecctz ~ was diagnosed, in spite of he was given the eoftriaxone therapy.. an amelioration was found only when a systemic treatment with vaucomyein was added. after days an intrathecal administration of vancomyein m~day was started: the norbmlization of the spinal fluid profile was uoted two days later and the infant receve~d progressively. the follow-up after eight months doem't evidentiate motosensorini sequelae-the individuation' of ~cscc~ pmmmsm/ae strains heta-loctam antibiotics resistant requires alternative therapeutic regimens: the k~terity quead vitam and quoad valetudinem of these infections justifies an intrathecal therapy, especially failing o prompt answer to the systemic treatment objectives: to evaluate the incidence of the burnout (bo) of the staff in a picu in a university hospital. the bo is a syndrome charactedzed by many factors like emotional stress, lack of personality and reduced work ability. this syndrome represents a kind of abnormal response in the working habitat, above all, where psychological and personal characters are mostly involved. the symptoms of bo are represented by demoralisation, demotivation, incapability, boredom, isolation up to organic disturbances, like migraine, insomnia, dizziness and gastrointestinal disturbances. the major incidence of this syndrome was found in the hospital staff, especially among the nurses, working in an atmospher of high emotional dsk, just like in an intensive care unit. methods: from january ' till april ' , all the staff of the picu of the a. gemelli hospital of rome, underwent a test to evaluate the bo. the test used was taken from the book "bumout: from tedium to personal growth", by pines and aronson. twenty seven people were studied ( females, males)i out of which doctors, residents and nurses. it was considered sign!ficant as mild bo, a score between - and as severe, the score of bo >. . results: subjects ( %) resulted positive for bo, out of which were females ( %) and were males ( %). the subjects with mild bo were / : was a doctor, residents and nurses. the subjects with severe bo were / , out of which resident and nurses. conclusion: the results obtained show that bo is a condition well represented in the staff of our picu. the category most at dsk seem to be the nurses ( subjects), as well as residents ( subjects), as in literature, which shows a major incidence of the syndrome in younger subjects and having a limited partecipation of functional decision. the results obtained obliged us to start a programme of serial controls so that the subjects most exposed can have a necessary psychological support to react adequately to this condition. the term systemic inflammatory response syndrome (sirs) was adopted by the consensus conference to denote a type of systemic response to severe infection or otherinsults in critically ill patients. when sirs occurs from infection it is called sepsis. sepsis occurs more frequently in persons with perexisting illness or severe trauma. there has been tremendous advances in prophylaxis, diagnosis, and treatment of sepsis. a comprehensive model of the disease progression from sirs to mods should be developed giving priority to severity of illness scoring system and other predictive methods. some recommendations for future clinical trials include: trials should not start with humans. before proceeding to human trials, animal studies should indicate an acceptable risk/benefit ratio. appropriate patient populations must be defined and treatment protocols should be standardized. full and rapid reporting of all results should be mandatory and a central repository of published and unpublished study results could be helpful. accrual at each center should be of sufficient size, and should include the number of patients accrued, mortality rates, and patient characteristics. pivotal trial should be preceded by sufficient pilot or phase ii studies. correct drug dosage and usage should be delineated in pilot studies. large, multicenter, trials should be used to enhance the unversality of trial results. analyses should be planned a priori. definitions for the target population should be explicit, reproducible, and include illness severity scores. outcomes should be relevant reproducible and include both measures of benefit and harm. mods and its reversal should be considered as an endpoint. quality of life should also be considered as an endpoint. the estimators of overall treatment effects should be controlled for base-line prognostic factors and subgroup anaiysis should only be used for hypothesis generation and not to modify the conclusoin of the trial. economic analysis should be included as part of clinical design. evaluatin of source control should be a critical component of any study. standardized clinical mediator assays should be pursued. placebo patients in clinical trials should be studied for a better understanding of the pathogenesis and epidemiology of sirs, evidence based medicine should be used to evaluate the validity of clinical. introduction: use of inhaled nitric oxide (no) as a modulator for optimizing ventilation-perfusion or lowering pulmonary artery pressure is becoming increasingly common. no is a free radical but little toxicological research has been published. clearance of nebulized mtc-dtpa is known to be, a sensitive indicator for early function impaimaent of the alveolocapillary barrier. we investigated whether exposure to no increased clearance of ~tc-dtpa from the lung. methods: three groups of white sealand rabbits (bw . kg) were anesthetized, tracheotomized and paralyzed. groups were ventilated for six hours at pressure regulated volume control, set to deliver ml/kg with a frequency of /rain, i/e ratio = : and peep = cm hzo using a modified servo ventilator (siemens, solna, sweden) with computerized no delivery system. gas mixture per group was either / or / [no (ppm) / fioz]. after six hours of ventilation in these groups and immediately after anesthesia in group (control), ~tc-dtpa was nebulized into the inspiratory line of the breathing circuit and administered as a fine aerosol. gamma counting was measured for minutes, monoexponential curves were fitted to the data and the clearance half-time (t was calculated. the t~/ mean • sd of the different groups were: t~a (mean -sd) h"e,i witl~ arf : di.ff:erent kinds, aged .q-ore mon't.hes to [ gears o : (bodi weight .~rom ., to kg), is presen .... "ed ( i,,~u::trl:e i:ibstraclive d:lse~se... ~ .ards'- ; :~,;,,arf o~ ::entral genes:i s .- , ,~ :inc lud ing men ingeenceph it :is- ~ reye ' s ~yrtdro~e-..#~,bri~:ln pes~.re~nimatior~ disease.." ). int:lrl~]. pa-. "iiulle'i,~s ariel regymes o+ l;mv,l;i"t"v were cle'l'.ermllled by ba- 'i~ier was. about . tuber,, dopamin tiara-:. t.io; was ~.".,,'.r:~r~led. cmv,cppv d~.!"~tion raniled -~rom f to dayns.,~ < .-:in , "t -irl lo;and> davs'-in 'l~atierr~{s i'i"ai s:ltiol~ o ; patterers to imv, simv modee was per.r:)rmed, ~herl pif:' decrease.d to - ml~ar, fi ~ecreased to , . lind less with a = /,,. i:lesq.lts:{ in pat:i.ents e{ group :l, who were tre,~d.ed w&th f'f'v, teoph :i. : . l:i.r~ (is- .mg/kg/day), g lucecdr t icostei~oids ( .... :~;mg/kg/day), when r exceeded in , -.];, times normal va i tea the e aqes/,'!:l"oln ~j,, ite :i.~;::.!;, ~ml"lrj), it was possible 't'(' ce 'e~ e aad]t:..~rom ! . '.' i', to !..'; , - , mml-lg in ~}.. :~.[~ houi,!; ~d'l(:i to ru:}l",g'd!~l:i. e i::h,:~e,'~c['el';i.stil obieetives : this chapter will describe what is knovca of the psychlogical responses of infant and children to hospiuiisation and attendant procedures. the factors which may modify these responses will he discussed and important considemtiorts will be outlined for optimal anaesthetic management and postoperative period of infants and children which will minimised the rise of emotional upset. methods : in this paper the autors will discttssed the probl of: . health children (asa i, ii) facing single uncomplicated surgical elective procedures . various abnormal situations including neurotic children, children facing repeted operations, chronically ill, buaaes and tsaumatically impired ones . unfortunate young patient facing and often expoclting fatal outcome from le "ul'ukaemia, tumors, cystic fibroses or otheq" disease. : management of each child must vary greatly, ifi general the phases of emotional conditioning include home and preadmissiun preparation, admitiun preoperated and operative care and postoperative period. the authors would be happy if the child passes all stages without any trauma which could be prolonged in the future life. introduction ino is used to selectively reduce pulmonary vascular resistan(~e. we applied ino in the postoperative intensive care of patients with pulmonary hypertension and the risk of right ventricular failure after surgical correction of a congenital cardiac defect. methods - ppm no were added to the ventilatory gas mixture using a specially designed equipment (messer-griesheim, germany/austria). indications for application included pulmonary artery pressure > % systemic pressure, critically depressed right, ventricular function or an oxygenation index > . assessment of n oefficiacy consisted of on-off-on measurements according to the clinical stability of the patient including hemodynamic parameters, pulmonary gas exchange, continuous monitoring of ventitatory function and transesophageal echocardiography of the right heart. results in situations ( patients, age days- , years), ino was applied - h postoperatively. oxygenation was improved in situations from _+ to + mmhg pc ; pulmonary pressure was reduced in situations from -* % to _+ % of systemic pressure. in situations, no reduction of pulmonary pressure was present, but measurement of cardiac output or echocardiographic analysis indicated an improvement of right ventricular function (right ventricular stroke volume + -* %, cardiac output + -* %). in situations (immediately postoperativ with suprasystemic pulmonary artery pressures [n= ], multi-organ-failure [n= ]), no response to ino could be determined. conclusions for a special group of patients, the selective reduction of pulmonary vascular resistance by ino has become an important part of postoperative therapy. using this selective afterload reduction, postoperatively depressed right ventricular function can be improved. this effect of ino seems to be the most important one in the postoperative period. thus, ino appears justified to be appfleo when impaired right ventdcular function could be improved even when pulmonary artery pressure is not raised or remains unchanged. obiectives : premature infant are exposed to danger of apaea due to anaesthesia during their tirst months of life. it is yet unknown whether prematurity is corelated to any other kind of reslgratory disorder due to anaesthesia within the tirst year of life. methods : we theretbre researched retrospectively for respiratory disorders in all infants under months of life belonging to asa group . they all had been anaesthetised in . in our clinic for the following surgical reasons: ingvinal haemia, umbilical haemia, hydrocelae testis and phymosis. results : in cases we tbund: lafingospasm during induction in anaesthesia ( , %), bronchospasm during induction in anaesthesia ( , %), impaired intubation ( , ~ postanaesthetic laringospasm ( , %), supposed aspiration ( , %),postanaesthetic inspiratory stridor ( , %), postinductional inngoedema ( , %), death after months in consequative of infection pneumonie ( , %), none of these disorders was correlated the prematurity, infants suffered of post anaesthetic apnea, of them had premature medical history. concludions : prematurity does not enhance the risk of respiratory disorders due to anaesthesia within the first year of life, except the danger of postanaesthetic almea needs spetial cosideration. it could be demonstrated that aepgi lowers pulmonary vascular resistance and indirectly improves cardiac function. this effect seemed to be selective, and was comparable to ino in the doses we have examined. therefore, aepgi could represent a clinically useful alternate to inc. however, further research is necessary to work up the benefits of either therapeutic strategy. objectives: heat and moisture exchange filtem (hme) are used as artificial noses for intubated patients to prevent tracheo-bronchial or pulmonary damage resulting from dry and cold inspired gases. furthermore they are used for the prevention of bacterial contamination of the anesthetic apparatus by the patient's exspired air. so they are considered as a time-and money-saving device in anesthesia. filters are mounted directly on the tracheal tube, where they collect a large fraction of the heat and moisture of the exspired air, adding this to the subsequent inspired breath. the effective performance depends on the water-and bacteria-retention capacity of the filter. this study evaluates the efficiency of four different filters under clinical conditions. methods: four different types of filters ( dar hygrobac, gibeck humidvent, medisize hygrevent and pall bb ) were investigated dudng mechanical ventilation over a pedod of hours. minipigs with hemorrhagic shock were intubated and ventilated for days in an animal intensive care unit (icu). after hours of mechanical ventilation the filter was randomly replaced maintaining the individual ventilatory conditions. the weight of the filter was determined before use and after removal after hours. the airway pressure was monitored online to record changes during use. tracheal secretions and both sides of the filter were microbiolologically tested to see whether bacteria of the animal's respiratory system could be found on the patient's side of the filter or if they even would have penetrated the barrier. results and discussion: over a pedod of hours of types of filters showed an increase in weight of + % and airway pressure. bactedal celonisation ccured in nearly all fillers ( of ) on the patient's side, whereas only three of four types of filters showed identical bacterial colonisation on both sides. the only filter that did not show bacterial penetration, increase in weight or airway pressure was the pall-hme, a condensation humidifier without hygroscopic salts for moisture retention. with respect to our data one should use a condensation humidifier if airway conditions should remain stable dudng mechanical ventilation and desinfection of the anesthetic apparatus should be avoided after each patient. aim: to assess the clinical uses of, and experiences with, the hayek oscillator. this is a non-invasive device capable ef delivering not only continuous negative pressure (cnp) but also external oscillatory ventilation around a negative baseline (eov-nb) using an external cuirass. this type of ventilation avoids the need for intubation and intermittent positive pressure ventilation (ippv) and facilitates weaning in ventilator dependent patients. patients and methods: patients in respiratory failure, age range weeks to years in a total of patient episodes were treated using either cnp or eov-nb mode. duration of treatment varied from hours to days. indications for use ef the device were: ) to facilitate weaning from ippv ) prevent reintubation of patients following unsuccessful extubation, and ) avoid intubation and ippv altogether using the hayek oscillator as the on[y means of respiratory support. results: there was an increase in pao :fio ratio after cnp and eov-nb (p < . , and p= . respectively, wilcoxon signed rank test). patients who were in respiratory failure with hypercapnia showed a statistically significant reduction in paco both with eov-nb and cnp (p= . and p= . respectively) but the magnitude of change was individually greater in the patients who were treated with eov-nb. all patients, however, showed a fall in respiratory rate (p< . ) after the application of the cuirass in cnp mode. there was no physiological deterioration related to the application of external extrathoracic negative pressure in either cnp or eov-nb modes. conclusion: the improvement in pao :fio , the fall in paco and respiratory rate were indicators of an improvement in ventilation. the proposed mechanisms include improvement in frc, recruitment of additional alveolar units, and improvement in secretion clearance resulting in reduction in the work of breathing. meek to ~ month of the lifo,the bemodyuanicfacls were defined uitb the help of tetropolar reography method!. the excretion of !he catbocholauines fcfi] mith the urine gas detertend by taylor ll,laoorsy ~ iacg/dayl. hsaltl in the hypercuagulation stage of bic we deflorteeed the acliuutiun of the tbrubio and plasiin syaet~ mitb the increase of the inhihitnrs, in this case we registered in full uahe dot this process coabined uitb the dayl~ excreliou with lho urine epinopbr ne e], nor~pinopbr no tel and dophanine io], lbat shod the inlensificatiou of the s~nthosis prnoe-s~es and the release of ea in blood fron hissue deport the actffat on of the svnpathadrenui systen ]sfisl assisted to furl the b?perd~nanical rosins of the eircuidion and increase the ,icrocirculatinn, the klinicai sings of the insufissieutly of the circulalion have not defined,that has been associated the conpensatury character uf the ehan~es of ~ and heludy~enic status, t~e uun~u|p-lion ceugulupatby bus been donoustraled in the hypocougulatien stage ~bat man xauifosted b the exhaust of lhe confulalion nod oessel-platel heuostasis, the consuxptton of cnnpononts tbronbln ,plnstin, kallek~eiu-kinln s~slots and the forniration eat in fell canoe clot uas accoqaued bs docrea,e of fl,nfl,o, the products of the xotabolisx of c~ and the activation of xonoaninoxydasu. the decrease of the extoll'on g and the exhaust deport co indicahd about t!e ]ou fund/anal reserve of ~fl~. it was one of the lain reason of ~bo heiod~uanic disbroed iheat insnfissient]~] and the uicrncireulaflion lintestinal codeme with the low effectife periferal flow] and nul[iplay organ failure,the distrued deport of sos mitb throubocytupenin no; be one of the nechanisn the dislrood of uessej-plalol heioshasis, the correlation bolueeo changes of boiostosis c~ and circulation ore reguired aduinistration nedidns, thai reslore the love s of c~ in the blood, prevent uulliplay organ failure and hetorrnge in children with sepsis, ~b~ectives: multi-measured correlative analysis of the most number of non-invasive indices of the cardiorespiratory system function was made to determine the structure of their interrelation and the ways of their adequate and effective correction. hethods: spiremetry, capno~raphy, oxygenography, indirect fick method at recurrent respiration, plethysmography, integral rheography -in all indices were used. the received data were processed on a computer by a standard package of statistical bmdp programs. results: women with ~h-gestosis (i group) and somatically healthy pregnant women (ii group) were studied. cluster analysis has shown that the rate of the mean correlation connection between ventilation indices was % in the ist group and % in the iind group; gaseous metabolism - % and %, respectively; central hemodynamics was ~ in both groups. conclusion: cluster interpretation allowed to suggest that an increase of the rate of the mean correlation connection between the indices was characteristic of effective adaptation as the system was multi-component and well-regulated. on the contrary, the increase of the rate of strong correlation connection between the indices reveals the rigidity of the system and the tensity of adaptation mschaniams, i.e. the proximity to decompensation. it follows from this that in cases of eph-gestgsis, the reliability of regulating ventilation and gaseous metabolism decreases. seve/e hypoxemia in non intubated patients represents a major contraindicafion to fiberoptic bronehoscopy (fob) and bronehoalveolar levage (bal), but these procedures are often required for a correct diagnosis of the causative agent of pneumonia. aim of this investigation was to veaify the safety and efficacy of bronehoseopic procedures during pressure support ventilation administered through facial mask (fm-psv). five intensive care patients, all immunoeompromised, ( males and females; mean age . • were enrolled in the study. all patients presented criteria for pneumonia with pao /fio ratio ~ and were responders to fm-psv. fob and bal were performed afte~ topical anesthesia with fm-psv ( ps = em h ; peep = emh ; trigger = -lemh ) continuously admires" tered ( ' before fob fio = . ; during fob, fio = and for ' alter fob, fio = . ). pao /fio ratio as well as saturation (sat) did not show signifteative changes during the procodure (fig.l) . no complication was observed and hemodynamic conditions were stable for all patients. cmv, pnenmoeystiis ( ), legionella and mycobaetermm tuberculosis were identified from bal allowmg a prompt and targeted therapy. we concluded that mask psv can represent an excellea~ technique to pexform fob and bal in severely hypoxemic patients without deterioration of gas exchanges and avoiding endotraoheal intubation. intensive care unit, hospital general of albacete, albacet~ spain. objective: to analyze the current incidence and epidemiology of total parenteral nutrition (tpn) among critically ill patients placed on mechanical ventilation. design: prospective observational study. setting: medical intensive care unit in a tertiary hospital. patients: a total of consecutive l'ritically ill patients with non-coronary related disease needing mechanical ventilation admitted in our icu during a months period. measurements: data of sex, age, diagnosis, and outcome were recorded. severity of illness and therapeutic effort in the first hours were measured using acute physiology score and chronic health evaluation (apache ii) and therapeutic intervention scoring system (ties). r~ults: mechanically ventilated patients, male and female, were studied. only ten patients needed tpn and their main diagnoses were: five cases of multiple organ failure secondary to pneumonia ( ), ards ( ) and septic shock ( ); two eases of acute panereatitis; and one mesenteric throngmsis, one status epilepticas, and one ,prolonged cholinergic crisis b~ suicidal organophnsphate insecticide subcutaneous injection. no statistically significant differences between both tpn and non-tpn groups were found: objectives: evaluate the efficacy of prone position in ards and determine its importance in the therapeutic algorithm. methods: consecutive patients with severe ards (murray-score > , ; pao / fit < mmhg; male, female, mean age years) were conventionally ventilated (pcv, peep - mbar, i:e=i:i, ppeak < mbar). if after hours pulmonary function did not improve patients were placed in prone position. change from prone to supine position was done every hours. beside ultimate survival, parameters investigated were aado , pao /fio , and venous admixture (qs/qt). results: during the first hours in prone position of patients showed a significant decrease in qs/qt ( . % vs. . %) and aado ( vs. mmhg), and an increase in pao /fio ( vs. mmttg). changes were most pronounced in patients with high qs/qt, and in patients with an onset of ards less than hours before first application of prone position. after an average of position changes ( to ) of patients could be weaned from the ventilator. patient could leave tile hospital. i the later course letality was primarily determined by additional organ failures and by the severity of the underlying disease. negative side effects were minor, including slight cardio-vascular depression and increase in p~co , and never posed a limitation to continuation of prone position. especially in patients with septic shock skin lesions in exposed areas could not always be prevented, prone position could easily be combined with all ventilation modes and with all intensive care interventions. also immediately after major surgery and in patients with open packing prone position was possible. conclusions: in this investigation prone position proved to be an efficient and safe method in the treatment of severe ards. patients with a pronounced ventilation/ perfusion mismatch and patients in the early stages of ards appear to profit most from prone position. though the immediate effect on oxygenation is striking, still more the % of all patients die from multi organ failure and underlying diseases. a proposed therapeutic algorithm for ards is as follows: if under conservative ventilation (pcv, peep < mbar, ppeak < mbar) pulmonary function does not improve within - hours prone position should be applied. when after - position changes no lasting effect can be achieved further ventilation modes (e.g. pc-irv, aprv, no, etc.) should be used in addition to prone position. standard intensive care principles, such as fluid restriction and optimization of circulation, apply also to patients in prone position. objectives: nitric oxide reacts with superoxide to form peroxynitrite, an extremely reactive and toxic species. we quantified the presence nitrotyrosine, the stable product of the interaction ' of peroxynitrite with tyrosine residues in the lungs of pediatric patients that died with respiratory distress syndrome (rds). methods: paraffin embedded lung sections, obtained at autopsy, were incubated with a polyclonal antibody raised against nitretyrosine, followed by a secondary fluorescent antibody. alveolar structure-associated fluorescence was quantified using existing methods. results: tissue sections from patients who died with rds exhibited significant specific immunostaining which was uniformly distributed across the blood-gas barrier. in contrast only background levels of fluorescence were seen in the lungs of patients who died from non-pulmonary causes. intense staining was also seen in the lungs of rats that breathed % for h, a condition known to result in rds-type illness; no immunostaining was observed in air-breathing rats. conclusions: significant levels of peroxynitrite may be formed in the lungs of patients with acute lung injury. peroxynitrite may be contributing to the pathology of rds by damaging key components of the alveolar epithelium including the pulmonary surfactant system. mechanical ventilation time was prolonged ,g • days in patients with ardsvs , _+ l, days in control . mean staylcuwas lg _+ ,g days in the ards group vs , • , days in control group postoperative mortality rate was % in ards patients vs , % in those without respiratory failure. -ards incidence in liver transplantation is low ( , % in our sene) but it causes high mortality ( %) page, gas ventilation of the perfluorocarbon-f'dled lung, supports gas exchange and circulation in small animals (< kg) with lung disease. we hypothesized that large animals could be supported by page without adverse effects on bemodynamics. we first elucidated the determinants of gas exchange in normal sheep, and applied them to a model of adult respkatory distress syndrome (ards). methods: using the ventilator settings determined to be optimal in our pilot study (fio of . , peep of cm h , imv of bpm, it of %, and tv of ml/kg), sheep weighing . ~ . ) kg had lung injury induced by instilling ml/kg of . n hc into the trachea. ten minutes after injury, sheep with pao < ton" were randomized to continue gas ventilation (control, n= ) or to institute page (n= ). page was instituted by instilling . l of unoxygenated pefflubron into the trachea and resuming gas ventilation at the previous settings. abg's were drawn at baseline, minutes after injury, minutes after injury, and then every minutes for hours. objectives: inhaled nitric oxide (no) can improve oxygenation and decrease mean pulmonary artery pressure (papm) in hypoxemic patients with ards. in severe hypoxemic copd patients, it is not known whether inhaled no can exert a similar effect on hemodynamics and gas exchange. therefore, we investigated die response of inhaled no in hypoxemic copd patients and the results compared with those obtained in a group of ards patients. methods: ten copd patients (age _+ y;fev~ . _+ . l) and ards patients (age _+ ; lis . _+ . ) mechanically ventilated were studied. hemodynamic parameters were measured using a swan ganz catheter. arterial and mixed venous blood gas determinations, sao , svo , hb and methb were measured (abl ,osm ). mean intratracheal concentrations of no and no were continuously monitored using a chemiluminescence analyzer (nox ) . during the study the ventilatory pattern and fioz were kept constant. the protocol was for ards group: basalt, no loppm, basal~; copd group: basalz, no lo ppm, no ppm, no ppm and basal . after a steady state of rain hemodynamic and gas exchange measurements were performed. a positive noresponse was defined as a % increment in pao . results: papm was similar in both groups and decreased significantly after no (ards, basal . _+ . mmhg, no . + . mmhg, p < . ) (copd, basal . _+ . mmhg, no- . _+ . nrmhg, p< . ). all other hemodynamic variables remained unchanged after no. basal oxygenation was higher in copd group (paojfio _+ mmhg) vs ards group (paojfio _+ mmhg)(p< . ). after no- , pao increased ( _+ mmhg to _+ mmhg, p< . ) and qs/qt decreased ( + % to _+ %, p< . ) only in ards group. in both groups, significant correlations between basal papm and inhaled no-induced decrease in papm were found. inhaled no-induced increase in pao /fio was not correlated with basal paoflfio . no responders were / ( %) in ards group and / ( %) in copd group (p< . ). conclusions. in hypoxemic ards and copd patients, inhaled no decreased mean pulmonary artery pressure. however, oxygenation only ameliorated in ards group because die number of responders to inhaled no were higher in ards group and this effect seems not to be related to the basal hypoxemia. these results might be explained by the v/q abnormalities present in copd patients. grant fis / . objectives: it has been recently reported that expired con slope as a function of time is modulated by total respiratory system resistance (rrs) in critically ill patients (chest ; : - ) . in this study, we analyze the relative contribution of disease (dis), endotracheal tube resistance (rtube), airway resistance (rmin), additional resistance (~rrs), autopeep (peepi) and dylmmic/static elastance (ed/es) to the co elimination in different clinical conditions. methods: we have studied adult patients ( controls, acute respiratory failure, severe ards and copd) mechalfically ventilated (servo and c, siemens) without peep. we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. objectives: alveolar ejection volume (van) can be defined as the fraction of tidal volume (vt) with minimal dead space (vd) contamination. according to the classical paradigm: limvd_~ [vco /vt] =facoz, vco vs vt relationship tends asyntotically to a constant slope when approaches end-tidal volume. we have defined van as the volume that defines this relationship until a limit of % variation. methods: six subjects with normal respiratory mechanics were studied during anesthesia for minor surgery. two subjects, otherwise normals but having high values of total resistance and dynamic compliance, were also studied. capnograms were recorded in steady-state at levels of vt ( . , . and . l) and four levels of peep ( , , and cmh objectives: patients with ards presented lung abnormalities which originate an increase in airway resistance (rmin), in additional resistance (~rrs) and in static elastance (ers). application of peep further increases ~rrs. capnographic indexes reflect lung ventilation]per fusion inhomogeneities. in these conditions, the effects of peep on lung mechanics could be better understood by simultaneous measurement of capnographic indexes. methods: we studied groups of subjects. n: normal subjects scheduled for minor surgery; arf: critically ill patients with mild acute respiratory failure; ards: patients with early ards (< h). we recorded tracheal pressure, airflow and capnograms. signals were analogic to digital converted for posterior data analysis. respiratory system mechanics was assessed by constant end-inspiratory and end-expiratory occlusions technique. at equal tidal volmne ( . l) a peep level of , , and cmh was applied in all patients. we calculated ers (cmh /l), rmin, c~rrs (cmh /l/s) and autopeep. capnographic indexes were alveolar ejection volume (vae)/vt ratio and expired co slope beyond vae (sipco in contrast to synthetic surfactant natural suffactants (alveofact| are able to inhibit pmn-activation. after incubation of activated neutrophils with surfactant, l-selectin expression is decreased. these effects depends on which preparation is used. we conclude, that natural surfactant (aveofact| can perhaps influence early recruitment (,,rolling") of pmn in patients with respiratory failure like ards. with ards hormann cb, baum m, putensen c, knapp r, lingnau w, putz g . clinic for anesthesia and general lntensiv care medicine, university of lnnsbruck, anichstrabe , innsbruck objectives: in thoracic ct scans of patients with severe ards atelectasis and pleural effusion can be found in the dependent lung regions. by rotating these patients from left lateral position to right lateral position a redistribution of the ct densities, a recruitment of atelectasis and therefore an improvement of gasexchange is possible within a few days ( , ). the objective of this study was to find out the mechanism of alveolar recruitment during lateral positioning by ct scanning in left and right lateral position. methodes: after approvel by the local institutional reviewboard we investigated ventilated patients with severe ards (entry criterias: murray score > , ) in the ct scann of the university hospital. after a stabilisation period of minutes in supine position a thoracic ct scan slice cm above diaphragm was taken. then two different positions of the patients were studied in a randomized order: a) degree of left lateral position, b) degree of right lateral position. each lateral position was held for minutes. at the end of each of these periods a thoracic ct scan slice cm above diaphragm was taken. quantitative analysis of ct scan data was based on the frequency distribution of the ct numbers. to quantify the alveolar recruitment during lateral positioning by means of ct scan we defined compartments within the lungs: a) normaly inflated lung, b) poorly inflated lung, c) noninflated lung ( = atelectases) ( ). results: independant of the side of lateral positioning (l) in the non-dependent upper lung a significant increase of the normaly inflated compartment (s: %; l: %) as well as a significant decrease of the noninflated compartment (s: %, l: %) was observed in comparison to supine position (s). in the dependant lower lung the normaly inflated compartment decreased significantly (s: %, l: %) whereas the noninflated compartment increased significantly (s: %, l: %). throughout the whole studyperiode we did not observe any significant change regarding gasexchange and hemodynamic parameters. conclusions: in lateral position the non-dependent upper lung is decompressed. therefore a significant recruitment of atelectases is observed in the upper lung within minutes. on the other hand the dependent lung is compressed by the weight of the upper lung and the mediastinum. a great amount of the alveoli of the dependant lung collapse in this short time intervall. therefore the net effect of recruitment of one positioning maneuver is very small. when positioning patients one should be aware, that the patient is kept in each lateral position long enough to clean up the atelectases in the non-dependant lung and short enough to compress less lung tissue in the dependant lung. objective: to analyze effects of low-dose no inhalation ia patients with severe aeut~ respiratory distress syndrome (ards) over five days. methods: we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who required no inhalation with a dose of ppm for at least days. entry criteria for no injaalafioa were murray score >i . aud pat/fie < nun hg with peep >~ em i~o for at least hours. all patients were sedated, intubated and mechanicauy vantil~ed with volume assist-control ventilation, and had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) to measure cardiac output (by thermodilufion) and relevant intravaseular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and endotraeheal tube and flow was adjusted to obtain ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endouacheal tube by the chemiluminiscence method (nox , see-seres, france). metahemoglobinemia levels were mesured daily. no inhalation was manteined if paojfio ~ improved at least % and was stopped when the change in pao /fio ~ was below % or when the patient presented a paojf > mm hg a~er minutes without no inhalation. every day we made an on-off test to determine if no inhalation improved pao /fio ~. statistics: analysis of vmiance. data: mean + standard deviation. results: the mean age was . +_ . years and mean lung injury score was . • . . mortality was % ( / ), metahemoglobinemia . • . %, and no concentrations zero. paojf~o always improved significantly al~er ppm no inhalation (see :~ conclusions: reintubation in salf-extubated patients strongly depends on the type of meehamcal venfilatory support: the probability of needing a reintabation ff ese occurs during fult vontilatory support is higher than ff ese occurs during weaning. these data suggest that some patients may remain under weaning from mechanical ventilation for unnecessarily prolonged periods of time. objective: the aim of this study was to evaluate the acute effects on gas exehonge and hemodynamics due to positional changes from supine (sp) to prone (pp) in patients with severe acute respiratory distress syndrome (ards). methods: nine intubated, sedated, paralyzed and mechanically ventilated patients with severe ards were prospectively studied. all had a murray score > . , and a pao /f~o < with peep ~ cm h for at least h. all patients had indwelling arterial catheters in the pulmonary artery as well as in the radial or femoral artery in order to measure cardiac output (by thermodilution) mad relevont pressures, and to withdraw blood samples. arterial blood gases and hemodynamie parameters were measured first in sp, and then in pp after minutes of stabilization. vontilatoly parameters remaing unchanged during all the study. statistical analysis was done by the non parametric wdeoxon test. data are expressed as mean ~= sd. results: there were men and women with a mean age of . years ( - ) and mortality was % ( / ). main results are shown below: objective: to describe and compare a new method for obtaining p-v loops (p-vcv) by using a two-way collins valve (twv) with thosu obtained by the supersyringe method (p-vss). methodology: we prospectively studied patients who had an aeute lung injury and were intubated, sedated and paralyzed, and mechanieany ventilated. we performed the p-vev loops and p-vss loops in random order, and the static inflation pressure was limited to emh with both methods. pressure (p) was measured at the airway opening by means of a differential p transducer, and volume was obtained from flow (measured with a pneumotacograph) integration. the p-vse method has already been described (h~trf a,et al.bepr ; : - ) . the p-vev method consists in the following: the inlet of a twv is connected to the ventilator's y-piece, and both outlets are couneeted to the endotraeheal tube by means of an additional y-piece; one of this outlets has a one-way rudolph valve in order to allow inspiration but not expiration during the inflation maneuver. changing the twv tap position allows basal ventilation or progressiveinflation of the respiratory system. this maneuver is as follows: during an end-expiratory occlusion, the ventilatory settings are adjusted to deliver a ml v r with a respiratory rate of /min and i/e ratio : ; at the same time the twv tap is ehonged in order to divert flow through the one-way valve. inflation then begins alter releasing the expiratory oonlusion. pressure and flow signals were digitized and acquired by a computer for subsequent data analysis. we analyzed the following parameters: inflation compllonee ( objective: to analyze the variables which eventually may differentiate ards patients who do and do not respond to low doses of inhaled no. we prospectively studied patients ( men, woman) with severe ards admitted to our icu between may and may who were treated with no ( ppm). the onta'y criteria for no inhalation were murray score >/ . and paojfo z < mm fig and peep >/ cm i~o for at least hours. all patients were sedated, intubated and mechanically ventilated with volume assist-control ventilation. tidal volume was between and ml&g, with constant inspiratory flow, respiratory rate was - /rain, and i/e ratio between : to : . all patients had indwelling arterial catheters (pulmonary artery, and radial or femoral artery) in order to measure cardiac output (by thermodiintion) and relevant intravascular pressures, and to calculate derived parameters. no was administered between y piece of the ventilator and ondotracheal tube, and flow was adjusted to obi~a ppm no in the inhaled gas. the no, no and no x concentrations were continuously measured at the distal end of the endotracheal tube by the chemilumiinscenee method (nox , see-seres, france). metahemogtobinemia levels were measured daily. we considered a response to no inhalation when an improvement in paoz/fo above % was observed after the inhalation of ppm no (group r) . when the cha~age in paojfi z was below % it was considered a lack of response (group non-r small airways functional abnormalities have been recognized as a common feature of lung pathology. however peripheral airways contribute relatively little (~ %) resistance to flow and there disturbances can not be adequately estimated by conventional measurements of respiratory mechanics. the purpose of the study was to evaluate the relationship between raw and small airways conductance following weaning from ventilator methods. patients (age: - years; males) with no serious complications al~er mitral or multiple valves replacements and with more than hrs on mechanical ventilation have been enrolled in this study. the modified flow interrupter technique (ptg "gould" with fleish head # ; differential pressure transducer pm- -tc "statham" w amplifier "kistler ") and flow-volume recording of forced expiration (fleish head # ) have been applied before surgery and following operation on mechanical ventilation (my), after extubation (t:xtijb), on ( nay) and ( day) days. airways specific conductance (sg aw) has been calculated as a mean of - consequent measurements in each patient at each stage. the sac was estimated by max expiratory flow at and % of vc on - f-v curves (mef .~ , mef ) all the data were statistically analyzed with t-test introduction : noninvasive ventilation (niv) reduces the need for endotracheal intubation, the length of stay in icu and the mortality rate in acute exacerbation of copd. however, some patients failed to be ventilated with niv. .objectives...; to further delineate patients who failed to be ventilated with niv and to obtain predicted factors of failure. patients : a cohort of patients ( • years) presenting with acute exacerbation of copd (fevi: • ml, paco : • , ph: . • . ) and nonmvasively ventilated (pressure support through a full-face mask) between april and may twenty-seven ( %) were successfully ventilated with niv (discharged alive without the need for endotracheal intubation) while ( %) failed, requiring endotracheal intubation. .methods : patients successfully ventilated and those who failed were compared according to respiratory and nonrespiratory variables univariate analysis (wilcoxon rank-sum test and fisher-exact test) was performed to select variables included in a multivariate analysis by stepwise logistic regression. results : underlying disease assessed by the simplified acute physiologic score ( • vs • , p = . ), creatinine serum concentration ( • vs • gm/l, p = . ), blood urea nitrogen (bun : • vs mm/l, p = . ), age ( • vs • , p = . ) were higher and encephalopathy ( vs %, p = . ) more frequent in patients who failed. multivariate analysis showed that encephalopathic patients (or (odd ratio) = , p = . ) older than years (or = , p = . ) and presenting with bun >_ mmyl (or = , p = . ) failed to be ventilated with niv. variables related to the respiratory" status (i.e. paco , pao , fev ) were unable to predict tile failure of niv. conclusion : copd patients older than years, presenting with acute exacerbation, encephalopathy and bun > ram/l, should be carefully monitored because of high probability of failure with niv. methods:from february to december we studied pa_ timnts, males and females(mean age +/- ); of the se had emphysema,lo chronic bronchitis, dilatative car diomyopatia,with tracheostomy and emphysema.mean pac at admission in icu was +/- mmhg,while when weaningbegan, +/- .mean autopeep was cmh ( - ).all patients were ventilated in crpv as long as four hours to calculate st tic and dynamic cmpliance and autopeep.then the ventila tion was continued with psv+cpap(peep cmh objectives: analysis of the incidence of neurogenic pulmonary edema (npe) in a population of headtrauma patients with acute respiratory failure (arf). npe can occur after a central nervous system insult. differential diagnosis: cardiogenic pulmonary edema and other forms of non eardiogenic pulmonary edema. true incidence and pathophysiohigy remain poorly defined, however the role of catecholamines seems undeniable. early onset npe (within h after trauma) is characterised by hypoxemia, transient pulmonary hypertension and bilateral central fluffy infiltrates on chestx-ray. characteristics of cardiogenic edema or pneumonia are absent. late onset npe, (beyond hours after trauma), is more insidious. the clinical and radiographic picture has to clear within to hours. ( ) methods: all headtrauma patients admitted from january to december , in a nearotrauma icu setting were retrospectively analyzed for arf with as sole criterinm a pao -fio ratio < . results: neurotrauma patients were admitted during . patients ( %) presented with severe head injury (gcs< ), patients ( . %) with moderate (gcs - ) and patients ( . %) with minor head injury (gcs - ). overall mortulity was . % early (within h. after trauma) and delayed onset respiratory incidents were distinguished, counting for ( . %), respectively patients ( . %), patients ( . %) had early and late respiratory complications. early respiratory insufficiency was caused in patients ( . %) by aspiration, in patients ( . %) by lung contusion, in patient ( . %) by fat embolism and in patients ( %) by npe. in the late onset group patients ( . %) presented with pneumonia, ( . %) with fat embolism and ( . %) with npe. the npe group, patients, presented as follows: patients ( . %) developed early npe, and ( . %) delayed onset npe. patients ( %) died within the first days after admission, showing high mortality. gcs was less than in patients ( . %), indicating severity of head injuries. conclusions: high incidence of arf with various etiology ( , ~ was found in this population. in about % of all admitted hcadtrauma patients ( , % of arf) npe was causing attetial hypoxemia. occurrence of npe seems to be related to the severity of the brain injury and thus to outcome. these data call for extreme vigilance in respect of the insidious occurrence of npe. were included if recovering from respiratory failure and if in the opinion of the primary physician were ready for extubation. patients were excluded if undergoing compassionate withdrawal of support or had tracheostomies. the attending physicians were blinded to the measurements. included patients were placed on pressure support (ps) of em h with demand-flow continuous positive airway pressure (cpap) cm h . after a minimum of minutes on the above sehiogs: gastric intramucosai pc'o , abg, and a p . were measured. the padents were then disconnected from the ventilator for a period of one minute and the patients" respiratory rate and minute ventilation were measured using a wrights respirometer to calculate the frequency to tidal volume ratio (f/vt). patients were then extubated. extubafion failure was defined as the inability to maintain spontaneous ventilation for hours for any reason. results: twenty patients met criteria and were studied over one month period in october . six of the twenty patients ( %) failed weaning. the mean and standard deviation is outlined in failure . +/- . . +/- . . +/- . . +/- . comparison between roc areas shows phi and p . to each show a statistically significant difference from an area of . (p<o. ). the area at which the test has no discriminative value. this is not the case for either the integrative index or the f/vt ratio. the differences between areas for each curve is not statistically significant. the area's for each roc curve is shown in table #' . results. of the newborns referred to us for ecmo-therapy developed barotrauma, of the required ecmo and one of the three other patients who did not recieve ecmo-therapy died. to determine the correlation between the risk factor barotrauma and the severity of the pulmonary situation, we determined the oxygenation index of each patient referred to us for ecmo-therapy . the table demonstrates , d- giessen, frg. inhalation of nitric oxide (no) and aerosulizatiun of prostaglandin (pg) i: have been suggested to achieve selective pulmonary vasodilation and improvement of arterial oxygenation in patients with acute respiratory distress syndrome (ards). we directly compared these two modes of transbronchial vasodilator therapy in ards patients mechanically ventilated for - h (mean murray lung injury score [ ] . + . ). patients were randomized to receive either first no and then pgi (n= ), or vice versa (n= ), with an intermediate baseline period. each drug was titrated individually to find the lowest effective dose for maximum improvement of arterial oxygenation. gas exchange variables, including data from the multiple inert gas elimination technique (miget), and hemodymmaics under application of no/pgi were compared to pro-and past-challenge values. no (mean dose . + . ppm) increased the mean oxygenation index (pao /fio ) from + to + mmi-ig (p < . ) and reduced the shunt-flow from . + . to . : . % (p < . ). aernselized pgi (mean dose . + . " ng/kg rain) augmented pao /fio from + to + mmhg (p < . ), and decreased shunt from . + . to . + . % (p < . ). the miget analysis showed predominant redistribution of blood-flow from shunt areas to regions with normal ventilation-perfusion ratios in response to both agents. in patients, both no and pgi caused an increase in pao /fio by at least rnmhg. two further patients displayed a corresponding improvement of arterial oxygenation in response to either no or pgiz. the mean pulmonary artery pressure decreased from . : . to . : . mmhg in response to no, and from . : . to . : . mmhg (p < . ) in response to pgi . cardiac output, systemic arterial pressure, and right and left heart filling pressures were not affected by either agent. we r that individually titrated doses of inhaled no and aerosolized pgi~ effect selective pulmonary vasodilation and redistribute blood-flow from shunt-areas to weu-ventilated regions with nearly identical efficacy profiles. obieetives: the use of extraeorporeal bypass systems for oxygenation and co -removal is performed in patients with acute respiratory distress syndrome (ards) to reduce mortality and to improve restitution of pulmonary functions. high-dose heparin -commonly used in such patients to prevent thrombotic complications -might cause incurable bleadings as a major risk. this lead to the development of heparinized bypass systems; results of animal and first clinical studies proposed that such systems might run with low-dose heparin or even without any systemic anticoagulation. methods: since , patients with severe ards were treated with extracorporeal lung assist (ela) using heparin-coated systems (type maxima, medtronic, carmeda coating) in our icu. they received a moderate systemic heparinization. standard clotting assays (act, aptt, tt, ptt, at-ill, fbg, fsp) as well as special tests (tat, r~-tg, pf , pal-l, d-dimers, protein c, cl-inhibitor) were performed. results: covalent heparin-eoating of the ela-systems combined with lowdose heparinization could not prevent major changes in coagulation: ) in mean, platelets dropped from /nl to /nl within h after onset of ela. ) tat levels were already elevated before ela start ( ug/]) and demonstrated an additional peak h after onset of ela (up to ug/[). ) in parallel, there was a transient peak of pai-i levels (from to au/ml} h after onset of ela. ) in mean, fibrinogen levels dropped from to mg/ ml within h after onset of ela. ) in mean, cl-inhibitor levels dropped significantly from % to % after onset of ela and reached the initial levels within h. ) after membrane change, there were significant changes for c -inhibitor, fibrin-d-dimers and tt. ) global clotting tests such as aptt, ptt and tt were within normal range. conclusions: patients with severe ards develop a prethrombotic state already before they get connected to the ela bypass system. after onset of ela, they experience additional involvement of procoagulant, anticoagulant, fibrinolytic, and complement systems. in parallel to laboratory findings, clinical data suggest that the use of heparin-coated systems with accompanying systemic low-dose heparinization does not avoid thrombembolic and hemorrhagic complications in tong-term ela patients. thus, at the present, higher dosed individually adjusted heparin treatment has to be recommended. thereby, standard clotting monitoring is not sufficient. objective: poor muscle performance contributes to prolonged dependence on mechanical ventilation. longitudinal data on muscle function in icu patients is scarce. we evaluated changes in inspiratory and peripheral muscle performance during prolonged intensive care in patients with acute respiratory failure. methods: patients requiring intensive care for more than one week were studied. maximum inspiratory pressure (pimax) was measured twice a week for a maximum of three weeks. handgrip power (dynamometer) and subjective fatigue (keldet score) were obtained in survivors only. one measurement was done on the date of extubation. pimax pressure was obtained by occluding the airway for seconds or at least five inspiratory breath attempts. obiectives -measurement of peep-induced changes in lung volume helps to assess respiratory mechanics in acute lung injury (ali). we evaluated the accuracy and stability of a new respiratory inductive plethysmograph (rip), in the measurement of peep induced changes in end-expiratory lung volume (eelv) and tidal volume (vt) against volume reference, pneumotachograph (pnt), methods -two hours periods of basal ventilation and stepwise increases and reductions of peep ( - - - - cm h ) were recorded in patients with all. in addition, the new rip device (respitrace plus tm) was compared to an older rip (respigraph tm, nims, fl, usa) to determine its thermal stability using cold and warm devices and a ventilated lung model. results -the difference between the new rip and pnt in the measurement of vt was - _+ mi (x _+ se) or a - . _+ . % error. increasing peep from to cm h induced a + ml change in eelv. a difference of + ml ( . % of max. eelv change) (ns) was found between rip and pnt eelv readings. during controlled ventilation with constant settings the mean change in eelv was _+ ml/ min (fig.i) . validation of calibration showed a mean error of -+ . % after rain. the new rip had a higher drift when cold (cold + ml/ min vs warm _+ ml/ min), whereas the old rip was thermally stable (cold - + ml/ rain vs warm i + ml/ min). trauma icu, hospital traumatologia y rehabilitacidn. vall d'rebron. barcelona. spain. recent data suggest that the proportion of patients with relevant discrepancies between two jugular bulb (jb) oxygen saturation (sjo ) values is higher than suspected. objectives: determine the incidence, the significance and the pro nosis value of those differences,if they exist,in severe head injured-patients. material and methods: severe head-injured patients, coma glasgow scale (gcs) , with diffuse brain injury according to marshall criteria in the first ct scan, icp recorded, with an interval from accident-double jb monitoring < than hours, were studied. data from bilateral sjo were obtained simultaneously, every hours. discrepancies were considered significant, when differences in sjo were > %. no chan es in treatment protocol (hyperventilation, man• etc) were carried out due to this study. results: men and women were studied, aged • yrs. at arrival at hospital, gcs were < in and ) in to. the incidence of high icp() mmhg) were sz at the entry. the mean therapy index level required to control lop was ~l all patients required vasopressor therapy to maintain upp over ds mmhg. in patients a s.s f swan-ganz fiberoptic catheter was used to obtain a continuous recording of sjo . in the others , sj were intermittently controhed.the mean time of monitoring were d. • days. ten patients died within this period. a total of . blood samples were analized. at arrival, sjo discrepancies were found in patients, b %. at hours, the incidence were lower, / , . %. at th day, were h/ , z and at day , when the catheters were retired, ii[ , z showed discrepancies. the ct showed new injuries in g z of patients with differences > ~ in sd values throughout treatment period. none of those were considered for neurosurgical treatment. no correlation was found between iop and sjo values and sjo differences. conclusions: the incidence of discrepancies between sjo was higher than expected in severe head-injured patients. these situation could reflect disturbances between demands. when differences are known, and those lend to change, the ct scan, nearly always, will show new injuries. platelet-activating factor (paf) is an inflamatory mediator implicated in the pathogenesis of bronchial asthma and acute respiratory distress syndrome (ards). its inhalation in healthy subjects produces transient bronchoconstriction and mild ventilation-perfusion mismatch, together with peripheral leukopenia as a result of intrapulmonary neutrophil (pmn) sequestration. likewise our group has shown in healthy subjects and asthmatic patients that aaibutamol (s) inhibits both pulmonary and systemic effects of paf, suggesting that s may inhibit paf-induced venoconstriction in pulmonary microoirculation. the aim of the present study was to investigate if s inhalation decreases pmn by lung sequestration induced by paf. we studied healthy, non-atop• nonsmoking subjects ( m/ f, + yr), which were pre-treated with s ( ,ug) or placebo, with a randomized, double-blind, crossover, design, before paf ( ,ug) inhalation. we measured the respiratory system resistance (rrs) by forced oscillation, arterial btood gases and both total white cell and pmn count every min over a min. period. simultaneously, we recorded continuously the lung dynamics of inm-neutrophil and tc m-erythrocytes activity, with a gammacamara. after placebo, paf inhalation decreased white cells (from to x /l), and pmn(from to _+ x /l), and increased aapo (from . _+ . to . + . mmhg, p<o. ) and rrs(from . . to . . cmh .s.i q ) (p < . each). the fall in total white cell count correlated with the intrapulmonary pmn retention (r = . , p < . ). by contrast, after s, paf did not induce any change in white ceil count (from to + x /i), pmn count (from to x /i), aapo (from . to . + . mmhg), and rrs (from . . to . . cmh .s.i ). compared with placebo, after s there was a lower ~lln-pmn lung activity ( . . vs . . cts/mci/pixel, p<o. ), lower intrapulmonary pmn retention ( . . vs . . %, p=o, ), and a faster washout ( . . vs . . s ~, p= , ). our results indicate that s inhibits paf-induced intrapulmonary pmn sequestration, being consistent with the hypothesis that s may offset the venoconstriction of pulmonary microcirculadon caused by this mediator. supported inpiratory muscle fatigue with failure of force generation as def'med by a tensiontime index (tti)> . - . has been shown to occur in normal volunteers and in stable copd patients with a specific imposed breathing pattern. its role, however, in hypercapnic respiratory failure is less certain. we studied failed weaning trials in copd patients in which breathing pattern, tension-time index (tti) of inspimtory muscles, dynamic peepi, dynamic lung elastance, lung resistance, and arterial paco and ph were measured at the beginning and end of a t-piece weaning trial. in addition, the change in esophageal pressure during a mueller maneuver (apes max) was measured. a weaning trail has been prospectively defined to have failed if one of the following criteria was met: a rise in pco > mmhg from baseline accompanied by a fall in ph< . ; a respiratory frequency (f) > /min; excessive accessory inspiratory muscle recruitment; and a marked increase in dyspnea. values are expressed as mean • se. weaning failure was characterized by a more rapid, shallow breathing pattern, worsened mechanics, hypercapnia and respiratory acidemia despite an unchanged tri and pes max. we conclude that in this setting hypercapnic respiratory failure is not a consequence of inspiratory muscle fatigue. rather the adopted breathing strategy and resultant hypercapnia may represent an adaptation to forestall the onset of muscle fatigue. concerning the investigated elf-par~eters, no stadstically signhqcant differences were detected between the pgi and the control group. histopathologlcal changes occured in both groups and consisted in rare focal flaaaning f tracheal epithelium with loss of cilia and slight inflammatory cell infiltration, as well as slight swelling of alveolar typo pneumoeytes. sections of generation , and from bronchial tree were free of pathological changes. conclusion: alter h inhalation of p~ji no signs of respiratory-lract tissue damage caused by the aerosol could be detected. the minor pathological findings in the trachea are most likely due to mechanical irritation by bronchoscopy, changes of the alveolar epithelium are known for long-term mechanical ventilation . objectives: the aim of this study was to evaluate of efficiacy of ganglion stetlate blockade in patients with respiratory failure. methods: two groups of patients were investigated: group i (n = ) trauma patients with acute lung injury (ali), group if (n = ) patients with asthmatic status. in all cases continuous mandatory ventilation (cmv) was used with bennett ae. in both groups bilateral ganglion stellate blockade with antero-lateral approach was performed, using . % marcain. the following parameters were analysed: pao , sao , paco~, pip and c~t~t. results: in trauma patients with aij after bilateral ganglion stellate blockade short -lived and slight improvement of pao and sao , decrease of pacoz and pir and increase of static compliance of respiratory system were found. in second group bilateral ganglion stellate blockade interrupted the asthmatic status and significant statistical improvement of parameters of oxygenation, ventilation and respiratory system mechanics were observed. conclusions: we suggest that the bilateral ganglion stellate blockade is a very useful method in treatment of patients with obstructive respiratory insufficiency. the aim of the study was to analyse whether there exists serum and urine electrolyte disorder in patients(pts.) with acute respiratory insufficiency(ari). the study included t pts. with ari (pao : , @ , kpa. paco : , i- , kpa, ph: ~: , , hco : , :~ , mmol/ , sao : , ~- , %) who were hospitally treated due to pneumonia( pts.),emboly of the pulmonary artery( pts.) and severe attack of bronchial asthma ( pts). among tham there were ( , %) males and ( , %) females, average age , ~: , years, otherwise previously healthy. electrolyte concentracions were measured at the onset of the disease in serum and urine collected during hours (sodium-na,potassium-k, chlorine-c , calcium-ca,magnesium-mgand phosphorus-p). the measured serum and urine electrolyte concentrations were compared with respective referent values (rv). by serum electrolyte analysis, the following average velues were obtained: na:l o, the object of our investigation was a group of pts with massive pneumonias, males ( . %), females ( . %),mean age yrs.thirteen ( %) of them were smokers, ( %) nonsmokers. only pt ( . %) had pre-existing chronic respiratory disease, and ( . %) were admitted for the first lime,with no previous respiratory anamnesis. diagnose was based on anamnestic data of productive cough in pts( . %),physicaly ~onchial breathing in i~s ( . %),white cell count onder x /l in pts( . %). radiographicly, bilateral massive homogeneous shadows were found in pts ( . %), onilateral in pts( . %),pleural effusion in pts ( . %). abnormal renal function was found in pts ( . %). sputum culture was positive in pts ( %): slr.pneumoniae, str.pyogenes, pse'udomonas aerug, in , , cases respectively. all patients had remarcable hypoxernia (pao range from , to , kpa) without hypercalmea. all patients needed oxygenotherapy together with antibiotics and other .symptomatic therapy. nineteen pts had anaelioration of general condition and normalization of blood gas analyses, while pts with the lowest hypoxcmia died.in conclusion, massive pneumonias are frequently followed by respiratory insufficiency which is one of the markers of pneumonia severity. as existing hypoxemia complicates the course of the disease,prolonges the recovery, makes therapy more complexe and may be cause of death , frequent blood gas measurement is recomanded. we studied the effects of bosentan (bos), an eta and etb receptor antagonist, to examine if endogenous et mediates pulmonary hypertension in anesthetized and ventilated dogs with acute lung injury due to oleic acid (oa). the gradient between pulmonary artery pressure (ppa) and occluded ppa (ppao), and gas exchange (evaluated by arterial blood gases and sf intrapulmonary shunt) were measured at controlled flow. in dogs (treatment), data were collected at baseline, during long injury (obtained rain after intravenous administration of oa . ml/kg), and again after bos ( mg/kg intravenously). in dogs (pretreatment), data were obtained at baseline, after bos and then after oa. in treated dogs, oa increased (ppa-ppao, mmhg, table, means + sem, * p < . vs base) and deteriorated gas exchange. after oa, bos did not affect pulmonary vascular tone nor gas exchange. in pretreated dogs, bos had no effect on baseline pulmonary vascular tone but prevented the increase in (ppa-ppao) after oa. the deterioration in gas exchange after oa was not influenced by bos pretreatment. objectives: the alveolar tension is measured by the application of the alveolar air equation in which the arterial pco is used or by the simplified form of this equation in which the respiratory exchange ratio is taken at the value of . . the purpose of this study was to estimate the effective alveolar tension (pao eff) during spontaneous breathing with a new bedside technique which is simple non-invasive in normal subjects and patients with chronic bronchitis-emphysema. we also compared these values with the ideal alveolar po (pao (i)), measured from the alveolar air equation in which paco was substituted by the effective alveolar pco (paco eff) and with the alveolar po measured from the simplified alveolar air equation (pa ). this study is complemantary to previous work for the estimation of paco eff. methods: the subjects breathed quietly through the equipment assembly (mouthpiece monitoring ring, fleisch transducer head) connected to a pneumotachograph and a fast response and co analyzer. the method is a computerised calculation of the effective alveolar po quite similar to that of paco eff, obtained from the simultaneously recorded at the mouth expiratory flow, and co concentration versus time curves. results: the results showed a mean difference (pao eff-pa (i)) of - . kpa in normal subjects and - , in patients. the mean of the difference (pao eff-paq ) and (pad (i]-pao z) was much greater than . in all subjects. the limits of agreement for the difference (paozeff-pa (i))were - . to . kpa in normal subjects and - . to . in patients, while those for the differences (pao eff-pad ) and (pao (i)-pad ) were very large ( > - . to > . ) in all subjects. conclusions: the effective alveolar po is very close to the ideal one in normal subjects, tn patients pao eff may excessively deviate from pa (i) due to the observed significant difference between the alveolar/tidal volume ratio for o and that for co . the alveolar po measured from the simplified alveolar air equation (pao ) differed substantially from pao eff and pad (i) in all subjects. the essential role of glucoprotein hormone erythropoietin is to control red cell production. hypoxemia, reduced blood -carrying capacity and increased affinity of hemoglobin for are the primary stimuli for erythropoietin production. both anemia and hypoxemia induce rapidly erythropoietin secretion. kidney erythropoietin rna levels correlate inversely with hematocrit and directly with plasma erythropoietin level. similarly, hypoxemia increases kidney erythropoietin rna and plasma erythropoietin. the effect of hyperoxemia (pa >lo mmhg) on erythropoietin secretion isn't very well understood. the purpose of this study was first to evaluate the erythropoietin secretion in patients with acute respiratory failure and second to determine the effect of hyperoxemia on erythropoietin secretion in patients with and without anemia. sixteen patients with acute or acute on chronic respiratory failure needed mechanical ventilation were included in this study. these patient were divided in two groups. the patient who developed anemia were included in group i and the patients without anemia in group i . erythropoietin was estimated in venous blood in three stages. the first sample was taken during hypoxemia, the second during hyperoxemia and third during normoxemia. all the patients had high erythropoietin level during the hypoxemia period (mean value • mu/ml). during hyperoxemia etythropoietin levels were reduced in both groups ( mean value . + . mu/ml in group i, . • mu/ml in group ii). in normoxemia stage, erythropoietin increased again in anemic patients, and decreased more in the patients of group i . we conclude that hyperroxemia inhibit erythropoietin secretion in spite of anemia and tow arterial oxygen content. hyperoxemia may be a factor of the insisted anemia in with oxygen treated icu patients. the purpose of this study was to determine the relationship between clinical features of acute lung injury (all) and parameters like total proteins, total and individual phospholipids, the presence of paf, and acetylhydrolase activity in bal of mechanically ventillated patients. acetylhydrolase catalyses the cleavage of acetyl-group from the second position of the glycerylether backbone of paf, leading to its inactivation. mechanically ventillated patients were divided to three groups. group i includes patients without all; group ii, comprisespatients with moderate degree all, ( . <g-i < . ); and group iii comprises patients with severe ards (all score > . ). broncoalveolar lavage (bal) was obtained after infusion of normal saline at ~ to intubated patients and cooled immediately. cells were removed after mild centrifugation ( x g, min, oc). aliquots from the supernatant were used for total protein, phospholipid and paf analysis and determination. acetylhydrolase activity was assessed after incubation of bal with h-paf labelled on the acetyl group. released label was measured by liquid scintillation counter in the supernatant after trichloroacetic acid precipitation of the non-reacted substrate. kinetic characteristics of the enzymes were also studied. total phospholipids appear reduced in bal of patients with all, while total proteins increase. these factors appear to correlate with the severity of all. paf was not present in bal samples pretreatad with equal volume of % acetic acid to denaturate acetylhydrolase. detection limit for paf under our experimental conditions: pg paf/ml bal. instead, acetylhydrolase activity was detected in amounts increasing with the total protein content. background: intubated patients without lung injury or impaired breathing control normally display an inspiratory peak flow of below l/s. the aim of our study was to investigate the inspiratory peak flow generated by patients with acute respiratory insufficiency (ari). we had to take into account that both an inspiratory pressure support (ips) and the resistance of the endotracheal tube considerably influence the flow pattern generated by the patient. patients and methods: to investigate the non-influenced flow pattern we developed a new ventilatory mode which automatically compensates for the flow-dependent resistance of the endotracheal tube (automatic tube compensation, atc). furthermore, the mode maintains a constant tracheal pressure in inspiration and expiratio n . consequently, the measured flow pattern exactly corresponds to the flow pattern generated by the patient except that the ventilator modified for this mode (evita, driiger liibeck, germany) was not able to deliver a gas flow of more than l]s. we have investigated patients with ari arising from different reasons. results: the inspiratory peak flow measured in the atc-mode was . l/s _+ . l/s. the maximal deliverable flow of l/s was obtained in of patients. the figure shows the flow pattern under atc and ips in [~s] oi:) one of these patients. conclusions: patients with ari display a highly increased inspiratory peak flow. ventilators used for spontaneous breathing should therefore be able to deliver a gas flow of more than l/s. an overproduction of no and reactive oxygen species (ros) has been demonstratred in septic shock. ros and nitric oxide (.no) are free radicals which are known to react together leading to peroxynitrite anions that can decompose to form nitrogen dioxide (no ) and hydroxyl radical (oh~ thus, no has been reported to have a dual effect on lipid peroxidation (prooxydant via the peroxinitrite or antioxidant via the chelation of ros). in the present study we have investigated in different models the in vitro and in vivo action of no on lipid peroxidation. copper-induced ldl oxidation was used as an in vitro model of lipid peroxidation. ldl ( ~g apob/ml) was incubated with cu + ( , ~tm) in presence or absence of no donor (sodium nitroprussiate or glutathione-no) from to ~m. oxidation of ldl was monitored continuously with conjugated diene formation ( nm) and hydroxy nonenal accumulation (hne). exogenous no prevents in a dose dependent maner the progress of copperinduced oxidation. ischaemia-reperfusion injury (i/r), characterized by an overproduction of ros, is used as an in vivo model. anaesthetized rats were submitted to hour renal isehaemia following by hours of reperfusion. sham operated rats (sop) were used as control. lipid peroxidation was evaluated by measuring the hne accumulated in rat kidneys in presence or absence of l-arginine or d-arginine infusion. l-arginine, but not darginine, enhances hne accumulation in i/r but not in sop (< . nmol/g tissue in sop versus . nmol/g tissue in i/r), showing that in this experimental conditions, no produced from l-arginine, enhances the toxicity of ros. this study shows that the pro-or antioxydant effects of no are different in vivo and in vitro and could be driven by environemental conditions such as ph, relative concentration of no and ros, ferryl species...these conditions are impaired in circulatory shock. methods:" the diagnostic and therapeutic approach was standardized so that data collected over a -year period were comparable. a progressive deterioration of clinical conditions and/or pulmonary gas exchanges was considered as indication for my. variables potentially predicting the need for hv were derived from clinical and arterial gas data, extrapulmonary diseases, use of drugs, chest x-ray and ecg abnormalities. results: rv, performed with external and/or internal ventilators, was necessary in patients ( %). at the hospital admission, pac was higher and ph was lower in patients requiring rv ( pneumomediastinum, pneumothorax, ateleetasis and myocardial infarction are rarely seen in bronchial asthma. these complications occur as a result of the severe asthma.the aim of our retrospective study was to analyse the complications seen in acute asthma attacks. during the years through , patients were admitted to hospital in acute asthma episode. there were ( , %) pts with complications; mean age of yrs; females ( %). clinical history, ecg and chest radiogr~hs were analysed. the mean duration of bronchial asthma was yrs (range from months to yrs), all patients were atopics. there were four ex-smokem and one smoker. the worsening of asthma symptoms begun two days before the admission (range from to days). on ecg all patients had tschycardia. rightward shift of the qrs axis and st-t changes indicative of right ventrieutur strain were found in three pts. these were the transient fmdings that improved after curing the acute asthma attack. non-q myocardial infarction oeeured in one patlent and resulted from the hypoxaemia of asthma. hyperinfl~ion was the usual finding on the chest radiograpk pneumomediastinum and subcutaneous emphysema were apparent in five pts and required no additional treatment unilateral pneumothoraccs were present in two pts and needed eontimous intrapleural drainage; one of these patienst died in eardiorespiratory insufficiency. ateleetasis of right upper lobe was present in one patient. it oceured due to inspissated secretions and needed no additional treatment all these patients, except one who died, improved on lreaanent with oxygcr~ steroids, beta-two agonists, theophylline and antibiotics. in conclusion, complications occur in acute asthma episodes as a result of the severe asthma mediastir,*l emphysema and atelectasis are not serious complications. pneumothorax and myocardial infarction are very serious life-treatening complications and always have to i:m considered in taati~ts with sev~ asthma. acute bronchial asthmatic episodes represent one of the most common respiratory mnergendes, its maximmum expression "status asthmatiens" is one entity of low incidence, still it is a risk to the physical integrity of the patient. during a total of patients with diagnosis of status asthmabcas were hospitalized. out of these palients six had a near-fatsl asthma and they were subjected to a complex examination. near-fatal asthma was defined as either respiratory arrest or acute asttuua with paco greater than , kpa and/or an altered state of consciousness. mean age was , -d: , yrs, four male and two female sex. at presentation two patients suffered from coma, others were confused. they exh'bited severe dystmoes, diffieul~ speaking, used accessory muscles of respiration, increased whee~tg while two cases had silent chest on auscultation. cyanosis indicated a very severe asthma attack in all six patients. mean respiratory rate was ~ /min and puts rate .d: bts/imn. arterial blood gases revealed a pao of , ~ , kpa, paco of , • kpa and ph of , -+- , . area-careful evaluation they received conventional therapy (immediately continuous oxygen, impelled nebulization with high doses of betatwo agonists and ipmtropium bromide, intmvanous st~oids and theophylline). in two eases signs and symptoms of deteriorating airflow and respiratory muscle fatigue determined the need for mechanical ventilation. out of six near-fatal attacks aggressive lrealanent was suscessfull in four patients and fatal in two eases. one patient admittcxl in coma died in severe hypoxae~a upon one hour and one mechanicaly ventilated died from cardiac arrhythmia. life-threatening attacks in asthmatics in our group developed gradual worsening despite neatment which r symptoms in most other patients. one patient had "brittle asthma", other long-standing acute episodes ireated with systemic steroids. conclusions: idantitiechon of fatality prone subjects may lead to fttrther muetion of seveze episodes. respiratory affest and coma upon admission, severe dyspnoca with silent chest on ausouhation, oyanusis and use of accessory muscles of respiration constitute the basic cfinieal picture. hypoxasmia must be immediately eon'ected.the patients and physicians should be able to assess the severity of asthma, a major factor in near-fatal and fatal asthma attacks. objectives :our purpose was to asses if the evolution of patients with a adult respiratory distress syndrome (ards) ,shows any relation to the pulmonary or systemic origin of the disease and whether or not there were differences in the frequency of the syndrome in both groups. methods : randomized prospective study in multidisciplinary icu. one hundred and sixteen patients with a high risk developing ards were distributed into two groups. one was named systemic origin group(so) and the other pulmonary origth group (po).ai patients only showed one cause (pulmonary or systemic) with potential risk of ards.the patient's hemodynamic and respiratory status was evaluated every hours the first day and every hours the second and third day. at the end of hours the patients were diagnosed as ards or non-ards. measurements and main results : of the total patients, were finally included in the so group and in the po group.patients in so group and po group had comparable ages (p<. ).peep in both groups was comparable (=. ) at the mmnent of admission to the study. there were no statistically significant differences for cardiac index and systemic vascular resistances. the pulmonary vascular resistances (pvr) showed significant differences at h.(p<. ) and h. (p<. ).the oxygen comsumption (vo) in patients of the so group showed statistically significant differences at h. (p<. ) with respect to initial values.fifteen cases of ards ( . %) in the so group and twenty five cases ( . %) in the po group were identified. the time of onset of ards was _+ hours in the so group and + b hours in the po group.the final outcome was very similar th both groups : mortality of % in the so group versus % in the pc group. conclusions : the pathogenesis of ards depends on whether the lesion is originated at or outside the lung. the po group showed a sborter thne of onset of ards, a faster and more severe increase of pulmonary shunt and a higher percentage of patients developing ards compared with patients of the so group.the so group showed a higher and faster increase in puhnonary resitances tbat po group and a decrease th oxygen comsumption earlier and more severe than in the po group. these data thus seem to show that there could be two mechanisms involved in the genesis of ards depending on the cause. the fact that the ards genesis is shorter in the cases of pulmonary etiology with faster impairment of pulmonary shunt, and a slower increase in pulmonary resistances in this pulmonary group, would indicate that the underlying mechanisms responsible for the hypoxemia are different to those which thitiate the increase in pulmonary resistances. finally, the exclusive inapairinent of oxygen consumption, which appears earlier than the onset of ards in the systemic origth group, could show the generalized character of the process in this group. perfusion of prostacyclin (pgi ) to treat pulmonary hypertension in adult respiratory distress syndrome (ards) worse pulmonary gas exchange due to a marked impairement of ventilation/perfusion mismatch. recently has been shown that if prostacyclin is given by aerosol instead of intravenous the net effect is an improvement of arterial oxigenation due to a redistribution of blood flow to well ventilated areas. objectives: to asses the effects of inhaled proatacyclin on pulmonary haemodynamics and gas exchange in patients with severe ards. methods : two patients with severe ards (murray score > ) recived inhaled pgi at - ng.kg.min " using an ultrasonic nebulizer. haemodynamic measurements, arterial and mixed venous blood gas analysis were performed before and after rain of pgi inhalation. results: short-terro p~i inhalation improved pulmonary g-~ e-'~hange in both patients. arterial oxygen partial pressure (pao ) increased from to mmhg in patient and from to in patient , the ratio pao to the fraction of inspired oxygen increased from to (patient ) and from to (patient ). venous admixture decreased from % to % and from % to % in patient and respectively. mean pulmonary artery pressure decreased slightly from to mmhg in patient and from to mmhg in patient . no effects on systemic haemodynamics were observed in any patient. conclusions: pgi inhalation improves gas exchange and produces selective pulmonary vaaodilation, thus can be an alternative therapy for the treatment of pulmonary hypertension and hypexemia in patients with severe respiratory falllure. methods: we treated ards-patients (age yr ( - ) mean, range) during - . the lowest pao /fio -ratio was ( - ), the worst murray score . ( . - . ), icu-stay ( - ) days and hospital mortality %. the costs of intensive care were calculated according to intensivity of patient care as assessed by tiss-scoring (therapeutic intervention scoring system). the more intensive the care, the higher are the costs. costs per year of life saved (=life-year" in us $) were compaired by other medical treatments ( - ). it is assumed that the mean expected length of remaining life in ards-survivors after intensive care is years. treatment life-year ($) ' bone marrow transplantation (acute leukemia) lowering cholesterol using iovastatin treating hypertension using nifedipine heart transplantation intensive care of ards-patients conclusions: intensive care of patients with severe ards is highly more cost-effective as compared with many other routinely used medical treatment strategies, the usually good recovery and the reasonable quality of life in survivors justifies investments to care of these patients ( ). there is a close correlation between these two methods of measuring evlw. however there is an underestimation of . % in this kind of pulmonary edema ( oleie acid induced ) with the double dilution method. although the size of the sample is small, in normal lungs there appear not to be this underestimation. the effect of peep on evlw has been studied with contradictory results, probably as a consequence oft differences in methods of measuring evlw, variations in the type and severity of lung injury, and different timings of peep application. objective= ) to analyse the effect of different levels of peep ( , and omh ) on evlw during hpe; ) to establish whether increases in intrathoracic pressure due to high peep levels can obstruct lymphatic drainage. material and methodet hpe was provoked in groups of dogs by inflating a foley catheter in left auricular to a pressure of - r~uhg. peep levels of , i or m~hg were applied. resultst objective: to assess the effect on extravascular lung water (evlw) of the application of peep and the reduction of vt in an oleic acid pulmonary edema model in pigs, using three ventila~ary strategies. material and methods: twelve adolescent pigs (weighing over kg) were randomly divided in three gmups immediately alter infusing via a central vein . ml/kg of oleic acid to produce a permeability pulmonary edema. the ventilatory parameters for each group were as follows: group i (n= ) : vt: - ml/kg; zeep. group :(n= ) : vt: - ml/kg; peep: cm h . group :(n= ) : vt: - ml/kg; peep: emil . (resulting in permissive hypereapnla) after a four-hour period of ventilation the animals were killed and the lungs excised to calculate gravimetrically the extravascular lung water using a standardized procedure ( hemoglobin content method ). ill evlw (ml/kg) group obiective: in the postoperative period, maintenance of adeguate arterial oxygen tension is a major problem in morbidly obese patients probably because of a large reduction in functional residual capacity (frc). the aim of this study was to evaluate the effects of peep on respiratory mechamcs and gas exchange in this kind of patients. methods: in nine postoperative mechanically ventilated morbidly obese patients (bmi> kg/m ) we partitioned the total respiratory system mechanics into its lung ( ) and chest wall (w) components using the airway occlusion technique associated with the esophageal balloon, during constant flow inflation (jap ; : ) . at three different levels of peep ( , , cmh ) we measured: compliance (cst), airway (rim) and "additional" (dr) resistance, frc and gas exchange. obiectives. to describe the use of prone position in our icu we analyzed the clinical records of all patients admitted in - , selecting adult patients with arf defined as: intubation and pao /fio < mmhg plus an fio > . or peep> cm i . results. patients met the arf criteria: of them ( . %) underwent prone positioning (p+). prone position use began in the early phase of arf ( . • days from the beginning, range - , median ). out of p+ pts were treated with controlled ventilation (cppv or pcv), while were on assisted ventilation (simv+ps) and on spontaneous breathing (cpap). only pts were awake when turned prone, while pts required adjuncts of sedation to tolerate the change of position. the duration of prone positioning was variable (average lenght . • h, range . - h). only minor side effects were observed (eyelids and facial edema, chest and facial pressure bruises). we consider responders (r+) those patients presenting at least . mmhg increase in pao /fio : / patients ( . %.) were responders when first pruned. the pao /fio changes induced by prone position are reported in the figure. pao /fio increased when patients were pruned (*p< . ) and remained higher than baseline values when returning supine(*p< . ). paco remained unchanged. prone positioning was used at least twice in / ( conclusions. this retrospective analysis confirms that prone positioning improves oxtgenation in the majorib' of arf patients. altough we have no available criteria to discriminate in advance r+ from r-pts, we now routinely consider the use of prone position in the treatment of severe arf. palo a, otivei m*, galbusera c, veronesi r, sala gallini g, zanierato m, iotti g, braschi a.servizio anest. e rianim. i, *laboratorio biotecnologie e tecnologie biomediche irccs s. matteo, pavia, italy inhaled no can improve arterial oxygenation and reduce pulmonary hypertension in ards patients; little information is, however, available about the dose-response curves. methods seven ards patients (lis . +. ) submitted to mechanical ventilation randomly received inhaled no doses in increasing or decreasing sequence: . , , , , , and ppm. reference measurements were obtained before and after the entire period of no inhalation. hemodynamic parameters and blood gases were measured after min in each condition. cmv was administered under sedation and paralysis, with constant ventilation, peep (lol-_ cmh ) and fit (. +. ). the changes in vt and fit due to the no ( ppm in n ) injection in the ventilator external circuit were compensated for. results . the dose of . ppm, ineffective on papm, significantly improved oxygenation. the increase of pat and the decrease of q'va/q' and papm were nearly maximal at - ppm. no deterioration of arterial oxygenation was observed at no doses as high as ppm. co exchange was not influenced by no inhalation. systemic hemodynamic variables did not change throughout the study. these results suggest that a concentration around ppm is adequate for obtaining maximum effects on hypoxemia and pulmonary hypertension in patients with ards. low-dose inhaled nitric oxide (no) induces redistribution of pulmonary perfusion in patients with severe ards and causes improvement of oxygenation [ ] . however, addition of exogenous lowdose no in the inspiratory gas mixture might be only a replacement of missing atmospheric no ( - ppb) in hospital central-supplied medical air. [ ] we have realised nitric oxide measurements in ten healthy volunteers, ( smokers and non-smokers) breathing with a mouthpiece and occluded nostrils through a ventilator circuit, with separation of inhaled and exhaled gases by a valve. no concentration was measured with a double-chamber chemiluminometer (environnement sa, france) and with charcoal/silicate purified compressed air. there was no nitric oxide detectable in the inspirat ry limb of the ventilator. unfiltered central supply medical air contained : - ppb of no and - ppb of no , whereas central supplied oxygen was no/no free. samples were taken after equilibration periods of minutes, with increasing fit levels of . , . and . for subsequent minutes periods; paired values were recorded every s. the mean no value was . ppb (sd . ) and n o significant differences were found for different fit levels both in smokers and non-smokers. these data suggest that the no concentration of pulmonary origin in the exhaled air of' healthy volunteers is probably lower than that reported by other authors [ ] and that, previously reported, differences between smokers and non-smokers are not always striking [ ] . we suggest the use of activated charcoal/silicate filters for clinical trials in order to achieve standard conditions. [ objective: to compare efficacy and safety of two doses of salbutamol. methods: sixteen adults who had severe acute a~hma were randomly assigned to receive either rag (n= ) or rag (n= ) of nebulized sulbutamol. both groups were similar with respect to age, duration of a~hma, duration of attack before arrival at the hospital and severity of a~hma according to baseline measurements (table) . evaluation was performed , , and rain after the start of nebulization. results: compared with mg regimen, mg regimen resulted in the same improvement in peak-flow and fischl index (figure). the changes in heart rate, respiratory rate and pace did not differ significantly between both groups. the incidence of side effects, which included tremor, palpitations, cardiac arrythmlas and other symptoms, was not sj~ificanfly different in the two populations. conclusion:the results of this study suggest that nebulization of ng of salbutamol is not more effective than rag in the initial treatment of acute severe asthma in adult patients. the prognostic factors of neutropenic patients admitted to the icu remain poorly known. the aim of this study was to determine the respective weight of underlying malignancy and organ system failures on the outcome of these patients. patients and methods: the charts of neutropenic patients (wbc < /mm and/or pmn < /ram ), admitted to the icu between and , were retrospectively reviewed. the characteristics of the neoplastic disease (h~emopathy or solid tumor, tumoral evolution, duration of cancer disease and of neutropenia), the mac cabe's score, the organ system (respiratory, hemodynamic, renal, neurologic, hepatic) failures and the severity scores (saps, saps ii ,osf) were registred within the st day in the icu. when discharged from the icu, the patients were classified as alive or dead. results: fifty-seven patients ( . %) had a h~ematologic malignancy, and ( . %) a solid tumor. fifty-nine of the patients died ( . %); the mortality rate did not differ between both groups ( . and % respectively, p = . ). with univariate analysis, none of the tumoral features is linked to the prognosis; only the respiratory (p < - ) and cardiovascular (p < - ) failures, and the number of organ system failures (p < - ) are associated to the risk of death. the saps (p < - ) and saps ii scores (p < - ) were higher in patients who died. with multivariate analysis (logistic regression), only the respiratory failure is correlated to the risk of death (p = - ); neither the features of the underlying malignancy (p > . ), nor the duration of neutropenia before admission in icu (p = . ), nor the severity scores figs ii: p = . ) are linked to the outcome. conclusions: the tumoral characteristics do not modify the prognosis after admission to the icu. they should not influence the decision to admit or refuse a cancer patient in the icu. respiratory failure at icu admission has the predominent weight on the risk of death in the icu. patients with respiratory acidosis due to asthma occasionally require levels of mechanical ventilation that place them at risk for barotrauma. a few case reports have described the use of an extra-corporeal membrane oxygenator(ecmo) circuit as an alternative means of co removal. generally, this has been used for short periods of time (< h) without serious complications and with low blood flows through the extra-corporeal circuit. we report a case of refractory asthma who could not tolerate even small-volume breaths from a mechanical ventilator due to severe bilateral airleak. ecmo therapy was initiated at the referring hospital prior to helicoptor transport. high blood flows were used ( % of the patient's cardiac output), sufficient to achieve both co removal and oxygenation. satisfactory gas-exchanged was accomplished (pco = - mmhg) with nearly total lung rest for a prolonged period ( h). however, the long ecmo duration was associated with two severe complica-ti ns: ) bilateral hemothoraces due to anticoagu!ation in the extra-corporeal circuit, and ) prolonged weakness as a result of neuromuscular blockade for six days. the patient was discharged from the hospital in good condition. we present the respiratory and hemodynamic features of this case aw well as the potential complications of ecmo therapy in asthma. objectives: parameters derived from tidal expiratory flow ~e) and volume (vt) can be used to detect airflow obstruction in copd patients who might be unable to perform forced spirometry (e.g., icu). however, indices such as ave/v t and at/re are highly variable (thorax, : ; ) . methods: we investigated whether the standardized for v m effective time (teff~) of a tidal breath, which is derived by asimple mathematical procedure (teff,= j'vdt/vt ), is a more reproducible and sensitive detector of airways obstruction, we studied nine normal subjects ( male, -+ yr) and copd patients ( male, -+ yr) in the seated position, with a noseclip on. they breathed quietly, through a pneumotashograph to measure flow (v). volume was obtained by numerical integration of thellow signal. each subject had an initial - min trial run, in order to become accustomed to the apparatus and procedure. when regular breathing had been achieved, all breaths over a min time interval were recorded. the mean value of six consecutive breaths (ers criteria) for each subject was used for analysis under the condition that within session variation of tidal volume (vt) was < %. lung function tests were: in normals (mean-sd), fevl%pred = • fevl/fvc%= -+ % , and in copd patients, fev~%pred= __. and fevi/fvc%= --. %. results: values are shown as mean-..+-sd in the following a su~ve~ os literature sources p~oves that t~aditlona], i.e. medicinal medication and physiothe~apeutic methods os t~eatment often p~ove to be insufficientl~ effective both currently and in the ~emote future. the goal of this study was to investigate the efficacy os t~eatment of b~onchial asti~ma patients by means os speleo-and artificial sp~ay therapy. speleotherapy t~eatment was conducted in the conditions os mic~oclimate os salt mine in solotvino hospital. a~tis sp~ay the-~apy was conducted by means os a self-made device. ou~ method is based on the p~inci-~ le os using the majo~ facto~ of speleo-he~apy -highly dispe~sed sp~ay s sodium chloride. the obtained ~esults ~e~e analyzed in five g~adations. at the end os the speleothe~apy improvement and considerable improvement was observed in , ~ os patients; inconsiderable improvement -in , ~ os patients. having evaluated the e~s os t~eatment using a~tis sp~ay therapy the indices a~e , h and , ~ ~espectively. remote ~esults of t~eatment a~e an important index os t~eatment, the ~esult os ~hich ~e~e studied by means s a ~uestionnaive-method. patients ~ho had been t~eated by speleothe~apy mo~e f~eguently ~e-po~ted a ~elapse in disease ust afte~ the course o~ t~eatment ( , h). ho~eve~, in a ]ate~ phase the ~emission ~ould last ]on-~e~ (s months in , ~ os patients, till one yea~ in ~ ~). in , ~ os patients who passed the co~se os a~tificial sp~ay therapy a ~elapse was ~egiste~ed immediately as the co~se os t~eatment. then thei~ condition stabilized ~hile in , ~ os patients a period os ~emission lasted s ha]s a yea~. , ~ of patients dida't ~epo~t a ~elapse of the disease du~in~ one yea~. evangelismos hospital, critical care department, athens, greece method#: mechanically ventilated patients ( copd, ards, other pulmonary diseases) were studied in two phases: ) during the acute phase of respiratory failure; ) during recovery - days later. we measured mip and monitored the pattern of breathing while the patients were breathing spontaneously through the respirator (pressure support mode with - cmh ) until either the point they were unable to sustain spontaneous breathing (sb) any longer (phase ) or for two hours when they could sustain sb indefinitely (phase ). subsequently the patients were sedated, paralyzed and mechanically ventilated. then we simulated the pattern of sb at the end of the sb trial by manipulating the variables of the ventilator and assessed respiratory mechanics b y the end-inspiratory and end-expiratory occlusion technique. . during recovery, a combination of reduced inspiratory load and increased venfilatory capability makes a patient previously unable to sustain sb to breathe spontaneously. . inspiratory load is reduced during recovery, mainly because both intrinsic peep and breathing frequency are diminished. obiectives: although elevated concentrations of a few cytokines have been shown to be present in the bronchoalveolar lavage (bal) fluid (balf) of patients with the adult (acute) respiratory distress syndrome (ards), the pethogenesis of ards is largely unknown. leukemia inhibitory factor (lif), a growth factor recently recognised as a polyfunctional cytokine integrated in cytokine networks was measured in unconcentrated balf of patients from different patient groups. methods: lif was measured in balf by means of a specific and sensitive elisa (detection limit pg/ml)in balf (lavage of x ml in the right middle lobe). results: lif was not detected in the balf of healthy control patients and in only one ( pg/ml) out of patients at risk for ards (after cadiopulmonary bypass surgery) who underwent bal h after the end of the extracorporeal circulation. high and detectable levels were found in the unconcentrated balf of out of patients with full-blown ards ( + , mean + sem, range - pg/ml). there was a good correlation between the level of lif in the balf and a number of markers of inflammation: neutrophils/ml (r: . , p= . ), albumin ( r: . , p= . ) and protein level (r: . , p= . ). conclusions:the biological role of lif in these balfs is not readily explained by its currently known actions and it is unkwon whether lif contributes to or is a response to local tissue damage. our results indicate that this cytokine with lots of interesting _functions is a pert of the inflammatory cytokine cascade in ards. background and obiective : we recently demonstrated that cisapride -a new prokinetic drug -enhanced enteral feeding in a heter genoas group of ventilated icu patients by significantly accelerating their gastric clearance (crit care meal, ; : - ) . it remains unknown, however, whether certain subgroups of patients might benefit more from adding cisapfide to their enteral nutrition regimen than others. patients with chronic obstructive pulmonary disease (copd) might represent such a subgroup since their illness and its specific treatment put them at risk for gastric emptying disorders. design and setting : prospective, consecutive sample study in an adult medical intensive care unit in a university hospital. patients : mechanically ventilated and hemodynamically stable copd patients. interventions : gastric emptying was evaluated by bedside scintigraphy and expressed as the time at which % of a tcg~-labelled test meal was eliminated from the stomach (t / ). baseline data (do) were recorded after enteral nutrition reached to ml daily. scintigraphic measurements were repeated days after cisapride ( ml orally, q.i.d) had been added to this regimen (d ). patients were considered cisapride responders when gastric clearance improved by more than % from baseline. results : normal values for the test meal and for scintigraphic acquisitions obtained in the supine position were found to be + min. in healthy volunteers (crit care med, ; : - ) . five patients responded to cisapride (t / : + rain vs. + min at do and d , respectively) and five did not (t / : + min vs. _+ rain at do and d , respectively). in contrast with non-responders, all five responders had clinically significant maldigestion at baseline (excessive (> ml) gastric residues, vomiting (> times/day and abdominal distension) which disappeared in of them after the administration of cisapride. conclusion : copd patients who tolerate enteral nutrition well have basal gastric emptying times which are comparable with those of healthy volunteers and are not influenced by cisapride. however, cisapride treatment provides both scintigraphic and clinical improvement in those copd patients who exhibit clinically obvious gastric emptying disorders. cernv v., dostal p., zivny p., zabka l. dept. of anesth. and critical care, charles university, faculty hospital, i-irade~ kralove , czech republic objective: the aim of the study was to evaluate the effect of early entera nutrition started within hours of injury on the incidence of multiple orgar failure (mof) in trauma patients requiring vantilatory support. methods: after institutional approval patients were enrolled in the study enteral feeding was begun within hours of injury in trauma patients (en group) admitted to icu. nasuenteric tube was placed as soon as possible after admission into the distal duodenum under endoscopy. additional parenteral nutrition was used to meet patients energy and protein requirements. the control group (pn) consisted of patients fed during this period paretuerally. severity score apache ii, trauma score, cumulative balance of nitrogen (g), incidence of mof (three and more organs) and length of ventilatury support (days) were calculated. values are expressed as mean + sd. results: tab introduction : parenteral nutrition (pn) is an important aspect in the optimal treatment of patients on gastroenterology or intensive care. the aim of this bi-center study in patients has been to assess tolerence and efficacy of a new protein-lipid mixture for pn from a simple preparation. patients and m~hods : patients were selected in two hospitals (tenon and saint-lazare, paris) and were divided into two groups : group a (gastroenterology~ l short bowel syndrome) and group b (intensive care, surgical patients). all patients likely to require pig for a period of days (group a) or days (group b) were studied. the pn regimens administered were the following : combination with g of mct/lct fat emulsion end , g of nitrogen, in liter end glucose requirements were met by imfizsion of l liter of glucose - % via a "y " connection. lipid thus provided % of the non introgen calories. total daily calorie intake was to ] kced. this study monitored, before and at the end of infusions, the sennn albumin (alb), preaiburtun (prealb), triglycendes (tg), cholesterol (cs), and the serum ammotransferases (sgot and sgpt) end alkaline phosphatase (alp) activities. statistical significances were calculated using the wilcoxon-tost. introduction: many cu patients present a catabolic illness in response to inflammation and infection, characterized by a rapid loss in skeletal-muscle mass despite optimal nutritional support. growth hormone (gh) is responsible for a rise of lipolysis, enhancing the energetic balance, and of protein synthesis. recombinant human gh (rhgh) is nowaday available for clinical use, but its cost is very high. therefore, rhgh should only be prescribed to icu patients when its efficacy can reasonably be anticipated (ie. when the patients are catabolic or stressed, but in order to avoid overprescription for unstressed patients and for those who are overly catabolic). hence, we, as others, recently demonstrated that rhgh had no favorable effect in highly stressed icu patients. objective: to detect on a clinical basis, low (ls), mild (ms) and severe stress (ss) states in icu patients and validate this clinical judgement by objective metabolic mesurements, in order to select early those icu patients potentially able to benefit from rhgh therapy. methods: consecutive icu patients were prospectively stratified as ls, ms and ss by two experienced icu senior consultants (temperature; agitation; heart rate; arterial blood pressure; presence of an infection; respiratory rate; exogenous catecholamines). anabolic (insulin, igf- , gh) and catabolic (cortisol, ghicagon) hormones, and nitrogen balance were determined for each patient within hours after admission in the icu. metabolic and clinical data were then compared. the clinical stress states determined by icu physicians correlate with an objective metabolic assessment. therefore, the patients who will more likely benefit from adjuvant rhgh therapy can be detected simply and early. a prospective study on rhgh therapy in ms icu patients is in progress. berger mm md , chiolero r md , pannatier a phd , berger l , cayeux c , voirol p , hurni m md . surgical icu, pharmacy, and cardiac surgery, chu vaudois, ch-iotl lausanne, switzerland objective. nutrition of the compromised cardiac surgical patient is challenging. numerous factors influence the gastrointestinal (gi) absorption function, among which gut perfusion, which depends largely on the systemic hemodynamic status. patients in hemodynamic failure are prone to organ failure, and may benefit from an early jejunal feeding. the study was designed to assess the absorption function after cardiac surgery in patients with adequate and altered hemodynamic status, using paracetamol as tracer of gi absorption. methods. after cardiac surgery, patients, aged _+ years (mean_+sd) were assigned to groups (anaesthesia: fentanyl gg/kg + midazolam): group (n= ): reference group, with normal hemodynamic status, easy recovery. group ('n= ): patients in low output syndrome, cardiac index < . i/m on day (d ) after surgery, requiring prolonged intensive care, mechanical ventilation + nutritional support. paracetamol g, was given intragastrically on d + d : plasma levels measured (h.p.l.c), at administration (to), t - - - - - and rain. hemodynamic status assessed with pulmonary artery catheter. healthy subjects served as controls. results. compared to healthy controls, absorption was strongly reduced on d in all patients (no difference between groups). on d , peak paracetamol level was significantly lower in group (low cardiac output): in group the area under the curve on d and d were similar. there was a large inter-patient variability, reflecting the hemodynamic status. conclusion. gi absorption was decreased on d in all patients, and reverted to normal between d and d in case of normal cardiac function, but not in case of low output syndrome. the decrease on d can be attributed to fentanyl, known to slow down the gi transit. in patients with cardiac failure, correction of altered absorption was correlated with the hemodynamic status, suggesting that gi absorption is dependent on adequate splanchnic perfusion. the aim of the work was to define specific significance and evaluate efficiency of enteral component of infusion therapy in the intensive care of gastroenterotogic patients of surgical profile with pyo-septic complecations. there were used the methods of radial diagnostics and polyelectrography; the laboratory control on oxygen-transporting function, volumetric and hemodynamic state, changes in metabolic, hormonal and immunologic status was conducted. from january, [ till november, there was carried out the randomized study of patients with general purulent peritonitis; among them persons constituted the control group and -the main one. in the main g~oup the intestinal lavage, enterosorption, enteral introduction of nutrient solutions with gradual turn to enteral nutrition by equalized mixture "ovolaet" were started from the first hours after operation. the data obtained allowed to define the specifity of the program of artificial medical nutrition in the group of examined patients, based on necessity of individual selection of media for enteral introduction depending on the stages of intestinal insufficiency syndrome. it was shown that inclusion of enteral component into the program of infusion therapy during early periods stabilized circulation in the regime of moderate hyperdynamia, considerably decreases the deficiency of circulating blood volume, normalizes the values of oxygen transport, consumption an}d extraction, provides the optimal level of mycardial adaptive possibilities without tension of its compensatory functions and pulmonary circulation overload. due to combined application of parenteral and enteral nutrition the metabolic processes are shifted towards anabolism. this is supported by decrease to normal values in the contents of blood aggresive hormones (acth,hydrocortisone) and increase in somatotrophic hormone. the complete parenteral-andenteral nutrition influences positively on restoration of cellular and tumoral immunity, activates the factors of organism nonspecific protection and recovery from immunodepression, prevents the development of immunodeficiency. impact tm vs control. s atkinson, n maynard, r grover, e sieffert, r mason, m smithies, d bihari departments of surgery and intensive care, guy's hospital, london, u.k objectives: comparison of the effect of an immunonutrient enteral feed versus a control on the outcome of a mixed intensive care unit (icu) population. methods: admissions to this multidisciplinary adu)t icu thought likely to stay more than three days and with tube access to the gi tract ~r randomised to receive either impact tm, a feed with supplemental arginine, dietary nucleotides and omega- fatty acids, or an isocaloric and isonitrogenous control feed. study end points included mortality and icu stay. approval was obtained from the hospital ethics committee. rosults: patients were entered into the trial. the two groups were well matched for age, sex, and admission apache ii with an overall mean admission risk of death of . (std. dev. -+ . ). on an intention to treat basis, there was a no significant difference in icu mortality, icu stay or standardised mortality ratio (s.m.r.) between the two groups (see table) . similarly, there were no differences after stratification for patients receiving or more litres of feed. conclusion: there is no evidence of an effect of impact@, an enteral immunonutrient feed, on pre-determined end-points (icu mortality, icu stay or standardised mortality ratio) in a mixed intensive care unit population over that of an isocaloric, isonitrogenous control feed. objeeflves: evaluate changes of blood laatate levels according to patient medical status after cvvhd initj,~ion using dialysate solution containing lactate. method: review of medioal records of consecutive patients ~eated by cvvhd (dialysate solution hmnosol lg , hospal,uk, lactate concentration retool/l). date obtained hr before and - hrs at~er cvvhd initiation were analysed. results: all data are presented as mean + sem. in one patient, pre end post filter lactate levds were measured during standard cvvhd setting (blood flow ml/mlu, dialysate solution flow i /hr), and approximate daily lactate flux into the patient was calculated to be as high as mmol/d. lactate leveh measured after cvvhd initiation increased significenfly compared to baseline levels ( . + . axtd . + . ,respectively; p< . ,paired t-test). when patiente with increased basal lactete (~- ) were compared to paliente with normal basal values (n= ), no difference in laotete increase was fmmd (p= . , manova). patiente with severe liver dysfunction ( points in mop scomlg, n= ) had higher basal laotate levels than patiente with normal or slightly abnormal liver teste ( or point in mof scoring, n=ll), rite values being . + . and . + . , respectively (p< . , student t-test). increase in blood lactate did not differ between these two groups after cvvhd was stetted (p= . , manova). in pafiente with invasive hemedynamio mo~, no oorrelation batween changes in lactate levels and eitlm" changes in oxygen ddivery (t =o.ol; p--o. ) or oxygen consumption (reversed fie, k) (r -q).o ;p-- . ) were found after cvvhd initiation. conclusion: blood lactate increases on cvvhd with dialysate soh~on rich in lactate. this increase is predominantly caused by influx of lactate into the blood via the filter end does not seem to depend on the liver fimotion and/or oxygen metabolism changes. objectives: the study was designed in order to determine the effect on plasmatic proteins, of two types of aminoacids solutions of parenteral nutrition (pn) adapted to stress, having different concentration of branched chain aminoacids (bcaa), when applying to politraumatized critical patients. methods: a prospective study was performed using a randomized double blind design of polytraumafized patients, split in two groups of ten patients each, with mean ages of _+ an -+ years. due to their condition, all patients required p.n. for at least days. both groups were subjected to isocalorie and isonitrogenous solutions ( ci/kg/ day and . g of nitrogen/ks/day), varying only in the concentration of bcaa; solution a having a % concentration and solution b %. blood samples determinations during days , , , after the beginning of treatment with p.n. were total proteins., albumin, trandferrine, protein binding retinol; prealbumine and fibronectine. the anova test (one and two way) was used to compare the values between the two groups. results: the administration of solution a, showed statistically significant increases in the determinations of the values of protein binding retino] (p < . ) and prealbumin (p < . ). no significant increases were observed in the values of total protein, albumin, transferrine and fibronectin. solution b produced statistically significant increases only in the values of total proteins (p < . ). the remaining proteins did not changed from their control values during the whole period of pn administration. comparing both groups, no statistically significant differences were observed related to the type of diet. nevertheless, differences were found in total proteins, albumin, protein binding retinoi, fibronectin (p< . ) and prealbumin (p < . ) in relation to the time course of pn therapy. only the albumin values showed significant differences (p < . ) when considering the interaction of both the type of diet and the time course of pn. conclusions: . solutions of pn adapted to stress, can maintain the control values of slow turnover proteins and improve the values of rapid turnover proteins. . no significant differences on plasma proteins were found between the two solutions having % or % concentration of branched chain aminoaeids. &determination of rapid turnover proteins does not seems useful for discriminating different solutions of bcaa during pn. obiectives; the hormonal changes in the post-traumatic situation often leads to an elevated blood glucose and a negative nitrogen balance. to reduce the elevated glucose production by aminoacids the apprication of xylitol may be an alternative energy source. in a double-blind randomized study we investigated the effects of a xylitol/glucose solution (group a: aminoacids g/i; glucose/xylito g/ g/l) on metabolism and particularly on pancreatic and liver enzymes compared to a glucose based nutrition solution regimen (group b: aminoacids g/i; glucose g/i). methods: the clinical trial was carried out after the approval by the local ethical committee on patients with severe brain injury. there was no difference in body mass index bmi (group a: . +/- . kg/m and group b: . +/- . kg/m=), age, and sex. daily individual energy expenditure was measured by indirect calorimetry (deltetrac "~). nutrition was started - hours after trauma or surgery with carbohydrates and aminoacids. fat was added h after nutrition had started. to analyze the effects on pancreatic and liver enzymes we investigated the following parameters for days: blood gtucose, serum lipase, serum amylase, asat, alat, ~gt, ap, and serum cholinesterase (che). results: due to the daily indirect calorimetric measurements energy requirements were satisfied. there was no difference in blood glucose concentration and cumulative nitrogen balance between the two groups. neither were there any significant changes in asat, alat, ap, and che for days in both groups. serum tipase steadily rose to lull in group a and . lull in group b, respectively. conclusions: there was no measurable influence of either nutrition solution on liver enzymes. the xylitol/glucose nutrition regimen does not have any advantage over the glucose based nutrition solution concerning blood glucose level or nitrogen balance. the elevation of serum lipase to a -fold level in either group needs further investigation on trauma patients. the effects of fat emulsions in lung function, particularly in lungdamaged patients, have been attributed to alterations in pulmonary vascular tone caused by eicosanoid production modificatione. as the eicosanoid production may depend on the fatty acid profiles of the intravenous fat emulsion, haemodynamic, pulmonary gas exchange and plasma levels of prostanoids were investigated in acute respiratory distress syndrome (ards) patients, during different intravenous lipid emulsions (providing different prostanoid precursors). we studied in a randomized double-blind design groups (n= each) with ards. group i (lct) received a fat emulsion with long chain triglycerids (lct- %), group ii (mct) an emulsion containing a mixture of medium and long chain triglycerids (mct/lct / - %) and group iii placebo (control), during h ( mg/kg/min each). we measured before, at the end of h infusion, and h after the end of the infusion: lipaemia, arterial and venous blood gases, pulmonary and systemic haemodynamics, and plasmatic levels (arterial and in mixed venous sample) of eicosanoids (txb=, -keto pgf~,, and ltb ). at the end of the fat emulsion, groups (i and il) to , • to , • mmol/i), the paoz/fio z remained unchanged in the three groups; no changes in intrapulmonary shunt (qs/qt) were shown; neither in the mean pulmonary artery pressure. in contrast, only in the lct group: cardiac output and oxygen consumption increased significantly ( . % and %) (p< . ). eicosanoids were increased at baseline compared to reference values (p< , ). a decrease (p<o, l in the arterio-venous difference of the vasodilatador prostanoid ( -keto pgf~=) was shown in lct group. our results indicate that fat emulsions in ards patient do not influence pulmonary gas exchange, provided that the perfusion rate were keept at mg/kg/min. the present study was designed to evaluate the metabolic changes of a carbohydrate-based diet versus a fat-based diet on oxidation rate of substrates and energy muscle metabolism in patients with an acute exacerbation of chronic obstructive lung disease. patients were mechanically ventilated with a volume-cycled respirator. after an overnight fast, patients were randomnly treated with a continuous enteral feeding over a nasogastrie tube with a carbohydrate/fat ratio of / in group i (n= ) , and a carbohydrate/fat ratio of / in group i] (n = ) during consecutive days. indirect calorimetry was set at baseline and hours later the enteral feeding was started. muscular quadriceps biopsy was performed on baseline and on day of enteral feeding. urine was collected during hours and was used to measure h urea nitrogen production. the caloric intake was set according to the measured resting energy expenditure. respiratory gas exchange rate were measured using a computerized open-circuit indirect calorimeter. quadficeps femoral muscle samples were obtained by muscular biopsy after local anesthesia. analyses of glycogen, glucose -phosphate, lactate, phosphocreatine and adenosine triphosphate (atp) and enzymes (glycogen synthase and glycogen phosphorylase) were determined. after h of nutrition patients in group i showed an increase in carbohydrate oxidation (from . % to . %, p= . ), and in group ii a decrease in protein oxidation (from % to %, p= . ). after days of enteral feeding a tendency to increase in glycogen concentration (group i, p= . ; and group ii,p= . ) was observed. while patients in group i showed a tendency (p= . ) to decrease glycogen phosphorylase, patients in group ii maintained these enzymatic levels. the increased in glycogen was correlated in group li with degradation enzyme (p = . ). in group i, the pao /fio ratio increased after days of treatment (from . to . ; p= . ), but no changes in days of mechanically ventilation, length of stay in icu, or mortality rate was evidenced between groups. it is concluded that the oxidation rate of substrates used for energy production varies according to the caloric sources administered. with nutritional therapy muscle glycogen concentration increases in both diets, with different enzymatic influence. more studies are warranted to further assess the clinical implications of the different pathophysiologic behavior of the two diets. under certain experimental and human conditions (radiation and/or thermal injury) the gi mucosa is unable to perform this protective function and could play an important role in the pathophysiology of the syndrome of multiple organ failure (smof). the objective of the present multicenter study was to know the gi mucosal permeability in critically ill patients and the relationship with their outcome. the method used to assess the integrity of the gi mucosal barrier measured mucosal permeability to various hydrophilic compounds. specifically, we measured the urinary excretion ratio (uer) of two sugars (lactulose and mannitol) that had been previously administered through a nasogastric tube. urinary excretion rate was measured in healthy humans (control) and in patients admitted to the intensive care unit (icu) at days , and . the apache ii of the patients studied was _+ . there was an increase of uer in the critically ill patients compared with controls (o. _+ . vs . _+ . ) (p< . ). in contrast, no changes in uer between days , and were observed ( . -+ . . significant changes were also established in the different groups: major and minor surgery, general and epidural anaesthesia , transfused and non transfused patients except for iron and ferritin plasma levels which didn't change significantly in patients who had received blood. a positive significant correlation was established between crp and ferritin (r= . ) for patients under general anaesthesia, but not on epidural, regardless of the type of surgery. conclusions: iron and transferrin plasma levels fell acutely in surgical patients while ferritin and crp rose. transfusion implied an acute iron load.the established correlation between cpr and ferritin in patients on general anaesthesia suggests that ferritin behave as an acute phase reactant in that setting, while epidural anaesthesia may ameliorate the inflammatory response. objectives: to analize the effect of gastrointestinal complicacions (gic) related to the enteral nutrition (en) in the real volume of diet administered to icu adult patients. a prospective multicenter study was designed (comgine study) in wich en application, gic definition and his management were defined by collaborative consensus.patients treated with en in one month pedod were included. in each case, daily volume of diet prescribed (pv) and administered (av) was recorded and the volume ratio calculated (vr=pvxl /av). patients were divided for days of en according to the presence (group ) or absence (group ) of gic (abdominal distension, increase of gastdc residuals,vomits or regurgitation, diarrhea,constipation and bronchoaspiration). differences between groups were analized by anova and mann-whitney u test with p< . for statistical significance. (vr%) group (vr%) tolerance to the enteral nutrition (en) has been related to the severity of illness in icu patients. the aim of this study was to evaluate this relationship. methods. a prospective, multicenter, study was performed (comgine study) in wich en application and related gastrointestinal complications (gic) were defined by collaborative consensus. adult icu patients treated with en in one month pedod were included. gic were classified as: ) abdominal distension (abd), ) increase of gastdc residuals (igr), ) vomits (vom), ) diet regurgitation (reg), ) diarrhea (dia) and ) constipation (con). patients were divided in two groups: group a: patients with gic dudng their evolution. group b: patients without gic. differences between groups were analized for apache ii admission score or evolutive variables ( carbon dioxide production is a major determent of work of breathing. increase in co production during nutritional support may precipitate ventilatory failure and difficulty in weaning from mechanical ventilation. in the present study, co output was calculated while passive mechanically ventilated patient were fed with different amount of calories and different proportion of protein, carbohydrate and fat. four clinical stable and mechanically ventilated patients were studied. carbon dioxide was calculated while patients were paralyzed, sedated and mechanically ventilated. six nutritional regimens were used: a) no calories, b) t gr glucose/ h, c) calories equal to rest energy expenditure in special formula with low carbohydrates and high fat (pulmocare) d) calories equal to rest energy expenditure in standard formula (nutdson) e) calories double to rest energy expenditure in standard formula (nutrison) and f) calories equal to rest energy expenditure parenterel (tpn). carbon dioxide output was low while no calories and/or only gr/ h glucose was provided, the mean values of vco output were _+_ and !-_ ml/min respectively. there was no difference in vco output between with low carbohydrates and high fat regimen and standard regimen, mean values were t . -+ and _+ respectively.the high calories regimen and tpn resulted in higher vco output, mean values _+ and • respectively. we conclude that the special with low carbohydrates and high fat regimen did not reduce vco output, in the contrary, high calories intake as well as tpn increased vco output under tested conditions. klouche k., cristol j.p., vela c., canaud b., b raud j.j. m tabolic intensive care unit and nephrology department. lapeyronie hospital. montpeuier france. predictive factors for rhabdomyolysis (rh) -induced acute renal failure (arf) were studied in a retrospective study from january to january . patients (pts) (male: , female:lo; mean age: + y.o.) were admitted with rh defined as cpk> iu/ . etiologies were: traumatic and ischaemic , infectious , toxic , excess activity . factors studied were: simplified acute physiologic score (saps: . + . ), organ systemic failure (osf: . _-!- . ), diagnosis delay (d: +_ h), clinical parameters (sepsis, dehydration), blood chemistry data (cpk, bun, creatinine, potassium, phosphorus, calcium, proteins, hematocrit) and urinary ph. severity of rh was estimated by ward score determined according to phosphorus, albumin, potassium, cpk, dehydration and sepsis. urea appearance rate (uar) and creatinine index (ci*) were determined over a hours period. arf was observed in pts. in non-arf and arf groups respectively, saps ( . _+ . vs . + . ), deshydratation ( vs ), sepsis ( vs ), phosphorus ( . + . vs . -+ . ), calcium ( . + . vs . _+ . ), ward score ( _+ . vs . + . ) were significantly different. however, no significance was observed in uar ( -+ vs -+ ) and ci ( _+ vs _+ ). patients required hemodialysis (hd) ( : sessions) and remained dialysis free. only osf ( . _+ . vs . -+ . ), ward score ( . _-/- . vs . _+ . ) and ci ( +_ vs -+ ) appeared significantly higher in pts requiring hd. pts died from associated disease. all patients suffering from arf recovered a normal renal function. we confwmed that an elevated ward score (over ) is a good predictive index of arf. in addition we found that ci is a severity factor for arf requiring hd. thus, patients suffering for rh with elevated ward score and ci, have a fair chance of dialysis and should be treated more intensively. * ci (expressed in mg/kg) = (car + feces creatinine) / weight. where car: creatinine appearance rate; feces cr~t..= mean plasmatic creatinine x . . tr~er k., cetin t.e., tugtekin i., georgieff m., ensinger h. universit~tsklinik flir an~sthesiologie, uim, germany introduction: endogenous as well as exogenous adrenergic agonists have a profound effect on carbohydrate metabolism in human critical illness. in this study the effects of noradrenaline (nor) and dobutamine (dob) on carbohydrate metabolism during a hr infusion were investigated. methods: after approval by the local ethic committee healthy volunteers were studied. hepatic glucose production (hgp [mg/kg/min]), using , -d glucose as stable isotope tracer, as well as plasma concentrations of glucose (glc [mmol/i]) and lactate (lac [mmol/i]) were measured prior and during infusion of nor ( . pg/kg/min) and dob ( pg/kg/min). blood samples were drawn before and during the agonist infusion. results: no major changes in insulin and gtucagon plasma concentrations could be found during the study period. ::i:::: :iiiii~ ~ i ::i: ~:: : :: i:ii. mean-+sd are shown. # p< . , anova for repeated measurments. conclusions: the effect of nor on hgp and glc were smaller as compared to adrenaline (i) with a similar time course. in contrast to the effects of adrenaline and nor, dob had a different effect on carbohydrate metabolism: a decrease in hcp and glc, which is uncommon for a / -adrenoceptor agonist. since hgp is an energy consuming process that might deteriorate hepatic oxygen balance in critical illness, the differential effects of adrenergic agonists may be of importance and need further clarification. the nutritional insufficiency often accompanies post-operative hypercaloric states, inanition, serious infections and weakening chronic illnesses. that is why the early nutritional support, sufficient and appropriate for each individual base, is a fundamental component of intensive care unit as an indispensable factor for recovery. per this reason, our unit, developed a software for the implementation and nutritional control of t~e assisted patients. this software is incorporated is an expert system called ~i~su, designed and developed by the computational division of our unit. this system arrives to inferred diagnoses such as : respiratory, hepatic, renal(with and without dialysis) dysfunctions, pancreatitis, ards, decrease of consciousness, diabetes. according to these data objectives: to compare the effect of short term enteral feeding versus parenteral nutrition, when a isonitrogenous and isocaloric feeding solution is administered by either mute. methods: in a prospective controlled clinical trial patients were studied; all exhibited moderate degree of malnutrition, normal liver and kidneys, and a functi ning gastrointestinal tract. the patients were randomized to receive a free amino acid and small peptide diet ( patients) or an isonitrogenous isocaloric parenteral support (tpn) ( patients) (total energy: kcal, nitrogen: . g, carbohydrates: g, fat: g, n/non protein calories: / ) at least for days. results: there were no significant changes in anthropometric parameters within either group. nitrogen equilibrium was aqhieved by day in the tpn group and by day in the enteral group ( . % of the enterally fed patients and % of the tpn patients maintained in positive balance the day of the study). there were no significant changes in serum albumin within either group. serum level of transferrin reached a significant increase in both groups (p= . ). thyroxine-binding prealbnmin rose significantly in both groups as well (p= . and . respectively). statistically significant rises in lymphocyte counts (p= . and . respectively), in levels of c (p= . and . ) respectively), iga (p= . ), igg (p= . and . respectively) and igm (p= . ) occurred in either treatment group. there was a high incidence of negative skin tests at the start of the study in the enteral group ( . %) and the tpn group ( %). by the end of the study the incidence of negative responsiveness was . % and . % respectively. despite maintenance of similar glucose levels in both groups, tpn led to significantly higher serum insulin levels. the serum insulin increased almost linearly over the study period and eventually prevented fat mobilization and lipolysis, so that free fatty acid levels had fallen significantly. a significant elevation of the liver enzymes over the study period occurred in . % of the tpn group, but not in the enterany fed patients. conclusions: the present findings provide no evidence that enteral diets containing free amino acids and small peptides, as their nitrogen sources, are in any way inferior to isonitrogenous isoealoric regimes parenterally given. aim: the aim of this study is to describe and explore the expectations of the functions of the critical care nurse to enable the formulation of guidelines for the scope of practice for the critical care nurse with a south african context, methods: phase i was to determine the expectations of the critical care nurse, the nursing service managers and the doctors with regard to the functions of the critical care nurse. a focus group interview was held with a group of experts in the field of critical care. the results were used to compile a questionnaire. this questionnaire was sent to the critical care nurses, the nursing service managers and the doctors in south africa for completion. from these results the functions of the critical care nurse were determined. phase ii was to formulate guidelines for the scope of practice for the critical care nurse within a south african context. through usage of the date (phase i) the scope of practice was formulated. guidelines were formulated for the practise, education and research regarding the limitations of the professional-ethical authoration and the implementation of the scope of practice for the critical care nurse. objectives : high output gastric aspirates arc occasionally observed during fasting in critically ill paticnts, preventing any attempt of feeding via the enteral route. although these patients are often said to suffer from "gastroparesia", the motor correlates of this condition arc lurgcly unknown. in this stud?', wc recorded the gastrointestinal motility of critically ill patients with abundant (> ml/ hours) fasting gastric aspirates. methods : antral ( sites separated each other from . cm), duodenal ( site) and jejunal ( site) contractions were recorded simultaneously by ~eans of a multihimen tube assembly positioned trader fluoroscopic control (perfused catheter technique). tracings from prolonged recordings were obtained on a multichannel recorder ( a recorder, hewlett-packard) then anal) ,ed visually, with a special attention for the following abnormalities which are characteristic of intcstinal pseudoobstmctiou: l) absence or aberrant propagation of the migrating motor complex (mmc), ) presence of bursts (> min) of nonpropagated phasic pressure and ) presence of sustained (> min) uncnardinate pressure activity. patients with a volume of gastric aspirates of • (sd) [median ml/ hrs were investigated for - [median minutes. results : only one patient had no detectable motor abnormality. mmcs were either absent (n= ) or migrated abnormally (retrograde propagation : n= ; retrograde and stationnary : n= ) in pts. bursts of nonpropagated phasic pressure activity were present in the duodenum in pts and sustained uncoordinate pressure activity was found in pts. additional abnormalities included episodes of prominent pyloric activity. (n=l) and sustained antral pressure activity (n= }. conclusion : critically ill patients with large volume of gastric aspirates have manometric evidence of intestinal pseudoobstruction. prokinetic therapy in these patients should thus focus not only on enhancing gastric motility, but also on restoring a normal propagative contractile activity in the intestine. this prospective, open-label, randomized placebo-controlled study included patients with hypokalemia in whom rapid potassium replacement ( meq kci in h) was performed: patients received mg sulfate ( g in hours) and patients received a corresponding saline infusion. measurements were made at time , + , + and + hours results: k levels increased more in mg treated patients than in the patients who received saline infusion at time and h (p < . -students-newman-keuls). (table ). introduction. dual lumen uaso-gastrojcjunal tubes are a major ads'ance in nutritional therapy of mechanically ventilated critically ill patients since the " authorizc jejunal feeding with concurrent gastric decompression, there,, reducing the risk for aspiration. unfortunately, placcmem of these tubes in the jejunum regularly dictates to resort to endoscopy in order to facilitate pyloric intubation. recently, the remarkable gastrokinetic properties of the well known macrolide antibiotic er}lhromycin have been demonstrated in gastroparetic critically ill patients . aim. in the presem stu~,, we evaluated the feasibility of placing dual lumen naso-gastrojcjunal feeding tubes at the bedside without endoscopy, using edthromycin to help iranspy'loric migration of the tube under fluoroscopic control. methnd each patient admitted in our icu during a months period and requiring artificial ventilation and enteral nutrition for a period of at least days was included in the study.. after inserting the tube (stayput| sandoz, usa) in the gastric anmnn, e.rythromycin ( rag) was aduunistored intravenously, to help fluoroscopic positioning of the tube into the jejunum. the total duration of the procedure (from nasal intabatiun to jejunal placement), as well as the duration of ftuoroscopy were recorded in each patient. results. patients (male/female : / : mean age : . + . years; mean apacbell score : .t • . ) wore enrolled into the study.the procedure was performed within the dab,s following institution of mechanical ventilation. jejunal access was obtained in all patients without resort to enduscopy in , • . min.(total duration of the procedure). mean duration of fluoroscopy was . + . rain. conclusion. we conclude that placement of dual lmnen naso-gastrojejunal tubes can be obtained in mechanically ventilated critically ill patients without resort to endoscopy., provided that e rythromycin is used as gastrokinetic agent to help pyloric intubation. the following ad and dis parameters were considered in all patients: -mid arm circumference, triceps skinfold thickness, serum transferrin, albumine and lymphoeites and urinary creatinine/height index. patients whose results were bellow % of normal values in or more of the above criteria were considered undernourished (und).statistical analysis was performed using % analysis.statistical significance was established at p<o.o . results: a total of patients( female, male) -with a mortality rate (~) of , % -were studied, aged -+ years and a median ]enght of stay of days. -nourished (nou) at ad and at dis - ; ~ %; -nou at ad and und at dis - ; ) , % ; -und at ad and und at dis - ; ~ . %; -und at ad and nou at dis - ; ~ , %. we observed a p< . when we compared groups and (p= . ), and groups and (p= . ). variation in nutritional status and longht of stay: -nou at ad and nou at dis = > median lenght of stay days; und at ad and und at dis = > median lengbt of stay days; nutritional status and age at admission: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) nutritional status and age at discharge: -age > = years : nou ( ) , und ( ) -age < years: nou ( ), und ( ) we observed a p<o. when we compared groups and (p=o. ) and groups and (p = . ) conclusion: such study permits to conclude that most of our patients ( . %), staying in icu for more than days, were und, namely the elder. we observed that this kind ef patient had a longer median length of stay in icu, associated with higher mortality rate. in conclusion, the nutritional management is an essential element in suportive care of critical)y ill patients. ohiectives: sirs is associated with hypercataholisnl and resistance to nutritional support, despite raised circu&ting levels of growth hormone and insulin. serum igf- levels however are low; thercti~re rhigf-i administration might produce nsefnl anabolic effects. the pharmacokinetics of exogenously administration rhlge-i in such patients are likely to differ from that seen in the less seriously ill due to changes in circulating blood volume, increased capillary permeability, poor nutritional stares, and alterations in binding proteins. the ol jective of this study was to determine the clearance, apparent vohnne (if distribution (vd), time to peak concentration (tmax) and elimination half-like (tia) of a single subctkaneous il~ieetion of rhlgf-i in patients with sirs on the intensive care unit (icu). methods: icu patients with sirs were entered into the study, which had been approved by the ethics comjnittee. in each patient baseline hlood samples for circulating gf-i were obtained over a hour period, prior to il!iection of p.g/kg of rhlgf- subcutaneously. a further l samples were taken fi'om each subject over the next hours. circulating ige-i was measured in serum at each time point by radioimmtme assay, and the area under the curve tbllowing administration of rhlgf-i was derived tbr individual patients fixm~ baseline a~!justed igf-i levels. clearance values were caietdated by dividing the administered dose of rh[ge-[ by the total area under the etnve. vd and tv were calculated by regression analysis of the terminal part nf the log sertnn concentration time profiles. results: results are expressed as median (range). age ( - ) years, apache ii score ( - ), and length of icu stay ( - ) days. baseiine circulating igf- levels were low ( < - ) ng/ml reaching a peak of only ( < - ) ng/ml. of the patients had basal levels predmnhaantly below the inwel-limit of detection of the assay, and showed no appreciable rise in serum igf-[ levels tbllowing rhigf-i injection. parmacokinetic variables could not therefi)re be determined in these two patients. following rhlgf-i injection in the remaining patients tmax was at ( - ) hours, clearance was ( - ) ml/min, vd was . ( . - . ) l/kg, and tia . ( . - . ) honrs. conchlsions: there was marked patient wu-iability in response to rhlgf-i administration. vd was similar to that seen in poshq~erative maior surgery patients ( . vs . l/kg), but clearance was greater ( vs ml/min), tmax earlier ( vs hours) and t~a shorter ( . vs i . homts). if riaigp-i is to be administered to dtically ill patients the dose should he nlodified m the light of these findings. baekgronnd: acute bacterial endoearditis continues to be a condition with high morbidity and mortality. the majority of patients are treated with high dose antibiotics, but a patient group requires surgical treatment. methods and results: from january to march , patients underwent surgery for acute bacterial endocarditis: had native valve endocarditis and had prosthetic valve endocarditis. there were men and women. streptococcus viridans was the predominant infecting agent in native ~alve endocarditis and staphylococcus epidermidis in prosthetic valve endocarditis. progressive congestive failure, uncontrolled sepsis and peripheral emboli were the most common indication for surgery. although the mitral valve is more commonly involved in acute bacterial endocarditis, the aortic valve most often requires surgical inlervetion. the postoperative bleeding in the no-aprotinin group was + cc and in the aprotinin was :t: (p < , ). the mortality in icu was , %, the staphyloccocical endoearditis mortality was , % and the no-staphyloccocical endocarditis mortality was , % (p< , ). conclusions: the early surgery is indicated if endocarditis has no response with medical treatment. the mortality of staphyloceocical endoearditis involving left valves was higher than caused by other infecting agents. aprotinin treatment improved prosta#andin metabolism and preserved pletelet function during open heart surgery and could be useful in this type of interventions. urgent surgery had a high mortality ( %). selective digestive decontamination (sdd) has increasingly become the subject of critical discussion sine~ the development of multiresistant organisms has become an issue. moreover, a selection of gram-positive pathogens must also be taken into account when using the sdd regimen, which is primarily directed at the gramnegative bacterial specumn, with the methicillin-resistant staphylococcus aureus strains (mrsa) being of particular importance. the objective of our study was to determine the extent to which colonization with mrsa strains is promoted by sdd. method: patients (ventilation period > days) were randomized and allocated to the sdd group (n= ) or the control group (n= ). in their general intensive care theraw, there were no differences between the groups. the sdd regimen consisted of the four times daily administration of rag polymi~ mg tobramycin and mg amphotericin b in the nesc, mnoth and stomach. systemic prophylactic ~dmini~/rution of antibiotics was not part of the sdd regimen. smears were taken from the nose and the rectum twice wceldy and from the pharynx and trachea once wceldy, and tested for mrsa. further samples were taken as clinically reqnircr results: smears were examined in the sdd group. mrsa strains were detected in samples ( . %) from patients, and in patients they were detected for a period of up to weeks. the positive smears were districted as follows: tracheal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal ( . %). severe mrsa-induced infections were observed in patients (infection rate . % of the colonized sdd patients). smears were examined in the control group. ivlrsa swains were r in samples ( . %) from patients, but only repeatedly over a period of up to days in patients. the po~tive snmars were distributed as follows: traclmal / ( . %), nasal / ( . %), pharyngeal / ( . %) and rectal / ( . %). there were no mrsa infections in the control group. conclusion: the data collected support the view that the use of sdd promotes a selection and persistence of mrsa strains. longer-term colonization with mrsa and sovere systemic inf~ons were only found in the sdd group. although the clinical and epidemiological impact of resistance develol~ng when sdd is applied ~maine unclear, this question should be given close scrutiny. tazobactam/piperacillin (taz/p p) is a new broad spectrum antibiotic, in which the acylaminopenicillin piperaeillin is protected by the betatactamase inhibitor tazobactam from hydrolization by bacterial enzymes. taz/pip has shown to possess a high antibacterial activity against almost all clinically relevant bacteria and is a registered drug in germany. obiectives: purpose of this investigation was to evaluate, whether faz/pip . g is suited for efficient antibacterial monotherapy of severe infections and what influence dosage frequency reveals on clinical efficacy. methods: hospitalized patients have been documented in this multicenter trial during a year period. as this investigation should reflect the usual clinical treatment, the only criteria for enrolment were the typical signs of infection as e.g. temperature > ~ leucocytosis or an isolated pathogen. exclusion criteria did not exist and the patients were treated in accordance to the severeness of infection, underlying diseases, risk factors etc. with taz/pip . g t.i.d, or b.i.d. results: patients suffered in most cases from infections of the lower respiratory tract (n= ), followed by intraabdominal (n= ) and skin and soft tissue infections (n= ). % of the lrtis wvre nosocomial acquired and in % the treatment was conducted as monotherapy. in % the lrti was treated with taz/pip b.i.d, and in % t.i.d. pseudomonas spp. (n= ) and staph..aureus (n= ) were the most isolated pathogens pretrcatment. the clinical response rates (cured/improved) after treatment with taz/pip . g b.i.d, and t.i.d, were % and % respectively. results for intraabdominal-and skin and soft tissue infections will be presented. conclusions: in hospitalized patients with severe infections successful treatment with taz/pip in monotherapy is possible. in this population a reduction of the dosage frequency to . g b.i.d, revealed equivalent clinical response rates. objectives. retrospective evaluation of cases of severe generalized tetanus (sgt), treated in our icu the last years. we review cases of sgt ( m, f), mean age . years. in eases the entry site of c.tetanus was a skin laceration, in case it proved to be the external genitalia, while in the rest no portal of entry could be determined. in the first cases incubation period was short ( - days) and so was the period of onset ( - days). all patients needed mechanical ventilation (range - days), initally through an orotracheal tube,and later through a tracheostomy, performed • days after admission. clinical manifestations of sgt included muscle rigidity and i generalized spasms, persisting for up to weeks in the most severe cases. significant autonomic nervous system dysfunction was present in cases occurring - days after the admission and following the time course of generalized spasm. besides general supportive measures, specific treatment included passive +active immunization, penicillin g, magnesium sulphate and sedation in a variety of regimens. neuromuscular blockade was required in cases. nosocomial infections occurred in eases, with sepsis and mof in one. average stay in the icu was - days. one patient died with severe septic complications and one was discharged with severe disability due to anoxaemie ancephalopathy, after a cardiac arrest on admission. ~ disinfectant in suspension test, without presence of organic load, disinfectants showed efficacy on lm. in the carrier test, in the presence of organic load, out of examined disinfectants did not exposed efficacy on lm. the results of examinations clearly showed that evaluation of disinfectant's efficacy partly depend on the used test method. antun basi , intensive care unit, kb firule split spin~ideva ! jugoslavia bacteremia and sepsis are frequent complications encouuntered in severe icu patients.microorganism identification with hemoculture presents the basis for adequate and successful antibiotic treatment.in many patients damage and vulnerability of the peripheral veins presents an obstacle for obtaining the blood culture from the central venous (cv) catheter sample could be also used. material and methods blood cultures were perfomed in lo patients on blood samples simultaneously obtained from the peripheral vein and cv catheter three times in a -hour period.criteria for the suspected bacteremia were body temperature above c and leucocytosis above ioooo leucocytes/dl. the site for venipuncture and the cv catheter stopcock port were cleansed with povidon iodine.after the initial ml of blood were discarded,lo ml were used for the blood culture.standard laboratory technique for blood cultures was used. results and discussion in ( %) patients hemocultures was negative at both sites,whereas in the remaining ( %) they were positive.for twentyone ( ~ of the positive patients the same results were obtained at both sites (peripheral vein and cv catheter),whereas in ( . %) patients the blood culture were positive only for the cv catheter samples.the cv catheters were in place for less than days in patients and for more than days in patients.from patients with positive blood culture from the cv catheter,one patient had the catheter for three days,whereas the other had the catheter from - o days. we neither found significant differences in hemodynamic dates : objectives: , to count and evaluate bacteria isolated from endotracheal (et) suctiori samples (with and without saline). . to establish the exogenous source(s) of pathogens isolated from carer's hands and the equipment involved in sampling in order to reduce the incidence of contamination and infection. method~: this prospective study included consecutive ventilated patients ( male and female, _ + yr; apache ii score -+ ) over a period of months. et aspirated samples with and without saline were taken daily from day of intubation until pathogen~ were presented in counts of _> per ml. at the same time, samples from both carer's hands were taken before and after et suction and a swab from the ventilator tube. results: the overall length of intubation varied between to days. bacterial transfer between staff and patients was noted in % of patients until day of intubation. there was no significant correlation between severity score and appearance of colonization. the incidence of pneumonia in studied patients was % with an overall mortality rate of %. acinetobacter anitratas (no ), staphylococcus aureus (no. ), klebsiella pna~moniae (no. ) and pscudomonas aeruginosa (no. ) isolates predominated in all our specimens. we noticed increased resistance to most antibiotics with the exception of imipenem for gram (-) bacteria and vancornycin for gram (+) bacteria. conclusions: i. tracheobronchial colonization appears directly in the maiority of intubated patients. . there is a close relationship between the microflora of personnel, patients and equipment. . bacteria transfer was noted both to and from patients. . strict hand disinfection policy remains an important measure for the proper care of mechanically ventilated patients to reduce respiratory infections. nnseeomial pneumonia is the most common nnsocomiai infection in the icu-settiag, reported in up to % of patients admitted to the icu following surgery. it is associated with significant mortality that ranges from ~ to %. enteric gram-negative bacilli have been implicated in % to % of ventilntor-associated pneumonias and pseudomonas aeruginosa accounts for % to % of these pneumonias. importantly, epidemics of/ - actamnse-pruducing enterobacter spp or klebsiella spp that are resistant to extended spectrum cephalosporins or penicillins, pose serious obstacles to effective antibiotic choices. carbapenems provide in ~tro activity against a wide range of enterobacteriaceaeand other gramnegative aerobic bacteria, except steaotrophomonns maltophilia. in vitro meropcnem is more active against pseudomonas spp than imipanem (especially p. aeruginosa and p. cepacia), imipenem and meropenem are effective against more than % of strains responsible for nnsocomial infections. all major pathogens associated with lrti are usually covered by the carbapenems, exceptions are pathogens involved in so-called atypical pneuomouia like mycoplasma, chlamydia and legionella. carbapenems are highly stable in the presence of most chromsomal and plasmid-mediated blactumases and usually offer a postantibiotie effect lasting for three hours against most of the enterubacteriaceae. reeent studies comparing imipenem/cilastatin with other ~-lactams and fluoroquinolones in severe lrti in icu patients resulted in favourable clinical cure rates and good tolerance, but development of resistance in p. aeruginosa and ;. aureus during treatment were of some concern. meropenem offers the advantage of greater stability against enzymatic degradation, so no concomitant administration of an enzyme inhibitor is necessary, and meropenem appears to be associated with a lower risk of seizures, particularly when used at high doses. results from studies with meropenem in lrti, especially in critically ill patients with acute exacerbations of chronic bronchitis, demonstrated excellent cure rates and better gastrointestinal tolerance of this new carbapenem. both earbapenems are effective candidates for use as empiric monotherapy in nosucominl infections of critically ill patients. qbl~ctives a favourable effect of iv immunoglobulins in septic surgical patients has been reported, but not sufficiently validated. we conducted this study on trauma patients to: i) investigate the effect of ivig on septic complications and il) quantify this effect by means of serum bactericidai activity (sba) assessment and iii) to explore the effect of temperature increase (from to ~ c) on the sba methods: twenty trauma patierits matched on admission for age, sex, inju~ severity score and glasgow coma scale, were allocated to receive either wig (ivig group; i patients) or equal volumes of human albumin % (control group; patients). wig (sandoglobulin) was administered in a total dose of g/kg divided in a four time regimen on days , , and post-admission. three blood collections were performe& before the first dose (day ) and hours after the third and the fourth dose (days and respectively). complement, lgg fractions, the sba at ~ and at o c and clinical parameters were recorded. results-similar lgg and igg] serum levels were found in groups ivig and control on day ( +_ vs • ns and + vs + , ns), whereas they were significantly higher (p< ) in the v g group on days ( _+_ vs + , p< ) and ( _+ vs +i , p< . ). the various complement-fractions increased in both groups without inter-group differences the mean (• sbas ( ~ c) at rain in ivig group vs control group were: - _+ vs - • ns for day , _+ vs - _+ p< for day and _+ vs - + p< for day . the mean (+sd) sbas ( ~ c) at rain presented a significant improvement over those of ~ c but for the control group remained negative a~d were respectively as following: -~ • vs - + , ns for day , +_ vs - _+ , p< . for day and _+ vs - _+ , p< . for day . the increase of temperature induced a -fold improvement of sba in iv g group and -fold ofcontrol-~oup positive blood cultures, and the product of the infectious episodes number multiplied by days of occurence, were significantly lower (p< ) in the ivig group than in the control ( vs , and vs , respectively). conclusions: our study shows a significantly favourable effect of ivig administration on septic complications and on sba of trauma patients. the increase of temperature results in a significant improvement of sba of patients that received ivig, which theoretically means a farther prevention of infection in the febrile state. pharmaceutical microbiology, university of bonn, meckanheimer aune , d- bonn, germany infectious diseases in intensive care patients are common in comparison to patients on other wards and out-patients. the main difference is that intensive care patients are much more sensitive even to less virulent bacteria. thus, the spectrum of infecting organisms is different. strains often regarded as pathogens with low virulence cause serious infections in these patients. strains such as serratia, however, have intrinsic resistance to most commonly used agents such as rd generation eephalosporins. furthermore, the common pathogens like staphylococci, psoudomonas aeruginosu, enterocneei and gram-negative bacteria, enterobacteriaeceae as well as the non-fermenters are less sensitive if isolated from intensive care patients. it is difficult to generalize on intensive care units as different patient groups are in different icus aud there are great changes from one hospital to another and from one country to another. if we take s. aurens strains from one study from the'overall resistance in intensive care units towards oftoxacin was %, whereas in other hospital wards the percentage of resistance was . %, in out-patients, however, only .$ %. the same trend was true for entercnecus faecnlis, coagulase-negntive staphylococci, and other bacteria as well as other drugs. one most striking difference was found with klebsialla pneumoniae and gantamycin resistance, which was $ times higher in intensive care units as compared with outpatients, whereas in the same species no difference was to be seen with the resistance towards carbapenems. however, differences between countries seem to be even more striking, as example gantamycin resistance and staph. anrens is given. the extreme difference is more than fold. thus, it is evident that there is a general trend towards higher resistance in intensive care units, but no generalizatiouis possible. therefore, surveillance studies in intensive care units are needed and the antibiotic policy has to be adapted to the specific needs of the unit. in the icu setting the most potent antimicrobial agents are required to address problem organisms including those resistant to penicillins, cephalosporins and aminoglycosides. carbapanems would appear to present a useful option in this setting. objectives of this study was the evaluation of systemic candid• in postoperative cardiac surgery patients (pts) with prolonged icu stay. methods: out of postoperative adults pts of mean age . + . years old, with a mean icu stay of . _+ . days, following an open heart surgery from july to april , pts ( %) remained in icu for more than days because of severe perioperative complications. patients were included in the protocol if they had clinical signs of infection or sepsis, and fungi isolated in blood culture or in culture from at least three different sites. the patients who developed systemic candidiasis received iv fluconazole ( mg/day) ( patients) or amphotericin-b for at least four weeks, and then they were closely monitored. results: out of postoperative pts with prolonged jcu stay, pts ( . %) developed systemic candid• usually after the th postoperative day. they were males and females of mean age +_ . years old. this group of pts had prolonged bypass and aortic cross-clamp time compared to control group ( min vs , and vs min). all these pts received inotropes per• (mean value= . ). during their icu stay, pts developed sepsis of bacterial origin, while the other two severe infection, and received antibiotic regimens for prolonged period. the patients were submitted to mechanical ventilation for a median period of days. the median icu and hospital stay was and days respectively. all pts have been improved and finally negative cultures were obtained. conclusions: . a significant percentage of patients who remained in the postoperative icu for more than days developed systemic candidiasis. . all patients who developed systemic candidiasis had received antibiotics because of sepsis or severe infection, for prolonged period. . fluconazole seems to be a very good alternative to amphotericin-b. . fluconazole is a safe antifungal agent with few side effects. botulism is the most severe and an odd food poisoning. although it is more commonly related to preserved meat derivatives, preserved fish and vegetables are also responsible for a number of cases. obiectives: to evaluate four familiar outbreaks of botulism . methods: we study the patients that were admitted in our hospital because of botulism from may to february . results: the thirteen pacients involved had a previous history of home preserved beans ingestion. after a -hours incubation period, gastrointestinal symptoms (abdominal pain, vomits, constipation) appeared and lead them to hospital consultation in the th to th day after ingestion. two patients died (acute respiratory failure before admission), seven were admitted in icu, two in ward and two of them were discharged from emergency room. clinical symptoms and the previous history of the ingestion established the diagnosis, that was emg confirmed. in all cases, symptoms were consistent with b-toxin botulism. b-toxin was isolated in serum and food proceeding from the third outbreak, and the serum was negative in the other ones. neurological symptoms were predominant: midriasis ( %), dry mouth ( %), dysfagia ( %), asthenia ( %), palpebral ptosis ( %), accomodation paralisis ( %) and urinary retention ( %). muscle weakness lead to acute respiratory failure in three patients (one of them required mechanical ventilation). four patiens developed infections (respiratory, urinary and phlebitis). both died patients and one another presented severe hypertension. all admitted patients were treated with polivalent anti-toxin. the two patients who underwent a more severe muscle weakness received also guanidine hydrochloride, with no answer in one case and provoquing a cholinergic crisis in the other one. icu length of stay was days. at hospital discharge, patients continued symptomatic, mainly with dry mouth, disfagia and impaired vision. conclusions: although botulism is a serious illness, the pronostic seems favorable if treatment and support measures are avaible. usually neurological symptoms we predominant and at discharge some of them could still persist. the arrow "hands-off" (aho) thermodilution catheter (tc) is completely shielded during balloon testing, preparation, and the insertion procedure. in order to assess the value of the aho thermodilution catheter in the prevention of systemic infections associated with pulmonary artery catheterization (siapa), we conducted a randomized prospective study over an -month period. methods : the patients (pts) were randomly assigned to two groups : group i for a standard tc customarily used in the department, versus group for the aho thermodilution catheter. the diagnosis of siapa was determined on the basis of a positive culture of tc and bacteremia with the same organism, with out any other nearby focus, in association with regression or disappearance of the clinical signs of infection after removal of the thermodilution catheter. results ( objectives: the mortality rate (mr) of tb requiring mechanical ventilation (mv) is high ( - %). the aim of the study was to evaluate mr, associated factors, and prognostic significance of mv and hemodynamic disorders from tb in icu in patients with tb. methods: clinical parameters on admission, and complications in icu were related by univariate analysis to icu, hospital, and month outcome. patients required mv; were immunocompromised (ic) including hiv. tb was pleuropulmonary in , disseminated in and meningeal in . results: mr was % in icu, % in hospital and % at month. / ( %) < . mortality was associated with a high saps score, initial shock, mv and nosocomial septicemia. the mr dramatically increased when ards occurred during illness, despite the lack of correlation between mr and initial po /fio ratio or initial murray score. the site of infection did not influence the mr. surprisingly, the mean therapy delay was shorter for non survivors. mr was not related to ic status, nor hivstatus, but was only related to previous steroid therapy. conclusion: mr of tb requiring icu is high ( % at month). need for mv increased mortality ( % vs %). general severity and respiratory dysfunction seem to be major prognostic factors in icu rather than tb per se or than therapy delay. in spite of the improvement in the prognosis of pneumococcal meningitis (pm) with third generation cephalosporins (tgc), this infection still presents a great mortality which could be increased with the appearance of antibiotic resistant streptococcus pneumoniae. objectives: to asses intensive care mortality and morbidity of pm and to define patients (pts) at risk of complicated evolution. patients and methods: a retrospective evaluation of pm cases (all diagnosed by csf culture) admitted in our icu from january tit march . in all pts we analized: demographic data, underlying disease, apache ii score, clinical symtomps, treatment, complications and outcome. statistical analysis was done using bmdp sofware package. results:a total f pts were studied, males; mean age , _+ ( - ); apache ii score , + , ; glasgow coma scale (gcs) at admission , _+ , ; ( %) pts suffer from cronic pathology; ( %) pts diabetes mellitus (dm), ( , %) pts had had a previous cranial traumatism. in cases the source of infection was otic and also in ( %) episodes of pm there were bacteriemia. in out of ( %) pts that ct was performed no radiologic abnormalities were shown, of them presented cerebral oedema and pts a cerebral abscess. twenty-eight percent presented seixures, % hemiparesia, , % respiratory failure, , % shock, i % renal failure, , % multiple organ failure (mof). as for treatment refers , % pts recieved only penicillin, , % pts only tcg, , % pts tcg followed by penicillin and , % pts tcg+vancomycin. seventy-five percelat of pts recieved corticosteroids and , % vasoaetive drugs. the mean icu stay was , : days ( - ). twelve ( , %) pts died, two of them presented pm relapse (resistant streptococcus pneumoniae) and another two pts developed neurological sequelae. factors associated statistically with bad prognosis were dm, the use of vasoactive drugs, shock, mof, the apache ii score at admission, the gcs at the and hours from admission in the icu but not the gcs at admission. didn't resulted statistiealy signifcative age, previous eronie pathology, seizures, baeteriemia, renal failure and coagulation disorders. conclusions: mortality was high and associated to apache ii score at admission, to gcs at and hours after admission, shock, vasoaetive drugs and mof. objectives:the aim of the study was to analyse some of significant immunologycai changes in surgical patients,requiring intensive health care,and to determinate the possibility for evaluation,dynamical examination and importance of immunologycal problems for treatment. methodes:the study concerns a number of patients with expanded surgical intervention or serious postoperative complications.the results has been carried out with fiowcytometryc analyses of lymphocytic suhpopulations and routins methods for investigation of humeral immunity.the"panel" for evaluation of (} immunologycal parameters has been offered:t-calls total/cd +/;t-helper/cd +/;t-supressor/cd +/ th/ts ratio;b-cells/cd +/;naturai kilier/nk/cells;skin test for cellular immune function;phagocytic and oxidative activity;serum levels of immunogiobulins-g ,a,m;protease inhibitors;c-reactive protein.all patients have been studied during suffering and after surgical procedures dynamicaly. results:there have been estimated significant changes in immunologycal parameters especially:decrease of t-cells: cd +mean= . %/ . %- . %/and cd +mean= . %/ % - . %/;inverted th/ts ratio ,mean=o. / . - , /;reduced or negative skin teste;reduced phagocytic and oxidative activity before septic complications. conclusions:dynamical examination of immunologycal parameters shows,that the prolonged t-total,t-helper lymphocytopenia with functional deficience of ceils-mediated immunity correlates with the stage of clinical condition of the patients and has prognostic importance.it's clear,that immunologycal monitoring gives a possibility for immunecorrection. patients (pts) with the human tmunodeficiency virus (hiv) infection have a decreased immune response and are particularly susceptible to infectious endocarditis (ie). the aim of our study was to analyze the prevalence of ie, its clinical and therapeutic implications in a hiv population we prospectively studied pts, . % ( / -group ie+) with ie during the clinical course of this disease. we analyzed the following parameters: age, gender, race, type of hiv, cdc classification, number of t and t type cell population and its ratio, therapeutic with azt, type and number of opportunist infections (inf, mycobacteriosis (mb), neoplasm's (nee) the echocardiographic parameters were lv internal diastolic and systolic diameters, lv percentage of fractional shortening, interventricular and posterior wall thickness, the degree of valvular regurgitations and the presence of pericardial effusion. el was located at the mv in . %, tv in . %, av in % and pv in . ~ and was multiple in . %. hiv el+ pts had larger lv diameters and more frequent significant valvular regurgitations ( % tr, pe %, mortality %). these two groups differed significantly in the following clinical parameters: the typical symptoms were watery diarrhea, high fever, tachycardia,luekocytopenia and oligouria within th postoperative days. the patients with mrsa enterocolitis had positive mrsa culture from the many materials except feces.mesa strains frequently had coagulase type ,enterotoxin a and toxic shock syndrome toxin- .eight of patients had postoperative organ failure.most of the mrsa strains in japan were similar in coagulase type to our hospital and our department.all of mesa strains were susceptible to vancomycin and arbekacin,tbough most of them showed resistant to many other antibiotics.we have employed guidelines for therapies such as oral or enteral administration of vancomycin and correction of the hemodynamics for dehydration and circulatory failure due to diarrhea from .futhermore we have placed colonized or infected patients in private room,worn gown and mask,and carefully washed our hands from . these countermeasures for prevention of nosocomial infections after significantly reduced the incidence of mrsa enterocolitis. conclusions:earlier diagnosis and treatment, and distric prophylactic measureres against mrsa infections are very important. -- cdo ivda leptespiresls affects all the organs with widespread hemorrhage that is more prominent in skin, mucosa, skeletat muscles, liver and kidneys. lung involvement is usually mild and less common. suli, it is very uncommon acute respiratory failure to be the pr sontirlg symptom. a case with leptosplrosl..,s which was presenting with acute respiratory failure is described. a year-old man admitted to icu becauso of fever, myaigla, aevere c~, hemopty~s. his blood gases showed: pao : mmhg with fio : . , pco : mmhg, ph: . , hco : mecl chest x-ray film demonstrated diffuse bilateral alveolar pattern occupying beth lung / ). trarmamlnase, bllllrubln, ~ and esr were elevated, wbc was . mm , platelet: . ram , hematesrlt: %, hemoglobin: .sgrldl=. there was no clinical or ecttlographlc evidence of left heart failure.patient fulfilled the criteria for diagnosis ards he was found to have an ~lutinatlon tlter for leptoq~lral antigens(indirect he~lutlnatlon atomy, ilia} very high ( / , negative<ill ) and iglm antibodies also very high (elisa, a= . , negative< . ) strongly suggesting leptospirosls. treatment with tetracycline and non-tnvaslve mechanical ventilation by nasal mask were started. pre~jre support mode and cpap was usod. the following days the clinical picture,the oxygenation and the chest x-ray of the patients were improved, and patient dl~herged from the icu. the control of leptosplremlc phase as well as his good cooperation during nipsv contributed to rapid recovery and excellent outcome in hiv infections, pneumonias (pnm), mainly due to pne~ mocystis carinii (pc) have an outstanding place in pu ! monary complications. the aim of this work was to compare two group> of patients admitted with pnm in our icu during the same period ( - ): group a, patients hiv+, and group b, patients hiv-. apache ii was identical in the groups (p=ns). group a required more often mechanical ventilation (p= ,o ), had a higher p(a-a)o (p= , ) and metabolic acidosis was more frequent (p= , ). regarding laboratorial parameters group a had a lower no. of linfocytes (p= , ), a higher ldh (p= , ) and a more marked hypoalbuminemia (p=o, ). mortality was higer in group a ( , %) than in group b ( , %), (p= , ). analysing the a group patients, we found no significant differences between alive and deceased patients, with exception for albuminemia, which was lower in the deceased patients (p= , ). in conclusion, the hiv+ patient's pnm have a more agres sive behavior when compared with community acquired hiv-patient's pnm. the prognosis was not influenced by the apache ii. perhaps other parameters such as p(a-a)o , metabolic acidosis, linfocytes, ldh and albumin shoud be more evaluated as possible predictive indices. some prognostic factors, usually accepted as predictive in the analysis of hiv+ patients do not seem to be worth in the late stages of aids, mainly when they reqquire intensive care. intensive care unit, onassis cardiac surgery center, athens, greece. objectives of this study was the comparison of two different antibiotic regimens as prophylaxis in cardiac surgery patients. methods: in a prospective randomised comparative study, two different forms of antibiotic regimens were investigated : a single dose of cefuroxime (zinacef, gr) (group a) given during the induction of anaesthesia, versus a four days combination of amoxiculine (amoxil, gr tid) plus netilmicin (netromycin, mg bid) (group b). a total of patients (pts) ( males and females, of mean age . + . years old) were included in the study over a period of one year; in group a and in the group b. patients were checked for the occurrence of infection during the first postoperative month. results: the total rate of infection in cardiac surgery pts was . %; . % in group a and . % in group b (p=ns). pts ( . %) developed infection following cabg, pts ( . %) following valve replacement and pts ( . %) after other cardiac surgery. they were males ( . %) and females ( . %). endocarditis has occurred . % in group a and . % in group b. severe wound infection was recorded in . % in group a and in . % in group b. one case of sepsis ( . %) in group a and in group b ( . %). respiratory infection occurred in pts of group a ( . %) and in pts of group b ( . %). two cases of urinary tract infection was in group a and one in group b. catheterrelated infection was occurred in ( . %) in group a and ( . %) pts in group b. pts ( . %) had fever of unclear aetiology in group b. conclusions: there was no statistically significant difference regarding the rate of infection in both groups. a single dose administration of cefuroxime is accordingly just as effective as a four days regimen of amoxicilline plus netiimicin. legionella pneumophila is a common bacteria of the environment, and it is an agent responsible for severe community acquired pneumonia (cap). we analyzed the patients with lpp admitted in our icu during the last years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . they represented . % of cap. seven patients were males and female, with mean age . + . years. tiss was . + . and apache ii . + . . all, but patient, were under mechanical yen tilation (mv) during a mean period of . • (min-l, max- ) days. two pneumonias occurred beyond the season, while patients had an epidemiological history. only patient had no risk factor. in all the others tobacco smoking and alcohol abuse was quite frequent. diagnosis was based on serologic test and culture or direct fluorescent antibody staining of bronchial secretions. seven patients had a multisystemic disease with hepatic dysfunction in , renal failure in (due to rhabdomy~ lysis in ). one patient had a prosthetic valve endocarditis and another developped ards. nosocomial septicaemie occurred in patients. mortality rate was %. deceased patients had initially higher apache ii, (a-a) , and lower natriemia. comparing lpp with the other cap (n= ), both submitted to mv, mortality rate was similar ( , % versus . %). in conclusion lpp can occur all over the year. there was a high incidence of severe complications and outcome was similar to the other cap when requiring mv. prospective specimen brash (psb) with culture > cfu cfu/ml. broncho-alv~lat lavage (bal) ~= c'fu/rnl or positive blood culture. were excluded for rapture of treatment ; were analysed (shift with oral antibiotic : ; prohibited antibiotics associations : ; resistant germ : ). clinical data : age , • , ; saps • , ; mac cabe i : , % -ii : , % -iii : , . , % of the patients were intubated and under mechanical ventilation. the pneumoaiae were : primitive in ( , %), copd ( , %), aspiration pneumonia ( , %). germs were isolated (psb , bal , blood culture ) : s. pneumoniac ( , %), h. influeazae ( , %), sttep~:occns ( , %), saar ns ( , %), enterobaetdrindr ( , %), mosexella catarrhalis ( , %), othem . / ( , %) were sensitive to freatment. the ltentment was mg/kg/d of ampiclllin and mg/kg/d of sulbactam in continuous iv adminisu'ation during at least days. clinical eff~ienev : success ( %), failures ( %) with superinfeetion , worsening or relapse , dead , side effects . there was no difference between etiologies : primiti~;e~ , %, copd , %, aspiration pneamoniae , %. the bacteriological effieieacy was evaluated only for patients with eradication ( , %), eradication but super~ection ( , %) : with pseadomoaas a&ogiuosa , eater~ac~ ; beeteriological failure ( , %). in conclusion, the aasor ampicillin -sulbactam is effective for the i~eatment of severe acquired community pneumonise. objectives : to assess the efficacy of chlorhexidine (cl) gel or suspension applied in the nose and in the op for the prevention of the tmcheobronchial colonization. methods : thirty-seven patients expected to be intubated for > h were randomized to received topical application oga cl suspension ( %) qshrs, a cl gel ( %) q hrs or a placebo. in addition all vpts received a nasal and a op spray ( %) of either cl or placebo administrated according to the same schedule. semi-quantitative cultures of the anterior nares, the oropharynx (op) and the trachea were obtained on admission and once a day until extubation (just before the next application). the results were assessed according to the following criteria: success = no acquisition of gnb in the trachea ; failure = acquisition of gnb in the trachea. acquisition was defined by a follow-up culture positive for a gnb not present in the trachea on admission. results : success failure nosocomialpneumonia overall morality clsusp. placebo clgel placebo n= n= n= n= / / / * / / / / * / / / / / / / / / i *p = , byfisher'sexacttest conclusions : these results suggest that topical cl gel administered q hrs may prevent tracheal colonization by gnb. f. daumal*, m. daumal**, c. plot**, v. vurmmen ~ e.colpurt**, b. manonry** * hygiene hospitali&e, ** service de r enmmtion, * service des admissiens-urgeuces centre hospitalier g- ndral - saint-quentin -france obiectives: evaluate the nosocemial risk due to peripheral venous inserted short catheters, and the quality of care. patients-methods: the intensive tare unit (i.c.u.) is a beds unit. the prospective study includes all the patients comn~ in from / / to / / . the recruitemont uses an evaluation schedule of local clinical signs. the nurses aimed to create this evaluation data which includes the place of entry site, the duration of catheterization and the cause ot withdrawal. only patients staying longer than days in the i.c.u. are accounted for. the diagnosis of uosoenmial infection is assured by the physician taking care of the patient and by the hospital epidemiologist on the next signs: evident pus at the catheter entry site, positive culture of the strain, with or without the same pathogen in the blood sla'uam,the patient having no other distant source of infection. analyses were performed on epi/nfo. results: the occurrence of nosoeomjal inthrtions: i abcess and bacteremia during the first part of the study lent the medical staff to modify the protocol of insertion end survey of the device. so we analysed different periods: period ( / / to / / ) and period ( / / to / / ) for all .e peripheral catheters inserted in the i.c.u. period , % , % en infection due to peripheral venous device is a daily threat. the severity of some clinical situations requiring admission in icu proves it. the motivation of nurses for rigid adherence to established protocol, the daily survey of the entry site, the withdrawal of the peripheral catheter every hours aimed to reduce significantly the local signs of inflammation end infection of peripheral catheters inserted inside the i.c.u. objectives: to investigate the use of a new metabolic monitoring device for different ips levels by comparing oxygen consumption (vo ) to measurements of the mechanical work of breathing (web) and p . . methods: the study was approved by the institutiotml ethics committee. eight patients were investigated during weaning after prolonged mechanical ventilation ( - days) for various diagnoses when the clinical physician judged the patient to be ready fur weainag. ips was setto , , , mbar far rain periods each. all patients had a peep between - mbar.. respiratory frequency (f), tidal volume (tv), minute ventilation (ve) were read from the ventilator display ( ae, puritan bennett, carlsbad, usa). flow and airway pressure were measured at the endotracheal tube site. esophageal pressure was measured using an esophageal balloon catheter (fa. ruesch, frg). web was determined as the area subtended by the pleural-pressure-vohime curve. p . was determined by using standard occlusion technique and graphical analysis of the airway pressure tracing. vo and vco were measured using the pb metabolic monitor (puritan bennett, carlsbad, usa) connected to the pb ae ventilator. all data are given as mean• deviation for each ips level. comparison between the different ips levels was performed using anova for repeated measurements. significance was considered at p< . , compared to ips mbar. results: the values for breathing pattern, web, p . , vo and vco are given in the table for the different ips levels; significance is indicated by ~. objectives: fluidized beds are often used in the management of critically ill mechanically ventilated patients. critically ill patients are increasingly colonized with resistent pathogens [ie: p. aeruginosa, methicillinresistent s. aureus (mrsa), extended spectrum i~-iactamase producing enterobacteriaceae ] that can ultimately cause nosocomial infection. methods: we prospectively monitored bacterial colonization of mechanically ventilated patients and of the fluidized bed (clinitron) inwhich they were treated. multiple samples for quantitative bacterial cultures were taken from oropharynx, trachea, feces and bedsores. samples of ceramic beads from the bed were also taken both during and after patient stay (after bed operation in the absence of patient). re,~ults: episodes in consecutive patients (mean age: . years) were analyzed. all had bedsores and/or urinary catheters and fecal incontinence, patients had nosocomial pneumonia, had urinary tract infection [ with extended spectrum imactamase producing k/ebsie//a pneumoniae (ki~lse)], one had positive blood cultures with mrsa, and one patient had a ki~lse found in high concentrations ( - s cfu/ml) in occasions in feces. patients were heavily colonized: the , samples from ceramic beads showed no growth or became sterile without any sterilisation procedure (even in one case of presence of kf~lse) during the patient stay. conclusions: fluidized beds do not put patients at high risk of acquiring nosocomin pathogens, and cross-contamination between patients seems unlikely, even when multiple resistent organisms were initially present. the recommandation from some manufacturers to undergo extensive sterilization of fluidized beds after use does not seem warranted, at least with the bed used in this study. ant. koutsoukou, a, tahmitzi, p. kithreotis, m. koutonlidou, k. stavrakaki, kainis e, g. vlahogiorgos and e. eliopoulos icu-centre for respiratory failure -chest diseases hospital of athens. the cost-effectiveness issue is becoming vital in modern medicine and may lead to moral dilemmas since sometimes certain groups of patients may not have access to highly specialised modalifies. objective: our study compared the mean daily cost for antimicrobial medication in copd patients treated in icu versus all other patients in the context of relevant epidemiological, prognostic and outcome data. methods: age, sex apache ii score, length of icu stay (los) and in -icu fatality were retrieved from the files of all icu admissions over . mean daily cost for antimicrobial therapy per patient (dcat) was estimated. these variables were statistically compared between copd and non-copd patients. significance was assumed at p< . results: of the total admissions were fully evaluable. of them ( %) were copd patients. data (m---sd) results for statistical test are given in table i . copd patients were significantly older spent more time in the icu and presented with significantly higher apache ii scores. outcome and dcat were comparable in the two groups. objectives: the use of heat and moisture exchangers (hmes) during long term mechanical ventilation (mv) is increasing. in icu patients, they are routinely changed every day, according to the recommendations of the manufacturers, but the clinical basis for such a daily practice is lacking. we therefore prospectively assessed whether changing hmes (dar hygrobac, spa, mirandola, italy) every h only would affect their clinical and bacteriological efficiency. methods: two consecutive groups of patients requiring mv for > h were compared: group = hme replaced every day, n= episodes of mv in patients; group = hme changed every h, n= episodes in patients. tubings were not changed in the same patient during the whole length of ventilatory support. diagnosis of nosocomial pneumonia (np) was based on a positive quantitative culture (~ cfu/ml) of a protected specimen brush in patients with clinical signs of pneumonia. quantitative cultures of pharynx, trachea and y-cannector were performed every h. results: the groups were similar in terms of age, indication for and overall duration of mv ( +_ . vs +_ days, p= . ), and severity of illness (saps: --- . vs . +_ . , p= . ). the maximal values for peak airway pressure were identical in both groups ( . -+ . vs . • cmh , p= . ). obstruction of the tracheal tube was observed in only one instance in a group patient who had tracheal bleeding. circuit colonization was very rare, and of low grade in both groups. the level of patient colonization and the type of organisms were identical in both groups. more importantly, the incidence of np was the same ( / vs / , p= . ), as was duration of mv before the occurence of pneumonia ( • vs . +_ . , p= . ) and overall mortality rate ( vs , p= . ). conclusions: the clinical efficiency of this hme does not seem altered after days of use. indeed, replacing this hme every h only neither affect circuit and patient bacterial colonization nor the incidence of np. therefore, substantial savings could be obtained changing hmes every other day only. obiectives: to evaluate the usefulness of different paraclinical investigations for the diagnosis and prognosis of acute viral encephalitis in icu patients. methods: we reviewed patients (pts) admitted to our icu from july to december with the diagnosis of acute viral encephalitis. all were in coma and were initially treated as presumed herpes simplex virus (hsv) encephalitis. the causative agents were: hsv ( cases), herpes zoster varicellae ( ), measle ( ), rabies ( ), unidentified ( ). eleven pts survived and three presented neurologic sequelae. twelve pts were investigated by mri, and eleven also by spect and multi-modality eps. including brainstem auditory eps (baeps). these investigations were obtained as soon as possible following admission and were repeated during icu stay when possible. the clinical outcome was noted. results: six pts ( / ) had an abnormal mri. among them, pts made a complete recovery, in comparison with / pts with a normal mri. in one hsv infected patient, mri remained normal despite clinical deterioration and bad outcome. when repeated, mri became abnormal in cases (with poor outcome in one) and was improved in one. spect was found abnormal in / pts (among them, pts had thus a normal mr/). the correlation regarding the topography of brain lesions was poor between mri and spect. the findings of spect could not be correlated with a poor outcome. the baeps confmned in % of the pts the clinical diagnosis of brainstem involvement. changes in visual and somatosensory eps were mild in all the pts and were not helpful for the prognosis. eps were otherwise interesting for the follow-up of the coma in these sedated and ventilated pts. conclusions: the value of mri and eps for the diagnosis of acute viral encephalitis is of limited interest. spect seems to show early modifications, even in pts with a normal mri, but this test is poorly specific and does not correlate with mri changes when present. concerning the prognosis, larger studies should probably confmn that a normal mri could usually result in a good outcome. this serie illustrates also that hsv encephalitis could be demonstrated only in a small number of cases and that the prognosis of non hsv encephalitis is not easily assessed. objectives: to study the influence of gram (-) bacterial lung infections on liver function i~ mv icu pts. pts and methods: we studied pts, # ( , %), ( , %). hean age: , • years ( - ). mean stay in icu: , • days ( - ). they were divided in groups: a( pts) who did not suffer from pneumonia and b ( pts) who developed a gram(-) bacterial pneumonia. both groups were consisted of pts with same age, sex and disease distribution and same systemic failures. we measured sgot, sgpt, total bilirubin(tb), direct bilirubin (db), alk.phosphatase (al.ph.), v-gt and albumin (alb.) times: on days o, and of the pneumonia for group b and respectively for g~oup a. conclusions: ) in elderly intubated pts of an icu, kp is isolated more frequently than in icu pts< years (p<o, ). ) the frequency of isolation of kp in icu pts during - was - %, but now ( - ) kp becomes more and more rare ( - %) and is isolated especially in elderly pts. ) its sensibility to antibiotics remains always the same. ) the prognosis of np in our study was independent from age (p<o, ), sex, presence of bacteremia (p< , ) and type of invading microorganism. gram neg bacteria and renal failure (rf) from aminoglycoside toxicity are common and serious complications in critically ill patients. the aim of this prospective, pilot study was to compare the safety and adequancy of the endotrecheal (et) vs the intravenous (iv) administration of aminoglycosides. were measured in the plasma and the bronchial secretions at and hours after the iv (bolus) or the et (nebulized) administration of mg of gm in seven criticcally ill patients ( with established renal failure). safety was defined as peak and trough plasma gm levels _< than and ijg/ml respectively and adequancy as gm levels in bronchial secretions _> , ijg/ml. results: gentamicin was administered by the et and iv routes in and separate sessions respectively. a total of samples were assayed, in bronchial secretions (bs) and in serum. the et route resulted in higher gm levels in the bronchial secretions compared to the iv route ( , + , vs , _+ , pg/ml respectively, p = ns ). adequate bronchial gm levels were achieved in % of patients after et administration, compared to % after iv aaministretion. the blood levels of gm were significahtly lower after the et vs the iv route ( , + , vs , • , pg/ml respectively, p _< . ). the et administration resulted in toxic bronchia~ gm levels in % of the specimens. % of these samples were from patients with renal failure, however toxic blood levels were reached in only % of these. gentamicin seems to be a safe and adequate alternative route of treatment for the lrti. however, in patients with renal failure the et administration of the aminoglycosides should also be modified and continuously monitored. in order to evaluate the pathogenic role of anaerobes in nosocomial pneumonia (np), we investigated the systemic humoral response in patients who developed a np with anaerobic bacteria, especially prevotella species. methods: blood samples from groups of patients were tested. group i: patients with a np in which prevotella spp. was isolated from protected specimen brush (psb), group ih a control group of patients with a np without anaerobic bacteria, group ill: a control group of patients with dental stumps but without pulmonary infection, group iv: a control group of healthy voluntary people with prevotella spp. isolated from the dental plaque. an elisa was used to evaluate the total antibodies level against a mixture of four prevotella strains and a western-blot method was done to identify the antigenic proteins. results: data are expressed as means .+ sd. the antibody levels in patients of group i ( • was statistically higher (p=o.o ) than in the control groups (respectively: + , _+ , _+ ). using western-blot method, the intensity of the response was roughly superposable to levels obtained by elisa and the profiles were different according to the prevotella species. the occurence of a np with anaerobic bacteria (prevotella species) isolated from psb leads to an antibody response which seems specific of the prevotella species isolated. fever is common in the intensive care unit, but is not always related to an infection. we sought to define the epidemiology of febrile patients in a general medical/surgical icu. methods: we prospectively analysed the source of fever (t > . ~ c) in all adult patients admitted for >- hours in the icu during a two month period. these patients were studied for consecutive days. and werc classified in groups according to the evidence of infection (center for disease control criteria) after complete evaluation: documented infection: cdc criteria + isolation of pathogen (d); possible infectron: cdc criteria without isolation of pathogen (p); unlikely infection: patients who did nol meet the cdc criteria (u). results: of a total of patients studied, dec'eloped fever ( %). including (after complete evaluation) d, p and u palients. both the highest temperature in tile first day of fever and the maximal temperature were higher in d than in u ( . • versus . • and . -~ . ~ versus . - . , respectively p= . and p= . ). most common sources of infection in d were the lungs in patients ( %) and urina .ry tract in ( %). of these patients had positive blood cultures ( %). the overall mortality was % ( % in d, % in p and % in u. differences ns). antibiotics were given in % of d, % of p and % of u ( patients). in p there was a non significant lower mortality." in patients who received antibiotics ( / ( %) versus / ( %) patients, respectively). conclusions: in febrile icu patients both the highest first day" temperaturc and maximal temperature are significantly higher in infected than in non infected patients, but the differences are too small to be useful clinicall). mortality rate is not significantly influenced either by the presence of an infection or by the administration of antibiotics, obiective: retrospective study to determine the influence of candida infection on icu outcome. methods: patieet with a stay of more than days in inteaasive care were screened for candida infection. patients were treated with antifungal therapy due to either an increased antigen titre of -> : or clinical evidence of candida colonization. serological candida-antigens (ramco, pastorex) and antibody titres (hemagglutination, lgg-, igm-elisa) were examined routinely. seroconversion was defined as a threefold increase of antibody titre or a titre of : or higher. results: the median length of stay was (ranging from to ) days, the mean apache ii score on admission was (+_ . sd) points. of patients patients died ( . %). in the group treated with antifungnls ( patients) patients died ( . %). although of the patients only ( . %) developed a candida infection as defined above the mortality in the group that showed signs of infection was significantly higher ( . % vs. . %, p < . [chi-square-test]). in patients an antigen concentration-> : was measured. seroconversion was found in patients. the most common fungus was candida albicans ( . %). furtberm re, candida glabrata was found in . %. most of the patients were treated with x mg fluconazole ( patients). in patients therapy was changed to amphotericin b/flucytosine. in patients therapy was started with amphotericine b and flucytosine. in patients a threefold decrease of candida antigen titre was found. patients showed a decrease of candida antibody titre. conclusions: meticulous screening for eandida infection seems to be necessary since the number of patients with fatal outcome is significantly higher in the group with signs of fungal infections and thus requires immediate antifungal treatment. objective: early diagnosis of patients with ventilator-associated pneumonia (vap), and subsequent identification of causative microorganism, and selection of the appropriate therapy are critical important points that affect morbidity and mortality. the results of the quantitative bacterial cultures are not available for at least hours, while a two hours period, since the specimen are obtained is enough to know the gram stain results. the aim of this study is to determine the usefulness of gram stain in specimens obtained by bronchoaiveelar lavage (bal), through the bronchoscope. material and methods: we studied patients ( males and females, age + ) with suspected ventilator-associated pneumonia. the bal gram stain was considered positive when the specimen after a centrifugation at rpm for min revealed: i) more than leukocytes per optic field, ii) squamous epithelial cell less than percent and iii) one or more microorganisms per optic field on magnification. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap and patients did not. in cases the bal specimens (quantitative bacterial cultures) established the diagnosis of vap in the remaining three patients the vap diagnosis was established by other procedures (blood or pleural fluid culture, clinical outcome, autopsy). apache fl score in patients with vap was , -+ , , while in patients without vap was , + , . there was a significantly higher incidence of vap in patients who had i) coma (gcs < ) and ii) been receiving neuromuscular blockade (p< . ) . the sensitivity of the gram stain for vap diagnosis was %, the specificity , %, the positive predictive value %, and the negative predictive value , %. conclusion: our data indicate that the gram stain of bal specimens is useful for the early diagnosis of vap and the subsequent administration of the appropriate treatment. the role of anaerobes in mechanically ventilated patients with pneumonia (mvp) have been poorly investigated aim of the study : analyse the prevalence of anaerobic isolation in mvp. methods : between october and february all suspected mvp were investigated using protected specimen brush (psb) technique. brushes were rapidly transported in shaedler broth to laboratory. a special care was tooken for anaerobic isolation. results : among the psb performed for suspected mvp ( nosocomial and community-acquired pneumonia), yielded at least one micro-organism (positive psb : %). of positive psb demonstrated only aerobic bacteria and ( %) yielded with anaerobes. in out patients, anaerobes were associated with aerobic bacteria. anaerobes were mostly isolated in nosocomial pneumonia ( / positive psb). strains of anaerobes were isolated. prevotella species represent out these strains ( %) the most frequent anaerobic species were prevotella oralis ( ) p. intermedia ( ) and p. buccae ( ). comments:using adequate methods, anaerobic bacteria are frequently isolated in mvp. it could be off importance to take in account anaerobes in the choice of empirical antibiotic therapy in mvp. objectives: the majority of patients with multiple trauma are considered immunocompromised. the aim of this study was to identify risk factors of pneumonia in mechanically ventilated patients with multiple trauma or after surgery. methods: in this prospective study we studied multi-trauma patients (mean age + years, apache ii . + ), admitted to a general intensive care unit (icu). all patients were intubated and mechanically ventilated. we were considered that a patient had ventilator associated pneumonia (vap) when the specimens of bronchoalveolar lavage (bal) or protected specimen brush (psi?,), ebb'ned through the bronchoscope, had one or more microorganisms in concentrations greater than and cfu/ml respectively. all patients had been receiving antibiotics, with no change during the last days, prior to bronchoscopy. results: patients had vap, and patients didn't. in the bivariate analysis, the glasgow coma scale (gcs)< (x = . , p< . ), the administration of neuromuscular blockade (x = . , p< . ), the duration of mechanical ventilation to be greater than days (x = . , p< . ), the flail chest (x = . , p< . ), the parenteral nutrition (x = . , p< . ), the ards (x = . , p< . ), the abbreviated injury scale (ais) of more than for thorax (:,: = . , p< . ), the pneumothorax (x = . , p< . ) were statistically significant related to development of vap. in multivariate regression analysis, using the stepwise technique, three of the seventeen studied factors showed to have an indepantent association with the development of vap:the administration of neuromuscular blockade (f: . , p< . ), flail chest (f: . , p= . ), and gcs (< ) (f: . , p= . ). conclusions: in patients admitted to icu for multiple trauma or major surgery, the administration of neuromuscular blockade, the flail chest, and the gcs (< ), in the population under study, were the indepedent risk factors for vap. mof is a sereous complication of differem states: infection, sterile inflamation, extensive fissure injure, intoxication, ets. there is close correlation between extension of mof and death, developement of nasocomial infection. immunologic disfunction. in order to prgnose probability of risk of mof development among the patients with sepsis and septic shock, we achived an eqation, allowing to recive a coeficient, closely connected with this probabiliti. we have used retrospective analisis of cases of sepsis. diagnosis of sepsis was based according to bone's criterions of sepsis. mof was assessed as disfunction of or more systems according to bone's classification of mof. having used correlation analisis we have estimated factors which have had high correlation coeficient with the probability of development of mof. there were: apache-ii score points, evidenceof septic shock, endocrinopathy. with the help of multyple regression analisis we acheved next equation: y= , + , x~ + , x + , x , were x i-apache-ii score points, x -evidence of septic shock, x -endocrinopathy. the explanatory power of this quation was evidenced by roc of . , se (v - . introduction: the presence of liver dysfunction in the process of multiple organ failure is associated with an adverse outcome, particularly when it becomes progressive to liver failure. disturbances of liver function may occur early and their detection may be of significant importance for the further development of organ failure. routinely used liver function tests appear to be inconsistent indicators of hepatic damage. in this study, we used p_lasma disappearance rate (pdr) of indocyanin-green dye (icg) as an early estimate of liver function. methods: we serially evaluated pdr and routine liver function tests (serum bilirubin, sgot, sgpt), as well as acute phase and non-acute phase proteins (crp, transferrin) in patients during the first week after trauma or the onset of sepsis. patients: group : (n = ) multiple trauma iss > , group : (n = ): abdominal sepsis, acute necrotizing pancreatitis (anp) grade iii. patients were selected on the basis of clin cal estimates that these patients would require continued icu observation. pdr was determined by means of a fiberoptic catheter and a computerized system (cold z- , pulsion), which permits repeated bedside measurements. the initial values of pdr, serum bilirubin and transaminases were not significantly different in trauma, sepsis and anp. in trauma patients pdr improved during the first week. in patients with sepsis and anp pdr remained low and worsened with time. the decrease in pdr preceeded an increase in biochemical liver function tests in these patients. + . &-_ ( - ) discussion: routinely available blood tests of liver function are usually altered several days after injury. however, they are generally non-specific indicators and they are influenced by extrahepatic factors. pdr seems to be useful to evaluate impaired liver function early after the onset of sepsis and trauma. objectives: to study frequency of organ system failure (osf) and it's influence on outcome in granulocytopenic patients with hematological malignancies and septic shock(ss). materials and method: retrospective review of medical records of granulocytopenie(wbc< , xl ) patients with hematological malignancies and ss, who were admitted to the intensive care unit (icu). frequency of osf before and after ss was analysed. the patisnts were categorised on survival and non-survival. results: signs of osf were observed in . % of patients before ss and in all patients after ss. only patients presented with hypotension refractory to inotropic therapy. nevertheless there was a significant increase of frequency of acute respiratory failure (arf), acute renal failure (arenf) and liver injury (li) after ss occurred(showed on the figure). only frequency of organ failure before and after objectives: statusmetria allows to define the effective level of oxygen status and accordance to it means of carbon dioxide and elec-trolyte in critical care. the conception of syndrome int~ive care (sic) is exhausted itself and invariable outcomes of sic of multiergan system failure (mosf) confirms that. therefore, an alternative to sic should be advanced. methods: efficlenoy of treatment has been asscsaed in patients with mosf using value of metabolic rate and ability of an organism to cover it by oxygen and substrate supply. oxygen pulse (op) and index of efficacy of oxygen transport (ieto ) was monitored. ~lt~.lntenaive care is considered to be homeostasis-securing therapy (hst) if energostructure deficit is eliminated and necessary for recovery regeneration rate is .restored. op in patients with mosf was . mt-m " , and le,~ and ie'i~ w~ . units in sic. we managed to maintain op of . - . ml.m " and ieto of . - . units in hst. patients from with mosf survived in sic and patients from survived in hst. efficiency of hst appeared to be two times as much as efficiency of sic. cr of homeostasia-se-'uring therapy is advancing. the conception provides restoration of regeneration rate due to effective then in sic elimination of en=gostructure deficit. the conception may be a basis of new technology for treatment of mosf. helen f goode phd, nigel r webster phd. anaesthesia & intensive care, university of aberdeen, ab zd, uk. objectives: xanthine dehydmgenase is converted under conditions of ischemia, reperfusion and endothelial damage to xanthine oxidase, with superoxide anion as a co-product of its catalytic activity. multiorgan dysfunction syndrome is associated with splanchnic vasoconstriction resulting in significant and prolonged gut ischaemia. aggressive volume resuscitation with prompt restoration of blood flow results in reperfusion of the tissue and is likely to cause xanthine oxidase-mediated release of oxygen-derived radicals. this study investigates xanthine oxidase activation and oxygen-derived free radical-mediated damage in such patients. methods: fourteen consecutive patients on itu who met established criteria for septic shock and secondary organ dysfunction were studied. serum xanthine oxidase activity was measured using oxidation of a chromagen in a dual enzyme system and plasma malondialdehyde was measured using a specific spectrephctometdc assay. apache ii scores, blood pressure, svr, cardiac output and day survival were also recorded. biochemical data were compared with results from healthy subjects. results: xanthine oxidase activity was . + . units/i in patients (mean :t: sem) and . + . units/i in controls (p<o. , mann whitney u test), and was highest in the patients who survived (p< . ). malondialdehyde concentrations were elevated ( . • . prnol/i compared with . • . pmol/i in controls, p< . ). xanthine oxidase activity did not relate to apache score or any of the cardiovascular parameters recorded, and was not influenced by the degree of organ dysfunction. conclusions: patients with sepsis and secondary organ dysfunction have xanthine oxidase activation and evidence of free radical damage. the finding that activity was highest in those patients who survived suggests that reperfusion was incomplete in patients who died, with decreased tissue xanthine oxidase ~tash out' into the circulation. influence objective : evaluation of the feasibility of measuring the intragastrie partial pr~sure of carbon dioxide (pco ) using a chemilumin~nt optode and fibre~ptics originally developed for intrav~cular blood gas monitorlng(p ) methods the pco electrode w~ calibrated i~-vitro according to the m~ufaeturers instructions the sensor w~ then stripped of its outer c~ing and threaded down the pile tube of a g~ c enema e (gt) so ha he ens ng portion sat well within the balloon. the modified gt was inserted n~og~trically after induction of anesthesia in ten patients undergoing c~diopuimonary byp~s throughout results: according to the datas of integral rheography % of patients were revealed to have hypodynamic type of blood circulation (cardiac output was decreased on - % and general peripheral resistance increased on - %). it was effective to use complamin (xantinoli nicotinas) in the complex therapy of su~h patients. the dosage was - mg/kg during - days. as a result of such therapy was also the oliguric stage shortening (ac n ).in , % of the cases unsatisfactory datas of central hemodynamic,combined with high (more than cm h ) venous pressure,lung oedema.then nanipruss ( , - , mkg/kg/min) was succesfutly used in complex with routine therapy.in the patients with low cardiac output and low general peripheral resistance mesaton ( , - , mg/kg) and dopamine ( - mkg/kg/min) were effective.change for the worse in the hemodynamics datas, inspire of therapy during - days,was prognostically unfavourable. conclusions:we consider early diagnostic of hemodynamic disorders and adequate correction of them is one of the most important factors, determined the outcome and prognosis in arf patients. obiective: to evaluate the results of renal replacement therapy (rrt) in surgical icu patients with acute renal failure (arf). arf in icu patients is associated with high mortality rates. we investigated the relation between mortality and organ failure in different categories of surgical icu patients receiving renal replacement therapy (rrt) for arf. methods: the records of surgical icu patients with arf requiring rri-(haemodialysis or cavhd) were examined. five different patient categories were defined; .ruptured aneurysm of the abdominal aorta (raaa) n = .elective vascular surgery (evs) n = .abdominal sepsis n - .trauma n = .others ( e.g. malignancy, obstetric emergencies) n- seven organ systems (cns,circulatory,respiratory,hepatic,renal,digestive,haematologic) were scored for possible failure using the mof score. results: mortality was as follows: all patients % , group % , group % , group % , group % , group % . mortality increased with the number of failing organ systems; mortality for all patients with > failing organsysterns was % the only exception being the subgroup of trauma patients where mortality under these circumstances was o% conclusions: mortality in surgical icu patients receiving rrt for arf is high. no significant difference in mortality is found between raaa and evs. mortality increases with the number of failing organ systems. the subgroup trauma patients shows a lower mortality compared to the group as a whole, even with > failing organ systems. to look for the most accurate scoring system to measure the severity of the complications occuring in the early phase ( first day) of kidney transplantation and to asses their prognostic value. methods: in our retrospective study we applied the apache li and the goris scoring system for the kidney recipients who developed multiple organ failure (mof) as a consequence of their pulmonary and. cardiovascular complications following kidney transplantation. we evaluated the recipients the distribution of the women and men ( % ~ % ) was the same as in the kidney recipients. applying the apache ii system most of the patients had their score between and , and the function of , or organs were affected at the time of the onset of mof. the apache ii system gave adequeate information about the disturbance of the function of other organs beside the kidney failure even at the time of the transplantation. the scores and the number of the affected organs correlated with the condition of the patients in the goris scoring system but not as sensitively as in the apache ii scoring system. conclusions: both the goris and the apache ii scoring system can be applied to measure the severity of the multiple organ failure occuring during the early phase of kidney transplantation. however the apache ii system is more suitable to follow not only the stateof the patients at the time of the admission but also the changes occuring in their condition during the complication. v.v.erofeev, v.v.ivleva scientific research institute for general reanimatulogy russian amsci, moscow, russia objectives: the analysis of ssc and results of their treatment in patients following critical states showed the necessity of developing a combined antibacterial therapy. methods: according to the protocol patients ( - years old) with combined trauma and massive hemorrhagy following vast aml traumatic operations were examined. microflora's composition and resistence to up-to-date antibiotics was studied using the anaiyser iems reader by "labsisteme"(finland). general clinical, bacteriological, immunological indices, as weil as the duration of the treatment and recovering rate served as criteria of the combined antibacterial therapy effectiveness. results: it was proved expedient to administer antibiotics in staphylococcus infection in the following combinations: riphampizin with fluoroquinolones; i-ii degeneration, cephalosporins with aminoglycosides; cephalosporins with fluoroquinolones. in case of singling out the exciters of the euterobacteriaceae family, including the pseudomonas aereginosa, -fluoroquinolones combined with modern amynoglycosides; fluuroquinolones with ureidopenicillines; ureidopenicillines with amynoglycosides; amynoglycosides with the ii-iii generation cephalosporins; cephalosporins with fluoroquinolones. in severe ssc caused by combined infection (including anaerobes) clindamicin with modern amynoglycosides was prescribed. conclusion: the combined antibacterial therapy allows: ) to increase the effect on microbic agents and the efficacy of treatment in combined infections; ) to lessen the possibility of the exciters'resistence to antibiotics; ) to prevent the development of superinfection: ) to decrease the doses of medicine and its toxic effect. objectives: two methods of blood volume measurement in a group of critically ill patients were compared to investigate the practical possibilities of a new easy to use method based on carbon monoxide (co) uptake. methods: all patients had multi-organ failure and haemodynamic monitoring with a swan-ganz catheter. mean apache ii score was ( - ). when indicated, patients had blood volume measurements simultaneously based on the techniques of, i) dilution of ~cr labelled red cells, and ii) inhalation of carbon monoxide gas with measurement of the rise of carboxyhaemoglobin produced. the co was administered via a newly designed, ventilator driven, fully closed circle system ensuring co retention and co removal with automatic addition of oxygen to m}ttch patient uptake. a portable computer performed all necessary calculations. results: volumes obtained by co uptake were compared with the "gold standard" radiolabelling method. mean blood volume determined by the co method was ml ( - ml) compared with ml( - ml) with slcr labelled red cells (r= . ). regression analysis produced an intercept at ml. the slope of the regression line was . ( . - . , % confidence limits). discussion: the co method produces volumes in excess of the radiolabelling method. there appears to be a systematic error, and one possible explanation is co binding to substances other than haemoglobin. conclusion: the co method is easier to use than radiolabelling and of the lower cost, since cohb measurement only is required. aceuraey is sufficient for clinical use and our preliminary findings suggest this system will meet the requirements. objectives: this study was conducted to determine the role of nitric oxide (no) in the pathophysiologic alterations and multiple organ damage, and the possible effects of " " " (l-n -monomethyl-l-arglnlne nmma) on hemodynamics and mortality in rats caused by a prolonged hypovolemic insult. methods: a prolonged hemorrhagic shock ( - mmhg for rain) was induced in anesthetized rats followed by adequate resuscitation. l-nmma was administered intravenously at doses of . mg/kg or . mg/kg at the end of resuscitation. results: infusion of . mg/kg l-nmma diminished the fall in mean arterial pressure, significantly increased the cardiac index (ci) and stroke volume (sv), together with remarkable protection from multiple organ damage compared to the controls. the h survival rate was significantly improved from . % in the control group to . % in the treatment group (p< . ). in contrast, the high dose of . mg/kg l-nmma resulted in a strong blood pressure response but a marked reduction in ci and sv concomitant with an increased total peripheral resistance index within the observation period, and caused severe damage to various organs at h after treatment. in addition, marked elevation in both endotoxin and tnf levels were observed in animals subjected to shock insult. conclusions: these results suggest that no induced by hemorrhagic shock in rats is an important mediator for pathophysiologic alterations associating with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. thus, regulation of no generation and use of no inhibitors might provide new aspects in the treatment of hemorrhage related disorders, and the use of l-nmma would be either deleterious or salutary in a dose dependent manner. (hebert, chest- ) . the purpose of this study was to assess the risk factors for hepatic dysfunction in mosf. methods: patients have been hospitalized in our icu from january to may . , ( %) with mosf. among mosf pati~ts, ( %) have had hepatic dysfunction defined according to hebert (bilirubin ~ ttmop , chest ). thirty six of these patients acquired hepatic dysfunction after admission in the icu. these patients were compared with mosf patients without hepatic dysfunction selected blindly. chrorfic diseases, severity scores, eanse of admission, clinico-biologieal and hemodyunrrfic parameters, use of vesopressors, use of hepaiotoxic drugs, use of nutritional support and mortality were compared for hepatic failare and non hepatic failure groups.twenty nine patients had postmortem hepatic histologic examination, results: univaciate analysis: only parameters with p _< . are pre~nted. including these paramet~'rs in a multivariate analysis, anly c~hosis and vascular surgery remain independent risk factors for hepatic dysfunction. in particular, pao /fio , arterial lactate, do were not different between the two groups, some de~'ee of histological abnormalities was found in all liver samples, despite a normal bilirubin level in % of the cases conclusions: in our patients, conu'ary to previous studies, hypoxic and hemody~anfic parameters were not independent risk factors for hepatic dysfantion. this might be due to the inadequacy of the usual biologic definition of hepatic dysfunction as well as to the poor sensitivity of general hamodynamic parameters. critical states of various origin are complicated with the mldtiorgan farm (moi~ oceuzr~ce. due to their and functional features the lungs become the primmy damage target in various critical.states. ard that occurs in such states is associated with pulmonary edema development because of capillary permeability increase mediated by humeral and cenular responses to amag/~ factors exposure. r nmst be emphasized that mediators and effecto~rs of this respo~e affect not only puknonary capillaries, but other organs capiu~es as wellenhancing their permeability. orsans edema is a conmm~ finding at the autopsy of patients died from mof.clinical and radiolosial findings allow to have a diagnosis of pulmonmy edema before ~mi!ar lesions in other organs occm. additionally, there are some techniques that permit quantitative assessment of pulmonary edema flv.id (evlw) volume. in conclusion, we suggest that evlw changes in .dyn~rmcs in patients with mof are considered as a critical state severity measure which reflects indirectly the edema in other organs. objectives: we compared three different dialysis membranes to find out whether or not there were differences between their clearance characteristics on substances such as inuline, creatinine, urea, and phosphate to be eliminated in acute renal failure (arf). moreover, if a loss of clearance did occur we were interested in whether this was due to heparinization and a high production of the thrombine-anti-thrombine-complex (tat). methods: we carried out a randomized controlled study on consecutive critically ill patients presenting with arf, most of them in association with multi-organ failure, to be treated by continuous pump-driven arterio-venous renal replacement therapy on continuous low-dose heparinization. three different types of high-flux filter membranes (f tm [fresenius] , ct tm [baxter] , and filtra tm [hospal]) were assessed. each filter was changed intentionally after a hours" use. together the data of filters were evaluated, each at three different times (immediately after its onset [ hi, after h, and after h). the clearances of creatinine, urea, phosphate, and inuline were measured. results: there were some significant differences in clearance characteristics of inuline, creatinine, urea and phosphate between the filters (p< , ) showing the f tm membrane excelling filtra mand ct tm the more. the loss of inuline clearance ( mi/min/m ) after h, however, was insignificant for all filter types. a continuous low-dose heparinization scheme was applied without any relevant prolongation of the aptt. even lower losses were noted for the clearances of creatinine, urea, and phosphate. we found the tat-producfion increased after h (p< , ), but it did not rise any further. conclusions: as we could demonstrate in our study the clearance data of different types of filter membranes applied during continuous renal replacement therapy do show significant differences. on the other side, no relevant loss of clearance occurs during a hours" period indicating a high efficiency over time. to consider commercial aspects as well it shows that inexpensive conventional filter membranes can successfully be applied even for a longer renal replacement period, if needed. a retrospective study was performed on patients with acute renal failure (arf). we analysed survival in continuous (cd) and intermittent dialysis (hi)). mean age of the patients was years (y), patients ( % ) were < y, patients ( %) were >= y. the incidence of dialysed arf in our mixed intensive care departement is %/admission/y. statistics: fischer's exact test, mann-whitney-u test. efioloev: the contribution sepsis, cardiac failure and aminnglycosidcs was respectively %, % and %. treatment: cavh (cd) or cvvh (cd) was used in patients ( %), hemedialysis (hd) was used in patients ( %). data: mean apache scores were the same for cd and hd ( for both groups), patients treated with continuous dialysis techniques had significantly (p<o, ) more need for ventilation ( % vs %), elevated bilirubin ( % vs %) and a higher vasopresser need ( % vs %@ than patients treated with hemedialysis. there was a trend towards more sepsis ( % vs %; p= . ) mad coaguiation disorders ( % vs %; p= . ) in cd. taere were sign/ficantly more younger patients (< y) treated with cd ( % vs %, p< .os). mean apache score was significantly lower in patiants< y than as patienta>= y ( vs ; p< . ). patients< y had significantly (i}< . ) more coagulation disorders ( % vs %) and elevated bilirabin ( % vs %). there was no significant difference in vasopressur need and ventihatio~ between age groups. outcome:. hi) had a better sr compared to cd ( % vs ~ p< . ). patiants>= y had a comparable sr vs patients< y ( ") */e vs %; p----a.s.). tha global survival rate (sr) was % ( patients). conclusions : diaiysed arf has a well known lowsurvival rate ( %): hc~raedialysed patients had a better survival rate than patients treated with continuous dialysis. this can be explained by the fact that the latter were in a worse condition considering organ failure (more vantilatian, elevated bflirubin and need for vasepressurs), apache score couldn't illustrate that. patient~ y with arf have the same survival rate as patients< y: although patients >=- y have a higher apache score they have less organ faille. the avacbe score is not a good oredictor of survival in p with organ failure. departments of surgery and intensive care, guy's hospital, london, u.g-obiectives: a randomised controlled trial of a management protocol utilising the regular measurement of gastric intramucosal ph (phim) to control the administration of dopexamine. methods: patients admitted to a multidisciplinary teaching hospital intensive care unit (icu) undergoing insertion of a pulmonary artery catheter were managed according to a resuscitation protocol. randomisation was to either the protocol alone or to insertion of a nasogastric tonometer and subsequent management guided by phim. phim < . initiated volume and inotrope resuscitation and, if unsuccessful in elevating phim, dopexamine was commenced. approval was obtained from the hospital ethics committee. results: patients were considered for analysis and the two groups were well matched for age and sex. overall, there was a high hospital mortality of . %. there was no difference in icu or hospital mortality between the two groups (see table) . objectives: to compare cardiac output (co) measurements between continuous termodilution (cco) by thermal wire on pulmonary artery catheter (cco/svo vigilance. baxter critical care), and co measurement using a trans-esophageal doppler (dco) ultrasound system (odm ii, abbott laboratories), in the immediate postoperative period of cardiac surgery. methods: patients undergoing myocardial revascularization were monitored with cco by a swan-ganz catheter and an intra-esophageal dco probe, after induction of anesthesia. exclusion criteria were: aortic valve disfunction, previous valvular surgery esophageal disease, absense of sinus cardiac rhythm, and need of ventricular or intraaortic assistance. hemodynamic parameters, co by both cco and dco, svo . sao , diuresis, pha, and hemoglobin were repeatedly registered during the first hours after surgery, as the patients were kept under sedation and mechanical ventilation. results were compared using the method described by bland and altman. results: measurements of co were obtained, ranging . objectives: a decreased tissue oxygen delivery is responsible for a higher morbi-mortality rate among surgical patients; this diminished oxygen delivery/consumption rate (dojvo ) may origin the lactic acidosis observed in the gastrointestinal tract, reported in patients undergoing hypothermic cardiopulmonary extra corporeal surgery, and can be registered by tonometry as result of the gastric mucose ph. the purpose of this study is to evaluate the reliability of the intramucosal ph (phi) measurement by a nasogastric catheter as indicator of the do /vo > its co> relation to other parameters of do /vo disturbance, and with postoperative complications and clinical course. methods: patients ( male, female) undergoing cardiac surgical procedures were included ( myocardiai revascularizations, valvular substitutions, constrictive pericarditis). mean age was + years, mean weight _+ kg. a nasogastric probe (trie tonometrics) was placed after anesthesia induction; phi values were registered in the postoperative period ( ', ', ", ' and h after surgery end). the corresponding hemodynamic parameters, venous oxygen saturation (svo ), diuresis and arterial ph (pha) were also recorded. results: phi values ranged . to . (mean . ( . ); the mean values of clinical evolution were: extubation time, _+ hr.; discharge from postoperative care unit, - hr.; and hospital total postoperative time, _+ . days. complications registered were: perioperative acute myocardial infarctions, cases of respiratory insufficiency, occlusion of coronary bypass, an ease of hyperamilasemia. all patients with severe complications needing specific treatment showed either a low phi value, or a considerable descent in comparison with the initial register. statistic correlation between low phi and presence of complications was found; the low significance (p > . ) degree may be due to the low population size. conclusions: phi measurement in cardiac surgery patients is a non invasive, uncomplicated method for prediction of doz/vo disturbances, thus reflecting risk of increased major complications, and may precede changes in other usual indicators (svo , pha, cardiac output, ...). work-in-progress with a greater population size may offer more significant results. references: ( ) gutidrrez g: lancet ; : - . ( ) landow i: acta anaesthesiol scand ; : - . the haemoglobin-level (hb) is besides the arterial oxygen saturation and the cardiac index one of the relevant parameters of oxygen supply to the tissue. in contrast to otherwise healthy patients, there is no agreement on tile so-called transfusion-trigger in critically ill patients. in i?ont of this background the question arises, whether and to what extent blood transfusion in critically ill patients improves oxygen supply io tile tissue. this study was performed in critically ill/septic patients in the postoperative period alier an inlcclive/scptie revision operation of the hip or knee joint. on cardiac/seplic reasons monitoring consisted beside other measures of a pulmonary arlery catheter and of an indwelling arterial line li~r measurering/calculating standard haem~dynamic as well as systentic oxygen parameters. the indication for blood transfusion was given by hb together with the cliuical slatus of thc patienl (asa-scorc and multiple organ dysfunction (moi))). statistical analysis w~ks performed by mann-whitney-u-test. by fisher's exact-test and by wii.coxon-test: statistical significance was set with p< . . according tu the pretransfusion value of hb and of lactate (lac) palicnts ;,,'ere divided into groups as follows: a: hb< and b: >sg/dl: i: ac< . and ii: > .smm. in either group blood transfusion results in zt significant increase in hb (a: . _+ . to . + . g/dl; b: .(~ . tt, . + . g/dl; i: . -+ . to . -+ . jdl; i : . -+ . to . + . g/dl). wlailc, however, haemodynamic parameters do not difl)r significantly from each other before and alter blood transfusion, oxygen delivery (do, -ml/min x m-') increases significantly hi either group studied (a: -+ to -+ ; b: + to + ; : -+ to -+ ; i : -+ to -+ ), in contrast oxygen consumption (vo~ -ml/min x m e) does not change significantly in either group (a: i -+ to -+ ; b: -+ to -+ ; i: -+ tu -+ ; : -+ to +_ ); oxygen exlraction ratio decreases. this study in critically ill/septic patients demonstrates, that in this group of patients studied blood transfusion at a base-line-value of > . -+ . g/dl expectedly rises do~, however, it does not improve vo=; even not in septic patients with elevated lac-values. paclitaxel in a new anticancer agent, extract from the bark of the yew tree (taxus brevifolia), employed against breast and ovarian cancers resistant to chemotherapy. it promotes the polymerization of tubuline, and disrupts the normal microtubule dynamics. hematologic toxicity, hypersensitivity reactions (bronchospasm, urticaria and hypotension), and peripheral neuropathy are the main reported toxic effects. cardiac side effects are rare: atrioventricular blocks of higher degree are reported in . % of patients; congestive cardiotoxicity was discussed only in one trial in patients treated with paclitaxel and doxorubicin. we describe the history of a -years-old worn an with a breast cancer, diagnosed in , initial staging t nim , treated with mastectomy, axillary lymphadenectomy, andchemotherapy with a cumulative dose of anthracyclines of mg/m until august . the patient complained of dyspnea and severe hypotension immediately after an intravenous infusion of mg paclitaxel, given over hour for the treatment of bilateral, malignant pleural effusion. at echocardiography die left ventricular ejection fraction was reduced to %. she died days later because of a severe cardiac low output with hepatic and renal failure; an impressive hepatic cytolysis was observed. the post mortem examination confirmed the dilatation of the cardiac cavities, especially of the right ventricle, bilateral pleural fluid, and ascites. the histology was suggestive for a cardiomyopathy secondary to anthracyclines. the electron microscopy revealed a deposition of an unusual pathological pigment in the myocytes; subsarcolemmal deposition or membranous were absent. we hypothesize that paclitaxel was the cause of a major hypersensitivity reaction with shock and severe hepatic cytolysis, worsening the myocardial damage induced by anthracyclines. the possibility that a low doge of paclitaxel could directly increase anthracyclines cardiotoxicity -as decribed in the medical literature -will be discussed. objectives: activated endothelial cells release soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selectin (selam- ). sicam- , svcam- , selam- , and inflammatory cytokines were determined. methods: sicam- , svcam- , and selam- were determined by elisa. tnf-a, il- , and il- were also measured by elisa. endotoxin was measured by an endotoxin-specific endospecy test after pretreatment of new pea method. results: the sicam- and s vcam-i levels were significantly higher in the septic multiple organ failure (mof) and sepsis groups than in the non-septic mof group. the selam- level was slightly higher in the septic mof group than in the sepsis withut mof group and non-septic mof group. the increases of soluble adhesion molecules were not in agreement with changes of plasma endotoxin level. levels of soluble adhesion molecules were correlated with the levels of plasma tnf-a and il- , but the level of il- . discussion and conclusion: the slcam- and svcam- levels in septic patients closely reflected the severity of the pathophysiological conditon. it was possible that the release of sluble adhesion molecules were not stimulated by plasma endotoxin, but endotoxin in the local infectious region. tnf-c~ and il- also were suggested to be involved in the release of these soluble adhesion molecules. obiectives: cardiopulmonary bypass (cpb) surgery is associated with a systemic inflammatory response attributable to the release of various inflammatory mediators and the activation of complement or coagulofibrinolytic system. in addition, adhesion molecules, such as icam- , elam- , and vcam- , appear to be of central importance in the inflammatory process following cpb surgery. we previously reported the effects of a synthetic protease inhibitor, fut- , reduced release of inflammatory cytokines (tnf, il-lg, il- ), activation of complement (c a, c a) or coagulofibrinolytic system (tat, pic, fpa) and protected platelet function (gpib, gpiib/llla) following cpb surgery. methods: in this study, we analyzed fut- on soluble adhesion molecules following cpb surgery. patients undergoing cpb surgery were divided into two groups, group a consisted of patients who received omg of fut- in priming solution, followed by a continuous infusion at mg/kg/hr during cpb in addition to initial heparin dose of mg/kg. group b, a control group, included patients who were injected with heparin only. the plasma slcam- , selam- , and svcam- concentration was measured by elisa. results: every soluble adhesion molecules decreased during cpb in both groups, and rose after cpb. selam- and slcam- reached their peaks on hours after cpb and on pod respectively in both groups, but they remained lower in group a (selam-i: . + . vs. . • ng/ml, p< . , slcam-i: • vs. • ng/ml, p< . ), svcam- , in both groups, remained lower than preoperative levels, but did much lower in group a. conclusions: fut- reduced adhesion molecules and suggested to be the effect on postoperative organ dysfunction. in the last few :,'ears the conditions of treatment in continuous hemofiltration/hemodiafiltration were discussed controversially. a significant removal of tnf-alpha and il-i could be demonstrated in cvvhd. the aim of our study was to investigate the elimination of tnf-alpha, l- , il- , il- , s-cd- and ifn-gamma in cvvh by measurement in plasma and hemofiltrate of critically ill patients with an acute renal failure. the patients of our study were treated with a continuous veno-venous-hemofiltration (polysulfone-filter, blood flow: - ml/h, filtration rate ml/h). the samples, hemofiltrate and plasma, were taken one hour after the start of treatment. the patients suffered from septic shock ( ), the so called hepatorenal s~aldrome ( ) and a severe pancreatitis ( ). the cytokine concentrations were measured with elisa-method. in contrast to elevated concentrations in plasma for tnf-alpha ( cases), scd ( cases), il- (l case) and il- ( cases), hemofiltrates contained no activities. only il- was removed in significant amounts with even higher levels in hemofiltrate than in plasma. this phenomenon was described so far for tnf-alpha and il- and may be due to the absence of metabolic properties (possibily enz~natic) in hemofiltrate. it can be shown, that tnfalpha, il- , il- could not be eliminated in cvvh with a filtration rate to ml/h. in contrast to findings of other investigators with a higher filtration rate (> ml/h), we found no significant concentrations of tnf-alpha and il in hemofiltrate. we conclude, that for a significant removal of important cytokines higher filtration rates (> ml/h) are necessary. objectives: multiple organ dysfunction syndrome including liver and renal impairment is a fatal complication in patients with the diagnosis of sever sepsis. this study focused to the effects of removing toxic substances from inflamnatory tissue by hemodiafiltration. ~ ethods: eleven patients were admitted to the icu in emergency center and met the criteria of systemic inflammatory response syndrome in association with infection. all patients developed liver and renal dysfunction and were treated by hemodiafiltration with high flux membranes (fb-u:nipro). the hemodiafiltration were performed times using nafamostat mesilate as an anticoagulant in hours with l of substitution fluid (hf-b:fuso). the serdm levels of endotoxin, cytokines, endothelin-i (et-]), human neutrophil elastase ~ -proteinase inhibitor complex (hne-pi), fibronectin (fn), lactate, and amino acids were measured before and after the hemodiafiltration. the hemodiafiltration would be effective to renal dysfunction by reducing endothelin and beneficial to tissue metabolism represented in fisher's ratio, but might be harmful to respiratory function by activating neutropila in patients of severe sepsss. background : intermittent hd may be poorly tolerated in the early phase of arf in hemodynamically unstable patients (pts). this technic may fail to achieve steady state urea low levels in hypercatabolic pts. method : nt = consecutive pts treated with hd; n = consecutive pts treated with cvvhf. hemodynamic unstability is defined by arterial hypotension and requirement of inotropie support despite adequate filling. rate of change in urea (u), ereatinin (cr), k + , ph were computed from a linear regression .analysis of data vs time in each treatment group during the first days of application of the two technics (anova). dally worst values were recorded. results : hd-group : apach% score = _+ ; mean number of organ system failure (osf) = . -+ ; mean blood pressure (mbp) = • mmhg (first day of application of hd). cvvhf-group : apachen score : + ; osf = -+ ; mbp = + mmhg (first day of application of cwhf discussion : during the first days of application of hd/cvvhf, u and cr decreased much more rapidly in the cwhf-group. k* and ph were maintained within normal range in the two groups. initial mbp which was much lower in the cwhf-group significantly improved during the application of cvvhf while mbp remained unchanged in the hd-group. conclusion : despite higher severity of disease in cvvhf group (apachen score, osf, lower initial mbp), we obtained a better performanco with cvvhf regarding the decrease of u and cr and the improvement of mbp. in relation to the different and continuous renal replacement techniques, the continuous venovenous one is the alternative method to continuous arteriovenous for critical patients with acute renal failure (arf). we present you our experience with cvvh in patients with mof. in our intensive care unit (icu) patients with mof were treated with cvvh in the period between january in to march in . the mean (• age of our patient population was , • years, being % male and % female the whole patient population was with mof iust at the moment the technique was accomplished; % was in mechanical ventilation, % needed vasopressor support and % required both of them (mechanical ventilation and vasopressor support) apache ii score mean of the patient population was , ~: , (range - ) and ati of them were with arf oligoanudc. technique: cvvh was accomplished using a single-d~al iumen catheter, ptaced in either a temoral or subclavian vein by the stand ard seld{nger technique. pol{sultone hemofitiers were also used, and the extracerporeal circuit used standard arterial-venous blcod tubing. blood flow and hence oltrafiltration pressure, within the circuit was generated by a roller blood pump. the modulus has a roller pump, a pressure transducer connected in an arterious and venous line, such as an air-transducer which is adapted to a drip-chamber in the return way. the replacement used was a peritoneal dialysis solution. medicine , st. george's hospital medical school, london. england. hepatic sinusoidal endothelium shows a major inflammatory response in porcine sepsis that can be attenuated by the administration of dopexamine hydrochloride. dopexamine is a beta and dopaminergic receptor agonist. the specific beta adrenoceptor antagonist ici has been shown to reduce the protective effects of dopexamine. we investigated the effect of this antagonist on hepatic ultrastructure in porcine sepsis. six pigs ( - kg) divided into groups were anaesthetised and intubated. cardiac output and portal blood flow were measured using standard techniques. the groups were; placebo, (peritonitis induced); blocker, (peritonitis induced and pg/kg ici bolus infused then given hourly). caecal content was aspirated and peritonitis induced. colloid was infused to maintain pawp at - mm hg for eight hours the animals culled, hepatic tissue removed and prepared for electron microscopy. in the placebo group hepatic endothelium was swollen and the sinusoids occluded by wbc. but in the ici blocker group, much of the sinusoidal endothelium was absent and there where large extra sinusoidal spaces among the hepatocytes. an assessment of the two groups showed worse hepatic architecture in the blocker group. the b antagonist blocked any protective effect of endogenous beta adrenoceptor agonist (adrenaline) on hepatic endothelium in porcine sepsis. george's hospital medical school, london. england. dopexamine hydr chloride, a beta and dopaminergic receptor agonist reduces hepatic damage in porcine sepsis. we tested dopexamine's effect on cerebral oedema. the beta adrenoceptor antagonist ici was infused to block any protective effect of dopexamine. nine anaesthetised pigs ( - kg) were randomised into groups; placebo, (peritonitis induced); dopexamine, (peritonitis induced and ~tg/kgdar of dopexamine infused); blocker, (as in dopexamine group but in addition pg/kg ici bolus given then infused at that rate hourly). caecal peritoneum was induced and colloid infused to maintain pawp at - mmhg for eight hours when the animals were culled, cerebral tissue removed, prepared for electron microscopy and digitisation. digitisation of the area of oedema surrounding the blood vessel and expressed as a percentage of the micrograph. . _+ . , dopexamine . + . ", blocker . + . . data expressed as mean + sd. significance p< . . * dopexamine compared to placebo and blocker. in the dopexamine group the area of tissue oedema was significantly lower than either the placebo or blocker groups. there were no significant differences between the placebo or blocker groups. the antagonist completely blocked the protective effect of the drug on cerebral oedema in porcine sepsis. beta adrenoceptor stimulation is protective of cerebral oedema in porcine sepsis. objectives: the hemodynamie~ of hepatic circulation during multiple organ failure (mof) have not been suffleienly studied. we investigated liver hemodynamics in two subgroups of patients with mof, those with either liver or lungs as the main organ of involvement. methods: three groups of patients were created: i) mof-hepatic involvement (mof-hi) ( patients) with bilirubin > . mg/dl and lung injury score < . , it) mof-ards ( patients) with respective values < . and > , iii) patients with head injury with respective values < and < , served as group control. all patients were in haemodynamieally stable state with an oxygen delivery index > ml/min/m prior to measurements. two swan-ganz catheters 'were inserted, one in the hepatic veins and one in pulmonary artery and the following measurements were determined: the hepatic vein free pressure (hvfp), the hepatic vein wedge pressure (hvwp), cvp, paop and co. the gradient of hvwp-hvfp represents liver perfusion pressures. by injecting contrast media at dose of iml/lokg with the balloon inflated to achieve sinusoidai image, the hepatic blood flow (hbf) was concluded by the time in seconds of media removal after balloon deflation. results: the co, cwp and cvp were comparable to all three groups. namely, for mof-hi, mof-ards and control groups the mean (+sd) value of co was . _+ . vs . _+ . (ns) and . _+ . respectively, of the paop was . +_ . vs +: (ns) and . + . respectively and of the cvp was .+. . vs . + . (ns) and . respectively. in contrast the two mof groups were different after the cut-offinclusion criteria ie the mean (+sd) value for bilirubin was . + . vs . + . ( < . ) and . _+ . respectively and lung injury score was . objectives: oxygen delivery (do ) and oxygen consumption (vo ) are increasingly monitored parameters in the icu. there still remain controversies about an oxygen supply dependency in critical illness particularly with respect to vo determination by either indirect calorimetry (vo m) or tick calculation (vo c). the purpose of this study was to investigate the changes in vo m and vo c following do increase. methods: the relatives of critically ill patients (mean age years, mean apache ii , mean mof-score ) gave their written informed consent to participate in this institutionally approved, prospective study. do was increased by fluid loading (hydroxyethylstarch %: mean volmne ml, mean duration of infusion min) and catecholamine support (dobutamine: mean dose , ~g/kg/min). changes in vo m and v c were recorded sinmltaneously before, during and following interventions. calorimetry was obtained with the metabolic monitor integrated in the ventilator (puritan bennett, carlsbad, ca adaptive endocrine response of organism to septic shock consisting in activation of the production of adrenal hormons, renin -angiotensin -aldosterone system (raas) and other hormonal systems has an influence over microvascular changes in these states and for development of multiple organ failure (mof). in patients with peritonitis of different origins ( nonsurvivors and survivors) were followed the changes in cortisol level and raas by radioimmunological methods and many variables for evaluation of respiratory, renal, hepatic function, coagulation etc. as a signs of mof. it was observed significant increase of the level of cortisol ( +_ , nmol/ i), aldosterone ( , • , nmol/i). by factorial statistical analysis we found significantly high correlations between hormonal changes and respiratory function (for example r=- , , p < , between cortisol and pao ; r = , , p < , between cortisol and d (a-v) ; olso renin -cao r=- , , p < , , renin d ~,vl o r = , , p < , ). such significant correlations was found and for raas with respiratory, renal function, byproducts of arachidonic acid thromboxan b and p fla, soluble fibrine degradation products etc. these correlations between the degree of endocrine changes and multiple organ failure in patients with septic shock produced by peritonitis suggest that their effects upon peripheral vascular resistance and constriction of the splanchnic, splenic, renal and other organ vasculatures are not always with physiologic expediency and there are perhaps the possibilities of therapeutic influence. intredu~on : dopexamlne has previously been shown to control hyperkalaemia ia patients with acdto renal failure (arf), however effects on the subsequent course of art are undomunente~ ob_iectlv~ : to evaluate clinical progress in patients with acute renal failure (arf) in an intensive care unit (icu) with regard to biochemical control, need for -and time to -dialysis, and outcome in patients receiving dopexamine. m~ods : consecutive patients meeting standard criteria for diagnosis of arf were included in the study. full cardiovas~dar, biechemical and intervention/outcome details were recorded. dopex.~min~ was infilsed at a dose of pg/kg/min in conjunction with a regimen of inotropir support and blood volume optimization. resn]~ : following the intzoduetion of dopc',~mine ilrinr vohlmes increased slightly over the next hrs fzom + ml/ hrs to + ml/ hrs (ns). data expres,uxl as mean + sem. three patients ( %) became polyuric with urine output > ml/hr within days and did not need dialysis. in the remaining patients the time to dialysis (to correct acid-base deficits or volume overload) was . + . days. serum potassium levels were well controlled. day or immediate pre-dialysis levels were . + . mmol/l compared with pre-lreatment . + . mmol/l overall mortality in this series was / ( %). duration of acute dialysis in survivors with renal recovery was . +_ . days. patients ( %) progressed into chronic renal failure and needed continuing renal replacement therapy. no adverse cardiovascular altects were seen at this low dopoxami~ dose although its competitive inhibition to adrenergic reuptake mechanisms meant that doses of pressor agents could often be reduced. : dopcx:~minr nsed in conjunction with inotropic support and blood volume oplimitntion, can safely postpone, or even avoid, the necessity for acute haemodialysis in icu patients. no evidence of tachyphylaxis to the effect on serum potassium levels was seen over the duration of the study. hen'era m., suarez g., dagn d., varela a., ramos j., garoia jm, aragdm c, jurado l, medina a. icu. hospital regional. malaga. spain. objective: to evaluate the haemodinamic tolerance to the veno-venous continuous hemefiltration (vvchf) system in patients with systemic inflammatory response sindrome (sirs), and the possible beneficial effect of this technique on the haemodinamics in these patients. material: patient admitted to the icu, with diagnosis of sirs and monitored with a pulmonary artery catheter at the beginning of wchf. we performed a complete haemodinamic study to all these patients (cardiac output, vascular resistanoss, ph and co in arterial and mixed venous blood samples, saturation of pulmonary mixed venous blood, do and vo calculations and temperature) and determined the respiratory mechanics (compliance and pao /fie relatinship) before starting the procedure, after minutes operating with the ultraflltrate branch closed (without filtered fluid production), afler and minutes of zero fluid balance bemofiltration and after minutes of filtration with negative balanos adjusted to the patients conditions. for the statistical analisis we have performed the anova test over the mentioned variables. results: we have not detected statisticaly significant differences of the analyzed variables before the beginning after operating the pun'@ for minutes without filtered fluid production and after minutes of zero fluid balance hf. only temperature shows a meaningful decrease in time. objectives: among many organs, playing the important role in pathogenesis of multiple organ failure, the particular place is taken by the intestine. ~ethods: the study was carried out in dogs !~n"~h pi was modelled by severe operative trauma (ot). the dcm was estimated by the indices values of work time (wt), contraction frequency (cf), mean amplitude of contractions (~ac) and motility index (mi) measured by method of tensography. "sl", created on the basis of sorbit and sodium lactate ( mosm/l), was injected in the dose of .o ml/ kg into v. cephalica antebrachii after hrs of ot. the results of the present study are the evidence of "sl" stimulative action on dcm and are experimental ground for "sl" using in complex therapy of pi in clinic. with splanchnic venous blood pc p.f. laterre p. goffette, j.p. fauville, a. poncelet, p. loneux, m.s. reynaert. intensive care unit, st. luc univ. hospital, brussels, belgium. determination of gastric intramucosal ph (phi) by gastric tonometry using the henderson-hasselback equation is expected to allow the detection of splanchnic ischemia in critically ill patients. because of bicarbonate concentration and acidbase balance influences on the calculation of phi, it has been proposed to use arterio-gastric pco,_ gradient [p(gast-a)co,] to assess splanchnic perfusion. htpothesis : pcoz in the gastric mucosa is in equilibrium with intraluminal co z and with co, in the blood leaving the stomach (mesenteric and portal blood). objective: mesure pco; and ph in portal vein blood and compare its value with pco and phi obtained simultaneously by gastric tonometry. material and method : in a patient ( y.), a fiberoptic catheter (baxter r) was positionned in the portal vein after transhepatic stent shunt repermeabilisation. hemodynamic parameters, do, (vigilance n baxter), gastric co and phi (tonometrics baxter) and portal blood gas were determined at regular intervals. results : sets of data were obtained and are expressed in mean + sd. gastric pco z was , + compared to , + . mmhg for portal pco . phi was . +._ , vs . +._o, for portal ph. no correlation was found for these parameters. p (gast-a) c was . + mm hg vs + . mm hg for p (portal-a) coz (no correlation). there was a good correlation between do e and p (portal-a) co z (r = , ) [figure] but no correlation with p (gast-a) c . obiectives: desaturation is a common finding during haemodialysis (hd). pulmonary oedema might be one cause for impaired gas exchange ( ). the aim of this study was to quantitate the amount of extravascular lung water (evlw) and gasexchange in chronic renal failure patients during and after a regular hemodialysis session. methods: chronic renal failure patients without symptoms or diagnosis of cardiac or respiratory disease were studied at the start (i), at the end (ii) and two hours after (iii) a regular bicarbonate hemodialysis session. the double-indicator dilution method, with indocyanine green and the stable isotope h as tracers, was used to measure evlw ( ). arterial bloodgases and endtidal co were registered. evlw data was compared to a group of renal healthy patients ( ). dcp n evlw, ml -pao , mmhg h~o +, nmol/l control group - -- l _+ "* -+ _+ crfgroup ii -+ ~ +- ns -+ "(" iii +- t _+ ns -+ t ** p < . dcp i from dcp , t p < . dcp li or i from dcp i, :~ p < . dcp ii from dcp i the evlw at the start of dialysis was larger in the crf group than in the control group. the evlw decreased significantly to a level not different from the control group in response to the reduction in weight after hd. pao~ was normal at the start of hd and showed a nun-signficant reduction after hd. paco ( . + . kpa) and etco ( . + . kpa) were unchanged while h o+ decreased and bicarbonate increased significantly. conclusions: the elevated level of evlw at the start of hd did not impair gasexchange. the decrease in evlw did not inhibit the decrease in pao . the reduction in h + followed by a fall in alveolar vantilation is the most plausible cause for the decrease in pao in bicarbonate dialysis. . prezant lung ; : - . . wallin j appl physio ; : - . a. dona~ d. battis& l col~ r danieli, d. achill~ l viglienz;~ c. giov-anaini, p. piaropao~ oblectives: to verify if intraoperative modifications of mtramucosal gastric ph (phi) below the normal lowest value . , can be predictive for important complications, as perforation, sepsis, mof or death. methocls: we have considered patients who andenvent major abdominal surgery. all patients received the same drugs in pre-anaesthasia, the same type of anaesthesia (balanced anaesthesia) and the same treatment with h -bloekers. after the induction of anaesthesia a gastric tonometer was positioned and a catheter was positioned in the radial artery. during the operation, every minutes, the following parameters were measured at the same time: phi, arterial ph (pha), blood lactate, mean arterial pressure. in follow up we considered death and complications happened during the hospital stay, in relation to intraoperative phi falls below . . results: among the patients, had a drop of phi below . during surgery. in three of them this fall was a single episode and happened within the first hour after the begiluting of the operation. after that phi rose to nomml values until the end of the operation these patients had a normal post-operative period, without complications, the other patients had a fall of phi during the demolitive manoeuvres. two paticots of them died. the first had a lowest phi= . and the second . . the first one ~zs operated on for hepatic istiecitoma, suffered a complete del'dseenco of the surgical wound on the th day after operation and died on the th day, the second one was operated on for a hepatic carcinoma had an intraoperative haemorrhage and died ~vo hours after the end of the operation. the other patients with a fall of phi had a lowest phi= . . . . . . . respectively.the first patient,operated onfor sigmoid carcinoma, underwent on a second operation for a transmural necrosis of the colic segment on the th day; the second one, operated for carcinoma of the right colon, had a cardiac ischelnia on the th pest-operative day and a dehiscence of the surgical wound on the th day: the third one, operated on for a sigmoid carcinoma, had melena in h post~ operative da b, and finally the fonrth patient, operated on for carcinoma of the tight colon, suffered a fistula of the surgical enteral anastomosis.all these patients were discharged alive from the hospital. the other patients, who had not reductions of phi ditring the operation, had a normal pest-operative period, without complications. conclusion: phi was able to predict the arising of some complications, probably due to intraoperative ischemic events. we can say that gastric tenometry, for its low invasivi.ty, can be included among the intraoperative monitoring in patients that tmdenvent on major abdominal surgery. (ttd),t"ea~rrerj.~ of hours duraticn. all l:atients nm.'-~ms_(~lly va~ ated in eantrol wcde ard_ la':'ad a a,~m--ganz catheter, with optic fibers for contirums mmsuremmt of svo mic studies were performed, c~e before the hegir~ of hd, c~e rain after the ~, ~ne at the middle, ~ne rain before lhe erd ard one rain after the erd of hd. paired t test ~as used far slatistical eval~ti~n. results: daring i~d there was a significant'reductton (p<o.~) of: c~tr~ venc~s eres~.re ( ve)emm to . ~ ~, ) ~arn'~w capil~ ~f~e pressure (i<~p) fr~n to ~mg hg, ) i~ from to . mmg hg. ~here was also a less pmnameed bat also-slatistics/ly significant r~ucticn (p<o. ) of: i) s~o~ from to patients undergoing surgical reconstruction of the aorta due to anenrysms of its abdominal part may develop transient and sometimes sustained episodes of dysoxia despite the conventional appeoreneas of being adequately resuscitated. indirect masurement of gastric mussel ph (phi) is being widely evaluated as a minimally invasive and sensitive means of assessing the adequaey of tissue oxygenation in these circumstances. the duration end degree of gastric intramucosal acidosis are related to the risk developing injured gastrointestinal tract end its putative consequences, i.e. translceation, cytokine release, organ dysfunction end failure, sepsis end death. measurement of phi is obtained indirectly by measuring pc in the lumen of the stomach with a silicone balloon tonometer (tonometrics, inc., worcester, ma, usa) and the bicarbonate concentration in arlz,,rial blood, end substituting these two values in the henderson-hasselbalch equation. objectives: to evaluate whether perioperative phi changes are predictive of complications end outcome end how they compare to standard haemodyuamic and oxygen trensport parameters. methods: patients ( males and female) urtderwent surgical replacement of abdominal aortic anonrysm with the aortic simple or bifurcated grail. patients were operated on eleetively, had an emergency surgery for raptured enentysm. haemodynamic, arterial ph and bicarbonate concentration measurements were taken before and after induction of anaesthesia, after cross-clamping and declamping of the aorta end at admission to itu. phi calculations ware done at the sime time except before induction, as tonometers were inserted after patient had been asleep. we used pulmonary utilizing a computer billing survey as well as hospital service transfer data from a month period ( / - / ), all obstetric patients that were transferred to the med/surg icu were identified, as well as their diagnoses and procedures. twenty-eight obstetric patients were transferred to the med/surg icu, compared to , deliveries occurring during that time period for a . % rate. the following procedural indications for icu transfer occured: insertions of endotracheal tubes, arterial catheterizations, temporary tracheostumy, and venous catheter. the following medical diagnoses were found: hypertensive/eclamptic episodes, hypotensive episodes, pulmonary embolism, mitral stenosis, and coagulation deficiency. there were four episodes of respiratory failure ( %). the historical rates of respiratory failure from the medical literature seen at a university hospital ore higher than those at our community hospital despite comparable icu transfer rates for critically ill ob patients. objectives: to evaluate the usefulness of several isss used in order to predict risk of death (rd). design: prospective data collection for months in a multidisciplinary -bed icu. methods: data from consecutive patients admitted to the icu from / / to / / were studied. all the necessary informations were stored in a computer using special software for every day computation of three isss (saps, saps ii, apache ii) and of the rd predicted by saps ii, mpm , mpm and odin. data from days of hospitalisation were used for comparative evaluation of isss and rd, while sensitivity and specificity in death prediction (cut off point of rd = %) were evaluated from data collected during the day of admission (saps ii, rpm , odin) or after hrs (mpm ). agreement between rd predictions was evaluated by bland and altman analysis. results:our results were the following: objectives: a) to create and validate software specially designed for the collection of demographic data and estimation of illness severity and predicted rd and b) to provide data necessary for the evaluation of the effectiveness and the efficiency of our icu. design: prospective data collection in a multidisciplinary -bed icu. methods: prospective data on specific physiological variables, selected demographic characteristics, comorbidity and the reason for icu admission were recorded every day for consecutive patients admitted to the icu from / / to / / . data were entered into a portable computer using specially designed software allowing the calculation of usual illness severity scoring systems (isss) and the corresponding predicted rd. results: we studied men and women, with a mean age of years. we conclude that, although observed mortality was higher than predicted rd, this difference was not statistically significant. the fact that the sd of predicted rd was too large, limits the usefulness of isss predictions for a comparative evaluation of different icus. objectives :the importance of objective evaluation of patients prognosis at their admission to an emergency department is clear. the aim of this study was to appreciate the prognosis of patients with the simplified acute physiology score ii (saps ii), and correlate this score to the prognosis and orientations of patients. methods : the score which is a reduced form of saps ii was calculated from clinical variables and laboratory items for patients. sensibili}y (se), specificity (sp) and accuracy (ac) were calculated to evaluate the performances of saps i . thresholds were calculated with the youden's test (se+sp- ). results : patients were admitted in the intensive care unit (icu)and patients in medical units; patients died. the saps ii was higher in patients which died than the survivors ( , + , vs. , + , , p< , ; respectively), the best threshold was , se was de %, sp was %, the ac was / . thus for patients admitted in icu than in medical unit ( , : : , vs. , + , , p< , ; respectively); the best threshold was , se was %, the sp was %, the ac was %. conclusions : these preliminary results suggest that saps ii can be used to determine the short term prognosis and the destination of patients seen in an emergency department. design: data was collected on all admissions over a six month period. all patients had a screening hiv elisa test. confirmatory ifa tests, western blot and flow cytometry were performed on hiv positive patients. the institutional ethics committee considered the major clinical impact of the study sufficient cause to waive the patient's right to informed consent, icu staff and patients were blinded to hiv results. following discharge patients were given the option of being advised of their hiv status. setting: the study was conducted in a bedded surgical icu at a tertiary care teaching hospital. patients, participants: all patients admitted during the period in question were included. interventions: "all patients were treated according to standard icu protocols. there were no interventions. results: most patients were admitted following trauma. there were no patients with aids, hiv positive and hiv negative patients. with respect to the latter two groups, the mean age and sex distribution was similar, there was a significant difference in organ failure ( % versus %, p < . ) and septic shock ( % versus %, p , : ) but no difference in icu/hosp[tal mortality or duration of icu/hospital stay. flow cytometry changes in hiv positive patients were consistent with the quiescent phase of hiv infection. conclusion: while morbidity is higher in hiv positive patients, there is no difference in mortality. hiv status should, therefore, not be an exclusion criterion for icu admission in this patient population. , n= ) and january-march (period , n= ) were studied. interventions: a resident micu team led by a trained intensivist took over the medical care from the primary physicians when the patients were admitted to the micu. the intensivist also vetted micu admissions and decided on micu discharge. in addition, there was a resident respiratory therapist to attend to vendlatory care during office hours. after office hours, the care of the micu was delegated to the on-call team on a rotational basis among the medical departments. results: the patients in the two groups were similar with respect to age, sex, race, source of admission and apache scores. the icu and hospital mortalities decreased from . % to . % (p=ns) and . % and . % (p=ns) respectively in period . the mean icu and hospital stay was also decreased from . __+ . to . + . days (p=ns) and . __+ to . • . days (p=ns) respectively. the improved micu length of stay for survivors in period was statistically significant ( . • . days vs . • . days = . ). there was no significant differences in the vse of peritoneal dialysis ( . % vs . %) and mechanical ventilation ( . % vs . %). however, utilisation of intra-arterial lines and pulmonary artery catheters increased from % in both to . % and . % respectively in period . conclusion: the duration of critical illness was reduced in period . hence, we believe that the closed |cu which was staffed by an intensivist and had the services of a respiratory therapist was beneficial for the care of the critically ill. the intensivist, was also more likely to utilise invasive monitoring. in the absence of liver transplantation, intensive care for patients with acute hepatic decompensation arising from alcoholic liver disease (ald) is indicated only for those who are likely to benefit from conventional means of organ support. we have attempted to elucidate potential risk factors and the efficacy of organ support in relation both to hospital outcome and icu costs so as to allow the earlier identification of relatively futile intensive care in this group of patients. methods: over a period of one year, ald patients ( males; females; median age years, median apache ii score ; hospital mortality %)with severe complications ( [ %] with bleeding oesophageal varices, [ %] with hepatorenel failure, [ %] with respiratory failure, [ %] with septic shock, and [ %] others) were studied in our liver icu. organ system failure, daily therapeutic interventions and icu costs were assessed using a patient management system (riyadh intensive care program). results: whilst survivors had a significantly lower admission apache ii score compared with non survivors (medians and , p< . ), or more organ systems in failure in the first hours of icu admission was associated with a % ( ) mortality. mortality was also related to child's grading and the numbers of organs supported. of the patients who received more than one form of organ support only one survived. organs supported mortality a (n= ) % none / ; % b (n= ) . % one / ; % c (n= ) . % two or more / ; % the icu costs for the patients were only s but s ( %, patient days) was utilised by the patients who died, giving an effective cost per survivor (ecps) of s . although the cost of treating the patients with or more organ systems in failure on the day of admission was s ( % of the budget) the ecps was s . conclusion patients with ald who have or more organ systems in failure early in their icu course have a poor prognosis and in the absence of liver transplantation, traditional strategies of organ support are ineffective. this begs the question whether such costly care is appropriate as although the ecps in this sub group is comparable with other patient groups with multiple organ failure, their outcome is considerably worse. objectives: to evaluate the economic impact to the healthcare sector of using dopexamine hydrochloride infusions to deliberately increase perioperative oxygen delivery in high-risk patients. methods: effectiveness data were obtained from a controlled clinical trial in which surgical patients were randomly assigned to either a control group (n = to receive best standard optimal fluid resuscitation perioperatively, or a protocol group (n = ) to receive, in addition, an infusion of dopexamine hydrochloride to increase the perioperative oxygen delivery index to greater than ml/min per square metre. resources consumed by patients during treatment were recorded prospectively and costs of resources at / prices were obtained retrospectively. cost-effectiveness ratios were estimated by dividing the total cost for each treatment group by the total number of patients in each group and by the clinical outcome of mortality days postoperatively. results: in the protocol group, there was a % reduction in mortality days postoperatively (p = . ), a significant reduction in the number of complications (p = . ) and a reduction in length of stay in the icu and surgical ward. the average cost per protocol patient to achieve a . % survival rate days postoperatively was s , , resulting in an average cost of s , per surviving protocol patient. the average cost of a control patient was s , to achieve a . % survival rate days postoperatively, resulting in an average cost of s , per surviving control patient. the use of dopexamine to deliberately increase oxygen delivery perioperatively generated a cost saving to the nhs of s , per patient together with a % reduction in mortality at days postoperatively. hence, the cost per surviving protocol patient was s . less than the cost of a surviving control patient. conclusion: the additional cost of dopexamine in protocol patients was offset by a lower incidence of complications and a shorter stay in the icu and on the surgical ward. hence, increasing oxygen delivery perioperatively in high-risk surgical patients saves both money and lives. objective: although king's college criteria are widely used, indication and timing for liver transplantation in acute liver failure is still far from certain. long-latency sensory evoked potentials -a proven measure of metabolic brain dysfunction (grimm et al. lancet ; : - ; madl et al. lancet ; : - ) -are markedly affected in patients with acute liver failure. serial sensory evoked potential recording should provide very useful information for the management of patients with acute liver failure. methods: recordings of standard bilateral sensory evoked potentials were performed in patients with acute liver failure. findings were focused on cortical n peak -a stable negative deflection occuring • ms after median nerve stimulation in healthy subjects, which can be recorded by skull electrodes over the sensory cortex. results: nine patients recovered spontaneously, patients were referred to emergency liver transplantation, and patients died. in all patients who recovered spontaneously, n peak was detectable between and ms. all patients who were referred to liver transplantation and of patients who died, developed a loss of a prior detectable n peak during the course of acute liver failure. objective: to determine high risk arid low risk patient groups in a medical intensive care unit regarding short term and long term outcome. methods: data on all admissions of the year were collected prospectively. according to their mode of admission patients were classified as admissions by the physician staffed ambulance service (as), admissions through the emergency department (ed)i referrals from non-intensive care wards (ni), and secondary referrals from other hospitals (oth). outcome was assessed in terms of in-unit mortality, in-hospital mortality, and long time mortality. patient groups were compared using the \ -test. life table analysis were per{ormed by kaplan-meier method comparing patient groups by log-rank test. the software spss for windows . . was used for statistical calculations. results: in-unit mortality: / patients ( . %) --oth . % > as . %> ni . % > ed . %; p = . . in-hospital mortality: / patients ( . %) --oth . % > ni . % > as . % > ed . %; p = , . mean survival time in days after discharge: as < ni < oth < ed ; p = . . conclusions: despite an excess in-unit mortality of secondary referrals from other hospitals the iongtime course of this special patient group is not different to others. solsuam, j, marrugat*, g, mirs, j, nolla, a, vazqu~z-sanchez, l alvamz, ~ioio s xndioina i~siw. ir~itate l(~icipal da l~sti~isn l~di~*, ~ospits dal objective: to study the influence of modifiable variables (complications derived from therapeutic activities) on the prognosis of ~atients admitted to the icu indapemently on thn severity of illnsss. patients am methods: between january asd ]lay data from , patients over years of aqe who retained in the icu for mare than hours ~ere pr~pectively regiatered. a cohort st~ly with follo~-~ nf patients durin~ ~eir stey in the hospital was deni~.el in all patients, reasons for a~issien, principal diagnosis sad severity of illn~s moasared by the saps scare vare recorded. fastens affecting patients' outcome that my be proventsd or modified included technical :omplisafioss, heapital-acqnired infections and in~pro~riate therapeutic decisions. a logistic regression model was used to assess the relative risk (l~} for in-heapital mortality adjusted for each variable. results: ic~ mortality ~s . % and in-hospitul mortality . %. patients who died showed a higher spas score then survivors ( , ~ i ,i). after adjusting hy severity of illness, co~;licetices that statistically increased the risk of in-hospital death were septic shock secomery to hoapitul-acqdired infection ( ~ . ; % el, . to . ), pmo~othor~x related to mocasnical ventilation (@ . ; % cl, . to . ) and delay in the insertion of a fln~-quidod catheter (ii~ . ; % ic, i.i to . ). col~lusien: registration of complicaticas derived from therapeutic activities is a valuable tool far quality central in the icu. g, ~i~ , j.l mle~ma, j, ~amqat*, j..~lla, a, vazquez-saltemz, f, alvamz , servioia de nndicina l~siu. i~stitutu ~icipal de ln~sti~acidn ~ i:a*, hospital dsl objective: to dstsr~ine the incidence of self-extebatien and its effect on ~ortality. patients and ]~etheds: betveen january and april , all i~tiente in whom selfextubatien w~s registered were inclnded in a prospective study. patients were divided into @nee who needed r~intabatinn within hoers and those who did not. in all patients, dsmoqraphie and ciinical data were recorded as well as icii mortality, in-hoapital mrtality and severity of illness according to saps score. eta were analyzed usi~ the cbj-square test for cathgorical verinbls, the analysis of varianc~ (anva) for aontinuc~ ~ria~les and a leqi tic regression anal~is to estimate the relative risk (iiii) for mortality as result of celt-nxtt~ation after adjusting for severity of illness. results: a total of intnmtsd patients amre stndied. self-extu~atien occurred in ( . %) patients and . % required reintuhot~pn. when a co,arise was made between patients who did not required reint@atinn and patien~.s who did, statistically significant differences in eqe ( . v_s . years, p = .~ ), ~verity of illness ( . ~ . spas score, p = . ), dia~isstia category ( s. % v_s . % of patients with res~iratury conditiono, p = , } and mean length of stay ( , ~ , days~ p = . ) were fo~m, a~ter ad~sti~ for severity, patients with self-ext@atinn who did not reqnired reintalatien showed a . iir for mortality ( % ci, .i to . ) as co~arod with patients in when self-ext@ation did mot occur. conclnsien: self-~extamtice that does not require reint@ation is associated with a isamr in-hospital natality probably dt~ to a prolonged period of weaming. patients' admissions to ices am often delayed doe to the shortage of beds available. @ile amaltieq icu admission, these patients are treated in observation nits of @e emergency services which bare ,either tile structure nor the trained ~reomenl that are available in leb~. objective: to daterdno the effect on the patient's proqusis of a delay in tile admission to the icu when criteria for icij admission are fulfilled. ~terials and methods: between jme am l?ece~ber all patients who fulfilled criteria to be almittod to the ic who for waste~r reason retained in tile observation unit for more than hours were included in a prospective stedy. in all patients, des~raphic end clinical dabs amre recorded as well as severity of illness aencrdi~j to saps score. a cesucontrol dasi~ was eend with a total ss~ln of , patients who suffered no delay is admission to icii over a period of years. data wen analyzed using the chl.-squ~re test (to aeons the association hetwenn in-patienty mortality end categorical vari~lns) and a maltipln logistic reqression model to sstimta odds ratio for) for in-hospital mortality as result of delay in icy admission as compared with early ad~issi| after adjusting for severity of illness end use of assisted mchenical ventilation. ~ &ults: a total of patients remained in the observation nit for more than hours with a del w in igd admission of . _+ . hoers. assisted mechanical ventilation was requited in % of patients and only monitericatien in %. itsse patients were cspared with ntients from the tet~l sample ratchod by age, sp~ score and rennoss of admission. in-hospital mortality for cases warn % as compared with . % for controls (p = s). after adjamtilg fen spas, age and mobamioal ventihtien, no statistically significant differences between both ~renpa were foam, altho~b there was a tendency towards a higher mortality amen@ patients with delay in icu admission (or = . ; % ci, , to , ). conclnnien: ~se findings suggest that prognosis of critically-ill patients is no worse as a result of admission to the loll being deln~d for borers. all data appropriate for the calculation of the apache ii score (aps) together wi'th other specific cardiac details relevant to these .patients were collected daily, verified and enter~ into a computer database. results: patients were studied. six patients died and five of thee underwent cardiac surgery. the mean aps was for survivors and t for non-survivors (p < . ). the mortality ratio was . and the major markers of mortality were apache ![ score, presence of chronic ill health, mean duration of ventiiation, mean length of icu stay and need for emergen~ surgery. sixteen percent ( ) of icu bed days were occupied by % of patients (non-sarvivors) which resulted in cancellation of cardiac sot#cat sessions in momhs. conclusions: this study concludes that apache t could be used as an audit tool in a cardiac surgical icu and demonstrates the severe compromis~don of cardiac surgical throughput by a few non-survivors, organ to determine the number of organ failure free days (offd) in a cohort of survivors and non-survivors with sepsis syndrome followed over a day period. ) to determine sample size requirements for clinical trials utilizing a increase in the number of organ failure free days as the primary outcome as opposed to mortality. methods: beginning december through to april , patients who met inclusion criteria of the "cardiopulmonary effects of ibuprofen in sepsis syndrome" and who did not have hiv/aids. brain death or moribund state were prospectively identified. presence or absence of failure of organ systems (pulmonary, cvs, renal, hepatic, gi, hematologic, & cns) was recorded daily until death or until days. a score of one was assigned to each organ system free of organ failure in patients still alive, ie, maximum daily off score= , maximum day off scorn= , sample size estimations were performed for variable detectable differences in off scores (delta). alpha was set at . (two-sided), with n/group = [(z a +z b ) o conclusions: a clinically relevant increase in off days may be detected with as small a sample size as to patients per group. this represents a significantly smaller sample size than needed to detect a change in mortality from % to % ( % relative risk reduction) where the n/group= . scoring patients in this manner prevents a lethal inte~entien from providing an improved organ failure score. in addition, an intervention that prolongs survival must also provide greater organ failure free days in order to be counted by this scoring method. survival as an outcome provides no information about the quality of that survival. off days provides a measurement of burden of illness. interventions which lessens this burden may be just as valuable as those that decrease mortality by providing a measure of the quality of survival and by decreasing costs of care. they may also prove to be an accurate surrogate marker of mortality. the advantage of this approach is that the event rote is much higher and sample size requirements are subsequently smaller. this would mean that clinical trials can be completed faster and at lower cost. outcomes such as mortality could then be assessed at a later date utilizing recta-analysis. we suggest that the use of off days is a valid outcome measure that may be utilized in clihieal trials of sepsis syndrome. the icu is perceived by many as being a stressful environment for both patients and staff. stress has been defined in three ways: a stimulus producing a particular response; the physiological and psychological response to a stimulus; an interaction butwom an individual and their environment. stress is currently thought to be a dynamic system of stimulus and. response which takes into account the individual's perception of the stimulus and their ability to respond effectively. stress may, therefore, be positive and allow personal development but an individual unable to respond effectively to a stimulus will experience negative effects or strain. critical illness is an intense stimulus to which the body needs to respond effectively. physiological responses are vital and most of intensive care involves supporting these. alternatively, blocking them, for instance with atom(date, increases mortality. psyehological responses are also vital but often poorly appreciated because of communication problems. many of the problems patients experience in an icu are evidence of psychological strain. this can be exhibited in various ways, for instance, anxiety, depression, passivity and confusion. dealing with critically ill patients is perceived as stressful. we recently studied occupational stress in our icu. most aspects of intensive care were not generally perceived as stressful indicating a self-selectien of icu staff. the most stressful aspects of icu work for nursing staff were the structure of the organization and career opportunities. medical and nursing staff had different stressors and different coping strategies. support for occupational stress, therefore, should focus on the individual and concentrate on information and communication. atmosphere, and especially at intensive care units, we face up to daily decision making. in most cases these are taken on the basis of personal opinion and the processing of a very limited amount of information. rising need to optimize the results of medical attendance becomes necessary to set structured system of d@cision making in which ethical basis have a sp@dial significance in view of next considerations: -we live into a pluralist society in which the importance of values is different. -most persons consider health as the first value only in the event of illness. -medical resources available are limited, whereas medical, attendance demand from population increases in a way many people consider it unlimited. in consequence, it becomes necessary to set up priorities in patients treatment. ehtical basis that rule decision making are essentially these ones: i. beneficence: to provide the patient that is being treated the highest profit. . non maleficence: it is our first duty to avoid hurting or damaging the patient."primum non nocere" . autonomy: in every particular medical attendance, the patient has ability to decide by himself. . justice: as equity: to provide the same treatment for those who have the same pathology, ignoring another factors such as age, sex or race. severe application of these principles can cause difficulty, which resolution requires a systematization of decision making. ( - ) . the lenght of stay between survivors and non survivors didn "t show statistical significance (p = . ). the mean aiii score when considering all admissions was , ( - ) . the initial score between survivors and non survivors showed ststistical difference ( . vs . ) respectively (p < . ). univariate logistic regresion analysis demostrated a % increment in death probability for every points augmentation in the aiii score with a sensitlbity of . % and specificity of . %, the roc curve showed that the best cut off point for death prediction was points with a sensitivity of . % and specificity of . %. if a patient is classified as high risk (> ) the bayesian analysis showed a . probability of death and for one class(fed as low risk (< ) a death probability < %. conclusions: the first day aiii score in this population showed to be a good discriminator between survivors and non survivors, and the risk of death augments as the aiii does. in this population an aiii score > points is asociated with a greater risk of death. using the aiii score in conjuntion with the clinical judgement will help clinicians reducing uncertainty in the every day decision making and better predict outcome, the results from this study should been taken with caution because the data were obtained from a small sample. objective: the quality of life has been considered a "uniquely personal perception" resulting from a mixture of health related factors and social circumstances [t. m. gill, jama , : ] . the aim of this study was to evaluate two measures of pqol in intensive care unit (icu) admitted patients. patients and methods: during icu stay and six-months after hospital discharge, co-operative icu admitted patients were directly interviewed about their pqol. we administered ftrstly the uniscale (pqolu) [sage et al crit. care med. , : - ] and then a step verbal scale (pqolv): best, good, fair, poor, worst. of the studied patients, at the first interview, were able to use both scales, but ( . %) understood only the verbal one. at the second interview, patients were not able to answer, used both scales and only pqolv. statistical analysis was performed using wilcoxon signed ranks, spearman rank correlation, student's t and chi square tests. results: of all cardiac surgery pts, pts ( . %) died in icu. they were males ( . %) and females ( . %). their mean age was (+ ) years and mean ef was . (+ . ). nineteen pts ( %) had low (< . ) preoperative ef. mortality was . % in the coronary artery bypass grafting (cabg) group (n= ) and . % in the valve replacement (vr) group (n= ). in the cabg +vr group, mortality was . % (n= ), and . % in the remaining pts (n= ). cardiogenic shock was the sole cause of death in pts ( %), septic shock in pts, whereas sepsis in combination with ards in pts, sepsis and stroke in two pts. in addition, pts died from cerebrovascular accidents, one from ards and one from pulmonary embolism. the pts who died in the icu had a significantly longer bypass and aortic cross clamp time and received more blood transfusions (p< . ) than a matched control group that survived to icu discharge. the duration of mechanical ventilation and length of icu stay were greater in the pts who died in the icu than in the control group. conclusions: . although cardiogenic shock is the main cause of death ( %)in cardiac surgery pts, sepsis and cerebrovascular accident are relatively frequent causes. . patients who died in the icu had longer bypass and aortic cross clamp time and received more transfusions, compared with the control group. . although renal or hepatic failure contributed to death in some pts, they were not the primary cause of death in any patient. objectives: evaluate the acute and follow-up outcome of patients (pts) treated with primary ptca (without prior thrombolysis) in acute myocardial infarction (ami) after and up to hours after onset of typical thoracic pain ("late" primary-ptca). methods and patients characteristics: from / to / consecutive pts with ami were treated by primary ptca in the wuppertal heart center pts ( , %) were admitted to our hospital > hours and < hours after symptom onset with ongoing chest pain and typical ecg-changes.mean age was years ( - ). pts were male, four female. % had an anterior wall myocardial infarction, % suffered an inferior/postero-lateral wall myocardial infarction.two pts were in cardiogenic shock at admission. singlevessel-disease was documented in . %, multi-vessel-disease in . %. average time of onset of pain to recanalisation was min ( - ). angiography revealed timi-flow in . % of the pts, timi-flow i in . %, timi-flow ii in . %. average follow-up (fu) period was months ( - months). timi iii lv-ef ~ -day major late re-late flow p.i.* aeute/fu mortality bleeds infarction mortality . % %/ % . % . % . % % early mortality occured in the two pts, who were in cardiogenic shock at admission no pt required emergency coronary artery bypass grafting.restenosis > % was seen in % of the pts. conclusions: "late" primary ptca achieves a favourable high recanalisation rate of about % (timi ill-flow) in our study group. additionally, there seems to be a trend for lv-ef improvement in follow-up. early high mortality is influenced by the patients admitted in cardiogenic shock. there might be a trend for increased major bleeding complications. objective: to assess the validity of saps ii (new simplified acute physiology score), comparing it with the previous version, (saps), in a sample of patients recruited by giviti, a network of icu's representative of the italian icu system methods: measures of calibration (goodness-of-fit statistics) and discrimination (receiver operating characteristics curve and area under the curve) were adopted in the whole sample and across subgroups differing in relevant prognostic characteristics. of the patients recruited during one month period, a total of patients were included in this study. for the purpose of the comparison of the two scores, patients with less than years, or having cardiac surgery or staying in the icu less than hours were excluded. vital status at icu discharge in the whole sample and at hospital discharge in half cases wher adopted as outcome measure. re$ ~: saps ii fits the data equally well compared to the older version (goodness-of-fit p= . and in the new and old versions, respectively) but its performance is somewhat better in terms of capability to distinguish patients who live from patients who die (areas under the curve . and . , respectively). furthermore, saps ii is better in terms of uniformity of fit across relevant subgroups, although substantial over prediction of mortality was observed in trauma patients and in patients admitted without organ failure to be intensively monitored. saps ii performed very wet] also in the subsample where hospital mortality was the dependent variable.satisfactory measures of calibration (goodness-of-fit p-- . ) and discrimination (receiver operating characteristics area= . ) were observed. c nr saps ii, a multipurpose scoring system developed in an international study, retains its validity in this independent sample of patients recruited in a large network of italian icus. although it has shown a good performance when adopted to predict icu and hospital mortality in the entire sample, further investigations are warranted. the observed over prediction of mortality in a few subgroups indeed call for a through assessment of the impact of confounders and biases on model performance when saps ii is adopted in samples that do not reflect the "average" icu patient. objectives: ) assess the effectiveness in a group of intensive care units by means of a quality performance index (qpi); ) assess the efficiency by means of a resource use index (rui); ) evaluate the performance of individual icus with respect to both indices (clinical and economical) while controlling for severity of illness. critical from ucis in catalonia patients alearic islands have been included in the study. inhospital mortality and weighted hospital lenght-of-stay (los) have been considered the outcome variables. severity of illness has been measured with the mpm ii at admission. in each icu, expected mortality has been obtained adding the probabilities of dying for its patients. expected los has been estimated adjusting a second order polynomial to the severity of illness. performance indices have been obtained by dividing the observed by the expected outcomes. re~ult~: the overall qpi was . and it ranged from . to . in the icus. the overall rui was and it ranged l~ont . to . . there was not a trade-offpattern between clinical performance and resource use. objectives: teaching hospitals often provide [cu care across a variety of specialized services. overall, this approach appears to result in the best risk adjusted survival rates, but at the highest cost (critical care medicine ; : - ): recently, there has been increasing focus on markers of overall hospital performance. however, in large teaching institutions, such markers may fail to detect intra-institntional variation at a large tertiary care medical center. methods: first intensive care unit (icu) day, acute physiology and chronic health evaluation iii (apache iii) and active therapeutic intervention scoring system (tiss) data were collected on random admissions to specialty icus with beds (range - ) between february i and december l, . post-operative solid organ transplant recipients were excluded. units included general medical, general surgical, and trauma, neurosurgery, cardio-thoracic surgery, and coronary care units. data were analyzed for risk adjusted outcomes: icu and hospital mortality and length ef stay (los); risk of requiring active cu treatment; and icu readmissinn using apache iii risk prediction models. results: the study icus cared for a diverse group of patients. mean apache iii scores ranged from . - . ; predicted risk of hospital death ranged from . - . %. standardized mortality ratios ranged from . to . with icus performing significantly better and performing worse than predicted (p< , ). los ratios and icu readmission rates ranged from . to . (ns) and . to . % respectively. patients predicted at low risk of requiring active icu treatment ranged from , to . % conclusions: there was wide variation in the mean level of patient severity between icus. after controlling for this severity, outcomes also varied widely. no clear pattern of overall institutional performance was evident. these data suggest that efforts to assess performance, improve quality, and maximize efficiency must be focused within individual units. programmatic evaluation of outcome allows for focused review of the processes of care contributing to good outcome (best practices) and where to focus ongoing quality improvement and cost reduction activities. background and method : we compared icu mortality in different age groups presenting with the same severity of disease. we assessed severity of illness by the physiological day -apache~ (physio-aa) score (thus excluding the age related points). for each of the following physio-a n score intervals ( - ; - ; - ; - ; > ) , we compared tcu mortality within age intervals (< ; - ; - ; - ; - ; > years - , - , - ) . in these groups mortality may be twice higher in the > years patients than in the _< years. mortality does not vary with age in low (physio a n = - ) and high (physio a n = > ) risk groups. in the low risk group, mortality is low in all the age intervals because of the begninity of illness. in the high risk group, extreme severity of disease probably blunts the impact of age and leads to high mortality rates in all age intervals. introduction: to access the actual social/clinical outcome of the patients who undenvent intensive care therapy oct) is rather difficult, quality of lilr is not easih.' defined and ohserver subjectivity is a prime factor in the evaluation. mortality ratio after discharge must be established and its causes understood. obieetives: the propose of this stud)-is to look into the mortality ratio that occurred on a series of patients that undorwent ict at our unit from of the ~iew point of severity of the original illness and the diagnostic groups. material and methods: during the period of one )-ear ( ), patients were treated at the unit, of them died, and ~ere not matched in our series because os incumpletc records. thirteen patients died in hospital after their reference to other departments, twelve patients were lost after discharge. thus. at the end. only patients were evaluated on the fu. the, were classified into the follov ng three groups: acute medical, elective surge d and acute and emergency postoperative. the patients were seen at , and months after discharge. the, were evaluated in accordance to their abili~, to being self supported in their daily life and capecity to fully return and hold to their pre~ ous jobs. apache scores were evaluated for each of the three groups and correlated to the icu dead, hospital dead, and mortality after hospital discharge, spss package was used for statistical analysis. remlts/conclasions: data shows that / patients died after discharge from the hospital, of ~itch nine died in the first three months. seventy-eight per cent of the patients were fully self supported in their daily life and % showed some kind of handicap. fosty-nine per cent of the patients wore on retirement either due to age or some form of chronic disease, when admilled to our unit. thirty-two peg cent had not been able to return to work, because the" were incapacitated on discharge. only % had return to their fully jobs but the period of the stu~, is not enough for all of them to be fully physically recovered. preliminmy statistical analysis shows us significant differences among groups. the aim of the present study is to compare the prognostic performance of five general severity indices ou coronary patienta and to find out if a proper ntatistical hundling of these indices could provide better results in these patients. methods: saps ii, mpm ii (mpm ii i mpmp ii ), apach ii end gaprik were evaluated o~ patients with acute myocardial infurction admitted to intensive care units from catulunye. calibration and discrimination were calculated for each index. calibration was calculated by th bosmer-lemeshow test. discrimination was evaluated by the area under the relative operating characteristic (roc)curve. if a model did not show a good performance it was customized using multiple logistic regression. finally, tworeduced models were developed, one fro~ the mpm series (mpm ii cor) and one from the group apache-saps (sapsiicor).their performances were again evaluated. results: discrimination was high enough for all models. neverthelees, oelibration of apache ii, saps ii and mpm was not satisfactory. thus,mpm ii , saps ii and gaprik were customized for coronary patients using the logits of both models, and obtaining good calibrations. mpm ii , and apache-saps were adapted and reduced to (mpm ii cor) end to variables (sapsiicor), respectively . both models showed better oalibrutions end discriminations than the original models. conolusion| models developed for multidisciplinary patients show a good discrimination when applied on aoronar i patients, but some needed customization in order to improve calibration. the number of variables of the principal model can be reduced (even to or variables) without loosing prognostic accuracy. objective: to compare the ability of two methods to predict outcome for intensive care patients. methods: we included consecutive intensive therapy unit (itu) admissions with an itu stay> hrs in a month prospective study (exclusion criteria: burn injury and age < yrs). data were couectsd applying the criteria described by the developers [ , ] . the definition of coma (mpm ii) was modified and the best assessment within in's, rather than the admission score, was used. statistical analysis included classification tables and receiver operaung characteristics (roc) curves to assess discriminative power, and lemeshaw-hosmer statistics and calibration curves to test accuracy of prediction. results~ average abe was yrs (ranse: - ) with a male:female ratio of . : . the actual hospital mortality was . %, mean predicted death rates were . % (mpmz ii) and . % (ap hi). non-survivors had siguitlcanfly higher predicted risks than survivors applying both methods (p< . l, t-test). the total correct classification rates (tccr) for apache iii were bett~r for all decision criteria applied (tccr, decision criterion %: apache ]/i . %, mpm ii . %). the area under the roc curve was . (ap iii) and . (mpm ii) confirming the better discrimination of apache ill. accuracy of risk prediction was similar for both models (ap nl ~ - , mpm b ;( - , lemeslmw-hosmer). showing some fluctuation, calibration curves lay close to the ideal line for predicted risks -< % with increasing deviation for higher risk groups (s. figure) . apache iii underestimated the risks of hospital death for almost all risk groups (curve above diagonal), whereas considerable overestimation for predicted risks > % ceenred with mpm~ii. objective: to assess the goodness-of-fit of the apache iii model for british itu patients. methods: we prospectively studied a cohort of adult patients consecutively admitted to a medical-surgical itu over a period of months. patients with burn injury, age < yrs and itu stay < hrs were excluded. using a eomputerlsed database, we routinely recorded hrs apache ill scores. predicted risks of hospital death were computed by critical audit ltd, london. accuracy of risk prediefion was assessed by hosmer-lemeshaw chi square (;( ) statistics and calibration curves [ ]. discrimination was tested employing classification tables and receiver operating characteristics curves (roc). restths: the mean age of the male and female patients was yrs (range: - yrs). of these patients, % were medical admissions, % were admired after emergency and % after elective surgery. the observed hospital mortality was . %, the overall mean predicted death rate was . %. mean predicted risks were siguifieanfiy greater for nonsurvivors ( . %o) than for survivors ( . %, p< . l, t-test). apache iii showed good calibration (z -~ , lemeshaw-hosmer). however, the calibration curve lay above the diagonal for almost all risk groups reflecting the tendency to underestimate actual mortality (s. figure) . the best total correct classification rate (tccr) was . % (decision criterion: %). the area under the roc curve was . % confirming the good discriminative ability of the model. objectives: the aim of this study is to point out the discrepancies between needs and actual treatment of less severely ili patients admitted in italian intensive cam units (icus) requiring only intensive monitoring, and verify the substantial likelihood of data comparing those collected from a national short term study with a regional long ternl use. ~: less severely ill patients ("observed patients") were only monitored; they did not require intubation, even if for a short period (less than houm) or major cardioeiranlatory supports, and were neurologically normal. epidemiologieal national data were obtained from giviti group (gruppo italiano valutazione interventi in terapia intensiva); this cohort study, collected patients, in two months in summer in all over italy. regional data were echieved in a three years entlection ( -i ) in lombardia' icus from archidia group (arehivio diagnostieo), including patients. mortality, severity score, diagnostic category and some typical intensive procedures were analysed and compared in both studies. patients' disgunstie categories were defined as surgical, medical and trauma, according to the main diagnosis and the presence/absence of surgical procedures. rr observed patients account for . % and % of all icu's patients respectively in national and regional data. very tow mortality rate was found in national data ( . %) and extremely low mortality in regional data ( . %). in both studies mortality, s.a.p.s. and length of stay were much lowor in "observed patients" than in general icu's population (mortality: . % and . %; .a.p.s. score: . and ; iength of stay: % and ). homologous distribution of patients in the two studies was noted for what concern their diagnostic category, aside from a slight prevalence of tranmatised patients in the giviti study. in the two groups the surgical patients were respectively % vs. %, medical patients were % vs. % and traumatised were % vs. %. % of "observed patients" in national study and % in the regional did not received any intensive procedure. only a minority of these patients availed haemodynamie eonu'ol with swan-ganz or renal haemofiltration. conclusions: these results underline that about one fourth patients admitted in italian icus benefit an oversized slructure i, relation to the real needs of their pathology. in hot more than % did non received any advanced treatment and mortality and s.a.p.s. score were substantially lower respect to general population. the results obtained from these two studies are similar, suggesting an uniform distribution of the case mix in italy, even if a different recruitment period and a different gengraphieal distribution were used. some discrepancies in the two studies were found in the diagnostic categories moreover regarding the tranmatised patients ( % vs. %); this can be explained from the seasonal (summer) characteristic of the national study. mutuality, yet very low, is different in the two groups, but these data do not allow any definite explanation. finally these epidemiologieal survey suggest need of further studies settling more strict criteria of admission in icu. this study aims to evaluate patients outcome, quality of care and effectivity of therapy in our intensive care unit. the main goal was to indentify factors that the most influence that outcome. during . the authors collected data of patients outcome and predictor variables. overall mortality rate was , %. the most common causes of death were infection. the diagnosis of sistemic inflammatory response syndrome (sirs) and multiple organ dysfunction syndrome (muds) significantly correlate with death ( %). average length of stay was . days ~. % patients died in the first ten hosiptal days and only % after days. age was directly correlated with death % of dead were older then sixty years. an analysis of physiological variables showed that serum levels of gl~cose ( %) and natrium ( %) were in optimal physiological values. serum proteins ( %) and haemoglobin ( %) levels were inversely related to death. multivariate showed that alveolo-arterio difference in content was the most informative of all mortality predictors (mean value , mmhg in % patients io>mrnhg). factor that most influence the patients outcome was infection (sepsis) and muds. use of predictive indicators of outcome in critically ill patients may help to assess treatment regimens and to compare patient groups. acute physiology and chronic health evaluation (apache if) score (crit. care had. ; : - ) and the sepsis score of elebute and stoner (br. h surg. ; : - ) have been used, objectives: to compare sepsis score and apache ii score in predicting outcome of critically ill patients. methods: overall survival during the past years for patients in our icu was calculated = % (prior probability). the outcome of patients who were admitted to our icu for > hours was observed. apache ii score on admission, patient predicted risk of death (apache ii risk) and the sepsis score on the first day of antibiotic course were prospectively recorded. discriminant function analysis of the scores in relation to outcome was performed. results: apache ii and sepsis scores in the survivors were significantly lower than in those who died ( . i . v~s . • . and . • v's . • . respectively p < . ). correct prediction of outcome by each score is shown in discussion and conclusions: although both scores have been previously evaluated in predicting outcome of icu patients, studies of the sepsis score were conducted in small numbers of patients or involved additional measurements not routinely available. this study demonstrates that the sepsis score alone or in combination with apache ii score is more effective than apache ii score in predicting outcome. objective to test the hypothesis that resuscitation titrated against gastric intramucosal ph (phi) improves survival in critically ill patients as suggested by gutierrez et al~. method emergency admissions to the intensive care unit were randomized into control and intervention groups. in the control group phi was measured at , and h while in the intervention group phi measurements were made hourly for h. both groups were managed according to the same guidelines to achieve the following targets: mean arterial pressure > mmhg, systolic arterial pressure > mmhg, urine output > . /ml/kg, haemoglobin > g/dl, blood glucose < mmol/ , arterial oxygen saturation > % and correction of uncompensated respiratory acidosis. if the phi was < . after achieving these targets, or after maximal therapy to achieve the targets, patients in the intervention group were given fluid to ensure an adequate cardiac preload and then dobutamine at then mcg/kg/h, titrated against phi. this additional therapy was continued until h after entry into the study. in each year patients were subdivided in two series with random selection, so that the st series contained abeat / and the nd / of the patients. the st series of all the years constituted the devdoping data set and the nd series the validation data set. with data of the st series ( patients), we created the predictive model, using stepwise logistic regression (bmdp, usa). each patient has been evaluated in die st, th, th and th day, calculating for each lime the apache ii score (for a total of records), independent variables were, besides time and apache ii of the time ( michaloudia g,, melissaki a., alexias g., gogafi c., kolotoura a., krimpeni g., pamouktaoglou f, filias n. objectives: to determine the medical staff's attitude towards various ethical issues methods : between january and february , anonymous questionnaires were sent to intensive care units, all over greece. results : questionnaires ( , %) were replied and returned back. of them , % were answered by male and , % by female. the doctors replied in the following rate : , % aged up to , % aged between and , % aged over . questions were answered and were divided into main topics, as following: . admission criteria: limited bed availability was the main cause for refusing admission in , % of icu's. , % evaluated each case's viability and only , % used some prognostic score system. , % of icu's accepted all cases and a significant percentage ( %) gave in to pressure coming from their colleagues ( , % female and , % male). . informing the patient/relatives: only , % was willing to tell the whole truth, while , % had given selective information.. in the case of iatrogenic incident, , % withheld it, because either they feared legal implications ( , %), or lost of trust ( , %). doctors are asking consent from the patient and/or his family, in order to include him/her in research protocols, in a rate of , %, while only , % found informed consent necessary for the proposed treatment procedure. . withdrawal of therapy/dnr orders/organ donation: , % were willing to withdraw complex treatment in patients with short life expectancy, except of administi'ating intravenous fluids, feeding and analgesics. in , % such a decis~n was unanimous, while the percentage of those carrying it out was , % ( , % female, , % male). in case of brain stem death , % ( , % female, , % male) withdrew any life support. , % would like therapy withdrawal to be legally established, while only , % would perform euthanasia, if there was substantial legal cover. for these cases, relatives' consent was considered to be necessary from a percentage of only , %. , % considered organ donation to be a necessary proposal, while , % refused to ask the patients' relatives for an organ donation, either because they didn't have the psychological strength for it ( , %), or because they doubted the procedures' objectivity ( , %). note: in greece, icu beds are less than % from the total number of hospital beds available. only a percentage of - % of these admissions comes from the same hospital, with a potentially direct evaluation. usually an icu doctor has to be informed through the telephone. finally, employment conditions in greece are such that any changes of the medical and nursing staffare limited. conclusions: the mathematical model we found has been validated also in the second series and the discrimination capability increases with time. using this model we can evaluate the probability of survive at every, time. its application at different times permits a better evaluation of haemodinamically instable patient trend. introduction: the feasibility to assess pulmonary capillary pressure (pcap) offers the opportunity to determine the longitudinal distribution of pulmonary vascular resistance (pvr). the purpose of this study was to measure pcap and to calculate pvr to determine whether relevant shifts in the distribution of pvr could be expected after routine cardiac surgery. methods: the study population consisted of consecutively admitted patients after cardiac surgery. surgical procedures included coronary artery bypass graft (cabg) (n= ) and mitral valve replacement (mvr) (n=t ). pcap was estimated by analysis of the pressure decay tracing after pulmonary artery occlusion. after estimation of pcap precapillary (ra) and postcapillary resistance (rv) was calculated. a complete set of hemodynamic variables was obtained at hour and at hours after operation. results: there were no significant hemodynamic changes during the first hours after surgery. the mvr group maintained pulmonary hypertension and higher levels of pcap. ra/rv, reflecting the longitudinal distribution of resistances, remained unchanged. however, rv predominated ra during the postoperative period in both groups. objectives: evaluation of the influence of long-term continuous i.v. administration of the ace-inhibitor enalaprilat on regulators of circulatory homeostasis. methods: t trauma and sepsis patients randomly received either . mg/h (group i, n= ) or . mg/h (group , n= ) of enalaprilat i.v. or saline solution (control, n= ) as placebo for days. plasma levels of endothelin- (et), atrial natriuretic peptide (anp), renin, vasopressin, angiotensin-ii, and catecholamines were measured before injection of enalaprilat (='baseline' values) and during the next days. results: except for et, plasma levels of all vasoactive substances exceeded normal range at baseline. angiotensin-ii significantly decreased during enalaprilat infusion ( . mg/h: from . • to . • pg/ml; . mg/h: . • to . • whereas it remained significantly elevated in the untreated control patients. vasopressin increased only in the control group (p< . ) and decreased after . mg/h of enalaprilat. et remained almostunchanged in group , whereas et increased significantly in the control patients (from . • to .t• on the th day). catecholamine plasma levels (epinephrine, norepinephrine) markedly increased in the control group (p< . ), but they did not change significantly throughout the study period in both enalaprilat groups. conclusions: continuous i.v. administration of the angiotensin-converting enzyme inhibitor enalaprilat beneficially influenced systemic and local vasoactive regulators of the circulation, which are normally increased in the critically ill. thus patients at risk of (micro-) circulatory abnormalities may profit from enalaprilat infusion. objectives: to determine the time taken for hemodynamic and gas exchange variables to a reach stady-state after a change from supine to trendelenburg position (trp). methods: we prospectively studied adult patients with severe sepsis or septic shock requiring hemodynamic monitoring. usual cardiorespiratory parameters were measured at baseline, min after the patient was placed in a trp and again min after the return to a supine position. a fiberoptic pulmonary artery catheter (svo~ oximetrix, abbott) allowing continuous svo monitoring wa~used. during the protocol we also continuously measured sao~ by pulse oximetry and vco~ and vo by monitoring partial concentration of o and co ir~ inspiratory and expiratory gases (deltatrac metabolic monitor, datex). therefore, we were able to monitor cardiac output variations by dividing vo~ with arteriovenous difference according to the fick equation (co-fick). results: no significant difference in hemodynamic status was observed min after the patients were placed in trp. despite the fact that no significant change was observed in co and vo~ estimated by thermodilution, co-fick had a tendency to dedrease continuously in trp and then to return to its initial value when patients regained supine position. respiratory gas analysis showed a small but persistent continuous increase in vco without a similar trend in vo values. conclusions: we conclude that no significant hemodynamic effect was detected in our patients after min in trp. evaluation of vo from respiratory gases analysis after a change in body's position should be interpreted with caution, since the patient may not yet have reached a stady-state after rain. since vo did not change, vco~ increase was probably due to position related changes in-pulmonary gas exchange and not to a change in patient's metabolic status. objectives: to determine whether changes in svo and/or other hemodynamic parameters during weaning trials could be used to predict successful weaning. methods: we prospectively studied adult patients with a history or clinical evidence of cardiovascular dysfunction, who were unable to tolerate spontaneous breathing (sb) for hours. for all these patients right heart catheterisation was considered necessary in order to detect hemodynamic alterations during weaning. a fiberoptic pulmonary artery catheter (svo ximetrix, abbott) allowing continuous svo monitoring was sod. hemodynamic status was evaluated ~t baseline and after one hour of spontaneous breathing through a t-piece. patients were assigned to one of two groups depending on whether they tolerated sb for hours. data were analysed by analysis of variance and unpaired student's t-test we also used multiple linear regression analysis to determine which hemodynamic variables were correlated with the magnitude of svo~ change and multiple discriminant analysis to determine if asy of the above variables were associated with toleration of sb for hours and/or successful weaning (s-w). (j physiol ; ." - ) . we tested the hypothesis that the ventilatory stimulation by dead space (vd) loading and % co inhalation is accompanied by a proportionate cardiovascular change. methods: six healthy subjects, mean age, year, performed three incremental exercise tests in a randomized order: ) inspiring air without vd (air control, ac); ) inspiring air with vd of ml (avd); ) inspiring % co ; % oxygen, balance nitrogen. the ventilatory responses were examined at matched heart rate (hr) equivalent to % peak hr. results: ventilation (vi) was significantly greater (p< . ) during the avd and co tests than during the ac test at the same work rates. end-tidal co (petco ) and estimated arterial co (paco ) were significantly greater (p< . ) at w and w. oxygen saturation was significantly lower (p< . ) during the avd test than during the ac and % co exerdse. at matched hrequivalent to % peak hr, vi was significantly greater (p< . ) during the avd and % co tests than during the ac exerdse ( l, l, and /). conclusion: we conclude that the increase in xri and petco due to vd loading and % co inhalation is not associated with an acceleration in hr. sup.ported by mrc (canada). objeetlve: the production of large amounts of oxygen radicals from the onset of ~en may be responsible, st least in part, for peroxidative damage to myocardial tissue. the aim of this study was to evaluate the time dependence of plasma tbars in patients with am] receiving thrombolytie therapy (tt). patients and m~hods: filiy eight patients admitted in icu ( men and women; mean age . - . years) rec~ving systemic tt for possible am] were ~died. all patients received recorabinant haman tissue-type plasminogen activator (r-tpa). the mean time fi'om the onset of symptoms and the be~nning of tt was . - . hours. peripheral veao~s blood samples were obtained fi'om each patient before and serially after tt ( , , and hours). tbars levels woe determined by using a spectrophotometrie technique. rq~r fusion was identified by the timing of ereatine phosphate kkmse (cpk) peak (< hours). table i list the variation of plasma eoneenlrations of tbars (mean -sd) in groups (a,b, and c) as a function of time from the beginning of tr. co,arisen oftbe time cuncentzatiens reveal a difference p<o. between group ami (a and b) versus group c. the between-groups (a-c) comparison showed significant differences (p<~). ) at , and hours fi-om de begin~g of'it. comparison ofthe , and hours eonocnlratiens did not reveafl any difference becween n~ (group b) and angor (group c). condmien: we have observed a maintenance of high level of tbars in reperfused patients enly. these results suggest that the increase of tbars levels may be due to phospholipid derangament of reperfused myocytes. objective: to detemline if tbars levels may be an early index reflecting peroxidative damage in ami patients. patients and methods: by using a spectrophotometric teclmiqtm, based on a modificatien oftbe buege and aust method, tbars levels ware determined in healthy subjects (group i) , patients with several risk factors of ischaemic cardiopathy (group if) and icu patients with possible aim ( were confirmed ami (group ma) and were angor (group iiib)). peripheral blood was obtained at the time of the icu admission in the group i . electrecardiographic data and eehocardiographic wall motion were used to identify ami location (anterior, inferoposterinr and indeterminate). statistical analysis was made with a standard statistical package (rsigma, horus hardware). , h , s, , h statistically significative increase of ' ix~e/ea.ee x~* tbars levels (p< . ) only in pstients with con/tuned ami (group ilia) . no differences were found between the rest of the groups. the figure shows the relationship between the tbars values and the time from the onset of the aim's symptoms. conclusion: we have found that in am/patients the tbars levels can be used as an early index reflecting peroxidative damage occurring to ischemie tissues. perioperative risk in patients with ischemic heart disease. the protective role of diltiazem. lg. hatziantoniou, p. tassiopoulos, c. fakiolas, ! g. foussas~ m. lycourinas perioperatlve morbidity and mortality are mainly of cardiac origin, particularly among elderly patients (pts) ~ith ischemic heart disease. we performed a randomized trial, in order to investigate the possible protective activity of diltiazem (d). methods: pts (aged zo• with a history of coronary insufficiency were subjected to major urological operations. they were randomized to two groups: group i ( pts) -p:ithout d and group ii ( pts) -d ~as administered . mg/kg iv bolus hours prior to anesthesia and . mg/kg/h upon the end of operation and for at least hours post-operatively. iv was substituted by oval administration of x mg starting the next day and for the rest of hospital stay. all pts underwent daily clinical, electrocardiographic and laboratory (ck-mb) control. results: are shown in the following interactions between the heart-lung unit and a cardiac assist device are the crucial issues for successful outcome of patients under mechanical circulatory support. several factors have been indicated and we can diffrentiate between anatomical and hemodynamic interactions. especially right heart failure and pulmonary hypertension have been proven to limit left ventricutar assist device (lvad) performance. in order to study the effects of right heart failure (rhf) and pulmonary hypertension (pht) on mechanical circulatory support, we designed an experimental study in dogs and combined in six groups left heart failure (lhf) and rhf and pht, respectively. in the control group we induced lhf with subsequent occlusions of lad and cx followed by reperfusion: in the next group we supported with an lvad during minutes starting minutes after cx occlusion (group if). in the next group we added right ventricular ischemia by occluding the rca simultaneously to the cx (group iii). these both groups we repeated only with pre-existing acute pht induced by the injection of o fm glass beads (groups vi and v). a last group was similar to group v (lhf and rhf and pht), but instead of a lvad, we used bvad support. in i and v no animal survived the second perfusion period ( hours). in ii and iii (no pht), all dogs survived in stable conditions. in iv (lvf, pht), % survived, the remainder died of incomplete recovery. in vi with bvad, only % survived. in iii and v, during occlusion of the rca, the right ventricle stopped contracting and right atrial pressure and mean pulmonary pressure equalized. this lead to a significant drop in inflow on the left heart side, which still provided sufficient lvad performance in case of absent pht (iii) and lead to death due to "low lvad output" syndrome in v. this "low lvad output" snydrome could be partly overcome by bvad support. we conclude that heart-lung interactions play a major role in lvad performance. by optimizing the perioperative management, they all can be overcome, except the occurrence of alveolar leakage syndrome. obiectives : we propose a new approach of transmural pulmtmary artery occlusion pressure (paoptm), in presence ef peep, from the folluwing hypothesis : if respiratory swings of paop are compared to those of alveolar pressure (apalv = plateau pressure -total peep), an index of transmission of airway pressures to pulmonary vessels is obtained (i t = apaop/apalv). the value of the product of it by peep can be substracted from end-expiratery paop (paopee) to obtain a calculated paoptm (paoptrnc). thus paoftmc = paopee -(apaop/apalv x peep). methods : we tested this hypothesis in patients by comparing paopee, paoptmc, and paopnadir obtained within the first seconds after disconnection from the ventilator, value of reference of paoptm in absence of intrinsic peep (peepi). at zeep, peepi was absent in patients (group a) but present in others (group b). patients were studied under the peep level chosen by the attending physician-(gr a : +_ ; gr b : _+ cmh ). results : l. gr a : paopee ( _+ mmhg) differed (p < - ) from paopnadir ( • mmhg) and paoptmc ( _+ mrahg). gr b : paopee, paopnadir, paoptmc differed between themselves ( " - , + , + mmhg respectively). . good correlatkm (r - (i. ) and agreement between paopnadir and paoptm were found in gr a, while there was no agreement in gr b (bland and altman analysis). . lung compliance (v t/bpah,) correlated well with i t in both groups (r - . ), suggesting that our hypt)thesis was strtmg even in patients with peepi. conclusions : paoptm under peep ventilation can be obtained, even in patients with peepi, from parameters easily measured at the bedside. introduction: cardiopulmonary bypass (cpb) may cause ischemia in several organ systems like the heart, brain and kidneys. reactive oxygen species (ros) are formed by subsequent reperfusion and stimulation of neutrophils by cpb. ros are harmful to biological systems e.g. cellular membranes, enzymes~ dna. many natural antioxidant systems protect against the effect of ros. in patients undergoing cabg we evaluated the production of ros by total plasma antioxidant status (tas) and lipid peroxidation measured by lipofuscin flip). methods: tas (randox, uk) and concentrations ofllp (tsuchida et al.) were measured in consecutive patients undergoing cabg. all the patients had a normal serum creatinine clearance (> ml/min). serum samples were obtained a) before operation, b) after removal of the aortic crossclamp, c) at admission to the icu, d) hours after operation, e) hours after operation. results: tas was significantly decreased after removal of the aortic crosselamp ( b, c and d lower than a), followed by a subsequent significant increase of lip ( c and d higher than b). the levels of tas and lip returned to baseline hours after operation. methods: patients with preoperative lvef< % undergoing coronary artery bypass grafting were studied. after surgery, a f femoral artery catheter was inserted and connoted to a fiberoptic monitoring system (cold z- t; pulsion medizintechnik, germany); this allows, with a double-indicator dilution technique, the calculation of cardiac index (ci,l/min/m ), intrathoracic bood volume (itbv,ml/m ), pulmonary blood volume (pbv,ml/m ) and extravascular lung water (evlw,ml/kg). with a f pulmonary artery catheter, wedge (w,nunhg) and central venous pressure (cvp,mmhg) were measured, while extraction ratio (o exr,%) and oxygen delivery (do ,ml/min/m ) was calculed. peak inspiratory pressure (pawp,cmh ) and mean airway pressure (mawp,cmh ) were measured with a varflex flow transducer (bicore,sensormedics,us). the patients were studied after minutes (to) of volume controlled standard ratio ventilation (vc), and after minutes (ti) of stabilisation period of pcirv ( % inspiratory time, % pause). vt,ve and total peep were held constant in every mode of ventilation. +_ . " *'p < , versus to conclusions: these data show that pcirv : is a safe ventilatory support also in cardiac patients with impaired ventricular function, and monitoring of itbv is more reliable to measure and optimise circulatory volume status, than w and cvp. c.ledeki-,g.rldisis,s.karotzai,c.micheilidis,m.agioutantb, g.beltapaulos. objeolivee:to evaluate the influence of lvswl on the well known correlation of sr and svo . paw eight patients ( melee end females) were included in this study regerdlen of the icu ~h"niseion couse. all paints were ,'~theta~ with e fiboroptir pulmonary artery catheter connected with an oxymetfir (r)~ so /co abbot computer.for any pulmonary artery catheter insertion, two pain= of sr and svo were obtained, one dudng inserlion and one during taking the catheter out. for any pair obtained, we eleo collected the deta concemig with the pedient's hemodynamir and oxygenation end we calculated the lvswi. were significantly (p<o. ) higher in group i. conclusion: breathing room air, the less hypoxemic patients had a rather satidactory do and tissue oxygenation (pro ) because they had properly adapted their ci. the absence of this mechanism (right heart impairement ?) in the hypoxemic patients, in spite of higher blood ne and e, was responsible for the poor do and pro . objectives: acute massive pulmonary embolism (pe) increases pulmonary artery pressure (pap) and dght ventdcular aftedoad, which may lead to dght ventdcular failure. inhaled nitdc oxide (no) selectively dilates pulmonary vessels. thus, inhaled no may be of potential therapeutic value in the management of the acute phase of pe. methods: following institutional approval, ten piglets (body weight + kg) were anaesthetised (midazolam/piritramide) and ventilated using a modified servo ventilator (siemens elema, sweden; fio . ). the following variables were obtained: systolic pap (spap), mean pap (mpap), diastolic pap (dpap), mean artedal pressure (map), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), cardiac output (co), and artedal (pao ) and mixed venous (pvo ) oxygen saturation. pulmonary vascular resistance (pvr) was calculated. to induce pe, pm microspheres (sephadex g coarse, pharmacia biotech, freiburg, germany) were injected in an amount sufficient to increase mpap to mmhg initially. rain after embolisation when haemodynamics were in a steady state (control ), inhaled no was administered. further measurements were taken min after ppm no (no ), min after ppm no (no ), and min after discontinuation of no administration (control ). the administration of inhaled no resulted in a significant decrease in spap, mpap, and pvr. the cessation of no inhalation led to a complete return to pretreatment control values (table) . co, map, cvp, pcwp, pao?, and pv~ remained unchan no administration. objectivss:evsluate the yield of recombinant tissue plasminogen activater(rt-pa, actiiyse ~ oehringer ingelheim) as a thrombolytic agent ie pulmonary embolism ie .kr~auma patients. methods: in five patients with diagnosed pulmonary embolism(blood gases, chest x-ray, echocardiography, perlesion lung scans) were given rag of actij.yse as ~ hrs infusion, followed by heparin~single j. ihjaction snd iefusion ie doses - j./kg/day).the effectiveness of rt-pg thrembo].ytic sctier~ was svaluated im . . hrs(blood gases) amd on the third dayafter t~eat-,ment(~chocardiography and lung scan). results: three hrs after actilyse was given we observed significant clinical imprevemeet,confirmed by elevation of pao and sao in dlood.echocardiegr~m on the third day showed regression of pulmonary hypertension and lung scans showed % improvement in total lung perfusien. except slight bleeding from the site of injection nc~ more thromboiytic complicatioos were observed. conclusiens: actilyse used in five hrauma patients with pulmonary embol.ism was a very effsctive and safe thrombolytic agerlt, inducing rapid and evident clinical improvement. intermittent positive pressure ventilation ( ppv) by increasing pleural pressure, decreases the pressure gradients for systemic venous return and left ventricular (lv) ejection. we have previously shown that when inspiration is synchronized with systole using synchfjv in patients with severe cardiomyopathy, that cardiac output (co) was increased relative to both ippv and non-synchronized hfjv ( ). however, it is not known if similar effects could be realized in ventilatordependent patients with lesser degrees of lv dysfunction and fluid overload. we thus compared synci-ifjv to ippv in stable patients following coronary artery bypas grafting. methods: normothermic who were stable (< % variance/h.) were studied following admission to the sicu. heart rate (hr), mean arterial (pa), pulmonary artery occlusion pressure(ppao), co by continuous thermodilutiun (vigilance, baxter, usa), mixed venous saturation (svoz) and arterial blood gases (abg) were measured after rain. of each step. ippv was simv adjusted for a rate, tidal volume and fit to insure both normal abg and a peak airway pressure < cm h,o. syncfifjv was delivered by a hfjv ventilator (acutronic) during systole with ventilator parameters adjusted to optimize abg. protocol: patients received three ippv runs (ippvi. , ) with synchfjv runs interposed (hfjvz ). statistics: anova for repeat measures and paired t-test were used to compareruns and demonstrate variability. results:no significant difference in any of the measured hemodynamic variables were seen among the ippv and synchfjv runs (table) . post hoc separation of patients by preoperative ejection fraction (ef; ef > % ; n= and < %; n= ) did not alter these results. back~ound: in man, vascular endothelium-bound ace is expressed in concentrations greater than x that in serum and is believed to be the site of synthesis of circulating angioteusin il it is unclear whether ace inlubitors interact similarly with ace in different vascular beds. coronary vessels possess all the components of the renin-angiotensin system, including ace which may be involved in normalcardiac homeostasis, as well as in the pathogenesis of various cardiomyopathies. obiecfive: to develop a method for assaying the interaction of ace inkibitors with coronary endothelium-bunnd ace in man, methods: ace a~aty was meas~ed in five patients undergoing cabg surgery, from the transeuronary hydrolysis of the synthetic ace substrate h-bpap. trace mnou~ of ~fi-bpap ( gci) were injec~d as a bolus in the root of the aorta and simultaneously blood was withdrawn from a coronary sinus catheter into a syringe containing protease inhibitors which prevented the convession of umeaet~ ai-i-bpap by blood ace. the sample was later centrifuged to separate cells from plasma and the radioactivities due to formed product (~rl-bphe) and total sh were astimated in a [b-counter. two additional such determinations of ace activity were perform~ the second in the presence of . pg/kg e (coinjected with ~-i-bpap) and the third ten minutes after e. results: all subjects were hemodynamically stable throughout the course of the there were no noticeable hemodynamic effects of e. control transcorunary metabolism of~-bpap averaged g -a: %, in agreement with previously reported data. in the presence of e, % metabolism of ~-bpap was reduced to • reflecting a • inhibition of normal ace activity. ten minutes after e, ~ri-bfap metabolism had partially recovered to :l: %, representing a -a: % inhibition of control ace activity. from this data, the dissociation constant of e for coronary ace in vivo was estimated as . x " sec "l. conclusions: we have demonstrated the feasibility of repeated, reproducible measures of coronary endothelium-bound ace activity and of its inhibition by e. this procedure is safe and can be used to study the role of ace in normal cardiac function and in card pathologies. objectives. primary pulmonary hypertension (pph) is a progressive fatal disease of unlmown origin, with median life expectancy of less than three years after diagnosis. the responsiveness of pulmonary hypertension to a variety of vasodilator agents led to the speculation that, concomitant with vascular renmdelling processes, persistent vasoconstriction is an important feature of the disease. long term use of ca-channel blockers and intravenous pgiz may improve mortality in certain populations of pph patients, but both of these treatments lack selectivity for tire lung vasculature. the aim of this study was to test the efficacy of aerosolised prostacyclin and its stable analogue, [loprost for selective pulmonary vasodilatation in pph. methods: in three patients with pph, we compared aerosolisation of prostaglandin iz (pgi ) and iloprost to a battery of vasodilatory agents (diltiazem, nifedipin, inhaled nitric oxide, intravenous pgiz). results: nebulisation of pgi and iloprost tumed out to be most favourable for achieving effective and selective pulmonary vasodilatation. pulmonary vascular resistance decreased from + to -+ dyn*s*cm (p< . ) and pulmonary artery pressure from . + . to + . mmhg (p < . ), cardiac output increased from . + . to . _+ . i/rain (p < . ), mixed venous oxygen saturation from . _+ . to . + . % (p < . ) and arterial oxygen saturation from . + . to . _+ . % (mean _+ sem of trials in patients). -month iloprost nebulisation in one patient ( gg/day in six aerosol doses) demonstrated sustained efficacy of the vasodilator r~men. conclusion: aerosolation of pgi or its stable analogue may offer as new strategy for selective pulmonary vasodilatation in pph. endothelial adhesion molecules may play an important role in the pathogenesis of myocardial cell damage, and may contribute to the progression of heart failure. we measured the plasma soluble intercellular adhesion molecule- (sicam- ), vascular cell adhesion molecule- (svcam- ), and e-selecfin (selam- ) levels in patients with acute myocardial infarction admitted within hours after onset. peripheral venous plasma-samples were collected at the time of admission, , , , , and hours after onset. plasma soluble adhesion molecule concentrations were determined by elisa. patients were divided into groups as follows: group ; killip's class (k) and without thrombolytie therapy, group ; k and with thrombolytic therapy and group ; k and . both plasma sicam- and svcam- concentrations in group and were elevated rapidly and significantly and maintained at a high level during the first days. plasma selam- level did not change in any of the groups. these results suggest that the adhesion molecules icam- and vcam- may play a role in the pathogenesis of myocardial reperfusion injury and may indicate its severity in myocardial infarction. objectives: nitric oxide (no) is known to exert cytotoxic and negative inotropic effects on cardiomyocytes. no synthase activity has been reported to be increased in infarcted area in animal model of myocardial infarction. these findings suggest that no may be an important regulator for myocardial damage and cardiac function after myocardial infarction. we measured plasma no no -(nox) levels and estimated serial changes in acute phase of myocardial infarction. methods: subjects were patients admitted within hours after onset. venous blood samples were collected at -hour intervals on the first day, -bour intervals on the nd day and -hour intervals on the rd day and th days after onset. plasma nox concentrations were determined by griess method. results: the time course of the plasma nox levels (mea~+sem) displayed a tendency to gradually increase and to make a biphasic pattern with two peaks about hours and - days after onset (basal level; . _+ . , first peak; . !-_ . , second peak; . + . ram/l). plasma nox concentration was not influenced by the thrombolytic therapy, and nox values at the time of hours after onset were significantly correlated with maximal plasma creatine kinase level (r= . , p< . ). the levels of plasma nox in the early stage of myocardial infarction (from admission to the th day after onset) did not correlate significantly with the hemodynamic parameters (left ventricular ejection fraction, pulmonary capillary wedge pressure). conclusion: the early and late increase in no production after myocardial infarction may be implicated in the deterioration of myocardial contractility and induction of myocardial damage in the early phase of myocardial infarction. range - ) fullfilling the high risk criteria of shoemaker (colectomy , gastrectomy , pancreaticoduodenectomy , others ). patients were admitted to the icu preoperatively. arterial and pulmonary artery catheters were inserted and hemodynamics and oxygen transport were measured at admission and after stabilization to predetermined physiological end points. patients were considered stable when ci > . l/min/m , pcwp > mmhg, hb > g/l, sat >. . objectives: evaluate the acute effects of , mg ipratropium bromide and , mg fenoterol (ibf) inhaled dose on pulmonary function in nonsmocers (nb:m) and smocers (s) with sever (new york heart association class ii-iii), stabile congestive heart failure(chf) and healthy subjects. methods: pulmonary function tests were performed < h postprandial. the tests consisted el arterial blood gas aspiration followed by routine spirometry and pletismography, and single-breath gas analysis. after performance of these maneuvers, the patients was administred puffs-ipratropium bromide ( , rag) and fenoterol ( , rag). for , h, spirometry was repeated. results: in resting, pulmonary abnormalities observer in the s group were more severe then abnormalities observere in the nsm group. after treatment with ibf the improvement in pulmonary function was even more marked in patients who had smoked. the mean changes by forced expiratory volume in second(eevt) was , % (p< , t) improvement and , % (p< ,ob), forced expiratory flow betwen % and % of the forced vital capacity (fef . ) was , % (p< , ) and , % (p< , ) and maxamal voluntary ventilation (mw) was , % (p< , ) and , % (p<o, ) improvement. the mean changes in normal subjects were mild (fev increased by , %,fef - by , % and mvv by , %). we observed no adverse heamodinamie conseevence and no arrthytmogenicity. conclusion." in patients with chf the airway response to ibf is highly significant. further study is needed to determine whether therapy with ibf will load to improvement quality of life in patients with chf with dearly documented venti/atory defects. compared with unilateral ima grafts, usage of bilateral ima grafts in cabg patients causes greater thoracic trauma and further reduces blood supply to the sternum and intercostal muscles. these effects may be associated with increased postoperative respiratory complications obiectives: to study the effects of bilateral ima grafts on postoperative respiratory morbidity in cabg patients. methods: two groups of patients undergoing cabg were prospectively studied: group (n= ) received both imas as grafts and group (n= ) received only the left ima. the two groups were matched for age, smoking habits, total number of grafts and preoperative ejection fraction. pao /fio ratio was measured in all patients in the icu, at , , minutes on mechanical ventilation (mv), at , , minutes after extubation (ex) and on postoperative day (pod) . in addition, radiografic scores of atelectasis and pleural effusion were assessed postoperatively. results: group had significantly longer bypass ( _+ vs + . p< , ) and aortic cross clamp time ( +- vs + , p= , ). pao /fi ratio was significantly higher in group only at minutes after extubation (table) . there was no difference in the incidence or severity of atelectasis or pleural effusion between the two groups. the duration of mv was longer in group ( +_ vs _+ , p= , ), but the length of icu stay and hospitalization were similar. there was one case of pneumothorax in group and one case of pulmonary infection in each group. after extubation m[n min min min* rain min pod ' _+ _+ + -+ - -+ _+ _+ _+ _+ -+ _+ _+ -+ mean_+sd, *p=o, o conclusions: compared with unilateral ima grafts, the usage of bilateral ima grafts in cabg patients is not associated with increased postoperative respiratory morbidity. the diagnosis of rv ischaemia is difficult in the critical care setting. the purpose of this study was to determine the ability of rv endomyocardial and interstitial ph electrodes to detect rv ischaemia in an animal model of rv infarction produced by fight coronary artery ligation. we hypothesized that changes in transmural and interstitial ph would accompany the induced tissue hypoperfusion. rv interstitial (phint) and transmural endomyocardial ph (phendo) were measured in adult anaesthetized pigs before and serially after coronary ligation. phendo and phint fell progressively and significantly following coronary occlusion. this was accompanied by ischaemic ekg changes. the absolute and relative rates of change were greater for phendo compared to phint, particularly after minutes of ischaemia, ph was unchanged in control experiments when the electrode was placed within the fight atrial or ventricular chambers, as well as when coronary ligation was not performed. these data suggest that rv myocardial ph measurements reflect coronary ligation induced rv ischaemia, ph recorded from an electrode placed against the rv endomyocardial wall via a central vein was as useful as an interstitial measurement that required a thoracotomy. this newly described technique may be helpful in clinical settings where differentiation between ischaemic and nonisehaemic causes of rv dysfunction is important. centre. depts of cardiac surgery and anesthesiology, university of bari, italy. lung injury secondary to cardiopulmonary bypass (cpb) is well recognized. nevertheless, mechanical respiratory changes after cpb have been poorly investigated. aim of the study was to evaluate the effects of cpb on respiratory mechanics. elastance of the lung (est l), chest wall (est cw), and total respiratory system (est rs) were measured in patients without previous pulmonary disease undergoing elective cardiac surgery. there were males and females; no pleurotomy was done. cpb was carried out with membrane oxygenator. mean cpb and cross clamping times were _. and • min. flow (pneumothacograph), airway opening and esophageal pressures (pressure transducers and esophageal balloon) were measured on patients sedated and paralysed. measurements were obtained before sternotomy, at the end of cpb after chest closure, four and seven hours later. est rs, est l and est cw, were measured by occluding the airways and the end of a tidal breath. before end cpb- h after h after stemotomy closed chest cpb cpb estrs (cmh /l) . + . . - . " . _+ . * . - . * est cw " . _+ . . • . + . . -+ . est l " . -- . . - . " . -_ . " . _+ . " x + sd. * p < . : anova vs "before sternotomy". our data show that cpb induces increase in est l, whereas est cw remains unchanged despite sternotomy. impairment in est l after cpb evolves within the first hours and stabilizes hours later. during the clinical course of human imunodeficiency virus infection (hiv), patients (lots) can develop congestive and dilated cardiomyopathy syndrome (dcm). the aim of our study was to analyze the prevalence of dcm among an hiv population, its clinical and echocardiographic changes under a long term follow-up and therapy with an ace-inhibitor agent (captopril). we prospectively studied pts, % ( / ) developed dcm during the follow-up study. among this group % ( / pts) were in class i and ii and % ( / pts) in class iii and iv of the nyha classification. we divided this population in a acei+ ( pts) and acei-( pts), according to the administration of captopril. we analyzed the following parameters: age, gender, race, ivda, type of hiv, cdc classification, number of t and t type cell population and its t /t ratio, therapeutic with acei, type and number of opportunist infections, mycobacteriosis and neoplasm's. we analyzed several echocardiographic parameters, which included the initial (i), final (f) and variation (a) of the lv internal diastolic (lvdd/mm) and systolic (lvsdimm) diameters, lv % of fractional shortening (lv%fs/%), ivs and posterior wall thickness and lv mass (lvm/g). the two groups differed significantly in the following parameters: left ventricular functional indices of patients (pts) with iscjhemic dilated cardiomyopathy (idcm) have a critical value in terms of clinical prognosis of this disease. three-dimensional echocardiography ( -de) is a recently developed method that gives a better evaluation of lv morphology and function. the purpose of our prospective study was to assess the clinical applicability of this new -de method in a population with ischemic dcm diagnosis and calculate its lv indices of global and regional function. we studied a group of idcm pts, mean age _+ yrs, % male gender, using a combined -de tee approach. all pts were in class ill/iv of the nyha classification. first, ekg gated images were acquired through a mechanical pullback of the tee probe, and each set of data was transferred to a conventional ibm-pc system using a dedicated -de software. computer processing and analysis of the tee images led to a -de reconstruction matrix and off-line calculation of several lv global and regional indices. in all idcm lots the lv cavity was clearly reconstructed and end-systole and diastole in several orthogonat projections, out in multiple planes and its function quantitated using -de derived indices. mean values of -de lvesv= -+ ml, lvedv= _+ ml, lvstv= _+ ml and lvef= -+ % were obtained. for all these -de parameters, good correlations were observed with -de lv measurements obtained through biplane tee analysis of the lv cavity (r>. ; p<. ) as well as regional analysis of sequential -de cut planes. conclusion: in our group of patients with the diagnosis of ischemic dilated cardiomyopathy, this new -de method could be applied. our results show that this method allows a better assessment of the lv morphology and spatial geometry, with the calculation of global and regional indices with critical clinical and prognostic value in this particular cardiovascular pathology. simultaneous left atrial (la) and left ventricle (lv) inflow analysis assessed by pulsed doppler tee illustrate the loading conditions and reflect the hemodynamics of the left heart. we performed a prospective tee pulsed doppler study with recordings of the transmitral lv filling and pulmonary venous (pv) flow drainage in a group of patients with dilated cardiomyopathy (dcm). a group of dcm patients, mean age _+ yrs, % male were studied. this population was divided according to tee severe lv dysfunction (group slvd+ % pts; group slvd- % pts) in each pt we measured the peak velocities (vel/m/sec) and time velocity integrals (vti/m) of the transmitral early (e) and late (a) filing waves, the vel and vti of the pv systolic (s), diastolic (d) and atrial contraction (c) reversal flows. -de tee evaluation of the lved, lves, lvst volumes and lvef were obtained. we calculated other parameters, such as e/a, s/d and a/c ratios and the sum of c+a vel, that refelect la systolic function and lv compliance. + -_ . simultaneous and quantitative analytical approach of the pulmonary venous and transmitral flows and ventricular volumes improve the non invasive assessment and understanding of left ventricular diastolic function and cardiac performance in dilated cardiomyopathy patients. objectives : to assess the hemodynamic effects of fluid loading (fl) in acute circulatory failure (acf) due to acute massive pulmonary embolism. methods : hemodynamic measurements (fast-response thermistor pulmonary artery catheter) were performed at baseline (baseline) and after a rapid fluid loading with (fl ) and (fl ) ml of dextl'an (rhemacrodex| in patients free of previous cardiopulmonary disease ( • yrs) with acf (ci < . l/rain/m ) due to angiographicalty proven mpe (miller score > ) . results : are expressed as mean _+ sem and compared by anova. a significant negative correlation (r = . ) was observed between baseline rvedv[ and the effects of fl on ci. such correlation was not observed between baseline rap and the fl induced increased in ci. conclusion : fusibmificantly increases ci in acf due to mpe. however, the simultaneous decrease of arterial content due to hemodilution, limits the benefits expected from improved ci on peripheral oxygenation. obiective: to examine the hemodynamic effects of external positive endexpiratory pressure (peep) on right ventricular (rv) function in acute respiratory failure (arf) patients. methods: incremental levels of peep ( - - - cmh ) were applied and rv hemodynamics were studied by a swan-ganz catheter with a fast response thermistor for right ventrieular ejection fraction (rvef) measurement in mechanically ventilated arf patients (lis = . ~- . sd). according to the response to peep , two groups of patients were defined: group a ( pts.) with unchanged or increased rv end diastolic volume index (rvedvi) and group b (h pts) with decreased rvedvi. results: in the whole sample cardiac index (ci) and stroke index (sj) decreased at all levels of peep, while rvedvi , rv end systolic volume index (rvesvi) and rvef remained anchange d. at zeep the hemodynamic parameters of the two groups did not differ. in group a, ci decreased at peep , rvef decreased at peep (~ . %)~ rvesvi increased only at peep (+ . %) and rvedv[ reded unchanged. in group b, ci and rvedvi started to decrease at peep , 'rvesvi decreased only at peep (- . %), anf rvef was unchanged. individual behaviors of the hemodynamic parameters at the levels& peep were studied. rvedvi and ci were significantly correlated in out of:l patients in group b, and in no patient of group a. on the contrary, mpap and rvesvi were significantly correlated in out of patients in group a, and in no patient of group b. the slope of the relationship between rvedvi and rv stroke work index (rvswi) expresses rv myocardial performance. this relationship was significant (no change in rv contractitity)in patients of group b and in patients of group a. in some patients of group a, increments of peep shifted the rvswi/rvedvi ratio rightward inthe plot (rv function decrease). conclusions: in arf patients peep causes more often a preload decrease with unclmnged rv conctraetility. on the contrary, the finding of increased rv volumes during the application of peep is related to a decrease in rv myocardial performance. thus, these data suggest that application of peep might be considered as a stress test to assess rv function. right introduction: after heart transplant (ht), the right ventricle can be subject to an acute pressure overload, especially in cases where there is a preexisting severe pulmonary hypertension. this provokes right ventricular failure and, occasionally, circulatory collapse in intensive care unit. desire the advances that have been made in systems for preserving the donor heart and in post-surgical management, we have failed in our attempts to totally avoid this problem. the right ventricular function, although it usually remains within tolerable limits in these patients during the post surgery period, represents a factor which limits the results achievable in clinical transplant programmes. objectives: to determine the maximum tolerance of the right ventricle (mxtrv) when faced with acute pressure overload. to study the function of both ventricles of the healthy heart (donor) when faced with different degrees of pulmonary hypertension. to detect possible interactions between the ventricles in the absence of the pericardium to approximate the experimental model to the clinical model of ht. materials and methods: the pulmonary artery is progressively constrained in an experimental model until biventricniar failure is detected. this experiment is performed in two diffferent situations: with and without pericardial integrity. results: when pericardial integrity is maintained the mxtrv faced with a pressure overload is . + . nun hg. when this pressure is exceeded there is a circulatory collapse with a sharp fall in the cardiac output and in the aortic pressure. however, when pericardectomy is performed (model similar to ht), only • . nun hg is tolerated (p < . ). conclusions: with the pericardium open, as in heart transplant, the maximum pressure that the right ventricle can support is significantly less than with the pericardium closed. the pericardium has a positive effect in protecting the systolic ventricular interaction. it is, therefore, advisable to close the pericardium after heart transplant. jb prrez-bernal, a ordrfiez, a. heroandez, jm borrego, map camacho, c cruz, mac s~nchez, j monterrubio, c garcia, e. gonz~lez. hospital uulversitario " virgen del rocio ". sevilla. espaiqa. introduction: nowadays cardiomyoplasty isused incases of cardiac insufficiency as an alternative to cardiac transplant. after surgery the patients show a noteable improvement with the aid of this "biological circulatory assistance". some researchers suspect that the improvement could also be due to the formation of new blood vessels from the muscle that wraps the heart, nourishing the ischemic myocardium. objectives: our cardiovascular research group has proposed as an objective, the detection of any possible myocardial neovascularization through the muscle used for cardiomyoplasty. in the case that there are new blood vessels to the diseased myocardium through the wide dorsal muscle in which it is wrapped and which aids it mechanically, it would be possible to confirm the worldng hypothesis that cardiomyoplasty not only improves the cardiocirculatory funcfinn mechanically but also by facilitating a better blood flow to the ischemic myocardium. materials and methods: the cardiomyoplasty technique is described using an experimental model of myocardial ischemia. the vascular cast is achieved by injecting methacrylate simulataneously into both the coronary tree and the wide dorsal muscle, in five experiments the connections between the coronary vascular system and the vascular structure of the wide dorsal muscle are demonstrated, conclusions: we have demonstrated that cardiomyoplasty, as well as improving ventricular function, favours the revascularization of the myocardium. cardiomyoplasty could be indicated for cases of ischemic cardiopathy in patients in whom it is not possible to perform direct revacularization using conventional methods. a the therapeutic cardiological manouevres necessary in cases of ischeima reperfusion have increased considerably: fibrinolysis, transluminal angioplasty, coronary revascnlarization surgery and cardiac transplant. the appearance of a specific pathology ht acute reperfusion has been related to free oxygen radicals (for) generated by oxidative damage. objectives: to evaluate the appearance of for during a conti-olled process of ischemia-reperfusion in an experimental biological model and compare it with that in clinical cases. materials and methods: transitory cardiac ischemia was performed in five rabbits by reversible surgical ligation of the descending anterior coronary artery. after minutes coronary reperfusion was performed. blood samples were taken in the basal situation, at the end of ischemia and at , and minutes after the start of reperfusion. malondialdehyde (mda) was measured to evaluate the degree of lipid peroxidation (oxidative damage to the membrane). in ten patients undergoing conventional cardiac surgery the production of for was measured after aortic clamping. results: we observed that after minutes of reperfusion there was a highly significant increase (p < . ) in the mda values (mean = . /zmols/l). these returned to basal levels after and minutes of reperfusion. conclusions: an "explosion" of oxygen free radicals was detected very quicldy, just a few minutes after post-ischemia reperfusion. thus, if antioxidant agents are to be used to reduce the toxic effects of the for, these will ordy have a therapeutic effect if they are administered in the early phases of reperfusion. introduction: aortic connterpulsation is a ventricular assistance widely used in intensive care units in patients with cardiogenic shock as a provisional ventricular assistance. paraaortic or external aortic counterpnlsation is been investigated as a definitive veutricular assistance in those cases of terminal congestive heart failure and when heart transplantation is counterindicated. aims: to assess the haemodynamic effects of an aortomyoplasty in a biological model of congestive heart failure. material and method: as specimens, we used "large white" pigs. mean weight was kg. after the administration of conventional anaesthesia, dissection of the ladssimns dorsi muscle was performed on the samples at the laboratory of experimental surgery of our hospital. then we performed a thoracotomy at the level of the fourth intercostal space to reach the thoracic aorta. the aorta is dissecated centimetres from the exit of the subclavia and it is wrapped by the dissecated muscle. a cardiomyostimulator is provided in order to allow the synchronization between the diastole and the muscle contraction. the model of heart failure was provoked using verapamil plus propanolol i.v.. results: a significant increase of the aortic diastolic pressures and a significant decrease of the left ventricle telediastolic pressures were observed. this improvement in the parameters (dpti/tti) implies an increase of the coronary perfusion in a model of heart failure. conclusions: using the external aortic counterpulsation, the aortomyoplasty improves the coronary perfnsion and the heart efficiency in patients with heart failure in whom no conventional therapeutic action is possible. the permanent character of the paraaortic counterpulsation is it main advantage. the appearance of specific pathologies as a resuk of myocardial reperfasion has been related to the oxidative damage secondary to the release of oxygen derived free radicals (ofr). during the myocardial ischemia induced during heart surgery with extraeorporeal circulation, severalsubproducts of the oxygen are produced that shall cause toxic effects after the reperfusion which could be counteracted by the physiological antioxidant systems and/or provided by the medication. aims: to asses the ofr during heart surgery. to check whether an antioxidant treatment administered in the preoperative period make decrease the levels of ofr before and after the myocardial reperfusion and to verify whether its administration have any beneficial effect on the intra and extraoperative management. material and method: the study comprehends patients studied as two groups of individuals each (a and b). all patients underwent conventional heart surgery of valvniar substitmion or myocardial revaseularization. group a patients were administered rag/ hours of vitamin e (tocopherol acetate) hours prior to the intervention as antioxidant treatment. group b patient were not administered vitamin e. we assessed the quantity of malondialdehido (mda) to assess the degree of lipidic peroxidation or oxidative damage of the membrane during the myocardial ischemia and nm after the reperfusion. conclusion: patients who underwent heart surgery and were treated with tecopherol acetate in the preoperative period presented levels of rlo significantly lower than those who were not administered the drug, both during the intraoperative period and after myocardial reperfusion. we detected in these patients a need for antiarrhythmicals and pharmacoiogical support with catecholaminas, although not significant, both in the introaperative period and the immediate postoperative period. recommendations for the treatment of pulmonary embolism (pe) in the presence of right atrial thrombus (at) are conflicting. because of a significantly higher mortality rate due to fulminam or recurrent pe, there is a necessity to treat patients (pts) with mobile type a thrombi compared to pts with adherent type b thrombi. therapeutic strategies include anticoagulation, thrombolysis (t) or surgical thrombembolectomy. combination thrombolysis (cot), predominantly used for the treatment of acute myocardial infarction proved to prevent reocclusion of the infarct related artery at a comparable rate of hemorrhagia. benefit has been related to the alteration of hemostatic proteins by non-fibrinspecific thrombolytic s. administration of cot in pe has been performed sporadically. in the present case, a -year old male with no history of prior cardiovascular disease developed acute dyspnea which was related to pe in the presence of deep vein thrombosis of the left femoral vein. therapeutic anticoagulation was installed for a couple of days until there were several bouts of deterioration. biplane transesophageal echocardiography (tee) was performed and revealed a large, wormlike, hypermobile thrombus within the right atrium. computer tomography (ct) of the chest detected a saddle embolus in the bifurcation of the pulmonary tmnk almost occluding the entire left pulmonary artery (pa) and parts of the right pat consisted of mg frontloaded rt-pa and the subsequent continuous administration of urokinase in a dosis of . u/hr for hrs followed by therapeutic anticoagulation. symptoms, blood gases and ecg improved steadily during infusion, no adverse effects, i.e. minor or major hemorragia were registered. follow-up ct promptly after termination of t showed almost complete resolution of the saddle embelus, whereas tee showed complete dissolution of the at. ' finally, the patient was switched to oral anticoagulants and had an uneventful clinical course until he was discharged. conclusion: in the present case, cot was effective for the treatment of a complicated pe without any adverse effect. introduction: nowadays we can assist hearts with problems of insufficiency by techniques other than transplant. many researchers believe that the best way of assisting insufficient heart muscle is with another muscle from the patient. this technique of ventficular assistance is known as cardiomyoplasty. we describe the surgical technique of cardiomyoplasty using a biological model. the transformed skeletal muscle is transferred to the thoracic cavity where it wraps the heart and assists it. the choice and preparation of this muscle is currently under investigation. our group has focussed on the development of protocols for electrical stimulation to transform a skeletal muscle into a muscle which resists fatigue and which is functionally similar to the myocardium. we detect the optimum time at which this muscle has been transformed, by studying the transmembrane action potentials using intracellular electrodes. when the action potential of the trained muscle behaves like cardiac muscle we consider it ready for cardiomyoplasty. conclusions: cardiomyoplasty is an alternative surgical technique to cardiac transplant, which has a great future in the treatment of patients with advanced cardiac insufficiency. we describe methodology which, by intracellular techniques, allows selection of the optimum moment of transformation of a skeletal muscle trained to perform,like cardiac muscle, without suffering fatigue. purulent pericarditis is a rare disease. its treatment associate systemic antibiotics and drainage of the pericardium. we report a ease of purulent constrictive pericarditis in which intraperieardial fibrinolysis was use. a years old patient admitted in our icu for a constrictive pericarditis as a complication of a purulent pericarditis diagnosed seventeen days before. he had also an aehalasia and the o'esogastric endoscopy had found an oesophageal neoplasm. a fistula was not seen, indeed pericardial of flora was the same that oropharyngeal. hemodynamie and echographic study had confirmed a constrictive pericarditis. because of the poor state of the patient an intraperieardial fibrinolysis was prescribed ( . ui of streptokinase on days , , , ). fluid drainage was improved and cardiac output was also improved (day : . .min "i, day : . l.min'l). no change ofhemostasis was noted. a pericardeetomy and an oesophagectomy were performed after days of evolution. eighteen months latter the patient was still alive. intraperieardial fibrinolysis seems an interesting therapeutic way if rapidly prescribed in the purulent pericarditis course. the decrease in the systolic pressure following a mechanical breath, termed ddown (delta down), has been shown to be a sensitive indicator of preload ( , ) . however, the clinical use of this method necessitates the introduction of a short apnea. we have therefore developed a respiratory systolic variation test (rsvt) which obviates the need for apnea. the test is based on the delivery of successive breaths of increasing magnitude ( , , , and ml/kg). a line of best fit is drawn between the minimal systolic values (one after each breath) and the downslope calculated as the decrease in blond pressure for each increase in airway pressure ( mmhg / cmh ). in mechanically ventilated patients the rsvt was performed during controlled mechanical ventilation under sedation. the test was repeated after the administration of ml/kg of plasma expander. the initial mean downslope of the rsvt was -. + . mmhg/cmh . following volume loading the downslope decreased to -. + . (ns). at the same time, cardiac output (co) increased by . + . l/min (p<. ), end-diastolic area (determined by tee) increased from . + . to . + . cm (ns), and paop increased from + to + mmhg ( p < . ). the preinfusion downslope value of the rsvt correlated significantly with the increase in the co (r = . ) and the eda (r = . ). methods: an expert system has been constructed running on a multimedia computer with the two objectives in mind, viz training of inexperienced staff, and protocol guidance with treatment regimes for all staff. the system is based on experience gained from two previous systems, the one for dealing with acid-base and electrolyte problems in icu patients; the second for stabilisation of patients with heart rate and blood pressure abnormalities. the training section takes the form of a stage-by-stage account of the insertion of the pac and displays of correct waveforms, coupled with indications of possible incorrect placements, and guidance when failing to achieve the perfect positioning. the treatment protocol section extends an existing protocol for correcting abnormalities in heart-rate and blood-pressure, and now takes account of all the indices as measured by the pac. the system will suggest treatment to correct such things as abnormal wedge pressures concomitant with parameter values throughout the rest of the cardiovascular system. the type of patient eg post-operative cardiothoracic or i. c. u. trauma, will be taken into account when recognising abnormal parameter values and when prescribing treatment. results: a working system which will be improved by the finetuning being carried out. the results and lessons learnt will be presented at the conference. method: septic shock was defined as severe sepsis with either persistent hypotension (mean arterial pressure; map < mmhg) or the requirement for a noradrenaline (na) infusion ~ . g/kg/ rain with a map --< mmhg. cardiovascular support was limited to na + dobutamine (db). c was given for up to h at a fixed dose-rate of either , . , , or mg/kg/h iv. during c infusion, na was to be reduced and if possible withdrawn, whilst maintaining map above mmhg and the cardiac index (ci) as clinically appropriate. assessments were made at baseline (t = ); at i h from the start of treatment (t - ); and at the end of treatment (t - ) with c . conclusions: c does not appear to increase mpap or worsen pulmonary gas exchange in patients with septic shock, when given by infusion for up to h. c is a novel vasoactive agent for the treatment of septic shock which will now he evaluated in a randomised, placebo-controlled safety and efficacy study. objectives : to compare cardiac output (q) data obtained for thermal indicators in pulmonary artery (qtpa) and aorta (qtao) and for the stable isotope hzo in aorta (q v~ o) with indocyanine green (icg) in aorta (qicg) as reference. methods : an indicator solution of ice cold h ( . ml), h ( . ml) and icg ( mg) was injected as bolus via the injection port of a swan-ganz catheter. qlco and qzmo was measured using a dual optical system (penn lab instruments, philadephia, pa, usa). qtpa and qtao was measured using a in contrast to the recoveries of thermal indicator in pa and h in aorta the :~covery of thermal indicator in aorta was significantly increased in group ii (n= boluses) over group i (n= boluses) ( . <- . vs. . +- . , p= . ). conclusions: the "overrecovery" of thermal indicator in aorta is in agreement with " biscks deconvolution study (i) and results in erroneous values for q. the most pausible explanation is the distortion of the thermal curve caused by the slow response time of the thermal detection instrument as shown by ganz ( ) objectives: to compare data obtained with the double indicator dilution method using indocyanine green (icg) and the stable isotope h for the estimation of extravascular lung water (evlw hzo) to gravimetriu lungwater data (evlwg~). methods: an indicator solution oflcg ( rag) and h ( . ml) was injected as bolus via the injection port of a swan-ganz catheter. dilution curves for icg and zh was registered in aorta with a dual optical system (penn lab instruments, philadephia, pa, usa). cardiac output and mean tranist time was measured for both tracers (qico, tlco, q n o, t o) ( ). data analysis: evlwg~av was reference for evlwzhzo calculated as q hzo times the difference in mean transit time between t nzo and rico (atm n). as reference for atzn o evlwg~,v was divided by q~cg to obtain atg~,. a reference distribution volume for h was calculated as the sum of central blood volume and evlwg=v. boluses were administrated in a group (i) of anaesthetized pulmonary healthy sheep while q was altered. another boluses were administrated in a group (ii) of anaesthetized sheep with stable oleic acid induced pulmonary oedema. evlwg~v measurement was performed postmortem. results: for boluses h parameters were not significantly different from their respective reference parameter: at vao . +_ . s vs. atg~, . + . s, evlwzh o -+ ml vs. evlwg~,~ + ml. in group i the ratio between hzo parameters and respective reference parameters (n= ) were independent of qlco from . to . l/min. obiectives: to assess the thermo dye method using indocyanine green (icg) and thermal indicator for the estimation of lung water (evlwt). methods: ice cold indicator solution of icg ( mg) in water ( ml the aim of the study was to assess left and right ventricular function in the early postoperative period after orthotopic heart transplantation to elaborate therapeutic approaches of heart function abnormalities correction. mathefial and methods. haemodynamic monitoring data of twenty one patients ( men, women ) age from to were studied. cardiac output, pulmonary artery, right atrium and pulmonary wedged pressure were measured with swan-gans catheter. central haemodynamic indices were calculated with the help of computer-based monitoring system. relations of ventricular stroke work index to it's end-diastolic pressure were used for ventficular function assessment. results. in most cases right ventricular disfunction was the main problem. isolated fight ventficular failure with high pulmonary vascular resistance (pvr) was observed in % ( pts), without high pvr-in % opts) and with left ventricular failure-in % ( pts). one of the most important reasons for fight ventricular failure was the time of heart ischemia more than min, which is of great importance in the ease of distance harvesting. the most effective treatment for cardiac failure was combination of dobutamine with i oprotherenol, atrial pacing and vasodilatators in case of right ventfieular disfunction. all cases with isolated right ventricular failure were treated sucsessfully. biventricular heart failure was a sighn of bad prognosis and the reason of death in cases. conclusion. right ventfieular disfunetion is the main problem during transplanted heart adaptation in the early postoperative period. optimal therapeutic management of cardiac disfunction includes infusion of dobutamine in combination with isoprotherenol, atrial pacing and vasodilatators. cardiology-department of clinical centre-kragujevac institution for occupational health "zastava"-kragujevac, sr yugoslavia the aim of the investigate is analisis five years survives patients with a.i.m.in dependence of locality and risk-factors. we ana~sed- ~-pat~e~ts ( males and woman), average , years. for statistic evaluation we used life-table slstem in oder to estimate prognostic determinants. patients with respkatory muscle paralysis may benefit from respiratory assistance by abdomino-diaphragmatie pneumatic belt. we used a non invasive technique, m-mode sonography, to assess the effect of this device on diaphragmatic excursion. we measured the amplitude of right diaphragm motion in seven patients with duehenne muscular dysl~ophy in supine position with various thoracic posture ( ~ ~ ~ without and during pneumatic belt respiratory assistance. without respiratory assistance, the thoracic posture had no significant consequence on the amplitude of diapttragm motion, either in quiet or deep breathing. the pneumatic belt increased the diaphragm motion amplitude from . +__ . mm to . +_ . ram (p = . ) at ~ tilt angle, and from . + . mm to . + . mm (p = . ) at " tilt angle. the tidal volume increased from + to + rut a * tilt angle, and from + to + ml at * tilt angle (p = . ). two patients could not bear the horizontal position ( ' tilt). in the five other patients, the pneumatic belt increased but not significantly the amplitude of diaphragm motion ( . + . mm to . + . ram). after an overnight respiratory assistance, pao increased from . +_. . to + . mmhg ( = . ), sao increased from . + . % to . +_. % (p = . ), and paco decreased from + . to . +_. mmhg (p = . ) according to the ventilatory pattern result, m-mode sonography allows to measure non invasively the improvement of diaphragm kinetics obtained by pneumatic belt respiratory assistance, and may be helpful for its adjustment. objective: to study the effect of flow triggering (flow sensitivity and l/min) vs pressure triggering (-lcmh ) on inspiratory effort during pressure support ventilation (psv) and assited/controlled mode (a/c) in stable copd patients non-invasively ventilated with a full face mask. methods: the patients were studied during randomized min. runs using a bird st ventilator at zero peep (zeep). trigger values for pressure (-lcmh ) and flow ( l/rain) were the lowest allowed by this ventilator. the transdiaphragmatic pressure time product per breath (ptpdi), dynamic intrinsic peep (peepi,dyn), maximal airway pressure drop during inspiration (apaw) andl ventilatory variables (ti,te,ttot,rr,vt and minute ventilation) were measured. results: no major problems due to airleaks or to auto-triggeriffg phenomena were observed in the patients, so that all of them were able to perform all the protocol runs. minute ventilation and respiratory pattern were not different using the two triggering systems. the ptpdi was significantly higher during both psv ( . + . cmh: x sec) and a/c ( . + . ) with pressure triggering, as respect to psv ( . + . , p< . ) and a/c ( . + . , p< . ) with flow triggering ( l!m). no differences were observed between and l/min flow triggers. apaw was also significantly larger during pressure triggering; peepi,dyn was reduced during flow triggering being . + . cmh (psv flow trigger) vs . + . (psv pressure trigger) and . +_ . (a/c flow trigger) vs'f~ +l (atc pressure trigger). conclusions: in stable copd patients non-invasively ventilated, flow triggering reduces the respiratory effort during both psv and aic mode as compared to pressure triggering. this may be partly due to a decrease in peepi,dyn using a flow-by system. objective. cardiac output is higher during alternating ventilation (av) (i.e. differential ventilation of the lungs with a phase shift of half a ventilatory cycle) than during synchronous ventilation (sv) of both lungs . we verified the hypothesis that the higher cardiac output depended on a lower central venous pressure and intrathoracic pressure, due to a lower mean lung volume, which we attributed to part of the expansion of the inflated lung at the expense of the expiring, opposite lung . we studied this interaction between the lungs during one-sided inflation, which we called cross-talk. method. in anaesthetized and paralyzed piglets we applied short periods ( s) of one-sided ventilation ( breaths per rain, bpm), while the other lung was open to the ambient air. the air flow into the non-ventilated lung during expiration of the ventilated lung was integrated to volume. we studied -to-r and r-to-i cross-talk at ventilatory rates of , and bpm. the amount of cross-talk was the volume displacement in the non-ventilated lung. results. during bpm the r-to-i crosstalk was _+ . % (mean +__ sd) of the tidal volume to the right lung and the -to-r crosstalk _ . % of the left tidal volume. both values increased at bpm to _ . % (p < . ) and _ . % (p < . ) respectively. the values at bpm were in between., conclusion. we concluded that the lower mean lung volume and lower thoracic expansion during av compared to sv depends on partial expansion of the inflated lung into the non-inflated lung, resulting in a lower mean intrathoracic pressure as the main reason for the higher cardiac output during av. obiective: natural surfactant given for rds in premature infants leads to a rapid improvement in oxygenation, but lung compliance did not improve in most studies. however, acute effects on lung mechanics during and immediately after surfactant administration have not been studied before. methods: a total of administrations of bovine surfactant in recommended doses was given via a small catheter into the distal endotracheal tube either as a bolus (n = ) or as a slow infusion (n = ) in infants with established rds. static compliance (c), resistance (r) and time constant (tc = cxr) of the lung were measured every minutes with a lung function cart (sensormedics ) without interrupting ventilation. infants receiving synthetic surfactant were studied as controls. results: after surfactant as a bolus or during infusion c first decreased but then increased, whereas r increased immediately with great fluctuations but did not return to baseline. this pattern was more pronounced in infusion than in bolus administration. change of c and r varied greatly in the individual case, maximum c was > %, maximum r > % of baseline value. retreatment was followed by an increase in r in all patients, but c increased only in the one who was responder. patients receiving synthetic surfactant had no change of c or r and were non-responders. ob~i ctives= acute lung injury (ali} sometimes induces severe hypoxernla which may be refractory to conventional modes of mechanical ventilation (mv). the elm of this study was to observe some cardio-pulmonary effects of an alternative method of ventilatory management of severe ali. five patients with severe ali (murray scores > ) requiring mv were studied. protocol inclusion was considered when a control-mode of mv (with a pzo~=l. and a peep level < cme=o} was not able to get either a p.ojf=o= ratio > or a s.o= > %. patients were sedated, paralyzed, and a ventilator (serve c) was used for pressuz'e-control ventilation (pcv). fio= was maintained at . and peep removed. continuous gas flow ( • ml/kg] was humidified and jet delivered through a tube ( ram id, ml capacity, . ml/cm h=o compllancel ended in a nozzle ( . mm is) attached to the endotracheal tube connector. a thermodilution flcw-dlrected catheter was inserted in pulmonary artery. following variables were recorded minutes before and after protocol started: tidal volume (vt), minute ventilation (vz), intratracheal pressures (p~w), wedge pulmonary artery pressure (wp), central venous pressure (cvp), mean arterial pressure (map), cardiac index (ci), arterial and mixed venous oxyhemoglobin saturation (sao=, svoa) , oxygen delivery (do~) , oxygen consumption (vo ) , intrapulmonary shunting (q./qt) , and oxygen extraction ratio (ero). this observation suggests that hfpv could allow to ventilate at lower fin and improve blood oxygenation during the acute phase after inhalation injury reducing toxicity risk related to high fin . further studies are necessary to confima these results and evaluate the possible implications on mortality alter smoke inhalation and for other icu pts. objectives: to design a system for volume controlled high frequency ventilation (hfv) and to estimate the dependence of the tidal volume (vt) on frequency (f) in normocapnic ventilation in rats at frequencies - hz. methods: a new system for volume controlled hfv was devised consisting of the generator of the constant flow during inspirium and the constant pressure during expirium. the ventilator allows ventilation at frequencies - hz with the relative inspiratory time (ti) . - . . the airway pressure was measured at the proximal port of tracheostomic cannula , at the same site inspiratory and expiratory flow was measured using modified lilly-type of pressure-differential flow sensor. non-linearity of flow sensor was compensated on line by derived equation based on calibration at static and dynamic conditions. flow and pressure data were evaluated on line using original software. value of the positive end expiratory pressure (peep) was serve-regulated by analogous feed-back. in animal experiments white wistar rats ( - g) narcotized with ketamine/xylazine with cannulated carotid and femoral arteries were kept at the rectal temperature ~ the arterial pressure was monitored. after traeheotomy the metal cannula ( mm [.d.) was inserted, animals were curarized and ventilated at the following condition: peep = . kpa, ti = . . the dead space of ventilator including canula was . ml. the initial frequency was hz and rain after each change of the ventitatory regimen the blood gases analysis was performed. the frequency was changed according to the following schedule : hz--> hz--> hz--> hz--> hz--> hz--~ hz--> hz. vt for each frequency was regulated to maintain normocapnie ventilation with arterial pco = + mm hg. the arterial po was always above mm hg. results: for normocapnie ventilation in rats the following tidal volumes vt [ ml/kg] were found : vt = . --+ . ml/kg for ft = hz, vt = . + . mukg for fz = hz, vt = . +_ . ml/kg forf = hz, vm = . + . ml/kg forf = hz andvmt= . + . mukg for fs = hz (presented as mean values _+ s.d., n = ). the regression analysis using the mean values resulted in the equation for normocapnic vt in rats in our experiments : vtn = . * f-e. . conclusions: the described system allowing ventilation in a wide frequency range - hz with accurate measurements of airway pressures and vt might be useful for optimisation of artificial ventilation in new-barns with different lung pathologies. supported by grants iga mz cr nr - and gacr nr . s intensive care unit. university. hospital of south manchester, uk. methods: measurements were conducted on ventilated patients (puritan bennett ac with metabolic monitor pb set to measure end tidal co ). all measurements were repeated with the patient stabilised at cm. cm and cm peep. inclusion criteria were: ) haemedynamic stab(l( .ty for hr; ) pulmonad" anon" flotation catheter in situ: ) volume control ventilation with plateau of . s: ) fio ~ > . to maintain pao~. > kpa with em peep: ) qs/ot > %; ) pao /fio ratio < . measured variab!es included: r minute volume: plateau ainvay pressure: applied and intrinsic peep: fractional end tidal co ; arterial and mixed venous blood gases and hacmod).ttamic variables. results: statistical analysis was performed using repeated measures anova. significant decreases in cardiac index (ch p< . ), compliance (p<t). ) and o,'gcn deliver, index (do , p< . ) occurred with increasing peep (table ) . no other variable showed any significant change. methods : all consecutive patients orally intubated in the micu between january to april were studied. etts were positioned according to the reference marks mentioned above (measurements from upper incisors). the position of the ett tip in relation to the carina was measured on the chest radiograph done with the patient's head in neutral position. results : a total of men and women were studied (n= ). the mean distance of ett tip to carina was . cm. using the reference markings, cases ( . %) had the ett tip < cm from the carina and cases ( . %) > cm. one case resulted in an endobronchial intubation. the mean height of all patients were cm ( - ) for males and cm ( - ) for females. of the patients with ett tip < cm from carina, the mean height was cm and cm respectively. ~ onclusion : adopting the above quoted reference marks did not result in ideal positioning of the ett in a significant proportion of cases ( . %). we postulate that [s because our asian population is generally shorter than those in previous studies. objectives: to measure the changes of pulmonary mechanics before and after tracheostomy in patients with prolonged mechanical ventilation and to determine factors that predict the outcome of liberation from mechanical ventilation. design: prospective. setting: respiratory intensive care unit (ricu) in a tertiary hospital. patients: twenty patients with chronic lung disease requiring long-term mechanical ventilation. tracheostomy is indicated for further care. intervention: tracheostomy. measurements and results: pulmonary mechanics including respiratory rate (rr), tidal volume (vt), peak inspiratory pressure (pip), intrinsic positive end ex~ piratory pressure (peepi), lung compliance (cld), mean airway resistance (rawm), work of breathing (wob), pressure time product (ptp) by bicore cp- pulmonary monitor were recorded hours before and after tracheotomy. ventilator setting parameters remained the same during surgical intervention and were also recorded for comparison. generally, the mechanics including pir wob, raw~x and ptp showed improvment after tracheostomy. but only pip was significantly reduced (pre . _+ . to post . _+ . , p < . ). changes of wobp showed significant correlation with pre-operation rr, minute volume (mv), wobp, and peep(. changes of raw m were also significantly correlated with pre-operation peep, vt, and raw m. the patients were divided into two groups according to their outcome after two week follow-up. group included eight patients who were completely weaned from ventilator; group included twelve patients who still remained ventilator-dependent or were mortality. there was no difference in age, duration of mechanical ventilation, pro, post or changes of several lung mechanics between the groups of patients. pre-tracheostomy peep i and cld showed significant difference between these two groups ( . _+ . vs . + . in peepi; . _+ . vs . _+ . in cld, p < . ). pre-tracheostomy ventilator setting in mode of assist/control also showed significant higher percentage in group ( % % in group vs . % in group ). conclusion: in prolonged mechanical ventilation patients with chronic lung disease, tracheostomy will significantly improve pip and slightly reduce wobp, raw m and ptr patients who used pressure support mode before tracheostomy had better underlying lung conditions (lower lung compliance and auto-peep) will have better chance to wean from mechanical ventilation. forty-eight infants with congenital diaphragmatic hernia presenting within the first hours of life, who underwent surgical rapair,were analysed prospectively in order to produce a reliable inde x of severity of disease that would reliably predict eventual outcome. there were survivors and deaths in this series (mortality %).using arterialpco values measured hours after surgical repairand correlating them with an index of mechanical ventilation,we have been able to clearly define two groups of diaphragmatic hernia based on their response to hyperventilation. the first group, with co retention and severe preductal shunting,was unresponsive to hyperventilation with high rates and pressures the mortality was %. the second group responded well to hyperventilation and demonstrated reversable ductal shunting only. survival in this group was %. arterial co accurately reflects the degree of lung development in this disease and separates those patients with severe pulmonary hypoplasia where the outcome is invariably fatal, from those with a well developed contralateral lung where there is excellent potential for survival. respiratory failure unit, dpt medicine, univ. thessaloniki, thessaloniki, greece the variability of arterial blood gases (po , pc ) and the ph (abg) was examined in stable icu patients, few hours before a successful weaning from the ventilator. all patients were lightly sedated and the ventgatory conti~ons were pressure support (ps) for and ps plus intermitted mantatory ventilation in ii. [n each patient, speciments of abg were measured at min intervals during a - study period. at the same time with abg the arterial blood pressure (bp), the heart rate (cf), the tidal volume (tv) and the respiratory rate (n r were measured. for all the patients, the mean coefficient of variation (c) was . percent for po , . percent for pco and . percent for hco . the average sd for ph was . , the corresponding c for systolic bp, diastolic bp, cf, tv, rf were . , . , . , . , . percent. we conclude that the spontaneous variability of arterial blood gases in icu patients is not substantial ~hen they have stable the heamodynamic and the ventilatory parameters. deptx?fa'aaesthesioiogy and reanimation, rhe sechenov medical academy, moscow, russia objective: ~he prevention and treatment of hypoxia in the critical patiems. methods: i~fusions of perphtoran -a blood substitute with gas-transporting fimclion based on perphtorhydrocarbon -in patients with acute hypovolemia, microcirculatory distnrbance~ tissue gas exchange and metabolism; pulmonary iavage in ; iongterm extrapulmonary oxigenation with tleoroearboa oxygenator in combination whb ~trafiltra!ion, hemosorption and hemodialysis -in patients. results: pe~htoran increases blood volume, co,sv, decreases svr, improves capillary blood flow, increases the blood oxygen capacity, tissue oxygen tension, del, vo by improving the rheologic properties of blood and plasma, normalizes ext., prevents and eliminates fat embolisation and ards. decreases the need for blood transfusions and infusions of plasma expanders by . - . limes. alveolar venti!ation-perfusion ratio remains unchanged with its increased effective utilization. there was no surfactant destruction during lavage. extrapulmonary oxygenation of small volumes of venous blood eliminates venous destruction and then arterial hypoxia and increases pulmonary oxygenation. the use of lluorocarbon cxygenators during hemosorption and hcmodialysis provides the atraumatic and iongterm oxygenation of arterial blood and increases elimination of co which prevents the development of hypoxic complications. conclusions: perphtoran and fluorocarb~n oxygenators are effective in the correction of hypoxia in the criticat patients. objeqtives: to determine if there are differences in oxygen consumption (vo ) during weaning from mechanical ventilation (during total ventilatory support and spontaneous ventilation with cpap), and to compare different predictive parameters of weaning in predicting success of weaning. methods; prospective study in critically ill patients treated with mechanical ventilation for at least h, who fulfilled at least of standard weaning criteria (vt> ml/kg; respiratory frecuency (f) < ; pimax > cm h ; pao /fio > ). baseline measurements: t, vt, p . , pimax, f/vt, p . *(f/vt), p . /pimax. study protocol: measurement of vo , vco (medgraphics), vt, f, ve, and arterial blood gases during total ventilatory support (cmv), and after and minutes of spontaneous ventilation with cpap cm h . the weaning trial was stopped, failure to wean diagnosed, and mv resumed it a patient presented significant tachypnea, tachycardia, bradycardia, cardiac rythm disturbances, hypertension, hypotension, hypoxemia or hypercapnia. results: four patients did not complete the weaning trial, were extubatad, and of them had to be reintubated before h, being considered also weaning failures. during cmv, vo /kg was . + . ml/kg/min, and . _+ . mlo- /kg/min after ' on cpap cm h (p < , ). of patients ( %) with standard criteria were extubated, while only of ( %) with criteria (p< , ). next objectives: compare the extent and distribution of lung injury in dogs preinjured with oleic acid (oa) and ventilated with high tpp and adequate peep in the prone and supine position. methods: lung injury was induced with oa ( . - . ml/kg) in anesthetized, paralyzed, and intubated dogs (n= ) during volume controlled ventilation: rate= /min, peep= cmh , ti/ttot= . , fio = . , vt= ml/kg. animals were rotated during the oa infusion and the following minute stabilization period to assure uniform injury. in the supine position, peep was set - cmh above the lower inflection point (as determined by the pressure-volume curve), and vt was set to obtain a tpp of cmh : animals were ventilated in either the prone (n= ) or supine (n= ) position for four hours. pulmonary artery occlusion pressure was maintained constant ( - mmhg) with saline infusion. at the end of the protocol the lungs were removed and divided by template into dependent (d) and nondependent (nd) sections for wet weight/dry weight (v~n/dw) and grading of nstologic lung injury (hli; scale - ). oseillatron | is a pneumatic device that generates high frequency, oscillation by means of a reciprocating system in the form of a membrane. it generates sinusoidai wave form at ( to ( cycles/rain. the system does not deliver gas but must be adapted to the proximal respiratory, circuit of a conventional ventilator, resulting in ci-ifo. it was developed to enhance intrapnlmona~ diffusion during mechanical ventilation and to mobilise endebronchial secretions. methods. we measured arterial blood gases and haemedynamics during a first period of conventional ventilation (cppv) followed by. two rain periods of chfo (sequences : ( and ) c/rain : group l, n = l: and c/rain : group , n = ). measurements were made at the end of each period. cardiac output was measured using thermedilution method: flu and peep were kept unchanged throughout the study. intrinsic peep was also evaluated by, means of an occlusive valve. results. pa is not significantly modified during chfo at or c/rain. paco is slightly decreased at c/rain (p = .( ). however, intrinsic peep remains unchanged. there is no sequential effect (gr. l vs gr. ). there is no more effect of chfo for patieets who are at a flu higher than . (n = ). no changes in haemodynurmcs are observed except a slight increase in central venous pressure (cvp) during ci-ifo (p < .ol). obiectives: to examine the effects of inspiratory muscles unloading on neuromuscular output at controlled levels of chemical stimuli. methods: the ventilatory response to co was examined in ten normal subjects using rebreathing method. ventilation ~) and respiratory muscle pressure output (pmus) at the same end-tidal partial pressure of co (petco~) were compared with and without combined flow and volumeproportional pressure assist in two protocols (a and b). protocol a (n = ): two levels of assist were studied; flow assist (fa) of cmh /i/sec and volume assist (va) of cmh /i (assist ), and fa of cmh /i/sec and va of cmh /i (assist ). all conditions were applied randomly. v~, tidal volume (vt) and breathing frequency (f) were measured breath by breath and plotted as a function of petco~. protocol b: in subjects, in addition to above measurements, esophageal (pes) and gastric (pg) pressures were measured and the time courses of transdiaphragmatic pressure (pdi) and pmus were calculated. one level of assist (assist ) was studied in this protocol. results: in both protocols inspiratory muscle unloading did not change the f response to c%. compared to control, with assist v t response was displaced upwards; at petco of mmhg v t was increased significantly by . + . i and . + . i in protocol a with assist end , respectively, and by . _+ . i in protocol b with assist (p< . ). ~/~ responses showed similar changes as vtresponses. in both protocols the slope of v~ response (s did not change significantly with unloading. at low petco~ ( mmhg), pdi and pmus waveforms did not differ with and without assist. with unloading, at high petco ( mmhg), pdi and pmus at the end of neural inspiration decreased by . -+ . % and . + . %, respectively, from control values. neither change was significant (p> . ). by theoretical analysis we estimated the expected changes in vt and ~/~ when the levels of assist used in both protocols were applied in the absence of : any change in neural output response to co z. the predicted response was similar to that observed, indicating that the small difference in pdi and pmus between control and unloading runs was due to intrinsic properties of respiratory muscles end respiratory system. conclusions: these results suggest that when chemical stimulus is controlled, respiratory motor output is not downregulated with unloading. the determinants of the response of the respiratory output to inspiratory flow rates (v~) were examined in awake normal subjects. subjects were connected to a volume-cycle ventilator in the assist/control mode and v~ was increased in steps from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. in six subjects the effects of breathing route (nasal or mouth) and temperature and volume of inspired gas (protocol a) and in subjects the effects of airway anesthesia (upper and lower airways, protocol b) on the response of respiratory output to varying v~ were studied. in protocol b, in order to calculate muscle pressure during inspiration (pmus), respiratory system mechanics were measured using the interrupter method at end-inspiration. independent of conditions studied breathing frequency increased . significantly and end-tidal concentration of c% decreased as v~ increased. the response was graded and reversible and not affected by breathing route, temperature and volume of inspired gas and airway anesthesia. with and without airway anesthesia (protocol ) neural inspiratory and expiratory time and neural duty cycle, estimated from pmus waveform, decreased significantly as v~ increased. at all conditions studied the rate of change in airway pressure prior to triggering the ventilator tended to increase as v~ increased. the changes in timing and drive were nearly complete within the first two breaths after transition with no evidence of adaptation during a given ~/~ period. we conclude that v~ exerts an excitatory effect on respiratory output which is independent of breathing route, temperature and volume of inspirate and airway anesthesia. the response most likely is neu~'al in origin, mediated through receptors not accessible to anesthesia such as those located in chest wall or below the airway mucosa. it has been shown, in mechanically ventilated awake normal humans, that increasing inspiratory flow rate (~/~) exerts an excitatory effect on respiratory output. it is not known if this effect persists during sleep. to test this seven normal adults were studied during wakefulness and nrem sleep. subjects were connected through a nose-mask to a volume-cycled ventilator in the assist/control mode and ~/t was increased in steps ( - breaths each) from to i/min and then back to i/min. v~ pattern was square, and all breaths were subject-triggered. forty-one trials during nrem sleep and during wakefulness were analyzed. both during sleep and wakefulness minute ventilation increased and total breath duration (ttot) decreased significantly in a graded and reversible manner as ~' increased. these changes were complete in the first breath after v{ transition. the response was significantly less during sleep than during wakefulness (p< . ); at i/min ttot, expressed as % of that at i/rain, was . +_ . % during sleep and . +_ . % during wakefulness. during wakefulness, at i/min, the rate of change in airway pressure prior to triggering the ventilator, an index of respiratory drive, was % of that at i/min (p< . ). the corresponding value during sleep, was % (p> . ). in four sleeping subjects the increase in v~ was sustained for . - min. there was no evidence for adaptation of the response; tro t, averaged over the last three breaths, did not differ from that obtained when vj was sustained for only - breaths. we conclude that ) vt exerts an excitatory effect on respiratory output, mediated by a reflex neural mechanism and ) the gain of this reflex is attenuated by sleep. chest radiographs is a common complementary technique for patients in critical care units, with a low cost and easily available. however, it has certain well-known limits in diagnosis, the most important derived from the low quality of some pictures. in this paper we make a general review of some new technical approaches developed for improving the quality of the images, and so incrensing the diagnostic value of conventional radiology. we begin deaeng with the correct positioning of the patient, trough the filtering techniques, the synchronization of radiology and ventilation, and we make reference to the new computerized systems for digital image processing. conclusions: the portable radiographic system is a device that probably with maintain for many years in critical care units as a basic non-invasive diagnostic tool. but we need an increase in the efficiency of it, applying means as simple as a correct positioning of the patient, or the use of fitlers or synchronizers. thus we should improve the general standards of portable radiography. "are circular circuits safe? quantifying undelivered tidal volume in pediatrics patients". objectives: to evaluate the overall influence of internal compliance of circular circuits on delivered tidad volume (vt). methods: we studied prospectively asa i pediatrics patients ( to yr. old) scheduled for elective general surgery. mechanical ventilation was supplied by an ohmeda excel (circular circuit). the internal compliance of the circuit (cc)-anesthesia machine plus external circuit-was determined by the supersyringe method: corrugated dar tubes of mm. id and . m. long (children < kg), and a corrugated dar set of mm. id and . m. long (children > kg) were respectively used for ccl an cc values of . and . ml/cm h . a vtof mlg/kg and respiratory frequency was adjusted for an end-tidal co (etpco ) between mmhg. tidal volumes (measured by spirometry) and airway pressure (paw) data were recorded every ten minutes. volumes and thorax-lung compliances were calculated as follows: (vt delivered = vtadjusted-vol compressible, being vol. compressible = co x ppeak (aw). apparent compliance (ca) = vt adjusted/pplateau(aw), and true compliance (ct) = =vt delivered/pplatean(aw)). comparative statistics were separately designed between calculated compliance data and tidal volumes on a paired sample ~test basis. results: calculated values for volumes and thorax-lung compliances were: conclusions: due to the elevated internal compliance of the circular circuit there is a remarkable dilference between adjusted and delivered vt: mean undelivered vt was . % and reached as high as . %. teere is also a significative error in calculating true thorax-lung compliance: its overestimation can be as high as . %. circular circuits are considered safe and cost-saving for anesthetical practice. nevertheless we conclude that anesthetists should bearin mind vt losses when using circular circuits, due to compressible volume. tracheal stenosis is one of the most serious complications of patients submitted to prolonged endotracheal intubation, in which the decrease in inner diameter of upper airway makes it very difficult to achieve a correct ventilation. objectives: compare the results of applying high frequency jet ventilation (hfjv) to some of these patients with conventional controlled ventilation (cmv). methods: we used a prototype of high frequency jet ventilator (santiago- ) developed in our university, and we developed a tracheal tube in wich we modified the distal tip (conic tip). we applied this system to two patients which were initially ventilated in the operating room with usuai controlled mecanical ventilation (cmv) following the standards of our department, and then intubated with the special endotracheal tube and ventilated with hfjv. results: we could verify a proper ventilation of both patients with cmv and hfjv. during hfjv, the airway pressures were lower than those recorded during cmv. a lower airway pressure prevents lesions due to high pressures. conclusions: hfjv is a good method of ventilation for patients with significative stenosis of the trachea, not only during surgical procedures, but also during ventilation for long periods in critically patients. the ventilatory setting is pressure support mode. the pressure level and fit were kept constant during h/d. arterial blood gas, wbc count, and mean bp was checked according to the schedule: '(immediately before h/d), ', ', ', ', ', '. respiratory drive (represented by poa), tidal volume(ti) and minute ventilation(ve) were continuously recorded by pulmonary mechanics monitor (bicore cp- ). the mean value of the breaths minutes before blood sampling were used to represent the ventilatory status of that period. anova test is used for comparison between groups. for poa, hierarchical cluster method is applied to divide the cases into two groups of similar change. conclusions: our data suggest that pl is very useful, non invasive and low-expensive emergenc e support for arf, expecially in the elderly with severe chronic pulmonary disease and relative controindications to eti. pl seems to be an effective alternative when it is not immediatly possible to perform etl. the multiple inert gas elimination technique (miget) can be used to assess the effects of any given mode of mechanical ventilation on the pulmonary and systemic factors determining arterial po and pco> however, a potential problem in mechanically ventilated patients is that the l mixing box (mb- l) placed in series in the expiratory side of the circuit of the ventilator to sample mixed expired gas may provoke substantial discrepancies between the tidal votume set in the ventilator and the effective tidal volume delivered to the patient, due to the increase in the compression volume (vc) of the circuit. the effects of the mb- l on the v c were compared with those produced by a new l mixing box (mb- l) specifically designed to produce adequate gas mixing and to prevent loss of the two most soluble gases (ether and acetone) used in the miget. at any given peak cycling pressure (p~ak, cm h~o), the v c (ml) provoked by the mb- l was substantially higher (vc= . *ppeak) than that provoked by the new mb- l (vc= . *ppeak). at a ppeak = cm h ~ the v c were ml (mb- l) and m{ (mb- l), respectively (p< . ). in a group of subjects ( m/ f, _+ years), for each of six the gases used in the miget, the regression line between the mixed expired partial pressures simultaneously obtained from mb- l and mb- l fell on the identity line. it is concluded that the new mb- l allows adequate assessment of the effect of different modalities of mechanical ventilatory support on pulmonary gas exchange, with less potential for gas compression and thus hypoventilation. objectives evaluate the influence of different pressure support ventilation (psv) levels on cardiovascular and respiratory funcion in icu polytrauma patients. metbed&we studied polytrauma icu patients , who were in weaning process , after long term mechanical ventilation for acute respiratory failure . mean age ( - ) yrs . they all were connected to servo ventilators siemens c , and all were in stable condition , without sedation , inotropes or diuretics. the hemodynamic studies were done with continuous svo , swan ganz catheter (oximetrix, abbott). they all were in spontanuous mode (spent) with cm h cpap for at least one hour. we turned them to psv with inspiratory assistance (psv cm h ) and after rain we applied psv cm h , and after min psv cm h . hemodynamlo and respiratory measurements were done before and after the application of insiratory assistance. the results were statistically analyzed with anova. resets . respiratory variables . no significant changes in minute volume (ve). tidal volume (vt) and mean airway pressure (mpaw) increased statistically significant (p< . ) . respiratory rate (rr) decreased significantly (p< . ) . blood gase showed no difference . cardiovascular variables. cardiac output (co) decreased ns , heart rate (hr) had no change , central venous pressure (cvp) , mean pulmonary artery pressure (mpap) , pulmonary capillary wedge pressure (pcwp) , increased ns , oxygen delivery (do ) decreased ns, oxygen consumption (vo ) decreased ns. conclusions. psv is a very useful respiratory mode helping patients to be weaned from long term mechanical ventilation . it has beneficial effects on respiratory function and oxygen consumption without affecting seriously the hemodynamic parameters, possibly due to a decrease of the work of breathing. a. michalopoulos, a. anthi, k. rellos, j. kriaras, s. geroulanos intensive care unit, onassis cardiac center, athens. objectives of this study was to examine the effect of different levels of peep on postoperative svo and pvo values in a group of patients, following open heart surgery. methods: upon transfer to icu, patients ( males and females) of mean age _-+ years, were randomly assigned to receive (n= ), (n= ), or cm of peep (n= ). there were no statistically significant differences in demographic data or preoperative respiratory status among the three groups. all patients were ventilated on the assist control mode with a tidal volume of ml/kg. the fraction of inspired oxygen (fio ) was adjusted to keep a pao around mmhg. mixed venous po and svo were measured at min, and hours after application of mechanical ventilation in the icu, just before extubation (be), half hour after extubation (ae), and at hours post-extubation. differences at each study time were analysed by anova. results: mean svo and pvo values among the three groups, for all study intervals, are presented in the table. conclusion: we found no differences (p=ns) in tissue oxygenation (expressed by svo and pvo ) among the three groups, at any study interval, in the early postoperative course of patients following open heart surgery. intrinsic peep (peepi), and high elastance and resistance increase inspiratory work load in copd. cpap reduces work of breathing by counterbalancing peepi. pav provides flow (fa) and volume (va) assistance proportionally to patient resistance and elastance and inspiratory effort. we studied the effects of partitioned support (cpap-fa-va) on breathing pattern and inspiratory effort in five copd patients on pav compared to spontaneous ventilation (sv) and full support (fs: cpap+fa+va). flow, volume, minute ventilation (ve) respiratory rate (rr), inspiratory swing in esophageal pressure (apes), and its integral per breath (pti/b) and per minute (pti/m) were measured. objectives: to evaluate airway pressure fluctuation (apf) during spontaneous breathing in a high compliance cpap system. methods: the cpap system consisted of two l weighted balloons in a wedge shaped holder. ventilating gas flowed from one balloon through a low resistance one way valve into a tracheal tube (ett) provided with a pycor co sensor to monitor rebreathing. the ett was connected to a piston drive mechanical lung. expired gas flowed through a low resistance valve into a second weighted balloon, from where it was exhausted through a peep valve connected in parallel with the second weighted balloon. we evaluated system performance at v r from to ml, at rr from to bpm, while closely monitoring cpap airway pressure swings. at v v of and ml the rr was limited to bpm. for comparison we explored aps of a one l balloon cpap system, the cpap mode of the puritan bennett , and siemens ventilators, when connected to a healthy adult volunteer breathing through an ett. results: the compliance (cpl.) of one l balloon system was linear over a range from . to . l, with a cpl. of . l/em h .the cpl. of the l balloon ( . l/em h ) was linear between a volume of and . l. apf of the weighted balloon system was under em h at all v r (except at a v r of ml aps was . em h ), while the apf in the l balloon was up to em h . apf witli human volunteers with the two commercially available ventilators in the cpap mode was about cm h ; while under identical conditions apf in the l balloon system was . emhzo; and in the two l balloon system was below lcm h . conelusions: cpap using the two balloon system exhibits lower airway pressure fluctuations than a single balloon system; and is substantially lower than found in the two commercially available ventilators when used in the cpap mode. objective: to perform independent lung ventilation (ilv) with individual tidal volume (vt) set at a value generating a plateau airway pressure (pplat) < crnh~o and to evaluate the usefulness of the continuous monitoring of endtidal co (etco ) as a guide to titrate individual lung vt during ilv and for the weaning from ilv. methods: in seven patients, ilv was performed with ttvo ventilators set with the same fio: and respiratory rate. each lung was ventilated with a vt that developed a pplat < cmh~o. this setting led to a lower vt on pathological lung (pl). vt was increased in pl following etco~ and paco -etco variations. ilv was discontinuated when etco~., vt and statical compliance (cst) were similar in both lungs. results: one hour after starting ilv (ti), pl mean vt was significantly lower than in normal lungs (nl) ( + ml vs + ml, p< ) two individual behaviours were observed on tl in pl: four patients presented low etco: (range - mmhg)and normal pacoz (range - mmhg), while three patients had normal etco (range - mmhg) with high pac (range - mmhg). one hour before stopping ilv (t ), vt, etc and paco were the same in each lung. the pao /fio: ratio improved in all patients from the beginning ofllv cst of pl was + % of the normal lungs' cst on ti and improved to . + % ofnl's cst on t (p< . vs conclusions: setting vt of pl to a value not overcoming a pplat threshold does not impair oxygenation and is helpful in avoiding barotraumatism. measurements of differential etco and of the differential paco -etco gradient can be used to titrate vt allocation during ilv and as a guide for the weaning from ilv. total respiratory resistance in mechanically ventilated patients exceeds values obtained in normal subjects, due to the added and highly flow dependent resistance of the endotracheal tube (rett). this can adversely effect the efficacy of pressure regulated modes of assisted ventilation, such as pressure support (psv) and proportional assist ventilation (pav). recent work demonstrates that the influence of rett during psv can be overcome by using tracheal (ptr) rather than airway opening (pao) pressure to regulate the pressure applied (intensive care med :$ , ) . the purpose of this study was to see if this approach would also be effective during pav. flow, volume, pao, ptr, and transdiaphragmatic pressure (pdi) were measured in intubated patients in which either pao or ptt were used to regulate the pressure applied during pav where volume assistance was varied from to % of respiratory elastance. representative results (mean + se) are shown below. compared to spontaneous breathing (pav %), pav increased tidal volume (vt) while reducing respiratory rate (rr) so that minute ventilation ('~e) also rose. this was associated with a reduction in inspiratory effort, as reflected by a decrease in the pressure-time integral ( [ p) of pes and pdi both per minute and per liter ~re. the effects on breathing pattern were similar for pao and ptr regulated pav. in contrast, the reduction in inspiratory effort was always greater for ptr regulated pav. in conclusion, the volume assistance provided by pav is more effective when ptr rather than pao is used to regulate the pressure applied. pav methods: retrospective data analysis of adult patients with normal pulmonary function before operation and uneventful course following coronary artery bypass graft surgery over an month period. we compared assist/controlled mandatory ventilation (s-cmv, patients), synchronized intermittent mandatory ventilation with inspiratory pressure support (s-imv/psv, patients) and biphasic positive airway pressure ventilation (bipap, patients). results: patients ventilated with bipap had a significantly shorter mean duration of intubation ( . h, p< . ) than patients treated with s-imv/-psv ( . h) and s-cmv ( . hi. with s-cmv . % of the patients required single or multiple doses of midazolam but only . % in the s-imv-/psv group and . % in the btpap group. the mean total amount of midazolam of these patients was significantly higher in the s-cmv group ( . mg) than in the s-imv/psv group ( . mg, p< . ) and in the bipap group ( . mg, p< . ). the consumption of pethidine and piritramide did not differ between s-cmv and s-imv/psv but was significantly lower during bipap (p< . ). after extubation the paco patients was highest in the s-cmv group. conclusion: ventilatory support with bipap reduces the consumption of analgesics and sedatives and duration of intubation. unrestricted spontaneous breathing as well as fully ventilatory support allow adequate adaptation to the patients requirements. bipap seems to be an alternative to s-cmv and sqmv/psv ventilation not only in patients with severe ards but also in short term ventilated patients. _objectitives: after end-inspiratory airway occlusion we examined the ensuing gradual decrease in tracheal pressure (ptr) with the following equations proposed by bates et al. and hildebrandt: pv = p'v e'~cccl~ +pst, rs (bates) [ ] where p'tr is tracheal pressure immediately after occlusion, to= is occlusion time, "r is viscoelastic time constant of respiratory system, and p t is static elastic recoil pressure of respiratory system. p~(t) = h -h log t (hildebrandt) [ ] where h~ and h are parameters depending on lung volume, and initial time is s for analytical reasons. materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecuronium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pressure was measured in the trachea. flow was measured with a pneumotachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a frequency of hz and processed on a pc. the influence of the cardiac artifacts during the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean (+ sd) coefficient of correlation using eq. was , -+ . , and using eq. was . + . . the values ofz~ (eq. ), however, decreased with increasing the tidal volume (vt) according to the following equation: "~ = . - . v t, similary, the values of h~ and h increased with increasing v t according to the following functions: h~ = . + v i and h = . + . v t. conclusions: the behaviour of "% of eq. suggests that the linear viscoelastic model is not sufficient to further describe the mechanical properties of the respiratory system over the vt range ( - ml/kg) in ventilated patients. infect this model predicts that "c is constant and independent of tidal volume. on the other hand the plastoelastic model is not sufficient to further describe the mechanical properties of the respiratory system. in fact "r obtained by fitting an exponential for data of eq. , is determined by the time of endinspiratory airway occlusion. obiectives: according to the viscoelastic model, the viscoelastic pressure of the respiratory system pv=rs during lung inflation with constant flow e~ is t/ r wh t lsms ira tlmeand r given by:pv~c.~ = d~( -'e-~ )[ ] ere " ' p" tory " and "r are resistance and time constant of viscoelastic unit. in the past, the viscoaletic constants were determinated by performing a series of occlusions at different lung volumes, or a sedes of occlusions at a fixed lung volume achieved with various inflation flows. in the present study we have developed a new method for determining "c and r which requires a single constant flow inflation. our method is based on determination of pv~r, during a single breath constant flow inflation, and of z during the ensuing end-inspiratory airway occiusion. dudng the occlusion the tracheal pressure p~, declines according the following function: ptr = p'lr e " too= " z + e~t.r= [ ] where p'~r is tracheal pressure immediately after occlusion, toc c is occlusion time, p,i.rs is static elastic recoil pressure of respiratory system, and ~ is viscoelastic time constant. we first determinated "~ by analyzing the time-course of ptr according to eq and next determining r according to eq. , using the expedmental values of p,i=~, ~ and ti, as well as "~ obtained with eq. . materials & methods: we studied healthy patients intubated, anestethized with propofol, paralyzed with vecurenium, and mechanically ventilated with constant flow ( . i/s) at zeep for minor surgery. pres-sure was measured in the trachea. flow was measured with a pneumniachograph and volume was obtained by numerical integration. the rapid occlusions were produced by an external valve. the signals were sampled at a fi'equency of hz and processed on a pc. the influence of the cardiac artifacts dudng the occlusion time ( s) was reduced by a software low-pass filter kaiser finite duration impulse response of elevated order. results: the mean coefficient of correlation with eq. was . . with v t of ml/kg, the mean values (+ sd) of ': and r of the subjects amounted to . • . s and . • . cmh i "~ s. with the traditional multi breath method the corresponding values were . + . s and . _+ . cmh i " s, respectively. with the t-test the difference between new and traditional "~ was statistically significant, between new and traditional r was not significant. conclusions: with the single breath method it is possible to compute ': and r . the mean values of r with v t of nd/kg, however, was slighuy different than those obtained with the traditional multi breath method. the application of modem principles of respiratory care and mechanical ventilation in icus has resulted in increased survival of critically ill individuals with neuromuscular, skeletal and irrevers~le pulmonary diseases. in these chronically ill individunts mechanical ventilation, long term therapy (ltot) and continuous home care is considered a chronic life supporltng technique that can not be withdrawn after their discharge from an icu. the aim of this study was to present the results of a rehabilitation programme and home care that runs in our ward. twenw three patients were referred to our clinic f~om icus during - . a specific rehabilitation programme designed according to individual's needs was performed. patients that benefitted from this programme were grouped into the following disorders. ) post tb respiratow failure ( %) ) neuromuscular diseases, ( %) } undiagnosed sas { %) ) cope) ( %) ( patients had a overlap syndrom). the programme consists of : ) assessment and mechanical support ff needed of the respiratonj system with non invasive methods (nasal or via tracheostomy). ) group and individual respiratory therapy ) mobilization ) nutritional support ) educational classes for the members of the family. three from the patients passed away (during the year), are under nippv during night with or without supply, pts recieve ltot. conclusion: the development of a programme for chronically ill individuals in especially designed wards in hospitals and the overall care at home is considered necessary at least in hospitals with icus. a rehabilitation programme and home care permits the fast but safe discharge of these patients from units of acute medicine that the cost of treatment is high and besides permits beds that are invaluable. we considered that the rehabilitation prod'amine and home care in our ward is the first performed in greek chronically ill pts and even though there is no special administxative support we think that the results are quite saltsfactory. objective: we postulated that the product of the respiratory frequency (f) and the ratio of inspiratory pressure (ip) to maximal inspiratory pressure (mip) would predict the weaning outcome in deeompensated copd patients better than either variable alone or other indices previously proposed. methods: in decompensated copd patients with difficult weaning, we measured, daily, respiratory mechanics data both during mechanical ventilation and after ten minutes of spontaneous breathing. then we calculated weaning indices reported in literature and some new integrated indices. according to the results of the discriminant analysis, we considered the integrative index crop (acronym of compliance, rate, oxygenation and pressure), the rapid shallow breathing index f/vt, the load/capacity ratio ip/mip, and the following new index: f x ip/mip. we used receiver-operatingcharacteristic (roc) analysis by calculating the area under the curve considered as the overall probability of correct classification. results: main results are reported in the following objective: to evaluate the reliability of some indices of endurance in predicting the weaning outcome of decompensated copd patients. methods: in decompensated copd patients with difficult weaning from mechanical ventilation (mv) we measured, daily, blood gas analysis, ventilatory and airway pressure pattern during mv, breathing pattern (frequency (f) and tidal, volume (v~)), inspiratory pressure (ip), and maximal ip (mip) during spontaneous breathing (sb). thereafter we calculated the following weaning indices: crop (compliance * mip * (pao /pao ) / f), flvt, ip/mip. data obtained the day at which the patient was considered ready for a trial of sb on clinical grounds but weaning failed (wf) and those obtained the day of the successful weaning (ws) were compared statistically through the wilcoxon rank-sum pair analysis. in order to quantify the predictive accuracy for each index with respect to successful weaning we calculated sensitivity, specificity, and diagnostic accuracy according with the standard formulas. methods : five patients ( + yrs) suffering from ards (lung injury score > . ) for hours or less entered into the study. irv (volume controlled, decelerating flow, % inspiratory pause, lie = / ) was compared to conventional ventilation (cv) (volume controlled, constant flow, no inspiratory pause, iie= / ). these two modes were applied for hours in a randomized order, with the same levels of total peep (peept = peep + peepi), tidal volume ( . • . ml/kg), respiratory rate ( • "bpm) mad fit ( • %). measurements (respiratory mechanics, hemodynamics, arterial and mixed venous blood gases) were performed after , , and hours of application of each mode. rvsuils : are expressed as mean + sem and compared by anova. backeround and methods: periodic breathing (pb) is characterized by repetitive cyclic variation in minute ventilation. pb is considewxl to be provoked by an instability in the respiratory control. inintubated, spontaneously breathing patients conventional modes of pressure support ventilation, i.e., triggered inspiratory pressure support ps), do not allow patients to breathe with theirinherent breathing pattern. therefore, pb, if existing, will appear mainiy after extubation. since our new mode of pressure support ventilation" automatic tube compensation" (atc) continuonsly corrects for the flow-dependent tube resistance during insnmdon and expiration ("electronic" extubatim), it pemaits patients to maintain their own inherent breathing pattern. then, ff necessary, tracheal pressure can be additionally supported by volume-proportioead and/or by flow-proportional pressure support (proportional assist ventilation, pav). (~as~: we report the case of a -year-old male patient who was intubated due to acute respiratory insufficiency after acute myocardial infarction with left ventricular dysfunction. during ips of mbar the patient showed a regular breathing pattem which became periodic during atc. in addition, proportional assist ventilation of mbar/l increased periodic breathing in such a way that the typical cheyne-stokes breathing pattem occurred (see figure) . baqkground: the hering-breuer reflex (hbr) is characterized by an inhibition of inspiration during lung inflation. this response has been recognized as an important vagally mediated mechanism for regulating the rate and depth of respiration in newborn mammals. in adult man the hbr is considered to be active only at lung volumes well above functional residual capacity, i.e., at tidal volumes above ml. assessment of the hbr requires specialized methods such as single breath or multiple occlusion technique. methods; in the presence of desynchronization between ventilator and patient, which frequently occurs during triggered inspiratory pressure support ventilation (ips)(see figure) , prolongation of the interval between inspiratory efforts (indicated by negative deflection of the esophageal pressure) due to lung inflation exposes an active hbr. we examined the occurrence of hbr in intubated critically ill patients. strength of hbr was assessed by the formula: prolongation [%] = ((inspiratory interval of interest -preceding inspiratory interval)/preceding inspiratory interval) * ( . rr of patients examined showed moderate to severe desynchronization. in of these patients a (re)activation of the hbr was found. the strength of hbr amounted to + %. there was a significant correlation between tidal volume and strength of hbr. in contrast to previous reports, an active hbr was shown during lung inflation well below ml. b pck~round: triggered inspiratory pressure support ventilation (ips) is commonly used to support inspiration in intubated spontaneously breathing patients. despite its usefulness ips shows some disadvantages which can be deleterious in crificauy ill patients: -additional work of breathing to be performed by the patient due to the flow-dependent tube resistance -desynchronization between patient and ventilator due to inherent triggering failures of the ips mode suppression of the patient's inherent breathing pattern -inability to predict successful extubation in difficult-to-wean patients methods: based on the known flow-dependent tube resistance our new mode "automatic tube compensation" (atc) compensates for the pressure drop across the endotracheal tube ("electronic" extubation). then, if necessary, tracheal pressure can be supported by volume-proportional pressure support (vpps) and/or by flow-proportional pressure support (fpps). results: hitherto, we have examined patients after open-heart surgery and patients with acute respiratory insufficiency (ari) or ards using atc with/without vpps/fpps. preliminary results suggest that the new mode avoids additional work of breathing due to accurate compensation of the pressure drop across the endotracheal tube during in-/expiration prevents desynchronization between patient and ventilator allows patients to breathe with their inherent breathing pattern accurately predicts the outcome of extubation even in difficult-to-wean patients due to "electronic" extubation conclusions: the new mode atc with/without vpps/fpps allows to support ventilation in a more physiologic manner and overcomes the disadvantages of conventional modes of pressure support in intubated patients. backgound: cheyne-stokes respiration (cs) is characterized by regula]; recurring periods of hyperpnea and apnea. in normal subjects, cs may occur after hyperventilation, after arrival in high altitude, or during sleep. it has also been observed in patients with prolonged circulation time due to congestive heart failure, as well as in some neurological patients. there is no report about the influence of sedative drugs on periodic breathing (pb) and cs. methods: in intubated patients conventional modes of pressure support do not allow patients to breathe with their inherent breathing pattem. therefore, periodic breathing and cs are rarely seen. since our new mode of pressure support ventilation "automatic tube compensation" (atc) continuously corrects for the flow-dependent tube resistance during inspiration and expiration ("electronic" extubation) it permits patients to maintain their own inherent breathing pattem even if pathological, e.g., periodic. results: using this new mode of pressure support ventilation, periodic breathing was unmasked in of intubated patients, of which showed cs. in of these patients the occurrence of cs was linked to impaired left ventricular function with increased circulation time. normal left ventricular and neurologic function was found in the remaining patients. in of these patients cs disappeared after intravenous administration of the benzo-diazepine antagonist flumazenil (figure). consequently, in this patient cs was induced by benzodiazepine sedation. objecti',~s: in contrast to conventional rhodes for pressure supported spontaneous breathing, our newly developed ventilatow mode ,,automatic tube compensation" (atc) completely compensates for the flow-depandant pressure drop tlpm-r across endotracheal ttlbe (ett). in the atc mode, the ventilator supplies a flow v' in order to maintain a constant tracheal pressure p~,,~. to this end, pk,,= has to be oontinuousiy determined. since continued measurement of p,,~ by introducing a catheter via the ett is not reliable, we opted for its continuous calculation socordng to the following equation: p~ = p,,, -aperr, pw being the continuously measured airway pressure. this also requires the continual measurement .of flow v' to calculata apm-r using the non-fineer approximation: aport = kvv' + k .w. the constant tube coefficients k~ and k are mathematically determined by mesns of a least-squares-fit procadum based on laboratory investigations. tracheal secretions, however, reduca the omss-saction of the ett. consequently, ~ values of ki end k are changed rendering the p~,ch calculations inaccurate. therefore, k and ~ have to be pedodcally updated to ensure an a~urete monitoring of pn,~ and a complete tube compensation under atc at any time. background: one of the first steps in weaning patients from controlled mechanical ventilation is to stop muscle relaxation and to reduce sedation. it can take several hours, however, until the patient is able to trigger the ventilator and to breathe spontaneously. during this period, many patients display a sudden increase in peak airway pressure of up to %. patients and methods: to investigate the reason for this potentially dangerous effect, we continuously measured lung and chest wall mechanics in post-operatively ventilated patients. lung mechanics (airway resistance and lung compliance) was measured using the esophageal balloon technique as described in [ ] . chest wall mechanics (tissue resistance and chest wall compliance) was calculated from lung mechanics and total respiratory system mechanics as described in [ ] . results: we found a decrease of chest wall compliance (cw) to be the main reason for episodes of sudden airway pressure increase while lung compliance (cl) remained unchanged. the decrease of c w can be inter- gil cano a, san pedro jm ~, sandar d, herntndez . , carrizosa f, , herrero a. emergency and intensive care department, hospital of jerez, spain objective: ) to determine the incidence of hypoteasion (h) associated with emergency intabatian of mechanical ventilation, and ) to establish its relauonship with respiratory mechanics (rm) and arterial blood gases. mechanical ventilation performed in the emergency room, in a prospective eans~eative manner, were evaluated. data collected included patient demographics, diagnoses, blood pressure and arterial blood gas levels before and at~er intabatian, and p_m, including calculated pulmonary end-inspiratory volume above functional residual capacity (veic) and calculated dynamic hypetinflatien (dhc). all patients received midazolen and awaanrinm to facilitate tracheal intubatien and rm measurement. hypotension was defined as a decrease in systolic pressure higher than mmhg or an absolute decrease in systolic blood pressure below to mhg within hour of intabatian. patients were excluded because met at least one of the following exclusion criteria: preexisting shock or h ( ), cardiac arrest ( ) . there weren't any association between peepi or other airway pressures (paw) and h, but calculated pulmonary volitmes had tendency to be larger in patients with h (p < . ). high paco before lrasheal intubatian ( . - mmhg) with a quickly decrease alter starting mechanical ventilation was a usual finding (p < . ) in patients who developed h. paw. ) thexe was a good relatienship between h and high arterial paco before traqueal intahatian and its fast "washing" with mechanical ventilation. ) because cao patients had the highest incidence of h, controned mechanicel hypoventilatien driven by paco changes and pulmonary volumes monitoring instead paw, should be attempted in these patients to avoid this cemplication after tracheal intubatiert. introduction: the endotracheal tube (ett) and demand valve devices cause an added work of breathing (wobadd), which is the work necessary to overcome the resistive load of the ett and the breathing circuit ( ). application of ips has been shown to partly compensate this added work ( ). since tbe amount of wobadd is flow dependent, a fixed ips is not adequate to completly compensate the wobadd ( ). therefore, atc has been developed as a new form of assisted spontaneous breathing ( ), which provides a flow-dependent pressure support. thereby, it theoretically should compensate all the wobadd due to the tube. the purpose of this study was to evaluate the reduction of wobadd with ips and atc for different ett. methods: a mechanical lung model (ls , dr*alger, liibeck, frg) was used to generate a constant spontaneous breathing pattern. the ls was connected to an artificial trachea (at, cm long, mm id). the at was intubated with three different tubes of . , . , . mm id and connected to an evita ventilator modified to provide atc as an option (dfager, liibeck, frg). flow and airway pressure were measured between the y-piece and the ett for four different modes of ventilation: cpap, ips of and cm i and atc all with a peep of cm h . the tracheal pressure (ptrach) was measured in the at. total wobadd was calculated as the area subtended by the ptrach-volume curve below peep. results: the results for total wobadd in nd/ are shown in the figure for the three different ett: breath/mln, s=success, f=failur% *~p<. , **-p< , ns = non significant, f versus s neveltheless, in / patients, invasive ventilation was necessary in mean . _+ hours after beginning of fmpsv. there was no significant difference between the two groups (success, failure) in following parameters : sex, age, previous histoly, medical treatment, saps & , clinical signs (rr, spo , heart rate, blood pressure, glasgow score...), radiological and echocardiographic findings and standard biological parameters. only two parameters were related with failure : .a low value of pac on admission until the patients were intubated. . an increased level of cpk in relation with an acute myocardial infarction ( / cases in the failure group, vs / cases in the success group, x~(with continuity correction) : p<. ). conclusion : fmpsv is a noninvasive, safe, rapidly effective method of treatment in acpe, which may avoid tracheal intubation. further studies are necessary to precise if association of arf and low paco (< mmhg) and/er acute myocardial infarction represents an indication of immediate invasive ventilation. introduction: since the added work of breathing (wobadd) imposed by the endotracheal tube (ets and the breathing circuit is regarded as an important contribution to the total work of breathing, considerable effort has been tmdettaken to compensate for this added work. ips has been fotmd to decrease the wobadd imposed by different ventilators ( , ). because of the flow dependent pressure drop across the etf the tracheal pressure (ptr) should be measured to estimate the total imposed wobadd (wobtut) ( , ). the aim of this study was to assess the circuit imposed work (wobcirc) and wobtot (including ett) for different demand valve ventilators during cpap and/ps. methods: a mechanical lung model (ls , driiger, lfibeck, frg) generated a constant spontaneuus breathing pattern. the ls was connected to an artificial trachea (at), intubated with an . nun et]', end connected to one of four ventilators (servo c and servo , siemens,-elema, sweden; evita , driiges, liibeck, frg; pb ae, puritan bennett, carlsbad, usa). three different modes of ventilator settings were tested (cpap, ips and mbar; trigger set at maximal sensitivity, peep always mbar). flow and airway pressure (paw) were measured between the y-piece and the etr; tracheal pressure (ptr) was measured in the at. wobtot was calculated as the area under the ptr-volume curve below peep, wobcirc was calculated as the area under the paw-volume curve below peep. results: in the foti g., patroniti n., cereda m., sparacino me., giacemini m., pesenti a. inst.of anesth.and intensive care-univ.of milan -sgh monza i aim of the study was to assess cpl,rs measurement obtained by the airway occlusion method during psv. we therefore studied paralyzed cppv ventilated ali patients (lung injury score = . • that were weaned to psv. we performed end inspiratory and end expiratory airway occlusions using the hold function of the ventilator (siemens serve c), first during cppv and then within the th psv hour. airway pressure and flow signals were recorded (cpi bicore) for subsequent analysis. an airway pressure plateau was defined as a flow tracing in which airway pressure was stable for at least . sec. end inspiratory (pel,rsi) and end expiratory (pel,rse) recoil pressures were then measured as the mean airway pressure during plateaus. cpl,rs was computed as tv/ (pel,rsi-pel,rse i) cpl,rs can be adequately estimated during psv using the airway occlusion method; ) during psv inspiratory plateaus are longer than the expiratory ones; ) the length of plateaus is negatively affected by the respiratory drive. foti g., de marchi l., *tagliabue m., gilardi p., giacomini m., sparacino me., pesenti a. inst.of anesth.and intensive care,-univ.of milan *dept.of radiology-sgh monza i we retrospectively compared ct scan and gas exchange findings between a group of patients successfully weaned from vcv to psv (group s = ii patients) and a group who failed the weaning (group f = patients). we selected ali patients (lis= . • in vcv mode who had available a chest ct scan performed within days from the weaning trial. a psv trial was began as soon as the patient reached hemodynamic stability and a pao > mmhg, irrespective of fie (peep < cmh ). maximum psv level was < (pel,rs-peep) measured during vcv, where pel,rs was the respiratory system elastic recoil pressure at end inspiration. psv ventilation was considered successful if a respiratory rate < bpm, an increase in fie lower than . compared to vcv, a pace increase < % of vcv value and hemodynamic stability were maintained during the next hours of psv. if any of these conditions was not met the trial was declared a failure. interdisciplinary critical care unit, regional hospital lugano-ch *surgical critical care unit, university hospital, geneva-ch objective: to assess the degree of correlation of cardiac output measured by thoracic electrical bioimpedance and thermodilution in mechanically ventilated patients with different levels of positive end-expiratory pressure (peep). methods: prospective study with ventilated patients, after head injury and with postoperative sepsis, with normal cardiac output: simultaneous determination of cardiac output by thermodilution and thoracic electrical bioimpedance performed with different levels of peep ( - - cm h ). results: cardiac output measured by thermodilution during sequential increment of peep did not vary: . + . for peep , . + . for peep and . + . l/rain for peep . simultaneously the bioimpedance device recorded a significant increase in cardiac output from . + . for peep to . + . l/mi for peep . (p < , ). conclusion: cardiac output measured by bioimpedance cannot replace the invasive thermodilution methods of cardiac measurement output during mechanical ventilation with peep. we also isolated a subset (h) of patients who had been hypercapnic (paco > mmhg) for at least days (range to days) before the end of cv. the psv trial was started as soon as pao was > mmhg, irrespective of fie and with peep < cmh and the psv level had to be < (pplateau-peep) as measured during cv. pace , pha, base excess (be) were collected before discontinuation of cv and on the ist day of psv: ) . ) weaning is more difficult in pts with head injury(p<o, ) and iss> (p<o,ol), in elderly(p<o, ) and in pts who need fi > , (p<o, ) and peep>io cm h (p<o, ). ) pts with iss> need longer duration of mv (p<o,ol). ) the mortality rate is higher in pts with iss> (p<o,o ), with head injury (p<o,ol) and in elderly (p<o, ). ) paradoxally, compliance was found to be higher in pts> years than in pts< years (p<o, ). s. crotti, p.pelosi, d.mascheroni, m.cerisara, a.lissoni, l.gattinoni. istituto di anestesia e rianimazione -irccs, milano, italia. obiectives. we investigated by ct scan the effects of extrinsic peep (peepe) on lung inflation, tidal volume distribution and regional compliance in sedated, paralyzed chronic obstructive pulmonary disease (copd) patients with dynamic hyperinflation (peep• methods. two ct section (end expiration, end inspiration) were obtained at lung base level in patients (individual analysis for each of the eight lungs) at peepe levels: peepe = cmh (zeep) and peepe amounting to %, % and % of the peep• at zeep ( . • cmh ). tidal volume was kept constant ( • . ml/kg). each lung section was divided into zones equally spaced along the vertical axis: upper (the most ventral), middle and lower (the most dorsal) zone. for each zone we computed: gas volume at end expiration (gase) and at end inspiration (gas• tidal volume (dgas=gasi-gase) and compliance (cpl=dgas/dp;.dp=plateau pressureactual peep• we also computed the lung inflation as the entire ct section gas volume at end expiration (total gase). results. at each peep level both gase and gas• were higher in the upper than in the lower zone ( we cone!ude that in copd patients with dynamic hyperinflation only the application of peepe higher than peepi produces a further increase of lung inflation, decreasing cpl of the upper zone (the more expanded one) probably by stretching phenomena, and causing dgas redistribution from the non dependent to the dependent lung zones. i. ravagnan, p. vicardi, f. valenza, d. tubiolo. p. pelosi l. gattinoni. st . anestesia e rianimazione, universita' di milano, ospedale maggiore -irccs, italy objectives: to investigate the effects of peep and ps on respiratory. pattern and inspiratory effort during ps ventilation in patients with acute lung injury or acute exacerbation of chronic lung disease. methods: pts with acute (a) (paco = • mmhg, pao /pao = . • and pts with chronic (c)(paco = • mmhg, pao /pao = . : . ) lung disease were studied in ps ventilation during the weaning phase. measuring airway pressure, esophageal pressure and gas flow we computed respiratory rate (ril bpm), tidal volume (tv, ml) and pressure time product (ptp, cmh *s/min), which is an index of oxygen muscle consumption. measurements were collected, after rain of stabilization, at and cmh ps and at two different peep levels ( and cndd conclusions: during psv: ) breathing pattern and ptp are different between a and c; ) in both groups peep does not modify breathing pattern; ) peep reduces ptp in c but not in a; ) ps modifies breathing pattern and reduces ptp in c but not in a. to test the performance of a new heat and moisture exchanger (hme): twistair, baxter. this is a hydrophobic-hydrophilic hme without hygroscopic salts. method: we evaluated the hme performance with a previously described method (i); it consists of a "lung simulator" connected to a mechanical ventilator and a flow divider, with a dry and a wet thermal probe inserted into inspiratory and expiratory limbs. on average ps level changes were associate( with opposed changes in both p . and rr. changes in p . were remarkable, homogeneous and highly significant (p<. ), while changes in rr were less pronounced, inhomogeneous and less significant (p<. ). it seems therefore that p . is a better index than rr for estimating a change in load for the respiratory muscles. recently, the lsf method has been described as an interesitng alternative to conventional tecniques used to measure total respiratory mechanics, providing, over these latter, advantages such as no need for hold maneuvers and no need for particular flow patterns. data on the reliability of the lsf method, however, are still few. methods. sets of measurements were obtained in each of ards patients, paralyzed and ventilated in cmv with constant inspiratory flow and an end-inspiratory pause equal to % of ttot. the lsf method provided data for total compliance (ctotlsf) and total resistance (rtotlsf) by multiple linear regression analysis of airway pressure, flow and volume change, applied over the entire breath. the lsf measurements were automatic and continuous, and each value used for analysis was the average of consecutive cycles. conventional measurements of dynamic.compliance (cdyn), quasistatic compliance (cqs), minimum inspiratory resistance (rmin) and maximum inspiratory resistance (rmax) were obtained by the constant flow, end-inspiratory occlusion method, each value being the average of measuremts. ctotlsf was compared with cdyn and cqs, while rtotlsf was compared with rmin and rmax. results. ctotlsf showed a high correlation both with cdyn (cdyn=. .ctotlsf+l. , r =. ), and with cqs (cqs =. .ctotlsf + . , r =. ). the average difference between ctotlsf and cqs, yet, was much lower (+. + . ml/cmh ) than the one between ctotlsf and cdyn (+ . + . ml/cmh ). rtotlsf correlated much better with rmax (rmax=. *rtotlso+. , r =. ) than with rmin (rmin =. .rtotlsf +. . , r =. ). the average difference between rtotlsf and rmin was + . + . cmh / /s, while the one between rtotlsf and rmax was +. + . , confirming the better agreement between rtotlsf and rrnax. conclusion.the agreement between rtotlsf and rmax suggests that rtotlsf takes into account both the airway and the tissue components of resistance, unlike rmin which only expresses airway resistance. the agreement between ctotlsf and cqs indicates that ctotlsf expresses the pure elastic components of the respiratory system. in the paralyzed patient, the expiratory time constant (rce) of the unit represented by total respiratory system and ventilator can be calculated from the slope of the expiratory flow-volume curve. recently it has been suggested that an estimate of this slope is provided by the ve/v'epeak ratio, ve being the exaled tidal volume and v'epeak the peak expiratory flow.the reliability of this method is still little known. methods. sets of measurements were obtained in mechanically ventilated ards patients during paralysis and cmv. measurements of ventilator expiratory resistance (rext) and of total respiratory mechanics were performed in order to calculate these reference measurements for ve/v'epeak: rcdyn=(rmin+rext)ocdyn, rcstat=(rmax+rext)ocqs, rclsf=(rlsf+rext)~ cdyn (dynamic compliance), cqs (quasistatic compliance), rmin (minimum inspiratory resistance), rmax (maximum inspiratory resistance) were obtained by the constant flow, end-inspiratory occlusion method. clsf and rlsf respectively corresponded to measurements of total respiratory system compliance and resistance by the least squares fitting method. ve/v'epeak showed a high correlation with all reference measurements, rcdyn (ve/v'epeak= . orcdyn-. , r =. ), rcstat (ve/v'epeak = . rcstat -. , r = . ), and especially rclsf (see fig the static pressure volume curve of the respiratory system (p/vst) provides valuable information, but the extensive data analysis prevents its use in clinical routine. dynamic p/vcurves are simpler to record. the objective of this study was to develop an automated method to obtain quasi-static p/v-curves (p/vqs) during low flow inflation as well as to measure resistance. preliminary tests were done in normal subjects and subjects with varying degree of lung disease. methods: a computer/ventilator interface (cvl) was constructed for control of a servo ventilator c during an automatic sequence: a) a normal breath, b) a prolonged expiration at zero peep, c) a low flow inflation of a predetermined volume, d) analysis of ventilator pressure and flow. pressure was corrected for tube resistance. airway resistance was calculated from a) and used to derive p/vqs from c). as reference, p/vst was obtained by the occlusion method. results: in non-obstructive diseases the method performed well at volume and pressure controlled ventilation. static and quasistatic compliance were virtually identical. p/vqs clearly reflected the lower inflection point and, when present, the upper inflection point (uip). in some patients uip was more evident in p/vqs, especially at an increased inflation flow rate. in obstructive diseases, the method for subtraction of resistive pressure was inadequate. conclusions: the system for automated computer controlled studies of lung mechanics based on a standard ventilator provides comprehensive information. differences between p/vst and p/vqs imply that the latter reflects also other factors than p/vst that contribute to impedance at hyperdistension. the clinical significance of the two curves remains to be shown. obiective: to evaluate the effect of combined high frequency jet ventilation (chfjv) in patients with severe respiratory insufficiency (sri). methods: in a retrospective study of the period - we analyzed patients suffering from sri who were refractory to conventional mechanical ventilation and were treated with combined high-frequency jet ventilation (chfjv). refractory to conventional mechanical ventilation was defined as a pao /fio < , despite maximal ventilator settings: peep > cm hz , fit > . . a total of patients matched these criteria, males and females with a median age of ( - ) years. seventeen suffered from severe trauma. chfjv was started following a median period of ( - ) days of conventional mechanical ventilation. prior to chfjv ventilation parameters expressed as median were the following: fit . , pao /fio , peep cm h peak airway pressure (pap) cm h . chfjv consisted of high frequency jet ventilation with a frequency of to breaths/minute, driving pressure of . to . arm, and inspiration time of to percent, superimposed on the whole cycle of conventional mechanical ventilation with a frequency of l to breaths/minute and tidal volumes of to ml. results: following two days of chfjv of patients showed an improvement of ventilatory parameters; peep could be reduced to < cm h in patients, the pap was decreased with > cm h:o in patients, fio could be reduced to < . in patients and finally the median pao /fio ratio changed from to . during chfjv patients died, of respiratory failure and due to multiple organ failure, died within two days of chfjv. the median duration of chfjv in survivors and nonsurvivors was days in both groups. conclusions: our data show that with chfjv in the majority of patients with sri who are refractory to conventional mechanical ventilatior" the ventilatory parameters can be improved. backeround and obiectives: although ventilation with peep above the inflection point (pinf) has been shown to reduce lung injury by recruiting previously closed alveolar regions, it carries the risk of hyperinflating the lungs. in the present study we set out to develop a new strategy to recruit the lung during ventilation with small vt, while maintaining peep levels as low as possible. we hypothesized that if the lung was recruited with a sustained inflation (si) to total lung capacity, recruitment would be maintained as long as the peep level was higher than the critical closing pressure of the lung, as observed on the deflation limb of the pv curve (ajrccm ; ( ) :a ). the purpose of this study was to examine the hypothesis that a strategy using si and a peep<pinf would induce less lung injury during small tidal ventilation than ventilation at the same low peep level without using a recmitment strategy in a model of respiratory distress syndrome. methods: we used a randomized protocol with groups to ventilate nonperfused, lavaged rat lungs with small vt ( to ml/kg) for hours and studied the effect on compliance and lung injury. group : peep>ping group : peep<pin f with an si, inflation to on h over sec, to recruit volume; group : peep<pinf without si; group : control group, lungs were inflated at peep<pin f, but not ventilated. results: in group and group static compliance did not change after ventilation (table) . in group static compliance fell significantly. group showed significant changes in the pv curve, which were less severe than in group . results from morphological examination are pending but preliminary results showed less lung injury in group , compared to group . conclusions: small tidal ventilation following a recruitment manoeuvre in a model of respiratory distress syndrome allows ventilation on the deflation limb of the pv curve at a peep below pinf. this strategy ( ) minimizes lung injury as well as, or better than using peep above pint" and ( ) ensures a lower peep to minimize the detrimental consequences of high lung volume ventilation. i~peep>pin~ _objectives-this report is presenting the results of the clinical study for using eeg examination as a method of the evaluation of patients ability for weaning. methods: the study inclljqles eeg examinations with fourier spectral analysis' of patients ~vith respiratory insufficiency and prolonged control mechanical ventilation (cmv). all patients have had a-rhythm of eeg before weaning. we have followed respiratory rate, tidal volume, respiratory pa{tern, end-tidal co and blood gases during weaning. results: patients had invariable eeg activity or short -waves period (till one hour). the weaning of this patients was fast arid sucsessful. other patients have had a decreasing of a-activity, an appearence of -waves for an hour and more, a short episodes of a-and e-activity. after that this patients had gas exchange and respiratory disorders with regression of the weaning right up to cmv. conclusion: eeg could be used as a method of the evaluation of patients ability for weaning from cmv. some eeg signs shows the overstrain of compensatory systems before the change to the worse of gas exchange and respiratory pattern. s. elatrous, p. aslanian, d. touchard, d. corsi, h. lorino, l. brochard. medical intensive care unit, inserm u , hopital henri mender, cr~teil, france. in vitro comparison of flow triggering (ft) systems demonstrated advantages compared to pressure triggering (pt) systems for some ventilators (puritan bennett ) but not others (siemens serve ). we studied the two types of systems in two groups of patients mechanically assisted with pressure support ventilation ( + cmh ). in the first group (pb ) the effort of breathing, assessed by the esophageal pressure time index, was significantly lower with the ft than with the pt ( + cmh .s/min - vs + , p< . ). by contrast no significant difference appeared in the second group (serve ), as predicted by the bench study despite marked interindividual differences ( + cmh .s/min - vs + , p = . ). we conclude that ) rigorously performed bench studies can predict in vivo effects, ) mild advantages can be found for the new triggering systems on some ventilators. objectives: pressore-volume curves (pv) of the respiratory system is of interest for the determination static compliance (cs , lower (lip) and upper (uip) inflection points which indicate zones of airway recruitment and overdistension. this study aimed to compare an "automated low flow inflation" method (alfi) to the reference occlusion (oc) method. the ability of the former method to identify cst, lip and uip was tested in icu patients. me,otis: ( arf and ards) sedated paralysed patients were studied using a serve c ventilator linked to a computer which automatically forced the ventilator to insufflate at a low constant flow a velum up to - ml or a maximum paw of cm h (alfi). the quasistatic elastic pressure (pel,qs was obtained by subtraction of the resistive pressure of tubing and patient and related to volume for calculation of compliance cqst. for oc tidal volumes (v from up to - ml were followed by a s post-inspiratury pause for determination of static pal (pel,st) in relation to volume. compliance was defined from the linear part of the p/v curves. lip and uip were defined from the consistent deviation of p/v data from extrapolated the linear part. ~,~ i~: in ards, mean cst was . + . and cqst . + . ml/cm h (us), lipst . + . and lipqst . + . cm h (us), uipst . + . and uipqst . + ~ cm h (us). nosocomial pneumonias (np) are frequent and often unsuspected during ards (bell, ! ). in the present study, we evaluated prospectively the onset of np during severe ards (group b of the european study). patients and methods: the charts of patients with severe ards have been prospectively recorded. a plugged telescopic catheter (ptc) specimen has been systematically performed every hours, for quantitative bacteriological analysis. the diagnosis of np was defined by a number > colony forming units / ml. results: for the patients studied, the mean saps score (+ sd) was +_ , the initial pao /fio ratio was -&-_ , the duration of mechanical ventilation (mv) was + days. the mean delay before the onset of the first np was . + . days ( - ), and the mean pao /fio ratio was +- . respiratory symptoms (purulent aspirates, new pulmonary infiltrates, or gazometric changes) were present in % of the patients studied. alteration of gas exchange was present in of the patients ( np) . a new pulmonary infiltrate was present in only np ( %). an increase of fever was noted in patients, an increase of leukocytosis > % in patients, an increase of volume and purulence of sputum in of the patients with np. the degree ofgazometric worsening (pao /fio before np minus pao /fio during np) during the first episode of np was + mmhg. excluding the bacteriological criteria of np, the number of criterias of np present was in / patients, ( / ), ( / ) or ( / ). two patients only had a pulmonary colonization (ptc: < cfu / ml) before the first episode of np. the incidence of np is high ( %) during severe ards. the first episode occurs in average:at the th day, and is the cause of a severe hypoxemia (pao /fio ) . the onset of a np may contribute to the high mortality rate observed in our patients ( %). each worsening of hypoxemia during severe ards should induce to suspect a np. respiratory system during mechanical ventilation. the me~hod quantifies the dissipative energy consumption of the respiratory system in terms of energy loss aek, inefficiency ~k~ and respiratory dissipative resistance rk~ over a given partition of the tidal volume. the method can be applied in intensive care units with no interference to ventilatory support. it allows for monitoring the combined effects of inhomogeneities, non-linearities and visco-elastic effects, that are subject to change in the respiratory system. the method is studied on pigs~ in the presence of a log-dose response curve of methacholine (mch) induced disease. in healthy pigs~ we find a mean value of energy loss, ae, of . • j/l, a mean value of inefflency, ~ of . ~= . and a mean value of resistance, ~, of . • cm h s/ . the respiratory resistance, rk, shows a variation over the partition of tidal volume with armax ---- . • . cm h s/l. during methacholine provocation~ ae rises more than five-fold up to . • j/l~ doubles to . • and t~ increases to a maximum of • cm h s/l, with armax : . • . cm h s/ . the variation in rk becomes more pronounced with higher doses of methacholine. methods: ards patients were prospectively studied. initially they were ventilated in the amv (assist mechanical ventilation) mode with the settings prescribed by their primary physician. after stabilization, ventilatory gas exchange and hemodynamic variables were determined. patients were then ventilated in the mrv (mandatory rate ventilation) mode with breaths as the target rate. in mrv the target rate is set and the ventilator autoregulates the pressure support level delivered ~o achieve this rate. after stabilization, the measurements done on amv were repeated. finally, patients were sedated and paralyzed and ventilated in cmv (control mechanical ventilation) with the ventilatory variables they had during mrv. measurements done in amv and mrv were repeated and respiratory mechanics were assessed with the constant flow end inspiratory occlusion method. results: two groups were recognized based on their response to mrv. tn group patients responded to mrv by decreasing their v and increasing the t/t t ratio. ve, vo , and aado decreased while paco increased and tda vo ume and co remained unchanged. on the contrary, in group v, vr and ve increased; ppeak and trr t remained unchanged, paco~ decreased while vo and aado increased with constant co, the pressure support level needed to achieve the target rate was much lower in group than in group ( , -+ . vs . _+ . ). obiectives : in the newly developed mode of ventilatory support ,,automatic tube compensation" (atc) the ventilator compensates for the flow-dependent pressure drop across the endetracheat tube (ett) thus allowing ,,e]ectronic extubation". the aim of the study is to investigate whether healthy subjects perceive atc in inspiration (atc-in) and in expiration (atc-in-ex) and whether atc provides an increase in subjective comfort compared with the conventional assisted spontaneous breathing mode (asb). methods : healthy volunteers (no preceding lung disease, non-smokers, male, - years)breathed spontaneously through an uncut ett of . mm id via a mouthpiece. the ett was connected with a prototype ventilator evita modified by the manufacturer (drfiger, lebeck) for atc. flow and airway pressure were measured at the outer end of the ett. three ventilatory modes, ( ) asb ( mbarover mbar peep), ( ) atcin, ( ) atc-in-ex were selected in random order. immediately following the transition from one mode to another the volunteers answered by hand sign how they perceived the new mode compared with the preceding mode: ,,better" (+ ), ,,equal" ( ) or ,,worse" (- ). inspiration and expiration were investigated separately by presenting mode transitions (in total; including ,,placebo" transitions). results : the difference between atc and conventional asb is perceived in inspiration and in expiration. atc is positively judged; asb is nega ively judged. the diagrams show mean values _+ sd of five volunteers investigated up to now. the new mode atc is perceived as an increase in subjective comfort. our explanation is that atc preserves the natural breathing pattern better than conventional asb. objectives: to determine the role of cerebral vasoconstriction in the delayed hypoperfusion phase in comatose patients after cardiac arrest. to correlate the results with indices of cerebral oxygenation and the levels of several vasoactive hormones in the jugular bulb. methods: in comatose patients after cardiac arrest we measured the pulsatility index (pi) of the medial cerebral artery by transcranial doppler sonography. the pi is a reliable indicator of cerebral vascular resistance. we also sampled blood from the jugular bulb and measured cerebral oxygen extraction ratio and jugular bulb levels of endothelin, nitrate and cgmp. the first measurement was done within hours after cardiac arrest and repeated , , , , and hours later. results: we studied patients, females, mean age , + , years. the pi decreased s!gnificantly between th~ first and the last measurement from . _+ . to . + . (p = . ). cerebral oxygen extraction ratio decreased also from . + . to . + . (.p = . ). endothelin levels were high, but didn't change during the studied period. nitrate levels varied in a wide range, but didn't change significantly. however, cgmp levels increased significantly from very low levels in the first measurement to very high levels hours later, rasp. . pmol/ml (median; th . - th . ) and . pmol/ml (median; th . - th . ) (p = . ). eighteen and hours after the first measurement we found a strong correlation between pi and cerebral oxygen extraction ratio ( r = . , p = . and r = . , p = . ). we.also found hours after the first measurement a significant correlation between pi and cgmp levels ( r = . , p = . ). we found no correlation between pi and endothelin or nitrate levels. conclusion.~; our results show a high cerebral vascular resistance in the first few hours after cardiac arrest, gradually decreasing during the next hours. this is accompanied by an initially high cerebral oxygen extraction ratio and low cgmp levels, suggesting that the cerebral vascular resistance is induced by active vasoconstriction because of insufficient cgmp levels, leading to a decrease in cerebral blood flow and a compensatory ~ncrease in cerebral oxygen extraction. objectives: sudden cardiac arrest is a major cause of mortality in western countries accounting for over half of all cardiovascular deaths. in most cases the mechanism of death is prolonged cardio-circulatory arrest due to ver:tricular fibrillation (vf) preceding final asystole. recurrent syncopes due to idiopathic vf with good neurological prognosis have been reported in patients with and without cardiac etiology ( , ). in the past measurements of cerebral hemodynamics have been repeatedly done in humans during cpr, but until today no studies of cerebral blood flow velocity (cbfv) have been reported during controlled cardiac arrest in humans not under-going cpr. it was the purpose of our study to evaluate the acute hemodynamic effects of untreated vf on cbfv. methods: after approval by the local university ethics comittee, five male patients aged - years without evidence of cerebral disease were investigated during vf while undergoing implantation of a pacer cardioverter defibrillator system (model d; medtronic| a standard anaesthetic regimen was used (propofol, fentanyl). after implantation of the automated cardiac defibrillator vf was induced by electrical countershock to test effective sensing, pacing, and defibrillation. to measure cerebral blood flow velocities (cbfvmca) the doppler probe was placed above the zygomatic arch between the lateral margin of the orbit and the ear and directed towards the m segment of the middle cerebral artery (mca). results: a total of phases of vf were investigated. duration of vf ranged from to seconds, with cbfvmc a (mean_+sd, cm sec - ) flow pattern changing from pulsatile to laminar flow immediately after onset of vf. conclusions: the underlying mechanism of the laminar cerebral blood flow observed during vf in our patients is uncertain, but it may provide insight into the prognosis of patients with idiopathic vf. theoretically, the laminar cerebral blood flow observed in our pulseless patients may provide a substantial amount of cerebral perfusion even during clinical cardiocirculatory arrest objective: to investigate whether the intensive care nursing staff can inflate more accurately a specific air volume with the laerdal resuscitation bag when they receive feedback after each inflation about the delivered volume compared to no feedback. method: icu nurses were asked to inflate a testlung model times with a specific air volume ( ml, ,ml or ml) under three different conditions (normal, decreased compliance and increased resistance) without and with feedback. we measured the mean absolute difference from the specific airvolume after each ten inflations. results: the largest absolute difference was found when icu nurses inflated ml ( ml). the mean inflated volume for this group was ml. when the icu nurses had to inflate ml the mean absolute volume difference was ml with a mean inflated volume of ml. inflating ml produced an absolute volume difference of ml with an mean inflated volume of ml. the absolute volume difference decreased when the compliance of the testlung was decreased and even more when the resistance of the used endotracheal tube was increased. when the icu nursing staff received volume feedback after each inflation the mean absolute volume difference was reduced between the ml and ml for all specific air volumes. % of the last inflations with feedback were significantly smaller than ml from the specific air volume (p < . ). conclusion: the majority of nurses overinflated the specific air volumes. the largest over inflation occurred when ml and the smallest when inflating ml. when nurses were provided with volume feedback the performed significantly better. we concluded that icu nurses are not able to inflate a specific air volume with the laerdal resuscitation bag without receiving volume feedback. feedback is desirable in order to reduce the volume trauma. objectives: a pro_found impairment in systolic and diastolic myocardial function following successful cardiopulmonary resuscitation (cpr) has been demonstrated by using langerdorff method in rats. in the present study we have investigated post resuscitation myocardial dysfunction in a porcine model of cpr. methods: ventricular fibrillation (vf) was electrically induced by alternating current applied to the ep{cardium of the right ventricle in domestic pigs. following rain of untreated vf, precordial compression and mechanical ventilation was initiated and maintained for min. electrical defibrillation was then attempted and of animals were successfully resuscitated. results: following successful cardiac resuscitation, stroke volume index (svi) decreased from prearrest value of . ml/kg to . ml/kg (p< . ), and left ventricular stroke work index (lvswi) from . to . mmhg,ml/kg (p< . ). both svi and lvswi remained depressed for another hours. these decreases were associated with increases in heart rate from bpm to bpm (p< . ). no significant changes from baseline in mean arterial pressure, mean pulmonary pressure, right atrial pressure and pulmonary artery wedge pressure were observed. prehospital resuscitation efforts c. k ppel. g. fahron, h. lufft, a. kruger, c. th(jrk, f. bertschat, f. martens dept, of nephrology add medical intensive care, virchow-klinikum, humboldt-universit~t, d- bedin, germany obiective: the success rate of prehospital resuscitation in patients with cardiocirculatory arrest in an emergency medical system (ems) may reach - % depending on the time of calling the ems, the distance to cover by the emergency ambulance and the training of the emergency physician and his staff. in the berlin ems, which is associated with the berlin fire brigade, the time between alarm and arrival at the scene ranges from - min, mean min. resuscftation is based on the advanced cardiac life support (acls) according to the guidelines of the american heart association. if resuscitation efforts fail to restore circulation, they are terminated after - min, depending on duration of cardiocirculatory arrest, pre-existing disease, age, absence of an even transient response to cpr. however, there is a lack of practical criteria for termination of cpr in individual decision making. patients: we report cases of prehospital cpr with primary asystolia terminated after - rain of frustraneous cpr efforts including highdose epinephrine and dopamine. results: after termination of cpr, the ecg monitor remained connected and showed permanent asystolia in all patients while the emergency physician completed his records. spontaneous resumption of respiration and circulation was observed in these patients after - min and cpr efforts were immediately resumed, nevertheless, of the patients died at the scene, while could be hospitalized with stable circulation. one of them died hours after admission to the icu, the other survived for weeks in a vegetative state. spontaneous resumption of circulation and respiration is most likely due to the development of extreme hypercapnia and acidosis, which -at least in some patients -seems to be a stronger stimulant of the circulatory and respiratory brainstem centers than cpr with high-dose catecholamines, conclusion: because of the legal and ethical implications of this rare phenomenon, emergency physicians should continue ecg monitoring for at least rain. after termination of cpr efforts. pulmonary artery catheterezation is used for patient's monitoring [ ]. we reported our results on such monitoring in [f.coaobbeb,r.fe enb~-kap~monorm~, ,n ,p. - ] .however not all of the received criteria assessments meet demands that are necessary for early diagnosis of critical states. here we report the data on po ,pco (mm rg),so ,ph levels in femoral [af) and pulmonary (ap) arteries blood, as well as on summary gas pressure (sgp) calculated from pe=(po +pco ) in mm hg in ap blood. these data were derived from:i) subjects free of cardiovascular pathology according to catheterization data during their spontaneous air breathing (n group in ap blood appears to be a measure of adequacy ratio between pc and sgp in ap blood during air breathing; partly its characteristics and variations ranges are presented earlier [ j. in control group it is equal to , • mm hg. tests on sgp neither exclude nor substitute conventional (pc and pco ) tests, but rather include them as a part choosing only additive characteristic -pressure. they appear to be a part of general system of human metabolism regulation by pressure (arterial,venous,intracardiac, tissue,liquor,onco-osmotic,etc ietraabdeminal pressure produces perturbations of cardiac, pulmonary, and renal physiology. this most often occurs fonowing eeliotomy for peritonitis or intestinal obstruction; bowel edema and distention prevent wound closure without unacceptable compromise of blood pressure or pulmonary compliance. a variety of temporizing measures have been reported for managing wounds that cannot be closed: ) using towel clips to reapproximate skin only, )i sewing silastic, marlex or other prosthetic grafts to the fascia to "enlarge" the peritoneal cavity, ) using loosely tied retention sutures for partial closure, ) simply packing the wound without attempts at c~osure. these techniques either traumatize the abdominal wall (complicating definitive closure), expose the bowel to damage, or allow excessive loss of fluid and heat. since we have evolved a suturelees technique which permits the abdomen to be partially closed in a quick, safe, sterile, sealed, atraumatic fashion -while providin! decompression of unphysiologic intraabdominal pressure. methods: whenever possible omentum is interposed between bowel and the open incision. viscera are covered by a layer of sterile, non-reactive plastic, placed deep to the fascia and extending we~t beneath the edges. sump tubes are placed above the plastic and covered in turn by two layers of an adhesive plastic drape which sticks to the skin and seals the wound in all directions, the patients remain intubated and paralyzed. results: we have used this technique in a total of patients, four of whom suffered from compartment syndrome. all of the latter were males and ranged in age from to . all four showed immediate physiologic improvement. all four incisions were eventually closed without complication. one compartment syndrome patient died t days later of multiple organ failure. there were no complications related to the closure technique in any of the patients. conclusions; . selected patients with abdominal compartment syndrome will benefit from decompression using this temporary sutureless technique. the technique a) is quick, safe, sterile, sealed, and atraumatic, b) minimizes loss of fluid and heat, c) facilitates eventual definitive abdomina| closure. although m. brunner m. mitllncr objectives: to determine incidence and predisposing factors for cardiac arrest occurring during the first hours after open heart surgery. methods: the study included patients who, following open heart surgery, had adequate cardiac function and in whom cardiac arrest was not anticipated. all data were prospectively recorded and analyzed. results: from / through / , pts underwent open heart surgery at our hospital. of th~se, pts ( %) (age _+ yrs) had a cardiac arrest during the first hours after transfer to icu. they were operated on for coronary artery bypass grafting (cabg) ( pts), valve replacement (vr) ( pts), cabg and vr ( pts) and aortic aneurysm ( pt). the preoperative ejection fraction was _+ % whereas bypass and aortic cross-clamp time were + and + rain, respectively. prior to arrest, they had a cardiac index of . _+ . l/min/m and were receiving . + inotropes. arrythmias leading to cardiac arrest were ventricular tachycardia/fibrilation ( pts) and bradyarrythmia ( pts). closed-chest cpr was initially performed on all pts and was followed by open-chest cpr in pts. eighteen pts ( %) survived to icu discharge. causes of arrest included perioperative myocardial infarct (t pts, %), tamponade ( pts, %), rupture of the proximal vein gra& anastomosis ( pt, %), graft occlusion ( pts, %); no cause was found in pts ( %). conclusions: postoperative cardiac arrest in stable cardiac surgery pts is relatively infrequent (- % incidence) and is associated with a high survival rate following successful cpr. perioperative myocardial infarct is the most common predisposing factor. group ~deptof anaesthesia and intensive care, semmelweis univ. medical school, buda military hospital intensive care unit, budapest background: when a cardiac arrest occurs in-hospital, the outcome can be improved by a higher quality of basic life support provided by the witnessing health care workers until the code team arrives. this basic life ~pport (bls) should include the best available method for airway management as well. since not all medical staff are ready for carrying out endatracheal intnbation, we investigated the effieacy of the use of different airway management methods during bls. methods: we have investigated the efficacy of airway management of doctors and nurses from different hospital wards: internal medicine, department of surgery, trauma, urology and gynaecolagy. comparing the bag-valve-mask, laryngeal mask and the endotracheal intubafion, we have measured the following parameters: time needs for correct application (sec.), number of incorrect applications (out of ten trial), efficacy of artificial ventilation provided by the device. we used a computerised als trainer manikin for the evaluation of the performance. total performance score was created after the measurement between - . after the first screening we held a x hours training. doctors and nurses were trained for the endotracheal intubation (group it , t ) , doctors and nurses were trained to use the laryngeal mask (group lm , lm ) . all respondent were trained to use the bag-valve-mask device. day, month and month after the training we have carried out retention study using the same method. results: we have found that the efficacy of the artificial ventilation using the above mentioned devices were poor before the training. the average after-training performance scores of the groups are presented in the table below. (bls) should be initiated by the witnessing health care professional. the cpr study introduced a multi level code system, which means bls included sophisticated airway management, early defibrillation and early epinephrine administration provided before the code team arrives. our previous studies confirmed a poor level of cpr performance and a high demand for cpr training among health care professionals. method: we established a cpr training course centre, where doctors and nurses are being trained for in-huspital basic and advanced life support. x hours of training were held. after the theoretical introduction a step-by-step training method ws used for trainees to be familiar with all sequences of basic and advanced life support. then we synthetised all separated sequences. afterwards, a r e play of rescue groups was taken in simulated situations. we also trained the multi level alarm system fur the in-hospital resuscitations. after the training all respondents had to sit for examination. the quality of performance was scored and compared to our previous results. semi-structured interviews were carried out before and aider the training among all respondents to collect information about the course. results: we have found a remarkably high interest among doctors and nurses in our cpr training courses. it was very important to use proper equipment for the training: audio-visual training facilities, computerised als trainer manikin, manual and automatic defibrillator units. the evaluation of the examination held immediately a~er the training course showed a significant higher quality of performance than before the training. the self.-eonfidence of the trainees for initiating and carrying out resuscitation had increased. their overall feeling about the course was positive and % responded the course "very useful". . % of doctors and . % of nurses claimed fur regular training facilities with als trainers, conclusion: the cpr training for health care werkers is mandatory including the training of sophisticated airway management and use of elad~l~ills~tt~r wlaa ~en ~r a~ti~atir ~nel r rm~a'*h*nr m~thnd for training will improve the efficacy, the satisfaction of trainees, therefore their compliance for further co-operation will also increase. s objectives: the effect of reinfusion in emergency surgery and gynecology. methods: we had an experience of autologous blood transfusion in patients whom was produce t an emergency surgical or gynecological interventions in occasion with break tubal pregnancies ( . %), penetrating abdominal wounds with injuries of mesenterial vessels ( . %), injuries of the liver ( . %), blunt abdominal trauma with lien ruption ( . %). in . % patients had the previous somatic pathology. blood loss volume was - ml, & the reihfuside blood volume was - ml, consisting - % of blood loss. it was needn't to fransuse donor blood in . % in further but - ml of contanined erythrocytes were frasfused for supporting of hb concentration on the g/l ( g/dl) rate at the other patients with isovolemie hemodiluttion. results: the arterial blood pressure fast stabilisation on the perfusion level had noted after reinfusion, excluding the case, when the volume of reinfused blood had conisted just % of blood loss at the patient with massive blood loss. complications have noted in two cases. one patient with slash wound, injury of arteria gastrica dextra and total blood loss of ml, has an episode of asystoly, dic (disseminated intravascular coagulation) syndrome, acute renal failure, and acute pancreatitis that we haven't connected to reinfusion. all the complications were successfully corrected and at thirty first day patient with subcapsular wound of the lien that has happened days before complicated with external rupture of the capsull & massive intraabdominal bleeding, has the hemolytical shock, dic syndrome, acute renal failure developed after reinfusion. he was died. all another have no complications. posthemorrhagic anemia had corrected rapidly than in case when hemorrange corrected exclusively by donor blood. conclusions: we consider that simplicity, accessibility, high effectiveness, quite well further results of blood reinfusion, except the case of blood reinfusing that was for time-expired out of blood vessels (more than days in our case) will promote to the wide spreading of this method, especially in emergency surgery, in massive injuries, & in disarters, all the cases of insufficiently of time for selection of lot of donor blood. objectives: study of a reaction of the oardioreepiratory system of pregnant women to i/v microperfusion of clophelinum which is known to eliminate hemodynsmic and endocrine nociceptive reactions and can be used for treating hypertensive syndrome in pregnancy and labor. methods: the following non-invasive methods were used: capnography, spirometry, oxygenography, indirect fick principle based on the circle breathing, plethysmography and integral rheography~ functional indices of cardiorespiratory function were evaluated. results: pregnant women with ~h-gestosis were examined before and after i/v infusion of i ml of . % clophelin solution, . mg/kg/hour. before the treatment intensification of carbohydrate metabolism, hyperventilation with moderate hypooapnia and complete respiratory compensation of metabolic acidosis~ increased alveolar ventilation, decreased alveolar volume, predomination of perfusion over ventilation, hypokinetio type of circulation with dominated load by peripheral vascular resistance to the blood flow was observed in this group of patients. microperfusion of clophelin imp~-oved the ventilation/perfusion ratio, ventilatory and gaseous exchange efficiency, resulted in a decrease of congestion in the pulmonary circulation, possibly owing to a decrease of peripheral vascular resistance by %, of the heart rate by io. %, of the oardial output index by . %. conclusionm: the resulted type of circulation with a decreased load on the heart both by resistance and volume allowed to improve the cardioreepiratory system function in pregnant patients. objectives: the injury severity score is a measure of severity of anatomic injuries. iss is a sum of squares of the highest degrees of the abbreviated injury scale (ais) for each of three most severity injured regions. the purpose of the study is to establish correlation between the iss values and mortality rate in older, polytraumatized patients. methods and results: iss was determined for patients. the mean iss value was . + . while the median value was . minor injuries were present in ( %) patients with iss less than , while ( %) patients with iss more than had severe injuries. increased mortality of the older patients was noted in the range - . all patients older than died while % of patients below yrs of age survived, indicationg correlation between iss and mortality rate in polytraumatized patients above yrs of age. conclusions: this mode of evaluating severity of injuries may help in triage, determining appropriate level of care and as an indicator of future outcome of polytraumatized patients. objectives : tissue hypoxia is a non exclusive cause of hyperlactatemia. other serious medical situations induce hyperlactatemia. therefore, lactatemia could be a non specific indicator of severity in patients admitted in emergency unit. the aims of this study were to examine the correlations between lactatemia with the short term survival course prognosis and the unit of hospitalisation; intensive care unit (icu) or medicine unit, in patients admitted in our emergency department. methods -lactatemia was measured as soon as the admittance, in arterial blood sample of patients which needed arterial blond gas. sixty-one patients were included during months. to assess the statistical performances of lactatemia, sensitivity (se), specificity (sp) and accuracy (ac) were calculated for the threshold determined by the youden's test (se+sp- ). results : fifteen patients were admitted in icu and in a medical unit. fifteen patients died. a group of patients had a lactatemia up to mmol.l" . in this group of patients, had acidocetosis, had asthma, had cerebral vascular ischemia, had neoplasia, had cardiogenic shock, was epileptic, had congestive heart failure, had acute respiratory failure, had septicaemia, had hyperosmolar status finally had medicinal intoxication. lactatemia was significantly higher in non survivor than survivor ( . • vs. . + . , p<o.oool, respectively), the cut point of lactatemia was . mmoll" se was %, sp was % and the accuracy was %. on the other hand lactatemia was higher in patients admitted in icu than in medical unit ( . + . vs. . • p<o. , respectively). conclusions : this preliminary results suggest that lactatemia is a good indicator of the short term survival course in patients admitted in an emergency unit. furthermore, hyperlaotemia is present in several pathology seen in emergency. objective: to determine the pattern of injury, total peripheral white cell, neutrophil, and lymphocyte responses, and the outcome of trauma patients who are leucopaenic on admission to the icu. design: prospective, descriptive study of consecutive admissions over months. setting: a -bed surgical intensive care in a teaching hospital. patients: thirty consecutive adults admitted to the icu following trauma. leucopaenia was defined as a total peripheral white cell count of < x , neulropaenia < x , and lymphopaenia < . x ~ cells per litre. measurement and results: the total peripheral white cell count was documented daily and the neurtophil and lymphocyte counts and differential percentages on days , , and . the incidence of leucopaenia was significanfiy higher in patients with gunshot wounds (p < . ) and hollow visceral intra-abdominal injury (p < . ). eight ( %) patients died. no significant differences were found in the initial mean total white cell, neutrophil, or lymphocyte counts nor in the differential percentages between survivors and non-survivors. the total peripheral white cell count increased significantly in survivors compared to those who died (p < . ) and significant differences were found in absolute neutrophil counts (p < . ) and differential percentages (p < . ) on days and . no significant differences were found in lymphocyte counts or differential percentages. conclusions: there is a signficant association between leucopaenia, neutrepaenia, and intra-abdominal hollow visceral injury and peritoneal contamination. survival is related significantly to resolution of these white cell deficiencies. these findings suggest a possible role of granulocyte colony stimulating factor in the trauma patient with intra-abdominal infection and persistent neutropaenia. amelioration of organization emergency care team in order to improve caring for urgent cases. objectives: emergency care team (ect), as integral part of health, respectively as activity of primary health protection care all acute difficult conditions which vitaly danger patients and distressed. the aim of our investigations was to indicate on the possibilities of amelioration of organization ect in order to improve caring for urgent cases. methods: in our investigations we used epidemiologicai and statistical metods all informations and matherials from terrain ects. results: the number of traumatized in traffic accidents etc. have a epidemic character. it is well known that . % traumatized died in first two hours. ect isn't enough qualified to care a traumatized on the place of accident and during transport. because that medical personnel must have an education with solid qualities. conclusions: . besides a physician specialized (vii --+ vii -~ viii gradus) in urgent medicine, it's necessary to introduce two ( ) medical technicians instead of one as is existing now ( ~ ). .the medical technicians can drive cars and one of them always, drives the ambulance car ("b" category). .the technicians have been specially educated for urgent cases (iv ~ v ~ vi). . such a new team structure should be more capable in professional sense. .we can see an importance of team-work in ects. . such teams should also be more economic in comparison with existing one. . we think, that on the general medical studies need to include a new discipline-urgent medicine! objectives: to detoxicate an organism since we have used biological sorbents: isolated from liver and spleen of human or animal cells or tissue fragments. methods: cellular dialysis ( dialyses) in patients with an acute hepatic insufficiency poisoning by hepatotropic poisons: cc , dichloethane, mushrooms -were conducted using "artificial kidney" apparatus, by means of arteriovenous shunt, formed at forearm with disposable dialyzers. hepatocytes suspension was poured into dializing circuit of dialyzer at - mg of cells per i kg of patients weight. dialysis was performed during - hrs. patients with purulent-septic states were treated as for hemoperfusion through prepared sorptional column: . ml of hemosorbent and . ml of fragmented spleen or hepatocytes suspension with the help of roller pump with the rate of - ml/min, during - min. average volume of hemoperfusion made . . conclusions: in all cases we used both native and cryopreserved biomaterial. analysis of the dynamics of clinical, biochemical, scintigraphic and us-investigastions allows to conclude that application of cellular-sorptional method of detoxication enable to prolong life and reduce lethal outcome in some severe category of patients with endotoxicosis. after infusion of diazepam ( . mg/kg),thiopentone ( mg/ kg) and vecuronium (lmg/kg),patient was intubated and mechanical ventilation was adjusted to mantain normoca= pnia. ct scan showed left parieto-occipital hypodensity with brain swelling. after admission in neurological icu,dexamethasone ( mg/ kg/die),mannitol ( .smg/kg) and diphenylydantoin ( mg/ kg/die) were administred. two hours later neurological status of the patien~ was normal and she was extubated. the risks of stereotactie radiosnkgety are related to: hemorrhgge during the latency interval;transient radia= tion effects;permanent radiatio~einduced complications; radiation induced neoplasia. no epilepsy is reported in pts with avm and no seizure before radiosurgery. in c nclusion, epilepsy can be a posmib~e delayed eompli c~t~n, ~fe~r rgdi surgery for cerebral avm. serum potassium deficiency is a frequently reported finding in the time course of acute myocardial infarction (ami). if this is also correct for patients with ami undergoing primary percutaneous transluminal coronary angioplasty (ptca) is unknown.for that reason we analysed in patients ( m., f., + y.) serum potassium concentrations on ad ,mission and directly after ptca.the reference intervall for potassium in our clinical laboratory is , - , mmol/l. although more than % of the patients with ami undergoing ptca showed normal potassium serum concentrations on admission a measurable decrease of potassium could be found in % of patients ( ) after ptca.therefore for the majority of patients with ami potassium supplementation prior to ptca can be justified to avoid electrolyte disturbances as a possible trigger factor for cardiac arrhythmias in the setting of ami and acute reperfusion due to primary ptca. objectives: diagnostic procedures are very important in the management of abdominal injures in trauma. the aim of this paper is to present our experience with peritoneal lavage as diagnostic procedure in abdominal injury. methods: we analyzed patients to whom peritoneal lavage was applied in the surgical emergency from st of january till st of december . results; in this four years period there were abdominal injures. there were blunt injures. among them in patients peritoneal lavage was applied. results were positive in patients and negative in patients. false positive finding were in patients and false negative in two patients. in patients with positive lavage there were more than , /mm red blood cells, more than , /mm white blood cells and the level of amylase was up to u/i. the gall, urine and stool were positive as well. in patients with negative lavage there were less than , /mm red blood cells, less than /mm white blood ceils and amylase were negative. conclusion: peritoneal lavage is useful and important diagnostic procedure in the management of abdominal injures in trauma. our experience with urgent surgical management of the acute gastric and duodenal bleeding s.se en md, z.milo~evi md, *s.srdi md, k.sar ev md. clinic for abdominal and endocrine surgery, institute for surgery; *clinic for cardiology, institute for cardiovascular diseases; school for medicine novi sad, university of novi sad, yugoslavia objectives: acute gastric and duodenal bleeding are very common complication of gastric and duodenal ulcer. the aim of this paper is to present efficiency of our surgical management of these acute conditions. methods: in this paper results of surgical management of patients with acute gastric and duodenal bleeding, treated in our clinic from the st of january till st of december , are presented. results: among operated patients there were females ( . %) and males ( . %). there were patients ( . %) with gastric bleeding and patients ( . %) with duodenal bleeding. bleeding from gastric ulcer were treated with the following methods: excision of ulcer with suture in patients ( . %), ulcer suture in patients ( . %), billroth i in patients ( . %) and billroth ii in patients ( . %). heinecke-mikulicz-weinberger pyloroplastica was the most frequently used in the treatment of the duodenal ulcer bleeding. bilateral truncal vagotomy was done in patients ( %), duodenotomy with ulcer suture was done in three patients ( . %) and three patients underwent billroth ii operation. we had three complicationsduodenal dehiscence in pyloroplasty. there were no lethal complications. conclusions: based on our own experience we conclude that acute bleeding from gastric and duodenal ulcer can be safely managed with urgent and modern operative techniques. dept. of anaesthesiology. emergency center of serbia, belgrade, srj b ectives and methods: cardiac contusion was evaluated by serial determination of cpk-mb fraction and co using non-invasive doppler technique in patients with blunt trauma of the chest. results: miooardial contusion was diagnosed in ( %) patients, while in ( %) it appeared unaffected. cpk-mb of % and more in comparison to total cpkwas . + , % in patients, and , + , % in pts (p< . ).c of . + . l/min in patients with cardiac contusion, measured hrs after admission at the latest, was significantly lower than in group of patients with co of . + . l/min (p< . ). conclusions: co values were significantly lower in patients with cardiac contusion and correlated with pathological values of cpk-mb fraction. objectives: extracorporal plasmophoresis (pph) was implemented by non-stop method in patients with obstructive jaundice. methods: changes of serotonin (s) and histamine (n) in arterial (ab) and venous (vb) blood were investigated before and after one-time session of pph. s and h in blood serum were determined with fluoremetric method. results: before pph the average s contents in ab and vb did not differ. after one-time pph session s in the blood outflowing lungs was % lower than in the blood inflowing. hours after extracorporal detoxication implemented the indices kept the same level. similar dynamics after pph was observed in h. before the session h contens was equal both in the blood inflowing and in the blood outflowing lunge. after pph h contents in ab was % lower compared to the vb and did not change for hours. conclusions: dynamics of changes of biogene amines shows that under the influence of pph there takes place not only mechanical removal of their surpluses together with plasm, but there sharply grows inactivating role of lungs towards ba substances, which is confirmed by reduction of their concentration in the blood outflowing lungs. this effect is probably connected with the "deplasmation" of the lung cellular elements. simultaneously lungs' cells are freed not only from plasm but from toxic adsorbents on their surface. as a result the lung cells activate absorption of the surplus number of amines from the vessel channel. it is not excluded that s inactivation is due to growing activity of monoaminooxidase resulting in deminishing of intoxication. acute pulmonary embolism: thrombolytic therapy or pulmonary embolectomy? i.lodiena md, phd, s.shevchenko md, pphd., medical university, kharkov, ukraine objectives: pulmonary embolism (pe) remains a challenging problem for diagnosis and management for the emergency physician. the aim of this work is to identify the best treatment for massive pulmonary thromboembolism. methods: during recent years patients with symptomatic acute serious pe were reffered to our observations. selective pulmonary arteriography confirmed this diagnosis in all cases. ( . %) underwent urgent surgery, of them ( . %) with cardiogenic shock and ( . %) with massive pulmonary embolism. patients ( . %) underwent thrombolytic therapy. results: in the patients who received thrombolytic therapy successful results were achieved in cases ( . %), in ( . %) patients subsequent pulmonary embolectomy was performed. mortality rate was ( . %) in the patients who underwent pulmonary embolectomy after unsuccessful thrombolytic therapy and ( %) in the patients with cardiogenic shock and massive pe. lower extremity deep venous thrombosis caused pe in % patients. pe mortality rate is repoted to be %, but all patients with cardiogenic shock and massive pe died. this very high mortality rate related to the clinical status of the patients whose condition became worse despite intensive treatment. conclusions: the results of this study show that in most cases thrombolytic therapy is an effective rapid method of treating pe. however, surgical treatment is preferable when the patients reveal adverse effects to drug therapy, when medical therapy is unsuccessful or when the patients are seriously ill with reccurent cardiac arrest. high-quality pulmonary angiography remains the most accurate and reliable means of diagnosing pe. this prospective study was conducted to investigate the serum thyroid hormone levels in traumatized critical ill patients. serum thyroid stimulating hormene(tsh),total thyroxine(tr ),free thyroxine(ft ),total tri-iodothyronine(tr ),free tri-iodothyronine (ff ) levels were measured within hr.of intensive care unit admission(first day) in multiple tratmmtized male patients(injury severity score higher than ). in fifth day the same hormone levels were repeated. tsh,et ,ft ,tr and ft levels were determined by radioimmueoassay(ria). the levels of 'i~sh,xt ,fr ,et and ft in survivors and nonsurvivors were compared with first and fifth days (table) . in conclusion, we are convinced that there was a high correlation between low ser~n thyroid hormone levels and mortality, serum thyroid hormone levels are prognostic value in traumatized critical ill patients. objectives: glucagon improves myokardium contractility, intensifies kidney blood flow, stops bronchospasm ( ), these were the reasons of investigating its effect on hemodynamics and metabolism in hypovolemic shock expermentally and in clinic. methods : in experiments on white rats with traumatic shock glucagon (novo nordisk) was injected intraperitoneally in dose rocg/kg. patients with hypovolemic shock (trauma, hemorrage) were injected glucagon intravenously in dose mg on the background of infusion therapy. results : glucagon hightened recovery indexes of glucose in rats and patients with shock, whereas in groups without glucagon hyperglycemia developed. rats with glucagon injection had double times urea content than the norm ( , + , mmol& norm - , + , mmol/i ), whereas rats without glucagon had urea content , + , mmol/ ( p < , ). osmolarity of blood plasma in rats having glucagon injections was , + , mosm/kg h , without the drug - , + , mosm/kg h ( p < , ), ldh activity - , + . and , + , ( p < , ) mcmol cec- accordingly. lethality in the group of rats without glucagon was % /n= /, with glucagon - (n = ). in patients with hypovolemic shock in minutes after glucagon administration stroke volume increased to % (sv), miocardium contractility -to % (mc), peripheral resistance of vessels ( vr ) decreased to %. in - , hrs sv increased to %, mc-to %, pvr -decreased to %. conclusion : the study provides the evidence that glucagon has an anti-shock effect, improves hemodynamics and metabolism indexes in cases of hypovolemic shock. reference : picazo j. glucagon in acute medicine : pharmacological, clinical and therapeutic implications (norwell, mass:kluwer publishing, ), p. n, vasina (t) ,n.sebbota hph ( ). dept; of acute endotoxicosis, n.v. s~lifosovslay scientific research institute of ermergency ltealth care, boscow, lk'ussia (i}. institute for problems of cryobiology and cryouledicine of the national academy of sciences of the f/maine, kl'k r-key, [ maine ( ), objectives: the investigation of isolated hepatocytes using's efficacy in patients with acute hepatic fai lln-e. methods: native and crioconsrved allo-and xeno-!mmatocztes fixed on semi;ermeable ~mbr~s were used. results: the artificial supporting system with isolated hepatocttes as metabolic ~its was. ap-plied in patients. during tl~ treatmen~ with this cytotherapz an improvement of clinic state and biochemical rates were observed even inthe first we~s. for instance, the kncreasing of glutamin acid's level in blood up to normal value and decreasing of ammontes -concentration from i ~ mmol/l down to # mol/l were discovered. ~ae diminution of ence,%halo;athy was noted too. general lethality was' equal z, there of i z concerned acute hepatic failure (/k~). conclusions: the using of sum~rting hepatic system is able to cope the ~nenomenon of ~i~. objectives: fat embolism (ee) is an important and insufficiently studied problem of the intensive care medicine. fe is clinically diagnosed in % and morphologically in - % of the victims with severe multiple skeletal injury that is accompanied by the shock. methods: during the last years patients with the cerebropulmonary form of fe were treated in the icu. the prognosis of the probability of fe development was done using the computer system "cite-prognosis" in which the triss-method, dynamic and statistical prognosis of the injury outcome~ and the values of the most severe injury in points were realized. the treatment consisted of the surgical stabilization of the fractures with the authors' design of the rod apparatus in the acute period, long-term mechanical ventilation with peep via tracheostomy, complex fluid therapy using perfluorochemical emulsions (pe), and electrochemically active solution of na hypochlorite (snh) via the central vein. results: the treatment of patients with fe gave a good result that was manifested by the complete regression of psychoneurologic and respiratory disorders. conclusions~taking into account the prognostic data~ it is necessary to provide early complex of intensive care to the polytraumatized patients. it includes the surgical stabilization of fractures, fluid therapy using pe and snh~ early long-term mechanical ventilation. dr. alexandr e. poladko, station of medical aid. kiev ukraine. objectives: the reason of investigation is to prove the necessity of beginning of the intravenous infusion of nitroglycerin before the hospitalisation. methods: from january i to june protocols of treatment myocardial infarction patients in kiev medical aid station. results: the results of treatment are better if infusion began early or prolonged during hospitalisation. conclusions: there were patients with acute myocardial infarction treated before hospital by the cardiological groups. patients were treated with the early infusion of nitroglycerin and without. the results of treatment were: in the group with infusion: mortality in the first hours % the full disappear of pain % in the group without infusions mortality in the first hours % the full disappear of pain % that's why our opinion is that infusion of n. is necessary in the treatment of the patients with myocardial infarction from the first minutes of illness. dr. gennady d. kyrzhner, station of medical aid, kiev, ukraine. object: looking for safe medication which is good for the treatment of arterial hypertension and is simple for use. we inspected the effect of prazosin in the conditions of the cail during the year. method: we used mg prazosin tablets sub lingua and measured blood pressure ones during hours. the parameters were registrated in protocol. result." one hundred patients took part in investigation. the middle age of patients was . the reason of hypertension was not taken into consideration. in two hours after beginning of the treatment we caught the reliable lowering of blood pressure in % of patients. the general condition of patients became better in - min. it was only one accident of complication during the treatment -the orthostatic hypoter~sion, conclusion: prazosin hydrochloride in the dose mg sub lingua is safe and simple for use in the urgent situations. objectives: hypomagnesemia is frequently observed in severely burned patients during the early period after injury. increased urinary excretion is insufficient to explain the magnitude of the magnesium (mg) depletion. the possibility of exudative cutaneous mg losses has been proposed, but not yet demonstrated. the study aimed at measuring the mg content of the cutaneous exudates and urine during the first week after major burns. methods: patients, aged _+ years (mean _+ sd), and burnt _+ % of body surface, were studied from day (d ) to d . serum samples were collected at do, serum and urine from d to d , and on dio, d , d . cutaneous exudates were extracted from the textiles surrounding the patients, collected over h periods from d to d , using bidistilled acidified water. mg supplements ( . to mmol/ h) were prescribed from d to dio according to the severity of hypomg (serum mg < . mmol/i). results: mg serum levels decreased below reference ranges in patients between d and d , and normalised thereafter during supplementation. urinary mg excretion was increased in patients, mean excretion being . _+ . mmol/ h until d . mean daily mg cutaneous losses, were mmol/ h, i.e. mmo; in days. large inter-& intra-patient variability: the daily exudative losses ranged from to mmol/ h. conclusions: the mean daily mg cutaneous losses after burns were larger than the urinary losses, and equivalent to the recommended intakes for mg; the addition of the exudative and urinary losses largely explained the increased mg requirements after burns. complex immunologic alterations occur following thermal injury. the activation and consumption of the complement and dotting systems are suggested to play an important role in the development of the capillary leak syndrome, tn burned patients, a generalized inflammatory reaction as well as the impairment of the host defense are considered to be the major reasons for complications, such as sepsis and multiple organ failure. in a pig model we investigated a possible protective effect of cl-inhibitor (berinert, behring). before conducting the animal experiments the human cl-inhibitor concentrate was analyzed for its inhibitory capacity on purified pig cls and its pharmacoldnetic behaviour in pigs (t / ,id ). pigs received anesthesia and analgesia and arterial, venous and pulmonary (swan ganz) katheters were placed into the carotis and jugular veins. the pigs were scalded for seconds with ~ hot water to achieve a % tbs partial-thickness burn. blood samples were taken prior and after surgery as well as , minutes, , , and every further hours after thermal trauma. two control groups (each n= ) included animals which were either scalded or not scalded and treated only by resuscitation of ringers lactat solution. besides various parameters blood samples were analyzed for complement. the pigs (n= ) received c -inhibitor concentrate at an initial dose of u/kg body weight either immediately or hours after thermal trauma (n- ), followed by three further applications (of reduced amounts) every hours. the clinical outcome as indicated by vital parameters and as well as demonstrated by reduced edema and inflammatory tissue destruction suggested a protective effect of cl-inhibitor. complement analysis revealed a faster recovery of the alternative and classical pathway activities in cl-inhibitor treated pigs as compared to the control group but only if the regulator was given immediately after thermal trauma. from these results a protective function of c -inhibitor on thermal trauma can be assumed. objectives: the aim of study was to characterise the pattern of secretion of interleukin- (il- ) and tumor necrosis factor alpha (tnf alpha) in multiply injured or not injured critically ill patients and to relate these results to their outcome. methods: blood samples of multiply injured ( ( ) ( ) ( ) il- (nis) ( ) ( ) ( ) il- (nin) ( ) ( ) ( ) conclusions: this data suggest tnf alpha is a better prognostic marker in patients with multiple injury, than in critically ill patients without injury. il- is not significantly higher in nonsurvivors of both groups. sepsis is associated with an increased production of nitric oxide (no), as reflected by a rise in plasma levels of nitrites (no ) and nitrates (no ). severe bum injury is associated with similar symptoms of inflammation like hypotension, high cardiac output low vascular resistance and increased vascular permeability so that an increased no production may be involved. the present study included patients admitted to the intensive care unit of the burn center of brussels (age : - years; burned surfaee area - %), and control (non-septic) patients hospitalized in the neurological rehabilitation unit of the erasme hospital (age - years). the patients in both groups were fed enterally with to kcal/kg/day of a standard solution. in the burn group, daring the study period, patients were mechanically ventilated, required vasopressor (dopamine) therapy, and received antibiotics; patients were discharged alive from the intensive care unit, and no patient died during the study period. plasma was sampled for no /no determinations (griess reaction) daily from day to day (n=ll) or to discharge (day , n= ; day , n= ) in the burn group, and once the control group. in the burn group, no /no levels were elevated at day ( _+ #moles/i), reached a maximal value on day ( - p.moles/l) and progressively decreased to day (fig). these values were higher than in the control group ( . :t: . #moles/l, all differences p< . ). however, no correlation was found between the plasma no /no levels and the age of the patient or the total burned surface area; burned patients who became infected tended to have higher plasma no /no levels than those who did not ( + vs - #moles/i, ns). the present study indicates that burn noa/noa (llmol**/l) injury is associated with increasedloo] [__ ] ~ no /no plasma levels, which are ao so consistent with an enhanced no pro- o duction, ao obiectives:urapidil has been recommanded for therapy of hypotension in neurosurgical patients, because it was found not to increase intracranial pressure in patients with compromised intracranial dynamics ( ). in contrast several authors reported an increase of icp after urapidil administration in patients with head injury ( ). our study was designed to determin the influence of urapidil on mean lumbar cerebrospinal fluid pressure (csfp) in awake humans with uncompromised intracranial compliance. methods: after approval by the local university ethics comittee, six volunteers (asa , male, female) were studied in the lateral decubitusposition with the vertebral column positioned horizontally. a gauge needle was inserted into the lumbar subarachnoid space at level l /l and connected to a trancducer (mx | medex inc.) for csfp measurements. the volunteers were advised to keep respiratory rate and etco constant. after a resting period of minutes basline measurements were performed including csfp, cvp, map, hr, etco (cardiocap | datex). then the volunteers were given urapidil . mg/kg over a period of minute. minutes later measurements were repeated. results: statistics: wilcoxon signed rank test, p< . significant; values: mean_+sd, si = mmhg. - _ " _+ * _+ * - _+ " _+ csfp: cerebrospinal fluid pressure, cpp: mean cerebral perfusion pressure. conclusions: during normoventilation urapidil leads to a decrease in map parallel by an increase in csfp and therefore in icp, most likley mediated by an autoregulatory dilatation of cerebral vessels. if this cerebrovascular response is suppressed by hyperventilation, no increase in icp is found despite a uredipil induced drop in map ( ). after longterm hyperventilation cerebralbloodflow is normalized. this might be the reason why the drop in bloodpressure following urapidil administration again led to an increase in icp ( background and objectives: the intestine is one of the most sensitive tissues to ischemia-reperfusion injury. reperfusion of the intestine is often associated with increase in mucosal permeability and ulceration. d(-)-iactate is produced by indigenous bacteria found in the gastrointestinal tract and mammals do not possess the enzyme systems to rapidly metabolize it. the present study was designed to determine the kinetics of plasma d(-)-iactate alteration in rats paused by acute intestinal ischemia-reperfusion injury. methods: following the anesthesia, the superior mesentcric artery (sma) was exposed and it was occluded by a micro-bulldog clamp applied at its origin from the aorta. after min of occlusion, the arterial clamp was removed and the supply area of the sma was allowed to be reperfused ( h). plasma d(-)lactate levels were measured by an enzymatic spectrophotometric assay. the endotoxin content of plasma sample was assayed by the limulus amebocyte lysate test with a kinetic modification of the test kit procedure. results: intestinal ischemia for min resulted in a significant increase in d(-)-lactate levels within the portal vein as compared to sham-operated animals. plasma d(-)-lactate levels had a tendency to further increase after reperfusion up to h. it was showed that significant elevation of endotoxin concentrations in portal vein was alread~r detected at the end of -min ischemia, reaching peak at . h post-reperfusion and decreasing gradually throughout the study period. at the end of ischemia, marked mncosai damaged such as edema, hemorrhage and necrosis was observed. there was evidence of injury to ti, e muscuiaris propria together with diffuse mucosal damage and destruction following reperfusion, particular at h postreperfusion. in addition, penetration of bacteria was commonly found in the intestinal wall at various time points following ischemia/reperfusion injury. conclusions: these data suggest that acute intestinal ischemia is associated with permeability change of mucosal barrier resulting in increased plasma d(-)qactate, which is also remarkably influenced by subsequent reperfusion. plasma d(-)-lactate may be a useful marker of intestinal injury following both ischemia and reperfusion insult. objective: to assess the clinical usefulness of two methods of intracranial pressatre (icp) monitoring: intraparonquimatous recording (icpc) and epidural recording (icpe), versus intraventricular icp (icpv) as a gold standard. we prospectively studied patients with severe head injury (glasgow coma score < ) admitted to our icu between fobmaly and december . icpv was monitored in all pativrats by means of a multipzffolated catheter connected to a water coinnm. six of patients were additionally icpc monitored by a fiber optic transducer (comma r~), and seven of patients were icpe monitored by a couplvd fluid system (plastimedr). icpc was placed homolatetal to the focal, lesion m two cases and contralateral in three; icpe was placed homolateral to the focal lesiou in two cases and contralateral in three. all three systems were calibrated at the ear level. stali~cs: correlation coefficient and lineal regression were done between icpe and icpv, and between icpe and icpv with the hourly p~rs of values obtained dttting assistontial period. results: of the six icpc -icpv studied pa~onts, we observed a correlation coef~cieut r = . (p < . ) with a regres~on line y = . + . x. four of ~hx lcpc -icpv patients had r > . when correlaliou eoet~dent was obtained indixddually. of the seven icpe -]cpv studied patients, we observed a cortelafiau ooeffioiont r = . (p < . ) with a regression line y = . + . x. corralalmu eoetfieiont was inwer than . in all seven patients. corrdation eoelfieients for levals of icpv > man hg, > mm hg and > tuna hg with icpe showed r = . , r = . and r = . respectively; and with icpe r = . , r = . and r = . . the obtained values did not change during the study. conclusdns: in our study icpe was considered a good type of icp monitoring. /cpe signiticantly infravalorates icp values. we observed a good correlatinn between icpc and icpv values in patients with high inttacramal presanre. objective: midazolam is a benzodiazepine agonist widely used for sedation in emergency medicine. few studies in animals and humans point to a direct analgesic effect of midazolam probably mediated by spinal antinociceptive receptors and/or peripheral benzodiazepine receptors ( , ). in our experience in the berlin emergency medical system (unpublished results) with anecdotal cases of extreme chest pain due to binge drinking but no evidence of acute myocardial infarction or extreme abdominal pain due to peritonitis, acute intermittent porphyria, peutz-jeghers syndrome or testicular torsion, we found that small doses of midazolam ( - mg i.v.) were much more effective in relieving pain than repeated administration of high doses of buprenorphine or morphine, which may be associated with a considerable respiratory depressant effect. the dose of midazolam required for pain relief in these patients is non-narcotic and allowed further communication on the character and localization of' the residual pain, which might be very important for the further diagnostic procedure. patients: ten patients with abdominal pain due to acute gastrointestinal bleeding, suspected pancreatitis, suspected acute porphyria, and chest pain with no evidence of acute myocardial infarction received first-line midazolam i.v. at an initial dose of mg and were asked how it affected the intensity and character of pain. results: at the chosen dose of midazolam ( - mg), all patients were responsive to detailed questioning on basic orientation, the character, intensity and localization of the pain, and medical history. none of the patients required an additional opiate. all patients stated that the pain was tolerable after midazolam alone. conclusion: our preliminary clinical observations suggest that low-dose midazolam might be an alternative to opiates in extreme pain of presumably visceral odgin. objectives: it is known that severe head injury in elderly patients is associated with higher mortality than in younger patients. it remains however to be clarified whether the preinjury pathology which is frequent among these patients, affects the outcome. methods: in an attempt to investigate this hypothesis, patients aged over years suffering from head injury, with glasgow coma scale (gcs) of or less, were studied retrospectively. twenty-six patients ( . %) had preinjury pathology i.e. diabetes mellitus, arterial hypertension, heart failure, alcoholism, parkinson's disease etc. (group a) and fifty-three ( . %) did not (group b). the following data were recorded: mortality in the i.c.u., duration of hospitalisation, incidence of infective complications and neurologic status at discharge. results: groups were comparable in terms of mean gcs ( . vs. . ) and median age ( . vs. ). the incidence of brain pathology in the two groups was the following: epidural haematoma . % vs. . %, acute subdural! haematoma . % vs. . %, intracerebral haematoma . % vs. . %, subarachnoid haemorrhage . % vs. . %, diffuse haemorrhage . % vs. . %, contusion . % vs. . % and non-visible pathology (normal ct) . % vs. . %. unilateral pupilary dilatation was found to be . % in group a and , % in group b. the mortality during hospitalisation in the i.c.u. was almost the same: % iu group a and . % in group b patients. however, group a patients had significantly more infective complications, required longer hospitalisation and had lower gcs at discharge. conclusions: the results show that the existence of preinjury pathology does not seem to affect the short-term outcome of elderly patients with severe head injury. it has however an impact on morbidity and perhaps long-term survival of these patients. the assessment of clinical development in intensive care patients with severe head injury still remains a problem. to optimize the monitoring of intracraniel prassure (icp) we rautlr~dly implant an eplduml measuring device in our hospital. the aim of this study was to prove the correlation of the icp-values with ct findings and clinical development. during a month period ( - r the icp was monitored in p~,tients ( male, female) with severe head injury by an eplclural measuring device (epldyn~/$plegelberg| the mean age was . years ( - ). the glasgow coma scale at admission was . ( - ). in all cases the device was placed wfihln the first hours after admission. the tcp was compared with physical examination, radioidglcal or intraoperatlve findings and cunlca! outcome. the average time of measuring was . days ( - ) . the traatment depended on the !cp values recorded. rising icp-valuea ~ed to radlologlcal c ntra!s by ct-scan. in case an intracranlai hemorrhage was detected and drained. the overall survival rate was . %. showed a complete resolutl n, in other . % psychological residuals like decreased mentatlon, in . % sensomotorlc residuals like cerebral nerve dysfunction and aphasia, and . % of the injured remained in a comatous status. in % of our cases the measured values correlated with clinical course and management. in cases ( . %) we observed a displacement of the icp-pevice. there was no icp induced infecllon. istituto di anestesiologia e rianimazione, universit& ,,la sapienza", rome, italy * istituto superiore di sanit& -servizio di epidemiologia e biostatistica, rome, italy objectives: acute renal failure (arf) can be a severe complication of trauma. the current incidence of post-traumatic arf is associated with high mortality . identification of risk factors and prevention of this complication could improve the outcome of trauma patients. methods: one hundred fifty three consecutive trauma patients (age . _+ . , injury severity score . + . ) admitted to icu were studied. incidence of arf was . % ( / ). arf was defined as persisteat plasma creatinine > mg/dl with or without oligoanuria . arf was defined as early when occurring within the first hours (earf) and late when the onset was after the first four days (larf). results: earf occurred in patients while larf developed in patients. age, iss, and incidence of rhabdomyolysis and acute respiratory failure were not different in the two groups. an higher incidence of multiple organ failure (mof) and sepsis ( . % for both) were observed in larf group, when compared to earf ( % and % respectively). abdominal trauma was more frequent in earf group ( % vs %). the gs for earf and larf were respectively _+ . and _+ . while in the group who not developed arf (narf) the gs was . • conclusions: gs score difference seems suggestive and can be that an abnormal cerebral activity (hipofisary hormones?) may play a crucial role on onset of arf in these patients. moreover the frequency of acute respiratory failure in the group of arf was higher ( . versus . ) than narf group. the early ipoxia in the early phase of trauma, then, may be another crucial point for development organ failure. these are preliminary data. a more exact statistical analysis must be perform to have definitive conclusions. to compare the active compression-decompression cardiopulmonary resuscitation (acd-cpr) with the standard cardiopulmonary resuscitation (s-cpr) in out of hospital cardiac arrest patients. is a controlled, randomized study. two groups of patients with cardiac arrest out of the hospitalwere formed. group i, (acd-cpr) and group ii (s-cpr). for the acd-cpr groupweusedthecardiopumpdeviceofambulnternational. asfortherest, the erc ( ) algorithms for acls were followed. the utstein style (for out of hospitat cardiac errest) was used for listing and evaluating all cases of the study. the cpr was contucted by the crew and the doctors of our mobile intensive care units (micu). we studied consequitive patients ( in group i) and ( in .group ii). demographics pre-cpr characteristics (e.g. ecg form of cardiac arrest) and procedures (eg bystanders or second tiers crew cpr, defibrillation, drugs) were quite similar for both groups. the mean arrival time of micu was min. in group i we recorded r.o.s.c. (return of spontaneous circulation) , %, death %, continuation of cpr efforts , %. while in group ii, %, %, and , % respectively (recorded percentage until the admission to the hospital). no significant difference was found in anyofthe short term outcome parameters. no complications related to the acd-cpr technique, were noted. not any significant difference between the two methods was proven (from this small evaluated sample). the results of previous clinical studies are controversial (i) . more sophisticated studies proved the superiority, in a certain number of parameters (e.g pressures, flow, etc) of the new technique although there are many difficulties for establishing clinical results. in the pre-hospital setting that is related to many parameters (speed of the intervention, effectiveness of bystanders cpr, education ofparamedics, etc.)the evaluation is even harder. the superiority ofthe acd-cpr can be proven when it is performed in almost times increased number of studied patients as w~ll as improvement of the technique could lead us to more established results. objectives; infectious morbidity is the major cause of mortality after burn injury, and is due to multiple factors. trace elements (te), which are involved in both humeral and cellular immunity, exhibit severely altered status after burns. te supplementation has been shown to be associated with increased leukocyte counts and shortened hospital stay. the trial aimed at studying the immune responses in severely burnt patients receiving normal te supplies or early large supplements. methods: patients, aged _+ yrs (mean_+sd), with burns covering + % of body surface were studied from day (d ) to d post-injury, were randomised in groups (g): g -control receiving recommended te supplies + placebo; g -receiving in addition large supplements of cu, se and zn from d to d . enteral nutrition was started within hours of injury in all patients. immunological parameters: peripheral leukocyte counts, proliferation of mononuclear cells to mitogens, cell surface molecule expression, and neutrophil chemotaxis at d and d . infectious episodes and micro-organisms were monitored until d . results: the patients' characteristics were similar g & g . the total leukocyte counts were higher in g between d and d , due to increased neutrophils (significant from d to d ). total cd + and cdlg+ cells did not differ, whereas cd + (monocytes) were significantly increased at d . proliferation to mitogens was significantly depressed in all patients. chimiotactism was not altered. the number of infectious episodes was significantly decreased in g with a mean of . _+ . infections during the first days versus . _+ . in the control group (p < . ). conclusions: the large te supplements for days was associated with a significant decrease of the number of infectious episodes. supplementation was associated with increases in total leukocyte, monoeyte and neutrophit numbers. further studies are required to determine the precise mechanism underlying the improved immune defences. objectives: evaluate the efficiency of local adsorption (la) with the use of carbon adsorbents in case of severe burns in expertment and clinic. methods: experimental studies on la were performed on a model of % body surface area iiib-iv burn in rats. a burn eschar was excised on the rd day after burn, the wounds were dressed with the gauze bandages (control) or with adsorptive dressings (la), dressings were regularly changed. clinical investigations were carried out in the course treatment of patients with severe thermal and radiation ilia-iv burn. in the dynamics of bum disease some indices of proteometabolism and intoyacation criteria were evaluated. results: the experiments have demonstrated that the application of la after early excision of a burn eschar exerts a pronounced normalizing effect on a protein electrophoregram and the activity of proteases and their inhibitors in burned tissues preserving vitality. thus, by the th day after burn infliction the activity of cathepsin d in injm'ed muscles is times lower under an adsorptive dressing than under a gauze bandage (control) (p< , ), the activity of trypsin-like proteases is . - . times lower and the antitryptie activity does not differ significantly from the normal level. the cytotoxicity of extracts of burned tissues after the adsorptive dressing application fn vivo and adsorption in vitro is - % and - %, respectively, of the toxicity of control extracts. a similar normalizing effect of la is ok~rved for an intact muscular tissue and blood serum. the dectron-spin-resonance studies have demonstrated that la allows to normalize antitoxic activity of liver and functional activity of kidneys. the application of la in the treatment of patients with severe burns have been shown to localize a region of irreversible tissue changes, accelerate rejection of a burn eschar, attenuate an endogenous intoxication level and, as a result, shorten the time for grafting of a burn wound and accelerate wound heating. conclusions: proceeding from the obtained results, we can consider la as an effective method of localization of a region of irreversible tissue changes as well as of correction of local and general metabolism failures and overcoming burn autointoxication during burn disease. c de deyne, t vandekerckhove*, j. decruyenaere, b. vaganee, v vandewalle*, f colardyn depts of intensive care and neurosurgery*-university hospital gent-belgium. jugular bulb oximetry is the first bedside available cerebral monitoring technique providing an estimation of the adequacy of cerebral perfusion. its routine use in all patients suffering from severe head injury admitted to our ic unit enabled an extensive analysis of all very early cerebral perfusion data in order to evaluate the incidence of abnormal sjo~ data (and their possible causes) in this very eady period after traumatic insult and to search for possible implications as to the emergency management. these very early data were defined as the first hours icu data and icu admission had to occur within h of traumatic insult. over the last years, pts with severe head injury (gcs< ) were monitored by jugular bulb oximetry, starting immediately after their arrival at the icu (mean of . h after trauma, range between - h). in a total of pts (= . %), jugular bulb desaturatiens (< %) were noticed during this early h period. in pts (= %), jugular bulb saturations higher than % were observed, whereas pts (= . %) revealed no abnormal sjo data ( - %) during these first h. concerning the periods with too low jugular bulb saturations (n: ), we found the following correlation ; in pts (= . %) cerebral perfusion pressure (cpp) was below mmng, in pts (= . %) paco~ was below mmhg and finally in pts (= %) we found primary intracranial hypertension. for the high jugular saturations (n: ) we found a primary intracraniaf hypertension in f pts (= %), and a pace level above mmhg in pts (= %). in all patients we could restore jugular bulb saturation within normal range ( - %) with the correct!on of the presumed causative factor. we can conclude that ultra early jugular bulb saturation data revealed a high incidence of abnormal values, with a predominance of jugular bulb desaturations, confirming once again the high incidence of disturbed and too low cerebral perfusion within the first hours after severe head injury. these jugular bulb desaturations were especially correlated to systemic causes, as a too low cpp (caused in the vast majority by primary map insufficiency, and not by intracranial hypertension) and hyperventilation were the major causes of the desaturation periods. as jugular bulb desaturatione are known to be significantly correlated to a worse neurological outcome after severe head injury, one might improve outcome by an emergency management avoiding these possible causes of jugular desaturation. therefore, extreme attention should be paid to the maintenance of an adequate mean arterial blood pressure (above mmhg?) even duhng the few time spent at the emergency department. one should be as attentive to the maintenance of normoventilation during this very early period of admission and hyperventilation without any knowledge of icp or sjo should be abandonned. recently, indomethacine has been proposed for the treatment of therapy refractory intracranial hypertension in pts suffedng from severe head injury ( ). indomethacine, a cyclo-oxygenase inhibitor, gives rise to a significant fall in cerebral blood flow by inducing cerebral vasoconstriction. therefore, its use could result in a drastic lowering of the intraeranial pressure (;cp) in pts suffering from intracranial hypertension secondary to cerebral hyperaemia and in whom the use of other cerebral vasoconstrictive drugs (barbiturates or hyperventilation) appears insufficient to control icp. for the last months, we included the use of indomethacine in our therapeutic flow chart for severe head injury management. pts revealing intracranial hypertension (icp> mmhg) and cerebral hyperaemia (sjo~> %) and in whom icp was not efficiently controlled by the combined use of hyperventilation and barbiturates were given indomethacine in a trial to control icp. a total of head injured pts received treatment for intracranial hypertension over the last months. six of them met the criteria set for the administration of indomethacine. in pts, no decrease in icp or in sjo was observed and both pts died due to therapy refractory intracranial hypertension. in the other pts, a significant fall in icp and in sjo was observed shortly after indomethacine administration. in pts we observed a catastrophic fall of sjo= even below %, indicating an extreme cerebral vasoconstriction with the possible risk of inducing cerebral ischaemia. in one of the pts, icp remained under control without further administration of indomethadne, but he died days later in multiple organ failure. the other pts, needed multiple indomethacine administrations (for pt even during consecutive days) to finally control icp. in all pts, icp was finally controlled, but only pt survived. both other pts died from systemic causes (multiple organ failure in pt, massive gut infarction in the other tat, possibly due to the systemic vasoconsttictive effects of the indomethacine administration). in conclusion, indornethacine might have a role in the treatment of intraoranial hypertension, especially when caused by cerebral hyperaemia. we observed however a poor final outcome and a threatening high incidence of systemic events (multiple organ failure, gut infarction) in those pts receiving indomethacine for icp control. therefore, indomethacine in the treatment of intracranial hypertension should be reevaluated in controlled study settings, before its routine use can be considered. untill recently, intracranial hypertension (ich) in pts suffering from severe head injury was managed in a staircase approach, with csf drainage as first therapeutic step, mannitol as second step, hyperventilation as third step, and finally, barbiturates as the last rescue step for therapy refractory ich. this staircase approach for the treatment of tch was only guided by the intracraniat pressure, and not by other parameters such as e.g. the actual state of cerebral perfusion of the concerned pt. jugular bulb oximetry provides us with the first, bedside and continuous available, estimation of cerebral perfueion. its implementation in a rigourous flow chart, based on as well icp-as jugular bulb oximetry-data might result in an altered strategy for ich management. we adopted a '~ugular bulb saturation (sjo~)-guided approach" for ich management in consecutive pts, suffering from severe head injury (gcs< ). we maintained csf drainage as first therapeutic step, but the decision for the second step was guided by sjo information. pts revealing ich and sjo=values above %, were treated with hyperventilation, and did not receive mannitol. if ich persisted, barbiturates were added as a third step. on the other hand, pts with ich and sjo= vales less than %, received mannitol administration as second step. hyperventilation and/or barbiturates were only added if ich persisted and if no cerebral hypoperfusion was discerned (sjo=> %). our objectives were to prospectively analyze this new therapeuticstrategy, as compared to the formerly used staircase approach of ich. we managed pts with ich, with an overall mortality of . % due to therapy refractory ich. all pts received standard primary care with head elevation, full sedation and normovenfilation. fer pts, csf drainage alone was sufficient to control ice of the remaining pts, pts received mannitol and pts were hyperventilated as second approach. in the third line, pts were managed with barbiturates, with mannitol and pts with hyperventilation. finally, barbiturates were used as the final rescue in pts. these results reveal a less frequent use of mannitol as only pts received mannitol, compared to the pts that would have received mannitol using the former staircase approach. hyperventilalien was used much earlier in the treatment course, as lots were already hyperventilated in the second line approach, were this was formerly exclusively reserved for the third line approach. finally, also barbiturates were used much eadier ( pts received barbiturates as third approach). we may therefore conclude to a important change in the management of ich, induced by a sjo -guided flowchart. however, future studies will have to elucidate if this new strategy for the intensive care management of severe head injury will also result in an improved outcome. obsectives: in a first series of experimental brain injury we investigated the course of brain po , icp and cerebral blood flow after traumatic brain injury (tbi), whilst accordingly there are very few data available and the mechanisms leading to secondary brain damage are poorly understood. methods: in piglets ( days old, , - kg) of either sex we produced a moderate brain injury ( , arm., msec.) using a lateral fluid percussion {fp) device. complete measurements were made before and min. after brain trauma and after , and hours including blood gases, cardiac output (htermodilution), heart rate, eeg, laser doppler flow probe (ldf} and icp values (camino), brain temp., po by a clake type oxygen electrode (licox) and coloured microspheres for regional blood flow. results: immediately after the trauma a typical "cushing"response to the icp peak up to mm hg being highly significant (before mean i mm hg, range - mm hg) could be observed: mean arterial blood pressure rose from appr. mm hg to ii mm hg for - min. in two animals this was followed by an ischemic period lasting min. accordingly icp values gradually returned to starting measures within hours; in the ischemic animals they remained at a level of about mm hg.-no secondary increase of icp could be observed, once icp dropped to starting values within hours. cerebral blood flow (ldf) fell from mean values being i before trauma to appr. zero and recovered to around . brain po started at mean values of mm hg (range - mm hg) and fell to around zero depending upon the severity of the ischemic reaction. on average values of mm hg were reached over the time course. conclusions: with our fp trauma model we can reproduce the well known "cushing"-response after brain injury; secondary icp elevations cannot be achieved, although local edema is observed. direct brain po measurement seems to be a very sensitive variable for detection of cerebral ischemia and anticipates eventually following icp elevations by far. pulmonary aspiration s,traoaras. v. sgountzos, p. agouridakis, m eforakopoulou, e. ioannidou. intensive care unit (tcu) of "kat" hospital, athens, greece ob!e=ives: the reported mortality rate after pulmonary aspiration is variable in several series. the purpose of this study was to find out the influence of preexisting disease or situation on morbidity and mortality of intensive care unit (icu) patients with pulmonary aspiration. methods: patients who were treated in icu and had pulmonary aspiration, were studied, entrance's criteria in the study, all of them obliged, were: ) suction of gastric contents from trachea during intubation, ) presense of a predisposing factor, e.g. coma. ) recent hypoxaemia or new infiltrates in xray. preexisting disease was recorded and correlated with complications and outcome. patients with glasgow coma scale , because of cerebral injury, and patients who died within days from cause other than aspiration, were excluded from the study. method of statistical analysis: chi-square test, results: one hundred forty five patients were studied. the trauma patients were and the non trauma patients . from the trauma patients, had cerebral injury and were polytreumatized without cerebral damage. from the non trauma patients, had malignant neoplasms, neurological diseases in terminal stage, old age, drug overdose, and several diseases. eighty seven from trauma patients ( %) and from non trauma patients ( %) manifested several complications (pneumonia, ards, etc), so there was no statistical difference in complications' frequency between the groups (p> , ). the severity of complications was also proportional in the groups. eighteen deaths were recorded in the trauma patients (mortality %). only deaths correlated directly or indirectly with the aspiration ( %). in non trauma patients, deaths were recorded ( %). twelve deaths were recorded in patients with neoplasms, deaths in patients with neurological diseases, deaths in aged patients, death in drug overdose patients, and death in patients with several diseases, the mortality difference in trauma and non trauma patients was statistically significant (p< , ). in patients with drug overdose the mortality was significantly lower from the other non trauma patients and the difference was statistically significant (p< , ). conclusion: the preexisting disease or situation plays a major role in the outcome of the patients with pulmonary aspiration. the mortality of patients with aspiration seems to be caused by severe preexisting situations rather, that lead to death, than from the pulmonary aspiration per se, which may be a final happening in a predetermined course. obiectives; the purpose of this study was to compare fluconazole and amfotericin-b in the treatment of fungal infections in severe trauma patients. methods: thirty five severe trauma patients who were treated in intensive care unit (icu), were studied prospectively. they all developed fungal infections, prooved with blood positive cultures and at least one of the following: fever, positive urine or bronchial secretions cultures, infiltrates in xrays. the patients were separated randomly in groups. the patients of group a ( patients) received fluconazole rag/day for days. and the patients of group ( patients) amfotericin-b rag/day for also days. compaiison's criteria were the clinical responce to treatment (fever etc), the fungal elimination (blood and other cultures), the relapses of the disease, the side effects of drug, and the outcome of the patients. as method of statistical analysis was used the chi-square test. results: nine patients from of the group a ( %), and from of the group b ( %), presented remission of fever (patients of group b had better clinical responce than patients of group a, and the difference was statistically significant, p< , ). all the patients before treatment had positive for fungi blood cultures. after days of treatment, patients of group a and none of group b had positive cultures. eight patients (from who had positive cultures of bronchial secretions before treatment) of group a. and (from ) of group . had positive cuttures of bronchial secretions after days of treatment, so positive bronchial secretions were fewer in group b than in group a, but this difference wasn't statistically significant, (p< , and p> , ): ten patients (from ) of group a and patients (from ) of group b had positive urine cultures, after days of treatment (positive urine cultures were fewer in group b than in group a and this difference was statistically significant. (p< , ). two patients of group a and none of group b had a relapse of fungal disease. in group a, no side effects were obsepced, while in group b were observed only minor side effects (small increase of serum creatinine in patients, chills and fever during infusion in patients, and hypokalemia in patients). three patients of group a and patient of group b died, because of sepsis. conclusion: amfotericin-b (even i~ short regimen of days), is superior to fluconazole in the clinical and laboratory responce and also in the relapse of fungal disease, fluconazole is superior to amfotericin-b as it has no side effects. ob!ectives: flail chest after thoracic trauma is a serious injury. it is controversial if flail chest by itself orthe concomitant intrathoracic injuries e.g. pulmonary contusion, is the cause of the reported significant morbidity and mortality. in this study we searched the influence of concomitant thoracic injuries in the course and outcome of patients with flail chest. methods: eighty five patients with flail chest after isolated chest injuries were studied, for the purpose of analysis, we separated the patients into groups, patients with isolated flail chest were included in group a, patients with flail chest and hemo-pneumothorax in group b, patients with flail chest and pulmonary contusion in group c, and patients with flail chest and hemo-pneumothorax and pulmonary contusion in group d. complications from the chest, duration of mechanical ventilation and mortality were compared in the groups. statistical comparison of results belween groups was made using chi-square and t-studend tests. results: the patients were . all patients received mechanical ventilation, twenty eight patients were ihcluded in group a, in group b, in group c. and in group d. seventy three patients manifested complications from the chest, especially pulmonary infections. there was no statistical difference among the groups as to number of complications ( twenty four patients had chest complications in group a, in group b, in group c, and in group d. p> , }. the duration of mechanical ventilation was not statistically different among the groups (the mean duration was , days in group a, , in group b, , in group c, and , in group d, p> , ). there was also no statistical difference in mortality among the groups (six patients died in group a. in group b, in group c, and in group d, p> , ). conclusion: flail chest by itself is a serious thoracic damage with many complications, regardless of the presense of other thoracic injuries, which don't contribute to greater morbidity and mortality. the present study investigated the correlation between blood lactate mortality and organ failure in trauma patients admitting between december , and july , in the icu. road traffic accidents were the most common cause of trauma in this studded population. brain damage was the main cause of mortality .nevertheless, of patients died from sepsis and multiple organ failure without significant brain damage and these deaths were potentially preventable. respiratory failure was the most common complication and was developed in ( %) of survivors and in ( %) of non survivors .we noted low fncidence of renal failure may be do to the early and aggressive ittv'asive hemodynamic monitoring and cardiopulmonary support. as part of our routine case protocol serial blood lactate levels were measured in each patient at least times a day until the valses returned within the normal range or until death. we analysed the blood lactate levels on admission, the highest value and the number of days until the first normal value (<l.smeq/i). initial lactate and highest lactate levels were significantly higher in patients with than without organ failure.( . vs . , . vs . meq/l, p< . )the duration of hyperlactemia also was higher in the patients with organ complications. ( . vs . days, p< . ). both initial lactate and highest lactate levels were higher in the non survivors than in the survivors.( . vs . , . vs . meq/l, p< . ) the present study demonstrated that not only the degree but also the duration of hyperlactemia can be related to the development of posttraumatic complications. serial blood lactate measurements are reliable indicators of morbidity and mortality following trauma. s current evidence suggest that peep only affects intracrenisl pressure (zcp)when it interferes with systemic arterial pressure, although the effects of peep over cerebral oxygenation remains unknown. objective: determine the effects of peep over icp and cerebral metabolism measured by sj , kjdo and ceo in severe head injured patients. meterial ~ methgds: patients with glasgow coma scale l at arrival, with difusse brain injury in the first gt, according to marshall criteria,lop and jo monitored, under analgesia and sedation, normoventilated with zeep, without mannitol treatment in the previous hours, normal x ray chest and within the first hours from injury, were considered candidates. peep value where increased fro~ zero to cmh , in three different steps, each one with min of duration. all date were analized on line, pmax p'p ..... p.._, from the ventilator, systemlc haemodynem]c data, cerebra perfuslon pressure (cpp), icp and sjo , in the case of hemodynamic deterioration, during the study, ppc ommhg, extra-volume were administered. if persistence, dopamine were begun or increased dosage. if no good response were obtained, patients were retired from the study. results. patients were candidates, of them were exc;uded due to haemodynamic instability, k total of completed all steps and were e~amined, men and women, age ! . yrs. at hospite; arrival, glasgow were < in patients, and > in the rest . patients mmhg at the beginning. zeep ob/ectives. critically ill patients are transpoded to an intensive care unit(icu), under conditions, which have not been systematically evaluated. therefore, we set suite investigate transportation and admission condition of these patients to our department. methods. we studied patients( females), aged (mean-..+-sd) . _ . yrs, which were consecutively (from august to march ) admitted to the icu, through the greek national emergency transporta~on service. apache ii severity score upon admission was . -+ . (range - ). the following data were evaluated: ) number of medical departments, where health care was provided until final admission to the icu, ) ambulance transportation conditions, ) catheters and tubes inserted before admission, ) vital signs upon admission ) information provided by referring physician (scored on a to scale: history, electrocardiogram, chest x-ray, laboratory data, drug therapy already administered), ) comparison of the state of the patient described by referring physicians, to the actual state u pen admission. resu/ts. one to four medical departments had provided health care before the palient was admitted the icu ( : . %, : . %, : . %, : %). thirty/ ( . %) patients were escorted by a physician. twenty-six/ ( . %) were transported on oxyge n, fio (mean__.sd): -+ %, pao : . -+ . mmhg. five of the remaining , for whom no oxygen was provided, had pao : . -+ mmhg. twelve/ ( . %) were intubated and ventilated during transportation. thirtyfour/ had a peripheral venous line, / had an arterial line, / had a nasogastdc tube, / had a urinary catheter. eleven/ were sedated and / were paralysed. three/ were on inotropes. vital signs upon admission were: arterial blood pressure, systolic . -+ mmhg, diastolic -+ mmhg, heart rate -+ bpm, temperature . -+ cc. patient information score was --. . . the actual state upon admission was found substantially different, as compared to the description of the referring physician, in / ( . %) patients. conclusions. we conclude that several aspects of the greek national emergency transportation service to an icu should be reevaluated and further improved, i. e. ventilatory support, adequacy of information provided and accuracy of prior description of the patient's state. a new perspective must be applied for critically ill patients transportation since . % of the patients were evaluated and treated in more than one, medical departments, mostly primary care, before they were finally admitted to our icu. dclhb is a human derived hemoglobin molecule that has been cross-linked to stabilize and permit heat pasteurization to remove residual proteins and inactivate viruses. dclhb is mixed with a lactated electrolyte solution to yield a total hemoglobin concentration of log/dl objective: to present an overview of four recently completed clinical safety studies of dclhb in the u.s. and europe, and to discuss the properties, actions and potential indications for dclhb. method: patient populations in the four studies included males and females ranging in age from to years. dosing ranged from mglkg to mg/kg. the controlled randomized safety studies were conducted in chronic renal failure patients, surgical patients undergoing total hip replacement or abdominal aorta repair and in hemorrhagic hypovolemic shock patients. these very diverse patient populations allowed safety evaluation of the product in patients who were generally elderly, often hypertensive with some degree of cardiovascular disease, and receiving medications for treatment of other conditions. results: over patients received dclhb in the four:studies. no product related sarious adverse events occurred during the clinical trials. conclusion: results from phase itll safety studies of dclhb in patients undergoing chronic renal dialysis, abdominal aorta repair, or total hip replacement and in patients in hemorrhagic hypovolemic shock, indicate that the product was well tolerated in these distinct populations. although these studies were designed to evaluate safety, the data suggest clinical benefit. follow-up efficacy trials are indicated. prehospital emergency services represent the extension of emergency care into the community and constitutes the manpower, communications, transportations and facilities used to provide care for patients outside hospital. one of the main points of the system is how to decide the hospitalization of patients and what kind of facilities to provide : emergency medical service, fire brigade, locat general praclitionner or ambulance officers. objectives : to realize guidelines for using the prehospital emergency medical service in case of patient'calls outside hospital. methods : from st june to july , all the calls for emergency care were analysed using a questionnaire of items (origin of the call, responses to the questions of an emergency practitionner, kind of emergency service provided and the issue of the patient). after taking account of the appropriatness of the decision, statistical method used was a logistic regression. results : calls were analysed. the criteria, for prehospital emergency medical service using, given by the logistic regression were as following : existence of a call for emergency, thoracic pain, dyspnea, seizures, cyanosis, drug intoxication, fall of the patient, fracture, age, the state of consciousness and the neurologic reactivity. the minimal and maximal predictive values of the model given by the logistic regression are respectively % and %. the performance of the model is %. conclusion : it seems possible to help medical decision of emergency medicine by using only some easy criteria and a predictive model. (italy) objective: to evaluate the incidence of blunt carotideal injury (bci) in patients admitted to our icu after head injury. methods: we reviewed the medical records of all patients diagnosed to have a bci. at admission, the severity of trauma was assessed either with glasgow coma scale (gcs) and with ct scan. bci was demostrated by doppler ultrasography (us) and by angiography (ang). results:since may to april , patients were admitted to our icu with bci ( m, f, age + ). a history of direct trauma was present in patients. admission gcs was in all patients, and was associated with hemiparesis in of them; the last became paretic hours thereafter. two patients had concomitant injuries (a homoiateral clavicular and a controlateral zygomatic fracture, respectively). the initial ct scan was negative in every patient, and showed signs of ischemia after a variable timespan ( - days) after the onset of the symptoms. the bci was diagnosed with us and ang, which demonstrated a thrombosis of the internal carotid artery (ic). in two patients, an intimai dissection was also present. three patients were treated with heparin associated with antiaggregating agents and were discharged alive. the last patient was referred to our icu after the development of a massive hemispheric infarction, and died three days after the admission. at necropsy, the ic thrombosis was associated to an extensive homolateral extra and intracranial venous thrombosis. conclusions:the presence of focal neurological signs despite a negative ct scan should address the diagnosis toward a bci, thus implementing the diagnostic workup with us and/or ang. tab i: distribution of l~tients (%) in the groups the outcome were monitorett results were sabmitted to statistical analysis using a continence table x in z test. res.cl~s: of patients were submitted to thrombolysts and died. the higher incidence of bracb, ar~lhmias (ii degree gg p t e and av block. i degree av block. avsb . <ii. sinus arrest) that requited the insertion of avsc . <cl temporar~ pace-maker was recorded in group a b vs c . ns in % of the cas ~. the rapid recognition of life tab li:;~ test. threatening conditions suggests the monitoring of v r-lead r b' in the course of inferior ami. the authors report their own expirience in application of ringer lact.(rl)and , %nacl/ %dextran . methods:in polytraumatized patients with developed hae morrhagic shock,injures of the chest(qg)and abdomen(q ) prevalid.replacement of the volume loss egan in institutions of general medicine,frequently by rl and dextran or haemaccel.after receiving necessary medical aid,polytraumatized patients wer transported to mma by helicopter,continuing replacing of circulation volume by the same solution. results:average quantities of the solution dministered ~o the injured wer~ - ml.a group of the inoured which,after the admission to mma was resuscitated by adml nistration of the , %nacl/ %dextran @(groupii)( -sml/kg observed to the final surgical management,had statistically higher map(increase of % in relation to admission), cvp(average increase of , cmh~o),diuresis(averagely omi after min.),better gas ~nalyses and acid-base status in relation to the group which was administered only rl(groupi)(increase of the map of q %,average increase c~ of cvp , cmh and average diuresis oml after omin). total quantity of the administered solutions was significantly smaller in the groupii( ml: ml).the only ob served complication was hyperhatr~f~a::and~moderat~hyper osmolerity of plasma which disappeared within hours. the quantity of replaced blodd was considerably smaller in the groupii(qooofnl: ooml).in the group i interstitial pulmonary oedema was observed in two patients(qo%),while: in the group ii no complication was observed.coagulation i disorder and hypotension were not recorded because of the fast infusion of hypertonic/hyperoncotic solution in the groupil as the infusion of , %nacl/ %dextran lasted minutes. w.scherzer(l~,k.lechner( ),r.simon( ). ll)dept.anaesthesiology,trauma hospital,vienna-meidlin !( )neurotraum.rehabilitation center,vienna-meidling both austrian workers'compensation board,vienna,austria what we usually call"unconcious" means only that the patient is not able to interact in any kind of way.experiences in intensive care medicine (robinson, ) ,in general anaesthesia (bennet, ) and with evoked potentials show,that unconcious patients are not automatically unhble to process and recall information.this implicates a challenge to start the efforts to restore the traumatica-!ly desintegrated brain function as early as possible in the acute phase ia (zieger, ) .we present a method to ~repare the patient for the rehabilitation goals of the postacute phase ib,the phase of stabilisation ii and of rehabilitation iii within one concept. to achieve sensory stimulation in phase la we use: attempt at some kind of dialogue by speaking to and tou-ching the patient,to make him experience his body limits, ~acio-oral therapy by ice application,tast and smell pro vocations and trials of feeding,early adaption to circadian rhythm and guiding the patient in every-day-life-ac-tivities e.g.:in the brushing of teeth,washing etc. to achieve motor stimulation and orientation in terms of ~-ace,time and gravity in phase la we use: avoidance of perceptual impairment as produced by air-:sack-beds or habituation to supine position,using method~ according to affolter( ) ,basal stimulation (bienstein, ) , bobath-therapy( ) and facilitation of a physiological moving pattern(pnf)according to knott( ) . conclusions: by integrating all these measures in the ~herapy and nursing even in the acute phase la one prei ares the comatose patient for multisensory stimulation nd motor training and all other rehabilitation activities in the following phases of therapy. s objectives." measurement of cardiac output (co) and stroke volume (sv) requires insertion of a central venous catheter and is associated with a considerable risk for complications. non-invasive methods for determination of hemodynamic parameters have been introduced recently. one of these methods is the aortic modelflow program, which provides co and sv continously using a three-element windkessel model. the aim of the study was to evaluate the accuracy of the aortic modelflow program in critically ill patients. methods: patients (mean age: ) admitted to the emergency department after cardiopuimonary resuscitation (n=ll) and for myocardial infaction (n= ), acute congestive heart failure (n= ) and anaphylactic shock (n=l) were included to the study protocol. after stabilization all patients received a swan-ganz catheter (baxter~; edwards swan-g-anz) via a central vein. co and sv were measured by the use of a cardiac output catheter and injection of rrd ice-cold glucose % non-invasive cardiac output measurement was done by using the continuous cardiac output software package modelflow (tno; portapres| results: overall, paired measurements were used for the evaluation of the accuracy of non-invasive obstained sv and co. mean values, standard deviation and range of co and sv evaluated by invasive and non-invasive methods are summarized in the aortic modelflow provides reliable hemodynamic data in critically ill patients. it may be a useful alternative due to its non-invasive approach and continous measurement. objectives: to determine the feasability and accuracy of a rapid urine screening test (triage tm, merck-diagnostika) in an emergency department. methods: prospective analysis of the triage tm testkit (tt) in patients admitted because of suspected drug abuse during an observational period of months. the tt is a eompetitve immunoassay which gives qualitative results within i minutes for methadone, benzodiazepines, cocaine, amphetamine, opiates, barbiturates and cannabis. urine samples were analysed with the tt and compared to the results of a enzyme-lihked tmmuno-assay (el.a) in our labratory (gold standard). results: during the study patients were enrolled, in of these patients substance abuse was proven by tt and verified by eia. we recorded no false positive or false negative results for benzodiazepines, barbiturates, opiates, cocaine and cannabis. two results were false positive and one false negative for methadone; one result was false negative for amphetamines. the triage-testldt had an overall sensitivity of . and specificity of . . conclusions: the triage tm testkit seems to be a a useful rapid test device in addition to quantitative tests for drugs of abuse in an emergency department. objectives: the purpose of this study was to evaluate the influence of several factors of the renin-angiotensin-aldosterone system on blood pressure response in patients with hypertensive crises. methods: patients with systolic blood pressure > rorohg and diastolic blood pressure > nunllg were included into the study. prior to treatment blood samples for determination of plasma renin activity (pra), angiotensin converting enzyme (ace), angiotensin ii (ang ii) and aldosterone (aldo) were collected. all patients received rog enalaprilat intravenously. success of treatroent was defined as a reduction of systolic blood pressure below mmi-ig and diastolic blood pressure below mmi-ig within minutes after start of treatment. results: patients were included in our study, ( %) patients responded successfully to treatment. mean arterial pressure decreased in responders by . mmhg and in non-respenders by . mmhg (p< . ). responders and non-respenders differed signii'icantly concerning pra (p= . ), ace (p= . ) and ang ii (p= . ). . . the extent of blood pressure reduction correlated positively with the pretreatment pra and ang ii concentrations (correlation coefficient for pra: r= . ; ang ii: r= . ). conclusion: our data confirm that in patients with hypertensive crises blood pressure response to ace inhibition is mainly determined by circulatory pra, ace and ang ii. as the extent of blood pressure reduction correlates with pra, ace-inhibitors in patients with suspected high renin status cannot be recommended, as excessive blood pressure reduction, which carries a considerable risk for further organ damage, may occur. f. staikowsky, n. grillon, f.pevirieri, c.jedrecy, c. zanker, f. michard, a. haft medical emergency department. hospital bichat, paris epidemiology of acute intentional self medications-poisoning (smp) in france is especially known by data of poison control centei,s and intensive care units (icu). the purpose of this study is pro~,ided characteristics of this problem in a med for adults. method: july to june , files of patients consulting to the ed for smp have been retrospectively analyzed. results: patients, women and men, . + years old (range - ) have been admitted for episodes of smp ( % of all consultations) whose relapses during the period of study. psychiatric disorders, drug addiction or hiv patients was found for respectively . %, . % and , % of patients. the interval of time between the ingestion and emergency consultation was noted for % of smp ( + min, ranges - ). the involved products name was known in totality in % of cases with an average number by episode of . + drugs (ranges - ). the most often, ( %) or ( %) different products were interfered. the nonbarbiturate psychotropic drugs accounted for . % of the products (benzodiazepines %, antidepressants . %, neuroleptics %, carbamates . %, imidazopyridines . %, cyclqpyrrol nes . %). analgesics and nonsteroidal antiinflammatories represented . % of all drugs, anticonvulsants . %, cardiovascular drugs %, antiinfective agents . %, drugs against cough . %, muscle relaxants . % and antihistamines h . %. the benzodiaz pines were present in episodes, alone in episodes. in . % of cases, there was a simultaneous intoxication with alcohol. the processing consisted of gastric lavage in . % of cases, activated charcoal in . % of cases, flumazenil in . % of cases, naloxone and acetylcysteine in . % of cases; orotracheal intubation was performed in patients. admission in hospital was effective for patients, in medical ward (n = ), psychiatry (n = ) or icu (n = ); no fatal case was recorded. conelusion: smp to ed are often benign. the benzodiaz pines are the most often incriminated but the new anxiolytics and hypnotics (imidazopyridines and cyclopyrrolones) take a growing place. the latsion burn center of athens. its planning constructive and functional refinements j. ioannovich, a. petalas-vourekus, d~ serbetis, h. carsin a bed burns unit is under construction following a donation to the general hospital of athens. the plan of the unit, covering a surface of approximately . m is based on the principle of three identical bed satelites which may function totally independent from each other. in the center of the unit the common facilities are installed, like operation theatres, storage rooms etc. this new modification in the plan of a burn unit is presented in this paper. the advantages from the fucntional, administrative and medical point of view are discussed. tiffs anisotropic conduodon could favour the ocenrence of a circular movement of the impulse that leads to tachyeardias by reentry. purposes of this work were to study, with the help of epicardial mapping, the influence of a trieyclie antidepressant, clomipramine (c), on the conduction velocity longitudinal (vl) and transverse (vt) to myocardial fiber orientation and on anisotropy (a = ratio vl/vt), and their modificutions by the sodium bicarbonate ( ). method: a plaque of electrodes, positioned on the left anterior ventricular wall of anesthetized dogs, allowed to deliver, thanks to central electrodes, programmed electrical stimulations inducing vcuttienlar complexes, and to collect them. each entailed unipolar dectrogram was processed by a computer system that drew the isochrones and a map of activation allowing the calculation of v. the c was infused ( . mg/kg/min iv) during rain; at t , dogs received the b until the retuni of qrs to its initial value fro). a lengthening of qrs of at least % of its value at to was demanded before the administration of b. results: dog was excluded because of an.~nsufficient prolongation of qrs before the administration of b. all values (map : mean arterial pressure, i-ir : heart rate, qrs andqt intervals, v) differed significatively ( < . ) compared to values control fro)except qrs at t . the b ( + ml/kg; ranges . and . ml/kg) modified no studied dements outside of the ( }rs. to ti t t t t t a , + , , + , , + , , + , , + , , + , , +- ,~ conclusion : the c slowed v l and v t without modify the anisotropy. the b did not modify the v of~conduction while the qrs prolongation was corrected. the c acts as a class i antiarrythmie drug on the inward sodium current during the phase of action potential; the gap junctions have shown to be important in the conduction and an action on the gap junctions such as a modulation of the junctional resistivity, can not be rule out. is the doctor a heroe ? p. t.schies~.he, t. bauer, m. seyr dept. of anaesthesiology and intensive care, aokh krems, austria objectives: helicopter emergency services (hes) are getting popular more and more. the results concerning outcome are encouraging. however, some recent accidents with dead or badly wounded hescrew-members have shown the relatively high risk for the crews. therefore we were interested to eval ate the motivation of physicians to participate in a hes. this survey was designed to investigate current concerns about safety and motivation of doctors on emergency call. methods: a questionnaire was sent to doctors of the austrian emergency system. the survey consisted of multiple choice questions and subjective scoring tables from (--full agreement) to (=disagreement). overall, "/. of the active emergency physicians participated in the survey. results: . % of the doctors assume the system is basically safe, experienced doctors tended to have less trust in safety. only % would not hesitate to go into action by dark. . % stdctly refuse night flights to accidents outdoors. although defibrillations are assumed to be safe dudng flight, only % would do it. . % of the doctors would rather stop flying. the most common reasons for ,uitting were wish of family and fear of an accident. . % conclusioq: short transportation times help to avoid trauma related stress, pain and shock-induced organ complications. therefore the physiologic and economic advantages of hes are undebatable. however, the survey data indicate a considerable concern about safety of the medical personal in a hes. crash landings within less than years with deadcases and badly wounded crew members in a small country like austda make desire for safe flying conditions understandable. obiectives: to evaluate the clinical usefulness of trachlight. methods: trachlight is a new device facilitating endotracheal intubation. a stylet with a lightprobe is inserted into the endotracheal tube. intubation is guided by the light glowing through the neck tissues, thus rendering direct laryngoscopy unnecessary. intubation using trachlight was studied in patients (age - years). the indication for intubation was elective surgery in patients (asa i-ii) and emergency intubation in patients. in the elective patients, anaesthesia was induced with thiopentone supplemented with fentanyl, and intubation was facilitated with vecuronium. the cause for intubation in the emergency patients was dyspnea in , cardiac arrest in , trauma in, and unconsciousness due to drug overdose or seizures in patients. intubation was facilitated with medication in patients. results: of the elective patients, ( %) were successfully intubated. six patients ( %) needed two attempts before successful intubation. the duration of intubation exceeded seconds in patients ( %). of the emergency patients, ( %) were successfully intubated. six patients ( %) needed two attempts, and the duration of intubation was more than seconds in patients ( %). in % of all patients, intubation was assessed as easy. no or insufficient glow, prolonging intubation or necessitating two attempts, was noted in patients ( %). oesophageal intubation occurred in patients. conclusions: trachlight may be a valuable adjunct for intubation in varoius settings provided that adequate training is provided. a learning curve was found to exist. objectives: to compare enoxaparin and standard heparin in cavhd and calculate the value of laboratory controls in the treaanent. patients and methods: twenty patients needing dialysis for acute renal failure participated in the study. the main exclusion criteria were massive bleeding or a thrombocyte level < x e /i. in each treatment the same type (av- , fresenius ag, germany) of a polysulfone capillary haemofilter was used. the study scheme consisted of two consecutive four-day cavhd treatments, one course for each type of heparin. the order of heparin administration was counterbalanced between patients. the standard heparin was given as a continuous infusion aiming at an activated coagulation time between and s. the initial enoxaparin dose was rag every :th hour intravenously, but was modified by any signs of coagulation in the dialysis blood lines or bleeding complications. results: the dialysis treatment was adequate in both treatment modes, with mean blood urea levels . and . mmol/l respectively (ns). the bleeding complications were moderate and similar in both treatment modes. the mean life-span of haemofilter using enoxaparin as an anticoagulant was some longer than using heparin ( . + . h versus . + h, ns). the mean aptt-levcl during heparin treatment was s and during enoxaparin treatment s (ref. - s). the mean daily dose of heparin was nag, that of enoxaparin lg mg. the mean anti-xa activities were . u/mi and . u/mi, respectively, reflecting a better bioavallability of enoxaparin. conclusions: both anticoagniation modes were equally effective and well tolerated. the amount of enoxaparin needed for a proper anticoagulation was, however, less than half of that of standard heparin. the changes in aptt level were too slight to make its use possible in controliing the dose of enoxaparin. the use of enoxaparin seems to be rather safe in cavhd even without laboratory controls. the adv~ucea in the management of computerized data of an intensive care unit have been petalled to the clinical advauces and the increasing sophistication of methods of diagnosis fop the clinical application an therapy. this has led our unit to design and develop a computational system called timbu which is used to help physicians assist patients. among its various uses, this system has a software for the hemodynsmic control of a critic patient. this program was carried out to get as fast as possible the hemodynamic data of the patients in an intensive care unit. as an example, we can mention that when we load data obtained through direct measurement from the monitors and the lab, the program calculates parameters that guide, intelligently, to the diagnosis and therapeutic behaviour of the hemodynamic problem through screen messages. the validation of this program in the unit of intensive care has demonstrated that its use allows a more efficient handling of the patient with serious hemodynamics and respiratory disorders. ohieetlve: traema is a heterogeneotm 'disease' that ecatr~ a~"o~s all age ~oupe with v~ying degrees of severity. this imerogeneity has made the di~e, trmma, diflkaflt to r the ehn of this stady wa~ to assr the fitaen of saps in ibis popeleties. methode: in order to compute the ~ probability, a model derived from logistic regression w~ developed. meam'e of calibration (goodaess-of-fit stetislj.r and di~'riminafion (roc ou~e) were adopted in developmm~ and validetlon set randomly taken from a database of pts eeeseemivety admitted in icu (arohidia). ~ witho= salm, p~ yom~ am is yam, with los ~horter thma hotam wore exr fa'om thi~ mmly~ir thi~ model v~s then evahmed on the ~per ~mbgro~ (i.e., trmma pts). if'it did t~t fit the data well ~, new model wm developed rer the logit only on trm=~apm. reims: data were availabte for pts during aperiod of three .y~m , treama pts were . %), teats of calibration iadioaled probability model did mot provide m adequate refle~on of the mortality ezperieace in pm with ireutae, being the observed mortality lower flma the expected (figm'o). a aew model was then variable. this oastomized model fit~ the de~t of trmara pts very well (g =- a p> . ; roc = , ). the di:lferencea between the two modele were evident. conclusion: this ltudy shows that mortality in iramna pts is over wcfe~d when ~se~ed by menm of saps. however the r mode! meets high standmcd in terms of calibration mid dil~'iminat'~o~ ']"he advaatage of ~imd models meaas the colleotion of the ~ set of variables for all pm admitted in icu e~einat the ase of diasma specific ~oring syatex~. ("sl"): effects on cardiovascular and hemostasis systems (cvs, hss) a.oborin~ph, ~.~yndiuk~ph, b.kondratsky ~pt. of'""su~gery and transfusiology, research institute of hematology, lvov, ukraine objectives: great interest has been shown recently in the use of hoss for the initial resuscitation of hypovolemic shock. methods: the study was carried out in dogs -~h hs was induced by jet momentary hemorrhage (h) from a. femoralls (the bloodloss volume made . + . ml/kg). the treatment was begun after .u+o. hrs of h. "sl", created on the basis of-sorblt and natrium lactate ( mosm/l) was injected into v. femofalls at the dose of io. ml/kg. results: it is established that before treatmen-~rterial blood and central venous pressures (abp, cvp) diminished to . mm hg and - . + . cm h (p .o ), while heart rate (hr)-increased to . + . per min (p<.o ). by this the indices of ~latelet counts (pic) and plasma fibrinogen (pf) lowered by . % (p<.i) and . % (p~. ), while fibrin degradation products (fdp) enlarged by . % (p~ . ). after - min of treatment termination abp and cvp increased to . + . mmhg and . +o. cm h (p<.o ), and ~[r diminished to t . + . per min (p>. ). at the same time the indtces of pic and pf enlarged by . % and . % (p>.i), while fdp diminished by . % (p>.i). one of dogs survived. life duration of the other dogs was . + . hrs. conclusions: the obtained data are ~he evidence of normalizing influence of "sl" on cvs and hss, and allow to recommend it as a mean of initial resuscitation of hs in clinic. oblectives: we prospectively studied icu patients with severe head injury (hi), which cerebral lesions monitorized with sjo through opljcal fiber and the cerebral flux with tcd. methods: since january until june , we collected ht admitted to the icu, and of them monitorized with optical fiber in the right jugular bulb and tcd. all patients needed mechanical ventilation related to gcs <__ , with ct in admission (classifing lesions according to marshall and al.) . we related the final results to the evolution of sjo and tcd, with other monitorizing methods like gcs, ct and icp. ~sults: conclusions: in patients with gcs _< , sjo is useful to evaluate the evolution towards vegetative state, still more in cases with ct type ii in admission and higher apache ill. elevation of icp implies an evolutive nsk to brain death and data of tcd is a good indicator of brain death, the complete monitorization of these patients can improve the therapeutic control of this neurologic problem, , ( m, f) , (m. age: + years), divided in two groups (a and b) under specific criteria(tremor and/or fever during admission in i.c.u., or not). the injury severity score was > in all studied patients. tbe group a ( m, ") had no tremor and/or fever on admisskm, while em group b (tin, the above criteria were ix)sitive. bhx~d samplings were taken - hours after accident and - rain. after admisskm in i.c.u. micro-eli~ method was used for measuring cytokinc-levcls. statistic analysis was performed by studcnt-t test. as control group, healthy people were examined. _resu!_ts-il-lct, il-ii~, il- and tnf-tt levels were similar to control group levels in both groups a and b. i!,- and g-csf levels were found increased in both groups (p< jxjl), while il- levels were statistically significant comparing to group a. in con_tin_skin, during immediate post raumatic period,proinflamatory cylokines il-i~, il-i~ and tnf.-ct, produced in an earlier stage than ,. , cannot be detected,whereas .- was increased significantly, especially in group b. g-csf was fimnd in increawal levels in both gr(mps, without statistically significant difference between gnmps a and i|. objectives-l~valantc proteolitic activity, disorders in" eariy, period after combined trauma and p(~.ssibilit, i' of their correction by injection of proteo[ysis inhibitors contrycal and s-fto~:nracil in combination with driving an isotonic snlu~ion of sodlum chloride and polig[ucine. methods: biochemicai studies of proteolitic activity in dogs with limited deep burn and acute bloodloss, . result:s: in case of deep % burn, cornplicated by bloodshed the of blood grows at - times. it; is the restdt of the pancreas glandischemi demage, caused by the centralised circulation of blood and intensifies the deviations of haemodiaamics and albumin exchange. the degree of endogene intoxication by mean mofecular peptides which are the products of albumin decay reses to %, and % in hours. in hours after the trauma the-process is accompanied b ! , % lower inhibitory activity of blood, where as at the peak of the trauma it was , ~ higher. that proves the nnfavuurahle process of the shock in case a combined trauma. conclusion: the vein injection of 'proteolysis inhihitotz cnntrycal and -fforuraei[ in cumbination with driving an isotonic solution of sodium chloride and p.dligh]cine to refill lhe loss of blood helps to lower at times the profeolitic activity of blood. but it still remains above the initial level. the degree of endogene intoxication lowers at times; [ emodinamics aml albumin exchange stahilised. objectives: nimodipine, a known calcium antagonist, has been shown to dispose a beneficial effect on patients with subarachnoid hemorrhage, but its efficacy on traumatic or spontaneous intracerebral hematoma has not been justified. therefore, we studied the effect of nimodipine on the histopathological changes following an experimental intracerebral haematoma in rabbits. methods: twenty-three new zealand albin rabbits of both sexes, weighing - , kgr and at age of - months were anesthetized and a small burr hold in the left parietal aerea was carried out under aseptic conditions. the dura was opened and . ml (this volume assuring a normal incranial pressure after kaufman ) of autologous blood was injected into a depth of mm via a needle of . mm bore. the wound was closed and the animals were left to recover. nimodipine, of , mg/kgr of by weight per day was given via a nasogastric tube to fifteen animals for a period of time of fifteen days (group b). six rabbits were given water and served as control (group a). both groups of animals weie sacrified on the fifteenth day, their brains were removed and immersed into % formalin solution. tissue sections of ~ were embedded into paraphin and stained with haematoxyline and eosin, mason and gfap stain for gliac cells. results: two animals died after the surgical procedure, because they developed large intracerebral bematoma. no animal developed neurological deficit except one of group a which manifested a right side hemiparesis. the results of the bistopathological changes are the following: i) the mean -+ sd diameter of the lesions in the group a was --. ~t while that of group b was + ~t (p< , ) ii) secondary ischaemic neural tissue changes, characterized by the extravasatlon of red cells, the presence of haemosiderin-containing macrophages and signs of low grade inflammation zpredominated in the specimens of group a and were totaly absent from those of group b. iii) a ring of gliac hyperplasia and a low grade local fibrosis was found, encircling the lesions in the specimens of group a in contrast to those of group b. conclusions: nimodipine when administered in rabbits following the development of a non increasing the icp experimental intracerebral haematoma, prevents the extention and the severity of the lesion. objectives: to study the efficacy and side effects of adding intramuscular clonidine (clophelinum) to analgesic regimen in early management of patients with serious burn injury. methods: pts with - % bsa second to third degree flame burns (respiratory tact injury excluded) to yrs of age were randomised to study (n= ) and control (n= ) groups. burn shock was treated with hypertonic saline -bicarbonate solutions ( mmol/l na +) ml/kg/%bsa for the first hours and ml/kg/%bsa for second day. analgesia in control group for the first hours was provided by regular hourly intramuscular administration of mg of morphine sulphate and mg of analgesic -antipyretic analgin with mg of diphenhydramine (dimedrol). from the rd day regular administration of morphine was finished. in the study group ixg of clonidine was added -hourly for hours and dose of morphine halved. vas, verbal rating scale for sedation (vrs, - ), sleeping time, spo , hr, bp, diuresis, vomiting and other complications were comparatively evaluated during patients' stay in icu. results: addition of ~g of intramuscular clonidine daily allowed to achieve better analgesia and sedation with halved consumption of morphine. mean vrs in study group for the first days was . - . vs . - . in control group with twice longer sleeping time. there was significantly less tachycardia in study group; dynamics of bp for the first hours did not differ considerably; later, there, was tendency for hypotension in study group without adverse effects on diuresis or other indices of tissue perfusion. because of high incidence of chronic ethanol abuse among study population pts of control group suffered from psychomotor agitation or delirium, probably as a sign of alcohol withdrawal syndrome (aws). this made regular evaluation of vas impossible. in the study group only pt showed sign of aws. mean vas score was in . - . range for first postburn days. pts appeared excessively drowsy due to clonidine, but it had no adverse effect on their overall clinical course. mean spo values in study group were in - % range, among controls - %; vomiting was absent in. cionidine group vs cases among controls conclusions: clonidine could be a valuable addition to analgesic -sedative regimen in burns, especially for prevention of aws and deserves further study in this regard. hemodialysis -hemoflltration modifications and/or intratracheal gas insuflation have been recently used for blood gas exchange in several models of respiratory failure. objectives: evaluate the combination of cavh-m and igi for respiratory support in experimental acute lung injury. methods: five mongrel dogs ( -+ kgr) were mechanically ventilated inroom air, paralysed, heparinized, connected with a cavh-m system (diafilter- polysulphone membrane) and remained stable for one hour (pao~= . • peco = -+ mmhg, ph= . -+ . , bp= -+ mmhg and pap= -+ mmhg). all was induced two hours after oleic acid infusion ( . ml/kgr) into the pulmonary artery (poo~= . _+ -p< . , paco~- . _+ -p< . , ph= . -+ . -p< . , bp= -+ -p=ns, and pap= _+ -p< . ). fio % for the next minutes did not significantly altered the b ood gas abnormalities. afterwards, pure oxygen applied simultaneously a) through the inlet of the filtrate's compartment of the hemofilter ( l/min) while filtrate and gas were removed from the outlet port (bypass flow ml/min) b) through a thin intratracheal catheter positioned cm above the carina ( l/min). the fio given through the ventilator readjusted to %. results replacement fluids/filtrate during the next four hours were not exceed . l/hour, whilst the blood gases and pressures were improved as follow: cavh-inlet:pao.= . objective. to compare the changes in humoral immunity in trauma patients following massive transfusion of autologous and homologous blood. methods. we studied randomised clinical groups of patients each containing patients with trauma and operation of large arterial vessels. the amount of autologous or homologous blood transfused to the patients was exceeding ml, while the patients in the control group did not recieve blood or blood products. results. we recorded most pronounced and characteristic changes on the -st and on the -th day in the group of patients recieving homologous blood transfusion, i.e. decreased amount of igg,iga,igm,c and c fractions of the complement system, haptoglobin and significant and sustained rise of circulating immune complexes up to the end of the study period. in the control group of patients the decrease was weaker and lasted only during the -st post-operative day; the dynamics of the circulating immune complexes level were almost the same as in the first group of patients. in the group of patients recieving autologous blood transfusion, the parameter values did not change significantly from preexisting levels after the -st day, while on the -th and on the -th day showed a tendency towards aslight rise. conclusions. autologous blood has a favourable effect upon humoral immunity and should be the transfusion medium of choice in cases where autologous blood reinfusion is technically possible. ivan petkov, m.d., rumen farashev, m.d. and dimitar terziiski, m. d. medicine, military medical academy, g. sofiiski str., sofia, bulgaria objective. the amount of blood lost during trauma and operation could hardly be forseen and donor blood supplies are not always available in sufficient amounts. rare blood group types and/or unexpected haemorrhage pose a great challenge to the transfusion therapy and the methods of intraoperative autologous blood transfusion. methods. we report a case of a -year old male patient with extremely massive intraabdominal haemorrhage ( m( blood loss ) during an abdominal aorta reconstruction following a traumatic injury of the abdominal aorta. we achieved a successful reinfusion of ml of autologous blood using an original autotransfusion system developed by us ( pat. no / . . ) . results and conclusions. the autotogous blood in the case reported here was the only and the most suitable transfusion medium for the rapid intraoperative compensation of the acute haemorrhage and the favourable outcome of the patient. the post-operative period was smooth and no significant disorders in the clinical course as well as in the laboratory tests ( morphological,biochemical,coagulation and immunological) were recorded. there were no complications during the postoperative period despite the fact that the amount of blood reinfused to the patient was slightly exceeding his own volume of circulating blood. objective. the haemoglobin concentration and the perfusion pressure value could not be the only criteria for the early signs of tissue and organ dysfunction. because of this, we employed the extensive monitoring of oxygen transport during severe trauma in order to. achieve dynamic evaluation of physiologic compensatory mechanisms and to assess the efficacy of intensive care management. methods. we conducted a prospective controlled trial on the blood oxygenation, oxygen transport and tissue perfusion during the first days after the trauma in patients with polytrauma. we used a swan -ganz pulmonary artery catheter (beckton -dickinson, u.s.a.), deseret cardiac output computer (medical inc., u.s.a.) and hewlett -packard monitor (hewlett -packard, germany) to measure and calculate all the parameter values. the severity of the injury was assessed using the apache ii score system. all the patients had scores over . results. the results show a significant decrease in the arterial blood oxygen content and in the arterio-venous difference, as well as an increase in alveolo-arterial oxygen difference and in the transpulmonary right-to-left shunt. the tissue oxygen supply and the tissue oxygen consumption reveal a tendency towards a decrease below the physiologic minimum of adeqate values. the erythrocyte current velocity and the ratio between oxygen transport and erythrocyte current velocity also decrease inspite of the optimal blood rheology. conclusions. the dynamics in the parameters values are most pronounced between the -nd and the -th hr after trauma, which predisposes patients to the risk of developing stable hypoxemia and characterizes this period as the most critical for tissue metabolism and organ dysfunction. posttraumatic changes in immune mechanisms in lung compartment in trauma were analyzed in ao and da inbred strains of rats which differ in their immunological reactivity: the former being low responder and lat-~er hiperresponsive. methods: the levels of tnf-alpha activity in the supernatants of cultured lung lobes and dynamics of cells migration from tissue explants in h lung cultures were assessed in ao and da rats subject ted to severe burn trauma. results: increased levels of tnf activity ( + pg/ml compared to + . pg/ml in control) were found od day following trauma in lung sups of ao rats while no changes in the levels of activity of this cytokine were found in lung-sups od da rats more pronounced extent and dynamics of cell emigration were noted in da rats, while almost unchanged in ao rats sharp rise in pmn percentages h following trauma ( - % compared to rare pmns in control), followed by increase in lymphocyte numbers at later time points among lung cell emigrants was detected in ao rats. slower but persistent increase ( %, h following trauma and % and % on days and after trauma infliction, respectively) in pmn numbers among da lung cell emigrants was detected, which appeared to be activated, as judged by their nbt reduction capacity. increased percentages of peripheral blood pmns and increased state of leukocyte aggregation/adhesion were detected in both strains, but different levels of plasma tnf: increased levels in ao rats on days and following trauma, and initially but persistently high levels of plasma tnf alpha in da rats ( - fold higher compared to initial levels in ao rats). conclusions:different patterns of local (lung) and systemic changes in cell numbers and cytokine levels implicate differential posttraumatic migratory capacity of pmns vs. lymphocytes in lungs in ao and da rats. early diagnosis of acute intestinal ischemia by color doppler sonography e. danse, b.van beers, p.goffette, f.hammer,aav.dardenne, f.thys, p-f.laterre, m,s. reynaert, .lpringot dept of radiology (profb.maldague) and dept of intensive care ( prof m,s.reynaert), st.luc univ.hospital, brussels, belgium ob emergeny medical squad service is the most important segment in the process of saving the people, in the cases of mass accidents, like industrial accidents caused by the: explosion, fire, chemical poisoning, traffic accident, elemental catastrophes and the war. because of that, each emergency medical squad service needs to have in its motor-pool vehicle for the mass accidents/ for provoding at least people, wounded as well as the people became ill/. objectives: presentation of such special vehicle, produced by "zastava-kamioni" and it's medical-technical equipment. methods: descriptive and comparative analysis of the medical and technical characteristics, based on the actual norms/din, , iso , yus.../ results: on the base of doctrinaired requirements of the emergency medical squad in the case of mass accidents, our researches resulted in the following medical and technical characteristics -the vehicles for mass accidents are gvw/with a payload off cca - t, with the fixed, closed body, type: universal van, -technical equipment aggregates, stretches, anti-fire device, equipment for pitching the tent and for maintaing technical conditions of the work -medical equipment: linen bags with complete sets of bandage material, means for the reanimation and immobilization, for the infusion, medical instruments and remedies as well as the tent for lodging at least wounded and sik people. in federal republic yugoslavia, it was proposed such vehicles for the emergency medical squad needs. conclusion: we suggest to introduce this vehicle in the production range of the ambulance vehicles for saving, especially in the circles where can occur serious accidents. introduction : carbon monoxide (co) poisoning commonly generates central nervous system abnormalities though an important cardiac morbidity and mortality must be considered. long-term exposure to co with cohb levels < % may be more dangerous than short-term levels of - %. we report a case of an adolescent who after prolonged exposure to co developed a severe reversible cardiac dysfunction with low levels of bloed cohe c a.ase history : a year old boy was found comatose at home. his mother in the neighbouring bathroom died severn hours earlier of what was later proven to be a co intoxication. on arrival the gcs was / and the patient was breathing spontaneously. a postictal status with eventual postanoxic encephalopathy was suspected. a coh'b level of % was objectivated. the cardiorespiratory situation quickly deteriorated requiring mechanical ventilation. chest x-ray showed diffuse bilateral patchy infiltrates. ecg revealed signs of ischemia. severe left ventricular dysfunction was evidenced by pulmonary artery catheterisation and echecardiography and later by isotopic angiography (lvef %). treatment was intensified with inotropic support, intta-aortic balloon counterpulsation and oxygen therapy. the clinical course was further complicated by a crush syndrome and renal failure. the patient's condition gradually improved and he fully recovered without any residual lesions (lwf %) conclusion : even after prolonged exposure cohb levels can be misleadingly low. high tissue levels of accumulated co can be associated with coma and fulminant cardiorespiratory failure requiring advanced life support facilities. introduction : both neuroleptics (nlp) and tricyclic antidepressive agents (tca) can induce arrhythmias, prolongation of the qt segment and the pr interval and hypotension. we report a case illustrating that combined overdose of these agents increases the toxicity of each compound and the risk for adverse cardiac events. .c, gse history : a year old male ingested mg doxepin (sinequanr), a tca and mg prothipendyl (dominalr), a potent nlp in an attempted suicide. upon arrival in the emergency department the patient was unconscious (gcs / ), breathing superficially, and presenting signs of recent vomiting. physical examination revealed a taehycardia of b.p.m., an arterial blood pressure of / mmh g. ecg showed a brood qrs complex tachycardia. a chest x-ray revealed the presence of an aspiration pneumonia. laboratory investigation demonstrated increased levels of crcatine phosphokinase, lactate dehydrogenase and aspartate transaminase ; hyperglycemia and leucocytosis were present. the plasma concentrations of doxepin and prothipendyl were respectively gg/l (toxic level #g/l) and i.tg/l (no reference). treatment consisted of mechanical ventilation, gaslric lavage and administration of activated charcoal and iv fluids and antibiotics. a hemodynamically well tolerated veatricular tachycardia developed / h later. nahco ( meq/ h) was administrated inducing an ectopic atrial tachycardia with a normal qrs complex and prolonged qt. h after admission a normal sinus rhythm was present; the prolongation of the qt segment persisted for days. the patient fully recovered. conclusion : the treatment with nahco~, alkalizing the blood and thus increasing the protein binding of the tricyclic antidepressant molecule, can readily correct the potentially life-threatening cardiac arrhythmias and therefore should be part of the routine treatment of combined tca-nlp overdose. ob/ectives: the development of diabetes insipidus (di) in patients with brain injury is a known negative prognostic sign. the aim of this study was to investigate whether this is also a reliable early prognostic sign of brain death. methods: this is a retrospective study of patients treated" during a two year period ( - - to - - ) in our i.c.u who meeted the following criteria: ( ) coma score _< gcs within the first hours, ( ) positive brain ct scan on admission classified according to marshall's diagnostic classification (classes - ), ( ) normal renal function during the entire icu stay. for the definition of di were used the usual di criteria plus hypematriaemia (serum na" >_ meq/l). survival was defined up to the th postadmission day. conclusions: according to the findings of this study, the development of diabetes insipidus in brain injured patients seems to be a highly specific index for brain death (positive predictive value = . ). however, further prospective studies are needed for the definitive evaluation of these findings in such patients. emergency care in italy, despite all efforts, is still lacking a nationwide organized prehospital care system and, until today, there are only different regional solutions. the majority of these realities imply rather simple ambulance first-aid services without attending emergency physicians and without resuscitation equipment. the emergency medical service (ems) system in falconara m., italy, was implemented in august by a collaboration between the school of anesthesiology and intensive care of the university of ancona and the, already existing, volunteer rescuer organisation "yellow cross". according to the guidelines pubblished in [ ] the pre-existing equipment of the volunteers was completed with type a ambulances and special equiped motorcar (patient monitor, defibrillator) for ambulance indipendent physician transpur[. a special data collecting schedule was created to memorise every emergency intervention in a computerised data-base. the intraining members of the school of anesthesiology and intensive care provide hour ready intervention. in this report the authors describe their experience concerning primary firstaid medical interventions. for a preliminary evaluation we considered, retrospectively, consecutive emergency interventions in the time period from novembre , to april , . the emergency physicians treated male ( %) and female ( %) patients, patients died before hospital admission and patients ( %) were treated at home by the ambulance indipendent physician and did not need any further medical treatment. in the same time period year earlier (november to april ) without attending physician the volunteer rescuers transferred all first-aid interventions to near-by hospitals. we conclude that the presence of an attending, iudipendently motorised physician in emergency interventions is essential for the establishment of precise priorities and may be helpful to reduce hospital admissions by ambulance intervention, though reducing primary" health care costs. we have developed the method of liquor filtration which allows to purify the cerebrospinal liquor from blood and its decay products in the subarachnoid bloodstroke. the hemipermeable dialysis membrane was used as a filter, which lets only in water, electrolytes and substances with small molecular weight. the liquor filtration was used for the treatment of patients with the subarachnoid bloodstrokes of different etiology. the perfusion of liquor was performed at the rate ml/min in the recirculatory mode. its duration was - min depending on the bloodstroke intensity. the filtration makes possible the most completely purifying of the hemorragic liquor, the reducing of the content of blood ceils and its decay products - times as less. the monitoring of the patient's state during the perfusion didn't revealed the departure from the norm of the main vital part. the liquor filtration technique compares favo-~ rsbly with the routine method of cleaning by the absence of toxical effect of heterogenous solutions on the central nervous system. the filtrstion of the cerebrospinal liquor in the subarachnoid bloodstroke sllows to provide the the early cleaning of liqour, the regression of meningeal syndrome and to improve the patient's state of health. e tabli~mczr bd ~ of rei~idnal medical first-aid zhoulittoing, ed., tan zi, m.d. dept. of sargery, the first teaching t[ospitat, yejin-l)a-l)ao, wuhan fltlna objectives: the medical first-aid is the most important task of the public hc atth department. in general, single hospital model couldn't fatty, effective ly rescue mony severe patients who need mergant treatment in the scene. bub establishing the medical first-aid network, the severe patients can be given the most timely und the most scientific emergent treatment. so that, the suc cessfut rate of the saving wilt be greatly increased. methods..; our hospital is a general big hospital. through developing and cons tructlng for more than ten years, the medical first-aid network distributed art over the area under our jurisdiction has been set up. it consists of thr ee units: the medical first-aid unib center comartd and mnagment unit, co m~nlcation and tiaison unit. the principle of the network operation is with oat having to far to mergoncy, specialized emergency and the best merge acy. results: the results of the network operation were notable. cmpari~ the to tat successful rate of the saving ( . ~), the successful rate of saving tra ma ( .~), the suscessfut rate of saving shock ( .~) and the successful rate of cardioputmonary resuscitation ( . ~) daring the three years after t he network operated with these before ( . ~), ( ]. ~), ( . ~) and ( ft. ~), the successful rates after operating were remrk~iy higher ( p<i).o ). conctusions~ the above results showed estabiishmnt and mena emont of region at medical first-aid network had very si~nificont action during mergentty s avin the severe patients. moreover, the regi~at medical first-aid network atso take an important part in prevention and health protection of the mass. objectives: se related mortality is due to the occurrence of both rv and lv dysfunction evoking cardiogenic shock and pulmonary edema (f. abroug, intensive care med ; s. nouira. chest ) . prospective evaluation of scorpion antivenon (sav), the only available specific treatment, is lacking. the aim of this study is to assess the effects of sav on the basis of a case-control study. methods:among consecutive victims of se presenting to the emergency department, were managed using sav (group sav+). these patients were matched to envenomated patients who did not receive sav (group sav- chest injuries are the cause of death in % of trauma fatalities and a major contributing factor in an additional %. pneumothorax is a major complication of chest injuries and can be initially overlooked bringing to additional morbidity and mortality especially in patients who require mechanical ventilation. the real incidence of pneumothorax in severe blunt chest trauma hasn't yet been established, as many pneumothorax can be missed on the initial chest x-ray (cxr) and computed tomography (ct) has not been routinely used. to evaluate the incidence of pneumothorax in patients with severe blunt chest trauma. methods: a prospective study. from january to december , all trauma patients with one of the followings conditions: fractures of four or more ribs, signs of lung contusion on the initial cxr or presenting a severe hypoxemia on admission (pao /fio < ) in the absence of pre-existing pathologies, were evaluated by initial cxr and subsequently submitted routinely to a ct. results: severe trauma patients were considered. of them, presenting a severe hypoxemia on admission, had no evidence of major chest trauma (ais< ). hypoxemia was the consequence of severe trauma in other districts; these patients were therefore excluded. patients with severe thoracic trauma (ais>= ) were admitted into the study. the mean iss was . ( - ). thirty-six patients required artificial ventilation for at least hours during the icu slay. three of them, who had a tension pneumothorax, were submitted to an emergency thoracic decompression on the field by the emergency helicopter team. in cases pneumothorax was diagnosed an the initial cxr more patients had a pnx which was identified only on the ct. in cases a large pnx with lung collapse was missed on the cxr. in our group of severe blunt trauma patients, % ( / ) presented a pnx that required the insertion of a thoracic drainage. only one third ( / ) of the pneumothorax could be recognised on the initial cxr, while other were decompressed before performing the cxr. as many as % of the cases of clinically significant pnx were missed on the cxr, and a ct performed soon after admission allowed an early diagnosis bringing to changes in the treatment. (as the patients were mechanically ventilated a chest tube was inserted in all these cases). in cases, the initial cxr overlooked a huge tended pnx which was the cause of hemodynamie instability. conclusion: in patients with severe blunt chest trauma even large pnx can be missed on the initial cxr. moreover due to the non compliant compressible lung, a % pneumothorax which can be recegnised only on a ct, can bring to high intrapleural pressure altering eardiopulmonary function. n. andoeli , .~osid, m.zesevid, m.risovid, d.stepi , d.djokid b~rga~yc~qterclinicalcaqterafserbia, belgrade cb~ctives:~lis study ~ the use of ~rq]ofol earbired with k~t~ine (aq a~sjgh~ic s@~qt widn inirjrsic armlgesic pro~mities) or with fsqtmtyl,with psrtial azgmsis an hgenxlyn-a~ic ~ durirg ~ ~ re:~ver~ f~m ~ in hxh ~ of ~ti~. ~: yali~mial and ~bod: a~it p~tie~ts a~ i-ii were included in ibis shxly. patients were rsrd]nly dieided in two ~ns. all d~tie~ts ~me given - prcpofol bolus doses (o, ~gkg) for ird~iqn of ~. ~ia ~s m~sjn~ with an infusion ~ ~ropafol. as sdflitianal were given fan-i~l (o, n]g) ~tely before ~ anj trad~e~ irfojoation followad by feasted bolus of o,i mg in ~ro o l.patients in gr~ o received i~ (an initial bolus dose of rg slowly intcavax~ rd mg as infusion over ~ rain) .infusions of pro~fol or imcpofol with kg~mine ~ stopfsj - rain ]:~o~ extuhation.arterial blood ~ (sistolic arterial blood preassu-re~zap,mean ~rterial blood pr~,d~lic arterial preassure-[zp a~ h~art rate-~) ~ m~ before induction of a~ io, snd rain aftem ~ intutation. results: arterial blood preasstre ~s decreases duri~ irn~ction of sn~wd~sia in hy~ ~n~s,tnt mare in th~ ~ who r~eived fsqtanyl.~ere w~s statisticslly sifnific~ntly difemerme dmir~ m~ of an~ia. arterial blood r~easatre and heart rate were stable in the t-..e~min -~a ~. all th~,fl-e keta'nire grcqo hsd e~rly :~e~y time. ctrmlusi~s: ~e ombiretion of protxfol wilh keta/ne for irduorion a~d ~ of sn~sd~esis w~s yell accept~ by p~tierfcs anj coald he ~ as an alterrstive ~o ccnva~icrsl a~es -d~sia. objectives : assess the relation between cytokine or endotoxin release and indices of splanchnic malperfasion after hemorragic shock in multiple trauma patients. ]~r study was approved by the local ethical committee. trauma patients admitted to the emergency room who met the entrance criteria of more than hour map < mmhg or use of vasoactive agents or blood lactates > mmol/ were selected for study. a nasogastric tonometer (tonometrics, inc, plastimed, france) and a swan ganz catheter were placed on admission. phi, lactates, hemodynamics, plasma cytokine and endotoxin concentrations were measured on admission and at . , , , hrs. an immunoradiometric assay was used to determine plasma concentrations of il (n< . ng/ml) and tnfc~ (n< pg/ml). plasma endotoxin concentrations were measured using a chromogenic limulus assay (n< . eu/ml)( endotoxine unit= pg). results : severe multiple trauma patients (age = _+ yrs, iss = -!-_ , saps = +'~, mean-+sd) were studied. they received + packed red cells during the first h. mean duration of collapsus before inclusion was . _+ . hrs. death occm'red in ~tients. ~ pglml, *: ng/ml, etox : endotoxin(eu/ml), lact: lactate (retool/l) a significant correlation between initial il level and saps was observed. in the early post-injury period phi, sao , svo , vo were significantly associated with ;il release (p< . at ho, h , h ). later a significant correlation existed between lactates and ii (h , h ). a peak of tnf was detected at and hrs. it was associated with low phi and low arterial ph of the early post-injury period (p< . iat ho, h , h ,h , h ) and with high lactate levels of later period (_>h ). only the late release of endotoxins (i{ ) was correlated significantly with initial !oxygea-delivered parameters. iconclusion : there was a marked increase in il in the early phase of trauma . i and tnf release after major trauma iwith hemorragic shock is associated with splanchnic malperfusion, as assess by the ivery low values of phi. lactates seem to be a later indice. toxic effects are a well-known complication of an overdosage of prescription theophylline. what is less known is that over-the-counter (otc) asthma medications contain theophylline, and that in some cases this might cause toxic effects. a case seen by us involved toxic effects from theophylline in an otc medication and to date is the only published case in the english literaturet the rationale for this study was to delineate the otc products containing theophylline from whatever data sources available. hyperthermia frequently occurs in intensive care treated patients and intentional application of whole body hyperthermia together with chemotherapy is a therapeutical access to treatment of malignant disorders. anaesthetic support is required in either condition. due to the marked decrease in systemic vascular resistance seen in hyperthermia an additional vasodilatory effect of the anaesthetic is unwanted. the vascular effects of anaesthetics in hypertherm organisms is not known in detail. therefore, we performed an experimental study to detect the effects of inhalational anaesthetics in whole body hyperthermia. in sprague-dawley-rats katheters were inserted into trachea, jugular vein, and carotid artery. for continuous monitoring of cardiac output a flow probe was placed around the aortic arch. the rats were mechanically ventilated with different concentrations of inhalational agents in oxygen. we compared the effects of enflurane, isoflurane, and halothane in stepwise increased body temperature by submerging in a temperature controlled water bath. results: isoflurane lowers arterial pressure more than halothane or enflurane. the inhalational anaesthetics lower the cardiac output similarily and independently of temperature. isoflurane decreases systemic vascular resistance independently of core temperature and the decreasing effect of halothane on the resistance is completely abolished in hyperthermia. conclusions: the influence of hyperthermia on the systemic vascular resistance is dangerous. this allows no additional effect of the anaesthetic management. in spite of the vasodilating effect of inhalational agents in normotherm subjects, this effect is abolished in hypertherms using halothane. the condition of management of analgosedation in hyperthermia is different from normothermia. objectives: to evaluate a bedside computer processed cerebral function monitor for assessment of brain wave activity when clinical/visual clues are not present. methods: ten icu patients undergoing neuromuscular blockade monitored with the aspect brain wave monitor from january to june , . results: time to onset and depth of sedation were readily apparent to icu physicians not specifically trained in eeg reading. objectives: to determine whether non-depolarising neuromuscular blockade reduces oxygen consumption (vo ) in sedated, apnoeic patients. methods: haemedynamic. metabolic and oxygen transport variables were determined in sedated, apnoeic patients with severe acute lung injury. all patients were ventilated using a puritan-bennett ae ventilator with integrated metabolic monitor. inclusion criteria were; ) stable cardiorespirator s" status; ) systemic and pulmonary artery catheters already in situ; ) inspired oxygen < %. patients were sedated with midazolam or propofol to abolish response to verbal stimuli, and sufficient morphine or alfentanil to abolish all spontaneous respiratory efforts. following baseline measurements, neuromuscular blockade was induced with intravenous vecuronium, ug/kg, followed by an infusion of ug/kg/h to maintain the train-of-four ratio at . a further four sets of measured and calculated variables were obtained at min intervals. results: statistical analysis was by repeated measures anova. there were no significant changes in any variable over time. the changes in calculated oxygen consumption (vo fick) , and measured oxygen consumption (vo gas), and in energy expenditure (ee), are shown in the table. objetive: to study the effects on coronary hemodyrtamics and myocardiai metabolism of administering propofol during postoperation sedation of patients with normal coronary circulation and good ventricular function undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mi~-a/ valvular cardiac surgery were selected, with an ejection fraction greater than . and normal coronary circulation. for postoperation sedation propofol was administered in . mg/kg i.v. bolus, followed by a . mg/kgth perfusion. all data were registered before administering propofol and after minutes, the patients being hemodynamically stable and a rectal temperature of _+ . -~ systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabofic variables were measured. results: the patients studied were about years old, and the average period of aortic cross-clamp was . min. the adminstering of propofol caused a decrease in the coronary blood flow (- %), great curonary vein flow (- %), myocardial oxygen consumption (- %), regional myocardial oxygen constanption (- %), myocardial oxygen extraction (- %), regional myocardial ooxygen extraction (- %), while coronary vascular resistances and global coronary vascular resistances did not change. oxygen saturation increased in the coronary sinus (+ %) as well as in the great cardiac vein (+ %). in no patient were significant changes suggestive of myocardial ischemia objectified. there was also found a decrease in systolic (- %), diastolic (- %) and mean (- %) arterial pressure, systemic vascular resistance (- %), and cardiac output (- %). conclusions: in accordance with the clinical conditions of this study, the administering of propofol is not likely to cause changes in coronary autoregulation, oxygenation and myocardial metabolism. obietive: analyse the effects of . % "end tidal" isoflurane (sedative dosage) on the metabolism and coronary hemodynamics during the postoperation period of patients undergoing cardiac surgery. patients and methods: patients ( women and men) undergoing aortic and/or mitral valvular cardiac surgery, with an ejection fraction greater than . and normal coronary anatomy, were selected. after the surgical operation, . "end tidal" isoflurane was administered for postoperadon sedation. the determination of variables to be studied was carried out before and minutes after administering isoflurane, die patients being hemodynamically stable and a rectal temperature of _+ . -+c. systemic and pulmonary hemodynamics, and global, as well as regional myocardial blood flow, and metabolic variables were measured. results: the average age of the patients studied was -+ . years. during surgical operation the period of aortic cross-clamp was . _+ . rain. the administering of isoflurane was followed by a statistically significant drop in coronary perfusion pressure (- %), coronary vascular resistance (- %), regional coronary vascular resistance (- %), regional myocardial oxygen consumption (- %), regional myocardial oxygen extraction (- %) and accompanied by a significant rise in oxygen saturation in the coronary sinus (+ %) and in the great cardiac vein (+ %). myocardial oxygen consumption, myocardial exu'action of lactate and regional myocardial lactate extraction did not change. in no patient were enzyme or electrocardiograph changes objectified. systolic (- %), diastolic (- %), mean (- % ) arterial pressure, and systemic vascular resistances (- %) decreased, while cardiac output did not. discussion: the administering of . % "end ddal" isoflurane, in the clinical conditions of this study, produced a decrease in systemic arterial pressure due to a reduction of systemic vascular resistance without deteriorate cardiac output. at coronary circulation level, has and effect on coronary autoregulation but had no effect on oxygenation and myocardial metabolism. the idea of tiva implies the realisation of major anesthesia components (los of consciousness, neurovegetative inhibition, analgesia, myorelaxatiou, providing the adequate gas-exchange) through i.v. introduction of drugs exclasively. aim: providing for the main tiva components with minimal side effects of the drugs used, taking into consideration the patients characteristics and the surgery specific character. methods: anaesthesias have been conducted in patients aged years ( females, males), undergoing planned and urgent operations with the pathology of lower, extremities, perinaeum, small pelvis, hypogastrium and with reserved spontaneus respiration against a background of % insnffladon through mask. operations lasted from . - . h. anaesthesia adequacy was assested by constant monitoring: "cardiocap" (nibr hr, rr, sao , t), through glykhaemia level and mimicry reactions. standart premedicatioo of m-cholinolytics ( . mg/kg) and h -blockers ( . mg/kg) on the operational table was sumplemented by administration of . - . mg/kg of lidocaine, . . mkg/kg of clonidine, . - . mg/kg of pentamidine by the tachifilaxia method. the premedication adequacy was assessed through haemodynamics characteristics. sedation: . - . mg/kg of droperidoi, .l- . mglkg of diazepam and analgesia: - mkg/kg of phentanyl, . -- . mg/kg of ketamine were introduced fractionally according to indications. infusion rate of ringer-lactat solution was - ml/kg/h and depended on the intraoperational blood loss volume and on the patients preoperational condition. the duration of postoperative analgesia was registered. results: clinical assessment of analgesia according to this techniques allowed to decrease the anaigetics dosage to the subauaesthetic levels. smooth stabilisation of haemodynamics (bp) at proper age norms in patients with the initial hypertension by the -th min. of anaesthesia as well as the absence of its increase in response to the additional introduction of anaesthetic have been achieved. (hr) had no abrupt changes and remained in the range of - per rain. adequate external breathing: decrease (rr) by - per rain., with sao increase from % to - %. hypoventilation was avoided by respirate ventilator. according to unauthentic data the glykhaemia level had been lowered by -t % to the end of the operation with the initial moderate hyperglykhaemia of up to mmol/l the cutaneous covering grew warm and got pink colouring. no mimicry reactions. in the postoperative period patients were in the superficial sleep state ( - ) and analgesia lasted - b. there were no complications due to anaesthesia. conclusion: combined using of bz, opiates, neuroleptics potentiate the i.v. anaesthetics effects allowing lowering of each tiva component dosage and, as a consequence avoiding their negative influence on respiratory and heart vascular systems. complex application of adrenergetics (therapeutic doses of cionidine and pentamini with using of taehfilaxy effects) permitted to provide for analgetic and neurovegetative components of general anaesthesia under subanacsthetic doses of tiva main components, and manifestation of hyperdynamic reactions of haemodynamics decreased while using of lidocaine -the economicai activity of heart-vascular system. good level of muscle relaxation was achieved allowing for widening of surgical intervention extent without respirator ventilators and inhalation anaesthetics application. anaesthesia is easily controlled due to fractional introduction of drugs with quick recovery of cns functions after anaesthesia. postanaesthetic analgesia is increased while concurrent opiates doses are decreased. absence of marced haemodynamic, endocrine and metabolic reactions during the operation and after it resulted in shortening the period of patients staying in hospital. a yo white man was admitted to hospital for dyspnea and a productive cough. he had cabg in past, but no recent cardiac ischemia. physical exam: decreased breath sounds over right lung. chest xray: consolidation of right lung. admission medications included diltiazem, furosemide (both were continued) and trazodone (which was discontinued). admission ecg: sinus rhythm, qt . /qtc . sec, with st and t wave abnormalities similar to prior tracings. he required intubation and mechanical ventilation for progressive hypoventilation and hypoxemia. between icu days and he received haloperidol, - mg/d (cumulative dose rag) for agitation and delirium. icu day : qt . /qtc . sec. icu day : for better control of delirium, trazodone " mg q hs was added. icu day : he developed frequent nonsustained ventdcular ectopy. icu day : qt . /qtc . sec, pha . , paco mm hg, pao mm hg, k . meq/l, mg . meq/l. later in icu day the patient had brief episodes of torsades de pointes, each responding to precordial thump, and finally rhythm stabilized with i.v. lidocaine and magnesium. haloperidor and trazodone were discontinued. ecg was unchanged and myocardial infarction was ruled out. next day, icu day : qt . /qtc . sec. torsades de pointes, a form of ventricular tachycardia characterized by a twisting qrs axis, is commonly associated with qt prolongation. haloperidol is used frequently in icu for control of agitation and delirium, with reported doses up to mg/day. over past decade, cases of torsades de pointes with prolonged qt related to haloperidol have been reported. trazodone may also prolong qt and cause ventricular arrhythmias, especially in patients with pre-existing cardiac disease. in this patient, trazodone likely exacerbated qt prolongation from halopeddol leading to torsades de pointes. critical care physicians must be aware of this interaction. it is imperative to follow the qt interval for patients receiving halopeddol, especially when another drug also known to prolong qt is added. one must consider discontinuing the drug when qt/qtc becomes prolonged. objectives: analgesics and intravenous anesthetic drugs are routinely used in critically fll patients, who often suffer from a secondary impairment of the immune system. previous in vitro studies have demonstrated inhibitory effects of these drugs on polymorpho nuclear cells (pmn). the potentially important role of endothelial cells (ec), however, was not investigated, since suitable test systems were not available until recently. therefore a physiologically more relevant in vitro migration assay through cultured human endothelial cell monolayers (ecm) we established. using this assay system, the comparative effects of fenlanyl, sufentanil, propofol and the known pmn inhibitor thiopontal were tested. methods: human umbilical vein endothelial cells (huvec) were isolated and cultured on microporous membranes (cyclopererm) until an ecm was grown. pmn from male and female volunteers were separated by standard procedures. ecm and pmn were preincubated with clinically relevant concentratious of thiopental ( m), propofol ( p_g/ml), the solvent of propoful (intralipid), fentanyl ( ng/ml) and sufentanil (sng/ml). after preincubatiun (ecm minutes, pmn minutes) with the reslx~tive drug, leukocyte migration towards the chemoatfractant fmlp ( o - m) was measured in a two chamber well system for hours. the migration rate of untreated (untr.) and treated (treat.) pmn through untreated and treated ecm were determined. as a control untreated pmn and untreated ecm were used. results are given as means from independent duplicate determinations and expressed as a percentage of control (table) . statistical analysis was done with student's t-test. results: clinical concentrations of fentanyl, sufentanil and prupofol showed similar inhibitor~ effects as the known pivin inhibitor thit e ). % conclusions: for the first time we could show that analgesics and anesthetics exert their inhibitory effects not only on pmn, but mainly on the interaction of pmn with endothelial cells. moreover, we could shmv a significant suppressive effect of the opinids fentanyl and sufentanil on both ec and pmn. the known inhibitory effect of thiopental obtained in ec-free test systems were also confirmed in our physiologically more relevant assay system. objectives: to investigate when and how sedation is used in a consecutive cohort of patients admitted in a large sample of italian intensive care units (icus), gathered in a network named giviti, representative of the italian icus system. methods; the study called for a recruitment period of one month, from january to february , , data collection included age and other demographic variables, acute diagnostic broad profiles, severity of illness scores, treatments, lenght of stay and vital status at icu discharge. as concerned sedation, each patient was observed until discharge or for a maximum period of seven days. information on all the drugs used for analgesia/sedation, the route and modalities of administration, the timing, dosages and purpose of the administration have been recorded. results: the study involved the cooperation of icus, of which enrolled at least one case. the total sample included patients. overall, . % of patients analyzed (t / ) received at least one prescription of sedative during their stay. globally, at least one sedative drug was prescribed to these patients in days in icu. although over drugs were reported to be used, pharmacological principles accounted alone for % of all prescriptions. opioids were actually used in % of prescriptions; propofol in % and benzodiazepine in . %. as regards the way of administration, intravenous administration was applied in % of cases and, followed by intramuscular in . %. moreover, non-steroidal anti-inflammatory drugs (nsald) were used in % of patients and neuromuscular blockade agents (nmba) in %. detailed analysis on certain subgroups (surgical, trauma, ventilated patients etc.) have been also carried out in order to describe the practice of sedation in these peculiar subgroups. findings will be widely discussed during the presentation. conclusions: these results should be interpreted keeping in mind how peculiar is the intensive care setting compared to many other less complex settings of hospital care. in conclusion we thought it was important to present the data currently available in the most neutral form, to start moving in a direction which will enable us -by means of more specific and detailed studies, and with the cooperation and involvement of all those participating in the project -to shed light on one of the many aspects of medical practice in the field of intensive care which deserve closer attention. introduction: the aged run perilously high risks in cardiac surgery: among others, of haemodynamic fluctuations, respiratory depresskm and organ failure. response to anaesthetics is a crucial determinant for post<)perative complications, none the less being reintubation due to mechanical ventilation difficulties which increase morbidity, mortality and intensive cdre unit (icu) stay. objective: we wanted to assess our a,aesthesia window (selection, and a view of the induction -extubation period) for predicting safe and swift awaking, thus: icu dismissal for the aged. methods: in , selected patients (pts) (> y, f) followed a regular elective cardiac surgery protocol (propofol given at precisely designated time intervals). upon cu arrival, they were subjected to an admission protocol. our predictive criteria for early extubation at h included: a) alertness and ready response to commands; b) adequate gag reflex and sufficient protection for respirak)ry tract; c) pao > mmhg with flu < . ; d) stable ph> . with spontaneous respiration; d) stable haemodynamics without dysrhythmias; e) adequate perfusion and diuresis (> .(i ml/kg/h); f) mediastinal bfeeding< ml/h for at least h; g) normothermia (core temp> ~ and no shivering). subsequent reintubation was for: ) rr> /min; ) spontancx)us ventilation for rain with paco > mmhg; ) pao < mmhg with fio > . ; ) ph> . ; ) heart rate>] bm; and/or ) non mental alertness; and ) other medical disorders, after which adequate weaning therapy was necessary. then, successful weaning after h was considered: ) spontaneous breathing without any forrn of mechanical assistance; ) stability in haemodynamics; and ) elimination of fever threat. results: pts ( %) were extubated at h without complication; other pts ( %) at h but had to be reintubated because they were hypoxic and began weaning therapy; finally, they were all re-extubated by h. only pts ( %) proved problematic. conclusion: a,aesthesia wimhlw options (selectkm, extubation, reintubation and weaning) predicted quick (times propofol administration) and safe (rigid criteria) extubation ( %= h and %= h), exempting pts with developed post-operative complications ( %=extubation< h) unrelated to al~aesthesia window or icu protocol. dismissal and recovery then became an abbreviated question of time. fifisetll p, domeneg~i ~, sforzini i., veronesi i~, maconi a.g. *, breg~ massone p.p h [] ic+pca request conclusions:using e~aprenorphine, a synthetic,long-acting, ago-antagemist opinid drug as analgesic, in the major surgery we obtained the best clinic results with association of conttheus infusion of haft dose drug with bohts of pca in the first - hours and just pca in the secmad day after surgery when the patient is less sleepy. in this way we dent have a great sav~g of suppled drug but the major well-belng of patient without ~erious side-effects and quick mobilization; the dosage used don't compromise a good awake of patient: all patients are sleepy but ready for answer, no allueinatian, bradipnea but not less than b/m without ipoxia. also the patient proffered this kind of truit meut than the traditional at demand. the ward staff feel it useful] and rehabl~ the negative feed-back technology of the electronic infuser system makes possible to use it safe in the ward with high drug's concentration too. the infusion rate of low dose of drug assure a continuative analgesic covering ~n the first postoperative periad; the pca mode involves the patient him-self in the managemenl of therapy and enables him to choose the best way to confront the dll~icuity of postoperative period without call medical stall using pca-device we have had no probicm~ no accident. analgesia during extracorporeal shook wave lithot ripsy a .levit, b.grinbezg regional hospital, ekaterinbu~g, russia b~ectives: our task was to compare ~he analgetic effect of norphin and tramel. methods: study was made of two groups of uro-li~patients aged - . group a ( patients) received baprenorphine hydrochloride (norphin) at dosages of #. • mg/kg. group b ( patients) received tramadel hydrochloride (t~aasl) st dosages of . z . mg/kg. before the procedure diazepam was administrated i.v. ( . ! . mg/kg). blood saturation (spoz), hemodynamics incides (bp, hr,sv,co,sap,svr) were examined and the patients' subjective assessments of snsesthesis quality were analyzed. the hospital ethics committee approved the investigation. results: when using norphin hr increased by . % on the onset of the procedure while sap and sv decreased by .%% and . %, respectively (p< . ). however, there were no reliable co chsnges. spoz ~educed by @. % (p< . ) and remained lower than the initial one after the procedure was oyez. when administrating tramsl min. after ste~ting the procedure sap and svr increased by ~ . % and . % respectively. sv and co decreased insignificantly. nine patients in group b saffeting some dlscomfo~t needed additional tm~msl in~ection. in the course of the whole p~oced~e spo, was constant and was highez than that in ~he case of nozphin (p<o. ). conclusion: respiratory suppression by no~phin can limit its use in case of lithotzip@y while the advantages of tremsl a~e: lack of dyspnoe and good contact with the patti-b_ the role of uncommon agents of antinociception, placed epidurally, in the control of pain transmission in the spinal cord is well documented. somatostatin as an inhibitory agent is found in the dorsal horn of the gray matter of spinal cord. the effects of somatostatin is similar to the opiates if injected into the epidural space (ref. i, , , ) . the aim of the present study is to present the clinical effect of above mentioned palliative therapy in the case of cancer and non cancer pain. informed consent had been obtained from every patient before treatment was initiated under the legalisation of the local ethics committee. using the permanent epidural catheter and continuous infusion pump, we administer somatostatin in the dose of up to microgram per hour for one up to three days. the patients paln feeling was evaluated using a vas (visual analogue scale). we found that the opiate resistant pain level decreased by %. the rest pain could be controlled by pereral opiate analgetics or by combination of somatostatin and an opiate plus a local anaesthetic agent epidurally. theoretically, it seems that epidural administration of somatostatin and local anaesthetic agent is useful in the control of acute pancreatic pain and systemic effect of somatostatin is beneficial in the treatment of acute pancreatitis. few studies have been performed in the critically ill (ci) and because of the complex pharmacodynamic and pharmacokinetic changes that occur, it is difficult to predict accurately drug responses and interactions in individual patients. midazolam (m) is a watersoluble benzodiazepine with a rapid onset and short duration of action in normal individuals; however its metabolism is decreased in the ci. critical care physicians every day experience suggest that among the ci there is a different pattern of response to m; here it is hypothized that such a response could be due to different metabolic behaviours of ci. m (i.v.infusion rate - rag/h) and antipyrine ( rag p.o.) were infused to ci with ( patients -group ) and without ( patientsgroup ) endotracheal intubation. blood samples were collected at fixed times during and after m infusion. total urine nitrogen and antipyrine elimination half-life demonstrated different metabolic characteristics in group chypermetabolizer") as compared to group chypometabolizer"). results follow. the results of our study are preliminary and more kinetic data in critically ill patients are needed to statistically confirm our approach of "hypometabolizer" and "hypermetabolizer". objectives: some clinieai and experimental studies suggest that propofol decreases myocardial contractility in coronary artery bypass grafting (cabg) patients. the intrinsic negative inotropic action of the drug may be independent from changes of preload and afterload, whereas the myocardial depression induced by propofol may depend on changes in ca ++ ious availability. aim of this study was to verify the hemodynamic effects of propofoi in a group of cabg patients with uneompromised contractile function and to minimize myocardial depression, during induction of anesthesia, choosing to associate calcium chloride (cac ) in an other group and to define its role in producing this effect. methods: fourty patients, randomly divided in two groups ( pts a and pts b), undergone elective cabg, were enrolled in this study. anesthesia was induced by senior anesthetist in both groups by means of fentanyl mg• kg < in ", pancuronium . mg x kg - and propofol mg • kg - in ". a blind investigator administered via another venous way at same speed ( ") saline in patients of group a and mg x kg - cac in patients of group b. hemodynamic data (heart rate hr, mean arterial pressure map, mean pulmonary artery pressure pap, pulmonary capillary wedge pressure pcwp, central venous pressure cvp, cardiac index ci, stroke volume index svi, systemic and pulmonary vascular resistances indexed svri and pvri) were obtained at baseline (to), ' after anesthesia induction (t ) and " after tracheal intubation (t ). results: hr decreased moderately in both groups (p = ns). map decreased as well, more markeatly in group a at ti and t . this trend was statistical significant (p < . ) in both groups. pap, pcwp and cvp unchanged following induction in any of two groups. ci decreased in group a (p < . ) dramatically dropping at t , while in group b it showed a negligible decrease at t (p = ns) and value similar to baseline at t . svri and pvri did not exhibit statistically significant changes. conclusions: the use of propofol as a starter of anesthesia in cabg patients allows to reduce total dose of fentanyi, dramatically reducing post-operative intubation time. propofol-fentanyl association prevented the hyperdynamic response to stress (i. e. laryngoscopy, intubation) but severely depressed ci and svi. cac simoultaneous administration effectively minimized the negative inotropic effect of propofol. moreover no unwanted side-effects due to cac were observed. diseoordinated labor activity (dla) is one of most serious in obstetric pathology.medication sleep effect to a woman in birth is of limitation of pathologic impulsation from the central nervous system, but it does not influence processes resulting in and supporting dla on the organ level. constant discoordinated uterine contractions during medication sleep (ms) imerease disturbances of uterine blood flow, organ hepoxemia connected with hyperergia of vascular wall and myometrium to catecholamines, that reduces efficiency of anesthesiologic protection. we applied hexoprenalin in complex with ms to primaparas. efficiency control was being accomlished through hysterograms, grade scale of analgetic effect where hemodynamics reaction to pain, significance of emotional reactions and their vegetative manifestations before and during ms were registered, and also through hydrocortisone level in plasma before and during ms. the examined women's average duration of ms was hours more than in control and made hours, though their average labor duration and in control was the same and made hours. % of the examined women experienced independant labor, as for the control group -only %. supplementary methods of anesthesia were required in % in control,that increased medicamentous depression of the fetus, but for the examined group -only in %. the examinees's newborns experienced favourable terminations, in control newborns were in state of light rate asphixia. analgetic effect was complete in control just in i %, and of examinees -in %. on the women's hysterogrnms before ms discoordinated contractions were registered on the background of increased tonus. during ms in control similar uterine contractions were constantly registered, but for the examinees they were not marked at all or had the proper character. the examinees' hydrocortisone level was reduced for % and in control only for %. the study has allowed to make a conclusion that hexoprenalin applications in complex with ms in case of dla make anesthesiologic care safer and more effective, promote simultaneous removal of patholgic processes in the central nervous system and uterus, which lead to dla development. objectives: the aim of report is to present a clinical study results for the evaluation of anesthesia for a patients in unconscious states by eeg examination: methods: the study was conducted on patients after a severe abdominal operations on stomach and intestine and on one patient after traumaticat exarticulation of upper extremity. all patients have different unconscious state levels from somnolence to coma ]. also thay hav~ had respiratory insufficiency and control mandatory ventilation have been used. we were used intrave,~ous injections of morphine hydrochloride from initial dose of mg. than we were increased the dose to mg i.v. by drops with an accompanying eeg monitoring and fourier spectral analysis. initially all patients have had -rhythm with slow and a-activity. an c~-activity index have been lower than %. results: after anesthesia the o-and a-activity have disappeared. the or-activity index have increased to %. also we have noted decreasing of the unconscious state levels to a possibility of a verbal contacts ( - points gcs). conclusion: the quality of anesthesia could be evaluated by eeg monitoring. a regaining consciousness afte~ the injections of high doses of morphine, probably, may be a result of an opiate deficiency (full or partial). anesthesia with the following drugs: clonidine, l-arginine, l-n-arginine-methyl-ester (l-name), and their combinations. tail-flick latency (tfl) was determined at time zero and min after each treatment. clonidine (i- ~g/mouse) prolonged tfl in a dose-dependent manner. at a clonidine concentration of gg/mouse, tfl increased . -fold compared to time zero. l-arginine increased tfl at a high concentration (i gg/mouse). l-name suppressed tfl . -fold compared to time zero at a concentration of gg/mouse. conclusion: we have found that no is involved in clonidine spinal analgesia. studies are currently being undertaken to assess the effect of combination treatment of the above drugs on clonidine supraspinal analgesia. objectives: hemodynamic changes ussualy accompany laryngoscopy and tracheal intubation.the aim of this prospective study vas tu present the effectivness sufentanil in preventing reflex circulatory respone of laryngoscopy and tracheal intubation and provides stable hemodynamio condition for induction of balanced anaesthesia. methods: adult asa i-ii patients sheduled for elective surgery.they were allocated randomly and divided into two groups:fifteen patients received single bolus of placebo prior to laryngoscopy.and tracheal intubation. anaesthesia induction was then performed with thiopental (smg/kg) and atracurium ( , mg/kg), followed by neurolept anaesthesia. mean arterial preassure (map) and heart rate (hr) were measured before, during and min after intubation. althought ecg was recorded at the same time intervals. results: the groups were compared with regard to the changes in arterial blood pressure,heart rate and electrocardiogram. mean arterial preassure and heart rate were incresed significantly during and after laryngoscopy and tracheal intubation in control group but remained unohange the baselin values in the group who received sufentanil. control group ecg suggested more changes than sufentanil group. conclusions: the results indicated that , mg/kg sufentanil for anaesthesia induction reducing the pressor response to laryngoscopy and tracheal intubation. obiective: the aim of this experimental study was to evaluate morphologically the influence of anesthesia in liver as well as in isolated hepatocytes (hc). methods: a total of female swine ( - kg) were used as liver donors and were randomly assigned to one of two groups regarding anesthesia protocol: group a (n= ): induction with intravenous sodium thiopental in a dose of mg/kg, group b (n= ): propophol in a dose of mg/kg for induction'and mg/kg/h for maintainance of general anesthesia. both groups were under the same preanesthetic regimen (diazepam, ketalar and atropin) and received standarised doses of fentanyl and pancuronium during anesthesia. in beth groups total hepatectomy was performed and the liver was perfused with - it of cold ( oc) university of wisconsin solution for a period of hours before hepatocyte isolation. liver tissue samples were fixed in formalin for the morphological study and stained with hematoxylin-eosin and pas. for hc isolation collagenase solution (type v, sigma, c- , . mg/ml) was infused via portal vein and the liver was incubated at oc for rain. cells were filtered and then washed in cold hanks' solution. isolated hc were fixed and prepared for staining or simply cryopreserved (- oc). results: histology was completed in / experiments ( in group a and in group b). mononuclear infiltration (halothane type injury) was found in all specimens ( / ). focal zonal necrosis and acidophilic bodies were found in specimens from group a ( / and / respectively) while portal inflammation with piece meal necrosis was found in one specimen from group b ( / ). smears of hepatocytes -beth formalin fixed and cryopreserved at - oc -were stained with hematoxylin-eosin and showed morphologically intact hepatocytes. conclusion: pre[imineq~' study of our material reveals mote frequent livet injury in the thiopental group, but this finding has yet to be established by increasing the number of observations. objectives: in this paper we present our experience and point out the importance of sedation of those patients who suffered severe head injuries/contusic cerebri with signs of decelebration/and who were put on ventilatory machine to obtain better mechanical ventilation in neurosurgical intensive care unit of emergency center in belgrade. methods: patients were treated from jan. till dec. results: in patients we successed to reduce agitation and decelebration. conclusions: the major demand of sedation in neurosurgical patients are that the patient should be calm, comfortable and painless. references we compared three analogous groups of patients in each, with orthopedic operations on lower extremities. in each group we applied different kind of analgesia: first group rece-ned local anesthetic ( ml . ~ bupivacaine) when analgesia was first demanded; second group received ml fentanyl via peridurai catheter when analgesia was first demanded, and third group received m] fentanyi intravenously on demand for analgesia. we used visual analog scale (vas) for estimation of pain intensity and success of applied therapy. statistical data analysis was performed using student's t-test. tha best vas had group in which local anesthetic was applied periduraly. second was the group with periduraly applied fentanyl, and third was the group with intravenously applied fentanyl the longest duration of the effect of analgesia ~/as in the second group. there were no adverse effects and complications, apart from mild sedation in the third group. for orthopedic operations on lower extremities, application of peridural catheter for anesthesia and successful postoperative analgesia with local anesthetic, or opioid analgesics is acceptable. background and obiective : tympanic temperature measurement (ttm) is a relatively new procedure which provides accurate estimates of core temperature in stable postoperative patients and in patients admitted to the emergency ward. however, experience with this technique in hemodynamically unstable adult icu patients is limited. design : prospective study with patients serving as their own control. se:ttijlg : adult medico-surgical icu in a tertiary care hospital. patients : consecutively enrolled patients with thermodilution catheters in place and without contraindieation for rectal temperature measurement and without hypothermia (core temperature < ~ interventions : tympanic temperature, measured by a commercialized tympanic thermometer (genius a first temp) was compared with pulmonary artery (pat) and rectal temperature (rt). within minutes, core temperature was assessed in each patient by the same trained individual using the three techniques in random order. measurements and main results : mean bias (ix~ and its variability (sdr of method comparison pairs were calculated using the methods comparison analysis as described by bland and alunan (lancet, ; i : - objective: to measure the prevalence of pressure sores on the intensive care unit and the effect of risk calculation on pressure score prevalence and pressure score severity. method:in during a period of months a series of prevalence studies was carried out on the sicu to investigate how many patient days with pressure sores were taken care for by the icu nursing staff, what kind of preventive interventions were done and what the patient risk was on developing a pressure score. results: on average there was a prevalence of pressure sores on the buttocks of . % on the short stay unit and . % on the long stay unit; preventive interventions increased when the pressure score was visible for the nurse and the majority of patients had a high risk or extra high risk for developing pressure sores according the pressure score risk calculator. as a result of these findings the nursing management decided in that nurses had to complete daily on every patient the pressure score risk assessment in order to be able to take adequate preventive interventions. when the results of the two studies were compared, the most important results were that: ) there is no indication of a reduction in patient days with pressure sores (short stay unit: %, long stay unit: %); ) there is a reduction in severity of pressure sores (grade iv decreased from . % to . %) because adequate preventive measurements are initiated by icu nurses in an earlier stage. possible explanations for the increase of patient days with pressure sores on the long stay unit are that the average pressure score risk score was increased from . to . and the mean frequency of nursing patients on alternate sides decreased from . to . times each day. conclusion: daily assessment of the individual patient risk on developing pressure sores does not decrease development but reduces the severity of the developed pressure sores. method: the conventional woundcare method of patients with an open abdomen is to change frequently the saline soaked ribbon gauze pads ( - times each day). this method is labour intensive for the itu nursing staff and rather uncomfortable for the patient. problems that often occur are: insufficient hygiene, frequent nursing interventions, a progressive risk for deterioration of the skin and underlying tissues, difficult to measure abdominal output and in case of bowel fistulas enteral feeding is hardly possible. in using the new method, stomahesive is applied on the skin surrounding the wound. a large size of surgical film dressing, opsite | is applied over the abdomen. two or more foley ~ catheters ch are inserted through an opening in the surgical filmdressing. the application of several lateral openings in the catheters is advised. the drains are held firmly in place between two layers of sterile opsite | "flexigrid ~'' x with the so called bookend method and are connected to a low vacuum suction system ( - kph) results: we studied the frequency of dressings changes on patients in the itu. in total they had days with an open abdomen. during this period there were dressing changes. this means one dressing change every days. further advantages of the new method are; more hygiene in patient care, no maceration and irritation of the skin, nursing on alternate sides is possible, output can be measured, in case of bowl fistula, enteral feeding is possible and an abdominal lavage is possible on the sicu by opening the opsite | conclusion: this new method of woundcare management is more patient friendly, prevents several nursing complications and decreases the work load for the nursing staff. objective: to investigate the interaction between the ventilator and the closed suction system related to possible induced negative pressure by this sytem. method: we studied in a testlung model what the effect was of the different ventilators (evita: dr~iger; servo c: siemens), ventilation modes ppv, simv) and ventilator settings (tv, trigger level, frequency, peep level) on the induced negative pressure by the closed suction system during suctioning. results: when using the evita the magnitude of the negative pressure increased when the ventilation frequency and tv decreased.. the largest negative pressure (- cm h ) was produced with a tv of ml and a frequency of /min in the ippv mode with trigger level on - cm h and a peep level of + cm h . the servo c showed a complete different pattern. the largest negative pressures were measured when no trigger level was set ( cm h ), the induced negative pressure was not depended on the tv or ventilation frequency but more depending on the ventilator mode. the simv mode produced the smallest negative pressures ( - cm h ) and the ippv mode the largest ( - cm h ). conclusion: the effectiveness of the closed suction system is very much depending on the kind of ventilator, ventilator mode and ventilator setting that is used. if the interaction with the used ventilator is not known by the icu nurse this piece of equipment can cause damage to the patient by inducing large negative pressure in the comprimised lung and there fore creating the possibility of alveolar collaps and atelectasis or oedema. introduction : ethical problems are daily and disturbing preoccupations for the icu staff. objectives : improving ethical management in icu by creation of an intelprofessional group of ethical reflexion ( iger ). methods : existing was evaluated by a preliminary formulated series of questions sended to the whole staff (q , n = , items) after two training sessions (laws, deontology, professional values, culture, norms of quality) followed by persons ( %) and directed by an external chairman, satisfaction and needs of the staff were evaluated by a second series of questions (q , n = , items). at the issue, iger was created. results : q : responders ( %). law's misinformation : to %, disagreement for limitation of intensive cares : %, hope to improve collective decisions and creation of iger : % q : responders ( %) : satisfied by the training sessions : %, non satisfied : %, want to continue the project : %, refuse : %. iger was constitute by physicians, nurses, secretary, dietetic (n = ). the first working theme was {< therapeutic's withholding and withdrawing decisions in icu ~>. four subgroups of iger's members (having access to an ethical library) worked independautly and submitted their reflexions in a tdmestrial plenary session of iger in the presence of an external chairman, allowing a synthesis. at the issue a report was writted to be used as a reference for bedside and individual decisions. conclusions : constitution of iger seems to improve ethical management in icu. the first result of iger is that it is now possible to began collectively a reflexion concerning therapeutic's withholding and withdrawing in icu. the work is going on and further subjects will be studied. objectives: ) to compare the value of heat-moisture exchangers with bacterial filters (hmef) and without bacterial filters (hme) in the prevention of colonization of ventilator tubing and ventilator-associated respiratory infections. ) to asses the temperature and relative humidity of inspired all using both types of heat-moisture exchangers. methods: mechanically ventilated patients were randomized, to either hmef or hme. endotraeheal aspirates, pharyngeal swabs and samples from tubing were collected for bacterial cultures on the st, nd day mechanically ventilation and weekly thereafter. temperature and relative humidity were measured in patients ( hmef and hme) h and h after placing the hme or the hmef. results: both groups were comparable as regards age, mechanical ventilation period, severity score (saps ii), leukocyte count, and number of patients with prior antibiotic treatment. from the hmef group, ( %) ventilator tubing yielded microorganisms in, at least, one sample as compared to ( %) of the hme group; p=ns. the incidence of respiratory infection was similar in both groups ( % vs %, p:ns, for hmef and hme respectively). among the bacterial species isolated from ventilator tubing in the hmef group, ( %) were not isolated from pharyngeal swabs. a similar ratio was shown in the hme group ( / , %). both heat-moisture exchangers were efficacious in keeping a good relative humidity of inspired air ( % • vs % • .%; p=ns, for hmef and hme respectively). relative humidity was significantly higher after h of mechanical ventilation in the hme group as compared to hme group ( . % • vs . % • %; p= . ). conclusions: both types of heat-moisture exchangers have the same effect on the prevention of colonization of ventilator tubing. similar relative humidities are achieved when using either type of heat-moisture exchanger. results: tumor and nontumer enhrgements of the thyroidea were present in ~ of the operated, surgicel adrenal disease in io!, hyperplssle or persthyroid gland tumor in ~ end endocrine pancreatic tumors in %. in the intensive oere unit, these patients wore screened by noninwsive monitoring in ~ of cases: and invasive monitoring was applied in % of ceses.the basic noninvesive methods included: electrocardiogram with standard end precerdial leeds, percutaneous eutomotlc measurement of systolic, diastolic and mean arterial pressure, measurement of hourly diuresis and body temperature, frequency, hearing capacity and rhythm of one s own breathbng bs well as pulse oxymetry. a special plece in monitoring and control of vital parameters in postoperative period belonged to the nurse, thoroughly trained for enelysis end interpretation of the observed parameters which would be discussed in the paper. it has been believed that the leader sits at the pinnacle of power. over the years, this has proven to produce frustruation and anguish instead of the expected results. leaders have not been able to produce the changes they know are essential to their organization's survival with this command-and-control paradigm. through literature reviews and evaluating leadership styles, one can clearly see the most effective form is that of empowering people to a new level of performance -not ordering it. changing the leadership paradigm to a manner/style that has been shown to be effective and one of people empowerment shifts the focus to personal responsibility for performance. removing obstae}es~ stimulating self-directed actions, and determining focus and direction are just a few elements used to create the successful environment of empowerment. with increasing pressure in the health care arena, it becomes critical that a leader's job is to get the people to be responsible for their own performance. developing ownership, creating an environment where people want to be responsible, being a mentor or coach, and learning faster while encouraging others to do so demonstrates the commitment to effective leadership. this presentation will illustrate the critical components that are achieved when every person in the institution is empowered to perform at a level that is directed toward positive, effective results. herrera m. (md) . icu. hospital regional. malaga. spain. the systems of veno-vanous continuous haemofiltration (wchf) have a high cost and a limited life span. in an attempt of lengthening their mean life it has been proposed to accomplish programmed washes of the ~-stems. this practice supposes an increase in nursing workload. in order to evaluate the real efficiency of this practice we have accomplished this study. material: prospective randomized study of all the filters of vvchf used during the last year in our icu. we have determined two groups of filters, in the first (group a) we accomplished washed in a programmed way, and in the other (group b) only when the alarms of the system suggested a clotting of the filter. for the statistical analysis we used the kaplan-meier test for survival analysis. results: we have studied a total of patient submitted to wchf during the last year. we used a total of filters with this results. objectives. sounding out the nurses about the need to inform patients" relatives and the rigth kind of such information, like a preliminary approach to an information cuality assessment, methods: we inquired all the nurses of the intensive care unit of an regional hospital by an semiestructurated questionary which included personal data: age, sex, contractual relation, professional experience.., and opinion data: do you think to inform relatives is a nurse task?. which of the next informafions do you think is more important?, please, write others topics about information you think are relevant. we process the data on epi-info estatistical program and use x test to compare the results. results" from nurses of staff refused to flu the quetionary, and were not available. of the remaining, %were v~men and % men. the mean age were . % had an svable contract and ( eventual, the mean professional experience were of years and % worked in the unit since more than years. the % answered that offer information to relatives is part of the nurse activities. we did not find differences with nurses who answered negatively comparing by sex, age, contractual relation or proffesional experience. the three information topics found out like more important were: ) to inform about patient mood. ) to inform about happenings from the last visit. ) to inform about dressing instrument required by the patient, nurses who answered negatively think that to inform is a doctors task or that nurses are not competent. conclusion~ intensive care unit teams (nurses, doctors and auxiliar personnel) should get accord on who and how to inform relatives, we consider the nurses' role on information as unquestionable. objective: investigate the respiratory and cardiovascular response after discontinuing oxygen therapy durir~ intr~/]o~pital transport. desiqn: fifty-one patients ( male and female, aged + , and , , years respectively, ~+sym) being on therapy were studied prospectively in two consecutive intrahospital transports. oxygen therapy was continued in the first transport while the second one was performed as usually, i,e, without . during transport each patient was monitored by pulse oxymeter and holter whereas arterlal blood gases were tested just before a~xl aft~-trar~portation. results: compared to daseline, pa and sa were signif~canthy decreased in the case of oxygen discontinuation (p< , i). paco was significantly inur~ds~i only in the subgroup of patients with obstructive lun[ disease (p< , ) . heart rate increased in all phases of the transport when administratlon was discontinued. blood pressure remained stable in either case. the percentage of supraventricu!ar extrasysto!es, ectopic v~r[hicui~r contractions and st-s ~ment depression was progressively increasing and became very high at the end of transport in the case of therapy discontinuation. other arrhythmias did not change significantly. conclusion: discontinuation of oxygen therapy during intrahospital transport causes severe drop of pao and sa , increases the heart rate and contributes to the appearance of arrhythmias which were not present before. methods:for evaluation of the functional state of brain the complex of methods was used,whieh included electro encephalngraphy ( brain mapping ), rheoencephalography, tetrapolar transtorax rheography. for the estimation of humoral status the level of histamine and serotonine, products of free-radical oxidation,enzimatic markers of ishemic damage of brain and of endogenous intoxication was investigated. results: patients with encephalopathies after resuscitation were observed.asystolia was as a result of:shock, trauma, asphyxia,poisonings,appiication of drugs, eclamp sia,injury of the heart,diseases of fhe cardiac vessels. all patients with postasystolic syndrome entranced in comafose condition.in the group (reconvalescents) the depth of coma by glasgo~ pittsburg"s scale was , +- , . the duration of coma was from rain. to hour,average , +- ,sh.ln the group (the deads) the depth of come was , +- , .the artificial lung ventilation was used in all patients:in the group , +- , days,in the ~ , +- , days.apallish syndrome developed in cases,in patients diagnozed <<brain death~. the th degree encephalopathy (coma) was found to be associated with disorganized eeg-pattern with predomi nant alpha-( group) and slow ( group) activity. the relative power of delta-and theta-ranges was about - per cent.the patients with apallich syndrome demonstrated greatly elevated theta-range power, that of beta -range was essentially decreased. the degree of disturbances of circulation in the both groups was different.cardiac index (ci) and stroke index (si) in the group decreased on , % and , z, in the -on , % and (; , %.general peripheral resistance (gpr) increased in the group on , %,in the -on (; , %.in the group brain blood flow was increased, in the -decreased on , n.in the group there was the normotonic type of reg-curve,in the -atonic or hypotonic type (without reaction on pharmacologic influ ence).disturbances of permeability of cellular membranes (enhanced free-radical oxidation with an increase in di enic conjugates on and n) and vascular ones (an increase of serotonin concentration on and %, hi stamine content on and %) resulted in hyperfermentia (an increase of concentration of creaune phosphoki nase in the group on %,in the - %.the level of middle molecules (mm) increased in the group on , %, in the -on , %,of polyamines (p) (spermidin,spermin,putrescin).coefficient of correlation between mm and p was , . immediate correction of neurocyte metabolism is impossible due to marked brain oedemaswelling,severe dis ordes of cerebral circulation, disturbances of membrane permeability.thus,the following treatment algorythm might be advisable: . protective inhibition of brain and reduction of its energy requirements. . recovery of cell and vascular membrane fuoctions. .recovery of blood circulatiom .oxygenation of nervous tissue and drainage of brain disintegration products.in patientshbo carried out. .active methods of detoxication (homo-and enterosorption). .correction of cerebral metabolism. . dehydrative therapy must be very cautious. conclusion: the activation of energetic metabolism in neurocytes must be carred out only under neurophysiolngical control and after definite preparation. ( ). the clinical estimation of acute cerebral failure carried out by olasgo-pittsburg"s classification of coma. we studied such groups of patients: poisoning co ( ), asystolia ( ), eclampsia ( ), acute renal failure ( ), control group ( ). methods: electroeneephalngraphy (brain mapping) was fulfilled by means of encephalograph <,medicor ~ in monopolar channels. the estimation of eeg patterns by zhirmunskaya method ( ) was carried out. there were analyzed and changes of eegb by results of rapid transformation furie after rhythmical photostimulation(phts) , , , hz. we studied also the figures of absolute and relative power in such diapason : delta ( - hz), theta ( - hz), alpha ( - hz), betal( - hz), beta ( hz and more). results: all eeo changes were divided into following types: -organized ( , groups); iii -asynehronic ( group); iv -disorganized with prevalence of alpha-waves ( , , groups); v -disorganized with prevalence of delta-and theta activity ( , , ; , groups) akkording to our model of hormonal-metabolic disbalance in pregnancy , one of the main reason of destosis is hypoergos , reesults in endotoxemia and neuro-endokrine disregulation. so, stady of central nervous system function give us the information about adaptation processes. the aim of our work is to study the degree of neurologikal deficit in destosis when olifen and lipin were used. there were studied pregnants with different severe forms of gestosis. the degree of neurologikal deficit was valued by datas of neurologikal status . eeg with ,~brain mappinng~, , electrikal resistance of the skin. the komplex inteensive therapy with applikation of olifen and lipin allowed to improve the patient,s condition , decrease the degree of neurolodikal deficit and mortality . kostenko v.phd,kabanko t.,phd,galalu s.md,beliavtseva n. ,shramenko k. phd intensive care department,donetsk medical university, donetsk, ukraine plasmapheresis (pph),as other extracorporal methods of detoxicatin,has a great importance in contemporary medicine. the role of pph is special,because of its simplicity, effectiveness, atraumatic.we incalcated pph in obstetrical clinic. there are rough changes in agregate condition of blood in more of pregnants.these changes lead to disturbances of central,organ and peripheral hemodynamic.the therapeutic effect of pph is due to influence on agregate condition of blood. we considered that application of pph is very effective in pregnants with:bronchial asthma, severe forms of diabet, psorias, gestosis, allergic diseases. we used the membrane pph in pregnants: apparatus-,,hemos-pf>,, plasmofllter pmf- ,with effective area- cm,the volume of extracorporal contour- ml.such pph has no the ~ agressive effect,,, as in cases of application another extracorporal methods. this method was incalcated in our practice recently, so results will be reported in further publications. ( ). post-operative cerebral neoplasm ( ), post-operative subdural hematoma ( ). icp was monitored via a catheter inserted in the lateral ventricle and values were continuously digitally recorded by means of a bedside computer data acquisition system (maclab). the fiberoptic tracheobroucosenpe, which guided the procedure, was passed between the nasotracheal tube and the trachea in order to avoid hypoventilalion. the patients had stable baseline hemodynaimcs. propofol infusion and fentanyl boli were administered to mantain stable mean arterial pressure values. peak (mean(sd)) icp duping the minutes pre-ciaglia procedure (baseline values) were compared with values during ciaglia procedure, and the minutes p st-ciaglia procedure. data were compared with repeated measures anova. results: ciaglia procedure duration was (mean(sd)) ( ) objectives: transient global amnesia (tga) is a syndrome caracterized by impairment of short-term memory, inability to form new memories, retrograde amnesia and repetitive queries, without other neurological signs and symptoms. the pathophysiology of tga is unknown; thromboembolic, epileptic, migrainous and metabolic mechanisms have been suggested. to address some of these issues, we undertook a study of cases of tga in whom we examined clinical, laboratory data, electroencephalogram, ct of the head, ultrasonography ecodoppler. methods: patients were included in this study: men and women. the mean age was years. all cases underwent a standard clinical examination, electrocardiogram, routinary humoral tests and x-ray, electroencephalogram (eeg), ct scan of the head, ultrasonography ecodoppler. results': the mean duration of amnesia was h. m. +/- h. m. hypertension was found in patients ( %), ischemic heart disease in patients ( %), hypercholesterolemia in patients ( %), hypertrigliceridemia in patients ( %), smoking in patients ( %), atrial fibrillation in patient ( %), history of epilepsy in patient ( %), migraine history was not recorded. ct scans of the head showed multiple small deep infarcts in patients ( %), a single hypodense lesion in patients ( %). in patients electroencephalogram was normal ( %), in patients there were widespread nonspecific electrical changes ( %), in patients there were focal nonspecific eeg abnormalities ( %). conclusion: in our study tga was more common in women ( %). we showed a prevalence of hypertension, hypercholesterolemia and cerebral infarcts compared to normal controls. we have demonstrated a higher incidence of nonspecific electrical changes in tga of lower length, while ischemic lesions in ct of the head were more frequent in tga of greater length. these data seem to be in agreement with the hypothesis that tga is a heterogeneous clinical syndrome, consisting of pure, epileptic, and ischemic types. however we did not find any correlation useful in discriminating pure from associated tga forms. from our study it is tempting to speculate that pure tga is a rare event, underlying still unknown mechanisms wich differ from ischemic, epileptic, migraineous causes. objectives: aneurysmal subarachnoid haemorrhage (sah) is special condition increasing intracranial pressure (icp) in various ways. at the other hand cerebral vasospasm and related delayed ischaemic deficit (did) could answer for the poor outcome. triple h therapy seems today a basic option to prevent did, but it may increase the icp worsening the altered intracranial pressure condition and thereby the cerebral perfusion pressure (cpp). is there any way to individualise the triple h therapy when it is necessary? methods: between sept. march thirty-seven patients with intracranial aneurysms were operated on within hours following sah. five patients were in hunt-hess iv at admission. all patients received triple h therapy in a preventive fashion following surgery and were monitored by daily transcranial doppler ultrasonography (tcd). icp and cpp was measured in twenty-four cases. twenty-two of them received lumbar liquor drainage (lld) and nineteen were administered induced hypertension. the other group was treated by basic triple h therapy. results: in group with monitored icp the outcome was twenty-one excellent, one poor, two died (one of them died from extracranial decease). in the other group four had excellent, six moderate, two poor outcome, and one died. conclusion: according to our recent observation the patients can be divided into two groups of therapy. in group i, the patients with elevated tcd values and either low or high icp reacted to lld. we are concerned that haemodilution and slight hypervolaemia should dominate in the triple h therapy. in group ii patients having high icp with tcd and/or symptomatic vasospasm should be managed by the induced hypertensionhypervolaemia dominated therapy focusing on cpp (icp) and focal neurological signs. air emboli were detected in lo% (n= ) of natients undergoing coronary srtery bypass craftin~ (cabg). central nervous system ~ysfunction occured in ~$ of the nstients with air embnli and in none of those ~ithhout air embo!i. hvtothermia is the classic form of oro-tect~on used dur~nc ~"~" " ~ ~ ca~.,~modu] :r, on~_,_. bj/oass. the surf~eon sho,;,ed thorough!~: evecnnte air from the heart, but the onesthesio!o[[ist can signifieamt!y influence the outcome by emt!oyin ~ methods to detect and treat air emboli. the changes in head rate are primarily due to alterations of autonomic tone. the heart rate variability (hrv), that express the degree of heart rate fluctuation around the mean heart rate, reflects somehow the condition of central nervous system. hrv may be measured by a number of techniques. short-term time-domain variables of hrv are reflect generally the vegal activity. in this study the changes in hrv variables of patients with brain damage, and in addition the changes in hrv measurements in comparison with the clinical evolution were evaluated. eight patient with brain damage and six normal individuals as control group were studied. a elecrocardiographer with availability of computation the sequence of beat-to-beat intervals for one minute was used. the following variables of hrv were measured: ) standard deviation (sd) of beat to beat r-r interval differences that reflects the respiratory control, )the maximum/minimum (max/rain) interval that reflect variability related to baroreflex and thermoregulation and ) the coel~cient of variation (cv), the results are shown in the in the patients with brain death and in vegetate state there were virtually no hrv. increased hrv pattern was found with clinical improvement, the changes of hrv precede of the changes of gcs, we conclude that time-domain hrv could reflects the degree of brain damage, it is good prognostic index of the brain damage and may change earlier than the gcs. objectives: cerebral co vasoreactivity is an important determinant of cerebral blood flow (cbf) and has been shown to be of prognostic value in head trauma (acta anaesthesiol. scand. ; : - ) . we wondered whether co vasoreactivity could be selectively altered in one hemisphere in comatose patients. methods: patients ( m/ f, age - yrs, glasgow - ) in coma due an acute brain lesion (trauma, hemorrhage, or infection) were studied. cbf was measured bilaterally using jugular thermodilution at paco , , , and mmhg by increasing pico with mechanical ventilation kept constant. normal co vasoreactivity was defined as an increase in cbf of at least i ml/min. g per mmhg paco . results: patients had normal co vasoreactivity bilaterally, patients had altered co vasoreactivity at both sides, and patients had a normal response at one side (left or right) with an altered response on the other side (dght or left). for the patients left cbf was in mean ! ml/min. g lower than right cbf (figure methods: following institutional approval piglets (body weight :tl . ) were anaesthetized by % fluothane. a catheter was placed in the right femoral artery for blood pressure monitoring and a fiberoptic catheter (oxymetncs- abbott) was advanced via the right internal jugular vein to the jugular bulb for sjo determinations. another catheter with a balloon on the tip was advanced in the right atrium via the right femoral vein. a mean arterial pressure (bp) at mmhg was achieved by appropriate balloon inflation for rain and two groups were cleated: i) the hypoxemic group by respirator disconnection (*) and it) the hyperoxemic group by fio =l on respirator (o). samples were obtained at time ( ), ' min at hypoperfusion ( ) arid at reperfijsion at ' ( ), ' ( ) and ' ( ). pao , pjo and oxidative brain stress evaluation was performed from jugular bulb blood. the latter included: i) no synthase (nos) and xanthine oxidase (xo) activities by a method based on the oxidation of scopoletin detected fluorometrically, it) no levels estimated as onoo-by luminol enhanced chemiluminescence in the presence of ~tm hydrogen peroxide (h ). resul'~s: the mean pao was mmt-ig for group i and methods: we retrospectively reviewed all upper gi-endoscopies, performed in the period january -july in patients ( men and women) admitted at the icu's of our hospital. results: it concerned surgical, medical, eardiological and neurological patients with a mean age of . yrs (range: - ). in %, the endoscopy was performed at the icu and in % at the endoscopy department. in % of the cases, the endoscopy was primarily diagnostic, of which % was performed for localization of upper gi blood loss. in % the endoscopy was primarily thempentic, of which % was performed for placement of a duodenal feeding canula. location of the upper gi bleeding was: variees ( %), duodenal ulcer ( %), oesophagitis ( %), gastric ulcer ( %), others ( %) and none ( %). as coincidental findings were noted: cesophagitis ( %), gastritis ( %), gastric deer ( %), duodenal ulcer ( %), duodenitis ( %), oesophageal ulcer ( %) and others ( %). conclusions: there were marked differences in indications and findings of endoscopy at the different icu's. these differences reflect an admission bias and differences in populations and treatment preferences. compared with cardiological and neurological icu's, substantially more endoscopies were performed at surgical and medical icu's. in a considerable number of cases, no source of upper gi blood loss could be found endoscopicaiiy. when upper gi blood loss was the icu admission diagnosis, the main cause was needing varices, which could be controlled endoscopically in the vast majority of cases. when upper gi blood loss was ndt the icu admission diagnosis, peigie ulcer and oesophagifis were the main causes of bleeding. because of the considerable number of coincidental almom~adities found at endoscopy, there is still room for debate whether antacid medication and/or motility stimulating agents should be given prophylactically at icu's. many studies have shown that blood lactate levels in survivors and nonsmvivors of traumatic and septic shock are significantly different. the degree of multiple organ failure is related to the duration of lactic acidosis ( ). the aim of this study was to evaluate blood lactate level as a prognostic marker of high risk postoperative patients who may benefit from invasive hemodynamic monitoring and aggressive fluids administration and early inotropic support based on oxygen transport parameters. methods: patients undergoing elective long term vascular and abdominal surgery (asa i-bi) were studied. blood lactate levels were measured after icu admission. in the case of blood lactate level above mmoltl, measurement was repeated every hours for hours or until normaiisation (blood lactate level less than mmol/ ). type of surgery, length of surgery, amount of fluids delivered intraoperatively and postoperatively, hemoglobin levels, hemodynamic variables, diuresis, postoperative complications, length of icu stay and clinical outcome were recorded. because no attempts were made to randomisr therapy or change our standard therapy protocol institutional approval was not required. rebuts: the frequency of postoperative complications was , % and mortafity was , % in a group of patients with blood lactate level less than , mmol/l (n = ). frequency of complications ( , %) was significantly increased in a group of patients with blood lactate levels , - mmol/l (n = ), mortality was , %. mortality ( %) and frequency of complications ( %) were significantly increased in a group of patients with blood lactate levels above mmol/l (n = ). conclusion: blood lactate levels can serve as early marker of high risk postoperalivr patients and may predict increased risk of postoperative complications mad ~e death. objective.~: investigated practicability and clinical value of the routine measurement of hepatic venous oxygen saturation (shvo ) after major liver surgery, as shvo is considered an indirect parameter for splanchthc and hepatic blood flow. methods: consecutive patients were included in this study after liver resections for primary or secondary liver tumors. patients suffered from liver cirrhosis (childs a). immediately after post-operative admission on the icu a pa-catheter ,was inserted under fluoroscopy via the right jugular internal vein into the hepatic vein contralateral to the resection area. hepatic venous and arterial blood samples were drawn every two hours. shvo was correlated to the clinical course, macro hemedynamics, abgs aug other established lab parameters. results: in out of attempts the catheter could be placed correctly. in four cases after right hemihepatectomy the left hepatic vein could not be intubated due to a dorso-lateral tilting of the left liver. this is also reflected in a significantly longer time of fluoroscopy for catheterization of the left hepatic vein ( . _+ % rain vs. . + . rain; p < . ). the procedure requires a total of between and minutes. relevant clinical complications were not observed except for short term supraventricular arrhythmias during passage of the catheter through the right atrium. hemodynamics and pulmonary function could be considered normal in all individuals at time of measurement. shvo showed a span from . % to . % with a mean of . % -+ . %. the following statistically significant findings could be obtained: (a) patients with liver cirrhosis showed a significantly lower shvq than patients without ( . % • . % vs. . % • . %; p < . ). (b) a negative correlation between shvo immediately after operation and the duration of intraoperative hepatic vascular occlusion could be observed (r = - . ; p < . ). this correlation could also be seen for the first post-operative hours (r = - . ; p < . ). (c) a negative correlation between shvo and the difference between arterial and hepatic venous lactate levels was found (r = - . ; p < . ). conclusions: the routine measurement of shvo appears to be a promising extension of post-operative monitoring after major liver surgery. it is a safe method easily feasible on any major surgical icu though relatively time consuming. a further validation of this method is necessary in larger studies. therapeutic recommendations on the basis of shvo findings cannot be given yet. methods: in cases after major liver resection, in which abnormally low readings of shvo suggested an impaired hepatic blood flow, pgi was applied at a dose rate of ng/kg/min. as shvo can be considered an indirect parameter for hepatic blood flow, the effect of pgi infusion on shvo was measured. moreover, the changes of macro hemodynamics and pulmonary function were monitored. results: before the application of pgi z mean shvo for all patients .was . % ( - - - ). in three cases without major structural alteration of the remaining liver tissue the continuous intravenous administration of pgi lead to a sustained increase of shvo z to an average of . % ( . - , ). the postoperative course in these three cases was uneventful. in two cases with compensated liver cirrhosis after hepatitis c no change in shvoz under pgi infusion could be observed. both patients died and days respectively after operation in protracted liver failure. side effects of pgi included a slight decrease of systemic and pulmonary vascular resistances. consequently map decreased by up to % as did intrapuimonary right-left shunt increase. in none of the observed patients did these side effects posed a limitation of continuous application of pgi z. conclusions: in patients without structural alteration of the liver the systemic application of prostacyclin at a dose rate of ng/kg/min could significantly increase an abnormally low hepatic venous oxygen saturation after major liver resections, tn two cases of severe liver cirrhosis a similar increase could not be observed. after first clinical investigations and with the results of recent studies in animal further controlled clinical studies of prostacyclin in the postoperative management after liver surgery appear justified. any delay in gastric emptying can promote micro-aspiration and give rise to ventilator associated nosoarnnial pneumonia. h -receptor antagonists have been suspected of promoting pneumonia by changing the gastric ph. in a few tri',ds on humans ranitidine was noted to delay gastric emptying. the aim of this prospective, randomised, blinded study was to evaluate in a ventilated icu population if there was a difference between cimetidine (c) and ranitidine (r) on the gastric filling index (gfi conclusion: in this population there was no difference in gfi between c and r; however the age and creatinine were significantly different and could have favoured the c group. also the very long t/ could have hidden smaller differences between c and r as has been described in volunteers. between april , and april , , patients with severe acute pancreatitis were admitted to participating hospitals. patients were entered into the study if severe acute pancreatitis was indicated, on admission, by multiple laboratory criteria (imrie score >_ ) and/or computed tomography criteria (balthazar grade d or e). patients were randomly assigned to receive standard treatment (control group) or standard treatment plus selective decontamination (norfloxacin, colistin, amphotericin; selective decontamination group). all patients received furl supportive treatment, and surveillance cultures were taken in both groups. results: fifty patients were assigned to the selective decontamination group and were assigned to the control group. there were deaths in the control group ( %), compared with deaths ( %) in the selective decontamination group. (adjusted for imrie score and balthazar grade: p = . ). this difference was mainly caused by a reduction of late mortality (> weeks) due to significant reduction of gram-negative panreatic infection (p = . ). the average number of laparotomies per patient was reduced in patients treated with selective decontamination (p < . ). failure of selective decontamination to prevent secondary gram-negative pancreatic infection with subsequent death was seen in only three patients ( %) and transient gramnegative pancreatic infection was seen in one ( %). in both groups of patients, all gram-negative aerobic pancreatic infection was preceded by colonization of the digestive tract by the same bacteria. reduction of gram-negative colonization of the digestive tract, preventing subsequent pancreatic infection by means of selective decontamination, significantly reduces morbidity and mortality in patients with severe acute necrotizing pancreatitis. ieco by sodium hypochlorite (nacio) infusion is considered to be a model of microsomal oxidation in liver on cytochrome p- . active c provides oxidation of toxic metabolic products in the blood and exfused during plasmapheresis plasma, and also hydrophobic to hydrofilic transformation of substanses. sterile nacio in necessery concentrations was obtained by electrolysis of saline ( , - , % naci solution) in electrochemical set e~io- (russin,moscow). methods: . the nacio in concentration ragfl ( - ml/ h ) was administred into central veins in patients with extensive peritonitis and endotoxicosis - /t. erytrocytes resistance to nacio, circulating blood volume glycemia and hemostasis were initially estimated. . after plasmapheresis exfused toxic plasma was mixed with nacio conccantration of i mg/t in : ratio in sterile "hemacons".the effectiveness of plasma detoxication and possibility of its reinfusion were evaluated by determination of albumin effective concentration (eca g/l), the concanlration of medium molecular oligopeptides (mm , ) and other biochemical tests (bilimbin, creatinine, carbomide and so on). results: . the intravenous administration of nac excels detoxicative effect of hemosortion by - % provides effictive presentation of protein components and blood cells and improves the transport function of albumin by %. . the return of exfused plasma after its purification ieco was - %. only the remaning - % of deficient plasma were compensated by fresh cryoplasma and albumin solutions. ischemic hepatitis (ih) is a severe complication in critically ill patients. acute circulatory failure of multiple etiology can lead to splachnic hypoperfusion and cause acute and reversible anoxic damage. over a period of mos pts, m and f, mean age + . yrs developed liver disease compatible with ih. eight pts had a documented hypotensive episode (six pts with septic shock and two hypovolemic shock), while cardiogenic pulmonary edema in the absence of hypotension was responsible for ih in the remaining four pts. all the pts had a rapid striking elevation of ast, &lt and ldh with equally rapid resolution of these parameters to near normal wimin days (mean . ). the mean peak level of ast, alt and ldh was iu/l (range to ), iu/l (range to ) and iu/l (range to ) respectively. serum total bilirubin levels rose transiently with a moan t:eak level of . mg/dl (range . to . ), while altered coagulation paran-,ete's (pt> . times normal) was observed in four pts and clinically significant coagulopathy with fibrin degradation products occurred in one pt ( . %). renal impairment (cr> . mg/dl) was manifest in all pts; six pts developed non-oliguric renal failure ( %) while two pts required hemodialysis. ten lots required vasoconstrictor inotropes [dobutamine (range - pg/kg/min) and dopamine (range - pg/kg/min), while replacement of circulatory blood volume was performed in two pts with hypovolemic shock. eight lots expired ( . %), but none died as a direct result of hepatic damage. the mortality rate was higher among pts with concurrent renal failure ( %). it is concluded that: ) ih is not uncommon complication in the icu with the prognosis depending on the underlying disease. ) clinically significant coagulopathy is uncommon complication of ih. ) titration of inotropes is required to obtain optimal cardiac output support and subsequently liver blood flow. it is difficult to ascertain the perfusion of free flaps such as jejunal loops after surgery. objectives: to assess ischaemia as evidenced by intramural ph of jejunal free flaps used for reconstructive surgery following total pharyngolaryngectomy. methods: the sigmoid ph tonometer ( tonometrics inc.,usa ) was used to monitor intramural ph of the jejunal free microvascular flaps ( phig ) in patients who underwent total pharyngolaryngectomy. a standard general anaesthetic was given and all patients were admitted to the icu for controlled ventilation and monitoring. all had similar postoperative care. phig was measured pre, post-revascularization of the flap and on icu admission, , and hours postrevascularization. objectives: to classificate the wide spectrum of itc of anp into distinct pathophysiological patterns according to presentation and course. patients (pts) and methods: pts, ~( , %), ( , %) were admitted in the icu because of anp and acute respiratory failure(arf), ilean age: , • years. hean stay in icu: , • days. pts were operated, of them twice. hean value of ranson's scale: , • ( - ). we analyzed hemodynamic measurements,arterial blood gases(abg), x-ray findings(xrf), ct-scans and operative records. results: patterns of pleuropulmonary complications were identified: a)early hypoxia without xrf - pts. b)early ards with typical xrf - pts( died), c)early arf with xrf(atelectasis,infiltrates)- pts( died). d)late ards with typical xrf- pts( died), e)pleural effusions in various combinations with the above patterns - pts. overall mortality rate: / = , %. conclusions: l)frequent x-rays and abg are important for the classification of itc of anp. )even though patterns of classification in anp are not clearly distinguishable,they facilitate an anticipatory management. )deterioration of abg and xrf indicates that preventive measures for arf must be intensified and agressive surgical therapy is required. )delay of surgical therapy is related to worse prognosis(p<o, ) and prolonged hospitalisation time(p<o,ol). in the contrary, the early timing of the operation before infection and extrapancreatic necrosis is essential for a better prognosis (p<o, ). objectives: the development of cholestasis during intensive care treatment is allied with an inferior prognosis. this study investigates the sensivity, specification and also the positive and negative forecast of patients survival -exemplary for bilirubine. methods: during a period of months all surgical patients on icu were registrated prospectively (n = ). for documentation of disease development a standard foldcrform based on a computer-data-system was used. the results of this kind of documentation showed aapprax. , m!ll. of single patient informatioas. results: of patients didn't suffer from liver disease or have any operation on liver or bile tract. of them have had a normal scale of bilimbine in the postoperative period, a higher scale of bilirabine was regisu'atcd by patients. at a ,,cut-off" of rag% (total-bilirubine) the sensitivity was , , specivity , , positive predicive level , , negative predictive level , for survival criteria of a patient. the max. reached level of bilirubine, also the daily increase turned out almost the same results as they were found for other parameters nf cholcstasis like ap or gamma-gt. objective: the aim of this experimental protocol was to evaluate the morphological and functional parameters of isolated pig liver grafts, perfused in an extracorporeal liver support system. methods: the system consists of the graft liver, a membrane oxygenator (oxygenation surface . cm z, flow= itlmin), a heater, a centrifuge pump and a fluid reservoir. twenty pig livers, mean weight gr (min , max gr) were obtained and after a mean cold ischemia time of min were perfused fo} a mean of . h (min . , max h). perfusion solution consisted of r/l and hemacell. inflow to the graft liver was performed through the portal vein at a mean pressure of ( - ) mmhg at ~ while outflow was secured through the suprahepatic inferior vena cava. during perfusion the following parameters were evaluated through pre-and posthepatic hourly (to-t ) sampling: po , " + + " pco , ph, hco -, na , k , ca , osmolality, glucose, lactate, ast, alt, alp, u bilirubin and coagulation factors i, v and viii. biopsies were obtained periodicallty. b_p_~: results were as follows: mean ph fell from . at t o to . at t while mean output po fell from at t o to at t . mean output ast values increased from at t o to > at t while mean output alp values increased from . at t o to at t . mean output k + values increased from . at t o to > at t . histology revealed lesions of ischemic necrosis, more prominent after t . conclusion: results show that the isolated liver graft presents satisfactory function and morphology at least for a five hour perfusion period in the described extracorporeal circuit. correction of ph contributed to an increase in bile flow. between and the practice of transplantation has changed drasticaily in switzerland -besides kidneys also hearts, heart and lung, lung, iiver and pancreas transplantation has started in several centers. major information efforts have been made, organ exchange rules were set up and a national coordination center was initiated. the aim of this retrospective single center study was to assess the influence of transplantation on organ donation. in the past eleven years organs were donated from potential donors i single, multi organ donations) analysis of refusal was evaluated categorized into medical and/or familiar reasons. the number of potential donors increased from ( ) ,to ( ) with a concomitant drastic reduction of donations from % in to % in ; amounting to a net unchanged number of donations over the last years ( = ; = ) . the import and export of donor organs was balanced since the introduction of the national coordination center. in contrast multi organ donation increased from % in to % in despite of the more stringeant selection criteria, in conc]usion the introduction of a full range of transplantation procedures at several new university programs and the increase of multi organ donation has not had the forecasted impact on organ donation despite a sustained informative and promotional campaign, objective: monitoring hepatic venous oxygen saturation (svho ) provides online information about hepatic-splanchnic oxygen supply-demand ratio [ ]. previously, x~ reported hepatic venous catheterization in patients undergoing orthotopic liver traru~lantation (olt) [ ] . in the present study, we assessed the effects of nitroglycerin (ng), a vasudilator that affects the venous capacitance vessels more than arterial vessels and prostaeyclin (pgi , flolan r~, wellcome, uk), an arterial and splanchnic vasodilator on hemodynamies and hepatic venous oxygen saturation (svho ) in human liver transplantation. methods: with institutional approval and informed consent, consecutive patients, mean age - -_ years, were studied following olt. postoperatively, fiberoptic pulmonary artery catheter was inserted into the right hepatic vein. timed infusions of ng at a rate of . gg/kg/min and pgi at ng/kg/min were initiated for a rain period. each sequence was followed by baseline therapy for rain. results are expressed as mean=tsd. statistical analysis was performed using friedman's-two-way-anova-test, significance was accepted at p< , . results: ng at . gg/kg/min induced a decrease of mean arterial pressure (map) ( _ [baseline] vs. + mmhg) and pulmonary artery wedge pressure (pcwp) ( j: [baseline] vs. : mmhg). cardiac index (ci) ( - vs. + l/rain/m ), oxygen delivery index (do i) ( -+ vs. + mgnfin) and svho ( _~ vs. -l-_ %) were decreased (p< . ). pgi at ng/kg/min induced a reduction in map ( • nm~. _g) and pcwp ( + mmhg). ci ( _+ l/rain/m ), do i ( : ml/min) and svhoz ( + %) were increased (!o< . ). vasedilatation induced by ng decreased systemic oxygen supply and impaired splanclmie oxygenation. pgi increased systemic oxygen delivery in parallel with svho , suggesting a corresponding improvement of hepatic-splanchnic okygenation. thus, if vasedilator therapy is indicated in th orient receiving liver grafting, pgi appears to be advantageous. however, due to its platelct aggregation inhibiting properties, the usefulness and safety of pgi in olt patients has still to be determined. objectives: to analyze the effect of steroid treatment given to donor on the early function of transplanted kidney. methods: from january, until now donors were involved into this prospective study. every other donor was treated with mg/kg solu-medrol one hour before organ retrieval. according to the steroid treatment of the donor the recipients were divided into two groups: group -steroid pretreatment goup (y~= ), and group -control group (n= ). the donors and the recipients were treated using the same kidney transplantation protocol onl~r the adults, and the first cadaver kidney transplanted patients were involved into the study. the daily routine parameters were analyzed pre-and intraoperafive, and on the - th, th and th postoperative days. results: we could not show any clinically important differences between the two groups in respect of donor parameters. preoperative, the patients in group had slightly lower ereatinin level ( -+ g.,non vs. -+ gmol/ ) which persisted into the early postoperative phase. the values of the other examined pre-and intmoperativc parameters were almost the same. during the first postoperative days the patients in group i needed less diuretics (furosemide and renal dose of dopamine) and their sodium excretion was closer to the physiological range than in group . the other parameters did not differ significantly. the less furosemide need in group ! pe~isted to the end of the first month. conclusions: according to our data the steroid treatment of the donors improves the early function of the transplanted kidney in some respects. to prove the real benefit of the donor steroid treatment needs more data and further analysis. objectives: severe infections may compromize the outcome of liver transplantation..determination of new parameters may increase the knowledge of pathophysiologic mechanisms and may lead to changes in postoperative therapeutic management of patients at risk. methods: between august and september , patients with transplants were monitored for cytokines and extracellular matrix pammeters on a daily basis. serious infections (n= ) included microbiologic evidence and more than secondary organ failures. patients with cholangitis (n=ll) or uneventful postoperative course (n= ) referred as control groups. results: -year patient survival was . % ( / ): patients died due to serious infections, while died for other reasons. mean bilimbin, stnf-rii-, ifn- -, il- -, il- -, il- -, laminin-and neopterin levels were significantly elevated in patients with serious infections compared with patients experiencing mild cholangitis or with an uneventful postoperative course. a further increase of all parameters was observed in patients who subsequently died; tnf-ri/: _+ pg/ml vs • pg/ml; ifn- : _+ pg/ml vs . -+ . pg/ml; il- : -+ pg/ml vs -+ pg/ml; il- : -+ pg/ml vs _+ pg/ml; il- : _+ pg/ml vs • pg/ml; laminin: -+ ng/ml vs -+ ng/ml; neopterin: _+ nmol/ vs _+ nmolb for non surviving vs-surviving patients. a significant decrease of sialic acid yeas observed in patients with serious infections; and a further decrease occurred in patients who subsequently died: -+ mg/l vs • mg/ . conclusions: the increase or decrease of various cytokines and extracellular matrix parameters may be indicative for severity of infectiolx routine monitoring of these parameters may improve current diagnostic tools and poss~ly lead to changes in therapeutic management of patients at ~k. objectives: evaluation of the cytokine network after liver transplantation may give some insight in pathophysiologic mechanisms of rejection and may lead to detection of patients at high risk. methods: patients with transplants were monitored for various cytokines on a daily basis between august and september . rejection was assessed by histology in combination with clinical signs of rejection and laboratory investigations. results: during the first postoperative month, patients ( . %) developed rejection; patients were successfully treated with methylprednisolone (steroid-sensible rejection), while further patients required additional treatment with fk or okt (steroid-resistant rejection). patients subsequently developed chronic rejection. mean levels of various cytokines and extracellular matrix parameters including tnf-rii, ifn- , il-ib, il- r, il- , il- , il- , hyaluronic acid and neopterin were significantly higher in patients with steroid-resistant than in patients with steroid-sensible rejection. a further increase of some parameters was observed in patients who subsequently developed chronic rejection; bilirubin: . -+ . mg/dl vs . -+ . rag/all; tnf-rii: -+ pg/ml vs _+ pg/ml; il- : +- pg/ml vs -+ pg/ml; neopterin _+ nmol/ vs -+ nmol/ ; hyaluronic acid: _+ ~tg/l vs _+ ~tg/l for patients with chronic versus patients with acute steroid-resistant ~ejection. sialic acid levels decreased in patients with acute steroidresistant rejection; and a further decrease was observed in patients who tieveloped chronic rejection: _+ mg/l vs _+ mg/ . ~onclusions: various cytokines and extraeeuular matrix parameters were indicative of severity of rejction. the extensive increase of bilirubin, tnf-ii, il- , hyaluronic acid and neopterin may indicate subsequent chronic ection. monitoring of these parameters may, therefore, lead to changes in immunologic management after liver transplantation. background : combined kidney and pancreatic transplantation is being performed with increasing frequency in patients with diabetes mellitus and renal failure, as it offers more chances of success and better results than kidney transplantation alone. mycotic arterial aneurysm constitutes a devastating complication following pancreatic transplantation. all cases of mycotic arterial aneurysms have been however reported with exocrine pancreatic drainage into the gastrointestinal tract. intervention : we describe a series of consecutive whole kidney-pancreas transplantation performed at the university of geneva hospitals ( beds) between december and may . exocrine pancreatic drainage into the bladder (epdb) was performed to improve early detection of rejection episodes. epdb was hypothesized to reduce the risk of contamination from the gastrointestinal tract and the subsequent possible occurrence of potentially fatal infectious complication. in all patients the dual transplantation was performed through a median incision according to the procedure described by nghiem. results : two out of the patients who received kidney-pancreatic transplant developed arterial mycotic aneurysms and days following surgery. aneurysms developed at the site of the arterial anastomosis used to rearterialize the homograft. both patients had peritonitis caused by candida albicans requiring surgical drainage and intravenous antifungal therapy. rupture with hemorragic shock occured in both patients leading to graft removal in one patient, and three episodes of lffetreateniug hemorragic shock followed by graft failure and removal days after transplantation in the other. conclusion : arterial mycotic aneurysm constitutes an early, lifetreatening complication of kidney-pancreatic transplantation; it mandates graft removal. although exocrine pancreatic drainage into the bladder consitutes a definitive advantage for caller diagnosis of graft rejection, it does not eliminate the risk for retrograde colonization and subsequent severe infection in our experience. s. bocharov, i. teterina, regional clinical hospital, irkutsk, russia acute profound loss of blood can result from the very different injuries and hepato-pancreato-duodenai operations enter such a rank. ill-timed and inadeguate correction of operation hemorrage is one of the reasons for postoperation complications, including polyorganic insufficiency. the pathogenesis seems to be very complex. in early stages of bleeding the liquid enters the vessel bed, followed by hypoproteinosis and hematocrit fall. however, as decompensation develops, the fluid leaves the vessel system in the result of increasing postcapillary resistance and lowering col-ioidnooncotic blood pressure (cop). the resulting hypovolemia causes primarily acute disturbance of central hemodynamics and then of microcirculations and transcapillary exchange. central hemodynamic failure after acute loss of blood manifests itself through cardiac output lowering and capillary blood flow deceleration. taking into consideration, that % is critical value for cpv loss and for cev it is %, we consider arising the level of cop to the immediate task. cop raising allows to normalize transcapillary exchange, which we assess through cop and mcp (mean capilary pressure) gradient. the next task is to make up for globular volume till homeostasis providing level. considerable attention is given to catabolism inhibition and maximum possible enegry provision. control over high proteolitic activity of blood and callicreinkinin system activity implies direct proteases inhibitors. reologic, membrane stabilizing, antihypoxanthine and anticoagulant therapies are obligatory. virehow clinic, dept. of surgery, humboldt university berlin, germany regarding a high mortality up to % of fulminant hepatic failure orthotopic liver transplantation seems to be the only promising therapeutic approach in many cases. this study shows experiences from a transplantation center. between june and april patients suffering fulminant hepatic failure were admitted to our surgical intensive care unit all patients showed severe liver dysfunction with grade ii to iv encephalopathy. after a period of diagnostics and conservative treatment ranging from few hours to days (mean . days) we reported of these patients as possible organ recipients to eurotransplant. all of these patients were transplanted within hours, ( %) of them even within hours. the principal aetiologies were hepatitis b ( ), hepatitis c ( ), nanb hepatitis ( ), mushroom poisoning (amanita phalloides ). after transplantation patients suffered from initial-non-function and underwent re-transplantation. the one-year-survival rate was %, patients died within months after transplantation due to various reasons. patients were not referred for liver transplantation. of them never met transplantation criteria, improved by conventional therapy and could finally be discharged from hospital. the known reasons for liver failure in this group were mushroom poisoning ( ), paracetamol intoxication ( ) and fulminant hepatitis a ( ). patients suffering from fulminant hepatitis ( ) or intoxication ( ) were excluded from emergency liver transplantation for various contraindications. of these patients ( %) died despite conventional intensive care. we don't know if some of the patients in the transplantation group would have survived without transplantation, because whenever we decided on transplantation we could perform the operation within hours. but the good survival rate in the transplantation group ( %) the % recovery rate in the group, where there was no transplant-indication in our opinion and the fatal outcome ( % mortality) in patients with contraindications are an encouraging proof of a successful therapeutic strategy in acute liver failure. these results are based on a close cooperation between experienced transplant surgeons, hepatologists and intensive care doctors, using sophisticated laboratory and imaging techniques in a specialized center. introduction: during brain death patients suffer from multiple endocrinologic disturbances. one of the most important are those related with thyroidal axis. it is well described the euthyroid sick syndrome whose more frequent pattern consist of decreased triiodothyronine (t ), increased reverse t (rt ) with normal levels of tetraiodothyronine ( " ) and tsh, this lacking in " " levels lead to a change from aerobic to anaerobic metabolism which results in tissular damage. objective: .to study thyroidal pattern in brain death patients potential organ donors. .to avoid organ impairment by administration of t . .to study the hemodynamic and hormonal changes after the administration of t in these patients. material and methods:population: brain death patients of any etiology potential organ donors admitted to the intensive care unit. patients were classified in hemodynamically stable (group ) and unstable (group ). group received a bolus of . p.gr/kg. and a perfusion at a dose of - . p.gr]h of t . hormonal assays: total t (tt ), total " (tt ), tsh. fxee t (ft ), free " (ft ) and rt were determine at the moment of clinical brain death ( hrs) and in group two these assays were repeted at hours , and . results: patients ( male) with a mean age of years (range to yrs.) were studied. the clinical brain death was confirm later with other explorations (eeg, doppler). there were patients in group ( , %) and patients in group ( , %). hormonal pattern: at the moment of brain death tt was normal in cases ( , %) and decreased in i ( , %); tt was normal in patients ( , %) and decreased in ( , %); ft was normal in cases (i , %), decreased in ( , %); fl' was normal in patients ( , %) , decreased in ( , %) .rt was normal in cases ( , %) and increased in cases ( , %). there were no statistically significant differences in hormonal pattern between the two groups. only t levels at hours , and were significant in group . in the cases with ft decreased, the tt was normal in ( %) and decreased in ( %), tt was decreased in ( , %) and normal in ( , %), tsh was decreased in i ( , %), normal in ( , %) and increased in i( , %) and ft decreased in ( , %) and normal in ( , %) and rt was normal in ( , %) and increased in ( , %). there were no statistically significant differences in cardiac index, vascular resistances and pulmonary shunt before and after the administration ef t . conclusions: . the hormonal pattern most often find in brain death patients was: normal tt , decreased tt , normal tsh, decreased ft , normal fr and normal rt . . there were discrepancies in the values of ft and tt . there were no statistically significant differences in hemodynamic and pulmonary parameters. objectives: magnetic resonance angiographie (mra), a non-invasive procedure, provides flow-related information additionly to the anatomy of the vascular system. measurement of signal intensity and edge detection of vessel structures permits to calculate blood flow velocity and vascular diameters. we examined whether cerebral hemodynamic changes by altering the arterial pressure of carbon dioxid (pace ) could be detected by mra. methods: following institutional approval and informed consent, mechanically ventilated patients without elevated intracraltial pressure underwent mra with defined periods of hyper-, hypo-and normoventilation (pace : , , mmhg; arterial blood gas probes; avl). mra was performed with a . tesla magnetom (vision, siemens). two different mra techniques were used: a conventional time-of-flight- d-angiography (tr: ms; te: ms; fl: deg; slab: mm) for vessel diameter detection and a flash- d-gradient-echo-sequence (tr: ms; te: ms; fl: dog) for measurements of blood flow velocity. an axial view parallel to the ac-pc-iine (anteriorposterior-commissur-line) was used for repeated imaging of identical regions of interest toi) of the proximal part of the internal carotid (ica) and middle cerebral artery (mca) as well as of peripheral branches of the mca and the posterior cerebral artery (pca). results: changes of pace correlated with changing signal intensities, whereby under hyperventilation a decrease of , % (p . ) and under hypoventilation an increase of . % (p . ) was observed compared with normoventilation. blood pressures were stable throughout the whole study period, pace dependent changes in vessel diameters were more pronounced in peripheral branches of mca and pca. a change from normo-to hyperventilation produced a decrease in proximal vessel diameter of - . % (p _< . ) and in peripheral diameter of - . % (p _< , ). a change from normo-to hypoventilation produced an increase in proximal diameter of + . % (p < . ) and of + . % (p -< . ) in peripheral diameter. conclusions: pace related changes of cerebral vessel diameter can be easily detected by mra without injecting a contrast agent. the results confirm that co -reactivity is more pronounced in peripheral cerebral vessels, which are subjected to greater changes in diameter than major basal arteries. hyperventilation leads to a decrease and hypoventilation to an increase in signal intensity thus reflecting the corresponding changes in blood flow velocity, intensive care unit (icu) of "kat" hospital, athens, greece, ob!ective$; the value of bronchoscopy in pulmonary atelectasis of icu patients is under question the presence of an air bronchogram sign in xrays, which is considered as evidence of central bronchus patency, is referred in several studies as a negative criterion for bronchoscopy, whereas its absence as a positive one. it is also referred that air bronchogram sign correlates with delayed resolution of atelectasis, probably because of obstruction of many periferal airways (not central). the purpose of this prospective study was the evaluation of the air bronchogram sign on frontal chest film as a negative criterion for bronchoscopy and as criterion of delayed resolution of atetectasis, methods: icu patients with atelectasis were studied prospectively. they underwent bronchoscopy, bronchoscopic findings, presense of air bronchogram sign, and outcome of atelectasis were recorded, correlations were made, between: ) bronchoscopic potency of airways and air bronchogram sign } resolution time of atelectasis and broncoscopic potency of airways. ) resolution time'of atelectasis and air bronchogram sign, methods of statistical analysis were the t-student test and the chi square test, results:the patients were , men women , seventeen patients had atelectasis of whole lung, of upper lobe, and of lower lobe. ten patients had atelectasis in right and in left lung. eight from patients had air bronchogram sign in x-ray, there was no statistical correlation between air bronchogram sign and bronchoscopic potency of airways [ from patients with air bronchogram sign ( %) and from without air bronchogram sign ( %), had bronchoscopic potency of airways, p> . ], resolution time of atelectasis didn't correlate statistically with bronchoscopic potency of airways (mean resolution time in patients with bronchoscopic potency , days and in bronchoscopically closed bronchi , days, p> , ). there was also not a statistical correlation between resolution time of atelectasis and air bronchogram sign (mean resolution time in patients with air bronchogram sign , days, and without air bronchogram sign , days. p> ). conclusion~i; the presense of an air bronchogram sign in x-ray of icu patients with atelectasis, does not coexist obligatorily with bronchoscopic patency of airways and cannot be used as a negative criterion for bronchoscopy, neither as a criterion of delayed resolution of atelectasis. th. wertgen chest sonography (cs) is routinely used in our department to examine icu patients with clinical symptoms of pulmonary embolism, pneumonia, pleural effusion or unclear chest pain. we perform cs with a sector transducer ( . mhz) and a linear transducer ( . mhz) using acuson xp/ c. the sonographic signs of pulmonary embolism and infarction are most well demarcated, mainly wedge shaped and triangular pleural based lesions, more roughly structured, observed with a hyperechoic reflex in the center corresponding to the bronchitic (fig. ) . pneumonia is characterized by homogenously hypoechoic, wedge shaped parenchymal lesions, containing air or fluid bronchograms; they move with respiration (fig. ) . pleural effusions are spaces of various echogenicities, from anechoic to homogeneously echogenic, which may contain floating strands or complex septa, located between visceral and parietal pleuras (fig. ) . from march to april we did examinations by cs in icu patients ( male, female; age from - ). patients examinations pulmonary embolism pneumonia pleural effusion us-guided thoracic punctions were performed in patients. in two patients we found pneumonia or pleural effusion caused by a lung carcinoma. another two patients showed a normal cs (diagnosis: inflammation of the gall bladder, inflammation of the myocardium). conclusion: cs is a very useful method for icu patients with chest diseases. it takes less time and is less expensive than ctand sometimes of a higher diagnostic value than x-ray. last but not least cs is invaluable for the icu patient, because the examination is done save and quickly at bed side and the results of cs are very helpful in diagnoses and treatment. results : inter-observer reliability was evaluated as an % concordance. results of the tee classification were : class : n = ( %) ; class : n = ( %) ; class : n = ( %) ; class : n = ( %) class : n = ( %). therapeutic implications of tee in class patients were : cardiac surgery in patients (two cases of acute mitral regurgitation, two valvular abscesses and one hematoma compressing the left atrium), discontinuation of peep in one ventilated patient with an atrial septal defect, weaning of mechanical ventilation in one patient with an atrial septal defect, prescription of antimicrobial therapy in patients with endocarditis and prescription of anticoagulant therapy in patients with left atrial thrombus. the only noteworthy complication was a case of spontaneously resolving supraventrieular tachycardia. conclusion : tee is safe and well tolerated, and is useful in the management of icu patients with shock, unexplained and severe hypoxemia or suspected endecarditis. the aim of this study was to determine whether ultrasound guidance can help interns to improve the results of jugular vein access in icu. methods : in a prospective and randomized study, we compared, in patients admitted to the icu, an ultrasound-guided method (ultrasound group : patients) with an external landmark guided technique (control group : patients). all jugular vein accesses were performed by young interns with an experience of < procedures. results : internal jugular cannulatian vein was aci~ieved in all patients in the ultrasound group and in patients ( p.cent) in the control group (p < . ). average access time was longer in the control group ( • sec. vs • see. ; p = . ) and puncture of the carotid artery occurred in patients in each group (p = . ). patients ( p.cent) in the ultrasound group and patients ( p.cent) ia the control group (p < . ) were cannulated in rain. or less. the cannula was therefore unabie to be inserted within minutes in patients in the control group, with failure of eannulation in of these patients ( p.cent). failure was due to thrombosis (n = ), small calibre of the internal jugular vein (< ram) (n = ), abnormal vascular relations (n = ) or cervical irridation (n = ). among the primary failures of cannulation, an internal jugular vein catheter was able to be inserted in cases by an experienced physician on the side initially selected and with ultrasound guidance in cases. the catheter was inserted into the contralateral internal jugular vein under ultrasound guidance in the remaining cases. jugular cannulation was obtained at the first attempt in p.cent in the control group and p.cent in the ultrasound group. conclusion : ultrasound guidance improved the success rate of jugular vein cannulation by inexperienced operators in icu patients. when the internal jugular vein has not been successfully eannulated within minutes by the external landmark guided technique, the authors recommend the use of the ultrasound guidance. in the majority of cases right atrial or ventricular thrombi represent pulmonary emboli in transit. these may be fatal in patients (pts) treated conservatively with anticoagulation only. in literature the incidence of right heart thrombi in pts with proven pulmonary embolism (pe) is said to be in the range of - %. extremely mobile, long, worm-shaped masses in the right heart cavities carry an especially high early thrombus-related mortality rate which ranges from - %. current therapeutic strategies favour fibrinolytic therapy with consecutive anticoagulation. we report five cases ( male, i female, - years) of right heart and pulmonary thromboembolism. in these pts diagnosis and regression of thromboemboli following systemic intravenous lysis therapy with recombinant tissue-type plasminogen activator (rt-pa) was documented by transesophageal echocardiography (tee). a submassive pe occured in pts, a massive pe in pts. one patient (pt) had a cardiac arrest. in all cases tee clearly identified the extensive thrombns formation in the right-sided cavities of the heart and in the central pulmonary artery in cases. all pts were treated with mg rt-pa, pts in a front-loaded regimen over minutes, pt over minutes, and, due to the life threatening situation, in one case a bolus injection as ultima ratio was performed with no intracerebral bleeding complication. regression of thromboembolic masses after fibrinolytic therapy was demonstrated by transthoracic and transesophageal echocardingraphy after to hours. all pts survived and were put on coumadine, pt developed an intracerebral bleeding with persistent hemiplegia. conclusions: the use of thrombolytic therapy is highly efficacious for the therapy of pts with pe and concomitant right or ventricular thrombus formation. transthoracic and especially transesophageal echocardiography are powerful bed-side diagnostic tools for the immediate diagnosis and follow-up of successful treatment in this life-threatening condition. although widely used, catheterisation of the femoral vein in the groin using "landmark" technique is frequently complicated by accidental arterial puncture. suboptimal hygiene and patient discomfort are also associated with this technique. with regard to these last two factors cannulation of the femoral vein - cm below the inguinal ligament would seem an attractive alternative. as "landmark" technique is not possible for the cannulation of the femoral vein in this part of the thigh, ultrasound was used to locate the vessel and the results of this technique were evaluated. methods: a portable compact ultrasound device (site rite,dymax corp.) featuring a . mhz transducer (ultrasound depth - cm) fitted with a needle guide and a cm screen was used by residents with no previous experience in ultrasound guided cannulation. patients consisted of a surgical icu population. results: in patients catheters were introduced.in cases more than one ( - ) attempt was made and in patients the procedure was unsuccesfull due to the fact that the vessel was situated out of reach of the ultrasound (vessel depth > - cm), during the procedures one accidental arterial punction was registered. the catheters remained in situ for a mean of days (range - ) and were used for volume suppletion, medication, parenteral nutrition and haemodialysis.co-ionisation rates compared to those of subclavian catheters in our icu. in the first patients cases of asymptomatic thrombosis of the femoral vein were seer on ct-scans performed for other indications, in the following patients duplex scanning performed after removal of the catheter yielded another cases of asymptomatic femoral vein thrombosis. conclusions: ultrasound guided femoral vein catheterisation - cm below the inguinal ligament is a safe and simple technique that can easily be performed by residents without prior experience. the incidence and impact of thrombo-embolic complications associated with this technique are still subject to further investigation. objectives: to estimate the cost of antibiotherapy (ab-cost) in a multidisciplinary -bed greek icu and to correlate ab-cost with total cost of drugs and consumables and with patient's outcome, severity of illness and type of admission. methods: prospective data from consecutive patients admitted to the icu from / / to / / were studied. a tick chart was designed to record all drugs, materials and consumables regularly used for icu patients, but did not include low price drugs and consumables, which are provided from hospital's pharmacy as stock and were included in a fixed icu cost calculated for a month period. the chart also contained demographic details and data necessary for the calculation of several illness severity scoring systems. obiectives: over years evaluate the necessary efforts and expenses to implement a cis in the routine of a -bed stcu. methods: in june a commercially available, unix-based cis was installed on a -bed surgical icu. the goal was a paperless documentation at the bedside. after more than years clinical experience two aspects were investigated: what effort is necessary to install and support a cis, and what is the benefit for patients and personnel on the icu? results: the installation and support of a full-fledged cis requires a considerable effort: (a) the conceptual framework for the cis has to be defined. this includes the definition of documentation standards, as well as nursing and therapeutic standards, which is the essential basis for the configuration of any cis. (b) configuring a cis, i.e. "fine-tuning" it to the user's specific needs, is always a laborious task. moreover, constant maintenance is necessary. these tasks require the following personnel: experienced health care professionals for defining the conceptual framework, - trained health care professionals for configuration, system administrator. on a single icu ( - beds) these are not considered full-time jobs. (c) training is best done employing the "train-the-trainers" approach. (d) beside the necessary amount of man power and money to install and purchase a cis, administrative and mis support is needed, especially when interfaces to the hospital and laboratory information systems have to be set up. in general, a cis needs the commitment of all people involved. without a really professional approach with a longterm goal any major cis can turn into an unnecessary but inevitable night mare. after years clinical use and a thorough implementation of a cis on a major sicu it can be said that full-fledged cis offers an opportunity to dramatically improve the working environment on an icu. moreover, it adds to patient safety, quality of care and cost efficiency in one of the most advanced and expensive areas of medicine. conclusion: a major investment in man power and money is necessary to install and maintain a full-fledged cis. a sincere professional commitment to the goals of a cis is necessary. in exchange, a well configured and well maintained cis dramatically improves the quality of therapy and care on the icu. even return of investment and financial profitability of a cis seem feasible todayl from the clinical perspective it appears that the users themselves are the central determinant whether a cis makes a dream come tree or turns into a night mare. objectives: to establish a relationship between the activities of the staff and the occurrence of auditory alarms on the i. c.u. ard to evaluate confusion between auditory alarms. methods: laboratory based studies which investigated aspects of confusion between alarms in current use on the i. c. u. the observational studies were conducted over an month period and examined the frequency and duration of alarms together with the concurrent activites being undertaken by staff on the unit. the laboratory based studies showed that there were enduring confusions between the alarms on various items of medical equipment, for example a ventilator alarm and an e. c. g. monitor alarm. the results of the observation studies demonstrated that alarms are activated when specific activities are being undertaken by staff. sounds could be used in future recommendations for alarms on medical equipment. suggestions are also discussed for improving and rationalising auditory warnings in the i. c. u. obiectives: we investigated inferior petrosal sinus (ips), the lowest affluent to jugular bulb (jb), as a possible source of contamination of samples in jb for monitoring oxyhemogiobin saturation (sjbo ). pulling back the catheter the oxyhemoglobin saturation usually rises indicating extracerebral contamination (jakobs en met al: j cereb blood flow metab ; : ). methods: the study was carried out on patients undergoing ips sampling to differentiate cushing disease from ectopic acth syndrome and to lateralize any resulting pituitary lesion. we studied the value of oxyhemogiobkn saturation high in jb (sjbo ), at ips (sipso ) and at mid jugular vein ( th cervical vertebra) (smj ) bilaterally. results: we found significant differences between right sjbo and both right sipso (p= . ) and right smjo ( p= , ) and between left sjbo and both left sipso (p= . ) and left smjo (p= . ) we did not fred any difference bilaterally. objectives: we studied various methods of receiving and editing of clinical datas in critically ill patients (different ethiology). patients were investigated in regional intensive care center. methods : the following datas were studied : anamnesis, status praesens objectivus ( organs and systems ) ,. clinical and biochemical markers of critical condition , datas of eeg ,rheography . the medical information complex contained : channel electroencephalograph, -channel roencephalograph, ad-converter ( analog inputs, bit resolution, k hz), ibm dx , software includes set of routines for spectral eeg analysis, eeg-mapping, correlative analysis, and brain bloodstream reg-monitoring (written in turbo pascal . ), expert programs for estimation objective and humoral patient status (written in clipper . ) and statistics. there were used following programme-language instruments : borland c++ . , nantucket clipper . , ca-clipper tools ii. as the methods of statistical processing of dates were used: t-students criterion , fisher criterion, methods of correlation analisis, calculation of the regression levels, dispersion analysis, results : there was created the optimal structure of hard and sofware complex of search steady objective regularity in dynamic of critically ill patients condition. conclusion : the created system allowed to value effectiveness of intensive care and give us new opportunities in study pathogenesis of systems disorders in critical condition . over a five year period a patient data management system has been installed which allows individualised patient data to be accurately collected. using this data a costing system has been developed which ascribes costs thus: . direct costs -drugs, fluids, consumables, interventions. these are ascribed to individual patients, according to data collected from the pdms. . indirect costs -energy, depreciation, admm costs, maintenance etc. these are summed for the year and ascribed as an overhead per patient day. n.b staffcusts contain art element of both cost types the aim is to make as many costs as possibie 'direct', hence 'activity costs' have been calculated winch comprise staff time, drugs and consumables -these are direct costs. these costs of patient care are then searnlessly integrated into the financial and budget management of the icu environment. it was found that by calculating costs in this manner % of the total cost of icu are captured within the 'direct' element, and so are able to be ascribed to individual patients. this is much more accurate than simply dividing the total costs of ~cu by the number of patient days. temporal costs (variations during patient stay) and cross sectional costs (cost differences between admitting specialities) were also noted with interest. results of the initial analysis of data captured by the system will be presented. little is known about the resource costs (not simply cash costs) of icu. even less is known about individual patient costs, with previous estimates of these costs varying widely. however, if cost effectiveness studies are to be undertaken accurate calculation of individual, group and total icu cost is an essential, prerequisite, which, via this system of costing, is now achievable. information about intensive care of cancer patients is limited in the literature, despite the increasing use of such facilities in oncology over the two last decades. in order to determine if and how critical care facilities can be used specifically for these patients, we performed a world-wide inquiry in anticancer centers selecting the hospitals by using the international directory of cancer institutes and organizations. we mailed a questionnaire to centers and we received responses ( . %). there was at least one uncological (i.e. with > % of cancer patients) icu in (% % an -year old woman with graves disease presents with sore throat, vomiting, diarrhea, sinus tachycardia at /minute and a temperature of ~ several weeks before, treatment with propylthiouraeil had been stopped (rash and fever) and replaced by methimazole and ledide prior to a minor surgery. however, both drugs were discontinued by the patient two weeks before admission. shortly after arrival in hospital, patient's condition progressed to respiratory failure (upper airway edema), delirium and shock requiring icu admission, intubation and resuscitation with fluids and vasopressors. white blood count was /mm ~ with neutrophils. patient's hemodynamic data showed initial hyperdynamic profile followed by low output state with decreased sv ( %) (n - %) and cardiac index ( , ) (n , - ). echocardiogram confirmed cardiac chambers dilation as previously described in thyroid storm. lithium carbonate, corticosteroids, antibiotics and beta-blocker perfusion were given. plasmapheresis was started. free t& (n= , - pmo/l) went from , to , after the first two pheresis. after a remarkable clinical recovery, sub-total thyroideetomy was done i days after admission. in life-threatening thyroid storm, plasmapheresis is a very effective therapy when anti-thyroid drugs are counterindicated. purpose: to compare the reliability of prognostic indexes in crhically iu patients admitted in an intesive care unit (icu) who had acute renal failure (arfi and were treated with different dialytic techniques. material and methods: patients were included in a prospective study from june to november . patients presented arf defined by creatinin serum leve(s greater than pmol/l and previous normal levels. patients were divided in three groups. group i (control) : patients with arf who did not receive substitutive techniques. group ih patients under intermittent hemodialysis (hd) or peritoneal dialysis (pd). group ii : patients under continuous hemodiafiltrstion (hf). the statistical analysis was chi-square test and analysis of variance. results: the table shows the results we obtained, we did not find any significant difference betwen the two groups of patients undergoing dialysis. d(fferences were observed only between group i and the other groups as shown below. we did not find any significant association between the theoretical mortality predicted and the observed mortality according to saps in the three groups. due to exposure to a wide variety of unpleasant stimuli, for example, tracheal suctioning, venipuneture and physiotherapy, most pataents admitted to the icu will require some form of sedation. this review will describe the suggested properties of an ideal sedative agent for use in the icu and review the current limitations of some of the available agents from this perspactive. methods used to quantify the level of sedation, such as the ramsay score, glasgow coma score, newcastle sedation score and visual analogue scores, and their deficiencies will be examined. consideration will be given to defining the optimal level of sedation and the circumstances under which sedation might be varied over the icu course will be discussed. preliminary results from an ongoing study examining the role of light versus heavy sedation and ischaemia in a cardiac surgical icu population will be presented. the pharmacceconomics of icu sedation will be briefly addressed. finally, the role that sedation may play in increasing morbidity, pastieuiarly nosocomial pneumonia, in the icu will be discussed. objectives : therapy cost(tc) in icu patients is a substantial component of total hospital care cost. estimation of tc during this year, partitioning to various groups of drugs used and attempt to minimise it, were considered practically useful. methods : in collaboration with the hospital pharmacy we were able to have a complete report of au drugs used for icu patients (including enteral and parenteral nutrition). mean apache ii severity score upon admission was . and mean length of tcu stay was . days. price per drug unit and cost per group of drugs were also available drugs were divided into two groups: antibiotics ( ) cardiovascular drugs ( ), gastrointestinal system drugs ( ), enteral and parenteral nutrition ( ), respiratory system drugs ( ), sedative, analgesics and paralysing agents ( ), parenteral solutions with electrolytes, vitamins and trace elements ( ), anti-inflammatory agents ( ), protein substitutes and immunomodulation agents ( ), anticoagulative agents ( ). antibiotics were further subdivided into those "freely" prescribed (a) and those whose prescription and administration requires filling of a relevant form (b). results : !) tc for icu patients/day was . drs ($ ). total tc/patient was . drs ($ . . ). ii) partitioning total tc per group of drugs reveals : ( ) %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %, ( ) . %. t ) concerning antibiotics which consist the major cost component, group a and group b contributed by . % and . % to the total icu tc respectively. group b were administered to . % of all icu patients. conclusions : i) for the above studied patient population antibiotics consist almost half of total tc followed by protein substitutes and immunomodulation agents. ii) if tc control could be attempted in the icu, prescription of beth groups must be reviewed. appropriate treatment should be prescribed and readily provided to any patient. clinical significance of routine protein substitution, currently controversial, should be re-evaluated. new antibiotics (third & fourth generation cephalosporins, quinolones, carbaponems) should be prescribed on the basis of strict diagnostic procedures using modern technology available. rationalisetion of antibiotic therapy will lead to cost control, redistribution of icu expenses and substantial contribution to infection policy in our country. objectives: i -to investigate the clinic efficiency of the monitoring of the rso cerebral, in relationship to the stroke prevention, in patient undergoing carotid surgery. -to determinate the variations of the rso during the different surgical and anesthetic procedures in these patients methods: ten patients undergoing carotid endarterectomy. precise neurological exploration previously to the surgery and in the immediate postoperative period. angiography evaluation to the extend of carotid artery disease. invasive blood pressure, ecg, pulse-oximetry ( pso ) and rso were collected previousty to the induction of anesthesia. the premedication was administered intravenously -midazolam ( mcgr/kg) and fentanyl (i rncgr/kg) -. thiopental ( mg/kg),fentanyl ( mcgr/kg) and atracnrium ( , mg/kg) have been used for induction of anesthesia. co te is monitoring al~er the orotraqueal intubation ! the anesthetic maintenance is accomplished with lsofluorane ( , - , %) and bolus of atracurium and fentanyh the surgical procedure is standard (without arterial shunt during the carotid cross-clamping). we register each minutes: blood pressure, cardiac frequency, pso , co te and rso . the rso cerebral variate in relation with: the anesthetic induction, blood ~ressure, co te, cross-ulampping carotid and with the modifications of the head position. the maximum decrease of rso cerebral was in relation with the :ross-clampping carotid ( minimal value: ). no patient had neurologic complications and postoperative stroke after carotid endarterectomy were not observed. objectives: there are more than anesthesia in chelyabinsk emergency hospital every year. to % patients of it emergency anesthesia is applied. more than patients have ishemie heart disease (ihd), hypertansion (hp) and previos miocardial infarction (pmi). more than % of all patients are old patients (op). the resalts deep noninvasive bioimpedance monitoring (nbm) in surgical patients have been studied by us. methods: our nbm system "kentavr" includes parameters of cardiac and vessels function. it is realised by monitors in operation theatres and computer network. moreover we are able to examine surgery patients before anesthesia and perioperatively by using special computers system for cardiovascular reflex control by fast fourie transform (fft) of parameters simultaneously. results: pathients extremly needed peryoperative monitoring of hemodinamics. from these patients more % had stroke volume (sv) less than ml, n -co less than . /mim/m , % -ejection fraction (ef) less than n and % -puls bioimpedans microvessels (pbm) less than morn. patient had intensive care in special department. out of died. comparing with survived with these patients before operation hr was larger, sv, co,ef, pbm and puls bioimpedance aortha was smaller. much more of these patients were with ihd, pmi, hd, op. even with survived patients these parameters decreased the towards the end of operation. surgery patients had different variability of basic hemodinamical parameters with common tendency to increase power amplitude in low frequency by fft. conclusions: using of bioimpedanee noninvasive parameters allows to have criteria for corrections (infusies, vasodilatators, inotrops and others) and then us the final goal, to have more sucssesful surgery. with survived patients was perioperatively and postoperatively care more intensive. obiectives: the aim of the study was to compare the phi with the hemodynamically derived tissue oxygenation indexes as: oxygen delivery (do ), oxygen consumption (vo ), cardiac index (el), and arteriovenous difference in oxygen [(a-v)do ]. methods: patients ( males and females) with major trauma or major abdominal surgery were studied. on admission, a nasogastric tube allowing phi measurement was introduced and a pulmonary artery catheter was inserted for optimal hemodynamic management. each phi measurement was accompanied with a complete hemodynamic study comprising systemic and pulmonary artery pressures, blood gases, and cardiac output measurements with the thermodilution method. derived parameters vo , do , ci, (a-v)do were measured according to the standard formula. hemodynamic parameters were opt• as soon as possible with fluids, inotrepes, and vasopressors according to repetitive hemodynamic measurements. all patients were under mechanical ventilation. after hemodynamic stabilisation phi and hemodynamic measurements were repeated every eight hours, during a -hour study period. a total number of measurements were obtained and compared. statistics: results are presented as means + sd, correlations were performed between phi and the hemodynamically derived oxygenation parameters. a p< . value was considered as significant. results: mean values were phi= . + . , do = + , vo = + , c. = . + . , (a-v)do = . + . . no correlation was found between phi and do , phi and vo , phi and c.i, phi and (a-v)do . on the contrary in patients phi remained below . for more than hours despite adequate hemodynamically derived tissue oxygenation parameters. mortality in this group of patients was very high ( %). conclusion: no correlation was found between phi and the hemodynamically derived tissue oxygenation parameters our data suggest that phi is a better oxygenation indicator than the hemodynamically derived tissue oxygenation parameters, because it is closely related to the patient's outcome. objectives: the pathogenesis of septic shock and multiorgan failure is believed to be related to tissue hypoxia of the gastrointestinal tract. therefore new monitoring techniques, preferably organ specific, are required to establish the adequacy of tissue oxygenation. peep is used to reduce pulmonary shunt volume and improve blood oxygenation, but is accused to impair splanchnic perfusion. we studied mucosal oxygenation and perfusion on the capillary level in the stomach and the duodenum. methods: we used the erlangen microlightguide spectrophotometer (empho ll) together with a specifically designed fibre probe (bodenseewerk ger~tetechnik, berlingen) in combination with a standard gastroscope. measurements were performed on ventilated, traumatized patients (ages - years), with no evidence of shock or severe infection, after informed consent was obtained from the relatives. all patients were hemodynamically stable without inotropic support. an area of cm was analysed in the gastric corpus, the antrum and in the duodenum. in three patients we simultaneously measured the muc sal blood flow using a laser doppler flowmeter ( objectives: to investigate the influence of hb-o affinity in the monitoring of svo~ during improvement of cardiac index (ci) in cardiogenic shock. design: to state whether changes in svo: were associated in changes in actual pso (p~ ) and standard p~ (ps st) consecutive measurements of artero-venous bga, before an.d after therapy-induced changes in ci, were evaluated in patients (mean age -* y) suffering from cardiogenie shock, all under mechanical ventilation in psv modality. methods: together the hemodynamic measures, m~xed venous samples were analysed at ~ c using the abl radiometer for po , pco: and ph, and the osm radiometer for hbo %, hbco% and methb%. psost (i.e. the p~ at ph= . , pco:= mmhg and temperature at ~ c) was calculated automatically by the instruments on mixed venous blood as was the ps "in vivo" (i.e. the pso at the patient's value of ph, pco and temperature), using siggaard-andersen's computerizated algorithm. mean time between paired measurements was . -* . houm. the data were compared by anova test for linear regression and t-test for paired samples. results: a dose linear relationship was found between svo and oxygen extraction ratio (oer), r= . ,p= . . the improvement of ci ( . -* . to . + . l/min/m , p< . ) induced a significant increase in svo~ ( . -* . to . • . %, p<. ). a significant decrease in p ( . • . to . • . mmhg, p< . ) without any significant change in p~ st ( . • . to . • . mmhg, p=ns) was also found. these data show that either oer or the shift to the left of the oxygen dissociation curve account for increase in svo occurring with restoration of systemic blood flow. the program is intended to help the intensive care unit interne providing him with a practical tool when making decisions concerning patients in a critical condition. in his daily practice in intensive care unit, in this case the interne of the unit, uses this program for each patient as follows: on the first stage of data collection he should complete the following modules: ( )personal data ( )patient's pathology ( ) laboratory and~ monitor lug data ( )drugs prescribed or toxic elements ingested. in this way, the system allows optionally the consult with a computerized data base about the drugs prescribed, standardized parameters and techinques performed by the central laboratory. ( )reference to an antibiotics guide regarding becterian sensitivety in our unit, whitch ee checked every six month ( ) access to de questionnaired apache ii to load up new data. ( ) statistcs about patient's admission and discharge. results: once all data collection is finished the system performs the followin duties: ( )detailed drugs interactions, including toxic elements ( )diagnosis starting from the clinical, laboratory and monitoring data. in some cases, it also establishes therapeutic strategies, e.g. a coagulopathy ( ) give the l~narmacological incompatibilities between the drugs p~escribed and %he diagnosis established, and ( )perform dosage adjustments based upon the personal and pathological data. objeatve: to assess the power of diseri~,~ion ofa multiperpose severity score (sai~) when applied to subgroups ofpatieals (pta) according to their lemg~ of ~ay (los) in icu. design: in order to compute the saps probability, a model derived fi~m legible regression was developed. meaumree of calibration (goodmem..of.fit statistics) end discrimination (roc cm've and relative area under the cm've) were adopted in develotammtul asd validation set. the whole databue was ~ati~ed in five gronps reeked on los as follows: los = days, los = - days, los = - da~, los = - days, los > day~. area under the carve (auc) was ud~ninted for each ro~. s~ing: imlimlcus. patents: of ~ pts comec~ively admired ~ a period of three yeet~ ( ) ( ) ( ) , a total of was i~leded in this study. pts without saps, p~ yolmger them yearn, p~ with los shorter ~ hom'~ were excluded from this maly~is. iaterventinns: nose mema'onm~ end result: the logistic model developed gave good remits in terns of calibration md discrimin~on, both in developmental set (do.s g : . , p > . ; auc = . i- . ) and in validation ~t (g.o.g g : . , p > . ; auc = . ..+ . ). auc of each grottp showed a loss in di~zimination (i.e., prediaton) closely related with los, being . i- . in pts with los = days el . ~. ia tm with los > da~ (figure). following the present guidelines of integral management, in order to achieve optimization of sanitary resources and better use of facilities, we feel that the setting up of objetives is a key factor in the continuous process of improvement of quality care. postsurgical intensive care services maintain an interdepent relationship with other hospital services. within the general plan of the hospital it's of the utmost importance to delegate autonomy to the various depertments and service units in determining and achieving objetives. it's also necessary to establish mechanism for coordination of the activities in order to assure the succes of the program. the objetives cannot be improvised, they must be carried out in a specific manner in the following stages: .-analysis of the present situation (starting point). where are we?. defining objetives and making explicit the activities and methods to achieve them is to anticipate the future; it is of the utmost importance to comunicate said plans to all whom affect by encouraging them to attain the desired results. in the present paper we intend to show the guidelines to follow in carrying out a course of objetives. introduction:we presents results related to the quality of life (qol)of critical patients, from paeec project data. material and methods: the paeec project is a multicentre study define the type of patients cared for in spanish icus, and the therapeutic activity provided. ninety-five icus from spain are taking part. this study analyzes the qol of critical patients prior to their icu admission.for the evaluation of qol a questionnaire designed by our team for critical patients was used, with items grouped in sub-scales: physiological functions ( items); functional capacity ( items) and subjective aspects ( items). qol is classified in levels: normality ( points); slight deterioration ( - points);moderate deterioration ( - points); significant deterioration (>i points). the we present results related to therapeutic activity in critical patients and their age, from the paeec project. material and methods: the paeec project is a multicentre study to define the type of patients in spanish icus, and the therapeutic activity provided. ninetyfive icus from spain are participating. this study analyzes therapeutic activity in the first hours as evaluated by tiss, and related factors. results: the sample was , patients, sge . ~ . years. severity by apache ii system was . • points. the tiss score was . • points, distributed as follows: i (<i points): %; ii (i - points): %; iii ( - points): %; iv (> points): %.there is a positive correlation between the level of therapeutic activity and severity by apache ii (r = . , p < . ), and a very weak but negative correlation between tiss and age (r = - . , p < . ), so that an increase in age corresponds to a lower level of therapeutic activity.patients the multivariate analysis of the relationship between tiss and age took into account: severity, existence of previous history, need for mechanical ventilation, size of hospital, diagnosis and mortality. it indicated that there continued to be a relationship between therapeutic activity and age, so that as age increased, therapeutic activity diminished. conclusions: therapeutic activity performed on critical patients is less in the oldest patients, in whom excessively aggressive procedures are limited. a relational data base management system in the icu. c. kotsavassiloglou*, d.matamis, g. dadoudis, j. kioumis, d. riggos. icu dep., g. papanicolaou gen. hosp., exohl, thessaloniki, and * a' neurological clinic of aristotelian university, thessaloniki, greece. objectives: the introduction of the information technology in the i. c. u seems to be unavoidable because of the large amount of produced data and the need for their systematic analysis. such an information system should be a) easy to use, b) friendly to the user, c) powerful and d) modular. on that basis, we created a patient data management system (pdms) according to the expectations of the medical staff of an eighteen bed multidisciplinary icu. methods: we selected paradox for windows v . for the implementation of a relational data base because this program meets the above mentioned criteria. informations regarding the patients include a) demographic data, b) previous medical history, c)diseases upon admission, d)complications during hospitalization and e) outcome data. the diseases' registration consists of items classified in categories upon the principal system affected. specific informations about the need and duration of mechanical ventilation, nutrition, renal replacement, right heart catheterization and icp monitoring are also available. an extension was added concerning icu infections and related informations about antibiotic-resistant pathogens. all icu pathogens can be matched to their resistance or sensitivity and cost of antibiotics. the program can perform queries and various statistical analyses based on complex criteria. new modules can be added later according to the future needs and remarks of the users. results: the program was well accepted by the medical staff and patients were registered as a test. the first analysis of the data related a) observed mortality versus the apache ii predicted mortality, b) mortality according to the age, gender, pathology aud duration of icu stay and c) pathology upon admission and icu related complications. conclusions: the long term use of this pdms can be an efficacious research tool. it can be used in retrospective or prospective studies by addition of necessary modules. the first data analysis revealed the iack of an international diseases' classification system. the development of a worldwide common classification system is essential for the compatibility of the data analysis among various icus. this will allow the realization of multicenter trials on a large scale. s. nanas= n. sphiris, a. precates, a. lymberis, m. pirounaki, and ch. roussos dept. of critical care, university of athens, athens, greece the complexity of the cases submitted to an icu, the variety of underline disease, tbe severity, as well as the large number of substances administered to each patient constitute obvious the need of support with an easy available dss. this system will assure the safety of the administered treatment will help to adjust the dose according to the situation of each patient and it will screen for possible interaction and incompatibilities between the administered drugs. the goal of the present effort is the design and development of a software system acting as a decision support tool to physicians of icu. the application is organised around a relation database management system (rdbms) that consist of: a) all available substances ( . ), b) all generic names of medications available in our country for each substance, c) incompatibilities ( . cases) and d) interactions with other substances ( . cases). the following figure shows the structure of the rdbms. y ta~ortato~ [ c~rs using the stored parameters for each patient the dose and the rate of administration of selected substances will be possible to calculate. the continuous monitoring of the treatment for each patient supports the medical staff to make the necessary changes of the prescriptions. the application is currently developing in wireless pen based computer systems which place patients at the centre of "islands of information" located throughout icu. in conclusion this dss is a powerful and useful tool for icu staff because it provides without additionai work to the routine of daily practice, the currently available information for each order concerning drug interaction and incompatibilities as well as treatment monitoring is to obsea~ among critically ill pfdieats, stdjdivided following the diagn~s at the adn~ssio~ the diffmeax:es in the ~ and oxyplx~efic l~mmems bawe~ strvwors [s] and non sumvors ins] and to test the pc~'bih'ty to have soar survival criteria, as earliest as tx~able. method~ :we made a ~ study on consexa~e ~ilically ill paliffas, subdivided in series following the diastases at the admission: medical pafiea~ ( s and ns), surgical patients ( s and ns), a~d poliwauntas ( s and ns). follow up was done at d,.ays from the admission in ice. all the patienls were ramitored with a ~ c~eter and laeno:lymmi. "c and o .x.xyphorefic txuamaers va:~e couected at fin~es (t): at fiae ~draission (t ), at x~ars from t (t ), at (f ), (y ), (t ), % (t ) and horus from t cf ). in~,h ~ies, for ~y ~ a all the lin'~ n~an and sandaid d~viation was ~ tx~h for s and for ns. th~ betw~ s and ns tl~ roeaas of ~h porarneter ~e ccmpared tt~ng t-lest and p < . w~ considered ska~ significant in each series in the t wheae the mast significative diffemx:as ~goeamd bet~en s and ns, we made a txedictive criterion, asamting as predictive indices for stnvival the i:r values, higher or lower than flae treans of the ~rar~ers of au flae patients, axx)rdhlg to those ones t~iatistically diff~'e~ betw~m s and ns. fhmlly xse co:weatxt onaong the series the nrametees of the st~rs with the analysis of variance, to daserve the lxjsable differealt irea~ of sty hflices, following the diagn~s of admission: :nedkal, angical patient or poll~tam results: we c~ld not find ~ predictive criterion for politraonaas, perhaps ixx:ause of the few ntanber of l~fients. for high ri~ saw~cal patieras the following criterion at t has a sensitivi .ly of ~ ,and a ~ecificity of . %: sv > . nffmin/n~, map> mmhg, pmap< nmalqg cvp<i nunhg will nmah& lvswi> g m/m , sxo > ~ do > mlhnin/m , o er< %. for lx~dical l~tienls at t the following criteric~a has a ser~tivi.ty of % and a ~zificity of . ~ cvp< . mn~g, sao > %, s,g) > ~ vo i< ml/nfin/m , o er< %, shunt< % survlvops' data of the series ~ signitic~atly differenl~ both for the t~mody~nic a~ for fl~e ox rphomfic lxlmn~s; moreover we ~ that the vatt~ of hemodynamic mad ox.~ho~tic indices were higher in politrautms. conclus'ions: acx~ording to the fftffe~mt patho!o~es, the ~ rnelabo~c needs are diffeten~ so that it is juslified to mash ~ the~alceutic goals, following the type oflmthology. hen~ we foru~d for high ~k mrgical pmka~ and for medical patier~s assme, ff mllslied, a good prognosis while, if n [ ntljsfled~ the plinsliclioil ofdl~tth is no[ g(ioct finally, ab~ high iis~ supgical palieaats, according to what other atmhors say, txatws sh ~'n~ers ' therapeutic goalsvvould seem inadeqt~te, bec~jse they need a gear physiologic and themtx~ic elth~ in rdation to the rretabolic needs. figure ) . thus, the smaller european nations had a greater participation than ~e larger ones, with the exception of norway. a similar result was evidenced for contributions to intensive care medicine (figure ). these findings can be explained by different submission policies and language banners. however, there was no significant correlation with the gross national product of each country. conclusion: we conclude that the smaller european countries generally contribute more to international intensive care journals than the larger ones. objectives: to evaluate the agreement between a new and three old methods measuring ctp and to assess their reproducibility. methods: we studied patients ventilated with a siemens c respirator. we measured ctp by dividing the tidal volume with the increase in airway pressure (paw), either with the respirator setting used (ca) or with a fixed setting (cf). by modifing the inspiratory time (ti) without changing inspiratory flow, we were able to deliver two series of inflations ( , ,... ml) before and after curarisation of the patient. the same volumes were also inflated in paralysed patients with a super syringe. at the end of each inflation a plateau of sec was performed and paw was recorded. the above three sets of pressure-volume (pv) points were used to reconstruct the corresponding pv-curves (( , c , c the new method for ctp measurement without a super-syringe had the best reproducibility in paralysed patients and gave similar results without curarisation in the majority of them. however, agreement between the methods tested was unacceptable for clinical purposes. further investigation is required in order to improve the accuracy of ctp measurement in icu patients. m kunert, r.sorgenicht, l.scheuble, k.emmerich, h.g ker med.clinic b (dept.of cardiology) i heart center of wuppertal/university witten-herdecke,germany objective to determine the accuracy of activated partial thromboplastin time (apl-l) and activated clotting time (act) studies when samples are drawn through heparinized central venous catheters (cvc). methods a total sample of paired act/p't-/" values was analysed in patients ( m., f., + y.) for monitoring heparin therapy.all patients had a cvc (certofix trio,braun,frg) in the internal jugular vein receiving a continous infusion of . u heparin via the central catheter.act (hr-act, hemotec,usa) and ap'i-f (neothromtin, behring,frg) samples were drawn from the cvc using the double syringe technique (removing and discarding ml blood before drawing the sample). these blood samples were compared to act/ap'cf blood samples obtained by venipuncture (v.fem.) at the same time, act values were analysed directly in the intensive care unit (icu),api-i samples were measured in the hospital laboratory within minutes. results ac-i -~ pi-f~ cact/~pi r = , ) cvc samples + + . v.femoralis samples " + + p-value n.s. n.s. conclusion there is no difference in heparin anticoagulation studies drawn from heparinized central venous catheters compared to those obtained by femoral venipuncture,withdrawing ml blood prior to obtaining the blood specimen is a safe way for eliminating heparin contamination.not only the aptt test but also the act test is a useful method for heparin anticoagulation assessment in the icu. objectives: evaluation of the delicate balance between filter-coagulation and patient-hemorrhage using heparin as anticoagulant in continuous renal replacement procedures. methods: from january through august , we studied filter surviva[ and hemorrhagic complications during filter periods in critically d[ patients, treated with continuous arterio-venous hemo(dia)filtration, with special emphasis on the heparin dose, concurrent use of coumarins, systemic activated partial thromboplastin tirne(aptr), platelet count, mean arterial bloodpressure and the type of filter used. results: filters ( %) were disconnected because of coagulation. mean survival of multiflow an filters was twofold shorter compared to survival of fh gambm filters. a total of hemorrhagic complications occurred of which three patients died at aptt values of respectively , and seconds. after adjustment for mean arterial bloodpressure, platelet count and the type of the filter, the risk for filter-coagulation decreased % (relative risk . , %c . - . ) for each ten seconds increase in aptt. the risk for patient-hemorrhage increased % (relative risk . , %ci . - . ) at an aptt-increase of ten seconds. the occurrence of filter-coagulation and patienthemorrhage was not correlated with the administered dose of heparin. concurrent use of cournarines had a positive effect on filter-survival, without increasing the overall incidence rate of patient-hemorrhage. conclusions: the systemic apt]" is a good predictor of the risk for filtercoagulation and patient-hemorrhage. heparine therapy seems optimal at an aptt between and seconds, although one should realize that fatal hemorrhagic complications still can occur. objectives: the alterations in vascular tone which are primarily regulated by adreno-sympathetic tone(ast) are compensatory responses in hemorrhagic patients. this study was designed to evaluate the correlation between vascular tone and ast in patients with hemorrhage, methods: the vascular tone was expressed by volume elastic modulus (ev) that is defined as; ev = ap/(av/v) (ap; the arterial pulse pressure, av/v; the volume change ratio). ev was measured using a non-invasive transmittance infrared photoelectric plethysmography (tipp) and a volume oscillometric sphygmomanometer . we prospectively studied patients with hemorrhage. the initial ev measurement was performed on arrival and repeated for a hours duration. as a parameters of ast, serum concentrations of adrenalin (ad), noradrenalin (nor), plasma renin activity(pra) were measured simultaneously. we analyzed the correlation of ev and conventional parameters to ast by multivariate statistical analysis. results: ev values at transmural pressure mmhg on admission and hours later were respectively . + . mmhg, . +_ . mmhg (mean + sd). systolic pressure(pas) and serum hormones on arrival and hours later were respectively, pas; . _+ . , + . mmhg, ad; . _+ . , . _+ . ng/ml, nor; . _+ . , . + . ng/ml, pra; . _+ . , . _+ . ng/ml/hr. the ev values correlated significantly with ad (r= . , p= . , n= ), nor (r= . , p= . , n= ), pra (r= . , p= . , n= ). by multivariate statistical analysis, ev correlated more significantly with ad and nor and pra (p= . ) than the conventional parameters such as pas, heart rate and pulse pressure. conclusions: the alterations of ev correlates closely with ast. the compensatory mechanism in hemorrhagic patients can be detected noninvasively by ev monitoring. obiectives and method: autologous oxygenator blood was processed at the end of cardiopulmonary bypass (cpb) by either hemofiltration (hf , , m , fresenius) or by cell washing with a onntinous autologous transfusion system (cats, fresenius). prospectively the blood of patients for each group was processed and then retransfused intravenously to the patient. besides, volume and time requirements, standard hematologic chemistry, coagulation and complement activation were measured. results (mean values for oxygenator blood at the end of cpb, and results of concentrate after processing by filtration or washing): both processing techniques show excellent hemoconcentration of the diluted cpb blood with a good transfusion effect for the patient. filtration retains all plasma proteins and large molecular weight plasma bound waste products. in contrast, cell washing with cats significantly depletes plasma proteins and waste products. the newely developped cats machine gives eonsisinnt laboratory result in a fully automatic continuous processing mode. in conclusion, both filtration and washing are effective for processing cpb blood. filtra tion yields a highly concentrated whole blood, whereas cats washing produces a high quality autologous erythrocyte concentrate. soluble fibrin has during the last years gained interest as a marker for the activation of the coagulation in connection with various clinical conditions, e.g. disseminated intravascular coagulation, deep venous thrombosis and myocardial infarction. elevated levels of soluble fibrin in plasma can be detected by the chromogenic assay coaset fibrin monomer, relying on the ability of fibrin to enhance the tpa-catalyzed conversion of plasminogen to ,plasmin. using this test, it has been shown that the level of soluble fibrin can be correlated to severeness of illness in critically ill intensive care unit patients. a revision of the coaset fibrin monomer kit has now been made and the new product, coatest soluble fibrin, is considerably more convenient to handle and gives higher resolution at low fibrin levels. the test is performed by the addition of a buffer dilution of the plasma sample to a microstrip well containing the colyophilized mixture of tpa, plasminogen and the plasmin specific cbromogenic substrate s- . the reaction is allowed to proceed at,. room temperature for minutes before discontinuation. the absorbance at nm, measured in a microplate reader, is proportional to the content of soluble fibrin in the sample. the assay is carefully standardized and calibration curves are provided in the kit. the convenient and rapid assay procedure makes the coatest soluble fibrin test well suited for single test analysis in acute situations. objectives : blood coagulation abnormalities have been reported in the systemic blood of patients with cerebral lesions. the physiopathology of such events is not yet completely understood. we compare the coagulation profile of blood from the right jugular bulb with systemic blood of patients with head injury. methods: we studied patients, who were admitted to our neurosurgical intensive care unit between january and march with head injury and no other associated pathology (age - yrs), a glasgow coma score <= g, no abnormality in baseline coagulation profile and no history of coagulopaties. the patients did not undergo angiography. a one-way gauge certofix catheter was inserted through the right internal jugular vein up to the jugular bulb. an identical catheter was inserted through a subclavian vein. blood was sampled from either catheter (a=atrial; j=jugular) - hours after trauma (t ) and t hours later (t the inddence dpontolx'rative thmmhi~e and haumord~gic complieatiom were assessed in padents treated with indobefen, heparin calcine caeca), low mollecolar weight heparin (lmwh) (f.nosheparin) and undergoing hemodiludun, blood predeposhing, intra mad postoperative blood saving. ]'he indolmfon tempota~.norks platelet aggregation through ,,elective inhibition of the cyclatygenasis and thus atacbldonicadd( ).tbe n'mimum effect occurs after hours from the fast administration and is still present after hours. ~- patients, mean age --- yrs., weight --- kg were studied. ( . %) were male and ( . %) female. onderwent hip prosthesis ( previously plate and screw removal) hip revim'un ( stem, cop and stem + cop), tutal knee prosthesis, in the st anaesthesidogy depl from - to - - . as for antithromboembolic ptephylam, apart from hemodihitiun pts were with treated indobufen ndo), with heparin ealdum caeca) and with low mo!lecular weight hepam (lwr, ). as the slightest clinical and/or imtmmental suspidon of deep vein thrombosis (dv'i') or polmonary umbolism(pe), a phlebogram or sdndgram were respectively carried out. -the inddence of homologom transhisiom was significandy lower (p= . l) in the padeats treated with indobufen ( . ) compared .'ith heca ( . %). the con~gency table shows statistical signifleance for the use of heca in patients with vein deficiency in the lower limbs, past dvr and/or pe, coronary heart disease (cdh'), while there is no correlation for renal, cardiac or liver defidency, obesity, systemic hypertemion, atrhythmy, diabetes, chronic bronchitis and rheumatoid arthritis. by comparing the postoperative cumplications with the risk factors, there ks a highly significant correlation (p= . l) between cdh and thrombotic and humord~agic complieatiom (pe, death, he~atoma, die use of hum_ologous blood). thee data show that hep~in, preferred in patients with c'dh, roost likely for leagal-tuedical reasons, did not have the de~'ed effect. conclusions -the stastisfical aar~ais shows ~nifieanfly different efflea~ (pro . ) between the therapies (see table) : it can be seen that in patients undergoing autotramfusiun and hemedihidon, indobufen produo~ a lower incidence of haemotrhagic complieatiens compared to heca and lmwh and is more effective in the prevention d ~c complications at clinical e~idence. the duration of i~toperadve hospital stay is signi~cantlylonger for patients transfused with homologous red ceils and treated with hec, .a ( . -+ . days) and lmwh ( . +- a days) compared with indo(ll. _+ a days). one of the main causes for postoperative complications in major orthopaedic surgery is postopemtive bleeding with local effects in the operation site (hematomata, pain and delayed mobilization) and/or systemic and subsequent cardiodrculamry repercussions that are sometimes severe. the aim of this study is to assess the possibility to apply a new system of monitoring, control and saving postopemtive blood loss from the drainage. the bt recovery dideco (marandola, modena-italy) ~ used since it is the only apparatus capable of doing this. the apparatus consists of a pressure transducer, adjustable from - a + mmhg, which activates a peristaltic pump connected m drainage robes. the bt recovery display shows hourly bleeding in the first hours, total bleeding, time passed since the start of monito~g and subsequent salvage and the aspimtioo pressure on the drainage robes; the latter is inserted at - mmhg and then modified according to bleeding/minute, g bt recovery also has an alarm that sounds automatically if.' blood loss is more than ml/hour; air is in the circuit; the batteries are running low. materials and methods: pts were studied ( m and ~), aged . -+ .lyears, basal hemoglobin . -+ (range . - . )g/all, treated from st january, to mst december, in the st service of anesthesia and intensive care unit of our hospital. the patients underwent the following surgical treatment: total hip revision ( pts), cup revision (~ipts), stem revision ( pts), total knee revision ( pts). the average dumtion of the operations was -+ min. intranpemtive monitoring and blood salvage was applied to all patients. genera! anesthesia was used on pts. and integrated (epidural analgesia + light general) on the remaining t . anttthromboembolic prophylaxis consisted of external pressure bandage, isovolemic hemodilution with iodobufen in ( . %)pts., calalc heparin in ( . %)pts., low molecular weight heparin in ( . %)pts.; pt did not give a predepoalt of blood, gave unit, pts units, pts units, pts units. the data obtained was statistically analysed using contingency tables and anova. results: average intmop salvage was -+ ml, average postop salvage was -+ mi the average intra+postop +- ml. average postop loss was -+ ml. the global incidence of postop complications was: h~natomata . %, dvt . %, pulmonary thromboembolism , , myocardiac ischemia . %, acute myocardic infarction . %, respiratory deflciecy . %, arrhythmia %, cystitis . % there were nn complications in . % of pts. postop bleeding over ml in under minutes (with bleeding alarm activation) occurred in pts ( . %). this sta~tically correlates only with the type of operation performed (more frequently in total hip revision p= . ) and with a significant decrease (p~ . ) in the pruthrombic activity detected about hours after the operation. this bleeding, also made the alarm sound, calling the attention of staff who could act accordingly, by making the drainage pressure positive and incre~sthg the tension of the external pressure bandage. conclusions postop monitoring, control and blood loss salvage combined with predepoalting and intmop salvage has enabled allogenic transfusions in % of cases to be avoided in operations with high postop blood loss like hip or knee revision. the usefulness of the system can be seen by the fact that in the patients with so much bleeding to set off the alarm, there was no significant difference in the incidence of allotransfusions and complications. references )borghi b., bassi a., de simone n., laguardia am., fonnaro g. an injury of the brain may result in various disorders of hemostasis caused by the release of • into the circulation through a damaged blood-brain bar tier. disseminated intravascular coagulation(dic) is one of these disorders. it is a freguent but relatively rare ly diagnosed complication of subaraohnoidal haemorrhage. the aim of this study was to evaluate some parameters of both blood coagulation and fibrynolisis in patients with sah.in addition one wanted to find out wh~ther potential changes correlated with the pa• condition in the acute phase of sah and whether they influenced the course of this disease. patients with sah were studied. in of them sah was due to closed eraniocerebral injury and in the rema ining resulted from vascular malformation. the following parameters were evaluated:the prothrombine time,the activated partial thromboplastin time, the thrombine time,level of factor v,fibrinogen degrada tion products and fibrin monomers. the results let us show the presence of oic in patients with closed craniocerebral injury and in with vas. cular malformation despite the lack of clinical symptoms the tests in posttraumatic patients and in patients from second group showed incomplete dic.on admission patients with such changes in measured parameters were in poor condition.the course of the disease and the effe cts of treatment were also worse in these patients. the results showed ihal in patients with sah complex disorders of both coagulation and fibrynolisis occur, and they depend on clinical condition of the patient. they also influence the course of the disease. methods : charts of all patients admitted with d.i.c. over a ten year period ( - ) were reviewed. diagnosis of dic was based on the association of fibrinogen < g/ -platelets < / -fpd > ~tg/ml in the hours of the admission. results : patients -mean age + y -saps +_ -gestanional age _+ weeks -the two first conditions associated with d.i.c. were placental abruption ( %) and preeclampsia or eclampsia ( , %). bleeding episode was present in pts ( %) and surgical treatment has always been necessary. pts ( %) were given packed red ceils ( + u) and fresh frozen plasma ( + u). patients were given platelets packs. heparin was never administered. pts required mechanical ventilation and two patients hemodialysis. all the patients survived. correction of prothrombin time (p.t.) and fibrinogen (f) was quick (p.t. at t h ~ % -f at t h , + , g/i). but platelets count remained low (plat. at t h + / ) -no difference was observed in patients who received platelets. conclusion : prognosis of critically ill o.p. is good. blood loss is the main complication. correction of hypovolemia and anemia with concomitant surgical treatment are essential. the administration of coagulation factors or platelets is still under discussion. objectives: to evaluate the effects of antithrombin iii i at-iii) and a protease inhibitor, gabexate mesilate foy), on the coagulation and fibrinolysis in disseminated intravascular coagulation (dic). methods: after the approval of our institution and consent from patient's family, patients with a dic score ( , japan) more than points (dic or having a risk for dic) entered this study. they were randomly divided into two groups, foy (i- mg/kg/h for days or more) treated group and no foy group, each of patients. platelet count (plt), fibrinogen (fen), at-iii fibrin degradation product (fdp), d-dimer (do), fibrin monomer (fm), thrombin-antithrombin complex (tat), plasmin-plasmin inhibitor complex (pic), and prothrombin time ratio (ptr) were measured before the start of treatment (at admission) and i, , and days after the admission. at-iii at units for days was administered if the at-iii at admission was less than %. finally the patients were divided into four groups: group a, foy (+) and the at-iii ~ %; group b, foy (+) and the at-iii < %" group c, foy (-) and the at-iii %; group d, foy (~) anffthe at-iii < %, each of patients, to match the patients for backsrounds. all parameters, dic score and survival rate in a month following treatment were compared among the four groups. results: the at-iii and plt from day to were significantly higher in groups a and c than in groups b and d. the fdp, dd, tat, and pic after treatment decreased significantly from the baselines in groups a and c but not in groups b and d. the fgn and fm were not significantly different among the four groups. the ptr decreased in groups c and d but increased in group b. the dic score decreased significantly in groups a and c than in groups b and d. survival rates were %, %, % and % in groups a, b, c and d, respectively, although not significantly different. conclusions: in patients with dic or a risk for dic, foy had no expected effects but at-iii had suppressive effects on the coagulation and fibrinolysis mechanisms. a prognostic factor ? carbon monoxyde intoxication is a classical complication of inhalation injury. carbon monoxyda is also physiologically produced during the heme metabolism: heme is conversed to bi]irubin by the hemeoxygenase which is an intracellular stress protein. icu patients (pts) were studied prospectively for apache ii score and carboxyhemnglobin (hbco) arterial level to assess if hbco level could be correlated with the severity of the pts. objective: to evaluate a new technique of non-surgical tracheotomy. patients: adults, mean age years and children, mean age months ( me.- yrs). method: through a needle inserted in the trachea, a guide wire is retmgradely pushed out of the mouth and attached to a special device formed by a flexible plastic cone with pointed metal tip joined to an armoured tracheal cannula. this device is then pulled back through the oral cavity, larynx and trachea, and outwards across the neck wall by applying traction on the wire with one hand and counterpressure on the neck wall with the fingers of the operator's other hand. when the cone and / of the eannula have emerged, the cannula is cut off from the cone, straightened perpendicular to the skin, rotated and advanced caudally to its final position. results: endoscopic control facilitates and improves the safety of all manoeuvres. the pointed cone easily pierces the tissues, and the cannula is extracted without difficulty since it has the same outer diameter as the cone. tissue adherence around the cannula is absolute thus preventing local inflammation. the time in apnea required for dilation and cannula placement does not exceed see., and it is well tolerated because within safety limits in patients hyperventilated with oxygen. only one case of bleeding occured in a patient on dialysis with severe coagulopathy. autoptic findings in subjects who died due to progression of primary disease showed a very regular stoma with an almost complete lack of hematic and flogistie infiltration in recent tracheotomies. .conclusions: translaryngeal tracheotomy (tlt), by virtue of its greater inherent safety and lower tissue trauma than percutaneous techniques, can also be carded out in infants and children, a severe test bench for any tracbeotomy technique. further specific indications are recently stemotomized patients, since tlt is associated with a low rate of infection, and short term tracheotomies after laryngeal surgery, to prevent obstructive complications. references: fantoni a., translaryngeal tracheotomy, apice, ed. gullo, trieste, , . background: inhalation of no has been shown to reverse hypoxic pulmonary vasoconstriction , to reduce pulmonary pressure in pulmonary hypertension of different origin and to improve gas exchange. in putmoflary embolism, pulmonary hypertension is caused by mechanical vascutar obstruction and by reactive vasoconstriction. the effects of inhaled no in putmonary embofism has been partiatly studied' the purpose of this study was to investigate and determine the effects of no inhalation on pulmonary hemodinamica and gas exchange in a hypoxic canine model of pulmonary embolism. methods: two groups of adult mongrel dogs were studied: group (control} dogs and group (no inhaled) dogs. both groups were anestesized with tiopental, mechanically normoventilated with an hypoxjc mixture of and n~ (f[q , ) and instrumented (swang-ganz catheter, femoral artery catheter) pulmonary embolism (pe) was induced by fisher's method s. no inhalation ( ppm) in group was started rain. pdor to pe and kept constant throughout the experiment. no inhaled concentration was analyzecf by chemiluminiscence technique. pulmonary artery pressure (pap), central venous pressure and sistemic arterial pressure were continuosly recorded. cardiac output, artedat po~ (pan ) and mixed venous po~ were measured in both groups under hypo)dr conditions, before pe and , , and rain. after pe. pulmonary vascular resistance (pvr) and gas exchange (pao fio:~ ratio), were calculate using standard formulas. data were process and analyzed with non pararnetdc test, and reported as mean -so and statistical significance was considered if p < , . : no produced an increase in arterial oxigenation (pao /fio~ ratio) and reduced pap before pe induction in group . after pe we found no significant difference with .respect to the time eour.se of pap, pvr and gas exchange between beth groups throughout the experiment. probably, the severe mechanical obstruction produced in pulmonary embolism masked the small effects of no inhaled. obiectives: blood volume measurement would be useful in critically ill patient management if it were easy to perform. this is not the ease and current methods are based on radiolabelled red cell dilution. inhalation and uptake of a known mass of carbon monoxide (co) gas and measurement of earboxyhaemoglobin increase can give results accurate enough for clinical use. this requires a rebreathing system providing oxygenation and carbon dioxide removal, yet complete retention of all carbon monoxide administer&l, and so most authors hand ventilate with a bag and waters soda-lime canister, adding oxygen as necessary. we aim to popularise this method by; i)design of an automatic co administration system driven by the itu ventilator and ii)writing of software for a portable computer to perform all necessary calculations method: we show the computer is use estimating the co dose required and later estimating the blood volume. we also show the new gas administration system. this is a fully closed circle attached to a "bag in bottle", driven by the ventilator. the novel feature is the mechanism by winch driving gas (set to % ) spills automatically into the circle, balancing o uptake by the patient, yet allowing no co loss. conclusions: this equipment is easy to use, reduces human error and allows optimum ventilator settings to remain. the operator merely administers the volume of co determined by the computer and takes blood on two occasions. carboxyhaemoglobin measurement is easy to perform, thus there is a cost saving also. with our modifications use of this technique may potentially become more widespread, the video demonstrates the method in use in our itu. - ( %) underwent conventional surgical therapeutics. " ( %) with resection of tracheal stenosis with end-to-end anastomosis(rts). i ( %) with broncoscopic dilatation. one patient died and the others still have stable patency(sp) without continued treatment. - ( , %) have received endoscopic laser ablation with or without calibration tubes. of them ( , %) are receiving continued endotracheal treatment until now. ( , %) have sp wihout continued treatment. -i ( , %) endoscopic laser therapeutic case turned to rts and is having sp. conclusion: conventional surgical aproach has been progressively replaced in our hospital by endoscopic laser ablation and silicone calibration tubes. this study suggests that these technics are effective and could be the elective treatment for iatrogenic stenosis. obiectives: hemorrhagic disorders due to thrombocytopenia and thrombocyiopathia remain one of the most serious complications during long-term extracorporeal membrane oxygenation (ecmo) in patients with severe acute respiratory distress ~drome (ards). in the presented study, nitric oxide (no), kwown as a potent endogenous platelet antiadhesive, disaggregating and antiaggregating compound, was evaluated for its possible antagonistic effect on platelet trapping when added to the gas compartment of membrane oxygenators (mo). meti~ods: two parallel separated extracorporeal circuits, consisting of heparin bonded hollow fiber oxygenators (minimax, medtronic, carmeda eioactive surface), tubing systems, low pressure reservoirs, and roller pumps were prepared. for each measurement, a pair of circuits was simultaneously filled blood from the same volunteer. low-heparinized fresh warm blood was obtained from four healthy volunteers, who had no drugs for at least two weeks. the gas inlets of both oxygenators received dry gas ( % oxxygen, % carbon dioxide, % nitrogen); gaseous no ( ppm) was added to the gas of one of the oxygenators (no-mo), whereas the other one (mo) was used as control. after minutes no gas was switched off, so that the no-mo received no more no, and no was added to the gas inlet of the membrane, which had no no before_ to assure iutracircnit volume stability, drawn blood for measurements was replaced with saline, and platelet counts were corrected for dilution by hemoglobin values. the mean of four platelet counts (coulter counter) of each timepoint (start, , , , , , , , and minutes) was used for statistical analysis (paired sample t-test). results: in the no-mo platelets remained at + , % (percentage of baseline value, mean -+ sd) until min. in contrast, platelets of the mo continuously decreased after start and were significantly lower after minutes ( , + , % vs _+ , %(p< . ); min. , -+ , %vs , _+ , %(p< . ); min. , _+ , % ( p < . ). after switching of no gas to the mo, further decrease of plateleta was stopped and platelets remained at , +_ , % until termination of circulation. platelets of the former no-mo decreased slightly after cessation of no gas to , _+ , %. conclusions: these data indicate that gaseous no significantly attenuates platelet trapping in hollow fiber oxygenators, when added to the gas compartment. this might be a new therapeutical approach for membrane oxygenator induced thrombocytopenia during long-term ecmd. objectives: nitric oxide (no) plays a pivotal role in regulation of vascular hemostasis. several studies elucidated the antiadhesive, antiaggregating, and disaggregating properties of endothelially synthesized no to platelets. additionally, agonist-induced no production in platelets by the l-arginine-no pathway was found as a negative feedback mechanism after platelet activation. although noplatelet interactions were intensively studied by several investigators, no data exist, about changes in platelet surface molecule expression in no-modulated platelets measured by flow cytometry using monoclonal antibodies (moabs). methods: p-selectin (alpha-granule-membrane protein, gmp- , cd p) and glycoproteiu (gp , lysosomal protein, cd ) are expressed only after platelet activation and degranulation. activation was quantified in thrombin ( . u/ml) and adp ( . ram) stimulated platelet rich plasma samples (prp). blood was obtained from healthy volunteers (n= ), who had no drugs for at least days. for evahiation of no-modulated activation, the spontaneously noreleasing compound sin-i ( . mm) ( -morpholino-syndonimin-hydrochlorid) was added in parallel prepared samples prior to the addition of agonist. platelet surface molecule expression was evaluated with moabs directed against cd a (gpilbliia, fibrinogen-receptor, phycoerythrin(pe)-conjugated), cd p (fitcconjugated), and cd (fitc). only cd a-positive signals were gated in sideangled light scatter, and assayed for activation marker expression (defined as percent of gated population). results: basal p-selectin expression was . + . %, and increased to . _+ . % after thrembin-activation, and to . + . % in adp-stimulated samples. addition of sin- attenuated p-selectin expression to . - - % in thrombin (p<. , two-tailed paired t-test), and . + . % (p<. ) in adpactivated platelets. basal gp expression was . _+ . % and increased to . + . % in thrombin, and to . _+ . % in adp-stimulated samples. with sin-l, gp expression decreased to _+ . % (p<. ) in thrombin, and . : . (p . ) in adp-stimulated samples. conclusions: these data implicate, that no leads to a significantly reduced activation of surface molecule expression in thrombin and adp-stimulated platelets. in addition, flow cytometry might be a useful tool for studying modulation of platelet activation by no or no-releasing compounds. introduction: acute cadmium poisoning is very rare. on initial presentation may mimic metal-fume fever, but acute inhalation cadmium toxicity may produce fatal chemical pneumonitis. case report: we present a case of acute fatal respiratory failure secondary to cadmium-fume irthalation. a year old patient was trasferred from another hospital with acute respiratory failure presumably due to pneumonia. the last days before he had had commom cold symptoms. he had been cutting with a welder during one hour without any respiratory protective measure. three hours after exposure he developed progressive dispnea and was admitted to hospital. with presumtive diagnosis of respiratory infection, antibiotics were begun, however be failed to improve. all microbiological studies were negative. chest x-ray showed bilateral diffuse infiltrates. on seventh day he needed intubation and mechanical ventilation and on th he was admitted to our icu. antibiotics were stopped and new microbiological studies were performed including brochoalveolar lavage and virologic studies. all results were negative. he developed progressive hipoxemia and hipercapmia and finally, multiorganic disfunction syndrome. he died days after exposure. the metal he had been working with was a % cadmium alleation. blood cadmilam concentration days after exposure was . mcg cd/g cr, and urine cadmium concentration was . mcg/l. on postmortem examination, tissue cadmium concentrations were: blood ng/ml, liver ng/g, kidney ng/g and lung ng/g. these values confirm that cadmium was the cause of the fatal respiratory illness in this patient. conclusion: this case evidences the considerable hazard of acute poisoning after inhalation of eadmium-fume and stresses the need of appropiated safety measures against metal-fume poisoning. aim : lactic acidosis is considered the hallmark of cyanide poisonirig. however, the relationship between plasma lactate and blood cyanide levels has not been determined. the aim of this study was to determine the significance of plasma lactate concentration (plc) during the course of cyanide poisonings. methods : the patients were included according to the clinical suspicion of pure cyanide poisoning at the time of presentation. fire victims were excluded. serial blood samples were collected before and after intravenous hydroxocobalamin (hoco). blood cyanide concentration (bcc) was measured colorimetrically. plc was measured enzymatically. results : patients were studied. on admission, plc ranged from . to mmol/l, and bcc from . to gmol/l. mean systolic blood pressure was • mm hg, mean arterial ph . • . , mean anion gap was . + . mmol/l and mean pao . • . kpa. three patients died. before antidotal treatment, there was a significant correlation between plc and arterial ph (p = . ), anion gap (p = . ) and bcc (p = . ) but not with heart rate, pao , paco and blood glucose, or blood pressure. during the whole course of the poisoning, a plc _> retool/ was a sensitive and specific indicator of a blood cyanide concentration > ~tmol/ . sustained catecholamine administration reduces the correlation coefficient. conclusion : baseline measurement of plc allows assessment of severity of acute cyanide poisoning. thereafter, plc may be used to assess the adequacy of antidotal treatment, more especially in patients not requiring sustained infusion of catecholamines. aim: the aim of this case report was [o study the correlation between the plasma lactate levels and several clinical, biological, and toxicological parameters serially measured during the course of a cyanide poisoning treated with a high dose of hydroxocobalamin. a -year-old male ingested potassium cyanide leading to cardiac arrest. cpr was performed prior to hospital arrival where the patient received g hydroxocobalamin. sbp rapidly returned to normal allowing withdrawal of epinephrine. the patient remained comatose and died from brain injury days after the ingestion. methods plasma lactate and blood cyanide levels were measured serially. blood cyanide levels were measured using a colorimetric method.~ plasma lactate levels were measured using an enzymatic method. for correlation spearman rank correlation test was used. results. initial plasma lactate and blood cyanide levels were mmol/l and gmol/l, respectively. there was no overall correlation between sbp and either blood cyanide or plasma lactate levels. similarly, there was no overall correlation between arterialvenous oxygen saturation difference with either blood cyanide or plasma lactate levels. in contrast there was a strong correlation between blood cyanide and plasma lactate levels (r= . , p< . ). the time-course of the blood cyanide concentrations was described by a mono-exponentiai decay (r = . ) with a blood half-life of . h. similarly, the time-course of plasma lactate levels was described by a mono-exponential decay (r = . ) with a blood half-life of . h. discussion. in this case of acute human poisoning, sbp was a much poorer indicator of continuing cyanide effect both before and after antidotal treatment, than was lactate production. this suggests a potential clinical role for following serial plasma lactate levels as a marker of the evolution of cyanide toxicity. aim : cyanide (cn) poisoning in fire victims is frequent and rapidly fatal. in a prospective study we tried to assess the clinical tolerance of a high dose of hydroxocobalamin (hoco) administered at the scene of the fire in fire victims suspected of cn poisoning. methods : inclusion criteria : soot in mouth or sputum ~ any degree of neurological impairment. exclusion criteria : children, pregnant women, burns of total surface body area > %, multiple trauma. protocol desigrl following examination and the collection of a blood sample in dry heparin, a g dose of hoco ( g in case of cardiovascular collapse) was administered intravenously over min. the systolic blood pressure was monitored before and after the administration of hoco, and one hour later. results : there were females and males. the mean blood cn concentration was • pmol/ . the mean blood carbon monoxide was . • . mmol/ . nineteen fire victims eventually died. among the non-cn-intoxicated patients (blood cn < ~mol/ ), there was no significant change in arterial blood pressure. in the cn-intoxicated patients (blood cn > gmol/ ) a significant increase in blood pressure was observed both immediately (p < . ) and hour later (p < . ) after the admistration of hoco. no allergic reactions were observed. conclusions : in fire victims with cyanide poisoning, the administration of a high dose of hydroxocobalamin was associated with an improvement in systolic blood pressure. hydroxocobalamin is well tolerated in fire victims without cn poisoning. objectives: tricyclic antidepressant (tca) overdose can lead to serious complications including cardiac arrhythmias [ ] . because of the known risk of early deterioration and the implication for management, emergent evaluation is essential. we determined the diagnostic usefulness of the electrocardiogram (ecg) in tca poisoning. methods: retrospective study of all patients with tca intoxication (pos. ,toxicology screening in urine and/or pos. history) in a -beduniversity hospital from through . the severity was graded with mild= no symptoms or agitation; medium= disorientation, somnolence, tachycardia, or convulsions; and sever~ coma, significant arrhythmias or death. we analysed the first ecg after admission with a special emphasis on qrs-and qtc-intervals and the terminal ms frontal plane qrs-vector (tqrs), which, was reported to lie typically between + and * + + • the best correlation with severity grade was found with qrs-and qtc-duration (p= . ), the tca-dose (p= . ) and hf (p= . ); tqrs did not correlate. patients died ( . %). conclusion: qrs-and qtc-prolongation in the admission ecg, and the reported dose of ingested drugs are useful predictors for severity of poisoning due to tricyclic antidepressants. we did not find additional benefit in determining the terminal ms frontal plane qrs-vector. objectives: since treatment of amphetamine poisoning is usually symptomatic and often associated with a fatal outcome, a search for specific drugs to help the amphetamine-intoxicated victim is sorely needed. methods: we report a case of a suicidal ingestion of large amounts of the amphetamine-derivative , -methylenedioxy-ethamphetamine (mdea) and heroin (diacetylmorphine) and present the hypothesis that the two drugs produce opposing clinical effects. results: a year old caucasian male was admitted to the emergency ward because of acute-onset confusion. at presentation, he was agitated and showed increased muscular rigidity. he had taken tablets of "eve" (mdea, approx. g) and g of "smack" (heroin) by oral route approximately h before admission. because of rapidly progressive tachypnea and exhaustion, the patient was intubated and ventilated. the serum concentration of "eve" on admission was ng/ml (lethal range - ng/ml). trace amounts of cocaine and substantial amounts of heroin ( ngtml; mean value in heroin-related deaths: ng/ml) were also found in the serum. the patient was successfully weaned from the ventilator by day and recovered without persistent neurobehavioral disturbance. despite high serum levels of both drugs, the patient did not present with the classic signs and symptoms normally seen during intoxication with these drugs. amphetamines in general, and mdea in particular, have opposite clinical effects to heroin or diacetylmorphine. none of these were however present in the case presented despite the high ingested doses and the serum levels in the lethal range. conclusions: the fascinating fact that, apart from the respiratory depression, none of the clinical signs reported after massive overdose with these two drugs were present, might be attributed to the opposite pharmacological effects of mdea and heroin. we believe that the patient unwittingly saved his own life by the oral coingestion of both mdea and heroin. our clinical data raise an interesting point about the pharmacological treatment of acute poisoning with amphetaminederivatives. introduction: the acute attack of aip still carries a significant risk of mortality of around %. a succesful outcome depends on early diagnosis, removal of pricipitating factors and provision of intensive supportive therapy. objectives: twenty one patients ( females, male) with documented aip were seen over a -year period in the university hospital. patient was in clinical remission and were with the acute attack of aip, among them with respiratory paralysis were required artificial lung ventilation and -assistant ventilation with peee pathologic treatment during the attack was normosany, adenil, androgenes, glueosa, riboxin parenteral and enteral nutrition via nasogastric tube. symtomatic treatment -pethidine, propranoton, antibiotics, bronchoscopia. methods: intermittent phasmapheresis was performed on patients. the following measurements were peformed: level of porphobilinogen (pbg) in the wire and delta-aminolevulinic acid in the blood. hematological and routine chemical evaluations, hepatic, hemodynamic and respiratory function. results: after plasmapheresis the median pbg excretion (normal range - mkg per/ kgr creatinine) fill from mkg on admission . mkg, then on - day raise to mkg and then during treatment with normosong and prasmapheresis lowest level was . mgk. fatalities occured in two females during attacks with proforma cerebral involvement and patients attained clinical remission. conclusion: after therapy with plasmapheresis normosong we found that there was consistently reduce the urinary excretion of pbg and shortening the duration of the acute attack. objectives: pigs has been reported to present with a higher pulmonary arterial pressure (ppa) and stronger pulmonary vascular reactivity than many other species, including man. aim of the present study was to compare pulmonary vascular impedance (pvz) before and after embolisation in weight-matched adult dogs and minipigs. methods: we investigated pvz spectra in anaesthetized and ventilated (fio . ) minipigs and dogs. after baseline measurements the animals were embolised with autologous blood clots to reach a ppa above mmhg. results: flow ( and ppa matched pvz data (mean-+sem) are shown in the table. [zo = hz impedance (z; {dyn.sec_em- }); zl = first harmonic z; zc = characteristic z; z phase = first harmonic phase a@e {radians}; fmin = frequency of pvz the first m{n~mam; *, f p at least < . between dog and minipig, and before v~. after embolisation respectively]. before case report: a -yr-o]d woman affected by legs recurrent thmmbophlebitis, was admired in medmine department for tach.~pnea, chest pain, tachycardia and cyanosis. before starting two-dimensional transesophageal echocardiography (tee) to confirm the suspicion of pulmonary embolism, she suddenly had ventricular fibrillation. resuscitation and defibrillation were readily performed. when sinus rhythm was reinstituted she was in superficial coma with preserved corneal and light reflexes: right hemiplegia, poor perfusion and h~posphygrma of the left arm. tee showed dilation of rigth ventricle (rv), incomplete occlusion of pulmonary arter~ (pal at it~ hifurcation, severe tigth-to-left shunt through a patent foramen ovate, paradoxical embolism with incomplete occlusion of left subclavian artery mechanically ventilated with vt= ml, rr= /mm, fio =l, the patient had ph= . , pao = mmhg and paco = . systemic bp was / mmhg and hr= b/min with low dose epinephrine ( . g/kg/min) a thrombolytic infusion (rtpa: mg/ h) through a peripheral vein was started tee imaging and clinical status hours later were unmodified. a new rtpa infusion was performed through the pulmonary hole of a swan-ganz catheter with the tip close to the embolus. one hour later pa pressure decreased from / mmhg to / mmhg, etco increased from to mmhg and sao improved from % to % three days later the parietal, spontaneously breathing and with normalized tee scans of rv and pa, was transferred to rehabilitation service to perform physical therapy. conclusions: massive pulmonary embolism in a patient with patent foremen ovale, paradoxical embolism and refractory hypoxaemia was unaffected by systemic rtpa infusion, while intrapulmonary rtpa administration dramatically improved gas-exchange, hemodinamics and the general conditions of the patient. the presence of a large rigth-to-left _atrial shunt and the rapid rtpa metabolism could likely explain the effectiveness of its intrapulmonary administration in front of failure of systemic thrombolysis. introduction. cardiogenic shock during massive pulmonary embolism (blpe) is due to an acute increase of right ventricle (rv) afterload and possibly rv ischemia causing a failure of rv pump function. the rec~;mmended therapeutic strategies are: xoiume augmentation ~n ~rder m }ncrease rv pre-h~ad, adrenergic drugs to increase t'ontractillly and maybe coronary perfusion, fibrinolytic drugs to delermine clot lysis. there have been several reports of noradrenaline (na) as a useful drug in this setting for its sluing ~z, but also ~, properties. case report.an obese },ears old woman was transferred to our icu for tetanus. she was given the usual antibiotic and immunoglobuline therapy. l'wo thoracic epidural catheters were put in place at different levels and replenished with marcaine qid. a continous infusion of sedation (diazepam § was started together with mechanical ventilation. curarization ~,as given occasionally. fraxiparine . /die was used for prophylaxis of thrombotic disease, on day th at . a.m. she started to be hypoxic (sa %), tach ,tardic l l(i b/rain.), her blood pressure(rp) dropped frum norma~ values to r mm/hg, the central venous pressure (cvp) raised [rom lb to mm/hg and the end tidal co was mm/hg lower than one hour before. the physical examination of the chest revealed a clear bilateral ventilation and the chest x-ray was normal apart from an elevation of the :tiaphragm as compared to the previous. an e.c.g. showed sinus tachycardia, right bundle branch block and a possible inferior necrosis (which was already present on admission). a trans-thoracic echozardiography was performed which showed "an acute overload of the right centricle wilh remarkable dilatation. tricuspidal regurgitation ++. paradoxical movement of septum. small left ventricle with normal wall kinetics". the cardiac enzymes were later shown to be normal. an acute massive pulmonary embolization was assumed m be present.. a bolus of streptokinase x i(i u. was given fonowed by a continous infusion . two liters of colloids were also given in a sh~rt time, two hours later the patient was still deeply hypotensive, hypoxemic and anurir(bp / mm/hg, cvs mm/hg, spo %) despite a cominnus infusion of dobutamine fag/kg/min and adrenaline . ~tg/kg/min. at this stage a bolus of aoradrenaline ,g was given followed by a cnntinous infusion of . !*g/kg/min. an immediate improvement of the hemodynamics was noticed and one hour later the bp was / mmhg, the cvp mm/hg, the sao % and a brisk diuresis started. the hemodynamics kept stable and weaning from vasoactive drugs was achieved within two days. one month iater the patient was discharged home in good conditions.. con c i u sio n.ne administration may help to restore rv coronary flow and ;~ump function during mpe. aeute putmonary t~omboembo~sm [ffe) cou be mamfeslated with either respiratory or cardiovascular syndromes or both. the arm of the study was to establish leading respn'atory symptoms, frequency and form of the roendganographic (rig) changes as well as blood gas disturbance degree in acute pte with dommam respiratory disease appearance. the study includes retrospeotive analysis of i pte patients (pts), males (average age , yrs) and .q females (average age , yrs). they were admitted at university, olinie" with suspection ofpleuropnlmonary disease, including pte. final diagnosis of pte was based o~ evident risk factors in , % of the eases (deep venous thrombosis, surgery, trauma, imobilisation, malignancy ere), acceptable clinical, rtg, sdntigraphic and laboratory findings, as well as deep veins examination by dopple~-sonographie and radioisotopic -~enogmphy. respiratory symptoms appeared in all cases: sudden pleural pain ( %), dyspnea ( %), hemoptysis ( %), cough ( %) with association of two or more symptoms in %. chest xrays findings were abnormal in % with diaphragmal elevation ( , ~ lung opaeilies ( , %), atelectasis ( , %), plemal effusion ( , %), main pulmonary brancah asimetry ( , ~ oligemia ( %), heart shadow changes ( , %) and pulmonary arteries "cut off' ( , %). the association of two or more abnormalities was found in , % while normal chest x-rot was found in ~ of the cases. hypoxemia with pao < , kpa was found in , % followed with hypocapnia and respiratory alealosis in , % in , % of the gas exchage analysis were within normal limits. among cardiovascular symptoms short syn~cpa appeared in i , %, ecg changes-st q t type in "~ , %. results show high frequency of positive ~g findings in pte pts that is opposite to oppinion that chest x-ray in acute fie is the most ofran normal. leading symptoms are pleural pain and dyspnea, while hemoptysis were found in a half of the study group. blood gas changes were present in two thirds of the cases. kakkar, in his classic work ,clearly demonstrated the efficiency of low doses of heparin in prevention of deep vein thrombosis (lancet : , ) .after this first study the application of heparin prophylaxis became more and more diffused until to be considered a routine in many surgical departement.actually application of blood saving technique induces postoperative hemodilution effect. in that condition prophylaxis routinely applied seems a nonsense and can be at risk for postoperative hemorrhage. methods: to analize this problem we compared patients arrived in our intensive care unit (i.c.u.) in. : (group a) with arrived in : (group b) .every patient was operated for major abdominal surgery.in each one we considered the hemoglobin (hb) value,hematocrit(hct), and coagulation pattern (c.p.) at the arrive in i.c.u. and hours later. the patients was also divided in those receiving heparin prophylaxis (i) from not treated patients (ii) results:the application of blood saving technique clearly appears from the hb and hct level wich have a mean value of , +/- , (hb) and +/- (hct) in group a while in group b mean value are , -/- , (hb) and +/- (hct).patients of group a (ii) are the only one where a pathologycal c.p. with statistical significance has been demonstrated.in this goup we got four cases of evidence of venous thrombosis and one of pulmonary embolism.in patients of group b(i) we encontered the incidence of two cases of severe hemorrhage despite the absence of statistical significance in c.p.modifications. oxygen desaturation during broncho-alveolar lavage: role of oxygen saturation monitoring in prevention of acute respiratory insufficiency g. galluccio, b. valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the broncho-alveolar iavage is a diagnostic procedure employed in interstitial diseases of the lung. it requests the introduction through the working channel of a fiberoptic bronchoscope, after occlusion of a segmentary bronchus, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove cells and proteins from elf (endoalveolar lining fluid), which is related to interstitial medium. bronchoalveolar lavage induces deep effects on pulmonary function: -lowering of the alveolar surface of exchange; -shunt effect, depending on the perfusion of non-ventilated districts; -increased pulmonary arterial pressure, due to hypoxic vasoconstriction; -decrease of lung compliance. in this report the authors present the result of oxygen saturation monitoring in a group of patients with interstitial lung disease, who underwent diagnostic broncho-alveolar lavage. in most patients with severe interstitial involvement, the lavage performed without supplement of oxygen induced a severe fall in the oxygen saturation during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. in patients without thickening of interstitium, in whom the lavage was performed in order to obtain material for bacterial or cytologic examination, no modification of oxygen saturation was observed in standard procedure. as conclusion the authors strongly reccomend monitoring oxygen saturation in patients with radiologic evidence of interstitial involvement also in patients with no evidence of dyspnoea. g. galluccio, b.valeri, s.batzella, m. di lazzaro*, servizio di endoscopia toracica, ospedale forlanini, rome, italy * servizio die anestesia a rianimazione, osp. forlanini the treatment of choice in patients with alveolar proteinosis consists of pulmonary lavage. this procedure requests the introduction, through the working channel of a fiberoptic bronchoscope, segment by segment, of aliquots of saline solution at c, subsequently gently reaspired, in order to remove the proteins deposited in the alveolar spaces. the method is very similar to that used in bronchoalveolar iavage, a diagnostic procedure used to obtain cells and substances from elf (endoalveolar lining fluid), which is related to interstitial medium. as known, bronchoalveolar lavage induces oxygen desaturation, because of shunt effect. understandably, one lung lavage has remarkably more deep effects on pulmonary function than bronchoalveolar lavage, for the amount of fluid introduced, the length of the procedure and the conditions of controlaterai lung. in this report the authors present the result of oxygen saturation monitoring in a patient who underwent pulmonary lavage for alveolar proteinosis. in the lavage performed without supplement of oxygen a severe fall in the oxygen saturation was observed during the late phase of the procedure. if supplementary oxygen was delivered during bronchoscopy, since its beginning, only slight modifications of the curve were detected. as conclusion the authors strongly reccomend the subministration of supplementary oxygen in pulmonary lavages, also in patients with excellent respiratory conditions. a. b. dublisky prof., m. r. isaakjan ass., v. a. zasukha, s. m. vinichuk prof., v. p. tserty ass. prof., chair of anaesthesiology, resuccitation and medicine of catastrophes, neurology of ukrainian state medical university, kiev, ukraine. objectives: detection of plasmophoresis's influence of results in treatment of ishemic insult. methods: we ve investigate patients with ishemic insult, treated with reverse plasmopheresis in complex treatment. after primary infusive therapy we took ml of patients' blood and separated it within min with rotation frequensy of /rain. after separation of erythrocytes from plasma, the latter has been returned to patients. we made - procedures during - days. hemoglobin, hematokrit, time of blood coagulation were determinated. the brain blood flow in internal carotid arteries, regional volum brain blood flow and total brain biood flow were evaluated with tetrapotar chest rheography and tetrapolar rheoencephalography. obtained date were comparised with control group after traditional treatment. results: it was found that after reverse plasmopheresis the hemoglobin and hematokrit levels decreased significantly in studied patients' plasma (from + . g/l to _+ . g/ and from + . % to _+ . % respectively). the time of blood coagulation by lee-white has increased by - . times (up to - rain). the level of brain blood flow has been increased significantly after reverse plasmopheresis in comparison with control group. the following tests of brain blood flow have been increased: a) the total volume brain blood flow from . + . ml/min to . _+ . ml/min (p < . ); b) the regional brain blood flow from . _+ . ml/min to . + . ml/min (p < . ); c) the brain blood flow in internal carotid arteries from . _+ . ml/min to . + . ml/min (p < . ). conclusions: the use of reverse plasmopheresis in complex treatment of patients with ishemic insult aiiows to improve rheological blood patterns, helps to increase volume brain blood flow. it results in quicer reparation of neurological functions. objectives: a prospective evaluation of the efficacy of continuous infusion of verapamil in reducing the incidence of postoperative atrial fibrillation after pulmonary surgery. methods: a total of consecutive patients, on verapamil, on placebo was included after lobectomy or pneumouectomy. a loading bolus of verapamil ( mg over minutes) was followed by a rapid loading infusion ( . mg/min) for minutes and finally a maintenance infusion ( . rag/rain) for hours. results: a mean plasma level of verapamil of ng/ml was obtained only after more than hours. atrial fibrillation occurred in five out of patients who tolerated the verapamil infusion, and in out of patients on placebo (p = . ). verapamil infusion was not tolerated in patients because of hypotension or a heart rate of less than /min, within hours of the start of the therapy. when atrial fibrillation occurred, the ventricular response, mean _+ sd, was not significantly slower during verapamil infusion ( + ) compared to placebo ( + ). conclusions: because of its frequent side effects and the only modest efficacy verapamil should not be considered for prophylactic therapy of atrial fibrillation after pulmonary surgery, and is probably not a good first choice for slowing the heart rate in case of rapid ventricular response once atrial fibrillation has occurred in these patients. results: study of haemostasis in these patients has showed deep disturbances of blood coagulation. fibrogen level has reduced to . + . g/l, fibrinogen and/or fibrine degradation products concentration have enhanced to . _+ . g/l, monofibrin soluble complex concentration to . -+ . g/l, blood plasmin level was enhanced to . + . mmol/ , plasminogen proactivator level was also enhanced to . + . ram, plateletes aggregation has decreased to %. after plasmopheresis aggregation was decreased in . times. it has been connected with decrease of fibrin and/or fibrinogen degradation products level and level plasmin in . times, and plasminogtnt activator level in . times. at the same time we have observed increase in total antifibrinalitic activity of blood in . times. activity of activators plasmine and plasminogene proactivators has decreased in . times and in the same time activity of activation inhibitors and antiplasmines has increased in times. conclusions: plasmapheresis leads to considerable improvement of a general condition and reduction of the haemorrhagic syndrom's sings (controlling of gastrointestinal haemorrage, reduction of intensity of subcutaneons haematoma). evaluation of continuous cardiac output (cc ) monitoring based on thermodilution technique in critically ill patients. methods: cardiac output (co) was monitored continuously using a modified pulmonary artery (pa) catheter, on which a heating filament is located and by which energy is transmitted to the circulating blood. a microprocessor calculated co by a new algorithm. standard bolus thermodilution technique ( ml of ice-cold saline solution) was used to compare cc with intermittent bolus cardiac output (ic ) measurements. the following subgroups were prospectively studied: i. heart rate (hr) > beats/min, . cardiac output > i/min . cardiac output < . i/min, . rectal temperature > . ~ and . pa catheter was inserted for more than days. results: a total of pairs of ic and cc measurements were obtained from the patients. bias (ico measurement minus cc measurement) of all measurements were . • i/min and the % confidence limits (mean difference• were - . / . i/min. also in the subgroups, cc measurement agreed closely with ico measurement (c > i/min: bias= . • i/min; co < . i/min: bias=- . • i/mln). elevated temperature and prolonged lay-days of the pa catheter did influence agreement of cc measurement with ic measurement neither (> ~ bias= . • i/min). conclusions: monitoring of cc using a modified pulmonary artery catheter with a heated filament has proven to be accurate and precise also in the critically ill when compared with "standard" intermittent bolus thermodilution technique. this method enhances our armamentarium for more intensive monitoring of these patients under various circumstances. background: the number of patients who need coronary artery surgery was) grows every year. most of these surgical operations are with extrar eircuiation (ecc). since january , this surgery is made without ecc in selected patients in our hospital. this technique is exceptional in spain. this type of surgery has proved useful in patients requiring revascularization of the left anterior descending, eireunflex or right coronary artery (not for grafting the pos~tefio~r descending branch}. blethods and results: since , patients aged to years (mean years) underwent cas without ecc. the mortality in programmed surgery was %. no patient was reexplored for hemorrhage. the mean values of some clinics parameters v~ere: a) blood requeriments: units per patient, b) need of mechanical ~entilation: i , hours, c) postoperative bleeding: cc, d) days at icui , . we used the student % t test or fisber~s exact test to compare these results with the mean values of surgery with ecc: a) blood requeriments per patient (p< , ), b) need of mechanical ventilation: hours (p< , ), c) postoperative bleeding: cc (p< , ), d) days at icu: (p< , ), e) programmed surgery mortality: % (p< , ). conclusion: our limited experience shows that this surgery is an alternative in the treatment of coronary disease, especially for aged patients with associated pathology and in jehova's witness. the need of mechanical ventilation, days at icu, blood requeriments and morbi-mortality were fewer than surgery with ecc. to study the hemodynamic and antiarrhythmic influence of ace-inhibitor enalapril in acute myocardial infarction (mi). methods: holter ecg monitoring, heart rate variability analysis, echocardiography ( and l days after beginning of the treatment), stress-echocardiography and stress ecg ( - -th day after the onset of mi). enalapril was included into the treatment of pts with mi (study group), with normal or increased blood pressure, from the -st day of the disease. the data were compared with pts treated without enalapril (control group). results: silent ischemia during stress-test was registered in pts of the study group and of control group, the arrhythmia episodes during stress test -in and pts and episodes of silent nocturnal isehemia -in and pts correspondingly. enalapril importantly attenuated the hypertensi~re re~aetioh % stress test. in pts of the study group the number of perifocal hypokinesis zones decreased; in the control group it didn't change. the quantity of ventricular extrasystoles in the patients of the study group decreased by %; the heart rate variability indices improved as well; in the control group the character of ventrieulir arrhythmias, heart rate and its va]~i~bili%y didn't change significantly. conclusions: the inclusion of enalapril into the treatment of mi is a useful t ol to improve hemodynamie parameters and decrease the incidence of ventricular arrhythmias. objectives: to study left ventricular (lv) systolic function in the patients with acute myocardial infarction (ami) before and after peroral captopril test. methods: the original echocardiographic parameter of lv contractility, "coefficient of effective systolic function" (cesf), was proposed in the study. cesf is calculated from lv stroke volume (sv), obtained from doppler aortic flow in lv outflow tract and lv end-diastolic diameter (edd): cesf =sv/edd. the study included patients with ami, who had local lv dyskinesia and global lv systolic dysfunction (ef< %). besides cesf, the ejection fraction was calculated before and after administration of mg eaptopril (on the fifth day of ami) by methods of bullet and simpson. results: the dynamics of these parameters, as well as heart rate (hr) and mean blood pressure (bp), is shown in the tabte. before cal~topril ef (bullet) . • . ef (simpson) . introduction: the cold system is a monitoring system for measurement of right (copa) and left (coart) ventricular cardiac output, cardiac function index (cfi), fight ventricular ejection fraction crvef), fight ventricular cnddiastolic volume (rvedv), intrathoracic blood volume (!tbv), global enddiastolic volume (gedv), lung water (etv) and excretory liver function (pdr). patients and methods: pts have been monitored by the cold system. above mentioned parameters are measured by thermal dye dilution and a fiheroptic femoral artery catheter. copa, rvef and rvedv measurements additionally were compared to measurements by the baxter explorer. :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ;;;k;;;;i cov (%) explorer ! ! [ gedv, itbv and pdr showed a significant decrease dufing the first - h after the operation, cfi and rvef si~canfly improved after k wheras etv showed a i~ in the early postoperative phase and fell to normal ranges at h. comparison of cold/explorer m~ements sb wed good correlations. discussion: concerning m ~toring of ri,ght ventric~ar function cold and explorer can he seen as equal. rvef gives an ar report about the performance of the right ventricle without use o f echocardiography. measuring itbv and gedv ~ improve ~gement and con~ol of th.e volume status, monitoring etv helps preventing lung edema. pdr shows good corre|ati n to liver blood chemistry and is bedside avai|ab|e. thus the cold system offers additional parameters for comprehensive m~nitofing of pts. ~e~ ~c surgery. obiectives: to evaluate the influence of an a!'~ered cardiac function on the cardiovascular response to the increase in oxygen demand induced by an increase in core temperature. methods: this preliminary study included adult critica!ly ill patients monitored by arterial and pulmonary artery catheters in whom thermodilution cardiac index {ci) and arteria! and mixed-vef)ous blood gases measurements could be obtained before and after an acute change in core temperature of at least . ~ (max rain apartl the patients were separated in two groups according to their cardiac function: patients had an impaired cardiac function as defined by a history of cardiac disease and an ejection fraction below % and patients had normal cardiac function. results: individual data are shown in the figure. in contrast to the control group (continuous line) in which c! increased without changes in oxygen extraction ( er), the q er in patients with impaired cardiac function (dottled line) increased without changes in ci. conclusions: the increase in oxygen demand associated with changes in temperature is met by an increase in c! in patients with unaltered cardiac function and in an increase in o er in patients with altered cardiac function. temperature should be taken into account in the assessment of the adequacy of cardiac output in patients with impaired cardiac function. objectives: to define the hemedynamic and metabolic response to physical therapy(pt) in relation to the type/level of sedation and the cardiac status in icu patients. methods: we studied mechanically ventilated icu patients ( • years) in stable hemodynamic status (no change in vasoactive treatment for at least hours), separated in groups: group = deep sedation, cardiac dysfunction required dobutamine (n= )r group = deep sedation (barbiturates), unaltered cardiac function (h=lo), group = moderate sedation, altered cardiac function (h= ) and group = moderate sedation, unaltered cardiac function (n= ). complete hemodynamic data, arterial and mixed venous blood gases, respiratory gas analysis (metabolic cart ccm, medgraphics) were obtained at baseline ( x) and twice (q. min) during leg mobilization. data were analyzed by anova. calcium channel blockers were used in complex preoperative preparation of hypertensive surgical patients. patients were allotted to groups based on their hemodynamic profile: hypokinetic: ejection fraction (ef)< . , patients; eukinetic (ef> . ),i patients and hyperkinetic (ef> . ),i patients. the most noticable change in hemodynamics was in the hypokinetic group: ef and cardiac output (co) were significantly decreased (p< . ) while systolic arterial pressure (sap) (p< . ) and peripheral resistance (pr) (p< . ) were elevated. the results showed that in hypokinetic patients on nifedipine ef (p< . t) stroke volume (sv) (p< . l) and co (p< . ) were increased while pr(p< . t), sap(p< . ) and diastolic arterial pressure(p< . ) were decreased. eukinetic type patients also showed an increase in ef,albiet to a lesser extent,than in the hypokinetic group. increased sv and co(p< . ) were observed in eukinetic patients though this was to a lesser extent than in the hyperkinetic group. in the hyperkinetic group of patients nifedipine had no effect on the aforementioned parameters except for a decrease in sap(p< . i). nifedipine increased ef in all hypokinetic patients. comparative results show that isoptin was less effective than nifedipine in decreasing peripl~eral vascular resistance and had a depressive effect on the myocardium. it can be concluded that the action of calcium channel blockers normalizing the circulation in the hypertensive surgical patient depends on: the condition of myocardium, the patients hemodynamic profile and their pharmacological properties. they were most effective in the hypokinetic group. zalo/nthinos e., daniil z. zakynthinos s., armaganidis a., kotanidou a., nikolaou ch..,roussos ch. critical care department, university of.athens, evangelismos hospital, athens, greece. introduction : surgical is the optimal treatrnent for ioculated effusions and the preferable procedure when multiple bands are seen in the pericardial sac by echo. patients : palients, post cardiac surgery, uremic ( men, women) with large pericardial effusion and clinical or echocardiographic findings of tamponade or both. these particular patients displayed numerous linear echo-dense bands and s~'ands crossing the pericardial space (in one of them a ioculated effusion compressed the left ventricule). one had aptt increased, four were mechanically ventilated. technklue : a fr polyurethane catheter with end and multiple side holes over ga needle was echo-guided to the ideal site (fluid abundant and closest to the transducer). the catheter was attached to a close system with a heimlich valve for continuous drainage (pneumothorax kit). subcostal entry was selected in one patient and chest wall in five. the patient's position was changed every hour at least. (we believe that the small changes in the position of the catheter and the mechanical breaking of the bands in relation with the movement of the heart assist the pericardial fluid to remove). results : in all cases only a small quantity of fluid was withdrawn in the first minutes( - ml) with some clinical and echo-findings improvement. the fluid was bloody or serosanuginous with high protein content (ht= % ,protein , gr/dl) in all cases. in first hours the mean volume of fluid removed was ml ( to ml). in that period echo showed no residual fluid. the catheter remained within the pericardium to days .. no complications are mentioned. conclusion : cardiac tamponade due to hemorrhagic high protein pericardial effusion in uremic and postcardiac surgery patients,, as it is revealed by echo dense bands, can be faced by -d echo guided perieardiocentesis. a -fr polyurethane catheter with multiple side holes, attached to a heimlich valve was effective to evacuate the pericardial fluid. no catheter was occluded though heparin infusions were not used. multiple changes of the patient's position may be fundamental. this -d echo guided pericardiocentesis performed in in~nsive care unit seems to be useful , safe and quick technique. determining the best inotropic drug represents a very serious problems. the use of more selective and potential inotropic and vasodilatative drugs does not always lead to improvement of hemodynamic parameters in patients with low cardiac output syndrome. this paper presents patients with acbp who need an inotropie support after extracorporeal circulation in first hours. the patients were divided into dobutamin et dopamine groups. the heart rate (hr). mean sistemic arterial pressure [map), central venous pressure (cvp). and termodilution cardiac index (ci) were measured. the measurements were without using inotropic drugs, and then using them after rain, min, and finally with one hour rate, within first hours. the statistical analysis shows that both drugs lead to an increase in hr in the first hour of the application. the final effect of dobutamine is no change in hr, whereas the effect of dopanime is very significant increase in hr. thus. an absence of taehyeardie response selects the dobutamine as a better choice. backeround: pulmonary vascular eadothelium possesses major metabolic functions, which when altered contribute to the development of serious pathologies such as ards. one such function is the conversion of angiotensin i to angiotensin ii, catalyzed by angiotensin converting enzyme (ace), located on the luminal surface of the endothelial cells. ace activity has been extensively studied in animals in vivo, by means of indicator-dilution techniques, providing: i) under toxic conditions, an early index of lung injury, and it) under normal conditions, estimations of dynamically perfused capillary surface area (pcsa). objectives: to validate the use of these techniques in matt: i) for pulmonary endothelial function assessment, and it) for pcsa estimation. methods: ace activity was estimated in ten adult haman volunteers, with no pulmonary medical history and normal pulmonary artery pressures, undergoing cardiac catheterization for coronary artery disease assessment. single-pass traspulmonary hydrolysis of the specific ace substrate hbenzoyl-phe-ala-pro (bpap; p.ci) was measured by means of indicatordilution techniques, and expressed as %metabolism (%m) and v=-hi( -m). bpap was injected as a bolus i) into a main pulmonary artery, and it) inside the right atrium, to assess ace activity in one and both lungs. we also calculated a,~,/i~, an index of pcsa. pulmonary plasma flow (fv) was determined by thermodilution. fp in one lung was estimated as . xf v. results: similar values of %m ( . + . vs . • and v ( . • vs . • were observed in both and one lung respectively. a~k~ decreased from • ml/min (both ltmgs) to :~ (one lung). conclusions: i) pulmonary endothelial ace activity and thus pulmonary endothelial function may be assessed in humans by means of indicator-dilution techniques, it) our data denote homogeneous pulmonary capillary ace coneentratious and capillary transit times in both haman lungs, iii) the % reduction of a=~/k~ in one lung suggests that this procedure can be used to quantify pcsa in man. (supported by the fonds de la recherche en saute du quebec and the national health system of greece). objective: verify whether antioxidant activity is higher in reperfused than in no-reflow myocardium after i.v. thrombolysis for acute myocardial infarction (ami). methods: patients with ami were included. blood for estimation of catalase (cat), glutathione peroxidase (gpx) and mn-superoxide dismutase (sod) was drawn before initiation of i. the mechanism of myocardial cell defence against free radicals is probably identical in both reperfusion and no-reflow phenomena. therefore, antioxidants cannot be used as reperfusion markers. objectives_ to evaluate the precipitating factors of hypothermic phrenic nerve injury following cabg with lima. methods: fifty two consecutive patients ( females), with a mean age of + (mean +sd) years were studied. during the ischemic arrest time topical hypothermia was obtained in al~ patients wffh ice slush and no cardiac insulation pad was used. all patients received a lima graft, with or whithout additional vein grafts. supramaximai, bilateral phrenic nerve stimulation was performed percutaneously preoperatively and whithin hours postoperatively. square wave stimuli of . msec duration were applied at the posterior border of the sternomastoid muscle. the compound muscle action potential of the diaphragm was recorded, using surface electrodes on the anterior chest wall. the time interval from the application of stimulus to the onset of diaphragmatic activity, phrenic nerve conduction time (pnct), was measured. values exceeding . msec were considered as abnormal. besults: preoperatively, all patients had normal (mean+sd) pnct, . • msec for the left nerve and . • mseo for the right nerve. on the first postoperative day, right pnct was normal in atl patients ( . • msec) , whereas left pnct was normal in patients ( . • msec) and abnormal in patients (incidence . %). in patients the left phrenic nerve was inexcitable and in patient left pnct was prolonged ( . msec). comparing patients with normal and abnormal pnct there was no difference in age, gender, number of grafts used, aortic cross-clamp and bypass time. however, patients with abnormal pnct had a lower preoperative ejection fraction ( • vs • p= . ). moreover, in all of them lima was dissected from its origin ligating all upper arterial branches, which provide the blood supply to the left phrenic nerve, whereas in those with normal pnct the small vessels originating from the upper to cm of lima were preserved (p= . ). conclusiojel~ a hypoperfused left phrenic nerve seems to be more susceptible to hypothermic injury during cabg with a lima conduit. objectives: to test if necessary interventions on systemic vascular resistance (svr) along with preset pump flew (q) during cpb could adversely affect autoregulatory response and cause vo shifts. methods: we studied males ( - yrs) who underwent cpb for cardiac surgery. at o oesophageal temperature - c we set pump flow at . i.m~ .min - . when map was higher than mmhg we calculated vo by using fick equation. then we infused sodium nitropruaside (sn) to control map at - mmhg for min and we calculated vq . without changing the sn infusion rate we set q at . i.m' .min " . ten min later we measured vo . we took vo changes into consideration if greater than %. statistical analysis using students-t-test for paired data and analysis of variance was used as appropriate. results: depending on the biphasic vo response to sn infusion during low and high q we classified pts in four groups (table). i. vo increases with sn and increases further during high q unmasking hypoperfusion and supply dependency. ii. vo increases with sn but the addition of high q results in systemic shunt. iii. vo increase during high q proves that vasodilatation can turn flow insufficient. iv. vo does not change with any intervention. the small number of pts and the wide standard deviation did not allow any statistical significance. conclusions: cpb is an interesting model for the behavior of microcirculation. intervention on svr and q can improve or impair effective regional oxygen delivery, resulting in either better perfusion or systemic shunt. vo monitoring seems necessary during cpb. preoperative cardiovascular optimization (opt) to ci > . l/min/m , _< paop < mm hg,and svri __< mmhg/ll/min/m decreases cardiac events (events) and mortality (mort) in peripheral vascular surgery patients (pvs). objectives: to determine if opt to the same endpeints decreases events in patients undergoing abdominal aortic aneurysm repair (aaar) and to study the r predictive value in pvs patients. methods: aaar patients and pvs patients were admitted to the s cu monitored with e pa and arterial catheters and treated to achieve opt. patients underwent surgery independent of success of opt data included demograph cs, incremental risk factors, laboratory and hemodynamic data pre, intra, a~nd postoperatively events, and mort. events included arrhythmias requiring treatment or prolonging the sicu stay > hours, a st depression > !mm or t wave inversion, an acute mr defined by a new q wave > . sec or cpk-mb > %. results are presented as means _ -. sd. opt was achieved in of ( %) and in of ( %) in the pvs and aaar group, respectively. events did nat differ between groups of ( , %) and of ( , %) in the pvs and aaar group, respectively (p>o. ). mort was of ( %) and of ( . %) in the pvs and aaar group, respectively (p > . ), while there was no difference in endpoints of opt between patients with and with.out events in the aaar group, there was a significant difference in ci between patients with and without events in the pvs group. of note, of ( %) patients who developed events in the pvs group had a ci < . in contrast to of ( %)in the aaar group. the positive and negative predictive value were % and % in the pvs and % and % in the aaar group. conciusione: f. the endpoints of opt used for pvs patients cannot be ~sed to reduce events in aaar patients; . pvs patients who have net achieved opt are at extraordinary risk of perioperative events; . preoperative card ovascu ar opt in aaar patients makes no difference in cardiac related events, background : comparison of the right and left filling pressures (cvp/pcwp ratio) is considered as a useful diagnostic clue : the normal ratio is _< . ; ratio >_ . may suggest right ventricul~ infarction while equalization of the cvp and pewp is a classic sign of tamponade ( ). however after cardiac surgery, many conditions (diastolic dysfunction, pulmonary hypertension, positive pressure ventilation) are susceptible to modify the '*normal" cvp/pcwp ratio. material and method : we determined cvp/pewp ratio in consecutive patients (pts) after uncomplicated cardiac surgery ( coronary artery bypass grafts; valvular replacements) measurements were made before and after tracheal axtubation. results :cardiac index : . _+ . /minlm~; laotate: + rag/i; cvp range : - rnmhg; pewp range : - mmhg. mean cvp/pcwp ratio before extubation is . ( % confidence imerval : . - . ) and after extubation, . ( % confidence interval : . -. . ), (ns, paired t-test). in % of the pts, cvp was higher than pewp. there are no correlation between the cvp/pcwp ratio and c! before (r = - . ) and after extubation (r = - . ) nor between the cvp/pcwp ratio and mean pulmonary arterial pressure (mpap), before (r = . ) and after extubation (r = - . ), discussion : cardiac performance is adequate according to ci and lactate. however the cvp/pcwp ratio is markedly higher than the "normal" (_< . ) ratio. this difference is not related to mechanical ventilation because the ratio is similar before and after extubation, nor to pulmonary hypetaension because of absence of any correlation with mpap, post-cpb diastolic dysfunction of the right ventricle could be an alternative explanation. in this group of pts, increased cvp/pewp is not associated with any impairment of cardiac performance (absence of correlation with ci), conclusions : cvp/pcwp ratio as high as within a large range of cvp ( - mmhg) and pcwp ( - mmhg) may still be considered as normal after cardiac surgery. this emphasizes the limitations of the hemodynamic monitoring after cardiac surgery (in comparison with echographic technics). careful analysis of the morphology of the cvp and right ventricular pressure curves (x descent, y descent, dip-plateau) is mandatory rather than relying on the quantitative assessment alone. reference : ( ) ntensive care.-university hospital -m~laga (spaink introduction. fibrinolitic treatment (ft) permits the treatment of acute myocardial infarction (ami) addressing the etiology, thereby eading to mproved ventncular function and a marked reduction m mortality. the main clinical oroblem is the reduced time of application. delay in hospitalization, which can be from to minutes, is potentially the most avoidable delay. method. to reduce delays in hospitalization, the following was carried out in two chases. audit: analysis of the time lapse from onset of symptoms to start of ft. showed that during "(he period june to december , patients with chest paros were treated within a eriod varying from minutes to hours from onset of symtoms. ages ranged from to (average , ), oelng males and females. they were glved initial ecgs to determine st mcreases suggesting ami. median t~me for this orocedure was l m.. potentia ami patients were then admitted to the coronary unit, [)atients, under age with no contraindications received ft the median time apse from admission to corona-y care and administration of ft was minutes ( . ), -he total median delay was minutes ~ -i h. min,~ delays n start of this procedure are grouped as follows: extra-hosdita delays (from onset of symtoms to arrival at hospital) diagnostic delays (from hospital arrival to ecg). treatment delays (from diagnosis to ft). objectives: protocol of procedure to implement a fast-track method. a protoco was drawn up with the object of reducing diagnostic delays to -i minutes and treatment delays to less than i minutes results. following rmplementatlon of this protocol in january , fts were glven, with an over all average delay of minutes. this fast-track method did not reveal any inappropnate ft or any increase m complications, conclusions: detailed study of the various times taken for diagnosis ane treatment of ami patients, showed up weaknesses in the system and improvements througn the protocol based on performence orocedures which led to a % reduction in the start of ft background: the importance of the early use of thrombo!ytic agents in acute myocardial infarction (ami) is based in the better remaining ventrictjlar function and smaller mortality rate because of the greater reperfusion and sma!ler infarction size, therefore, it is very impodant to apply this treatment to the maximum number of patients without thrombolytic contraindicati n, and within the minimun period of time. the "thrombolytic fast track" implementation allows to optimize the time to administrate thrombelytic agents avoiding multiple delays~ methodology: we anal!ze the application of thromboly c agents to patients with suspect of ami from the begin!ng of september until the end of february . in this time there are two different periods, during the first months thrombolytic agent were admin!strated at intensive care unit (icu), and during the second period we carried out a protocol of quick detection and thrombolysis therapy in susceptible patients at the emergency room in order to reduce the time to treatment. ma!n results are shown in the faffewins de ay h=hours m=minutes the implementation of the fast track does not need supplementary personal or equipment but a protocelized approach and training of the personal involved the main problem detected was the usual attendance overload of the emergency department that makes difficult to follow many structurated actions. conclusions: pratocqlized changes in the management of ami can significantly reduce the detay in the administration ef thrombolytic agents. it is not necessary to eomplet the procedure iq the emergency department, as the use of bolus schedules allows to begin the treatment in this area and to transfer the patient to icu afterwards. elective cardiac surgery. b calvet, f ryckwaert, p trinh duc, p colson. anesthesia -reanimation, hopital arnaud de villeneuve, montpellier, france. obhectives: the study was aimed at analysing the incidence of renal dysfunction following cardiac surgery and its prognosis (acute renal failure, post-operative morbidity and mortality). methods: two hundred and thirty seven patients (aged from to ) were consecutively operated on for elective cardiac surgery and retrospectively included in the study. patients with preoperative infections and operated on in emergency were excluded. each patient had preoperative invasive cardiac investigation with angiography and calculated ejection fraction (ef). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest management were similar in all patients. general body temperature was reduced to - ~ c. renal dysfunction was defined as a % increase from baseline of serum creatinine. demographic data, asa, treatments, pre-operative creaunine level, cpb and clamping (axc) times, intra and postoperative use of inotrope, serum lactate level before surgery, at the end of cpb, at the time of admission in intensive care unit (icu) and on post operative day one and apache score were compared in patients with or without renal dysfunction using anova test for repeated mesures and x when appropriate. data are expressed as mean +__sd. p value less than . was considered statistically significant. results: thirtytwo patients ( , %) suffered from renal dysfunction. age, serum lactate level at the end of cpb, at admission in icu, at pod and apache level at admission in icu, intra-operative use of inotropes were statistically different in patients with or without renal dysfunction (p< , ). mortality rate was statistically different in patients with or without renal dysfunction(~, , % and %, respectively, p= , ). incidence of acute renal failure following renal dysfunction was , % ( patients required hemodialysis). conclusions: although our cdteria for defining renal dysfunction were very sensitive, the incidence of renal dysfunction following elective cardiac surgery was lower than communly accepted in the litterature ( ). however renal dysfunction appeared significantly associated with a poor prognosis. reference: -settergren g, ohqvist g current opinion in anaesthesiology , : - r ; , tzelepis, g. , , late complications were observed in % of cannulations: local infection in (i, %), catheter displacement by the patient in cases ( , %), catheter displacement during nursing care in ( , %) and malfunction in cases ( , %). conclusions: central venous catheterizations are followed by immediate and late complications in almost the same percentage acute poisoning with amphetamines (mdea) and heroin: antagonistic effects between the two drugs methods: after institutional approval and informed consent, selected patients ( _+ years) undergoing peripheral vascular surgery (n= ) or carotid endarterectomy (n= ) were investigated. patients included had either documented cad (n= ) or two or more (n= ) dsk factors (age > years, smoking, diabetes meltitus, hypertension, hypercholesterolaemia > mg/dl). -lead ecg recordings were carded out preoperatively, on ardval in the postanaesthetic care unit, and h, h, h, and h postoperatively. ecg recordings were analysed by an independent blinded cardiologist for signs of pmi (new st segment depression > . mv and/or new t inversion). in addition results: of the patients investigated developed ecg-documented pmi, % occurdng in the immediate postoperative phase. troponin i levels > . ng/ml were found in of these patients thus, comparing a cardiac troponin i cut-off level of ng/ml with intermittent -lead ecg recordings, we found a sensitivity of % and a specificity of % methods: demographic, clinical and ecg data were analyzed. . % of patients were male; . % female. cad was the most common underlying cardiac disease ( . %) and . % underwent open heart surgery. % received proeainamide for supraventricular and % for ven~cular arrhythmias. % received a loading dose. maintenance was provided by iv route in . % and by po in . % ( . %sr end . % ir). . % of patients were obese right ventricular function following cardiopulmonary bypass: is important the mode of myocardial protection we underwent this study in order to examine its safety and usefulness in pts with trustable coronary conditions (unstable angina ua the mean age for group a was • years, for group b • years, and for group c • years. a history of previous myocardial infarction was present in pts of group a, in of group b and in of group c. three pts in group a, in group b and in group c had previous coronary artery bypass grafting. the median time between the onset of symptoms and a was days ( - ) for group a we used a continuous fixed intravenous a infusion at a dose of the sn was % in groups a and b, % in c, and sp % for group a, (fixed defects included) and % for groups b and c. there was no difference of side effects among groups: chest pain (i pt -group a, pts -group b, and pts -group c), transient hypotension ( pt -group c), headache ( pts, group c), dyspnea ( pt -group a), while st depression was seen in pts of group b and in pts in group c. the rate of a infusion was decreased to /kgr/min in one group b pt due to development of chest pain s five year follow up of humoral immunity in paced patients athens polyclinic hospital, department of cardiology athens, greece author index a abiad ch bertschat, e betbes blanch, l del nogal saez e -meneza nolla, j. nolla-salas pilz~ u puig de la bellacasa e scarpa, n. van de wetering objectives: only % of patients suffering from acute guillain-barr@ syndrome (gbs) respond promptly to established therapies like plasma exchange or intravenous immunoglobulines. in contrast to serum, cerebrospinal fluid (csf) of gbs and ctdp patients contains enriched portions of antiexcitatory factors(i) and cytokines ( ) able to induce pronounced conduction block ( ). to reduce or remove such pathologic factors we introduced a technique with direct access to the subarachnoid space. methods: with informed consent we lumbally inserted g catheters in gbs-and cidp -patients under sterile conditions. some of them had not responded very well to established therapies. - ml of csf were withdrawn and retransfused by a bidirectional pump (flofors) after passing newly developed filters (pall). daily filtrations with several cycles were performed ( - ml) over one week. results: the gbs patients improved after days (median) for one grade (according to the gbs-scale from the gbs study group) . the ventilator dependent patients were weaned after days (median). patients not at all treated before ( / ) responded better than patients that had been pretreated ( / ) with plasmaexchange or intravenous immunoglobulines. / cidp patients drew benefit from treatment, stabilized iongterm. conclusions: csf-filtration is a relatively save and well tolerated additional procedure. the costs are considerably lower ( / ) than those for plasmaexchange or intravenous immunoglobulines. references:( )wsrz aet al: csf and serum from patients with inflammatory polyradiculopathy have opposite effects on sodium channels. muscle nerve ( ) . ( ) clinical observations were made in patients admitted to the clinic. they were in coma associated with acute alcohol intoxication.standard evaluations (ecg-monitoring, electrocardiography, neuromonitoring, studies of acid-alkali condition, biochemical and toxicologic investigation of blood and urine) prior to and following the treatment conducted were undertaken in all the patients.to correct irreversible impairement of functions twofold laser blood irradiation by means of alok- apparatus, the exposure within minutes, was carried out.the data obtained confirm more rapid coma withdrawal of the patients, reconstruction of the heart and central nervous system electrophysiologic indeces, reliable reduction in complications compared with the control group. objective: to know the actual incidence of the critical illness polyneuropathy(cip). setting: fourteen intensive/critical care unit beds, in bed university hospital, covering . inhabitants (majority rural area). the icu patients are medical, surgical and coronary, excluded the neurotrauma and neurosurgical. design: a conseculive and prospective study. all the patients admitted during three months, from january lth to march th , were eligible (patients with admittance diagnosis of polyneuropathy were excluded ). methods: patients with apache ii score > , at the admission and six days after admissions were included into the study protocol. diagnosis of sepsis, mof, and all the drugs administered days before were recorded. a complete neurological exam, by a neurologist, in absence of ssdatives and muscles reliant ( th, ~ and th days after icu admittance) was made. we evaluated the nerve and muscles function with and electromyography study in all patients, at same days. in some paeents with cip we performed a nerve biopsy. results: from patients ( apache ii score: . ) admitted in the icu, ( . %) enter the study protocol. seven ( , %) had an axonal polyneuropathy(cip), three very severe. only four of the patients with cip had pathologic clinical exam. apache ii score: cip vs non-cip was . vs . . the incidence of cip by diagnosis (cip/diagnosis) was: sepsis, / and mof, / . conclusions: . -we think that it is necessary to define the "critically ill" for some score, before designing a study to know the incidence of this syndrome. . -we think that the incidence of the cip is lower that the latest papers say. objectives:acute pancreatitis(ap)is becoming a more important problem among the elderly as the population ages. the increasing presence of gallstone disease,as well as the use of certain drugs,may also contribute to the occurrence of pancreatitis. methods:all patients(> years)admitted to our medical department over an eight year period were included.pancreatitis was confirmed by biochemical tests and imaging techniques.scores were developed using ranson's criteria and a multiple organ system failure(mosf)index . overall, patients were evaluated; ( %)had pancreatitis of unknown etiology . results:( )patients with pancreatitis of ~nlqnown etiology were sicker and had greater morbidity( % vs %),mortality( % vs %),and longer hospital stays than p~tierf~ with pancreatitis of known cause.( )the best predicto~of severity and outcome was the mosf index and not ranson's criteria;the higher the score,the greater the associated disease,the worse the outcome.( )curlously,no difference existed in associated medical conditions between patierts withknown and ur ~own causes of pancreatitis. conclusions:greater organ dysfunction exists in patients with pancreatitis of unknown etiology, even though age and associated medical conditions do not differ . the application of the total enteral nutrition in the burns disease has minimized the complication rate and consequently increased the survival rate of children and adults. time of initiation, composition, duration and way of administration are very important in obtaining the optimum beneficial effect from the treatment and diminishing the complication rate and side effects. the above features will be discussed in view of our experience in cases. ta buckle?,, ra freebalm, c gomersall g joynt, r young. tg short. department of anaesthesia and intensive cm+e, prince of wales hospital. the chinese university of hong kong, shatin, hong kong introduction: gastric mucosal ph (phi) monitoring has been proposed as a relatively noninvasive index of the adequacy of aerobic metabolism in the gut. to examine the accuracy of gastric intramucosal pit measurements as a function of time and as a function of the catheter itself to determine whether the measurement error between catheters is clinically acceptable. patients with a gastric tonometer (trip tm, tonometrics, worcester. ma) insitu for > days were studied. following informed consent two new tonometers were inserted equidistantly & correct position was confirmed radiographically. measurements of intramucosal gastric ph were then performed over a hr period. eight -ten measurements were made in each of ten critically ill patients.percent differences between the two new catheters were . % ie at ph . _+ . ( % limits) and between old & new catheters were . %, ie ph j _+ . ( % limits). conclusions: the results suggest that the function of the tonometer deteriorates over time and that the absolute values of phi m~ not ~ufficiently accurate. however as a trend monitor phi may be useful in the clinical setting. despite a continuous decline both in li'equency and severity of gastro-intestinal stress-lesion/-bleeding (gisb) due to both improvement in preclinical support and in intensive care medicine, patients with cerebral lesion are still considered at high risk for developing gis . therefore the question arises, whether m> specific (}lsb-prophylaxis besides general and neurological intensive care, specific pharlnaeothcrapy or even the combination of two specific drugs reveals any protective efli~ct on frequency and severity of gisb.this pntspcclive randomized study has been perfornted in patients snfrering t'rttna head-injury/cerebral lesion and with a glasgow-coma-scale on admission (gcs:,)of < . according to randomization the patients have been grouped as tbllows: h analgesia/sedation (n= ); ih analgesiajsedation plus pirenzepine mg/day (n= ); .[ih anatgcsia/sedalkm plus sncraltate x [ g/day (n= ); iv: analgesidsedatkm plus pirenzcpine mghlay plus sucralfate x e/day (n= ). slalislical analysis has been performed by chl:*tt~sl. rank correlatinn and unpaired t-test; statistical significance has been set with p < . . / patients ( . %) developed gisb. although the mean gcs~-value (x -+ sd) did not reach significance between patients with and without gisb ( . + . vs . -+ . ). a significant inverse correlation between gcs:, and the incidence of gtsb (rs~ = . ) has been shown. the frequency of gisb among the groups is as follows: h . %; lh . %; llh . %; iv: . % (ch -~ = . ; not signilicant). no gisb-induced blood translusion or mortality, respectively, could be demonstrated. survival rate between the groups did not differ significantly (chi-" = . ; p= . ) and reached an overall-value of . %.drug-specific glsb-prophylaxis -administered either as monotherapy (pirenzepine, sueralfate) or in combination of these two specific-drugs -reveals no additional significant influence on the incidence of gisb in patients with cerebral lesion compared to no specific prophylaxis besides the general trauma-/disease-specific intensive care measures. critical care dpt, evangelismos hospital, athens university scho~" of medicine objectives: the correlation of longterm presence of nasogastric tube (ngt) to gastroesophageal reflux (ger) is still in question. in case of positive correlation, peg should represent an alternative to tube feeding in patients unable to be fed orally. therefore, we investigated: i) the correlation between ng and ger and ii) the effect of peg on ger. methods: a -h esophageal ph-metry was performed in patients in recumbent position at ~ who had a ngt for more than days and were on sucralfate for gastric mucosal protection. the tip of the ph-probe was lied cm over the esophagogasttie junction, confirmed by x-rays. patients who presented a percentage of ger-total (i.e. with a ph less or more than ) (ger-t) more than %, underwent ~t peg. the presence of a creseent-notch on the esophagogastric junction persisting on inspiration and the grade os endoseopic and histologic esophagitis (scale= - ) was noted. two ph-metrles repeated on h and on days post-peg were compared to the pre-peg one, with the followin~ parameters taken in consideration: i) % ger-t, ii) number of ger-total per hour (no/h ger-t) and iii) the duration that ph was less than (tph< ). in case ot ger persistence at the ph-metry on ?th day post-peg (group ii) another endoscopy was performed, while patients with reduced ger (group i) were considered as esophagifis-free.results: out of patients presented a ger-t> %. eleven out of group i group (n= ) i ( objectives: the aim of the present study was to compare the performance of a specially modified version of a photo-and magnetoacoustic (pa/ma) gas analyzer (br~)el & kjaer, denmark) with a conventional quadrupole mass spectrometer (ms) (innovision, denmark) in inert gas rebreathing (rb) tests such as determination of functional residual capacity (frc), pulmonary capillary blood flow (pcbf) and lung tissue volume (vtc). methods : from simultaneous readings of inert gas concentrations with the ms and the pa/ma analyzer during rb experiments a comparison was made of the pcbf, vtc and frc values. the rb tests were performed during rest and exercise ( , and w) in ten healthy subjects. results: the differences (mean +/-sd) between simultaneous estimates of rebreathing parameters were the following (pa/ma -ms) for pooled data, pcbf: . +/- . i/min, vtc: - +/- ml and frc: . +/- . liters. conclusions: smell but significant differences were found between the estimates of pcbf, vtc and frc using the ms and pa/ma, respectively. reference: p. clemensen, p. christensen, p. norsk, and j. gr~nlund. a modified photo-and magnetoacoustic multigas analyzer aplied in gas exchange measurements. j appl physiol ; : - . objectives: because transcranial doppler (tcd) has been proposed to explore cerebral co vasoreactivity in brain injury (stroke ; : - ), we compared this technique with the kety-schmidt reference method to assess cerebral vasoreactivity in comatose patients. methods: mechanically ventilated patients (age - yrs, glasgow - ) in coma due to acute brain injury were investigated during stepwise changes in paco ( , , , and mmhg) by increasing inspired pco . middle cerebral artery velocity (vm) was measured by tcd. after insertion of a catheter in the ipsilateral jugular bulb, cerebral blood flow (cbf) was determined by the kety-schmidt method, using the inhalation of % n through the inspiratory line of the ventilator. for each patient a cerebral co~ vasoreactivity index was calculated as the slope of linear relationship between vm or cbf and paco . objectives: after cardiac surgery the fluid shill, between interstitial and intravasal space may be marked. this is due either to the intraoperative volume loading by the extracorporeal circulation or the increased postoperative diuresis. therefore, infusion of a large amount &fluids is necessary during the first postoperative hours. it still remains unclear which of the substances at disposal is the best for this purpose. aim of the present study was to compare the different fluids with special regard to postoperative bleeding and rheological behaviour. methods: patients undergoing cabg-surgery were investigated and randomizedly distributed to three different groups of postoperative volume replacement to stabilize the mean arterial pressure at mm hg. . ringer's solution, . . % gelatine solution, . % hydroxyaethylstarch (mean m.w. . ). we evaluated the following parameters within intervals of min: arterial and central venous pressure, heart rate, postoperative bleeding, urinary output, volume replacement. results: there was no statistically significant difference between the groups with regard to urinary output and bleeding. in spite of larger amounts of fluids necessary in the ringer treated group patients of this group showed symptoms of hypovolemia. hematocrit was increased in the ringer patients. this was statistically significant. introduction: pulmonary wedge pressure (pcwp) and central venous pressure (cvp) are frequently used as parameters for cardiac preload, although it is known that both are poorly correlated to the cardiac index (ci). it has been claimed that intrathoracic blood volume (itbv) measured with the thermal dye dilution method reflects cardiac preload better than pcwp and cvp. we studied the correlation between itbv and ci in a mixed population of critically ill patients. methods: in consecutive patients ( sepsis/sirs, acute heart failure, ards, transjugular intrahepatic portosystemic shunt) monitored with a pulmonary artery catheter, itbv was measured on regular intervals using the pulsion cold z- system (pulsion, munich, germany). ci, pcwp, and cvp were recorded simultaneously. results: a total of ol measurements was made. pcwp and cvp did not correlate to ci, nor did apcwp or acvp correlate to aci. itbv was correlated to ci in a non-linear fashion (f - , df = , p < . , (figure) ). aitbv was correlated to ac in a linear fashion (r = . , f = , df = , p < .o ). a rapid and efficient circulatory support system may save a patient in cardiogenic shock. left heart bypass with percutaneous and transseptal placement of the aspiration canuia simplifies the circuit and avoids the need for an oxygenator. we assessed this preclinical set-up in anaesthetized pigs using a centrifugal pump with a f arterial catheter and a f left atrial aspiration line. animals were supported for two hours at a mean flow of . liter ( ' rpm), a mean hematocrit of % and low heparinisetion (act double baseline). hemodynamic and laboratory samples were taken at baseline (a), minutes (b), one hour ( pulmonary hypertension (ph) usually involves obliteration and loss of functional pulmonary microvasculature. the microvaseular endothelium normally acts as a major metabolic organ, converting angiotensin i to angiotensin ii via the angiotensin-converting ectoenzyme (ace). it is unknown whether the loss of functional vasculature and altered pulmonary blood flow seen in ph will affect lung ace metabolic activity. we therefore estimated pulmonary vascular ace activity in patients with ph of various causes: primary; post atrial septal defect closure (asd); chronic thromboembolic (te); anorexigen; iv drugs; collagen disease. single-pass transpulmonary hydrolysis of the specific ace substrate h-benzoyl-pbe-ala-pro (bpap) was measured and expressed as % metabolism (%me . we also calculated an index of peffused functional capillary surface area (amax/km). all patients with ph had an abnormality of %met or amax/km, or both. as compared to control humans (mean %met = . % _+ . % s.d.), the mean %met in ph patients was . % _+ %. the %met in ph patients correlated inversely with cardiac output (r= . ), possibly reflecting more complete bpap hydrolysis with longer pulmonary transit times. amax/km was markedly decreased in ph ( + ml/min) as compared to controls ( _+ ml]min), consistent with a significant loss of functional capillary surface area. patients with collagen disease, asd and anorexigen-induced ph had the most marked abnormalities. in conclusion, patients with pulmonary hypertension have decreased pulmonary endothelial angiotensin converting enzyme activity, likely due to a loss of functional or perfused pulmonary microvaseulature. supported by the funds de la recherche en same du quebec and the national health system of greece. objective: to investigate adrenocortical function in patients with ruptured aneurysm of the abdominal aorta (raaa). studies investigating adrenocortical insufficiency in critically ill patients report an incidence ranging from % to less than %. this may in part be explained by difference in methods used (single cortisol measurement vs short acth stimulation test) and populations studied (heterogenous groups of patients with great individual variation in underlying disease as well as duration and severity of illness). methods: we investigated the adrenocortical function in patients with (raaa).a short acth stimulation test (synacthen test; ug - acth iv) was performed at hrs within hrs of admission. plasma cortisol was measured before (cort basal) and after stimulation (cort stim). a plasma cortisol level > . umol\l before or after stimulation was considered normal, severity of illness was assessed using apache ii. results: of the patients investigated died and survived. mean cort basal in nonsurvivors was significantly (p< .o ) higher than in survivors; . (range . - . ) vs . (range . - , ). this difference between nonsurvivors and survivors was also present for cort stim but lacked significance; . (range . - . ) vs . (range . - . ). while patients showed a cort basal < . , no cort stim < . was found. there was no significant difference in mean age or apache ii score between survivors and nonsurvivors; vs and vs . conclusions: single plasma cortisol levels were inadequate to assess the adrenocortical function in the patients studied, judged by a short acth stimulation test, our investigation in patients with raaa showed no adrenocortical insufficiency. mortality in raaa is associated with elevated plasma cortisol levels. obiectives: mortality in acute myocardial infarction (ami) prinicipally depends on hemedynamic impairment. thus, patients (pts) with elevated pulmonary wedge pressure (pwp) present high in-hospital mortality. however, the complete right heart catheterization is laborious, so the central venous pressure (cvp) alone is frequently used to assess the severity of ami. the accuracy of cvp in estimating pts with ami was tested in this retrospective study. methods: pts. aged + years, admitted to our ccu from to with their first ami, were inctuded in this study. all had undergone right heart catheterization because of overt or suspected heart failure. swan-ganz catheters ( f, cm, abbott, il, usa) had been used, every treatment had been temporarily interrupted l h before the calheferization. based on ecg findings the pts were retrospectively divided into groups. in group a we included pts with anterior ami, in group b, pts with inferior ami, and in group c, pts with inferior and right ventricular ami. the initial values of cvp and pwp were considered for the linear regression of the pwp variable on cvp and p< . was accepted as statistically significant.results: in g~oup a, the cvp and pwp vaiues were + mmhg and _+ mmhg respectively. despite the signifanf correlation (p< . ) between the two variables, it was not possible fo predict the exact value of pwp based on cvp value, pts ( %) presented cvp> mrnhg and of these ( %) had pwp_> mmhg. in group , the cvp was _+ mmhg and the pwp, _+ mmhg. significant correlation (p< . ) between the two variables also existed, however it was impossible to predict the pwp value. pts ( %) had cvp> mmhg but only of these ( %) had pwp> mmhg, similar was the relation between cvp and pwp in group c (p< . ). cvp averaged + mmhg, and pwp, _+ mmhg. pts ( %) had cvp> mmhg and from these ( %) presented pwp> mmhg,conclusions: a single measurement of cvp in ami does not ensure an accurate assessment of pwp. because every pt with ami needs optimal values of pwp in order to prevent pulmonary congestion or manifestations of low preload, the significance of complete right heart catheterization becomes apparent. in patients (pts) with advanced hf the need and the prognosis for heart transplantation (ht) can be predicted from vo= max. indirect measure of functional capacity with the six-minute walk test can also predict smvival in moderate hf. to predict vos max from indirect astinmtions of functional capadty such as - ~q~/, pulmonary and heart function tests, and to assess the prediddve value of the above parameters in hf pts survival. we evaluated pts (age + yeats nyha class: ii, hi, iv) with hf for pit. they underwent a pmgmmive exercise test on cycle ergometer for vo max determination, a -mw, a right heart catheterization and a spirometry and dlco estimation. introduction: brain death causes myocardial impairment by mechanisms that are not well understood yet. the aim of this work was to assess the echocardiographic features found in these patients from the clinical onset of brain death to somatic death, methods: seven brain dead patients were studied (patients" relatives refused to allow them to be used as donors). mean age was . ( - ) years old. four of the patients were female, none of the patients had any history of cardiac disease. transthoracic echocardiogram (echo) and electrocardiogram (ecg) were obtained at the onset of clinical brain death and were repeated every hours until somatic death. we we detected severe diffuse hypokinesia (ef< %) in patients and mild hypokinesia in others (ef - %). systolic function was strictly normal in only patients. corrected qt interval (qtc) in ecg was . _+ . msec (normal range - msec) just before somatic death (b). conclusion: in patients with brain death we observed a significant increase of left ventricular mass due mainly to ivs "hypertrophy" without any important change in the dimensions of the left ventricle. to our knowledge, this finding has never been reported before and its importantance in heart transplantations may be of particular interest. predict right ventricular outcome. l. jacquet, r. dion, p. noirhomme. m. van dijck. m. goenen cardiothoracic intensive care unit, st-luc univ. hospital(ucl) we have registred: heart rate (hr), blood pressure (bp), pulmonary artery pressures (pap), central venous pressure (cvp), pulmonary capillary wedge pressure (pcwp), pulmonary and systemic vascular resistances (pvr, svr), right ventricle end-diastolic end end-systolic volume (redv, resv), right ejection fraction (ref), right sistolyc ventricular work (rsvw) and cardiac output (co) using a thermodilution thechnique and a microprocessor (model ref- ; baxter-edwards laboratory); duration of cpb and aortic clamping, and the requirements of haemodynamic support after cpb.results: in the c group an increase post-cpb of the fc ( + . + . , p < . ) was produced without significantly changes in the redv, resv, ref, rsvw neither co. in the w group, hr increased from . + . to . + . (p < . ); redv was reduced from . -+ to . _+ . (p < . ); resv was reduced from • . to + . (p < . ). there were not changes in the other haemodynamyc parameters. there was a trend (no significantly) to an increase of ref in the w group ( . + . |• . ) compared with the c"group ( • . ($ . • . ) post-cpb. the need for haemodynamic support was similar in both groups.conclusions: the warm, continuous, anterograde-retrogade myocardial protection has obtained a decrease of preload, hr, and a trend to an increase in the ref, making an improvement in the right ventricular global performance when is compared with the classic form of cold myocardial protection. objective: to evaluate the effect of dobutamine on gastric mucosal ph (phi) after coronaly artery bypass surgery. design: prospective study in a university hospital intensive care unit (icu). subjects: elective cardiac surgery patients. interventions: dobutamine was infused at ug/kg/min for hours immediately after admission to the icu. hemodynamics were measured every minute periods until hours and again hours after stopping dobutamine. results: there were no significant differences in mean gastric phi between the groups but mean phi decreased in both groups during the study period. oxygen delivery and consumption both increased during dobutamine infusion but decreased to the control group level after stopping the dobutamine infusion. lactate levels did not change. baseline objectives: the aim of the study was to evaluate the usefulness of a low dobutamine dose in conjunction with intraaortic balloon pumping and mechanical ventilation in cardiogenic shock. we studied patients . -+ t . years of age suffered of post infarction cardiogenic shock characterized by a systolic arterial pressure< mmhg, urine output< ml/h and mental confusion or purpueral signs of low output, non responded to dobutamine infusion up to pg/kg/min. all patients underwent mechanical assistance by the intra-aortic balloon pump (iabp). five patients were additionally placed on mechanical ventilation due to blood gases disturbances. the end points in our study were: reversion of cardiogenic shock, improvement of patients survival or both on the th post infarction day and months later. results: three patients refused iabp treatment and / survived on the th day. on the th day / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p < . ). on the th month / supported by the iabp and / that underwent mechanical ventilation plus iabp were alive (p< . ). conclusions: in conclusion, the combined use of mechanical ventilation and iabp assistance in severe cardiogenic shock might improve survival. obiectives: the study was aimed at analysing predictive factors of swan ganz pulmonary catheter (pc) requiremen t during elective cardiac surgery according to the need of sustained inotropic support after surgery. methods: three hundred patients (aged from to ; females and males)were consecutively operated on for elective coronary artery bypass surgery (cabg, n= ), valvular replacement (vr, n= ), combination of both (vr-cabg, n= ), or others (n= ) and retrospectively included in the study. each patient had preoperative invasive cardiac investigation with calculated ejection fraction (ee). anaesthesia, cardiopulmonary bypass (cpb) and cardiac arrest managements were similar in all patients. pc requirement was estimated from the need of either dobutamine, adrenaline, dopamine or enoximone use during the first hours after cardiac surgery. demographic data, asa and nyha classifications, preoperative ef and treatments, type of surgery, cpb and aortic cross clamping (axc) times, and postoperative incidence of complications were compared in patients with or without inotropic support using either student's t test or x with continuity correction when appropriate. results: seventy hree patients ( . %) required inotropic support after surgery. axc .and cpb times, mean stay in icu were significantly longer in patients with inotropie support (p< . ). type of surgery, preoperative ef, and nyha classification are the first significant factors related to inotropic support (p< . ). most patients operated on for double-vr or vr=cabg required inotropic support ( and %, respectively). postoperative mortality was higher in patients receiving inotropic support ( , % vs , % 'overall mortality, p= . ). conclusions: since pc insertion is most.often justified because inotropes are required, these results suggest that elective rather than routine systemic pc insertion could be helped by considering several but selected preoperative factors. background: cardiovascular depression due to anaesthesia, old age and major gastrointestinal surgery is becoming an increasingly frequent challenge .to the anaesthesia-surgory team. deliberate preoperative manipulation of haemodynamics and oxygen transport parametres towards prede~t~mined optimal values may prove to be effective "in reducing morbidity ~nd mortality in high risk surgical patients,. a new concept of using conlimaous perioperative measurement of cardiac'output to obtain and maintain supranormal oxygen delivery (do i) is presented. methods: continuous measurement of cardiac output is a relatively new form of on-line monitoring, in which trains of impulses are emitted from a thermal filament mounted on a pulmonary artery catheter. computer software recognizes patterns generated by minute changes in blood temperature and ealoalates cardiac output every - seconds. cardiac output and mixed venous blood oxygen saturation are displayed graphically on line. in tins tm study cardiac output was measured continuously by vigilance cardiac outpu t compl/ter (baxter). preoperative haemodynamic optimization was performed with the goal of increa- sing do i to at least ml/min/m accordfing to shoemaker's algorithm . this was.done by infusing colloids (albumin or hydroxy ethyl starch (haes-steril| until the desired do was reached. infusion was stopped if cardiac output ceased to increase with infusion, if there were signs of pulmonary oedema or if wedge pressure reached mmhg. vasoactive or inotropic drugs were infused if the desired do was not reached by infusion alone. anaesthetic technique included continuous thoracic epidural and isoflourane anaesthesia. expected mol:bidity and mortality rates were calculated by the "possum" score aasing preoperative clinical and paradinical estimates of organ function as well as surgery characteristics . materials: asa group ill-iv patients with a mean age of years (range - ) and a mean weight of kg (range - )) scheduled for major abdominal surgery were included. results: patients were excluded because do i could not be raised at all. mean do i was increased from ml/min/m (range - ) to ml/min/m (range - ). mean volume of preoperativdy infused colloid was ml (range - ). during surgery ml (range ) of colloid was infused. mean length of surgery was minutes (range - ). mean blood loss was ml (range ). expected mortality and morbidity rates ("possum") were % and %, respectively, whereas patient follow up upon discharge or at death revealed mortality and morbidity rates of % and %, respectively. conclusion: based on experience from the present study, continuous measurement of cardiac output has proved to be a valuable tool for perioperative optimization of do in asa group ili and iv patients during major surgery. however further studies including a greater number of patients are necessary to confirm the promising preliminary findings. we studied the hemodyn~c effects of three different combinations of positiv inotropic .agents, vasodilators, diuretics and av-filtration (av) in patients (pts) with severe left heart faille (left veutrieul x filling pressure (lvfp) > mmhg) due to acute myocardial infarction. hemodynamic measurements (intravascular pressures (lvfp), thermodilution (cardiac index (ci)) were made before (control) and after each therapy. in furosemide (f) + d butamin (d) + nitroglycerin (ni) reduced lvfp and a small increase of ci occurred. in of these pts :(group a) nitroprusside (hip) instead of ni increased ci significantly, in the other pts adding of amrinone (a) resulted in a pronounced increase of ci. group c (n= ): the combination of ni and av reduced lvfp but did not increase ci which was achieved by av+d+ni. in order to optimize the treatment of acute heart failure a combination of inotropic agents, vasodilators, diuretics and av-filtration should he used guided by hemodynamic monitoring. arias jr, miragaya d, sandard, san pedro dm ~, herndndez d, valenzuela . objectives: to evaluate the variation in nomdrenaline (na) plasma concentrations in patients with acute myocardial infarction (am ) after thrombolytic therapy with noniltvasive reperfusion criteria (clinical, electrocardiographic and enzymatic), in relation to infarct size and location.methods: consecutive patiens with ami, from october , to february , , admitted within hours alter onset of symptoms, undergone successfull systemic thrombolysis. of them were anterior (group a) and inferior (group b) . noradrenaline plasma levels at (na ), (na ) and (na ) minutes after admission were compared with ck-peak plasma levels by linear regression. differences were tested for significance by student-t-test for paired and unpaired values. na plasma concentration was measured by high-presssure liquid chromatography. p< ns . ns means -sem (normal limit for our laboratory: na < / pg/ml; ck < u/i ) conclusions: . the na plasma levels at admission (nai) are more increased in anterior than inferior amis, probably in relation to infarct size. . the decrease in na is more evidence in amis with anterior location. . this decrease is probably due to the major efficacy of thrombolytic therapy in amis with anterior location. arias jd, miragaya (group b) , probably due to certain degree of t~cg'rfueion. . there is not significant variation in na in conventional treated ami (group c). v.suchanov, a.levit, p.trofimov, icu, regional hospital, ekaterinburg, russiaobjectives: our task was to improve the technique of preservation of platelet rich plasma. methods: patients scheduled for multiple cardiac valve replacement in were divided into two groups: group i ( patients) -without pp; group ii ( patients) -pp was performed preoperatively. the first pp was made ten days and the second - days before the operation. prp was preserved by cryoconservation. our technique of cryoconservation is distinguished by the speed of freezing ( - ~ and absence of dmso. this made it possible to preserve % functionally active platelets during days. the prp was transfused back after heparin neutralization. the hospital ethics committee approved the investigation.results: the blood loss through the st p. o. d. was significantly greatest in the group i ( _+ ml) and all the patients required transfusion of the donor blood ( + ml) whereas the blood loss in group ii was +_ ml and olny patients required the donor blood. the number of platelets on the st p.o.d, was _+ . /l (group i) and + . /l (group ii), p < . .conclusions: our technique of prp cryoconservation makes it possible to avoid the crystallization phase during freezing of prr thus the infusion of prp may improve hemostasis after open heart surgery and limit the use of the donor blood. in-hospital outcome of women suffering an ami is generally considered worse than that of men, but it is still debated whether female sex is per sea negative prognostic factor or is merely associated with other negative determinants of prognosis. the purpose of the present study is to evaluate the independence of the association between female sex and mortality (in the patients of the swiss centers) and in the patients randomized in the isis- trail mortality rate in women was . % ( / ) compared to . % ( / ) in men; in switzerland: in-hospital mortality for women was . % ( / ), for men . % ( / ).the table shows the results of isis- in terms of odds ratios and their % confidence intervals either after unadjusted analysis or after adjustment for age, known to be the major confounding variable when prognosis of women after myocardial infarction is considered, and for all the available clinical and epidemiological characteristics collected at trial entry: these observations suggest that there is a small but independent effect of female sex on short-term mortality after acute myocardial infarction. ( ) and bubble ( ) oxygenators a, ere used. anaesthesia was balanced and pts were extubated to hrs after cpb. pts were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that time qs/qt was calculate( according to )be standard shunt equation. after the sgc had been removed, an estimated shunt was calculated. measurements of qs/qt were performed: before induction of anaesthesia ( ), after induction of anaesthesia (i[), mins after cpb (iii) (iv) and (v) hrs afiter cpb, rains after extubation (vi), hrs after cpb (v[ ) and on the nd, rd, th, th and tb postoperative day (pd) (viii, x, x, xi, xi , respectively). analysis of data was performed by two-way analysis of variance, p < . being regard as significant.results: the figure shows the values for qs/qt expressed as means + sd. there was a significant increase in qs/qt above b~setine throughoul the whole investigated period except on the th pd. qs/qt reached maximum at rains after extubation (vi). objectives: many stndies have shown advantages of membrane oxygenalors over ubbie type oxygenators. the aim of this study was to evaluate the influence of x 'genator type on pulmonary shunt (as/at) after coronary surgery. methods: patients (pts) gave their informed consent to the study which was approved by the university ttuman research committee. pts were divided into two groups: a (n = ) with a membrane o~genator and a (n = ) with a bubble oxygenalor used during cardiopulmonary bypass (cpb). ths were monitored with swan-ganz catheters (sgc) for hrs after cpb. at that tfme os/ot was calculated according to the standard shunt equation. alter the sgc had been removed, an estimated shunt was calculated..measurements of os/qt were performed: betore induction of anaesthesia (i), mins after extubation ( ), hrs alter cpb ( ) and on the nd, rd, th, th and th postoperative day (iv, v, vi, vii> viii, respectively). analysis of data was performed by one-way analysis of variance, p < . being regarded as significant.results: the figure shows the values for qs/qt expressed as means _+ sd. os/qt was significantly greater at rains after extubation (ii) in a group. the difl'ereuce between the two groups was no more significant from hrs after cpb (iii) to the end of the investigated period. ! i * p < a. s betw~n ~o~ conclusions: membrane ox 'genation during cpb is accomplished by reduction in blood cellular destruction and less alteration in blood. the results of our study show the influence of oxygenator type on value of qs/ot only after extubation ( to hrs after cpb). the difference in qs/qt disappeared his after cpb and since that time the oxygenator type had no influence on qs/qt. it may be of particular importance in patients with severe forms of cardiopulmonary disease who are at risk of higher postoperative morbidity and mortality. objectives: hypomagnesemia has been reported with a variable prevalence ( to % ) in icu patients. magnesium deficiency can induce a number of climcal symptoms (primarily cardiovascular and neuropsychiatric) but can also be clinically silent ( - % are asymptomadc), methods: we measured whole blood ionized magnesium (lmg++) in patients on admission to the icu, using a nova electrolyte analyzer (nova biomedical), containing an img++ electrode. blood was collected in syringes with dry heparin (radiometer qs ). normal range of img++ was found between . - . mmot/l (healthy volunteers). results: for the entire population, we found a % prevalence ( / ) of hypomagnesemia (figure ) . among the surgical patients, the prevalence was highest after cardiac surgery ( %) and after thoracic surgery ( %) and was lowest after neurosurgery ( %). hypomagnesemia was also common in patients after liver transplantation (lvtx) or with hepatic failure ( % for both groups). conclusion: our findings confirm that hypomagnesemia is common in acutely ill patients, especially in those after cardiothoracic surgery or those with liver disease. nevertheless. it is difficult to define the associated factors with sufficient specificity, so that measurements of img++ are warranted to diagnose hypomagnesemia. hepariu influences platelet function and may lead to thrombocytopenia called heparin-associated thrombocytopenia (hat) regardless of the dose and route of administration. additinnal venous and/or arterial thrombosis may lead to life-threatening complications. the incidence of so-calied heparin-associated thrombocytopenia and thrombosis (hatt) ranges between i- %. hatt is confirmed by a heparin induced platelet activation assay (hipa). results: from / to / consecutive patients of our icu were reviewed retrospectively. all patients were treated with heparim the incidence of hatt was % ( ). in all cases diagnosis was proven by a positive hipa. / patients died. in / hatt could be confirmed before severe thromboembolic complications occured. / patients developed a deep vein thrombosis (dvt), / dvt and pulmonary embolism (pe), / dvt, pe and arterial thrombosis (at) and / a dvt, pe~ at and a sinus thrombosis. conclusion: the incidence of hatt in a r series of pts. is %. presence of thrombocytopenia and thrombosis of the great 'vessels is associated with a significant mortality ( / ). computed tom graphy (ct) and transthoracic/transesophageal echocardiography (tte/tee) are important tools in diagnosing and monitoring the extent of cenlrai venous and arterial thrombosis. a. cabral md, m. shahla md c. meneses-oliveira md and jl vincenl md.phd. department of intensive care. erasme university hospital, brussels, belgium objective: to determine extreme hemodynanuc patterns in cardiogenic shock. although ~.~xdiogenic shock is characterized by a low cardiac index (ci), high systemic w~,scular resistance index (svri), and high cardiac filling pressures, some patients may develop art atypical pattern. we reviewed the hemodyuamic pattern of patients with cardiogenic shock, as defined by an initial ct below . l/rain/m: in the presence of myocardial dysfimction attributed to ischemic heart disease (n= ), heart failure (n= ), valvulopathy (n= ) or recent cardiac surgery (n= ). after exclusion of patients with concurrently suspected/documented infection, this study included patients, of whom ( . %) survived. treatment of shock included dopamine (n= ), dobutamine (n= ), norepinephrine (n= ) and epinephrine (n= ). patients with arterial hypertension (ah) and initially law plasnla renin activity (pra) had been studied. in all patient changes of arterial pressure (ap) after single administration of enap was studied. nypotensive reaction wiht deereasin e of average ap about - mm hg ayter single drug administration observed only in patients. ezap monotherapy accomplished during one week with mg daily dose. hypotensive effect observed in patients including ones which were susceptible to single enap administration. after that first stage of therapy all patints began to combinate enap with hypothyazid in dose of mg per day~ after week of treatment such drugs combination lead to veritable ap lowering in addition patients. in the remaining resistant to such drug combination patients was add corinfar in daily dose of mg. this new drug combination permits to lower ap in patients. subsequent discontinuation of enap administration to such patients aid not connected with increasing of again.therefore the most of the patients with ah and law pra( , %)did not susceptible to enap therapy and enap and hypothyazid combination. on the contrary-combination of corinfar with hipothyazid was effective in % patients with ah and low pra. methods: in patients with cardiogenic shock due to ischemic heart disease (n= ), heart failure (n= ) and valvulopathy (n= ), hemod aamic data including measures of intravascular pressures, cardiac output and mixed venous gases were collected at regular times intervals, at least times a da?. all measurements were obtamed in a relative steady state and in the absence of severe anemia or hypoxemia. treatment of shock included dobutamine (n= ), dopamine (n= ), norepinephrine (n=i ) and epinephrine (n= objective: based on our previous studies of the function of isolated liver grafts, this experimental protocol aims at developing a novel extracorporeal liver support circuit, with an incorporated pig liver. methods:the graft liver was obtained from pigs weighing - kg. under general anesthesia the aqimals underwent total hepatectomy,following cannulation of the portal vein, the infrarenal aorta and the infrahapatic vena cava and peffusion wit h it of heparinised r/l solution at ~ the circuit consisted of the graft liver connected to a fluid reservoir and a centrifuge pump. ten healthy pigs weighing - kgr were connected to the circuit as follows: the rt carotid artery was connected to the portal vein of the graft and the rt jugular vein was connected to the fluid reservoir, through the centrifuge pump. the fluid reservoir collected the outflow from the graft's suprahepatic inferior vena cava. the cystic duct of the graft was ligated and the bile.duct cannulated for bile collection and measurement. bridges were adapted to the circuit to bypass the graft liver when necessary, in cases of by pass blood perfusing the graft was oxygenated through a bubble oxygenator. mean total priming volume of the circuit was ml. temperature was maintained at ~ and portal vein pressure at ( - ) mmhg. the flow was . - . ml/gr of graft liver mass per minute. observation period was hours (t ). results: results of the hemadynamic and metabolic monitoring of the recipients [map (t = mmhg , t = mmhg), hr (t = , t = ), rap (t = mmhg , t = mmhg), pap (t = mmhg, t = mmhg), pcwp (t = mmhg, t = ~mhg), svr (t = dyn'sec/cm ' , t = dyn'seclcm~ pvr (t = dyn.sec/cm o, t = dyn.sec/cm ,'~), co (t = . t/min, t = . t/min), do (t = ml/min, t = . ml/min), vo (t = ml/min, t = ml/min), o er (t = . %, t = . % ), ph (to= . , t = . ), po (t = mmhg, t = mmhg), pco (t = mmhg, t = mmhg), pvo (t = mmhg, t = mmhg), svo (t = %, t = %), be, na, k, ca ++, lactate, osmolality, ast, alt, pt, aptt, revealed hemodynamic and metabolic stability of the animal. consumption, co production and tissue oxygenation of the graft were also studied. conclusion; the described circuit proved to be safe and well tolerated by healthy animals but its value for temporary liver support is currently being estimated, in a surgically induced experimental fulminant hepatic failure modal. introduction: prosthetic materials like silikone, dacron, teflon e.tc. produce auto immune responses and may even trigger clinical syndromes like scleroderma, sjogren, sle el.c. in our study we followed the evolution of humorial immunity parametrs for up to five years in a cohort of paced pts with implanted metallic and silicone materials. method: paced pts (mean age +- yrs) without clinical or laboratory findings of malignancy or immune disorders were included. we measured the immunoglobulins, the complement, the auto antibodies and the proteins involved in inflammatory reactions every months. the initial and final mean values are shown in the obiectives: hsp, a systemic leucocytoclastic vasculitis and anaphylactoid purpura can be accompanied by abdominal pain and life-threatening intestinal bleeding. recently we could disclose, that these patients develop severe fxiii-deficiency and immense haemorrhagic oedema of the intestinal wall. by the following case report we will demonstrate and discuss the importance of fxiiideficiency for pathogenesis, therapy and outcome in hsp. case report: a year old man developed typical skin manifestations of hsp following an episode of severe (biliary ?) pancreatitis and percutaneous draining of a pancreatic pseudocyst. two days later he had a paralytic "ileus with immense hemorrhagic wall-oedema and massive dilatation of the small bowel. he got fever up to . ~ and developed severe gastrointestinal haemorrhage (blood transfusions necessary). the coagulation data disclosed a severe fxhi-deficiency (activity %), whereas quickvalues, platelet count and atiii-level were found to be within the normal range. elastase was markedly elevated. substitution of fxiii to normal levels leeds to the cessation of bleeding symptoms and abdominal pain, later resulting in a restitutio ad integrum. conclusions: hsp with intestinal involvement is a life-threatening vasculitis, in which careful and frequent examinations of the coagulation system, especially of fxiii are necessary. detailed analysis of the coagulation data suggest, that the severe fxiiideficiency is due to a specific degradation by proteolytic enzymes (like elastase) as well as consumption within the immense haemorrhagic oedema of the intestinal wall. knowing these facts, even most severe cases of hsp with intestinal involvement can be successfully treated by substitution of fxih. a -year-old woman presented a year history of occasional self-limited episodes of weakness, generalized edema and o!!~aria. the immunologic testing showed no~nnai levels of complements, clq inhibitor, and serum chemistry values, between or during a attack, she was not treated. she was a~mitted to the hospital with symptoms including nausea, vomiting, weakness and ol!guria. on examination, the patient presented facial and g~neralized edema. the systolic blood pressure was mm hg, pulse beats/mir~ute, hematocrit . , seln~n protein /i, and se~um albumin q/l. an leg-kappa pa[apfotein was demostrated ( . g/l) and urine was neaative for puotein. c~'stalloid and colloid don't increased the blaod pressure but resulted in anasarca, with a total of ii lit[as of in~ravenous fluids. therapy wink flozen plasma, . units of clq inhibitor, cortlcosteroids, annihistwnines and antifibrinolytic agents was uns~iccessfull. the a~minist~ation of dopamine, norepineph~ne and epinephrine was inefective. the patient died at the bores, only a few cases have been reported, all had igg paraprotein, the pathophysio!o~] is urd~no~n% but is possible that the paraprotein may be zesponsib!e for the increased capillary pe~leabilityo despite efforts to res~scinate the patients during an acute attack, the syndrome is often fatal. the variable course of systemic uapiliary leak syndrome and the unpredictability and self-limited nature of attacks cloud assessment of therapeutic inte~-vention. the purpose of the present work is to provide some information about the nursing care and results from our experience in continous arteriovenus hemofiltration (cavh).cavh is an extracorporeal technique, especially applicable in the critically ill patients, for disturbances, and for the control of azotemia.we used this method in critically ill patients men and women ages from - who had sepsis -arf congestive heart failure postoperative multiple organ failure and polytrauma .this method was applied to these patients from to hours. % of the patients recovered completely their kidney function, % improved their kidney function and % died.we concluded therefore that this method was very effective for the critically ill patients to whom it was applied, but it requires excellent and continuous nursing care; under the above mentioned circumstances the method works effectivelly. an animal model with rats undergoing a dialysis procedure was designed to test the hypothesis that recovery from ischemic acute renal failure (airf) may be affected by the type of membrane used in hemodialysis. male sprague dawley rats were allocated to groups: in group i, (n= ) airf was inducted by bilateral renal artery clamping for rain. group h (n= ) rats underwent a sham procedure. in each group, rats were dialyzed twice ( th and th day) with either a cuprophan (cupro), a hemophan (hemo) or a pan (an ) minidialyscr or stayed nondialyzed (no hi)). renal function was monitored daily by measuring urea and creatinine values and by two single shot inulin clearances on the days following dialysis. additionally hemolytical activity of complement was determined. inulin clearance on day was reduced significantly but there was no difference in the degree of decrement in glomular filtration rate (gfr) between dialyzed and undialyzed rats, nor between the dialyzed animals with different membranes (gfr: no hi): . _+ . ; cupro: . _+ . ; hemo: . _+ . ; an : . _+ . ). the evaluation of renal function by day nine revealed significant recovery for all airf-groups compared to day (p< . ), irrespective of wether they underwent dialysis or not, or the type of dialysis membrane. complement activation could be detected in all dialyzed groups but no statistical differences between the animal groups dialyzed with different membranes were noticed. our findings refute the hypothesis that in airf exposure to complement-activating cellulosic membranes impairs the recovery of renal function in rats. changes patients: patients who underwent first cadaver kidney transplantation in our unit between january and december in were involved. the recipients were divided into groups: group i." non functioning graft (n= ); group ii: delayed graft function (n= ), group ili: good graft function (n= ). the grouping criteria were: a/haemodialysis in the fii~t postoperative days, b/diuresis in the i st postoperative day, c,' scram crcatininc difference between the st postoperative day and the preoperative level. all of the parameters were involved into the exarainatio, which we measllre in our every, day practice. results: the preoperative haematocrit level differed significantly between group i. ( . ) and croup ii. and iii. ( . and . , p< . ). intmo! emtive significant differences were found between the different groups in systolic blood pressure (group i. hgrmn, group ii. hgnnn, group iii. hgmm, p< . ), mean arterial pressure (group i. hgmm, vs. group ii. hgnun p< . , vs. group iii. hgmm p< . ), and pulse-amplitude and rate-pressure product too. the second warm ishaemic time in group iii. was significantly shorter than in the other two groups (group iii. inin. vs. group ii. rain. p< . , vs. group i. rain. p< . !). the rejection rate was higher in the first days in the patients with non-functioning grafts (group i. % and group ii. % vs. group iii. %) . the other examined parameters have not differed significantly. conclusion: according to our results the success of the kidney transplantation is mnitifactorial. the most important factors of this relationship are: the perioperative fluid-balance, the maintenance of adequate perfusion blood pressure during the operation, good surgical technique and immunological problems. key: cord- -eff z i authors: ahluwalia, ranbir; rocque, brandon g.; shannon, chevis n.; blount, jeffrey p. title: the impact of imposed delay in elective pediatric neurosurgery: an informed hierarchy of need in the time of mass casualty crisis date: - - journal: childs nerv syst doi: . /s - - -x sha: doc_id: cord_uid: eff z i sars-cov- covid- , coronavirus, has created unique challenges for the medical community after national guidelines called for the cancellation of all elective surgery. while there are clear cases of elective surgery (benign cranial cosmetic defect) and emergency surgery (hemorrhage, fracture, trauma, etc.), there is an unchartered middle ground in pediatric neurosurgery. children, unlike adults, have dynamic anatomy and are still developing neural networks. delaying seemingly elective surgery can affect a child’s already vulnerable health state by further impacting their neurocognitive development, neurologic functioning, and potential long-term health states. the purpose of this paper is to demonstrate that “elective” pediatric neurosurgery should be risk-stratified, and multi-institutional informed guidelines established. the covid- pandemic has created unique challenges for pediatric neurosurgeons. elective procedures have been postponed at virtually all major pediatric neurosurgery centers. while there has been some centralized effort in adult surgery to standardize and stratify low vs. high acuity [ ] , this has not yet occurred for pediatric neurosurgery. given these new restrictions, many fields of medicine have made some general recommendations including head and neck surgery [ ] , anesthesia [ ] , cardiac electrophysiology [ ] , and colorectal surgery [ ] . while some recommendations apply to neurosurgery, particularly endoscopic sinonasal and skull base recommendations [ ] , no manuscripts exist to systematically stratify risk associated with delay in common pediatric neurosurgical procedures. the purpose of this paper is to outline the risks associated with delaying elective pediatric neurosurgery. urgent cases that present an immediate threat to the patient's life or neurologic well-being (e.g., shunt malfunction, acute hematoma evacuation, tumor with hydrocephalus, empyema, spinal cord compression) are straightforward and undergo prompt surgical intervention. elective surgery is readily defined as cases that offer a negligible or minimal threat of harm to the patient if surgery is delayed for several months. examples might include skull dermoids/epidermoids, prophylactic spinal lipoma untethering operations, and some craniofacial procedures. these are similarly less challenging in the current environment. however, there are a large number of procedures which are less straightforward in which lack of prompt surgery, while not emergent, may result in neurologic harm to the patient. delaying all "elective" surgeries in this population poses health-related risks, and a review of best available evidence on harm imposed by delaying these operations is warranted. previous presentations: this abstract has not been previously presented. * ranbir ahluwalia ra @med.fsu.edu the authors have identified a sample of pediatric neurosurgery procedures that are neither clearly emergent nor purely elective. cases considered for review include the following diagnoses/scenarios: . tumor recurrence without hydrocephalus . chiari i malformation . medically resistant epilepsy . craniosynostosis-single suture and syndromic multisuture synostosis . tethered spinal cord . brachial plexus . moyamoya disease a pubmed-based literature survey was conducted for manuscripts that addressed morbidity arising from delay in intervention for these diagnoses. manuscripts were prioritized on the basis of relevance of study design and evidence quality and were excluded for the following reasons: opinion paper, review paper, single case report, lack of outcomes results, or pertaining to the adult population. papers that presented outcomes from delayed surgery were included in this review. . tumor recurrence without hydrocephalus or symptoms of mass effect (i.e., purely radiographic recurrence): i. issues/threats with surgical delay: (a) sudden decline from hemorrhage into tumor or acute development of hydrocephalus (b) risks of dissemination or de-differentiation into higher grade lesion. supporting evidence low-grade neoplasms characteristically show slow, linear growth with a minimal risk of rapid decline from mass effect [ ] . for pilocytic astrocytomas, the greatest risk is likely the development of a cystic component that may show focal accelerated growth [ ] . other lesions such as craniopharyngiomas show highly variable growth patterns and often have a cystic component that may expand more rapidly to cause mass effect or obstruction [ ] . another important consideration in predicting potential risk for focal mass effect is the degree of surrounding edema elicited by the tumor. this risk also correlates with tumor histology [ ] . low-grade tumors such as pilocytic astrocytomas, glioneuronal tumors (dnt, ganglioglioma, etc.) and grade i gliomas typically offer a low risk for acutely developing edema [ ] . high-grade pediatric lesions such as pnts, embryonal tumors, choroid plexus carcinomas, or high-grade gliomas (e.g., glioblastoma multiforme) harbor substantially greater risk for edema and secondary rapid increase in mass effect [ ] . similarly, the incidence of hemorrhage into a tumor recurrence is predominantly determined by histologic diagnosis [ ] . the pediatric brain tumors with the highest risk for hemorrhage include high-grade embryonal neoplasms of infancy [ ] , glioblastoma [ ] , and mixed malignant germ cell tumors [ ] . as such, the prior histology of a recurrent lesion is the principle determinant of the acute risk for a sudden decline from hemorrhage or sudden edema. for example, donofrio et al. [ ] noted thin-walled, small, and closely packed vascularization in pediatric patients with cerebellar hemorrhage from pilocytic astrocytomas ]. white et al. [ ] characterized three distinct histological subtypes which correlated with hemorrhagic events in pilocytic astrocytomas [ ] . specifically, thick-walled hyalinized vessels with glomeruloid structures of vascular endothelial hyperplasia with ectatic vessels serve as a nidus for bleeds [ ] . multiple studies in the literature outline the relationship between histologic features and intratumor hemorrhage [ , [ ] [ ] [ ] [ ] . pagano et al. [ ] describe recurrent hemorrhage of pilocytic astrocytomas and stressed the importance of vegf for aberrant neov a s c u l a r i z a t i o n a n d h y p e r p e r m e a b i l i t y [ ] . immunohistochemistry is now being better understood through genetic markers. as described by phoenix et al. [ ] , medulloblastoma genotype highly dictates the vascular environment and hemorrhagic tendencies of tumors [ ] . most recently, ishi et al. demonstrated the association of fgfr mutation with hemorrhagic events in low-grade pediatric gliomas [ ] . i. issues/threats with surgical delay: (a) neurologic decline in upper extremities from syrinx (b) dysesthetic pain from syrinx. supporting evidence chiari i malformation has a range of clinical presentations from headaches to brainstem-related symptoms [ ] . when patients are asymptomatic, the clinical course is benign overall [ , ] . however, neurologic deficits arising secondary to syringomyelia may not be reversible with surgery. a recent practice preference survey by rocque et al. [ ] of the membership of the american society of pediatric neurosurgery (aspn) demonstrated a strong preference for using presence of a syrinx regardless of symptoms in the setting of chiari i malformation as a threshold for surgery [ ] . most surgical series have reported a - % incidence of syrinx with cim but larger radiographic series show that only - % of patients with a c m have a syrinx [ , ] . this suggests that patients with syrinxes are selected in surgical series. several principles emerge that are helpful in approaching the dilemma of acceptable delay challenge for an asymptomatic patient with a c m-related syrinx: ( ) the onset of neurologic symptoms from a c m syrinx is usually insidious and gradual but can rarely be acute [ ] . only a limited number of papers address acute decline from c m related syringomyelia [ , [ ] [ ] [ ] [ ] . massimmi [ ] and colleagues identified patients in their center experience and then identified more patients from the literature that showed acute clinical decline [ ] . they concluded in that only of such patients had ever been identified and concluded that sudden presentation is extremely rare [ ] . however, morbidity (irreversible motor %, % respiratory failure) and mortality ( %; . % cardiac arrest) were severe when it did occur [ ] . almotairi and colleagues [ ] observed patients to acutely decline in a cohort of ( / = . %) adult patients from sweden who were followed and treated for c m-related syrinx [ ] . in this series, the patients that declined acutely demonstrated longer and wider syrinxes that extended more rostrally (above c ) than the larger group who demonstrated no acute decline [ ] . the extent of tonsillar herniation did not correlate [ ] . ( ) the response time of a syrinx to operative decompression is unknown and appears gradual. wetjen and oldfield [ ] studied patients who underwent posterior fossa decompression for c m and found a median time of . months ( %ci = . - . months) [ ] . experienced chiari surgeons typically advocate mri imaging follow-up in - months. ( ) surgical decompression has a consistently good but variable impact on syrinx. tubbs et al. [ ] found that only out of patients with syrinx demonstrated progression after posterior fossa decompression and cranioplasty [ ] . zhang and colleagues [ ] demonstrated that % of patients who underwent posterior fossa decompression with duraplasty showed a reduction in size. less is written or available on the time course of syrinx change and the common time point for observations is months. a large meta-analysis by durham and fjeld-olenec [ ] that compared techniques of c m decompression (decompression alone vs. decompression with duraplasty) demonstrated - % syrinx resolution with operative decompression [ ] . however, small numbers of syrinxes associated with chiari i decrease in size over time without operative intervention and some syrinxes do not change after posterior fossa. ( ) recovery of neurologic symptoms from a chiari related syrinx is typically incomplete and permanent. the presence of a syrinx then represents a non-predictable risk factor for irreversible neurologic dysfunction from intrinsic chronic stress and injury to the spinal cord. sudden decline is very rare but can occur especially from minor injury [ , [ ] [ ] [ ] [ ] . thus, it appears that there is a strong preference by experienced pediatric neurosurgeons to intervene for a syrinx associated with a c m but the supporting evidence is incomplete and imperfect. the presence of the syrinx represents a threat to stress and low-grade chronic injury to the cord. it is very uncommon for acute symptoms to develop and the response to treatment usually occurs over months. therefore, a modest delay appears of low risk but the presence of a syrinx appears to be a justifiable intervention in an environment of imposed surgical slow down due to rare but possible neurologic insult that is permanent. by convention, only children with medically resistant epilepsy (mre) are candidates for epilepsy surgery and most epilepsy surgery can be elective. there are however important criteria within the designation of mre that help stratify patients with regard to the risk associated with operative delay. these include the risk for sudden death in epilepsy (sudep), the frequency and severity of status epilepticus (including status epilepticus in sleep or eses), the overall seizure burden for the child, and the degree of medical resistance that the seizures demonstrate. issues/threats with surgical delay: (a) acute threat of catastrophic epilepsy: sudden death in epilepsy (sudep), non-reversible injury to the brain from status epilepticus, and eses (b) sub-acute/chronic impact of uncontrolled seizures: the adverse effects to normal neurologic development from prolonged seizures (c) presence of a lesion (e.g., tumor, cavernomas) (d) palliative interventions: e.g., vagus nerve stimulator implantation. medical resistance/acute threats of mre defining and characterizing medical resistance (mre): candidacy for epilepsy surgery hinges upon defining medical resistance as a failure of anti-epileptic medications at proper dose to confer control of seizures. approximately one-third of patients with epilepsy will demonstrate mre. these patients are candidates for surgical intervention and the overwhelming majority can be evaluated and operated upon electively. however, an increased percentage of children have catastrophic epilepsy which is characterized by highly resistant and threatening generalized seizures. these often culminate in repeated episodes of status epilepticus and raise the risk for sudden death in epilepsy (sudep). children with congenital or acquired s t r u c t u r a l a n o m a l i e s o f t h e b r a i n s u c h a s hemimegalencephaly, holohemispheric dysplasias, hemispheric atrophy, and cystic encephalomalacia (often due to perinatal infarcts/ischemia) are more frequently found to have catastrophic epilepsy than those patients with more normal mri findings. syndromic epilepsies such as lennox-gastaut and rasmussen's encephalitis are highly resistant and associated with progressively severe and difficult to control disease. similarly recurring episodes of status epilepticus, epilepsia partialis continua, or electrical status epilepticus in sleep (eses) threaten the child's safety and neurologic development. children with malignant, threatening patterns such as these warrant an assertive, proactive approach to control and localization of their seizures. when accompanied by a structural change, these epilepsies are typically focal in onset and are amenable to surgical resection. due to the acute risk and lack of other effective strategies, surgery for these cases is often considered urgent and is justifiable and appropriate to proceed to surgery in an environment in which elective cases are suspended. there remains little doubt that uncontrolled epilepsy in children is injurious to the developing brain and adversely impacts normal neurocognitive development. the timing of epilepsy surgery is critical to achieve optimal long-term neurocognitive benefit. a retrospective study conducted by jenny et al. [ ] demonstrated higher seizure-free rate in infants ( . %) vs. children ( . %) [ ] . additionally, binary logistic regression demonstrated that younger children (less than years of age) were . times more likely to achieve a seizure-free outcome compared with older children ( to years of age) [ ] . furthermore, developmental outcome as assessed by loddenkemper et al. [ ] using bayley scales of infant development demonstrated that younger age at time of epilepsy surgery was correlated with a higher improvement in the development quotient (correlation coefficient . , p < . ) [ ] . finally, pelliccia et al. [ ] performed multivariate analysis using stepwise logistic regression to determine factors associated with seizure freedom and found a shorter duration of epilepsy to be significant (or . , % ci . - . ; p < . ) [ ] . lesional epilepsy represents a unique situation with regard to surgical decision-making. there are often indications for intervention: ( ) removal and histologic diagnosis of the lesion and ( ) improved seizure control. the presence of a visible lesion in the region implicated by eeg and functional imaging to be epileptogenic markedly increases the likelihood of successful surgery. the most common etiologies for lesional epilepsies in children are ganglioneuronal tumors, cavernomas, and visible cortical dysplasias. gang liog liomas (ggs) and dy sembryoplastic neuroepithelial tumors (dnets) are low-grade brain tumors that commonly present with seizures. seizure-freedom in this group of children is critical. as demonstrated by englot et al. [ ] , seizure freedom is achieved with higher success in children less than or equal to year of life compared with those greater than year of age (or . ; % ci, . - . ). nolan et al. [ ] performed a univariate chi-squared analysis to determine factors influencing favorable prognosis in children with dnts and found shorter duration of epilepsy (p = . ) and younger age at surgery (p = . ) to be significant [ ] . finally, when evaluating cognitive outcomes, earlier surgery for tumor-related epilepsy is ideal. ramantani et al. [ ] conducted a retrospective review in children with glioneuronal tumors to determine factors that influenced cognitive outcomes. lower full-scale iq (fsiq) and verbal iq (vq) were related to longer duration between diagnosis and surgery, when controlled for age at epilepsy onset (fsiq r = . , df = , p = . ; viq r = . , df = , p = . ) [ ] . the nearly uniform good outcomes from lesional resections for epilepsy along with a need for histopathologic diagnosis in many cases make a convincing case for proceeding to surgery even in the presence of initiatives to limit elective cases. ( ) issues/threats with surgical delay: ii. candidacy for endoscopic techniques-typically endoscopic preferred less than months iii. capacity for bony defects to fill in declines with age iv. thicker bone is more rigid and offers greater technical challenges with more bleeding, higher morbidity, and associated longer stay and higher cost. ( ) supporting evidence: endoscopic techniques in craniofacial surgery are being increasingly utilized due to good outcomes, lower morbidity, costs, blood loss, and equivalent or superior aesthetic outcomes. as demonstrated by thompson et al. [ ] , endoscopic treatment utilizes less blood ( % vs. %, p < . ), coagulation products ( % vs. %, p < . ), anesthesia ( vs. min %, p < . ), surgical duration ( vs. min %, p < . ), days in icu ( vs. %, p < . ), and hospital los ( vs. %, p < . ) [ ] . however, if a child is not seen within an appropriate timeframe, endoscopic craniosynostosis repair is no longer possible. while there remains debate about the superiority of endoscopic versus open repair, it is clear that in older children, only open repair can be performed. as the skull matures, the capacity for spontaneous filling in of bony defects or gaps between bone grafts becomes reduced. under the age of months, the gaps between bone grafts are largely filled with fibrous tissue and islands of cartilage. the capacity to spontaneously fill and remodel bony defects dissipates with increasing age resulting in less satisfactory results in older children. a retrospective study spanning years, states, and children under the age of was conducted by bruce et al. [ ] to determine the optimal time to surgically repair craniosynostosis. using the healthcare cost and utilization project kids' inpatient database (kid), the overall complication rate was . %: . % for children aged to months, . % for patients aged to months, and . % in children aged to months [ ] . additionally, a multivariable logistic regression model to identify factors that increase perioperative surgical complication demonstrated age as a significant factor (or = . at years vs. < , % ci . - . ) [ ] . another study using the kid database showed delayed repair of craniosynostosis to be associated with longer length of stay (los) and increased cost [ ] . in a sample of patients with an average age of days, los directly impact mean charge and total cost [ ] . when creating a regression model for factors that significantly impacted the length of stay, age was the most significant [ ] . older aged children had up to a three times greater odds of a longer los [ ] . syndromic multi-suture synostosis (e.g., apert, crouzon, saethre-chotzen, or cloverleaf deformity): multiple suture synostoses can give rise to brain constriction and elevated intra-cranial pressure that can be threatening to brain growth and optic nerve function. in the syndromic cases, the characteristic brachycephaly requires bi-frontal orbital advancement or distraction. the skull characteristically can be molded and reossification occurs readily until about the age of years. after this, the bone is thicker, more brittle, and does not contour as readily. consequently, there is likely limited harm in delaying syndromic cases inside of years of age. treatment of midface hypoplasia occurs in mid-childhood via distraction or lefort midface advancement procedures. the tethered cord syndrome (tcs) may arise from a variety of pathologic entities that share the capacity to fix the spinal cord to surrounding mesenchymal structures (e.g., bony spine or surrounding muscle and connective tissues) [ ] . symptoms usually consist of pain in the back, buttocks, and legs and variable but progressive loss of neurologic function in the legs and bladder [ ] . prevailing wisdom in pediatric neurosurgery is that once function is lost, it is typically not regained. thus, the critical immediate distinction in tethered cord is between symptomatic and asymptomatic tethered cord. intervention for asymptomatic tethered cord is largely prophylactic and is variably controversial depending on the underlying tethering lesion. for example, split cord malformations have a high incidence of inducing progressive neurologic decline unless repaired whereas the natural history of a low-lying spinal conus medullaris is less well established and there is significant controversy surrounding prophylactic untethering. the fundamental question is the likelihood that delay in surgery may impart a decline in neurological function. koyangi et al. [ ] retrospectively described the efficacy of surgery given the natural history of tethered cord syndrome. post-operatively, / ( %) asymptomatic patients remained this way, / ( %) improved, and / ( %) patients were unchanged [ ] . hoffman et al. [ ] describe a similar relationship in a cohort of pediatric patients. fifty-six patients presented before the age of months, and of these patients were neurologically intact [ ] . however, of the patients presenting after the age of months, only patients were neurologically intact [ ] . surgery should be performed prior to the onset of neurologic deficits. as demonstrated by kanev et al. [ ] in a cohort of patients presenting with neurologic deficit, / ( %) of patients regained bladder or bowel function post-operatively [ ] . a logarithmic model developed by kanev et al. using data from two series [ , ] demonstrates that all patients would develop neurological deficits over time by years of age [ ] . while these studies do not provide definitive evidence of a danger with delay, they do suggest that prevention of deficit or worsening of deficits might be more successful with earlier surgery. prompt neurosurgical evaluation is necessary to determine the level of the lesion and distribution of neurological injury [ ] . while the most common presentation is that of an upper plexus injury (erb's palsy) with damage occurring to the c and c roots [ ] , the most serious lesion is a total plexus lesion, which involves c , c , c , and c , with or without t [ ] . the patient will present with a flail limb and possibly horner's syndrome [ ] . prevailing opinion among surgeons from multiple disciplines is that these children require urgent exploration of the brachial plexus with appropriate nerve grafts and transfers [ ] . for patients with an erb's palsy, upper plexus, and pattern of lesion, there are multiple competing studies of various quality regarding the ideal time of surgery [ ] [ ] [ ] . a recent multicenter study [ ] evaluated microsurgical outcomes in children who underwent plexus reconstruction before versus after months of age. in the multivariable model, accounting for horner syndrome and baseline toronto score, there was no statistical difference in outcome between the early and late surgery (ams score difference = . , % ci = − . to . , p = . ) [ ] . in sharp contrast, total obstetric brachial plexus palsy injury requires more prompt surgical treatment and should ideally be performed around months of age [ ] . in a cohort of patients with total obstetric brachial palsy injury, younger age at the time of surgery correlated with better functional recovery (r = − . , p = . ), particularly with finger and thumb flexion [ ] . the onset of covid- and the national guidance to delay elective surgery has changed the paradigms of operative pediatric neurosurgical practice. the need for social distancing and preservation, or limited availability, of personal protective equipment has resulted in widespread curtailment of elective operative procedures. during this time, it is essential to establish an informed hierarchy of need for pediatric neurosurgical cases. many pediatric neurosurgery cases are urgent and must proceed. examples include shunt obstructions, infections, post-traumatic hematomas, and myelomeningocele closures. other cases are clearly elective and results are not likely impacted by limited delays. however, there exist a significant number of pediatric neurosurgical cases for which the impact of time delay in intervention is unknown. some cases appear elective but review of published experience demonstrates that poorer outcomes or higher risk accompanies delay. an informed hierarchy of need incorporates the potential increase into adverse outcomes associated with delay as well as the imminent threat to the patient in the short term. the cases selected for this report are not comprehensive but are representative of a substantial component of elective pediatric neurosurgical practice. within these cases, there are multiple examples of how a delay in performing surgery during an optimal eligibility window is associated with more adverse effects over the life span. additional factors that should be considered include the potential for exposure of risk to the operative team. exposure risks not only center on airway control and intubation but also extend to risks associated with aerosolized particles including blood, csf, and bone. cases involving invasion into the airways and bony sinuses also carry elevated risks. examples would include anterior skull base procedures, craniofacial procedures, and evacuation of empyemas that arise from erosion through bony sinuses. presurgical covid screening should be implemented in areas where there is no current shortage of testing for symptomatic patients. if limited testing is available, cases in which exposure is gained endonasally should require preoperative covid screening. ultimately, ideal timing should be explored for all pediatric neurosurgery. however, an effort that exhaustive is outside the scope of this manuscript's purpose of creating awareness on delay of common pediatric neurosurgical procedures. for the sake of completeness, some basic recommendations can be made regarding the procedures listed. for example, craniosynostosis repair should not exceed months to prevent open surgery. total obstetrical brachial plexus repair should be performed by months of age to prevent neurologic deficit. additionally, asymptomatic tethered cord and chiari i malformation with syrinx should not be postponed longer than months as the purpose of surgery is symptom prophylaxis. lesional epilepsy represents a more complex disease process and a case-by-case evaluation is necessary depending on seizure burden, medication use, and concurrent tumor. as the referenced literature demonstrates, there are clear transition points in childhood ( year of age and years of age) that represent important checkpoints for intervention. in sum, there are multiple levels of consideration when properly assessing the timing of surgery. imminent danger to the patient is foremost but the potential for adverse outcomes from missing an optimal time window of eligibility should also be considered. this review has demonstrated multiple examples of common pediatric neurosurgical procedures where such phenomena are observed. finally, considerations of operative team exposure and resource utilization need to be considered. proper evaluation of the timing of a pediatric neurosurgery case must extend beyond the period of an imminent threat to the patient. evaluation of a representative sample of pediatric neurosurgical cases demonstrates how adverse outcomes arise consistently when important optimum time windows of candidacy are missed. in addition, exposure risk and resource consumption in an era of scarcity must be considered to attain the best overall decision regarding the timing of pediatric neurosurgical intervention. conflict of interest the other authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. the authors have no personal or institutional financial interest in drugs, materials, or devices described in their submissions. covid- : guidance for triage of non-emergent surgical procedures safety recommendations for evaluation and surgery of the head and neck during the covid- pandemic anesthesia procedure of emergency operation for patients with suspected or confirmed covid- guidance for cardiac electrophysiology during the coronavirus (covid- ) pandemic from the heart rhythm society covid- task force electrophysiology section of the american college of cardiology; and the electrocardiography and arrhythmias committee of the council on clinical cardiology management of pediatric low-grade glioma pilocytic astrocytoma: pathology, molecular mechanisms and markers pediatric craniopharyngiomas: a primer for the skull base surgeon histology and molecular pathology of pediatric brain tumors pediatric gliomas: current concepts on diagnosis, biology, and clinical management significance of hemorrhage into brain tumors: clinicopathological study aggressive infantile embryonal tumors bleeding cerebral neoplasms with symptomatic hematoma mixed malignant germ cell tumour of third ventricle with hydrocephalus: a rare case with recurrence pediatric cerebellar pilocytic astrocytoma presenting with spontaneous intratumoral hemorrhage rate of spontaneous hemorrhage in histologically proven cases of pilocytic astrocytoma pediatric cerebellar 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national study on craniosynostosis surgical repair. the cleft palate-craniofacial journal : official publication of the american cleft palate-craniofacial association pathophysiology of tethered cord syndrome: correlation with symptomatology surgical treatment supposed natural history of the tethered cord with occult spinal dysraphism. child's nervous system management of lipomyelomeningoceles. experience at the hospital for sick children reflections on the natural history of lipomyelomeningocele obstetrical brachial plexus palsy the natural history of recovery of elbow flexion after obstetric brachial plexus injury managed without nerve repair. the journal of hand surgery the surgical treatment of obstetric brachial plexus palsy comparison of the natural history, the outcome of microsurgical repair, and the outcome of operative reconstruction in brachial plexus birth palsy microsurgery for brachial plexus injury before versus after months of age: results of the multicenter treatment and outcomes of brachial plexus injury (tobi) study total obstetric brachial plexus palsy: results and strategy of microsurgical reconstruction publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -f mzwhrt authors: aggrawal, anil title: agrochemical poisoning date: journal: forensic pathology reviews doi: . / - - - - _ sha: doc_id: cord_uid: f mzwhrt a general increase in the use of chemicals in agriculture has brought about a concomitant increase in the incidence of agrochemical poisoning. organophosphates are the most common agrochemical poisons followed closely by herbicides. many agricultural poisons, such as parathion and paraquat are now mixed with a coloring agent such as indigocarmine to prevent their use criminally. in addition, paraquat is fortified with a “stenching” agent. organo-chlorines have an entirely different mechanism of action. whereas organophosphates have an anticholinesterase activity, organochlorines act on nerve cells interfering with the transmission of impulses through them. a kerosene-like smell also emanates from death due to organochlorines. the diagnosis lies in the chemical identification of organochlorines in the stomach contents or viscera. organochlorines also resist putrefaction and can be detected long after death. paraquat has been involved in suicidal, accidental, and homicidal poisonings. it is mildly corrosive and ulceration around lips and mouth is common in this poisoning. however, the hallmark of paraquat poisoning, especially when the victim has survived a few days, are the profound changes in lungs. other agrochemicals such as algicides, aphicides, herbicide safeneres, fertilizers, and so on, are less commonly encountered. governments in most countries have passed legislations to prevent accidental poisonings with these agents. the us government passed the federal insecticide, fungicide and rodenticide act (fifra) in and the indian government passed the insecticides act in . among other things, these acts require manufacturers to use signal words on the labels of insecticides, so the public is warned of their toxicity and accompanying danger. a general increase in the use of chemicals in agriculture has brought about a concomitant increase in the incidence of agrochemical poisoning. organophosphates are the most common agrochemical poisons followed closely by herbicides. many agricultural poisons, such as parathion and paraquat are now mixed with a coloring agent such as indigocarmine to prevent their use criminally. in addition, paraquat is fortified with a "stenching" agent. organochlorines have an entirely different mechanism of action. whereas organophosphates have an anticholinesterase activity, organochlorines act on nerve cells interfering with the transmission of impulses through them. a early humans are believed to have started agriculture around bce. as the knowledge of chemistry grew, so did the use of chemicals in agriculture. today, chemicals are used in agriculture for three main purposes: to increase farm production (fertilizers and related chemicals), to kill pests (pesticides), and to preserve farm products (preservatives). unfortunately, all three classes of chemicals can cause serious poisoning in humans, mainly through improper labeling, storage, or use. most poisonings with agrochemicals occur in predominantly agricultural economies where a lack of hygiene, information, or adequate control creates unsafe and dangerous working conditions. cases of such poisonings also occur in small factories where pesticides are manufactured or formulated with little respect for safety requirements. accidental poisonings may also take place at home when pesticides are mistaken for soft drinks or food products, and often the victims are curious children who can easily reach pesticides if they are not kept safely away from them. then, there are the intentional poisonings, where compounds, such as phosphorus, arsenic, paraquat, organophosphates, and strychnine, are used as agents for suicidal or even homicidal purposes. this may happen because these chemicals are easily available, relatively cheap, and almost certainly cause death. poisoning occurring as a result of improper use of chemicals used in agriculture has been termed "agrochemical poisoning." agrochemical poisoning can be classified as shown in table . agrochemical poisoning remains one of the major causes of morbidity and mortality around the world today ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , and a review of this relatively untouched subject seems to be justified. experience has shown that above the wide range of chemicals a vast majority of poisonings occur because of pesticides only. the annual report of the american association of poison control center's (aapcc) toxic exposure surveillance system listed a total of , , human exposures to poisons occurring in the united states during the year alone ( ) . out of these, there were , exposures to pesticides ( % of all exposures) and , exposures to fertilizers ( . % of all exposures); a total of fatalities caused by pesticides and one caused by fertilizers were reported. the break-up for pesticide exposure is shown in table , and the fatalities caused by pesticides are given in table . two categories in which deaths were not reported at all were fungicides and repellants. most deaths (n = ) were to the result of insecticides. herbicides and rodenticides accounted for five deaths each, and one death was caused by fumigants. a comparison of poisoning data for the years to ( ) ( ) ( ) ( ) indicates that, although the absolute number of pesticide exposure has been increasing, it is more or less stable at around % of all exposures to poisons; fatalities owing to pesticide poisoning amount to . to % of all fatalities resulting from poisons (table ). in the following sections, those agrochemical poisons that are important from a medicolegal and pathological point of view will be discussed. organophosphorus insecticides are derivatives of phosphoric acid (h po ) or phosphonic acid (h po ) in which all h atoms have been replaced by organic moieties (figs. - ) . l represents the so-called "leaving moiety" and is the most reactive and most variable substituent. it is called so because this moiety "leaves" the organophosphate molecule after it is attached to the esteratic site of the acetylcholinesterase (ache, also known as true cholinesterase type che). r and r are less reactive moieties. most commonly they are poisonous plants (used as green manure, e.g., ricinus communis). . chemicals used to kill pests (pesticides) (i) acaricides (used to kills mites and ticks, also known as miticides, e.g., avermectins, azobenzene, benzoximate, bromopropylate, dofenapyn, nikkomycins, tetranactin). (ii) algicides used to control growth of algae in lakes, canals, and water stored for agricultural purposes (e.g., cybutryne, hydrated lime [component of bordeaux mixture]). (iii) aphicides (used to kill aphids, e.g., triazamate, dimethoate, and mevinphos). (iv) avicides (used to kill birds harmful to agriculture, e.g., -aminopyridine, -chloro-p-toluidine hydrochloride). bactericides (e.g., bronopol, nitrapyrin, oxolinic acid, oxytetracycline). (vi) fumigants (gas or vapor intended to destroy insects, fungi, bacteria, or rodents, used to disinfect interiors of buildings, as well as soil, before planting, e.g., carbon disulfide, sulfuryl fluoride, methyl bromide). (vii) fungicides (e.g., sodium azide, various compounds of copper and mercury, thiocarbamates, captan, captafol). (viii) herbicide safeners (e.g., benoxacor, cloquintocet, cyometrinil, dichlormid, dicyclonon). these compounds basically protect crops from herbicide injury by increasing the activity of herbicide detoxification enzymes, such as glutathione-s-transferases and cytochrome p- . (ix) herbicides/weed killers (e.g, paraquat, diquat, - dichlorophenoxyacetic acid, mecoprop). (x) insecticides (e.g., organophosphorus compounds, organochlorine compounds, carbamates). (xi) microbial pesticides (those pesticides whose active ingredient is a bacterium, virus, fungus, or some other microorganism or product of such an organism, e.g., bti which is made from the bacterium bacillus thuringiensis var. israelensis and used to control mosquito and black fly larvae, bacillus sphaericus and laegenidium giganteum, a fungal parasite of mosquitoes). (xii) molluscicides (used to kill molluscs, such as snails and slugs, e.g., metaldehyde). (xiii) nematicides (used to kill nematodes that feed on plant roots, e.g., , dichloropropene, , -dibromoethane, ethylene dibromide, diamidafos, fosthiazate, isamidofos). (xiv) ovicides (used to kill eggs of insects and mites). (xv) pesticide synergists (e.g., piperonyl butoxide, n-octyl bicycloheptene dicarbozimide, piprotal, propyl isome, sesamex, sesamolin). (xvi) rodenticides (used to kill rodent pests, e.g., strychnine, vacor, antu, cholecalciferol, anticoagulants and red squill). (xvii) virucides (e.g., ribavirin, imanin). (xviii) miscellaneous chemical classes including contaminants and adjuvants of some pesticides which are toxic on their own (e.g., dioxins, present as contaminants of some herbicides produce toxicity of their own). . chemicals used to disturb the feeding/growth/mating behavior etc. of pests, or used for other miscellaneous agricultural purposes (i) bird repellents (e.g., anthraquinone, chloralose, copper oxychloride). (ii) chemosterilants (e.g., , -dibromo- -chloropropane, apholate, bisazir, busulfan, dimatif, tepa). (iii) desiccants (chemicals which promote drying of living tissues such as unwanted plant tops or insects). (iv) defoliants (chemicals which cause leaves or foliage to drop from a plant, usually to facilitate harvest). feeding deterrents or antifeedants (chemicals having tastes and odors that inhibit feeding behavior, e.g., pymetrozine, azadirachtin a). (vi) insect attractants (substances that attract or lure an insect to a trap, e.g. brevicomin, codlelure, cue-lure, dominicalure, siglure). (vii) insect growth regulators (chemicals which disrupt the action of insect hormones controlling molting, maturity from pupal stage to adult, or other life processes, e.g., hexaflumuron, teflubenzuron and pyriproxyfen). (viii) insect repellents (e.g., butopyronoxyl, dibutyl phthalate, diethyltoluamide). (ix) mammal repellents (e.g., copper naphthenate, trimethacarb, zinc naphthenate, ziram). mating disrupters (e.g., disparlure, gossyplure, grandlure). (xi) plant activators (a new class of compounds that protect plants by activating their defense mechanisms, e.g., acibenzolar, probenazole). (xii) plant growth regulators (substances [excluding fertilizers or other plant nutrients] that alter the expected growth, flowering, or reproduction rate of plants through hormonal rather than physical action). . chemicals used for preservation of grains (i) aluminum phosphide. (ii) nitric oxide. available as dusts, granules, or liquids, organophosphorus insecticides are among the most popular and widely used insecticides throughout the world. they began to be synthesized first around with the esterification of alcohols to phosphoric acid. the earliest synthesis of an organophosphate, tetraethyl pyrophosphate, was reported by phillipe de clermont at a meeting of the french academy of sciences in ( ) . many different organophosphorus compounds were synthesized in the early s, but their toxicity was first recognized by lange in . lange stated that inhalation of the vapor of dimethyl or diethyl phosphofluoridate produced a choking sensation and dimness of vision. as nations started looking for lethal gases with the start of world war ii in , interest in these compounds was rekindled. by , schrader in germany and saunders in england and their study groups had synthesized a number of highly toxic organophosphates for possible use in warfare. most notable among these were soman, sarin, and tabun. currently, about organophosphorus compounds are in use as insecticides worldwide. of these, parathion is the most effective for insecticidal use. tetraethyl pyrophosphate enjoys two distinctions among organophosphates: it was the first organophosphate to be synthesized in and is the organophosphorus insecticides are basically ache inhibitors allowing the accumulation of excess acetylcholine at various nicotinic and muscarinic receptors throughout the body including the central nervous system (cns). this essentially results in acetylcholine toxicity. the main symptoms can be remembered by either of the two acronyms sludge (salivation, lacrimation, urination, defecation, gastrointestinal distress, emesis) or dumbels (diarrhea, urination, miosis, bronchospasm and bradycardia, emesis, lacrimation, salivation). rarely, there is chromolachryorrhoea (shedding of red or bloody tears) ( ) because of a disturbance in porphyrin metabolism and its accumulation in lacrimal glands. ld (lethal dose; the amount of a material, given all at once, which causes the death of % of a group of test animals) of these compounds varies from to mg/kg (extreme toxicity) to more than mg/kg (slight toxicity). compounds that are extremely toxic are chlorfenvinphos, diazinon, and methyl parathion, whereas those that are slightly toxic are malathion, acephate, and trichlorphon ( ) . most patients who have ingested a fatal dose will die within hours of ingestion. organophosphorus toxicity has recently been reviewed extensively by rousseau and co-workers ( ). signs of asphyxia are commonly found in fatal intoxications with organophosphorus insecticides. there is congestion of the face and cyanosis of the lips, nose, fingers, and acral parts of the extremities. one of the most remarkable findings is the characteristic odor emanating from the corpse: it has been described as garlic-or kerosene-like and is due to the fact that organophosphates are dissolved on a kerosene base. there is often frothy, bloody staining at the mouth and nostrils, and the pupils may be constricted. a coloring agent, indigocarmine, is added to parathion (e ® ) to prevent its accidental ingestion or criminal use as a poison. this gives rise to a bluishgreenish discoloration of the lips and oral mucosa. the addition of indigocarmine, however, is not a general practice worldwide. for instance, in india and several other asian countries, this practice is not followed. an interesting sign to be observed (albeit only in somewhat less modern mortuaries) is the death of bluebottles and others insects and flies dying immediately after they alight on an opened cadaver at autopsy ( ). the gastric mucosa is congested and may appear hemorrhagic (fig. ) and the stomach contents often contain an oily, greenish scum. the mucosa of the respiratory tract is congested and the airway passages contain frothy hemorrhagic exudate. the lungs show congestion, hemorrhagic pulmonary edema, and subpleural petechiae. the brain is swollen and there is generalized visceral congestion. parathion (e ) has been studied most extensively for histopathological lesions and these are considered to be representative of other organophosphorus insecticides, too ( ) . in the kidneys, there is epithelial necrosis in the straight sections of the renal tubules. in the epithelia of the remaining renal cortical sections, there is pronounced plasma granulation, nuclear wall hyperchromatosis, and clumping and reduction in the chromatin and marginal nucleoli. epithelia in loops of henle and collecting tubules appear swollen. the liver is more resistant to the effects of organophosphates, partly because of its ability to manufacture serum cholinesterase on its own. hepa- tocytes show opaque swelling and glycogen depletion; there are destructive changes in the liver cell strands, detached hepatocytes, and perivascular edema. myocardium, medulla oblongata, and vagal nuclei of the brain show fine, maculate perivascular hemorrhages. limaye has described a type of toxic myocarditis that he had observed in autopsy cases ( ) . kiss and fazekas described focal myocardial damage with pericapillary hemorrhage, micronecrosis, and patchy fibrosis in victims of organophophorus poisoning ( ) . pimentel and da costa ( ) have described the following myocardial ultrastructural changes in fatal poisonings with organophosphorus: multiple circumscribed necroses are found in the skeletal musculature. the oolemma is damaged and sometimes even necrotic. the glomus caroticum shows an increase in the number of dark-cell nuclei, perhaps as a consequence of increased nuclear metabolism owing to augmented demand. ache and butyrylcholinesterase (bche, also known as pseudocholinesterase or type che) levels are depressed in deaths owing to organophosphorus insecticides. the measurement of their levels can assist in the determination of the cause of death ( ) . ache is found mostly in red blood cells, motor endplates, and gray matter, whereas bche is found mostly in plasma, white matter, liver, heart, and pancreas. the physiological function of bche is unknown ( ) , but it is established that bche hydrolyzes suxamethonium (succinylcholine), and for this reason it is of interest to anesthesiologists as well. postulated functions of bche include its role in transmission of slow nerve impulses, lipid metabolism, choline homeostasis, permeability of membranes, protection of the fetus from toxic compounds, and degradation of acetylcholine and in tumorneogenesis ( ) . the plasma cholinesterase (pseudocholinesterase) is more sensitive and levels fall more rapidly than those of the red blood-cell cholinesterase. red blood-cell cholinesterase levels are more satisfactory for the diagnosis of organophosphorus poisoning because they represent the true cholinesterase levels. sample collection and storage (time and temperature) are critical to the catalytic stability of che and thus influence the quality and interpretation of results of the toxicological analysis. fluids and tissues that should be collected at autopsy are blood, cerebrospinal fluid (csf), semen, muscle, brain, liver, heart, and pancreas. the recommended procedures for collection and storage of biological fluids are as follows: . blood must be collected in heparinized tubes. . the samples must be collected and stored in glass rather than plastic containers to avoid contamination by leachates from plastic. . sample contamination with acid or alkali must be avoided. . samples must be immediately refrigerated because che catalytic activity is temperature dependent. . fluid and cellular components of blood, csf, and semen have to be separated. . determine enzyme activity as soon as possible. if enzyme activity is not determined immediately, samples can be stored for several days at °c. if tissues are intended to be stored for longer periods, the storage temperature should be - °c or below. . tissue should be homogenized at ph . to . using a sonicator or nonmetallic homogenizer and then should be stored as indicated above. che activity in blood, serum, and tissues can be measured by a number of methods. one of the most popular is the ph method by michael ( ), whereby a change in ph is measured when che acts on acetylcholine. the principle is that cholinesterase hydrolyzes acetylcholine, thus producing acetic acid, which in turn decreases the ph of the reaction mixture. electrometric determination of the change in ph from . for a definite period of time (e.g., hour) at a specific temperature (e.g., °c) represents the enzyme activity. normal values of che activity as measured by this method (in Δph/hour/ . ml red blood cells or plasma at °c, mean ± standard deviation) are given in table ( ) . in deaths owing to organophosphorus insecticides, the values will be much lower. a % or greater depression of the red blood-cell che level is a true indicator of poisoning. death occurs when levels have decreased by more than %. blood and urine should be preserved for toxicological analysis of che levels. samples from lung, liver, kidney, skeletal muscle, brain, and spinal cord, as well as gastric contents, must similarly be preserved for toxicological analysis of cholinesterase levels ( ) according to the precautions detailed in steps - in section . . . . paranitrophenol is a metabolite of many organophosphates. it is excreted in urine and its presence in urine is characteristic of organophosphorus poisoning. organophosphates usually resist putrefaction and can be detected in the viscera for quite some time after death. wehr ( ) studied five exhumations where the decedents were suspected having been poisoned with parathion. he could detect the degradation products of parathion (aminoparathion and p-nitrophenol) up to years after burial, but after years, neither parathion nor any of its degradation products were detectable. pohlmann and schwerd found evidence of parathion in a corpse exhumed after months ( ) . more recently, karger and co-workers ( ) described a case where they detected paraoxon, the main conversion product of parathion, from the abdominal cavity of a -month-old boy, months after his death. his mother had poisoned him with parathion; her deed was detected when, several months later, her second child-a -year-old girl-also suffered the same fate and parathion was detected in her blood. carbamates (fig. ) are derivatives of carbamic acid. their structure is similar to that of organophosphates (fig. ) . the first recognized anti-che was in fact a carbamate, physostigmine (also called eserine), obtained in pure form in by jobst and hesse from the calabar bean ( ) . some common carbamates used as insecticides today are aldicarb, carbaryl, γ-benzene hexachloride, triallate, propoxur, methomyl, carbofuran, and carbendazim. like organophosphates, carbamates are inhibitors of ache, but instead of phosphorylating, they carbamoylate the serine moiety at the active site. this is a reversible type of binding, and therefore, their toxicity is less severe and of lesser duration ( ) . because they do not penetrate the cns to any great extent, the cns toxicity of carbamates is relatively low. signs and symptoms are the same as those seen in poisoning with organophosphates/organophosphorus insecticides but they are milder in nature. convulsions are not seen in carbamate poisoning. postmortem findings in carbamate poisonings are mostly similar to those found in organophosphates. a bluish discoloration of the mucosa of the mouth and stomach is not seen because the blue green dye indigocarmine is usually not mixed with carbamates. determination of cholinesterase levels is not of much help because these are restored very rapidly in carbamate poisoning. organochlorine pesticides are nonselective insecticides. they are cyclic in nature, have molecular weights between and d, are cns stimulants, and have limited volatility. they are poorly soluble in water but readily soluble in organic solvents and fats, which is the way how they accumulate in the human body. they are very stable, both in the environment and in the body tissues, and can be demonstrated in the bodies of most people born since . based on their chemical structures, organochlorines can be divided into four categories ( fig. ) ( ): (a) dichlorodiphenyltrichloroethane (ddt) and related analogs, such as methoxychlor, (b) hexachlorocyclohexane or lindane, (c) cyclodienes and related compounds (e.g., aldrin, dieldrin, endrin, endosulfan, chlordane, chlordecone, heptachlor, mirex, isobenzan), and (d) toxaphene and related compounds. the best known organochlorine, ddt, was synthesized by the german chemist othmar zeidler in , but he failed to realize its value as an insecticide. it was the swiss paul hermann müller ( - ) who recognized its potential as an effective insecticide. in , ddt was tested successfully against the colorado potato-beetle by the swiss government. the united states department of agriculture used it successfully in . in january , ddt was used to quash an outbreak of typhus carried by lice in naples, italy; this was the first time a winter typhus epidemic could be stopped. so revolutionary was his work that müller was awarded with the nobel prize in medicine in . it is ironic that just years later, in , ddt was banned in the united states. it is perhaps a unique example in the history of science that a nobel prize-winning work was banned within such a short period of time. the main driving force behind this ban was the ecologists' concerns about the persistence of ddt in the environment and its resulting harm to the habitat-humans are equally affected by persistent ddt in the environment. it was rachel carson's book silent spring, published in , which brought the problem to everyone's notice. endrin, one of the cyclodienes, is chiefly used against insect pests of cotton, paddy, sugarcane, and tobacco. it is active against a wide variety of insect pests, and hence is commonly known as plant penicillin. it has been banned in most western countries, but unfortunately continues to be used in several agrarian economies. the mechanism of action of organochlorines is entirely different from that of organophosphates and carbamates. organochlorines act on axonal membranes affecting the sodium channels and sodium conductance across the neuronal membranes. organochlorines also alter the metabolism of acetylcholine, noradrenaline, and serotonin. lindane and cyclodienes appear to inhibit the γaminobutyric acid-mediated chloride channels in the cns. therefore, not very surprisingly, the main symptoms induced by poisoning with organochlorines are cns-related and include vertigo, confusion, weakness, agitation, hyperesthesia or paresthesia of the mouth and face, myoclonus, rapid and dysrhythmic eye movements, and mydriasis (in contrast to organophosphates and carbamates, where miosis is found). other symptoms include nausea, vomiting, fever, aspiration pneumonitis, and renal failure. the fatal dose of ddt and lindane is to g, whereas that of aldrin, dieldrin, and endrin is to g ( ). the conjunctivae are congested and the pupils are dilated. there may be a kerosene-like smell emanating from the mouth and nostrils. this is because most organochlorines are poorly soluble in water and are dispensed as solutions in organic solvents that may have a kerosene-like smell. fine white froth, which may or may not appear hemorrhagic, can be seen around the mouth and nostrils; this is a general effect of pulmonary edema coupled with respiratory distress and therefore, signs of cyanosis are seen on the face, ears, nail beds, etc. the mucosa of the respiratory tract appears congested and the respiratory passages contain frothy mucus which may or may not be tinged with blood. subpleural and subpericardial petechial hemorrhages are common. the lungs appear large and bulky, showing pulmonary edema. the mucosa of the esophagus, stomach, and bowel is congested owing to the irritating effect of organochlorines on the gastrointestinal tract. the stomach contents smell kerosene-like. the visceral organs are congested. hepatic necrosis may be found on cut sections of the liver. in animals killed by ddt, vacuolization around large nerve cells of the cns, fatty change of the myocardium, and renal tubular degeneration can be detected histologically ( ). feces, urine, and subcuatenous adipose tissue (placed in a glass-stoppered vial or a vial with a teflon-lined cap [ ] ) should be collected for toxicological analysis. samples must be frozen before onward transmission to the toxicology laboratoy. nicotine salts, such as nicotine sulfate, were very popular pesticides in the s and s. these compounds generally contained % nicotine (fig. ). now, because most countries have banned nicotine-based insecticides, less than % of home garden insecticides are nicotine-based. these are usually available in powder form. main among these is black leaf- (manufactured by black leaf products company, elgin, il). when nicotine-based insecticides come in contact with moist skin, fatal doses of nicotine may be absorbed through the skin ( ) . apart from occupational exposure to nicotine spray, other methods of fatal exposure include careless storage and inadvertent mixing with foodstuffs, fruits, and vegetables. these insecticides have also been used successfully with suicidal or homicidal intention. brownish froth around the mouth and nostrils is a frequent finding in nicotine poisoning. there is a characteristic odor of stale tobacco emanating from the gastric contents. the esophageal and gastric mucosa is intensely congested, showing a brownish discoloration. liver and kidneys show considerable acute congestion ( ). the liver shows plaque-like granulations in the cytoplasm of centrilobular and intermediary hepatocytes. intrapulmonary hemorrhages and pulmonary edema are typical and there often is detachment of the alveolar epithelium. in the kidneys, there is necrosis and detachment of the epithelia in the straight and convoluted renal tubules. a variety of arterial wall lesions, including lacerations of the elastic interna, are seen that have been connected with extreme fluctuations in blood pressure from the effects of nicotine ( ). an estimated % of all plant species are weeds, with a total of some , species. chemicals, such as common salt, have been used for centuries for weed control. the era of chemical weed control is generally recognized as starting in . bonnet in france found that the bordeaux mixture, already being used on vines to control powdery mildew, also provided control of specific weeds. by the s, farmers were still using simple chemicals for this purpose; for example, copper sulfate (blue vitriol), which was first used for weed control in , was still in use at this time. in the early th century, scientists in europe started using the salts of heavy metals to control weeds but when this was attempted in the united states, the low humidity in the western states prevented these chemicals from being absorbed by the weeds. other chemicals were tried, but most of them had drawbacks. for instance, carbon bisulfide used to control thistles and bindweeds smelled like rotten eggs and was, therefore, quite understandably unpopular. most chemical weed killers of those times (such as sodium arsenate, arsenic trioxide, and sulfuric acid) were highly toxic to humans and had to be used in large quantities (several kilograms per hectare), which was another serious drawback. the first synthetic organic chemical for selective weed control was introduced in . its chemical name was -methyl- , -dinitrophenol, and it could control some broadleaf weeds and grasses in large seeded crops, such as beans. more modern herbicides are now available. these have to be sprinkled in very low doses (grams per hectare) in order to kill weeds and the crop is spared. herbicides are categorized as selective when they are used to kill weeds without harming the crop and as nonselective when the purpose is to kill all vegetation. killing of all vegetation is generally not intended in an agricultural setting. it is required more often in places such as recreational areas, railroad embankments, irrigation canals, fence lines, industrial sites, roadsides, and ditches. both selective and nonselective herbicides can be applied to weed foliage or to soil containing weed seeds and seedlings depending on the mode of action. the term true selectivity refers to the capacity of an herbicide, when applied at the proper dosage and time, to be active only against certain species of plants but not against others. selectivity can also be achieved by placement, such as when a nonselective herbicide is applied in such a way that it reaches only the weeds but not the crop. herbicides can also be classified as contact or translocated. contact herbicides kill the plant parts to which the chemical is applied. translocated herbicides are absorbed either by the roots or the above-ground parts of plants and are then circulated within the plant system to distant parts. timing of herbicide application regarding the stage of crop or weed development forms another basis of classification. a preplanting herbicide is sprinkled on the farm before the planting of the crop. a preemergence herbicide is sprinkled after planting but before emergence of the crop or weeds. finally, a postemergence herbicide is used after the emergence of the crop or weed. herbicides can be applied to weeds in a number of ways. a band application treats a continuous strip, such as along or in a crop row. broadcast application covers the entire area, including the crop. spot treatments are confined to small areas of weeds. directed sprays are applied to selected weeds or to the soil to avoid contact with the crop. in the more recent overthe-top-application, herbicides are applied "over the top" of the crop and weeds shortly after germination. the crops in these instances are naturally tolerant to the specific herbicide or have been genetically engineered to be tolerant to the herbicide used. from a toxicological point of view, the following herbicides are the most important. dipyridyl weed killers include paraquat, piquat, and morfamquat ( fig. ). paraquat is the most important of these three. paraquat ( , ′dimethyl- - ′bipyridylium dichloride) is an important agricultural chemical from a toxicological viewpoint. out of the deaths caused by pesticides reported by the aapcc annual report ( ) , two were the result of paraquat poisoning. paraquat was first synthesized in , but its herbicide activity was discovered very late. its use as an herbicide was first reported in , and paraquat was introduced commercially as a nonselective herbicide in . the introduction of paraquat caused an agricultural revolution because it has some unique properties. it can be sprayed from the ground level or the air and is totally denatured when it comes in contact with the earth. thus, it cannot harm the seeds or young plants that will be placed in the same ground a short time later. indeed, the crop can be planted within days, if not hours, after herbicidal treatment with paraquat. an additional advantage is that plowing is unnecessary aggrawal in many cases with much less soil erosion. paraquat is therefore of immense value in an economic sense ( ) . in countries like sri lanka, its use has resulted in three crops, instead of two, per year being taken off the same field ( ) . paraquat is highly soluble in water and is marketed most commonly as a concentrate containing g paraquat dichloride per liter ( % wt/vol); this is an odorless brown liquid. a "stenching" agent (a pyridine derivative) is added to prevent accidental or criminal poisoning; a bluish-greenish dye is also added for the same reason, and an emetic may be added as well. paraquat is sometimes sold in combination as a mixture with diquat and other herbicides. the liquid concentrate is known as gramoxone (not to be confused with gammexane, which is the trade name for lindane); a weaker, granulated preparation for horticultural use, known as weedol, is also available ( % wt/vol). the solution may be decanted in soda bottles and left unlabelled. because it looks like a cola drink, accidental ingestion may occur. it may be mistaken for vinegar as well; one patient is reported to have sprinkled it on his french fries. wesseling and co-workers ( ) reported that paraquat is the pesticide most frequently associated with injuries among banana workers in costa rica; the injuries involve mostly the skin and eyes. although most fatalities caused by paraquat occur from ingestion, absorption through the skin can also cause fatalities. wohlfahrt ( ) reviewed paraquat poisoning in papua new guinea from to and found that out of fatalities caused by paraquat, six were the result of transdermal absorption. diquat ( , ′-ethylene- , ′-dipyridylium dibromide) is less commonly used than paraquat. it has the same indications and mode of action as paraquat. diquat is, however, used additionally for the control of aquatic weeds. jones and vale ( ) compiled all cases of diquat poisoning published between the years and and found that only cases were reported in detail in the literature, of which ( %) were fatal. conning et al. showed that out of the three dipyridyl weed killers, it was only diquat that produced bilateral cataracts ( ) . diquat was introduced in as a fast-knockdown, contact herbicide and plant desiccant. diquat-only formulations manufactured by syngenta (formerly imperial chemical industries) or its subsidiaries do not contain the dye, "stenching" agent, or emetic added to paraquat ( ). the symptoms include intense pain in the mouth and pharynx, with inflammation and even ulceration of the oral mucosa. esophageal ulceration may lead to perforation with all its attendant risks. renal and hepatic failure develop within to days. the most important effect is on the lungs (pneumotropism), where massive, irreversible pulmonary fibrosis is seen. pulmonary fibrosis is thought to be the result of an increase in the pulmonary concentrations of prolyl hydroxylase, an enzyme which promotes collagen formation. paraquat is one of the few poisons that may produce necrosis of the adrenal glands, possibly leading to hypotension. the fatal dose is to g (about a mouthful of gramoxone). subcutaneous injection of just ml of gramoxone has shown to be fatal ( ) , with death occuring after to weeks as a result of respiratory failure caused by pulmonary fibrosis; greater doses can kill a human within hours. why does paraquat show such remarkable pneumotropism? it has been postulated that inside the pneumocytes, the paraquat dication pq + accepts one electron from reduced nicotinamide adenine dinucleotide and becomes the monocation pq + . (pyridinyl-free radical) (fig. ). the monocation pq + . is unable to cause any injury on its own, but in the presence of molecular oxygen (o ) in the lungs, it is oxidized once again to its dication form (pq + ). in this process, it passes on its electron to the molecular oxygen (o ), which, in turn, becomes the superoxide anion radical (o -. ). this process, known as redox cycling, is sustained by oxygen in the lungs. the superoxide anion radical o -. (reactive oxygen species) generated as a result of this cycle is responsible for cell death. this also explains why oxygen enhances the toxicity of paraquat and should never be administered during paraquat intoxication; by administering oxygen, one is supplying the "raw material" for the formation of the damaging superoxide radical. formation of free radicals is implicated in injuries caused by at least two other poisons-myocardial injury caused by doxorubicin and liver injury by carbon tetrachloride. the related bipyridylium compounds, such as diquat and morfamquat, do not affect the lung as seriously, but rather cause liver damage ( ). there is ulceration around lips and mouth, although it is not as bad as is seen after ingestion of inorganic acids, such as nitric or sulfuric acids. the oral and esophageal mucosa is reddened and desquamated. a unique feature of paraquat ingestion is the formation of pseudomembranes in the pharynx resembling to that seen in diphtheria ( ). patchy hemorrhages in the stomach mucosa are a frequent finding. the liver is pale, showing fatty changes. the kidneys may exhibit pallor of the cortex. the most striking findings are found in the lungs. both type and type alveolar epithelial cells accumulate paraquat and are thereby destroyed. this destruction is followed by inflammatory cell infiltration and hemorrhages; fibroblast proliferation then leads to fibrosis and impaired gas exchange. the lungs are congested, appear stiffened, and retain their shape during evisceration. each lung is typically approx g or more in weight. teare ( ) reported a case of paraquat poisoning (a -year-old man dying of suicidal ingestion of paraquat after days of illness), with the left lung weighing g and the right lung weighing g. blood-stained pleural effusions and fibrinous pleurisy are other typical autopsy findings. cut surfaces of the lungs reveal edema and fibrosis. subendocardial hemorrhages may accompany the aforementioned pathological findings. the pathological features of paraquat poisoning have been reviewed in detail by vadnay and haraszti ( ) . at the beginning of the toxic process, severe degenerative changes appear in the pneumonocytes with fatty infiltration, desquamation, necrosis, and detachment ( ) . later, there is splintering of the basement membranes, fragmentation, aneurysma formation, and multiple ruptures. fibrinous edematous fluid is seen in the interstitium and within alveoli and hyaline membranes can be observed. there is a large-scale dissolution of the pulmonary structure. there may be active proliferation of the bronchial epithelium, forming small adenomata within the pulmonary parenchyma. marked proliferation of fibroblasts with an increase in macrophages in the alveoli (these two mechanisms obliterate the alveolar spaces) can be seen. acute tubular necrosis is a frequent finding in the kidneys. extensive renal cortical necrosis is also seen at times. in the liver, centrilobular hepatic necrosis, cholestasis, and giant mitochondria with paracrystalline inclusion bodies can be detected ( ) . in the myocardium, there is edematous disaggregation of the sarcoplasm and sporadic fragmentation of the myofibrils. paraquat-type herbicides in aqueous solutions have traditionally been determined by colorimetric methods. these involve measurement of the complex formed with some chemical (α-dipicrylamine hexanitrodiphenylmethane). plasma paraquat levels can be assayed by spectroscopy, high-performance liquid chromatography ( ) or radioimmunoassays; levels greater than . μg/ml confirm death by paraquat intoxication. urine paraquat levels can be deter-mined using spectrophotometry, too; levels greater than μg/ml confirm death by paraquat intoxication ( ) . berry and grove introduced an ion exchange and colorimetric method in for the determination of paraquat in urine ( ) . diquat (reglone) is selectively concentrated in the kidneys and causes marked renal tubular damage. in a case of fatal diquat poisoning, mccarthy et al. found esophagitis, tracheitis, gastritis, and ileitis ( ) . autopsy findings and toxicokinetic data in diquat poisoning have been described in detail by hantson et al. ( ) . morfamquat is used far less commonly than the other two bipyridyls, paraquat and diquat. conning et al. have shown that rats that fed on morfamquat developed renal damage ( ). chlorophenoxy herbicides (fig. ) are growth regulators or auxins. they cause abnormal plant growth, thereby ultimately destroying the plant. chlorophenoxy herbicides are commonly used for control of broadleaf weeds in cereal crops and pastures ( ). - dichlorophenoxyacetic acid ( , -d; trimec) has been and continues to be one of the most useful herbicides developed; it is frequently applied to lawns to control broadleaf weeds and is often found in fertilizer products along with other phenoxy herbicides, such as dicamba, mecoprop, and ( -chloro- -methylphenoxy)acetic acid. , -d is easily absorbed through the skin and lungs ( ). on ingestion, , -d causes peripheral neuropathy, muscle weakness, cheyne-stokes respirations, hyperthermia, acidemia, and coma ( ) . the patient is hypotonic, hyporeflexive, hypotensive, and comatose ( ) , and nasogastric aspirate may be guaiac-positive ( ). , -d earned a notorious reputation during the vietnam war as an ingredient of agent orange sprinkled by united states troops over vietnam (see subheading . ). suicidal ingestions of , -d are occasionally reported ( , ) . postmortem findings in deaths caused by chlorophenoxy herbicides are nonspecific. the gastrointestinal mucosa may be intensely congested and/or hemorrhagic. all internal organs are usually congested. confirmatory tests of suspected poisonings with chlorophenoxy herbicides are the demonstration of these herbicides in plasma and urine,which can be detected by radioimmunoassay ( ) and gas liquid chromatography ( ). this category comprises mainly dinitrophenol (dnp), dinitro-orthocresol (dnoc), and pentachlorophenol ( ) . these substances are used in agriculture mainly as selective weed killers for cereal crops. the effects of dnp in stimulating metabolism have been known since , and dnp was used at one time for "slimming." dnp (fig. ) is a potent "uncoupler" of oxidative phosphorylation, causing the energy obtained from the oxidation of nicotinamide adenine dinucleotide and reduction of o to be released as heat. it has been demonstrated that these compounds are dangerous to humans and thus, they are no longer used for medicinal purposes. the principal risk of poisoning is in the agricultural use of concentrated solutions for spraying crops aggrawal (as weed killers). dinitrophenol (dnp) is also used in agriculture for the control of mites and aphids ( ) . absorption occurs by inhalation and thus, breathing apparatus are a must for those who are exposed to this poison. absorption also occurs by ingestion and through the skin. excretion of dnp is extremely slow, so the poison accumulates in the body gradually. the symptoms are fatigue, insomnia, restlessness, excessive sweating, weight loss, and thirst. clinical signs include tachycardia, increase in the rate and depth of respiration, rise in temperature (up to °c and higher) and some yellow discoloration of the sclera. in severe cases, body temperature may keep rising and just before death, it may reach °c. when death occurs, the onset of rigor mortis is rapid. sodium chlorate is a nonselective herbicide. it acts as a soil sterilant at rates of lbs/acre. it is also used as a foliar spray at lbs/acre as a cotton defoliant. it was once avidly advocated as a weed killer, not only because it is effective, but also because it was considered safe. this fallacy was so prevalent that containers of sodium chlorate used to be marked as "nonpoisonous." however, chlorates cause methemoglobinemia. severe hemolysis is a constant clinical feature in sodium chlorate poisoning, with presence of heinz bodies in the red blood cells. acute renal failure and anuria sets in later. anuria occurs because of (a) a direct damaging action of chlorates on the renal tubular epithelium, and (b) mechanical obstruction of the renal tubules by the hemoglobin set free by hemolysis. the fatal dose of sodium chlorate is to g with death occuring within to days. poisoning with sodium chlorate can occur accidentally, suicidally, or even homicidally. accidental poisoning is probably the most common. a -year-old gardner was severely poisoned in a curious way. he was using a concentrated solution of sodium chlorate in an atomizer while a strong wind was blowing. consequently, spray was blown onto his face and he inhaled and ingested some of the solution. symptoms of poisoning started the same evening. he was saved with some heroic effort on the part of the doctors, yet he could only return to full-time work after about year ( ). the skin has a distinctive chocolate-brown color. blood smears may show evidence of hemolysis and heinz bodies. the kidneys are enlarged and their principal change is a brown streaking of the cortex; microscopical examination reveals acute renal tubular degeneration with blockage of tubules by broken red blood cells and brown pigment granules (released hemoglobin owing to hemolysis). glyphosate is an important agricultural chemical from the toxicological viewpoint. out of the deaths caused by pesticides reported by the aapcc annual report ( ) , one was caused by glyphosate. glyphosate is a broad-spectrum, nonselective, systemic herbicide used for control of annual and perennial plants including grasses, sedges, broad-leaved weeds, and woody plants. it can be used on non-cropland as well as on a great variety of crops. although glyphosate itself is relatively harmless, its chemical formulations (e.g., roundup ® , rodeo ® , touchdown ® , gallup ® , landmaster ® , pondmaster ® , ranger ® ) have been used successfully for committing suicide. this is because glyphosate invariably is formulated in a surfactant (polyethoxylated tallow amine), which is quite toxic ( , ) . glyphosate is generally distributed as water-soluble concentrates and powders. mild poisoning results only in gastrointestinal symptoms, such as vomiting, abdominal pain, diarrhea, and nausea, which usually resolve within a day or two. severe poisoning results in intestinal hemorrhage and ulceration, acid base disturbances, renal failure, hypotension, cardiac arrest, pulmonary dysfunction, convulsions, coma, and death. postmortem findings are nonspecific. glyphosate and the concomitant surfactant are demonstrated by toxicological analysis in the gastric contents and other visceral organs. glyphosate levels of mg/ml or more can be detected postmortem in blood, liver, and urine in less than a minute by using p nuclear magnetic resonance ( ). among the several arsenical herbicides available are cacodylic acid, calcium hydrogen methylarsonate, disodium methylarsonate, hexaflurate (asf k), methylarsonic acid, monoammonium methylarsonate, monosodium methylarsonate, potassium arsenite, and sodium arsenite. cacodylic acid (fig. ) is also known as dimethylarsinic acid. cacodylic acid is a white crystalline substance, readily soluble in water and alcohol, and is still used as an herbicide. when it unites with metals and organic substances, it forms salts known as cacodylates. cacodylic acid contains . % of arsenic. fungicides, or antimycotics, are toxic substances used to kill or inhibit the growth of fungi that cause economic damage to crop or ornamental plants. most fungicides are applied as sprays or dusts. seed fungicides are applied as a protective covering before germination. systemic fungicides, or chemotherapeutants, are applied to plants, where they become distributed throughout the tissue and act to eradicate existing disease or to protect against possible disease. bordeaux mixture (cuso cu[oh] caso ) was one of the earliest fungicides to be used ( ) . bordeaux mixture is a liquid composed of hydrated (slaked) lime, copper sulfate, and water. it was accidentally discovered in in the modoc region of france, where farmers, tired of schoolboys pilfering their grapes, sprayed their grapevines with a poisonous-looking mixture of lime and copper sulphate; it was a desperate idea meant just to deter schoolboys from stealing their grapes. however, in , pma millardet from the university of bordeaux observed that the very same mixture effectively controlled the downy mildew of grapes as well. burgundy mixture is a mixture of copper sulfate and disodium carbonate. both bordeaux mixture and burgundy mixture are still widely used to treat orchard trees. copper compounds and sulfur have been used on plants separately and together. synthetic organic compounds are now more widely used because they give protection and control over many types of fungi. cadmium chloride and cadmium succinate are used to control turfgrass diseases. mercury(ii)chloride, or corrosive sublimate, is used as a dip to treat bulbs and tubers. mercury salts used as fungicides include mercurous chloride, mercuric chloride, mercuric oxide, phenylmercury nitrate (fig. ) , tolylmercury acetate, and ethylmercury bromide. organophosphorus fungicides include ampropylfos, ditalimfos, edifenphos, and fosetyl (fig. ) . carbamate fungicides include benthiavalicarb, furophanate, iprovalicarb, and propamocarb (fig. ) ; the toxicity of organophosphates and carbamates has been dealt with earlier. among the most important inorganic fungicides are potassium azide, potassium thiocyanate, sodium azide, and sulfur. other substances occasionally used to kill fungi include chloropicrin, methyl bromide, and formaldehyde. many antifungal substances occur naturally in plant tissues. creosote, obtained from wood tar or coal tar, is used to prevent dry rot in wood. the most important fungicides-from the toxicological viewpoint-aside from organophosphorus and carbamates, are sodium azide and compounds of copper and mercury. copper compounds are also especially important because they are used in agriculture as insecticides and algicides. somerville discussed the metabolism of several fungicides including maneb, mancozeb, zineb, captan, chlorothalonil, benomyl, triadimefon, triadimenol, and cymoxanil ( ). sodium azide is important because it is a potential intentional or accidental poison. aside from being used in agriculture, sodium azide is also used widely in hospitals where it is used as a component chemical in the fluid used to dilute blood samples. sodium azide, like dnp, is an "uncoupler" of oxidative phosphorylation; it also inhibits the enzymes catalase and cytochrome oxidase. ingestion of sodium azide results in nausea, vomiting, diarrhoea, hypotension, and cns symptoms, such as headache, hyporeflexia, seizures, and coma. postmortem findings include edema of the brain and lungs. edema of the myocardium with myocardial necrosis has also been reported ( ) . fig. . fosetyl, an organophosphate fungicide. salts of copper, although mostly used as fungicides, are used for a large number of other purposes in agriculture as well. copper acetate, copper carbonate, cupric -quinolinoxide, copper silicate, and copper zinc chromate are used as fungicidal agents only; copper arsenate is used as insecticide and copper sulfate as algicide, fungicide, herbicide, and molluscicide; copper acetoarsenite is employed as insecticide and molluscicide; copper hydroxide is used as bactericide and fungicide; copper naphthenate is used as fungicide and mammal repellent; copper oleate as fungicide and insecticide; and copper oxychloride as bird repellent and fungicide. chronic exposure to bordeaux mixture in vineyard sprayers causes the socalled "vineyard sprayer's lung." observed mainly in portugal, the disorder includes pulmonary fibrosis ( ) and may lead to lung cancer ( , ) . bordeaux mixture is the only other significant pesticide aside from paraquat that induces significant pulmonary fibrosis with organophosphates coming in a distant third ( ) . the radiological picture in vineyard sprayer's lung resembles that of silicosis with micronodular features in the early stages of the disease ( ) . only in later stages does a picture of massive fibrosis emerge with continuing development of respiratory insufficiency. plamenac et al. ( ) examined the sputum of rural workers engaged for years in spraying of vines. sputum specimens were tested for copper by rubeanic acid. macrophages containing copper granules in their cytoplasm were found in % of the workers engaged in vine spraying compared with none in a control group. other abnormalities, such as eosinophils, respiratory spirals, respiratory cell atypia, and squamous metaplasia, were also found in the sputum. atypical squamous metaplasia was observed in % of vineyard workers who were also smokers ( ). eckert et al. ( ) exposed mice to copper sulfate aerosol for a longer period of time and were able to replicate these changes in the animals' lungs. the authors concluded that the changes seen in vineyard sprayer's lung are a result of copper sulfate toxicity. pimentel and menezes studied the liver of vineyard sprayers by percutaneous biopsy and also at autopsy ( ) . they found histiocytic and noncaseating granulomas containing inclusions of copper as identified by histochemical techniques. they also found that the affected individuals were prone to liver fibrosis, cirrhosis, angiosarcoma, and portal hypertension ( ) . copper sulfate is a popular suicidal poison in india ( ) and copper sulfate was once a very popular homicidal poison ( ) . although no reports of suicide and homicide with bordeaux mixture exist, this is certainly possible. quite possibly such cases did, and still do, occur but have never been reported. mercury is widely used as a fungicide in agriculture. both inorganic and organic salts are used. inorganic mercury fungicides being used as fungicides include mercuric chloride, mercuric oxide, and mercurous chloride. organomercury fungicides include ( -ethoxypropyl)mercury bromide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury , -dihydroxypropyl mercaptide, ethylmercury phosphate, n-(ethylmercury)-ptoluenesulphonanilide (fig. ) , hydrargaphen, -methoxyethylmercury chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, -phenylmercurioxyquinoline, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol (fig. ) , phenylmercury nitrate, phenylmercury salicylate, thiomersal (fig. ) , and tolylmercury acetate. the ingestion of wheat and barley seed treated with methyl mercury fungicides for sowing by a largely illiterate population in iraq led to a major poisoning with mercury in to with a high fatality rate ( ) . the seed-about , tons of it-was intended for spring planting; there had been ample warning that the seed was unfit for consumption, but this warning was disregarded. there was a latent period of several weeks after which pares- thesias began to appear in several victims. paresthesias involved lips, nose, and distal extremities. more serious cases progressed to ataxia, hyperreflexia, hearing disturbances, movement disorders, salivation, dementia, dysarthria, visual field constriction, and blindness. in the most severe cases, individuals remained in a mute rigid posture altered only by spontaneous crying, primitive reflexive movements, or feeding efforts. there were victims with deaths ( ) ( ) ( ) ( ) . seven children remained permanently incapacitated both physically and mentally. this was the second major mercury disaster after the minamata bay disaster in japan occurring between and , when about people were poisoned and died ( ) . phenylmercury acetate has been found to be embryotoxic and teratogenic ( ). in deaths caused by acute mercury poisoning, the mucosa of the mouth, throat, esophagus and stomach is greyish in color showing superficial hemorrhagic erosions; a softened appearance of the stomach wall is characteristic. in cases where the patient survived a few days, the large bowel may show ulcerations. the kidneys appear pale and swollen owing to edema of the renal cortex. microscopically, the kidneys usually demonstrate necrosis of the renal tubules ( ). sperhake et al. ( ) reported the case of a -year-old chemist who died of mercury poisoning. an autopsy carried out hours postmortem revealed unspecific signs of intoxication including severe edema of the lungs and brain, dilatation of the bowel, and marked congestion of the parenchymatous organs. the stomach contained ml of a reddish fluid. between the gastric folds, the mucosa appeared highly preserved with a brownish discoloration, but streaklike erosions in the exposed parts. the mucosal surface of the oral cavity and esophagus also appeared brownish and discolored. histologically, the pre-served areas of the gastric mucosa were totally unaffected by autolysis with an intact epithelial layer, whereas the eroded areas showed loss of mucosal lining with infiltrates of polymorphonuclear granulocytes and lymphocytes. mercury was detected in the epithelial layer of the gastric mucosa in situ using , diphenylcarbazone staining ( . % in % ethanol). tubular necrosis was present in the kidneys. a case of chronic arsenic poisoning in a -year-old man has been described; the man used a sodium arsenite-based fungicide for cultivating his vine yard ( ). methyl bromide (ch br), also known as bromomethane, monobromomethane, embafume, or iscobrome, is mainly used as a gas soil fumigant against insects, termites, rodents, weeds, nematodes, and soil-borne diseases ( , ) . it has been used to fumigate agricultural commodities, mills, grain elevators, ships, furniture, clothes, and greenhouses. its main advantages are its effective penetrating power and absence of danger of fire or explosion hazards. methyl bromide acts rapidly, controlling insects in less than hours in space fumigations, and it has a wide spectrum of activity, controlling not only insects but also nematodes and plant-pathogenic microbes ( ) . about % of methyl bromide produced in the united states goes into pesticidal formulations. pure methyl bromide is a colorless gas that is heavier than air. odorless and tasteless in low concentrations, it has a musty, acrid smell in high concentrations. occupational exposure to methyl bromide also occurs frequently. it is estimated that about , american workers are occupationally exposed to this gas annually. its toxicity is severe and, despite safeguards, cases of acute and chronic intoxication occur, mainly in the fruit and tobacco industries. the maximum allowable concentration of methyl bromide is ppm. concentrations of ppm or less are considered safe. death has been reported to occur at ppm ( ) . methyl bromide can enter homes through open sewage connections, thus causing fatalities. lagard et al. ( ) reported an interesting case of methyl bromide poisoning where methyl bromide caused toxicity in this manner. the sewage pipes serving two houses (one house was fumigated and in the other the poisoning occurred) had been sucked empty only to hours prior to the start of fumigation. because it depletes ozone into the atmosphere ( ) , methyl bromide has been banned in several industrialized countries, except for exceptional quarantine purposes. phosphine, sulfuryl fluoride (see subheading . .) , and carbonyl sulfide are considered viable alternatives. the mucosa of trachea and bronchi is congested and shows petechial hemorrhages. the lungs show subpleural hemorrhages and pulmonary edema. bilateral bronchopneumonia may also be present. the brain is edematous with necrosis of cortical cells, especially in the frontal and parietal lobes. multiple perivascular hemorrhages may be detected throughout the brain and small subarachnoid hemorrhages may be seen in some cases. circumscribed hemorrhages may also be present in stomach, duodenum, myocardium, spleen, and retina. the kidneys are acutely congested and show tubular necrosis on the micromorphological level; the proximal tubules are most commonly affected. in severe cases, the loops of henle and the distal tubules are also affected. the liver is also congested, but liver cell necrosis is not a common feature ( ) . methyl bromide can be detected and quantitatively determined in various biological samples by headspace gas chromatography ( ). sulfuryl fluoride (f o s) is an important agricultural fumigant. according to the annual report of the aapcc ( ), the only death that occurred as a result of fumigants was caused by sulfuryl fluoride (fig. ) . it is an inorganic gas fumigant used in structures, vehicles, and wood products for control of drywood termites, wood-infesting beetles, and certain other insects and rodents. it is also used as a gas fumigant for postharvest use in dry fruits, tree nuts, and cereal grains. it is available under the trade name vikane™ gas fumigant. because methyl bromide has now been graded as an ozone-depleting substance and is being gradually phased out, sulfuryl fluoride is taking its place. because sulfuryl fluoride is an inorganic material, as opposed to the organic methyl bromide, it does not bind onto items being protected and therefore, less quantities of gas are required for the same insecticidal effect. sulfuryl fluoride is a colorless and odorless gas. it does not cause tears or immediately noticeable eye irritation and lacks any other warning property. chloropicrin is added to products containing sulfuryl fluoride to serve as a warning indicator; chloropicrin is a gas that causes eye and respiratory irritation and vomiting. sulfuryl fluoride acts as a cns depressant. symptoms of poisoning include itching, numbness, depression, slowed gait, slurred speech, nausea, vomiting, stomach pain, drunkenness, twitching, and seizures. inhalation of high concentrations may cause respiratory tract irritation and respiratory failure. skin contact with sulfuryl fluoride normally poses no hazard, but contact with liquid sulfuryl fluoride can cause pain and frostbite-like lesions owing to rapid vaporization. occupational sulfuryl fluoride exposure may be associated with subclinical effects on the cns, including effects on olfactory and some cognitive functions ( ) . the oral ld for sulfuryl fluoride in rats and guinea pigs is mg/kg. scheuerman has reported two cases of suicide by sulfuryl fluoride ( ). according to scheuerman, toxicological analysis should include a plasma and urine fluoride level because the toxic effects of sulfuryl fluoride are probably related to this ion. concentrations of fluoride in his cases were and . mg/l, respectively. however, all values have to be interpreted in the light of all information available (kind and length of exposure, symptoms, autopsy findings, etc.) in a given case. aluminum phosphide (alp) is an ideal grain preservative for a number of reasons. it is highly toxic to almost all stages of insects with remarkable penetration power. alp dissolves well in water, oil, and fat. it is considered an ideal seed fumigant since the seeds' viability is not affected and is practically free from residual toxic hazards-provided the seeds have less than % water content. alp is minimally absorbed and easily desorbed from the treated commod- ity, such as wheat grains. it is inflammable at the prescribed dosage and devoid of tainting on fumigated stock. it has a distinct odor, which has been described as a fishy odor. because of this and also because of delays in evolving, phoshine provides considerable safety in handling this fumigant. safety in handling is due to both these reasons. because it has an odor, it is difficult for handlers to accidently ingest it. because the tablet generates the predetermined weight of gas, it is very convenient to administer the exact dose. cost of fumigation is low and its effects on the fumigated stock last longer. alp is easy to transport and handle. unfortunately, no specific antidote to alp is known. alp is used very extensively throughout agrarian economies like india. on exposure to moisture it releases the poisonous phosphine, which percolates through the grain: alp+h _ al(oh) +ph . as long as the grain is stored in airtight godowns, the liberated phosphine remains in the environment, repelling all pests. when the grain is to be used, it is brought out and aerated. this releases phosphine, leaving behind virtually no or only nontoxic residues. alp is generally available as tablets (alphos ® , celphos ® , fumigran ® ), which are dark brown or grayish in color, g in weight, and measuring mm in diameter and mm in thickness. they come in an aluminum container containing ten tablets. alp is also available as . -g pellets. the tablets are composed of pure alp (the active ingredient) and ammonium carbamate/carbonate (the inert ingredient). the ratio of the active and inert ingredient is generally about : . on contact with moisture, each -g tablet evolves about g of phosphine along with carbon dioxide and ammonia, which prevents self-ignition of phosphine gas. this is why it is also called a "protective gas." carbon dioxide and ammonia are liberated by combination of water with other inert ingredients in the tablets. the main function of the inert ingredients is to produce these gases, so phosphine may not ignite easily. the phosphine gas, once liberated, spreads quickly and kills insects and rodents almost in all stages of their development. after complete decomposition of the tablet, alp is left behind as a harmless and nontoxic grayish white residue, which is less than % of the original tablet weight. alp is the leading cause of accidental and suicidal deaths in india ( ) ( ) ( ) ( ) ( ) . it has been implicated in several homicides including dowry deaths (deaths of newlywed brides occurring in relation to dowry and covered under section b of the indian penal code). the mortality rate for poisoning with alp is almost % ( ) . there is an intense garlic-like odor emanating from the mouth and after opening of the stomach at autopsy. all internal organs are congested and show petechial hem-orrhages. pericarditis may be present ( ) . the stomach contents are hemorrhagic and the mucosa shows detachment. residues of alp may be demonstrable in the stomach contents, but rarely can alp itself be detected because it readily reacts with acid and water within the stomach. misra et al. ( ) described eight cases of alp poisoning after ingestion of alp tablets for attempting suicide; the mean age of the patients was years (age range - years). six of the patients died; the mean hospital stay was hours (range - hours). an autopsy was carried out in two patients, revealing pulmonary edema, congestion of the gastrointestinal mucosa, and petechial hemorrhages on the surface of liver and brain. anger and co-workers ( ) reported the case of a -year-old man who committed suicide by ingestion of alp. autopsy revealed signs of asphyxia with marked visceral congestion. the authors also toxicologically analyzed peripheral blood, urine, liver, kidney, adrenal, brain, and cardiac blood. phosphine gas was absent in peripheral blood and urine but present in the brain ( ml/g), the liver ( ml/g), and the kidneys ( ml/g). high levels of phosphorus were found in the blood ( . mg/l) and liver ( . mg/g). aluminum concentrations were highly elevated in peripheral blood ( . mg/l), brain ( μg/g), and liver ( μg/g) compared with the reference values. histopathological findings in alp poisoning have been described in detail by chugh et al. ( ) . various viscera show congestion, edema, and inflammatory cell infiltration. in the myocardium, there are patchy areas of necrosis, whereas the liver shows fatty changes and the lung parenchyma displays gray/red hepatization. the adrenal cortex shows complete lipid depletion, hemorrhage, and necrosis. chugh et al. assumed that the changes in the adrenal cortex could be both a sequel of shock and/or a cellular toxic effect of phosphine. in out of the patients studied by chugh and associates, there was a significant rise in the plasma cortisol level (> nmol/l). in the remaining patients, the adrenal cortex was critically involved and the cortisol level failed to rise beyond normal levels (< nmol/l). pillay ( ) noted that in alp poisoning the heart shows features of toxic myocarditis, necrosis may be seen histologically in both liver and kidneys, and the lungs may demonstrate evidence of adult respiratory distress syndrome (ards). ards has also been reported by chugh et al. ( ) . the dose of the intoxicant in chugh's cases varied from two g) to three tablets (corresponding to and g, respectively). all patients were in shock at admission and developed ards within hours after ingestion of alp. according to these authors, the exhalation of phosphine (which they detected by a positive silver nitrate paper test) was the possible noxious triggering factor in developing ards. in misra at al.'s series ( ) , histopathological changes included pulmonary edema, desquamation of the lining epithelium of the bronchioles, vacuolar degeneration of hepatocytes, dilatation and engorgement of hepatic central veins and sinusoids, as well as hepatocytes showing nuclear fragmentation. in anger's single case ( ) , microscopic examination revealed congestion of inner organs and pulmonary lesions that were attributed to asphyxia. silo filler's disease is another disorder associated with agrochemical poisoning during preservation. corn used for silage is usually grown under conditions of heavy sunlight and drought and its nitrate content is usually very high. when this silage is stored in a silo, the nitrates are fermented into nitrites, which in turn combine with organic acids to form nitrous acid. nitrous acid decomposes into water and a mixture of nitrogen oxides. these are nitric oxide (no), nitrogen dioxide, and dinitrogen tetroxide. the decomposition starts within approx hours of putting the crops into the silo and continues for about days. when entering these silos (which virtually turn into a kind of gas chamber), farm workers may suffer acute poisoning from these gases, and many such deaths have occurred. this type of death in a silo was first described in , but at that time it was wrongly attributed to asphyxia ( ). nos, being relatively poor soluble in water, can reach the terminal bronchioles and even alveoli. within the lungs, the nos react with water to form nitrous and nitric acids, which cause extensive lung damage, resulting in chemical pneumonitis and profuse pulmonary edema. nos trigger histamine release, which causes bronchoconstriction resulting in increased airway resistance. douglas and colleagues ( ) examined patients of silo filler's disease between and . all exposures had occurred in conventional top-unloading silos. acute lung injury occurred in patients, one of whom died. in the fatal case, autopsy findings included early diffuse alveolar damage with hyaline membranes, hemorrhagic pulmonary edema, and acute edema of the airway walls. poisoning with and fatalities owing to fertilizers are rarely encountered but do occur. the annual report of the aapcc toxic exposure surveillance system reported one death caused by fertilizers ( ) ( table ). used as a fertilizer, anhydrous ammonia is a respiratory irritant, which, in high doses, causes pulmonary edema ( ) . exposure most often occurs during transfer operations. ammonia reacts with water to form the strong alkali ammonium hydroxide, which causes severe tracheobronchial and pulmonary inflammation with bronchiolitis obliterans. normally, the peculiar odor of ammonia warns the potential victim. during world war ii, in london, a brewery cellar having ammonia-carrying condenser pipes was temporarily converted into a bomb shelter. during a bombing, a bomb fragment pierced one such pipe resulting in a mortality rate of the affected individuals as high as % ( ) . saito et al. ( ) described the case of a -year-old male who presumably consumed water contaminated with a nitrate fertilizer. on admission to hospital, the man showed drowsiness, deep cyanosis, and dyspnea; the patient died hours later. at autopsy, no particular morphological changes were noted except for the blood being a chocolate-brown color. postmortem toxicology of the blood revealed a methemoglobin concentration of % and the concentrations of nitrate and nitrite were . and . μg/ml, respectively. in deaths caused by nitrate fertilizers, methemoglobinemia and the presence of appreciable quantities of nitrites and nitrates may be demonstrated in cardiac blood and gastric contents (stored at - °c until toxicological analysis) ( ) . capillary gas chromatography-mass spectrometry and capillary gas chromatography with a nitrogen-phosphorus detector can be used to detect nitrates and nitrites in blood. sato and colleagues ( ) described the case of an -year-old woman who supposedly consumed agricultural fertilizer containing ammonium sulfate. she was found lying dead on the ground outside her house. a thorough autopsy could not determine the cause of her death. a beer can was found next to her, and when it was examined, it was found to contain ammonium sulfate. subsequently, ammonium and sulfate ions were detected in her serum samples and gastric contents. the cause of her death was determined as poisoning by ammonium sulfate. in order to further confirm that this death was indeed a result of an ammonium sulfate fertilizer, the authors administered a total dose of mg/kg of ammonium sulfate to three rabbits. the animals developed mydriasis, irregular respiratory rhythms, and local and general convulsions until they came into respiratory failure with cardiac arrest. electroencephalogram showed slow, suppressive waves and a high-amplitude with a slow wave pattern that is generally observed clinically in hyperammonemia in humans and animals. there was a remarkable increase in the concentration of ammonium ions and inorganic sulfate ions in the animals' serum and blood gas analysis showed severe metabolic acidosis. the authors suggested that when the cause of death can not be clearly determined and the previous history is suggestive of ammonium sulfate intake, measurement of ammonium ions, inorganic ions, and electrolytes in blood, as well as in stomach contents, are a prerequisite for the diagnosis. villar and co-workers reported poisoning and death in animals who drank fertilizer-contaminated water ( ) . the water had been hauled in tanks previously contaminated with a nitrogen-based fertilizer. in udaipur, india, chronic fluorotic lesions in cattle and buffalo have been described following consumption of fodder and water contaminated by the fumes and dusts emitting from superphosphate fertilizer plants ( ) . similar lesions have been reported from australia where the main source of fluoride appeared to have been gypsum that was included in a feed supplement and also ingested from fertilizer dumps on paddocks ( ) . gypsum fertilizers have caused several deaths in animals ( ) . similar morbidity and mortality may be seen in humans who drink contaminated water either intentionally or out of ignorance as well. the latter situation is quite possible among the uneducated farmers of agrarian economies. adrian ( ) drew attention to a very unique situation of poisoning related to fertilizers. in several countries, sewage sludges are used on farms as fertilizers because they do contain these materials. however the sewage-not surprisingly-also contains industrial wastes, such as chromium, lead, zinc, cadmium, and mercury. when this sewage is used as fertilizing material, plants tend to concentrate these heavy metals, especially chromium. ingestion of such farm produce may lead to heavy metal poisoning. several other cases of fertilizer poisoning, especially among animals, have been reported, too ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . in several countries, poisonous plants, such as castor, are used as green manure which can cause poisoning of both humans and animals. soto-blanco and colleagues from the university of sao paulo, brazil, described a case of canine poisoning where castor bean (ricinus communis) cake was used as a fertilizer ( ) . the authors stressed that these cakes may be accidentally ingested by humans as well, and recommended that cake production should include heat treatment to denature the poisonous proteins. nematicides can cause poisoning in banana plantations. wesseling and co-workers, studying pesticide-related illness and injuries among banana workers in costa rica, reported that workers at highest risk per time unit of exposure were nematicide applicators ( ) . slugs are major pests of oilseed rape that are poorly controlled by conventional bait pellets. therefore, compounds, such as metaldehyde and methiocarb, are used as seed dressings to control slugs ( ) . metaldehyde is a popular molluscicide that can cause fatal poisoning; the aapcc annual report ( ) mentions as many as cases of exposure to this agent. kiyota ( ) reported the case of a -year-old mentally retarded man suffering from pica, who ingested about . g of metaldehyde. despite medical treatment, he developed acute lung injury and died after days; he was found to have ascites and splenomegaly. high-performance liquid chromatography revealed . μg/ml metaldehyde in the serum. jones et al. ( ) developed a method to detect metaldehyde in samples of stomach contents by gas chromatography-ion trap mass spectrometry for forensic toxicology investigations. a suicide attempt using metaldehyde was reported by hancock and co-workers ( ) . a case of homicide using metaldehyde has been described by ludin ( ) . detailed overviews of metaldehyde toxicity have been provided earlier by booze and oehme ( ) and longstreth and pierson ( ) . avermectins used as acaricides (avermectin acaricides), insecticides (avermectin insecticides), and nematicides have been used for suicidal poisoning. chung and co-workers ( ) from taiwan studied the clinical spectrum of avermectin poisoning reported to a poison center from september to december . eighteen patients with abamectin (agri-mek; % wt/wt abamectin) exposure and one with ivermectin (ivomec; % wt/vol ivermectin) ingestion were identified ( males, females; age range - years). fourteen out of the patients had been exposed as a result of attempted suicide; one patient died days later as a result of multiple organ failure. algicides have not been reported to cause fatal poisoning in humans; minor ailments owing to algicide exposure include, e.g., contact dermatitis ( ) . aphicides are known to persist in crops ( ) ; their toxicity in house sparrows has been described in detail by tarrant and co-workers ( ) . bird repellants are trigeminally mediated avian irritants ( ) . toxic effects to humans have apparently not been reported so far. chemosterilants are chemicals that aim at destroying the fertility of pests. , -dibromo- -chloropropane is used to induce infertility in rats ( ) . the chemosterilant bisazir is extremely hazardous. ciereszko and co-workers ( ) have recommended that special safety measures are necessary when handling this chemical. however, toxic effects to humans have not been reported in the medical literature so far. antifeedants are chemicals having tastes and odors that inhibit feeding behavior. several chemicals, such as silphinene sesquiterpenes ( ), , , oxadiazoles ( ) , and ryanoid diterpenes ( ) , are used as antifeedants; again, toxic effects to humans have not been reported so far. herbicide safeners are compounds protecting crops from herbicide injury by increasing the activity of herbicide detoxification enzymes such as glutathione-s-transferases ( ) ( ) ( ) and cytochrome p- s. several herbicide safeners are used in agriculture such as benoxacor ( ) and dichloroacetamide ( , ) ; there toxicity in humans has not been reported so far. insect attractants attract or lure an insect to a trap. several of them are available, such as boll weevil attract and control tubes ® (plato industries, houston, tx) ( ), imidacloprid ( ) , and gf- fruit fly bait ( ) . their toxicity has been studied in detail by beroza et al. ( ) . the secondary effects of conventional insecticides on the environment, vertebrates, and beneficial organisms have caused a move to the use of more target-specific chemicals, such as insect growth regulators (igrs) ( ) . igrs are chemicals disrupting the action of insect hormones controlling molting, maturity from pupal stage to adult, or other insect life processes. several igrs are known, such as halofenozide ( ), s-methoprene ( , ) , buprofezin ( ) , tebufenozide ( ) , the chitin synthesis inhibitors teflubenzuron, diflubenzuron ( ) , and hexaflumuron, as well as the juvenile hormone mimic pyriproxyfen ( ) . halofenozide (rh- ) is a novel nonsteroidal ecdysteroid agonist that induces a precocious and incomplete molt in several insect orders ( ) . the antifeedant , , -oxadiazoles also show a considerable amount of igr activity ( ) . the toxicity of these antifeedants to animals has been studied by wright ( ) . pesticide synergists are chemicals that, although they do not possess inherent pesticidal activity, they nonetheless promote or enhance the effectiveness of other pesticides when used combined (synergism). synergists usually increase the toxicity of a pesticide so that a smaller amount is needed to bring about the desired effect. this may reduce the cost of application. an example of a synergist is piperonyl butoxide, often used with pyrethrin, pyrethroid insecticides, rotenone, and carbamate-containing pesticides. piperonyl butoxide is a liver toxicant and a possible human carcinogen ( , ) ; it also inhibits t-cell activation and function ( ) . -chloro-p-toluidine hydrochloride (cpth) is an aniline derivative registered as a selective, low-volume-use (< kg/yr) avicide. rice baits are treated with cpth to cause poisoning in birds harmful to crops ( ) . cpth may be mutagenic. stankowski et al. ( ) conducted three in vitro mutagenicity tests of cpth according to methods recommended by the united states environmental protection agency, e.g., the ames/salmonella assay, the chinese hamster ovary (cho)/hypoxanthine-guanine phosphoribosyl-transferase mammalian cell forward gene mutation assay, and the cho chromosome aberration assay. they found that cpth did not display mutagenic activity using the ames/salmonella or cho/hypoxanthine-guanine phosphoribosyl-transferase assays. however, cpth induced statistically significant, concentration-dependent, metabolically activated increases in the proportion of aberrant cells. the authors concluded that the results were suggestive of minimal mutagenicity effects associated with exposure to cpth ( ) . stahl and co-workers draw attention to the consumption of cpth treated rice baits by nontargeted bird species, such as pigeon (columbia livia) and house sparrow (passer domesticus). cpth can persist in the breast muscle tissues of both targeted and nontargeted birds which may be a potential secondary hazard to scavengers and predators ( ) . toxicity of cpth both in humans and animals has been discussed by several other authors as well ( ) ( ) ( ) ( ) ( ) . if a particular agrochemical poison has been banned in a country, it is not necessarily that poisoning with this agent will not be seen in that particular country. for example, in japan, production of azomite emulsion (an acaricide) has been stopped since . however, moriya et al. in ( ) described a recent azomite-related fatality. poisoning with azomite was confirmed when aramite and azoxybenzene, two effective components of azomite emulsion, were detected in the patient's serum when qualitatively analyzed with gas chromatography-mass spectrometry. the authors concluded that even if an agrochemical poison is banned, the pathologist must still keep the possibility of its ingestion in mind. many times, it is not the active agricultural chemical that is responsible for poisoning but impurities (such as dioxin), surfactants (e.g., polyethoxylated tallow amine used with glyphosate) and adjuvants used along with the chemical. these adjuvants, or "inert" ingredients, could be solvents, stabilizers, preservatives, sticking or spreading agents, or defoamers ( ) and may constitute petrochemical solvents, such as acetone, fuel oil, toluene, and other benzene-like chemicals. these could sometimes be more toxic than the active ingredient. rubbiani drew attention to several of these adjuvants and clinical syndromes produced by them ( ) . according to harry ( ) , toxicity is often due to solvents or surfactants included in the composition of a formula used as an agricultural chemical. when the obligatory declaration on the label about identity and concentration of some of these substances is not provided by the actual legislation in a particular country, the problem becomes more acute. it is also often difficult to determine if the cause of the poisoning is the actual agricultural chemical itself or its adjuvants. metabolites are breakdown products that form when a pesticide is exposed to air, water, soil, sunlight, or living organisms and often the metabolite is more hazardous than the parent compound. an estimated three million cases of agrochemical poisoning are reported from around the world every year, making it one of most serious toxicological problems of the present times. an overwhelming majority of these-more than %-are reported from developing countries, such as india, presumably because these are predominantly agrarian economies. in the united kingdom, pesticides are responsible for only about % of deaths ( ) , whereas in united states, as seen in table , the figure varies between and %. the equivalent figures in india have been reported to be as high as % ( ) . figure shows some common pesticides used in india. accidental poisoning may occur in a number of ways. accidental poisoning can occur if the insecticide is stored inadvertently with foodstuffs ( ) . one of the most shocking cases of mass agrochemical poisonings occurred in the indian state of kerala in (known popularly as the "kerala food poisoning case of ") when bags of foodstuffs, such as wheat and sugar, were inadvertently stored together with those of folidol (parathion) in the same cabin on a ship ( ) . the insecticide leaked and contaminated the foodstuffs; more than people were accidentally poisoned when they consumed these contaminated foodstuffs. out of these, more than people died. mixing of pesticides with foodstuffs may be intentional, albeit entirely because of ignorance and without any criminal intent. such a case came to notice in the late s in lakhmipur in kheri district, in the indian state of uttar pradesh. farmers in this state were found to be preserving food grains with benzene hexachloride. a severe convulsive epidemic broke out among several hundred people because of this ignorance and more than people died. in , improper use and application of benzene hexachloride in the town sunser in the indian state of madhya pradesh resulted in many people falling ill. fortunately, no human died, but there were reports of several bird casualties. in march , a case of agricultural poisoning from india was reported where an entire family was poisoned owing to leakage of pesticides into cereal (sorghum/jowar) stored in the same room ( ) . the indian state of kerala is a major cashew growing region. there have been attempts at aerial spraying of this cash crop with endosulphan. because these areas are close to local residential areas, deleterious effects occurring in humans have caused a major controversy in recent times ( ) . pillay ( ) suggests that accidental poisoning due to pesticides can occur in four different scenarios: (a) occupational exposure among agriculturists and those engaged in the task of pesticide spraying, (b) contamination of foodstuffs on account of negligence, (c) inadvertent ingestion by children, and (d) reusing pesticide containers for storing food or drink (the latter is very common among third-world countries). instances of fatalities among agricultural workers due to accidental exposures have been reported from time to time ( ) . accidental poisoning owing to some pesticides, such as paraquat, occurs in a number of scenarios, e.g., when the mouthpiece of fumigation equipment is sucked by the operator while cleaning and it is suddenly cleared of obstruction, confusion under the influence of alcohol, consumption of contaminated water or foods, accidental ingestion by children, and accidental cutaneous exposure or oral topical application for toothaches by ignorant persons ( ) . robert g. book of bloemfontein, south africa, reported a unique case of accidental poisoning with paraquat: a young woman tried to "achieve a high" by spiking her coca-cola with paraquat. she died after a few days of hospitalization. at the time of her admission she had told the doctor that her husband had maliciously put paraquat in her drink a few days before; however, only days later she changed her version as just mentioned ( ) . it is noteworthy that in india it is very common for married women at the time of their death to shield their murderous husbands by making such statements. whether the woman's first or second statement was correct is anybody's guess. according to harry ( ) , accidental pesticide intoxications are mainly caused by ingestions of diluted fertilizers, low-concentration antivitamin k rodenticides, ant-killing products, or granules of molluscicides containing % metaldehyde, whereas voluntary intoxications are mostly by chloralose, strychnine, organophosphorus or organochlorine insecticides, concentrated antivitamin k products, and herbicides, such as paraquat, chlorophenoxy compounds, glyphosate, and chlorates. suicidal poisoning with agrochemicals, especially organophosphates and alp, is very common in countries like india. one of the main reasons is the easy availability of these agrochemicals. many companies now add an emetic to dangerous agrochemicals, such as paraquat and alp. addition of a "stenching" agent to paraquat has apparently not deterred suicidals from consuming this poison. homicidal poisoning with organophosphorus compounds is possible and from time to time, one gets to hear or read about cases of a homicide commit-ted with these substances. svraka and colleagues have described four cases of homicide with organophosphorus compounds ( ) . however, homicidal poisonings with organophosphorus compounds are rare because of the unpleasant taste of most agrochemicals, especially of organochlorines, such as endrin, but they have been mixed with alcohol, especially toddy (a strong liquor that is very popular in india), which masks its smell and has been used with organophosphorus compounds for homicidal purposes in this way. homicidal poisoning with parathion is much easier ( ) ( ) ( ) ( ) . to prevent this, a coloring agent, such as indigocarmine, is added to parathion. this is, however, not a universal practice. in india for instance, addition of indigocarmine to parathion is not practiced. the commonly used herbicide paraquat is odorless and gives rise to symptoms mimicking viral pneumonitis. these two properties-classically hailed as the properties of an ideal homicidal poison-make it very attractive as a homicidal poison. paraquat is supposed to have a burning taste, but this can be masked in hot liquids or spicy foods ( ) . several homicide cases with paraquat undoubtedly must have gone unnoticed. teare and teare and brown ( , ) described five cases of paraquat poisoning, of which, two were homicidal in nature. the first is a well-documented case (reg vs kenyon and roberts) in which a -year-old man, keith william kenyon, was killed by his wife jennifer kenyon and her friend, david roberts, a consultant on the effects of agricultural chemicals. she purchased gramoxone along with her friend olive hemming (who turned out to be the chief prosecution witness) from a farm shop, and most likely administered it to her husband in repeated small doses. kenyon was taken ill on november , and died days later, on december . during his illness, he displayed all the classical symptoms and signs of paraquat poisoning. postmortem examination confirmed death by paraquat intoxication. mrs. kenyon was convicted of murder, whereas david roberts was acquitted because of lack of evidence against him ( ) . the second case occurred only month later. after christmas , on the falkland islands, four local agricultural workers had been having a boxing day party when some gramoxone was slipped for some unknown reason into one of their beers. the man died after displaying typical symptoms of paraquat poisoning. autopsy confirmed poisoning by paraquat. criminal charges against the other three laborers were contemplated, but eventually it was decided to drop them. paul ( ) described the case of a -year-old woman who killed her husband by mixing paraquat in his steak-and-kidney pie twice. when he developed a sore throat and was prescribed medicine for treatment, she mixed paraquat in the medicine as well. the husband died on june , after suffering a day illness. the cause of death was attributed to cardiac arrest in combination with renal failure and bilateral pneumonia and it was only by a curious chain of circumstances that paraquat was detected in the young man's tissues preserved in the mortuary in a bucket, months after the man's death. his wife and her paramour were found guilty and sentenced. stephens and moormeister from the medical examiner's office of san francisco, ca, reported four cases of homicidal poisoning by paraquat ( ) . of these, the first three murders were perpetrated by one man against members of his immediate family, and the fourth case was equivocal-it could either have been suicide or homicide. the first three murders were committed by a man who had been married five times. his first three wives were alive and healthy. when the fourth wife threatened to divorce him, she found herself ill and died days after the onset of her illness ( days after hospitalization). eight years later, when his fifth wife threatened divorce, she suffered the same fate, and a few months later, his -year-old mother also died. all three showed typical symptoms of paraquat poisoning. the postmortem findings seemed to suggest natural disease of the lungs. although a suggestion of paraquat poisoning was made in all three cases, the concerned pathologist was reluctant to sign death certificates as paraquat poisoning. toxicological analysis in the second and third cases revealed the presence of paraquat in the victims' tissues and this resulted in conviction of the murderer. it was found that the defendant worked as a mechanic on a large agricultural ranch and had easy access to paraquat; his thumb print was found on one of the opened paraquat containers, although he had earlier denied having to do anything with those containers. the fourth case involved a -year-old man, a registered herbicide and pesticide user, who had marital difficulties with his aggressive, "shrew-like" wife who also stood to benefit from a large insurance policy upon his death. while in hospital, the victim denied suicidal ingestion; he died days after the start of his illness. no testing of toxic effects from the compounds he worked with was ever performed, nor was any consideration given to this possibility. the case did not result in court charges for anyone. stephens and moormeister concluded that the reason why such cases will often go unnoticed is because of the reluctance on the part of both clinicians and forensic pathologists to even think in the direction of paraquat poisoning when they see such a clear and typical picture of "viral pneumonia." in their opinion, the clinician should suspect paraquat ingestion in all cases in which there is progressive pulmonary involvement with no features of viral infection ( ) . the pathologist conducting the postmortem would do well to go through the clinical history, if available, in detail to rule out the possibility of paraquat poisoning. in all doubtful cases, a full toxicological analysis should be done and the tissues should be particularly analyzed for paraquat. daisley and simmons from the university of the west indies in trinidad reported two cases of homicide by paraquat poisoning ( ) . both cases occurred in children and the common clinical presentations were gastrointestinal ulceration and acute respiratory distress with pneumomediastinitis. at autopsy, the most prominent finding was bullous lung emphysema. the authors stress that pathologists should be aware of this finding because they feel that if this autopsy finding is seen combined with the typical clinical presentation mentioned in sections . . . and . . ., it is almost diagnostic of acute paraquat poisoning. da costa et al. have dealt with the medicolegal aspects related to paraquat poisoning in detail ( ) . another weed killer that has been used commonly for homicidal purposes is sodium chlorate. in reg vs hargreaves, hampshire (winchester) assizes, april , a -year-old woman was charged with the murder of a -year-old man whom she had known for the last years as an uncle. in august , he made his last will, written out by the accused in her favor. on january , the accused bought the weed killer sodium chlorate apparently for a friend who was a gardener. on january , , the old man died and the postmortem examination showed signs of death from sodium chlorate poisoning. the victim had consumed beer and the remaining beer in the mug contained some mg of sodium chlorate. the jury found the woman guilty of manslaughter and sentenced her to months of imprisonment ( ) . one of the biggest and most well-known medicolegal controversies in connection with herbicides has been that of agent orange. agent orange is the name given to a mixture of herbicides that united states military forces sprayed in vietnam from to during the vietnam war for the dual purpose of destroying crops that might feed the enemy and defoliating forest areas that might conceal viet cong and north vietnamese forces. the defoliant consisted of approximately equal amounts of the unpurified butyl esters of , -d and , , -trichlorophenoxyacetic acid ( , , -t). agent orange also contained small, variable proportions of , , , -tetrachlorodibenzo-p-dioxin-commonly known as dioxin-which is a byproduct of the manufacture of , , -t and is toxic even in minute quantities; dioxin is considered one of the most toxic compounds synthesized by humans. agent orange was delivered in -gallon drums with an orange stripe to distinguish the drums visually from those containing other chemical agents (hence the name). about million liters of agent orange were sprayed over vietnam from low-flying aircrafts. among the vietnamese, it is considered to be the cause of an abnormally high incidence of miscarriages, skin diseases, cancers, birth defects, and congenital malformations (often extreme and grotesque). alterations in manufacturing procedures had reduced the dioxin content in agent orange later to minimal levels. today, , , -t registrations have been cancelled and agent orange was voluntarily removed by the manufacturers in . many united states, australian, and new zealand servicemen who suffered long exposure to agent orange in vietnam later developed cancer and other health disorders. a class-action lawsuit was brought against seven herbicide makers that produced agent orange for the united states military. the suit was settled out of court with the establishment of a $ , , fund to compensate some , claimants and their families. separately, the united states department of veterans affairs awarded compensation to about veterans. agent orange has now been replaced by agent white, a mixture of , -d and picloram, which is longer lasting and more effective. in the united states, the federal insecticide, fungicide and rodenticide act (fifra) was passed in (amended in , , and [ ] ). this act divides all pesticides in four broad classes depending on their toxicity. the label of each pesticide has to contain a signal word depending on its toxicity. the criteria established by the fifra are given in table . according to the fifra, toxic category i pesticides must have the signal words danger and poison (in red letters) and a skull and crossbones prominently displayed on the package label. the spanish equivalent for danger, peligro, must also appear on the labels of highly toxic chemicals. toxic category ii pesticides must have the signal word warning (aviso in spanish) displayed on the product label. toxic category iii pesticides are required to have the signal word caution on the pesticide label. toxic category iv pesticide products shall bear on the front panel the signal word caution on the pesticide label. pesticides formulated in petroleum solvents or other combustible liquids must also include the precautionary word flammable on the product label. this was obviously done to prevent cases of accidental poisoning, and similar acts exist in almost all countries. in india, a predominantly agricultural country, handling of insecticides is governed by the insecticides act and the insecticide rules, (amended in ) ( ) . section of the insecticide rules, classifies insecticides on a similar basis. section also insists on affixing a label to the insecticide container in such a manner that it cannot be ordinarily removed. among other things, it must contain a square, occupying not less than onesixteenth of the total area of the face of the label, set at an angle of °(diamond shape). this square is to be divided into two equal triangles, the upper portion of which shall contain the signal word, and the lower portion the specified color. the classification of insecticides, signal words to be used, and the color of the identification band on the label according to the insecticide rules, of india are given in table . if a pesticide is misused in any way, the person who bought and stored the pesticide may be legally responsible. in the united states, the food quality protection act was passed in as a complementary set of regulations, which, among other important features, specifically recognizes the special situations and usages of pesticides for public health. these laws regulate the registration, manufacture, transportation, distribution, and use of pesticides. the regulations are administered by the environmental protection agency. more than , bright green ld : lethal dose in % of the exposed subjects intoxications caused by plant protection chemicals in forensic toxicology in urban south africa patterns and problems of deliberate self-poisoning in the developing world pesticide poisoning agricultural and horticultural chemical poisonings: mortality and morbidity in the united states 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aluminium phosphide fatal aluminum phosphide poisoning adult respiratory distress syndrome following aluminium phosphide ingestion. report of cases four cases of sudden death in a silo silo filler's disease chemical hazards to agricultural workers ammonia gas poisoning. forty-seven cases in a london shelter a case of fatal methemoglobinemia of unknown origin but presumably due to ingestion of nitrate a case of fatal intoxication with ammonium sulfate and a toxicological study using rabbits acute poisoning of cattle by fertilizer-contaminated water industrial fluorosis in cattle and buffalo around udaipur chronic gypsum fertiliser ingestion as a significant contributor to a multifactorial cattle mortality sheep deaths after accidental ingestion of gypsum fertiliser contribution of the incidence of urban sewage spreading to dietary chromium hyperkalemia after house plant fertilizer poisoning accidental superphosphate fertilizer poisoning in pregnant ewes urea poisoning in suckler cows acute, fatal illness in cattle exposed to boron fertilizer suspected superphosphate poisoning in calves forensic pathological studies on autopsy of a patient who died after ingesting the liquid fertilizer hyponex nitrite poisoning in herring gulls (larus argentatus) and ringbilled gulls (larus delawarensis) accidental ammonia exposure to county fair show livestock due to contaminated drinking water ricinus communis cake poisoning in a dog seed dressings to control slug damage in oilseed rape case report-fatal snail bait (metaldehyde) overdose presenting aspiration pneumonia determination of metaldehyde in suspected cases of animal poisoning using gas chromatography-ion trap mass spectrometry attempted suicide with a pesticide mixture murder by metaldehyde poisoning metaldehyde toxicity: a review metaldehyde poisoning from slug bait ingestion agricultural avermectins: an uncommon but potentially fatal cause of pesticide poisoning -chloro- , -dinitrobenzene as an algicide. report of four cases of contact dermatitis aphicide persistence on spinach and mustard greens biochemical and histological effects of the aphicide demeton-s-methyl on house sparrows (passer domesticus) under field conditions bird repellents: interaction of chemical agents in mixtures (dbcp)-induced infertility in male rats mediated by a post-testicular effect efficacy of animal anti-fertility compounds against sea lamprey (petromyzon marinus) spermatozoa silphinene sesquiterpenes as model insect antifeedants the toxic and anti-feedant activity of h-pyridazin- -one-substituted , , -oxadiazoles against the armyworm pseudaletia separata (walker) and other insects and mites selective insect antifeedant and toxic action of ryanoid diterpenes tissue-specific expression and localization of safener-induced glutathione s-transferase proteins in triticum tauschii structure of a tau class glutathione s-transferase from wheat active in herbicide detoxification partial characterization of glutathione 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selective pesticides against the storage mite tyrophagus putrescentiae (acari: acaridae) pulse-exposure effects of selected insecticides to juvenile australian crimson-spotted rainbowfish (melanotaenia duboulayi) laboratory evaluation of selected larvicides and insect growth regulators against field-collected culex quinquefasciatus larvae from urban dhaka inter-regional differences in baseline toxicity of bemisia argentifolii (homoptera: aleyrodidae) to the two insect growth regulators, buprofezin and pyriproxyfen significance of penetration, excretion, and transovarial uptake to toxicity of three insect growth regulators in predatory lacewing adults cytotoxic effects of two antimolting insecticides in mammalian cho-k cells persistence and residual activity of an organophosphate, pirimiphosmethyl, and three igrs, hexaflumuron, teflubenzuron and pyriproxyfen, against the cowpea weevil, callosobruchus maculatus (coleoptera: bruchidae) environmental and toxicological aspects of insect 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a case of murder by parathion (e ) which nearly escaped detection homicidal poisoning by paraquat poisoning by paraquat murder under the microscope-the story of scotland yard's forensic science laboratory homicide by paraquat poisoning the forensic medical aspects of paraquat poisonings sodium and potassium compounds fifra- , glp, and qa: pesticide registration the insecticides act, with the insecticide rules, , as amended by the insecticide (amendment) rules, . delhi law house acknowledgment i wish to thank my wife marygold gupta, a chemist, and my son tarun aggrawal for their whole-hearted support during the writing of this chapter. marygold was especially helpful in making me comprehend the chemical structures of several pesticides. tarun drew several chemical structures and figures on his computer. key: cord- - nvrakbs authors: patel, zara m.; hwang, peter h. title: acute bacterial rhinosinusitis date: - - journal: infections of the ears, nose, throat, and sinuses doi: . / - - - - _ sha: doc_id: cord_uid: nvrakbs acute bacterial rhinosinusitis (abrs) is a highly prevalent disease associated with significant direct and indirect costs. it is paramount that a practitioner can distinguish between acute viral rhinosinusitis and abrs to avoid unnecessary antibiotic usage. it is also important to understand that establishing a diagnosis of abrs does not necessitate the prescribing of antibiotics, unless the abrs patient presents with severe or worsening symptoms or an abrs complication. complications include extension of infection to the orbit and central nervous system. injudicious use of antibiotics imparts societal costs in terms of financial expense as well as contributing to higher levels of bacterial resistance. this chapter reviews the epidemiology, clinical features, diagnosis, and treatment of abrs. acute sinusitis, also known as acute rhinosinusitis, is an inflammation of the nasal cavity and paranasal sinuses that lasts up to weeks [ , ] . we preferentially use the term rhinosinusitis in place of sinusitis to acknowledge that the inflammation seen in sinusitis involves the nasal cavity as well. although many patients present with rhinosinusitis that has lasted longer than weeks, these more protracted forms of sinusitis-subacute and chronic rhinosinusitis-are discussed in chap. . the definitions for the various types of rhinosinusitis are summarized in table . . it is estimated that % of the u.s. population is affected by acute and chronic rhinosinusitis [ ] . women appear to be affected more than men, and the most commonly affected age group among adults is mid- s to mid- s [ ] . older age, smoking, air travel, exposure to changes in atmospheric pressure as with flying or diving, swimming in chlorinated pools, asthma and allergies, dental disease, and immunodeficiency are all considered risk factors for the development of ars [ ] . direct costs from managing acute and chronic sinusitis are estimated at $ billion dol-lars per year in the u.s., not accounting for significant indirect costs attributable to lost work productivity and reduced job effectiveness [ , ] . acute rhinosinusitis is the fifth most common diagnosis for which antibiotics are prescribed; thus correct diagnosis of ars and judicious treatment with antibiotics are particularly important in an age of growing bacterial resistance [ ] . most patients suffering with sinus symptoms will have a viral etiology of their inflammation [ ] . it can be quite difficult for a primary care physician to distinguish between simple upper respiratory infections (uri), episodes of acute viral rhinosinusitis (avrs), and episodes of true bacterial rhinosinusitis (abrs). almost % of patients with viral uris have evidence of avrs [ ] . the most common viruses that cause vrs are rhinovirus, influenza virus, and coronavirus; others include parainfluenza virus, adenovirus, respiratory syncytial virus, and metapneumovirus [ ] . patients with avrs typically develop symptoms - days after infection. viruses attach to the nasal epithelium and can spread from the nasal cavity to the paranasal sinuses. once within the paranasal sinuses, viruses may exert direct toxic effects on mucociliary clearance, and may induce epithelial permeability and hypersecretion from inflammatory cytokines. these alterations lead to the mucosal edema, thickened secretions, and ostial obstruction characteristic of acute rhinosinusitis. acute bacterial rhinosinusitis most commonly occurs as a complication of viral infection, complicating . - . % of cases of the common cold [ ] , however, other factors may also predispose to abrs, such as allergy, immune dysfunction, impaired ciliary function, anatomic narrowing of the sinuses, or poor dentition [ ] . the most common bacteria associated with abrs are streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis. microaerophilic streptococci and anaerobic bacteria are commonly identified if the abrs originates from an odontogenic source. when a sinus culture is positive in a patient with abrs, a single pathogen is usually found in high concentration, although in approximately % of the patients, two pathogens can be found in high concentration [ ] . the usefulness and validity of sinus cultures have recently been reconsidered as more is understood about the complex commensal bacterial community comprising the sinus microbiome. however, cultures are still helpful in some clinical situations such as complicated or nosocomial abrs. nosocomial bacterial sinusitis may develop in patients on transplant services or in the intensive care unit, particularly in those who have had prolonged intubation or who have nasogastric tubes or feeding tubes. in contrast to communityacquired sinusitis, nosocomial sinusitis is more likely to involve resistant bacteria, including staphylococcus aureus and gram-negative bacilli such as pseudomonas [ , ] . patients with acute rhinosinusitis typically complain of nasal congestion and obstruction, purulent nasal discharge, and facial pain or pressure that is worse when bending forward. maxillary tooth discomfort may be present if the maxillary sinus is involved. other less specific symptoms can include fever, fatigue, cough, hyposmia, ear pressure, headache, and halitosis. these symptoms apply to both avrs and abrs. therefore, it is not possible for patients nor clinicians to discern a viral from bacterial infection based on symptoms alone. another diagnostic fallacy is that if nasal drainage is colored it must be from a bacterial infection [ ] . to discern avrs from abrs, the clinician should focus on the duration and course of the symptoms. acute viral rhinosinusitis will typically have partial or complete resolution of symptoms by days, with a peak at - days [ ] . if symptoms persist beyond days, or if symptoms improve but worsen again within days ("double-worsening"), there is a higher likelihood that the patient has abrs [ ] . on physical examination, findings may include purulent drainage in the nose or posterior pharynx and nasal speech. although many physicians have been taught to percuss the sinuses to evaluate for pain, this has not been shown to be useful [ ] . similarly, transillumination of the sinuses to detect an air-fluid level is an insensitive test and not recommended [ ] . examination of the nasal cavity with either anterior rhinoscopy (performed with a handheld otoscope or nasal speculum) or nasal endoscopy (using a flexible or rigid endoscope) may show diffuse mucosal edema, narrowing of the middle meatus, inferior turbinate hypertrophy, and purulence. a complete head and neck examination is important to both confirm the suspected diagnosis of acute rhinosinusitis as well as rule out any other possible diagnoses and evaluate for any possible complications. complications from abrs, less commonly seen in adults than children, are rare but can be potentially serious, even life-threatening. bacterial sinusitis can spread beyond the paranasal sinuses and nasal cavity to the orbit or surrounding tissues directly, or to the central nervous system (cns) either directly or hematogenously. chapter discusses complications of abrs in children. orbital complications include preseptal cellulitis, orbital cellulitis, subperiosteal abscess, orbital abscess, and cavernous sinus thrombophlebitis. the chandler classification, the most common method of characterizing orbital complications, organizes orbital complications in terms of progressive severity (see fig. . ) [ ] . infection in preseptal cellulitis involves the eyelid skin in front of the orbital septum and tarsal plates of the eyelids, while infection in orbital cellulitis, subperiosteal abscess, and orbital abscess involves the orbit. in orbital cellulitis, there is diffuse inflammation of the orbital fat and extraocular muscles. in subperiosteal abscess, there is a collection of pus in the space between the orbital bony wall and periorbita, and in orbital abscess, there is a collection of pus in the orbital fat. it is important to distinguish preseptal cellulitis from orbital infection (cellulitis or abscess), because preseptal infections do not threaten vision while orbital infections do. patients with preseptal cellulitis will present with lid swelling and redness of the periorbital region but will not have involvement of the orbit (postseptal compartment) so will not have any of the three "orbital signs": impaired extraocular motility, decrease in vision, or proptosis. patients with orbital cellulitis or abscess will present with similar lid changes, but in addition will have one or more orbital signs as a result inflammation of the extraocular muscles and fat within the orbit. patients with orbital cellulitis or abscess may also have chemosis (edema of the conjunctiva), pain with eye movement, and/or diplopia. in general, patients with subperiosteal or orbital abscess have more pronounced orbital signs than those with orbital cellulitis. because most sinogenic orbital abscesses arise from the ethmoid or medial frontal sinuses, the inflammation in the orbit is often most pronounced medially and/or superomedially, and the eye may be displaced inferolaterally. patients with chronic sinus obstruction with nasal polyps may develop a frontal sinus mucocele that silently erodes the frontal sinus floor (orbital roof); an acute superinfection may cause orbital cellulitis or abscess ( fig. . ). cavernous sinus thrombophlebitis can sometimes be insidious, but advanced cases will be marked by cranial nerve palsies involving iii, iv, vi (sometimes also v and v ), fever, photophobia, visual loss, and signs of contralateral orbital involvement. acute bacterial rhinosinusitis may also lead to cns infections, including meningitis, epidural abscess, subdural empyema, or brain abscess. symptoms of meningitis include fever, headache, photophobia, nuchal rigidity, and mental status changes. symptoms of epidural and brain abscesses may include headache, mental status changes, lethargy, and nausea and vomiting. there may or may not be papilledema or unilateral neurological findings on examination. osteomyelitis of the paranasal sinus bones can occur as a consequence of abrs but is a rare complication. patients usually complain of dull pain at the involved site and have localized tenderness, warmth, erythema, and swelling; fever may be present. chronic frontal sinusitis may lead to osteomyelitis of the anterior table of the frontal sinus with frontal "bossing"-i.e., swell- patients with any of the signs or symptoms suggesting a complication of abrs should be urgently referred to an emergency department for evaluation and management. while preseptal cellulitis alone may respond to oral antibiotics, patients with any other orbital or any cns complication require intravenous antibiotics, close inpatient monitoring, and may require emergency surgery to drain an abscess if one is present. an ophthalmologist should be consulted for patients with orbital complications, and consultation with a neurologist or neurosurgeon is usually indicated for patients with cns complications. orbital cellulitis or abscess may lead to permanent loss of vision if not appropriately and promptly treated. neurologic complications may progress rapidly and lead to permanent disability or death if not recognized and treated promptly. adequate clinical suspicion as well as prompt recognition and treatment of extrasinus complications are essential. imaging is not indicated in uncomplicated abrs. a practitioner should consider ordering an imaging study only to rule out a complication of abrs or to establish an alternative diagnosis. it is important to remember that "abnormal" findings involving the sinuses do not necessarily confirm a diagnosis of acute rhinosinusitis, as % of normal individuals may demonstrate some form of abnormal mucosal thickening of the sinuses on ct [ ] . equally important, imaging cannot distinguish between viral and bacterial rhinosinusitis [ ] . when there is sufficient indication, ct with contrast or magnetic resonance imaging (mri) are the studies of choice. computed tomography better delineates bony detail, while mri provides superior delineation of soft tissue detail. when a complication is suspected, contrast-enhanced imaging is indicated to demarcate areas of extrasinus infection. plain films are no longer indicated in evaluating adult sinusitis [ ] . no role has been established for routine cultures in uncomplicated abrs. cultures may be considered when there is concern for a complication of sinusitis, antimicrobial resistance, or an unusual organism-the last might be suspected in the case of an immunocompromised host. nasal cavity cultures from blindly obtained swabs are not reliable indicators of true pathogens in the sinuses and are therefore not useful in the diagnosis of abrs [ ] . the gold standard in the diagnosis of abrs is a maxillary sinus antral puncture and aspiration via an inferior meatal or canine fossa approach. however, sinus aspiration is invasive and not available to most primary care physicians. endoscopic culture of the middle meatus is minimally invasive alternative and has been shown to correlate well with maxillary sinus cultures obtained by antral puncture [ ]. there are many conditions that can cause symptoms of rhinorrhea, facial pain, or dental pain, mimicking the presentation of abrs. the common cold, allergic and nonallergic rhinitis, and primary dental pathology are the most typical. temporomandibular joint disorders, neuralgias, and other causes of atypical facial pain should also be considered, as well as primary headache disorders such as migraine, tension headache, and cluster headache. importantly, in immunosuppressed patients, acute invasive fungal sinusitis must also be considered (see chap. ). acute bacterial rhinosinusitis is generally a selflimited disease and can resolve on its own without antibiotics. systematic reviews and meta-analyses have found that the majority of patients with abrs will resolve their symptoms without antibiotic therapy within weeks [ ] . therefore, contrary to conventional wisdom, the successful distinction of abrs from avrs does not equate with an automatic indication to prescribe antibiotics. in the first days of symptoms, supportive therapy alone is indicated for uncomplicated abrs in adults regardless of whether a diagnosis of avrs or abrs has been made, except for cases of "double worsening" or severe symptoms persisting for at least days. severe symptoms are defined as high fever (temperature °f or higher) and purulent nasal drainage [ , ] . "double worsening" refers to worsening of symptoms after initial improvement. this is suggestive of an initial viral infection followed by a bacterial superinfection. guidelines regarding treatment of abrs have been published for adults by the american academy of otolaryngology -head and neck surgery (aao-hns) [ ] , for both adults and children by the infectious disease society of america (idsa) [ ] , and for children by the american academy of pediatrics (aap) [ ] . the idsa and aap guidelines are similar, but these differ from the aao-hns guidelines in that the latter offers the option of "watchful waiting" rather than antibiotics for up to days beyond abrs diagnosis for adults whose followup is assured. the aap also offers the option of "watchful waiting" in children diagnosed with non-severe "persistent" uncomplicated abrs but only up to days. figure . shows the aao-hns decision tree, table . compares aao-hns and idsa guidelines for adults with abrs, and table . summarizes the aap guidelines for children with abrs. the antibiotic options for children are further discussed in the aap guidelines [ ] . it is important to note that daytime cough is a symptom of abrs for children, unlike adults, and the aap recommends a clinical diagnosis of abrs in children who have ( ) nasal drainage or daytime cough persisting for more than days without improvement, ( ) worsening or new onset of nasal discharge, daytime cough, or fever after initial improvement, or ( ) severe onset, which is defined as fever ≥ °c ( . °f) plus concurrent nasal discharge for at least days. part of the risk-benefit analysis of treating abrs with antibiotics involves an appreciation for potential complications of antibiotic therapy. a cochrane review in found that although using antibiotics can help shorten the course of abrs, the number of adults needed to treat to see that benefit is greater than the number needed to see adverse effects [ ] . metaanalyses of randomized controlled trials have found that, compared with placebo, adults with abrs may benefit from antibiotics at the cost of increased adverse events. estimates of the number needed to treat to benefit range from to patients, while the number needed to harm is approximately eight patients [ ] . the clinician should consider that results of these metaanalyses may be influenced by inclusion and exclusion criteria. the cochrane review analyzed ten trials that randomized antibiotics versus placebo to treat adults with clinically diagnosed abrs [ ] , but many of these trials did not meet current criteria for abrs so probably included avrs as well as abrs. for example, some trials included patients with only or even days of symptoms [ ] . exclusion criteria also may have influenced results, and common exclusion criteria in the ten trials were recent antibiotic use ( % of the trials), severe symptoms ( %), prior ear-nose-throat disease ( %), previous sinus surgery ( %), immune deficiency ( %), and comorbidities such as diabetes, heart failure, or pulmonary disease ( %) [ ] . of course, exceptions to clinical guidelines always exist, especially in immunocompromised patients and any patient in whom a complication is suspected. the individual clinical situation should dictate therapy above all and may warrant immediate antibiotic treatment and referral to a specialist. the clinician should decide if the risk of watchful waiting in the individual patient outweighs the benefit. this was illustrated by a complication that occurred in a patient randomized to the placebo arm of one trial of amoxicillinclavulinate; the patient had persistent symptoms despite weeks of placebo followed by week of antibiotic and was found to have a brain abscess (the abscess pathogen was susceptible to the antibiotic) [ ] . as cultures are not indicated in abrs, the initial choice of antibiotic treatment is empiric and is based on the most common pathogens (as outlined above). therefore, first-line therapy for adults would be oral amoxicillin or amoxicillinclavulanate ( / three times daily or / mg twice daily), depending on the resistance patterns within the community. in communities with a higher prevalence of beta-lactam resistance among haemophilus influenzae and moraxella catarrhalis isolates, amoxicillinclavulanate is preferred [ , ] . macrolides and trimethoprim-sulfamethoxazole are not recommended due to high rates of s. pneumoniae resistance (and for trimethoprim-sulfamethoxazole, also h. influenzae resistance) [ , ] . all doses given are for patients with normal renal function. in adults with specific risk factors for antibiotic resistance, high dose amoxicillin with clavulanate ( g/ mg twice daily) would be indicated. examples of risk factors for resistance include living in communities where the prevalence of penicillin-non-susceptible s. pneumoniae exceeds %; age > years; hospitalization in the last days; antibiotic use in the previous month; immunocompromise; multiple comorbidities; or severe infection with evidence of systemic toxicity and threat of suppurative complications [ , ] . for adults with penicillin allergy, oral doxycycline ( mg twice daily or mg daily) is a table . adult acute bacterial rhinosinusitis (abrs): recommendations for evaluation and treatment by the american academy of otolaryngology-head and neck surgery (aao-hns) [ ] and the infectious disease society of america (idsa) [ ] recommendation aao-hns idsa clinical diagnosis of acute bacterial rhinosinusitis (abrs) symptoms of acute rhinosinusitis that: ( ) persist ≥ days or ( ) worsen after initial improvement ("double worsening") same as ( ) and ( ) the aao-hns states that "watchful waiting" in adults "should be offered only when there is assurance of follow-up such that antibiotic therapy is started if the patient's condition fails to improve by days after abrs diagnosis or if it worsens at any time" [ ] . b first-line therapy with amoxicillin-clavulanate rather than amoxicillin is generally recommended by the aao-hns for the following: older age (age > years), immunocompromise, comorbid conditions (chronic cardiac, hepatic, or renal disease), history of recurrent abrs, moderate to severe symptoms, or risk factors for resistant organisms such as antibiotics within the past month, contact with health care environment, contact with child in daycare, high prevalence of resistant bacteria in the community. the aao-hns recommends high-dose amoxicillin (idsa recommends high dose amoxicillin-clavulanate) for adults at increased risk for infection with amoxicillin-resistant organisms c both aao-hns and idsa recommended either doxycycline or a respiratory fluoroquinolone such as levofloxacin in penicillin-allergic patients, but the food and drug administration subsequently recommended against use of fluoroquinolones for abrs unless no alternatives exist (see the text). reasonable alternative, as is a combination of clindamycin plus a third-generation cephalosporin such as cefixime or cefpodoxime [ ] . fluoroquinolones have traditionally been another alternative, but are now highly cautioned against due to an increasing recognition of serious side effects, including tendinitis, tendon rupture, and peripheral neuropathy. the food and drug administration has advised that fluoroquinolones should be used for abrs only when no alternative options exist [ ] . for children with abrs, the first-line treatment recommended by the aap is amoxicillin at standard pediatric dosing ( mg/kg per day in divided doses) for children aged and older with uncomplicated abrs of mild to moderate severity and who do not have risk factors for antimicrobial resistance (no antibiotics within weeks and no day care), or high-dose amoxicillin ( - mg/kg per day in divided doses, up to a maximum of g per dose) in communities with high prevalence of resistant bacteria (i.e., penicillin non-susceptible s. pneumoniae) [ ] . for children presenting with moderate to severe abrs, as well as children under age years, attending day care, or who have recently received an antibiotic, the aap recommends high dose amoxicillin-clavulinate. a single mg/kg dose of intravenous of intramuscular ceftriaxone may be given to children who are vomiting, unable to tolerate oral medications, or are unlikely to be adherent to initial doses of antibiotics [ ] . oral antibiotics may be started h after this parenteral dose, to complete the course of therapy. for additional details regarding treatment of children with abrs, including treatment in patients with penicillin allergies, the reader is referred to the aap guidelines [ ] . note that these guidelines do not apply to children younger than age . the recommended duration of antibiotic treatment is - days in adults (longer in children), provided the patient is improving. longer courses ( ) persistent nasal drainage or daytime cough or both for > days ("persistent illness") or ( ) worsening course (see text) or ( ) severe onset of symptoms (t °f plus nasal drainage) lasting ≥ days cough is not included as a symptom of abrs in adults (see table . ) use of radiologic imaging (ct with contrast) only for suspected complication involving orbit or central nervous system similar recommendations for adults initial therapy of abrs antibiotics for worsening course or severe onset (" " or " " above), but antibiotics or watchful waiting (for up to days) for "persistent illness" (" " above) if a patient does not improve or in fact worsens with first-line therapy, a change in therapy is indicated. there is not good evidence to guide the choice of second-line therapy, but one may consider either increasing the dose or changing class of antibiotics. options in adults include high dose amoxicillin ( g twice daily) with clavulanate, doxycycline, levofloxacin, and moxifloxacin. the latter quinolone options should again be prescribed with caution, with regard for potential adverse effects of fluoroquinolone use [ ] . if patients with abrs have failed to respond to both first-line and second-line therapies, or if at any time a potential complication is suspected, they should be referred for further evaluation to a specialist and possibly undergo radiologic imaging. the use of over-the-counter antipyretics and analgesics can help to treat fever and pain in abrs [ ] . saline irrigations offer the opportunity for symptomatic relief with a favorably low side effect profile (minor nasal burning and irritation) [ ] . however, there are no randomized controlled trials of the use of saline irrigations in abrs [ ] , so their benefit is unknown. in addition, patients cannot obtain sterile solutions for nasal irrigations so whether or not there is risk with nasal irrigations with non-sterile solutions is unknown. intranasal glucocorticoid sprays can be helpful in abrs. a meta-analysis of three studies has shown a minor benefit in adding nasal steroid sprays to the treatment regimen of patients with abrs [ ] . other therapies that are sometimes used in supportive treatment of abrs include oral and topical decongestants, antihistamines, and mucolytics. however, none of these therapies has good evidence to support its use; some may actually cause harmful side effects, such as raising blood pressure (associated with oral decongestants), and irritating or overdrying the nasal lining (associated with antihistamines) [ ] . acute bacterial rhinosinusitis is one of the most common infections treated by primary care providers. the distinction between abrs and viral upper respiratory tract infections is usually made based on duration and time course of compatible symptoms, with abrs characterized by either persistence of symptoms for at least days, worsening of symptoms (or double worsening), or severe onset of symptoms including high fever for days. radiologic imaging and sinus cultures are not indicated for uncomplicated abrs. adults with non-severe, uncomplicated abrs and whose follow-up is assured may be observed without antibiotics (watchful waiting) or treated with antibiotics. patients with orbital or cns complications require aggressive treatment with intravenous antibiotics and possibly surgery. rhinosinusitis: establishing definitions for clinical research and patient care clinical practice guideline (update): adult sinusitis summary health statistics for u.s. adults: national health interview survey in the clinic. acute sinusitis antimicrobial treatment guidelines for acute bacterial rhinosinusitis productivity costs in patients with refractory chronic rhinosinusitis medical management and diagnosis of chronic rhinosinusitis: a survey of treatment patterns by united states otolaryngologists clinial practice. acute sinusitis in adults acute community-acquired sinusitis mandell, douglas, and bennett's principles and practice of infectious diseases european position paper on rhinosinusitis and nasal polyps . a summary for otorhinolaryngologists sinusitis of the maxillary antrum nosocomial sinusitis in patients in the medical intensive care unit: a prospective epidemiological study nosocomial sinusitis rhinovirus infections in an industrial population characteristics of illness and antibody response adult acute rhinosinusitis a practical guide for the diagnosis and treatment of acute sinusitis the pathogenesis of orbital complications in acute sinusitis endoscopically directed middle meatal cultures versus maxillary sinus taps in acute bacterial maxillary rhinosinusitis: a meta-analysis a -year-old woman with acute onset of facial pressure, rhinorrhea, and tooth pain: review of acute rhinosinusitis clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children, aged to years antibiotics for clinically diagnosed acute rhinosinusitis in adults predicting prognosis and effect of antibiotic treatment in rhinosinusitis effect of amoxicillin-clavulinate in clinically diagnosed acute rhinosinusitis. a placebo-controlled, double-blind, randomized trial in general practice fda drug safety communication: fda advises restricting fluoroquinolone antibiotic use for certain uncomplicated infections; warns about disabling side effects that can occur together saline nasal irrigation for acute upper respiratory tract infections intranasal steroids for acute sinusitis key: cord- - nfkms authors: kumar, anupam; hadley, ryan title: respiratory failure in a patient with idiopathic pulmonary fibrosis date: - - journal: evidence-based critical care doi: . / - - - - _ sha: doc_id: cord_uid: nfkms the triggers as well as etiologies for acute exacerbation of idiopathic pulmonary fibrosis (ae-ipf) are not known. ae-ipf is defined as an “acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality typically less than month’s duration. the underlying pathologic insult is classically described as diffuse alveolar damage. ideally, infection is excluded by bal as in the case presentation, but the severity of hypoxemia and the desire to avoid endotracheal intubation may preclude the performance of this procedure. supportive care is the mainstay of therapy as there are no proven therapies, although corticosteroids, cytotoxic agents and anti-coagulation have all been suggested as possible treatments. the mortality is high, particularly once invasive ventilation has been instituted. the triggers as well as etiologies for ae-ipf are not known. the criteria proposed by idiopathic pulmonary fibrosis network (ipfnet) defined acute exacerbation of ipf as acute clinical worsening (< days) in a patient with known or newly diagnosed ipf with acceleration of dyspnea and/or hypoxemia and new radiologic changes, typically ground glass opacities, on a background of fibrotic disease (example fig. . ) [ , ] . the revised criteria in did not set a definite -day duration of onset of symptoms but defined ae-ipf as an "acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality typically less than one month's duration" [ ] . common mimics like fluid overload due to heart failure and infections should be excluded although this is not straightforward in some patients. the underlying pathologic insult is classically described as diffuse alveolar damage (dad) [ ] , the histologic finding of acute respiratory distress syndrome (ards), which has been superimposed on usual interstitial pneumonia. however, biopsy of the lung to prove dad is rarely ever pursued due to the morbidity and mortality of the procedure. common concomitant symptoms mimic a viral lower respiratory tract infection with fever, malaise, flu like symptoms and cough; though these symptoms are not needed to make the diagnosis [ ] [ ] [ ] . ideally, infection is excluded by bal as in the case presentation; however given the worsening hypoxemia in addition to typical poor baseline pulmonary health, a bal may precipitate a life-threatening impairment in gas exchange. if a bal cannot be completed, treatment for typical bacterial organisms or hospital acquired organisms are employed presumptively, as applicable. if structural lung disease exists (as most patients usually have traction bronchiectasis) it may be worthwhile to treat pseudomonas on an empiric basis, though evidentiary support for this is lacking. other conditions that need to be excluded are pneumothorax, pulmonary hypertension, left ventricular failure from systolic or diastolic dysfunction, pulmonary embolism, or ards of other known causes (e.g. sepsis, pancreatitis, trauma, pneumonia). diagnostic specificity of ae-ipf is further limited due to unavailability of specific serologic markers. cross-sectional imaging is used to rule out small pneumothorax not seen as well as to confirm radiologic changes, which are typically ground glass in appearance, but dense infiltrates can also be seen. a ct pulmonary angiogram has the advantage of evaluating for pulmonary embolus in patients without renal impairment. in summary, ae-ipf is diagnosed when a patient with ipf has acute worsening of dyspnea and/or hypoxemia as well as new ct opacities after exclusion of the conditions in table . . diffuse alveolar damage is the typical underlying histopathology. based on prospective trials of ipf the incidence of acute exacerbation in ipf is approximately - % per year [ ] [ ] [ ] . acute exacerbations are often devastating with a median survival of usually about months [ ] . if an ipf patient requires mechanical ventilation, mortality has been reported to be - % [ , ] . some authors have proposed that mechanical ventilation in ipf patients is futile and these patients should not receive this intervention [ , ] . others have argued, and shown, that even short-term survival allows a window for pulmonary transplantation [ ] . additionally, it is noted that mortality is not absolute, and thus not "futile" in all cases. due to the poor prognosis, an accurate diagnosis of ae-ipf is of utmost importance to exclude reversible causes; however, this is often challenging. the risk factors for ae-ipf are not well known. it remains unclear if the acute worsening of ipf is simply an accelerated progression of the underlying interstitial lung disease (ild) or a maladaptive response to an external trigger such as micro aspiration of gastric contents, trauma, mechanical stretch or infections. it is likely that ae-ipf is the result of interactions between genetic and environmental stimuli in a significant fraction of patients with ipf. the classical description of pathologic insult due to acute exacerbation of ipf is diffuse alveolar damage [ ] , which is the same as ards, but here is superimposed on the pathological findings of idiopathic pulmonary fibrosis: usual interstitial pneumonia. as idiopathic pulmonary fibrosis is a rare condition, and acute exacerbations occur spontaneously and abruptly, large a b prospective randomized trials evaluating treatment are lacking. expert consensus recommends treatment with corticosteroids, though recommended dosages have not been established [ ] . dosing ranges of methylprednisolone from mg/kg up to "pulse" doses of mg per day [ ] . it is our practice to use mg/kg/day of methylprednisolone in divided doses daily similar to what has been studied in ards [ ] , given the similar underlying histopathologic insult. supportive care is essential for treatment of idiopathic pulmonary fibrosis given the lack of evidence-based therapies. endotracheal intubation and invasive mechanical ventilation is sometimes needed, but noninvasive ventilation can be attempted in the appropriate candidate (see below). while evaluation for conditions listed in table . is suggested, this is not always possible in a given patient. presumptive treatment with antibacterial agents, diuretics in conjunction with systemic corticosteroids are typically administered unless significant contraindications exist. acute exacerbation of idiopathic pulmonary fibrosis can often be a terminal event. patients and family should be made aware of the poor prognosis to make appropriate decisions about possibly limiting intensive care interventions. ideally, goals of care planning would occur in the outpatient setting prior to clinical worsening. in patients who are not transplant candidates, palliative care is often a valid choice [ ] . the diagnosis of acute exacerbation of ipf is in the domain of the intensivist. however diagnosis and management of idiopathic pulmonary fibrosis is usually the realm of the pulmonologist. ensuring that the patient has an accurate diagnosis of idiopathic pulmonary fibrosis is critical to determining prognosis for the underlying condition. fibrotic lung disease associated with collagen-vascular disease, such as polymyositis, has also been associated with acute exacerbations, and may have a better prognosis [ ] . many pulmonologists who are less familiar with interstitial lung diseases often incorrectly attribute all types of lung fibrosis to idiopathic pulmonary fibrosis [ ] . given the disparate outcomes, accurate discrimination of ipf from other fibrotic lung diseases is critical. clues on ct scan suggesting the diagnosis of ipf are basal, subpleural predominance of interlobular septal thickening with honeycombing and traction bronchiectasis (see fig. . ) [ ] . in the absence of ae-ipf, evidence of extensive ground glass infiltrates and nodules on ct imaging typically argues against ipf [ ] . clinical findings should include a conspicuous absence of inhalational exposures and rheumatologic conditions. "velcro" rales are typically present on physical exam. if the diagnosis is in doubt, consultation with a pulmonary specialist with experience in interstitial lung disease is recommended. often, patients with ipf undergo surgical biopsy to establish a diagnosis of ipf. additionally, patients with ipf are at higher risk of lung cancer which may require surgical treatment. thoracic surgery for lung cancer resection or surgical lung biopsy can precipitate an acute exacerbation of ipf [ ] [ ] [ ] [ ] . interestingly the insult is often radiologically worse in the nonoperative lung [ ] . this is theorized to be due to the ventilator-associated lung injury from excessive stretch from single lung ventilation during the operation to de-gas the operative lung. some have suggested restrictive intraoperative fluid management may minimize post-operative ae-ipf risk, but this has not been prospectively validated [ ] . ae-ipf after non-pulmonary operation has been reported, but rarely [ ] . given the poor prognosis of patients who require mechanical ventilation, some have suggested that noninvasive ventilation would be a good strategy for patients with clinical deterioration and idiopathic pulmonary fibrosis. small, retrospective studies have shown improved outcomes in ae-ipf patients supported with noninvasive positive pressure ventilation (nippv) [ ] [ ] [ ] , however a selection bias may account for the better prognosis as patients who can be successfully supported with nippv are likely less ill. of the patients in these studies who failed nippv, mortality was reported as - % [ ] [ ] [ ] . high flow nasal cannula has been shown to have salutatory affects in idiopathic pulmonary fibrosis patients without an acute exacerbation, specifically decreased minute ventilation, respiratory rate, capillary carbon dioxide were seen [ ] . additionally, small increases in airway pressure were reported, suggesting a partial "peep" affect [ ] . a recent multi-center open label trial that compared high flow oxygen therapy with standard therapy and non-invasive ventilation, in patients with non-hypercapnic hypoxic respiratory failure of various etiologies, reported non-significant improvement in rates of intubation, but a significant improvement in day mortality in favor of high flow therapy [ ] . in a retrospective study of patients with ae-ipf, ito and colleagues demonstrated a decreased mortality rate and need for mechanical ventilation or nippv in the epoch after implementation of high flow nasal, suggesting significant benefit of hfnc in ae-ipf [ ] . randomized, prospective data does not exist for high flow nasal cannula use in ae-ipf. anecdotally, we have used high flow oxygen therapy with great success in patients with ipf and acute exacerbations and would recommend routine use. the optimal ventilator settings for acute exacerbation of ipf are not known, however to the extent possible, we adhere to lung protective with low tidal volume ventilation similar to ards. unfortunately, the need for mechanical ventilation in a patient experiencing acute exacerbation portends poor prognosis due to high mortality (reported mortality of - % if intubation required) [ , ] . therefore, noninvasive methods that support and permit safe oxygenation should be employed whenever possible. patient and families should be educated about the poor outcomes of mechanical ventilation prior to pursuing it. higher levels of peep have been associated with higher mortality in single retrospective analysis [ ] . a selection bias for patients with worse hypoxemia requiring higher levels of mean airway pressure is one explanation; however multiple variables were accounted for in the analysis. it may be true that patients with acute exacerbation of ipf have a different physiology and those with ards where higher levels of peep are felt to be beneficial. a single, unblinded prospective study has shown a benefit in patients admitted with clinical worsening of idiopathic pulmonary fibrosis treated with anticoagulation [ ] . anticoagulation was initiated at the time of clinical worsening, which may or may not have been an acute exacerbation. warfarin was used in the outpatient setting and low molecular weight heparin was used if the patient was admitted, such as with ae-ipf. all patients were treated with corticosteroid as well. in the subset of patients who had ae-ipf, anticoagulated patients had a lower mortality ( % vs. %). however, % of patients randomized to the treatment arm dropped out of the study. additionally, pulmonary embolism was not excluded as a cause of clinical worsening, and may have played a role in some patients [ ] . a large, double blind prospective trial of warfarin in the treatment of ipf was stopped early due to increased mortality in warfarin arm [ ] . no difference in incidence of ae-ipf was observed. use of anticoagulation in ipf patients without thromboembolic disease was recommended against by a panel of experts [ ] . anticoagulation specifically used to treat ae-ipf currently does not have sufficient data to support its use. cyclophosphamide has been used in case series for treatment of ae-ipf. morawiec and colleagues described patients who were treated with cyclophosphamide and pulse dose methylprednisolone during acute exacerbations with and % at month and months survival rates, respectively [ ] . these results were compared to reported outcomes and not historical controls at the same institution. lack of randomization significantly limits this utility of this study and a prospective randomized trials are needed prior to wide spread adoption. using propensity score analysis, others have failed to show benefit of cyclophosphamide in patients with ae-ipf, but also with low numbers of patients studied [ ] . a multicenter study, double blind randomized study of cyclophosphamide in addition to corticosteroids for treatment of ae-ipf is currently planned [ ] . inase and coworkers retrospectively analyzed patients after ae-ipf. all patients received pulse methylprednisolone followed by oral prednisone, and received cyclosporine a titrated a to serum levels of - in addition to steroids [ ] . in the patients treated with cyclosporine a none experienced a re-exacerbation of ipf. all patients with steroids alone died of respiratory failure within weeks, whereas four out of the seven treated with cyclosporine a survived for over years after their exacerbation. sakamoto also evaluated the use of cyclosporine a in ae-ipf retrospectively [ ] . similar to inase, all patients were treated with pulse methylprednisolone followed by prednisone. two out of eleven patients treated with cyclosporine a died during their initial exacerbation, compared to six out of eleven patients who were treated with steroids alone. prevention of re-exacerbation was not observed with five patients experiencing repeat exacerbations while on cyclosporine a. in a relatively large retrospective database review, aso and colleagues were unable to demonstrate a difference of in hospital mortality in ae-ipf patients treated with cyclosporine a and corticosteroids as compared to corticosteroids alone [ ] . similar to cyclophosphamide, lack of large scale randomized prospective trials limit widespread adoption of cyclosporine a for treatment of ae-ipf. several other agents have been studied in small scale to treat acute exacerbation of ipf. rituximab in combination with plasma exchange was used in patients experience ae-ipf in an attempt to target an autoimmune pathway of inflammation [ ] . nine out of the eleven patients responded with improvement in oxygenation, although a few experienced relapse. in some patients, when the above treatment protocol was combined with intravenous immunoglobulin, a sustained improvement in gas exchange without relapse was observed. this study result has not been reproduced in largescale studies, and has limited clinical application currently since the serologic markers used to determine active autoimmunity are mostly research-based biomarkers and not currently available for clinical use. other agents studied for acute exacerbation of ipf have included recombinant thrombomodulin and hemoperfusion with polymixin b immobilized fiber. recombinant thrombomodulin is used on the premise of its anti-coagulant and antifibrinolytic properties. small studies that have compared recombinant thrombomodulin with conventional therapy for ae-ipf demonstrated a significant mortality benefit compared to conventional arm; with a similar adverse effect profile [ , ] . although the above small studies are provocative, routine use cannot be advised until further study. mizuno retrospectively evaluated patients with ipf after pulmonary resection of non-small cell lung cancer and found that higher positive intraoperative fluid balance was associated with ae-ipf after multivariate analysis [ ] . prospective use of restrictive fluid practices towards the prevention of postoperative ae-ipf have not been established. in patients without other medical comorbidities, lung transplantation can be performed in patients with idiopathic pulmonary fibrosis. in patients who are already listed for transplant and develop acute exacerbation, extracorporeal life-support or mechanical ventilation are not contraindications to transplantation; though vigilance of maintaining a robust functional status and avoiding critical care weakness are major challenges. de novo evaluation of patients with acute exacerbation for pulmonary transplantation is difficult as the typical preoperative studies, such as colonoscopy, heart catheterization, informed consent, etc. become much more perilous in a patient with severe respiratory failure or on extracorporeal life-support. however, this has been reported successfully [ ] . age limitations for lung transplant vary greatly among centers, and if in doubt, discussion with a transplant center is advised. outcomes of patients with respiratory failure and ae-ipf are poor, as described above. theoretically, extracorporeal support eliminates ventilator induced lung injury and may lead to improved outcomes. data to support this assumption does not exist. the largest case series of ecls in ild included all subtypes of ild, with only out of patients having ipf [ ] . despite including potentially reversible causes of respiratory failure (e.g. pneumonia, pneumothorax, connective tissue disease exacerbation), the outcomes remained dismal with a % mortality if the patient did not receive a lung transplant. ecls did allow time for evaluation, listing, and transplant of a few select patients. in patients who are not listed for transplant nor candidates for pulmonary transplantation, we suggest against extracorporeal life support for ae-ipf given the overall poor prognosis of the condition. we do, however, use ecls as a bridge to transplant or a bridge to decision in appropriate cases. when in doubt, discussion with and ecls capable transplant center is advised. two anti-fibrotic medications, pirfenidone and nintedanib, have been approved for treatment of ipf. pirfenidone, an inhibitor of transforming growth factor beta (tgf-β), has pleiotropic effects that regulate important profibrotic cascades, fibroblast proliferation, and collagen synthesis [ ] . nintedanib is a broad-spectrum tyrosine kinase inhibitor that targets several pathways including vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor [ ] . early studies suggested use of pirfenidone lowered the rate of acute exacerbation of idiopathic pulmonary fibrosis [ ] , though this was not seen on subsequent studies [ ] . in a combined analysis, nintedanib significantly reduced the time to adjudicated ae-ipf, but not investigator reported ae-ipf [ ] . it is noted that this was a secondary analyses and the studies were not specifically powered to evaluate prevention of ae-ipf. the initiation of pirfenidone or nintedanib as a treatment specifically for ae-ipf is not currently recommended, but use of nintedanib as an adjunctive treatment of ae-ipf has been reported in a single case report [ ] . in those that survive to hospital discharge, antifibrotic medications should be considered to prevent further deterioration in pulmonary function. acute exacerbation of idiopathic pulmonary fibrosis acute exacerbations of idiopathic pulmonary fibrosis acute exacerbation of idiopathic pulmonary fibrosis. an international working group report acute exacerbation in idiopathic pulmonary fibrosis. analysis of clinical and pathologic findings in three cases double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis randomized trial of acetylcysteine in idiopathic pulmonary fibrosis efficacy and safety of nintedanib in idiopathic pulmonary fibrosis acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features invasive mechanical ventilation in patients with fibrosing interstitial pneumonia outcome of patients with idiopathic pulmonary fibrosis (ipf) ventilated in intensive care unit outcome of patients admitted to the intensive care unit for acute exacerbation of idiopathic pulmonary fibrosis an official ats/ers/jrs/alat statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome clinical features and outcome of acute exacerbation of interstitial pneumonia: collagen vascular diseases-related versus idiopathic idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? the importance of intraoperative fluid balance for the prevention of postoperative acute exacerbation of idiopathic pulmonary fibrosis after pulmonary resection for primary lung cancer predictive factors for postoperative acute exacerbation of interstitial pneumonia combined with lung cancer acute exacerbation of interstitial pneumonia following surgical lung biopsy mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia exacerbations in idiopathic pulmonary fibrosis triggered by pulmonary and nonpulmonary surgery: a case series and comprehensive review of the literature role of non-invasive ventilation in managing lifethreatening acute exacerbation of interstitial pneumonia noninvasive ventilation in acute exacerbation of idiopathic pulmonary fibrosis why do patients with interstitial lung diseases fail in the icu? a -center cohort study effects of nasal high flow on ventilation in volunteers, copd and idiopathic pulmonary fibrosis patients high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure respiratory management of acute exacerbation of interstitial pneumonia using high-flow nasal cannula oxygen therapy: a single center cohort study ventilator settings and outcome of respiratory failure in chronic interstitial lung disease anticoagulant therapy for idiopathic pulmonary fibrosis a placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses efficacy of corticosteroid and intravenous cyclophosphamide in acute exacerbation of idiopathic pulmonary fibrosis: a propensity score-matched analysis study protocol: exploring the efficacy of cyclophosphamide added to corticosteroids for treating acute exacerbation of idiopathic pulmonary fibrosis; a randomized double-blind, placebo-controlled, multi-center phase iii trial (exafip) cyclosporin a followed by the treatment of acute exacerbation of idiopathic pulmonary fibrosis with corticosteroid cyclosporin a in the treatment of acute exacerbation of idiopathic pulmonary fibrosis effect of cyclosporine a on mortality after acute exacerbation of idiopathic pulmonary fibrosis autoantibody-targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis recombinant human soluble thrombomodulin treatment for acute exacerbation of idiopathic pulmonary fibrosis: a retrospective study recombinant thrombomodulin for acute exacerbation in idiopathic interstitial pneumonias extracorporeal membrane oxygenation as a bridge to pulmonary transplantation outcome of patients with interstitial lung disease treated with extracorporeal membrane oxygenation for acute respiratory failure a phase trial of pirfenidone in patients with idiopathic pulmonary fibrosis pirfenidone in idiopathic pulmonary fibrosis therapeutic effect of nintedanib on acute exacerbation of interstitial lung diseases key: cord- -yl vanuh authors: herberg, jethro; pahari, amitava; walters, sam; levin, michael title: infectious diseases and the kidney date: journal: pediatric nephrology doi: . / - - - - _ sha: doc_id: cord_uid: yl vanuh the kidney is involved in a wide range of bacterial, viral, fungal, and parasitic diseases. in most systemic infections, renal involvement is a minor component of the illness, but in some, renal failure may be the presenting feature and the major problem in management. although individual infectious processes may have a predilection to involve the renal vasculature, glomeruli, interstitium, or collecting systems, a purely anatomic approach to the classification of infectious diseases affecting the kidney is rarely helpful because most infections may involve several different aspects of renal function. the kidney is involved in a wide range of bacterial, viral, fungal, and parasitic diseases. in most systemic infections, renal involvement is a minor component of the illness, but in some, renal failure may be the presenting feature and the major problem in management. although individual infectious processes may have a predilection to involve the renal vasculature, glomeruli, interstitium, or collecting systems, a purely anatomic approach to the classification of infectious diseases affecting the kidney is rarely helpful because most infections may involve several different aspects of renal function. in this chapter, a microbiologic classification of the organisms affecting the kidney is adopted. although they are important causes of renal dysfunction in infectious diseases, urinary tract infections and hemolytic uremic syndrome (hus) are not discussed in detail because they are considered separately in chapters and respectively. elucidation of the cause of renal involvement in a child with evidence of infection must be based on a careful consideration of the geographic distribution of infectious diseases in different countries. a history of foreign travel; exposure to animals, insects, or unusual foods or drinks; outdoor activities such as swimming or hiking; and contact with infectious diseases must be sought in every case. the clinical examination should include a careful assessment of skin and mucous membranes and a search for insect bites, lymphadenopathy, and involvement of other organs. a close collaboration with a pediatric infectious disease specialist and hospital microbiologist will aid the diagnosis and management of the underlying infection. a tantalizing clue to the pathogenesis of glomerular disease is the marked difference in the incidence of nephrosis and nephritis in developed and underdeveloped areas of the world. in several tropical countries, glomerulonephritis (gn) accounts for up to % of pediatric hospital admissions; the incidence in temperate climates is -to -fold less. this difference might be explained by a complex interaction of several different factors, including nutrition, racial and genetically determined differences in immune responses, and exposure to infectious diseases. a growing body of evidence, however, suggests that longterm exposure to infectious agents is a major factor in the increased prevalence of glomerular diseases in developing countries. renal involvement in infectious diseases may occur by a variety of mechanisms: direct microbial invasion of the renal tissues or collecting system may take place in conditions such as staphylococcal abscess of the kidney as a result of septicemic spread of the organism or as a consequence of ascending infection; damage to the kidney may be caused by the systemic release of endotoxin or other toxins and activation of the inflammatory cascade during septicemia or by a focus of infection distant from the kidney; ischemic damage may result from inadequate perfusion induced by septic shock; the kidney may be damaged by activation of the immunologic pathways or by immune complexes resulting from the infectious process. in many conditions, a combination of these mechanisms may be operative. in the assessment of renal complications occurring in infectious diseases, the possibility of druginduced nephrotoxicity caused by antimicrobial therapy should always be considered. the nephrotoxic effects of antibiotics and other antimicrobial agents are not addressed in this chapter but are covered in chapter . bacterial infections associated with renal disease and the likely mechanisms causing renal dysfunction are shown in > impaired renal function is a common occurrence in systemic sepsis ( ) . depending on the severity of the infection and the organism responsible, the renal involvement may vary from insignificant proteinuria to acute renal failure requiring dialysis. the organisms causing acute renal failure as part of systemic sepsis vary with age and geographic location and also differ in normal and immunocompromised children. in the neonatal period, group b streptococci, coliforms, staphylococcus aureus, and listeria monocytogenes are the organisms usually . responsible. in older children, neisseria meningitidis, streptococcus pneumoniae, and s. aureus account for most of the infections. in people who are immunocompromised, a wide range of bacteria are seen, and, similarly, in tropical countries other pathogens, including haemophilus influenzae, salmonella species, and pseudomonas pseudomallei, must be considered. where h. influenzae type b vaccine has been introduced, however, the incidence of severe systemic infections due to this organism has shown a sharp fall. systemic sepsis usually presents with nonspecific features: fever, tachypnea, tachycardia, and evidence of skin and organ underperfusion. the pathophysiology of renal involvement in systemic sepsis is multifactorial ( , ) . hypovolemia with diminished renal perfusion is the earliest event and is a consequence of the increased vascular permeability and loss of plasma from the intravascular space. hypovolemia commonly coexists with depressed myocardial function because of the myocardial depressant effects of endotoxin or other toxins. the renal vasoconstrictor response to diminished circulating volume and reduced cardiac output further reduces glomerular filtration, and oliguria is thus a consistent and early event in severe sepsis ( , ) . a number of vasodilator pathways are activated in sepsis, including nitric oxide and the kinin pathways. this may lead to inappropriate dilatation of vascular beds. vasodilation of capillary beds leading to warm shock is common in adults with sepsis due to gram-negative organisms but is less commonly seen in children, in whom intense vasoconstriction is the usual response to sepsis. if renal underperfusion and vasoconstriction are persistent and severe, the reversible prerenal failure is followed by established renal failure with the characteristic features of vasomotor nephropathy or acute tubular necrosis. other mechanisms of renal damage in systemic sepsis include direct effects of endotoxin and other toxins on the kidney, and release of inflammatory mediators such as tumor necrosis factor (tnf) and other cytokines, arachidonic acid metabolites, and proteolytic enzymes ( ) . nitric oxide (no) is postulated to play a key role in the pathophysiology of renal failure in sepsis. whether the renal effects of increased no are beneficial or harmful remains unclear. trials of selective no synthetase inhibition did not offer any advantages over saline resuscitation ( ) . no in endotoxemia is possibly beneficial because it maintains renal blood flow and glomerular filtration. activation of coagulation is an important component of the pathophysiology of septic shock and may contribute to renal impairment. activation of multiple prothrombotic and antifibrinolytic pathways occurs, together with downregulation of antithrombotic mechanisms such as the protein c pathway. treatment with activated protein c has been shown to improve outcome of adult septic shock, but has not been confirmed to have benefit in pediatric sepsis, and may carry a risk of bleeding particularly in infants ( ) . the renal findings early in septic shock are oliguria, with high urine/plasma urea and creatinine ratios, low urine sodium concentration, and a high urine/plasma osmolarity ratio. once established, renal failure supervenes, and the urine is of poor quality with low urine/ plasma urea and creatinine ratios, elevated urine sodium concentration, and low urine osmolarity. proteinuria is usually present, and the urine sediment may contain red cells and small numbers of white cells ( ) . the management of acute renal failure in systemic sepsis depends on early diagnosis and administration of appropriate antibiotics to cover the expected pathogens. . in addition, management is directed at improving renal perfusion and oxygenation. volume replacement with crystalloid or colloid should be undertaken to optimize preload. central venous pressure or pulmonary wedge pressure monitoring is essential to guide volume replacement in children in severe shock ( , ) . the use of low-dose ( - pg/kg/min) dopamine to reduce renal vasoconstriction together with administration of inotropic agents such as dobutamine or epinephrine to improve cardiac output may reverse prerenal failure. early elective ventilation should be undertaken in patients with severe shock. if oliguria persists despite volume replacement and inotropic therapy, dialysis should be instituted early, because septic and catabolic patients may rapidly develop hyperkalemia and severe electrolyte imbalance. in most children who develop acute renal failure as part of systemic sepsis or septic shock, the renal failure is of short duration, and recovery can be expected within a few days of achieving cardiovascular stability and eradication of the underlying infection. occasionally, renal cortical necrosis or infarction of the kidney may result in prolonged or permanent loss of renal function. meningococcus n. meningitidis continues to be a major cause of systemic sepsis and meningitis in both developed and underdeveloped parts of the world ( ) . in developed countries, most cases are caused by group b and y strains, particularly after introduction of meningococcal c vaccination, whereas epidemics of meningococcus groups a, c and w continue to occur in many underdeveloped regions of the world ( , ) . infants and young adults are most commonly affected, but cases in adolescents and young children are also common. there are two major presentations of meningococcal disease ( ) : meningococcal meningitis presents with features indistinguishable from those of other forms of meningitis, including headache, stiff neck, and photophobia. lumbar puncture is required to identify the causative agent and distinguish this from other forms of meningitis. despite the acute nature of the illness, the prognosis is good, and most patients with the purely meningitic form of the illness recover without sequelae. meningococcemia with purpuric rash and shock is the second and more devastating form of the illness. affected patients present with nonspecific symptoms of fever, vomiting, abdominal pain, and muscle ache. the diagnosis is only obvious once the characteristic petechial or purpuric rash appears. patients with a rapidly progressive purpuric rash, hypotension, and evidence of skin and organ underperfusion have a poor prognosis, with a mortality of - %. adverse prognostic features include hypotension, a low white cell count, absence of meningeal inflammation, thrombocytopenia, and disturbed coagulation indices ( ) . renal failure was seldom reported in early series of patients with meningococcemia, perhaps because most patients died rapidly of uncontrolled septic shock. with advances in intensive care, however, more children are surviving the initial period of profound hemodynamic derangement, and renal failure is more often seen as a major management problem. approximately % of children with fulminant meningococcemia develop renal failure, which usually occurs - h after the onset of illness ( ) . the pathophysiology of meningococcal septicemia involves the activation of cytokines and inflammatory cells by endotoxin ( , ) . mortality is directly related to both the plasma endotoxin concentration and the intensity of the inflammatory response, as indicated by levels of tnf and other inflammatory markers ( ) . patients with meningococcemia have a profound capillary leak leading to severe hypovolemia. loss of plasma proteins from the intravascular space is probably the major cause of shock ( ) , but myocardial suppression secondary to il- production is also important ( ) . intense vasoconstriction further impairs tissue and organ perfusion, and vasculitis with intravascular thrombosis and consumption of platelets and coagulation factors is also present ( ) . oliguria is invariably present in children with meningococcemia during the initial phase of the disorder. this is prerenal in origin and may respond to volume replacement and inotropic support. if cardiac output cannot be improved and renal underperfusion persists, established renal failure supervenes. occasionally, cortical necrosis or infarction of the kidneys occurs. children with meningococcemia should be aggressively managed in a pediatric intensive care unit, with early administration of antibiotics (penicillin or a third-generation cephalosporin), volume replacement, hemodynamic monitoring, and the use of inotropic agents and vasodilators. if oliguria persists despite measures to improve cardiac output, elective ventilation and dialysis should be instituted early ( , ) . because activation of coagulation pathways occurs, severe acquired protein-c deficiency may result and is usually associated with substantial mortality ( ) . protein c is a natural anticoagulant which also has important antiinflammatory activity. despite evidence for impaired function of the activated protein c pathway in meningococcal diseases ( ) , and adult trials suggesting benefit of activated protein c administration in septic shock (prowess trial) ( ) , pediatric trials of activated protein c showed no clear benefit, and were associated with increased risk of intracranial bleeding in very young infants ( ) . the role of apc therapy in pediatric sepsis remains unclear. most patients who survive the initial - h of the illness and regain hemodynamic stability will ultimately recover renal function even if dialysis is required for several weeks. the least common presentation of meningococcal sepsis is chronic meningococcemia. patients with this form of the illness present insidiously with a vasculitic rash, arthritis, and evidence of multiorgan involvement. the features may overlap those of henoch-schonlein purpura or subacute bacterial endocarditis (sbe), and the diagnosis must be considered in patients presenting with fever, arthritis, and vasculitic rash, often accompanied by proteinuria or hematuria. response to antibiotic treatment is good, but some patients may have persistent symptoms for many days resulting from an immunecomplex vasculitis. staphylococcal infections may affect the kidneys by direct focal invasion during staphylococcal septicemia, forming a renal abscess; by causing staphylococcal bacteremia; or by toxin-mediated mechanisms, as in the staphylococcal toxic shock syndrome. staphylococcal abscess. staphylococcal renal abscess presents with fever, loin pain and tenderness, and abnormal urine sediment, as do abscesses caused by other organisms ( ) . the illness often follows either septicemia or pyelonephritis. the diagnosis is usually considered only when a patient with clinical pyelonephritis shows an inadequate response to antibiotic treatment. the diagnosis is confirmed by ultrasonography or computed tomographic scan, which shows swelling of the kidney and intrarenal collections of fluid. antibiotic therapy alone may result in cure, but if the patient remains unwell with evidence of persistent inflammation despite use of appropriate antibiotics, surgical intervention may be required. percutaneous drainage under ultrasonographic or computed tomographic scan guidance is often effective and may avoid the need for a more direct surgical approach ( , ) . staphylococcal toxic shock syndrome. the staphylococcal toxic shock syndrome is a systemic illness characterized by fever, shock, erythematous rash, diarrhea, confusion, and renal failure. the disorder was first described by todd et al. in in a series of seven children ( ) . during the s, thousands of cases were reported in the united states. most cases were in menstruating women, in associated with tampon use. although most cases worldwide are seen in women and are associated with menstruation, children of both sexes and of all ages are affected ( ) . the illness usually begins suddenly with high fever, diarrhea, and hypotension, together with a diffuse erythroderma ( ) . mucous membrane involvement with hyperemia and ulceration of the lips and oral mucosa or vaginal mucosa, strawberry tongue, and conjunctival injection are usually seen. desquamation of the rash occurs in the convalescent phase of the illness. confusion is often present in the early stages of the illness and may progress to coma in severe cases. multiple organ failure with evidence of impaired renal function, elevated levels of hepatic transaminases, thrombocytopenia, elevated cpk and disseminated intravascular coagulation (dic) is often seen. according to cdc criteria, the diagnosis is made on the basis of the clinical features of fever, rash, hypotension, and subsequent desquamation along with deranged function of three or more of the following organ systems: gastrointestinal (gi), mucous membranes, renal, hepatic, hematologic, central nervous system, and muscle. other disorders causing a similar picture, such as rocky mountain spotted fever, leptospirosis, measles, and streptococcal infection, must be excluded. the staphylococcal toxic shock syndrome is now known to be due to infection or colonization with strains of s. aureus that produce one or more protein exotoxins ( ) . most cases in adults are associated with toxic shock toxin i; in children, many of the isolates associated with the syndrome produce other enterotoxins (a to f). the staphylococcal enterotoxins appear to induce disease by acting as superantigens ( ) , which activate t cells bearing specific v beta regions of the t-cell receptor; this causes proliferation and cytokine release ( ) . the systemic illness and toxicity are believed to result largely from an intense inflammatory response induced by the toxin. the site of toxin production is often a trivial focus of infection or simple colonization, and bacteremia is rarely observed. renal failure in toxic shock syndrome is usually caused by shock and renal hypoperfusion. in the early stages of the illness, oliguria and renal impairment are usually prerenal and respond to treatment of shock and measures to improve perfusion. in severe cases and in patients in whom treatment is delayed, acute renal failure develops as a consequence of prolonged renal underperfusion, and dialysis may be required. in addition to underperfusion, direct effects of the toxin or inflammatory infectious diseases and the kidney mediators may also contribute to the renal damage. recovery of renal function usually occurs, but in severe cases with cortical necrosis or intense renal vasculitis, prolonged dialysis may be required. the management of staphylococcal toxic shock syndrome depends on early diagnosis and aggressive cardiovascular support with volume replacement, inotropic support, and, in severe cases, elective ventilation. if oliguria persists despite optimization of intravascular volume and administration of inotropic agents, dialysis should be commenced early ( ) . anti-staphylococcal antibiotics should be started as soon as the diagnosis is suspected and the site of infection identified. initial empiric antimicrobial therapy should include an anti-staphylococcal antibiotic effective against betalactamase-resistant organisms and a protein synthesisinhibiting antibiotic such as clindamycin to stop further toxin production ( ) . if there is a focus of infection such as a vaginal tampon, surgical wound, or infected sinuses, the site should be drained early to prevent continued toxin release into the circulation. the intravenous administration of immune globulins may be considered when infection is refractory to several hours of aggressive therapy, an undrainable focus is present, or persistent oliguria with pulmonary edema occurs ( ) . with aggressive intensive care, most affected patients survive, and renal recovery is usual, even in patients who have had severe shock and multiorgan failure. relapses and recurrences of staphylococcal toxic shock syndrome occur in a proportion of affected patients because immune responses to the toxin are ineffective in some individuals. panton valentine leucocidin (pvl) producing staphylococcal infection: in recent years there have been increasing reports of severe staphylococcal disease, associated with shock and multiorgan failure, caused by strains of staphylococci producing the pvl toxin. panton-valentine leukocidin (pvl) is a phage-encoded toxin, which profoundly impairs the host response due to its toxic effect on leucocytes (see review ( ) ). pvl producing strains are associated with tissue necrosis and increased propensity to cause abscesses in lung, bone, joint, and soft tissue infections. perinephric abscesses have been reported ( ) . there are increasing numbers of children and adults admitted with fulminant sepsis, and shock due to pvl producing strains, and renal failure is a significant component of the multiorgan failure. in addition to intensive care support, antibiotic treatment of pvl strains should include antibiotics which reduce toxin production, such as clindamycin, linezolid or rifampicin, as well as vancomycin if the strain is resistant to methicillin. beta-lactam antibiotics should be avoided, as there is some data to suggest that pvl toxin production can increased by these antibiotics under some conditions ( ) . immunoglobulin infusion may also be of benefit. aggressive surgical drainage of all collections requires close consultation with orthopedic and surgical teams. the group a streptococci (gas) are a major worldwide cause of renal disease, usually as poststreptococcal nephritis. however, in addition to this post-infection immunologically mediated disorder, in recent years there have been increasing reports of gas causing acute renal failure as part of an invasive infection with many features of the staphylococcal toxic shock syndrome ( ) . acute poststreptococcal glomerulonephritis. acute poststreptococcal gn (apsgn) is a delayed complication of pharyngeal infection or impetigo with certain nephritogenic strains of gas. different strains can be serotyped according to the antigenic properties of the m protein found in the outer portion of the bacterial wall. apsgn after pharyngeal infection is most commonly associated with serotype m . in contrast, in apsgn after impetigo, serotype m is most commonly identified ( ) . on occasions, other serotypes and non-typeable strains have been described as causing gn. the pathology and pathogenesis of the disorder is discussed in detail in chapter . apsgn has a worldwide distribution. epidemiologic differences are observed between pharyngitis-associated and impetigo-associated streptococcal infections. pharyngitis-associated apsgn is most common during school age and has an unexplained male/female ratio of : . it occurs more often in the cooler months, and familial occurrences are commonly described. the latent period is - weeks, in notable contrast to impetigo-associated cases, which have a latent period of - weeks. in many developing countries, children have chronic skin infections, and it may be difficult to establish the latent period with accuracy. impetigoassociated cases are more common in the warmer months, sex distribution is equal, and children tend to be younger. introduction of a nephritogenic strain into a family often results in the occurrence of several cases within that family, and in some cases, attack rates of up to % have been described ( ) . the incidence is linked to poor socioeconomic conditions. renal involvement in apsgn can be mild, and in many patients, the disease may not be manifested clinically. studies of epidemics with nephritogenic strains of streptococci have shown that up to % of those infected had subclinical evidence of renal disease ( , ) . in a typical case a sudden onset of facial or generalized edema occurs. hypertension is usually modest but is severe in % of cases, and occasionally may lead to encephalopathy or left ventricular failure. the urine is smoky or tea colored in - % of cases. pallor, headache, backache, lethargy, malaise, anorexia, and weakness are all common nonspecific features. the urine volume is decreased. proteinuria is present (up to mg/dl), and microscopy shows white cells, red cells, and granular and hyaline casts. urea, electrolyte, and creatinine levels are normal in subclinical cases but show features of acute renal failure in severe cases. it may be possible to culture gas from the skin or the throat in some patients. other evidence of infection with a gas can be obtained through the antistreptolysin-o titer (asot), which is increased in - % of cases. early antibiotic treatment can reduce the proportion of cases with elevated asot to %. anti-deoxyribonuclease b and anti-hyaluronidase testing has been shown to be of more value than asot in confirming group a streptococcal infection in impetigo-associated cases. measurement of anti-m protein antibodies is of more value for epidemiologic purposes than for the diagnosis of individual cases ( ) . decreased c and total hemolytic complement levels are found in % of cases during the first weeks of illness and return to normal after - weeks. penicillin should be given to eradicate the gas organisms. erythromycin, clindamycin, or a first-generation cephalosporin can be given to patients allergic to penicillin. antibiotic treatment probably has no influence on the course of renal disease but will prevent the spread of a nephritogenic strain ( ) . close contacts and family members who are culture-positive for gas should also be given penicillin, although antibiotic treatment is not always effective in eliminating secondary cases. recurrent episodes are rare, and immunity to the particular nephritogenic strain that caused the disease is probably lifelong. antibiotic prophylaxis is therefore unnecessary. most studies suggest that the prognosis for children with apsgn is good, with more than % making a complete recovery. however, % of cases may have a prolonged and more serious course with long-term chronic renal failure ( ) . other streptococci. apsgn has also been described after outbreaks of group c streptococcus infection ( ) . this has occurred after consumption of unpasteurized milk from cattle with mastitis. patients developed pharyngitis followed by apsgn. endostreptosin was found in the cytoplasm of these group c strains, and during the course of the illness, patients developed anti-endostreptosin antibodies. this antigen has been postulated to be the nephritogenic component of gas. in addition, strains of group g streptococci have been implicated in occasional cases of apsgn ( ) . isolates possessed the type m protein antigen identical to the nephritogenic type m antigen of some group a streptococcal strains. streptococcal toxic shock syndrome and invasive group a streptococcal infection. since , there have been several reports of an illness with many similarities to the staphylococcal toxic shock syndrome, occurring in both children ( ) and adults, associated with invasive group a streptococcal disease ( , , ) . patients with this syndrome present acutely with high fever, erythematous rash, mucous membrane involvement, hypotension, and multiorgan failure. unlike staphylococcal toxic shock syndrome, in which the focus of infection is usually trivial and bacteremia is seldom seen, the streptococcal toxic shock syndrome is usually associated with bacteremia or a serious focus of infection such as septic arthritis, myositis, or osteomyelitis ( , ) . laboratory findings of anemia, neutrophil leukocytosis, thrombocytopenia, and dic are often present, together with impaired renal function, hepatic derangement, and acidosis. acute renal failure requiring dialysis occurs in a significant proportion of cases. it is not clear why there are increasing numbers of cases with invasive disease caused by gas, nor why there has been an emergence of streptococcal toxic shock syndrome, and indeed a similar syndrome caused by some pseudomonas and klebsiella strains. the most common antecedent of invasive gas disease is varicella infection, with the streptococcal infection developing after the initial vesicular phase of the disease is subsiding. strains causing toxic shock syndrome and invasive disease appear to differ from common isolates of gas in producing large amounts of pyrogenic toxins that may have superantigenlike activity. another important mechanism is the production by invasive gas of an il protease. il serves as a molecular bridge between receptors on neutrophils and the vascular endothelium. cleavage of this protein prevents neutrophil attachment to the endothelium, and results in uncontrolled spread of the bacteria through the tissues ( ) . in severe cases necrotizing fasciitis occurs with extensive destruction of the subcutaneous tissues, and is often associated with multiorgan failure. the pathophysiology of streptococcal toxic shock syndrome and that of invasive disease is similar in that superantigen toxins that induce release of cytokines and other inflammatory mediators play a role in both conditions. however gas toxic shock is usually more severe, carries a higher mortality, and is more often associated with focal collections or necrotizing fasciitis. treatment of streptococcal toxic shock syndrome depends on the administration of appropriate antibiotics, aggressive circulatory support, and treatment of any multiorgan failure. surgical intervention to drain the infective focus in muscle, bone, joint, or body cavities is often required. antibiotic therapy with beta-lactams should be supplemented by treatment with a protein synthesisinhibiting antibiotic, such as clindamycin, and it is suggested that this limits new toxin production ( , ) . a number of new therapies are in development. firstly, pooled intravenous immunoglobulins are now in widespread use in the treatment of toxic shock, particularly when caused by streptococcus ( , ) . the role of steroids remains unclear, with their hemodynamic benefit set against the detrimental effects of hyperglycemia secondary to gluconeogenesis. ( ) . the benefit of insulin therapy to control hyperglycemia is unclear. a recent study in adults found that intensive insulin therapy increased the risk of serious adverse events ( ) . in contrast to adult patients, in children with severe sepsis, the use of activated protein c (drotrecogin) cannot be recommended, as in a multicenter trial, fatality was increased in the treatment group ( ) . recovery of renal function occurs in patients who respond to treatment of shock and the eradication of the infection. leptospirosis is an acute generalized infectious disease caused by spirochetes of the genus leptospira ( ) . it is primarily a disease of wild and domestic animals, and humans are infected only occasionally through contact with animals. most human cases occur in summer or autumn and are associated with exposure to leptospiracontaminated water or soil during recreational activities such as swimming or camping. in adolescents and adults, occupational exposure through farming or other contact with animals is the route of infection. the spirochete penetrates intact mucous membranes or abraded skin and disseminates to all parts of the body, including the cerebrospinal fluid (csf). although leptospires do not contain classic endotoxins, the pathophysiology of the disorder has many similarities to that of endotoxemia. in severe cases, jaundice occurs because of hepatocellular dysfunction and cholestasis. renal functional abnormalities may be profound and out of proportion to the histologic changes in the kidney ( ) . renal involvement is predominantly a result of tubular damage, and spirochetes are commonly seen in the tubular lesions. the inflammatory changes in the kidney may result from either a direct toxic effect of the organism or immunecomplex nephritis. however, hypovolemia, hypotension, and reduced cardiac output caused by myocarditis may contribute to the development of renal failure. in severe cases, a hemorrhagic disorder caused by widespread vasculitis and capillary injury also occurs ( , ) . the clinical manifestations of leptospirosis are variable. of affected patients, % have the milder anicteric form of the disorder, and only - % have severe leptospirosis with jaundice. the illness may follow a biphasic course. after an incubation period of - days, a nonspecific flu-like illness lasting - days occurs, associated with septicemic spread of the spirochete. the fever then subsides, only to recur for the second, ''immune,'' phase of the illness. during this phase, the fever is low grade and there may be headache and delirium caused by meningeal involvement, as well as intense muscular aching. nausea and vomiting are common. examination usually reveals conjunctival suffusion, erythematous rash, lymphadenopathy, and meningism. the severe form of the disease (weil's disease) presents with fever, impaired renal and hepatic function, hemorrhage, vascular collapse, and altered consciousness. in one series the most common organs involved were the liver ( %) and kidney ( %). cardiovascular ( %), pulmonary ( %), neurologic ( %), and hematologic ( %) involvements were less common ( ) . vasculitis, thrombocytopenia, and uremia are considered important factors in the pathogenesis of hemorrhagic disturbances and the main cause of death in severe leptospirosis ( ) . urinalysis results are abnormal during the leptospiremic phase with proteinuria, hematuria, and casts. uremia usually appears in the second week, and acute renal failure may develop once cardiovascular collapse and dic are present ( ) . the clinical features of leptospirosis overlap with those of several other acute infectious diseases, including rocky mountain spotted fever, toxic shock syndrome, and streptococcal sepsis. the diagnosis of leptospirosis should be considered in febrile patients with evidence of renal, hepatic, and mucous membrane changes and rash, particularly if a history of exposure to fresh water is found. diagnosis can be confirmed by isolation of the spirochetes from blood or csf in the first days of the illness or from urine in the second week ( ) . the organism may be seen in biopsy specimens of the kidney or skin or in the csf by dark-field microscopy or silver staining. serologic tests to detect leptospirosis are now sensitive and considerably aid the diagnosis. immunoglobulin m (igm) antibody may be detected as early as - days into the illness, and antibody titers rise progressively over the next - weeks. some patients remain seronegative, and negative serologic test results do not completely exclude the diagnosis. in one series levels of igm and igg anticardiolipin concentrations were significantly increased in leptospirosis patients with acute renal failure ( ) . leptospirosis is treated with intravenous penicillin or other beta-lactam antibiotics. the severity of leptospirosis is reduced by antibiotic treatment, even if started late in the course of the illness ( ) . supportive treatment with volume replacement to correct hypovolemia, administration of inotropes, and correction of coagulopathy is essential in severe cases. dialysis may be required in severe cases and may be needed for prolonged periods until recovery occurs. infection with s. pneumoniae is one of the most common infections in humans and causes a wide spectrum of disease, including pneumonia, otitis media, sinusitis, septicemia, and meningitis. despite the prevalence of the organism, significant renal involvement is relatively rare but is seen in two situations: pneumococcal septicemia in asplenic individuals or in those with other immune deficiencies presents with fulminant septic shock in which renal failure may occur as part of a multisystem derangement. the mortality from pneumococcal sepsis in asplenic patients is high, even with early antibiotic treatment and intensive support. the second nephrologi syndrome associated with s. pneumoniae is a rare form of hus. in , gasser and colleagues described hus as a clinical entity in children, and they included two infants with pneumonia among the five patients they described ( ) . hus associated with pneumococcal infection is induced by the enzyme neuraminidase released from s. pneumoniae ( , ) . thomsen-friedenrich antigen (t antigen) is present on the surface of red blood cells, platelets, and glomerular capillary endothelia against which antibodies are present in normal serum. neuraminidase causes desialation of red blood cells, and possibly other blood cells and endothelium, by the removal of terminal neuraminic acid, which leads to unmasking of the t antigen. the resultant widespread agglutination of blood cells causes intravascular obstruction, hemolysis, thrombocytopenia, and renal failure. results of the direct coombs test are frequently positive, either from bound anti-t igm or from anti-t antibodies. the diagnosis of thomsen-friedenrich antibody-induced hus should be suspected in patients with acute renal failure, thrombocytopenia and hemolysis after an episode of pneumonia or bacteremia caused by s. pneumoniae. fragmented red blood cells will usually be present on blood film. association with s. pneumoniae is defined by culture of pneumococci from a normally sterile site within a week before or after onset of signs of hus. clues to a pneumococcal cause, in addition to culture results, include severe clinical disease, especially pneumonia, empyema, pleural effusion, or meningitis; hemolytic anemia without a reticulocyte response; positive results on a direct coombs test; and difficulties in abo crossmatching or a positive minor crossmatch incompatibility ( ) . however, when renal disease is seen in the context of severe pneumococcal infection, it is important to maintain a broad diagnostic perspective, because the occurrence of acute tubular necrosis due to septic shock and dic is well described ( , ) . therapy for this syndrome should be with supportive treatment and antibiotics (usually a third generation cephalosporin); dialysis may be required if renal failure occurs. because normal serum contains antibodies against the thomsen-friedenrich antigen, blood transfusion should be undertaken with washed red blood cells resuspended in albumin rather than plasma ( , ) . exchange transfusion and plasmapheresis have been used in some patients, with the rationale that these procedures may improve outcome by eliminating circulating neuraminidase ( , , ) . intravenous igg has been used in a patient and was shown to neutralize neuraminidase present in the patient's serum ( ) . in comparison to patients with the more common diarrhea-associated hus, s. pneumoniae-induced hus patients have a more severe renal disease. they are more likely to require dialysis. their long-term outcome maybe affected by the severity of the invasive streptococcal disease itself, and a significant proportion of surviving patients ( - %) develop end-stage renal failure ( , ) . a recent review of uk cases found an eightfold increase in early mortality as compared to diarrhoea-induced hus ( ) . gastrointestinal infections (escherichia coli, salmonella, campylobacter, yersinia, shigella, vibrio cholerae) the diarrheal diseases caused by escherichia coli, salmonella, shigella, campylobacter, vibrios, and yersinia remain important and common bacterial infections of humans. although improvements in hygiene and living conditions have reduced the incidence of bacterial gastroenteritis in developed countries, these infections remain common in underdeveloped areas of the world, and outbreaks and epidemics continue to occur in both developed and underdeveloped countries. renal involvement in the enteric infections may result from any of four possible mechanisms. regardless of the causative organism, diarrhea results in hypovolemia, abnormalities of plasma electrolyte composition, and renal underperfusion. if severe dehydration occurs and is persistent, oliguria from prerenal failure is followed by vasomotor nephropathy and established renal failure. e. coli, shigella, and salmonella (particularly salmonella typhi) may invade the bloodstream and induce septicemia or septic shock. acute renal failure is commonly seen in infants with e. coli sepsis but is also reported with klebsiella, salmonella, and shigella infections. its pathophysiology and treatment were discussed previously. enteric infections with e. coli, yersinia, campylobacter, and salmonella have been associated with several different forms of gn, including membranoproliferative gn (mpgn), interstitial nephritis, diffuse proliferative gn, and iga nephropathy ( ) ( ) ( ) . in typhoid fever, gn ranging from mild asymptomatic proteinuria and hematuria to acute renal failure may occur ( , ( ) ( ) ( ) . renal biopsy findings show focal proliferation of mesangial cells, hypertrophy of endothelial cells, and congested capillary lumina. immunofluorescent studies show igm, igg, and c deposition in the glomeruli, with salmonella antigens detected within the granular deposits in the mesangial areas. in the iga nephropathy after typhoid fever, salmonella vi antigens have been demonstrated within the glomeruli. yersinia infection has been reported as a precipitant of gn in several studies ( , ) . transient proteinuria and hematuria are found in % of patients with acute yersinia infection, and elevated creatinine levels in %. renal biopsy reveals mild mesangial gn or iga nephropathy. yersinia antigens, immunoglobulin, and complement have been detected in the glomeruli. yersinia pseudotuberculosis is well recognized as one of the causes of acute tubulointerstitial nephritis causing acute renal failure, especially in children; patients have histories of drinking untreated water in endemic areas ( ) ( ) ( ) . the illness begins with the sudden onset of high fever, skin rash, and gi symptoms. later in the course, periungual desquamation develops, mimicking kawasaki disease. elevated erythrocyte sedimentation rate, c-reactive protein level, and thrombocytosis are noticeable, and mild degrees of proteinuria, glycosuria, and sterile pyuria are common. acute renal failure, which typically develops - weeks after the onset of fever, follows a benign course with complete recovery. renal biopsy mainly reveals findings of acute tubulointerstitial nephritis. antibiotic therapy, although recommended, does not alter the clinical course, but reduces the fecal excretion of the organism ( , ) . hus is characterized by three distinct clinical signs: acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia. it was first described in and was associated with infection by shiga toxin-producing shigella dysenteriae. a major breakthrough in the search for the cause of hus occurred in the s when karmali et al. reported that of children with diarrheaassociated hus had evidence of infection with a strain of e. coli that produced a toxin active on vero cells ( ) . in diarrhea-associated hus in the united states and most of europe, e. coli :h is the most important of these strains. e. coli :h occurs naturally in the gi tract of cattle and other animals, and humans become infected through contaminated food products. most outbreaks have been associated with consumption of undercooked meat, but unpasteurized milk and cider, drinking water, and poorly chlorinated water for recreational use have also been implicated as vehicles for bacterial spread. hus is discussed in detail in chapter . the global epidemic of mycobacterium tuberculosis is growing. several factors have contributed to this increase, including the emergence of the human immunodeficiency virus (hiv) infection epidemic, large influxes of immigrants from countries in which tuberculosis (tb) is common, the emergence of multiple-drug-resistant m. tuberculosis, and breakdown of the health services for effective control of tb in various countries. it is generally estimated that, overall, one-third of the world's population is currently infected with the tb bacillus. there are more than million cases of tb, which result in the death of approximately million people each year. furthermore, - % of people who are infected with the tb bacillus develop tb disease or become infectious at some time during their lives ( , ) . after respiratory illness in children, mycobacteria are widely distributed to many organs of the body during the lymphohematogenous phase of childhood tb ( ) . tubercle bacilli can be recovered from the urine in many cases of miliary tb. hematogenously-spread tuberculomata develop in the glomeruli, which results in caseating, sloughing lesions that discharge bacilli into the tubules. in most cases, the renal lesions are asymptomatic and manifest as mycobacteria in the urine or as sterile pyuria. tuberculomata in the cortex may calcify and cavitate or may rupture into the pelvis, discharging infective organisms into the tubules, urethra, and bladder. dysuria, loin pain, hematuria, and pyuria are the presenting features of this complication, but in many cases, the renal involvement is asymptomatic, even when radiologic and pathologic abnormalities are very extensive. continuing tuberculous bacilluria may cause cystitis with urinary frequency and, in late cases, a contracted bladder ( ) . the intravenous urogram is abnormal in most cases. early findings are pyelonephritis with calyceal blunting and calyceal-interstitial reflux. later, papillary cavities may be seen, indicating papillary necrosis. ureteric strictures, focal calcification, hydronephrosis, and cavitation may also be seen. renal function is usually well preserved, and hypertension is uncommon. in some cases, either the infection itself or reactions to the chemotherapeutic agents may result in renal failure with evidence of an interstitial nephritis ( ) ( ) ( ) . classic symptomatic renal tb is a late and uncommon complication in children, rarely occurring less than or years after the primary infection, and therefore is most commonly diagnosed after adolescence ( , ) . adult studies have shown that - % of renal tb coexists with active pulmonary tb and - % of screened sputumpositive pulmonary tb patients have renal involvement. the diagnosis is established by isolation of mycobacteria from the urine or by the presence of the characteristic clinical and radiographic features in a child with current or previous tb. renal tb is treated with drug regimens similar to those used for other forms of tb, with isoniazid, rifampicin, pyrazinamide and ethambutol administered initially for months, and isoniazid and rifampicin then continued for a further - months. late scarring and urinary obstruction may occur in cases with extensive renal involvement, and such patients should be followed by ultrasonography or intravenous urogram. mycobacteria, both m. tuberculosis and atypical mycobacteria, have also emerged as important causes of opportunistic infection in immunocompromised patients undergoing dialysis and in patients undergoing renal transplantation. the possibility of mycobacterial disease must be considered in patients with fever of unknown origin or unexplained disease in the lungs or other organs. results of the mantoux test are often negative, and diagnosis depends on maintaining a high index of suspicion and isolating the organism from the infected site. renal involvement has been well documented in both congenital and acquired syphilis, with an estimated occurrence of . % in patients with secondary syphilis and up to % in those with congenital syphilis ( , ) . the most common manifestation of renal disease in congenital syphilis is the nephrotic syndrome, with proteinuria, hypoalbuminemia, and edema. in some patients, hematuria, uremia, and hypertension may be seen. the renal disease is usually associated with other manifestations of congenital syphilis, including hepatosplenomegaly, rash, and mucous membrane findings. nephritis in congenital syphilis is usually associated with evidence of complement activation, with depressed levels of clq, c , c , and c . histologic findings are a diffuse proliferative gn or a membranous nephropathy. the interstitium shows a cellular infiltrate of polymorphonuclear and mononuclear cells ( ) . immunofluorescent microscopy reveals diffuse granular deposits of igg and c along the glomerular basement membrane (gbm). mesangial deposits may also contain igm. on electron microscopy, scattered subepithelial electron-dense deposits are seen, with fusion of epithelial cell foot processes ( ) . good evidence exists that renal disease is due to an immunologically mediated reaction to treponemal antigens. antibodies reactive against treponemal antigens can be eluted from the glomerular deposits, and treponemal antigens are present in the immune deposits. treatment of both congenital and acquired syphilis with antibiotics results in rapid improvement in the renal manifestations ( , ) . renal involvement is surprisingly rare in mycoplasma pneumoniae infection considering the prevalence of this organism and its propensity to trigger immunologically mediated diseases such as erythema multiforme, arthritis, and hemolysis. acute nephritis associated with mycoplasma infection may occur - days after the respiratory tract infection ( , ) . renal histopathologic findings include type mpgn, proliferative endocapillary gn, and minimal change disease ( ) . antibiotic treatment of the infection does not appear to affect the renal disease, which is self-limited in most cases ( , ) . since its recognition in , legionnaires' disease, caused by legionella pneumophila, has emerged as an important infectious diseases and the kidney cause of pneumonia. the disease most commonly affects the elderly but has been reported in both normal and immunocompromised children ( , ) . renal dysfunction occurs in a minority of patients ( ) . patients who develop renal impairment present with oliguria and rising urea and creatinine levels. they are usually severely ill, with bilateral pulmonary infiltrates, fever, and leukocytosis. shock may be present, and the renal impairment has been associated with acute rhabdomyolysis with high levels of creatine phosphokinase and myoglobinuria. renal histologic examination usually shows a tubulointerstitial nephritis or acute tubular necrosis ( , ) . the pathogenesis of the renal impairment is uncertain, but the organism has been detected within the kidney on electron microscopy and immunofluorescent studies, which suggests a direct toxic effect. myoglobinuria and decreased perfusion may also be contributing factors, however. mortality has been high in reported cases of legionnaires' disease complicated by renal failure. treatment is based on dialysis, intensive care, and antimicrobial therapy with erythromycin ( ) . steroid therapy may be effective for tubulointerstitial nephritis ( ) . the rickettsial diseases are caused by a family of microorganisms that have characteristics common to both bacteria and viruses and that cause acute febrile illnesses associated with widespread vasculitis. with the exception of q fever, all are associated with erythematous rashes. there are four groups of rickettsial diseases: . the typhus group includes louse-borne and murine typhus, spread by lice and fleas, respectively. . the spotted fever group includes rocky mountain spotted fever, tick typhus and related mediterranean spotted fever and rickettsial pox, which are spread by ticks and mites, with rodents as the natural reservoir. . scrub typhus, which is spread by mites. . q fever, which is spread by inhalation of infected particles from infected animals. rickettsial diseases have a worldwide distribution and vary widely in severity, from self-limited infections to fulminant and often fatal illnesses ( ) . in view of the widespread vasculitis associated with these infections, subclinical renal involvement probably occurs in many of the rickettsial diseases. however, in rocky mountain spotted fever, tick typhus, and q fever, the renal involvement may be an important component of the illness. rocky mountain spotted fever is the most severe of the rickettsial diseases ( , ) . the onset occurs - days after the bite of an infected tick. high fever develops initially, followed by the pathognomonic rash, which occurs between the second and sixth days of the illness. the rash initially consists of small erythematous macules, but later these become maculopapular and petechial, and in untreated patients, confluent hemorrhagic areas may be seen. the rash first appears at the periphery and spreads up the trunk. involvement of the palms and soles is a characteristic feature ( ) . headache, restlessness, meningism, and confusion may occur together with other neurologic signs. cardiac involvement with congestive heart failure and arrhythmia are common. pulmonary involvement occurs in - % of cases. infection is associated with an initial leucopenia, followed by neutrophil leukocytosis. thrombocytopenia occurs in most cases. histopathologically, the predominant lesions are in the vascular system ( ) . rickettsiae multiply in the endothelial cells, which results in focal areas of endothelial cell proliferation, perivascular mononuclear cell infiltration, thrombosis, and leakage of red cells into the tissues. the renal lesions involve both blood vessels and interstitium, and acute tubular necrosis may occur. acute gn with immune-complex deposition has been reported ( ) , but in most cases the pathology appears to be a direct consequence of the invading organism on the renal vasculature ( , ) . renal dysfunction is an important complication of rocky mountain spotted fever. elevation of urea and creatinine levels occurs in a significant proportion of cases, and acidosis is common. prerenal renal failure caused by hypovolemia and impaired cardiac function may respond to volume replacement and inotropic support, but acute renal failure may subsequently occur, necessitating dialysis. rocky mountain spotted fever is diagnosed by the characteristic clinical picture, the exclusion of disorders with similar manifestations (e.g., measles, meningococcal disease, and leptospirosis), and detection of specific antibodies in convalescence. culture of rickettsia rickettsii, immunofluorescent staining, and polymerase chain reaction (pcr) testing of blood and skin biopsy specimens are available only in reference laboratories. antibiotics should be administered in suspected cases without awaiting confirmation of the diagnosis ( ) . doxycycline is the drug of choice for children of any age. chloramphenicol is also effective ( ) . intensive support of shock and multiorgan failure may be required in severe cases, and peritoneal dialysis or hemodialysis may be required until renal function returns. before the advent of specific therapy, mortality was %. today the overall mortality in the united states is still - %. death predominantly occurs in cases in which the diagnosis is delayed. q fever is caused by coxiella burnetii and has a worldwide distribution, with the animal reservoir being cattle, sheep, and goats. human infection follows inhalation of infected particles from the environment. the clinical manifestations range from an acute self-limited febrile illness with atypical pneumonia to involvement of specific organs that causes endocarditis, hepatitis, osteomyelitis, and central nervous system disease ( ) . proliferative gn may be associated with either q fever endocarditis, rhabdomyolysis or a chronic infection elsewhere in the body ( ) . renal manifestations range from asymptomatic proteinuria and hematuria to acute renal failure, hypertension, and nephrotic syndrome. renal histologic findings are those of a diffuse proliferative gn, focal segmental gn, or mesangial gn. immunofluorescent studies reveal diffuse glomerular deposits of igm in the mesangium, together with c and fibrin. c. burnetii antigen has not been identified within the renal lesions. treatment of the underlying infection may result in remission of the renal disease, but prolonged treatment may be required for endocarditis. tetracycline has been used in conjunction with rifampicin, co-trimoxazole, or a fluoroquinolone. nephritis has been reported in association with the presence of a wide range of microorganisms that cause chronic or persistent infection (> table - ) ( , ). it is likely that any infectious agent that releases foreign antigens into the circulation, including those of very low virulence, can cause renal injury either by deposition of foreign antigens in the kidney or by the formation of immune complexes in the circulation, which are then deposited within the kidney. nephritis is most commonly seen in association with intravascular infections such as sbe or infected ventriculoatrial shunts, but it is also seen after focal extravascular infections; ear, nose, and throat infections; and abscesses. renal involvement is one of the diagnostic features of bacterial endocarditis. virtually all organisms that cause endocarditis also produce renal involvement ( > table - ). although endocarditis caused by bacteria is the most common and is readily diagnosed by blood culture ( ), unusual but important causes of culture-negative endocarditis include q fever ( ) and legionella infection ( ) . in the immunocompromised individual, opportunistic pathogens such as fungi and mycobacteria are important causes. the usual renal manifestations of sbe are asymptomatic proteinuria, hematuria, and pyuria. loin pain, hypertension, nephrotic syndrome, and renal failure may occur in more severe cases. the renal lesions occurring in endocarditis are variable, and focal embolic and immune-complex-mediated features may coexist ( , , ) . embolic foci may be evident as areas of infarction, intracapillary thrombosis, or hemorrhage. more commonly, there is a focal necrotizing or diffuse proliferative gn. immunofluorescent studies show glomerular deposits of igg, igm, iga, and c along the gbm and within the mesangium. electron microscopy reveals typical electron-dense deposits along the gbm and within the mesangium ( , , ) . early reports suggested that the renal lesions were caused by microemboli from infected vegetations depositing in the kidney, a hypothesis supported by the occasional presence of bacteria within the renal lesions. most subsequent evidence, however, indicates that immunologic mechanisms rather than emboli are involved in the pathogenesis in most cases: bacteria are rarely found within the kidney, and renal involvement occurs with lesions of the right side of the heart, which would not be likely to embolize to the kidney. immune complexes containing bacterial antigens are present in the circulation, and both bacterial antigens and bacteria-specific antibodies can be demonstrated within the immune deposits in the kidney. serum c level is usually low, and complement can be found within both the circulating and the deposited immune complexes. these features all support an immune-complex-mediated pathogenesis of the renal injury ( , , ) . treatment of the endocarditis with antibiotics usually results in resolution of the gn and is associated with the disappearance of immune complexes from the circulation and return of c levels to normal. the prognosis of the renal lesions in sbe generally depends on the response of the underlying endocarditis to antibiotics or, in cases of antibiotic failure, to surgical removal of the infective vegetations ( ) . in patients previously treated by shunting for hydrocephalus, there is a well-documented association of gn with infected ventriculoatrial shunts. this condition is another example of an immune-complex nephritis similar to that seen in endocarditis ( ) . coagulase-negative staphylococci are the causative organisms in % of cases. the clinical and pathologic findings are similar to those in sbe. presenting features are proteinuria, hematuria, and pyuria, and they may progress to renal failure. immune complexes containing the bacterial antigens and complement are present in the serum, and c is depressed. histologic findings are those of a diffuse mesangiocapillary gn. immunofluorescent microscopy demonstrates deposits of immunoglobulin and c along the gbm, and bacterial antigen can be demonstrated in the renal lesions ( ) . the prognosis for the renal lesion is good if the infection is treated early. this usually involves removal of the infected shunt and administration of appropriate antibiotics ( , ) . the possible progression to end-stage renal disease requires frequent nephrologic monitoring of patients with ventriculoatrial shunts ( ) . there are a few reports in the literature of a similar renal complication occurring in chronic infection of ventriculoperitoneal shunts. gn has been reported after chronic abscesses ( ), osteomyelitis, otitis media, pneumonia, and other focal infections ( > table - ). acute renal failure has been the presenting feature of focal infections in various sites, including the lung, pleura, abdominal cavity, sinuses, and pelvis. many different organisms have been responsible, including s. aureus, pseudomonas, e. coli, and proteus species. this is probably another example of immunecomplex gn. c level is decreased in approximately onethird of reported cases, and immunofluorescent studies reveal diffuse granular deposits of c in the glomeruli of all reported instances, with a variable presence of immunoglobulin. the renal lesion is that of mpgn and crescentic nephritis. the renal outcome is reported to be good with successful early treatment of the underlying infection. the role of viral infections in the causation of renal disease has been less well defined than that of bacterial infections. clearly defined associations of renal disease have been made with hepatitis b virus (hbv), hepatitis c virus (hcv), hiv, and hantaviruses, but the role of most other viruses in the pathogenesis of renal disease is not clearly defined. most viruses causing systemic infection may trigger immunologically mediated renal injury. with increasing application of molecular techniques, it may be that a significant proportion of gns currently considered to be idiopathic will ultimately be shown to be virus induced. in children with immunodeficiency states and those undergoing renal transplantation, viruses such as cytomegalovirus (cmv) and polyoma virus have been recognized to be associated with nephropathy. since the discovery of hepatitis b surface antigen (hbsag) in , hepatitis virus has been shown to infect more than % of the world's population and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. some million people have hbsag in the circulation (who figures). the infection is most common in africa and the orient, where it is acquired in childhood by vertical transmission from infected mothers or by horizontal transmission from other children or adults. in developed countries, transmission in adults occurs more often by blood product exposure, sexual contact, or intravenous drug use. the epidemiology of hbv infection in children is changing following the widespread use of effective vaccination at birth, in both developed and developing countries. hbv is a complex dna virus with an outer surface envelope (hbsag) and an inner nucleocapsid core containing the hepatitis b core antigen (hbcag), dna polymerase, protein kinase activity, and viral dna. incomplete spherical and filamentous viral particles consisting solely of hbsag are the major viral products in the circulation and may be present in concentrations of up to particles per ml of serum. hepatitis b e antigen (hbeag) can be released from hbcag by proteolytic treatment and may be found in the circulation either free or complexed to albumin or igg antibodies. the presence of hbeag correlates with the presence of complete viral particles and the infectivity of the individual ( ) . infection with hbv may result in either a self-limited infectious hepatitis followed by clearance of the virus and complete recovery, or a chronic or persistent infection in which the immune response is ineffective in eliminating the virus. chronic hbv infection with continued presence of viral antigens in the circulation caused by an ineffective host immune response provides the best-documented example of immunologically mediated renal injury caused by persistent infection ( ) . development of chronic hbv infection is positively associated with infection at a younger age, particularly in infancy, where the rate of chronic infection is up to %. in contrast, the likelihood of an acute, symptomatic illness increases with age, to a level where approximately % of infections are symptomatic in children above years. in the early prodromal phase of hbv hepatitis, before the onset of jaundice, some patients develop fever, maculopapular or urticarial rash, and transient arthralgias or arthritis. occasionally, proteinuria, hematuria, or sterile pyuria are observed. the syndrome usually lasts - days and often resolves before the onset of jaundice ( , ) . there have been no histologic studies of the renal changes during this prodromal period. since , numerous reports have linked hbv infection with polyarteritis nodosa (pan). most of these cases have been in adults, but the disorder has also been reported in children ( , ) , where it is estimated that approximately one third of pan cases are caused by hbv ( ) . hbv pan appears to be uncommon in africa and the orient, where infection is usually acquired in childhood, and has declined in incidence following the introduction of hbv vaccination ( ) . hbv pan presents weeks to months after a clinically mild hepatitis but may occasionally predate the hepatitis. after a prodromal illness, frank vasculitis affecting virtually any organ appears. abdominal pain, fever, mononeuritis multiplex, and pulmonary and renal involvement may occur. the renal involvement may appear as hypertension, hematuria, proteinuria, or renal failure (see chapter ) . laboratory investigations reveal a florid acute-phase response, leukocytosis, and anemia. transaminase levels are usually elevated, and hbsag is present in the circulation. the pathology consists of focal inflammation of small and medium-sized arteries, with fibrinoid necrosis, leukocyte infiltration, and fibrin deposition. renal pathology may be limited to the medium-sized arteries or may coexist with gn ( , ) . circulating immune complexes containing hbsag and anti-hbs antibodies are usually present in the circulation ( , ) . c , c , and total hemolytic complement levels are depressed. hbsag, igg, and igm antibodies to hbv and c have been identified by immunofluorescence in the blood vessels ( ) . a positive anca excludes hbv-pan ( ) . although most evidence suggests that the pathogenesis involves an immunecomplex-mediated vasculitis, autoantibody or cell-mediated vascular injury may coexist. if the condition is untreated, the mortality is high ( ) . most studies suggest that steroids or immunosuppressants help to suppress the vasculitis but potentially predispose to chronic infection . ( , ) . successful treatment of hepatitis b-associated pan with nucleoside analogues such as lamivudine or newer anti-viral drugs, either alone or in combination with interferon-alpha and conventional immunosuppressive therapy, has been reported ( ) ( ) ( ) . hbv is now the major cause of membranous gn (mgn) in children worldwide. the proportion of patients with mgn caused by hbv is directly related to the incidence of hbsag in the population, with - % of all cases of mgn in some african and oriental countries being associated with hbv ( , ) (see chapter ) . hbv mgn usually presents in children aged - . there is a striking male predominance; in the united states, % of patients are males ( ) . the virus is usually acquired by vertical transmission from infected mothers or horizontally from infected family members. unlike adults with hbv mgn, children do not usually have a history of hepatitis or of active liver disease, but liver function test results are generally mildly abnormal. liver biopsy specimens may show minimal abnormalities, chronic persistent hepatitis, or (occasionally) more severe changes ( ) . the renal manifestations are usually of proteinuria, nephrotic syndrome, microscopic hematuria, or (rarely) macroscopic hematuria. hypertension occurs in less than % of cases, and renal insufficiency is rare. hbsag and hbcag are usually present in the circulation, and hbe antigenemia is seen in a high proportion of cases. occasionally, hbsag may be found in the glomeruli but is absent from the circulation. c and c levels are often low, and circulating immune complexes are found in most cases. immunohistologic study reveals deposits of igg and c and (less commonly) igm and iga in subepithelial, subendothelial, or mesangial tissue. hbv particles may be seen on electron microscopy, and all the major hepatitis b antigens, including hbsag, hbcag, and hbeag, have been localized in the glomerular capillary wall on immunofluorescence. immunologic deposition of hbv and antibody in the glomerular capillary wall is clearly involved in the glomerular injury, but the underlying immunologic events are incompletely understood ( , ) . passive trapping of circulating immune complexes may be involved, but the circulating immune complexes containing hbsag are usually larger than would be expected to penetrate the basement membrane. hbsag and hbcag are anionic and are therefore unlikely to penetrate the glomerular capillary wall. in contrast, hbeag forms smaller complexes with anti-hbe antibodies and may readily penetrate the gbm. this may explain the observation that hbeag in the circulation frequently correlates with the severity of the disease ( ) . an alternative mechanism for immunemediated glomerular injury is the trapping of hbv antigens by antibody previously deposited in the kidney. anti-hbe antibodies are cationic and may readily localize in the glomerulus and subsequently bind circulating antigen and complement. the third possibility is that the depositions of hbv and antibodies are consequences of glomerular injury by cellular mechanisms or autoantibodies. little evidence supports this view at present ( ) . a transgenic mouse model of hbv-associated nephropathy has been developed, in which hbsag and hbcag is expressed in liver and kidney, particularly tubular epithelial cells, without viral replication. in these mice, gene expression analysis revealed upregulation of acute-phase proteins, particularly c , although measurable serum c levels were reduced. this supports the notion that local persistent expression of hbv viral proteins contributes to hbv-associated nephropathy ( ) . hbv infection has been associated with a variety of other forms of gn in both adults and children. in one small series in children, mpgn was found to be equal in incidence to mgn in the spectrum of hbv-associated gns ( ) . both mpgn and mesangial proliferative gn may be triggered by hbv. in several countries where hbv is common, the proportion of patients with these forms of nephritides who test positive for hbv greatly exceeds the incidence of positivity in the general population ( ) . as with mgn and hbv-associated pan, circulating immune complexes and localization of hbv antigens in the glomeruli have been reported in both mpgn and mesangial proliferative gn, and it is likely that similar mechanisms are occurring ( , ) . several other forms of gn have been associated with hbv, including iga nephropathy, focal glomerulosclerosis, crescentic nephritis, and systemic lupus erythematosus, but the evidence for these associations is less consistent than for the entities discussed earlier ( ) . hbv is normally cleared as a result of cell-mediated responses in which cytotoxic t cells and natural killer cells eliminate infected hepatocytes. it is not surprising, therefore, that the administration of steroids and immunosuppressive agents either may have no effect on hbv disease or may increase the risk of progressive disease ( ) . children with hbv mgn have a good prognosis, and two-thirds undergo spontaneous remission within years of diagnosis. steroid therapy does not appear to provide any additional benefit ( , , ) . antiviral therapy with pegylated interferon-alpha and lamivudine shows promise in facilitating clearance of hbv, and in some cases, elimination of the infection with antiviral therapy in both children and adults is associated with improvement or resolution of the coexisting renal disease. there is considerable effort being put into the development of newer anti-viral agents which avoid the common problems of resistance associated with lamivudine ( - ). hcv is an enveloped, single-stranded rna virus of approximately . kb in the flaviviridae family. there are six major hcv genotypes. hepatitis c is a common disease affecting approximately million people worldwide. in the united states, . million persons are estimated to be anti-hcv positive, and . million may be chronically infected ( ) . an estimated , children in the united states have antibody to hcv and , - , are chronically infected ( ) . children become infected through receipt of contaminated blood products or through vertical transmission. the risk of vertical transmission increases with higher maternal viremia and maternal co-infection with hiv. acute hcv infection is rarely recognized in children outside of special circumstances such as a known exposure from an hcv-infected mother or after blood transfusion. most chronically infected children are asymptomatic and have normal or only mildly abnormal alanine aminotransferase levels. although the natural history of hcv infection during childhood seems benign in the majority of instances, the infection can take an aggressive course in a proportion of children, leading to cirrhosis and end-stage liver disease during childhood. the factors responsible for this more aggressive course are unidentified ( ) . even in adults, the natural history of hcv infection has a variable course, but a significant proportion of patients will develop some degree of liver dysfunction, and - % will eventually have end-stage liver disease as a result of cirrhosis. the risk of hepatocellular carcinoma is significant for those who have established cirrhosis. hepatitis c is currently the most common condition leading to liver transplantation in adults in the ''western world.'' gn has been described as an important complication of chronic infection with hcv in adults. the clinical presentation is usually of nephrotic syndrome or proteinuria, hypertension, or hematuria, with or without azotemia ( ) . mpgn, with or without cryoglobulinemia, and mgn are most commonly described. isolated case reports of other, more unusual patterns of glomerular injury, including iga nephropathy, focal segmental glomerulosclerosis, crescentic gn, fibrillary gn, and thrombotic microangiopathy, have also been associated with hcv infection ( , ) . glomerular deposition of hepatitis antigens and antibodies has been described and is believed to play a role in pathogenesis. cryoglobulinemia is a common accompaniment of gn that is associated with the depression of serum complement levels ( ) . renal failure may develop in - % of patients who have mpgn ( , ) . the presence of virus-like particles as well as viral rna within the kidney sections of patients with hcv-associated glomerulopathies has been reported ( ) . the diagnosis should be suspected if glomerular disease is associated with chronic hepatitis, particularly with the presence of cryoglobulins, but renal biopsy is necessary to establish a definitive diagnosis. hcv infection is relatively common in children with end-stage renal disease and is an important cause of liver disease in this population. acquisition of hcv infection continues to occur in dialysis patients because of nosocomial spread ( ) . elevation of transaminase level is not a sensitive marker of infection in children and hcv enzymelinked immunosorbent assay or pcr testing should be used to increase sensitivity ( ) . hcv-infected renal transplant recipients had higher mortality and hospitalization rates than other transplant recipients ( ) , and hcv infection has been reported to be associated with de novo immune-mediated gn, especially type mpgn, in renal allografts, resulting in accelerated loss of graft function ( , ) . no large randomized, controlled trials of treatment of children with chronic hepatitis c have been performed, although one study (peds-c) is currently recruiting patients into a trial of pegylated interferon +/À ribavirin ( ) . small heterogeneous studies of interferon monotherapy have reported sustained virologic response rates of - % ( ) . in adults, improvement of proteinuria and renal function often follows interferon-alpha treatment ( , ) , but relapses are common after cessation of treatment. combination of interferon with ribavirin in infectious diseases and the kidney patients with chronic liver disease has been shown to increase the rate of sustained response in these patients ( ) . as yet, however, there are few data regarding the use of combination therapy with interferon and ribavirin in children. moreover, interferon-alpha therapy is associated with acute or subacute renal failure in more than one-third of the patients with renal transplants ( ) . hepatitis c may be complicated by systemic mixed cryoglobulinemic (mc) vasculitis, and in some cases by a polyarteritis nodosa (pan)-type non-cryoglobulinemic vasculitis ( ) . treatment with interferon-a (ifn-a) and ribavirin mostly is associated with an improvement of vasculitic symptoms. in some cases, exacerbation and rarely new onset of vasculitis of the peripheral nervous system have been described after this treatment. in fulminant cases immunosuppressive therapy with steroids, and cyclophosphamide, or rituximab may be needed to control life threatening vasculitis prior to antiviral treatment ( ) . cytomegalovirus cmv is one of the eight human herpes viruses. transmission of the virus requires exposure to infected body fluids such as breast milk, saliva, urine, or blood. individuals initially infected with cmv may be asymptomatic or display nonspecific flu-like symptoms. after the initial infection cmv, like all herpes viruses, establishes latency for life but will be periodically excreted by an asymptomatic host. cmv replicates within renal cells, and on biopsy samples from immunocompromised hosts, viral inclusions can be visualized by light microscopy in cells of the convoluted tubules and collecting ducts ( ) . glomerular cells and shed renal tubular cells may have characteristic inclusions, but clinically evident renal disease is rare and is seen virtually only in immunocompromised or congenitally infected children ( , ) . the clinical manifestations of cmv-induced renal disease in congenitally infected infants are variable and range from asymptomatic proteinuria to nephrotic syndrome and renal impairment. in congenital cmv infection, histologic changes of viral inclusions commonly occur in the tubules. in addition, proliferative gn has been reported, with evidence on electron microscopy of viral immune deposits in glomerular cells ( , ) . in cmv-infected immunocompromised patients, immunecomplex gn has been documented with mesangial deposits of igg, iga, c , and cmv antigens within glomeruli. eluted glomerular immunoglobulins have been shown to contain cmv antigens ( ) . cmv is the most common viral infection after kidney transplantation. experience with pediatric kidney transplant recipients suggests a % incidence of cmv infection ( ) . the direct and indirect effects of cmv infection result in significant morbidity and mortality among kidney transplant recipients. cmv-negative patients who receive a cmv-positive allograft are at risk for primary infection and graft dysfunction. patients who are cmv seropositive at the time of transplantation are also at risk of reactivation and superinfection. tubulointerstitial nephritis is a well-characterized pathologic feature of renal allograft cmv disease, which can be difficult to distinguish from injury caused by rejection. histologic evidence of endothelial cell injury and mononuclear cell infiltration in the glomeruli has been reported ( ) . cmv glomerular vasculopathy in the absence of tubulointerstitial disease, causing renal allograft dysfunction, has also been reported ( ) . beyond the acute allograft nephropathy associated with cmv viremia, cmv is known to cause chronic vascular injury. this may adversely affect the long-term outcome of the allograft and may be the explanation for the observed association with chronic allograft nephropathy ( ) . newer techniques for rapidly diagnosing cmv infection are becoming widely available and include shell vial culture, pp antigenemia assay, pcr, and the hybridcapture rna-dna hybridization assay for qualitative detection of cmv pcr. quantitative plasma pcr testing (pcr viral load) is increasingly used for diagnosis and monitoring of cmv viremia in renal transplant recipients. antiviral agents that have been shown to be effective against cmv include ganciclovir, valganciclovir, foscarnet, and cidofovir. ganciclovir remains the drug of choice for treating established disease. intravenous ganciclovir therapy is preferred in children because of the erratic absorption of oral ganciclovir. major limitations of ganciclovir therapy are the induction of renal tubular dysfunction and bone marrow toxicity, principally neutropenia and thrombocytopenia. dosage adjustments are necessary for recipients with renal dysfunction. oral valganciclovir is now used for cmv prophylaxis post-transplant ( ) . use of other antiviral agents such as foscarnet and cidofovir is limited because of nephrotoxicity and difficulty of administration. a number of reports have demonstrated the effectiveness of high-titer cmv immune globulin therapy in reducing severe cmv-associated disease when used in combination with ganciclovir ( , ) . the association of varicella with nephritis has been known for more than years since henoch reported on four children with nephritis that occurred after the appearance of varicella vesicles. varicella, however, is rarely associated with renal complications ( ) . in fatal cases with disseminated varicella and in the immunocompromised individual, renal involvement is more common. cases in which varicella infection caused gn in renal transplant recipients have been reported ( ) . histologic findings in fatal cases include congested hemorrhagic glomeruli, endothelial cell hyperplasia, and tubular necrosis. in mild and nonfatal cases and in non-immunocompromised individuals, varicella is occasionally associated with a variety of renal manifestations, ranging from mild nephritis to nephrotic syndrome and acute renal failure ( ) . histologic findings include endocapillary cell proliferation, epithelial and endothelial cell hyperplasia, and inflammatory cell infiltration ( ) . rapidly progressive nephritis has also been reported. immunohistochemical studies reveal glomerular deposition of igg, igm, iga, and c . on electron microscopy, granular electron-dense deposits have been found in the paramesangial region, and varicella antigens may be deposited in the glomeruli. the features suggest an immune-complex nephritis. elevated circulating levels of igg and iga immune complexes and depressed c and c levels support this possibility ( ) . fulminant disseminated varicella and varicella in immunocompromised patients should be treated with intravenous acyclovir. renal involvement is common during acute infectious mononucleosis, usually manifesting as an abnormal urine sediment, with hematuria in up to % of cases. hematuria, either microscopic or macroscopic, usually appears within the first week of the illness and lasts for a few weeks to a few months. proteinuria is usually absent or low grade. more severe renal involvement with proteinuria, nephrotic syndrome, or acute nephritis with renal failure is much less common. acute renal failure may be seen during the course of fulminant infectious mononucleosis with associated hepatic failure, thrombocytopenia, and encephalitis. it is usually caused by interstitial nephritis that is likely the result of immunopathologic injury precipitated by epstein-barr virus (ebv) infection. however, the identification of ebv dna in the kidney raises the possibility that direct infection might play a role ( ) . the renal involvement must be distinguished from myoglobinuria caused by rhabdomyolysis, which may occur in infectious mononucleosis, and from bleeding into the renal tract as a result of thrombocytopenia. renal histologic findings in ebv nephritis are an interstitial nephritis with mononuclear cell infiltration and foci of tubular necrosis. glomeruli may show varying degrees of mesangial proliferation. on immunohistochemical study, ebv antigens are seen in glomerular and tubular deposits. the prognosis for complete recovery of renal function is good. treatment with corticosteroids may have a role in the management of ebv-induced acute renal failure and may shorten the duration of renal failure ( ) . ebv-associated post-transplantation lymphoproliferative disease is a recognized complication in renal transplant recipients. latent infection of ebv in renal proximal tubular epithelial cells has recently been described as causing idiopathic chronic tubulointerstitial nephritis ( ) . the herpes simplex virus (hsv) causes persistent infection characterized by asymptomatic latent periods interspersed with acute relapses. as with other chronic and persistent infections, immunologically mediated disorders triggered by hsv are well recognized, and it is perhaps surprising that hsv has rarely been linked to nephritis. acute nephritis and nephrotic syndrome have been associated with herpes simplex encephalitis. renal histology shows focal segmental gn with mesangial and segmental deposits of igm, c , and hsv antigens. as with other herpes viruses, hsv has been suggested as a trigger for iga nephritis, mpgn, and membranous nephropathy. elevated levels of hsv antibodies have been reported in patients with a variety of forms of gn, but no conclusive evidence exists of an etiologic role for hsv ( ) . adenovirus and enterovirus, are unrelated ubiquitous pathogens that infect large proportions of the population annually and yet are rarely associated with renal disease. the literature contains scattered reports of acute nephritis after infection with each of these viruses. adenovirus is a major cause of hemorrhagic cystitis and was implicated as the cause of hemorrhagic cystitis in - % of children with this disorder ( ) . boys are affected more often than girls, and hematuria persists for - days. microscopic hematuria, dysuria, and frequency may occur for longer periods. adenovirus types and are the usual strains isolated. picornaviruses, including enteroviruses, echovirus and coxsackieviruses, have been linked with acute nephritis and acute renal failure associated with rhabdomyolysis. coxsackie b virus can be isolated in urine. direct infection of kidney cells is supported by in vitro work demonstrating lytic infection of human podocyte and proximal tubular epithelial cell cultures, although different strains exhibit variable degrees of nephrotropism. renal damage in vivo may have both a direct lytic mechanism and an immune-complex basis ( ) . in the newborn, enteroviruses cause fulminant disease with dic, shock, and liver failure, and acute renal failure may occur. renal involvement from measles virus is uncommon, although measles virus can be cultured from the kidney in fatal cases. an acute gn has been reported to follow measles with evidence of immune deposits containing measles virus antigen within the glomeruli. the nephritis is generally self-limiting ( ) . mild renal involvement is common during the acute phase of mumps infection. one-third of children with mumps have abnormal urinalysis results, with microscopic hematuria or proteinuria. mumps virus may be isolated from urine during the first days of the illness, at a time when urinalysis findings are abnormal. plasma creatinine concentrations usually remain normal, despite the abnormal urine sediment, but more severe cases in adults have been associated with evidence of acute nephritis with impaired renal function. renal biopsy specimens demonstrate an mpgn with deposition of iga, igm, c , and mumps virus antigen in the glomeruli, which suggests an immune-complex-mediated process ( ) . despite the increasing availability of interventions to limit vertical hiv transmission, an estimated , children renal involvement in hiv infection was first described in in adults ( ) ( ) ( ) and in children ( ) , and renal involvement occurs in - % of hiv-infected children in the united states ( ) ( ) ( ) . since the development of highly active antiretroviral therapy (haart), however, the incidence of end-stage renal disease in hiv infection in both adults and children in industrialized countries has declined, but it is predicted that the dramatic decline in aids-related deaths will lead to an ageing population of hiv-infected individuals who will be at risk of non-hiv related renal problems, such that the numbers of hiv-positive esrd patients will increase in the united states ( ) . hiv infection is associated with a number of renal pathologies. hiv-associated nephropathy (hivan) is a syndrome of glomerular and tubular dysfunction, which can progress to end-stage renal failure. it is discussed more fully below. glomerular syndromes other than hivan include mgn that resembles lupus nephritis and immune-complex gn, with iga nephropathy and hcv-associated mpgn being the most common forms. there have also been several case reports of amyloid kidney ( , , ) . the kidneys may be affected by various other mechanisms. opportunistic infections with organisms such as bk virus (bkv) that give rise to nephropathy and hemorrhagic cystitis have been reported in association with hiv infection ( ) . systemic infections accompanied by hypotension can cause prerenal failure leading to acute tubular necrosis. acute tubular necrosis has also been reported in hiv patients after the use of nephrotoxic drugs such as pentamidine, foscarnet, cidofovir, amphotericin b, and aminoglycosides. intratubular obstruction with crystal precipitation can occur with the use of sulfonamides and intravenous acyclovir. indinavir is well recognized to cause nephropathy and renal calculi ( ) . mpgn associated with mixed cryoglobulinemia and thrombotic microangiopathy/atypical-cal hus in association with hiv infections have been reported ( , ) . hivan is characterized by both glomerular and tubular dysfunction, the pathogenesis of which is not entirely known. hivan is a clinico-pathologic entity that includes proteinuria, azotemia, focal segmental glomerulosclerosis or mesangial hyperplasia, and tubulointerstitial disease ( ) . in adults in the united states, there is a markedly increased risk of nephropathy among african american persons with hiv infection. this appears to be true in children as well, but the data are sparse. the spectrum of hivan seems to be coincident with the degree of aids symptomatology. it is thought that hivan can present at any point in hiv infection, but most patients with hivan have cd counts of less than  / cells/ml, which suggests that it may be primarily a manifestation of late-stage disease ( ) . although a spectrum of clinicopathologic entities including mesangial hyperplasia, focal segmental glomerulosclerosis, minimal change disease, and systemic lupus erythematosus nephritis has been described, the classic pathologic feature of hivan is the collapsing form of focal and segmental glomerulosclerosis ( ) . in the affected glomeruli, visceral epithelial cells are hypertrophied and hyperplastic, and contain large cytoplasmic vacuoles and numerous protein resorption droplets. there is microcystic distortion of tubule segments, which contributes to increasing kidney size. podocyte hyperplasia can become so marked that it causes obliteration of much of the urinary space, forming ''pseudocrescents'' ( ) . capillary walls are wrinkled and collapsed with obliteration of the capillary lumina. the interstitium is edematous with a variable degree of t-cell infiltration ( ) . the bowman capsule can also be dilated and filled with a precipitate of plasma protein that represents the glomerular ultrafiltrate. one of the most distinctive features of hivan, however, is the presence of numerous tubuloreticular inclusions within the cytoplasm of glomerular and peritubular capillary endothelial cells ( ) . immunofluorescence testing is positive for igm and c in capillary walls in a coarsely granular to amorphous pattern in a segmental distribution ( , ) . the presence of the hiv genome in glomerular and tubular epithelium has been demonstrated using complementary dna probes and in situ hybridization. proviral dna has been detected by pcr in the glomeruli, tubules, and interstitium of micro dissected kidneys from patients who had pathologic evidence of hivan, but it has also been detected in the kidneys of hiv-positive patients with other glomerulopathies ( ) . a combination of both proliferation and apoptosis of renal cells may cause the loss of nephron architecture. apoptosis has been demonstrated in cells in the glomerulus, tubules, and interstitium of biopsy specimens from hiv-positive patients with focal segmental glomerulosclerosis. in addition, the role of various cytokines and growth factors, specifically transforming growth factor beta (tgf-beta), in the development of sclerosis has been studied ( , ) . transgenic murine models provide some of the strongest evidence for a direct role of hiv- in the induction of hivan. these mice do not produce infectious virus but express the hiv envelope and regulatory genes at levels sufficient to re-create the hivan that is seen in humans ( ) . serial deletion experiments have concluded that the nef and vpr genes are necessary though not sufficient for hivan pathogenesis. additional factors such as genetic predisposition are thought to explain the fact that african americans have a far greater likelihood of developing hivan than other racial groups, and that hivan is more likely in patients with a family history of esrd. hivan can manifest as mild proteinuria, nephrotic syndrome, renal tubular acidosis, hematuria, and/or acute renal failure ( ) ( ) ( ) ( ) . nephrotic syndrome and chronic renal insufficiency are late manifestations of hivan. children with hivan are likely to develop transient electrolytic disorders, heavy proteinuria, and acute renal failure due to systemic infectious episodes or nephrotoxic drugs. early stages of hivan can be identified by the presence of proteinuria and ''urine microcysts'' along with renal sonograms showing enlarged echogenic kidneys. urinary renal tubular epithelial cells are frequently grouped together to form these microcysts, which were found in the urine of children with hivan who had renal tubular injury ( ) . advanced stages of hivan typically present with nephrotic syndrome with edema, heavy proteinuria, hypoalbuminemia, and few red or white blood cells in urinary sediments. hypertension may be present, but usually blood pressure is within or below the normal range. hivan in adults follows a rapidly progressive course, with end-stage renal disease developing within - months, but in children this rapid progression does not necessarily occur. definitive diagnosis of hivan should be based on biopsy results, and biopsy should be performed if significant proteinuria is present, because in approximately % of hiv-infected patients with azotemia and/or proteinuria (> g/ h) who undergo renal biopsy, the specimen will have histologic features consistent with other renal diseases ( ) . when available, haart should be given to children with symptomatic hiv disease. specific treatment of hivan remains controversial. several studies have looked at the role of haart, angiotensin i-converting enzyme (ace) inhibitors, steroids, and even cyclosporin with somewhat encouraging results. however, as yet no randomized case-controlled trials have been undertaken. most of the studies have been small and retrospective, and many have included patients both with and without renal biopsy-proven hivan. cyclosporin has been used to treat hivan in children with remission of nephrotic infectious diseases and the kidney syndrome ( ) . similar responses have been reported to treatment with corticosteroids in various studies ( ) ( ) ( ) ( ) . ace inhibitors have been used with encouraging results ( ) . the general regimen used to treat patients with hiv, including haart, should be applied to children with hivan. the dosages of some medications must be adjusted to the patients glomerular filtration. there are reports of spontaneous regression of hivan with supportive management and treatment with haart, particularly with regimes containing protease inhibitors ( ) ( ) ( ) ( ) . it should be emphasized that the improvement reported with other modalities of treatment such as corticosteroids, cyclosporin, and ace inhibitors always occurs when these agents are given in conjunction with antiretroviral therapy. the kidneys of transgenic mice have been found to have elevated levels of tgf-beta messenger rna and protein ( ) . furthermore, gene expression analysis on tubular epithelial cells from a patient with hivan found upregulation of several inflammatory mediator genes downstream of interleukin and of the transcription factor nfkb ( ) . several other therapeutic options have been suggested, aimed specifically at the presumed role of tgfbeta in the pathogenesis of hivan. treatment directed at its synthesis using gene therapy to block tgf-beta gene expression is being explored. therapy directed at decreasing the activity of tgf-beta using anti-tgf-beta antibodies or other inhibitory substances is also an area of investigation. in addition, blocking renal receptors for chemokines such as rantes (regulated upon derivation, normal t cell expressed and secreted), interleukin- , and monocyte-chemoattractant protein- has been proposed as another possible treatment alternative ( ) . in the haart era, the outlook for hiv patients with esrd has improved, but these patients fare worse than esrd patients without hiv ( ) . most reports of hivinfected patients on hemodialysis have shown poor prognosis, with mean patient survival times ranging from - months. mortality is therefore still close to % within the first year of dialysis. in general, improved survival is associated with younger age at initiation of hemodialysis and with higher cd counts. access complications such as infection and thrombosis tend to occur at a higher rate in hiv-infected hemodialysis patients. cross infection with hiv in dialysis patients is very rare. no patient-topatient hiv transmission has yet been reported in a hemodialysis unit in the united states, although several such cases have occurred in south america ( , ) . peritoneal dialysis is an alternative for hiv-infected patients. the incidence of peritonitis varies across studies, but some studies did report a higher incidence of pseudomonas and fungal peritonitis in the hiv-positive population ( ) . infections with unusual organisms such as pasteurella multocida, trichosporon beigelii, and mycobacterium avium intracellulare complex have also been reported. several studies, however, have suggested that there is no significant difference between the hiv-infected and non-hiv-infected populations. of note is that virus capable of replication in vitro has been recovered from the peritoneal dialysis effluent, and it can be recoverable for up to days in dialysis bags at room temperature and for up to h in dry exchange tubing ( ) . previously, long-term dialysis had been thought to be preferable to renal transplantation, primarily because of the concern that the immunosuppressive therapy required after transplantation could promote progression of hiv/ aids. a multicenter prospective study has been addressing these questions ( ) . data so far indicate that the outcome for liver and kidney transplantation is not considerably different from patients without hiv, with good graft persistence, and a low rate of development of opportunistic infections in those with well-controlled hiv and relatively high cd counts ( ) . the human polyoma viruses are members of the papovavirus family and have received increasing attention as pathogens in immunocompromised patients. they are nonenveloped viruses ranging in size from - nm, with a circular, double-stranded dna genome that replicates in the host nucleus. the best-known species in this genus are the bkv, the jc virus (jcv), and the simian virus sv . bkv was first isolated from the urine of a -year-old man who developed ureteral stenosis months after renal transplantation ( ) . the name of the virus refers to the first patients initials, which is also true of jcv. bkv establishes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including nephropathy and hemorrhagic cystitis. bkv-associated nephropathy has become an increasingly recognized cause of renal dysfunction in renal transplantation patients ( ) ( ) ( ) ( ) ( ) . jcv establishes latency mainly in the kidney, and its reactivation can result in the development of progressive multifocal leukoencephalopathy. there are a few reports of nephropathy in association with jcv infection (see references in ( ) ), but bkv poses a much bigger problem in this regard. recent studies have reported sv in the allografts of children who received renal transplants and in the urine, blood, and kidneys of adults with focal segmental glomerulosclerosis, which is a cause of end-stage renal disease and an indication for kidney transplantation ( ) . seroprevalence rates as high as - % have been reported among adults in the united states and europe. the peak incidence of primary infection (as measured by acquisition of antibody) occurs in children - years of age. bkv antibody may be detected in as many as % of children by years of age, and in - % of children by or years of age; antibodies wane thereafter. bkv infection may be particularly important in the pediatric transplantation population, in whom primary infection has a high probability of occurring while the children are immunosuppressed ( ) . primary infection with bkv in healthy children is rarely associated with clinical manifestations. mild pyrexia, malaise, vomiting, respiratory illness, pericarditis, and transient hepatic dysfunction have been reported with primary infection. investigators hypothesize that after an initial round of viral replication at the site of entry, viremia follows with dissemination of the virus to distant sites at which latent infection is established. the most frequently recognized secondary sites of latent infection are renal and uroepithelial cells. secondary infection has been reported to cause tubulointerstitial nephritis and ureteral stenosis in renal transplantation patients. it may be that renal impairment in immunocompromised patients and in non renal solid organ transplant recipients is found to be frequently associated with bkv infection. the reported prevalence of bkv nephropathy in renal allografts is between and % ( , , , , ) . asymptomatic infection is characterized by viral shedding without any apparent clinical features. viruria, resulting from either primary or secondary infection, can persist from several weeks to years. tubulointerstitial nephritis associated with bkv in renal transplant recipients is accompanied by histopathologic changes, with or without functional impairment. ''infection'' and ''disease'' must be differentiated carefully. bkv infection (either primary or reactivated) can progress to bkv disease, but will not always do so ( ) . furthermore, not all cases of bkv disease lead to renal impairment. however, infection can progress to transplant dysfunction and graft loss, although the diagnosis may be complicated by the coexistence of active allograft rejection. bkv nephritis is reported to have a bimodal distribution, with % of bkv-related interstitial nephritis cases occurring - weeks after transplantation and the remainder of patients developing disease months to years after transplantation ( ) . allograft failure is due mainly to extensive viral replication in tubular epithelial cells leading to frank tubular necrosis ( ) . although damage is potentially fully reversible early in the disease, persisting viral damage leads to irreversible interstitial fibrosis. tubular atrophy and allograft loss has been observed in % of affected patients ( , ) . in most cases, bkv nephropathy in adult renal transplant recipients represents a secondary infection associated with rejection and its treatment. in children, however, primary bkv infection giving rise to allograft dysfunction may occur ( ) . the definitive diagnosis of bkv nephropathy requires renal biopsy. histopathologic features include severe tubular injury with cellular enlargement, marked nuclear atypia, epithelial necrosis, denudation of tubular basement membranes, focal intratubular neutrophilic infiltration, and mononuclear interstitial infiltration, with or without concurrent tubulins. this constellation of histologic features, particularly severe tubulitis, is often misinterpreted as rejection, even by the experienced pathologist. the presence of well-demarcated basophilic or amphophilic intranuclear viral inclusions, primarily within the tubular and parietal epithelium of the bowman capsule, can help distinguish bkv disease from rejection ( , , ) . additional tests such as immunohistochemistry, pcr analysis, or electron microscopy of biopsied tissue aimed at the identification of bkv may be required. a practical diagnostic approach for identifying bkv in renal transplant patients is summarized in > table - . bkv infection may cause ureteral obstruction due to ureteral ulceration and stenosis at the ureteric anastomosis. bkv-associated ureteral stenosis has been reported in % of renal transplant patients and usually occurs between and days after transplantation. ulceration due to inflammation, proliferation of the transitional epithelial cells, and smooth muscle proliferation may lead to partial or total obstruction. high-level bkv replication is implicated in acute, late-onset, long-duration hemorrhagic cystitis after bone marrow transplantation ( ) . there are two case reports in children of renal carcinomas arising in the transplanted kidney in association with bk virus nephropathy. it remains unclear whether infectious diseases and the kidney bk virus itself has oncogenic potential in the transplant setting, but this is possible given that the big t antigen (t-ag) expressed by polyomavirus family viruses has been shown to have the ability to disrupt chromosomal integrity ( , ) . whether patients with asymptomatic viremia or viruria need specific therapeutic intervention is not certain. review of the literature suggests that careful reduction of immune suppression, combined with active surveillance for rejection, will result in clinical improvement. reduction in immunosuppression may precipitate episodes of acute cellular rejection, which need to be judiciously treated with corticosteroids. the outcome of bkv nephropathy is unpredictable, and stabilization of renal function may occur regardless of whether maintenance immunotherapy is altered or not ( ) . some reports favor the use of cidofovir. cidofovir has important nephrotoxic side effects in the usual therapeutic dosage recommended for the treatment of cmv infection, and for bkv nephropathy a reduced dosage regime is generally used. the efficacy of cidofovir in reducing viremia has been demonstrated (see review in ( )). however, spontaneous clearance of viral infection after reduction of immunosuppression (without cidofovir) has also been reported. there are also case studies of the use of leflunamide. presence of bkv by pcr or decoy cells in urine signifies bkv replication. decoy cells are caused by infection of the urinary epithelial cells with human polyoma viruses. the nuclei are enlarged and nuclear chromatin is completely homogenized by viral cytopathic effect. positive pcr results for bkv viruria and presence of decoy cells have poor predictive value. specificity is increased if > cells/ cytospin along with presence of inflammatory cells. presence of antibody is usually indicative of previous infection; however, positive results for bkv dna pcr on serum signifies bk viremia. bkv pcr testing of plasma has proven to be a sensitive ( %) and specific ( %) means to identify bkv-associated nephropathy in adults. viral load has also been used to monitor infection and clearance. however, because primary infection occurs in childhood, it might not be applicable to the pediatric population. the definitive diagnosis of bkv nephropathy requires renal biopsy. histopathology might mimic rejection or drug toxicity. however, characteristic findings have been described. electron microscopy and immune staining are helpful in confirming the diagnosis. pcr assays of viral load in tubular cells have been reported to be a sensitive marker for diagnosis and monitoring. viral hemorrhagic fever involves at least distinct rna viruses that share the propensity to cause severe disease with prominent hemorrhagic manifestations ( > table - ) . the viral hemorrhagic fevers, widely distributed throughout both temperate and tropical regions of the world, are important causes of mortality and morbidity in many countries. most viral hemorrhagic fevers are zoonoses (with the possible exception of dengue virus), in which the virus is endemic in animals and human infection is acquired through the bite of an insect vector. aerosol and nosocomial transmissions from infected patients are important for lassa, junin, machupo, and congo-crimean hemorrhagic fevers, and marburg and ebola viruses ( ) . viral hemorrhagic fevers have many clinical similarities but also important differences in their severity, major organs affected, prognosis, and response to treatment. in all viral hemorrhagic fevers, severe cases occur in only a minority of those affected; subclinical infection or nonspecific febrile illness occurs in the majority. fever, myalgia, headache, conjunctival suffusion, and erythematous rash occur in all the viral hemorrhagic fevers ( ) . hemorrhagic manifestations range from petechiae and bleeding from venepuncture sites to severe hemorrhage into the gi tract, kidney, and other organs. a capillary leak syndrome, with evidence of hemoconcentration, pulmonary edema, oliguria, and ultimately shock, occurs in the most severely affected patients ( ) . renal involvement occurs in all the viral hemorrhagic fevers, proteinuria is common, and prerenal failure is seen in all severe cases complicated by shock. however, in congo-crimean hemorrhagic fever and hemorrhagic fever with renal syndrome (hfrs), an interstitial nephritis, which may be hemorrhagic, is characteristic, and renal impairment is a major component of the illness. dengue is caused by a flavivirus that is endemic and epidemic in tropical america, africa, and asia, where the mosquito vector aedes aegypti is present ( ). classic dengue is a self-limited nonfatal disease; dengue hemorrhagic fever and dengue shock syndrome, which occur in a minority of patients, have a high mortality if not aggressively treated with fluids. after an incubation period of - days, the illness begins with fever, headache, arthralgia, weakness, vomiting, and hyperesthesia. in uncomplicated dengue the fever usually lasts - days. shortly after onset a maculopapular rash appears, sparing the palms and the soles, and is occasionally followed by desquamation. fever may reappear at the onset of the rash. in dengue hemorrhagic fever and dengue shock syndrome, the typical febrile illness is complicated by hemorrhagic manifestations, ranging from a positive tourniquet test result or petechiae to purpura, epistaxis, and gi bleeding with thrombocytopenia and evidence of a consumptive coagulopathy. increased capillary permeability is suggested by hemoconcentration, edema, and pleural effusions ( ) . in severe cases, hypotension and shock supervene, largely as a result of hypovolemia. renal manifestations include oliguria, proteinuria, hematuria, and rising urea and creatinine. acute renal failure occurs in patients with severe shock, primarily as a result of renal underperfusion. however, glomerular inflammatory changes may also occur. children with dengue hemorrhagic fever show hypertrophy of endothelial and mesangial cells, mononuclear cell infiltrate, thinning of basement membranes, and deposition of igg, igm, and c . electron microscopy shows viral particles within glomerular mononuclear cells ( ) . the diagnosis of dengue is made by isolation of the virus from blood or by serologic testing. there is no specific antiviral treatment, and management of patients with dengue shock syndrome or dengue hemorrhagic fever depends on aggressive circulatory support and volume replacement with colloid and crystalloid ( , ) . with correction of hypovolemia, renal impairment is usually reversible, but dialysis may be required in patients with established acute renal failure. yellow fever is caused by a flavivirus, and is transmitted by mosquito bites, typically aedes species. it remains an important public health problem in africa and south america. renal manifestations are common and include albuminuria and oliguria. over the next few days after first manifestation of infection, shock, delirium, coma, and renal failure develop, and death occurs - days after onset of symptoms. laboratory findings include thrombocytopenia and evidence of hemoconcentration, rising urea and creatinine levels, hyponatremia, and deranged liver function test results. pathologic findings include necrosis of liver lobules, cloudy swelling and fatty degeneration of the proximal renal tubules, and, often, petechiae in other organs. the oliguria appears to be prerenal and is due to hypovolemia; later, acute tubular necrosis supervenes. at present, there is no effective antiviral agent for yellow fever. . congo-crimean hemorrhagic fever, first recognized in the soviet union, is now an important human disease in eastern europe, asia, and africa ( ) . severely affected patients become stuporous or comatose - days into the illness, with evidence of hepatic and renal failure and shock. proteinuria and hematuria are often present. the disease is fatal in - % of cases. the virus is sensitive to ribavirin, but in one small trial of i.v. ribavirin versus supportive treatment only, there was no significant improvement in outcome in the treatment group ( ) . rift valley fever is found in many areas of sub-saharan africa. in humans, most infections follow mosquito bites or animal exposure. the infection may present as an uncomplicated febrile illness, with muscle aches and . ( ) . clinical entities include korean hemorrhagic fever, nephropathia epidemica in scandinavia, and epidemic hemorrhagic fever in japan and china. in general, hfrs due to hantaan, porogia, and belgrade viruses is more severe and has higher mortality than that due to puumala virus (nephropathia epidemica) or seoul virus. hantaan is predominant in the far east, porogia and belgrade in the balkans, and puumala in western europe; seoul has a worldwide distribution ( ) . the clinical features of the disease vary. the incubation period is - days. although hfrs occurs with the same clinical picture in children as in adults, both incidence rates and antibody prevalence rates are very low in children under years of age. men of working age make up the bulk of clinical cases ( ) . mild cases are indistinguishable from other febrile illnesses. in more severe cases, fever, headache, myalgia, abdominal pain, and dizziness are associated with the development of periorbital edema, proteinuria, and hematuria. there is often conjunctival injection, pharyngeal injection, petechiae, and epistaxis or gi bleeding. the most severely affected patients develop shock and renal failure. the disease usually passes through five phases: febrile, hypotensive, oliguric, diuretic, and convalescent. laboratory findings include anemia, lymphocytosis, thrombocytopenia, prolonged prothrombin and bleeding times, and elevated levels of fibrin degradation products. liver enzyme levels are elevated, and urea and creatinine levels are elevated during the oliguric phase. proteinuria and hematuria are consistent findings. the renal histopathologic findings are those of an interstitial nephritis with prominent hemorrhages in the renal medullary interstitium and renal cortex. acute tubular necrosis may also be seen. immunohistochemical analysis reveals deposition of igg and c , and the gbm, mesangial, and subendothelial deposits may be seen on electron microscopy ( ) . recovery from hantavirus-associated disease is generally complete, although chronic renal insufficiency is a rare sequela of hfrs. in mildly affected patients, the disease is self-limiting and spontaneous recovery occurs. however, in severe cases, with shock, bleeding, and renal failure, dialysis and intensive circulatory support may be required ( ) . mortality rates vary depending on the strain of virus; rates are - % for hemorrhagic fever and renal syndrome in china and significantly lower for the milder finnish form associated with the puumala virus strain. ribavirin is active against hantaan viruses in vitro, and clinical trials indicate that both mortality and morbidity can be reduced by treatment with this antiviral agent if it is administered early in the course of illness. dosages of mg/kg followed by mg/kg every h for days and then mg/kg every h for days have been used ( ) . lassa fever is a common infection in west africa, caused by an arenavirus, and usually manifests as a nonspecific febrile illness. in % of cases, a fulminant hemorrhagic disease occurs. in severe cases, proteinuria and hematuria are usually present, and renal failure may occur. ribavirin is effective in decreasing mortality. as in other hemorrhagic fevers, intensive hemodynamic support and correction of the hemostatic derangements are important components of therapy ( ) . junin and machupo viruses, the agents of argentine and bolivian hemorrhagic fever, respectively, cause hemorrhagic fevers with prominent neurologic features and systemic and hemorrhagic features similar to those of lassa fever. oliguria, shock, and renal failure occur in the most severe cases. marburg and ebola viruses have been associated with outbreaks of nosocomially transmitted hemorrhagic fever. both viruses cause fulminant hemorrhagic fever. onset is with high fever, headache, sore throat, myalgia, and profound prostration. an erythematous rash on the trunk is followed by hemorrhagic conjunctivitis, bleeding, impaired renal function, shock, and respiratory failure. the mortality rate is high. renal histopathologic findings in fatal cases are of tubular necrosis, with fibrin deposition in the glomeruli. there is no specific treatment for these disorders. the important role played by a number of other recently characterized viruses is only now being recognized, as improved molecular diagnostic techniques allow identification of hitherto unrecognized viruses. two examples of recently described viruses are metapneumovirus ( ) and bocavirus ( ) . while both have significant prevalence, and may make an important contribution to the burden of childhood viral infection, as yet there are no reports indicative of significant renal pathology in association with these infections. influenza virus has been linked with nephritis and acute renal failure. an emerging infectious disease is avian flu, caused by highly pathogenic h n strains which have hitherto been confined to an avian reservoir, and there have been several outbreaks of infection in humans, particularly in the first part of this decade. commonly, these patients develop a flu-like illness with prominent respiratory and gastrointestinal symptoms. renal failure may develop alongside multi-organ failure in the context of acute respiratory distress syndrome ( ) . as yet, there is no clear correlation of degree of initial renal insufficiency, and outcome ( ) . there is little data available on treatment, but based on the known resistance patterns of h n strains, oseltamivir and zanamivir are the preferred agents to be used for treatment of infection with h n . severe acute respiratory syndrome (sars) is a newlyemerged infectious disease which was first seen in south china in . it is caused by a sars coronavirus (sars cov). predominantly, it causes a viral pneumonia, with diffuse alveolar damage; it has considerable mortality ( ) . renal effects are not generally significant in the pathophysiology of sars. however, sars cov has been found in kidney tissue at post-mortem ( ) ( ) . sars cov enters cells via angiotensin converting enzyme (ace ) ( ) , and it is thought that the invasion of kidney tissue reflects the virus' tropism for ace , which is expressed on kidney cells. chronic exposure to infectious agents is a major factor in the increased prevalence of glomerular diseases in developing countries. malaria is the best-documented parasitic infection associated with glomerular disease, but other parasitic infections including schistosomiasis, filariasis, leishmaniasis, and possibly helminth infections may also induce nephritis or nephrosis. malaria is estimated to cause up to million clinical cases of illness and more than million deaths each year ( ) . the association of quartan malaria and nephritis has been well known in both temperate and tropical zones since the end of the nineteenth century. epidemiologic studies provide the most conclusive evidence for a role of plasmodium malariae in glomerular disease ( , ) . chronic renal disease was a major cause of morbidity and mortality in british guiana in the s. the frequent occurrence of p. malariae in the blood of these patients led to detailed epidemiologic studies that implicated malaria as a cause of the nephrosis. after the eradication of malaria from british guiana, chronic renal disease ceased to be a major cause of death in that country ( ) . the link between malaria and nephrotic syndrome was strengthened by studies in west africa in the s and s that demonstrated a high prevalence of nephrotic syndrome in the nigerian population ( ) . the pattern of nephrotic syndrome differed from that in temperate climates, with an older peak age, extremely poor prognosis, and unusual histologic features. the incidence of p. malariae parasitemia in patients with the nephrotic syndrome in nigeria was vastly in excess of that occurring in the general population, whereas the incidence of plasmodium falciparum parasitemia was similar to that in the general population. the age distribution of nephrotic syndrome also closely paralleled that of p. malariae infection ( ) . in some affected patients, circulating immune complexes and immunoglobulin, complement, and antigens were present in the glomeruli that were recognized by p. malariae-species antisera. there is now a view that the patterns of childhood renal disease described in the last century may no longer be representative of the current situation. the variable patterns of renal disease throughout africa may no longer reflect a dominant role for ''malarial glomerulopathy,'' and the relative causative role of tropical infections in nephropathy remains an unanswered question ( ) . most patients have poorly selective proteinuria and are unresponsive to treatment with steroids or immunosuppressive agents. the characteristic lesions of p. malariae nephropathy are capillary wall thickening and segmental glomerular sclerosis, which lead to progressive glomerular changes and secondary tubular atrophy ( ) . cellular proliferation is conspicuously absent. electron microscopy shows foot-process fusion, thickening of the basement membrane, and increase in subendothelial basement membrane-like material. immunofluorescent studies show granular deposits of immunoglobulin, complement, and p. malariae antigen in approximately one-third of patients. in addition to the histologic pattern, termed quartan malaria nephropathy, p. malariae infection is associated with a variety of other forms of histologic appearance, including proliferative gn and mgn ( ) . although quartan malaria nephropathy has been clearly linked to p. malariae infection in nigeria, a number of studies from other regions in africa have not revealed the typical histopathologic findings described in the nigerian studies ( ) . furthermore, quartan malaria nephropathy may be seen in children with no evidence of p. malariae infection or deposition of malaria antigens in the kidney. this, together with the fact that antimalarial treatment does not affect the progression of the disorder, raises the possibility that factors other than malaria might be involved in the initiation and perpetuation of the disorder. although there is undoubtedly a strong association between p. malariae infection and nephrotic syndrome on epidemiologic grounds, the direct causal link is not proven. most likely, a number of different infectious processes, including malaria, hepatitis b, schistosomiasis, and perhaps other parasitic infections that cause chronic or persistent infections and often occur concurrently in malaria areas, may all result in glomerular injury and a range of overlapping histopathologic features. the prognosis for the nephrotic syndrome in most african studies has been poor, regardless of whether the histologic findings were typical of quartan malaria nephropathy or whether p. malariae parasitemia was implicated. treatment with steroids and azathioprine is generally ineffective, and a significant proportion of patients progress to renal failure. p. falciparum appears to be much less likely to cause significant glomerular pathology. epidemiologic studies have failed to show a clear association between p. falciparum parasitemia and the nephrotic syndrome. whereas renal failure appears to be a common complication of severe malaria in adults, it seldom occurs in children. renal biopsy specimens from adult patients with acute p. falciparum infections who have proteinuria or hematuria show evidence of glomerular changes, including hypercellularity, thickening of basement membranes, and hyperplasia and hypertrophy of endothelial cells ( ) . electron microscopy reveals electron-dense deposits in the subendothelial and paramesangial areas. deposits of igm, with or without igg, are localized mainly in the mesangial areas. p. falciparum antigens can be demonstrated in the mesangial areas and along the capillary wall, which suggests an immune-complex gn. the changes, generally mild and transient, are probably unrelated to the acute renal failure that may complicate severe p. falciparum infection ( ) . heavily parasitized erythrocytes play a central role in the various pathologic factors ( ) . renal failure occurring in severe p. falciparum malaria is usually associated with acidosis, volume depletion, acute intravascular hemolysis or heavy parasitic infection that leads to acute tubular necrosis. recent studies have confirmed an important role for volume depletion in children with severe falciparum malaria, who characteristically have evidence of tachycardia, tachypnoea, poor perfusion and in severe cases hypotension ( ) . volume expansion with either colloid or crystalloid results in improvement in hemodynamic indices and reduction in acidosis ( ) . there is growing evidence that volume expansion with albumin is associated with a better outcome than saline or synthetic colloids ( , ) . treatment with antimalarials, correction of hypoglycemia and infectious diseases and the kidney electrolyte imbalance, and volume expansion reduces mortality to less than %. although renal failure is usually associated with infection by p. falciparum, acute renal failure has been described with plasmodium vivax infection and mixed infections ( ) . the term blackwater fever refers to the combination of severe hemolysis, hemoglobinuria, and renal failure. it was more common at the start of the twentieth century in nonimmune individuals receiving intermittent quinine therapy for p. falciparum malaria. blackwater fever has become rare since , when quinine was replaced by chloroquine. however, the disease reappeared in the s, after the reuse of quinine because of the development of chloroquine-resistant organisms. since then, several cases have been described after therapy with halofantrine and mefloquine, two new molecules similar to quinine (amino-alcohol family) ( ) . renal failure generally occurred in the context of severe hemolytic anemia, hemoglobinuria, and jaundice. the pathophysiology of the disorder is unclear; however, it appears that a double sensitization of the red blood cells to the p. falciparum and to the amino-alcohols is necessary to provoke the hemolysis. histopathologic findings include swelling and vacuolization of proximal tubules, necrosis and degeneration of more distal tubules, and hemoglobin deposition in the renal tubules. recent studies indicates a better outcome with earlier initiation of intensive care and dialysis combined with necessary changes in antimalarial medications. schistosomiasis affects million people living in endemic areas of asia, africa, and south america ( ) . the infection is usually acquired in childhood, but repeated infections occur throughout life. schistosoma japonicum is found only in the orient, whereas schistosoma haematobium occurs throughout africa, the middle east, and areas of southwest asia. schistosoma mansoni is widespread in africa, south america, and southwest asia. human infection begins when the cercarial forms invade through the skin, develop into schistosomula, and move to the lungs via the lymphatics or blood. they then migrate to the liver and mature in the intrahepatic portal venules, where male:female pairing takes place. the adult worm pairs then migrate to their final resting site -the venules of the mesenteric venous system of the large intestine (s. mansoni) or in the venules of the urinary tract (s. haematobium). the females release large numbers of eggs, which may remain embedded in the tissues, embolize to the liver or lungs, or pass into the feces or urine. clinical manifestations may occur at any stage of the infection. cercarial invasion may cause an intense itchy papular rash. katayama fever is an acute serum sicknesslike illness that occurs several weeks after infection, as eggs are being deposited in the tissues. deposition of the eggs in tissues results in inflammation of the intestines, fibrosis of the liver, and portal hypertension. with s. haematobium, chronic inflammation and fibrosis of the ureters and bladder may lead to obstructive uropathy ( ) . renal manifestations of schistosomiasis occur most commonly in s. mansoni infection. schistosomal nephropathy usually presents with symptoms including granulomatous inflammation in the ureters and bladder, but glomerular disease (probably on an immune-complex basis) may also occur. renal disease usually occurs in older children or young adults with long-term infection, but serious disease may also occur in young children ( ) . the early renal tract manifestations of schistosomiasis are suprapubic discomfort, frequency, dysuria, and terminal hematuria. in more severe cases, evidence of urinary obstruction appears. poor urinary stream, straining on micturition, a feeling of incomplete bladder emptying, and a constant urge to urinate may be severely disabling symptoms. the fibrosis and inflammation of ureters, urethra, and bladder may be followed by calcification and may result in hydroureter, hydronephrosis, and bladder neck obstruction. renal failure may ultimately develop, and there is a suspicion that squamous cell carcinoma of the bladder may be linked to the chronic infective and inflammatory process. secondary bacterial infection is common within the obstructed and inflamed urinary tract ( ) . the hepatosplenic form of s. mansoni infection may be accompanied by a glomerulopathy in - % of cases, manifested in the majority as nephrotic syndrome ( ) . histopathologic findings include mesangioproliferative gn, focal segmental glomerulosclerosis, mesangiocapillary gn, mgn, and focal segmental hyalinosis ( ) . immune complexes may be detected in the circulation of these patients, and glomerular granular deposition of igm, c , and schistosomal antigens are seen on immunofluorescence. usually schistosoma-specific nephropathy is a progressive disease and is not influenced by antiparasitic or immunosuppressive therapy ( ) , but isolated case reports of remission after treatment with praziquantel have been reported ( ) . the diagnosis is confirmed by the detection of schistosoma eggs in feces, urine, or biopsy specimens. eggs are shed into the urine with a diurnal rhythm, and urine collected between am and pm is the most useful. urinary sediment obtained by centrifugation or filtration through a nuclepore membrane should be examined. in cases in which studies of urine and feces yield negative results in patients in whom the diagnosis is suspected, rectal biopsy specimens taken approximately cm from the anus have a high diagnostic yield for both s. mansoni and s. haematobium infection. biopsy of liver or bladder may be required to establish the diagnosis. antibodies indicating previous infection can be detected using enzyme-linked immunosorbent assay or radioimmunoassay. the tests are sensitive but lack specificity and may not differentiate between past exposure and current infection. praziquantel is the drug of choice for treatment of schistosomiasis. a single oral dose of mg/kg is effective in s.haematobium and s. mansoni infection and is usually well tolerated. the alternative drug for s. mansoni infection is oxamniquine. complete remission of urinary symptoms may occur in renal disease of short duration, but in late disease with extensive fibrosis, scarring, and calcification, obstructive uropathy and renal failure may persist after the infection has been eradicated. there are reports of a drastic decrease in the number of severe hepatosplenic forms of s. mansoni infection after mass treatment of the population in endemic areas with oxamniquine. this also reduced schistosomal nephropathy ( ) . visceral leishmaniasis is a chronic protozoon infection characterized by fever, hepatosplenomegaly, anemia, leukopenia, and hyperglobulinemia. proteinuria and/or microscopic hematuria or pyuria have been reported in % of patients with visceral leishmaniasis ( ) . acute renal failure in association with interstitial nephritis has also been reported ( ) . renal histologic analysis in patients with visceral leishmaniasis reveals glomerular changes, with features of a mesangial proliferative gn or a focal proliferative gn, or a generalized interstitial nephritis with interstitial edema, mononuclear cell infiltration, and focal tubular degeneration. immunofluorescence reveals deposition of igg, igm, and c within the glomeruli, as well as electron-dense deposits in the basement membrane and mesangium on electron microscopy ( ) . circulating immune complexes together with immunoglobulin and complement deposition in the glomeruli suggests an immune-complex cause. renal disease in leishmaniasis is usually mild and may resolve after treatment of the infection. renal dysfunction may be associated with treatment for visceral leishmaniasis with antimony compounds. proteinuria is more common in filarial hyperendemic regions of west africa than in nonfilarial areas. renal histologic analysis has shown a variety of different histopathologic appearances; the most common is diffuse mesangial proliferative gn with c deposition in the glomeruli ( ) . renal biopsy specimens also demonstrate large numbers of eosinophils in the glomeruli, and microfilariae may be seen in the lumen of glomerular capillaries. filarial antigens have been detected within immune deposits within the glomeruli. echinococcus granulosus causes chronic cysts within a variety of organs. in addition, nephrotic syndrome in association with hydatid disease has been reported. membranous nephropathy, minimal change lesions, and mesangiocapillary gn have been described in association with hydatid disease ( , ) . immunofluorescence reveals deposits of immunoglobulin, complement, and hydatid antigens within the glomeruli. remission of nephrotic syndrome has been reported with treatment by antiparasitic agents such as albendazole ( , ) . few reports have been published of renal disease occurring in patients with trypanosomiasis. the trypanosomal antigens can induce gn in a variety of experimental animals ( ) . nephrotic syndrome has occasionally been reported as a manifestation of congenital toxoplasmosis. dissemination of previously latent toxoplasma infection in patients undergoing treatment with immunosuppressive drugs has been increasingly recognized in recent years. reactivation of toxoplasmosis or progression of recently acquired primary infection should be considered in patients undergoing renal transplantation or immunotherapy for renal disease who develop unexplained inflammation of any organ. fungal infections of the kidneys and urinary tract occur most commonly as part of systemic fungal infections in patients with underlying immunodeficiency, as focal urinary tract infections in patients with obstructive lesions, or as a result of indwelling catheters. although candida infection is the most common fungal infection in both immunocompromised and non immunocompromised hosts, virtually all other fungal pathogens may invade the renal tract during severe immunocompromise. urinary infection with candida albicans is most commonly a component of systemic candidiasis in patients who are severely immunocompromised. systemic candidiasis is also seen in premature and term infants with perinatally acquired invasive candidiasis. presentation is usually with systemic sepsis, fever or hypothermia, hepatosplenomegaly, erythematous rash, and thrombocytopenia. systemic candidiasis may be seen on ophthalmologic investigation as microemboli in the retina. the first clue to the underlying diagnosis may be the presence of yeasts in the urine ( ) . candida involvement of the urinary tract may affect all structures including the glomeruli, tubules, collecting system, ureters, and bladder. microabscesses may form within the renal parenchyma, and large balls of fungi may completely obstruct the urinary tract at any level. acute renal failure caused by systemic candidiasis or obstruction of the renal tracts with fungal hyphae is a wellrecognized complication of systemic candidal infection ( , ) . indwelling catheters (which form a nidus for persistent infection) should be removed. successful treatment of non-obstructing bilateral renal fungal balls by fluconazole either alone or in combination with liposomal amphotericin b has been reported ( , ) . in the presence of obstruction, however, percutaneous nephrostomy to relieve the obstruction with antegrade amphotericin b irrigation, coupled with systemic antifungal therapy, is the mainstay of treatment ( ) . amphotericin b is the most effective antifungal agent, but it is not excreted in the urine. local irrigation via nephrostomy provides good results, however. for treatment of urinary tract candidiasis, it is usually combined with fluconazole or -flucytosine, both of which are excreted in high concentrations in the urine. treatment is required for weeks to months to ensure complete elimination of the fungus, and the ultimate outcome is largely dependent on whether there is a permanent defect in immunity. in , levin et al. first described hemorrhagic shock and encephalopathy, which appeared to be distinct from previously recognized pediatric disorders ( ) . other cases have subsequently been reported from several centers in the united kingdom, europe, israel, the united states, and australia, and the syndrome is now recognized as a new and relatively common severe childhood disorder ( ) . hemorrhagic shock and encephalopathy usually affects infants in the first year of life, with a peak onset at - months of age. a prodromal illness with fever, irritability, diarrhea, or upper respiratory infection occurs - days before the onset in two-thirds of cases. affected infants develop profound shock, coma, convulsions, bleeding and evidence of dic, diarrhea, and oliguria. laboratory findings include acidosis, falling hemoglobin and platelet levels, elevated urea and creatinine levels, and elevated levels of hepatic transaminases. despite vigorous intensive care, the prognosis is poor, and most affected infants die or are left severely neurologically damaged ( , ) . a small number of patients have been reported to survive without residual sequelae. the renal impairment appears to be largely prerenal in origin, and when aggressive volume replacement and treatment of the shock results in improved renal perfusion, rapid improvement in renal function is usually observed. in patients with profound shock unresponsive to initial resuscitation, vasomotor nephropathy supervenes and dialysis may be required. myoglobinuria in association with hemorrhagic shock and encephalopathy has been reported. following the description of the mucocutaneous lymph node syndrome by kawasaki in , kawasaki disease has been recognized as a common and serious childhood illness with a worldwide distribution. although the etiology remains unknown, epidemiologic features clearly suggest an infective cause. the disease occurs in epidemics, and wavelike spread has been demonstrated during outbreaks in japan. deposition of amyloid within the kidney is an important complication of chronic and persistent infection. amyloidosis is most common in patients with chronic osteomyelitis and chronic pulmonary infections such as bronchiectasis and is seen occasionally in those with persistent infections such as leprosy or malaria ( ) ( ) ( ) . paediatric emergencies, nd edn. black ja shock in the paediatric patient vasoactive hormones in the renal response to systemic sepsis renal effects of nitric oxide in endotoxemia drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase iii randomised controlled trial treatment of meningococcal disease in childhood pathophysiology and management of meningococcal septicaemia severity of meningococcal disease: assessment by factors and scores and implications for patient management case records of the massachusetts general hospital. case plasma endotoxin as a 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occurrence and significance of papovaviruses bk and jc in the urine polyoma-virus induced interstitial nephritis in two renal transplant recipients: case reports and review of the literature late-onset hemorrhagic cystitis associated with urinary excretion of polyoma-viruses after bone marrow transplantation collecting duct carcinoma arising in association with bk nephropathy posttransplantation in a pediatric patient. a case report with immunohistochemical and in situ hybridization study association of renal adenocarcinoma and bk virus nephropathy post-transplantation clinical course of polyoma virus nephropathy in renal transplant patients epidemiology of haemorrhagic fever viruses virus and hemostasis dengue and dengue haemorrhagic fever glomerular changes in dengue haemorrhagic fever intravenous fluids -getting the balance right comparison of three fluid solutions for resuscitation in dengue shock syndrome epidemiology and clinical features of crimean-congo haemorrhagic fever in 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therapy for the management of bk virus associated nephropathy in children and adults antiviral therapy and prophylaxis for influenza in children infectious diseases and the kidney key: cord- -pep opiq authors: remy, kenneth e.; verhoef, philip a.; malone, jay r.; ruppe, michael d.; kaselitz, timothy b.; lodeserto, frank; hirshberg, eliotte l.; slonim, anthony; dezfulian, cameron title: caring for critically ill adults with coronavirus disease in a picu: recommendations by dual trained intensivists* date: - - journal: pediatr crit care med doi: . /pcc. sha: doc_id: cord_uid: pep opiq in the midst of the severe acute respiratory syndrome coronavirus pandemic, which causes coronavirus disease , there is a recognized need to expand critical care services and beds beyond the traditional boundaries. there is considerable concern that widespread infection will result in a surge of critically ill patients that will overwhelm our present adult icu capacity. in this setting, one proposal to add “surge capacity” has been the use of picu beds and physicians to care for these critically ill adults. design: narrative review/perspective. setting: not applicable. patients: not applicable. interventions: none. measurements and main results: the virus’s high infectivity and prolonged asymptomatic shedding have resulted in an exponential growth in the number of cases in the united states within the past weeks with many (up to %) developing acute respiratory distress syndrome mandating critical care services. coronavirus disease critical illness appears to be primarily occurring in adults. although pediatric intensivists are well versed in the care of acute respiratory distress syndrome from viral pneumonia, the care of differing aged adult populations presents some unique challenges. in this statement, a team of adult and pediatric-trained critical care physicians provides guidance on common “adult” issues that may be encountered in the care of these patients and how they can best be managed in a picu. conclusions: this concise scientific statement includes references to the most recent and relevant guidelines and clinical trials that shape management decisions. the intention is to assist picus and intensivists in rapidly preparing for care of adult coronavirus disease patients should the need arise. t he worldwide pandemic of coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus has already resulted in critical care demands overwhelming resources in nations such as italy ( ) . this has stressed local healthcare systems requiring new approaches for triage and acute care. with significant resource limitations, especially in differing geographic locales, this pandemic may exhaust existing capacity making it difficult to maintain adequate critical care necessitating adaptations. fortunately, covid- disease has been uncommon in children with a reported mean age for most icu patients between and years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . many of these patients have comorbidities such as hypertension, type diabetes, coronary vascular disease, cerebrovascular events, and chronic obstructive pulmonary disease (copd). patients commonly present on day - of illness with acute hypoxemic respiratory failure ( , , , , ) and the frequent icu complications include shock differences between adults and pediatric advanced life support cardiopulmonary resuscitation (cpr) and life support algorithms for adults are deliberately similar to pediatric patients. identical approaches should be taken toward both ventricular fibrillation/pulseless ventricular tachycardia and asystole/ pulseless electrical activity ( ) . the advanced cardiac life support algorithm for symptomatic bradycardia does not include cpr and uses atropine iv ( . mg every - min, maximum mg) as a first-line agent followed by early consideration of epinephrine or dopamine infusions and transcutaneous pacing ( ) . tachycardia with hemodynamic instability due to regular rhythms (e.g., atrial flutter) requires synchronized cardioversion with - j while irregular rhythms (e.g., atrial fibrillation [af]) require - j. cpr on adults is similar to pediatrics: push hard (although deeper, > inches), fast ( - per min), and allow complete recoil ( ) . advanced directives and patient prognosis in determining code status should be considered at picu admission in every patient and in some cases, the team may determine to limit resuscitation. picu epidemiology favors smaller sizes/heights thus deficits in supplies tend to occur when dealing with taller (> cm) and heavier (> kg) adults. table provides a list of commonly used supplies to consider for these larger individuals. central venous catheters for vascular access or dialysis placed in the right internal jugular or subclavian often require ~ - cm length which most picus stock. we recommend adding cm catheters that are better for adult left sided upper body and femoral approaches. as the covid pandemic has driven use of telecommunications in lieu of in person meetings, it is our anticipation that most picus will have access to a full suite of adult physician consult services. in table , we outline the most likely needed consultations for acute covid- issues. we include procedures which may be performed in the acute setting by the consultant (table ) , purposely omitting those which do not offer therapeutic potential and thus may be deferred. likewise, we omit consultative services where pediatric specialists can provide support, or the entire consultation may be performed by telecommunication. for procedures, the consulting physicians and picu team will need to determine whether the services can be safely rendered within the pediatric facility or require transport to an adult hospital. many procedures are now feasible at the bedside in adult hospitals such that a similar approach would appear to be less problematic than transport of a highly infectious and critically ill covid patient across centers. - . mm-cuffed tube. morbidly obese adults are often best preoxygenated in a reverse trendelenburg position with the head of bed elevated to drop abdominal weight off the chest. with covid- , we recommend the use of video laryngoscopy for rapid sequence intubation (rsi) by the most experienced operator ( ) to maximize success and prevent aerosols. central venous catheters are placed infrequently in the femoral position due to heightened risk of deep venous thrombosis and infection ( ) . arterial catheters are used more frequently than in the picu and often employ a preloaded needle/wire introducer kit. thoracentesis and lumbar puncture (lp) in a cooperative adult may have more success with the patient sitting upright and from behind with ultrasound guidance. obese patients often require longer needle lengths than the standard . cm ( . in) for lp ( ) with various lengths up to cm available. the length needed can be estimated in cm as . × body mass index + . ( ) . table provides a list of commonly prescribed medications for adults which may not be commonly stocked in pediatric centers (at least not in large supply) as well as recommendations on whether continuation is critical and whether substitutions can be made with agents more often found in a pediatric formulary. escalation of respiratory support in adults generally includes nonrebreather mask, venturi or oxymask, high-flow nasal cannula (hfnc), or noninvasive positive pressure ventilation (nippv) ( ) ( ) ( ) ( ) ( ) . with covid- , there is concern for generating infectious aerosols in when using hfnc and nippv such that some institutions are avoiding greater than l flow ( ) , although recent society of critical care medicine/european society of intensive care medicine guidelines include both modalities ( ) . this risk is minimal with good cannula or mask fit on the patient ( , ) and with use of protective filters ( ) . negative pressure isolation rooms mitigate this concern. oxymask allows titration of oxygen flow but not titration of the fio , whereas hfnc and nippv allow fio titration and use with inhaled pulmonary vasodilators ( , ( ) ( ) ( ) . commonly used settings are listed in table . for covid- patients we recommend rsi in a negative pressure room ( , , , ) . in rsi, bag-valve-masking is minimized and patients receive an induction agent (propofol at . - . mg/ kg, or etomidate . mg/kg) "immediately" followed by a neuromuscular blocker (succinylcholine at . mg/kg, rocuronium at . mg/kg, or cisatracurium at . mg/kg) and intubation within a minute. succinylcholine and propofol use in adults is common and offers the advantage of rapid and favorable intubation conditions with less safety concerns compared with other agents ( ) . mechanically ventilated adults are mostly managed with assist-control ventilation, rather than synchronized intermittent mandatory ventilation based on studies showing improved work of breathing, synchrony, and extubation rates ( ) . volume modes, such as volume control (vc) or pressure regulated vc (vc+), permit maintenance of lower tidal volumes ( - ml/ kg) based on predicted body weight and lower plateau pressures (< cm h o) in acute respiratory distress syndrome (ards) ( , ) . in the absence of ards, ml/kg is safe ( ) . positive end-expiratory pressure (peep) is titrated based on fio using validated protocols ( , ) to levels higher ( - cm h o at fio = ) than encountered in pediatrics ( ) . our experience and that of many centers is that covid- hypoxemia responds well to peep increases. however, notable exceptions have been found where lower peep is preferred ( ) . these cases may be the result of pulmonary microthrombi reducing blood flow ( ) as covid- patients are recently reported to develop coagulation abnormalities ( ) . in these cases, higher peep may be deleterious by increasing pulmonary vascular resistance. highfrequency oscillation is not used in adults due to randomized trials showing increased mortality ( ) and greater need for sedation ( , ) . assessment for extubation readiness is typically done using a combined spontaneous awakening-spontaneous breathing trial ( ) in which all sedation is lifted and the patient is placed on a continuous positive airway pressure (table on dosing) opioid, benzodiazepine, and dexmedetomidine iv infusions and/or boluses are used for sedation in adults and pediatrics in similar dose ranges despite the common practice in adults of using absolute doses (e.g., mg/hr) as opposed to weight-based dosing (e.g., mg/kg/hr). propofol use is common in adults due to few reports of propofol infusion syndrome ( , ) with dose range of - µg/kg/min employed for continuous prolonged sedation or up to µg/kg/min for brief procedures. multiple randomized trials have failed to demonstrate any optimal adult sedative ( ) ( ) ( ) ( ) ( ) . propofol or dexmedetomidine produces more hypotension than midazolam and opioids but are metabolized more rapidly. sedation interruptions or closely titrated sedation based on clinical scores (i.e., richmond agitation-sedation scale) are superior to both or minimal sedation in producing patient comfort and hemodynamic stability ( ) ( ) ( ) . prone positioning for at least hours daily in adults with severe ards may increase ventilator-free days, reduce in-hospital mortality, and reduce the need for rescue therapies like inhaled nitric oxide and extracorporeal membrane oxygenation (ecmo) ( , ( ) ( ) ( ) ( ) . the surviving sepsis guidelines for covid- for moderate to severe ards recommend proning within hours of presentation ( ) . our collective experience supports impressive responses in oxygenation following proning in covid- . prone patients typically require additional staff for patient manipulation, deep sedation, and often neuromuscular blockade. care should be taken to minimize complications such as endotracheal tube obstruction, pressure sores, facial edema, and ocular injury ( - ). copd is a common chronic illness worldwide and leading cause of both morbidity and mortality ( ) . patients with copd are at high risk to develop acute exacerbation of copd (aecopd) during the covid- pandemic and early recognition and treatment is essential. the mainstay of treatment for aecopd are short-acting bronchodilators, short courses of steroids, oxygen therapy to target oxygen saturations of - %, and short courses of antibiotics ( - d [ ] ). inhaled bronchodilators (short-acting β agonists and muscarinic antagonists) are effective in the treatment of acute exacerbations. nebulization should be avoided due to risk of viral aerosolization rather these medications should be administered via meter-dose inhalers. prednisone or iv methylprednisolone ( - mg daily) for - days is recommended ( ) . nippv is the standard of care especially for aecopd as it has been demonstrated to decrease intubation rates, and overall mortality due to respiratory failure ( , ) . akin to intubated asthmatics, intubated aecopd with covid may require lower respiratory rates and higher tidal volumes to avoid autopeep and increased intrathoracic pressure, decreased venous return, and hemodynamic compromise. adults with ards may receive a survival and disability benefit from venovenous ecmo when offered within days of initiation of mechanical ventilation ( ) ( ) ( ) . venovenous ecmo has been found to be safe and effective, especially in ards patients during the h n influenza pandemic ( ) ( ) ( ) . evidence from adults with covid- in japan and south korea suggest that carefully selected patients with severe ards failing conventional treatment can be successfully supported with venovenous ecmo ( , , ) . venovenous ecmo flow rates needed to support oxygenation in adults are generally - ml/kg/min ( ) . "lung rest" ventilation should target fio less than or equal to %, peep ~ , and plateau pressure ~ - ( ) . covid- appears to cause myocardial injury with increased mortality in these patients ( ). selected adults progressing to cardiovascular failure may benefit from venoarterial ecmo, although this is associated with a higher risk of stroke, bleeding, and renal failure and should only be considered only in experienced, resourced centers ( ). cerebrovascular accident (cva) is a leading cause of death in the united sates with an overall prevalence of . % in those greater than years old ( ) ( table ) . most cva ( %) is ischemic. immediate evaluation to stabilize hemodynamics, decipher if intracranial hemorrhage or ischemia is present, and then decide on reperfusion therapy is temporally critical. sudden loss of focal brain function is a core feature of ischemic stroke onset. management of cva includes stabilizing the patient's airway, breathing, and circulation (abcs), reversing contributing issues, determining the etiology (for ischemic strokes, consider thrombolysis or endovascular thrombectomy), and preparation for post intervention surveillance/management. pediatric intensivists should calculate a national institutes of health stroke scale score, obtain immediate acute imaging to exclude hemorrhage, assess the degree of brain injury, and identify the vascular lesion responsible for the deficit. imaging may be difficult given isolation for covid- ; however, these studies are time critical as thrombolysis must occur in less than . hours from symptoms ( ) ( ) ( ) ( ) ( ) ( ) ( ) . imaging includes hyperacute mri, noncontrast ct, or ct angiography. reperfusion is the most effective maneuver for salvaging ischemic brain that is not already infarcted and is time sensitive as the benefits of reperfusion for ischemic stroke diminish over time. recent guidelines for early stroke management are published ( ) . consultation with a stroke team (telestroke) is recommended. mounting evidence demonstrates that up to % of covid- patients have direct cardiac injury with increases in arrhythmia, myocardial infarction (mi), myocarditis, and acute heart failure ( , , , , ) . thus, we provide considerations for these common complications with guidance on management. acute or new onset atrial fibrillation. af is the most common cardiac arrhythmia in adults, more prevalent in men, and prevalence increases with age ( , ) . af presents as an irregularly irregular pulse which on electrocardiogram (ecg) has rr intervals without repetitive pattern and often absent p waves. af and resultant tachycardia may compromise cardiac output and result in atrial thrombus formation with potential for embolic stroke. understanding the immediate etiology for af is important, as some causes are reversible (i.e., mi, active infection, electrolyte disturbance). management of af centers on rate and rhythm control. rate control to slow the ventricular rate is best achieved via use of beta-blockers (metoprolol or esmolol) or calcium channel blockers (diltiazem). a transesophageal echocardiogram is recommended to evaluate for signs of acute heart failure or left atrial appendage thrombus. to immediately restore normal sinus rhythm direct electric cardioversion within hours of onset is warranted if af is causing hemodynamic embarrassment. direct current cardioversion may be more successful with use of amiodarone infusion for hours. in the setting of persistent af with lower blood pressures, digoxin and amiodarone may be considered for rate control. management of af is the subject of a recent guideline update ( ) . acute coronary syndromes (including demand ischemia). assessment of chest pain and acute coronary syndrome (acs) must be undertaken immediately. if a patient experiences chest pain, arm pain, dizziness, or new onset arrhythmia a stat ecg should be ordered to determine if there is st elevation. patients experiencing an acute st elevation myocardial infarction (stemi) require immediate interventional cardiology consultation to consider percutaneous intervention within minutes. if angiography is deemed unacceptable due to covid- infection risk, thrombolysis is an option ( ) . in the absence of stemi, these symptoms with troponin elevation mark unstable angina (usa) or non-stemi. treatment of usa/non-st elevation myocardial infarction (nstemi) consists of anticoagulation, aspirin ( - mg), β blockade and if needed, oxygen ( ). these same treatments applied for usa/nstemi are often employed initially in the setting of stemi until reperfusion occurs. persistent chest pain may be treated with . mg sublingual nitroglycerin every minutes or a nitroglycerin drip assuming blood pressure is adequate. severe critical illness in adults with limited coronary perfusion may result in troponin elevation due to demand-mediated myocardial ischemia (dmmi). management of dmmi is to minimize myocardial oxygen demands and patient stress (e.g., β blockade, sedation/paralysis); however, there is no role for aspirin or anticoagulation ( ) . bedside echocardiogram or point of care ultrasound to evaluate for focal wall motion abnormality can help distinguish infarction from dmmi. laboratory evaluation of acs should include electrolytes (with correction of abnormalities), serial troponins, platelets, and coagulation indices. mi should be treated with high dose statin therapy (e.g., mg atorvastatin daily). recommendations from suggest nstemi patients should also receive p y inhibitor ( ). typically, before administering additional antiplatelet therapy, a cardiology consult is warranted to discuss the timing of angiography. congestive heart failure. acute decompensated heart failure (adhf) is one of the main causes of respiratory distress in adult patients requiring the icu ( ) . heart failure with preserved ejection fraction (hfpef) or reduced ejection fraction (hfref) have similarities and differences in management. hfref shares similarities to the congestive heart failure (chf) seen in the picu. respiratory distress is typically a result of elevated left ventricular end-diastolic pressure (lvedp) resulting in pulmonary congestion. diuresis is helpful in both clinical presentations, although patients in hfref generally are more hypervolemic. in general, icu patients in adhf do not require maintenance iv fluids. hfpef patients have diastolic dysfunction and often present with tachycardia and hypertension; subsequently elevating lvedp. these respond well to vasodilators and β blockade directed at restoring "normal" range heart rates and blood pressures ( ) . af should be rate controlled immediately as it can exacerbate hfpef. point of care cardiac ultrasound can assist in identifying patients with reduced ejection fraction ( - ). hypertensive patients with hfref require afterload reduction to optimize cardiac output and may require low-dose inotropic support. home medications (angiotensin blockade and β blockers) should be discontinued at admission to the icu and assessed for continuation after the patient has reached clinical stability. in patients with significant hypervolemia, high venous pressures may contribute to poor renal perfusion and poor diuretic response ("cardiorenal syndrome"). aggressive diuresis (occasionally dialysis) with inotropic or vasodilator support may be needed to improve oxygenation. weighing the patient daily may assist in targeting appropriate fluid balance. myocardial ischemia should be considered as a cause of adhf and ruled out with serial troponins. acute pulmonary embolism and deep vein thrombosis prophylaxis. acute pulmonary embolism (pe) is a common and fatal complication of hospitalization that account for over , deaths in the united states annually. the diagnosis and management of pe is summarized ( ) ( ) ( ) ( ) . pe in the icu may present as hemodynamic stability or increased hypoxia not explained by new chest radiograph findings. this diagnosis is rarely seen in the picu and a high index of suspicion should be maintained when caring for adults. definitive imaging includes ct pulmonary angiography and less commonly ventilation/perfusion scan ( , ) . treatment is identical to pe for presence on ultrasound of deep vein thrombosis (dvt) in the setting of pe symptoms. the mainstay of therapy is systemic anticoagulation ( ) with unfractionated heparin or low molecular weight heparin that should not be withheld due to delay in obtaining imaging especially due to quarantine for covid- . hemodynamic instability including right heart strain should warrant consideration for thrombolysis or acute thrombectomy ( , , ) . to prevent dvt, especially given immobility with covid- in the icu, the use of sequential compression devices and, if not contraindicated, prophylactic anticoagulation ( , ) is recommended. the common adult conditions causing acute gastrointestinal bleeding (gib) are distinguished based on whether their origin is in the upper or lower gastrointestinal tract. the most common etiologies of upper gastrointestinal bleeding are peptic ulcer disease, variceal bleeding, mallory-weiss tears, and carcinoma ( ) . the most common cause of lower gastrointestinal bleeding are diverticular disease, angiodysplasia, neoplasms, colitis, and anal lesions like hemorrhoids and fissures ( ) . in critically ill intubated adults stress ulcer prophylaxis with a proton pump inhibitor (ppi) has a small benefit in preventing gib ( ) . as with pediatric patients experiencing acute gib, the initial priorities are managing the abcs particularly hemorrhagic shock. to facilitate transfusion, two large bore ( gauge) iv catheters should be established and hypotension managed aggressively with iv fluids and the transfusion of blood and blood products as necessary. a ppi should be administered for upper gib. we recommend pantoprazole mg iv bid as an initial approach with an immediate gastrointestinal consult. upper endoscopy can be both diagnostic and therapeutic in upper gib, whereas colonoscopy is primarily diagnostic. a nasogastric tube may be helpful to differentiate the source of bleeding or remove stomach contents and blood prior to endoscopy. this helps to identify a source and allow specific treatments to be provided. if no source is found on the initial endoscopy and the patient remains unstable, additional diagnostic testing including computerized tomography and/or angiography can be pursued while resuscitation continues. surgery remains an option for those in whom the source remains elusive. hyperosmolar hyperglycemic state (hhs) is an acute metabolic emergency classically affecting type diabetics. it is distinct from diabetic ketoacidosis (dka) in that it typically presents with higher levels of hyperglycemia (plasma glucose > mg/dl), a greater degree of dehydration, minimal acidosis (ph > . ) and ketosis ( , ) . treatment principles of hhs are insulin infusion titrated to decrease blood glucose to less than mg/dl (which is the threshold of glucosuria which drives dehydration/electrolyte abnormalities) and aggressive hydration. total fluid resuscitation requirements are usually much greater than in dka ( ) , although in covid- this must be balanced against the risks of volume overload and chf. resolution of hhs is indicated by improvement in osmolality, dehydration, and altered mental state ( ) . disease aki is the most common organ dysfunction in critically ill adults ( %) and is associated with high in-hospital mortality ( %) ( ) . patients with advanced chronic kidney disease or end-stage renal disease may already be on intermittent hemodialysis (ihd) through a tunneled percutaneous hemodialysis catheter or a matured arteriovenous fistula. temporary catheters can be used for ihd or continuous renal replacement therapy, but an arteriovenous fistula is reserved for ihd. the prevalence of aki in covid- is low ( %) similar to that seen in the severe acute respiratory syndrome (sars) epidemic ( . %) ( , ) . like sars, covid- may cause an acute tubular necrosis ( ) . patient in the sars epidemic who developed aki had a higher overall mortality compared with those without renal impairment ( . % vs . %) ( ) . management should include avoidance of nephrotoxic agents and use of ph balanced crystalloids ( ) . delirium is common among adult icu patients (prevalence: - %) ( ) and caused by an underlying medical condition, intoxication, or medication effect. it is a significant contributor to both morbidity and mortality, including worse long-term cognitive outcomes ( ) ( ) ( ) . delirium can occur in agitated, hypoactive, and mixed subtypes, with the overwhelming majority of patients falling into the latter two categories. there are several validated scales for delirium assessment in the icu, with the confusion assessment method for the icu being the most widely used ( , ) . many of the risk factors are modifiable and include exposure to psychoactive or centrally-acting medications, sleep-wake cycle disruption, immobility, polypharmacy, and unmanaged pain ( ) ( ) ( ) . nonpharmacologic approaches to these modifiable risk factors include frequent environmental reorientation, cognitive stimulation, minimizing sleep interruptions, engaging familiar visitors, limiting use of sedative medications, and scheduled sedation "holidays." these strategies have consistently shown improved clinical outcomes in critically ill patients and are now considered standard of care ( ) . although there is some evidence suggesting the prophylactic use of certain pharmacologic agents (antipsychotics, dexmedetomidine, ketamine, etc.), this is currently not recommended due to the inconsistency and lower quality of most of the studies and lack of benefit in other patientcentered outcomes ( ) . for severe agitation posing risk of self-harm or interruption of care, a trial of short-term lowdose antipsychotics (haloperidol, quetiapine, and olanzapine) may be helpful ( ) . although children can develop pressure-related injury (pi), it affects a higher frequency (~ - %) of critically ill adults ( ) . severity ranges from nonblanchable skin erythema (stage ) to full-thickness destruction of dermis and subcutaneous tissue (stage ) ( ) . some of the healthcare burden from pi's is preventable with good risk assessment and implementation of skin care protocols ( ) . distinct icu risk factors include prolonged mechanical ventilation and bedbound status which is often exacerbated by higher prevalences of neuromuscular weakness in adults ( ) ( ) ( ) , hypotension and vasopressor administration ( ) and should be considered along with general risk factors (age, comorbidities, obesity, mobility, and nutrition) when utilizing risk assessment tools like the braden scale ( ) . pi preventative strategies include use of protective silicone foam dressings, frequent repositioning, use of support surfaces, and nutritional optimization. although the use of silicone foam dressings has proven effective, evidence for the other strategies remains limited ( ) . early consultation of a wound care team (if available), coverage with a transparent film for stage injuries, maintaining a moist wound environment with occlusive dressings for stage injuries, and possible debridement for stage and injuries form the basis for preventing pi progression ( ) . efforts should be made to efficiently incorporate these strategies into the overall care of the patient in a way that limits patient staff interactions. about - % of adult icu patients have an alcohol use disorder and are at risk for developing alcohol withdrawal syndrome (aws) ( , ) . aws carries significant morbidity and mortality in hospitalized patients and requires careful management. without treatment, symptoms begin within - hours after cessation of drinking and may include anxiety, agitation, tremors, diaphoresis, headache, hallucinosis, withdrawal seizures, and delirium (i.e., delirium tremens). symptoms may be measured using the clinical institutes withdrawal assessment scale for alcohol and management tailored based on severity of symptoms. a high index of suspicion and preemptive treatment with folate ( mg daily) and thiamin ( mg iv daily) is important to avoid wernicke-korsakoff syndrome. withdrawal symptoms are managed first line using titrated doses of benzodiazepines with potential benefit from other therapies such as dexmedetomidine, ketamine, phenobarbital, and antipsychotics ( ) ( ) ( ) . propofol may be added in agitated intubated patients. critically ill adults typically require surrogate decision-making while incapacitated ( ) and many have a prepared advanced care document (i.e., durable powers of attorney for healthcare www.pccmjournal.org july • volume • number (dpahc) and living wills) to express healthcare wishes ( , ) . dpahcs authorize particular person(s) as legally recognized medical decision-makers if the patient lacks capacity. living wills summarize medical care that a patient would or would not want under specific circumstances such as serious illness or hospitalization. particularly in a setting of critical resource limitation, an ethical duty to plan compels physicians to identify these advanced directives or identify a surrogate decision-maker, as misapplication of these resources may detract from other patients. do-not-resuscitate (dnr) orders should be entered in the medical record for patients who do not desire cpr. public health ethics, which focuses on overall community good, differs from clinical ethics, which focuses on the good of the individual patient ( , ) . crisis resource allocation and rationing strategies, often designed to save the most possible lives and the most possible life years, deserve early institutional articulation ( ) . such policies may create tension during the care of adults in pediatric settings, as many allocation guidelines give preference to younger patients. palliative care consultation should be engaged early, which may reduce icu resource utilization by increasing transition to dnr status without increasing overall mortality ( ) . additionally, if crisis resource allocation is used, patients (and/or surrogates) should be proactively informed and palliative care should be provided to those who do not receive icu resources. consultation with adult practitioners in cases where limitation of life sustaining therapy is being considered would be prudent. finally, adults receiving medical treatment in a pediatric facility will certainly recognize differences in the typical standard of care and should receive transparent communication about these deviations. hospitals should clearly define and document their triggers for adopting altered standards of care. this approach creates a helpful framework for physicians and also engenders discussions with patients about the care they can expect to receive. with significant resource limitations, the covid- pandemic may challenge picus to adapt to the 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guide for clinicians peptic investigators for the australian and new zealand intensive care society clinical trials group, alberta health services critical care strategic clinical network, and the irish critical care trials group: effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine- receptor blockers on in-hospital mortality among icu patients receiving invasive mechanical ventilation: the peptic randomized clinical trial hyperglycemic crises in adult patients with diabetes hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment acute kidney injury enhances outcome prediction ability of sequential organ failure assessment score in critically ill patients acute renal impairment in coronavirus-associated severe acute respiratory syndrome smart investigators and the pragmatic critical care research group: balanced crystalloids versus saline in critically ill adults delirium in the critically ill patient clinical 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alcohol withdrawal syndrome in critically ill patients approach to the complicated alcohol withdrawal patient the use of dexmedetomidine as an adjuvant to benzodiazepine-based therapy to decrease the severity of delirium in alcohol withdrawal in adult intensive care unit patients: a systematic review proxy decision making for incompetent patients. an ethical and empirical analysis advance directives and outcomes of surrogate decision making before death approximately one in three us adults completes any type of advance directive for end-of-life care allocating scarce life support in a public health emergency who should receive life support during a public health emergency? using ethical principles to improve allocation decisions fair allocation of scarce medical resources in the time of covid- early palliative care consultation in the medical icu: a cluster randomized crossover trial the authors would like to offer support and expertise to our pediatric critical care colleagues caring for adult patients during this pandemic. as such, we have provided the emails of the combined adult and pediatric critical care medicine authors and will do our best to respond promptly to questions: dr. verhoef's institution received funding from national institutes of health national heart, lung, and blood institute k award. dr. dezfulian's institution received funding from mallinckrodt pharmaceuticals. the remaining authors have disclosed that they do not have any potential conflicts of interest.for information regarding this article, e-mail: dezfulianc@upmc.edu; kremy@wustl.edu key: cord- - fccnygg authors: roden, anja c.; tazelaar, henry d. title: pathology of lung rejection: cellular and humoral mediated date: - - journal: lung transplantation doi: . / - - - - _ sha: doc_id: cord_uid: fccnygg acute rejection is an important risk factor for bronchiolitis obliterans syndrome, the clinical manifestation of chronic airway rejection in lung allograft recipients. patients with acute rejection might be asymptomatic or present with symptoms that are not specific and can be also seen in other conditions. clinical tests such as pulmonary function tests and imaging studies among others usually are abnormal; however, their results are also not specific for acute rejection. histopathologic features of acute rejection in adequate samples of transbronchial lung biopsy of the lung allograft are currently the gold standard to assess for acute rejection in lung transplant recipients. acute alloreactive injury can affect both the vasculature and the airways. currently, the guidelines of the international society of heart and lung transplantation consensus conference are recommended for the histopathologic assessment of rejection. there are no specific morphologic features recognized to diagnose antibody-mediated rejection (amr) in lung allografts. therefore, the diagnosis of amr currently requires a “triple test” including clinical features, serologic evidence of donor-specific antibodies, and pathologic findings supportive of amr. complement d deposition is used to support a diagnosis of amr in many solid organ transplants; however, its significance for the diagnosis of amr in lung allografts is not entirely clear. this chapter discusses the currently recommended guidelines for the assessment of cellular rejection of lung allografts and summarizes our knowledge about morphologic features and immunophenotypic tests that might help in the diagnosis of amr. acute rejection is the host's response to the recognition of the graft as foreign. it can occur days, months, or even years after transplantation. rejection can be divided into cellular and humoral forms. acute cellular rejection is the predominant type of acute rejection of lung allografts. it is mediated by t lymphocytes that recognize foreign human leukocyte antigens (hla) or other antigens [ , ] . humoral rejection is mediated by preformed or de novo recipient antibodies (therefore, also referred to as antibody-mediated rejection [amr]) against antigens of the donor organ cells. acute rejection is an important complication in patients with lung allografts. twenty-nine percent of adult patients have at least one episode of treated acute rejection between discharge from the hospital and year after transplantation [ ] . moreover, . % and . % of all deaths that occur within the first days or between days and year following lung transplantation are due to acute rejection, respectively [ ] . in addition, the frequency and severity of acute rejections are thought to represent the major risk factor for the subsequent development of bronchiolitis obliterans syndrome (bos) [ , [ ] [ ] [ ] . hla mismatch, genetic and recipient factors, type of immunosuppression, vitamin d deficiency, and infection are risk factors of acute rejection. for instance, the recipient alloimmune response is thought to be related to the recognition of differences to donor antigens leading to acute lung allograft rejection. indeed a higher degree of hla mismatch has been shown to increase the risk of acute rejection although this effect is not consistent across all hla loci or studies [ , [ ] [ ] [ ] [ ] . mismatches at the hla-dr, hla-b [ ] , and hla-a [ ] loci, as well as a combination of all three loci [ ] , appear specifically important. for instance, acute rejection within months after transplantation has been shown to be associated with hla-dr mismatch, while acute rejection at years has been found to be associated with hla-b mismatch [ ] . several host genetic characteristics have been studied that may modulate acute lung rejection. for instance, a genotype leading to increased il -production may protect against acute rejection [ ] , while a multidrug-resistant genotype (mdr c t) appears to predispose to persistent acute rejection that is resistant to immunosuppressive treatment [ ] . the incidence of acute rejection appears to be age-dependent, with the lowest incidence of acute rejection in infants (< age ) [ ] . however, children have a higher risk for acute rejection than adults [ ] . furthermore, the registry of the international society of heart and lung transplantation (ishlt) showed that the incidence of acute rejection between discharge and -year follow-up was slightly higher in younger adult lung allograft recipients (age - years) ( %) [ ] when compared to the entire adult population in which % had at least one acute rejection episode [ ] . the incidence of acute rejection does not seem to change in older lung transplant recipients (age and higher) [ ] . regimens of immunosuppression might also play a role in acute rejection. for instance, the rate of acute rejection in the first year after transplantation was highest among recipients who were on cyclosporine-based regimens and lowest among those on tacrolimus-based regimens [ ] . vitamin d deficiency might also play a role in acute rejection. a study found that % of lung recipients were (oh)d deficient around the time of transplantation and that vitamin d-deficient recipients had more episodes of acute cellular rejection and infection [ ] . a similar association between vitamin d deficiency and acute rejection has been described in other solid organ recipients including the liver, kidney, and heart. although the exact mechanism for this phenomenon is not entirely clear, it is speculated that ( ) vitamin d might slow down the maturation of antigen-presenting cells as in vitro studies have shown, ( ) vitamin d might induce dendritic cells to acquire tolerance, and/or ( ) a synergistic effect between vitamin d analogs and immunosuppressants occurs [ ] . viral infections have also been thought to modulate the immune system and to increase alloreactivity. indeed, a high incidence of acute rejection has been found in lung transplant recipients after community-acquired respiratory tract infections with human influenza virus, respiratory syncytial virus, rhinovirus, coronavirus, and parainfluenza virus [ ] [ ] [ ] . chlamydia pneumoniae infection has also been linked to the development of acute rejection in one study [ ] . the significance of cmv infections and the impact of cmv prophylaxis strategies on acute rejection frequency are not clear at this time [ ] . the clinical course of acute rejection can be variable. acute rejection is often identified on surveillance transbronchial biopsy in an asymptomatic patient. if symptoms occur, they might be non-specific and overlap with those seen in other complications and diseases in this patient population. these symptoms might include dyspnea, fever, leukocytosis, and a widened alveolar-arterial oxygen gradient. higher-grade rejection appears to cause more severe symptoms and can lead to acute respiratory distress [ ] . in patients with rejection, pulmonary function testing may show a decrease in forced expiratory volume in s (fev ) and vital capacity (vc). although spirometry has a sensitivity of greater than % for detecting infection or rejection of grade a and higher, it cannot differentiate between the two [ ] . furthermore, the usefulness of spirometry is diminished in single lung transplant recipients, as the dysfunction of the native lung confounds the pulmonary function test results [ ] . although in approximately half of the cases of acute rejection, chest x-ray studies are normal, ill-defined perihilar and lower lobe opacities, along with septal lines and pleural effusions, may be seen. findings on ct scan might include ground-glass opacities, septal thickening, volume loss, nodules and consolidation, and pleural effusions. infiltrates observed on imaging studies during the first week after lung transplantation are usually caused by the reimplantation response, i.e., reperfusion edema and other factors. infiltrates that persist beyond the first week following transplantation suggest acute rejection or infection. however, although early, the authors of small studies have attempted to demonstrate the usefulness of chest x-rays and chest ct scans in the diagnosis of rejection, more recent data show a very low sensitivity for acute rejection (as low as %) and no discriminatory value between rejection and other processes [ ] . exhaled nitric oxide (no) can also serve as a marker of lung injury; it is often increased in patients with lymphocytic bronchiolitis and acute rejection [ ] [ ] [ ] . furthermore, in a study of inert gas single-breath washout, the slope of alveolar plateau for helium had a sensitivity of % for acute rejection [ ] . although the presentation of the patient and several ancillary studies may suggest the presence of acute allograft rejection, none of these findings are specific. therefore, tissue diagnosis is necessary for a definitive diagnosis. histopathology of adequate lung biopsy samples obtained from transbronchial biopsy is currently the gold standard to assess lung allografts for rejection and to distinguish rejection from its clinical mimickers such as aspiration, infection, drug toxicity, and recurrent disease. recently, the transbronchial cryobiopsy technique was introduced which yields larger biopsies containing more alveoli, small airways, and veins and venules while exhibiting less procedural alveolar hemorrhage and crush artifact than conventional forceps transbronchial allograft biopsies [ ] [ ] [ ] . although cryobiopsies appear to be as safe as forceps biopsies, complications can occur which is one of the reasons that this technique has so far not been universally performed for this purpose [ ] . other lung tissue specimens from lung allografts include wedge biopsies, explants for retransplant, or autopsy specimens from lung transplant recipients. wedge biopsies, although seldom obtained in clinical practice, and specimens from explants provide useful histopathologic insights into the etiology of lung allograft dysfunction in advanced stages following all possible medical interventions. cellular alloreactive injury to the donor lung affects both the vasculature and the airways [ ] . perivascular mononuclear cell infiltrates are the hallmark of acute cellular rejection. these infiltrates may be accompanied by subendothelial chronic inflammation (e.g., endotheliitis or intimitis) and also by lymphocytic bronchiolitis, which is characteristic of small airway rejection. the histologic changes are divided into grades based on intensity of the cellular infiltrate and the occurrence of an accompanying acute lung injury pattern. in , the ishlt sponsored the lung rejection study group (lrsg), a workshop to develop a "working formulation" for the diagnosis of lung rejection by transbronchial biopsy [ ] . since then the grading scheme has been revised twice, in [ ] and [ ] . the grading scheme is strictly pathologic, based on morphologic features recognized in transbronchial biopsies of the allograft. clinical parameters are not considered. due to overlapping histologic features between acute rejection and infection, the grading scheme relies on the absence of concurrent infection. furthermore, infection and rejection may occur together. therefore, the lrsg recommends grading rejection only after the rigorous exclusion of infection [ ] . the most recent classification of lung allograft biopsies is the ishlt consensus classification of allograft rejection [ ] (table . ). an attempt should be made to accurately distinguish the grade of rejection since treatment is largely dependent on the histologic grade assessed by an experienced pulmonary pathologist familiar with the histopathologic features and criteria used for grading. however, inter-and intra-observer variability in grading can impact treatment and outcome [ , ] . two studies using the grading system found relatively good interobserver agreements for the a grades (kappa of . and . ) [ , ] ; however, these results could not be replicated in another study in which the kappa was . in spite of dichotomization of the a grades to a /a versus a - [ ] . intraobserver agreement for acute rejection has been found to be good with kappa values of . and . [ , ] . using the revised ishlt classification, bhorade and colleagues showed an overall concordance rate of % for grade a and % for grade b specimens between a site pathologist and a central pathologist [ ] . however, the weighted kappa scores in that study showed only fair to moderate agreement for a grades (kappa values varied between . and . ) and less than a chance agreement to moderate agreement for b grades (kappa values varied between − . and . ). interestingly, the kappa values for a and b grades were dependent on the time that had elapsed between transplantation and biopsy. the best agreement occurred in biopsies taken within weeks of transplant. slightly higher agreements ( % and %, for a and b grades, respectively) were shown in a study that evaluated the interobserver agreement between two transplant pathologists from the same institution using the revision grading scheme [ ] . although cryobiopsies are larger and appear to be easier interpretable, interobserver reproducibility did not improve with the use of cryobiopsies in that study [ ] . acute rejection is defined by the presence of perivascular mononuclear cell infiltrates with or without endotheliitis [ ] . with progression, this infiltrate becomes more widespread and extends into the alveolar septa and, subsequently, into the alveoli. the majority of the mononuclear cells in acute rejection are t cells, although a few studies have described increased populations of b cells or eosinophils [ , , ] . the histologic features of rejection are summarized in table . . features of acute cellular rejection are lacking, although the biopsy may not be entirely normal. scattered infrequent blood vessels, particularly venules, in the alveolated lung parenchyma are surrounded by a relatively thin (ring of two to three layers) chronic mononuclear cell infiltrate ( fig. . a , b). the lymphocytic rim can be loose or compact and is in general circumferential but does not spill into the adjacent interstitium. endotheliitis and eosinophils are absent. in adequately alveolated and artifact-free speci-mens, the lymphocytic infiltrates may be detected at low magnification, but often higher power study is needed to identify the infiltrates. although in mild acute rejection the perivascular infiltrate of lymphocytes is still confined to the perivascular adventitia without infiltrating the adjacent interstitium or air spaces, there are more layers of lymphocytes surrounding vessels ( fig. . a, b ). in addition, the perivascular mononuclear infiltrates surrounding venules and arterioles are more frequent than in grade a . they are typically recognizable at low magnification. these infiltrates usually consist of a mixture of small round lymphocytes, activated lymphocytes, plasmacytoid lymphocytes, macrophages, and eosinophils. the cellular infiltrates can be compact or loose. subendothelial infiltration by mononuclear cells may be noted which can be associated with hyperplastic or regenerative changes in the endothelium. concurrent lymphocytic bronchiolitis may be seen. venules and arterioles are cuffed by easily recognizable dense perivascular mononuclear cell infiltrates that are commonly associated with endotheliitis ( fig. . a-c). eosinophils and even occasional neutrophils are common. in a b moderate acute rejection, the inflammatory cell infiltrate extends into the adjacent alveolar septa where it can be associated with type ii pneumocyte hyperplasia. the inflammatory infiltrate can also extend into adjacent airspaces and be associated with collections of intra-alveolar macrophages and lymphocytes. histologic features of acute lung injury may become apparent in the form of airspace fibrin. in severe rejection, there are diffuse perivascular, interstitial, and air space infiltrates of mononuclear cells with prominent alveolar pneumocyte damage and endotheliitis ( fig. . a-f). this may be associated with necrotic intra-alveolar epithelial cells, hemorrhage and neutrophils, and usually morphologic evidence of acute lung injury in the form of organizing pneumonia, fibrin deposition, or hyaline membranes. parenchymal necrosis, infarction, or necrotizing vasculitis may be identified; however, these features are more evident on surgical rather than transbronchial lung biopsies. it should be noted that a paradoxical diminution of perivascular infiltrates can occur as cells extend into interalveolar septa and air spaces where they are admixed with macrophages. protocol surveillance biopsies of lung allografts are performed in many institutions. even though these patients are in general asymptomatic and clinically stable, one study showed that % of surveillance biopsies reveal acute cellular rejection with % showing features of minimal rejection, % mild rejection, and % moderate rejection [ ] . a more recent prospective study identified morphologic findings of acute cellular rejection only in % of surveillance biopsies [ ] , while a retrospective study of a b surveillance biopsies taken within days of transplantation revealed histologic findings of either acute cellular rejection or obliterative bronchiolitis in % of biopsies with % within the first days and % between and days following transplantation [ ] . evidence suggests that acute cellular rejection is an important risk factor for the development of bos [ ] . indeed, studies have demonstrated an increased risk of bos with single episodes, increased frequencies, and increased severity of acute cellular rejection. moreover, patients with multiple episodes of even minimal acute cellular rejection were shown to be at increased risk for bos [ ] , and yet a single episode of minimal acute rejection without recurrence or subsequent progression to a higher grade has been identified as an independent significant predictor of bos [ ] . because of these findings, patients who are asymptomatic but are found to have acute cellular rejection (even minimal acute cellular rejection) on a surveillance allograft biopsy might be treated accordingly. however, several centers do not utilize surveillance transbronchial lung biopsies and/or treat asymptomatic patients with no clinical evidence of allograft dysfunction. prospective well-designed clinical studies are needed to provide evidence to support surveillance transbronchial lung biopsies and therapeutic interventions. this grade applies only to small airways such as terminal or respiratory bronchioles. bronchi, if present, should be described separately. it is important to mention in the pathology report whether or not small airways are present. if no small airways are identified or the biopsy has obvious infection, the grade "bx" should be used. the r behind grades and denotes the revised version. the small airways appear unremarkable without evidence of bronchiolar inflammation. low-grade inflammation is characterized by lymphocytes within the submucosa of the bronchioles ( fig. . a-c). the lymphocytic infiltrates can be infrequent and scattered or form a circumferential band; however, intraepithelial lymphocytic infiltration is not present. occasional eosinophils may be seen within the submucosa. there is no evidence of epithelial damage, neutrophils, necrosis, ulceration, or significant amount of nuclear debris. in high-grade small airway inflammation, there is marked lymphocytic infiltrate of the airway epithelium and airway wall. the mononuclear cells in the submucosa appear larger, and a greater number of eosinophils and plasmacytoid cells can be seen (fig. . a-c) . in addition, there is evidence of epithelial damage including necrosis, metaplasia, and marked intraepithelial lymphocytic infiltration. in its most severe form, high-grade airway inflammation is associated with epithelial ulceration, fibrinopurulent exudate, cellular debris, and neutrophils. it is important to exclude an infectious process, especially if the number of neutrophils is disproportionally high when compared to other mononuclear cells within the airway wall. small airways might not be evaluable for several reasons including lack of small airways due to sampling problems, infection, tangential cutting, artifact, etc. in patients who are known to have an infection that could cause lymphocytic bronchiolitis, the allograft biopsy should also be classified as ungradeable for small airway rejection. chronic airway rejection is restricted to submucosal and intraluminal scarring of small airways including terminal and respiratory bronchioles. when large tissue sections of the lung are examined, obliterative bronchiolitis may be recognized as a panlobar process but is usually patchy. the small airways appear similar in size to the accompanying artery with a ragged inner surface. fibrosis is not present. narrowing of the small airways due to fibrosis in the airway wall is the hallmark of chronic airway rejection. the fibrosis may be eccentric or concentric. the type of fibrosis depends on the acuteness of the process, the degree of organization, and the amount of accompanying inflammation. the fibrosis can range from loose myxoid granulation tissue with variable numbers of inflammatory cells filling or partially obstructing the airway lumen in the more acute phase (fig. . a) to dense hyalinized collagen in the wall of bronchioles that is a characteristic of the chronic phase ( fig. . b) . metaplastic squamous or cuboidal epithelium may overly the bronchiolar fibrosis. sometimes, only a slit-like lumen of the airway may remain as a result of a confluent submucosal scar or intraluminal polyps of scar tissue. there may be rather prominent capillaries supplying the intraluminal fibrotic areas. ultimately, the bronchiolar lumen might be entirely occluded by dense scar tissue (fig. . c, d) . in these cases, only an elastic stain highlighting residual elastic tissue, the vicinity of the scar to a pulmonary artery, and residual smooth muscle may indicate that a small airway has been replaced by fibrotic scar. in the chronic phase, inflammation may be minimal or absent. usually, the scarring process is confined exclusively to respiratory bronchioles and terminal bronchioles, although it may occasionally involve adjacent alveoli. obliterative bronchiolitis is only infrequently identified in lung allografts by transbronchial biopsy, and the sensitivity of this morphologic finding for the presence of chronic rejection is only between and % [ ] [ ] [ ] . in a recent study, all seven conventional transbronchial biopsies that were included from patients clinically known to have bos, the clinical equivalent to morphologic obliterative bronchiolitis, failed to reveal morphologic findings of obliterative bronchiolitis [ ] . although cryobiopsies contained more small airways, all nine cryobiopsies that were also included in that study from patients with clinically proven bos did not reveal obliterative bronchiolitis in the tissue [ ] . this low sensitivity is largely due to sampling and its patchy nature. therefore, bos is used and more reliable for the clinical assessment of chronic airway rejection. bos is calculated as < % fev in at least two consecutive lung function tests of the patient's maximum fev posttransplantation [ ] . despite the low sensitivity of transbronchial biopsies for obliterative bronchiolitis, the specificity of this morphologic finding in an allograft biopsy is high, ranging from to % [ , ] . therefore, an attempt to diagnose obliterative bronchiolitis should be made in lung allograft biopsies. the pulmonary arteries appear of a similar size as the accompanying airways. the intima is slender and the media not thickened. chronic vascular rejection rarely is identified on biopsies since they usually lack vessels of sufficient size. wedge biopsies, explants, or autopsy material may reveal it. therefore, according to the ishlt, the d grade of rejection is not applicable to allograft transbronchial biopsies. although cryobiopsies contain a higher number of venules and small veins, in a recent small study, no difference was found in the number of cases with possible vascular rejection when compared to transbronchial biopsies [ ] . vascular rejection is characterized by thickened pulmonary arteries and more often veins, due to fibrointimal connective tissue ( fig. . a, b) . also, thickening is usually concentric. chronic vascular rejection may be patchy. chronic vascular rejection usually starts with intimal proliferation. subsequently, the internal elastic lamina may become fragmented and discontinuous. occasionally the underlying muscular wall becomes thinned. in approximately half of the reported cases, a concurrent endovasculitis has been observed. the process is similar in pulmonary veins, although the intimal deposits may be less cellular and more waxy, eosinophilic, and sclerotic. recanalized thrombi may mimic chronic vascular rejection. in contrast to heart allografts, chronic vascular rejection in lung transplants has not resulted in graft loss; however, some patients develop pulmonary hypertension particularly those with bos [ , ] . infection can mimic acute cellular rejection. for instance, viral infection, particularly cmv ( fig. . a-e) but also pneumocystis jirovecii pneumonia, can be associated with perivascular mononuclear cell inflammation mimicking acute cellular rejection [ ] . infection can also cause small airway inflammation imitating lymphocytic bronchiolitis. mimickers of severe acute rejection include conditions that might present with acute lung injury or diffuse alveolar damage. these conditions include infection, drug toxicity, aspiration, amr, or harvest/reperfusion injury. the presence of perivascular inflammation is helpful in establishing the diagnosis of rejection. however, perivascular inflammation is not entirely specific for acute rejection, and many other conditions may simulate or mimic alloreactive lung injury [ ] . marked perivascular and/or peribronchiolar mononuclear infiltrates might also raise the possibility of posttransplantation lymphoproliferative disease (ptld), and in such cases, an appropriate workup should be performed, including doing studies for epstein-barr virus, which is ubiquitous in ptld. further differential diagnosis of perivascular and interstitial infiltrates include recurrent primary diseases. small airway rejection and the perivascular infiltrates of grade a rejection should be distinguished from bronchiolar-associated lymphatic tissue (balt) . balt is found in the vicinity of airways, usually contains black anthracotic pigment, and presents as a rather nodular collection of chronic inflammatory cells which does not surround a vessel (fig. . ). epithelial injury, neutrophils, or eosinophils should not be seen in balt collections [ ] . originally recognized in kidney transplant patients who presented with acute allograft rejection, anti-donor antibodies, and poor prognosis [ ] , amr is now well established in kidney and heart allografts. in lung transplantation, amr is still an evolving concept but likely explains acute and chronic graft dysfunction/failure in a subset of patients. evidence suggests that amr occurs due to circulating antibodies that are either ( ) preformed because of pregnancy, blood transfusion, or previous organ transplantation or ( ) arise de novo after transplantation due to hla mismatch. furthermore, the recent development of very sensitive and specific solid-phase flow cytometry and luminex-based methodologies has allowed for more accurate detection of antibody specificities in sensitized recipients, and it has become clear that more patients than previously expected have or develop preformed anti-hla antibodies. immune stimulation by prior infections or autoimmunity may also contribute to the development of antibodies in those patients with no identifiable risk factors. overall, these preexisting or de novo antibodies can react with donor antigens, leading to immediate graft loss (hyperacute rejection), accelerated humoral rejection, and/or bos [ ] . in addition, recent studies have consistently demonstrated an increased incidence of acute rejection (a threefold increase in one study) [ ] , persistent rejection, increased bos [ ] , or worse overall survival [ ] in patients with anti-hla antibodies. this effect is seen both with pretransplant hla sensitization and with the development of de novo anti-hla donor-specific antibodies after transplantation [ ] . about - % of lung transplant recipients are pre-sensitized to hla antigens [ ] . even though "unacceptable antigens" are avoided during the virtual crossmatch, patients with positive pretransplant pra are at higher risk for posttransplant complications. their posttransplant pra can stay stable or increase via generation of either donor-specific or non-donor-specific anti-hla antibodies. similarly, patients that had negative pra screening tests before transplantation can develop de novo non-donor-specific or donor-specific anti-hla antibodies after transplantation. the mechanisms by which antibodies promote lung allograft injury remain poorly understood. antibody binding to allo-hla or other endothelial or epithelial targets in the lung allograft can activate the complement cascade. complement deposits lead to endothelial cell injury, production of proinflammatory molecules, and recruitment of inflammatory cells. complement-independent antibody-mediated mechanisms can also induce endothelial cell activation without cell injury, leading to increased gene expression and subsequent proliferation [ ] . furthermore, as demonstrated by in vitro studies, anti-hla antibodies can cause proliferation of airway epithelial cells as well, producing fibroblast-stimulating growth factors [ ] , potentially contributing to the generation of obliterative bronchiolitis. although the diagnosis of amr in lung allograft biopsies remains challenging, when the triple test criteria are met (graft dysfunction, positive panel reactive antibodies, and evidence of complement deposition in the graft), the disease can be life-threatening, and prognosis can be poor. although the optimal treatment of amr in the lung is currently not known due to the lack of clinical trials, treatment is typically comprised of plasmapheresis, possibly intravenous immunoglobulin (ivig), and medications such as rituximab and bortezomib, among others. as such, the associated histopathologic and clinical parameters are the subject of intense investigation. deposition of complement d (c d), a complement split product, on the capillary endothelium has been suggested as a surrogate marker for amr in heart, kidney, and pancreas transplants [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, the role of c d deposition in the diagnosis of amr in lung allografts is still unclear. moreover, reproducibility of c d deposition in allograft lung tbbx is problematic, even among pathologists who routinely evaluate c d in lung allograft biopsies [ ] . furthermore, there are currently no specific or sensitive morphologic features of amr in lung allografts, although some features that are more commonly identified in these patients have emerged in some recent studies [ ] . studies have attempted to evaluate immunoglobulins (ig) and complement deposits in the subendothelial space. septal capillary deposits of igs and complement products such as c q, c d, c d, and c b- have been described in association with anti-hla antibod-ies [ , ] as well as allograft dysfunction and bos [ , ] . however, except for c d and in some institutions c d, these studies have in general not been implemented for the workup of lung transplant biopsies for possible amr. one of the reasons for the difficulties in lung is the relatively high background that is encountered in immunohistochemical as well as immunofluorescence studies. often, c d binds to the vascular elastic lamina or shows other non-specific binding such as intracapillary serum. staining is commonly only focal, and, therefore, sensitivity and specificity have not been established. only linear, continuous luminal endothelial staining of capillaries, arterioles, and/or venules by c d should be interpreted as positive. in addition, c d is not specific to amr but also can be seen in infection, and harvest/reperfusion injury, or any process that is associated with complement activation. in general, the concept of specific histopathologic features associated with amr remains controversial in lung transplantation. the ishlt revised consensus classification [ ] did propose histopathologic features that might be specific for amr. because of the lack of specific histologic findings of amr, a multidisciplinary approach to the diagnosis was recommended that includes the following: ( ) the presence of circulating antibodies (hla antibodies, anti-endothelial and anti-epithelial antibodies), ( ) focal or diffuse c d deposition (fig. . a-c), ( ) histologic features of acute lung injury or hemorrhage (diffuse alveolar damage, capillary injury associated with neutrophils and nuclear debris, i.e., capillaritis), and ( ) clinical signs of graft dysfunction [ ] . in , the pathology council of the ishlt published findings in a summary statement with recommendations for the pathologic evaluation of amr [ ] . this report included suggestions for protocol biopsies with serologic evaluation for donor-specific antibodies (dsas) at or near time of biopsy. in addition, this statement included recommendations for histopathologic patterns in amr (fig. . a-e) and indications for immunohistochemical or immunofluorescence studies to further elucidate findings in amr (box . ). the morphologic features were confirmed by the consensus report of the ishlt [ ] . the consensus report confirmed the need for a multidisciplinary approach to establish a diagnosis of amr in the lung that "integrates the clinical presentation with available immunologic and pathologic diagnostic tools" [ ] . an amr staging was also proposed (table . ) [ ] . recently, wallace and colleagues reported findings of the banff study of the pathology of allograft lungs with dsa [ ] . nine experienced lung transplant pathologists from multiple institutions performed digital slide interpretation to study transbronchial biopsy specimens from patients with known antibody status (established within days of biopsy) and negative infectious workup. the study demonstrated that biopsies from patients with dsa more commonly showed morphologic features of acute lung injury with or without diffuse alveolar damage than biopsies from patients with non-dsa or no circulating antibodies. endotheliitis was more common in patients with dsa than patients without circulating antibodies. however, there was no difference in occurrence of endotheliitis between biopsies from patients with circulating non-dsa vs dsa or non-dsa vs no circulating antibodies. specimens associated with dsa had a significant higher frequency of capillary inflammation, including neutrophilic margination, increased neutrophils, or capillaritis with karyorrhexis than patients with non-dsa or no circulating antibodies. c d staining was positive in less than % of capillaries in % of biopsies and in more than % of capillaries in % of biopsies. while there was no difference between the groups in biopsies with < % staining, biopsies with dsa more often had over % capillaries staining for c d than biopsies without any circulating antibodies. there were no significant differences identified between hla classes of the dsa and any of the evaluated pathologic findings. taken together, this study identified capillary inflammation, acute lung injury, and endotheliitis as morphologic features in lung allograft biopsies that correlate with the presence of circulating dsa. however, none of these histopathologic features were specific to patients with dsa. morphologic findings of acute lung injury with diffuse alveolar damage had the highest odds ratio for the presence of circulating dsa. this study also cautioned the usefulness of c d immunohistochemical stain for the diagnosis of amr in lung allografts because of its infrequent diffuse positivity. although the study shows that some morphologic features correlate with the presence of circulating dsa and, therefore, might be histopathologic markers to at least suggest the possibility of amr, the reproducibility of these morphologic features is quite problematic even among experienced lung transplant pathologists. in fact, the interobserver reproducibility kappa values ranged between . and . , indicating a less than a chance to moderate agreement. the lowest agreement was noted for suspicion for aspiration (median kappa, . ) and the highest for acute cellular rejection, alveolar hemosiderosis, and c d staining (median kappa, . , all). although a definite diagnosis of amr seems to elude pathologic interpretation at the current time, in a fully contextualized clinical environment, the findings from the biopsy specimen may aid the clinician to make a reasonable diagnosis of amr if other relevant clinical and serologic features are present. the proposed "triple test" [ ] of clinical features, serologic evidence of dsa, and pathologic findings supportive of amr including capillary inflammation, acute lung injury with or without diffuse alveolar damage, and endotheliitis may currently be the best guide to the diagnosis of amr. there is no ihslt recommendation at this time regarding the coexistence of amr and acute rejection, but it clearly does occur. hyperacute rejection is a severe form of amr mediated by preexisting antibodies to abo blood groups, hla class i or ii, or other antigens on graft vascular endothelial cells. this rejection occurs within minutes to a few hours after the transplanted organ begins to be perfused. as in any form of amr, the preexisting antibodies can result from previous pregnancies, blood transfusions, or previous transplant, and their binding to donor antigens provokes complement and cytokine activation resulting in endothelial cell damage and platelet activation with subsequent vascular thrombosis and graft destruction. the outcome is commonly fatal. in hyperacute rejection, lungs are edematous, cyanotic, and heavy, have a firm consistency, lack crepitation, and show red hepatization [ ] [ ] [ ] [ ] . the cut surface reveals patchy poorly defined areas of hemorrhagic consolidation. anastomoses are intact and typically widely patent. histologically, alveolar hemorrhage, platelet and fibrin thrombi, neutrophilic infiltration, necrosis of vessel walls, and diffuse alveolar damage are observed [ - , , ] . c d deposition has been described. although hyperacute rejection is a wellknown complication in kidney and heart transplantations, in lung transplantation, it appears to be rather rare with only eight cases reported. six patients died within h and days after transplantation [ ] [ ] [ ] [ ] [ ] [ ] . only two patients survived [ , ] . one of these two patients was treated with plasmapheresis, antithymocyte globulin, and cyclophosphamide immediately after hyperacute rejection was diagnosed [ ] . the other patient was highly presensitized when he underwent double lung transplantation [ ] . this patient was treated with multiple plasma exchanges and intravenous immunoglobulin pre-and posttransplantation together with posttransplant rituximab and bortezomib and later with anti-c antibody and eculizumab. although in pretransplant, panel reactive antibodies (pras) were negative in four of the eight reported patients, crossmatch was positive in all reported cases. collectively, although hyperacute rejection is rare after lung transplantation, one should keep this reaction in mind given that false-negative pras may occur and pretransplantation crossmatch is not often possible [ ] . at least five pieces of well-expanded alveolated parenchyma are required for adequate evaluation of a transbronchial lung allograft biopsy specimen for acute rejection by the lrsg [ ] . this specimen requirement was based on the "uniform opinion of the consensus meeting." to ensure that the minimum number of required pieces of alveolated lung parenchyma is available for pathology review, it is recommended that the bronchoscopist needs to take more than five pieces. even more pieces might be necessary to provide small airways for review. interestingly, a prospective -month single-operator study by scott and colleagues [ ] including transbronchial allograft biopsies with to samples per procedure (mean . samples per procedure) taken from lobes (or lobes and the lingula of lung) of heart-lung transplant and single lung transplant recipients revealed a sensitivity of % and a specificity of % for identification of rejection by histopathology. this study estimated that samples per procedure are needed to have a % confidence of finding rejection. therefore, false-negative results due to patchy distribution of acute rejection are likely not uncommon. the absence of histologic and immunophenotypic features of acute rejection or antibody-mediated rejection requires clinicopathologic correlation as a negative biopsy does not necessary rule out rejection. furthermore, the bronchoscopist should be familiar with imaging studies, especially high resolution computed tomography studies if available, and aim to sample radiologically abnormal bronchopulmonary segments. if such imaging was not recently performed or the results are normal, then samples should be obtained from different lobes to try to minimize sampling error. specimens should be gently agitated in formalin to open up the alveoli. there is currently no recommendation for cryobiopsies. in a recent study using cryobiopsies to evaluate rejection in lung allografts, a median of three pieces provided twice as many alveoli and small airways than a median of ten pieces by conventional forceps biopsy [ ] . the ishlt recommends a minimum of three levels from the paraffin block for hematoxylin and eosin (h&e) staining for histologic examination [ ] . in addition, "connective tissue stains" such as trichrome or verhoeff-van gieson (vvg) stain are recommended to evaluate airways for the presence of submucosal fibrosis and vessels for graft vascular disease. stains for microorganisms including gomori-grocott methenamine silver stain (gms) and acid fast bacilli (afb) may be added. while silver stains are routinely performed on lung allograft biopsies in some institutions, they are currently not mandated by the lrsg because many microbiologic, serologic, and molecular techniques are available and used to identify infections in these patients [ , ] . bal may be performed at the time of biopsy and is useful for the exclusion of infection but currently has no clinical role in the diagnosis of acute rejection. the transbronchial allograft biopsy is currently the gold standard to evaluate the graft for cellular rejection and to exclude its clinical mimickers in lung transplant patients. when reviewing transbronchial biopsy material of these patients, attention must be paid not only to features of rejection but also to its morphologic mimickers, especially infection, ptld, and abnormal drug effect. before a diagnosis of acute cellular rejection can be rendered, an infectious process should be excluded by using stains for microorganisms and/ or clinical tests including cultures of bal and/or tissue and serology. while studies to identify histopathologic and immunophenotypic features of amr are evolving, there are currently no specific morphologic findings, and clinical and serologic correlations are required for the diagnosis. prospective, well-designed long-term studies with longitudinal data of therapeutic intervention of acr on histopathology in totally asymptomatic patients with no physiological or hrct evidence of allograft dysfunction are 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pathologic changes in lung allograft biopsy specimens with donor-specific antibodies c d deposition in lung allografts is associated with circulating anti-hla alloantibody acute humoral rejection of human lung allografts and elevation of c d in bronchoalveolar lavage fluid c d and the septal microvasculature as a predictor of chronic lung allograft dysfunction c d and c d deposition early after lung transplantation pathology of pulmonary antibody-mediated rejection: update from the pathology council of the ishlt antibody-mediated rejection of the lung: a consensus report of the international society for heart and lung transplantation hyperacute rejection after single lung transplantation: a case report fulminant hyperacute rejection after unilateral lung transplantation hyperacute rejection of a pulmonary allograft. immediate clinical and pathologic findings susceptibility of lung transplants to preformed donor-specific hla antibodies as detected by flow cytometry hyperacute rejection following lung transplantation hyperacute rejection after lung transplantation caused by undetected lowtiter anti-hla antibodies hyperacute rejection in single lung transplantation-case report of successful management by means of plasmapheresis and antithymocyte globulin treatment treatment of hyperacute antibody-mediated lung allograft rejection with eculizumab prospective study of transbronchial biopsies in the management of heartlung and single lung transplant patients practical applications in immunohistochemistry: evaluation of rejection and infection in organ transplantation key: cord- - ioiwsd authors: varghese, praveen mathews; tsolaki, anthony g.; yasmin, hadida; shastri, abhishek; ferluga, janez; vatish, manu; madan, taruna; kishore, uday title: host-pathogen interaction in covid- : pathogenesis, potential therapeutics and vaccination strategies date: - - journal: immunobiology doi: . /j.imbio. . sha: doc_id: cord_uid: ioiwsd abstract the current coronavirus pandemic, covid- , is the third outbreak of disease caused by the coronavirus family, after severe acute respiratory syndrome and middle east respiratory syndrome. it is an acute infectious disease caused by severe acute respiratory syndrome coronavirus virus (sars-cov- ). the severe disease is characterised by acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. currently, no drugs or vaccine exist against the disease and the only course of treatment is symptom management involving mechanical ventilation, immune suppressants, and repurposed drugs. as such the severe form of the disease has a relatively high mortality rate. last months have seen an explosion of information related to the host receptors, virus transmission, virus structure-function relationships, pathophysiology, co-morbidities, immune response, treatment and most promising vaccines. this review takes a critically comprehensive look at various aspects of host-pathogen interaction in covid- . we examine genomic aspects of sars-cov- , modulation of innate and adaptive immunity, complement-triggered microangiopathy, and host transmission modalities. we also examine its pathophysiological impact during pregnancy, in addition to various gaps in our knowledge. the lessons learnt from various clinical trials involving repurposed drugs have been summarised. we also highlight the rationale and likely success of the most promising vaccine candidates. receptor on enterocytes in the small intestine and is consistent with clinical reports of gastrointestinal symptoms and viral shedding in faeces ( , ) . this has been further resolved with the comprehensive identification of host cells/tissues expressing both ace and tmprss ( figure ). thus, likely targets for sars-cov- primarily include secretory goblets of the nasal mucosa, lung type ii pneumocytes and absorptive erythrocytes of the small intestine ( ) . of note, this study also showed that the ace receptor is an interferonstimulated gene in sars-cov- infection in the cells of the human upper nasal epithelium and lung, predominatly mediated by ifn-α and ifn-γ ( ) . moreover, bystander cells are subject to interferon-mediated effects (upregulation of ace receptor) rather than sars-cov- infected cells, suggesting a mechanism of enhanced viral targeting and entry during pathogenesis and a possible avenue for therapeutic intervention ( ) . analysis of genetic variation in the ace gene has identified single nucleotide polymorphisms (snps) that differ in frequency globally among the human population, particularly between males and females ( ). characterising these snps more fully with epidemiological and clinical data on covid- will in time shed light on the precise molecular mechanisms of transmission and disease. furthermore, in the sars-cov- viral s protein, amino acid substitutions have been described, although these occurred outside the rbd that directly interacts with ace ( ) . of paramount importance is characterising the genetic variation and its consequences in the s protein and its rbd, as this will determine whether the sars-cov- virus is evolving and is likely to be a seasonal infection with new variants for the human population. undoubtedly, variation in the s protein and ace , the central interface of hostpathogen interaction in covid- will have evolved from natural selection contributing to the pathogenesis of this disease. proteins and transported into the endoplasmic reticulum (er). these proteins are processed via the secretory pathway and are transported into the er-golgi intermediate compartment ( , ) , where the full-length viral genomes are packaged with the nucleocapsid n protein, budding from the membrane, and thus forming the enveloped mature virion ( ) . the n protein has two domains that can bind the rna genome, with the aid of nsp protein, and attaching it to the rtc, facilitating the packaging of the virus ( ) ( ) ( ) . the viral m protein has three transmembrane domains and is responsible for the majority of protein-protein interactions needed for virus assembly, including membrane curvature and binding the nucleocapsid ( , ) . pseudo-virus particles can also only be formed when there is a co-expression of m protein and e protein, indicating the requirement of both these two proteins to form the coronavirus envelope ( ) . the viral e protein is also involved in structural shaping of the viral membrane envelope and in inhibiting m protein aggregation, as well as a role in pathogenesis ( ) ( ) ( ) ( ) . after the assembly of the mature virions, they are transported in vesicles, where they are released from the infected cell via exocytosis ( ) . unlike sars, covid- patients had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. in a study involving covid- patients in hong kong recorded high viral load on presentation with the onset of symptoms and also when the symptoms are mild ( ) . sars cov- viral rna load was detected in the deep throat (posterior oropharyngeal) saliva samples for days or even longer. the peak of the viral load correlated positively with age. viral load in posterior oropharyngeal saliva samples was higher during the first week of symptom onset, which gradually declined. thus, the location of sample collection and the timing for the onset of symptoms both are important factors to be considered for the detection of sars cov- positive cases. in the same study, most of the patients showed rising antibody titres days after symptom onset, though the serum antibody levels did not show correlation with clinical severity ( ) . the patient's antibody to sars-cov- viral nucleocapsid protein using infected cell lysates was identified on the th day after symptom onset by western blot ( ) . in another study involving patients with covid- , all were tested positive for antiviral igg within days after symptom onset. both igg and igm titres reached a plateau within days after seroconversion ( ) . in wuhan tongji hospital, around convalescent patients tested positive for the igg against the virus, while patients tested negative for igm, where igg titre was higher comparatively. both the antibody titres showed a decrease when tested weeks apart ( ) . thus, titres of sars-cov- antibodies can reflect the progress of viral infection and can be a vital component to understand the development and prognosis of the disease and similarly timing of antibody seroconversion is also crucial for determining the optimum duration for collecting serum specimens for antibody diagnosis. as previously mentioned, several other studies also confirmed the presence of sars-cov- nucleic acids in the faecal, urine samples and rectal swabs of covid- patients and thus it becomes essential to ascertain viral load dynamics in such samples too ( ) ( ) ( ) . transmission sars-cov- is transmitted through "respiratory droplets", which are large droplets of virusladen mucus or through close contact with infected individuals ( ) ( ) ( ) ( ) . at the same time virus has also been reported to spread via asymptomatic but infected individuals in several countries, including china, germany, usa, and india ( , ( ) ( ) ( ) ( ) . a systematic review and meta-analysis of observational studies with no randomised controlled trials and relevant comparative studies in health-care and non-health-care settings revealed transmission of virus decreased as physical distancing increased to metre or more ( ) . eye protection, n or similar respirators in health-care settings and - -layer cotton or surgical masks in the community were found to greatly control the transmission ( ) . studies have also established that the median half-life of the aerosolised virus is ~ . hours under lab conditions, similar to the sars-cov. however currently, no evidence supports real-world airborne transmission of the virus through aerosols ( ) . sars-cov- was found to remain viable for up to hours on copper surfaces, up to hours on cardboard surfaces, and up to hours on plastic and stainless-steel surfaces. thus, there exists a possibility of contact transmission to occur, although no confirmed cases of contact transmission have been reported ( ) . the virus was also found in the faeces of infected patients showing that the virus can survive and replicate in the digestive system ( ) . this suggests that there may be a possibility of an oral-faecal route of transmission, though again no confirmed cases have been reported ( ) . the royal college of obstetricians and gynaecologist uk have reported that transmission from mother to baby antenatally or intrapartum is possible although this requires further study for confirmation; there appears to be no evidence supporting vertical transmission to the foetus ( ) ( ) ( ) . additionally, as reported by who and cdc, the virus has not been found to be transmitted by breastfeeding and has not been found in breastmilk of covid- mothers ( , ) . covid- was found to have low severity and mortality than sars, but it is highly contagious and affecting comparatively more men than women ( , , ) . the difference in fatality rate between males and females may probably be explained by the fact that as ace is located on the x chromosome. there may be alleles that confer resistance to covid- , at the same time, oestrogen and testosterone sex hormones have different immunoregulatory functions that may contribute to protection or severity of the disease ( , ) . the disease has also been found to disproportionately affect older aged persons and people suffering from social deprivation, diabetes, severe asthma, cardiovascular disease, obesity, haematological malignancy, recent cancer, kidney, liver, neurological or autoimmune conditions ( ) . studies have also reported that members of minority communities such as the black and south asian populations, are at a higher risk of the disease ( ) . the incubation period of the disease ranges between to days and the median incubation period is approximately - days before symptom onset ( , , , ) . during the onset of the illness, the common symptoms that most patients exhibited were fever and cough. other symptoms include conjunctivitis, myalgia (muscle pain) or fatigue, headache, dyspnoea (short of breath), chest pain, diarrhoea, nausea, rhinorrhoea (runny nose), vomiting, loss of appetite, abdominal pain, gastrointestinal bleeding, autoimmune haemolytic anaemia, and sometimes haemoptysis (coughing of blood) ( , ( ) ( ) ( ) ( ) ( ) . patients have also reported anosmia (loss of smell), dysgeusia (distortion of the sense of taste) ( ) ( ) ( ) ( ) . for sars-cov- asymptomatic patients, anosmia, hyposmia, or dysgeusia are symptoms that were suggested for screening ( ) . in addition to these, neurological manifestations such as dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia, seizure, nerve pain, skeletal muscular injury manifestations, intracerebral haemorrhage, central nervous system vasculitis, encephalopathy, encephalitis, cranial neuropathies and psychosis were reported predominantly in older people ( ) ( ) ( ) . in paediatric patients, an autoimmune and autoinflammatory disease, paediatric inflammatory multisystem syndrome (pims), also known as multisystem inflammatory syndrome in children (mis-c), has been reported to occur after sars-cov- infection ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . cutaneous manifestations of covid- have also been reported ( ) ( ) ( ) . a case report from strasbourg, france reported purpuric lesions in the lower extremity ( ) . an italian study reported patients presenting with an erythematous rash, urticaria and chickenpox-like vesicles mainly in the trunk with little or no itching that did not correspond to disease severity ( ) . the prolonged use of personal protective equipment and repeated washing have also led to an increase in dermal conditions such as pressure injury, contact dermatitis, itch, pressure urticaria, and exacerbation of pre-existing skin diseases ( ) . the first step of infection is the inhalation of viral particles present in respiratory droplets from an infected host. once inhaled, the virion enters the nasal cavity of a healthy host and likely binds to goblet and ciliated cells in the nose that express ace ( ) . at this time, a limited innate immune response may occur, and the virus replicates and moves further down the respiratory tract via the conducting airways. as the virions proliferate and spread towards the upper respiratory tract, usually a robust innate immune response is triggered by the detection of the virions by pattern recognition receptors (prrs) like toll-like receptors, rig- , and mda- . this may present several symptoms starting from dysphonia (hoarseness), ulceration of the epiglottis and subglottis, and profound oedema and granulations in the subglottis and also in the upper trachea ( ) . in a few patients, mild tachypnoea and coarse breath sounds were also observed while the virus is in the upper airway ( ) . furthermore, the detection by prr leads to the expression of type interferons (ifn) in the early stages of infection, which helps establish an anti-viral state in the cells by producing inflammatory cytokines and chemokines. the sars-cov produces an enzyme that adds ' o-methyl group to viral rna, which helps it evade detection by mda- , thereby delaying the induction of ifn. studies have established that unlike an early ifn response, a delayed ifn response causes an inability to control viral replication, leading to cellular damage of airway epithelia and the lung parenchyma and an eventual lethal inflammatory cytokine storm ( ) ( ) ( ) . the sars-cov- papain-like protease, which is essential to generate the rtc, has been shown to preferentially cleave the ubiquitin-like protein isg from interferon responsive factor (irf ), attenuating type i interferon responses ( ) . the c-terminus of the sars-cov- non-structural protein was reported to bind to the s ribosomal subunit and block the mrna entry tunnel ( ) . this obstruction effectively inhibits the rig-i-dependent innate immune response ( ) . accordingly, no significant expression of ifn was detected up to hours post-infection with sars-cov- . only il- , which correlates with respiratory failure, acute respiratory distress syndrome (ards), and adverse clinical outcomes were upregulated. monocyte chemoattractant protein- (mcp ), c-x-c motif chemokine (cxcl) , cxcl , and cxlc , were also upregulated h post-infection with sars-cov- ( ) . the suppression of innate immune activation and annihilation of t cells can help explain the mild or even the lack of symptoms in many infected patients. the increased viral replication efficiency in the respiratory tract early on leads to the highly efficient person-to-person transmission of the virus in the community ( ) . the virions further migrate towards the lower respiratory tract and reaches the alveoli where it binds to the type pneumocytes and begins replication. as the type pneumocytes undergo apoptosis after viral release, they secrete inflammatory mediators like cxlc proteins that attract macrophages and neutrophils ( figure ) ( ) . the stimulated macrophages further secrete cytokines such as il- β, il- and tumor necrotic factor α (tnf-α). the released cytokines trigger a "cytokine storm", which stimulates the release of vascular endothelial growth factor (vegf), monocyte chemoattractant protein- (mcp- ), il- , and additional il- , as well as reduced e-cadherin expression on endothelial cells causing vasodilation and increase capillary permeability ( ) . this causes the plasma to leak into the interstitial spaces and alveoli, increasing interstitial and alveolar oedema. the increased alveolar oedema decreases the level of surfactant in the alveoli. this causes an increase in the surface tension in the alveoli, which leads to alveolar collapse. oedema and alveolar collapse may present as multiple peripheral ground-glass opacities in subpleural regions of both lungs, which is observed in many patients ( ) . chest ct scan of patients also revealed bilateral multifocal infiltrates and mediastinal and hilar lymphadenopathy in some patients ( ) . these decrease the gas exchange efficiency causing hypoxemia and increased work of breathing presenting as dyspnoea (shortness of breath), culminating in ards ( ) . abnormal coagulation parameters, mainly elevated d-dimers seem to be associated with a higher risk of development of ards in covid- patients ( ) . the aberrant wound healing may even lead to fibrosis than other forms of ards ( ) . stimulated neutrophils secrete reactive oxygen species (ros) and proteases which destroy both infected and uninfected type and type pneumocytes, leading to further reduced gas exchange and alveolar collapse, respectively ( ) . furthermore, the dead pneumocytes slough off into alveoli filling them up with fluid, protein deposits, cell debris, macrophages, and neutrophils. this causes pulmonary consolidation, which leads to altered gas exchange and causes hypoxemia ( , ) . the consolidation also leads to productive cough. the hypoxemia can further trigger chemoreceptors that stimulate the sympathetic nervous system (sns) that causes tachycardia (increased heart rate) and tachypnoea (increased respiratory rate) ( , ) . the central nervous system (cns) is also affected by the high concentrations of il- β, il- and tnf-α in the blood, as these cytokines stimulate the hypothalamus to release prostaglandins such as pge , which causes an increased body temperature leading to fever ( ) . studies have also reported elevated levels of myeloperoxidase (mpo)-dna and citrullinated histone h (cit-h ), which are markers used to detect neutrophil extracellular traps (nets), in the serum of covid- patients ( ) . furthermore, control neutrophils treated with covid- patient serum exhibited netosis ( ) . nets, while protecting the host from invasive pathogens, have been attributed to play a role in many autoimmune and vascular diseases. for example, nets are known to contribute to ards, pathogen-induced acute lung injury, thrombosis and can contribute to further cytokine release lading to the inflammation ( ) . an increased frequency of neutrophils, eosinophils and monocytes was reported in severe covid- positive patients; severe patients showed further increase in neutrophils though their activation status had not altered. there was no significant change in the immature granulocyte frequencies. however, there was an inverse correlation between frequency of immature granulocytes in moderate and severe patients with the duration since the appearance of symptoms. severe patients exhibited lower percentages of both conventional and plasmacytoid dendritic cells (dc) ( ) . response syndrome (sirs). the spread of the inflammation from the lungs into the circulatory system causes increased capillary permeability within the systemic circulation. this leads to a decrease in blood volume along with increased vasodilation of systemic arteries, leading to decreased peripheral resistance. the decreased blood volume, along with peripheral resistance, causes hypotension (decreased blood pressure), which decreases perfusion to other organs leading to multisystemic organ failure (mof) ( - ). the cytokine storm has also been shown to trigger autoimmune haemolytic anaemias (aiha) (with warm or cold antibodies) ( , , ) . most of the studies report manifestation of aiha early, during the active phase of covid- (within to days), a timeframe matching that of the cytokine storm ( , , , ) . as a result of ards, sirs and mof, patients suffering from severe sars-cov- infection exhibit significantly elevated levels of, il- , il- , il- , g-csf, gm-csf, mip- α, crp, and ddimer, in addition to il- , il- β and tnf-α ( ). there are reports suggesting that in addition to the lungs, sars-cov- infection may induce the multiorgan injury in patients involving brain, heart, liver, kidney, intestine and eyes ( , ) . covid- associated neurological complications the neurological pathologies observed in covid- are similar to those observed in previous coronavirus epidemics ( ) . myoclonus and demyelination are reported in a few cases ( , , ) . a study conducted in wuhan, china involving covid- patients, reported that patients developed neurological manifestations ( ) . in another study from strasbourg, france where effectively patients were recruited for an observational study, reported agitation in % of the patients, confusion in %, and % of the patients had corticospinal tract signs ( ) . a systemic review and meta-analysis of literature databases for psychiatric and neuropsychiatric presentations in coronavirus infections reported transient encephalopathies with features of delirium and psychosis ( ) . the study also reported cognitive dysexecutive syndrome and delirium with agitation in a few cases ( ) . there is also a reported case of autoimmune encephalitis with the typical clinical features of opsoclonus and myoclonus, and another case of autoimmune encephalitis with a radiological imagery showing typical limbic encephalitis ( ) . the exact mechanism for encephalopathy may be multifactorial (effect of sepsis, hypoxia, and/or cytokine storm) ( ) . a few cases of guillain-barré syndrome (gbs) associated with sars-cov- have been reported from italy ( ) . however, further epidemiological and mechanistic study is required to confirm the incidents of gbs in covid- . the binding of the virus to the ace- receptors on endothelial cells causes extravasation of red blood cells leading to cerebral microbleeds ( , ) . there have also been reports of severe strokes in covid- patients, but further study is required to determine its association with covid- ( ) . magnetic resonance imaging (mri) revealed abnormalities such as meningeal enhancement, ischaemic stroke, perfusion changes, microhaemorrhages, medial temporal lobe signal abnormalities similar to that seen in viral or autoimmune encephalitis ( , ) . very few cases have been reported where sars-cov- was detected in csf and its supportive histopathological features; no reports of the virus in the brain exist yet ( , , ) . thus, it is important to establish whether the above-described syndromes may be caused due to either direct viral injury, hyperinflammation, vasculopathy and/or coagulopathy, autoantibody production to neuronal antigens, sepsis and hypoxia, or a combination of these ( ) . out of the first patients diagnosed with covid- in wuhan, of them had myocardial injury associated with the sars-cov- , which mainly manifested as an increase in highsensitivity cardiac troponin i ( ) . the hemogas analysis showed hypoxia; laboratory tests showed elevation of c-reactive protein, transaminases and lactate dehydrogenase, and lymphopenia ( ) . several patients showed abnormal myocardial zymogram, showing high levels of creatine kinase ( ) . because of an excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation (dic), covid- patients may predispose to both venous and arterial thromboembolic disease ( , , ) . it has also been observed that concomitant acute thrombosis of the abdominal aorta and pulmonary embolism induces cardiovascular complications in covid- patients, suggesting an association of hypercoagulable condition with the disease ( ) . covid- patients with abnormal liver function were also documented, where patients had alanine aminotransferase (alt) or aspartate aminotransferase (ast), bilirubin, acute phase recants (apr) like crp, fibrinogen and il- above the normal range ( , ) . sepsis, hypovolaemia, and nephrotoxins were found to be important contributors to kidney damage in covid- patients. cardiorenal syndrome, particularly right ventricular failure, might lead to kidney congestion and acute kidney injury in covid- patients ( ) . symptoms such as olfactory and gustatory dysfunctions were also found to be related to covid- ( ) . sars-cov- , facilitated by tmprss and tmprss , was found to infect and reproduce in ace- + mature enterocytes ( ) . however, the virions released into the intestinal lumen were inactivated by stimulated human colonic fluid and no infectious virions were recovered in stool samples, in spite of the presence of viral rna in stools. this study thus established the intestine as a site of viral replication and its effect on local and systemic illness and overall covid- progression ( ). as in the case respiratory infections by respiratory syncytial virus and sars-cov, the eyes have been shown to act as a portal of entry for the virus. while there have been no reports of sars-cov- transmission in humans via ocular tissues, further studies are required to exclude the eyes as a source of infection and as a portal of entry. moderate conjunctivitis could be the first sign of severe respiratory distress in covid- patients ( ) . studies from china on patients with covid- reported conjunctivitis and other ocular manifestations, such as epiphora, conjunctival congestion, or chemosis in patients with severe covid- ( ) ( ) ( ) ( ) . the studies also reported a few patients with positive conjunctival swab for covid- determined by rt-pcr ( , , ) . similar results were also reported in a study conducted by the national institute for infectious diseases in rome, italy ( ) . in addition to the conjunctivitis, the ocular swabs were positive for sars-cov- even when nasopharyngeal swabs tested negative for the virus. this suggests that the conjunctiva may sustain viral replication for an extended period of time ( ) . there are reports from france, italy, united kingdom and the united states of america, suggesting the presentation of autoimmune and auto inflammatory diseases in children, especially in children of african descent, such as paediatric inflammatory multisystemic syndrome (pims), also known as, multisystemic inflammatory syndrome in children (mis-c) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . this syndrome includes kawasaki-like disease, kawasaki disease shock syndrome, toxic shock syndrome, myocarditis and macrophage activation syndrome ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the exact cause for kawasaki disease remains unknown; however, it is believed that it is caused by an apparent atypical immune response to pathogens in genetically predisposed individuals ( ) ( ) ( ) . previous studies have implicated the pathogenesis of kawasaki disease with the infection of certain members of the coronavirus family ( , ) . the temporal association between the beginning of covid- , sars-cov- infection and the onset of pims suggest a causal link ( ) . this is further supported by the fact that in most cases, the patients exhibiting pims tested positive for igm or igg sars-cov- antibodies ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the presence of igg antibodies clearly indicates a delayed onset of pims following sars-cov- infection ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the onset of pims occurred - weeks after acute covid- ( ) . the patients presented with fever, diffused skin rashes, rash/oedema of hands and feet, conjunctivitis, dry cracked lips, cervical lymphadenopathy and arthritis. the kawasaki-like disease caused by covid- exhibited a few differences in both clinical and biochemical features from patients suffering from kawasaki disease without sars-cov- infection. clinically, the patients suffering from covid- associated kawasaki-like disease were older and the disease occurred in both sexes, unlike the classical kawasaki disease that occurs in younger male children ( ) . the covid- associated kawasaki-like disease also had a higher incidence of abdominal pain and/or more frequent diarrhoea, meningeal and respiratory involvement, and a strikingly different myocarditis severity and frequency when compared to classical kawasaki disease ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . biochemically the patients exhibited leukopenia with thrombocytopenia, increased ferritin, elevated myocarditis markers and high levels of procalcitonin, crp and cytokines were observed when compared to classical kawasaki disease ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . nearly % patients also showed resistance to the initial treatment with intravenous ivig infusion, and required a second infusion for successful treatment ( , ) . while the children exhibited the devastating effects of the cytokine storm associated with covid- , such as heart failure, pneumonia, gastrointestinal, neurological and renal manifestations, the paediatric patients in the french study rarely had respiratory manifestations ( ) . this suggests a different host immune response in children compared to adults. treatment for pims involves the administration of il- receptor antagonist, il- receptor blockers such as tocilizumab or sarilumab, ivig, and steroids or biologics to control inflammation ( , ) . covid- is known to affect older members of the population disproportionately, with adults over the age of years making up to % of hospitalization and having a -fold greater risk of death ( , ) . one possible explanation for this could be the increased baseline inflammation, called inflammaging, commonly observed in individuals over the age of ( ) . studies have shown increased baseline serum concentrations of crp and cytokines such as il- and il- ( ) . inflammaging could be the result of the accumulation of mis-folded proteins, compromised gut barrier, obesity and impaired clearance of dead or dying cells ( , ) . senescent nonlymphoid cells have been known to secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases ( , ) . this increased baseline inflammation inhibits antigen-specific immunity affecting the efficacy of many vaccines ( ) . studies have shown that treatment with rapamycin, mapk inhibitor or steroids reduces this excessive inflammation and enhances vaccine efficacy ( , , ) . in case of covid- , this baseline inflammation may itself not be detrimental but contributes to the initiation of an inflammatory cascade that ends in the deadly cytokine storm ( ) . furthermore the accumulation of senescent cells in the lungs of older patients could inhibit t cell response, induce nkr ligand expression, which marks the cells for elimination by infiltrating t cells expressing nkrs ( ) . as observed in the case of vaccines against other respiratory viruses, inflammaging may reduce the efficacy of covid- vaccinations in this already disproportionately affected group. as with any infection, both the innate and adaptive arms of the immune system are required to mount a successful defence against a viral incursion. in case of covid- , a decrease in the circulating t helper cells (cd + cells), cytotoxic t cells (cd + cells), b cells, natural killers cells, lymphocytes, monocytes, eosinophils and basophils has been reported ( , , , ) . a retrospective, single-centre study involving patients revealed a significant decrease in the total number of regulatory t cells, memory t cells and suppressor t cells ( ) . the study also reported an increase in the percentage of naïve t cells ( ) . as naïve t cells help respond to novel pathogens that the immune system has not yet encountered by managing release of cytokines, this may help explain the hyperinflammation ( ) . the lower levels of memory t cells reported may also explain the relapses reported in covid- convalescent individuals ( ) . direct infection of thp- cells, human peripheral blood monocyte-derived macrophages and dendritic cells by mers-cov and infection of t cells and macrophages by sars-cov has been reported ( , ) . hence, it can be speculated that sars-cov- may also infect monocytes and macrophages by a mechanism that is yet to be elucidated ( ) . receptors such as cd on the surface of t cells and other immune cells may mediate viral entry ( ) . the clinical trial with anti-cd monoclonal antibody, meplazumab, showed promising efficacy and safety in covid- patients ( ) . however, cd did not show a direct interaction with the s protein of sars-cov- ( ) . similarly, lymphopenia can be attributed to sars-cov- direct infection and lymphocyte death, destruction of the lymphatic organs, and/or high levels of the programmed cell death protein (pd- ) on cd + t cells (which is known to trigger t cell exhaustion) ( , , ) . lymphocytopenia, neutrophilia and neutrophil-to-lymphocyte ratio are being used as a predictor for the severity of the illness during early stages of infection and a poor outcome in covid- ( , , , ) . this further alludes to the hyper-inflammatory nature of covid- . furthermore, covid- patients were reported to have elevated serum levels of highsensitivity c-reactive protein and procalcitonin, whose levels have been associated with high risks of mortality and organ injury ( ) . lower percentage and count of cd + , cd + , and cd + lymphocytes populations serve as a prognostic marker for mortality, organ injury, and severe pneumonia ( ) . sars-cov exposed as well as a subset of non-exposed people exhibit a cross-reactive t cell repertoire ( ) . studies have also reported the presence of sars-cov- spike glycoprotein-reactive cd + t cells in peripheral blood of a subset of donor who were not infected with sars-cov- ( , ) . these s reactive cd + t cells were found to primarily react with the c-terminal of the s epitope ( ) . this binding preference could be attributed to the presence of overlapping human coronavirus mhc-ii epitopes in the c-terminal domain. hence, these cd + t cells are cross reactive clones generated during previous infections with endemic human coronavirus ( ) . a long-term information and knowledge for ageing -camden' (linkage) sub-study is currently underway to study if pre-existing antibodies and specific t cells contribute to the devastating effect observed in old people ( ) . the b cell response occurs alongside the t helper cell response (~ week post infection) in covid- patients and helps mount a humoral response via antibodies that would help neutralise the virus ( ) . characterisation of the transcriptome during the recovery stage of the disease revealed significantly lower levels of naive b cells, while plasma b cell levels had increased in peripheral blood mononuclear cells ( , ) . it was found that a certain subset of patients who contract the disease may not develop long-lasting antibodies against the pathogen; it is possible that these patients may be susceptible to the re-infection ( ) . immune cell profiling of covid- patients in the recovery stage by single-cell sequencing has identified several new b cell-receptor changes such as ighv - and ighv - , and isotypes used earlier for vaccine development including ighv - , ighv - , and igkv - ( ) . the strongest pairing frequencies, ighv - -ighj , has been suggested to indicate a monoclonal state associated with sars-cov- specificity ( ) . antibodies analysed from the serum of covid- patients revealed no cross-reactivity with the s subunit of the sars cov spike antigen, while some reactivity was observed between the nucleocapsid antigens of sars-cov and sars-cov- ( ) . the rbd-specific igm and igg antibodies were significantly elevated in the severe and recovered patients ( ) . investigations conducted on covid- recuperating rhesus macaque models, re-infected with sars-cov- , reported no measurable viral spreading, clinical manifestations, or histopathological changes associated with covid- ( ) . the study found lower viral loads in nasopharyngeal or anal swabs or days after reinfection, compared to the recorded viral loads or days after the initial infection with sars-cov- at similar sites. similarly, increased levels of leukocytes and neutrophils were recorded days after reinfection, compared to the levels measured during the initial infection. significantly higher specific antibody titres were recorded day post reinfection. there were also increased activation of cd + t cells, changes in cd + tcm cells and memory b cells. thus, increased production of neutralising antibodies protected the primates against covid- re-infection ( , ) . a study on covid- convalescent individuals revealed that plasma collected after days of symptom manifestation had a variable half-maximal pseudovirus neutralizing titres of less than : in %, below : , in %, and only % showed titres above : , ( ) . interestingly, in spite of the low titres reported, antibodies specific to three distinct epitopes on the rbd of the sars-cov- s protein neutralized at half-maximal inhibitory concentrations as low as single digit ng/ml ( ) . hence, a vaccine that can elicit the production of such highly potent antibodies, or monoclonal antibodies raised against the rbd of the sars-cov- s protein, may be highly protective. however, studies on sars-cov and mers-cov revealed that neutralizing antibodies to s protein can potentially augment severe lung injury by exacerbating inflammatory responses ( , ( ) ( ) ( ) . hence, therapeutic antibodies should be carefully studied to minimise any unwanted pro-inflammatory activity while retaining maximum virus neutralizing capacity. additional specific insights on the intracellular life cycle have also been gained from nextgeneration sequencing (ngs) studies on the transcriptome and epi-transcriptome profile of sars-cov- virus and infected host cell. this fundamental approach has given an insight into the specific molecular dialogue between the pathogen and the host cell. this dialogue is complex. the sars-cov- transcriptome has been studied in high resolution. it has revealed its highly complex nature, mainly as a result of numerous discontinuous transcription events, revealing canonical and non-canonical rna transcripts with rna modifications ( ) . in addition to the canonical full-length genome and other sgrnas, this study also found numerous non-canonical rna transcripts of unknown orfs that contained rna modifications. putative rna medications were identified at an aagaa motif. these previously unknown orfs represent the epi-transcriptome of sars-cov- and has revealed numerous viral transcripts that may be involved in pathogenesis ( ) . another study looked at transcriptome profiling in the primary human lung epithelium and compared differences between sars-cov- and sars-cov infection and identified several pathways potentially involved in pathogenesis and gender-specific differences in clinical presentation ( ) . among the genes that were upregulated were a cluster involved in the cytokine-mediated signalling pathways, and in particular, the il- signalling pathway ( ) . specifically, cytokine pathways driven by nuclear factor kappa-light-chain-enhancer of activated b cell (nf-κb), toll-like receptors (tlrs), mitogen-activated protein kinase (mapk), bone marrow stromal cell antigen (bst ), il- , tnf alpha induced protein (tnfaip ), tnfaip interacting protein (tn p ), intercellular adhesion molecule (icam- ), intercellular adhesion molecule (icam- ), matrix metallopeptidase (mmp ), baculoviral iap repeat containing (birc ), and rho family gtpase (rnd ), were significantly upregulated during sars-cov- infection, suggesting a significant role in pathogenesis ( ) . moreover, rela (nf-κb p subunit) seems to be significantly upregulated in sars-cov- infection, leading to il- involvement ( ) . of note is the expression of oestrogen receptor (esr ), which was also enhanced under sars-cov- infection, suggesting sex hormones may be involved in differential expression during viral infection and may have implications for the differences in clinical severity seen between genders ( ) . additionally, over and hour post-infection, cxcl- was significantly upregulated in sars-cov- infection compared to sars-cov ( ) . a recent study using single-cell rna-seq in human, non-human primate and mouse tissues/cells was able to resolve further the host cellular targets for sars-cov- and their abundance in specific tissue/cell types ( ) . the study identified ace and tmprss co-expressing cells (lung type ii pneumocytes, ileal absorptive enterocytes and nasal goblet secretory cells) and also determined that that ace is induced by interferon-stimulated gene, suggesting a possible mechanism for enhanced viral infection ( ) . the clinical pathways of covid- disease severity may also depend on host-specific factors that may contribute to the 'cytokine storm', or cytokines release syndrome (crs), which is the massive release of pro-inflammatory cytokines including cytokines (il- β, il- , il- , il- , il- , and tnf-α) and chemokines such as cxcl and ccl in the lungs ( , ) . these genomic approaches also shed light on the specific genetic host factors that predispose individuals to this severe clinical presentation. proteomic and transcriptomic studies on bronchoalveolar lavage (bal) samples from covid- patients have also revealed considerable insights into the expression of sars-cov- receptors, co-receptors, immune responses, as well as risk factors for severe disease e.g. age and co-morbidities. asthma, chronic obstructive pulmonary disease (copd), hypertension, smoking, obesity, and male gender status were all associated with higher expression of ace and cd in bal, as well as bronchial biopsy and blood from covid- patients ( ) . furthermore, there was a positive correlation between the expression of cd -related genes in bal and the age and body mass index (bmi) of covid- patients ( ) . in another study on bal from covid- patients, an association was observed between covid- severity and enhanced levels of certain cytokines, e.g. ccl /mcp- , cxcl /ip- , ccl /mip- a, and ccl /mip b ( ) . this study also found that sars-cov- triggered apoptosis and the p signalling pathway in lymphocytes, probably causing additional lymphopenia in these patients ( ) . a comparison of transcriptome profiles between patients with covid- and influenza a virus infection revealed an absence of significant type i interferon/antiviral responses with sars-cov- infection, with enhanced expression of genes involved in metabolic pathways e.g. haem biosynthesis, oxidative phosphorylation and tryptophan metabolism, suggesting an important role for mitochondria during sars-cov- infection ( ) . furthermore, a meta-analysis on bal data from covid- patients also revealed an excess for neutrophils and chemokines ( ) . in meta-transcriptomic sequencing of bal from covid- patients, the expression of proinflammatory genes, especially chemokines, was significantly elevated in these patients compared to community-acquired pneumonia patients and healthy controls, suggesting hypercytokinemia ( ) . it also revealed enhanced dendritic cell and neutrophil activity ( ) . in contrast to sars-cov, which induces an ineffective interferon response, sars-cov- was found to strongly initiate expression of numerous interferon stimulated genes, which are thought to significantly contribute to immunopathogenesis ( ) . similarly, an analysis of rna-seq data sets of bal from covid- patients identified upregulation of neutrophil, inflammatory genes and chemokines, which may be involved in immunopathology, e.g. tnfr, il- , cxcr , cxcr , adam , gpr , mme, anpep, and lap ( ) . chronic co-morbidities for covid- patients include cardiovascular disease, hypertension, diabetes, stroke and malignant tumour ( ) . it was also found that parameters such as older age, underlying hypertension, high cytokine levels (il- , il- , and tnf-α), and high lactate dehydrogenase level were significantly associated with severe covid- during hospital admission ( ) . in a study involving icu patients with covid- pneumonia, all of them showed an incidence of thrombotic complications such as symptomatic acute pulmonary embolism (pe), deep vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism ( ) . approximately, one-third of patients experienced gastrointestinal symptoms. during hospitalization, a substantial proportion of patients presented cardiac injury, liver, and kidney dysfunction, and hyperglycaemia. icu covid- patients had higher plasma levels of il- , il- , il- , gscf, ip , mcp- , mip- , and tnf-α, compared to non-icu patients. majority of icu patients diagnosed with covid- were found to be at highest thrombotic risk ( ) . patients with severe covid- likely developed ards and died of respiratory failure. biopsy samples at autopsy from a patient who died from severe covid- showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates, and mononuclear inflammatory lymphocytes in both lungs ( , ) . diffuse alveolar damage with fibrin rich hyaline membranes are pathological results of covid- . in a study, covid- -infected cancer patients were found to have underlying diseases, such as hypertension, diabetes and chronic obstructive pulmonary disease ( ) . cancer patients with accompanying covid- infection showed deteriorating conditions and poor outcomes, and thus it was recommended to avoid treatments causing immunosuppression ( ) . the complement system is an integral part of the innate immune response. it consists of a group of plasma proteins produced mainly by the liver or membrane proteins expressed on cell surface. these proteins interact in a cascade that leads to the opsonization of pathogens and the induction of inflammatory responses. the complement system comprises of three distinct activation pathways, i.e. classical, alternative or lectin (mbl). the activation of these pathways is based on different molecules present on the pathogen surfaces. the classical pathway is initiated by the binding of c q to the pathogen surface or antibody complex. the initiation of the alternative pathway is triggered by the binding of a spontaneously activated complement component to pathogen surface. the binding of the mbl to mannose-containing carbohydrates on pathogens triggers the initiation of the lectin pathway. the early events of three pathways eventually converge to generate a protease called, c convertase, which is covalently bound to the pathogen. the c convertase then cleaves c , present in plasma, into c a and c b. the c b binds to the pathogen and targets it for destruction by phagocytes. furthermore, c b binds with the c convertase to form c convertase, which produces c a and c b. c b triggers the late events of the complement cascade, which are a series of polymerization reactions where c , c , c and c interact with each other to form the membrane attack complex (mac). the mac can damage the membrane of certain pathogens by creating a pore in it. the c a and c a produced are important small peptide mediators of inflammation [reviewed in ( ) ]. studies in c -/-(gene-deficient) mice infected with sars-cov revealed the presence of c activation products such as c a, c b, ic b, c c, and c dg day post infection ( ) . the c deficient mice showed significantly less respiratory dysfunction and lower weight loss as compared to control. the mice also showed significantly lower levels of neutrophils and monocytes compared to the control. lower il- , tnf-α and il-  levels were reported in the lungs of the c deficient mice ( ) . the study also reported lower weight loss in mice deficient in factor b or c . in view of the critical role of the complement system in sars-cov infection since the first day of infection, it raised possibility for complement involvement in sars-cov- . levels of the terminal component of the complement system (mac) and c a are increased in patients with ards ( , ) . mac is known to damage endothelial cells, and thus, regulation or inhibition of mac by its known regulators such as cd or clusterin could be a potential treatment for endothelial dysfunction/damage in ards or covid- ( ) ( ) ( ) . considering the lectin pathway of the complement system, mbl was shown to bind sars-cov in vitro and inhibit its infectivity ( ) . the n-protein of sars-cov and sars-cov- has been shown to interact with mbl-associated serine proteases- (masp ), which is known to initiate the lectin pathway ( ) , leading to over-activation of the complement system. this same study also highlighted excess complement proteins found in post-mortem covid- patient lungs ( ) . furthermore, deletion of masp or perturbance of the masp- -n protein interaction was found to reduce lung injury. these studies, along with human proteomic studies, demonstrate the activation of multiple complement pathways during a coronavirus infection. in case of covid- , the alternative and lectin pathways of the complement system seem to be preferentially activated ( ) . increased levels of plasma c a and mac were recorded in patients with moderate and severe covid- ( ) . a post-mortem study of lung and skin vasculature in covid- patients showed significant deposits of mac and c d that colocalized with the sars-cov- s-protein, and masp in the micro-vasculature. this study did not find prominent classical features of ards such as hyaline membranes and inflammation in the histopathological examination ( ) . a recent study reported an increase in levels of c a, which correlated with increased covid- disease severity, as well as high levels of expression of c ar in blood and pulmonary myeloid cells of covid- patients ( ) . furthermore, use of anti-c ar monoclonal antibodies in human c ar knock-in mice was found to successfully prevent c a-mediated myeloid cell recruitment and activation, thereby inhibiting acute lung injury ( ) . a recent genetic study in covid- patients as reported that gene variants associated with complement regulatory protein, cd (decayaccelerating factor, which accelerates the decay of complement proteins, and thus inhibits complement activation) is associated with increased risk in clinical outcome (odds ratio . - . ); gene variants that map to c showed some protective effect (odds ratio . - . ) ( ) . neutrophils along with the complement system are another important component in the defence of the host against invading pathogens. neutrophil infiltration in pulmonary capillaries, acute capillaritis with fibrin deposition, extravasation of neutrophils into the alveolar space, and neutrophilic mucositis have been reported in the case of sars-cov- infection ( ) . the neutrophilic extracellular traps (nets) and the neutrophils activated by sars-cov- infection contain c , factor b and properdin, triggering the alternative pathway of the complement system ( ) . while this is usually beneficial, the sustained activation and nets formation leads to a hyper-inflammatory immune response that damages and destroy surrounding tissue. this aberrant behaviour, in concert with the abnormal complement activation, leads to the well recorded clinical manifestations observed in the case of covid- such as ards and pulmonary inflammation ( ) . additionally, nets have been reported to induce the production of excessive thrombin and subsequently generate c a ( ) . hence, it has been speculated that feedback loop that begins with complement activation leading to netosis causing an increases in thrombin production, that further stimulates the complement activation causing enhanced net formation ( ) . microangiopathy refers to a disease of the small blood vessels. the term is used when small blood vessels pathologically thicken or weaken, which leads to impaired flow of blood as well as leaking of cells and proteins. sustained inflammation in the vascular system due to the sars-cov- infection leads to thrombosis and microangiopathy ( , ) . this is supported by reports of increased lactate dehydrogenase, bilirubin, activation of platelets, elevated d-dimer levels and hyper-fibrinolysis ( ) . a post-mortem case series of patients with covid- found thrombotic microangiopathy, which was restricted to the lungs, along with diffuse alveolar damage could have contributed to causing death ( ) . another such study of cases found similar diffuse alveolar damage with significant capillary congestion and microthrombi despite anti-coagulation therapy ( ) . due to the presence of severe pulmonary vascular dysfunction in ards, it has been argued that ards is a type of vascular microthrombotic disease with lung phenotype involvement. this argument is supported by the association of mortality in ards with thrombocytopenia and mof as a result of disseminated intravascular coagulation ( ) ( ) ( ) . in recent times, a couple of theories on the pathogenesis of ards in sepsis have evolved: the 'two-path unifying theory' in which certain homeostasis mechanisms lead to microthrombogenesis, and the 'twoactivation theory of the endothelium' in which the complement mac leads to inflammation via cytokines and microthrombogenesis via platelet activation ( , ). the complement system plays a key role in the pathogenesis of thrombotic microangiopathy. this is a syndrome characterised by thrombocytopenia (low platelet count), microangiopathic haemolytic anaemia and systemic organ damage. atypical haemolytic uremic syndrome (ahus) is an example of such a disorder that typically leads to kidney damage. it is caused by excessive activation of the alternative pathway due to mutations in complement regulators factor h (common), factor i, membrane-cofactor protein, or c . analysis of renal tissue morphology from autopsies of covid- patients revealed strong c b- staining (via the alternative pathway) on the apical brush border of tubular epithelial cells with minimal deposition on glomeruli and capillaries of the kidney ( ) . treatment with eculizumab (c inhibitor) dramatically improved outcomes of survival in ahus. features similar to complement-mediated thrombotic angiopathy such as kidney and cardiac injury increased lactate dehydrogenase and d-dimer, and decreased platelets were observed in covid- ( , ) . eculizumab was used successfully as part of management of four covid- patients with severe pneumonia or ards in the intensive care unit, and this preliminary data is being used to conduct further full-fledged clinical trials with eculizumab ( ) . considering the overlap with complement-mediated thrombotic angiopathy in covid- , few studies are underway to test the effectiveness of complement regulators. a recent case study demonstrated a favourable outcome for the compstatin-based c inhibitor amy- . the study, which involved a -year-old caucasian male with severe pneumonia and systemic inflammation, found that amy- was safe and had a favourable outcome in improving the clinical presentation of the patient significantly ( ) . furthermore, treatment with a recombinant c a antibody on male covid- patients aged and years showed significant benefit in suppressing complement hyperactivation, which contributes to the excessive immune response causing aggravated inflammatory lung injury, a hallmark of sars-cov- pathogenesis and lethality ( ) . one of the many challenges includes determining patients who have a dysregulated complement activation. c bound to erythrocytes has been detected in patients with covid- ( ) , which may prove to be a useful blood marker as well as in identifying patients who potentially merit intervention with complement regulators ( ) . in covid- , endothelial injury has been found to be a key pathophysiological feature. a case series found direct evidence of viral infection of endothelial cells and endothelial inflammation, leading to endothelial cell death ( ) . in covid- patients, endothelial cell abnormalities were recorded in the kidney, lung, heart, small bowel, and liver. of deceased covid- patients were found to have suffered endothelial cell swelling with variable foamy degeneration in the glomeruli and an additional patients were found to have severe injury to the endothelium due to segmental fibrin thrombi in glomerular capillary loops ( ) ( ) ( ) . mac deposition has been observed in the endothelium of covid- patients ( ) . such studies have led to notion that in covid- , there are strong vascular and inflammatory components as well, which play a significant role in the pathophysiology of the illness ( ) . consistent with endothelial injury, the significantly elevated levels of von willebrand factor found in the patient with severe covid- has led to the idea that the infection of the ace expressing endothelium by sars-cov- induces injury and activates the complement , which sets up a feedback loop that maintains a state of inflammation ( , ( ) ( ) ( ) . it is worth noting that ards may occur in covid- despite well-preserved lung gas volume, which could indicate a key role for inflammatory processes, leading to vascular constriction and subsequent low oxygen levels in the blood ( ) . furthermore, d-dimer (a fibrin degradation product) levels are also found to be elevated in covid- and are associated with poorer prognosis ( , ) . these factors add to the importance of understanding vascular changes in this disease, including microangiopathic processes and coagulopathies in patients with covid- . pregnancy is associated with several maternal adaptations in both immune function (immunosuppression) and cardiovascular physiology (increased cardiac output, physiological anaemia, cardiac hypertrophy) that would likely alter susceptibility to viral respiratory infections including sars-cov- . maternal death occurred in % of patients admitted to the icu for covid- and in % of those who required invasive mechanical ventilation ( ) . to date, the literature consists of case reports, case series and retrospective studies. the most common presenting symptoms of maternal covid- are fever, cough, dyspnoea, and gastrointestinal symptoms ( ) . clinical findings of respiratory manifestations were similar to those seen in the non-pregnant populations, with similar ct findings together with elevations in c-reactive protein with decreased white blood cell counts ( ) . although the portal of entry is inhalational, there are widespread systemic effects. the immobility, hypoxia and acute inflammation lead to a prothrombotic hypercoagulable state, and indeed, elevated ddimers are correlated with disease severity ( ) . covid- is thus associated with venous or arterial thromboembolism ( ) . the mechanism by which this occurs is currently thought to be as a result of inflammatory cytokines ( ) inducing production of tissue factor with subsequent thrombin activation. the elevations of d-dimer (often seen in acute phases of infection) may be related to this increased thrombin generation. while serious maternal morbidity has been seen, the vast majority of pregnant women with sars-cov- infection remained asymptomatic for respiratory symptoms ( ) ( ) ( ) . pregnancy is coupled to physiological changes in cardiorespiratory status ( ) which might be expected to alter susceptibility to a respiratory upset. nevertheless, the evidence suggests that this is less prevalent than thought. however, the changes in immune function and coagulation in pregnancy appear to increase some complications. similarly, the coagulopathies seen in covid- in the non-pregnant population might be expected to have deleterious effects in pregnancy, which is already a prothrombotic state. covid- has been seen to be associated with preeclampsia ( , ) with one non-peerreviewed report suggesting a causal link ( ) . the placenta has also been reported as having vascular malperfusion and thrombosis ( , ) , which may provide an underlying explanation for the preeclampsia, a disease, associated with poor placental perfusion and altered vascular function ( ) . evidence of increased clotting at the placental surface suggests that this mechanism may be responsible (in part) for the increased incidence of preeclampsia. sars-cov- virions have been seen in the syncytiotrophoblast, the part of the placenta responsible for the angiogenic imbalance seen in preeclampsia and effects on the release of known factors associated with the disease (sflt- -soluble fms like tyrosine kinase and plgf -placental growth factor) are unknown. the disease is also linked to preterm premature rupture of membrane (pprom) ( , ) , and preterm labour ( ) , both of which are linked to inflammation. the underlying mechanism by which pprom occurs is not entirely elucidated. however, reports have suggested that activation of the coagulation system and thrombin causes fetal membrane weakening and subsequent rupture of membranes ( , ) . the alterations in clotting and thrombin seen in covid- may well provide a mechanism for this. similarly, thrombin has been related to the induction of preterm labour and weakened fetal membranes by induction of decidual colony-stimulating factor (csf)- ( ). at present, there are no drugs, therapeutics, or vaccines approved for curing, preventing, or treating sars-cov- specifically. as of june , a total of ( in human trails, in preclinical development) therapeutic drugs are under development against covid- . the current treatment for sars-cov- patients involves the management of clinical symptoms and providing supportive care. while research into developing new drugs and treatments against sars-cov- are ongoing, much of the effort currently focuses on the repurposing existing medicines used against viruses, multiple sclerosis, arthritis, blood plasma derivatives and malaria. moreover, although immunosuppressive treatments, e.g. corticosteroids have shown promise for covid- , there is considerable concern about possible side effects. other immunotherapeutic approaches given as adjunct therapy and based on neutralizing inflammatory cytokines and other immunomodulators, passive viral neutralization to reduce lung pathology and viral load, could be a promising approach ( ) . a number of these approaches are discussed below. the antiviral drug remdesivir, developed by gilead sciences, is an adenosine analogue, which incorporates into nascent viral rna chains and results in premature termination, effectively inhibiting viral rna synthesis ( ) . it was developed for the treatment of ebola and marburg virus infections ( ) , and animal studies have shown that it is effective against the other coronavirus ( ) . in vitro studies have established its efficacy against sars-cov- ( ) . an open-label trial across the united states, europe, canada and japan showed clinical improvement of of the covid- patients who were treated with a -day course of remdesivir on a compassionate basis ( ) . however, a follow-up multi-centre, randomized, double-blinded, placebo-controlled trial of patients showed that the drug was not associated with a difference in time to clinical improvement. compared to the placebo, the drug was found to have a non-significant but, numerically faster time to clinical improvement in patients with a symptom duration of days or lower ( ) . currently, japan and the usa have allowed the use of the drug under emergency use authorization for the treatment of covid- . in a randomized, open-label, multi-centre phase clinical trials, a -day course remdesivir brought about a significant clinical improvement compared to standard alone in patients with moderate covid- . this clinical study assessed the effect of -day (n= ) and -day (n= ) investigational remdesivir courses plus standard of care, versus standard of care alone (n= ) on clinical improvement on day ( ) . in case of patients with severe disease, both day and courses of the drug have been found to have similar clinical outcomes, but as the study lacked placebo control, the magnitude of benefit cannot be determined ( ) . umifenovir, marketed as arbidol, is a derivative of indole carboxylic acids used for the treatment of influenza a and b virus infection, and other arboviruses ( ) . it functions by incorporating into cell membranes and interfering with the hydrogen bonding network of phospholipids, blocking both the fusion of the virus to the cell membrane and the virusendosome fusion ( ) . in vitro studies have established anti-viral efficacy against ebola virus, human herpesvirus , hepatitis c virus, tacaribe arena virus, sars-cov and sars-cov- ( ) ( ) ( ) . a retrospective study on sars-cov- patients treated with umifenovir did not reveal any improvement in clinical prognosis or accelerated viral clearance ( ) . currently, two randomized and open-label trials to determine the safety and efficiency of the drug are ongoing in china. favipiravir, another anti-viral drug, developed by fujifilm toyama chemical (as avigan) and zhejiang hisun pharmaceutical, is a pyrazinecarboxamide derivative. it is converted into an active phosphoribosylated form (favipiravir-rtp) in cells and is recognized as a substrate by viral rna polymerase, thereby blocking the activity of rna-dependent rna polymerase. it was developed as a treatment against influenza. the drug is currently approved for the treatment of sars-cov- in china and italy. a study with sars-cov- patients treated using the drug has reported that better efficacy was observed in anti-viral activity and lower adverse reactions compared to the control group that was treated with lopinavir/ritonavir ( ) . another prospective, multi-centre, open-label, randomized superiority study with sars-cov- infected patients was conducted at three hospitals. they showed faster recovery from clinical symptoms when compared to the controls that were treated with umifenovir, even though similar numbers required the use of ventilators and oxygen ( ) . there are currently six trials ongoing in china evaluating the efficiency of this drug against other antivirals for the treatment of covid- and a phase clinal trial to assess its effectiveness and safety is scheduled in japan and usa. anti-malaria drugs, chloroquine and hydroxychloroquine, are lysosomotropic agents that function by increasing late endosomal and lysosomal ph, which results in impaired viral release from the endosome or lysosome ( ) ( ) ( ) . in vitro studies have shown antiviral activity against sars-cov- with hydroxychloroquine, a weak diprotic base, to have higher potency against the virus ( , ) . in sars-cov- , chloroquine, along with its lysosomotropic activity, is believed to reduce glycosylation of ace affecting the binding of the virus to the cells ( ) . furthermore, chloroquine is also shown to block the production of proinflammatory cytokines such as il- preventing ards ( ); hydroxychloroquine was found to possess an anti-inflammatory effect on th -related cytokines (il- , il- and il- ) ( ) . initial clinical studies in china involving sars-cov- infected patients, who were treated with chloroquine, showed amelioration of pneumonia, shortened disease progression, increased resolution of lung lesions on ct, and a better virus-negative conversion ( , ) . hydroxychloroquine and combination therapy with azithromycin was found to reduce viral load in a french open-label non-randomised clinical trial and in an observational pilot study ( , ) . nevertheless, these studies were plagued with several limitations, such as small sample size, very short observation period, no randomisation, lack of reports on clinical progression, poorly described inclusion and exclusion criteria, and low national early warning score ( , , ) . another trial with sars-cov- infected patients treated with hydroxychloroquine for seven days in china and a study with effectively sars-cov- patients, revealed no significant difference in the nasopharyngeal viral carriage when compared to the controls that were provided with the local standard care ( , ) . a third randomized clinical trial conducted in china with patients exhibiting mild sars-cov- when treated with hydroxychloroquine were found to have recovered faster from cough and fever when compared to the placebo. however, the result of this study cannot be extrapolated to patients with severe sars-cov- ( ). a retrospective cohort study of random sample of inpatients with laboratory-confirmed sars-cov- admitted to hospitals in the new york city was conducted. it did not find any significant differences in in-hospital mortality associated with the treatment with hydroxychloroquine, azithromycin, or both, compared to the controls where the patients were given neither of the drugs ( ). the us fda and european medicines agency (ema) and many other countries like india and poland have authorized emergency use of hydroxychloroquine to treat sars-cov- infected patients. however, the fda and ema have issued warnings against the reported side effects of the drugs. these include abnormal electrical activity that affects the heart rhythm (qt interval prolongation, ventricular tachycardia, and ventricular fibrillation), particularly when taken at high doses or in combination with the antibiotic azithromycin. other side effects reported are liver and kidney problems, nerve cell damage that can lead to seizures and hypoglycaemia ( , ) . around clinical trials have been registered to study the effects of hydroxychloroquine and chloroquine independently or in combination with each other on sars-cov- have been registered in the usa and china ( ) . another anti-parasitic drug, ivermectin, has been shown to be effective against sars-cov- in vitro ( ) . a clinical trial to assess the efficiency of ivermectin against sars-cov- has been planned to take place in japan soon. the corticosteroid, dexamethasone, functions as an immunosuppressant. the drug is believed to modulate the lung injury caused by a dysregulated immune system, thereby reducing the progression to respiratory failure and death ( ) . in a randomized, controlled, open-label, adaptive, platform trial, , patients treated with mg of dexamethasone (orally or intravenously) for days were found to have a significantly reduced day mortality rate among those receiving mechanical ventilation by . %, and by % among those receiving oxygen without mechanical ventilation, compared to , patients treated with standard care ( ) . treatment with the drug did not provide any benefit to patients who did not require oxygen or mechanical ventilation, hinting at possible harm. the use of corticosteroid in the case of severe respiratory infections requires the use of "the right dose, at the right time, in the right patient" ( ) . this is because a high or an early dose may help the virus proliferate by suppressing the immune system, instead of reducing inflammation. in case of covid- , the peak of viral shedding is higher early in the disease. the benefit of dexamethasone when patients require respiratory support or after the first week of the disease suggest that this stage is dominated by an irrepressible immune response versus active viral replication ( ) . dexamethasone is the first drug found to reduce mortality in covid- ( ). lopinavir/ritonavir is a drug combination. lopinavir is a protease inhibitor, developed by abbott laboratories against hiv- that functions by blocking essential viral proteases ( ) . due to poor pharmacokinetics, it is administered exclusively in combination with ritonavir which increases lopinavir's plasma half-life through inhibition of cyp a-mediated metabolism of lopinavir, thereby increasing its exposure and improving the anti-viral activity of the drug ( ) . in vitro studies have revealed that lopinavir inhibited the replication of the sars-cov- virus in vero e cell ( ) . in a randomized, controlled, open-label trial with patients with laboratory-confirmed sars-cov- infection, no benefit was observed with lopinavir-ritonavir treatment beyond standard care ( ) . another single-blind randomised controlled trial in china treated patients with mild/moderate covid- for days, or umifenovir or standard care with no antiviral ( ) . in the study, no differences were found in the time taken for viral clearance, as assessed by pcr of nasopharyngeal swabs, fever, cough, or lung ct findings. clinical status deterioration to severe/critical from mild or moderate clinical status and gastrointestinal side effects was seen highest in patients treated with lopinavir/ritonavir when compared to umifenovir treated or those treated with standard care and no antivirals ( ) . both these randomised clinical trials suffer from small sample sizes and lack of blinding. a multi-centre, prospective, open-label, randomised, phase trial in hong kong with sars-cov- infected patients involved treatment for days with only lopinavir-ritonavir (control), or with a combination of lopinavir-ritonavir, ribavirin, an oral hepatitis c virus drug, and ifn-. it found that the combination treatment was effective in reducing symptoms and viral shedding faster, as well as duration of hospital stay ( ) . currently, about a dozen trials are studying the effect of the drug against sars-cov- . one such study is a phase randomized controlled trial in china in which the effectiveness of lopinavir-ritonavir against influenza drugs, umifenovir and oseltamivir, is to be studied. another south korean trial is looking to compare the efficacy of lopinavir-ritonavir against hydroxychloroquine. the who solidarity trial and uk-based recovery trial is looking to study the effectiveness of lopinavir-ritonavir independently; the who solidarity trial also looks to the explore the drug in combination with interferon-. another second-generation protease inhibitor against hiv- , darunavir, has shown significant inhibition of sars-cov- replication (in vitro). according to a press release by johnson & johnson, an unpublished single-centre, open-label, randomized, and controlled trial in china in which sars-cov- patients were treated with darunavir and cobicistat was not effective in treating sars-cov- ( ). however, a further three clinical studies in china are scheduled. other drugs currently being tested against sars-cov- include tocilizumab, a monoclonal antibody against il- developed by roche, which is used for the treatment of moderate to severe rheumatoid arthritis by blocking il- activity. the drug was found to have helped cure of covid- patients in a trial conducted in china ( ) . another open multi-centre randomized controlled trial french study awaits publication, in which patients were split into two groups, i.e. routine treatment with and without tocilizumab: in the group treated with tocilizumab, the combination of ventilation requirement (mechanical or non-invasive) or death was achieved in a significantly lower proportion of patients ( ) . a phase trial to test its efficacy in treating patients with severe covid- has been authorised by the fda. moreover, an italian multi-centre, retrospective study of patients with severe covid- pneumonia, revealed that the use of tocilizumab given either intravenously or subcutaneously was associated with reduced risk of mechanical ventilation and death ( ) . anakinra is a recombinant il- receptor antagonist that has shown promise in treating severe covid- disease. in a retrospective cohort study of patients with covid- and ards that were managed with non-invasive ventilation (outside the icu), their treatment with high-dose anakinra was observed to be safe and associated with clinical improvement in % of patients ( ) . another study has also described the early use of anakinra in covid- patients with cytokine storm syndrome (css) and acute hypoxic respiratory failure (ahrf) which may be beneficial in preventing the need for mechanical ventilation ( ) . these results have encouraged further clinical trials to validate its safety and efficacy ( ) . approaches targeting inhibition of bruton tyrosine kinase (btk) has also shown promise. btk plays a significant role in human innate immune responses. tlrs recognize ssrna of viruses like sars-cov- and induce signalling via btk-dependent activation of nf-κb, initiating a pro-inflammatory response ( ) ( ) ( ) ( ) . btk also plays a key role in the activation of the nlrp inflammasome, resulting in maturation and secretion of il- β, a key pro-inflammatory cytokine ( ) ( ) ( ) . thus, btk seems a favourable target against the cytokine storm in covid- . in one study, acalabrutinib (a selective inhibitor of btk) was given to patients with severe covid- and clinical improvements were observed over a -week treatment period, with reduced biomarkers of inflammation (c-reactive protein and il- ) to normal levels ( ) . other dual inhibitors e.g. ibrutinib which target btk/il- -inducible t-cell kinase (itk) signalling have also shown promise ( ) . in one study of patients given ibutinib for treatment of b-cell malignancies and chronic graft-versus-host disease (cgvhd), there was evidence that ibutinib may also protect against pulmonary injury in covid- , which these patients subsequently had, suggesting ibutinib as a possible prophylactic for vulnerable patient groups ( ) . similar findings demonstrating a possible protective role of btk inhibitors in cancer with covid- have also been subsequently described ( ) ( ) ( ) . these promising findings now merit a controlled randomised trial to demonstrate efficacy and drug safety of these btk inhibitors. intravenous immunoglobulin (ivig) is a pooled preparation of normal igg obtained from several thousand healthy donors. it is generally used in the immunotherapy of several autoimmune and inflammatory diseases, ( ) , and thus has been investigated for treating covid- to mitigate the css. ivig therapy has shown promise through several studies, although careful selection of covid- patients and timing of ivig administration appear to be the key for good clinical outcome. preliminary findings from one multi-centre study showed that early administration of high dose ivig improved the prognosis of critical patients with covid- ( ) . similarly, patients with severe covid- who received high-dose ivig made a satisfactory recovery ( ) . in another study, the use of ivig as an adjuvant treatment for covid- pneumonia within hours of admission to the icu reduced the use of mechanical ventilation, icu and hospital time, and the -day mortality rate of patients with severe covid- pneumonia ( ) . in a case study of a covid- patient with respiratory failure and shock, treatment with plasma exchange before ivig treatment resulted in prompt recovery without the need for mechanical ventilation and may be an additional early treatment step to treat critically ill covid- patients ( ) . ivig treatment of severely-ill covid- patients on mechanical ventilation has also shown promise. in one study of patients, treatment with ivig improved clinical and respiratory outcome, particularly saturation o levels, resulting in earlier extubation of the patients ( ) . furthermore, ct graphs obtained after ivig therapy also revealed improvements in pulmonary lesions of these patients ( ) . convalescent plasma therapy (cpt) is another classical adaptive immunotherapy used for the treatment of infectious disease for over a century. it has currently been approved for covid- by the fda under compassionate use rules. the treatment involves the transfusion of high neutralizing antibody titre containing blood plasma from sars-cov- recovered patients. this provides immediate short-term immunity. this is accomplished by binding of the pathogen to the antibody, which results in the activation of the immune system causing cellular cytotoxicity, phagocytosis, or direct pathogen neutralisation. five clinical studies, conducted involving covid- patients who were treated with cpt, revealed significantly lower viral titres, increased levels of neutralizing antibody, improved clinical symptoms such as apyrexia, resolved ards and unassisted breathing ( ) ( ) ( ) ( ) ( ) . among the cpt-treated patients, no fatalities were recorded, and no severe adverse reactions or treatment complications associated with cpt were reported ( ) ( ) ( ) ( ) ( ) . while providing with valuable initial data, these studies suffer from several limitations such as lack of proper control groups, non-randomized evaluations, concomitant drug treatments, poor participant selection, lack of proper cpt dosage, and duration of therapy ( ) . three clinical trials are currently being evaluated by the fda to test the safety and efficiency of cpt in patients who have been exposed to the virus and are at high risk of developing severe covid- , patients who are admitted in hospital with acute respiratory symptoms, and for covid patients under mechanical ventilation ( ) . further trials are also planned or ongoing in china, columbia, iran, mexico and the netherlands ( ) . early safety indicators of covid- cpt were evaluated in a study of , patients and showed that the mortality rate was not unduly high and concluded that transfusion of convalescent plasma appears safe in hospitalized patients with covid- ( ) . while the repertoire of antivirals and repurposed drugs tested against sars-cov- are expected to help manage the disease, the development of a safe and effective vaccine would help cut down the overall number of deaths and prevent the population from getting the disease in the first place. a recent study suggested that mandatory bcg vaccination can possibly be associated in flattening the curve in the spread of covid- . it analysed the rate of day-wise increase in positive cases in countries and deaths in countries for the first -day period ( ) . while arguments for the potentially beneficial effects of pre-existing vaccines have been sporadically made, including giving mmr (mumps, measles and rubella) vaccines to elderly population, generating a sars-cov- specific vaccine seems a logical and obligatory choice. as of july , the who landscape document reports candidate vaccines developed on various platforms ( figure ) in preclinical stages of development: only are under clinical evaluation. mrna- vaccine is a sequence optimized mrna/lnp expressing a perfusion stabilized form of sars-cov- s- p a transmembrane anchored protein with the native furin cleavage site, developed by moderna in collaboration with the national institute of allergy and infectious diseases vaccine research center ( , ) . the vaccine is undergoing an openlabel phase clinical trial that started in march, with healthy adult ( - -year-old) volunteers for six weeks in three dose cohorts ( µg, µg and µg) as two doses approximately days apart via intramuscular injection in the upper arm. three cohorts of - -year-old volunteers and three cohorts of healthy volunteers aged and above are being enrolled in addition to the initial volunteers. the volunteers will be followed through months after the second vaccination to assess safety data, common vaccination symptoms, review trial data and advise niaid ( ) . a phase ii trial with healthy participants in two cohorts ( - years old adults and adults aged years and above) treated with a placebo, a μg or a μg dose has begun from may, th , . the in vivo studies in murine models suggested the vaccine to be immunogenic and could elicit igg a and igg subclass s-binding antibodies. mrna- immunized mice splenocytes showed higher secretion of ifn- than il- , il- or il- upon re-stimulation with peptide pools (s and s ). a dose of μg of mrna- was found to induce robust cd + t cell response to the s peptide pool with balanced th /th ab isotype response in mice. thus, a μg dose of vaccine has been decided for human trial in phase study, which is equivalent to μg dose induced in mice ( ) . the fda has granted fast track designation for the vaccine. the pfizer licensed biontech's bnt vaccine development programme has developed four coronavirus vaccine candidates ( ) . two of the vaccines contain mrna coding for the spike protein of sars-cov- , while the other two contain only the rbd of the spike protein ( ) . furthermore, the four vaccine candidates are made of three different mrna formats. two of the vaccine are based on nucleoside modified mrna (modrna), which incorporates modified nucleosides in the mrna ( ). this suppresses intrinsic immune activation and the production of anti-drug antibodies against the mrna itself ( ). the suppressed immune activity against the therapeutic mrna helps produce the antigenic protein for longer periods ( ). the next vaccine candidate is based on the optimised unmodified mrna (urna) format ( ). urna uses uridine in the mrna, making it more immunogenic ( ). finally, the last vaccine candidate uses self-amplifying mrna (sarna) ( ). it is based on the principle of viral replication. the sarna, in addition to encoding a protein of interest, also encodes, replicase ( ). this enables the self-amplification of the mrna inside the cell ( ). the dsrna intermediate created during the replication of the rna triggers an immune response making sarna a potent activator of the immune system ( ). a phase / , randomized, placebo-controlled, observer-blind, dose-finding, and vaccine candidate-selection study to evaluate the safety, tolerability, immunogenicity, and potential efficacy of the candidate in healthy adult volunteers is ongoing ( ). another frontrunner among the candidates is cansino bio's ad -ncov ( ) . it is a genetically engineered vaccine candidate with the replication-defective adenovirus type (live virus) as the vector to express sars-cov- spike protein. this would help the body to produce neutralizing antibodies against sars-cov- . it has been shown to induce a strong anti-viral activity against sars-cov- in animal and in vitro studies. a single-centre, non-random, open, and dose-escalation phase i clinical trial for recombinant novel coronavirus vaccine (adenoviral vector) in healthy adults aged between and years were conducted. the vaccine has been administered as a liquid formulation intramuscularly in the deltoid muscle ( ) . three different doses were chosen: (a) low dose of x viral particles/ . ml; (b) intermediate dose of . x viral particles/ml; and (c) high dose combines both low and intermediate dose (one in each arm). the volunteers are assessed for a period for months to study any adverse reactions or other relevant outcomes ( ) . most common systematic adverse reaction observed were fever, fatigue, headache and muscular pain but with no serious adverse effect were noted within days. participants showed four-fold increase in anti-rbd antibodies in all the groups; neutralizing antibodies increased gradually being highest at days post vaccination. ad neutralizing antibody titres were boosted significantly postvaccination. il- and tnf- were detected and polyfunctional memory cd + t cell phenotypes were higher than cd + t cells. this suggested ad vectored covid- vaccine to be immunogenic and capable of stimulating both b and t cell response. for phase clinical trial, intermediate dose was chosen and is expected to be completed by january ( ) . the vaccine may have some negative effects in older age people thus in the nd clinical trial participants above years will be included. t cell response peaked earlier from th day after the st shot of vaccine whereas the antibodies production level peaked at th day post vaccination. the study also highlighted the possibility of negative effect on vaccine elicited immune response due to pre-existing ad immunity ( ) . chadox -ncov is being developed by oxford university, uk ( ) . it is a replication deficient simian adenovirus vector chadox , containing full length s-protein of sars cov- along with a tissue plasminogen activator leader sequence. the vaccine is reported to be effective in inducing an antiviral response in animal models ( ) . chadox -ncov was found to be immunogenic in mice mounting robust anti-viral response. single dose of this vaccine was capable of inducing humoral and cellular immune response in rhesus macaques ( ) . a phase i/ii single-blinded, randomised, multi-centre study to determine efficacy, safety and immunogenicity of the vaccine in about healthy adult volunteers aged - years was initiated on april rd , ( ). the volunteers have been subjected to either one dose of x vp of chadox ncov- , an additional booster dose of . x vp of chadox ncov- , or a control of menacwy vaccine delivered intramuscularly ( ). the volunteers were assessed for a period for months to study any adverse reactions or other relevant outcomes ( ) . the results showed increase in s-specific antibodies with a single dose by th day and increase in neutralizing antibodies with booster dose in all participants. chadox -ncov was also capable of inducing heightened effector t-cell response quite earlier than antibody response. t cell response peaked on day th and sustained up to days. the results showed chadox ncov- vaccine to be safe, tolerant and immunogenic, which further supported phase trial which is now underway ( ) . picovacc is a purified inactivated sars-cov- vaccine candidate which is capable of inducing neutralizing antibodies in mice, rats, and nonhuman primates specific to sars-cov- . cn strain of sars cov- virus was chosen to develop picovacc which was inactivated with β-propiolactone. this inactivated vaccine candidate was able to produce about -fold higher s-specific antibody titres in murine model when compared to covid- recovered patients. efficacy of picovacc was also tested in rhesus macaques with an intramuscular low ( . µg), medium ( µg) and high ( µg) dose administered three times ( , th and th day) and on day nd sars cov- cn strain was inoculated through intratracheal (lungs) route. all vaccinated macaques showed protection towards sars cov- infection and their viral loads declined significantly. no notable haemato-and histopathological changes were observed; human clinical trials are awaited ( ) . a group of us scientists have come up with a series of prototype dna vaccines expressing variants of the sars-cov- spike protein. the efficacy of the dna vaccine candidates was evaluated in rhesus macaques ( - -year-old). intramuscular dose ( mg) of dna vaccine was administered, followed by booster dose on rd week and antigenic challenge ( . x viral particles) on th week (both intranasal and intratracheal route). dna vaccine was found to be protective with dramatic reduction of viral replication and enhanced production of sspecific binding as well as neutralizing antibodies compared to controls. the study has not yet addressed the possibility of mutations that may emerge in escaping neutralizing antibodies, though it seems to be protective in primates against sars-cov- ( ). j o u r n a l p r e -p r o o f ino- , developed by inovio, is a dna vaccine candidate ( ) . the optimized spike protein of sars-cov- virus dna plasmids are introduced into cells by the use of a proprietary platform, cellectra®, via electroporation ( ) . once inserted, the plasmids are expected to strengthen the body's own natural response. a phase i open-label study to evaluate the safety, tolerability and immunogenicity of ino- as a prophylactic vaccine against sars-cov- in healthy volunteers aged - years is ongoing ( ) . the volunteers will be treated with either one or two doses of mg of vaccine administered intradermally followed by electroporation the following day ( ) . the volunteers will be assessed for a period for year to study any adverse reactions or other relevant outcomes ( ) . once the initial safety and immunogenicity of the vaccine are satisfied, phase ii efficacy studies are planned. qualitative and quantitative properties of cd + and cd + t cell responses in covid- and prophylactic vaccine development necessitate identifying viral regions and potential epitopes. thus, a total of peptides ( -to -mer), which span the full proteome of the sars-cov- excluding orf- , were designed and used to assess the memory t cell responses upon challenge on patients following recovery from covid- . peptides were identified containing cd + and/or cd + epitopes. the memory of t cell responses from convalescent individuals with covid- was found to be greater in severe covid- cases compared to mild ones. immunodominant epitope clusters and peptides were most markedly observed to belong to spike, m, and orf proteins. in about % of study groups, strong cd + t cell responses specific to the np protein were observed, suggesting the possibility of inclusion of non-spike proteins in future covid- vaccine design ( ) . in another study, a comprehensive immunogenicity map of the sars-cov- virus was carried out; peptide sequences ( -mers) were generated based on computational algorithms. a single -mer peptide containing multiple epitopes that can possibly present on hla class i and class ii across majority of population and provide long-term immunity in most people acting as b and t cell epitopes had been identified. this in silico analysis needs further evaluation for safety and efficacy as a vaccine ( ) . in an unprecedented short span of time and speed since the beginning of the covid- pandemic, significant progress has been made in our understanding of the pathogenesis of sars-cov- infection. however, there are endless unanswered questions; hopefully and most likely, they will be answered in near future. why there are a huge population that are asymptomatic carriers? what are the genetic contributors to susceptibility and resistance to developing covid- ? how pregnant women are so resilient to developing covidsymptoms; for that matter young children as well! what happens during the period of latency, i.e. between being infected and showing symptoms? how far the lung surfactant system gets affected during severe symptoms? what triggers thrombotic microangiopathy in addition to complement activation. on the adaptive immune aspects, what variations exist within population in terms of the proportion of neutralising antibodies? persistence of neutralising antibodies and recall memory magnitude following second infection (on vaccination trials) will yield serious information about how to finetune the dose, duration and vaccination strategies. in this acute crisis, a number of existing drugs have been repurposed empirically; clinical trials have yielded variable results. it is becoming clear that combination therapies are more likely to be successful. deciphering, at high resolution, the mechanisms and consequences of hostpathogen interactions in covid- will lead to novel therapies and preventative vaccination strategies. primary cellular host and co-receptor for sar-cov- . ) attachment and entry of sar -cov- requires priming by transmembrane serine protease (tmprss ) which cleaves the s protein into s and s portions, facilitating, ), s targeting and binding of the receptor angiotensin-converting enzyme (ace ), followed by receptor-mediated endocytosis of the virion into the host cell. j o u r n a l p r e -p r o o f tmprss is the key protease involved in priming sars-cov- , which forms a receptorprotease complex with ace on the host cell surface, thus facilitating viral targeting and entry to the host cell. co-expression of aec and tmprss has been found in proximal as well in distal airways. the nasal cavity has the highest expression of both the receptors in ciliated and secretory (goblet) cells compared to lung bronchi (ciliated and secretory cells) and lung parenchyma (alveolar type progenitor cells, at ). structural conformation of receptor-binding domain (rbd) present in s region of sars-cov- spike protein is capable of influencing the ace -binding affinity. in case of sars-cov- , the rbd contains a four-residue motif glycine-valine/glutamine-glutamate/threonineglycine which enables the binding loop to take a different conformation. it can undergo two possible conformational changes, a "lying down state" which has low affinity towards aec and a "standing up state" with high binding affinity. sars-cov- rbd is found mostly in lying down state, and thus being less accessible to aec . this hidden conformation of rbd in the spike protein can possibly be a masking strategy for immune evasion by sars-cov- . ( ) the sars-cov- binds to the cell via the ace receptor using the s subunit of the spike protein. once bound, the s subunit facilitates virus-cell membrane fusion by two tandem domains, heptad repeats (hr ) and heptad repeats (hr ) to form a six-helix bundle ( -hb) fusion core, bringing viral and cellular membranes into close proximity for fusion and infection. type ii pneumocytes infected with sars-cov trigger the release of cytokines, chemokines and interferons. the secreted inflammatory mediators recruit macrophages, neutrophils and activated t cells. the stimulated macrophages secrete il- , il- and tnf-α. this increases capillary permeability, causing plasma to leak into the interstitial space and the alveolus. the stimulated neutrophils release reactive oxygen species and proteinases, which destroy infected cells. the cell debries and the plasma combine to form a protein-rich fluid. the increasing fluid leads to dyspnoea and pneumonia. it also dilutes the surfactant lining of the 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recombinant adenovirus type- vectored covid- vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial chadox ncov- vaccination prevents sars-cov- pneumonia in rhesus macaques a study of a candidate covid- vaccine (cov ) -full text view -clinicaltrials.gov safety and immunogenicity of the chadox ncov- vaccine against sars-cov- : a preliminary report of a phase / , single-blind, randomised controlled trial development of an inactivated vaccine candidate for sars-cov- dna vaccine protection against sars-cov- in rhesus macaques tolerability and immunogenicity of ino- for covid- in healthy volunteers broad and strong memory cd + and cd + t cells induced by sars-cov- in uk convalescent covid- patients identification of sars-cov- vaccine epitopes predicted to induce long-term population-scale immunity key: cord- -v hh w r authors: leung, c.w.; chiu, w.k. title: clinical picture, diagnosis, treatment and outcome of severe acute respiratory syndrome (sars) in children date: - - journal: paediatr respir rev doi: . /j.prrv. . . sha: doc_id: cord_uid: v hh w r children are susceptible to infection by sars-associated coronavirus (sars-cov) but the clinical picture of sars is milder than in adults. teenagers resemble adults in presentation and disease progression and may develop severe illness requiring intensive care and assisted ventilation. fever, malaise, cough, coryza, chills or rigor, sputum production, headache, myalgia, leucopaenia, lymphopaenia, thrombocytopaenia, mildly prolonged activated partial thromboplastin times and elevated lactate dehydrogenase levels are common presenting features. radiographic findings are non-specific but high-resolution computed tomography of the thorax in clinically suspected cases may be an early diagnostic aid when initial chest radiographs appear normal. the improved reverse transcription-polymerase chain reaction (rt-pcr) assays are critical in the early diagnosis of sars, with sensitivity approaching % in the first days of illness when performed on nasopharyngeal aspirates, the preferred specimens. absence of seroconversion to sars-cov beyond days from disease onset generally excludes the diagnosis. the best treatment strategy for sars among children remains to be determined. no case fatality has been reported in children and the short- to medium-term outcome appears to be good. the importance of continued monitoring for any long-term complications due to the disease or its empiric treatment, cannot be overemphasised. severe acute respiratory syndrome (sars), a newly described infectious disease caused by the novel sarsassociated coronavirus (sars-cov), has become a major threat to public health globally. - sars is highly contagious and has been aptly coined 'the first plague of the twenty-first century'. the disease is characterised by transmission in healthcare and household settings and through intriguing superspreading events which were pivotal in its global spread. [ ] [ ] [ ] [ ] [ ] [ ] [ ] superspreading events including a major hospital outbreak, in-flight transmission on board commercial paediatric respiratory reviews ( ) summary children are susceptible to infection by sars-associated coronavirus (sars-cov) but the clinical picture of sars is milder than in adults. teenagers resemble adults in presentation and disease progression and may develop severe illness requiring intensive care and assisted ventilation. fever, malaise, cough, coryza, chills or rigor, sputum production, headache, myalgia, leucopaenia, lymphopaenia, thrombocytopaenia, mildly prolonged activated partial thromboplastin times and elevated lactate dehydrogenase levels are common presenting features. radiographic findings are non-specific but highresolution computed tomography of the thorax in clinically suspected cases may be an early diagnostic aid when initial chest radiographs appear normal. the improved reverse transcription-polymerase chain reaction (rt-pcr) assays are critical in the early diagnosis of sars, with sensitivity approaching % in the first days of illness when performed on nasopharyngeal aspirates, the preferred specimens. absence of seroconversion to sars-cov beyond days from disease onset generally excludes the diagnosis. the best treatment strategy for sars among children remains to be determined. no case fatality has been reported in children and the short-to medium-term outcome appears to be good. the importance of continued monitoring for any long-term complications due to the disease or its empiric treatment, cannot be overemphasised. ß elsevier ltd. all rights reserved. abbreviations: sars, severe acute respiratory syndrome; sars-cov, sars-associated coronavirus; rsv, respiratory syncytial virus; ards, acute respiratory distress syndrome; cxr, chest radiograph; hrct, high-resolution computed tomography; boop, bronchiolitis obliterans-organising pneumonia; npa, nasopharyngeal aspirate; rt-pcr, reverse transcription-polymerase chain reaction; ifa, immunofluorescence assay; elisa, enzyme-linked immunosorbant assay. *correspondence to: c.w. leung; e-mail: leungcw@ha.org.hk. airliners, transmission in a hotel and a large-scale community outbreak in a densely populated residential complex, primarily resulting from environmental contamination by a 'superspreader' with diarrhoea, were well described. , , [ ] [ ] [ ] [ ] the disease first started as a mysterious outbreak of atypical pneumonia in the guangdong province of southern china in november . by july , , up to countries and regions of the world had been affected by sars. a worldwide total of cases of probable sars, ( %) of these being healthcare workers and deaths ( . %) were recorded. in hong kong, the toll was affected individuals, including ( %) healthcare workers and deaths ( %). the subsequent reemergence of the first six sporadic cases of sars, two of which were probably laboratory-acquired, did not result in local transmission in singapore, taiwan and china. [ ] [ ] [ ] [ ] children appeared to be less affected by the disease, with smaller case numbers and less severe illness reported. [ ] [ ] [ ] [ ] all age groups are susceptible to sars-cov, which is new to humans. however, rapid isolation of diseased adults, whose infectivity is lower in the first few days of illness, has contributed to reduced frequency of household exposure for children. the exact number of children affected by sars worldwide is unknown as the age breakdown of reported cases was not available or incomplete for some of the affected countries (who sars surveillance team, personal communication). it is estimated that children < years of age only accounted for about % of the total affected. there was no reported mortality in children (who sars surveillance team, personal communication). a total of children aged < years were registered in the e-sars database of the hospital authority of hong kong, accounting for % of all patients notified. the crude age-specific attack rate for children in hong kong was . per persons < years of age. serologic confirmation of sars was documented in children ( . per persons < years of age). sixty-four children with clinical disease and seroconversion to sars-cov were managed in the authors' hospitals. the experience with this cohort of laboratory-confirmed patients forms the basis of the clinical information presented in this review. , most children reported worldwide were previously healthy and there was no sex predominance. thirty-five ( %) of the children managed by the authors were girls. the male to female ratio was : . . their mean and median ages were . and years, respectively. the youngest patient was a -day-old premature infant, which is the youngest case reported to date. comorbidity was only present in children ( %) but none of them were immunocompromised. an epidemiologic link was available in the vast majority of children with sars, which appeared to be the most important clue leading to diagnosis in an epidemic situation. worldwide, children were usually secondary household contacts of affected adults, some of whom were healthcare workers or international travellers returning from areas with local transmission of sars. transmission among children or from children to adult contacts was uncommon. about % of serologically confirmed children in hong kong were victims of a point source community outbreak due to environmental contamination. the actual proportion of children being secondary household contacts in the particular outbreak could not be determined given the short incubation period between exposure, either to a common environmental source or an index household member, and presentation. there is no published report on the differences in susceptibility and communicability between children and adults. any apparent difference might be related to different risks of exposure for the two age groups. sars is largely an atypical pneumonia with minimal or no extrapulmonary manifestation, apart from diarrhoea. cellular tropism of the sars-cov has been demonstrated primarily in pneumocytes and surface enterocytes of the small bowel. the clinical presentation of sars is nonspecific, with features overlapping those of atypical pneumonia caused by other respiratory pathogens such as influenza virus (including highly pathogenic avian influenza viruses), parainfluenza virus, adenovirus, respiratory syncytial virus (rsv), mycoplasma pneumoniae, chlamydia pneumoniae, chlamydia psittaci and legionella pneumophila. the clinical course of sars in adult patients is well described and appears to follow a triphasic pattern. , [ ] [ ] [ ] [ ] [ ] following an incubation period of - days (mean . days, % ci . to . ), adults present with a prodrome characterised by high fever (temperature > c), chills or rigor, malaise, headache, dizziness and myalgia. upper respiratory symptoms such as coryza and sore throat are mild and uncommon. diarrhoea is a presenting feature in - % of adult patients. , , after - days the disease progresses to involve the lower respiratory tract and a dry, non-productive cough or dyspnoea becomes prominent. in - % of cases, progression to acute respiratory distress syndrome (ards) necessitating intubation and assisted ventilation is observed. mortality results primarily from respiratory failure and a significant proportion of patients recover from pulmonary destruction over an extended period. sars appears to run a less aggressive clinical course in children compared with adults. the severity of illness varies and the extent of asymptomatic infection is unknown, although it is believed to be uncommon. children are usually hospitalised - days after the onset of symptoms. in one paediatric case series, the mean duration of fever before admission was . ae . days (median , range - ). the most common presenting clinical features in children include fever, malaise, cough, coryza, chills or rigor, sputum production, headache and myalgia (table ) . , lethargy, poor feeding or anorexia, nausea, vomiting, diarrhoea, abdominal pain, sore throat, dyspnoea and dizziness are less commonly encountered. less than % of children may pass loose to watery stools, but profuse diarrhoea is rare throughout the course of illness. blood and mucus in the stool, features suggestive of inflammatory enterocolitis, have not been reported. cough, predominantly unproductive in nature, is only found in just over half of the children at presentation. definite physical signs of consolidation are hardly evident and crepitations (crackles) on chest auscultation are unusual despite prominent radiographic evidence of pulmonary infiltrates, even in patients who develop respiratory distress, hence the description of 'atypical' pneumonia. lymphadenopathy, hepatosplenomegaly or clinical bleeding is absent. skin rash is an exceedingly rare manifestation. hypoxaemia is seldom noted at presentation and generally develops towards the end of the first week or the beginning of the second week of illness in severe cases. the youngest patient, however, presented with a cyanotic attack, dyspnoea, cough and hypothermia with subsequent development of fever. teenagers (aged > years) may resemble adults in presentation and disease progression. they tend to have more constitutional upsets and systemic symptoms of malaise, chills or rigor, headache, myalgia and dizziness are significantly more common ( table ) . they appear sicker, have a greater need for oxygen therapy and other respiratory support and may require intensive care. children years of age generally have milder symptoms and coryza is significantly more common ( table ) . they appear to run a milder and shorter clinical course. the clinical picture is sometimes indistinguishable from other viral infections of the upper respiratory tract, thus posing a diagnostic challenge. the clinical course of sars in the majority of children follows a biphasic pattern. the phase of viral replication, which lasts for a few days, is characterised by an abrupt onset of fever and constitutional symptoms in association with an increase in body viral load. the phase of immunopathologic damage is marked by the progression of pneumonia and hypoxaemia, when the body viral load declines and an exaggerated host immune response supervenes. the prodromal and pneumonic phases of the disease, however, may be less distinct in comparison with adult patients. progression to ards, or the third phase as in adults, is only seen in a very small number of children, predominantly adolescents. the natural history of untreated sars in both adults and children remains unclear. as most patients worldwide had received some form of empiric treatment in the form of antiviral agents with or without corticosteroids, the probability of spontaneous recovery could not be ascertained. nevertheless, three children with mild disease had recovered on supportive therapy alone in the authors' cohort. , anecdotal reports of extrapulmonary manifestations of sars, in the form of central nervous system dysfunction and probable viral hepatitis, have been described in adults. [ ] [ ] [ ] atypical presentation of sars, in the form of non-specific febrile illness or febrile non-pneumonic respiratory illness, have been observed in both children and adults. , , such cases are likely to evade clinical detection in the absence of a definite contact history with patients with suspected or confirmed sars. the full spectrum of clinical as well as subclinical illnesses caused by infection with sars-cov will unfold with further epidemiological studies and case reports. as sars is basically a pneumonic infection, chest radiograph (cxr) is therefore an essential diagnostic tool. the principal radiographic abnormality of sars in children is illdefined airspace shadowing, which presents as ground-glass opacities and/or unifocal, lobar or multifocal areas of consolidation. [ ] [ ] [ ] [ ] , unilateral focal opacity was reported as the most common finding in one paediatric case series and was evident in % of children at presentation (fig. ). in adults, regions of airspace disease predominate in the lower lobes but are also noted elsewhere. there appears to be no predominant distribution pattern of consolidation in children. [ ] [ ] [ ] cxr opacities are most often peripheral or mixed central and peripheral in location. the lung opacities show a tendency to progress, with increase in size or involvement of multiple areas either unilaterally or bilaterally in moderate to severe cases. rapid progression to unilateral multifocal or bilateral involvement, with reduction in lung volumes in the second week of illness, is typical in children who develop severe hypoxaemia (fig. ) . in the advanced stage of the disease, which only occurs in a very small number of children, widespread ground-glass opacities and diffuse patchy consolidations are seen, likely representing progression to ards. pneumonic changes may not be apparent at presentation as mildly symptomatic individuals may be identified early in the prodromal period through contact tracing of patients diagnosed with sars. repeat cxr examination, as guided by failure of resolution of symptoms or change in clinical condition, will clarify the picture by revealing new pulmonary infiltrates as the disease progresses. frequent monitoring of cxr changes has the additional benefit of detecting early radiographic deterioration in many patients, heralding clinical deterioration. radiographic resolution, on the other hand, generally lags behind clinical improvement. complete resolution of the airspace opacities can take more than a month in the most severely affected children. no preliminary evidence of pulmonary fibrosis, bronchial wall thickening, bronchiectasis or lung volume loss was observed on follow-up in one paediatric case series. viral pneumonias tend to show reticulo-nodularity as well as a symmetrical perihilar peribronchial pattern of infiltration which is sometimes marked by hilar adenopathy. in contrast to pneumonias caused by other respiratory pathogens, the cxr of children with sars shows no evidence of interstitial disease, hilar adenopathy, mediastinal widening, significant pleural effusion, cavitation, abscess formation, pneumatocele, pneumothorax or pneumomediastinum. [ ] [ ] [ ] [ ] , nevertheless, the radiographic features of sars in children are non-specific. radiological differentiation of sars from other commonly encountered childhood respiratory illnesses causing airspace disease can be difficult. high-resolution computed tomography (hrct) of the chest has been used as an early diagnostic tool in clinically suspected children with initial negative or equivocal chest radiographs. [ ] [ ] [ ] [ ] hrct findings may include groundglass opacification, unifocal or multifocal consolidation in subpleural, peripheral or central regions and interlobular septal and intralobular interstitial thickening (fig. ) . the characteristic peripheral alveolar opacities are reminiscent of bronchiolitis obliterans-organising pneumonia (boop). , , in general, hrct is sensitive in detecting more extensive airspace consolidation and ground-glass attenuation than cxr. the investigation is particularly useful when lung parenchymal abnormalities are minimal early in the course of illness, or being obscured by the diaphragm and the cardiac silhouette. the utility of chest hrct lies in the early confirmation of airspace disease in radiographically inapparent cases with a strong contact history and clinical features highly suspicious of sars, thus allowing prompt isolation and monitoring for clinical and radiological deterioration. the haematological and biochemical abnormalities of sars in children are neither diagnostic nor specific. like adults, the most consistent haematological finding is lymphopaenia, which is present in about % of children at presentation and about % during the course of illness. , depletion of lymphocytes may be secondary to the direct cytopathic effect of the virus, cytokine-mediated apoptosis, lymphocyte margination due to increased cortisol secretion from activation of the hypothalamic-pituitary-adrenal axis or the administration of high-dose glucocorticoids, which have a profound lympholytic effect, especially on t lymphocytes. [ ] [ ] [ ] other haematological abnormalities such as leucopaenia, thrombocytopaenia and mildly prolonged activated partial thromboplastin times are observed in about % of children. anaemia is rarely found at presentation and is only detected in < % of children. , unlike adults, a significant drop in the haemoglobin level during the course of illness that necessitates discontinuation of empiric antiviral therapy, namely ribavirin, has not been observed. [ ] [ ] [ ] reactive thrombocytosis on recovery from sars is significantly more common in children years of age. this phenomenon is sometimes observed in children recovering from systemic viral infections and is probably not related to the use of corticosteroids. despite an abnormal clotting profile with elevated d-dimer levels and the detection of lupus anticoagulants in a small number of children, bleeding events or thrombotic complications have not been reported. , the most common biochemical abnormality in children with sars is an elevated lactate dehydrogenase level, which is present in about % at presentation and about % during the course of illness. elevated alanine aminotransferase levels are seen in < % of children at presentation and < % during the course of illness. elevation of creatine kinase levels vary from % to % between case series. , teenage patients tend to have more derangement of laboratory parameters and they may take longer to resolve. similar to human infection with avian influenza a h n virus, cytokine dysregulation is believed to be pivotal in the immunopathogenesis of sars among adults and children. serial monitoring of the plasma inflammatory cytokine profile using flow cytometry in a cohort of eight paediatric patients suggests that the caspase- -dependent pathway in infected macrophages is selectively activated, as reflected by substantial elevation of circulating interleukin- b levels. conversely, interleukin- and tumour necrosis factor-a levels, which are markedly increased in human infection with avian influenza a h n virus, are not overtly elevated throughout the course of illness. , the predominant activation of the th immune response facilitates viral clearance and may explain the rapid recovery of children. as sars is a newly emerging infectious disease with unknown aetiology initially, the initial case definitions of suspected and probable sars promulgated by the world health organization were meant for surveillance and were necessarily broadly inclusive and non-specific. patients were categorised based on clinical, radiologic and epidemiologic features and after exclusion of alternative diagnoses. the original who surveillance case definitions for sars required that lower respiratory symptoms of cough, short-ness of breath or difficulty breathing were present. applying this would have missed many children who do not present with the above symptoms. the lack of sensitivity and specificity of the initial who case definitions have generated uncertainty in individual case management at the point of care. , with more understanding of the disease and identification of a novel coronavirus as the causative agent, the case definitions of sars were revised on may , . as the clinical and radiologic features were non-specific, much emphasis was placed on the identification of an epidemiologic link to suggest the diagnosis. the vast majority of patients in the last epidemic had a clear history of exposure, either to patients suspected of or diagnosed with sars, or to a setting where recent local transmission was occurring. when the epidemic was over, an epidemiologic clue became more difficult to ascertain in sporadic cases that re-emerged. the latest who case definitions in the post-outbreak period now incorporate both clinical and laboratory elements, with further emphasis on clearly defined microbiologic criteria besides exclusion of alternative diagnoses (table ) . nevertheless, careful epidemiologic history taking remains essential in the diagnostic work-up and early implementation of appropriate infection control measures in suspected patients. important questions to ask in the 'peace time' include: ( ) history of recent travel to pre-viously sars-affected areas or areas with an increased likelihood of animal to human transmission of sars-cov infection; ( ) close contact with a suspected sars patient; ( ) history of recent hospitalisation or contact with a healthcare facility; ( ) individuals who are either healthcare workers or laboratory workers with potential exposure to sars patients or live sars-cov; and ( ) link to a cluster of cases of unexplained respiratory illness in the community. microbiological investigations are the cornerstones for the confirmation of sars. the diagnostic work-up should include tests for pathogens which cause communityacquired pneumonia in children. a blood culture is also needed. for children with productive cough who are old enough to produce a reliable specimen, sputum for bacterial culture should be performed. nasopharyngeal aspirate (npa) should be saved for rapid antigen detection of influenza a and b, rsv, adenovirus and parainfluenza types , and , using direct immunofluorescence assays. urine samples may be tested for legionella pneumophila and streptococcus pneumoniae antigens. npa specimens should also be inoculated into different cell lines for isolation of respiratory viruses. serologic studies should include mycoplasma pneumoniae igm and paired acute and convalescent sera for igg against mycoplasma pneumoniae, chlamydia pneumoniae, chlamydia psittaci, legionella pneumophila, influenza a and b, rsv, adenovirus and parainfluenza types , and . specific tests for the detection of sars-cov include: ( ) molecular or nucleic acid amplification test using reverse transcription-polymer-ase chain reaction (rt-pcr); ( ) antibody tests; and ( ) cell culture. in view of the high transmissibility of sars in hospitals, laboratory confirmation of the diagnosis early in the course of illness is vital to allow for the best utilisation of the limited isolation and cohorting facilities in most hospitals. rapid diagnosis with rt-pcr tests targeting specific segments of the sars-cov genome, primarily the polymerase gene, were used extensively during the last epidemic. [ ] [ ] [ ] [ ] [ ] [ ] [ ] the method can be applied to nasopharyngeal aspirates, nose and throat swabs, saliva, sputum, endotracheal aspirates, bronchoalveolar lavage, stool, urine, plasma and serum. nasopharyngeal aspirates, combined nose and throat swabs and stool are the most commonly used. experience in hong kong and toronto suggests that the first generation conventional rt-pcr assays in use at the time of the initial outbreak lacked sufficient sensitivity to clinically rule out sars. , despite initial optimism, the test has a sensitivity of % in npa, % in combined nose and throat swabs and % in stool in the first days of illness. it only reaches a maximum sensitivity of % when performed on upper respiratory specimens collected between days to from onset of fever (government virus unit, public health laboratory centre, hong kong special administrative region. data on file), where day coincides with the maximum viral load in npa specimens as clinical picture, diagnosis, treatment and outcome of sars in children a person with a history of: fever (! c) and one or more symptoms of lower respiratory tract illness (cough, difficulty breathing, shortness of breath) and radiographic evidence of lung infiltrates consistent with pneumonia or rds or autopsy findings consistent with the pathology of pneumonia or rds without an identifiable cause and no alternative diagnosis can fully explain the illness laboratory definition of sars a person with symptoms and signs that are clinically suggestive of sars and with positive laboratory findings for sars-cov based on one or more of the following diagnostic criteria: (a) pcr positive for sars-cov using a validated method from: at least two different clinical specimens (e.g. nasopharyngeal and stool) or the same clinical specimen collected on two or more occasions during the course of the illness (e.g. sequential nasopharyngeal aspirates) or two different assays or repeat pcr using a new rna extract from the original clinical sample on each occasion of testing (b) seroconversion by elisa or ifa negative antibody test on acute serum followed by positive antibody test on convalescent phase serum tested in parallel or four-fold or greater rise in antibody titre between acute and convalescent phase sera tested in parallel (c) virus isolation isolation in cell culture of sars-cov from any specimen and pcr confirmation using a validated method measured in adult patients. the low viral load in the upper respiratory tract in the initial few days of illness poses a diagnostic challenge. the lower respiratory tract as the primary target of sars-cov infection is the probable explanation. sputum specimens appear to have a higher diagnostic yield but productive cough is uncommon in sars patients in the early phase of illness and sputum is difficult to obtain in children. the overall diagnostic yield in the second week of illness increases to > % when stool specimens are also examined, with stool yielding better results than respiratory specimens. improving rna extraction from the specimen can markedly improve the sensitivity of conventional rt-pcr assays. when a modified rna extraction protocol is combined with an optimised real-time rt-pcr assay, a sensitivity of % and specificity of % can now be achieved in the first days of illness, using npa as the preferred specimen. a recently described real-time nested pcr assay performed on throat swabs is capable of detecting < copies of viral genome per reaction and achieves a much shorter turn-around time than conventional nested rt-pcr. the technique of real-time rt-pcr has also been applied to plasma and serum samples. it has been shown that % of plasma and % of serum samples are positive for sars-cov rna during the first week of illness in adult sars patients. a detection rate of . - % obtained in the plasma of eight paediatric patients within the first week of illness similarly suggests that plasma sars-cov rna quantification is a very sensitive and potentially useful early diagnostic tool. the potential advantages of realtime rt-pcr include an increase in sensitivity, reduction in analytical time, reduction of risk of carry over contamination and availability of quantitative result for disease monitoring and prognostic purposes. interestingly, despite a milder clinical course in paediatric patients, no significant differences in plasma viral loads are observed in plasma samples taken from paediatric and adult sars patients within the first week of admission and at day after fever onset. obtaining an npa specimen has been regarded by some as a hazardous procedure posing significant risk to the operator, although it is the best specimen for the rapid diagnosis of sars and the exclusion of other pathogens in the early phase of illness. to obviate the need for the protection of healthcare workers, an ingenious method for self-obtaining nasopharyngeal specimens through conjunctiva-upper respiratory tract irrigation (curti) has been described as an alternative. the lack of serologic evidence of prior sars-cov infection in humans suggests that the virus has only recently entered the human population, presumably from an animal reservoir in southern china. , specific igm and igg antibodies appear in response to sars-cov infection, with their levels changing during the course of the infection. serum antibody testing by immunofluorescence assay (ifa) or enzymelinked immunosorbant assay (elisa) have been developed to diagnose sars. , , , the ifa test detects igm and igg antibodies and yields positive results in % and % of cases, respectively, after days of illness. both are detectable in % of ifa tests by days. an indirect immunofluorescence test for igg antibody provides a sensitivity and specificity of %. the elisa test detects a mixture of serum igm and igg antibodies, % and % respectively being positive by the second week. detection rate for both is % by week . the decay curves suggest that igm seropositivity is lost by about weeks, while igg titres peak at weeks and remain elevated until weeks. the antibody response is usually negative until days from onset of symptoms. by day , seroconversion is demonstrated in % of sars patients despite corticosteroid therapy. seroconversion from negative to positive or a !four-fold rise in igg antibody titres indicates recent infection. no detection of antibody in serum obtained > days from onset of illness indicates an absence of sars-cov infection and is the only laboratory method for excluding the diagnosis. , serologic testing appears to be the best method for confirming sars, with positive rates ranging from % to %. , , igm or other antibody assays have not been successful in closing the diagnostic window within the first week of illness. even if some patients seroconvert early, the utility of serology is confined to retrospective diagnosis given the generally long lag time to seroconversion. igg usually remains detectable after resolution of the illness but the duration of persisting protective neutralising antibodies and their boosting response remain unknown. sars-cov can be isolated from respiratory secretions, blood or stool by inoculating cell cultures and growing the virus. vero e cells and fetal rhesus monkey kidney cells are suitable to support the viral growth, with the cytopathic effect demonstrable by - and - days respectively after inoculation. [ ] [ ] [ ] the cultured virus must be identified as sars-cov with further tests, primarily rt-pcr assays. the major limitation of viral culture in sars is its very low sensitivity. in one paediatric series, the virus was only successfully isolated from npa cultures in % of children. negative cell culture results, like negative rt-pcr results, do not exclude sars infection. cell culture is also a very demanding test and primary virus isolation takes too long to be meaningful for early diagnosis. furthermore, amplification of the viable virus is associated with a potential biohazard, necessitating biosafety level three containment. culture-based diagnostic techniques are unlikely to be widely available but with the exception of animal inoculation, it is the only way to show the existence of viable sars-cov. , the usual 'gold standard' of microbiological diagnosis, namely the isolation of the pathogen, has limited application in sars. during the global outbreak of sars, it was understandable that treatment was empiric, given the explosive epidemic of a life-threatening infection in multiple countries before the viral agent was even identified. time for planning, let alone conducting, a well-designed prospective clinical trial to assess the efficacy of any treatment regimen was simply not there. a proposed regimen consisting of antibiotics, ribavirin and corticosteroids was based on initial anecdotal successes in outbreak studies in adult patients. , subsequently, a standard treatment protocol was developed by a group of physicians in hong kong, which included ( ) antibiotics for treatment of community-acquired pneumonia caused by usual and by atypical pathogens, ( ) ribavirin as a broad-spectrum antiviral agent targeting the presumed viral etiology of sars, and ( ) immunomodulating agents in the form of glucocorticoids. a similar regimen in children consisting of antibiotics and ribavirin, with or without corticosteroids, was used. , , in adult patients, the high incidence of deranged liver function, leucopaenia, severe lymphopaenia, thrombocytopaenia and progression to ards suggests severe systemic inflammatory damage induced by sars-cov. the pathogenesis of the infection is postulated as an over-exuberant immunopathological reaction or a ''cytokine storm'' resulting from unrestricted viral replication during the early stages of the disease. findings consistent with cytokine dysregulation are the radiological changes of multifocal, flitting, boop-like features with progression to ards, the histological changes of macrophage infiltration and diffuse alveolar damage and the dramatic clinical and radiologic improvement with high-dose corticosteroid therapy. , the viral load in sars followed an inverted v pattern, with progressive fall in viral shedding after day - , correlating with seroconversion. the logical approach to preventing severe disease is to restrict viral replication and to modulate inappropriate immunological responses. in principle, antiviral agent should be prescribed first during the phase of active viral replication, followed by an immunomodulator if the former fails and the patient is affected by immune hyperactivation. the use of ribavirin in adults and children has been reported by groups of investigators worldwide. , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] , [ ] [ ] [ ] [ ] [ ] [ ] ribavirin was empirically chosen in sars because of its broad-spectrum of activities against dna and rna viruses. ribavirin was also known to be effective in the treatment of fulminant murine hepatitis, which is caused by an animal coronavirus. in the murine hepatitis model, ribavirin exerted an immunomodulatory effect by decreasing the release of proinflammatory cytokines from the macrophages and switching the immune response from a th to a th response. , however, it was later learnt that ribavirin demonstrated no or minimal activity against sars-cov isolates in vitro. , in vitro testing indicated that ribavirin failed to inhibit replication or cell to cell spread at low drug concentrations. although inhibitory activity was demonstrated at high drug concentrations, the resultant cytotoxic effects were undesirable. it appeared that due to the low activity of ribavirin in vitro, inhibitory concentrations might not be achieved clinically without causing significant toxicity. investigators in canada have generally used ribavirin at a higher dosage similar to that recommended for treatment of several viral haemorrhagic fever syndromes and have observed severe adverse events in adult patients. booth et al. reported that % of patients had elevated hepatic transaminase levels, % had sinus bradycardia, % had haemolysis with haemoglobin levels declining by at least g/ dl in % and that % had to discontinue treatment. knowles et al. reported that %, % and % of patients had haemolytic anemia, hypocalcemia and hypomagnesaemia, respectively. children appear to tolerate ribavirin much better than their adult counterparts. [ ] [ ] [ ] [ ] solid clinical data to demonstrate the efficacy of ribavirin is lacking. the limited data suggest that, at least in adults, dosages of about g/d might be effective while not causing severe adverse reactions. such doses should be considered for further studies. doses lower than g/d appear ineffective. the only randomised controlled trial involving the use of ribavirin in the treatment of sars was conducted in china by zhao et al. the open-label study failed to demonstrate any efficacy and led the investigators to conclude that ribavirin, given at - mg/d, was less effective than early and aggressive use of corticosteroids combined with non-invasive ventilatory support. non-randomised studies of corticosteroids have been reported in both adults and children with seemingly favourable outcomes in terms of clinical and radiologic improvements, suggesting that the combined use of ribavirin and corticosteroids might be effective. , , [ ] [ ] [ ] , , , , , , other reports on the combined regimen were inconclusive or failed to demonstrate obvious benefit. , , in the paediatric series reported by leung et al., % and % of the children with laboratory-confirmed sars were treated with ribavirin and corticosteroids respectively, without significant adverse events and all patients recovered. in the series reported by chiu et al., % and % of the children received ribavirin and corticosteroids, respectively and achieved similar outcomes. all were subsequently confirmed by seroconversion to sars-cov after the report was published. bitnun et al. reported the use of ribavirin without corticosteroids in children with probable sars but virologic confirmation was lacking. in contrast, zeng et al. treated children with chinese traditional medicine and antibiotics with good results. only of the children had an epidemiologic link to sars, however, and virologic data were not available. the use of corticosteroids in viral infections is controversial and is potentially hazardous. as an immunosuppressive agent, corticosteroids might promote viral replication, enhance infectivity and possibly cause a rebound of infection. it is known that in acute viral respiratory infections, early-response cytokines such as tumour necrosis factor, interleukin- and interleukin- mediate lung injury. the rationale for using corticosteroids is to suppress the ''cytokine storm'' which is thought to be the main factor accounting for the progression of disease. but using corticosteroids with possibly ineffective antiviral therapy in patients with viral pneumonitis can be hazardous. despite the initial success of corticosteroids in the treatment of sars, the report of an adult patient whose clinical course was complicated by fatal aspergillosis was disturbing and had even led others to recommend close laboratory monitoring for aspergillosis in sars patients receiving corticosteroids. , in retrospect, we do not think that ribavirin alone has any significant effect in halting disease progression and corticosteroids are probably unnecessary for children who do not develop moderate to severe hypoxaemia. in our experience, as with others, corticosteroids may be life saving in patients who are threatened by impending acute respiratory failure. we cannot categorically recommend this treatment strategy in view of the small number of children treated and the lack of objective evidence from a controlled trial. the place of corticosteroids in the rescue therapy of patients who have clearly experienced failure of supportive care remains to be determined. no evidence-based therapeutic approach for sars exists although more than papers have been published internationally that mention antiviral treatment. various other antiviral and immunomodulating agents have been used in adult patients with preliminary success. these include the use of lopinavir / ritonavir in combination with ribavirin and corticosteroids, interferon a plus corticosteroids and convalescent plasma from patients. [ ] [ ] [ ] [ ] their true role in the treatment of children is unknown. knowledge generated by detailed bioinformatic analysis of the sars-cov genome can be harnessed to identify possible targets for antiviral therapy, such as enzymatic proteins of the viral replicase-transcriptase complex. this approach has been reviewed by davidson and siddell who concluded that the most economical and effective way to contain the virus would be the therapeutic use of antiviral agents to block viral entry to target cells or to inhibit intracellular viral replication. in vitro studies have highlighted the antiviral potential of several compounds, including recombinant human interferon b- a, interferon b- b, glycyrrhizin, human monoclonal antibody against the spike protein of sars-cov and small interfering rna. [ ] [ ] [ ] [ ] [ ] with more understanding of the pathogenesis as well as the clinical course of the disease, treatment will evolve. the best treatment for sars in adults and children remains unknown. time is now on our side to plan for clinical trials should the disease re-emerge. with increased vigilance, rapid detection and effective infection control measures, outbreaks of sars seem less likely. it might never be possible, therefore, to recruit a sufficient number of patients to complete the trials and give us an early answer. in adults, the risk factors for severe illness are advanced age, high initial absolute neutrophil counts, low platelet counts, high initial or peak lactate dehydrogenase levels and positive rt-pcr results for npa specimens. , [ ] [ ] [ ] [ ] only one paediatric series has identified risk factors for severe illness in terms of requirements for oxygen and intensive care. these include a sore throat, a high neutrophil count at presentation, and peak neutrophilia. the finding of sore throat as an independent risk factor is intriguing but may be incidental, given the small number of patients. no association between the presence of sore throat and the detection of sars-cov by rt-pcr or culture in npa specimens, which might correlate with higher viral load, could be demonstrated. the short-term outcome of sars among children is good in comparison to adults. no case fatality has been reported. the need for intensive care and mechanical ventilation was up to . % and . % respectively in adults. chiu et al. reported that . % of children required oxygen supplementation and none required assisted ventilation. leung et al. reported an oxygen requirement in . % and assisted ventilatory support in . % of children. the figures for oxygen requirement and assisted ventilation in the two paediatric series combined are % and %, respectively. diffuse thinning and shedding of hair was observed in . % of children in one series, generally at - months after disease onset. the condition was self-limiting and spontaneous recovery occurred within - months. this is consistent with acute telogen effluvium secondary to febrile systemic illness, critical care or severe psychologic stress in life-threatening situations. li et al. examined the radiologic and pulmonary function outcomes of children, months after diagnosis and detected mild radiologic abnormalities with hrct and in pulmonary function testing in % and . % respectively. however, all children were asymptomatic and had normal clinical examination, premorbid hrct and pulmonary function test results were not available for comparison. in contrast, some adult patients have devel-oped pulmonary fibrosis despite recovery from the primary illness. the psychological impact of separation, isolation in an intimidating hospital environment, bereavement and family disintegration following the death of close adult family members in children who recovered from sars are immense. however, children appear to be more resilient than adults in psychological adjustment to sars and serious psychological sequelae were not evident months after discharge. continued monitoring for delayed onset of psychological problems in children is essential. children who have recovered from the acute illness should be monitored for the possibility of continued viral shedding and the development of pulmonary sequelae and postviral complications (e.g. chronic fatigue), as well as for any long-term complications of high-dose corticosteroid therapy. children are susceptible to infection by sars-cov. despite the milder clinical picture, the good short-to medium-term outcome and the availability of reliable early diagnostic techniques, treatment remains controversial. the long-term outcome of sars in children remains unknown. there are still enormous gaps in our knowledge about sars. much work needs to be done, urgently. sars is largely an atypical pneumonia with minimal or no extrapulmonary manifestation apart from diarrhoea. the clinical picture of sars is milder in children but teenagers may develop severe illness resembling adults. the clinical, radiologic and laboratory features of sars are non-specific. an epidemiologic link is the most important clue to diagnosis in an outbreak situation. refined rt-pcr assays can achieve a sensitivity of % in the early diagnosis of sars in the first days of illness. npa specimens are the preferred specimens for rt-pcr assays in the first week of illness. both npa and stool specimens should be tested in the second week. a negative rt-pcr result cannot exclude the diagnosis. absence of seroconversion beyond days from disease onset generally excludes the diagnosis. apart from supportive treatment, including oxygen therapy and assisted ventilation, other treatment modalities remain unproven. molecular biology of sars-cov and mechanisms of its genome expression. pathogenesis of sars-cov infection. natural history and full spectrum of sars-cov infection. improved early diagnostic techniques. 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med doi: . /nm sha: doc_id: cord_uid: p g p severe acute respiratory syndrome (sars) was caused by a previously unrecognized animal coronavirus that exploited opportunities provided by 'wet markets' in southern china to adapt to become a virus readily transmissible between humans. hospitals and international travel proved to be 'amplifiers' that permitted a local outbreak to achieve global dimensions. in this review we will discuss the substantial scientific progress that has been made towards understanding the virus—sars coronavirus (sars-cov)—and the disease. we will also highlight the progress that has been made towards developing vaccines and therapies the concerted and coordinated response that contained sars is a triumph for global public health and provides a new paradigm for the detection and control of future emerging infectious disease threats. of these deletions, however, is not clear. similarly, sars-cov in individuals before february was genetically more diverse than the later isolates , , . the spike protein (the viral surface glycoprotein which mediates viral attachment and entry into the cell; fig. ) of early isolates contained higher rates of nonsynonymous mutations, probably reflecting the ongoing adaptation to the new host. the relative genetic homogeneity of sars-cov isolates from later in the outbreak - may reflect a virus better adapted to the new host. the fact that much of the global spread arose from one index case in hotel m in hong kong , may also contribute to this genetic homogeneity. a ban on the sale of wildlife in wet markets in guangdong imposed during the later period of the sars outbreak was lifted in september . between december and january , there were four new cases of sars, the first nonlaboratory-associated cases diagnosed in humans since the end of the sars outbreak in july . epidemiological linkage and phylogenetic data suggest that the associated viruses were new introductions from animals (y. guan, unpublished observations) , , . these human cases were relatively mild and did not lead to secondary transmission, reflecting that the animal precursor virus is probably not well adapted to efficient human-tohuman transmission. this is probably a recapitulation of events in late in the run-up to the sars outbreak in . this time, the findings led to the reintroduction of the ban on wild-game animal markets and there have been no further naturally acquired human cases since. it is likely that the precursor of sars-cov has repeatedly crossed the species barrier but only occasionally has it succeeded in adapting to human-human transmission. this adaptation clearly occurred in late and it may happen again in the future. but given the present understanding and awareness about sars, we expect that such reemergence is unlikely to lead to a global outbreak on the scale of . the major routes of transmission of sars are droplet infection, aerosolization and fomites (refs. , and world health organization, http://www.who.int/csr/sars/en/whoconsensus.pdf ) . deposition of infected droplets or aerosols on the respiratory mucosal epithelium probably initiates viral infection. whether infection can occur through the oral or conjunctival routes is unknown, but sars-cov has been detected in tears . although exposure to the animal precursor of figure the global spread of sars. the number of probable cases of sars and the date of onset of the first case in each country (or group of countries) is denoted. the countries denoted in red are those where substantial local transmission occurred. the data are based on world health organization, http://www.who.int/csr/sars/country/table _ _ /en_ /en/print.html and the figure is adapted from ref. . wet markets in guangdong: 'wet markets' selling live poultry, fish, reptiles and other mammals are commonplace across southeast asia and southern china to service the cultural demand for freshly killed meat and fish produce. in some regions (e.g., guangdong province, china), increasing affluence has led to the proliferation of markets housing a range of live 'wild' animal species, such as civet cats, pictured, linked to the restaurant trade servicing the demand for these exotic foods. , , once the virus had adapted to human-to-human transmission in the later part of the outbreak, asymptomatic infection seemed to be rare . other peculiarities about sars-cov transmission were also evident. transmission was infrequent during the first five days of illness and, unlike transmission of influenza, was relatively inefficient in the household setting . despite sars's fearsome reputation and global spread, the average number of secondary infectious cases generated by one case (r ) was low ( . - . ); in contrast, the r of influenza ranges from to (ref. ) . although not unique to sars, 'superspreading events' (in which a few affected individuals disproportionately contribute to transmission) were characteristic of the outbreak , . the factors underlying the superspreading phenomenon of sars are poorly understood but may include coinfection with other viruses and host factors, as well as behavioral and environmental factors. the clinical symptoms of sars-cov infection are those of lower respiratory tract disease [ ] [ ] [ ] [ ] . besides fever, malaise and lymphopenia, affected individuals have slightly decreased platelet counts, prolonged coagulation profiles and mildly elevated serum hepatic enzymes. chest radiography reveals infiltrates with subpleural consolidation or 'ground glass' changes compatible with viral pneumonitis. but although the main clinical symptoms are those of severe respiratory illness, sars-cov actually causes infection of other organs: some affected individuals have watery diarrhea, and virus can be cultured from the feces and urine, as well as the respiratory tract [ ] [ ] [ ] . in addition, rt-pcr has identified the virus in the serum, plasma and peripheral blood leucocytes , . individuals with sars also have a pronounced peripheral t-cell lymphocytopenia: numbers of cd + and cd + cells are both reduced, and more than one-third of individuals have a cd + t-cell count of less than cells/mm (refs. , ) , suggesting increased susceptibility to secondary infections. the mechanisms underlying the t-cell lymphopenia remain to be elucidated. around - % of individuals with sars require management in intensive care units and the overall fatality rate is ∼ % (world health organization, http://www.who.int/csr/sars/en/whoconsensus.pdf). the age dependence of disease severity and mortality is notable; during the outbreak, mortality rates of affected individuals in hong kong who were - , - , - and > -year old were %, %, % and %, respectively (world health organization, http://www.who.int/ csr/sars/en/whoconsensus.pdf). none of the - -year-olds infected with sars-cov in hong kong had disease severe enough to require intensive care or mechanical ventilation , . this progressive age dependence in mortality is not totally explained by comorbid factors and the underlying biological basis remains unclear. quantitative studies of viral load have provided insights into the pathogenesis of sars. viral load is higher in the lower respiratory tract than in the upper airways , . viral load in the upper respiratory tract and feces is low during the first days and peaks at around day of illness. in marked contrast, viral load in influenza peaks soon after onset of clinical symptoms . this unusual feature of sars-cov infection explains its low transmissibility early in the illness. it also explains the poor diagnostic sensitivity of the first-generation rt-pcr diagnostic tests on upper respiratory tract and fecal specimens collected early in the illness (reviewed in ref. ) . affected individuals with high serum viral loads have a poor prognosis . between days - of illness, high viral load in nasopharyngeal aspirates, feces and serum, as well as detection of virus in multiple anatomic sites, are independently predictive of adverse clinical outcome . serial studies of viral load throughout illness also reflect clinical outcome . taken together, these findings suggest that poor clinical outcome is associated with continued uncontrolled viral replication. sars-cov rna can be invariably detected in the lungs of individuals dying of sars, but viral load is higher in those dying earlier in the course of the illness (< days) . the respiratory tracts of affected individuals who die during the first ten days of illness show diffuse alveolar damage with a mixed alveolar infiltrate, lung edema and hyaline membrane formation. macrophages are a prominent component of the cellular exudates in the alveoli and lung interstitium , . multinucleate syncytia of macrophage or epithelial cell origin are sometimes seen later in the disease. immunohistochemistry, in situ hybridization and electron microscopy on autopsy or tissue biopsy have unequivocally demonstrated sars-cov replication in pneumocytes in the lung and enterocytes in the intestine [ ] [ ] [ ] [ ] . individual reports of virus detection by in situ hybridization or immunohistochemistry in other tissues await confirmation by electron microscopy . in the large and small intestines, the virus replicates in enterocytes . viral particles primarily are seen on the apical surface of enterocytes and rarely in the glandular epithelial cells. but there is no villous atrophy or cellular infiltrate in the intestinal epithelium and the pathogenic mechanisms responsible for watery diarrhea in individuals with sars is unclear. some human intestinal epithelial cell lines support productive replication of sars-cov and gene expression arrays have shown that virus replication is associated with the expression of an antiapoptotic host cellular response, perhaps explaining the lack of enterocyte destruction in vivo . studies using pseudotyped lentiviruses, carrying the spike, membrane and envelope surface glycoproteins of sars-cov (fig. ) separately and in combination demonstrated that the spike protein is both neces- sary and sufficient for virus attachment on susceptible cells [ ] [ ] [ ] [ ] . the sars-cov spike protein uses a mechanism similar to that of class fusion proteins in mediating membrane fusion , . there is no consensus as to whether the virus entry occurs through a ph-dependent receptor-mediated endocytosis or through direct membrane fusion at the cell surface , , . the receptor for sars-cov was identified as the metallopeptidase ace- (refs. , ) . the soluble ace- ectodomain blocks sars-cov infection , and amino acids - of the spike protein are required for interaction with ace- (ref. ) . other coronaviruses use different cell receptors and enter cells either by means of fusion at the plasma membrane or through receptor-mediated endocytosis . immunostaining techniques have identified ace- on the surface of type and pneumocytes, the enterocytes of all parts of the small intestine and the proximal tubular cells of the kidney. this localization explains the documented tissue tropism of sars-cov for the lung and gastrointestinal tract and its isolation from the urine. but it is notable that colonic enterocytes lack ace- protein expression although sars-cov replication does occur in colonic epithelium , . in contrast, whereas ace- is strongly expressed on the endothelial cells of small and large arteries and veins of all tissues studied and the smooth muscle cells of the intestinal tract, there is no evidence of virus infection at any of these sites. this lack of virus infection in tissues that express the putative receptor prompts the question of whether a coreceptor is required for successful virus infection . vasculitis is known to occur in individuals with sars but its relation to infection of endothelial cells is unknown. because only the basal layer of the nonkeratinized squamous epithelium of the upper respiratory tract expresses ace- (ref. ) , undamaged epithelium of the nasopharynx is unlikely to support sars-cov replication. other receptors for virus entry that are independent of ace- expression may exist. pseudotyped virus containing the spike protein has also been shown to bind to dendritic cell-specific intercellular adhesion molecule grabbing nonintegrin (dc-sign) . dc-sign is a type-ii transmembrane adhesion molecule found on dendritic cells consisting of a c-type lectin domain that recognizes carbohydrate residues on a variety of pathogens. unlike the ace- receptor on pneumocytes and enterocytes, dc-sign does not permit sars-cov infection of the dendritic cells. instead, binding of sars-cov to dc-sign allows dendritic cells to transfer infectious sars-cov to susceptible target cells . a similar mechanism has been described for dengue virus, human immune deficiency virus (hiv) and cytomegalovirus, and may be relevant in sars pathogenesis. many details of sars-cov pathogenesis remain to be elucidated, but the development of a full-length infectious cdna clone of sars-cov should permit precise manipulation of the virus genome and will help our understanding of the viral determinants of pathogenesis . several inflammatory cytokines (il- β, il- and il- ) and chemokines chemotactic for monocytes (mcp- ) and neutrophils (ip- ) are elevated in adults and children with sars [ ] [ ] [ ] [ ] . the increased levels of monocyte-tropic chemokines may contribute to the prominently monocytic macrophagic infiltrate observed in the lung . but increases of these same chemokines occur in other viral diseases (e.g., influenza) and are not a unique feature of sars. in addition, elispot assays of peripheral blood leukocytes have revealed prolonged immunological dysregulation in individuals with sars . it is difficult to evaluate the overall pathogenic significance of these findings because immunological markers in the peripheral blood do not always reflect the local microenvironment of the lung . genetic factors associated with susceptibility to, or severity of, sars are under investigation. hla-b* has been associated with severe sars disease in taiwan but not hong kong . hla-b* has also been associated with disease susceptibility and hla-drb * with resistance to sars. the coinheritance of b* and b was significantly higher in individuals with sars than in the general population . the mechanisms underlying these disease associations remain to be elucidated. key to the development of effective antiviral drugs and vaccines against sars-cov was the development of animal models of sars ( table ) . sars-cov seems to cause infection in cynomolgous macaques following intratracheal inoculation [ ] [ ] [ ] . but whereas some researchers find evidence of disease pathology reminiscent of that seen in individuals dying of sars and can show sars-cov antigen and viral particles in the pneumocytes of infected macaques , , others only find evidence of a mild upper-airway disease and low levels of virus by rt-pcr . these differences in outcome may reflect differences in the viral strain, pre-exposure history and age of the animals, route of inoculation, stage of infection at which necropsy was performed or other factors. other animal models include ferrets, cats, golden syrian hamsters, mice and african green monkeys ( table ) [ ] [ ] [ ] [ ] [ ] . these animal models support viral replication in the upper and lower respiratory tracts [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ferrets and hamsters also develop notable lung pathology. infected cats and ferrets transmit sars-cov to noninfected animals held in the same cage . natural asymptomatic infection in cats was documented during the community outbreak at amoy gardens, hong kong (world health organization, http://www.who.int/csr/sars/en/ whoconsensus.pdf). these animal models of sars differ from natural human disease in that the period between infection and peak disease pathology or peak viral load is shorter than is found in human disease and because the disease pathology, when present, is self-limited and rarely progresses to a fatal outcome as occurs with sars. they also do not accurately reproduce the intestinal component of the human disease. but these models provide the only options presently available for addressing questions relevant to therapeutics and vaccine development. they can provide useful information providing their limitations are recognized. several potential antiviral agents have been evaluated in vitro, and a few have been tested in animal models. screening of currently available antiviral drugs and chemical libraries reveals that interferons, glycyrrhizin, baicalin, reserpine, niclosamide, luteolin, tetra-o-galloylβ-d-glucose and the protease inhibitors have in vitro activity against sars-cov - . differences in in vitro susceptibility of sars-cov to interferon (ifn)-β b, ifn-α and ribavirin , - probably relate to differences in the testing methods used. overall, ifn-αn /n , leukocytic ifn-α, ifn-β and the hiv protease inhibitors (especially nelfinavir) are consistently active in vitro and should be considered for animal studies and randomized placebocontrolled clinical trials. type interferons render uninfected cells refractory to sars-cov replication through a mxa-independent mechanism , whereas the hiv protease inhibitors may block the activity of the main sars-cov proteinase . so far, only interferons have been tested in animal models: in cynomolgous macaques, pegylated ifn-αn provided prophylaxis but was only marginally effective for early treatment . no randomized placebo-controlled trials have been performed for any of these antiviral drugs, although treatment studies using historical controls have suggested clinical benefit from ifn-α (infacon- ) and the combination of a protease inhibitor with ribavirin . the rapidity with which the sars-cov genome was sequenced, the determination of the structure of potential drug targets and the prediction of functional properties of sars-cov proteins based on prior knowledge of homologs from other coronaviruses have allowed identification of potential new drug targets. peptides derived from the heptad-repeat- region of the spike protein have been shown to block virus infection, albeit at much higher molar concentrations than similar inhibitors needed to prevent hiv entry , . short interfering rnas also seems to be effective in decreasing viral replication in cell lines [ ] [ ] [ ] , but this remains an experimental strategy rather than one immediately amenable to clinical application. screening of combinatorial chemical libraries has identified inhibitors of sars protease, helicase and spike-protein-mediated cell entry . for successful treatment of influenza, antiviral drugs must be administered within hours of disease onset to obtain substantial clinical effect. but because the sars-cov load increases until day of illness , and in light of the correlation of high viral load in the second week of illness with adverse outcome , the window of opportunity for antiviral therapy may be wider. much scientific effort has been focused on developing a vaccine to protect against future outbreaks of sars-cov. the commercial viability of developing a vaccine for sars-cov will ultimately depend on whether the virus re-emerges in the near future. as discussed above, it is unlikely that future outbreaks will reach global proportions, but nevertheless, vaccines or passive immunization would be relevant in the context of protecting high-risk individuals such as laboratory and health-care workers. a vaccine could also be considered in the setting of the farmed-game-animal trade, if farming of civets for human consumption continues. in the short time since the virus was identified, substantial progress has been made toward developing a vaccine. immunodominant b-and t-cell epitopes of sars-cov are being defined [ ] [ ] [ ] . natural human infection with sars-cov leads to a long-lived neutralizing antibody response and immune sera crossneutralize diverse human sars-cov , suggesting that active immu- (in the press) ( ) nization against sars may be a feasible proposition. but so far there has been no known instance of human re-exposure to sars-cov to confirm that the naturally acquired immune response confers protection from reinfection. when sars-cov spike, envelope, membrane and nucleocapsid proteins were individually expressed in an attenuated parainfluenza type vector, only the recombinants expressing the spike protein induced neutralizing antibody and protected from challenge in hamsters ( table ) . mucosal immunization of african green monkeys with this parainfluenza-spike protein chimeric virus led to neutralizing antibody and protection from viral replication in the upper and lower respiratory tracts after challenge with live sars-cov , and spike protein-encoding dna vaccines stimulated neutralizing antibody production and protection from live-virus challenge in mice . these studies confirm the assumption that the spike protein is the dominant protective antigen for sars. experiments using adoptive transfer and t-cell depletion showed that humoral immunity alone can confer protection . other vaccine strategies have included the use of naked dna - , adenoviral vectors or modified vaccinia (ankara) and inactivated whole virus , . many investigators have optimized the codon usage of the gene target to improve expression. in summary, all vaccines based on the spike protein seem to induce neutralizing antibody responses, and those carrying nucleoprotein can induce nucleoprotein-specific cellmediated immunity. but thus far only four studies have used live sars-cov to challenge immunized animals ( table ). an inactivated vaccine with alum adjuvant, which induces neutralizing antibody in mice, is entering phase human clinical trials in china . experience with coronavirus vaccines for animals is relevant for sars vaccine development . one problem facing animal coronavirus vaccines has been strain variation among field isolates, leading to variable vaccine efficacy. a further concern is the experience with feline infectious peritonitis coronavirus, in which prior immunization led to enhanced disease rather than protection . in the case of sars-cov, neither vaccination nor passive transfer of antibody has yet been reported to lead to disease enhancement, but challenge with live sars-cov has occurred soon after immunization. whether waning immunity or low titers of antibody lead to sars disease enhancement remains unclear; the recent suggestion that immunized ferrets became more ill after challenge clearly needs to be confirmed or refuted . passive transfer of immune serum protects naive mice from sars-cov infection , and hyperimmune globulin with sufficient neutralizing activity for use in humans could be prepared from pooled convalescent human plasma or from horses immunized with inactivated vaccine. alternatively, monoclonal antibodies with sufficient neutralizing antibody activity have been developed by screening phage-display antibody libraries and by immortalizing b-cell repertoires of convalescent sars individuals with epstein-barr virus ( table ) [ ] [ ] [ ] . one of these ( r) blocks the virus-ace- receptor interaction through binding to the spike protein s domain . passive immunization of ferrets and mice was effective in suppressing viral replication in lungs, but less so in the nasopharynx , . no randomized placebo control trial evaluated antibody therapy for pre-or post-exposure prophylaxis in at-risk groups during the sars outbreak. retrospective analysis of outcome in a limited human study using human sars convalescent plasma suggested that passive immunization had no obvious adverse effects . the antigenic diversity of sars-cov-like precursor viruses in the wild-animal reservoir is undefined. in the event of a new interspecies transmission event prompting another sars outbreak, the crossprotection afforded by current vaccine constructs based on the human sars-cov of is unknown and is likely to influence the efficacy of both passive and active immunization strategies. sars provided a painful reminder of the global impact of emerging infectious diseases. it illustrated how microbes, with their evolutionary drive to preserve and propagate their genes, exploit new opportunities and niches created by modern society . interspecies transmission of viruses to humans clearly has occurred throughout human history. but recent developments allowed sars-cov increased opportunity to adapt to human-to-human transmission and, subsequently, to spread globally. in particular, large centralized wet markets and hospitals proved to be venues for amplification of transmission to humans, and the burgeoning increase of international travel (currently ∼ million travelers annually) exploded the local outbreak of an emerging infection into a potential pandemic. because most recent emerging infectious disease threats have a zoonotic origin, we need to better understand the microbial ecology of livestock and wildlife. in the context of increased attention and research funding directed at preparedness to combat bioterrorism threats, it is relevant to note that nature remains the greatest 'bioterrorist.' although microbes that cause commercially important diseases in livestock are well studied, organisms that pose threats to human health are not necessarily ones known to cause disease in livestock, or for that matter, in wildlife. nipah virus, hendra virus and sars-cov all have a wildlife reservoir. furthermore, at present there is concern over the possible role played by wild birds and ducks in the maintenance and spread of avian influenza a (h n ) in asia . greater understanding of the viral ecology of apparently healthy domestic animals and wildlife is therefore important. for example, the attention on ecological studies arising from the nipah virus and sars outbreaks have already led to the identification of a number of new viruses, including tioman, menangle, australian bat lyssavirus and a novel group coronavirus , . some of these are now known to be associated with human or livestock disease. but prioritizing such research efforts and assessing the public health relevance-if any-of such findings, poses challenges. three incidents of laboratory-acquired sars have arisen from biohazard level and laboratories, with community transmission arising from one (world health organization, http://www.wpro.who.int/ sars/docs/update/update_ .asp). these incidents were associated with lapses in biohazard level and practices. sars-cov can be safely handled in biohazard level laboratories provided that biohazard level practices are rigorously complied with. but as hospital health-care workers learned to their cost, sars-cov is an unforgiving virus; one lapse may be one too many, and it is irrelevant whether the lapse occurs in a biohazard level or laboratory. despite the impressive speed of scientific understanding of the disease, the global success in containing sars owed much to traditional public health methods of clinical case identification, contact investigation, infection control at healthcare facilities, patient isolation and community containment (that is, quarantine) . but the application of such measures in modern society during the control of sars highlighted several ethical and medical dilemmas, many of which arose from the need to balance individual freedoms against the common good , . sars signaled a paradigm shift in international public health. it highlighted the need for rapid information exchange regarding unusual infectious disease outbreaks and the possibility of , and the need for , a coordinated global response to emerging infectious disease threats. during the early stages of the outbreak, the who acted independently, issuing travel alerts and geographically specific travel advisories, without the express consent of the countries affected. the need for such 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authors declare that they have no competing financial interests. key: cord- -u k pds authors: mason, jay w.; trehan, sanjeev; renlund, dale g. title: myocarditis date: journal: cardiovascular medicine doi: . / - - - - _ sha: doc_id: cord_uid: u k pds viruses are the most common cause of myocarditis in economically advanced countries. enteroviruses and adenoviruses are the most common etiologic agents. viral myocarditis is a triphasic process. phase is the period of active viral replication in the myocardium during which the symptoms of myocardial damage range from none to cardiogenic shock. if the disease process continues, it enters phase , which is characterized by autoimmunity triggered by viral and myocardial proteins. heart failure often appears for the first time in phase . phase , dilated cardiomyopathy, is the end result in some patients. diagnostic procedures and treatment should be tailored to the phase of disease. viral myocarditis is a significant cause of dilated cardiomyopathy, as proved by the frequent presence of viral genomic material in the myocardium, and by improvement in ventricular function by immunomodulatory therapy. myocarditis of any etiology usually presents with heart failure, but the second most common presentation is ventricular arrhythmia. as a result, myocarditis is one of the most common causes of sudden death in young people and others without preexisting structural heart disease. myocarditis can be definitively diagnosed by endomyocardial biopsy. however, it is clear that existing criteria for the histologic diagnosis need to be refined, and that a variety of molecular markers in the myocardium and the circulation can be used to establish the diagnosis. treatment of myocarditis has been generally disappointing. accurate staging of the disease will undoubtedly improve treatment in the future. it is clear that immunosuppression and immunomodulation are effective in some patients, especially during phase , but may not be as useful in phases and . since myocarditis is often selflimited, bridging and recovery therapy with circulatory assistance may be effective. prevention by immunization or receptor blocking strategies is under development. giant cell myocarditis is an unusually fulminant form of the disease that progresses rapidly to heart failure or sudden death. rapid onset of disease in young people, especially those with other autoimmune manifestations, accompanied by heart failure or ventricular arrhythmias, suggests giant cell myocarditis. peripartum cardiomyopathy in economically developed countries is usually the result of myocarditis. jay w. mason, sanjeev trehan, and dale g. renlund • viruses are the most common cause of myocarditis in economically advanced countries. • enteroviruses and adenoviruses are the most common etiologic agents. • viral myocarditis is a triphasic process. phase is the period of active viral replication in the myocardium during which the symptoms of myocardial damage range from none to cardiogenic shock. if the disease process continues, it enters phase , which is characterized by autoimmunity triggered by viral and myocardial proteins. heart failure often appears for the first time in phase . phase , dilated cardiomyopathy, is the end result in some patients. diagnostic procedures and treatment should be tailored to the phase of disease. • viral myocarditis is a significant cause of dilated cardiomyopathy, as proved by the frequent presence of viral genomic material in the myocardium, and by improvement in ventricular function by immunomodulatory therapy. • myocarditis of any etiology usually presents with heart failure, but the second most common presentation is ventricular arrhythmia. as a result, myocarditis is one of the most common causes of sudden death in young people and others without preexisting structural heart disease. • myocarditis can be definitively diagnosed by endomyocardial biopsy. however, it is clear that existing criteria for the histologic diagnosis need to be refined, and that a variety of molecular markers in the myocardium and the circulation can be used to establish the diagnosis. • treatment of myocarditis has been generally disappointing. accurate staging of the disease will undoubtedly improve treatment in the future. it is clear that immunosuppression and immunomodulation are effective in some patients, especially during phase , but may not be as useful in phases and . since myocarditis is often selflimited, bridging and recovery therapy with circulatory assistance may be effective. prevention by immunization or receptor blocking strategies is under development. • giant cell myocarditis is an unusually fulminant form of the disease that progresses rapidly to heart failure or sudden death. rapid onset of disease in young people, especially those with other autoimmune manifestations, accompanied by heart failure or ventricular arrhythmias, suggests giant cell myocarditis. • peripartum cardiomyopathy in economically developed countries is usually the result of myocarditis. the difficulty of diagnosing and treating myocarditis was recognized by senac in : "the inflammation of the heart is difficult to diagnose and when we have diagnosed it, can we then treat it better?" after sobernheim in defined myocarditis as any inflammation or degeneration of the heart, the term myocarditis was used for nonvalvular myocardial diseases, including ischemic and hypertensive cardiomyopathies. nearly a century later, white suggested that the term myocarditis be restricted to "true inflammation of the myocardium." the last half-century has seen the development of endomyocardial biopsy techniques, histologic criteria, and serologic methods to diagnose myocarditis. as our knowledge of the immunopathologic mechanisms evolves, new therapeutic strategies are developing. the world health organization/international society and federation of cardiology task force on cardiomyopathies classified cardiomyopathies whenever possible by etiologic/pathogenetic factors. this classification recognizes chronic viral, postinfectious autoimmune, and primary autoimmune forms of dilated cardiomyopathy (dcm). the classification states that "myocarditis is diagnosed by established histological, immunological and immunohistochemical criteria." the dallas criteria provide consensus-derived histologic criteria: "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of ischemic damage associated with coronary artery disease." however, many have speculated that less pronounced histologic abnormalities may be present and that additional molecular, immunologic, and immunohistochemical diagnostic criteria can be used productively. [ ] [ ] [ ] [ ] [ ] [ ] myocarditis, irrespective of the etiopathologic factors, remains an inflammatory cardiomyopathy associated with cardiac dysfunction. a wide variety of infectious and noninfectious causes are associated with myocarditis (tables . to . ) . several epidemiologic observations linking these agents with myocarditis have been corroborated by serologic, polymerase chain reaction (pcr), or in situ hybridization methods. the incidence of infectious myocarditis in the general population is largely unknown. in a prospective study over several years, in a predefined subpopulation, an incidence of . % was found. these cases were confirmed by myocardial enzyme leak and characteristic electrocardiographic (ecg) changes. the ecg abnormalities suggesting asymptomatic myocardial involvement, in the absence of enzyme release, have been noted in . % of military conscripts during the course of other acute infectious diseases. during an epidemic of influenza a, the incidence rose to . %. in a prospective trial of consecutive patients admitted to a large infectious disease hospital in sweden, % showed ecg abnormalities suggestive of myocarditis. approximately % of a virus-infected population may experience symptoms or findings suggestive of cardiac involvement. the incidence of myocarditis associated with nonviral infections is even more difficult to estimate. although the list of possible etiologic agents is large, the enteroviruses, specifically coxsackievirus b, over decades have been the most commonly identified etiologic agents of inflammatory cardiomyopathy. among healthy active adults, at least % have detectable serum antibodies indicating prior infection with coxsackievirus b. , the world health organization has surveyed viral infections related to cardiovascular disease globally. in a year period from to , coxsackievirus b had the highest incidence of cardiovascular disease ( . cases per population), followed by influenza b ( . cases), influenza a ( . cases), coxsackievirus a ( . cases), and cytomegalovirus (cmv) ( . cases). the predominance of enteroviruses among myocarditisassociated agents has been substantiated by several laboratory and clinical studies. [ ] [ ] [ ] using serologic methods, vikerfors and associates reported that nearly % of consecutively studied myocarditis patients had enterovirus immunoglobulin igm. frisk and coworkers found a similar incidence of coxsackievirus b igm antibodies by reverse herpes simplex in two, and cmv in one patient. the control group did not demonstrate any viral genome sequences. just as the incidence of specific viral infections varies over time, so should the relative proportion of agents responsible for myocarditis. in a recent study, bowles and colleagues supported the observation by martin and coworkers that adenovirus is the most common agent associated with myocarditis in children, but they also found that adenoviruses predominated over enteroviruses in adults. figure . shows the dominant role of adenoviruses and enteroviruses in myocarditis. note that parvovirus was detected in young people. parvovirus b- has recently been identified as a cause of myocarditis and, in some regions, it has been found in adults as well as children. [ ] [ ] [ ] [ ] [ ] these differences between previous and newer studies are due, at least in part, to geographical and temporal variation in the incidence of specific viral infections. cytomegalovirus is a recognized cause of acute infectious myocarditis, although it is rare in healthy individuals. , maisch and associates demonstrated, using in situ hybridization techniques, cmv-specific nucleotide sequences in % of patients with acute myopericarditis. certainly in transplant recipients, cmv infection is fairly common and has been reported to affect the transplanted heart. , hepatitis c virus infection is frequently noted in patients with dcm, and hepatitis c virus rna has also been recovered from lymphocytes infiltrating the myocardium in chronic active myocarditis. matsumori and colleagues , found a high incidence of hepatitis c viral genomic material in a wide variety of cardiac disorders in japan. myocarditis is a well-recognized complication of corynebacterium diphtheriae infection, although this is now rare in the western world. myocardial dysfunction is also seen in association with salmonella septicemia, although it is rarely clinically severe. , myocardial dysfunction is primarily related to the toxemia of the severe infection, which is also observed in meningococcal and nonrheumatic streptococcal infections. perhaps the best-recognized bacterial agent thought to be responsible for myocarditis is the β-hemolytic streptococcus that causes rheumatic fever. fortunately, rheumatic fever is seen in the western world with only a low frequency of sporadic cases in regional clusters. the incidence in the united states is less than per , , but in the developing world, rheumatic heart disease continues to be the leading cause of cardiac hospitalization in the -to -year-old age group. although the inflammatory component of rheumatic carditis is largely restricted to the valves, it has been believed to cause myocardial dysfunction. myocarditis is a well-documented complication of borrelia burgdorferi infection (lyme disease) and is reported in up to % of cases. cardiac involvement is often characterized by the development of atrioventricular (av) block and rarely progresses to left ventricular dysfunction and cardiomegaly. mycoplasma pneumoniae infection has also been associated with myocarditis. lewes and coworkers demonstrated asymptomatic myocardial involvement as documented by ecg changes in a third of the cases with acute mycoplasma infection. six percent of military conscripts with clinical myocarditis were found to have active m. pneumoniae infection. chlamydia infections have also been associated with myocarditis, especially among small children, often having fatal outcomes. c. pneumoniae infection has also been noted in a few cases of mild myocarditis and has been found with respiratory infection associated with myocarditis, resulting in sudden death in a young athlete. chlamydia psittaci infection may be associated with myocarditis in % to % of those affected, usually with minimal clinical signs or symptoms. pericarditis is more frequent and likely to cause cardiac morbidity with ornithosis. other causative infectious agents rickettsial infections, like rocky mountain spotted fever and scrub typhus, are frequently accompanied by myocardial involvement, although vasculitis is more prominent with these infections. q fever may also be associated with myocarditis. trypanosoma cruzi is a well-recognized cause of myocarditis and cardiomyopathy in south america (chagas' disease). toxoplasma gondii poses a significant problem among cardiac transplant recipients because a large number of the recipients lack antibodies against this agent, which may cause myocarditis. toxoplasmosis also poses a major threat to patients with aids. myocarditis has frequently been seen in human immunodeficiency virus (hiv)-infected populations with or without concomitant toxoplasma infection. , in two autopsy studies of patients with aids, myocarditis was found in almost half of the cases; in another study, % of prospectively studied patients with aids had echocardiographic evidence of myocardial dysfunction. , myocarditis may also occur in patients with aids as a result of t-cell restitution after antiviral therapy. myocarditis can also be seen with parasitic infections such as trichinella spiralis, which has an affinity for striated muscle, including the heart. other noninfectious causes noninfectious causes of myocarditis include druginduced hypersensitivity, - direct toxicity of specific pharmaceutical agents, , [ ] [ ] [ ] and systemic collagen vascular disorders. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] eosinophilic myocarditis [ ] [ ] [ ] [ ] and giant cell myocarditis (gcm) [ ] [ ] [ ] [ ] [ ] [ ] [ ] are distinct forms of inflammatory myocarditis of uncertain etiology. microorganisms are rarely isolated or demonstrated in heart muscle; hence, identification of a specific infectious etiologic agent depends on recognition of its systemic manifestations. once specific noninfectious and nonviral infectious agents are excluded, myocarditis is often assumed to be of viral etiology. although definitive serologic evidence of viral infection can be obtained in many patients, it is absent in the majority of patients with presumed myocarditis. a significant number of cases of myocarditis is due to autoimmune phenomena either induced by a viral infection or resulting from systemic autoimmune disease. since the establishment of definitive etiologic diagnoses is ambiguous, the terms viral myocarditis, idiopathic myocarditis, lymphocytic myocarditis, autoimmune myocarditis, and interstitial myocarditis are frequently used interchangeably. the pathophysiologic mechanisms of myocarditis in humans are not fully understood. clearly, multiple mechanisms exist, including direct infection by viruses, bacteria, and other organisms; noninfectious causes, such as toxins and drug hypersensitivity; and parainfectious etiologies, resulting from the immune response to infection. most cases of overt heart failure due to myocarditis in north america, europe, and japan are thought to arise from the latter type of mechanism, during and after viral infection of the heart. a triphasic disease process is observed , (fig. . a ). in the first phase, active viral infection of the myocardium results in a variable extent of muscle damage, which often may not be clinically apparent. phase develops in an unknown proportion of infected individuals after partial or complete resolution of active infection and is characterized by further myocardial damage, both by ongoing immune activation and by newly developed autoimmune activity. a small proportion of patients develops dilated cardiomyopathy, the third phase of disease, resulting from the cumulative damage caused by infection, immunity, and autoimmunity. during this phase, a considerable body of evidence suggests that the immune and autoimmune processes persist, in part as a result of viral persistence. figure . b depicts the three roles virus may play in bringing about dilatation and chronic heart failure. after the initial injury that occurs during active viral replication, latent, nonreplicating viruses can still alter myocyte function through viral genomic expression. even if the virus is completely eliminated and the immune response ceases, through the various mechanisms of adverse remodeling, the cardiomyopathy may progress inexorably. the most widely accepted models for the study of human myocarditis are those of enteroviral myocarditis induced by coxsackievirus b (cvb ) and the encephalomyocarditis virus. induction of chronic murine myocarditis by cvb requires the virus to have a cardiovirulence capacity and murine strains of certain genetic background. , infection of syngeneic weanling mice with cvb results in brief cardiac infection lasting about a week, beyond which the virus cannot be cultured. however, viral rna persists for several months after the initial infection. , several mechanisms have been hypothesized to explain the initiation of chronic inflammatory response in myocytes by the viral infection: . although antibodies to these antigens are frequently identified in association with myocarditis, the clinical significance and causal relationship are yet unresolved. cytotoxic lymphocytes (ctls) from mice with cvb induced myocarditis possess the ability in vitro to recognize and kill neonatal myocytes, fibroblasts, and endothelial cells infected with the same strain of the virus, suggesting that the recognition of a novel tissue antigen is induced by the infection. cross-reactive, concurrent recognition of unrelated cardiac epitopes also occurs because ctls also lyse uninfected myocytes in vitro. the production of perforin, a pore-forming protein, has been proposed as one of the mechanisms for the cytolysis induced by lymphocytes. perforins, when inserted into myocyte membrane, induce a lethal augmentation in cell permeability that results in cellular edema and death. perforin-independent mechanisms have also been proposed, including a fas (cd /apol)-based inositol- , , -triphosphate-mediated cytolysis that can be demonstrated in perforin-deficient gene-knockout mice. coxsackievirus-infected mice also develop additional immune sensitization to cardiac heavy chain myosin, possibly owing to the release of the sequestered myosin antigens from the virus-damaged cells. immunization of mice with the heavy chain myosin and an adjuvant produces a histomorphologically similar picture to cvb -induced myocarditis. adoptive transfer of splenocytes can also produce experimental autoimmune myocarditis after myocardial infarction in syngeneic rats. the sensitized lymphocytes when transferred to normal rats cause cardiac-specific cellular infiltration with accompanying myocyte necrosis. the genetic susceptibility, kinetics, and cellular composition of the infiltrates in these models are similar and suggest the role of endogenous antigens as an epitope for the inflammatory response. the pathways and cellular participants in the immunopathogenesis of experimental viral myocarditis are well recognized. the replicating viral particles can be readily identified in cardiac myocytes within a few hours of inoculation of cvb into mice. , the viral particles reach a numerical peak in to days, and usually at to days, they are no longer detectable. the inflammatory infiltrate is detectable by day and reaches a plateau by days to . the early inflammatory infiltrate consists of lymphocytes, macrophages, neutrophils, natural killer cells, and the associated cytokines and humoral effectors. [ ] [ ] [ ] the natural killer cells are the first to appear and are detected in the activated state in to days. these cells are capable of lysing virusinfected cells in vitro. the t lymphocytes and macrophages follow the natural killer cells in the temporal sequence and become the predominant cells infiltrating the myocardium in to days. although cvb replicates readily in myocytes in vitro, the cells are resistant to lysis in comparison with other cultured cell lines. direct myocytolysis appears to play a minimal role in cell lines derived from normal mice. the immunodeficient severe combined immunodeficiency (scid) mouse model has provided valuable insight into the early immune activity in response to the viral infection. the scid mice lack mature t-and b-lymphocyte function and develop extensive myocardial necrosis with pleomorphic infiltrates, rapid viral proliferation, and profound virus-associated myocytolysis when inoculated with cvb . the macrophage and natural killer cell activity is unaffected in the scid mouse model and may participate in the myocytolytic activity, although direct viral myocytolysis predominates. pharmacologically immunosuppressed mice demonstrate similar characteristics, with higher viral loads, delayed clearance, and extensive myocyte necrosis, although direct viral myocytolysis is not frequent in immunocompetent mice. , , - even noncardiovirulent strains may have sufficient time to replicate and transform into quasicardiovirulent species in the absence of a functional antiviral immune response, which can then result in fatal myocarditis. this may also explain the clinical observation that many severe and fatal cases of myocarditis develop in young children with immature and incompletely developed immune systems. virus-specific ctls play a major role in the inflammatory response to viral infection of the myocytc. , the inflammatory response can be diminished significantly by t-lymphocyte depletion with either antithymocyte globulin or thymectomy and irradiation. , the ctls must recognize the foreign antigen in association with the syngeneic major histocompatibility complex (mhc) class i antigen that is found on immune-derived cells. the cvb -infected cells can readily express mhc class i antigens. the mhc class i molecules provide peptide-binding sites that evoke effector responses on recognition of the foreign peptide by the antigenspecific receptors of the t lymphocyte. however, tlymphocyte depletion and specific immunosuppression using cyclosporine have varying effects, depending on the murine model, the virus, and the time of therapy, and are not uniformly beneficial. [ ] [ ] [ ] the virus can no longer be cultured from cells after to days; however, areas of inflammatory infiltrate and myocyte necrosis do demonstrate persistence of viral rna, and the virus-specific ctls may continue to see these as immunologic targets and, hence, perpetuate the myocyte damage. the infected myocyte can still remain a target for the ctls, even if the viral antigens are cleared, owing to expression of "neoantigens" either induced by the virus or unsequestered due to the injury. , even nonviral antigens on infected myocytes can react with ctls, such as those induced by actinomycin d, and new glycoproteins have been identified on the surface of cvb -infected cells that can be recognized by ctls from other syngeneic-infected mice. recent observations suggest that co-stimulatory molecules b - , b - , and cd- may be expressed on myocytes in patients with myocarditis and may make the myocytes into antigen-presenting cells for ctls and natural killer cells, thereby playing an important role in the direct myocardial damage by these lytic cells. another mechanism for ongoing myocyte damage is the antibody-mediated autoimmune response. since the majority of the proteins identified as cardiac autoantigens are intracellular, it is unclear how these antibodies could harm normal intact myocytes. several mechanisms are proposed. one suggests that after the antibody response is initiated, the circulating antibodies to intracellular antigens crossreact with the native membrane cardiac tissue proteins. thus, after a small number of myocytes are damaged by the viral infection and release intracellular antigens, the resulting antibody response may affect normal myocytes, leading to global myocardial dysfunction. this hypothesis is supported by the demonstration of a number of cross-reacting antibodies. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] also, the antibodies against the intracellular mitochondrial adenine nucleotide transferase protein cross-react with the myocyte sarcolemmal calcium ion channel protein, and binding of these channels can physiologically alter the metabolism and contractile function of the myocyte. another theory holds that ctls and antibodies target uninfected myocytes by recognition of self-antigens that were previously sequestered from immune surveillance. the processing and presentation of the self-immunogenic peptides complexed with the mhc is a prerequisite for this hypothesis. normal human cardiac myocytes do not express detectable levels of mhc class ii antigens, and their constitutive expression of mhc class i molecules remains controversial. a significant increase in the expression of mhc class i and class ii antigens by the myocytes has been demonstrated in association with myocardial inflammation, such as that seen with viral myocarditis or transplant rejection. [ ] [ ] [ ] the increased mhc expression has also been demonstrated in endomyocardial biopsy specimens from patients with idiopathic dcm and myocarditis, [ ] [ ] [ ] and immune regulatory dysfunction may have a genetic predisposition. there is also evidence for aberrant expression of intracellular antigens, such as adenine nucleotide translocator (ant) and branched-chain α-keto acid dehydrogenase (bckd), on the surface of the myocytes. the formation of antiidiotypic antibodies is an additional mechanism of immune regulation in which an antibody is formed to the idiotypic determinants (antigen recognition site) of the primary antibody. the antiidiotypic antibody may cross-react with unoccupied viral receptor sites on uninfected myocytes. this phenomenon has been reported with the reovirus, polyomavirus, and coxsackievirus b models of myocarditis. [ ] [ ] [ ] the passive transfer of antiidiotypic b cells from a cvb myocarditic mouse to a syngeneic mouse can cause nonviral myocarditis. the presence of a complex, cytokine-rich microenvironment is suggested by the heterogeneous inflammatory cell populations in the hearts of infected mice. the cytokines perform myriad immunomodulatory functions, including regulation of antibody production, preservation of self-tolerance, , conscription of ancillary cells in the inflammatory milieu, , and maintenance of clonal expansion of ctls. , certain cytokines regulate the collagenogenic and collagenolytic activity of fibroblasts. although mounting evidence supports the negative inotropic effects or the blunting of catecholamine response in myocytes exposed to various cytokines, there is no direct evidence to suggest that the cytokines are directly responsible for myocytolysis. in an in vitro model, barry demonstrated that high concentrations of interleukin (il)- , tumor necrosis factor-α (tnf-α), interferon-γ (ifn-γ), and il- have no effect on myocyte survival over hours, whereas the ctls from a mixed lymphocyte reaction cause virtually % killing. gulick and colleagues demonstrated that cultured neonatal myocytes, when exposed to macrophage-derived il- and tnf-α, have reduced levels of cyclic adenosine monophosphate and have a reduced inotropic response to catecholamines. the mechanism for decreased responsiveness to catecholamines is believed to be modulated by increases in nitric oxide production mediated by increased inducible nitric oxide synthase (inos) activity, and the blunting of the catecholamine response can be inhibited by the l-arginine analogue n g -monomethyl-l-arginine (l-nmma). the decreased contractile response of cardiac myocytes to β-adrenergic agonists following induction of inos also requires the presence of insulin and the co-induction of enzymes responsible for the production of tetrahydrobiopterin, a cofactor for nitric oxide synthase. the role of inos remains controversial because increased expression of inos mrna and that of other proinflammatory cytokines is evident and is associated with contractile dysfunction. there is evidence to support the idea that inos induction is crucial for the host response to cvb infection, and inos-deficient mice have significantly increased viral loads with extensive myocardial damage. inhibition of inos through suppression of nuclear factor (nf)-κb induction has recently been shown to prevent encephalomyocarditis virus myocarditis. other investigators have suggested that inflammatory cytokines may have direct negative inotropic effects, independent of the responsiveness to the β-adrenergic agonists. high doses of il- during chemotherapy have been reported to result in depression of myocardial function. exposure of cardiac myocytes to endotoxin results in increased nitric oxide production and direct depression of contractility owing to increased levels of cyclic guanosine monophosphate. further, tnf-α may induce direct negative inotropic effects by decreasing the ca + transient, with no change in the l-type ca + current and independent of nitric oxide synthesis. although the extent to which cytokines cause direct negative inotropic effects or attenuation of endogenous β-adrenergic agonist activity remains unclear, they do produce myocyte dysfunction and cardiac decompensation. transgenic mice with overexpression of tnf-α develop biventricular dilatation and cardiac failure, resulting in premature death. pathologic specimens from these mice reveal globular dilated hearts and transmural myocarditis with myocyte apoptosis. increased levels of intracellular adhesion molecule (icam- ), il- α, il- β, tnf-α, and macrophage-stimulating factor have been demonstrated in patients with myocarditis and idiopathic dcm. , furthermore, the susceptibility of mice in the cvb myocarditis model can be increased by pretreatment with these cytokines. transforming growth factor-β is identifiable by immunohistochemistry in the prenecrotic regions of infiltrates in the murine myocardium and decreases when the macrophages and fibroblasts migrate to the necrotic foci. these growth factors may be responsible for recruitment of the immunologic effectors and may directly affect cardiac function. an intriguing feature of cytokine activity remains their possible role in the secondary development of myocyte hypertrophy and interstitial fibrosis, characteristic of dilated cardiomyopathy. among animals with different forms of viral myocarditis associated with similar intensity of initial myocyte necrosis, only those animals with persistent inflammation develop interstitial fibrosis, reflected by fibroblast proliferation and an increase in the extracellular matrix. myocardial fibrosis correlates well with the presence of t lymphocytes and macrophages, which in their activated state release fibrogenic cytokines such as fibroblast growth factor and transforming growth factor-β. matrix metalloproteinases (mmps), and their inhibitors, are thought to play a critical role in the process of myocardial remodeling. some of the cytokines elaborated during the course of viral myocarditis, such as tnf-α, disturb the balance between mmps and their inhibitors by increasing mmp, leading to failure of collagen cross-linking and worsened ventricular function ( fig. . ). this pathophysiology may present opportunities for prevention of the development of dilated cardiomyopathy resulting from myocarditis. extracardial reservoir secondary transfer to the target organ (e.g., heart) viral replication in the target organ viral protein expression lymphocytic myocarditis models in animals have conclusively demonstrated the association of viral infection and myocarditis. this association clearly exists in humans, but the proportion of cases that can be accounted for by viral infection is not known. the myocardial damage in murine models of viral myocarditis occurs in two distinct phases: an early phase of direct viral cytotoxicity in which virusspecific t-lymphocyte-and antibody-mediated cytotoxicity predominate; and a late or chronic phase in which the persistent viral genome, reactive ctls, autoantibodies, cytokines, and microvascular damage mediate myocyte damage and dysfunction. the hypothetical mechanisms of virusinduced autoimmune heart disease are presented in figures . to . . the recognition that immune responses to specific viruses are consequential in the development of myocyte injury has led to exhaustive research to exploit the possibility of designing immunomodulatory and antiviral therapies. the pretreatment of mice with inactivated virus vaccine prevents the manifestations of encephalomyocarditis virus myocarditis. the administration of antiviral therapies reduces the viral load and attenuates the histologic findings of myocarditis. , the antiviral response can be augmented by ifn-α or the exogenous administration of il- . , recombinant murine ifn-γ has also been demonstrated to improve the prognosis of acute murine myocarditis caused by encephalomyocarditis virus by suppressing replication. the murine model has also been the subject of intensive study with clinically applied immunosuppressants, such as corticosteroids, nonsteroidal antiinflammatory agents, , and cyclophosphamide, all of which have demonstrated deleterious effects when given in the acute viremic phase. cyclosporine, when administered in the early viremic phase, worsens myocardial injury but, in the late immune phase, has a beneficial effect. , , similar results have been reported with tacrolimus, and survival improves significantly when immunosuppressants such as cyclosporine, azathioprine, and -deoxyspergualin are used in adjunct to immunomodulators, such as ifn-α. antibodies to tnf-α have been demonstrated to improve survival and reduce myocardial injury. cytokine inhibitors have had promising results in animal models, but human clinical trials have been inconsistent. vesnarinone, a phosphodiesterase iii inhibitor, has demonstrated beneficial hemodynamic effects and inhibits the production of tnf-α and favorably modulates induction of inos. amlodipine has also been shown to increase survival of mice with viral myocarditis by inhibiting expression of inos and production of nitric oxide in vivo and in vitro. the diversity of immunopathogenetic mechanisms and variability in the severity of observed disease in the murine model are only a preview to the potpourri of clinical manifestations of myocarditis in humans. the presentation of unexplained progressive cardiac dysfunction or ventricular arrhythmias should lead to the suspicion of myocarditis, especially when routine cardiac diagnostic studies do not reveal an etiology. the history of an antecedent viral infection or prodrome is often sought but seldom reported and rarely confirmed by convalescent serologies. the presence of mild elevation of creatine kinase mb isoenzyme (ck-mb) or troponin, leukocytosis, or ecg changes may further underscore the possibility of myocarditis. most patients with myocarditis likely remain asymptomatic and never seek medical attention. the high frequency of exposure to cardiotropic viruses and the observation of a fairly high incidence of ecg abnormalities in apparently healthy individuals support this speculation. the incidence of myocarditis in an autopsy series following traumatic deaths in previously healthy individuals has been reported at . %. others have reported incidences ranging from . % to as high as % in unselected autopsy series. , these studies may suggest that at any given time, a significant percentage of the asymptomatic general population has myocarditis. the most common presentation of myocarditis is an acute febrile syndrome associated with pericardial and sys- temic complaints. cardiotropic viruses may cause pericardial inflammation, and patients often present with a syndrome of myopericarditis. chest pain is the most common symptom and is secondary to pericarditis or myocardial injury. a rather dramatic presentation of myocarditis is one indistinguishable from an acute myocardial infarction, complete with chest pain, ecg features suggesting acute ischemic injury, enzymatic evidence of myocardial damage, and echocardiographic or ventriculographic regional wall motion abnormalities, but on endomyocardial biopsy myocarditis is confirmed. [ ] [ ] [ ] most patients presenting with this acute syndrome completely recover, although there are isolated instances where progressive myocyte loss and cardiac failure or sudden arrhythmic death is reported. the segmental wall motion abnormalities result from virus-mediated injury, although local coronary arteritis and vasospasm have been suggested as possible culprits. , symptoms of right and left ventricular failure and even cardiogenic shock are frequently found in patients with biopsy-proven myocarditis, since it is these symptoms that lead to medical attention. however, the true incidence of heart failure in patients with myocarditis is probably much lower. in patients presenting with recent-onset heart failure and biopsy-proven myocarditis, % to % have had an antecedent flu-like illness. neonatal myocarditis is often a fulminant syndrome consisting of fever, tachycardia, tachypnea, cyanosis, and rapid progression to circulatory collapse. mortality rates are the highest in this subpopulation, approaching %. children are known to present with syncope due to heart block. other atrial arrhythmias described with myocarditis include sinoatrial block, atrial standstill, av block, intraatrial conduction abnormalities, atrial tachycardia, flutter, and fibrillation. [ ] [ ] [ ] [ ] [ ] [ ] histologic evidence of possible myocarditis has been described in up to two thirds of patients with lone atrial fibrillation. complete heart block has also been described in certain viral infections, such as epstein-barr virus or mumps, and also with rickettsiae. [ ] [ ] [ ] myocarditis may also manifest as myocardial thickening and fibrosis presenting as diastolic dysfunction or restrictive cardiomyopathy, and asymmetric septal thickening resembling hypertrophic cardiomyopathy. [ ] [ ] [ ] lieberman and coworkers proposed a clinicopathologic description of myocarditis based on the initial manifestations, endomyocardial biopsy, and recovery (fulminant, acute, chronic active, or chronic persistent myocarditis). ventricular arrhythmias are frequently encountered in patients with myocarditis, ranging from innocuous premature ventricular contractions to malignant and incessant ventricular tachycardia, and myocarditis is often incriminated in otherwise unexplained ventricular arrhythmias and sudden death. , myocarditis has been documented as a cause of ventricular repolarization abnormalities in athletes with or without arrhythmias. , ventricular arrhythmias may also be precursors to sudden cardiac death in young athletes with occult myocarditis. in autopsy series, myocarditis accounts for % to % of sudden deaths in young, healthy people. , , , in a population-based retrospective study from turin, italy, an incidence of only . % was reported among , autopsies performed over three decades, but the application of standardized systematic histologic examination and criteria tends to give a higher incidence, in the range of %, among autopsies performed at a general hospital. wesslen and associates reported signs of active, healing, or healed myocarditis in of cases of sudden death in young swedes. among high-performance athletes, sudden death due to undiagnosed myocarditis often stirs media attention. myocarditis has also been anecdotally implicated in sudden infant death syndrome. ventricular arrhythmias are frequently the initial and most prominent presentation of giant cell myocarditis. [ ] [ ] [ ] [ ] , ventricular arrhythmias and sudden death are common in all forms of myocardial failure, but specific immunemediator-induced effects on myocyte electrophysiology could also account for a portion of these arrhythmias. binah summarized a number of the mechanisms recognized by work in his laboratory and in others. as noted above, perforin elaborated by ctls is capable of forming membrane channels that pass charged ions, resulting in action potential shortening and diastolic oscillations. in addition, fas ligand can lengthen the action potential and induce afterpotentials, in part through inhibiting i to and augmenting i cal . the physical findings in acute myocarditis are dependent on the extent of myocardial or pericardial involvement, inciting agent (cardiotropic virus), and other factors. fever occurs occasionally, and in the myocarditis treatment trial (mtt), it was noted in % of patients with myocarditis. sinus tachycardia may frequently accompany the febrile state but is often out of proportion to the fever and is more likely adrenergically mediated, owing to the hemodynamic alterations of the failing heart. significant ventricular dysfunction may also be associated with hypotension, gallops, murmurs of regurgitation, rales, jugular venous distention, hepatomegaly, ascites, pleural effusions, and peripheral edema. pericardial involvement may result in a friction rub. the physical findings are not specific for myocarditis. patients with myocarditis frequently have serologic evidence of an inflammatory state with elevation of nonspecific markers of inflammation, such as erythrocyte sedimentation rate, c-reactive protein, and leukocyte counts. a fourfold increase in virus-specific igg titers in the convalescent period is considered reliable evidence of recent infection and is found in % of patients with myocarditis. , in the mtt, more than half of the patients with biopsy-proven myocarditis had an elevated sedimentation rate. other markers noted to be elevated in myocarditis include tnf-α, icam- , vascular cell adhesion molecule- , interleukins, and soluble fas. , , , unfortunately, these markers are not specific for myocarditis. myocarditis, although associated with myocyte damage and necrosis, results in ck-mb elevation in only % of patients with biopsy-proven myocarditis. more recently, lauer and colleagues reported on ck-mb elevation in only one of fi ve patients with histologic evidence of myocarditis, but cardiac troponin t (ctnt), which is extremely specific for myocardial damage, was elevated in all five. additionally, ctnt was elevated in patients, of whom had immunohistologic evidence of myocarditis. thus, ctnt elevation appears to be highly predictive for myocarditis. in an analysis of stored sera on patients from the mtt, cardiac troponin i (ctni) was elevated in % of patients ( of ) with myocarditis, compared with % ( of ) without myocarditis. in contrast, ck-mb values were elevated in only . % of patients ( of ) with myocarditis. further, the ctni elevations correlated with less than month's duration of heart failure symptoms. antibodies to cardiac antigens can be detected in the serum of patients with myocarditis. , , anti-α-myosin igg antibodies may have promise as a diagnostic tool, and, along with other antibodies, probably play a functional role. , the clinical efficacy of igg immunoadsorption , in dcm supports this notion (see also fig. . ). historically, acute myocarditis was diagnosed with the constellation of clinical symptoms, physical signs, and ecg abnormalities. although no particular feature on the electrocardiogram is pathognomonic of acute myocarditis, sinus tachycardia, repolarization abnormalities, conduction abnormalities, and arrhythmias are common findings. in a series of patients with biopsy-proven myocarditis, morgera and associates noted an abnormal qrs duration in %; abnormal q waves in %; left bundle branch block (lbbb) and right bundle branch block (rbbb) patterns in % and %, respectively; st elevation in %; t-wave inversions in %; and advanced av block in %. in patients presenting earlier in the course of the disease, with symptoms of less than month's duration, % had advanced av block and % had st elevation with t-wave inversions. the latter finding has been noted to portend a poorer prognosis. other predictors of poor outcome include lbbb, rbbb, and other conduction abnormalities, which seem to suggest active, severe, and extensive myocarditis. patients may present with sustained ventricular tachycardia, and continuous ecg monitoring of patients with myocarditis often reveals complex ventricular ectopy and nonsustained ventricular tachycardia. , echocardiography is useful in assessing the extent of left ventricular systolic dysfunction, which may range from mild segmental hypokinesis to severe global hypokinesis or akinesis associated with severe congestive heart failure (chf). patients presenting with chest pain or arrhythmias without chf often have normal echocardiograms. the ventricular dimensions may remain normal or may be only mildly enlarged. there may be an increase in left ventricular sphericity and right ventricular elongation and an increase in wall thickness and left ventricular mass with the interstitial edema and compensatory hypertrophy. , restrictive filling patterns in the left ventricle identifying diastolic dys-function have been reported consistently in biopsy-proven myocarditis. mural thrombi in diffusely hypokinetic ventricles have been reported frequently. hyperrefractile myocardium and other qualitative and quantitative analyses of myocardial texture have been described to assess the degree of active myocardial inflammation. pericardial effusion is a helpful echocardiographic finding, reported in % of patients with myocarditis, though hemodynamic compromise with cardiac tamponade is infrequent. urhausen and associates recently demonstrated that cardiac tissue velocity imaging by ultrasound is more sensitive than magnetic resonance imaging (mri) in some cases in detecting myocarditis with subtle ventricular functional impairment. imaging of leukocyte-mediated inflammation through ultrasound fracture of phagocytosed microbubbles shows promise as a means for detecting many forms of myocardial inflammation, although the method remains to be fully evaluated in humans. cardiac scintigraphy has been proposed as a convenient, noninvasive test with high sensitivity to diagnose active myocarditis. gallium- imaging, which identifies areas of increased inflammation, has been studied in clinical settings and noted to have sensitivity and specificity of % and %, respectively, with a negative predictive value of % for the diagnosis of myocarditis. indium- antimyosin monoclonal antibodies have been extensively studied to identify areas of myocyte damage in acute myocarditis. , this technique has extremely high sensitivity and often detects myocarditis that, on endomyocardial biopsy, is not seen by routine histologic assessment but is detected by immunohistochemistry. dec and coworkers studied patients with dcm with radiolabeled antimyosin antibody and endomyocardial biopsy. thirty-nine patients had abnormal antimyosin scans, but only of had evidence of myocarditis (predictive value of %). however, functional improvement was more likely in antimyosin scan-positive patients irrespective of the biopsy. the left ventricular ejection fraction (lvef) improved significantly in both concordant-positive (scan and biopsy both positive) and discordant-positive (scan positive, biopsy negative) patients, but it did not markedly improve in the negative scan and negative biopsy subset. the investigators proposed that discordant-positive scans represented patients with myocarditis in whom there may have been a sampling error on biopsy, hence the reason for missing the diagnosis. anastasiou-nana's group in athens reported that a combination of minimal or no left ventricular dilatation and a positive indium- antimyosin monoclonal antibody scan is highly specific for myocarditis. other nuclear techniques, such as technetium- m ( m tc)-mibi single photon emission computed tomography (spect) imaging, may also be useful in detecting myocarditis. contrast media-enhanced cardiovascular mri in patients with myocarditis has also been demonstrated to be an excellent tool in visualizing the location, activity, and extent of inflammation. early in myocarditis (day ), the enhancement on mri signals is accentuated and focal, whereas later (day ), this seems to be attenuated and more diffuse. furthermore, the severity of change correlates with prognosis. myocardial phosphorus- magnetic resonance spectroscopy has been utilized in assessing abnormalities in cardiac high-energy phosphate metabolism in patients with dcm and allograft rejection, but its role in the diagnosis of active myocarditis remains to be elucidated. the antemortem diagnosis of myocarditis was made feasible by the development of the endomyocardial biopsy technique. myocardial samples could be obtained via a transvascular approach with minimal discomfort to the patient and a low complication rate. whereas other approaches for acquiring myocardial tissue included percutaneous biopsy and mediastinotomy, , these were fraught with complications, precluding their acceptance into clinical practice. the safe and successful transvascular endomyocardial biopsy first described by sakakibara and konno was readily accepted for surveillance of cardiac allograft rejection in transplant recipients. the use of endomyocardial biopsy for the diagnosis and management of myocarditis was first reported in . subsequently, many reports , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] documented myocarditis in patients presenting with unexplained heart failure or ventricular arrhythmias (table . ). however, there was considerable incongruity in the diagnostic criteria used in these largely anecdotal reports. the dallas criteria were developed in preparation for a large, randomized, multicenter clinical trial of immunosuppressive therapy in myocarditis. these criteria define active myocarditis (see also fig. . a) as "an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical of ischemic damage associated with coronary artery disease." furthermore, other causes of inflammation (e.g., connective tissue disorders, infection, drugs) should be excluded. , the dallas criteria also defined borderline myocarditis as an inflammatory infiltrate that is sparse and lacks myocyte injury, and often ( %) on repeat biopsy, borderline myocarditis will histologically progress to active myocarditis. a limitation of endomyocardial biopsy is possible sampling error. the inflammation in myocarditis may be patchy or focal, unlike allograft rejection, which is a relatively diffuse process. although obtaining four samples from the right ventricular septum provides a high sensitivity for detection of allograft rejection in transplant recipients, this may not hold true for myocarditis. in an autopsy study of the right ventricular biopsy technique ( samples taken from the apical septum), only six of patients dying of myocarditis were correctly identified. left ventricular biopsy missed the diagnosis in eight of . in another study using the standard four to six samples, the sensitivity of right ventricular endomyocardial biopsy was reported at %. dec and colleagues reported that employing repeat left and right ventricular biopsies in patients with suspected myocarditis with an initial negative biopsy increases the yield by %. because an ideal study to evaluate sampling error has not been done, the true yield is unknown, but clearly a negative biopsy does not exclude active myocarditis. in the mtt, only % of patients screened had histologic evidence of myocarditis. the european study of epidemiology and treatment of cardiac inflammatory disease (esetcid) demonstrated a % incidence of biopsy-proven myocarditis by expanding the dallas criteria with the use of newer techniques of pcr and in situ hybridization. as discussed earlier, [ ] [ ] [ ] [ ] [ ] [ ] there is a need for validation of new histologic and nonhistologic criteria for diagnosis of this disease to improve upon the dallas histologic criteria. coronary arteriography is usually normal, although in animal models, coronary vasculitis has been reported. the one major exception is kawasaki disease, in which coronary artery aneurysms are frequently seen in association with myocarditis. ventriculograms may demonstrate global or regional ventricular dysfunction, associated valvular regurgitation, and mural thrombi. localized ventricular aneurysms with normal global systolic function have also been reported. the hemodynamic profiles of patients with acute myocarditis are representative of the extent of myocardial and pericardial involvement. in patients with significant ventricular dysfunction, elevated filling pressures with depressed cardiac output and stroke work indices are seen. a restrictive hemodynamic profile can be seen and must be differentiated from that seen with postviral constrictive pericarditis. the true natural history of myocarditis is largely unknown because the great majority of cases is perhaps subclinical and resolves without any significant residual cardiac dysfunction. clinically apparent myocardial dysfunction as seen with acute coxsackievirus b infections also resolves without any adverse sequelae in most cases. it has been estimated that only % of patients with clinically suspected acute myocarditis will proceed to develop dcm, but the true incidence is unknown. the murine myocarditis models frequently develop a pathologic process indistinguishable from that of the human form of idiopathic dcm. the direct link among viral infection, myocarditis, and dcm has not been conclusively proven. isolation of infectious virus from the heart has been achieved in only a few cases of acute fulminant myocarditis in neonates and infants. , given the hypothesis that dcm may develop after viral infection has been eradicated, the presence of virus in the myocardium is neither sufficient nor necessary to link virally mediated myocarditis with dcm. the indirect evidence of viral etiology of dcm relies on ( ) progression of viral myocarditis to dcm in experimental animal models, ( ) apparent progression of myocarditis in some patients to dcm, ( ) increased enteroviral antibody titers in patients with dcm, ( ) presence of viral genomic material in the myocardial tissue of patients with dcm, and ( ) improvement of ventricular function in subjects with dcm receiving immunomodulatory treatments. the major limitations are as follows: the relevance of disease in mice to humans is suspect, most cases of dcm are not preceded by documented myocarditis, and epidemiologic serologic evidence is incomplete. whereas coxsackievirus b igm antibodies are detected with greater frequency in patients with dcm than in normal controls, the frequency is similar to matched community controls and household contacts. , enteroviral genomic sequences are detected in the myocardium of % to % of patients with active myocarditis and in % to % of patients with dcm, but in data derived from most published studies, the average detection frequencies are % for active myocarditis, % for dcm, and not significantly different from % among healthy controls. , in a metaanalysis of the association of enteroviruses with human heart disease, baboonian and treasure concluded that although the causative role of enteroviruses in acute myocarditis, particularly in children, was supported by an overall odds ratio of . [confidence interval (ci), . to . ], and the association of dcm was suggested by an overall odds ratio of . (ci, . to . ), six of studies did not demonstrate an increased presence of viral remnants. the same investigators demonstrated more recently that pcr positivity is not found in minimally affected first-degree relatives of patients with familial dcm, suggesting that in this group, genetic predisposition to viral myocarditis does not underlie the inherited predisposition to development of dcm. in recent studies, other investigators have found strong evidence for a viral link, while others have found no viral vestiges in the myocardium of patients with end-stage heart failure. , regional variation in the etiology of dcm may be responsible in part for the reported differences in pcr positivity. responsiveness of patients with dcm to immunomodulatory interventions provides an interesting line of evidence supporting a viral/immune etiology of dcm. one would expect immune suppression to be an effective treatment in dcm if postviral and other forms of autoimmunity play a causative role in the disease. efficacy of such interventions has been reported in carefully selected patients. , , [ ] [ ] [ ] although the link between myocarditis and dcm is unclear, certain prognostic factors are identifiable. the presence of an abnormal qrs complex on ecg correlates with more severe left ventricular damage and is an independent predictor of survival. left atrial enlargement, atrial fibrillation, and lbbb are also associated with increased mortality. higher baseline lvef is positively associated with survival, whereas intensity of conventional therapy at baseline is negatively associated with survival. the presence of right ventricular dysfunction, as evidenced by abnormal right ventricular systolic shortening on echocardiography, was shown to be the most important predictor of death or need for cardiac transplantation in a group of patients with biopsy-proven myocarditis who were followed longterm. in addition, a net increase in lvef (between initial and final ejection fraction) was associated with improved survival, whereas baseline ejection fraction was not predictive of outcome. the presence and degree of left ventricular regional wall motion abnormalities did not affect the clinical course. light microscopic findings on biopsy have not been found to predict outcome in myocarditis. however, the extent of myocardial inflammation was a predictor of outcome after surgical ventricular remodeling for heart failure. higher baseline serum antibodies to cardiac igg by indirect immunofluorescence was associated with a better lvef and a smaller left ventricular end-diastolic dimension. general supportive measures for patients with myocarditis include a low-sodium diet, discontinuation of ethanol, and fluid restriction, especially in the presence of heart failure. patients with myopericarditis may need analgesics for pain control. recommendations for the limitation of physical activity are based on the murine model of cvb myocarditis, in which forced exercise during the acute phase of illness was associated with higher titers of infectious virus, increased inflammatory and necrotic lesions, and mortality. , , ibuprofen, indomethacin, and salicylates administered to mice after inoculation with cvb also resulted in increased viral titers, increased histologic severity of myocarditis, and increased mortality. this led to the suggestion that even nonsteroidal antiinflammatory drugs should be avoided in patients with active acute myocarditis. the american college of cardiology task force on myopericardial diseases recommends a convalescent period of approximately months after the onset of clinical manifestations before a return to competitive sports. the management of patients with presumed or confirmed myocarditis is primarily directed toward treatment of chf, arrhythmias, and symptoms from pericardial disease. diuretics, vasodilators, and digoxin should be administered to patients with mild-to-moderate systolic dysfunction. inotropic therapy and mechanical support with intraaortic balloon pump or ventricular-assist devices may be required for patients in refractory cardiogenic shock. cardiac transplantation is reserved for those patients who do not improve despite the measures described previously. although there are multiple studies on the use of angiotensin-converting enzyme inhibitors (aceis) in heart failure, the utility of aceis in myocarditis has been studied only in the murine model. early treatment with captopril in a cvb myocarditis model resulted in less inflammatory infiltrate, myocardial necrosis, and calcification. heart weight, heart/body weight ratio, and liver congestion diminished. even with delayed therapy, a reduction in left ventricular mass and liver congestion was evident. the aceis exert a potent vasodilator response, improve pump function, prevent ventricular remodeling, and may have antiarrhythmic properties. hence, all patients with systolic dysfunction, including those with myocarditis, should be placed on maximally tolerated doses of aceis. the use of beta-blockers in patients with mild-tomoderate heart failure due to dcm has been reported to be beneficial, but once again, no trials in humans with myocarditis have been performed. metoprolol-treated mice in an acute cvb murine myocarditis model have increased viral replication, myocyte necrosis, and -day mortality rates. carteolol, a nonselective beta-blocker, has been studied in a chronic myocarditis model and found to have beneficial effects with improved histologic scores, reduced heart weight and volume, and liver congestion. it appears that in the acute setting, beta-blockers should be avoided, and in the chronic heart failure stage, the nonselective beta-blockers may be beneficial. antiarrhythmic therapy may be needed for control of ventricular and supraventricular dysrhythmias. although the data from clinical trials of antiarrhythmic therapy in heart failure have not shown a primary mortality benefit, patients with active myocarditis were excluded in these trials. since immunosuppression is probably not helpful in myocarditis and no other specific therapy is available, one might consider treating the arrhythmias in the usual fashion, but there appears to be a rationale for making the diagnosis of myocarditis in patients who do not have profound ventricular dysfunction along with their arrhythmia. first, the majority of patients with myocarditis have a spontaneous resolution. second, current antiarrhythmic therapy of ventricular tachyarrhythmias is exacting, involving electrophysiologic studies and use of potentially toxic drugs or implantable defibrillators. the benefit of making the diagno-sis of myocarditis is that the patient may require only shortterm protection while the underlying process resolves, which can be provided by using amiodarone or other antiarrhythmic drugs under inpatient monitoring. if myocarditis resolves, antiarrhythmic therapy can be withdrawn. patients whose arrhythmias fail to improve despite histologic resolution of myocarditis, or who survived cardiac arrest, may be candidates for aggressive electrophysiologic approaches and implantable defibrillators. temporary and permanent pacemakers may be required in patients presenting with conduction system abnormalities. clinical trials of immunosuppressive therapy were first reported in children with clinical evidence of myocarditis, prior to the introduction of endomyocardial biopsy. in two series, in a total of eight children presenting with acute onset of severe chf, rapid improvement and survival were noted with adrenocorticotropic hormone or hydrocortisone treatment. , mason and associates reported patients with biopsy-proven myocarditis, half of whom improved with azathioprine and prednisone. gagliardi and coworkers followed children with biopsy-proven myocarditis who were treated with cyclosporine and prednisone. at year, of patients still had histologic evidence of myocarditis. no patient died or required transplantation. however, there was no control group. the data supporting an immunologic basis of myocarditis resulted in multiple treatment trials using immunosuppressants (table . ). the average proportion of patients showing improvement with a variety of immunosuppressants was %. a large number of the trials predated the development of the dallas criteria; thus, the histologic definition of myocarditis was not uniform. immunosuppressive regimens were arbitrary, and the lack of control groups made interpretation of these trials arduous. it was unclear whether immunosuppression was beneficial in those patients with myocarditis, as they can improve spontaneously. further, the infectious complications of immunosuppression were frequently seen and occasionally reported. , the conflicting results from these nonrandomized observations led to the mtt. in a multicenter, prospective, randomized design, the mtt enrolled patients with heart failure of recent onset (< years), left ventricular dysfunction (lvef < %), and biopsy-proven myocarditis (per the dallas criteria). the study screened patients; ( %) had endomyocardial biopsy evidence of myocarditis, and patients had a qualifying lvef of less than % and agreed to enrollment. patients were randomized to three treatment arms: prednisone and cyclosporine, prednisone and azathioprine, and no immunosuppressant treatment. all patients received conventional therapy for heart failure. the prednisone and azathioprine group was subsequently eliminated owing to low patient recruitment in the trial. patients were treated for weeks, and the primary end point was comparison of the mean increase in lvef at weeks. secondary analysis of other markers of left ventricular function, survival, and several immune parameters was performed. at both and weeks, no difference in lvef was observed in immunosuppressive-treated patients compared with untreated patients. at and years, there was no difference in survival or need for cardiac transplantation between groups (fig. . ) . on multivariate analysis, better baseline lvef, less intensive conventional therapy, and shorter illness duration were independent predictors of improvement in lvef during follow-up. analysis of immunologic variables (cardiac igg, circulating igg, natural killer and macrophage activity, helper t-cell level) suggested an association between better outcome and a more robust immune response. a higher level of cardiac igg was associated with a higher lvef and a smaller left ventricular size. the mortality rate for the entire trial was % at year and % at . years. the results of the mtt were important for diagnostic management because the authors recommended that in patients with unexplained chf, the performance of endomyocardial biopsy for the sole purpose of instituting immunosuppressive therapy was not warranted. nonetheless, certain subgroups may benefit from immunosuppressant therapy, including those with gcm, hypersensitivity myocarditis, or cardiac sarcoidosis. using a multicenter database, cooper and colleagues reviewed patients with gcm. the rate of death or cardiac transplanta-tion was %. median survival was . months from symptom onset to death or transplantation. the median survival in patients treated with corticosteroids was . months versus . months in untreated patients. however, patients treated with corticosteroids and azathioprine had an average survival of . months. cyclosporine in combination with corticosteroids, corticosteroids and azathioprine, and corticosteroids, azathioprine, and orthoclone okt survived an average of . months. the uncontrolled nature of this report decreases the reliability of its conclusions. patients with myocarditis associated with a known immune-mediated disease, such as systemic lupus erythematosus, may benefit from immunosuppressive therapy. other potential indications for a trial of immunosuppressant therapy include failure of myocarditis to resolve, progressive left ventricular dysfunction despite conventional therapy, continued active myocarditis on biopsy, or fulminant myocarditis that does not improve within to hours of full hemodynamic support, including mechanical assistance, and persistent ventricular tachycardia or fibrillation. smaller studies have used differing immunosuppressant regimens. kühl and schultheiss treated patients with biopsies classified as immunohistologically positive (more then two cells per high-power field and expression of adhesion molecules), negative dallas criteria, and left ventricular dysfunction. patients were treated with conventional therapy for months, followed by gradual tapering of methylprednisolone doses over weeks (following biopsy and lvef response). therapy was associated with an improvement in ejection fraction in % and improved new york heart association (nyha) functional class in %. four patients ( %) had no change in ejection fraction despite improvement in inflammatory infiltrates. however, study conclusions are limited by the absence of a control group. drucker and coworkers retrospectively reviewed children with congestive cardiomyopathy and dallas criteria of borderline or definite myocarditis. twenty-one patients were treated with intravenous igg ( g/kg over hours) and were compared to historical controls. overall survival was not improved, although there was a trend toward improvement in -year survival rates in the treated group. in the intravenous igg group, the left ventricular function was improved and persisted after adjustment for age, biopsy status, and use of aceis and inotropes. in a comparative study of ifn-α, thymomodulin, and conventional therapy in patients with biopsy-proven myocarditis or idiopathic dcm, an improvement in the active treatment groups was reported for ejection fraction (at rest and during exercise), maximal exercise time, functional class, and ecg abnormalities. in patients with chf, nyha class iii or iv, with symptoms of less than months' duration, intravenous igg resulted in an improvement in lvef and a functional improvement to nyha class i or ii at year of follow-up, in all nine patients who survived, regardless of biopsy results. perhaps strategies with alternative immunosuppressive regimens and different diagnostic criteria will be more successful in demonstrating the utility of immunosuppressants. the esetcid , is a prospective multicenter, placebocontrolled, double-blind study intended to address the natural course of myocarditis, myopericarditis, pericarditis, and the treatment regimens include conventional therapy with diuretics, aceis, digoxin, and antiarrhythmics or defibrillators; specific therapy for cmv and enteroviral myocarditis; and prednisolone and azathioprine for myocarditis without detectable virus. the duration of blinded therapy is months, with follow-up for months. the possible utility of more flexible diagnostic criteria for identification of responders to immunosuppressive therapy was recently suggested in a retrospective analysis by frustaci and colleagues. they found that the patients who had improved with immunosuppression had detectible circulating cardiac-specific autoantibodies but no detectible viral genomic material in their myocardium, while nonresponders had the opposite findings. these observations could be explained by successful suppression of an autoimmune response without the liability of suppressing ongoing antiviral immune activity. immunomodulatory therapies should be considered in cases of myocarditis that display ongoing adverse immune and autoimmune activity. immunosuppressive drug therapy, intravenous igg, tnf-α, and immunoadsorption are the forms of immunomodulation discussed above that have been used in humans (fig. . ). immunoadsorption has been applied primarily in dilated cardiomyopathy, but may hold promise in myocarditis, perhaps especially in phase ( fig. . a) of lymphocytic myocarditis. manipulation of cytokines, chemokines, and other factors that regulate proinflammatory and antiinflammatory processes , , , [ ] [ ] [ ] [ ] should receive attention in the development and assessment of new immunomodulatory therapies. myocarditis has emerged as a special indication for device therapy in recent years. circulatory-assist devices are especially attractive in myocarditis because the disease is usually self-limited. as a result, a relatively short period of circulatory assistance may allow time for the myocardium to recover and the injurious infectious, immune, and autoimmune processes to dissipate. this concept has been successfully tested in patients with severe heart failure due to myocarditis. [ ] [ ] [ ] implanted cardioverter-defibrillator devices have been used to treat ventricular tachyarrhythmias commonly associated with myocarditis. while such therapy may be lifesaving, consideration should always be given to antiarrhythmic drug therapy with protracted monitoring so as to avoid device implantation if possible. those patients with myocarditis who have survived cardiac arrest are candidates for implantable defibrillator devices. in a small series (n = ) composed predominantly of female patients ( %), the outcome of patients with active lymphocytic myocarditis confirmed by histologic examination of the explained heart was significantly worse than in controls undergoing transplantation for other diagnoses. this concern has not been validated in the analysis of outcome of , cardiac transplant recipients in the registry of the international society for heart and lung transplantation. one-year actuarial survival in all groups transplanted (idiopathic dcm, myocarditis, peripartum cardiomyopathy, versus other diagnoses) was %. nonetheless, myocarditis may recur in the transplanted heart. prevention prevention of myocarditis is an important developing strategy given the likelihood that a substantial proportion of cases of dcm worldwide are the result of preceding or ongoing myocarditis. several strategies have been considered, including immunization against the most common cardiotropic viruses, , , [ ] [ ] [ ] [ ] functional disablement of the coxsackie-adenovirus sarcolemmal receptor, , and early induction of immune tolerance. while immunization seems to have the greatest potential, scientific, medical, geographic, and political impediments are formidable. the advances in treatment strategies for hiv-infected patients have successfully resulted in prolonged survival times, and noninfectious complications of aids, such as dementia and heart disease, have become increasingly prevalent. early in the history of the aids epidemic, reports emerged of a rapidly fatal dcm affecting hiv-infected patients. , since the early reports, several clinical and echocardiographic series , [ ] [ ] [ ] [ ] [ ] have suggested that a subgroup of hiv-infected patients are predisposed to the development of progressive heart disease. in a prospective echocardiographic survey of hiv-infected adults over a period of years, patients were found to have significant cardiac dysfunction. dilated cardiomyopathy occurred in of and was strongly associated with a cd count of less than /mm and poorer survival. it has been estimated that clinically significant cardiac disease occurs in % to % of hiv-seropositive individuals. an interesting hypothesis to explain the high frequency of dilated heart muscle disease is the presence of myocarditis in hiv-infected patients with left ventricular dysfunction. reilly and colleagues reported in an autopsy series of consecutive aids patients a significantly higher incidence of myocarditis in those with clinically apparent cardiac disease or dcm. there have been other reports of higher prevalence of myocarditis in an endomyocardial biopsy series of hiv-seropositive patients compared with those without risk factors for hiv who were biopsied for suspected myocarditis. human immunodeficiency virus-related myocarditis has unique and atypical immunopathogenic features. it is characterized by increased cd t lymphocytes and sole induction of mhc class i, perhaps as a part of the systemic depletion of cd t cells. the myocarditis may not be readily apparent on histology owing to the accompanying lymphopenia, and special immunohistology and histochemistry techniques may need to be employed. although in situ hybridization techniques have demonstrated hiv- transcripts in cardiac myocytes, interstitial dendritic cells, and endothelial cells, the pathologic significance of this finding is still unclear because patients with evident transcripts may or may not have clinical disease. also, it is not evident that myocyte injury is a result of direct cytotoxicity of the virus, transcripts, cytokines, or other cardiotropic viruses. a large number of hiv-seropositive patients with left ventricular dysfunction also manifest evidence of nonpermissive or latent infection of myocytes with cmv immediate-early (cmv ie- ) genes. although evidence for classic intranuclear inclusions of active lytic cmv infection is rarely found, there is increasing speculation that the latent viral infection may be responsible for enhanced mhc expression and provide a stimulus for ongoing immune injury, as seen with most models of myocarditis. a role for direct cytokine-mediated cardiac injury has also been proposed in hiv-infected populations with myocardial dysfunction. both tnf-α and il- , known to be elevated in hiv infection, directly inhibit cardiac contractility in vitro, and the former has been implicated in causing myocardial dysfunction. increased catecholamines may be responsible for microvascular spasm and chronic ischemic dysfunction. the clinical management of patients with hiv-related myocarditis and cardiomyopathy is targeted toward improving congestive symptoms, afterload reduction, and digitalis for improved neurohormonal axis. a specific role for antiviral therapies is controversial, since medications like zidovudine and ifn-α are themselves recognized as cardiotoxins. zidovudine has been known to result in premature termination of myocyte mitochondrial dna chain replication. despite worldwide eradication of smallpox, the bioterrorism threat arising from the existence of stored variola virus has prompted military and civilian smallpox vaccination programs in the united states. myocarditis emerged as a known, rare complication of smallpox vaccination during the eradication effort in the s and s. its incidence varied with the vaccinia strain used to produce the vaccine, and with the method used to detect myocarditis. the true incidence is not known. current vaccination programs use the original new york city board of health strain of vaccinia (dryvax) and new vaccines. while the occurrence of myocarditis in the united states's current military dryvax vaccination program appears to be higher ( . %, or about one in , ) than historical estimates, its incidence after new vaccines has not been determined. previously vaccinated individuals have a much lower risk of developing myocarditis. full functional and symptomatic recovery occurs in most patients. while involvement of eosinophils has been noted, the mechanisms responsible for postvaccination myocarditis are not known. bacterial infection of the myocardium occurs frequently in association with infective endocarditis, usually in the form of myocardial abscesses adjacent to the valve ring (see chapter ) . myocardial involvement has also been reported in association with a wide range of bacterial pathogens in the absence of endocarditis. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] with most of these agents, myocardial involvement is uncommon and occurs principally in the setting of overwhelming systemic infection. cardiac involvement after streptococcal infection is usually manifested as acute rheumatic fever, which develops to weeks after onset of pharyngitis and has a distinctive histologic appearance (see chapter ) . streptococcal pharyngitis may also be associated with a nonrheumatic form of myocarditis that occurs concurrently with the febrile illness. [ ] [ ] [ ] [ ] the most common clinical manifestations are chest pain and marked st-segment and t-wave abnormalities on the electrocardiogram, which correlate with segmental wall motion abnormalities observed with echocardiography. cardiomegaly and chf are uncommon. histologic examination reveals lymphocytic infiltrates and myocyte necrosis in the absence of aschoff bodies, similar to the findings in viral or idiopathic myocarditis. bacteria are not present in the myocardium, and it is hypothesized that inflammation is caused by streptococcal exotoxins in a manner similar to that in diphtheritic myocarditis. although vaccination has virtually eliminated diphtheria in most western nations, it remains an important public health problem in many underdeveloped countries, and may be the most common etiology of myocarditis worldwide. infection with c. diphtheriae is usually confined to the respiratory mucosa. systemic manifestations are due to secretion of a potent exotoxin. the ecg abnormalities suggesting myocardial involvement are present in a high proportion of patients, but clinical evidence of cardiac dysfunction occurs in only % to % of cases. nevertheless, cardiac involvement is the most common cause of death in fatal infections. disturbances of av conduction, including bundle branch blocks and complete av block, are observed frequently in affected patients and are associated with a mortality rate of % to %. patients may also present with progressive cardiac dilatation and chf. histologic study reveals diffuse mononuclear cell infiltrates associated with myocyte necrosis. corticosteroid therapy does not appear to be effective in the prevention or treatment of diphtheritic myocarditis, although only one prospective trial has been performed. one report suggested that administration of carnitine may decrease the incidence and severity of cardiac involvement. spirochetal myocardial disease lyme disease lyme disease is caused by the spirochetal organism b. burgdorferi, which is transmitted to humans by certain species of deer ticks in endemic areas of north america, europe, and asia. the acute phase of the illness is characterized by fever, myalgia, lymphadenopathy, and a characteristic rash known as erythema chronicum migrans. the organism persists in many tissues, and chronic manifestations include arthritis and a variety of neurologic syndromes. manifestations of cardiac involvement develop in % to % of patients at an average of . weeks (range, days to months) after the acute illness. , , disturbances of av conduction are the most common manifestations, occurring in % of cases, with complete or high-grade block in more than %. the av block is usually supra-hisian, with a narrow complex escape rhythm. temporary transvenous pacing is required frequently, but av block almost always resolves within to days. endomyocardial biopsy may reveal lymphocytic infiltrates with associated myocyte necrosis, and spirochetes may be identified in biopsy specimens. lyme carditis occasionally develops in patients without a preceding rash or other symptoms of acute lyme disease. therapy with a to week course of antibiotics (doxycycline, amoxicillin or cefuroxime) is recommended for patients with lyme carditis. , antibiotic therapy has proved effective in the prevention and treatment of chronic arthritic and neurologic syndromes, but its use in cardiac disease has not been tested prospectively. evidence of diffuse myocardial involvement is common, including evolving stsegment and t-wave abnormalities on the electrocardiogram, reversible abnormalities of left ventricular wall motion, and diffuse myocardial uptake on gallium scan. one fatal case of pancarditis has been reported, but frank heart failure is uncommon. a high incidence of positive serologies for b. burgdorferi was reported in european patients with chronic dcm, and in two patients the organism was cultured from myocardial biopsies. , it has been suggested that unrecognized lyme carditis may be responsible for a small but significant proportion of cases of idiopathic dcm. evidence of severe myocarditis is present at autopsy in a high proportion of fatal cases of leptospirosis and relapsing fever. , nonspecific ecg abnormalities are common in these diseases, but clinical evidence of left ventricular dysfunction is rare. although previously uncommon, the incidence of fungal infections of the heart has increased markedly since the early s. this increased incidence is due to several factors, including the increasing use of antibiotics, immunosuppressive agents for transplantation, and chemotherapy, as well as the increasing application of cardiac surgery and the increasing prevalence of intravenous drug abuse. candida infection the most common fungal organisms causing cardiac infection are candida species. candida endocarditis occurs most frequently after thoracic surgery and in intravenous drug abusers. immunocompromised patients, on the other hand, are more likely to develop candida myocarditis without involvement of the valves or endocardium, usually in the setting of disseminated systemic infection. [ ] [ ] [ ] autopsy studies reveal extensive myocardial involvement in % to % of patients who die of systemic candidiasis. histologically, candida myocarditis consists of focal abscesses (usually microscopic, although gross nodules may be present) interspersed with areas of normal myocardium. clinical manifestations typically include nonspecific ecg abnormalities, disturbances of av conduction, including complete heart block, and tachyarrhythmias. cardiomegaly and chf are rare. myocardial involvement is usually not recognized antemortem. myocardial involvement is present in % of patients with disseminated aspergillosis, and myocardial invasion is almost always present in patients with aspergillus endocarditis. as in other tissues, histology is characterized by microscopic and macroscopic abscess formation. , extensive vascular invasion by fungal hyphae results in thrombosis and coagulation necrosis. although aspergillus endocarditis has been treated successfully, myocarditis is uniformly fatal. cardiac involvement in actinomycosis occurs in only % of cases and usually develops by direct extension from a contiguous focus of pulmonary or mediastinal infection. [ ] [ ] [ ] hematogenous seeding of the myocardium occurs occasionally. myocardial involvement is characterized by necrotizing abscess formation with masses of mycelial bodies and characteristic sulfur granules. in many cases, cardiac symptoms are absent, but patients may present with chest pain characteristic of pericarditis, pericardial tamponade, or chf. myocardial involvement has rarely been reported in immunocompromised patients with disseminated coccidioidomycosis and cryptococcosis. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] cardiac involvement is usually not clinically apparent antemortem, although death due to progressive chf has been reported. cardiac involvement with blastomycosis and histoplasmosis is extremely uncommon and usually results from direct extension from a contiguous intrathoracic focus. rocky mountain spotted fever caused by infection with rickettsia rickettsii is characterized by a diffuse vasculitis, and in fatal cases, death is usually due to vascular collapse. vasculitis of the coronary vessels may also be present, and lymphocytic infiltrates with myocyte necrosis are present in approximately % of fatal cases. , although cardiac dilatation and cardiogenic pulmonary edema occur infrequently, echocardiography demonstrates systolic left ventricular dysfunction in the majority of patients. , clinical evidence of myocarditis has been reported in association with scrub typhus due to rickettsia tsutsugamushi, whereas q fever (coxiella burnetii) usually causes endocarditis in its chronic form. it is estimated that to million people in south and central america are infected with t. cruzi, and chagas' cardiomyopathy resulting from this infection is the most common cause of chf and cardiac death in these endemic areas. , the parasite is transferred to humans by triatomine insects known as reduviid bugs. the clinical course of infection is characterized by an acute phase, an indeterminate or latent phase of variable duration, and a chronic phase. , after inoculation, parasites are disseminated throughout the body, with the highest concentrations appearing in striated and cardiac muscle and autonomic ganglia. a lesion may appear at the point of entry, and an acute illness develops, characterized by fever, myalgia, edema of the face and lower extremities, hepatomegaly, and generalized lymphadenopathy. because of the nonspecific nature of the symptoms, the acute phase of the disease is usually unrecognized. rarely, acute inflammatory myocarditis develops during the acute phase, with ecg abnormalities, cardiomegaly, and chf. histologic examination in these cases demonstrates inflammatory infiltrates adjacent to myocytes containing large numbers of intracellular parasites. these findings suggest that cardiac manifestations during the acute phase of the illness may be due to direct lysis of myocytes by parasites. , the acute illness resolves over a period of weeks to months, and patients enter the indeterminate phase. these patients are asymptomatic, with low-level parasitemia, and antibodies to t. cruzi are present. although the electrocardiogram is normal, echocardiography and left ventricular cineangiography demonstrate focal wall motion abnormalities in a high proportion of cases, most commonly involving the left ventricular apex and posterior wall. endomyocardial biopsy is frequently normal but may reveal hypertrophy, fibrosis, and inflammatory infiltrates in up to % of patients without clinical manifestations. manifestations of chronic chagas' disease develop in % to % of infected patients after a highly variable period, which may be as long as years. , involvement of autonomic ganglia may cause megacolon or megaesophagus, but the heart is the organ most commonly affected. histology is characterized by focal areas of inflammation or fibrosis interspersed with areas of normal myocardium. endomyo-cardial biopsy reveals myocarditis in approximately % of patients. , this process frequently involves the specialized conducting tissue, and therefore disturbances of av conduction, especially rbbb with or without associated left anterior fascicular block, are present in up to % of patients. complete heart block may require permanent transvenous pacing. ventricular arrhythmias are also frequent, and the initial manifestation of the disease may be sudden death due to ventricular tachyarrhythmia or complete heart block. decreased ventricular function is present in almost all patients with chronic chagas' disease, and in its most advanced form, chagas' disease presents as a congestive cardiomyopathy with four-chamber dilatation. a characteristic apical aneurysm is usually present. [ ] [ ] [ ] left ventricular thrombus is frequently observed, and systemic embolization is common. , this advanced form of the disease is usually fatal within a few years. diagnosis of chronic chagas' cardiomyopathy is dependent on detection of circulating antibodies to t. cruzi by one of several serologic methods. parasites are usually not detected in the myocardium, but low-level parasitemia can be demonstrated by hemoculture or xenodiagnosis, using uninfected reduviid bugs allowed to ingest the patient's blood. the pathogenic mechanisms leading to myocardial injury, in some patients occurring many years after the initial infection, are poorly understood. the presence of inflammatory infiltrates in the absence of detectable parasites suggests the possibility of autoimmune injury, as postulated for viral and idiopathic myocarditis. support for this hypothesis includes the demonstration of antibodies to t. cruzi as well as antiidiotypic antibodies that cross-react with myocyte antigens. , histologic studies demonstrate loss of autonomic ganglia, and physiologic studies are suggestive of marked autonomic dysfunction. [ ] [ ] [ ] withdrawal of parasympathetic tone may lead to excess sympathetic stimulation, which can cause cardiomyopathy. histologic studies also demonstrate abnormalities of the microvascular bed, , and in vitro experiments demonstrate altered endothelial cell function and increased platelet-endothelial cell adhesion. , all three reports suggest that progressive focal myocardial disease is the result of ischemia due to obstruction of the microvascular bed. treatment of chronic chagas' cardiomyopathy is supportive, with the use of standard therapy for chf. dynamic cardiomyoplasty has resulted in symptomatic improvement in some patients. the role for left ventricular reduction or the commonly known batista procedure is controversial. antiarrhythmic therapy may be indicated for sustained ventricular tachyarrhythmias, and a permanent pacemaker should be implanted in patients with high-degree av block. two antiparasitic drugs are available for the treatment of american trypanosomiasis. both nifurtimox and benznidazole decrease the level and duration of parasitemia and decrease mortality in patients with acute chagas' disease. low-level parasitemia persists in most treated patients, however, and it is unclear whether therapy in the acute phase decreases the incidence of subsequent progression to chronic chagas' disease. whereas earlier studies with these drugs have not been shown to decrease progression from latent phase to chronic disease or to decrease symptoms or improve cardiac function in patients with chronic disease, , the recent studies with itraconazole and allopurinol have shown partial success with parasitologic cure and normalization of ecg changes in nearly half the patients. in a randomized, placebo-controlled trial of benznidazole, there was successful negative seroconversion of % of patients with early chronic disease as manifested by seropositivity for t. cruzispecific antibodies after treatment for days. immunosuppressive therapy in patients with malignancies or after organ transplantation has been associated with reactivation causing acute chagas' disease. , reactivation of chagas' disease in this setting has usually responded promptly to therapy. [ ] [ ] [ ] african trypanosomiasis african trypanosomiasis is caused by trypanosoma gambiense or t. rhodanese and characteristically presents with progressive somnolence owing to central nervous system involvement. autopsy studies demonstrate a pancarditis involving the mural and valvular endocardium as well as the myocardium in up to % of fatal cases. [ ] [ ] [ ] [ ] the conduction system and autonomic ganglia may also be involved. nonspecific abnormalities are often present on the electrocardiogram, but other clinical manifestations of the frequent cardiac involvement are apparently uncommon. patients with acute infection by t. gondii are usually asymptomatic, but they may have a transient syndrome of fever and lymphadenopathy. the infection usually persists in a latent phase, with cysts deposited predominantly in the brain and myocardium. immunosuppression after chemotherapy, in transplant recipients, and in patients with aids may be associated with disseminated infection characterized by severe encephalitis and myocarditis. [ ] [ ] [ ] [ ] myocarditis after transplantation occurs frequently in seronegative recipients of hearts from seropositive donors. [ ] [ ] [ ] endomyocardial biopsy demonstrates intracellular toxoplasma pseudocysts and a mixed interstitial infiltrate, frequently including eosinophils ( fig. . d ). toxoplasma myocarditis can be successfully prevented by a -week course of pyrimethamine imitated after early transplantation or treated with pyrimethamine and sulfadiazine. cardiac involvement in metazoal infections is uncommon. up to % of patients with echinococcosis have cardiac cysts. [ ] [ ] [ ] these patients may present with pericardial or atypical chest pain, chf owing to inflow or outflow obstruction, ventricular arrhythmias, or pulmonary hypertension owing to diffuse pulmonary embolization of scolices. the diagnosis is usually documented by two-dimensional echocardiography, and surgical excision is indicated, when possible, even in asymptomatic patients. trichinosis, caused by the parasite t. spiralis, is usually a benign syndrome characterized by fever, myositis, and eosinophilia. mild, asymptomatic myocardial involvement is probably common, as suggested by frequent ecg abnormalities and pericardial effusion noted by echocardiography. rarely, a severe myocarditis develops, which is the apparent cause of death in most fatal cases. [ ] [ ] [ ] eosinophils are prominent in the interstitial infiltrate. t. spiralis does not become encysted in the heart, and larvae are seldom identified in the myocardium. myocardial injury is thought to be immune mediated, and therapy with corticosteroids is generally recommended, although prospective trials have not been performed owing to the infrequent occurrence of this syndrome. the mucocutaneous lymph node syndrome or kawasaki disease occurs predominantly in children under the age of years and is most prevalent in japan. , it has been recognized worldwide, and in the united states and the developed world, it has replaced rheumatic fever as the most common cause of acquired heart disease in children. it is widely believed to have an infectious etiology, but no agent has yet been identified. its diagnosis is based on recognition of clinical features of the illness, which include remittent high-spiking fever with distinctive conjunctival injection, anterior uveitis, strawberry tongue with erythema, dryness, fissuring and peeling of the lips and mouth, erythematous truncal rash, redness of palms and soles with periungual desquamation, and cervical lymphadenopathy. the principal cardiovascular manifestation of the disease is a multisystem arteritis with frequent involvement of the coronary arteries. coronary arteritis leads to aneurysm formation and thrombosis. the most common cause of death is myocardial infarction due to aneurysm rupture or coronary occlusion. myocardium obtained by endomyocardial biopsy or at autopsy reveals histologic evidence of myocarditis in a high proportion of patients. [ ] [ ] [ ] [ ] segmental wall motion abnormalities and nonspecific ecg changes are frequently present in the absence of coronary aneurysms. , these findings have been attributed to myocarditis, but they might also reflect ischemia due to small vessel arteritis. congestive heart failure in the absence of infarction is uncommon. intravenous gamma-globulin and high-dose aspirin are effective in the prevention of coronary aneurysms and thrombosis, but their effect on myocarditis is not known. giant cell myocarditis is a rare but frequently fatal disorder. it is defined histologically by extensive but patchy myocyte necrosis with areas of intense multicellular inflammatory infiltration that includes histiocytes, lymphocytes, and the characteristic multinucleated giant cells (fig. . b) . , [ ] [ ] [ ] there has been a great deal of controversy as to whether gcm and cardiac sarcoidosis are distinct pathologic entities because multinucleated giant cells in gcm seldom organize to form granulomas. , , litovsky and associates showed that gcm is characterized by myocytic destruction mediated by cytotoxic t cells, macrophagic giant cells, and eosinophils. in contrast, cardiac sarcoid is an interstitial granulomatous disease without myocytic necrosis. although the etiology of gcm is unknown, it has been associated with a medley of autoimmune disorders and perhaps is immunologically mediated. thymomas, systemic lupus, rheumatoid arthritis, wegener's granulomatosis, ulcerative colitis, chronic hepatitis, myasthenia gravis, myositis, pernicious anemia, takayasu's arteritis, and lymphomas have been associated with gcm. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the clinical presentation of gcm may mimic lymphocytic myocarditis, although arrhythmias and heart failure are usually more severe and rapidly progressive. , frequently, patients with gcm present with conduction system abnormalities, ventricular tachycardia, or even sudden cardiac death. [ ] [ ] [ ] [ ] , , , , giant cell myocarditis has also been reported to present as asymmetric septal hypertrophy. the natural history of gcm is obscure owing to its rare occurrence, but the isolated reports in the literature suggest that it carries a poor prognosis. davidoff and coworkers reported that % of patients with gcm required cardiac transplantation or died during a -year follow-up period compared with the % of patients with lymphocytic myocarditis. cooper and colleagues reported on patients with gcm collected in a worldwide registry. the registry patients had an % rate of death or need for transplantation, which was significantly worse than that for the patients with lymphocytic myocarditis seen in the mtt. the median survival with gcm was . months. the patients treated with immunosuppressive regimens including cyclosporine, azathioprine, and prednisone had an average cardiac survival of . months compared with . months for the untreated patients. the rate of recurrent gcm in the transplanted patients was % (nine of ). the role of immunosuppressive therapy for gcm is unknown, but at least anecdotal and registry reports suggest possible benefit of cyclosporine and prednisone with or without azathioprine. cardiac transplantation remains the last therapeutic resort for these patients, although there is risk of recurrent disease, , , which seems to be associated with abatement of immunosuppressive therapy after transplantation and may represent atypical rejection in the allograft. it usually resolves with intensification of the immunosuppressive regimen. eosinophilic myocarditis loffler first described the association of eosinophils with cardiac disease, and reported "endocarditis parietalis fibroplastica" in association with eosinophilia. the endocardial disease with eosinophilia is well recognized and extensively reviewed elsewhere. , myocardial involvement is rare and frequently fatal; hence, diagnosis is often made postmortem. endomyocardial biopsy is essential to the antemortem diagnosis of eosinophilic myocarditis (fig. . c ). myocarditis is believed to represent a more fulminant and necrotic form of the endocardial disease. eosinophils have the ability to secrete highly toxic cationic proteins into areas of inflammation and to produce harmful oxygen radicals and potent lipid mediators, leading to myocyte necrosis as seen in proximity to degranulating cosinophils. animal experiments have confirmed that exposure of myocytes to eosinophil granule proteins is lethal, and ventricular function in the intact heart is reduced in hypereosinophilic states. eosinophilic myocardial infiltrates have been reported in association with profound eosinophilia caused by an allergic diathesis, parasitic infection, drug hypersensitivity, vasculitis, or churg-strauss syndrome, , , but eosinophilic myocarditis can occur in the absence of profound eosinophilia. further, eosinophilic myocarditis may present as acute myocardial infarction, sudden death, cardiogenic shock, or nonspecific chest pain and dyspnea. the natural history of eosinophilic myocarditis is usually swift and ominous with rapid evolution to refractory heart failure or intractable arrhythmias, leading to death. early biopsy-aided histologic confirmation is fundamental to antemortem diagnosis. clinical improvement may occur with corticosteroid therapy. cardiac sarcoidosis sarcoidosis is a multiorgan, noncaseating granulomatous disorder of unknown etiology. histologically, it may involve the lung, lymph nodes, skin, liver, spleen, parotid glands, and heart. right heart failure owing to pulmonary manifestations of pulmonary hypertension and pulmonary fibrosis is the predominant cardiac finding. asymptomatic cardiac involvement is common, with a quarter of the patients having sarcoid granulomas in the heart at autopsy. characteristically, the noncaseating granulomas infiltrate the ventricular walls and become fibrotic. they may involve the conduction system, although there is no definite predilection for specialized tissues. there may be transmural involvement with fibrous replacement of portions of the myocardium and aneurysm formation. the fibrous transition of granulomas may result in early diastolic dysfunction, but as the disease progresses and with extensive involvement, systolic impairment occurs. whereas cardiac involvement in sarcoidosis commonly occurs as part of the systemic affliction, isolated cardiac sarcoidosis in the absence of systemic disease has been described. the clinical presentation of cardiac sarcoidosis is variable and may depend on the amount of myocardium replaced with granulomas and the amount and location of scar tissue. rhythm abnormalities and conduction disorders predominate, although asymptomatic patients with mildly restrictive filling patterns may elude medical attention. patients with chf may show clinical features of restrictive cardiomyopathy or dcm. papillary dysfunction with mitral regurgitation and pericardial involvement with effusiveconstrictive disease have also been described. radionuclide myocardial imaging with thallium and gallium is helpful in identifying patients with myocardial involvement. magnetic resonance imaging has also been proposed as a diagnostic modality. , histologic diagnosis with endomyocardial biopsy is corroborative, but a negative biopsy does not rule out the possibility, owing to sampling error. the combination of bilateral hilar adenopathy and myocardial disease suggests cardiac sarcoidosis in a young person. corticosteroids are indicated when myocardial involvement, conduction abnormalities, and ventricular arrhythmias are present. patients with scintigraphic uptake of gallium may be more responsive to corticosteroid therapy. perma-nent pacemakers may be needed to treat the conduction abnormalities. implantable defibrillators may be utilized in the prevention of sudden death. heart failure is treated in the conventional manner, whereas heart transplantation is reserved for intractable heart failure. heart-lung transplants are performed infrequently for patients with pulmonary involvement, but there is a significant risk of recurrent disease. peripartum myocarditis/cardiomyopathy virchow and porak first reported the association of pregnancy with dcm in in an autopsy series. peripartum myocarditis/cardiomyopathy occurs in one of every , to , pregnancies. the incidence is higher in africa, and it increases with older age, multiparity, multiple gestations, and prior history of peripartum myocarditis/cardiomyopathy. peripartum cardiomyopathy is currently believed to be a myocarditis of unknown etiology, perhaps an infectious, autoimmune, or idiopathic process. the viral myocarditis hypothesis stems from the observations that pregnant mice are more susceptible to cardiotropic viruses, with increased viral replication, and with the increased hemodynamic burden of pregnancy, the myocardial lesions worsen. recently, it has been postulated that after delivery, the rapid degeneration of the uterus results in fragmentation of tropocollagen by enzymatic degradation. this releases actin, myosin, and their metabolites, and antibodies are formed that then cross-react with the myocardium. an association between tocolytic therapy and cardiomyopathy has also been reported. while the diagnosis of peripartum myocarditis/cardiomyopathy is traditionally made during the last trimester or during the first months postpartum, earlier occurrence has been reported. the presentation is usually of decompensated ventricular systolic failure in the absence of any identifiable cardiac pathology. the lvef normalizes in approximately % of women and is more likely to normalize if the initial lvef is > %. therapy is tailored to the decompensated state with diuretics, digoxin, and vasodilators (aceis are contraindicated in pregnancy). inotropic therapy may be needed for supporting those in cardiogenic shock, along with the use of mechanical circulatory-assist devices. although there are anecdotal reports of benefit of immunosuppressive therapy, the routine use of these agents cannot be recommended; in fact, the only indication would be biopsy-proven fulminant myocarditis. cardiac transplantation is an alternative therapeutic option and may be offered to those with intractable heart failure, but it is preferred that transplantation be delayed. the early outcome after transplantation in these patients is often unfavorable, with increased allograft rejection, and the natural history of peripartum myocarditis/cardiomyopathy suggests that more than half of the patients have spontaneous resolution. there are perhaps two different subgroups. one presents with a rapidly progressive, fulminant course with often nearcomplete resolution of myocardial dysfunction within days and excellent long-term prognosis. the other group has late, insidious onset and presents with progressively worsening heart failure with poor prognosis. it is often difficult to differentiate this from the common variety of dcm. myocarditis is a focal or diffuse inflammation of the myocardium, which has multiple infectious and noninfectious etiologies. autoimmunity, triggered most often by viral infections, is a prominent pathophysiologic mechanism of myocarditis. overt and clinically inapparent myocarditis is an important cause of dilated cardiomyopathy. virus-induced lymphocytic myocarditis progresses through three stages: active viral infection, autoimmunity, and dilated cardiomyopathy. myocarditis is no longer a diagnosis of exclusion; histology, histochemistry, dna and rna detection, tissue and circulating antibody detection, and a variety of imaging techniques can be used together or, in some cases, independently to make the diagnosis and to establish the disease stage. treatment of myocarditis must be tailored to the phase of disease. many new therapies based on knowledge of the molecular pathophysiology of 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transplantation peripartum cardiomyopathy: a comprehensive review viral myocarditis during pregnancy: encephalomyocarditis virus infection in mice viral myocarditis and cardiomyopathy peripartum heart failure associated with prolonged tocolytic therapy pregnancy-associated cardiomyopathy: clinical characteristics and a comparison between early and late presentation peripartum myocarditis and cardiomyopathy peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics key: cord- -tuxwmv v authors: alawadhi, abdulla; saint-martin, christine; bhanji, farhan; srour, myriam; atkinson, jeffrey; sébire, guillaume title: acute hemorrhagic encephalitis responding to combined decompressive craniectomy, intravenous immunoglobulin, and corticosteroid therapies: association with novel ranbp variant date: - - journal: front neurol doi: . /fneur. . sha: doc_id: cord_uid: tuxwmv v background: acute hemorrhagic encephalomyelitis (ahem) is considered as a rare form of acute disseminated encephalomyelitis characterized by fulminant encephalopathy with hemorrhagic necrosis and most often fatal outcome. objective: to report the association with ran binding protein (ranbp ) gene variant and the response to decompressive craniectomy and high-dose intravenous methylprednisolone (ivmp) in life-threatening ahem. design: single case study. case report: a -year-old girl known to have sickle cell disease (scd) presented an acquired demyelinating syndrome (ads) with diplopia due to sudden unilateral fourth nerve palsy. she received five pulses of ivmp ( mg/kg/day). two weeks after steroid weaning, she developed right hemiplegia and coma. brain magnetic resonance imaging showed a left frontal necrotico-hemorrhagic lesion and new multifocal areas of demyelination. she underwent decompressive craniotomy and evacuation of an ongoing left frontoparietal hemorrhage. comprehensive investigations ruled out vascular and infectious process. the neurological deterioration stopped concomitantly with combined neurosurgical drainage of the hematoma, decompressive craniotomy, ivmp, and intravenous immunoglobulins (ivig). she developed during the following months crohn disease and sclerosing cholangitis. after -year follow-up, there was no new neurological manifestation. the patient still suffered right hemiplegia and aphasia, but was able to walk. cognitive/behavioral abilities significantly recovered. a heterozygous novel rare missense variant (c. a>g, p.lys glu) was identified in ranbp , a gene associated with acute necrotizing encephalopathy. ranbp is a protein playing an important role in the energy homeostasis of neuronal cells. conclusion: in any ads occurring in the context of scd and/or autoimmune condition, we recommend to slowly wean steroids and to closely monitor the patient after weaning to quickly treat any recurrence of neurological symptom with ivmp. this case report, in addition to others, stresses the likely efficacy of combined craniotomy, ivig, and ivmp treatments in ahem. ranbp mutations may sensitize the brain to inflammation and predispose to ahem. acute hemorrhagic encephalomyelitis (ahem) or acute hemorrhagic leukoencephalitis is considered a rare and extremely severe form of acute disseminated encephalomyelitis (adem). ahem is characterized by an acute and rapidly progressive encephalopathy including hemorrhagic necrosis of the parenchyma of the central nervous system. it is usually fatal ( ) ( ) ( ) . many treatment options have been used including intravenous (iv) steroids, intravenous immunoglobulins (ivig), and plasmapheresis ( ) . there have been few reports of survival following early intervention with high-dose corticosteroid therapy and/or decompressive craniotomy ( ) ( ) ( ) ( ) ( ) . ranbp , a nuclear pore protein, has numerous roles in the cell cycle. ranbp is associated with microtubules and mitochondria suggesting roles in intracellular protein trafficking or energy maintenance and homeostasis of neuronal cells. ranbp mutations have been reported in acute necrotizing encephalopathy (ane) which could present with coma, convulsions, and encephalopathy. the hallmark of ane is multiple, symmetric brain lesions located in the thalami bilaterally, putamina, deep periventricular white matter, cerebellum, and brainstem. it could be triggered by a viral infection in previously healthy children ( ) . we report a new case of ahem associated to a ran binding protein (ranbp)- variant and responsive to combined craniectomy, intravenous methylprednisolone (ivmp), and ivig as inaugural manifestation of multisystemic autoimmunity in a girl with sickle cell disease (scd). a -year-old girl known for scd treated on folic acid and hydroxyurea was admitted for new-onset diplopia [day (d ): refers to the start of the diplopia] weeks after respiratory tract infection due to rhinovirus. she was diagnosed with a fourth nerve palsy secondary to an acquired demyelinating syndrome. the initial brain magnetic resonance imaging (mri) performed at d after onset of neurological symptom showed left midbrain and pontine edema with expansion of the brainstem, right caudate nucleus, and scattered supratentorial white matter foci of high t /flair signal (figure ). brain mr angiography (mra) showed a normal appearing circle of willis. the cerebrospinal fluid (csf) obtained by lumber puncture was normal (wbc cells/μl, rbc cells/μl, glucose . mmol/l, protein . g/l, and absent oligoclonal bands). the infectious workup including blood bacterial culture, csf bacterial and viral cultures, nasopharyngeal aspirate (tested for influenza a, influenza b, parainfluenza - - , respiratory syncytial virus, adenovirus, coronavirus e, coronavirus oc , metapneumovirus, enterovirus, and rhinovirus), and serologies for epstein-barr virus, mycoplasma pneumoniae, htlv i, htlv ii, hiv , and lyme disease were negative. bartonella henselae igg was positive ( : , ) reflecting a previously acquired common and self-limited infection in our area. antinuclear antibodies (ana) were positive ( : ). b and folate levels were normal. smooth muscle antibodies were negative. anti-mitochondrial antibodies were positive. sedimentation rate was mm/h. she was treated with five doses of ivmp ( mg/kg/day) followed by days of oral prednisone ( mg/kg/day). at discharge, her neurological exam was significant only for vertical diplopia. she presented month later with days of upper respiratory tract infection symptoms, fever, headache, and a rapidly progressive right-hand weakness (d ) with normal alertness. she had normal blood pressure ( / mmhg). she was started on cefotaxime, vancomycin, and acyclovir. white cell count was . × /l, hemoglobin was . g/l, and platelets were × /l. while in the mri machine (d ) she deteriorated with vomiting and reduced level of consciousness (glasgow coma scale dropped from to over min). brain mri showed a rapid progression over a few sequences of an active bleed involving both superficial and deep gray matter as well as subcortical white matter of the left hemisphere anterior quadrant. brain mra was normal (figures a-f) . the patient was immediately brought out of the magnet and her physical exam demonstrated unequal dilated pupils. she received iv mannitol and hypertonic saline for the management of acute intracranial hypertension/ herniation and was taken for surgery. she underwent left frontotemporoparietal decompressive craniotomy, evacuation of left frontoparietal intracerebral hemorrhage, and insertion of an external ventricular drain (evd). upon opening the skull, there was significant dural tension, and on opening the dura mater, there was a large amount of bleeding, in addition to brain swelling and necrosis. estimated blood loss was . l. she received units of packed red blood cells, units of cryoprecipitate, units of fresh frozen plasma, and units of platelets. coagulation profile showed international normalization ratio = . , prothrombin time = . s, and partial thromboplastin time = s. an intraventricular pressure monitor was inserted. she returned with stable vitals to picu. at d , the ct scan showed extensive multi-compartmental bleed involving the left frontoparietal lobes, the interhemispheric fissure, and the left hemispheric arachnoid spaces. new white matter lesions were detected in the left posterior parietal and occipital lobes and in the left caudate head. mri at d showed interval worsening with disseminated gray and white matter non-hemorrhagic lesions in the right cerebral and both cerebellar hemispheres, bilateral deep gray nuclei, as well as new necrotic non-hemorrhagic lesions in the left hemisphere (figures g-i) . she was started on ivmp ( mg/kg/ day for days) and ivig ( g/kg/day for days). repeat mri at d showed no new parenchymal hemorrhage and partial resolution of the non-hemorrhagic lesions (figure ) . prednisolone was tapered course over weeks. at discharge (d ), she was able to say a few words and had better power of her right side. brain mri performed months later showed complete resolution of the non-hemorrhagic non-necrotic lesions, mainly seen in the right cerebral hemisphere and the cerebellum. brain biopsy of the hematoma, some small vessels, cortex, and white matter showed necrotic area, reactive and non-specific findings which could be entirely explained by compressive changes adjacent to a hematoma. there was diffuse microglial activation and signs of early microinfarcts. blood, csf and urine culture, and pcr (hsv / ) were negative for bacteria and for viruses. csf obtained through craniotomy and evd performed at d showed elevated proteins . g/l, glucose . mmol/l, white blood cells cells/μl, and red blood cells , cells/μl. ana and anti-dna antibody were negative. anti-extractable nuclear antigens (ssa-ro, ssb-la, smith, rnp) were negative. serum autoimmune antibodies panel (nmo, nmdar, ampa i/ii, gab, mag, vgcc, mog, yo, hu, ri) were negative but gad antibody was slightly positive, possibly due to the ivig infusion. ebv showed no signs of recent infection. after discharge, the patient was started on regular transfusion exchange. six months later, the patient was diagnosed to have crohn's disease and primary sclerosing cholangitis. two years later, the patient still suffers right hemiparesis but is able to walk without support. she presents an expressive aphasia. her intellectual abilities are average, or below the mean but in the normal range, except for the speed of information processing, verbal working memory, and some elaborated executive functions. a gene panel ( table ) targeting inflammatory disorders and post-infectious necrotic encephalopathies found a heterozygous ranbp missense mutation (nm_ . , c. a>g, p.lys glu). this mutation has not been previously reported in the hgmd database. this variant has been observed at a frequency of < . % across the entire broad exac dataset of individuals without severe childhood onset disease ( / , alleles). analysis of amino acid conservation indicates that the wild-type amino acid lys is conserved in of mammals examined, including of primates, and in of nonmammalian vertebrates increasing the likelihood that a change at this position might not be tolerated. in silico tools predict that this variant is damaging (sift and align gvgd). several differential diagnoses of acute encephalopathy in a patient with sickle cell anemia can be considered. an infectious encephalitis, including herpes encephalitis, was ruled out by blood and csf bacterial and viral cultures and negative hsv i/ ii pcr. nasopharyngeal aspirate was negative for viruses. some infections have been previously associated with necrotizing encephalitis such as influenza a ( ) . scd patients are prone to ischemic or hemorrhagic strokes ( ) . primary hemorrhagic stroke is uncommon in pediatric scd. most cases were from adults and have been described in the context of previous ischemic stroke, aneurysms, low hemoglobin, acute chest syndrome, and hypertransfusions. moreover, although hemorrhagic stroke has been described in scd patients receiving transfusion or corticosteroids, it was in the context of elevated blood pressure which was not present in our case ( ) . this was ruled out as the mri findings were not consistent with a specific vascular territory and normal arterial and venous flows were shown on vascular imaging. another differential is posterior reversible encephalopathy syndrome which has been reported in scd patients ( ) ( ) ( ) ( ) . however, it is unlikely in our case due to the severity of the brain injury and the absence of classic precipitating factors of posterior reversible encephalopathy syndrome such as high blood pressure. macrophage activation syndrome could also lead to acute necrotic brain injury. however, it is associated to high ferritin and low triglycerides at the time of the encephalopathy, other multisystemic injuries, typical neuropathological findings, and recurrence over time, which were not noted in our patient ( ) . parvovirus b has been described to cause encephalopathy in sickle cell patients. it is associated with aplastic anemia. it caused punctate areas of hemorrhages in the basal ganglia, periventricular white matter, and mainly along the posterior parietal cortex. this was attributed to parvovirus b -induced vasculitis ( ) . in our patient, there was no sign of aplasia or any neuroradiological finding of parvovirus b infection. finally, acute encephalitis has been observed in scd patients in the context of arterial hypoxemia from fat embolism, pulmonary embolism, sudden anemia, or acute chest syndrome due to pneumonia ( ) . this was ruled out as the patient did not have clinical or radiological signs of acute chest syndrome or embolism and there was no arterial hypoxemia. acute hemorrhagic encephalomyelitis has been described in pediatric patients following adem or adem-like episodes ( , ) . ahem is the most plausible diagnosis in our patients based on the clinical and radiological presentation, the preceding adem-like episode, and the exclusion of other etiologies of acute encephalopathy. other patients with ahem have been described in the scd context ( , ) . many treatment options have been used to treat ahem; of these, iv steroids have been associated with survival following aggressive, high-dose corticosteroid therapy ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . autosomal dominant mutations (with incomplete penetrance) in ranbp have been associated with susceptibility to infectioninduced necrotizing encephalopathy ( , ) . previously healthy patients with pathogenic mutations in ranbp can present acutely with encephalopathy and convulsions in the context of an infection, with brain imaging revealing involvement of the brainstem, thalami, putamina, cerebellum and external capsules, and claustrum ( ) . our patient has a similar presentation and imaging features as infection-induced necrotizing encephalopathy, including bilateral thalamic involvement. the rare heterozygous previously unreported variant we identified in ranbp affects a very conserved aminoacid and is predicted deleterious using in silico tools (a prediction tool performing a fast bioinformatics analysis which can predict the pathogenicity of a variant based on the change to an amino acid). it is possible that this variant is pathogenic and responsible for the clinical phenotype. there is an overlap between the diagnostic criteria of ahem and those of acute hemorrhagic encephalopathy ( , ) making possible that both entities might be part of the same pathophysiological continuum. ranbp is a protein playing an important role in the energy homeostasis of neuronal cells ( ) . hence, ranbp dysfunction might make neuronal cells much vulnerable to energy failure and necrosis when exposed to inflammatory or other stresses, such as those implicated in ahem. this study was carried out in accordance with the recommendations of our institutional ethic committee. written informed consent was obtained from all the participants for the publication. all authors participated in gathering the data, designing the article, and discussing and editing the manuscript. acknowledgments we thank dr. s. abish, dr. n. ahmed, and mrs. c. guiraut for their help. we are grateful to the hoppenheim fund from the montreal children hospital foundation. the first author of this article received a scholarship from the hoppenheim fund, montreal children hospital foundation ( ). this work was supported by grants from heart and stroke foundation of canada (grant number: g- - ), and foundation of stars. acute hemorrhagic leukoencephalitis: a previously undefined entity acute necrotizing hemorrhagic encephalopathy acute hemorrhagic leukoencephalitis mimicking herpes simplex encephalitis: case report plasmapheresis in fulminant acute disseminated encephalomyelitis acute hemorrhagic leukoencephalitis: report of three 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recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, ranbp ranbp mutation and acute necrotizing encephalopathy: cases and a literature review of the expanding clinico-radiological phenotype ranbp modulates cox and hexokinase i activities and haploinsufficiency of ranbp causes deficits in glucose metabolism key: cord- - qtjr a authors: barrett, bruce title: productive cough (acute bronchitis) date: - - journal: essential family medicine doi: . /b - - - - . - sha: doc_id: cord_uid: qtjr a nan c h a p t e r productive cough (acute bronchitis) . acute bronchitis is a very common diagnosis and is usually caused by viral infection. . other causes of acute cough, such as pneumonia, gastroesophageal reflux disease, and allergy, should be considered. . the best available evidence suggests that antibiotics may reduce symptoms and illness duration slightly. costs and side effects make the benefit-harm trade off tenuous at best. . neither age nor smoking status has been linked to antibiotic effectiveness. . only doxycycline, erythromycin, and trimethoprim/sulfamethoxazole have been tested in positively reported randomized, controlled trials (rcts); hence, these are the only antibiotics that should be considered. . there is very little rct-based evidence for or against the effectiveness of antitussive treatments. however, limited use may be supported, especially when the cough is interfering with sleep. . nonsteroidal anti-inflammatory drugs are effective for pain, but significant toxicity risks raise the need for caution. . over-the-counter cold formulas containing decongestants and/or antihistamines are not appropriate treatments for acute bronchitis but may be helpful if nasal congestion or drainage is present. . mucolytics and expectorants have not been adequately assessed for acute bronchitis, but evidence from common cold and chronic bronchitis suggests possible effectiveness. jane doe is a -year-old woman who presents at your clinic with productive cough of days' duration. jane first felt ill weeks ago on the first of october. she remembers feeling a scratchy throat, which progressed to sore throat, general malaise, and cough. the cough has been bothersome both during the day and at night. it has kept her awake and has awakened her out of sleep. during the past week, she has coughed up phlegm. at first, it was clear to white. now it is green or brown. there has been no blood. she felt alternately "slightly feverish" and "chilly" during the first few days of this illness but denies high temperatures and has not felt feverish for the past several days. she denies nasal symptoms, chest pain, shortness of breath, and vomiting. she may have had some increased dyspnea on exertion, especially in the beginning of the illness. she denies sensations of maxillary pain or postnasal drip. her sore throat has resolved. this acute illness has caused her to reduce smoking to "a few cigarettes a day." she notes that "i really should quit that stuff." she has been using an over-the-counter combination cold formula, which she believes has helped manage the cough, although it does make her "a bit groggy." you have known jane since she first came to you about years ago with chest pain. previously, she had neglected her health care for many years. that original chest pain was burning in quality, bothered her most when she felt stressed, and was diagnosed empirically as reflux esophagitis when it responded to antacids. her heartburn is now well controlled with lifestyle modifications and ranitidine (zantac), mg once or twice daily. routine health screenings revealed tobacco use (one pack per day for years) and hyperlipidemia, which is now well controlled on a statin. she also takes a daily aspirin for heart attack and stroke prevention. her blood pressure has ranged from normal to borderline. random blood glucose screening was normal. she has had two urinary tract infections since coming to you, both of which resolved with fluids and short courses of antibiotics. with motivational counseling, she reduced her cigarette consumption to less than half a pack per day, has improved her diet, and walks a brisk mile several days per week. mammograms, pap smears, and a screening sigmoidoscopy have all been negative. jane received all recommended childhood immunizations but has declined influenza vaccination. she remembers receiving antibiotics for acute coughing illnesses several years before meeting you. jane's father died of a heart attack at age . he was a smoker. jane's mother is alive and well at but was diagnosed with type diabetes and hypertension in her s. jane's grandparents died in their s and s of unknown causes. she has a brother and two sisters but is unaware of any major health issues. jane is married with three adult children. she works as an office manager. she attributes daily work stress and relationship stress as the primary obstacles to smoking cessation. her husband nags her to quit smoking. she denies physical or sexual abuse. in addition to the acute symptoms mentioned, jane has occasional mild heartburn, generally well controlled with antacids or ranitidine. she denies any chest pain or pressure with exercise. she also denies weight loss and feels that her general health, energy, and quality of life have improved slightly over the past years. she is not aware of any significant occupational or environmental exposures but does live in a city that has occasional ozone alerts. jane is feet inches and pounds (body mass index = . ). her blood pressure today is / mm hg, her heart rate is beats per minute, and her temperature is ˚c ( . ˚f) by ear thermometer. her respiratory rate is about breaths per minute. her mucous membranes (ocular, nasal, and oral) are moist, without any abnormal signs. tympanic membranes are clear, with normal light reflex and no signs of middle ear fluid. posterior pharynx is somewhat erythematous but is without exudates, swelling, or signs of postnasal drainage. there is no tenderness to maxillary percussion. there are two small, smooth, mobile, and nontender lymph nodes palpable in the anterior chain on the left side of her neck. posterior auscultation of the lungs reveals neither rales nor rhonchi. inspiratory effort is good, with full and symmetrical chest wall expansion. heart sounds are normal. you consider a chest radiograph, peak flow, complete blood count, c-reactive protein, and/or testing for streptococcal pharyngitis or pertussis but decide to order no tests. although you have not seen jane before with this specific constellation of symptoms, you presumptively diagnose acute bronchitis, most likely caused by recent and perhaps ongoing upper airway viral infection with mid-airway inflammatory sequelae. chronic exposure to tobacco smoke and possibly to other airborne pollutants is likely an underlying contributory factor. the list of possible causes of acute coughing illness includes asthma, bronchiectasis, cancer, chemical bronchitis, chronic obstructive pulmonary disease, drugs (e.g., angiotensin-converting enzyme inhibitor), eosinophilic bronchitis, gastroesophageal reflux disease, interstitial lung disease, pneumonia, and sinusitis. infectious viral respiratory pathogens include adenovirus, coronavirus, enterovirus, influenza, parainfluenza, respiratory syncytial virus, and rhinovirus. each of these classes of virus has many subtypes; hence, there are several hundred specific viral strains that can lead to upper respiratory infection with cough. you know that influenza and respiratory syncytial virus are confined to the months november through april in your locale and thus are not in today's differential diagnosis. last year, your state experienced an epidemic of pertussis, which was eventually controlled with an aggressive test-and-treat strategy. this year, your state public health department has reported only rare cases. sinusitis is excluded by lack of fever, face pain, maxillary tenderness, or purulent discharge in nasal passageways or posterior pharynx. there is no history of occupational or environmental exposure. the history of esophageal reflux suggests a possible contribution, but the symptoms are much more specific for acute infectious bronchitis, presumed viral. chapter productive cough (acute bronchitis) acute bronchitis, presumed viral, is a very common clinical diagnosis . there are no sensitive or specific supporting tests. the main diagnostic job of the clinician is to rule out other causes. jane has neither paroxysmal nor whooping cough and has no known exposure risk factors. therefore, you decide not to do the uncomfortable nasopharyngeal swab required for pertussis polymerase chain reaction testing. with normal vital signs and lung sounds and with the lack of chest pain or pressure, persistent fever, and shortness of breath, you decide the pretest probability of pneumonia is too low to order a chest radiograph. you are aware of recent research showing that c-reactive protein might be useful in the absence of a chest radiograph (almirall et al., • b ; flanders et al., • b ; garcia et al., • b ) but also know it to be too nonspecific to be helpful in this case. you do note the history of heartburn responsive to h blockers and discuss the possibility that esophageal reflux disease may have contributed to jane's symptoms. together you decide to schedule an upper endoscopy sometime in the next month or two. after careful consideration and a detailed discussion of risks and benefits, you suggest conservative treatment: drinking lots of fluids, rest, and cough medicine. jane will try an over-the-counter dextromethorphan-guaifenesin combination cough syrup. if that is unsuccessful, and especially if the cough keeps her awake at night, she will fill your prescription for a codeine-guaifenesin cough syrup. she will avoid cold formulas with antihistamines or decongestants, as she has neither allergic symptoms nor nasal congestion and these agents have side effect risks as well as being an expense. you specifically ask jane whether she wants or expects an antibiotic prescription. she says she would take any medicine that you think would be helpful and asks your opinion. you discuss the fact that antibiotics may be slightly better than placebo in relieving the symptom severity and duration of acute bronchitis. however, you also note the risk of side effects and touch on the societal problem of antibiotic resistance. you offer a "delayed fill" antibiotic prescription, but jane declines. you also provide reassurance that the symptoms will go away and give her a few specific signs that would require a return visit (hemoptysis, shortness of breath or difficulty breathing, chest pain or pressure, persistent fever, cough lasting more than weeks). you gently discuss the association between smoking and bronchitis and mention that more than a million americans have kicked the habit and that you believe that she can too. you see jane again for smoking cessation counseling and follow-up after an upper endoscopy performed by a gastroenterologist colleague, which showed a small hiatal hernia but no specific lesions or signs of esophageal inflammation. although smoking cessation is initially unsuccessful, after several attempts over a few years, jane eventually kicks the habit. in the meantime, she has two other occurrences of acute bronchitis, both of which she treats at home with fluids, rest, and over-the-counter cough suppressants. acute bronchitis is a very common result of upper respiratory infection. although bacterial and chemical causes are known, the vast majority of cases of acute bronchitis stem from viral agents. there are no known effective treatments for acute bronchitis. whether a cough is productive and the color of the phlegm are not predictive of etiologic agent (virus vs. bacteria) or response to therapy. systematic reviews of rcts of antibiotics suggest small but statistically significant benefits of antibiotics over placebo in terms of persistence and severity of cough (anonymous, (smucny et al., a • a ). of the nine published rcts, three are "positive" in that they report statistically significant benefits of doxycycline (verheij et al., • a ) and erythromycin (dunlay et al., (franks and gleiner, • a ) failed to find substantial benefit, most primary outcomes trended toward benefit, and a few secondary outcomes reached statistical significance. it should be noted that the number of unpublished rcts is unknown. however, it is suspected that several negative trials conducted by drug companies remain unpublished. because positive trials are more likely to be published than negative trials and because internal biases tend to favor treatment over placebo, actual benefits may be less. there are no rcts that specifically address the question of whether antibiotics are useful for tobacco smokers with acute bronchitis. however, linder and sim ( • a ) reviewed the nine trials chapter productive cough (acute bronchitis) noted above ( participants), looking specifically at the smokers included. there were no statistically significant differences between smokers and nonsmokers. however, trends actually suggested that antibiotics were less effective for smokers than nonsmokers. this is a secondary analysis ("data dredging"); hence, conclusions are tentative but certainly do not support the widespread practice of justifying antibiotic prescriptions with smoking status. although it may be reasonable to prescribe antibiotics for some patients with acute bronchitis (e.g., if early pneumonia is suspected or if there is underlying chronic lung disease), most experts recommend against this practice (anonymous, • a ; gonzales et al., a,b• c) because societal harms (antibiotic resistance) and individual adverse effects may outweigh potential benefits. side effects of antibiotics, such as nausea, diarrhea, vaginal candidiasis, and allergic reaction, occur frequently with most antibiotics. when using antibiotics for acute bronchitis, the number needed to treat (walter, ) and the number needed to harm are similar and in the range of to (anonymous, (cantrell et al., • b ; walter, ; stone et al., • b ) . this unfortunate situation is due both to patient demand and to physicians' beliefs and prescribing habits. education, in the form of a pamphlet or physician advice, significantly reduces the desire for antibiotics (macfarlane et al., • a ) . some evidence suggests that writing a delayed prescription may reduce antibiotic use (arroll et al., • a ) . unfortunately, there is very little reliable evidence regarding the effectiveness of cough treatments. systematic reviews of rcts have concluded that there is neither good evidence for nor good evidence against the effectiveness of antitussives (anonymous, a • a ; schroeder and fahey, • a ; smith and feldman, • a ). however, with the definite possibility of specific effectiveness (parvez, • a ) and with evidence suggesting that the placebo effect for cough treatments is substantial (eccles, ; lee et al., • b ), the use of over-the-counter dextromethorphan-containing formulations and/or limited use of prescription codeine or hydrocodone may be reasonable. although benzonatate (tessalon) has been approved as a prescription cough medicine, there is virtually no evidence for or against its effectiveness. furthermore, the number and quality of rcts on beta agonist (e.g., albuterol inhaler) used in the setting of acute bronchitis are limited. although some evidence supports use (hueston, • a ), the weight of evidence currently suggests that beta agonists are not very helpful in this setting (anonymous, b • a ; smucny et al., b • a ). expectorants and mucolytics have not been adequately assessed in the setting of acute bronchitis. however, evidence from trials for common cold and in the setting of chronic lung disease suggests possible benefits and little harm (anonymous, a • a ; schroeder and fahey, • a ; smith and feldman, • a ). neither antihistamines nor decongestants have been shown to be helpful for bronchitis, and both carry risks. antihistamines can cause drowsiness, which may lead to a motor vehicle accident. decongestants are contraindicated in the settings of hypertension and heart disease. for children, there is no evidence of any benefit of any over-the-counter medicine for colds or bronchitis and reasonable evidence of potential harm (anonymous, a• a ; gunn et al., ; schroeder and fahey, • a ). nonsteroidal anti-inflammatory drugs may help if pain is present. however, the widespread use of nonsteroidal antiinflammatory drugs is associated with major morbidity and mortality, with more than , americans dying each year, mostly from gastrointestinal bleeding, but also from congestive heart failure and renal failure (fries, • b ; heerdink et al., • b ; page and henry, ; wolfe et al., • b ) . although the effectiveness of nonsteroidal anti-inflammatory drugs appears similar, risks vary, with ibuprofen being among the safest. acetaminophen, not a nonsteroidal anti-inflammatory drug, is even safer. there is a broad body of robust evidence that tobacco smoking cessation can be facilitated through a variety of physician-assisted modalities . although no specific evidence links acute illness with readiness to quit, it makes good sense that the occasion of an episode of acute bronchitis might provide opportunity and incentive to support active attempts at tobacco cessation or at least to "plant the seed." the fact that jane's father smoked and died of a heart attack at age might also be diplomatically used as a motivational tool. acute bronchitis is the most common diagnosis when a patient presents with prolonged acute cough. there are no specific methods for diagnosing bron-chapter productive cough (acute bronchitis) chitis or for distinguishing bronchitis from upper respiratory infection with cough. the first job of the clinician is to rule out other causes, such as pneumonia, asthma, bacterial sinusitis, and gastroesophageal reflux disease. once the diagnosis of acute infectious bronchitis is reached, the clinician's task turns to supporting the patient, in terms of both reassurance and selection of therapy. in most cases, antibiotics should be avoided. until and unless better evidence emerges, the use of over-the-counter and prescription antitussives can be cautiously supported in adults. decongestants should be avoided, especially if hypertension or heart disease is present. beta-agonist inhalers may help those with wheezing or a history of asthma. supportive home treatments, such as fluids, rest, and avoidance of stressors, make good sense but are largely unsupported by evidence. unless symptoms dramatically worsen, most patients with acute bronchitis do not need a return visit. contribution of c-reactive protein to the diagnosis and assessment of severity of community-acquired pneumonia : .• a anonymous. beta -agonists are ineffective but increase adverse effects in acute bronchitis without underlying pulmonary disease delayed prescriptions for reducing antibiotic use in acute respiratory infections. cochrane database syst rev erythromycin in the treatment of acute bronchitis in a community practice antibiotic prescribing in ambulatory care settings for adults with colds, upper respiratory tract infections, and bronchitis a placebo-controlled, double-blind trial of erythromycin in adults with acute bronchitis quantitative systematic review of randomized controlled trials comparing antibiotic with placebo for acute cough in adults performance of a bedside c-reactive protein test in the diagnosis of community-acquired pneumonia in adults with acute cough • a fries jf. nsaid gastropathy: the second most deadly rheumatic disease? epidemiology and risk appraisal c-reactive protein levels in community-acquired pneumonia principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background nsaids associated with increased risk of congestive heart failure in elderly patients taking diuretics albuterol delivered by metered-dose inhaler to treat acute bronchitis effectiveness of erythromycin in the treatment of acute bronchitis training health professionals in smoking cessation. cochrane database syst rev antibiotic treatment of acute bronchitis in smokers: a systematic review • a nhs centre for reviews and dissemination. quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults objective evaluation of the pharmacodynamic response of and mg of dextromethorphan in acute cough doxycycline in acutse bronchitis: a randomized double-blind trial over-the-counter medications for acute cough in children and adults in ambulatory settings nicotine replacement therapy for smoking cessation over-the-counter cold medications: a critical review of clinical trials between and telephone counselling for smoking cessation antibiotic prescribing for patients with colds, upper respiratory tract infections, and bronchitis: a national study of hospital-based emergency departments randomised controlled trial of antibiotics in patients with cough and purulent sputum effects of doxycycline in patients with acute cough and purulent sputum: a double blind placebo controlled trial number needed to treat (nnt): estimation of a measure of clinical benefit a randomized, controlled trial of doxycycline in the treatment of acute bronchitis gastrointestinal toxicity of nonsteroidal antiinflammatory drugs key: cord- -nsdhvc w authors: maki, dennis g. title: sars revisited: the challenge of controlling emerging infectious diseases at the local, regional, federal, and global levels date: - - journal: mayo clin proc doi: . / . . sha: doc_id: cord_uid: nsdhvc w nan i n , a blue-ribbon panel was commissioned by the institute of medicine of the national academy of sciences to advise the us government on emerging infectious diseases that posed a threat or potential threat to the health of people living in the united states and assist in the federal allocation of public health resources. , emerging infections were defined as infections caused by newly identified human pathogens-such as the legionella bacillus, the reemergence of previously controlled pathogens-such as measles, or the appearance of anti-infective resistancesuch as methicillin-resistant staphylococcus aureus, the incidence of which had increased significantly within the past decades or threatened to increase in the near future. since the outbreak of severe pneumonia in us veterans attending a convention at the bellevue-stratford hotel in , found months later to have been caused by a previously unknown and remarkably ubiquitous waterborne bacterium, legionella pneumophila, more than dozen human pathogens have been identified as agents of emerging infectious diseases in the united states (table ) . the most recent and perhaps most fearsome emerging infections are the appearance of west nile virus encephalitis in new york city in and its rapid spread westward ; inhalation anthrax, deriving from use of bacillus anthracis spores as a biologic weapon against the us civilian population in ; the global outbreak of severe acute respiratory syndrome (sars) in ; and the looming threat of pandemic influenza, especially global disease caused by the highly virulent avian subtype a (h n ). [ ] [ ] [ ] during the past months, mayo clinic proceedings has published reviews of diseases caused by of these emerging pathogens, west nile virus, the sars coronavirus (sars-cov), and avian influenza virus. efforts to better inform readers about the consequences of emerging infectious diseases continue in this issue of the proceedings, in which chiang et al report a study of cases of nosocomial sars acquired in taipei hospitals during . most of the patients, of whom were followed up for at least months, were health care workers, and because few had underlying diseases, all except survived; thus, this study provides some of the best data on the long-term effects of sars on the lung. the clinical features and natural history of sars encountered by chiang et al are similar to those reported in much larger cohorts. , all their patients had fever, and most had cough and dyspnea as well; however, % had diarrhea, and % had myalgias, indicative of the severe systemic immunoinflammatory response to this unique new human infection. , similarly, all their patients had lymphopenia, and most had elevated levels of lactate dehydrogenase, now well-defined surrogate laboratory markers for patients presenting with sars. , however, chiang et al also found that patients with a very high c-reactive protein or lactate dehydrogenase level at the outset were far more likely to have progression to a severe stage of disease requiring mechanical ventilatory support, information of value to clinicians who might be called on to manage patients with sars in the not-too-distant future. most interestingly, chiang et al show that whereas bilateral fibrotic changes were demonstrable by high-resolution computed tomographic imaging to months after the acute infection, most of the survivors showed near-normal spirometric lung volumes (forced vital capacity, forced expiratory volume in second), albeit one third with reduced diffusion capacity, but none required home oxygen. it is likely that most of these individuals will have recovery of normal lung function. these findings are very similar to the well-documented long-term pulmonary effects of garden-variety acute respiratory distress syndrome, stemming from overwhelming pneumonia, gastric aspiration, near drowning, trauma, pancreatitis, or systemic sepsis, in which most survivors have gratifying recovery of lung function in the early years after the acute episode. [ ] [ ] [ ] because sars is such a unique human viral infection and induces such an unusually severe systemic inflammatory response, , it will be important to closely follow survivors of severe sars for considerably longer to be certain that latently expressed progressive pulmonary fibrosis does not occur. between the first reports from the world health organization and the centers for disease control and prevention (cdc) that defined sars as a global threat in march , and control of the epidemic in southeast asia and north america months later, more than persons in the republic of china, hong kong, singapore, vietnam, taiwan, and canada became infected, and ( . %) died of the infection ; mortality exceeded % in patients older than years. , since the last communication on sars in the proceedings in april , there have been extraordinary advances in our understanding of the disease in terms of its pathogenesis, epidemiology, management, and control: editorial • like many of the emerging human pathogens such as borrelia burgdorferi (mice, deer), us hantavirus (mice), west nile virus (wild birds), variant creutzfeldt-jakob prions (cattle, potentially free-ranging cervids), monkeypox virus (exotic african rodents and primates, us prairie dogs), and avian influenza virus a (h n ) (edible birds), infection by sars-cov can legitimately be considered a zoonosis, and wild mammals formed the initial reservoir of the virus-sars-cov has been isolated from palm-top civets and raccoon dogs in the live animal markets in southern china, and purveyors of these animals commonly show asymptomatic sars-cov seropositivity. , the genomic evidence that sars-cov is an animal-human recombinant is compelling, [ ] [ ] [ ] [ ] and sars-cov appears to have had a biologic origin remarkably similar to the human influenza a viruses and human immunodeficiency virus. although the sars virus originated in animals and made the leap to humans, once established in the human population, the virus has spread rapidly person-toperson, and the major reservoir of human disease is humans in the early stage of infection, before they have been diagnosed as having the virus and placed in respiratory and barrier isolation. • elegant molecular epidemiology has traced the origins of sars-cov to foshan in guangdong province, southern china, from whence it spread to beijing, then to hong kong, and from hong kong to vietnam, singapore, and canada. , a -year-old chinese physician who traveled to hong kong on march , , where he spent only day, appears to have been the source of sars-cov that ultimately resulted in thousands of cases of sars in countries and continents. • sars-cov is a new human pathogen to most of the world. studies by the cdc have shown no serologic evidence of past infection in more than specimens from us residents collected long before the sars epidemic. • as a new human pathogen, there is, understandably, little if any natural immunity. virtually all persons who became infected by sars-cov became symptomatic, and studies of exposed health care workers show that less than % to % of those infected experience mild or subclinical infection. • sars spreads almost exclusively person-to-person by respiratory droplets, rarely by the airborne route ; the roles of contact or fecal-oral transmission are less clear but probably occur. , the puzzling large outbreak in amoy gardens in hong kong was recently traced to virus-laden aerosols generated from sewage, using sophisticated airflow-dynamic studies and computational fluid-zone modeling. however, whereas the outbreak in the amoy gardens complex represents distant airborne spread, distant spread is probably rare, as evidenced by the very low risk of infection in patients with no plausible face-to-face exposure to a patient with symptomatic sars, by the effectiveness of simple isolation measures in hospitals that did not have sophisticated negative-pressure air-controlled rooms with separate roofline exhaust, and by the relatively few secondary cases on commercial airliners. , [ ] [ ] [ ] in an investigation of flights in which an airliner transported or more symptomatic infected passengers, laboratory-confirmed cases of secondary sars were detected on flight, with the greatest risk to other passengers close to the index case (seated within rows, relative risk . ); on flight carrying symptomatic infected persons, possible transmission occurred to only other passenger, and no secondary illness was documented on another flight that carried person with early sars. • simple control measures, most importantly the use of a high-quality filtration mask, ideally an n- -type mask but even a surgical mask, combined with full-barrier precautions in a single room were highly effective in preventing spread to other patients and health care workers where it was most carefully studied, in hong kong, singapore, and canada. , , , • patients with early sars do not pose a risk to others until they become symptomatic and start to cough, but there is considerable variability in contagiousness, probably based on the quantity of virus in the respiratory secretions and the degree of coughing. very close proximity to an infected patient who is coughing heavily poses the greatest risk. it appears that most spread of the virus can be linked to "super spreaders," and most infected persons are probably not very contagious. , , [ ] [ ] [ ] [ ] understandably, the risk of acquisition of sars-cov is far higher in the hospital than in the community. , • the mean incubation period of sars is approximately days (range, - days) and is considerably longer than that for most other human respiratory viral infections, such as the common cold or influenza a, which permits case-contact investigations and quarantine of exposed contacts before those destined to become infected and contagious can spread the disease to others. • because so few persons develop clinical sars more than days after exposure, there is no need to extend quarantine of exposed persons beyond days. • fever is so ubiquitous in sars that monitoring the body temperature of quarantined contacts and health care workers caring for patients with sars is a sensitive and specific method for detection of early infection, especially for health care workers before they become symptomatic and contagious. all health care workers caring for patients with suspected or proven sars should be monitored to times daily; fever constitutes grounds for quarantine and diagnostic studies. , for personal use. mass reproduce only with permission from mayo clinic proceedings. • to control sars, early diagnosis is essential. clinical predictors for sars, based on study of large cohorts of patients in hong kong, suggest that fever, myalgia, malaise, an abnormal chest radiograph, lymphopenia, thrombocytopenia, and, most importantly, previous contact with a patient with sars are each associated with a greatly increased likelihood of sars. in contrast, in a newly symptomatic patient older than years or younger than years without a plausible face-to-face exposure who has a cough productive of sputum, abdominal pain, sore throat, rhinorrhea, or leukocytosis, sars is unlikely. • modern-day virology has shifted rapidly during the past decade, from tissue cultures and serologic techniques to detection of the viral genome in clinical specimens by nucleic acid amplification techniques, such as polymerase chain reaction (pcr) or, for rna viruses, reverse transcriptase-pcr (rt-pcr). highly sensitive and specific rt-pcr assays were developed in most of the countries afflicted by sars, most notably in hong kong, singapore, and canada, and were invaluable in early confirmation of sars-cov infection. the sensitivity of second-generation assays has been as high as % in the first days of illness. [ ] [ ] [ ] [ ] whereas a pcr assay developed at the cdc was given immediate investigational device exemption approval by the food and drug administration, no commercial pcr assay has yet been licensed for clinical use in the united states. if sars returns and spreads in the united states, it will be essential that reliable real-time pcr assays are available in us hospitals. public health laboratories are not clinical service laboratories and are unlikely to be able to meet the need if sars reappears on a major scale. private companies should be given access to clinical strains of sars-cov and, if available, clinical specimens from infected patients in order to test and validate commercial assays that hopefully will be as accurate as, perhaps more accurate than, the current cdc assay. • ribavirin was used empirically in many patients with sars in southeast asia with the impression that it was effective therapeutically; however, in vitro studies have shown that sars-cov is not susceptible to ribavirin at concentrations achievable clinically. hence, it is unlikely that the drug is active therapeutically. uncontrolled trials suggest that interferon alfa may be of benefit. , there are a number of compounds and antiviral drugs with in vitro activity against sars-cov, including interferon alfa, interferon beta, and glycyrrhizin (licorice-root extract). theoretical rna virus targets, such as protease inhibitors and fusion inhibitors, also need to be assessed for efficacy. if sars returns on a major scale, it will be essential that the efficacy of antiviral drugs, such as commercial interferons, is tested in randomized, double-blind trials. • whereas uncontrolled studies of treated cohorts in asia have suggested that using moderate doses of corticosteroids, to mg/kg of a prednisone-equivalent daily, at the first evidence of severe sars, specifically hypoxemia, may improve survival, , , corticosteroid therapy for sars has had serious adverse effects, and a single randomized trial of preemptive pulse corticosteroid therapy did not show benefit. if sars returns, it will also be essential that efforts are made to determine the efficacy of corticosteroids in a large prospective, randomized, doubleblind trial. • advancing age (> years) and coexisting illnessespecially diabetes or heart failure-greatly increase the likelihood of severe sars (requiring mechanical ventilatory support) and the risk of death. , , inexplicably, sars is usually very mild in children, who do not appear to be very contagious. also, maternal-fetal transmission does not appear to occur. • while coronaviruses are more resistant than most other respiratory viruses, sars-cov appears to be susceptible to the commercial microbicides used for surface decontamination in hospitals. • most importantly, outbreaks in hong kong, singapore, vietnam, canada, and elsewhere in the world were successfully controlled, but only by an intensive, coordinated effort in which the national public health authorities worked very closely with the regional public health agencies and, especially, hospital infection control officers and clinicians caring for patients with sars. [ ] [ ] [ ] [ ] the measures needed for control of sars are clear , , : ( ) earliest detection of cases, having at-risk individuals isolated and queried about their face-to-face contacts during the to days before the onset of illness; ( ) expeditious contact tracing, with uncompromising home quarantine for all contacts of suspect and proven cases; and ( ) stringent isolation of symptomatic suspect and proven cases, focusing most heavily on techniques to prevent droplet and airborne spread (eg, single negative-pressure rooms, ideally with separate roofline exhaust or filtration of outlet air; fit-tested high-filtration mask respirators and a face shield or goggles or a powered air-purifying system for all health care workers and others entering the room of the case, as well as the use of nonsterile gloves and gowns to prevent contact transmission). , the value of border screening and temperature monitoring of travelers is questionable. the resources needed to control an outbreak in a city or a country are huge. in north america, the toronto outbreak consisted of documented cases in hospitals. to control sars in toronto required home quarantine of more than , contacts and an informational hotline that handled more than , calls; the economic cost of the epidemic to the city and the city and provincial govern- ments was estimated at $ . billion (canadian). the longterm psychological impact of sars on patients, families, and health care workers was also very substantial. [ ] [ ] [ ] • efforts are now under way to test candidate sars vaccines. the national tragedy of september , , was followed by the most serious instance of bioterrorism involving the us civilian population in history, the spread of anthrax through the us mail. these events coincided with growing awareness that weaponized smallpox virus almost certainly yet exists in the world, with strong suspicion that the former soviet union, as well as countries that have sponsored international terrorism, such as iran and north korea, , retained smallpox virus as a potential weapon. the unthinkable has become plausible: weaponized smallpox virus in the hands of international terrorist groups. as a consequence, the federal government has undertaken major steps to greatly improve emergency preparedness at all levels, especially the capacity to respond to the use of biologic agents such as smallpox or anthrax as weapons against the civilian population as well as our military (table ) . , billions of dollars have been appropriated to improve the capacity of public health and clinical laboratories to reliably detect infectious agents that might represent biologic weapons; to improve the likelihood that emergency department physicians and all primary care providers could recognize anthrax, smallpox, and other infectious diseases that might denote bioterrorism; to establish and coordinate surveillance programs at the regional, state, and federal levels; and to train more than a million public protection personnel and greatly improve preparedness of the us hospitals. at my center, we have spent hundreds of person-hours identifying and retrofitting a bed patient-care unit for the potential accommodation of patients with smallpox or other highly contagious infections such as sars or pandemic influenza caused by a new strain. this local effort has focused on air control and negative-pressure isolation rooms, which have the capacity for supporting mechanical ventilation, and developing comprehensive guidelines for health care workers who would staff the unit. for the first time in our generation, there has been a major injection of federal dollars into the public health sector at the state, regional, and municipal levels. the challenge will be to provide sustained support, rather than a limited bolus of supplemental funding. hopefully all this effort will never be needed to control smallpox-or an even more terrifying engineered pathogen , -that might be used as a biologic weapon. if it is not, the effort will not have been wasted because it is likely that all the planning and resource allocation will prove invaluable for controlling the spread of natural emerging pathogens, such as sars-cov or a new strain of influenza virus, which are probably far more likely to pose a serious threat to human and animal health in the united states and worldwide. the greatest and most immediate threat is the longoverdue reappearance of pandemic influenza a. the leading and most dreaded candidate for the new pandemic subtype is avian influenza a (h n ), recently reviewed in this journal, which was first recognized in a large poultry outbreak in the live-animal markets of hong kong in , where the virus had acquired the capacity to spread from infected birds to humans and killed of infected persons. to control the outbreak, authorities killed nearly million chickens to eliminate the reservoir of infection. since that time there have been contained outbreaks of different subtypes of avian influenza-h n , h n , and h n -that have caused disease in poultry, with secondary infections reported among pigs and humans, but infrequent and mild human disease, such as conjunctivitis or mild influenza-like illness. there was only human death among cases in a large h n outbreak in the netherlands in . in january , a highly pathogenic strain of avian influenza a (h n ) was identified in south korea and spread rapidly over the succeeding months to other asian countries, cambodia, china and hong kong, indonesia, japan, laos, thailand, and vietnam. [ ] [ ] [ ] to date, there have been confirmed cases in humans, nearly all in children or young adults; ( %) have proved fatal. more than million edible birds have been slaughtered by governmental authorities. all species of domestic birds appear to be susceptible to the h n strain, which is probably transmissible to all species of wild birds, some of which migrate transcontinentally. the epidemic a (h n ) strain appears to be gaining virulence and was recently shown to have acquired the capacity of infecting mammalian species, domestic cats and wild felines within zoos and pigs. most alarmingly, there is growing evidence that person-to-person spread can occur, albeit yet rarely. the epidemic strain further shows high-level resistance to amantadine and rimantadine but is thus far susceptible to neuraminidase inhibitors, such as oseltamivir or zanamivir. if the strain acquires recombinant genes that facilitate human infection and person-to-person transmission, pandemic disease could prove more catastrophic than the great h n influenza epidemic of . even more concerning has been the challenge of developing an avian influenza vaccine. current influenza vaccines are unlikely to provide any protection against the new h n avian strain. the standard method for manufacturing influenza vaccines, growing the vaccine strain in chicken embryos, does not work because the avian a (h n ) strain is so virulent that it kills the embryo before there is sufficient virus to harvest. novel genetic techniques, under way in the united kingdom, will be needed to alter the strain's phenotypic features so that it can be grown in sufficient quantities in fertilized eggs and an effective vaccine can be constructed. vaccine manufacturers are understandably reluctant to make the investment to develop and manufacture a new vaccine, particularly in large quantities, when there is uncertainty whether the avian strain will indeed spread and necessitate administration of hundreds of millions of doses. similarly, the sole manufacturer of the only oral neuraminidase inhibitor likely to be effective against avian influenza (oseltamivir) has very limited production capacity, and less than million doses are currently available in us pharmaceutical stocks; the director of the cdc has stated that it would be desirable to have at least million doses available. in summary, cases of cutaneous or inhalation anthrax traced to domestic bioterrorism and the global sars outbreak represent ill winds that have blown considerable good. the greatly expanded us federal effort to improve national preparedness for bioterrorism has strengthened public health at every level, and whereas we are far from being able to consider the united states as fully prepared, we are better prepared than only years ago. the recent us epidemic of monkeypox, traced to importation of infected exotic african rodents and the burgeoning domestic trade in us prairie dogs, could be considered a live tabletop exercise-with a relatively innocuous pathogen-for the recognition and containment of smallpox. similarly, the global sars emergence has proved the enormous power of modern-day molecular biology to identify and characterize new pathogens, to detect clinical infections far more rapidly than in the past, and to quickly unravel the epidemiology of new infectious diseases-the scientific foundation for strategic control. the sars outbreak was contained only by unprecedented international cooperation under the leadership of the world health organization and successful coordination within the affected countries between national and regional public health agencies and health care providers. controlling the next influenza pandemic, especially if it is caused by a highly virulent subtype such as the current a (h n ) avian influenza virus, will require even greater international collaboration and vertical coordination in public health within the involved countries. it will also require an unprecedented commitment by the industrialized countries of the world to meet the needs of afflicted developing countries with limited public health resources. we are all in this together: it is in every country's self-interest to work collaboratively toward a common goal-the prevention of communicable disease and improvement of health of every citizen of the world. methicillin-resistant staphylococcus aureus: interstate spread of nosocomial infections with emergence of gentamicin-methicillin resistant strains update: investigation of bioterrorism-related anthrax and adverse events from antimicrobial prophylaxis world health organization. summary of probable sars cases with onset of illness from world health organization international avian influenza investigative team world health organization. cumulative number of confirmed human cases of avian influenza a (h n ) since west nile virus: epidemiology, clinical presentation, diagnosis, and prevention sars: epidemiology, clinical presentation, 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associated with severe acute respiratory syndrome the genome sequence of the sars-associated coronavirus mosaic evolution of the severe acute respiratory syndrome coronavirus phylogenomics and bioinformatics of sars-cov comparative full-length genome sequence analysis of sars coronavirus isolates and common mutations associated with putative origins of infection coronavirus genomic-sequence variations and the epidemiology of the severe acute respiratory syndrome severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts sars working group. a novel coronavirus associated with severe acute respiratory syndrome prevalence of asymptomatic infection by severe acute respiratory syndrome coronavirus in exposed healthcare workers [abstract cluster of severe acute respiratory syndrome cases among protected health care workers-toronto evidence of airborne transmission of the severe acute respiratory syndrome virus low risk of transmission of severe acute respiratory syndrome on airplanes: the singapore experience assessment of in-flight transmission of sars-results of contact tracing expert sars group of hospital authority. effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) clinical progression and viral load in a community outbreak of coronavirusassociated sars pneumonia: a prospective study transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions transmission dynamics and control of severe acute respiratory syndrome modeling the sars epidemic epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong nosocomial transmission of the severe acute respiratory syndrome (sars) [abstract abstract k- . . world health organization. severe acute respiratory syndrome (sars): who guidelines/recommendations/descriptions. available at: www.who.int/csr/sars/guidelines/en. accessibility verified hospital authority sars collaborative group. a clinical prediction rule for diagnosing severe acute respiratory syndrome in the emergency department molecular and diagnostic clinical virology in real time early diagnosis of sars coronavirus infection by real time rt-pcr detection of sars coronavirus in plasma by real-time rt-pcr detection of sars coronavirus in patients with suspected sars centers for disease control and prevention. severe acute respiratory syndrome (sars) and coronavirus testing--united states description and clinical treatment of an early outbreak of severe acute respiratory syndrome (sars) in guangzhou, pr china preliminary results on the potential therapeutic benefit of interferon alfacon- plus steroids in severe acute respiratory syndrome : . abstract k- e development of a standard treatment protocol for severe acute respiratory syndrome high-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome fatal aspergillosis in a patient with sars who was treated with corticosteroids the use of corticosteroids in sars clinical presentations and outcome of severe acute respiratory syndrome in children sattar sa. microbicides and the environmental control of nosocomial viral infections world health organization. a multicentre collaboration to investigate the cause of severe acute respiratory syndrome the international response to the outbreak of sars in public health measures to control the spread of the severe acute respiratory syndrome during the outbreak in toronto world health organization working group on prevention of international and community transmission of sars. public health interventions and sars spread the immediate psychological and occupational impact of the sars outbreak in a teaching hospital post-traumatic stress disorder and quality of life in patients diagnosed with sars [abstract severe acute respiratory syndrome-related psychiatric and posttraumatic morbidities and coping responses in medical staff within a primary health care setting in singapore canadian researchers testing sars vaccine in china the chilling true story of the largest covert biological weapons program in the world, told from the inside by the man who ran it the looming threat of bioterrorism available at: www.bt.cdc.gov/planning/tprstrategy/index.asp. accessibility verified october , . . public health security and bioterrorism preparedness and response act of expression of mouse interleukin- by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox human influenza a h n virus related to a highly pathogenic avian influenza virus transmission of h n avian influenza a virus to human beings during a large outbreak in commercial poultry farms in the netherlands the evolution of h n influenza viruses in ducks in southern china avian h n influenza in cats. science [serial online thais suspect human spread of bird flu uk 'developing bird flu vaccine experts confront major obstacles in containing virulent bird flu hospital preparedness for severe acute respiratory syndrome in the united states: views from a national survey of infectious diseases consultants the detection of monkeypox in humans in the western hemisphere key: cord- -klkoyw r authors: nan title: covid- medical sequelae date: - - journal: bull acad natl med doi: . /j.banm. . . sha: doc_id: cord_uid: klkoyw r nan the medical sequelae, including psychic ones, of covid- q are non-or poorly-reversible post-acute phase organic damages, or poorly qualified disorders occurring after healing. the lung is often affected and interstitial pulmonary fibrosis can persist after an acute phase that appeared to be mild. it is due to an increased cytokine production, an airway hyperpressure associated with ventilation, or an anoxia due to an imbalance between oxygen needs and supply. fibrosis causes a decline in the respiratory function, an extension of ct scan lesions and an increased susceptibility to respiratory infections. a low degree of fibrosis may increase mortality in the elderly. inflammatory myocarditis, as evidenced by elevated troponin and ''b-type natriuretic peptide'' (bnp), often found in intensive care patients, may lead to a left ventricular failure. myocardial infarction may occur, linked to a plaque rupture favored by infection or to a prolonged anoxia. a right ventricular failure secondary to pulmonary arterial hypertension as a consequence of fibrosis or an acute pulmonary embolism, and rhythm disorders (extrasystoles, ventricular tachyarrhythmia, atrial fibrillation) are sometimes observed. frequent in the acute phase, proteinuria, microscopic hematuria and moderate elevation of creatinine reflect renal damage. to evaluate tubular lesions, ''kidney injury molecule- '' (kim- ) and ''neutrophil gelatinase-associated doi of original article:https://doi.org/ . /j.banm. . . . ଝ press release of the french national academy of medicine, july q , . lipocalin'' (ngal) should be used. reversible acute renal failures, related to fluid and electrolyte disturbances, have been observed. tubular damage causes necrosis, which may lead to end-stage chronic renal failure, in a silent course that requires a prolonged surveillance. brain damage may be related to the virus or may result from anoxia in ventilated patients, strokes or acute disseminated autoimmune encephalomyelitis which, if it affects the peripheral nerves and the diaphragm, may worsen respiratory disorders. brainstem damage has the same effect. sarcopenia is almost constant in patients who are immobilized in intensive care. it requires prolonged rehabilitation. psychic sequelae affect patients coming out of resuscitation and then of convalescence. they require a psychological support. this is also the case for nursing staff subjected to long working hours and increased responsibilities leading to fatigue, anxiety and lack of sleep; disabled children and young adults who have left their host institutions; children deprived of school; and students whose studies have been interrupted. after an often short acute phase, poorly qualified disorders may be observed. testing for the virus is negative. the presence of specific ig g confirms the previous infection. episodic or prolonged, symptoms include general malaise, muscle pain, arthralgia, fatigue at the slightest effort, memory loss, and sometimes acute tachycardia. the clinical examination is negative, except often for weight loss. it is difficult to distinguish between the consequences of covid- from other causes. despite paracetamol, psychological support and renutrition, treatment is difficult. these medical sequelae, the national academy of medicine recommends: • resumption of physical activity, especially walking, as soon as possible • attention to the most affected functions (heart, brain, muscles, lung) • monitoring these after-effects through a cohort study • recruitment of medical personnel to reduce the risk of burn-out and the increase of their remuneration • in the event of reconfinement, assistance to parents of disabled children key: cord- -tx hirm authors: whiteside, james l; whiteside, john w title: acute bronchitis: a review of diagnosis and evidence-based management date: - - journal: primary care update for ob/gyns doi: . /s - x( ) - sha: doc_id: cord_uid: tx hirm abstract obstetricians and gynecologists are increasingly involved in primary care. acute bronchitis is among the most common ambulatory complaints. although the cause of acute bronchitis is predominantly viral, – % of patients presenting with this condition are treated with antibiotics. because of the increasing bacterial resistance to antibiotics, the cost of prescription drugs, and the potential adverse reactions to them, the present management of acute bronchitis has important shortcomings. also, inhaled bronchodilators are underused for symptomatic management. improved awareness among physicians about the recommended management of acute bronchitis has been targeted as an important means of decreasing unnecessary antibiotic use. patient satisfaction motivates physicians to prescribe antibiotics in managing acute bronchitis. however, patient satisfaction does not necessarily correlate with prescribing of antibiotics but rather with patient education. we present a review of the diagnosis and differential diagnosis of acute bronchitis and its management. the practice of obstetrics and gynecology in the united states is in transition. a key feature of this transition is enhanced emphasis on primary care. acute bronchitis is a common problem for primary care physicians, representing roughly the ninth most common health problem encountered in an ambulatory setting. , in a recent survey, more than % of those obstetricians and gynecologists surveyed independently manage acute upper respiratory tract infections (uris), and nearly % manage acute lower respiratory tract infections without aid of consultation. more common and apparently insignificant disorders such as acute bronchitis are often overlooked in physician training; yet management of acute bronchitis has been shown to often be inappropriate, even among internists and family practitioners. acute bronchitis accounts for an estimated to million physician visits per year in the united states. , , in , upper respiratory tract illness and acute bronchitis precipitated . million emergency department visits, making them the leading infection-related cause for emergency department visits in the united states. although acute bronchitis is caused by a virus in nearly % of patients, % of patients with symptoms of acute bronchitis are given prescriptions for antibiotics. , thus, acute bronchitis is among the most important targets for decreasing inappropriate antibiotic use in ambulatory practice. from $ to $ mil-lion annually is spent needlessly in the united states to treat acute bronchitis, regardless of the risks incurred from increased microbial resistance and potential antibiotic side effects. also, effective treatments for cough associated with acute bronchitis are underused, further contributing to its societal costs. obstetricians and gynecologists should be adept at diagnosing and managing acute bronchitis to practice effective primary care medicine and limit public costs. we review the cause, diagnosis, and evidencebased management of acute bronchitis. in addition, we consider the barriers to evidence-based management of acute bronchitis. acute bronchitis was described originally in as inflammation of the mucous membranes of the bronchi. today, it is still thought of as inflammation of the airways in response to infection. specifically, mucous membranes of the tracheobronchial tree become hyperemic and edematous, with increased bronchial secretion and impaired mucociliary function. , in addition, airway reactivity and resistance are heightened, not unlike in asthma, manifesting as a cough or signs of bronchial obstruction such as wheezing or dyspnea on exertion that can persist up to weeks. , unlike the case in asthma, the in-flammatory changes of the tracheobronchial tree found in acute bronchitis are transient and resolve with clearance of the infection. infectious agents, in most cases, are the same respiratory viruses associated with the common cold, such as rhinovirus and coronavirus, but include more invasive viruses such as adenovirus and influenza virus. other less common viral causes of acute bronchitis include measles virus, respiratory syncytial virus, parainfluenza virus, and herpes simplex virus. nonviral causes of acute bronchitis represent less than % of cases and include bacteria and inhaled lung irritants. mycoplasma pneumoniae, bordetella pertussis, and chlamydia pneumoniae (taiwan acute respiratory strain) are the accepted bacterial causes of acute bronchitis. , the role of streptococcus pneumoniae or the haemophilus species in acute bronchitis is unclear because these organisms may represent transient indigenous flora of the upper respiratory tract. results of spirometric studies done in patients with acute bronchitis mirror the results of studies in patients with mild asthma. in one study, % of patients had spirometric studies, such as forced expiratory volume in second (fev ), peak flow value, and mean forced expiratory flow between % and % of forced vital capacity (fef %- % ), in which the values were less than % of the predicted values. patients in whom acute bronchitis is diagnosed are more likely than normal subjects to have the diagnosis of asthma in the future, despite the aforementioned spirometric abnormalities having been shown to be reversed after weeks. , this suggests that many patients with acute bronchitis may actually have an irritable airway that reacts to common triggers such as uris. despite being a common ambulatory complaint, acute bronchitis lacks precise diagnostic criteria. acute bronchitis is a clinical diagnosis, and physicians would have better agreement on treatment if the consensus on diagnosis were better. even among family physicians, the diagnostic criteria used to identify acute bronchitis vary considerably. current textbooks and studies of acute bronchitis have varied in their descriptions; yet most physicians think that acute bronchitis is distinguished by the presence of cough with accompanying clinical features of a uri such as rhinorrhea and sore throat. clinically, a better definition might be acute onset of cough without a history of chronic pulmonary disease or evidence of pneumonia or sinusitis. this definition highlights the first two steps for treatment: ) identify patients who have chronic pulmonary disease or other coexisting medical illnesses such as congestive heart failure or immunosuppression and ) appropriately rule out other causes of acute cough, such as pneumonia and sinusitis. after this has been done, the bulk of outpatient presentations of acute cough will be from "uncomplicated acute bronchitis," which has a nonbacterial cause in more than % of cases. on the basis of pathophysiologic findings in acute bronchitis, symptoms of airway obstruction would be expected. cough, either dry or productive with a clear to yellowgreen sputum; chest tightness; or burning with or without wheezing are all commonly associated with acute bronchitis. as expected for a viral syndrome, characteristic symptoms also include headache, low-grade fever, rhinorrhea, sore throat, malaise, and myalgia. the cough, which often is worse in the morning and disrupts sleep, typi-cally lasts between and days. however, it can persist for more than a month in up to % of patients. physical examination may show signs of airway constriction such as wheezing or prolongation of the expiratory phase, but this sign is inconsistent. to elicit wheezing, auscultation of patients during forced expiration in a prone position has been recommended. patients with acute bronchitis would not be expected to have focal changes on auscultation, such as crackles, fremitus, or egophony. diagnostic studies cannot be recommended routinely because no available test can lead to definitive diagnosis of acute bronchitis. studies are used mainly to rule out other diseases included in the differential diagnosis. for example, chest radiographs may be useful for patients with suspected pneumonia. a productive cough, either purulent or otherwise, is not predictive of bacterial infection, and microscopic examination or culture of sputum is nearly always unrevealing. spirometric studies, although potentially abnormal during an episode of acute bronchitis, should be performed only when asthma or chronic obstructive lung disease is suspected and then only after resolution of the acute illness. the loose definition of "acute bronchitis" as cough in the presence of other respiratory symptoms leaves room for its inappropriate use by clinicians. during the examination, other potential causes of cough must be considered. an important cause of acute and chronic cough is postnasal drip. this is not associated with airway inflammation and can result from viral uris, acute sinusitis, or allergic rhinitis. patients with pneumonia can also present with cough associated with fever, wheezing, and malaise. how-ever, these patients usually have focal changes on lung auscultation and radiographs. clearly, patients with asthma and many of those with chronic obstructive lung disease are predisposed to the development of obstructive airway symptoms in response to common triggers such as uris. patients with lung neoplasms and congestive heart failure exacerbations can present with a new cough and dyspnea. inhalation of toxic or irritating substances such as air pollution, ammonia, chlorine, sulfur dioxide, nitrogen dioxide, or ozone can also lead to airway irritation and cough. other more chronic causes of cough include cystic fibrosis, gastroesophageal reflux, and medications such as angiotensin-converting enzyme inhibitors. clearly, the differential diagnosis for acute cough includes many diseases that are not selflimited and some that may be lifethreatening. these alternative diagnoses must be considered in all patients and an appropriate evalua t i o n m u s t b e p e r f o r m e dparticularly in those older than years of age with marked lung impairment or those who have a poor performance status with other coexisting medical conditions. for the patient who presents with acute onset of cough and no history of chronic pulmonary disease or evidence of other more serious illnesses, studies have consistently shown either no benefit or, at best, modest benefit from the use of antibiotics. this benefit, where evident, has shortened the duration of cough or sputum production by approximately day. for an illness that spontaneously resolves in to days, this cannot be regarded as a substantial benefit. the value of this benefit is further challenged by the cost of antibiotics, the risk of adverse effects, and the negative consequences on antibiotic resistance patterns among bacteria colonizing the individual patient and existing at large. some studies have identified subgroups in which antibiotics might have a justifiable benefit. data are weak, but authors of recent metaanalyses have suggested that patients older than years of age and those without coryza and sore throat may benefit from antibiotic therapy. least likely to benefit are those whose symptoms have been present for less than week and whose cough is accompanied by uri symptoms. on the basis of microbiologic findings of acute bronchitis, it is not unexpected that antibiotics would have little benefit. however, antiviral agents are available for treating influenza, and this pathogen is frequently associated with acute bronchitis. these antiviral agents include neuraminidase inhibitors such as oseltamivir and zanamivir, as well as amantadine and rimantadine. the major advantage of neuraminidase inhibitors is their activity against influenza b. however, although patterns change yearly, % of reported influenza cases in the - season were from influenza a. although it would seem that these agents would hold great promise for the treatment of a primarily viral illness, their usefulness in the treatment of acute bronchitis is hindered severely by their weak efficacy against influenza in general. also, these drugs are relatively expensive and, historically, physicians have been poor at accurately predicting the presence of influenza, even at the height of a seasonal epidemic. these agents have been shown to decrease the duration of influenza symptoms by about day, but only if the treatment is initiated within the first hours of the symptomatic period. , however, because of problems with cost, poor efficacy, and difficulties with accurate diagnosis of influenza, these agents cannot be recommended for routine treatment of acute bronchitis. patients with acute bronchitis desire treatment of their symptoms and, in particular, relief from coughing. albuterol has been studied as a treatment for acute bronchitis and has inconsistently demonstrated benefit in decreasing the duration and severity of cough. a meta-analysis of the studies by the cochrane collaboration is currently ongoing. preparations containing dextromethorphan and codeine and humidification of the airways may slightly improve the cough of acute bronchitis, but there is little supporting evidence for this. decongestants may also help a cough precipitated by postnasal drip. patients often perceive antibiotics as a panacea and seek an antibiotic prescription at any sign of potential infection. physicians are generally aware of this and feel obliged to comply with this perceived demand. failure to comply leads to patient dissatisfaction, and ultimately it may lead a patient to seek care from another provider. furthermore, to the individual physician, the negative effect of antibiotic overuse is difficult to appreciate. clinicians do prescribe antibiotics in response to patient expectations. the assumption, however, that patients are more satisfied with an antibiotic prescription is false. hamm et al. found no association between patient satisfaction and prescriptions for antibiotics among patients seeking care for respiratory infections. instead, educating patients about the cause of their ailment and spending time with them correlated with patient satisfaction. gonzales et al. reinforced this finding by comparing antibiotic prescription rates for acute bronchi-tis with a baseline period and a study period at four primary care practices. they found that antibiotic use decreased in practices that provided education and clinical contact to patients. an examination of factors associated with an antibiotic prescription for acute bronchitis showed that physicians respond to clinical factors such as cough, sputum production, pharyngeal erythema, and cervical lymphadenopathy. because these signs and symptoms are equally common in patients with and those without pneumonia, physicians appear to prescribe antibiotics based on the diagnosis of acute bronchitis alone. , this pattern is remarkable given the abundant information urging physicians to refrain in most instances from prescribing antibiotics for this condition. even more disappointing is that physicians nationally are more likely to prescribe antibiotics for cough to patients who are white, non-hispanic, and younger than years, a population arguably least likely to benefit from such an intervention. the risk to the individual and to the community from the rise in antibiotic resistance is also important. the cause for this rise is multifactorial; however, selective pressure of frequent antibiotic use encourages resistant strains to multiply and spread. for example, it has been demonstrated in daycare centers that previous antibiotic use is the most consistent factor for carriage of penicillin-resistant pneumococcus. before the mid- s, virtually all strains of streptococcus pneumoniae were sensitive to penicillin. today, in some areas of the country, more than % of s. pneumoniae isolates demonstrate an intermediate to high level of resistance to penicillin. usually, these strains are also resistant to other antibiotics such as macrolides, trimethoprim-sulfamethoxazole, and cephalosporins. the risk of adverse effects is at least as important as the benefit associated with the use of antibiotics. recent meta-analyses have shown that with antibiotic use, the "number needed to harm" ranges from to , whereas the "number needed to treat" ranges from to . , this means that the use of antibiotics for treating acute bronchitis is almost as likely to result in adverse effects as it is to result in reducing cough. in fact, all three recent meta-analyses on the topic concluded that routine antibiotic treatment for acute bronchitis in adults is not justified. , , acute bronchitis is an important medical problem that is commonly seen in an ambulatory care practice. despite a predominantly viral cause and numerous randomzied controlled studies documenting no meaningful benefit from antibiotics, more than % of patients presenting with acute bronchitis are given antibiotic prescriptions. consequently, penicillin resistance of s. pneumoniae and other bacteria has increased, prompting requests to reduce unnecessary antibiotic use. diagnosis and management of this problem are flawed, even among providers most involved in ambulatory medicine. obstetricians and gynecologists are increasingly involved in providing primary care and should be knowledgeable about the evidence regarding the cause and management of acute bronchitis. antibiotics for acute bronchitis (cochrane review) current management of acute bronchitis in ambulatory care: the use of antibiotics and bronchodilators primary care by obstetricians and gynecologists: attitudes of the members of the south atlantic association of obstetricians and gynecologists antibiotic prescribing for adults with colds, upper respiratory tract infections and bronchitis by ambulatory care physicians how do we achieve cost-effective options in lower respiratory tract infection therapy? airway infection antibiotic prescribing for patients with colds, upper respiratory tract infections, and bronchitis: a national study of hospital-based emergency departments acute bronchitis diagnosis of acute bronchitis in adults: a national survey of family physicians pulmonary function test in acute bronchitis: evidence for reversible airway obstruction an association between acute bronchitis and asthma principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background factors associated with antibiotic use for acute bronchitis antibiotics in acute bronchitis: a meta-analysis efficacy and safety of the oral neuraminindase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial neuraminidase inhibitors for preventing and treating influenza in healthy adults (cochrane review) treatment of acute bronchitis in adults without underlying lung disease antibiotics and respiratory infections. are patients more satisfied when expectations are met? decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on the treatment of uncomplicated acute bronchitis in adults clinical prediction rule for pulmonary infiltrates national trends in the use of antibiotics by primary care physicians for adult patients with cough drug resistant streptococcus pneumoniae: kentucky and tennessee are antibiotics effective treatment for acute bronchitis? a meta-analysis antibiotics for acute bronchitis (cochrane review) quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults key: cord- -sg n hs authors: suri, h. s.; li, g.; gajic, o. title: epidemiology of acute respiratory failure and mechanical ventilation date: journal: intensive care medicine doi: . / - - - - _ sha: doc_id: cord_uid: sg n hs acute respiratory failure, and the need for mechanical ventilation, remains one of the most common reasons for admission to the intensive care unit (icu). the burden of acute respiratory failure is high in terms of mortality and morbidity as well as the cost of its principal treatment, mechanical ventilation. very few epidemiologic studies have evaluated the prevalence and outcome of acute respiratory failure and mechanical ventilation in general. most of the published literature has focused on specific forms of acute respiratory failure, particularly acute lung injury (ali) and acute respiratory distress syndrome (ards). in this chapter, we provide a brief review of the pathophysiology of acute respiratory failure, its definition and classification, and then present the incidence and outcomes of specific forms of acute respiratory failure from epidemiologic studies. acute respiratory failure, and the need for mechanical ventilation, remains one of the most common reasons for admission to the intensive care unit (leu). the burden of acute respiratory failure is high in terms of mortality and morbidity as well as the cost of its principal treatment, mechanical ventilation. very few epidemiologic studies have evaluated the prevalence and outcome of acute respiratory failure and mechanical ventilation in general. most of the published literature has focused on specific forms of acute respiratory failure, particularly acute lung injury (ali) and acute respiratory distress syndrome (ards) . in this chapter, we provide a brief review of the pathophysiology of acute respiratory failure, its definition and classification, and then present the incidence and outcomes of specific forms of acute respiratory failure from epidemiologic studies. normal respiration requires the integrated function of several components of the respiratory system (fig. ) . dysfunction of any component results in the impairment of normal gas exchange and may lead to acute respiratory failure and the need for mechanical ventilation. according to the underlying pathophysiologic mechanism, acute respiratory failure is usually divided into four patterns: types i-iv ( ta ble ). type i and type ii respiratory failure are also referred to as hypoxemic and hyper- capnic respiratory failure, based on a predominant gas exchange abnormality. in many disease states however, more than one pathophysiologic mechanism is operational and clinical criteria that incorporate setting, acuity, and severity are used more often ( table ) . acute episodes (exacerbations) of respiratory failure in patients with chronic compensated respiratory insufficiency are usually referred to as 'acute on chronic' respiratory failure. a consensus definition of acute respiratory failure is not available and most studies have used the combination of mechanical ventilation (of variable duration) with or without evidence of severe hypoxemia on arterial blood gas analysis. while some studies utilized a more strict definition than others, the essential component in all has been the need for mechanical ventilation. the indications for mechanical ventilation , however, are mostly based on clinical observations (increased respiratory rate, use of accessory muscles, paradoxical chest wall movements, changes in mental state), none of which has sufficient accuracy or precision. therefore, the epidemiology of acute respiratory failure has so far been restricted to 'treated' acute respiratory failure, possibly explaining the wide variations in the reported incidence and outcomes of acute respiratory failure and associated clinical syndromes. since the availability of intensive care and mechanical ventilation vary greatly in different parts of the world, the burden of acute respiratory failure may be severely underestimated depending on the access to leu services. the incidence of acute respiratory failure varies according to the definition used and the population studied ( table ) . two european studies , one conducted in germany [i] and the other in sweden, denmark, and iceland [ ] , estimated very similar incidences, . and . cases per , person-years. both studies used an identical definition (intubation and mechanical ventilation for > h regardless of arterial blood gas findings) and employed a multicenter approach with large patient cohorts over a short period ( weeks). on the other hand, behrendt reported a much higher incidence of acute respiratory failure in the usa, . per , patient-years. this incidence was estimated based on the icd- -cm disease codes for diagnoses and treatment in patients > yrs old observed over a l-year period [ ] . the significant variation between the us and european incidences may in part be explained by the differences in study design ( table ) and in part by incons istent indications and access to mechanical ventilation in different countries. acute respiratory failure is often accompanied or followed by a failure of other vital organs, and death most often occurs becau se of multiorgan failure (mof) and the withdrawal of mechan ical ventilati on when the chances for a meaningful recovery of the patient's qual ity of life are deemed to be exceedingly low. imprecision of clinical prognostic criteria, variations in available resources, and patient and provider preferences limit the interpretation of mortality data from different epidemiologic studies. reported mortality rates for acute respir ator y failure from the s are remarkably similar, approximately % in spite of differences in study designs and the definit ions applied ( table ). lewandowski and coworkers [ ] studied patients from icus in berlin, germany and reported mortality rates of - % depending on the lung injury score (lis). in a large prospective study from scandinavia, luhr and coworkers reported an all-cause -day mortality of % [ ] . in a large, prospective international cohort involving icus, esteban and coworkers reported an icu mortality of . %. mortality increased significantly in patients with sepsis, shock, ards, or liver failure [ ] . vincent and coworkers used sequential organ failure assessment (sofa) score criteria and the need for mechanical ventilation to define acute respiratory failure and estimated an overall icu mortality of %. the mortality was much lower ( %) when the lung was the only organ involved [ ] . recently, flaatten and coworkers reported the mortality from acute respiratory failure at different time points after disease onset . mortality was again the lowest in single organ acute respiratory failure and rose with each add itional organ failure. higher mortality rates were found days after the onset compared to at icu or hospital discharge [ ] . mof following an icu admission , presence of circulatory shock on icu admission , older age, and pre-existing comorbidities (cirrhosis, malignancy and chronic renal failure) were independent risk factors for the mortality rate reported in several studies [ , [ ] [ ] [ ] . acute lung injury (ali) ali and its more severe form, ards, are clinical syndromes defined as an acute onset of hypoxemic respiratory failure with diffuse pulmonary infiltrates in the absence of left atrial hypertension as the principal cause of acute pulmonary edema. ali is a major cause of acute respiratory failure in the icu and is associated with high morbidity and mortality. since it was first described by ashbaugh and colleagues [ ] and than redefined in [ ] , there have been significant advances in the understanding of etiology, pathophysiology, and the epidemiology of ali. clinical risk factors for ali are usually divided into direct (pulmonary) and indirect (extrapulmonary). pneumonia, aspiration, lung contusion; and inhalation injury are the principal pulmonary risk factors, while sepsis, shock, trauma, pancreatitis, and multiple transfusions represent the most important extrapulmonary risk factors. in recent years, transfusion-related ali (trali) and novel viral pathogens (severe acute respiratory syndrome [sarsj) have emerged as important risk factors for ali. the reported incidence of all has varied significantly. the report of the national heart and lung institute task force on respiratory diseases, estimated , cases of ards per year yielding the annual incidence of per , person-years . subsequent studies reported an incidence of all ranging from to cases per , person-years in european countries [ , ] and australia [ ] , and a much higher incidences of ali in the usa, per , persons-years ( , cases per year) [ ] [ ] [ ] . while a significant minority of patients with all is treated with non-invasive ventilation (niv), the majority of studies included only patients treated with invasive ventilation. a recently completed, retrospective, community cohort study in olmsted county, minnesota included patients treated with niv and found an even higher incidence of ali, per , person-years (personal communication, rodrigo cartin -ceba), mortality from ali varies greatly depending upon the age of the patient, underlying chronic illnesses, ali risk factors, and non-pulmonary organ dysfunctions [ ] . two decades ago, the mortality rate from ali ranged from - % [ , , , ] , but has since declined and more recently has been estimated to be about - % [ , , , ] . advances in general supportive care [ ] and the use of new mechanical ventilation strategies [ ] may account for most of the change. both the incidence of and mortality from all increase exponentially with age [ - , , ] . mof [ , , ] , liver failure, severe sepsis [ , , , ] , aspiration [ ] , presence of infection and neurological failure on icu admission [ ] , and pree-xisting cirrhosis [ , , , ] , bone marrow transplantation, human immunodeficiency virus (hiv) [ ] , hematologic [ , ] or active malignancy [ , ] , and charlson comorbidity score [ ] have been associated with a higher mortality. persistent severe hypoxemia and cardiovascular failure also predict poor outcomes [ , ] . non-survivors of ali die predominantly of moe a landmark study published in reported that only % of deaths were caused by respiratory failure [ ] . similar results ( % and %) were reported by two stud ies conducted in recent years [ , ] . mof, septic shock , and underlying comorbidities are the most common causes of death in patients with ali. survivors of ali often have a prolonged recovery and significant short and longterm disability. while lung function usually returns to normal within several months [ ] , neuromuscular and neurocognitive sequelae may persist much longer [ , ] . the most important predictors of prolonged disability are the use of systemic steroids during the icu stay, presence of a complicating illness acquired during the icu stay, and the rate of resolut ion of ali and mof [ ] . neuropsychological sequelae are also common and about % of long-term survivors develop posttraumatic stress disorder [ ] . with a decline in mortality from ali, more survivors are at risk of prolonged morbidity ('chronic critical illness') contributing to substantial increases in the utilization of health care resources. cardiogenic pulmonary edema is a common cause of acute respiratory failure. in about % of the mechanically ventilated patients in an international cohort study, cardiogenic pulmonary edema was the principal reason for instituting mechanical ventilation [ ] . other epidemiologic studies reported similar rates of cardiogenic pulmonary edema [ , ] with mortality ranging from - % [ , ] . in the past two decades, niv, both continuous positive airway pressure (cpap) and bilevel positive airway pressure (bipap) ventilation, have received a great deal of interest in the management of patients presenting with acute cardiogenic pulmonary edema . randomized trials comparing either cpap or bipap with standard medical therapy, found similar improvements in arterial blood gases and breathing rates, reduced need for intubation, and improved outcome [ ] . according to the world health organization, chronic obstructive pulmonary disease (copd) ranks fourth among all causes of death with an age-adjusted mortality rate of . per , person-years. the th century pandemic of cigarette smoking is taking its toll, evident by the increase in the annual hospitalization rate for acute exacerbation of copd from . in to . % in . moreover, about % of all hospitalizations are directly or indirectly attributable to copd [ ] . many patients with acute exacerbation of copd require admission to the icu for acute respiratory failure. in an international cohort study [ ] , acute exacerbation of copd was a principal indication for initiating mechanical ventilation in % of patients with acute respiratory failure. the hospital mortality rate of copd patients admitted with acute exacerbation varies between . - %, depending on the methodology of the data collection and the patient population. seneff et al. [ ] reported a hospital mortality rate of % in admissions for acute exacerbation of copd selected from the acute physiology chronic health evaluation (apache) iii database of , admissions in a prospective multicenter trial. mortalities rose to % at hospital discharge and doubled to % at the l-year follow-up. invasive mechanical ventilation was instituted in of patients with a mortality rate of %. after controlling for the severity of illness , mechanical ventilation at icu admission was not asso ciated with either hospital mortality or subsequent survival. development of non-respiratory organ dysfunction was the most important predictor of hospital mortality, while the abnormalities in gas exchange (pac , ph , pa ) indicative of advanced dysfunction were strongly associated with six month mortality. esteban et al. [ ] reported a hospital mortality of % in patients receiving mechanical ventilation for acute exacerbation of copd. liu et al. [ ] retrospectively studied a cohort of patients with copd requiring invasive mechanical ventilation for acute respiratory failure. the cause of acute respiratory failure was acute exacerbation of copd in % and pneumonia in % of patients. the hospital mortality rate was . % in all patients and . % in the acute exacerbation of copd subgroup. respiratory acidosis was corrected (ph> . ) in . % of survivors but only in . % of non-survivors. in a recent study, conse cutive patients hospitalized with acute exacerbation of copd were followed prospectively for years [ ] . the in-hospital mortality rate was . %. the overa l -month mortality was %, with -, -, and -year mortality rates of %, %, and %, respectively. more severe gas exchange abnormalities and longer hospital stays were associated with the hospital mortalities. long-term mortality was associated with longer disease duration, lower serum albumin, low body mass index, and lower pa ' mof and sepsis were the most common immediate causes of death in patients with acute exacerbation of copd admitted to the icu. in another prospective study of patients with acute exacerbation of copd [ ] , invasive mechanical ventilation was started in % and niv was tried in % of patients and was successful in % of them. median duration of ventilation was days. after several clinical tr ials reported improved outcomes [ ] , niv has become the principal init ial mode for providing mechanical ventilation to patients with acute exacerbation of copd [ ] . since the indications for niv are more liberal than those of invasive ventilation, it is difficult to directly compare the outcomes of mechanically ventilated patients treated with the two modes. in a study by girou et al., however, adjusted odds of death ( . ; % confidence interval [ci], . - . ) suggested that the mortality in patients with similar severity of illness treated with niv was significantly lower. severe status asthmaticus is a rare cause of acute respiratory failure requmng mechanical ventilation ( . % of patients in the international cohort study) [ ] . patients in status asthmaticus who require invasive mechanical ventilation are at high risk of severe complications (pneumothorax, cardiopulmonary arrest) and mortality. afessa et al. reported the incidence and outcomes of status asthmaticus in a us inner city hospital, from to [ ] . forty-eight out of hospital admissions required mechanical ventilation ( %). mechanically ventilated patients had significant mortality ( %) and high complication rates. sixteen patients developed non-pulmonary organ failure and four developed pneumothorax requiring chest tube drainage. interestingly, all patients who died in this study were female . pneumonia is a common cause of hypoxemic acute respiratory failure. approximately - % of acute respiratory failure episodes requiring mechanical ventilation are due to pneumonia. icu mortality rates from acute respiratory failure due to pneumonia range from - % [ , , , ] . in many patients with pneumonia, however, complications such as septic shock and ali, or acute worsening of underlying chronic lung disease (copd) are the principal reasons for instituting mechanical ventilation . compared to other ali risk factors, pneumonia is associated with higher mortality (see ali paragraph above). the majority of patients with interstitial lung disease and acute respiratory failure admitted to the icu require invasive mechanical ventilation . interstitial lung disease is, however, an uncommon cause of acute respiratory failure (less than % of patients in the international cohort study [ ] ). in a retrospective review [ ] of patients with interstitial lung disease who were mechanically ventilated at mayo clinic from to , acute respiratory failure was the most common cause of icu admiss ion ( %), followed by sepsis ( %) and cardiopulmonary arrest ( %). seventeen patients were initially treated with niv but eventually all patients required invasive mechanical ventilation. hospital mortality was %. patients with idiopathic pulmonary fibrosis tended to have a higher mortality rate than non -idiopathic pulmonary fibrosis forms of interstitial lung disease. conventional lung protective mechanical ventilation was not associated with improved outcome. worsening hypoxemia and higher positive end-expiratory pressure (peep) settings were associated with increased mortality. in an earlier study, saydain and coworkers observed the clinical course of patients with idiopathic pulmonary fibrosis admitted to the icu. acute respiratory failure was the most common reason for icu admission. while % of the patients survived to hospital discharge, of survivors ( %) died within months after hospital discharge [ ] . patients with neuromuscular disease are frequently treated with both acute and chronic mechanical ventilation. neuromuscular disease accounted for % of patients receiving mechanical ventilation in the international cohort study [ ] . compared to other causes of acute respiratory failure, patients with neuromuscular disease had higher costs and length of icu stay and % required tracheostomy [ ] . hospital mortality was %. epidemiologic studies looking at the outcomes of acute respiratory failure due to specific forms of neuromuscular disease are scarce. recently, ali et al. [ ] reported on the outcomes of patients with guillain-barre syndrome who required mechanical ventilation. all but six patients ( %) required tracheostomy. forty-six patients ( %) survived to hospital discharge, and ( %) were alive at the l-year follow-up according to the international cohort study [ ] , in . % of patients mechanical ventilation was employed because of trauma. hospital mortality for these patients was %. in a retrospective incident study of acute respiratory failure in the usa [ ] , acute respiratory failure related to trauma was more common in the younger age group and trauma without mof was associated with a very low mortality rate. in a scandinavian study, approximately % of cases of acute respiratory failure were caused by trauma [ ] . of the cases of acute respiratory failure in the berlin study, were due to trauma with mortality of % [ ] . complicating coma, shock, and ali are common indications for mechanical ventilation in patients with trauma. about - % of cases of ali are related to trauma [ , , ] with mortality lower than that for other ali risk factors ( %, see above) [ ] . shock is characterized by global hypoperfusion leading to lactic acidosis, hyperventilation and hypoperfusion of respiratory muscles, resulting in type iv respiratory failure. up to % of oxygen consumption in shock may be used by the respiratory muscles contributing to a global imbalance between oxygen delivery and consumption . pulmonary edema, ali, and anemia often contribute towards respiratory distress. work of breathing may ultimately overcome respiratory reserve leading to the development of acute respiratory failure. early use of mechanical ventilation in severe shock may be justified to limit the work of breathing and decrease oxygen consumption by respiratory muscles. septic shock, in particular, is commonly associated with acute respiratory failure and ali. in the international cohort study, septic shock was a primary indication for mechanical ventilation in % of patients with mortality of % [ ] . coma is a non-specific syndrome of widespread central nervous system impairment resulting from various metabolic and structural etiologies. it usually results in type ii respiratory failure due to upper airway dysfunction and hypoventilation. intubation and invasive mechanical ventilation are usually required to protect the airway and maintain gas exchange. in the study by esteban et al. [ ] , % of patients required mechanical ventilation because of coma. reported icu mortality was % in patients with coma who received mechanical ventilation. advances in mechanical ventilation have dramatically changed the management and outcome of patients with acute respiratory failure. with increased access to mechanical ventilation , the burden of acute respiratory failure may grow beyond the health care budget of even the richest societies. inconsistent use of standardized definitions for acute respiratory failure and, in particular, indications for mechanical ventilation, present the major impediment to the meaningful understanding of clinical research results and will have to be overcome in future studies. population studies are needed to determine the risk factors, prevalence, and the attributable outcomes of various forms of acute respiratory failure in the community. such studies will help identify the best strategies for the prevention and treatment of acute respiratory failure, will pinpoint important uncertainties that need to be tested in clinical trials, and will allow informed decisions regarding allocation of scarce resources so that bedside practitioners may best improve the quality-adjusted survival of their patients . incidence, severity, and mortality of acute respiratory failure in incidence and mortality after acute respiratory failure and acute respiratory distre ss syndrome in sweden, denmark, and iceland. the arf study group acute respiratory failure in the united states: incidence and -day survival character istics and outcomes in adult patients receiving mechanical ventilation: a -day international study epidemiology and outcome of acute respiratory failure in intensive care un it pat ients outcome after acute respiratory failure is more dependent on dysfunct ion in other vital organs than on the severity of the respiratory failure the epidemiology of acute respiratory failure in critically ill pat ients identification of patients with acute lung injury. predictors of mortality the changing face of organ failure in ards acute respiratory distress in adults the american-european consensus conference on ards. definitions, mechan isms, relevant outcomes, and clinical trial coordination acute respiratory distress syndrome : an audit of incidence and outcome in scottish intensive care units incidence and mortality of acute lung injur y and the acute respiratory distress syndrome in three australian states incidence of acute lung injury in the united states incidence and outcomes of acute lung injury ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome acute lung injury in the medical icu: comorbid conditions, age, etiology, and hospital outcome survival following mechanical ventilation for acute respiratory failure in adult men acute lung injury at baragwanath icu. an eightmonth audit and call for consensus for other organ failure in the adult respiratory distress syndrome hemodynamic profile in severe ards: results of the european collaborative ards study early predictive factors of survival in the acute respiratory distress syndrome. a multivariate analysis outcome of respiratory failure in hematologic malignancy six-month survival of patients with acute lung injury: prospective cohort study causes of mortality in patients with the adult respiratory distress syndrome is outcome from ards related to the severity of respiratory failure? neuropsychological sequelae and impaired health status in surv ivors of severe acute respiratory distress syndrome one-year outcomes in survivors of the acute respiratory distress syndrome health-related quality of life and posttraumatic stress disorder in survivors of the acute respiratory distress syndrome how is mechanical ventilation employed in the intensive care unit? an international utilization review noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta -analysis factors affecting survival of hospitalized patients with copd hospital and i-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease analysis of risk factors for hospital mortali ty in patients with chronic obstructive pulmonary diseases requiring invasive mechanical ventilation prognostic factors, clinical course, and hospital outcome of patients with chronic obstructive pulmonary disease admitted to an intensive care unit for acute respiratory failure non-invasive positive pressure ventilation for treatment of respiratory failure due to exacerbations of chronic obstructive pulmonary disease secular trends in nosocomial infections and mortality associated with noninvasive ventilation in patients with exacerbation of copd and pulmonary edema clinical course and outcome of patien ts admitted to an icu for status asthmaticus hospital survival rates of patients with acute respiratory failure in modern respiratory intensive care units. an international, multicenter, prospective survey gajic ( ) ventilator settings and outcome in pat ients with interstitial lung disease requiring mechanical ventilation in the intensive care unit outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit gajic ( ) mechanical ventilation in patients with guiilain-barre syndrome key: cord- -yn pvb authors: nan title: full issue pdf date: - - journal: jacc case rep doi: . /s - ( ) -x sha: doc_id: cord_uid: yn pvb nan t he coronavirus disease- (covid- ) pandemic has revolutionized clinical practice in recent months unlike any other health emergency in recent years. jacc: case reports has taken this challenge very seriously, dedicating to it an entire issue. we have received excellent case reports from across the world. our goal is to provide a comprehensive report of representative cardiovascular involvement in covid- (central illustration). besides the concern regarding qt interval prolongation with hydroxychloroquine and azithromycin treatment, covid- is strongly associated with the occurrence of sudden unexpected arrhythmias. given the general ignorance of the pathophysiological mechanisms of the virus at the time of submission of these case reports, it is hard to state with certainty that covid- has been the cause of these arrhythmias, but they surely offer an interesting direction for future research in the field. included are cases of brugada type i pattern positivization ( ) in the context of fever, one of the most common presenting symptoms of the disease ( ); electrical ventricular storm ( ); transient atrioventricular block in the absence of myocarditis ( ); sinus node dysfunction requiring pacemaker implantation ( ) ; and finally a provocative report on the use of amiodarone as a possible treatment for covid- ( ) . overall, the cytokine storm has proved to have a strong impact on the conduction system. the clinical presentation of patients with covid- has ranged from asymptomatic to acute respiratory distress syndrome requiring mechanical ventilation. one cause of sudden respiratory deterioration is the increased risk for venous thromboembolic disease in these patients ( ) (figure ). these events have been noted both early and in the recovery phase of covid- . furthermore, thromboembolic events have occurred despite the use of prophylactic anticoagulation or even full anticoagulation ( ) . a majority of patients have elevated levels of d-dimer and laboratory findings consistent with sepsis-induced diffuse intravascular coagulation, suggesting a coagulopathic process, yet no prospective studies have demonstrated the predictive nature of these markers for the occurrence of a thromboembolic event, only a higher risk for mortality ( ) . the early recognition and treatment of venous thromboembolic disease has therefore been a dilemma. we therefore provide commentary and suggest treatment algorithms ( ) . we received case reports in general categories detailing an increased risk or arterial thrombosis during the covid- pandemic. causing stemi in infected patients ( , ) . second, there were a number of cases of stemi in patients younger than years without risk factors for atherosclerosis ( ) . this phenomenon occasionally occurred before covid- , but the increased incidence reminds us to always include myocardial infarction in the differential diagnosis of a younger patient with chest pain and to always consider performing screening electrocardiography. third, a number of cases of stemi mimics were submitted, including patients with st-segment elevation due to myopericarditis, brugada pattern, takotsubo cardiomyopathy, or endothelial dysfunction due to infection or cytokine storm. as many as % of patients with covid- and st-segment elevation may have normal coronary arteries on angiography, complicating the decision whether to administer fibrinolytic therapy to patients without early access to primary percutaneous coronary intervention. finally, there were reports of spontaneous thrombosis ( ) involving the ascending and descending aorta, the cerebrovascular arteries, the mesenteric and renal arteries, and the peripheral arteries, underscoring an increased systemic risk for arterial thrombosis in patients with covid- . the development of heart failure in patients infected with severe acute respiratory syndrome coronavirus- has been described to involve different, and overlapping, mechanisms. one is cytokine release resulting in myocardial inflammation (figure ) , and affected patients has demonstrated both inflammatory infiltrates and viral particles. the heart failure cases presented in this special issue, however, describe more varied presentations of patients, some with pre-existing heart failure and others with no known cardiac disease prior to becoming ill with infection. in addition to cases of direct myocardial injury, some with pathological evidence, we also present cases of takotsubo cardiomyopathy ( , ) two cases highlight the special circumstances faced by patients with left ventricular assist devices ( , ) , which include the inability to tolerate prone positioning to augment respiratory support because of the mechanical equipment and the hypothesis that mechanical circulatory support may provide a type of protection against the most serious hemodynamic consequences of severe acute respiratory syndrome coronavirus- infection. included also is a case series of pediatric patients who had hemodynamic collapse and cardiac dysfunction ( ) , a presentation that has been rare in this younger age group. the now well-recognized thromboembolic disorders encountered with this disease include a case in this issue of massive pulmonary embolism and resultant severe right heart failure ( ) . and separate reports describe patients with concomitant noncardiac disease, with human immunodeficiency virus infection ( ) and with influenza ( ) . all the cases of heart failure represent the investigators' best attempts at providing supportive and emerging therapies at a time when they had no established guidelines and no best practices to follow. from the beginning of the pandemic, we believed that it was very important to publish the "voices" of our frontline colleagues across the world, to help cardiologists to get acquainted with mechanical ventilation ( ) , to describe the first evidence of sex differences in covid- ( ) , and to discuss the significant changes in health care with telemedicine and virtual clinics. the impact of covid- on african americans has also recently been described in jacc (table ) revealed leukopenia, normocytic anemia, thrombocytopenia, and significant increase in c-reactive protein levels. a nasopharyngeal swab sample tested positive for severe acute respiratory syndrome-coronavirus- (sars-cov- ) using real time-reverse transcriptionpolymerase chain reaction. the patient had a medical history of bipolar disorder and hypothyroidism. he reported having fever for week. given the patient's presentation of prolonged asystole, differential diagnosis included metabolic disorders, pharmacologic agents and extracardiac diseases with special attention to thyroid hormone levels. to recognize cardiovascular complications among covid- patients. to demonstrate arrhythmic risk related to covid- disease. to manage sick sinus dysfunction in covid- disease. during the following days, the patient had episodes of asystole associated with hypotension but without loss of cardiac output ( figure ). moreover, alternating episodes of bradycardia and tachycardia note bilateral ground glass opacities. once reversible causes were excluded, symptoms were related to dysfunction of the intrinsic sinus node, and the patient underwent dual-chamber ratemodulated implantation of a pacemaker (pm) ( figure ). because of evidence of sinus tachycardia, bisoprolol was administrated. further and later pm control showed only this episode. transthoracic echocardiography was repeated before the patient was discharged and showed no differences from the previous one. in consideration of his progressive clinical improvement, the endotracheal tube was removed, and the patient began to breath spontaneously. on psychiatric indication, therapy for bipolar disorder was reintroduced. this could be due to hypoxia and electrolyte abnormalities, which could lead to episodes of cardiac arrhythmia, or due to central nervous system alterations caused by sars-cov- disease. increasing evidence shows that covs are not always confined to the respiratory tract but may also invade the central nervous system, inducing neurological diseases ( , ) , and some covs have been shown to be able to spread to the medullary cardiorespiratory center through chemoreceptors and mechanoreceptors in the lung and lower respiratory airways through a synapse-connected route ( ) . considering that most covs share a similar viral structure and infection pathway ( ) , the infection mechanisms previously found for other covs may also be applicable to sars-cov- . furthermore, the transsynaptic transfer also has been reported for avian bronchitis virus ( ) in fact, the intrinsic cardiac nervous system has regional control over different cardiac functions, such as sinus node electrical activation and propagation, as well as atrioventricular nodal conduction, and consists of ganglia composed of afferent, efferent, and interconnecting neurons to other cardiac ganglia. these ganglia coordinate the sympathetic and parasympathetic inputs received from the rest of the cardiac autonomic nervous system. generally, autonomic dysfunction refers to a disorder of an autonomic nervous system that may arise from intrinsic or extrinsic mechanisms. intrinsic autonomic dysfunction arises from diseases that directly affect the autonomic nerves, such as diabetes mellitus and the various syndromes of primary autonomic failure. extrinsic autonomic dysfunction often is secondarily induced by cardiac or other disease ( ) . patients with autonomic dysfunction commonly have poor long-term prognosis, and death can occur from pneumonia, acute respiratory failure, sudden cardiopulmonary arrest, or fatal arrhythmias related, for example, to ssd. specifically, ssd includes a spectrum of heart rhythm disturbances related to abnormal sinus impulse formation or propagation ( ) and has different presentations, such as bradycardia, alternating episodes of bradycardia and tachycardia and sinoatrial block. in some cases, ssd presents with sinus node arrest and prolonged asystole, such as in the present patient. symptoms related to ssd are generally fatigue and syncope or presyncope, but patients can be asymptomatic in the early phase of the disease. when symptoms are related to dysfunction of sinus node, pm implantation is required. currently, data regarding the neuroinvasive potential of sars-cov- with subsequent autonomic dysfunction are less described. furthermore, to these authors' knowledge, this is the first case in medical literature of ssd related to covid- infection. an improved understanding is crucial primarily for guiding the need for additional arrhythmia monitoring during hospitalization and after discharge ( ) . the present authors believe that recognition by the scientific community of these risks related to covid- disease may be helpful for strict monitoring of affected patients and also for furthering knowledge of such complications for global public health. diagnostic coronary angiography performed through the right radial approach revealed angiographically normal coronary arteries (figures and ) . ventriculography confirmed the globally mildly reduced ejection fraction. the patient was admitted to a dedicated coronavirus disease- (covid- ) intensive care unit. the covid- results became available within h and were positive. his condition continued to improve, and he required minimal supplemental oxygen to maintain arterial saturation. all serial troponin values were negative. two days later he developed a brief episode of supraventricular tachycardia that was successfully terminated with intravenous adenosine ( figure ). four days after the initial presentation, he was doing well without fever. the c-reactive protein level had decreased to . mg/l, and the ecg demonstrated nearly complete resolution of the initial brugada-like ecg pattern ( figure ). the patient was discharged to home after the -week hospital stay. diagnosis and treatment of st-segment elevation myocardial infarction during the covid- pandemic present multiple diagnostic and logistic challenges ( ) . myocardial injury, myocarditis, acute coronary syndromes, and arrhythmias have all been described in the setting of covid- infection ( ) . st-segment elevation in the right precordial leads and brugada-like ecg patterns have previously been associated with various conditions (e.g., fever, myocarditis toxicity, metabolic disorders, certain drugs). these brugada-like patterns usually disappear once the inciting event is removed ( ) . a brugada-like ecg pattern presents an additional diagnostic and therapeutic challenge because it may be seen in patients presenting with chest pain, thus mimicking st-segment elevation. atrioventricular nodal re-entrant tachycardia, such as developed in our patient, has similarly been associated with brugada syndrome ( ) . most recently, covid- infection has been described as unmasking brugada syndrome in a patient who presented with syncope ( ). our case is important because it demonstrates the need to differentiate between the brugada syndrome and the brugada-like ecg configuration. given that our patient had a covid- -associated brugada ecg pattern with no history of syncope, observation therapy was recommended because the risk of major adverse cardiac events is low ( ) . covid- manifests mainly as a respiratory syndrome that includes pneumonia and, in the worst case scenario, acute respiratory distress syndrome ( ) . we have also learned that, in a not negligible number of cases, the virus can provoke myocardial ischemia and/or inflammation, with or without an associated respiratory syndrome ( ) . there are already numerous cases of covid- manifesting as st-segment elevation myocardial infarction that have triggered activation of primary percutaneous coronary intervention protocols. the cause of this stsegment elevation is unknown: it has been linked to traditional plaque rupture in those patients who have required coronary angioplasty, but it has been suggested that myocarditis or microvascular thrombosis could be the cause when no obvious thrombus or coronary flow interruption is detected. if all this were not sufficient, here comes brugada type i pattern, interfering with and complicating the lives of interventional cardiologists. indeed, in the case reported by vidovich ( ) , the patient presented with shortness of breath, substernal chest pain, and fever. the electrocardiogram showed a brugada type i pattern in the right precordial leads with no reciprocal changes; the presence of chest pain, shortness of breath, and reduction of systolic left ventricular function, assessed with a -dimensional echocardiogram, led to urgent coronary angiography, which excluded an ongoing acute coronary syndrome. no significant electrolyte imbalance was found. vidovich's ( ) conclusion was that the brugada type i pattern, completely unknown to the patient until this admis- a link between fever and a brugada type i pattern is very well known and has been described extensively ( ) ( ) ( ) . in fact, the international guidelines on sudden cardiac death recommend lowering body temperature as soon as possible in those patients with an established diagnosis of bs, as well as in carriers of the mutations with a proved inducible brugada type i pattern ( ) . the increase in body temperature has indeed been proven to cause a higher degree of inactivation of sodium channels, both mutated and wild ones: in the subjects who are genetically predisposed, this reduced sodium flow can result in a dangerous transmural heterogeneity that is the basis for phase re-entry ventricular arrhythmias and sudden death ( , ) . it would also be of interest understand whether the virus itself could interact directly with the myocardial ion channels and provoke the electrocardiographic modification typical of bs. the take-home message is therefore that patients with bs and concomitant covid- infection should be monitored in the intensive care unit or in the telemetry ward until the fever is resolved, regardless of their respiratory conditions. further research will be needed to help clinicians to navigate this uncharted sea. a -year-old man presented to the emergency department with acute-onset high-grade fevers accompanied by dry cough and shortness of breath that had been ongoing for a week before presentation. he denied any associated nausea or vomiting, diarrhea, sore throat, congestion, or skin rash. of note, he had recently returned from a high-prevalence area for coronavirus disease- (covid- ) within the united states and was in self-quarantine. he was monitoring his symptoms; however, when his shortness of breath was not improving with his asthma medications (albuterol inhaler and cetirizine), he presented to the emergency department. on arrival, he was noted to be febrile at . f, he was tachypneic to breaths/min, he was normotensive at / mm hg, his heart rate was beats/min, and he was saturating % oxygen on room air. physical examination was remarkable for decreased breath sounds bilaterally. his past medical history was significant for mild intermittent asthma. our patient's clinical presentation was concerning for viral or bacterial lower respiratory tract infection. an electrocardiogram revealed normal sinus rhythm with normal pr ( ms) and qrs ( ms) intervals to anticipate and diagnose conduction disturbances associated with the novel coronavirus. to understand the mechanism responsible for high-degree av block associated with covid- without evidence of overt myocarditis. ( figure ). no acute st-t wave changes were noted. a single-view chest radiograph showed blunted costophrenic angles bilaterally with concern for right middle lobe opacity ( figure inflammatory markers were mildly elevated; the ferritin level was mg/ml (normal range to ng/ml), and c-reactive protein was elevated at . mg/dl (normal range to . mg/dl). the procalcitonin level was negative at . ng/ml (normal range to . ng/ml), and thyroid hormone levels were within normal limits. his nasopharyngeal swab tested positive for sars-cov- ribonucleic acid. given the patient's underlying asthma, which predisposed him to an increased risk for pulmonary patients were noted to have cardiac arrhythmias ( ) . covid- involvement of the heart has ranged from asymptomatic myocardial injury to acute coronary syndrome, mild to fulminant myocarditis, stress cardiomyopathy, and cardiogenic shock; however, the mechanism of cardiac involvement is not exactly clear ( ) . furthermore, underlying cardiovascular disease or risk factors and myocardial injury have been shown to portend poor prognosis in these patients ( ) . in this case, we present a patient with moderate covid- infection who showed evidence of transient conduction disturbances with highdegree atrioventricular (av) block. high-degree av block is known to be an uncommon presentation of acute myocarditis in adults, more commonly seen in cardiac sarcoidosis and giant cell myocarditis ( ) . however, because our patient did not have any other overt evidence of myocardial involvement, with normal cardiac biomarkers and a normal echocardiogram, his presentation is unusual and interesting. it is possible that covid- may have caused subclinical myocarditis leading to high-degree av block in this case. ace receptors are abundant in the heart and are present in multiple cell types, including macrophages, endothelial cells, smooth muscle cells, and cardiomyocytes ( ) . further, animal models have shown the presence of ace receptors in sinoatrial nodal cells in rats ( ) , and conduction disturbances and ventricular fibrillation have been noted with overexpression of the ace receptor in experimental mice models ( ) . hence, another possibility is that isolated involvement of the av node and infra-hisian conduction system by sars-cov- may have caused transient high-grade av block. whether this block is secondary to direct viral involvement or is an autoimmune response is unknown at this time. our patient did not have a recurrence of these conduction disturbances after he was started on supportive her medical history included mild asthma, heart failure with preserved ejection fraction, coronary artery disease (percutaneous coronary intervention ), paroxysmal atrial fibrillation (af), hypertension, obesity, and total hip arthroplasty -month prior. her differential diagnosis included bacterial/viral pneumonia, acute on chronic heart failure with preserved ejection fraction, pulmonary embolism, and coronavirus disease- (covid- ) . on arrival she was hemodynamically stable: heart rate beats/min, blood pressure / mm hg, respiratory rate of , and oxygen saturation % on l nasal canula. physical examination noted bilateral rales. chest x-ray showed patchy bilateral consolidations with mild interstitial edema ( figure ) . a computed tomography pulmonary angiogram revealed no pulmonary embolism but bilateral interlobular septal thickening and peripheral ground glass opacities most prominent in the posterior and lower zones. laboratory tests were remarkable for a white blood cell count of . k/ml, absolute lymphocyte count of /ml, the differential for electrical storm in covid- remains broad. myocarditis and cytokine storm may not be universal drivers of cardiac sequelae in covid- . management of these arrhythmias requires consultation with expert, multidisciplinary teams. hemoglobin . mg/dl ( . mg/dl month prior), hyponatremia to mmol/l, ferritin of , ng/ml, nterminal pro-brain natriuretic peptide of pg/ml, and c-reactive protein of . mg/dl (figure a ). remaining laboratory tests were within normal limits. a nasopharyngeal swab was sent for severe acute respiratory syndrome-coronavirus- (sars-cov- ) and respiratory viruses, blood cultures were collected, vancomycin and cefepime were started, and the patient was admitted to a negative-pressure room. were mildly elevated at admission and continued to rise with ast, reaching a peak on day of admission. similarly, alt peaked on day of admission. by discharge, the transaminase levels were downtrending ( figure ). an abdominal ultrasound showed normal liver size ( . cm) with increased liver echogenicity and a nodular contour suggestive of liver fibrosis, likely due to fontan associated liver disease (fald). his cbc was trended with normalization of his platelet count by day of hospitalization. in the emergency room, the patient was hypoxic with oxygen saturations of % on right atrium with accompanying dyspnea. he was placed on to l of oxygen via a nasal cannula, which led to an improvement in the oxygen saturations to low s. ggt (g-glutamyl transferase) being the most common ( ) . this patient had modest transaminitis likely due to the effects of covid- on his underlying fald ( ) . the patient was discharged after a -day hospitali- over the -month period preceding the sars-cov- -related stay-at-home order, a total of patients followed by the achd service at the university of washington medical center with defects of various severities died in an acute setting. in this report we unexpected mortality among patients with achd appears to have acutely increased at a single academic achd center during the sars-cov- pandemic. the ongoing sars-cov- pandemic appears to be contributing to increased achd mortality by delaying patient contact with health care. routine follow-up care for high-risk groups, including those with congenital heart disease, during the sars-cov- pandemic is critical to ensure appropriate triage and care for vulnerable populations. even with prior clinical stability, these populations remain at risk for acute cardiovascular complications and increased mortality. describe a series of acute-setting achd deaths that occurred within a single week at the time of the effective stay-at-home order. acute-onset death was defined as death that occurred either out of the hospital or within h of presentation to a medical facility. with the exception of patient (case ) who was called but did not answer the phone days prior to being found dead at home, none of the patients had a missed clinic appointment since the initiation of the stay-at-home order, and none had made contact with the medical system to report concerning symptoms prior to their deaths. a after the procedure, the impella cp catheter was removed without complications, and the femoral access was closed with the use of proglide closure systems (abbott vascular, santa clara, california). the staff allowed to enter the catheterization lab since its outbreak in italy in mid-february, covid- has spread rapidly, with over , cases and more than , deaths to date. epidemiologic analysis shows that the presence of comorbidities significantly increases mortality: . % in patients with cardiovascular diseases; . % in patients with diabetics; . % in patients with chronic respiratory diseases; % in patients with hypertension; and . % in oncologic patients ( ) . given the high number of infected patients, we often diagnose cardiovascular diseases at different stages during the viral pathology. in this perspective, some selected patients could benefit from treatments that deviate from current guidelines. we report the first case of a patient with covid- and acute coronary syndromes treated in italy for unprotected lmca stenosis with protected percutaneous coronary intervention. the use of the impella cp cardiac assist system to provide left ventricular support during high-risk percutaneous coronary interventions is recommended in such settings, because its efficacy is supported by randomizedcontrolled trials ( ) and large registries ( , ). nevertheless, this case also highlights the importance the patient had no significant medical history. he never smoked. there was no family history of cardiovascular disease (cvd). an early viral panel polymerase chain reaction was negative for multiple respiratory viruses. a severe acute respiratory syndrome-coronavirus- (sars-cov- ) nucleic acid amplification test early and rapid testing is critically necessary in patients with suspected covid- to prevent severe evolution. ecg st-segment elevations in inferior leads have been described in several covid- patients, with variable clinical significance. an accurate evaluation of the true incidence of acute myocardial injury related to covid- requires a standardized definition, which should include a combination of ecg changes, biochemical markers, and imaging abnormalities. given the very low pre-test probability for coronary artery disease and the absence of coronary calcifications on the chest ct scan, a coronary ct angiogram was not indicated, and the patient was not referred for invasive coronary angiography. the patient was treated conservatively, without thrombolytic agents or initiation of the acute coronary syndrome management protocol. the covid- pandemic represents the largest worldwide health care challenge to date. limited but rapidly emerging data have documented the role of cvd in increasing both the risk of infection and the severity of its clinical presentation ( ) ( ) ( ) ( ) . in particular, cvd is associated with a sharp increase in overall mortality, which reaches almost % of patients hospitalized ( ) . however, although such an association can be anticipated to a certain degree (on the basis of existing data from previous outbreaks of influenza and severe acute respiratory syndrome), the incidence of myocardial injury in covid- infection appears to be higher ( ) . furthermore, the definition of covid- -associated "myocardial injury" lacks standardization and is based primarily on elevated (and highly variable) serum levels of cardiac-specific troponins as the single most common defining markers. this myocardial injury has been associated with possibilities. logistically, we now understand that the decision to proceed with angiography carries a significant risk for nosocomial spread of the virus endangering hospital staff. we are also learning that acute kidney injury is quite prevalent and highly associated with mortality in covid- patients ( ). one should think twice before administering intravenous contrast medium in these patients. consensus documents from our professional societies that are based on early covid- observations have resurrected considering the use of fibrinolytic therapy for stemi ( ) . in a setting of limited staffing and resources, and where time to treatment is expected to be significantly delayed, fibrinolytic therapy provides a more rapid and logistically easier approach to reperfusion therapy while reducing staff exposure to infection. however, contraindications to fibrinolytic therapy have to be absent, and stemi mimics have to be excluded. the fibrinolytic strategy is probably most reasonable for hospitals without pci capability or immediate availability. at pci-capable hospitals with adequate staffing, primary pci is still preferred ( , ) . until there is universal availability of rapid testing (< min) for both the virus and the antibodies, our approach to stemi will have to be modified. this is primarily the result of new infection control considerations that will have to be included in our daily workflow. the current door-to-balloon time quality metric should be suspended by hospital quality improvement committees as a measure of system performance because of the current diagnostic and logistical challenges in delivering stemi care. in the american college of cardiology national cardiovascular data registry cathpci registry reporting form, noting a "system delay" as a reason for a prolonged door-to-balloon time will avoid any external quality of care penalties. we now work in the era of covid- stemi care. the patient remained asymptomatic, and no confirmatory tests were performed for the same reason as in the first patient. very late lad artery stent thrombosis was found, and a new des was implanted. the patient was asymptomatic, but because the covid- pandemic had reached its peak, a pre-admission polymerase chain reaction test was performed, with a positive result. the patient had a favorable course and was discharged days later. as antiplatelet therapy. ten days later, prasugrel was replaced by clopidogrel (after antiviral treatment was completed), and the patient was discharged. the covid- pandemic has significantly decreased worldwide interventional cardiology activity. in spain, cardiac catheterization procedures have been reduced by %, with a reduction of % for primary angioplasty ( ) . similar data have been reported in we present case of acute stent thrombosis and very late stent thrombosis cases ( table ) . despite no initial covid- testing in cases, symptoms and subsequent testing ( figures a to d ) supported that the patients were infected at the time of stent thrombosis ( table ) . the patient reported an active lifestyle with a history of playing competitive football and had a body mass st-segment elevation myocardial infarction with a high thrombus burden can appear as the first and only onset of covid- symptoms. plaque rupture in predisposed patients with cardiovascular risk factors can be enhanced by severe inflammation and worsened by prothrombotic characteristics of this new infectious disease. in the course of this covid- pandemic, sars-cov- infection should probably be ruled out in patients with unusual or severe thrombotic and ischemic events, even when there are no symptoms of covid- disease. index of kg/m . he had no significant medical history except for past smoking ( pack-years), which he had quit years before. he had no family history of cardiovascular disease and was taking no medication or drugs. no diagnosis other than a stemi was possible. the initial electrocardiogram displayed a sinus rhythm with an anterior st-segment elevation and q waves with negative t waves in the inferior leads the patient did not develop heart failure, or heart rhythm disturbances, or other complications of myocardial infarction. furthermore, he remained free of covid- disease symptoms. in the context of the covid- pandemic, unusual myocardial infarction presentations, such as in young individuals at low cardiovascular risk, should lead to with t-wave inversion in diii and avf ( figure ). the patient had no past medical history and was not on any medications. to describe the management of patients with refractory ards requiring coronary angiography. to describe the feasibility of coronary angiography with the patient in prone position. the differential diagnosis included acute myocardial infarction, myocarditis, and takotsubo syndrome. there was no evidence of obstructive coronary disease, and the final diagnosis was myocarditis, although we were not able to perform cardiac magnetic resonance in this highly unstable patient. with a rapid spread worldwide, covid- has become a public health emergency of international concern ( ). the clinical course of sars-cov- infection is mostly characterized by respiratory tract symptoms, including fever, cough, pharyngodynia, fatigue, and complications related to pneumonia and ards, often in a patient in prone position, the geometry and orientation of the heart as well as the coronary anatomy do not allow to obtain perfectly symmetric pictures of the coronary arteries using usual views. consequently, the interpretation of coronary angiography was simply done following the heart's shape. with unchanged cranial/caudal tilts ( , ) or using the double-inversion technique to normalize all angiographic pictures such as in a left-located heart ( ) is usually enough to perform and analyze coronary angiography in such patients. finally, even though we did not perform percutaneous coronary intervention, performing percutaneous coronary intervention with a patient in prone position would not be a critical issue for an experienced operator. pandemic, the most plausible diagnosis seemed to be a severe acute respiratory syndrome-coronavirus- (sars-cov- ) infection. tables and summarize the biochemical tests and atrial blood gas analysis before, during, and after amiodarone therapy. figure shows the illness clin- no adverse events were reported. the patient was discharged on day . infection in cell cultures and mouse models ( , ) . amiodarone is a widely available, low-cost antiarrhythmic drug that in the past has been considered as a possible antiviral medication ( ) . amiodarone and its main metabolite (mono-n-desethyl amiodarone) were shown to inhibit the entry of filoviruses (a family of single-stranded, negative-sense rna viruses that includes ebola virus) at the same serum concentration found in patients treated for arrhythmias ( , ) . amiodarone also proved able to remain to be investigated, and drug interaction with other treatments (e.g., hydroxychloroquine, lopinavir/ritonavir, atazanavir, and darunavir/cobicistat) are major concerns ( ) . notably, amiodarone toxicity at follow-up visit, days after discharge, the patient was asymptomatic. in this case, amiodarone was given for research purposes in a hospital setting. this is an approach still under investigation. do not try this at home. to diagnose acp in patients with sars-cov- -related ards. to appreciate potential role of almitrine in improving oxygenation and rv function. to understand sars-cov- -related atypical type of ards. medical history included only an overweight with a body mass index of . kg/m . the differential diagnosis included pulmo- and septal dyskinesia disappeared ( figure c ). moreover, rv global longitudinal strain improved from - . % to - . % ( figure d ). twelve hours following almitrine infusion, rvswi decreased from . to . g/m/beat/m . the clinical spectrum of sars-cov- -related cardiovascular complication includes myocarditis, pericarditis, vasoplegia, rv failure, and acute coronary syndromes ( , ) . in this case, we highlight the rv dysfunction another explanation is the impact of ards and mechanical ventilation on the rv. acp is a well-known complication of ards despite a protective ventilation, with an incidence of %. hence, acp may be related to a high driving pressure, leading to an increased rv afterload ( ) . moreover, the patient was on norepinephrine, which may increase rv afterload. another explanation is that hypoxia could lead to rv dysfunction in its own right ( ). ventilation-to-perfusion ratio ( ) . moreover, previous studies in the s showed that at a low dose, the deleterious effect on pulmonary vascular resistance was negligible, especially when associated with nitric oxide ( ) . hence, we hypothesized that almitrine use in the case of sars-cov- atypical ards might be useful. in the present case, almitrine infusion was associated with rv function improvement and decrease in pulmonary vascular resistance. this is probably due not only to a better oxygenation, but also to a better distribution of pulmonary vascular flow to aerated lung areas. before almitrine infusion, we observed a high rvswi with a normal-to-low range of ci, suggesting a hemodynamic disconnection between the rv and left ventricle. the reduction in rv afterload by almitrine infusion resulted in an improvement in this disconnection (decreased rvswi and improved ci). as almitrine infusion could induce reversible lactic acidosis and hepatic dysfunction ( ) to describe high-risk clinical features in a patient on durable lvad support who developed covid- . to illustrate potential complications and clinical dilemmas in managing covid- in a patient supported with a durable lvad. reverse transcription polymerase chain reaction results for severe acute respiratory syndrome-coronavirus- (sar-cov- ) was positive at the initial emergency department visit and at the authors' institution. serial laboratory and imaging tests are detailed in table . several markers of disease severity were abnormal including absolute lymphocyte count, c-reactive protein level, and cardiac enzymes. chest radiographs showed bilateral infiltrates concerning for atypical pneumonia (figure ). the patient was quarantined in a negative-pressure intensive care room. the host response to covid- infection is often localized in the lung parenchyma, but a surge in proinflammatory cytokines can occur ( , ) . known as a "cytokine storm," this phenomenon is described in dynamics. we should closely monitor for: ) rv failure and need for inotropic support; ) drops in lvad speed or suction events, low flow, or pulsatility index events due to vasoplegia associated with infection. to limit health care workers' exposure to covid- , nonessential testing such as echocardiograms, the antimalarial medication hydroxychloroquine, which was chosen as the initial treatment agent for our patient, was shown to reduce in vitro sar-cov- cell entry, and a retrospective study suggested its clinical benefit in covid- ( , ) . a major side effect is qtc prolongation, so the present protocol provides monitoring guidance of this complication. immunomodulatory biological agents such as tocilizumab are reserved for severe covid- , defined by the values in bold are in-hospital values that were consistent with baseline values. *last visit values were the latest values obtained within the previous months. baseline ldh, wbc, platelet, absolute polymorphonuclear leukocytes, and absolute lymphocytes were recorded as an average of the previous values measured within year. †this patient was placed on ventilator support on the night of hod and was given tocilizumab on the evening of hod . ‡this patient experienced pulseless electrical activity arrest after the return of spontaneous circulation. krelative change is the percentage of increase or decrease from baseline value. alt ¼ alanine aminotransferase; ards ¼ acute respiratory distress syndrome; ast ¼ aspartate aminotransferase; bnp ¼ b-type natriuretic peptide; ck-mb ¼ creatine kinase mb; cvp ¼ central venous pressure (obtained from right heart catherization at baseline, and from central venous line in the hospital); egfr ¼ estimated glomerular filtration rate; fio ¼ fraction of inspired oxygen; hod ¼ hospital day; ldh ¼ lactate dehydrogenase; lvad ¼ left ventricular assist device; map ¼ mean arterial pressure (obtained from doppler or arterial line); pao ¼ arterial partial pressure of oxygen; wbc ¼ white blood cell. presence of both worsening respiratory failure and a cytokine storm as shown by increasing inflammatory markers. still, caution is warranted as major adverse effects of tocilizumab include infection, infusion reactions, dyslipidemia, neutropenia, and potential malignancy ( ) . patients on lvad support are particularly vulnerable to infectious complications due to the inherent presence of hardware and driveline finally, prone ventilation is beneficial in cases of severe ards. the maneuver has been effective in improving lung mechanics and gas exchanges, and in some cases, it may prevent the need to escalate to venous-venous extracorporeal membrane oxygenation ( , ) . although there are no published outcomes, early experience in wuhan, china indicates that prone position was widely used in patients with covid- -related severe ards with possible benefits ( ) . nonetheless, it may be prohibitive in heart failure patients on lvad support. a -year-old woman presented with productive cough, fatigue, fever, and diarrhea for the previous days. physical abbreviations as in figure . ( ) . stress cardiomyopathy has also been reported with viral infections ( ) . histological studies have shown mild inflammatory infiltration ( , ) , and it is possible that heightened inflammation with viral infections, particularly that seen with covid- , may contribute to development of stress cardiomyopathy. overall, the prognosis of stress cardiomyopathy is favorable, with the majority of patients fully recovering lv function by months ( ). twitter: @ferrasdabbagh . he had a history of hypertension and was taking lisinopril. the differential diagnosis included sars-cov- causing severe ards and acute cardiac injury from direct viral toxicity (i.e., myocarditis), acute coronary syndrome (acs), demand ischemia, and stress cardiomyopathy. prevalence and prognostic implications of cardiac injury (defined as troponin elevation > th percentile upper reference limit) in covid- . considerations for differentiating causes of cardiac injury in covid- . management strategies for myocarditis and severe ards in covid- . and mortality benefit in animal models ( ) . improved airway inflammation has also been observed in animals treated with aris ( ) . other viral infections such as influenza and respiratory syncytial virus were considered, but the pre-test probability for covid- was high because other residents at the facility had been diagnosed with covid- recently. in the emergency department, the patient was tachypneic with an initial oxygen (o ) saturation %. table lists the results of his initial laboratory testing including normal levels of ferritin, procalcitonin, interleukin (il)- , and il- . levels of c-reactive protein, lactate dehydrogenase, and troponin were elevated. there was a reduced white blood cell count without lymphopenia. a chest radiograph had no air space or interstitial infiltrates (figure ). there was a single low-flow lvad alarm noted days prior to presentation. based upon the adequate room air saturation, absence of pulmonary infiltrates, and minimally abnormal inflammatory markers, the patient was classified as having a mild case of covid- . due to persistent breathlessness, hydroxychloroquine was initiated on day with qtc monitoring. to the best of our knowledge, this is the first re- in the current covid- pandemic, lopinavir/ritonavir was studied in a randomized, controlled trial in table ) . the patient was discharged to his nursing facility on hospital day once a room was available where he could be quarantined, and he continued to feel well days later. mahmood et al. to make a diagnosis of fulminant myocarditis concomitant with covid- pneumonia. to understand the value of serial cardiac magnetic resonance after myocarditis due to covid- . sinus tachycardia ( beats/min) with negative t waves from v to v . to be able to arrive at the differential diagnosis of acute cardiac dysfunction in the setting of severe covid- disease early after heart transplantation. to understand the need for individualized management, balancing risks of infection and rejection in heart transplantation recipients with severe infections early after transplantation. was discharged to isolation at home with pulse oximetry and plans for daily telemedicine assessments. three days later the patient presented to the emergency department with rapidly progressive respiratory distress and hypoxia. the patient had a history of end-stage non- figure . the patient reported continued gradual recovery by weekly telemedicine assessments after discharge. he had a history of pityriasis lichenoides chronica. he had no personal or family history of congenital heart disease, immunodeficiency, or autoimmune disease. the differential diagnosis included viralinduced myocarditis or underlying cardiomyopathy unmasked by an acute viral illness. table ) . the patient has had no recurrent episodes of chb since day of admission, and a repeat echocardiogram on day of admission demonstrated lownormal biventricular systolic function. and conduction abnormalities appears to be a rare manifestation of sars-cov- infection in children ( ) ( ) ( ) . nonetheless, evaluation for myocardial injury may be warranted in pediatric patients with symptomatic sars-cov- infection, particularly in patients whose clinical symptoms (e.g., dyspnea, hypoxia) seem out of proportion to chest imaging findings. on autopsy, histopathologic examination of the heart showed mild to moderate myocyte hypertrophy with mild to moderate diffuse interstitial and perivascular fibrosis (figures a and b) . the impact of influenza co-infection in this patient with covid- must also be considered because this virus is known to contribute to cardiovascular morbidity and mortality secondary to up-regulation of the inflammatory response and endothelial dysfunction ( ) . as such, influenza a likely had significant effects on her cardiac functioning. coinfection with sars-cov- is of great concern, with limited data delineating the the patient's medical history showed arterial hypertension, dyslipidemia, and impaired fasting blood sugar. covid- has extrapulmonary and cardiovascular manifestations. covid- may be associated with exaggerated inflammatory response with an abnormal activation of coagulation, so a screening of coagulation setup may be indicated. covid- may show up with takotsubo syndrome. the differential diagnosis included acute myocardial infarction, takotsubo syndrome, myocarditis, and coronary embolism. the patient was transferred to our center for an urgent coronary angiography, which revealed nonsignificant coronary atherosclerosis. figures and , videos and ). our priority was to treat the patient with enoxaparin , iu twice daily as per the patient's weight. during the first days of hospitalization, and taking into consideration that the patient was hypotensive (systolic blood pressure: mm hg; mean blood pressure: < mm hg), we treated the patient with chest radiography was repeated in the following days and showed progressive reduction of interstitial pneumonia. also, blood test results revealed an improvement of inflammation indexes ( table ) . on day of hospitalization, the nasopharyngeal swab was repeated, with a positive result. the first negative result was registered on day . on the th day, we performed another transthoracic echocardiography, which showed the resolution of the thrombi ( figure ) and a complete restoration of lvef ( %) (video ). his past medical history was notable for type diabetes mellitus, remote prostate cancer, and ventricular tachycardia. covid- and concern over prolonged separation from his family. our service is modeled after previously published "e-consultation" workflow recommendations in "peacetime" prior to the sars-cov- outbreak ( ). in phase , we implemented these processes, and all emergent cases were treated as puis. as we approach phase , our processes continue to undergo iterative improvements and all cases coming to the ccl will be considered puis. our approach to stat and routine tee is outlined in remote monitoring is used for electrophysiology clinic device checks, with patients triaged to present for evaluation if they develop concerning arrhythmias, heart failure alerts, or device-related issues. *vt storm that has failed medical treatment including at least antiarrhythmic drugs (including propranolol), treatment of underlying reversible condition if present (qtc prolongation due to ischemia, medications, or metabolic/electrolyte imbalance), general anesthesia, and left stellate ganglion block (if available). †not reversible or fails to respond to chronotropic drugs such as isoproterenol, dopamine, and/or scopolamine, and temporary pacing cannot be safely maintained in an intensive care setting. in this scenario a screw-in active fixation lead connected to an externalized generator or an active fixation temporary pacing lead may be considered depending on the patient's clinical condition and could be performed in the intensive care setting under fluoroscopic guidance (if available) or in an operating room with negative airflow capabilities and fluoroscopy. cied ¼ cardiac implantable electronic devices; eos ¼ end of service; eri ¼ elective replacement indicator; vt ¼ ventricular tachycardia. in the wake of this pandemic, formal medical student and trainee didactics were disbanded to allow for social distancing. additionally, several states expe- her past medical history included hypertension and diabetes mellitus. the differential diagnosis included communityacquired pneumonia, atypical pneumonia, and coro- figures a and b ). the patient was started on therapeutic enoxaparin and was closely monitored for hemodynamic instability. she declined to take hydroxychloroquine, recommended by some experts for management for covid- . she remained hemodynamically stable and was transitioned to oral anticoagulant therapy (apixaban) with plans to continue anticoagulation for months. the covid- outbreak is an unprecedented global public health challenge. since the end of december , when the first cases of sars-cov- infection were detected in wuhan, china, the disease has spread exponentially ( ). on january , , the world health organization declared covid- , the disease caused by the novel coronavirus, a public health emergency of international concern and later officially upgraded it to a global pandemic. as of april , , more than , , confirmed cases from more than countries and more than , deaths have been documented worldwide. the projected u.s. death toll is > , , with an estimated total burden of more than million covid- cases. in approximately % of cases, fever is the most common presentation, followed by cough ( %), vomiting ( %), and diarrhea ( . %) ( ) . in up to % of patients, the natural course of the disease is complicated by severe interstitial pneumonia, which can lead to acute respiratory distress syndrome, multiorgan failure including acute kidney injury, dissemi- to suspect pe early in the disease process in confirmed or suspected covid- patients. to identify high-risk patients early and to offer appropriate therapies while mitigating patient and provider risk. the patient was managed with intravenous unfractionated heparin (ufh) and dobutamine; infection. cdt is associated with early improvement in rv function and hemodynamics in deteriorating patients with lower doses of tpa ( , ) ; however, pui approximately times less frequent ( , ) . importantly, a substantial proportion of the thrombotic events were diagnosed very early during the hospital stay, suggesting that they had already occurred before admission ( ) . in view of the previously mentioned (preliminary) findings, and although it cannot yet be concluded with safety that the thrombosis risk among patients with severe covid- is substantially higher than that of patients with severe infection caused by other bacterial or viral pathogens ( , ) , thrombotic events are very likely to be a key aspect of covid- -associated morbidity and mortality ( ) . it is therefore now necessary to make the patient's medical history was notable only for obesity (body mass index kg/m ) and type diabetes. the primary differential diagnosis for the patient's the usual risk stratification schema for acute pe rely on a combination of hemodynamic clinical parameters, such as hypoxemia, tachycardia, and hypotension along with serum biomarkers, such as troponin or brain natriuretic peptide, followed by confirmatory imaging tests ( ) . severe covid- -related ards may present with many similar hemodynamic and biomarker derangements masking underlying vte. illness. figure ). an axillobifemoral bypass was performed, followed by therapeutic anticoagulation with good initial results. the patient died days after surgery from a major hemorrhage. case . the third patient was a -year-old male with history of hypertension, diabetes, and coronary artery disease ( table ) who was admitted for hypoxic ct angiography of patient shows a nonobstructive thrombus formation of descending aorta (arrow) in an axial view (a) and a sagittal view (b). disease. a recent paper attributes this state "to excessive inflammation, platelet activation, endothelial dysfunction, and stasis" ( ) . others have suggested that formation and polymerization of fibrin are responsible for this hypercoagulability ( ) . therefore, recent recommendations insist on thromboprophylactic measures to prevent thromboembolism ( , , ) . a recent publication found evidence of the presence of virus in endothelial cells ( ) . one explanation is that the angiotensin-converting enzyme receptor that the virus uses to infect cells is widely expressed in endothelial cells. this causes endotheliitis, which could explain why covid- patients seem prone to venous and arterial thrombosis. this paper ( ) blockade may also be considered ( ) . it should be noted that mild ards may be managed with noninvasive forms of ventilation. however, during the present pandemic, modifications to usual critical care may be necessary. given concern for viral transmission, current recommendations advise it is also important to monitor the patient's driving pressure, or difference between the peep and plateau pressure, as increased driving pressures have been associated with higher mortality in ards ( ) . with a basic understanding of these fundamentals, it is possible for all cardiologists to provide safe and effective care for our patients with covid- . as many of us prepare to use skill sets long forgotten, it will be important to remember to ask for help when needed. one of the few bright spots in this pandemic has been the resurgence of interdisciplinary team- and is thought to protect against lung injury. these functions may be due to differences in the location of the ace proteins, transmembrane or in the plasma ( ) . the ace gene is located on the x chromosome, which suggests that women might have higher ace levels and thus be protected against more severe disease compared to men ( ) . there has been recent concern in the cardiology community about the possible negative effect of italy, as it has done in the past, will improve its health and economic systems after this tragedy. probably nothing will be like before, and this catastrophe will be a great opportunity to further improve an efficient and effective national universal health system. heroes, we look like prey in heroes' capes. that kind of bravery, that work integrity, is not boundless. no one is so fearless or short-sighted as to discount all risks. when i try to figure out how i feel in this moment, the italian motto "andrà tutto bene" ("everything will be alright") that has been viral since the onset of the the ccl nursing staff was reinforced to speed up procedures. all noncritical equipment or supplies were removed from the ccl to facilitate cleaning and disinfection procedures. availability of ppe is a concern, so we created sets of ppe to best manage available resources: a mid-level kit and a fullprotection kit for suspected and confirmed cases. despite the concern of the medical community, we believe society has largely adhered to the social isolation recommendations, as we are looking at a constant drop in admissions to intensive care units and an increase in patients successfully discharged. the availability of masks for everyone is still not a reality as we are conceiving the first draft of a plan to reduce restriction measures. subsequently, as we are receiving more papers, we have decided to divide jacc: case reports publications into sections: acute coronary syndromes, heart failure, arrhythmias, thromboembolic events, and stories from the front line, in the format of "voices of cardiology" papers. all these papers have been highlighted in this issue ( ) . recognizing the value of not overloading our audience with publications, and in an effort to keep the quality high and up to the standards of jacc journals, we accepted approximately % to % of the manuscripts submitted. we selected the best of the best cases and brought together world-renowned specialists to write editorials. although we understand that clinical cases have been of crucial importance for our understanding of covid- , it is of equal importance that they cannot substitute for large studies and pharmacological trials. therefore, unless we were dealing with an impressive side effect of a medicine, we have been very cautious in publishing pharmacological evidence, as large trials would prove the benefits and side effects of these medicines currently under trial. another important task of jacc: case reports is that to ease navigation on the acc covid- hub, its content was organized into sections on clinical guidance, practice considerations, and frontline perspectives. given the novelty and rapidity of the covid- pandemic, most of the initial content was based on analyses of frontline experiences and expert opinion. the hub executive team and sqc worked to ensure that the content struck a balance between reasonable, actionable suggestions and acknowledgment that more rigorous research was needed to better inform the best approach to covid- management. going forward, the hub will continue to generate content but now turn its attention to highlighting the growing peer-reviewed research on covid- and cv disease. the acc has commissioned a task force to promote research in this area, and the hub will serve as a primary dissemination platform, in conjunction with jacc and other cardiology-focused journals. in addition, the hub will highlight best practices and frontline experiences from its membership on "reopening" protocols. with projections that covid- will ebb and flow worldwide over the next several years, our membership will need to navigate the best way to continue to treat cv disease during this time. the acc covid- hub has proved to be a useful resource to assembling and distributing information broadly during a rapidly evolving pandemic. lessons learned include the need to build a nimble process to commission, organize, and distribute content, an ability to engage with experts to generate content, a method to closely monitor of member and community needs to inform content development, and an emphasis on highlighting rigorously conducted research and expert consensus over mere opinion and speculation. sars-cov- infection in children available at: https:// picsociety.uk/news/pics-statement-regardingnovel-presentation-of-multi-system-inflammatorydisease covid- and the heart sars-cov- and viral sepsis: observations and hypotheses myocardial localization of coronavirus in covid- cardiogenic shock: covid- does not spare the heart cardiac involvement in a patient with coronavirus disease (covid- ) the cytokine release syndrome (crs) of severe covid- and interleukin- receptor (il- r) antagonist tocilizumab may be the key to reduce the mortality epidemiology of covid- among children in china cardiac 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with novel coronavirus pneumonia acute pulmonary embolism and covid- pneumonia: a random association? clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study direct oral anticoagulants for the treatment of left ventricular thrombus-a new indication? a meta-summary of case reports doacs in left ventricular thrombosis decision making in advanced heart failure: a scientific statement from the american heart association informing candidates for solid-organ transplantation about donor risk factors united states public health service. phs guideline for reducing human immunodeficiency virus, hepatitis b virus, and hepatitis c virus transmission through organ transplantation disclosure of infectious risk to heart transplant candidates: shared decision-making is here to stay decline of increased risk donor offers on waitlist survival in heart transplantation heart expand continue access protocol prevalence of comorbidities in the middle east respiratory syndrome coronavirus (mers-cov): a systematic review and meta-analysis acute myocardial infarction after laboratoryconfirmed influenza infection clinical characteristics of coronavirus disease in china integrating inpatient electronic consultations in cardiology fellowship clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china covid- and the cardiovascular system catheterization laboratory considerations during the coronavirus (covid- ) pandemic: from acc's interventional council and scai quote from a venture capitalist meeting in california covid- and health care's digital revolution making emergency supplemental appropriations for the fiscal year ending september , , and for other purposes association of veterans health administration home-based programs with access to and participation in cardiac rehabilitation cardiac arrest deaths at home in new york city have increased by a startling % long distance 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mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis care for critically ill patients with covid- for the acc critical care cardiology working group. positive pressure ventilation in the cardiac intensive care unit driving pressure and survival in the acute respiratory distress syndrome key words acute respiratory distress syndrome, coronavirus, coronavirus disease- , mechanical ventilation available at: http:// globalhealth .org/covid clinical characteristics of patients who died of coronavirus disease in china clinical characteristics of coronavirus disease in china sex differences in public restroom handwashing behavior associated with visual behavior prompts gender differences in the utilization of health care services characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for figure sex differences in risk factors and mortality from the covid- 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worries doctors: where are the heart attacks and strokes? reduction in st-segment elevation cardiac catheterization laboratory activations in the united states during covid- pandemic sented at: international conference and exhibition on pediatric cardiology professor sir magdi yacoub and the aswan heart centre pitfalls of judgment during the covid- pandemic covid- faq's in pediatric cardiac surgery resource allocation and decision making for pediatric and congenital cardiac catheterization during the novel coronavirus sars-cov- (covid- ) pandemic: a u.s. multiinstitutional perspective covid- : crisis management in congenital heart surgery considerations for triaging lessons from sars: a retrospective study of outpatient care during an infectious disease outbreak effects of response to ebola outbreak on deaths from malaria, hiv/aids, and tuberculosis, west africa critical care utilization for the covid- outbreak in at the epicenter of the covid- pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation covid- and italy: what next? italy's health performance, - : findings from the global burden of disease study coronavirus infections-more than just the common cold the obelisk press-seurat editions, ; new address for correspondence: dr e-mail: george.collins@ucl.ac.uk. twitter: @drgeorgecollins clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china the use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease (covid- ): the experience of clinical immunologists from china exploring personal protection during high-risk pci in a covid- patient: impella cp mechanical support during ulmca bifurcation stenting for the american college of cardiology's interventional council and the society for cardiovascular angiography and interventions. catheterization laboratory considerations during the coronavirus (covid- ) pandemic: from the acc's interventional council and scai reacquainting cardiology with mechanical ventilation in response to the covid- pandemic the covid- pandemic and cardiovascular complications: what have we key: cord- -p twx a authors: lau, arthur chun-wing; yam, loretta yin-chun; so, loletta kit-ying title: management of critically ill patients with severe acute respiratory syndrome (sars) date: - - journal: int j med sci doi: nan sha: doc_id: cord_uid: p twx a severe acute respiratory syndrome (sars) is frequently complicated with acute respiratory failure. in this article, we aim to focus on the management of the subgroup of sars patients who are critically ill. most sars patients would require high flow oxygen supplementation, – % required intensive care unit (icu) or high dependency care, and – % developed acute respiratory distress syndrome (ards). in some of these patients, the clinical course can progress relentlessly to septic shock and/or multiple organ dysfunction syndrome (mods). the management of critically ill sars patients requires timely institution of pharmacotherapy where applicable and supportive treatment (oxygen therapy, noninvasive and invasive ventilation). superimposed bacterial and other opportunistic infections are common, especially in those treated with mechanical ventilation. subcutaneous emphysema, pneumothoraces and pneumomediastinum may arise spontaneously or as a result of positive ventilatory assistance. older age is a consistently a poor prognostic factor. appropriate use of personal protection equipment and adherence to infection control measures is mandatory for effective infection control. much of the knowledge about the clinical aspects of sars is based on retrospective observational data and randomized-controlled trials are required for confirmation. physicians and scientists all over the world should collaborate to study this condition which may potentially threaten human existence. in , an outbreak of severe acute respiratory syndrome (sars) caused by the sars-associated coronavirus involved countries and patients, resulted in deaths [ ] . thereafter, sars has re-emerged sporadically in both laboratory and community settings. its clinical spectrum varies from minimal respiratory symptoms to severe respiratory failure. we have previously contributed to an overview on the contemporary treatment of sars [ ] , and the whole topic has also been reviewed elsewhere [ ] . in this article, we aim to focus on the management of a subgroup of critically ill sars patients with more significant respiratory failure. critically ill sars patients frequently demonstrate the following clinical features: persistent pyrexia (occasionally from admission but often recurring after an initial period of defervescence), tachycardia (infrequently bradycardia), tachypnoea and significant oxygen desaturation. more than onethird of all the sars patients required high flow oxygen therapy [ ] , - % required intensive care unit (icu) admission or high dependency care, and - % developed acute respiratory distress syndrome (ards) [ , ] . the clinical course of some of these patients can progress relentlessly irrespective of all attempts at pharmacological treatment, eventually resulting in septic shock and/or multiple organ dysfunction syndrome (mods). lymphocytopaenia, neutrophilia and thrombocytopenia are frequently seen in critically ill sars patients. neutrophilia could be due to sars per se, to superimposed infection or related to corticosteroid administration. pancytopaenia, if present, could be due to haemophagocytosis syndrome [ ] or reactivation of latent human parvovirus (unpublished data). prolonged activated partial thromboplastin time and picture of disseminated intravascular coagulation has been reported [ ] . coinfections with other agents including chlamydia-like agents [ ] , metapneumovirus [ ] or influenza virus (unpublished data) have been reported. persistent and increasing elevations of creatine kinase, lactate dehydrogenase, and transaminases levels are common [ , , ] . associated lung damage is believed to be the result of a virally-triggered inflammatory reaction mediated by a host of cytokines [ , ] . in sicker patients, levels of pro-inflammatory cytokines (il- beta, il- , il- , il- , tnf-α) and tgf-β were higher, with slower decline on clinical recovery [ ] . radiographic abnormalities in the chest usually progress upwards from initial unilateral or bilateral lower-to mid-zone peripheral ground-glass shadows, to focal, multifocal or diffuse consolidation. peak radiographic changes occurred at . days after fever onset, with . % showing two peaks at . and . days, and % showing relentless progression [ ] . cavitation is rare but may be associated with superimposed infection in patients with a prolonged illness course and who are mechanically ventilated [ ] . high-resolution computer tomography (hrct) of the thorax showed focal ground-glass and scattered "crazy paving" patterns at presentation, followed by development of interstitial thickening, consolidation, pleural reaction, and scarring and fibrosis in later stages [ , ] . small (< cm) pulmonary cysts may be detected even if the patient is not receiving ventilatory assistance [ ] . subcutaneous emphysema, pneumothoraces or pneumomediastinum are distinct complications of severe sars [ ] . hrct features of late-stage ards caused by sars are similar to those arising from other causes [ ] . lung biopsy and postmortem studies [ , ] showed acute-phase diffuse alveolar damage (dad), airspace edema, bronchiolar fibrin, increased numbers of interstitial macrophages (with focal haemophagocytosis) and alveolar macrophages in patients with shorter duration (< days) of illness. on the other hand, histology after > days of illness showed organizing-phase dad with increased fibrosis, hyperplasia of type ii pneumocyte, squamous metaplasia, multinucleated giant cells, and acute bronchopneumonia [ ] . in patients who died late in the course of this disease, high loads of viral rna were detectable by reverse transcriptase polymerase chain reaction (rt-pcr) in the lungs, bowel, lymph nodes, spleen, liver, and kidneys [ ] . general principles anti-bacterial therapy for community-acquired pneumonia in accordance with standard guidelines [ ] should always be administered before laboratory confirmation of sars-cov infection. where effective anti-viral therapy is available, it should be started as early as possible after diagnosis, and even empirically if suspicious clinical features and especially epidemiological links are present. since critically ill patients are deemed to have already progressed from the viral replicative phase to the immunopathological phase [ ] , concomitant institution of an immunomodulatory therapy should also be considered [ ] . since there are no consensus regarding the most optimal treatment regimen in these respects, we will thus review the more commonly used agents and discuss their relative merits based on published reports. when respiratory failure eventually sets in, oxygen supplementation, assisted ventilation and intensive supportive treatments will be required. ribavirin was the most commonly used empirical antiviral agent for sars. it is a broad-spectrum purine nucleoside analogue which inhibits both rna and dna viruses by interfering with nucleic acid synthesis. there is experimental evidence to show that it has immunomodulatory effects in the treatment of mouse coronavirus hepatitis [ ] . subsequently, it was found that ribavirin has no direct in vitro activity against sars-cov [ ] . higher doses given intravenously resulted in more frequent and severe adverse effects including haemolytic anaemia, elevated transaminase levels and bradycardia [ ] . lopinavir-ritonavir co-formulation (kaletra ® , abbott laboratories, usa) is a protease inhibitor for the treatment of human immunodeficiency virus (hiv) infection. it can inhibit the coronaviral proteases, thus blocking the processing of viral replicase polyprotein and preventing the replication of viral rna. ritonavir inhibits lopinavir metabolism thus increasing its serum concentration, but it has no activity against sars-cov. in a retrospective analysis in hong kong [ ] , patients who had received kaletra as rescue therapy together with high dose corticosteroids had no difference in rates of oxygen desaturation, intubation and mortality compared with a matched cohort. however, when given as initial treatment in combination with ribavirin in another subgroup of patients, there were significant reductions in the need for rescue pulsed corticosteroid therapy, intubation rate and overall mortality. in addition to the prevalence of diarrhoea among these patients which may render oral drugs more appropriate and useful, synergism between kaletra and ribavirin might have contributed to the benefits since either drug alone has only weak anti-viral activities. another hong kong study of sars patients treated with a combination of lopinavir/ritonavir and ribavirin compared with patients (historical controls) treated with ribavirin only showed that adverse clinical outcomes (ards or death) were significantly lower in the treatment group than in the historical controls at day after symptom onset. further randomised placebo controlled trials are required [ ] . interferons are a family of cytokines with important roles in the cellular immune response. interferon α has been used for sars treatment in china and canada [ , , ] . in an open-label uncontrolled study [ ] , nine patients treated with corticosteroids plus interferon alfacon- (infergen ® , intermune inc., usa) showed better oxygen saturation, faster radiographic resolution and lesser need for supplemental oxygen compared to given corticosteroids alone. in vitro testing showed that interferon β was more potent than interferon α or γ, being effective even when administered after sars-cov infection in cell culture [ ] . traditional chinese herbal medicine has been used concomitantly with other drugs to treat sars in mainland china with good results reported [ ] . however, its value in critically ill patients has not been reported. glycyrrhizin, an active component derived from liquorice roots, is effective against sars-cov in vitro [ ] . its clinical utility remains uncertain. another herbal compound, baicalin, also demonstrates anti-sars-cov activity in vitro (unpublished data). in the absence of an effective antiviral agent in the outbreak, most physicians had opted to use immunomodulatory agents, most commonly corticosteroids, in the treatment of sars [ , , , ] it is generally agreed that corticosteroids should not be used during the early viral replicative phase, and that its administration should best coincide with the onset of the immunopathological phase [ ] . clinicoradiological surrogate criteria have been used to indicate the onset of this immune hyperactive phase, thus providing a practical guide to the timing of starting corticosteroids [ ] . corticosteroid dosages should be high enough, especially in the severe cases, to abort the cytokine storm, and maintained for long enough to prevent the rebound phenomenon [ , , ] . this may be achieved by using a weightadjusted [ ] and radiographic extent-modified dosages [ ] for a period of - weeks. in one-third to half of sars patients, fever may recur while on immunomodulatory treatment due to superimposed infections, too rapid tailing of corticosteroids or persistently severe and uninhibited cytokine storm. empirical anti-pseudomonal antibiotics should then be given first. if there is no apparent clinical response, opportunistic infections like fungal infection should be excluded. if fever is accompanied by obvious respiratory deterioration in the absence of superimposed pulmonary or systemic infection, most patients can be presumed to be suffering from a severe recrudescence of the sars illness. in such critically ill sars patients, further escalation of immunomodulation is warranted. such deterioration could sometimes occur very rapidly; immediate administration of pulsed methylprednisolone therapy at - mg per day intravenously for days, followed by tapering doses in the subsequent weeks, has been associated with improved outcome [ , ] . up to one-third to one-half of critically ill sars patients may benefit from this strategy [ , , ] . because radiographic abnormalities may lag behind clinical improvement, persistent radiographic shadows per se, when accompanied by clinical improvement, do not warrant additional corticosteroids [ ] . human gamma immunoglobulins have been used in selected sars patients who continued to deteriorate despite treatment [ , ] . an igm-enriched immunoglobulin product (pentaglobin ® , biotest pharma gmbh, germany) has been used in hong kong and mainland china [ , , ] . pentaglobin at mg/kg/day for three days given to patients who deteriorated despite repeated rescue methylprednisolone and ribavirin therapy had shown some improvement in radiographic scores and oxygen requirement [ ] . it has been reported that the use of combined methylprednisolone and highdose intravenous immunoglobulin ( . g/kg) daily for three consecutive days in probable sars patients with acute lung injury (ali) or ards had resulted in lower mortality and a trend towards earlier recovery [ ] . randomized controlled trials in larger numbers of patients are required to confirm its efficacy. based on the assumption that the neutralizing immunoglobulins in convalescent plasma can curb increases in viral load, convalescent plasma collected from recovered sars patients has been used in hong kong to treat severely ill patients not responding to corticosteroids. some clinical benefits were reportedly observed in a small number of patients [ ] . despite all efforts, at least % of sars patients would still develop acute hypoxemic respiratory failure, with up to % requiring supplemental oxygen [ ] overall, - % of patients had been admitted into icu, and - % eventually required intubation and mechanical ventilation [ ] . both non-invasive and invasive ventilatory support has been applied to critically ill sars patients. niv delivers continuous positive airway pressure (cpap) or bi-level pressure support through a tight-fitting facial or nasal mask. it was commonly employed in many chinese hospitals [ , , , , ] and our own centre in hong kong [ , , ] . early application may be beneficial because it could rapidly improve vital signs, oxygenation and tachypnoea [ , ] , and may reduce the need for increasing dosages of corticosteroids for progressive respiratory failure. it could avoid intubation and invasive ventilation in up to two-thirds of critically ill sars patients [ , , ] . use of niv in immunocompromised subjects of other diseases has reported similarly reduced rates of endotracheal intubation and serious complications [ ] . niv in sars may be of particular benefit, since high dose corticosteroids per se would already predispose to ventilator-associated pneumonia, and risks to healthcare workers (hcw) could also be markedly reduced through obviating the need for intubation, a potentially highly infectious procedure. patients who respond to niv will usually do so within hours, non-responders who will eventually need endotracheal intubation can thus be identified early [ ] . niv is indicated in the presence of ali and early ards when oxygen saturation (spo ) could not improve to more than % despite > litres per minute of oxygen; persistent tachypnoea of at least breaths per minute; and progressive radiographic deterioration in the lungs [ ] . the usual contraindications to niv apply, including impaired consciousness, uncooperative patient, high aspiration risk, and haemodynamic instability [ ] . sars-related respiratory failure responds readily to niv given at low pressures. cpap of - cm h o, or bi-level pressure support with inspiratory positive airway pressure (ipap) of < cm h o and expiratory positive airway pressure (epap) of - cm h o are reasonable starting pressures [ ] . higher pressures should be avoided whenever possible, because it may increase the risk of pneumothorax and pneumomediastinum, which are frequently spontaneous complications of sars even without assisted positive pressure ventilation [ ] . when patients do not improve within one to two days of niv or continue to deteriorate, or if niv is contraindicated, endotracheal intubation and mechanical ventilation should be considered. most centres [ ] adopted a ventilatory strategy similar to that recommended for ards from other causes [ ] . both pressure and volume control ventilation may be employed [ ] . the tidal volume should be kept low (e.g. - ml/kg predicted body weight), and plateau pressures maintained below cm h o. because of a higher risk of barotraumas in sars, the lowest positive end-expiratory pressure (peep) which could achieve satisfactory alveolar recruitment and oxygenation, usually - cm water, should be employed. other adjunctive measures employed in the usual ards cases had been tried in sars, including: prone positioning [ , ] , high frequency oscillatory ventilation [ , ] , nitric oxide [ ] , high peep and regular lung recruitment [ ] , but their efficacy is uncertain. tracheostomy is required in patients requiring prolonged mechanical ventilation and icu stay. strict adherence to infection control guidelines is mandatory in performing tracheostomy in the icu or operating room, as well as during subsequent changes of the tracheostomy tube [ , ] . critically ill sars patients on high dose corticosteroids and mechanical ventilation are particularly susceptible to superimposed bacterial and opportunistic infections. their peripheral blood cd +, cd + and cd + were also lower than normal [ , ] . ventilator-associated infection with organisms like pseudomonas aeruginosa, methicillin-resistant staphylococcus aureus, acinetobacter baumanii, as well as invasive mucor sp [ ] and aspergillosis [ , ] have been reported. strict control of hyperglycaemia during corticosteroid administration is essential to reduce the chance of septic complications [ ] . spontaneous subcutaneous emphysema, pneumothoraces and pneumomediastinum are common complications that are potentially aggravated by noninvasive or invasive ventilation [ ] . while chest drain insertion is useful to relieve pneumothoraces, prolonged air leak may sometimes occur. by itself, sars predominantly results in single organ failure of the lungs. other complications reported are more likely the result of sepsis and its attending problems, including acute renal failure ( %), acute liver failure ( %), rhadomyolysis, cardiovascular dysfunction, or of prolonged immobilization and underlying co-morbidities, including deep vein thrombosis, pulmonary embolism, ischaemic strokes, etc [ ] . the case-fatality ratio (cfr) of sars has been estimated to range from % to > % depending on the age group affected. the overall cfr is approximately % [ ] . variability may be due to different host and viral factors as well as treatment strategies. cfr may also be significantly affected by the duration of follow-up and inclusion of different mixes of suspected, probable and laboratory confirmed cases in different series [ ] . based on the treatment principles presented above, we have developed a standard treatment protocol early on in the outbreak, comprising initially high (but not pulsed) dose methylprednisolone with tapering over three weeks [ ] . this protocol was eventually applied to consecutively admitted sars patients [ ] . their mean age was years, with % having laboratory-confirmed sars. a low overall mortality of . % ( / ) was obtained, with all three deaths occurring in patients over the age of years. twenty four percent required icu admission: % received niv (bi-level pressure support) alone and % had both niv and invasive mechanical ventilation. hrct thorax in all survivors taken days after commencement of treatment showed most did not have clinically significant lung scarring. another multi-centered study comparing four treatment regimens in guangzhou, china, also found that a regimen of high dose corticosteroids adjusted according to clinical and radiological severity, coupled with nasal cpap ventilation, produced the best result: zero mortality in all clinically-defined sars patients, mean age . years. with % treated with cpap and none requiring mechanical ventilation. subsequently, very low mortality was again recorded among a further patients treated with the same regimen [ ] . many prognostic factors have been reported to independently predict adverse outcome in sars. they include advanced age [ , , , ] , diabetes [ , , ] , heart disease [ , ] , other significant coexisting conditions [ , , ] , shortness of breath on admission [ ] , degree of hypoxaemia [ ] , high total leukocyte count on admission [ , , ] , high initial lactate dehydrogenase [ , , ] , low platelet counts [ ] , and use of pulsed doses of corticosteroid [ , ] . compared to patients with nasopharyngeal aspirates negative for sars-cov by rt-pcr, pcr-positive ones are more likely to require icu care and mechanical ventilation, develop acute renal failure and die [ ] . in particular, mortality was high among icu patients: -day icu mortality was variously reported to be - % [ , , ] . older age, severity of illness, lymphocyte count, decreased steroid dose, positive fluid balance, chronic disease or immunosuppression, and nosocomial sepsis were associated with poor icu outcome [ ] . patients who had diarrhoea were more likely to require ventilatory support and icu care [ ] . higher serum sars-cov concentration in the early stage of the disease was a prognostic indicator for later icu admission [ ] . patients presenting with more extensive radiographic involvement also predicted the need for icu care or death [ ] . age alone is a consistent and strong prognostic factor in all series. age-stratified death rates were estimated to be < % in patients below years of age, % between and years, % between and years, and > % in elderly patients over years old [ ] . corresponding estimates in hong kong were % in those below years of age, and % in those over years [ ] . the cause of death in sars is usually progressive respiratory failure with or without concomitant sepsis. sudden cardiac arrest is also possible, and has been hypothesized to be due to hypoxemia (which would worsen during activities including defaecation), direct viral myocardial injury and extreme anxiety, all of which may lead to electrical instability in the myocardium and induction of arrhythmia [ ] . sars is primarily transmitted by direct or indirect contact of mucous membranes (eyes, nose, or mouth) with infectious respiratory droplets or fomites [ , ] . transmission risks increase with duration and proximity of contact. infection control precautions in the icu are shown in appendix [ ] . endotracheal intubation should be considered earlier and in anticipation of impending deterioration, so that ample time is available for preparation. it should be performed by the most skilful airway practitioner in a negative-pressure room behind closed doors. should the operator choose to wear additional personal protective equipment like the airmate hepa powered air purifying respirator system ( m, mn, usa), he/she must be familiar with its mode of operation and the precautions required for gowning and degowning, and must be assisted by a colleague with similar knowledge [ ] . a "modified awake" intubation technique has been suggested as the best possible compromise between patient and operator safety by administration of a combination of midazolam, fentanyl and lidocaine until the patient reaches the desired level of sedation [ ] . the patient is then paralysed after intubation to minimize coughing. alternatively, the "rapid sequence induction" technique with intravenous administration of midazolam and suxamethonium can also minimize patient coughing. it should however be emphasized that, unless there is prior preparation for a surgical airway, neuromuscular paralysis should be avoided in anticipated difficult intubation in order to maintain spontaneous respiration [ ] . both bronchoscopy and niv should be performed in a negative pressure room. although there is widespread fear of infective risk by niv [ , ] , centres with such experience, including ours, have found that its use is safe if the necessary precautions are taken [ , , , ] . finally, strict adherence to infection control measures in the form of strict isolation and effective cohorting, early diagnosis and contact tracing, timely reporting and institution of public health measures, as well as enhancement of environmental ventilation is key components in the effective management of infectious diseases. managing critically ill sars patients is a challenging task. most, if not all, 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in the plasma and serum of patients with severe acute respiratory syndrome prognostic significance of the radiographic pattern of disease in patients with severe acute respiratory syndrome acute respiratory syndrome in critically-ill patients with severe acute respiratory syndrome short-term outcome of critically ill patients with severe acute respiratory syndrome update -sars case fatality ratio epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong cardiac arrest in severe acute respiratory syndrome: analysis of cases effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) sars: ventilatory and intensive care a practical approach to airway management in patients with sars infection control precautions in the icu effective staff education in infection control, emphasizing on • precautions to be used in high-risk procedures and alternative procedures to reduce risks • limit opportunities for exposure, e.g., avoid aerosol generating procedures & limit number of health care workers (hcws) present, alternative nursing practices to limit number of hcws exposed to each patient • effective use of time during patient contact • "gowning" and "degowning" without contamination precautions: disposable gloves, gown, cap • eye protection with non-reusable goggles and face-shield • powered air purification respirators (papr) are optional ppe when performing high-risk procedures • pens, paper, personal items and medical records should where feasible, increase to ≥ ach + re-circulate air through hepa filter • preferred: negative pressure isolation rooms with antechambers • a viral/bacterial filter should be placed at the expiratory port of bag-valve mask • place two filters per ventilator: between expiratory port and the ventilator, and another on the exhalation outlet of the ventilator • use closed-system in-line suctioning for endotracheal/tracheostomy tubes • handle contaminated heat and moisture exchangers (hme) and heated humidifiers carefully • scavenger system for exhalation port of ventilator is optional if negative pressure with high air change (> /hour) is achieved • preoxygenate patient and temporarily switch off machine whenever ventilator circuit disconnection is required the authors have declared that no conflict of interest exists. key: cord- - dn a authors: peng, liang; gao, zhi-liang; wang, yu-ming; he, deng-ming; zhao, jing-ming; bai, xue-fan; wang, xiao-jing title: clinical manifestations and laboratory tests of aechb and severe hepatitis (liver failure) date: - - journal: acute exacerbation of chronic hepatitis b doi: . / - - - - _ sha: doc_id: cord_uid: dn a this chapter describes the clinical symptoms and signs of aechb and hbv aclf, classification, grading of hbv aclf and their features, diagnostic principles and standards in liver pathology, biochemistry, and virology of hbv aclf. . liver failure is defined as serious damage to the liver cause by a variety of etiologies, leading to liver function disorder or even decompensation, and clinical syndromes with coagulopathy, jaundice, hepatic encephalopathy, and ascites. . severe hepatitis b can be indicated pathologically by apparent hepatocellular necrosis, including extensive multifocal, confluent, bridging, sub-massive or massive necrosis. . laboratory tests during the course of severe exacerbation of chronic hepatitis b can reflect pathological changes and liver function in a timely manner, providing objective and informative reference data for evaluation of disease severity and treatment efficacy. among the most important laboratory tests are those for prothrombin activity, international normalized ratio, and increases in total bilirubin concentration. . severe hepatitis b is associated with interactions between the virus and host factors. detection of hbv dna, hbv genotype, quasispecies and hbv mutation can provide important theoretical bases for the prevention, control or mitigation of the progress of severe hepatitis b. . noninvasive imaging modalities can be used to visualize the entire liver and parts of it. measuring liver volume to evaluate liver size and liver reserve capacity is regarded as important in diagnosis, surgical approach and prognostic evaluation of patients with severe exacerbation of chronic hepatitis b and liver failure. . model for end-stage liver disease (meld) is the first quantitative method developed to assess whether a patient with liver failure requires a liver transplant. the predictive value of the meld model has been improved by the meld-na, imeld, and meso models. several other valuable prognostic models have been developed. for example, for patients with hbv-aclf, the established tppm scoring system was found to be more predictive than meld score. can reflect pathological changes and liver function in a timely manner, providing objective and informative reference data for evaluation of disease severity and treatment efficacy. among the most important laboratory tests are those for prothrombin activity, international normalized ratio, and increases in total bilirubin concentration. . severe hepatitis b is associated with interactions between the virus and host factors. detection of hbv dna, hbv genotype, quasispecies and hbv mutation can provide important theoretical bases for the prevention, control or mitigation of the progress of severe hepatitis b. . noninvasive imaging modalities can be used to visualize the entire liver and parts of it. measuring liver volume to evaluate liver size and liver reserve capacity is regarded as important in diagnosis, surgical approach and prognostic evaluation of patients with severe exacerbation of chronic hepatitis b and liver failure. . model for end-stage liver disease (meld) is the first quantitative method developed to assess whether a patient with liver failure requires a liver transplant. the predictive value of the meld model has been improved by the meld-na, imeld, and meso models. several other valuable prognostic models have been developed. for example, for patients with hbv-aclf, the established tppm scoring system was found to be more predictive than meld score. liang peng, zl huang, yy mei and zhi-liang gao currently, both clinical and pathophysiological diagnoses are made of severe hepatitis (liver failure) in china. according to the guideline for the prevention and treatment of viral hepatitis ( ), severe hepatitis is classified as acute severe hepatitis, subacute severe hepatitis, and chronic severe hepatitis. acute severe hepatitis is initially diagnosed due to acute jaundice that rapidly progresses to liver failure within weeks. subacute severe hepatitis can be identified in patients with acute jaundice hepatitis that progresses to liver failure anywhere from days to weeks. chronic severe hepatitis often develops with pre-existing chronic liver diseases. the clinical manifestations of chronic severe hepatitis are similar to those of subacute severe hepatitis in some patients, or, in some patients, appear similar to decompensated cirrhosis at disease onset. the diagnostic criteria for severe hepatitis in china remain to be fully developed and hence have not been introduced internationally. to meet the clinical requirements and standardize the diagnosis and therapy of liver failure, the branch of infectious diseases and the branch of hepatology of the chinese medical association invited experts in china to develop the first guidelines for the diagnosis and therapy of liver failure in . in those guidelines, liver failure refers to severe liver damage caused by multiple factors. that damage to the liver results in either the severe impairment or decompensation of synthesis, detoxication, excretion, and biotransformation in the liver and subsequent clinical manifestations characterized by coagulation disorder, jaundice, hepatic encephalopathy, and ascites. on the basis of pathological features and disease progression, liver failure is classified as acute liver failure (alf), subacute liver failure (salf), acute-on-chronic liver failure (aclf), and chronic liver failure (clf). alf is characterized by the rapid appearance of clinical manifestations. patients with alf usually develop a clinical syndrome of liver failure characterized by highgrade hepatic encephalopathy (he, >grade ) within weeks. patients with salf typically present with a clinical syndrome of liver failure anywhere from days to weeks. finally, aclf refers to the acute decompensation of the liver function in the presence of pre-existing chronic liver diseases, and clf refers to chronic decompensation of the liver function characterized by ascites or portal hypertension, coagulation disorder, and he due to progressive liver dysfunction in the presence of hepatic cirrhosis. the published guidelines systemically and extensively reflect the current status of the diagnosis and therapy of liver failure. in addition, the guidelines, for the first time, focus on liver failure rather than severe hepatitis, which broadens our horizons and highlights practicability. in china, acute severe hepatitis, subacute severe hepatitis, and chronic severe hepatitis correspond closely to alf, slf, and aclf, respectively, as illustrated in table . . in some patients, chronic severe hepatitis is similar to clf in other countries. on the basis of available guidelines for liver failure, we define severe hepatitis b as liver failure due to hepatitis b virus infection. clf is the most common, and alf and slf are rare. acute exacerbation of chronic hepatitis b (aechb) is a dynamic process, including mild, moderate, severe chronic hepatitis b and chronic aclf defined in above guidelines. the reference index of abnormality in laboratory examination is shown in table . . in addition to viral replication, other factors also contribute to the pathogenesis of hepatitis b-induced liver failure, such as concomitant infection of other hepatitis viruses (especially the hepatitis e virus), immune status, pregnancy, drug and/or alcohol consumption, concomitant bacterial infection, mental stress, and concomitant disease processes (e.g., hyperthyroidism). the liver is the largest solid organ in humans and has complex functions. hepatic parenchymal cells are responsible for metabolism, secretion, synthesis and bioconversion. factors that can cause severe damage to hepatocytes (i.e., parenchymal cells, kupffer cells) may result in disorders of metabolism, secretion, synthesis, detoxication and immunity. in turn, that damage can lead to jaundice, liver shrinkage, coagulation dysfunction, hemorrhage, secondary infection, hepatorenal syndrome, he, and other clinical entities described in detail here. the physical condition of patients deteriorates, and affected individuals usually develop weakness, extreme fatigue, and a severely diminished quality of life. they frequently require assistance to perform basic personal needs, such washing their face, brushing their teeth, and using the toilet. in the early stage of jaundice, in addition to developing extreme fatigue, gastrointestinal symptoms become evident, including extremely poor appetite, anorexia, intolerance of oily foods, nausea, vomiting, abdominal discomfort, and hiccups. in the jaundice stage, the gastrointestinal symptoms deteriorate further. patients can develop refractory vomiting, hiccups, evident abdominal distension, and reduced/ lack of borborygmus. clinically, patients initially note their urine color darkens, becoming a strong-tea like color. next, a yellowish pigmentation of the ski and conjunctival membranes develops. that jaundice progressively becomes deeper, characterized by hepatocellular jaundice. in this stage, serum bilirubin increases rapidly. in fact, the daily increment in serum bilirubin may be > μmol/l (> mg/dl). the sulfur-containing amino acids in the intestine are degraded into mercaptans that have the odor of rotting fruit. mercaptans cannot be metabolized in the liver and are therefore excreted from the respiratory tract. this distinctive odor is specifically noted in patients with he. the severity of hepatic foetor may, in some cases, reflect the severity of liver injury. the occurrence of coagulation dysfunction is primarily ascribed to the reduced synthesis of coagulation factors by the liver. a majority of the both coagulation and anticoagulant factors are synthesized in the liver. in addition, some coagulationrelated factors and their inhibitors are also metabolized in the liver. the outcome of coagulation dysfunction is dependent on the severity of damage to the hepatocytes. thus, even patients in an early stage of liver failure may present with coagulation dysfunction. prothrombin (pt) activity is often abnormal in the early stages of liver failure and may therefore serve as a sensitive indicator for the prognosis of liver failure. common clinical manifestations of coagulation dysfunction are mucocutaneous bleeding (i.e., spontaneous bruising, gingival bleeding, subconjunctival hemorrhage), ecchymosis at the site of injection/puncture, and purpura in more severe cases. gastrointestinal bleeding is also common in affected individuals, whereas bleeding into/from the genitourinary tract, lung, kidney, and retroperitoneum is rare but occasionally observed in some patients. if intracranial hemorrhage develops, it is frequently life threatening. in ahf, the incidence of bleeding and severe bleeding is as high as and > %, respectively. another cause of coagulation dysfunction is thrombocytopenia and platelet dysfunction. of the two, thrombocytopenia is more common. because platelets are derived from megakaryocytes in bone marrow, bone marrow fibrosis and either reduced bone marrow regeneration or invasion of lymphoma cells in the bone marrow can reduce the number of platelets. platelets perform multiple activities, including adhesion, aggregation, release, and shrinking blood clots. additionally, they play an important role in coagulation. platelet dysfunction may also increase capillary permeability and fragility, which may cause either spontaneous bleeding of the skin and mucous membranes or difficult hemostasis following vascular injury. in patients with slf, thrombocytopenia is mainly diagnosed in the latter stage of disease in which massive hepatocyte necrosis leads to posthepatic cirrhosis, portal hypertension, and hypersplenism. in clf patients, thrombocytopenia might be present, and hepatocyte necrosis may aggravate portal hypertension and hypersplenism, resulting in worsening thrombocytopenia. splenomegaly and splenic sinus hyperplasia increase the phagocytosis and destruction of platelets. further, splenomegaly can cause enlargement of the platelet pool within the spleen. as a result, the platelets in the spleen may account for > % of platelets in the body. the above pathological changes may finally cause a reduction in the circulating platelets. the reason for thrombocytopenia in liver disease patients without hypersplenism is still poorly understood and might be ascribed to following factors ( ) the hepatitis b virus may significantly inhibit the megakaryocyte system of the bone marrow, resulting in reduced production of platelets; ( ) the thrombopoietin (tpo) level is reduced. the division of megakaryocytes into platelets in the bone marrow is controlled by both megakaryocyte colony stimulating factor (meg-csf) and tpo. meg-csf primarily regulates the proliferation of megakaryocyte progenitor cells, whereas tpo stimulates the maturation of megakaryocytes and production of platelets. tpo is almost exclusively produced by hepatocytes, and only a minority of tpo is produced in the kidney and other organs. tpo is a key factor affecting the production of platelets, and the synthesis of tpo is reduced significantly in patients with either severe hepatitis or hepatic cirrhosis, which affects the production of platelets. in patients with parenchymal liver diseases, abnormalities of platelets are present in both quality and quantity. for example, when the platelet membrane glycoprotein gpi -ix is reduced, the aggregation of platelets following ristocetin treatment and the shrinkage of blood clots are markedly compromised; and ( ) patients with liver diseases usually develop immune dysfunction and are therefore susceptible to infection. bacterial toxins and systemic inflammatory response syndrome may also cause thrombocytopenia. one published study of icu patients found that infection was an independent risk factor of thrombocytopenia. he he is both a neuropsychiatric syndrome, a type of central nervous system dysfunction, and metabolic disturbance due to hepatocellular dysfunction and portosystemic shunting. he is clinically characterized by mental and neurological abnormalities, such as abnormal personality and behaviors, irritability, sleep perversion, drowsiness, and complete loss of consciousness or coma. he is one of the major causes of severe complications and death in patients with liver failure and is typically classified into one of the four following stages: stage : the prodromal stage. this stage usually manifests with mild abnormal personality changes and behaviors, such as euphoric excitement, indifference, taciturnity, being sloppily dressed, and inappropriate defecation/urination. the affected individual can usually provide correct responses to questions but they are inarticulate and have slow speech. flapping tremor/hepatic tremor might also be present. to test for flapping tremor, patients are asked to close their eyes with their arms stretching straight, elbows flexed, palms in dorsal extension, with separated fingers. a positive response is determined when the metacarpophalangeal joint, wrist, elbow, and shoulder show irregular movements (jitter) when held in that position within s. physicians may also ask the patients to hold the their hand for min. if the physician feels the hand tremor, the test suggests a positive diagnosis of flapping tremor. the condition is caused by afferent dysfunction of joint-reticular formation of the brainstem and a characteristic neurological manifestation. that said, flapping tremor has no specificity fro he and can also be found in patients with either uremia or hypoxemia due to chronic respiratory disease/heart failure. the presence of flapping tremor in a patient with severe liver disease, however, is helpful for early diagnosis of he. patients with he usually have a normal electroencephalogram. stage of he lasts anywhere from several days to several weeks. several patients with he in the prodromal stage may have no evidence of clinical symptoms; therefore, misdiagnosis is possible. stage : the precoma stage. patients with he in this stage usually presents with confusion, sleep and behavioral disorders, and symptoms as described in the prodromal stage further deteriorate. patients suffer from disorientation and understanding disorders as well as conceptual confusion over time, place, and person. patients are unable to perform simple intellectual composition (e.g., building blocks, arranging matchstick into pentagon), and have decreased computing capacity (e.g., - and continuing). slurred speech, writing disorders, and abnormal behaviors are also common. sleep perversion and daytime sleep and night awaking may be present. further, hallucinations, fear, and mania are also observed, and some patients can be misdiagnosed with mental diseases. patients with liver failure in this stage usually have evident neurological signs such as tendon hyperreflexia, increased muscle tone, ankle clonus, and presence of the babinski sign. flapping tremor and an abnormal electroencephalogram can also be observed. patients may also suffer from uncontrolled muscular activities and ataxia. stage : the lethargic stage. patients with he in the lethargic stage mainly manifest lethargy and insanity, and neurological signs continue and deteriorate. in the majority of time, patients are in a lethargic state, but can be waken up. patients respond to questioning, but may present confusion and hallucination. flapping tremor is also present. muscular tension increases, and there is resistance in the passive limb movements. pyramidal signs and abnormal waves in eeg can also be noted. stage : the coma stage. patients have complete loss of consciousness and are unable to be awakened. in a light coma, patients are responsive to painful stimuli and uncomfortable postures, have tendon hyperreflexia, and increased muscular tension. patients in this stage are usually unable to co-operate during an examination, and a flapping tremor may not be inducible. in a deep coma, various reflexes disappear; muscular tension reduces; pupils become dilated; and there are paroxysmal convulsions, ankle clonus, hyperventilation, and abnormalities on an electroencephalogram. stage of he is an important indicator of severity of disease. it may reflect not only the severity of brain damage but also the severity of liver disease. it is important to recognize that there is no clear boundary between two neighboring stages and that there might be some overlap between two neighboring stages (therefore missing the middle stage of he). when the disease condition either deteriorates or improves after therapy, the severity of he may be reduced by one or two stages. as mentioned above, the initial symptoms of he are personality changes. patients with extrovert personalities (i.e., lively, cheerful) may become depressed, whereas patients with introverted personalities (i.e., withdrawn, reticent) may become euphoric and garrulous. the second most common symptom is a change in behaviors. initially, patients have sloppy behaviors, such as meaningless behaviors like scattering garbage all over the place and defecating/urinating anywhere, looking at clothes, and touching the bed. those changes are usually only identified by close observation and careful experience. there are also changes in sleep habits. patients are often drowsy during the daytime but have difficult sleeping at night or show sleep perversion, which predicts imminent he. hepatic foetor is also an important feature of he. he patients usually have brain edema and present with nausea, vomiting, dizziness, headache, and either irregular breathing or even apnea. as blood pressure increases there might be a paroxysmal or sustained increase in systolic blood pressure. bradycardia may be also observed. muscular tension can increase or the patient can develop a decerebrate posture or even opisthotonus with severe he. the pupillary light reflex can become blunt/absent, the pupils can become mydriatic, and anisocoria can occur. achilles and knee tendon hyperreflexia may be observed. it is important to note that some signs might not be obvious in a patient with late-stage he. in clinical practice, clinicians may indirectly evaluate the severity of brain edema according to chemosis. accurate evaluation of brain edema is dependent on the subdural, epidural, or cerebral parenchymal measurement of intracranial pressure. the normal intracranial pressure is < . kpa ( mmhg), and brain edema is diagnosed once intracranial pressure is > mmhg. the most important sign of he is flapping tremor, which means the presence of he in stage ii. in addition, thinking and intelligence tests (such as number connection test, signature test, mapping test, and computing capability test) are abnormal in he patients. in some he patients (especially those with hyperammonemia due to he), slow waves with high amplitude may be observed on electroencephalogram, and positive-evoked potential is also a characteristic change. brain edema is a complication of alf. typical clinical manifestations of brain edema are sustained increase in blood pressure, abnormal pupils, irregular respiration, and papilledema. more than % of patients with he in stage or are likely to develop brain edema, and severe brain edema may result in cerebral hernia. brain edema has the clinical presentations of increased intracranial pressure and cerebral dysfunction, which can sometimes overlap with the manifestations of he. it is therefore sometimes difficult to differentiate the two, potentially resulting in misdiagnosis. he patients with brain edema may present dysphoria, irascibility, and increased muscular tension, which are more common than in patients with he without brain edema. if there are concomitant changes in pupils and respiration together with convulsions and/or seizures, cerebral hernia is suspected. in the late stages of liver failure, patients may develop intracranial hemorrhage, causing respiratory and circulatory arrest and even sudden death. thus, once cardiopulmonary arrest of unknown cause is present, intracranial hemorrhage should be considered. concomitant gastrointestinal bleeding in patients with severe hepatitis can be caused by multiple factors, including ( ) decreased coagulation factor synthesis by hepatocytes and/or significant inactivation of active coagulation factors in the liver; ( ) endotoxemia and disseminated intravascular coagulation consuming a large amount of coagulation factors; ( ) hypersplenism causing abnormalities in the quality and quantity of the platelets; ( ) portal hypertension causing the rupture of esophageal and gastric varices; and ( ) stress response in severe hepatitis leading to diffuse gastric corrosive erosion. of the possible complications occurring in liver failure patients, bleeding is the most common and severe. in clinical practice, gastrointestinal bleeding with severe hepatitis seems to make the primary disease worse. it may worsen liver ischemia and hypoxia and aggravate liver dysfunction and ascites. blood in the gastrointestinal tract can be degraded into ammonia and increase the production of sulfur-like substance, resulting in he. in addition, bleeding may reduce immune function, which make infections difficult to control. the reduction in effective circulating blood volume may also induce hepatorenal syndrome. taken together, bleeding may cause multiple organ dysfunction, thereby complicating treatment and reducing the success rate of therapy. the causes of upper gastrointestinal bleeding are different among patients with different types of liver failure. in alf and slf, bleeding is related to reduced synthesis of coagulation-related factors and stress-induced gastric mucosal lesions. in clf, however, rupture of esophageal and gastric varices and gastric mucosal lesions secondary to portal hypertension are the main causes of gastrointestinal bleeding. in some cases, there is more than one cause of bleeding. in liver failure, the ability of the monocyte-macrophage system to clear intestinerelated endotoxins is reduced significantly, which may lead to intestine-related endotoxemia and deterioration of liver function. this clearly forms a vicious cycle and may cause multiple organ failure if it is severe enough. in addition, patients usually have compromised immune function and are susceptible to infection. invasive manipulations and use of broad-spectrum antibiotics and immunosuppressants further increase the possibility of secondary infection. concomitant infection in liver failure patients has the following characteristics: ( ) a high incidence; ( ) infection may occur at different sites either simultaneously or sequentially, and abdominal and biliary tract infection is the most common. once pulmonary infection is present, the disease condition will likely deteriorate, directly causing death; ( ) a majority of infections are nosocomial infection, and pathogens are usually resistant to common antibiotics, making therapy challenging; ( ) the pathogens causing infection are diverse but mainly gram-negative bacteria, although the incidence of gram-positive and fungal infections is increasing; ( ) infection is closely related to the prognosis for liver failure patients. in sum, the more severe the disease, the higher the incidence of infection is and secondary infection may worsen the condition or cause death. the early diagnosis of secondary infections is based on clinical findings such as signs of infections (i.e., fever, increase in peripheral white blood cells, deterioration of primary disease, specific symptoms of infection of a particular organ). some patients may not present with an obvious fever and instead only show focal signs of infection. for example, in spontaneous bacterial peritonitis, examination could reveal abdominal tenderness and rebound tenderness and a slight increase in peripheral white blood cells and polymorphonuclear proportion (although they are in normal ranges). in contrast, pulmonary infections can present only with fever while the respiratory symptoms are not obvious/absent and thoracic radiographs fail to show abnormalities in affected patients. in such cases, computed tomography is required to identify the pulmonary lesions. in addition, liver failure patients are vulnerable to fungal infection, especially for those receiving long-term therapy with broad-spectrum antibiotics. gastrointestinal candidiasis is the most common fungal infection. oral candida albicans infection is characterized by thickening and a bean residue-like coating on the tongue, gastrointestinal fungal infection is characterized by increased stool frequency and stool with mucus, and pulmonary fungal infection (especially aspergillus infection) is a severe complication of liver failure that can progress rapidly and has a high mortality rate. once a pulmonary fungal infection is suspected, computed tomography of the thorax should be performed to confirm the diagnosis, and effective antifungal therapy should be initiated as early as possible. hepatorenal syndrome (hrs) refers to progressive functional renal failure in the absence of primary kidney disease in patients with severe liver diseases. hrs is most often diagnosed in the late stages of severe hepatitis and hepatic cirrhosis. the main clinical manifestations of hrs include: . late stages of liver failure; . renal failure after a reduction in effective circulating blood volume (e.g., water and electrolyte disorder, following paracentesis for ascites, excessive urination due to diuresis, gastrointestinal bleeding, secondary infection, vomiting, and diarrhea). however, hrs may present abruptly with no evident/discoverable causes; . hrs is often found in patients with moderate to severe ascites; . hrs has no significant relationship with jaundice and he; and . blood pressure reduces during hrs. thus, when patients are treated with propranolol for portal hypertension, physicians should pay attention to the baseline blood pressure because reduction in blood pressure after pharmacotherapy may reduce the blood supply to the kidney and decrease glomerular filtration rate, inducing hrs; . the abrupt decrease in urine output suggests the presence of hrs. diuretics usually fail to increase the urine output. patients often have a reduction in urine sodium and concomitant hyponatremia; . urinalysis shows similarities to prerenal azotemia but displays opposite features to acute tubular necrosis; . the symptoms of uremia may overlap with those of liver failure and cause the deterioration of original symptoms. in patients with progressive liver diseases, secondary renal dysfunction is closely related to the deterioration of their general condition, suggesting the aggravation of liver failure. in addition, the presence of uremia may contribute to metabolic complications. coagulation dysfunction in liver disease patients may be deteriorated due to compromised aggregation of platelets during uremia. uremia may also aggravate immune dysfunction. on the basis of clinical characteristics, hrs can be classified into two types. type i hrs is rare, has an acute onset, and is characterized by progressive renal dysfunction. serum creatinine may be either × that at baseline (i.e., > μmol/l or . mg/dl) within weeks or creatinine clearance decreases by % within h (i.e., creatinine clearance of < ml/min). patients with type i hrs have a poor prognosis, with % of patients dying within weeks of diagnosis and only % of patients can survive for > months. the course of disease is short, and symptoms of uremia are not obvious. in type ii hrs, which is often found in clf patients with pre-existing hepatic cirrhosis, has a chronic onset. ascites patients with type ii hrs are usually nonresponsive to diuretics. in type ii hrs, renal failure shows a slow progression (lasting for several weeks to months), but the survival rate of patients is lower than that of hepatic cirrhosis patients with ascites. the main clinical consequence is refractory ascites nonresponsive to diuretics in patients with type ii hrs. a follow-up study of hepatic cirrhosis patients with ascites showed the accumulative incidence of hrs was % within year and % within years. a retrospective study showed about % of patients with ascites on admission had hrs and hrs patients accounted for % of hepatic cirrhosis patients died. however, for hepatic cirrhosis patients, the -year and -year incidence of hrs is % and % after development of ascites. a majority of patients ( - %) die within weeks after development of azotemia. hps refers to a series of pathophysiological changes and clinical manifestations (including hypoxemia) due to abnormal pulmonary vascular dilation, gas exchange disorder, and abnormal arterial oxygenation. abnormal arterial oxygenation due to a gas exchange disorder may increase the alveolar-arterial oxygen pressure difference. hypoxemia is an important pathophysiological basis of hps, and hps is a severe pulmonary complication of end-stage liver disease that is clinically characterized by dyspnea and cyanosis. hps was first reported by rydell hoffbauer in , but it wasn't until that kenned and knudson proposed the full concept of hps. hps per se refers to pulmonary vascular dilation and the shunting of venous blood with low oxygenation to arteries in the presence of severe liver disease. hps is mainly identified in patients with clf (child c hepatic cirrhosis). in addition, patients with either acute or chronic liver disease may present with a pulmonary vascular abnormality and arterial hypoxemia. hps occurs most commonly in patients with hepatic cirrhosis secondary to chronic liver disease, including hepatitis-induced cirrhosis, cryptogenic cirrhosis, alcoholic cirrhosis, and primary biliary cirrhosis, all of which have similar pathophysiological processes as hps. in hps, severe ascites, portal hypertension, and arterial hypoxemia (pao < kpa) may be related to the intrapulmonary vascular shunt, excessive production of nitric oxide, lung ventilation-perfusion imbalance, and interstitial fibrosis. the incidence of hps varies among studies. the incidence of hps is about - % in chronic liver disease patients but higher in patients with hepatic cirrhosis. the most common clinical manifestations of hps are dyspnea, hypoxemia, and cyanosis caused by intrapulmonary vascular dilation and poor arterial oxygenation in the presence of primary liver disease: patients usually progressively develop respiratory manifestations (e.g., cyanosis, dyspnea, clubbed-fingers/toes, orthostatic hypoxia, supine breathing). progressive dyspnea is the most common pulmonary symptom of hps, and cyanosis is a unique and reliable clinical sign. supine breathing and orthostatic hypoxia are characteristic manifestations of hps. pulmonary examination often fails to identify clinically important signs, and hps is not associated with the either the cause or severity of liver disease. in a fraction of patients with stable liver disease, there is progressive lung dysfunction. research shows that hps is associated with esophageal varices and spider angiomas. intrapulmonary vascular dilation (i.e., pulmonary spider angiomas) is frequently found in liver disease patients with subcutaneous spider angiomas susceptible to hypoxemia. spider angiomas have been regarded as a marker of extrahepatic involvement. if patients have no primary heart and lung disease, concomitant lung disease (such as chronic bronchitis, emphysema, pneumonia, and pleural effusion) may coexist with hps. affected patients usually have obvious respiratory symptoms; therefore, physicians should differentiate between the conditions. hps is an independent risk factor for prognosis. specifically, studies have reported that the median survival time is . months after the diagnosis of hps. to date, no effective strategies have been developed for the therapy of hps. orthotopic liver transplantation should be performed as early as possible for hps patients. in liver failure, there is massive hepatocyte necrosis that may cause a reduction in glycogenolysis and abnormal gluconeogenesis. thus, patients are vulnerable to hypoglycemia, shock, coma, and impaired glucose tolerance. the synthetic function of the liver is impaired in such patients, and the serum level of cholesterol and triglycerides decreases. serum cholesterol has been used as an indicator for the prediction of prognosis of liver failure patients. the frequent use of diuretics can cause water and electrolyte imbalance, of which hypokalemia and hyponatremia are the most common. such imbalances may also induce he and brain edema. ap is a rare, but severe, complication of liver failure. the inciting cause(s) and pathogenesis of ap in patients with viral hepatitis remain unclear but might be associated with viral infection, biliary tract lesions, drugs (steroids and diuretics), and other factors. the reported incidence is . - %, but one autopsy study shows that the incidence of ap is as high as % in patients with severe hepatitis and hepatic cirrhosis. evidence shows that the incidence of ap is relatively high in patients with advanced liver failure. further, high serum bilirubin, low albumin, and a significant reduction in prothrombin activity may predict a poor prognosis for ap patients with severe hepatitis and a high mortality. two of the following three criteria are required for the diagnosis of ap: ( ) patients have abdominal pain characteristic of ap; ( ) serum amylase and/or lipase is ≥ × the upper limit of normal; and ( ) there are characteristics of ap on medical imaging. that said, in cases of severe hepatitis with concomitant ap, the symptoms of ap are usually atypical, diverse, and easy to be masked by symptoms of severe hepatitis. thus, severe hepatitis is often considered the cause of abdominal distension, nausea, and vomiting, even in the presence of ap. in some patients, ap may be misdiagnosed as spontaneous bacterial peritonitis, cholecystitis, or gastritis, which may delay treatment and therefore worsen the patient's condition. the clinical manifestations of ap are usually atypical in patients with preexisting liver failure, therefore, physicians should highlight the diagnosis of ap in affected patients. when the following findings are observed, ap should be suspected and laboratory and imaging examinations should be performed as soon as possible for the confirmed diagnosis: . patients with severe hepatitis develop abrupt and persistent upper abdominal pain/peritoneal irritation that is nonresponsive to general antispasmodics; . patients present with severe vomiting, severe sialorrhea of unknown cause, and refractory hiccups; . patients manifest repeated and transient episodes of conscious disturbance, which are refractory and not caused by hepatic coma and hypoglycemia-like reaction; . patients have prior chronic cholecystitis or gallstones, receive treatment with diuretics or steroids, and have symptoms and signs described in ( ) after exclusion of spontaneous peritonitis. for patients with severe hepatitis, routine blood testing and urine amylase detection should be performed dynamically. imaging examinations can be performed simultaneously. abdominal ultrasonography may be performed within - h after the onset of abdominal pain, which is helpful for the morphological change in the pancreas and the exclusion of biliary tract disease. however, gas in the gastrointestinal tract during ap may affect the performance of ultrasonography and make accurate diagnosis of ap impossible. thus, computed tomography is recommended as a standard imaging examination for the diagnosis of ap. computed tomography is helpful for the early diagnosis and subsequently timely therapy, which may improve the prognosis. to facilitate the determination of therapeutic efficacy and the evaluation of prognosis, the branch of infectious and parasitic diseases and branch of hepatology of chinese medical association published the guideline for the prevention and therapy of viral hepatitis in (xi'an conference). on the basis of those guidelines, severe hepatitis can be classified as early, intermediate, and advanced severe hepatitis. specifically, early severe hepatitis meets the diagnostic criteria for severe hepatitis (i.e., severe fatigue, gastrointestinal symptoms, deepening jaundice, serum bilirubin > × the upper limit of normal, prothrombin activation of ≤ - %, or pathological characteristics), but patients have no evidence of he and no ascites. intermediate severe hepatitis patients have grade he or obvious ascites, bleeding tendency (i.e., bleeding point, ecchymosis, and a prothrombin activation of ≤ - %). advanced severe hepatitis patients develop refractory complications and hrs, gastrointestinal bleeding, severe bleeding tendency (i.e., ecchymosis at the injection site), severe infection, refractory electrolyte imbalance, he >grade brain edema, or a prothrombin activation of ≤ %. currently, some investigators classify the natural history of liver failure into the following: prejaundice stage, bilirubin increase stage, bilirubin plateau stage, and bilirubin reduction stage. those stages are based on disease progression, serum bilirubin level, and recovery of liver failure patients. in the prejaundice stage, patients have fatigue, anorexia, and an intolerance of oil. they deteriorate gradually, the urine becomes yellow, liver function detection usually shows a significant increase in aspartate aminotransferase and alanine aminotransferase (higher than several thousand), and the prothrombin activity increases. serum bilirubin increases progressively (i.e., a daily increment of > . μmol/l), and symptoms (fatigue, anorexia) deteriorate after the appearance of jaundice (which is different than manifestations of acute jaundice hepatitis). when the serum bilirubin peaks and remains relatively stable, the disease may be in the bilirubin plateau stage in some patients with no severe complications but present improved mental status and appetite. with the regeneration of hepatocytes, the disease progresses into the bilirubin reduction stage, in which the coagulation, mental status, and appetite improve. when the disease recommences its deterioration, it may progress from the so-called bilirubin increase stage directly to the end stage. in patients with alf, the bilirubin plateau stage is not obvious, and patients might die shortly after disease onset. if patients survive alf, the disease may be pathologically classified as a hepatocyte edema type, and liver function will improve in a short period. not all types of liver failure (including severe hepatitis b) have clear stages based on their natural history and characteristics, and the respective features are discussed in detail as described in the following sections. there is still no consensus on the definition of alf. in , the us acute liver failure study group published guidelines for the management of acute liver failure. in those guidelines, they emphasized that liver failure within weeks after onset can be diagnosed with alf in mother to child transmission of hepatitis b infection (or autoimmune hepatitis), although it has the possibility of progressing into hepatic hepatitis. in addition, some physicians propose that liver failure with an abrupt attack either secondary to chronic hepatitis b or in the presence of other hepatitis virus infection can also be classified as alf. the pathological basis of alf may be classified as necrosis-and degeneration-dominant (acute edema) type. in alf of the necrosis-dominant type, hepatocytes become diffuse and massive necrosis occurs soon after disease onset. in alf of the degeneration-dominant type, hepatocytes show diffuse and severe swelling. alf secondary to acute hepatitis b virus (hbv) infection is rare in clinical practice. patients with alf secondary to acute hbv infection usually have no history of hbv infection, are relatively young, and often have predisposing factors (e.g., stress, absence of rest after disease onset, malnutrition, alcoholism, use of liver damaging drugs, pregnancy, concomitant infection). moreover, it usually progresses rapidly, and patients may develop coagulation dysfunction before the jaundice becomes evident. such patients present with symptoms of liver failure characterized by he >grade within weeks, a prothrombin activation ≤ %, an obvious bleeding tendency (i.e., massive petechiae at an injection site), patients have no ascites, disease progresses rapidly and has a poor prognosis, and patients frequently die of complications such as brain edema or cerebral hernia within weeks. some patients may recover rapidly after appropriate therapy and are usually diagnosed with liver failure of extensive hepatocyte swelling. after recovery, the risk for hepatic cirrhosis is relatively low. another situation is the presence of a history of hbv infection in which patients have a good liver condition and no evidence of/mild liver lesions. for hbv patients with alf, the liver condition is good (as in alf patients without prior hbv infection) and both alf patients with and without prior hbv infection share pathological basis, pattern of disease onset, and clinical course. alf usually progresses rapidly, and the four stages of alf (i.e., prejaundice stage, bilirubin increase stage, bilirubin plateau stage, and bilirubin reduction stage) are difficult to identify. alf may result in high mortality, and a majority of patients directly develop alf of the bilirubin increase stage or even terminal stage. pathologically, slf not only has extensive hepatocyte necrosis but also an obvious inflammatory reaction and formation of regenerative nodules in residual hepatocytes. slf usually has an origin of alf. when slf occurs in patients with or without mild liver lesions, it often shows an abrupt onset. in the early stages, slf is similar to acute icteric hepatitis and patients progressively deteriorate. affected individuals may also develop clinical symptoms of liver failure from days to weeks, including severe fatigue, loss of appetite, frequent vomiting, and deepening jaundice (i.e., a daily increment of > . μmol/l or > mg/dl and an increase in serum bilirubin of > μmol/l or mg/dl). patients usually have hepatic foetor, refractory abdominal distension, ascites (susceptible to concomitant peritonitis), evident bleeding tendencies, and mental and neurological symptoms. in the late stages, hepatorenal syndrome may be present and patients often develop complications (such as gastrointestinal bleeding and hepatic coma) before death. the liver either shrinks or remains normal in size. the course of slf lasts for several weeks to several months. patients surviving slf following therapy usually develop postnecrotic hepatic cirrhosis. clinically, slf can be divided into two types. first, the ascites type results in profound jaundice (serum bilirubin of ≥ μmol/l or > × the upper limit of normal), ascites, and evident bleeding tendencies (i.e., a pta ≤ %). he might be absent or present in the late stages. patients often die of hrs, upper gastrointestinal bleeding, severe secondary infection, and intracranial hemorrhage. slf of the ascites type accounts for a majority of slf. second is the encephalopathy type. such patients have he as an initial symptom and present manifestations as in ash except for course of disease lasting for > days. patients usually die from either brain edema or cerebral hernia. slf of the encephalopathy type is also not rare. slf often has an abrupt onset, and the four stages (i.e., the prejaundice, bilirubin increase, bilirubin plateau, and bilirubin reduction stage) of liver failure are difficult to identify. it is usually associated with a high mortality rate. the pathological basis of aclf is similar to that of slf; therefore, they both share clinical characteristics. a majority of patients with aclf have ascites, spontaneous peritonitis, and biliary tract infection. in the late stages, patients may develop portal hypertension and other complications, repetitive he and hrs, and most die of gastrointestinal bleeding and hrs. according to the guideline for the prevention and therapy of viral hepatitis ( ), a fraction of patients with csh meeting the diagnostic criteria can be grouped with aclf. that is, patients have either chronic hepatitis or compensated hepatitis cirrhosis that remain stable, but some predisposing factors cause the deterioration of liver function, which, thereafter, progresses to liver failure. aclf refers to acute decompensated liver function in the presence of chronic liver disease. the previously mentioned guidelines emphasize pre-existing chronic liver disease and liver failure due to acute liver dysfunction. it is important to note that controversy regarding the basis of chronic liver disease persists. in , an english physician proposed that aclf was diagnosed in chronic liver disease patients with compensated liver function presenting with acute aggravation of liver function within - weeks due to accidents characterized by jaundice, he, and/or hrs. german physicians subsequently proposed that the diagnostic criteria for aclf included ( ) the liver has the histological, laboratory, or ultrasound evidence of hepatic cirrhosis; and ( ) patients develop jaundice, ascites, coagulation dysfunction, and/or grade - he, meeting the definition of decompensated liver function. the guideline for the diagnosis and therapy of liver failure ( ) does not detail chronic liver diseases as a basis of liver failure. however, in general, hbv carrier status may not serve as a baseline liver disease for patients with either chronic hepatitis or hepatic cirrhosis. the term aclf also highlights that acute or subacute deterioration of liver function occurs, which rapidly progresses to liver failure. patients often display an abrupt onset and develop severe fatigue and evident gastrointestinal symptoms. in the early stages, there is acute liver damage; therefore, patients usually present with a significant increase in transaminase levels. thereafter, the disease condition becomes aggravated, and patients may manifest symptoms of liver failure. aclf can also be divided into the brain type and ascites type, of which aclf of the brain type has a higher incidence. further, the four stages (prejaundice, bilirubin increase, bilirubin plateau, and bilirubin reduction) of liver failure are very clear in patients with aclf. one goal for physicians and researchers is to determine individualized therapy for aclf patients according to the specific stage of aclf. patients with clf usually have decompensated hepatic cirrhosis that progressively evolves into chronic liver failure, resulting in clinical manifestations of chronic decompensated liver dysfunction characterized by ascites, portal hypertension, coagulation dysfunction, and he. the pathological basis of chronic liver failure is hepatic cirrhosis, chronic and progressive aggravation of hepatocyte injury, and reduction in hepatocytes that are unable to maintain normal liver function. physical examination usually shows signs of chronic liver diseases (such as liver palms and spider angiomas), imaging examination shows characteristics of chronic liver diseases (such as spleen thickening), and laboratory examination also supports the diagnosis of chronic liver diseases (increased gamma-globulin and reduced/inverted albumin/globulin ratio). of note, a majority of patients have no clear history of liver disease and may initially be misdiagnosed with alf. further examinations may provide evidence of hepatic cirrhosis. when patients with hepatic cirrhosis become decompensated, the liver dysfunction usually presents with acute deterioration due to complications or gradually aggravates in a small fraction of patients. on the basis of the above findings, liver failure secondary to decompensated hepatic cirrhosis can be divided into slowly progressive liver failure and acutely deteriorating liver failure. the former shows a chronic status of liver failure and is characterized by repetitive ascites and he. the latter shows an acute deterioration of liver function in the presence of chronic liver dysfunction, which is similar to aclf in the disease onset and clinical course. hepatopulmonary syndrome is often noted in acutely deteriorated liver failure, and patients usually die of heavy gastrointestinal bleeding, hrs, and severe infection. clf is generally characterized by slow progression of liver failure, and the course of clf is relatively long. the four stages (prejaundice, bilirubin increase, bilirubin plateau, and bilirubin reduction) of liver failure are difficult to identify. as such, finding ways to best preserve residual hepatic function reserve is one of the important therapeutic goals in affected individuals. yu-ming wang, deng-ming he liver failure is a clinical syndrome with high mortality by severe liver damage. it is caused by a variety of causes, results in serious obstacles or decompensation of liver synthesis, detoxication, excretion and biotransformation and appears with coagulation disorders, jaundice, hepatic encephalopathy and ascites as main manifestation. hepatic failure can be divided into acute liver failure (alf), subacute liver failure (salf), acute-on-chronic liver failure (aclf), and chronic liver failure (clf). although the incidence of liver failure is not high in western countries, the relevant papers, reviews, conferences and other exchanges have increased markedly in recent years. aasld, easl and apasl had established a thematic seminar and the definition diagnosis and classification of liver failure has been consistent. at the same time, there are different understandings. therefore, it is necessary to discuss the main differences of liver failure diagnosis and classification, so as to develop a more rational diagnosis and classification scheme. the classification of liver failure involves classification of hepatic injury. a variety of factors (drugs, virus, alcohol, etc.) can cause liver cell damage. although course and prognosis of liver cell damage are different, the most common mechanism is inflammation. wieland et al. found that there were two mechanisms of liver cell injury in the immune clearance of hbv; non-soluble cell damage occurring early and soluble cell damage, early mainly non-soluble cell injury, by the study of gorillas with hbv infected. in , bonino et al. proposed the theory of nonsoluble liver cell damage in the study of fibrosing cholestatic hepatitis (fch) study. however, this theory was ignored because many scholars believed that it ignored the background of immunosuppression. at that time, fch was still considered as the injury of endoplasmic reticulum and golgi apparatus by the excess replication of hbv as well as overexpression of hbv antigen during immune inhibition. however, in , masayoshi et al. reported that most effective antibodies had been detected in children after living donor liver transplantation who received chickenpox vaccine, attenuated vaccines in children, such as measles, rubella, and mumps. according to this, immune suppression cannot stop antibody production and in fch, non-cellular immune injury may be present. recently, we found that there were two types of hbv reactivation in immune-suppressed; high alt type (> × uln) and low alt type (< × uln) and both with bad prognosis. we proposed that there may be different injury mechanisms, both immune and non-immune damage. in , rolando et al. found that . % of acute liver failure patients with systemic inflammatory response syndrome (sirs), and there was significant correlation between the progress of hepatic encephalopathy and infection and between the degree of hepatic encephalopathy and the occurred rate of infection. infection aggravates degree of illness and fatality rate in liver failure patients. accordingly, we speculate that serious primary liver injury can cause injury to other organs by cytokines, while injury to other organs can aggravate liver injury. corresponding with this, we summarized relevant literature and referred that alf can occur secondary in the development process of multiple organ failure induced by non-primary liver damage. this suggests that this type of liver failure is a special type of liver failure, which is a result of rapid changes in internal environment and inflammatory factors induce liver damage. therefore, liver failure can be divided into one with primary injury and with secondary injury. liver failure mainly caused by non-soluble cell injury is extremely rare; as "paralyzed type", "stunned type" or "edematous type", and with the good prognosis. in , small-for-size syndrome after partial liver transplantation was defined by dahm et al., which is a hepatic failure due to less of liver tissue. actually, this syndrome can also be seen as a special type of liver failure caused by non-soluble liver cell damage. soluble cell injury of liver is relatively common, such as the early hepatic failure in hepatocellular carcinoma after interventional therapy, some drug-induced alf, etc. liver failure caused by immune injury is more common in liver failure caused by autoimmune liver disease. liver failure caused by non-immune injury is more common in liver failure patients with severe cellular immunity damaged (hiv/ aids patients, chemotherapy patients) or immunity inhibited (in patients after organ transplantation). primary type is common in fulminant hepatic failure (fhf), the secondary type is seen in severe systemic diseases, such as severe sepsis and acute hemorrhagic. in fact, clinical liver failure is the result of combination of different proportions of various types of damage factors. based on the role of various factors in liver failure, it can be categorized. according to acute and sustained, the clinical course and the image changes, liver failure can be divided into different stages with some or certain factors dominated. we have divided it into two categories, necrosis type and the decompensation type. although this classification is based on practice and clinical management, large-sample analysis is needed in the future. no matter what the cause, liver failure may be divided into two major categories on the pathophysiology. one type is necrosis induced by hepatic inflammation; the other type is decompensation of liver cells. in particular, alf and salf are types of necrosis, aclf and clf are decompensated type. mixed type, both necrosis type and decompensation type, is possible, which treatment should be considered. the relevance of these two type of liver failure mainly reflects in treatment. necrosis type mainly focuses on treatment of the cause (as antiviral treatment for hbv infection and corticosteroid treatment for autoimmune hepatitis) and symptomatic support treatment (as anti-inflammatory treatment and integrated symptomatic support treatment). decompensation type mainly focuses on intensive treatment (as control infection for sirs and control bleeding for gastrointestinal hemorrhage). some pathophysiological processes such as hepatic encephalopathy (he) are in both type, but are different in different liver failure type. for example, cerebral edema is more prominent and progressive and less to do with high protein diet in he patient of necrosis type of liver failure, while is just the opposite in decompensation of hepatic failure. based on pathologic features and speed of progression, liver failure can be divided into four categories: alf, salf, aclf, and clf (tables . and . ). alf occurs liver failure syndrome characterized with varying degrees of hepatic encephalopathy ( ): - (article in chinese) [ ] in weeks except for liver cirrhosis. salf occurs liver failure syndrome in days to weeks. aclf is acute hepatic decompensation on the basis of chronic liver disease. clf refers to chronic hepatic decompensation characterized by ascites, portal hypertension, coagulation disorders or hepatic encephalopathy based on cirrhosis. diagnosis and classification of liver failure are the most controversial part, but has tended to unify in recent years. in , professor roger william from the university of london proposed the same type criteria as chinese. the only difference is limited to weeks for alf and no aslf. due to aslf belonging to alf, this part is not contradictory for two criteria. in recent years, a discussion of aclf proposed many times by sarin from india made aclf more valued and accepted. clf is also getting more recognition. recently, to clarify meaning and avoid misunderstandings, it was recommended that clf be converted into end-stage liver failure (eslf). although issues related to classification of liver failure have largely agreed, there are some differences in practical application. dispute over whether to set up subtypes (namely aclf/saclf) of aclf occurred during drafting the new version of guide. two suggestions of modification are: ( ) with existence of cld, clinical manifestation of acute (within weeks) and sub-acute ( ~ weeks) liver function decompensation occur; ( ) with existence of cld, clinical manifestation of acute (within weeks) liver function decompensation occur (this actually is the original version). the reasons are: ( ) the classification of guide has only been published for years, and it was not easy for it to be widely recognized home and abroad. it requires more time to accumulate experience in this field, so frequent revision are inappropriate; ( ) as is generally accepted home and abroad, aclf mostly occurs within month ( weeks) after onset, while those as late as weeks after onset are rare (the document of our department indicates the same result); ( ) it still requires medical evidence and extensive clinical summary and proof to have the new diagnostic term "saclf" in english and chinese established and accepted; ( ) clinical significance and importance of salf classification are neither prominent nor urgent. after multiple discussions, diagnostic classification in the guide applied the latter one (table . ). despite the differences, academia has become unified about the classification of liver failure in the world. the differences towards the convergence of: ( ) in terms of naming and classification. naming has simply become to acute liver failure (including acute and subacute) and clf (include acute-on-chronic and chronic decompensation), and tend to be more simplified. aasld guidelines clearly stated that nouns used to differentiate the length of the course (such as hyper acute, acute, and subacute) had claimed not to use. ( ) in terms of clinical diagnosis. because of many cause of liver failure, it is very difficult to achieve unity. the only way is to combine the clinical diagnosis (such as acute hepatitis) and the pathophysiologic diagnosis (such as alf). ( ) if hepatic encephalopathy as a prerequisite for liver failure. currently, it is a prerequisite for alf, and not necessary for clf because hepatic decompensation is the main clinical manifestations. according to the severity of the clinical manifestations, liver failure can be divided into early, middle and late stage. . extreme weakness, severe gastrointestinal symptoms such as significant loss of appetite, vomiting and abdominal distension; . progressive jaundice (serum total bilirubin ≥ μ mol/l or increased by ≥ . μ mol/l daily); . bleeding tendency, % < prothrombin activity (pta) ≤ % (or . < inr ≤ . ); . no hepatic encephalopathy or other complications. based on the early stage of liver failure, further develop to one of the following two: . below grade ii hepatic encephalopathy and/or obvious ascites and infection. . obvious bleeding tendency (bleeding point or ecchymoses), and % < pta ≤ % (or . < inr ≤ . ). based on the middle stage of liver failure, further aggravating, severe bleeding tendency (such as ecchymoses on injection site), pta ≤ % (or inr ≥ . ), achieve one of the following four: hepatorenal syndrome, upper gastrointestinal bleeding, severe infection and above ii° hepatic encephalopathy. considering the notorious difficulty to treat hepatic failure and its high mortality rate, special attention has to be paid to and active treatment has to be performed on patients showing the following early-stage clinical features of hepatic failure. . extreme weakness, severe gastrointestinal symptoms such as significant loss of appetite, vomiting and abdominal distension. . progressive jaundice ( μ mol/l ≤ t.bil ≤ μ mol/l), and increased by ≥ . μ mol/l daily; . bleeding tendency, % < prothrombin activity (pta) ≤ % (or . < inr ≤ . ). clinical practice has shown that, with or without history of chronic liver disease, there are patients with grade ii hepatic encephalopathy in a short period, with rapid development, poor prognosis. these patients should be regarded as fulminant type. meanwhile, in asia, including china, there are some patients with severe jaundice, ascites and bleeding as the main presentation, with relatively slow development and very poor prognosis, but without hepatic encephalopathy. these patients should be classified as subacute type. fulminant type must have a hepatic encephalopathy. however, it is not necessary for subacute type, which mainly characterized by severe jaundice and ascites. compared with severe hepatitis in china, fulminant type amounts to acute severe hepatitis and chronic severe hepatitis with acute onset, subacute type amounts to subacute severe hepatitis and chronic severe hepatitis with subacute onset. currently, a large divergence of these two types is about time, from days to weeks. according to clinical features of alf, alf can be further divided into fulminant type and subacute type interval for weeks. however, according to more researches, fulminant hepatitis, characterized by massive necrosis of liver, brain edema, and hepatic encephalopathy, concentrated in weeks, most of them in days or less. taking into account the subacute type belongs to acute category, subacute are not be established in international classification. alf are defined as liver failure in weeks. on the difference between acute and chronic liver failure, most chinese scholars depend on the past history, which be ignored internationally. the difference lies in this onset. acute inflammation, necrosis and chronic decompensated were classified as acute and chronic processes, respectively. most typical example is that patients with acute heavy syndrome of onset in hbv carrier were divided into alf by the scholars from hong kong, macao and taiwan. similarly, liver failure caused by hepatitis flares in chronic hbv carriers, reactivation of chronic hepatitis b, super infection with hdv and hbeag seroconversion are included in alf. it is inconsistent with classification methods in china. the reason lies in greater emphasis on the continuous development processes of hepatitis chronicity and severity in china, and focused on the acute effects this time abroad. some scholars suggest that considering the significant difference between clf and the other three types in clinical manifestation, it is worth discussing whether to list clf as a type of hepatic failure. we believe that significance and importance of clf classification are: ( ) clf are similar to crf (uremia) in nephrology and chronic cardiac failure (congestive heart-failure) in cardiology. although their clinical manifestation differ significantly, the "coexistence of acute and chronic failures" is shared by failures of all those organs; ( ) clf classification has been generally recognized at home and abroad, and the necessity of classification are further proved by the difference between clf and the other three types; ( ) clf cases are relatively large in proportion (nearly %), which is still increasing (since the proportion of alf/salf are lowering); ( ) complications of clf are common and are found in various forms, with bad prognosis; ( ) in clf patients with correlation to hbv, virus replication are commonly found, which is closely related to decompensation. the efficacy of nucs are satisfying, which, if taken for a long term, can reverse decompensation, avoiding liver transplantation; it also increases support means in a fast rate, creating more chances for treatment. if the strict definition of acute and subacute liver failure as "no past history of liver disease" is executed, how to name the patients who had a history of chronic liver disease (caused by hbv from mother to child transmission in china)? as for alf and salf, rigorous definition for the past history of liver disease (including hbv carrying history) is necessary in china, and more interested is in this attack instead of the latent infection in the past, even a dominant attack in europe and america. in clinical practice, past history should not be ignored, because patterns of chronic hepatitis b reactivation vary. we summarize them into four types: ( ) burst type: suddenly attack based on immune tolerance state, eventual liver failure; ( ) recurrent type: repeated unequal flares, finally developing into liver failure; ( ) occult type: no obvious attack, presenting with symptoms of decompensation; ( ) document type: compensated cirrhosis, acute decompensation in certain situations (mainly due to sepsis and other infections). in burst type absence of history, or only carrier state, the past history can be ignored. in recurrent type, history of recurrent injury is important, which the significance lies in the extent of the occurrence, duration and consequences. because these factors determine the basis of injury to the patient's liver, the patients with mild liver disease have mild or even have no hepatic fibrosis and liver cirrhosis, otherwise, the symptoms will be serious and obvious. the former attack often leads to liver necrosis, the latter often lead to decompensation. the difference between occult type and document type is in the speed of decompensation; the former is slow and the latter is fast. in summary, although history has the certain reference value, pathophysiological changes in attack is main of necrosis or decompensation, or a combination of both. whether hepatic encephalopathy should be considered as a complication of liver failure is controversial, because many scholars have listed it as a prerequisite for liver failure, but in recent years, some patients do not necessarily have encephalopathy. from the complete course and early prevention and treatment of liver failure, it is necessary to incorporate non-encephalopathy type, but the effect and prognosis of the rescue treatment should be divided into the encephalopathy type and nonencephalopathy type, because they are different. hepatic encephalopathy is divided into a, b, c type in international guidelines. type a is acute hepatic encephalopathy (alfa-he), which does not include acute hepatic encephalopathy associated with chronic liver disease. some patients with a long-term hbv carrier were diagnosed with aclf or clf on the first time severe, especially in china. in fact, this type of patients with acute or subacute liver necrosis caused by alf. the mechanism of hepatic encephalopathy in this type liver failure is different from alfa-he, as well as treatment. liver failure classification has the greatest impact on treatment of hepatic encephalopathy, based on the following facts: ( ) in acute phase of alf, fasting protein diet on the first day, unnecessary in the short term ( days); however, chronic hepatic encephalopathy of clf don't have to fast; ( ) the metabolism of branched chain amino acids (bcaa) in alf was reduced and increased in clf. this suggests that the former should not be added bcaa, and the latter can supplement the bcaa. ( ) high blood ammonia in clf is more than in alf. the effect of clf was better than that of alf patients, but the effect was not good for deamination drugs. ( ) because cerebral edema in alf is more than in clf, it is better to reduce the intracranial pressure in alf treatment, and in clf with poor efficacy; ( ) as for type a and c according to the international consensus of hepatic encephalopathy are equivalent to the current alf and clf. severe cerebral edema has been found in alf and its mechanism is not clear. study on cerebral edema treatment have been found that hypothermia therapy can reduce the cerebral blood flow and brain edema. in th easl, larsen from affiliated hospital of university of copenhagen in denmark reported that therapeutic hypothermia did not support application in the treatment of patients with alf in a prospective, multicenter randomized controlled experimental study (the study was carried out in - ). the study results are different from previous studies. we believe that the reason is likely from the bias of group selection. in addition, there is a great difference of the mechanism of hepatic encephalopathy in patients with chronic hepatic failure and alf, so the response to hypothermia therapy will vary greatly. based on the existing research, hypothermia therapy has better effect on hepatic encephalopathy in alf patients caused by cerebral edema, and has bad effect on hepatic encephalopathy in the chronic decompensated liver failure caused by metabolic abnormalities. as for hepatic encephalopathy in aclf patients, the effect depends on the roles of cerebral edema in pathogenesis. therefore, it is recommended that the patients should be carefully screened to obtain a comparable result in the study of the hypothermia therapy in hepatic encephalopathy. we believe that, with the gradual elucidation of the pathogenesis of liver failure, the treatment measures will also be more targeted, the efficiency may be further improved. glucocorticoids (gcs) therapy in chronic active hepatitis b began in the s to s. however, compared with the control group, gcs did not show better effect. there have been reports that, after stopping the treatment of immunosuppressive therapy, early re-given long-term high-dose gcs can prevent severe hepatitis in hbv reactivation patients. however, this result had not been affirmed in the future clinical practice. although more application of gcs before s, each effect is different. there is a negative trend in s. we have analyzed, the effect may involve two major factors: one is the choice of indications, dose and duration of treatment; another is the prevention of adverse reactions and complications of gcs. according to the guidelines for diagnosis and treatment of liver failure ( ) in china, liver failure without viral infections, such as autoimmune hepatitis and acute alcoholism (severe alcoholic liver disease), etc. are gcs indications. at the early stage of liver failure caused by other reasons, in the patients with developed rapidly and no serious infection, bleeding and other complications, gcs may be appropriate to use. gcs can improve the survival rate of patients with autoimmune hepatitis and severe alcoholic hepatitis, and has been recognized by most scholars. for hepatitis flares in chb patients, if on the basis of combined application of nucs, gcs will inhibit excessive hyperactivity of host cellular immunity and excessive release of cytokines, and help preventing liver cell death. at the same time, the role of gcs in the treatment of chb and the specific usage, as well as the effect of combined treatment is still controversial. the reason is that the advantages and disadvantages of gcs are very prominent. the key of success or failure lies in the clinical skills. in recent years, the reports of gcs for the treatment of hbv related liver failure increased. there are three main reasons: ( ) nucs can effectively resist hbv replication due to gcs; ( ) application of proton pump inhibitors can effectively prevent gastrointestinal bleeding due to gcs; ( ) increasing of infection prevention and treatment can effectively fight infection due to gcs. even so, the above three aspects of the problem have not been satisfactorily resolved. therefore, we put forward several viewpoints on the current application of gcs: first, to fully analyze the advantages and disadvantages, to consider the main function and purpose after the gcs application and the risk of adverse events before expanding the indications of gcs. secondly, both short course treatment ( - days) and long course treatment has drawbacks. the former may not be sufficient to adequately inhibit a strong immune response, and induce a stronger immune response after a sudden stop; the latter can induce bleeding, infection or viral resistance. finally, in a common clinical liver failure induced by hbv reactivation under immunosuppression, the mechanism is often unrelated with immune activation. the typical representative is fch, and the prognosis is extremely bad. it should be vigilant, focus on prevention. our department has treated a chronic hepatitis c (chc) patients after kidney transplant and taking large doses of gcs. severe fch was induced, resulting in liver failure and eventually died. in recent years, the hepatic stem cell therapy of liver failure was concerned, human stem cell transplantation in the treatment of clinical study on severe hepatitis/liver failure were carried out and the results were satisfactory. however, due to the difference of the patient's condition or stage, and most of which are case report, it is difficult to draw an objective conclusion. we have repeatedly reported that the human umbilical cord blood stem cells and bone marrow stem cells in vitro and in vivo can be successfully transformed into liver cells, but the biggest obstacle to its application to clinical practice is the limited number. it is difficult to repopulate the whole liver or at least part of liver compensatory function. in addition, considering the part liver failure patients with cirrhosis background, which clinical manifestations as aclf and clf in the practical application, there are the following issues: ( ) it is difficult to provide effective growth and functional support for implanted cells in a diseased liver; ( ) the original portal hypertension can be aggravated by portal vein implanted cells; ( ) input cells by vein can obstruct the pulmonary vein, thus affect the pulmonary circulation; ( ) if the implanted cells for allogeneic or xenogeneic tissue, may have compatibility problems; ( ) when using gcs to prevent rejection, severe hepatitis patients are easy to infection and other related adverse reactions. finally, it is pointed out that there is a tendency of the academic circles to the understanding of liver failure for decades, that is, the existence of the chronic process is often neglected in the process of analysis, and vice versa. a typical example, until nearly a few years ago, many scholars in the world still do not recognize the existence of aclf and clf. chinese research papers on liver failure published very little in the international, the main reason is that the aclf and clf is not clearly defined. the papers are often rejected because the diagnosis of type does not conform to the international. in contrast, as previously mentioned in the definition of aki and hrs, the existence of alf (including salf) is ignored. another example: in the report of antiviral treatment of hbv related liver failure, some foreign scholars put forward that the liver failure should be changed to the decompensated liver cirrhosis, the reason is that acute hbv infection is self-limited. however, at present, there has been a clinical recognition that the hbv related alf is actually an acute episode of chronic carrying process and should be referred to as aclf. in chinese guidelines for the diagnosis and treatment of liver failure ( ), liver failure was divided into four types, mainly because of their different mechanisms and treatment (sometimes even the opposite). due to limitation of the space and data, we have not discussed infection, bleeding and other complications in relation to liver failure. these pathological processes are closely related to the classification, and should be studied further in relation to liver failure. in future, we should develop classification of liver failure according to the mechanism of liver injury with different causes, and provide the basis for clinical types of hepatic failure. in order to improve the level of diagnosis and treatment of liver failure, the mechanism based classification should be carefully assessed and evaluated. standard' of definite diagnosis, severity evaluation and treatment effect assessment, and it is irreplaceable compared with other examinations. histopathological evaluation of aechb and liver failure not only contribute to the definite diagnosis of severity of aechb and provide pathological evidence for effective clinical treatment of hepatitis b, but also is helpful to the early detection of histopathological proof of aechb by pathological examinations and of pre-warning function for clinical treatment of aechb. this section mainly focuses on pathological features of aechb and other types of liver failure. aechb, clinicopathological manifestation of aggravation of liver necroinflammation and disease deterioration of chronic hepatitis b, tends to be of poor prognosis without positive and effective intervention. its pathological characteristics mainly include: ballooning degeneration of diffuse hepatocytes, significantly increased focal necrosis, confluent necrosis, bridging necrosis, extensive and intensive interface hepatitis, massive or submassive necrosis, many neutrophil infiltrations in hepatic lobules and portal areas and moderate intrahepatic cholestasis. prominent hepatocyte necrosis is the pathological foundation of aechb and manifests extensive multifocal necrosis, confluent necrosis, bridging necrosis and other forms of necrocytosis. severe ones can even occur submassive and massive necrosis leading to the extreme form of aechb, severe hepatitis (liver failure). ballooning degeneration of diffuse hepatocytes is one of pathological characteristics of aechb ( fig. . ). the hepatocytes manifest sparse and granular cytoplasm, sometimes can be micro-bubble like. the degenerated hepatocyte is - times bigger than the normal hepatocyte. sometimes the ballooning degenerated hepatocytes can fuse and transform into multinucleated cells, and this lesion is similar to that of neonatal giant cell hepatitis when it is relatively extensive. the general performance of the liver is increased volume, tense capsular and cutting edge eversion due to tension. ballooning degeneration of hepatocyte is not specific histological manifestation of hepatitis band also can occur in liver tissues of hepatitis caused by factors such as alcohol or drugs. extensive and diffuse ballooning degeneration of hepatocyte can make the hepatocytic plate wider, and hepatic sinusoid is pressed to be narrower, causing microcirculation disorder of liver tissue and exacerbation of disease. liver lobular inflammation activity is enhanced, and apoptotic bodies and focal necrosis increased significantly when aechb occurs. hepatocyte apoptosis is the programmed necrosis and one of the major forms of hepatocyte death in hbv infection. histopathology manifests cell membrane shrinkage, deepened cytoplasmic staining, eosinophilic degeneration. free apoptotic bodies in liver sinus are large or the apoptotic cell fragments, sometimes containing nuclear fragments. focal necrosis is another form of liver cell necrosis and manifests as an interruption of the hepatocytic cords or replacement by focal lymphocytes and macrophages, with hepatic regeneration that often causes irregular arrangement of hepatocytic cords. this necrosis often inferred from the disappearance of the hepatocytes and the infiltration of inflammatory cells rather than what is actually seen under a microscope. swelling hepatocytes presented increased size and loosing cytoplasm, further develop to ballooning degeneration showed almost spherical in size and transparent cytoplasm, predominantly in the lower right confluent necrosis and bridging necrosis are the common histopathological changes, play important roles in the progression of aechb and are closely related to the adverse prognosis of hepatitis b. due to the larger necrosis range of confluent necrosis and bridging necrosis, even during repair stage after going through the active stage, the liver tissue often undergoes fibrous repair, resulting in liver fibrosis and hepatic lobule reconstruction, thereby causing liver cirrhosis. statistics show that about % of the patients with viral hepatitis who had bridging necrosis progress to cirrhosis. confluent necrosis is regional lytic necrosis of hepatocytes on a larger scale and is common in active stage or aggravation of viral hepatitis, or drug-induced liver injury, which often occurs around the central veins and inflammatory cell infiltration is not obvious. specific confluent necrosis can also be seen in other parts. take ferrous sulfate poisoning for example, confluent necrosis is more common in zone of liver acinus, and when confluent necrosis expands to connecting vascular or portal area, bridging necrosis occurs ( fig. . ). bridging necrosis is large area hepatic lytic necrosis that connect the portal area to central area (p-c), portal area to portal area (p-p), and central area to central area (c-c). it can be caused by the expansion and confluence of interface hepatitis, or a one-time large-scale translocular necrosis. p-c necrosis: it starts on the periphery of the lobules, affects the central hepatic lobules when it expands, and forms bridging necrosis phenomenon. the currently acknowledged mechanism is as follows: the initial pathological change is serious periphery necrosis of hepatic lobules. with the aggravation of the disease, microcirculatory disturbance occurs in the lobules and causes the hypoxia, degeneration and necrosis of central area liver cells. p-p bridging necrosis: most scholars think it is caused by the expansion of interface inflammation, especially based on the fibrous septum, hbv load increasing significantly, immune response enhancing, activating the signal pathway of liver cell death. with the enhancement of the lesion activity, fresh and severe necrosis occurs. c-c bridging necrosis: it is usually seen in serious disease with bridging necrosis of hepatocytes, but mononuclear cells infiltration is rarely seen in the necrosis area and serum transaminase increases significantly (up to iu/l above). histological manifestations of bridging necrosis can vary due to the different stages of the disease. in the early stage, the liver parenchymal cells necrotize and then disappears, reticular framework residue accompanied by the infiltration of lymphocytes and macrophages. with the time extending, reticular framework collapses and forms the sparse interval crossing the liver tissues. when bridging necrosis is accompanied with reticular framework collapse, with hepatic necrosis and regeneration, disorder of hepatic lobules occurs. at this time, it is difficult to distinguish the fibrous septa between bridging necrosis and chronic hepatitis, and elastic fiber staining can help to solve this problem. the elastic fiber staining of bridging necrosis is negative, because elastic fiber formation often takes several months. interface hepatitis, formerly known as piecemeal necrosis, is one of the symbolic histological manifestations in the chronic activity of chronic hepatitis b. it mainly refers to single or small clusters of liver cells around the portal areas necrose and shedding, leading to worm-eaten defect of limiting plates. significant lymphocytes infiltration is commonly seen in and around the portal area. mononuclear cells extend to the hepatic lobules along the destructive limiting plates and encase the necrotic liver cells, resulting in the enlargement of portal areas ( fig. . ) . interface hepatitis increases significantly and extensive interface hepatitis occurs in aechb. the interface hepatitis area can exceed % of portal areas periphery and be more than a third of the depth of hepatic lobules, even causing bridging necrosis (p-p and p-c). because the limiting plate of the lobules is an important structure to maintain a whole hepatic lobules, interface hepatitis destroys the integrity of hepatic lobule structure. extensive and intensive interface hepatitis can often cause bridging necrosis and bridging fibrosis, and is an essential part of poor prognosis of aechb. massive necrosis and sub-massive necrosis are considered to be the basic pathological changes of severe hepatitis (liver failure) and major substratum for histologic diagnosis of liver failure. massive necrosis is the diffuse lytic necrosis of the liver parenchyma involving more than / of hepatic lobules. thorough and rapid liver tissue necrosis is shown with invisible necrosis process, and only reticular framework remained and is filled with red blood cells ( fig. . ) . sub-massive necrosis is diffuse liquefaction necrosis of the liver parenchyma involving / - / of hepatic lobules. reticular framework collapses and forms reticular fiber bundles, residual liver cells and bile ducts proliferate. massive necrosis and sub-massive necrosis will seriously affect the prognosis of patients with high fatality rate once they occur. the cause of massive necrosis and sub-massive necrosis remains unclear, and the possible causes include excessive virus replication, virus mutation, overlapping with other virus infection and microcirculation, etc. when extensive confluent necrosis, massive necrosis and sub-massive necrosis involve the entire hepatic lobule and even several adjacent hepatic lobule, causing a lobular or adjacent several lobular hepatocytes lytic necrosis, then the panacinar or multiacinar necrosis occur, which is the most severe form of necrosis of aechb. in panacinar and multi-acinar necrosis, with large range of liver cell necrosis, only a small amount of liver cells remain. residues of clump, rosetting, island or glands-like arrayed liver cells are commonly seen around the collapsed reticular framework after necrosis or loose fibrous connective tissue. due to distortion, normal structure cannot be recognized and sometimes can only be identified by portal area range around the necrotic area. cells proliferation can be observed in periportal area, arraying like bile duct structure and these cells can express hallmarks of hepatocyte and bile duct epithelial cells at the same time, which is considered to be the histological manifestation of liver stem cells (hepatic stem cell) activation and proliferation. infiltrating inflammatory cell types tend to be multiple, and the quantity varies. when there is less infiltrating inflammatory cells, the main cell type is macrophage, often containing brown pigment particles. notably, the liver biopsy might be error in diagnosing the necrosis of wide range of diffuse dissolved necrosis of liver parenchyma (above / lobule), with only the mesh stents remained the whole lobules and multi-lobules, and that is due to limited amount of liver biopsy specimens. for example, multi-acini necrosis occurs only in the area under the liver capsule, and liver biopsy pathological examination may overestimate the severity of illness. in aechb, types of infiltration inflammatory cells in the liver tissue are various, and most of them contain many neutrophils. it is different from obvious lymphocyte accumulation within liver parenchyma and portal area common seen in hepatitis b. usually, cd + t cells/cytotoxic t lymphocytes (ctls) are the major effector cells of the inflammatory response in hepatitis b. but when exacerbation occurs, the neutrophils in inflammatory cells infiltrating liver acinus and portal area increase significantly. neutrophils play an important role in innate immunity, and are the first inflammatory cells migrating to the lesion during inflammatory response. these neutrophils kill the invading pathogenic microorganisms through releasing protease and anti-microbial proteins, and producing reactive oxygen. meanwhile, neutrophils have important functions in activation and regulation of innate immunity reaction and adaptive immunity reaction and could release cytokines such as il- to participate in regulating adaptive immunity reaction. although cytokines produced by neutrophils are less than mononuclear macrophages, since neutrophils are the first inflammatory cell moving to inflammatory lesion, the immune regulator function of neutrophils is more important during the early or acute stage of immunity reaction. evidently increased neutrophils in liver tissues of aechb might be beneficial for eliminating infected cells, but it is also a "double-edged sword". accumulation of neutrophils may cause extreme immune response and excessive inflammatory reaction might lead to deterioration. therefore, when increasing neutrophils appear in liver tissues of hepatitis b patients, more attention should be paid to identify whether virus mutation, overlap infection, drug-induced liver injury occur and cause aechb. intrahepatic cholestasis (cholestasis), especially moderate or severe cholestasis, is one of the common histologic manifestations of aechb. intrahepatic cholestasis takes shape from the bile thrombus within the cholangioli around the central vein which is hard to be identified, forming cholestasis in expansive interlobular bile duct and large "bile lake" in hepatic tissue ( fig. . ) . microscopically, bile can be characterized by dark brown, green or yellow color, occasionally also can present the gray which is difficult to recognize. bilirubin is revealed as green in van gieson staining, which is helpful to pathological diagnosis of intrahepatic cholestasis. moderate and severe intrahepatic cholestasis often cause feather-like degeneration of hepatocytes, even intrahepatic cholestasis infarction. with the extension of duration of intrahepatic cholestasis, the inter-hepatocyte structure relation of - normal liver cells surrounding the capillary bile duct also changes. the number of liver cells around the bile duct increases, and the bile canaliculi expands, causing the cholestasis related rosette structure forms and the fusing multi-nucleus giant hepatocyte appears. kupffer cells with brown bile pigment can be seen in the hepatic sinusoid. remarkably, although intrahepatic cholestasis is often associated with clinical symptoms such as jaundice and risen serum bilirubin, the severity of intrahepatic cholestasis is not consistent with clinical symptoms and serum bilirubin level. severe hepatitis b (liver failure) is the most severe liver syndrome complex, which is characterized by poor clinical course and high mortality rate. over the years, scholars have continued to explore the definition, classification, diagnosis and treatment of liver failure, but so far no consensus has been reached. according to histopathological features and progression of the disease, china released guidelines on diagnosis and treatment of liver failure in , which divided liver failure into four categories: acute liver failure (alf), sub-acute liver failure (salf), acute-onchronic liver failure (aclf) and chronic liver failure (clf). hbv infection is the most common cause of liver failure in china. acute liver failure is characterized by acute onset, and hepatic encephalopathy (above stage ii) often develops within weeks of the onset, which results in high mortality rate. former knowledge about acute severe hepatitis mostly comes from the autopsy. nowadays, with the development and universal application of biopsy technique, and the further study on acute liver failure, we have better understanding of the development and process of necrotic lesions, and can predict prognosis and outcome according to the necrotic area and type. in alf, liver atrophy is significantly present in gross pathology inspection, especially for the left lobe. coverings shrinkage, thin edge, soft liver texture, section may be yellow or reddish-brown, and some area is red alternating with yellow, and the weight of the liver drops sharply to - g. histopathology emphasizes extensive and consistent liver cell necrosis caused by one-time strike, and most patients die in the short term. the morphology of liver tissues is relatively simple, manifested as massive or sub-massive necrosis of liver cells, dissociation of liver cords and hepatolysis. the regeneration of liver cells is not obvious, and surviving liver cells show clear ballooning degeneration. hepatic sinus expand and, congest with blood and occur hemorrhage. kupffer cell proliferates and sinusoidal mesh stent does not collapse or completely collapse. quantity of liver cell necrosis is closely correlated with prognosis. if the amount of necrosis is over %, mostly the patient will not survive. if the amount is less than %, the patient is expected to resume with rapid regeneration of hepatocytes. if there is diffuse small steatosis, the prognosis is often poor. concerning the hepatic regeneration of acute liver failure, former pathology emphasizes on liver cell and bile duct cell proliferation of sub-acute liver failure, and relatively neglects cell regeneration of acute liver failure. based on the authors' knowledge, in some acute liver failure cases, liver tissue demonstrates obvious bile duct-like or acinar-like regeneration within days after onset. the regenerated liver cells were co-expressing albumin and ck , ck , indicating these cells have double markers of hepatocytes and biliary epithelial cells, which presumably come from liver pluripotent stem cells. the regenerated liver cells in acute liver failure have their unique characteristics that degenerated and regenerated cells co-exist in the liver. as the time of liver biopsy is different, the morphological change is also varied because of the rapid restoration. the usual dual-core, large nuclear or nuclear fission are rarely seen in regenerated liver cells; liver cell body swelling, transparency of cytoplasmic periphery and slightly basophilic center are commonly seen in regenerated liver cells. because of cell enlargement and transparent cytoplasm, it is often difficult to distinguish from serious ballooning degeneration; in some cases, it shows bile granules within the cytoplasm, bile thrombus within bile capillary with cell swelling and transparency symptoms, which is also similar to the feather-like degeneration caused by bile salt siltation. however, unlike feather-like degeneration which was scattered by small groups or disorderly arranged severe ballooning degeneration, cell enlargement often shows the pole adenoid arrangement, which is known as a sign of liver cell proliferation. the outcomes of continuous liver biopsy also prove its rapid regeneration. nayak et al. also proposed that hepatocyte swelling during the acute liver failure recovery stage indicates good prognosis. the continuous liver biopsy of liver transplant centers in europe also confirmed that the appearance of liver cells enlargement after days of partial liver transplant of acute liver failure with massive necrosis, cells linked to sheets, and lobular structure are basically recovered in to months. the vacuolation, cholestasis and duct-like structure presented by these regenerated enlarged liver cells will be gradually disappeared. the onset of salf is acute, and liver failure syndromes appear within days to weeks, mostly caused by delay of acute liver failure. in salf, liver atrophy is mainly presented as in gross inspection, and variable sizes of regenerative nodules, the yellow-green cutting surface due to cholestasis. histopathology manifests the new and old sub-massive necrosis of liver tissues, or bridging necrosis. in older necrosis area, reticular fibers collapse, or collagen deposit. survived liver cells may have varied degrees of regeneration, and are arranged in nodular. fine, small bile duct proliferation and cholestasis are commonly seen in the periphery lobe. the sinusoids congest in the early stage, collapse in mid-stage, and occlude in late stage. the histopathological distinction of salf and alf is based on the consistency of necrotic lesions. alf emphasizes consistency of necrotic lesions, that is, 'onetime strike', while the necrotic lesions of salf are mixed, caused by 'multiple attack'. in addition, differences also exist in aspects such as cell regeneration and extracellular matrix (ecm) expression between alf and salf. liver stem cells play an important role in the liver cell regeneration process of alf. the regenerated liver cells express dual markers of liver cell and bile duct cell, and are often orderly proliferated along mesh stents. whereas salf presents unipolar regeneration of liver cell and bile duct cell, and the regenerated liver cells is disorderly arranged. due to the different length of disease course, there is no obvious ecm deposit in alf, while salf presents in iii collagen-based ecm deposit. this type of liver failure often develops into post-necrotic cirrhosis. acute-on-chronic liver failure (aclf) refers to acute liver function decompensation occurring on the basis of chronic liver disease. liver gross manifestation of acute-on-chronic liver failure differs with the different stages of chronic liver disease. for instance, aclf occurring in the stage of cirrhosis is accompanied by hepatic cirrhosis nodules besides liver atrophy. the main histology of aclf is new and varied degrees of liver cells necrosis, hepatocyte focal and spotty necrosis, bridging necrosis, confluent necrosis, massive necrosis and sub-massive necrosis on the basis of chronic liver injury. the common chronic changes are as follows: fibrosis in collapsed reticular framework or periportal area with obvious extracellular matrix deposit, forming of large number of fibrous septa, sparse scars, or bridging fibrotic septa when distortion of lobule structures associated with disproportionate numbers of central veins and portal area, pseudolobule formed; twin-cell or multiple-cell of liver plate is commonly seen and the liver plate lose the radiated array, activated regeneration of liver cell caused the occurrence of tumor-like cell. chronic liver failure is chronic liver function decompensation caused by progressive deterioration of liver function on the basis of liver cirrhosis, with ascites, portal hypertension, blood coagulation dysfunction and hepatic encephalopathy as main symptoms. liver gross appearance of clf is significant liver atrophy and nodular liver cirrhosis. histopathological changes are mainly those of liver cirrhosis, including diffuse liver fibrosis, nodular liver cirrhosis with unevenly distributed liver cells necrosis. progression of hepatitis b is an interaction between hbv infection and body response. development of aechb is mainly caused by obvious increased viral load and/or decreased immune clearance. large number of hbv replication can activate hepatocyte death pathways, leading to serious liver inflammation, necrosis and aggregation of disease. additionally, hbv infection overlapping with hcv/hiv, or with etiological factors like drugs and ethanol, could also affect disease progression. fibrosing cholestatic hepatitis (fch), a new clinicopathological type, develops in stages of severe immunosuppression caused by various reasons, especially in hepatitis virus-infected patients lots of immunosuppressant after organ transplant. due to immunosuppressor, hbv replicates rapidly in the patients, leading to quick progression of hepatitis and progressive failure of liver function. the histopathological features of fch are as follows: fibrosis straps starching from the portal area to hepatic sinusoid and circumvoluting basal plates of biliary epithelial; obvious intrahepatic and hepatocytes cholestasis, bile embolism forms in small bile duct; hepatocytes ballooning degeneration with disappearance of cells; mass ground-glass hepatocyte; mild to moderate mixed inflammatory reaction ( fig. . ) . fch could quickly proceed to liver failure with blood coagulation dysfunction and hepatic encephalopathy, and mostly die in several weeks to months. due to common transmission, coinfection with hbv and hcv or hiv is not rare clinically. - % of the chronic hbv infected patients carry hcv antibody and there are - million coinfectious patients all over the world. studies showed that hbv and notable intrahepatic cholestasis (black arrow) and ballooning degeneration and/or feathery degeneration (red arrow), a large number of ground glass hepatocytes (blue arrow), associated with inflammatory response (green arrow) hcv coinfection could promote the synthesis of collagen and promote disease progression to liver fibrosis. compared to the single hbv infection, hbv and hcv coinfection presents more severe liver fibrosis and inflammatory necrosis. studies demonstrated that hbv and hcv coinfection could promote chb progression, cause severe damage of the liver function and then exacerbation, increasing the probability of liver fibrosis, liver cancer and liver failure in chb patients. in hbv and hiv coinfection, hiv infection can affect the natural history of hbv and accelerate the development to end-stage liver disease and liver cirrhosis. immune deficiency induced by hiv infection fosters hbv replication, and even fibrotic cholestasis hepatitis in severe cases. histologically, chb caused by hbv and hiv coinfection had a severer fibrosis than that by simple hbv infection. cases of hepatitis b overlapping drug or alcohol induced liver damage are not rare. even antiviral drugs can cause aechb, and there is previous case report on hepatitis b patient died of acute liver failure induced by anti-hepatitis b virus medication lamivudine. abuse or nonstandard drug use and alcoholism have become the common causes of aechb. pathology manifests features of overlapping drug or alcohol induced liver injury on the basis of hepatitis b changes. for instance, in aechb caused by overlapping drug-induced liver injury, liver tissues present histological characteristics of hepatitis b accompanied with drug-induced liver injury, such as evident increased percentages of infiltrated eosinophils and neutrophils in liver tissues, confluent necrosis with less inflammatory cell infiltration in acinus three area, cholestasis of bile canaliculi and so on. in summary, aechb has its relative histopathological features. understanding of these pathological characteristics can not only help with clinical diagnosis and effective treatment, but also aid to prevent aechb. it is important to note that despite the value of histopathological examination in diagnosis, classification and prognosis assessment, considering the significantly decreased coagulation function of liver failure patients and liver biopsy examination has certain risk, hence more attention should be paid to indications of liver biopsy in clinic. laboratory tests for liver diseases is the important basis to help and ascertain the clinical diagnosis, and the important reference to evaluate disease severity, make classification, predict outcome and guide therapy. the laboratory tests may reflect the pathological change and the functional status of liver in time, and may provide the objective and detailed data as reference for clinical classification and evaluating therapeutic effects, so that clinical intervention and effective treatment can be performed successfully. the liver is a complicated organ and the laboratory test items of relevance to severe hepatitis b are many, there are various biochemical items reflecting liver function, including coagulation function, immune and inflammatory cells and genetic markers. in this section only those laboratory tests that are relevant to acute exacerbation of chronic hepatitis b and severe hepatitis b will be described. for nonspecific laboratory tests, the reader is referred to other more general pathology books and literature. serum bilirubin is not a sensitive parameter of hepatocellular injury, but a significant increase (commonly ≥ ten times of upper limit of normal value) is usually a specific manifestation of acute exacerbation of chronic hepatitis or liver failure, which is also necessary condition to diagnose severe hepatitis or liver failure. in the course of acute exacerbation of hepatitis both direct and indirect bilirubin rise markedly due to the disturbance of bilirubin metabolism and secretion because the injury and hypofunction of hepatocytes, paracholia, and the rupture of bile capillary and biliary duct. the main enzymes reflecting liver function are alanine aminotransferase (alt), aspartate aminotransferase (ast), γ-glutamyltransferase (γ-gt, ggt) and cholinesterase (che). enzyme protein content in the liver account for . % of total liver protein. because the aminopherase content of the liver is times that of blood, in a pathological condition, as long as % of the enzyme in the liver is released into blood and keep active, this will be enough to keep the activity of enzyme in the serum increasing at rate of double. alt is an enzyme with the highest increasing amplitude and highest positive incidence when acute liver damage is occurring, with activity in the liver times that of serum. there is a large range of activity in daytime, commonly higher in the afternoon than the morning. although the activity of alt is almost coincident with the degree of liver damage, the activity of the enzyme decreases rapidly when liver failure or hepatocyte necrosis becomes widespread, with significantly increasing levels of serum bilirubin, manifesting the disassociation of enzyme and bilirubin. alt mainly resides in the cytoplasm of the hepatocyte, whilst ast is found more in the mitochondria. when liver cellular necrosis and change of cell membrane permeability appear, there is more release of alt than ast, but in very severe damage of liver, mitochondria damage is witnessed with elevation of ast and significant elevation of ast/alt. che in the serum is mainly produced by liver, with its activity and synthesis decreasing when liver damage occurs. although the change of che is less compared to the aminopherase when liver cell damage occurs, it will drop dramatically when there is severe liver necrosis and liver decompensation, especially in liver encephalopathy. the half life of human serum albumin is - days. because the occurrence of low levels of serum albumin is usually a late marker, the albumin level cannot accurately reflect acute liver cell damage, especially during the acute exacerbation of chronic hepatitis b. serum globulin, especially the γ-globulin, is only elevated in particular chronic hepatitis situations such as decompensated cirrhosis and autoimmune liver disease. the half life of serum prealbumin is only . days, and its reaction is more rapid and sensitive, which can reflect liver cell damage earlier. serum prealbumin has special diagnostic value with acute exacerbation of liver especially acute and subacute severe hepatitis. total cholesterol is composed by cholesterol ester and free cholesterol in healthy people. when hepatocellular damage appears, its cholesterol esterification noticeably decreases. it has been reported that α lipoprotein decreased significantly in patients with liver failure and this indicates a poor prognosis, while the changes of other lipoprotein and serum triglycerides were not specific for the severe type of patients. it has been reported that patients with severe liver dysfunction usually have bile acid metabolism abnormalities, indicating that serum total bile acid is a sensitive indicator reflecting functional recovery of liver cell and improvement of pathogenetic condition, just like alt. detecting serum total bile acid plays an important role in predicting disease prognosis of severe liver failure and evaluation of therapeutic effect. plasma coagulation factor xii (hageman factor) can produce activating factor xii by surface activation, which can further activate kallikreinogen (also called prekallikrein, pk) to produce kallikrein, kallikrein then makes prokinin release bradykinin, which cause vasodilatation, increasing capillary permeability with decreasing blood pressure. because of the short plasma half-life of pk, its plasma content decreases rapidly during liver failure, so pk has important diagnostic value with acute severe type hepatitis and liver failure. it was reported that its content was ± % in healthy controls, ± % in survivors with decompensatory liver cirrhosis, while only ± % in non-survivors. a content level below % predicts poor prognosis, with patients usually dying of liver dysfunction within - days. gst is a protein rich in the liver, the renal tubules and intestine cells in mammals. its major function is detoxication by combining with multiple metabolistic organics such as bilirubin, bromphenol, cholecystographic agent and epoxide. because of the high content of gst in the hepatocyte, its small molecular weight and short half-life (only min), it can be released into the blood after hepatocyte necrosis with high concentration. thus, gst has become a good predictor of observing hepatocyte necrosis especially in patients with acute liver failure and fulminant hepatitis, not only for early diagnosis of hepatocyte necrosis, but also for predicting prognosis. other factors such as multiple circular lysosomal enzyme and serum hyaluronate are all significantly elevated during a course of liver failure. these markers can also be used for monitoring and diagnosis of the disease. severe hepatitis and liver failure caused by hbv infection and other pathogenic factors are not obviously different under laboratory examination, although they have different etiological factors, pathogenesis and clinical manifestation. the major liver function, including protein (especial various kinds of coagulation factors) synthesis, metabolism and detoxication, are the first to lose function, and so result in severe hemorrhage and hepatic encephalopathy. because of the difference on the production of coagulation factors and the steps they involve in, not all coagulation factor detections are suitable for detection of severe type hepatitis and acute exacerbation of hepatitis b. vitamin k dependent factors mainly includes prothrombin (factor ii), pre-convert in (factor vii), christmas factor (factor ix) and fibrin stabilizing factor (factor x). patients with severe type hepatitis can manifest vitamin k deficiency caused by bile accumulation exterior and interior of liver, ingestion reduction or diarrhea. factor vii with the shortest half-life ( - h) is influenced firstly, which cause prolonged prothrombin time (pt). factor ii is not sensitive on vitamin k deficiency, while factor ix and factor x are moderately sensitive. factor vii can be considered as a reliable indicator, and it has important clinical value on prediction of prognosis of acute liver failure because of its short half-life and less influence by other factors, such as inflammation, dic, fibrinolysis, etc. it was reported that when the level of factor vii was below % of normal controls, the probability of death increased significantly, with predicting value of % sensitivity and % specificity. human fibrinogen-like protein /fibroleukin prothrombinase is a mediator of inflammation produced by activated macrophages, which belongs to fibrinogen superfamily and can catalyze and convert prothrombin to activate thrombin directly, thereby starting the clotting process and promoting thrombogenesis. some studies have demonstrated that the level of human fibrinogen-like protein /fibroleukin prothrombinase, if expressed highly and specifically on pbmcs and liver tissue in patients with acute-on-chronic liver failure, can be correlated with disease severity. other clotting factors such as factor vii, xi, xii, i, c protein, plasminogen and platelet count are all decreased in various types of liver diseases, with no special changes on the course of severe-type hepatitis or acute exacerbation. so they are not suitable for evaluation of acute exacerbation of chb. some scholars considered that combination detection of antithrombin iii (at iii), hepaplastin test (hp) and thrombin time (tt) has important value on early predicting fulminant hepatitis. pt is mainly used to detect activity of factor vii, x, ii, v and i. it has three measurable methods: one is the prolonged pt, normal pt is to s, with abnormality above s of normal control value; another is prothrombin activity (pta), which can be calculated by mathematical formula. normal pta is - %, usually below % in liver failure. the third is international normalized ratio (inr), which can be calculated by certain correction factor: pt in patients/pt in healthy. inr is above . in abnormality, and it is generally over . in liver failure. pta and inr detection values have been included in diagnostic criteria of international and domestic liver failure. ptt is a screening test of intrinsic coagulation system. ptt can prolong when it is faced with factor vii, ix, xi and xii deficiency or factor i, ii, v and x reduction and increment of anticoagulant substances. because ptt can be prolonged in a variety of liver diseases, demonstrating that ptt is not necessarily specific for the diagnosis of liver failure. tt tests for the activity of plasma fibrinogen. tt can be prolonged when fibrin degradation product (fdp) is increasing, fibrinogenolysis activity increasing, or fibrinogen (fib) decreasing, or heparin-like anticoagulant substances occurrence. apart from tissue-type plasminogen activator (tpa) and plasminogen activation inhibitor- (pai- ), other proteins and molecules involved in the course of fibrinolysis are all synthesized in liver. so plasminogen, α antiplasmin and thrombin activation fibrinolysis inhibitor (tafi) all decreased significantly in severe liver disease such as decompensated cirrhosis. as a result of dysfunction of liver clearance, the tpa level elevates inversely, while with normal or less elevated pai- in patients with cirrhosis, can cause proportion disequilibrium and final hyperfibrinolysis. in patients with acute liver failure, because of large elevation of pai- as acute phase reactive molecule, the activity of fibrinolysis decreases. on the contrary, taf- decreases by almost %, which induces elevation of fibrinolysis activity. although synthesis of partial coagulation factors and clotting dysfunction usually appear during the course of acute exacerbation of hepatitis b and development of severe-type hepatitis/liver failure, with manifestation of prolonged pt/decreased pta/elevated inr, some investigators had observed conflicting results recent years. specifically, although the mean inr was . ± . in acute liver injury/acute liver failure patients complicated by hepatic encephalopathy, concentrations of factor v and factor vii also decreased, the mean values of the indicators mentioned above detected by thromboelastography (teg) were normal, and also five teg parameters were normal in % patients. we think that the reason of normal clotting function detected by teg in patients with ali/alf might be the normal value of platelet count and fibrinogen quantitation. furthermore, more platelet and factor vii can be produced, and the levels of anticoagulant protein (protein c, protein s and antithrombase) decrease, which also compensates for the defect of the other coagulation factors. in total, clotting parameters such as inr, etc. can be considered as valuable indicators for predicting prognosis, although they cannot be used to reflect hemorrhage severity in patients with ali/alf. ammonia has been considered as a precipitating factor of hepatic encephalopathy for more than years. during severe liver dysfunction, carbamide synthesis is injured, and brain tissue becomes a major organ of ammonia detoxication. with glutamine synthetase, astrocytes in brain can convert glutamate to glutamine to remove accumulated ammonia in vivo by the amidation of ammonia. because the synthesis of glutamine consumes energy, the large consumption of atp can cause energy exhaustion. excess accumulation of glutamine in astrocytes induced by high blood ammonia can cause increasing osmotic pressure and brain cellular edema. this has been confirmed by mri, while with the recovery of liver antidotal function after liver transplantation, previous hepatic encephalopathy can be reversed. in patients with acute liver failure, the risk of cerebral hemorrhage increases rapidly when arterial blood ammonia is above μmol/l. about % patients can have acute intracranial hypertension when arterial blood ammonia exceeds μmol/l. bernal w, et al. in their study which involved patients with acute liver failure, observed that the level of arterial blood ammonia on admission was an independent risk factor of hepatic encephalopathy and intracranial hypertension, and the sensitivity was % for predicting severe hepatic encephalopathy with arterial blood ammonia above μmol/l. combining with the meld score can further increase specificity and sensitivity. the toxicity of ammonia is multiple. the accumulation of ammonia not only influences brain metabolism, injuries brain cellular organelle directly and indirectly, causes disequilibrium of brain internal inhibitory and excitatory neurotransmitter and injuries brain energy metabolism, but also changes a series of gene expressions that are important proteins maintaining brain function. autoregulation of cerebral blood flow is affected and the blood brain barrier broken down. latest studies have revealed that ammonia can injury many important functions of neutrophil, such as chemotaxis, phagotrophy and degranulation, and can also stimulate and produce large reactive oxygen species (ros), cause sirs, which then further aggravates the toxic effects of brain cells from ammonia resulting in a vicious cycle. the liver is an important site of amino acids metabolism. except for bcaa (leucine, isoleucine and valine) metabolism in skeletal muscle, almost all essential amino acid metabolism occurs in liver. because of this, patients with liver failure or cirrhosis, have large amounts of amino acids accumulate in the blood. fischer, et al. demonstrated that disequilibrium of plasma amino acids might be reason of encephalopathy, and further indicated that the molar ratio of valine+leucine+isoleucine and phenylalanine +tyrosine (bcaa/aaa) was closely related with the severity of hepatic encephalopathy. the analysis of plasma amino acids in animals with hepatic encephalopathy demonstrated that other concentrations of amino acids increased significantly except the concentration of arginine, which declined. analysis of brain homogenates from cases of fatal hepatic encephalopathy demonstrated that the concentration of aspartate, arginine and glutamate decreased significantly, and this was closely related with the severity of hepatic encephalopathy. other amino acids, especially the aromatic amino acids, such as tryptophan, phenylalanine and histidine, increased but with carrying amounts; thus, the concentration of the aromatic amino acids was closely related to the severity of hepatic encephalopathy, implying that these aromatic amino acids may play important roles in the pathogenesis of hepatic encephalopathy, although perhaps not as the primary driver. jiang y, et al. conducted a clinical study which enrolled patients with acute hepatitis, patients with chronic hepatitis, patients with severe hepatitis and cirrhosis patients. they observed the ratio of bcaa and aaa was normal in acute hepatitis, mildly lower in the chronic hepatitis (p > . ), significantly lower in the severe grade of chronic hepatitis (p < . ), and the lowest in the patients with severe-type or cirrhosis (p < . ). as for the child-pugh grading, the ratio of bcaa and aaa: c grade <b grade <a grade, with significantly different among the groups (p < . or p < . ). of the patients with severe-type hepatitis and cirrhosis, the ratio of bcaa and aaa in the patients with hepatic encephalopathy was lower than that without hepatic encephalopathy (p < . ); the ratio of bcaa and aaa was significantly lower in the non-survivors compared with survivors (p < . or p < . ). they concluded that detection of bcaa/aaa can reflect the degree of liver damage, the lower the ratio was, the worse the liver injury was, and with high risk to develop hepatic encephalopathy; the ratio might also have certain predictive value for prognosis. elevation of plasma free tryptophan has been correlated with aggravation of hepatic encephalopathy; while in patients with acute liver failure, serum methionine concentrations clearly increase, there is no overlap between acute hepatitis and acute liver failure, and this can be used for differential diagnosis between the two kinds of liver diseases. endotoxin is produced by gram-negative bacteria, and has many biological activities, which can cause endotoxemia, with multiple pathological changes, such as fever, shock, dic and granulopenia. critically ill patients even have acute respiratory distress syndrome (ards), acute renal failure (arf) and multiple organ dysfunction syndrome (mods)/multiple organs failure (mof). wang mr, et al. revealed that the incidence of endotoxemia is - % in severe-type hepatitis patients, . - . % in decompensated cirrhosis, . % in compensated cirrhosis, and % in acute viral hepatitis. it has been considered that the main mechanism of endotoxemia in patients with cirrhosis and severe-type hepatitis is: ( ) intestine mucosal nutritional disturbance, epithelial atrophy, shedding and ulceration, which cause injury of intestine mucosal barrier; ( ) intestine mucosal congestion, edema and increased intestinal wall permeability; ( ) alteration of intestinal flora resulting in translocation of bacteria from the intestinal tract and increasing endotoxin production and absorption; ( ) low ability of clearance of endotoxin absorbed by intestine or endotoxin into systemic circulation from bypass circuit. most studies have demonstrated that endotoxemia and liver injury are interrelated; the liver injury can be aggravated when accompanied by endotoxemia. the detection of endotoxemia is beneficial for predicting clinical course, disease severity and prognosis. medium molecule substance was discovered in patients with uremia accepting hemodialysis, and these molecules have molecular weight of - d. thereafter, it was confirmed to play an important role in hepatic encephalopathy. medium molecule substance can inhibit na + -k + -atp enzymatic activity of brain cells, which result in na + retention and cause cerebral edema. studies have confirmed that medium molecule substance in the blood increased when acute liver failure patient presented with hepatic encephalopathy, which indicated that an increasing amount of medium molecule substance was closely correlated with hepatic encephalopathy and could be used for predicting clinical severity and prognosis. as for the property of medium molecule substance, it has not been totally characterized. the clearance of human medium molecule substance is mainly by secretion and filtration from the glomerulus. according to clinic observations, the contents of medium molecule substance can be detected in the plasma when plasma creatinine (cr) concentration is above . μmol/l or creatinine clearance rate (ccr) is below ml/min. lactic acid is an intermediate product of glycometabolism. the concentration of lactic acid can reflect glycometabolism, peripheral circulation, tissue blood-supply and oxygen-supply indirectly. large studies has demonstrated that total blood lactic acid levels are correlated with disease severity and prognosis. the higher the lactic acid is, the worse the clinical condition is, and also for predicting a poor prognosis. some studies have revealed that the arterial blood lactic acid has a low predictive value for liver failure caused by hepatitis virus infection, toxin and immunity, but a better predictive value for acute and super-acute liver failure caused by acetaminophen over-dose. however, this is controversial. schmidt le, et al. showed that the predictive specificity of lactic acid was not high, even for liver failure caused by acetaminophen. furthermore, lactic acid cannot be used as an indicator for of liver transplantation, and if used, must be done in association with the current king's college hospital (kch) criteria. procalcitonin (pct) is a precursor of human calcitonin, with composed of amino acid residues, kd of relative molecular weight, and also has no hormone activity as a glucoprotein. pct mainly originates from the c cells of the thyroid. during pathologic conditions, multiple tissue and organs can become production areas, such as liver, lung and glandular tissue. the production of pct can be regulated by bacterial toxin and multiple inflammatory factors, and bacterial toxins are a major stimulating factor inducing production of pct. pct is the best ideal indicator for early diagnosis of systemic infection, and has high specificity. serum pct concentration is positively related with the degree of bacterial systemic infection, but can also descend to normal level gradually accompanied with control of bacterial infection and improvement of clinical condition. as for the cirrhosis patients with ascites, detection of serum and ascitic pct can be of benefit to the clinician for predicting early diagnosis and the curative effect and evaluation of spontaneous bacterial peritonitis (sbp). the pct levels can decrease significantly in cirrhosis patients with sbp upon effective antibiotics treatment. so, pct can be considered as a good predictive factor on diagnosis and differential diagnosis of cirrhosis ascites complicated by bacterial infection. it has been reported that the blood lactic acid and pct levels were elevated to different levels when facing patients with either acute liver failure or acute exacerbation of hepatitis b complicated by intestine endotoxemia. a persistently elevated compared to an or not decreasing level of lactic acid and pct are usually indicative of poor prognosis and therapeutic efficacy. combined detection of blood lactic acid and pct does have certain predictive value for acute exacerbation of hepatitis b. in patients with chb, peripheral blood tregs were positively related with serum virus load, while in patients with acute hepatitis b, peripheral blood tregs experienced process from low to high, and usually are normal in the acute, convalescence, and recovery stages respectively. for the patients their treg were rejected, the ability of ifn-γ secretion in the pbmcs increased significantly upon antigen stimulation. while the tregs isolated from the patients with hbv infection could inhibit proliferative response of hbv antigen treated with autologous pbmcs obviously, which might indicate that the peripheral blood and liver in the patients produced hbv antigen specific tregs. so, tregs not only play an important role on regulating immune response of hbv infection, but also influence the prognosis of the patients with hbv infection. natural killer cell (nk) and natural killer t cells (nkt cells) construct the first line of defense of body to defense pathogen invasion, which account for % and % respectively in peripheral lymphocytes, while higher with % and % in the liver. the content of nk cells account for % in liver lymphocytes. the accumulation of nk and nkt cells in the liver demonstrates that they have important function, which can directly eliminate virus by killing infecting cells or secreting cytokines. under the condition of virus specific igg antibody production, nk cells can mediate surface igg fc receptor (fcγriii), identify and kill target cells with complexed igg specifically by antibody dependent cell mediated cytotoxicity (adcc). furthermore, nk cells can also play a role in immunoregulation by secreting cytokines, such as ifn-γ, il- and tnf. nkt cells are a group of inherent t cells which can recognize lipoid and glycolipid antigen presenting by mhc-i molecules associated with antigen presentation, with cd d molecule restriction. nkt cells manifest phenotype of both t cells and nk cells (tcr and nk . [nkrp c], ly- ). nkt cells have two subtypes: type i nkt cells, also called inkt cells, and type ii nkt cells, also called non-inkt cells. the important characteristic of inkt cells is to produce th and th type cytokines rapidly by activation of tcr signal, and also activate multiple other cell types, such as dc, nk cell, b cells, and conventional t cells rapidly by activation of tcr. so, inkt cells can influence adaptive immunoresponse and series of host defense reaction and pathological course effectively. tian et al. demonstrated that nk cells exist abundantly in normal liver, which account for % of lymphocytes within liver and can play important roles on natural immunoresponse of anti-hbv infection. nk cells within the liver can be directly activated by virus or indirectly activated by other cells, such as nkt cells and antigen presenting cells (apc), and exert antiviral effects by their natural cytotoxicity and production of high level of antiviral cytokines. also they can regulate the function of lymphocytes, such as t cells, b cells, apc, and co-ordinate an adaptive immune response. after the binding of fasl expressed by ctl and nk cells and fas expressed by liver cell, the intracellular region of fas protein binds with fas associated death domain (fadd) protein by its c-terminal death domain (dd), then fadd protein activates caspase and lead to apoptosis. malhi h et al. showed that the role of nk cells and nk t cells was a major factor leading to mass death of hepatocyte during the clinical course of viral hepatitis. dendritic cells (dc) are antigen presenting cells with the most powerful function not only playing an antiviral role by secreting cytokine, such as il- and ifn-α, but also by promoting immunoclearance by t lymphocytes activated via antigen presentation. furthermore, dc also can regulate the equilibrium of th and th . so, the abnormity of number, phenotype and function of dc is bound to influence the outcome of hbv infection. some studies illustrated that during liver failure the number of pdcs and mdcs in the liver increased significantly; ifn-α produced by pdcs in the liver was correlated with the production of il- and il- ; the ability of ifn-α production by pdcs in the peripheral blood decreased and the degree correlated with disease severity, which indicated that the dcs in the peripheral blood had accumulated in the liver and activated when hbv associated acute-on chronic liver failure occurred. after dc activation, the role of antigen presentation was enhanced, and the immune response activated and even to a peak level. zh qian et al. observed that the dc of peripheral blood in patients with chronic severe hepatitis b manifested dysmaturity, dysfunction of cytokine excretion, especially the low secretion of il- which mediated cellular immunity, a high level of secretion of il- and tnf-α which mediated inflammatory reaction, and finally become an important factor of aggravating liver inflammatory reaction leading to severe hepatitis. th cell is a new discovered subgroup of cd +t lymphocytes, with significantly different biological function, cytokine expression and differentiation compared with th and th cells. th cells can mobilize, recruit and activate neutrophil leukocytes by secreting cytokines such as il- , il- and tnf-α, in order to mediate inflammatory reactions more effectively. zhang et al. detected the th cells in the peripheral blood and liver of chronic hepatitis b (chb) and hbv associated acute-on-chronic liver failure (aclf) patients. they observed the level of th cells and its associated cytokines increased in chb and aclf patients, and the increasing of th in the peripheral blood and liver is significantly positively associated with hbv dna load, serum alt level and histological index of activity. in vitro, il could promote mdcs and monocyte activation, increase its secreting ability of proinflammatory factors, such as il- , tnf-α and il- , which demonstrated that th might lead to aggravation of liver injury in chb patients, and th can be considered as one of the immunologic indicators reflecting clinical prognosis of hbv associated aclf patients. wu, et al. observed that the ratio of peripheral th in patients with ahb and severe hepatitis increased significantly compared with general patients with chb and health volunteers. th cells were significantly positively associated with serum alt increasing in severe hepatitis, while there was no correlation with hbv dna quantitation. furthermore, serum il- levels were significantly negatively associated with the ratio of th cells, which indicated that th cells correlated with the course of hbv and the severity of liver injury. ye et al. also observed that the ratio of secreting il- and secreting ifn-γ in the liver of the child-pugh c patients with hbv infection was significantly higher than that of child-pugh b; the numbers of the cells secreting il- in the patients with severe liver injury were more than the cells secreting ifn-γ; the degree of cell infiltration with il- secreting were significantly positively correlated with liver inflammation grading, expressing of il- in the liver and neutrophilic leukocyte infiltration. chen et al. observed that increasing serum ifn-γ levels was correlated with disease progression of chb. ifn-γ might be involved in inherent and acquired immunity after hbv infection; ifn-γ can be considered as a potential biomarker for predicting clinical severity of hepatitis b, especially for predicting the tendency of liver failure. il- is a suppressive cytokine which can be produced by th cells, kupffer cells and liver cells, with major functions of suppressing antigen presentation of macrophage, production of multiple proinflammatory cytokines and th response. zheng et al. observed that high expression of il- promoted active viral replication in chb patients, induced excessive immune response. il- can be used to evaluate disease severity and prognosis of severe type b hepatitis. serum il- levels decreased significantly in severe hepatitis b patients complicated by bacterial infection or overlap with other hepatitis virus infections, which indicated endotoxemia and concurrent viral infection play important roles on promoting occurrence of severe hepatitis b. tnf-α is mainly produced by active mononuclear macrophages. the concentration of tnf-α is low under normal conditions, with the function of regulating the immune response. persistent high level of tnf-α can induce liver apoptosis or necrosis. tnf-α has two surface receptors: tnfr and tnfr . du et al. observed that levels of serum tnf-α, tnfr and tnfr increased significantly in patients with acute fulminant liver failure compared with subacute fulminant type, acute type patients and health volunteers, and levels of tnfr were even higher in nonsurvivors. another study showed that expression of tnf-α and tnfr was obviously positively correlated with apoptosis liver cells in patients with fulminant liver failure; tnf-α might lead to widespread liver apoptosis by inducing fas gene transcription and other signal transduction system. except for inducing apoptosis, tnf-α can also induce production or release of other cytokines, such as il- , il- , and so on, to promote intrahepatic inflammatory reaction and aggravate liver cell necrosis by cascade amplified action. ip- is a recently discovered cxc chemokine, mainly induced by ifn. ip- has strong function of chemiotaxis and activation on t cells expressing specific receptor cxcr , and also plays important role on lymphocytic accumulating to inflammatory reactive site, which may be an important factor of inflammatory cell migration toward hepatic tissue and causing large area hepatic cell necrosis. detecting serum il- concentration can indirectly reflect expression of ip- in local hepatic inflammatory response. luo et al. observed that the levels of serum ip- in patients with severe hepatitis b were higher than that of chb group, indicating the higher degree of liver inflammation and injury, the higher serum il- levels. so, serum levels of il- might reflect the degree of inflammation in hepatitis b patients. trail is a new member of tnf α superfamily. a large number of studies indicated trail-r /dr play an important role on apoptosis. the trail induced apoptosis pathway may play an important role in the pathogenesis of severe type hepatitis. trail receptor/ligand system can specifically kill cells infected by virus in hbv infection. vander sloot am et al. observed that affecting hepg cell strain by soluble trail produced by cultural monocyte after lps stimulation can cause apoptosis; higher levels of soluble trail, more obvious apoptosis, which demonstrated that trail induced hepg apoptosis was dose dependent. further studies have shown that serum soluble trail increased significantly in patients with severe type hepatitis and was positively correlated with serum lps concentration and severity of liver injury, which illustrated that decrease of lps degradation accompanied with the degree of liver injury can stimulate mononuclear macrophage and dc to express more trail, shedding strail also increased, cause liver apoptosis and aggravated liver injury after its binding with receptors on liver cells. interleukin- (il- ) is one of the major cytokines secreted by th , and is a member of the il- cytokine family. th is one of the major cells secreting il- . osteopontin (opn) is a secretary phosphorylated glucoprotein which contains rgd (arginine, glycine and aspartic acid) protein with an integrin binding region discovered in . it was isolated from bone matrix by herring in who found that opn was a key cytokine which accumulates in immunocytes and initiates th cell immunity, and is involved in multiple pathological process of inflammatory reaction. some studies demonstrated that levels of peripheral blood opn were significantly high in patients with severe hepatitis b. it also confirmed that nkt cells can secrete opn, and opn also can enlarge activation of nkt cells, to further trigger neutrophil infiltration and activation. further studies on pathogenesis of opn in hepatitis demonstrated that the opn transgenic mice, after been treated with cona, manifested large necrosis of liver cells and monocytes infiltration, while with only minor liver injury on the controls. so it presumed that opn might cause immune disequilibrium of th and th , induce large hepatonecrosis. in patients with fulminant hepatitis, opn increased significantly, indicating that opn can initiate the effect of th cytokine network such as il- and ifn-γ by an autocrine pathway, to further cause macrophage activation and severe hepatonecrosis. as a specific receptor of endotoxin, toll-like receptor (tlr ) can recognize serum endotoxin, bind with lps/lbp/cd , and recruit myd , activate irak (il- r correlated kinase) and mapkkk (mapk kinase kinase) family, induce activation of nf-κb, activate target genes transcription, release a series of cytokines, and cause hepatocytes damage. in patients with severe hepatitis, because of intestinal microbial population derangement, bacterial overgrowth and intestinal mucosa congestion, the ability of endotoxin production and absorption increases, which is accompanied by severe hepatonecrosis, immune dysfunction and a decrease in kupffer cells clearance, which further causes a reduction of exdotoxin and exdotoxin immunocomplex clearance, and finally gives rise to endotoxemia. lipopolysaccharide (lps) is a major component of gram-negative bacteria, with important physiopathologic function. tlr is a key receptor for lps via signal transduction. regulating expressing of tlr should control lps related inflammatory reaction. xu, et al. designed and constructed tlr sirna expression vector, evaluated mouse phagocyte raw . gene silencing efficiency by transfection, and evaluated therapeutic efficacy of tlr gene silencing in the mouse hepatic injury model. it demonstrated that the expression of tlr mrna and protein decreased significantly in raw . cells; tlr sirna can inhibit obviously the up-regulation of tnf-α and mip- treated with lps; the activation of p -mapk and erk / by lps can down-regulate by tlr sirna. further studies demonstrated pretreatment of tlr sirna can be of benefit to control lps inflammatory reaction, reduce hepatic lesion of g bl/ mouse treated by d-ga n/lps, and reduce mortality of mice with acute hepatic injury. some studies also showed that the tlr protein expression on the surface of pbmcs and mrna were obviously higher in patients with chronic hepatitis b compared with the healthy controls; levels of tlr in severe-type patient of chb were significantly higher than that of chb, which indicated tlr played important roles during the course of liver injury with hbv infection, and with obvious increasing accompanied with clinical severity. fan jg, et al. observed the expression of tlr increased accompanied with the degree of endotoxemia and the prolong of stimulus duration; lps can positively up-regulate expression of tlr and enlarge biological effect of lps. so the severe hepatonecrosis and weakening of kupffer cell deactivation can accelerate the occurrence of endotoxemia, while endotoxin also can regulate liver cell metabolism or influence tlr mediated immune reaction to aggravate the clinical situation. the two aspects interact quite closely. all the studies mentioned above indicated high expression of pbmcs tlr in patients with chronic hepatitis, especially with severe-type presentation. monitoring dynamic changes of tlrs might be benefit for treatment. nitric oxide (no) is a biological regulatory factor with an extremely short halflife, produced by l-arginine catalyzed by nos (no synthetase), with extensive biological functions. it is now believed that no has potential antiviral inductive activity, and also might be one of the factors mediating liver injury. the studies of mouse model with inos defection demonstrated that the mouse model can tolerate ctl induced immunologic injury during the course of inhibiting virus replication because of no dyssynthesis, and also opposed against injection of fatal anti-fas antibody, further caused no obvious hepatonecrosis after treated with anti-fas antibody. in severe-type patients with hepatitis, serum no levels significantly increase during the early stage, then no levels decrease significantly with extenuation of inflammatory reaction, liver function recovery in the convalescence phase. these studies revealed that no is related to the degree of inflammation and clinical severity, and can play an important role in the clinical course of severe-type hepatitis. some studies demonstrated that inos gene was related closely with viral hepatitis. the expression of inos gene was extremely low in normal hepatic cells. once invasion of hepatic cells by virus appeared, it can induce hepatic cells to activate inos gene expression and produce large amounts of no, not only to kill liver tumor and pathogens such as virus, bacterium, parasites, play broad-spectrum antiviral function, but also injury to adjacent normal liver tissue by cell toxic action, and cause liver cell death. gong fj, et al. presumed that pre-s protein can downregulate inos transcriptive activity by its trans-regulation, further inducing the decline of no production and blocking the clearance of hbv in hepatocytes by no, and finally accomplishing long-term hbv chronic infection. so, expression of inos can be considered as an important factor of inflammatory injury. neutrophil gelatinase-associated lipocalin (ngal) was considered as a novel troponin-like biomarker, which was discovered in by kjeldsen, et al. who studied neutrophil matrix metalloproteinase (mmp- ) at that time. it was believed that ngal could be used to monitor acute kidney injury/acute renal failure. renal dysfunction is extremely common during the clinical course of severe liver disease such as decompensated cirrhosis and liver failure. serum cr levels can increase rapidly when acute renal failure occurs and is easily detected, while it is not easy detected or diagnosed when complicated by chronic kidney injury. furthermore, other diagnostic methods based upon glomerular filtration rate (gfr) are needed to detect clearance rate, and are not suitable for routine application. the detection of serum cr is simple, while is not accurate on detection of kidney injury based upon cirrhosis. gerbes al, et al. observed cirrhosis patients with ascites whose serum cr below . mg/dl, compared the levels of serum ngal and cr. the patients was divided into two groups, the gfr was ± ml/min and ± ml/min, and with serum cr of . ± . mg/dl or . ± . mg/dl respectively, with no obvious difference. the estimated gfr was ± ml/min and ± ml/min respectively, also with no difference. while in the study, serum ngal was ± ng/ml and ± ng/ml, demonstrating significant difference (p < . ). furthermore, levels of urinary ngal is similar with the blood ngal, especially the patients in the group , with urinary ngal above ng/ml. area under the curve (auc) analysis also revealed that ngal was better than serum cr assay when gfr < ml/min, with auc = . ( . ~ . ) of the former, and . ( . ~ . ) of the latter (p < . ). macrophage inflammatory protein (mip) is a novel protein first discovered in by wolpe, et al. which can be divided into five subtypes: mip- , mip- , mip- , mip- and mip- . mip- has a binding site for heparin, which can interact with heparin dextran sulphate in endothelial extracellular matrix, and enhance adhesion of leucocytes and vascular endothelial cells. mip- is involved in the whole process of inflammation by chemical chemotaxis and activation of inflammatory cells, with neutrophils as specific target cells. mip- can also activate neutrophils specifically and has been considered as an important proinflammatory cytokine during the early stage of inflammation. chen z, et al. observed that the levels of mip- in severe-type patients with hepatitis b was significantly higher than other groups. persistent high expression of mip- can be used to predict acute exacerbation of hepatitis b and clinical severity of patients with hepatitis b. thymosinβ (tβ ) is one of the important actin regulatory molecules in human body. it can bind with globular actin (g-actin), inhibit production of fibrous actin (f-actin), reduce formation of microthrombi and microcirculation dysfunction in patients with liver failure, and inhibit occurrence and development of mof. tβ can also reduce the levels of free radicals, slow lipid peroxidation and inhibit production of proinflammatory factors. patients with liver failure usually manifest a large amount of mononuclear macrophage infiltration, secretion, releasing proinflammatory factors and aggravate systemic inflammatory reaction. liu y, et al. observed that the levels of serum tβ decreased significantly in patients with liver failure compared with the cirrhosis group, chb group and healthy controls. dynamic changes of serum tβ can be considered as a novel predictive indicator for prognosis in patients with liver failure. t cell immunoglobulin mucin (tim- ) is a surface molecule correlated with function of t cells, which was discovered in . the studies on mouse model revealed that tim- can be expressed on the surface of th selectively as a negative regulatory molecule; the interaction of tim- and its ligand plays a down regulatory role on th cellular mediated immune response. sabatos ca, et al. observed that the levels of peripheral tim- in chb patients increased significantly, and it indicated the expression of tim- can be induced by regulating treg whose activity was modulated during the chronic infection period in patients with chb, and then inhibit specific th cell responses. zhou xq, et al. observed that the levels of tim- was significantly higher than other groups in severe-type patients with hepatitis b, which can be used to predict and monitor the clinical severity of hepatitis b patients. with the progression of chb, serum inos and ngal all increased, with the highest levels in severe grade of chb, while decreased inversely in the serum of the severe-type patients with hepatitis b, which can predict acute exacerbation of chronic hepatitis b. it was reported that the crosspoint of persistent elevation of tim and mip , and declining of inos and ngal, demonstrated important clinical significance on predicting acute exacerbation of chb. recent studies have demonstrated that genetic variation of hormone receptor gene was significantly different between chb patients with acute exacerbation and hbv carriers, which could explain the sexual difference on different clinical course of hepatitis b. clinical studies further demonstrated that male patients with hbv infection had higher incidence and ratio of chronicity; male patients with hbv infection had higher activity frequency, which indicated the sex hormone and its receptor might influence the process of hbv infection by regulating host immuno response and level of viral replication. it is now believed that immunoresponse of viral clearance might down-regulate male sex hormones and up-regulate female sex hormones. furthermore, steroid hormones might regulate replication of hbv mediated by androgen receptors. it has been proved that androgenic hormone can inhibit cellular and humoral immune reaction; estrogenic hormone can inhibit cellular immunoresponse and enlarge humoral immunoresponse inversely; progestogen can promote conversion from cellular immunity to humoral immuno reactivity. several studies have reported the action of estrogen receptor (esrs) in the diseases of multifactorial inheritance, and its roles have also been observed by geneticists and virologists. large number of studies have demonstrated that esr played important roles on regulation in patients with persistent hbv infection, and esrs genes were correlated with host hereditary susceptibility. because of low expression of esrs in hbv carriers, the reaction of immune system to sex hormone was insufficient, which make clearance of hbv difficult and can lead to hbv persistent infection. human esrs are divided into two types: estrogen receptor a (esr ) and estrogen receptor b (esr ). all the genetic variations can cause degression of estrogenic function, which may further cause different kinds of host hereditary susceptibility after hbv infection. of them, esr gene can mutate, with tendency of sex hormonal resistance. sex hormone mainly plays the role of binding esr , and esr gene is the true minor gene with host hereditary susceptibility after hbv infection. deng gh, et al. observed the relationship between esr gene polymorphism and chronic persistent hbv infection in a large sample study. they found that the susceptibility increased significantly compared with the individual of esr t/t genotype and the individual containing at least one c isoloci site (p < . ). linkage disequilibrium plotting analysis indicated that t c polymorphism included a linkage disequilibrium area sited from esr promoter to intron , which indicated that the esr t c convention originated from esr itself, and esr gene polymorphism in the chinese population was positively related with hbv persistent infection. the negative feedback regulation of hypothalamus-pituitary gland-genital gland axis can be performed by serum testosterone (t) and estradiol (e ) through central nervous system feedback, and control releasing of luteinizing hormone (lh) and follicle stimulating hormone (fsh) . some studies demonstrated that the levels of serum t and e decreased in male patients with hepatitis b cirrhosis, and the levels of lh and fsh increased correspondingly, which indicated liver injury might be an important reason of sex and hypophyseal hormone abnormality. until now, the studies on changes of sex and hypophyseal hormone in acute exacerbation of hepatitis b and severe-type hepatitis are still limited, while it is certain that precise detection of sex hormone and correlated hypophyseal hormone can reflect the severity of liver injury to a certain degree, and can be considered as a useful indicator evaluating the clinical course of hepatitis b, cirrhosis and its complication, hepatocellular carcinoma. it is now believed that the priming or control point of severe-type hepatitis occurrence and development is influenced by two aspects: virus (such as viral variation, viral protein and viral genotype) and host (such as cell immunity, cytokines and apoptosis), and of them, viral replication is the necessary condition and cause of severe-type hepatitis. some studies demonstrated that viral replication was relative vigorous during the early stage of severe-type hepatitis, which indicated viral factor occupy a central position in the occurrence and development of acute exacerbation of hepatitis b. the changes of host transcription factors and hbv genetic variation all possibly cause the changes of hbv transcription and replication, resulting in acute exacerbation of hepatitis b. hepatocyte nuclear factor (hnf ) is a protein with the function of genetic transcription and modulation, and is mainly found in liver. long ce, et al. observed that the hnf binding sites, located in enh i/xp and enhii/c promoter, is an important factor regulating c promoter activity and . kb mrna transcription, and has an important role on hbv replication and expression with high tissue specificity. previous studies demonstrated the expression of hnf increased in patients with chb, and the level of hnf is positively correlated with hbv replication. furthermore, from a study on liver biopsy specimens using gene array in patients with hbv infection, honda m, et al. observed hbv infection can cause more gene transcription of hnf , rxr/ppar and c/ebp, and possibly related with liver injury. so, the interaction of hnf and hbv genetic transcription and control might play an important role on the pathogenesis of severe-type hepatitis b. deng et al. studied cxcl snp variation on th immune response pathway, and observed that the polymorphism site g- a existed in cxcl gene promoter region was significantly related with disease progression in male hbv carriers. an emsa study revealed that the g- a site can change its binding ability with nucleoprotein; and reporter gene assays also revealed that this site can influence the transcriptional activity of cxcl gene promoter region; mrna real time quantitative experiments further revealed that the expression of susceptible allelotype - g in pbmcs was significantly higher than allelotype - a; elisa and immunohistochemical assays revealed a higher expression of cxcl protein in plasma and liver tissue of patients with chb that progressed than that of nonprogressive patients. all the studies mentioned above demonstrated that g- a is a new functional polymorphism site, cxcl protein involved in the process of inflammation and necrosis in liver tissue of patients with hepatitis b, and influence the progression of chb. furthermore, yan z, et al. reported that mutation of ifn-γ gene can influence expression of ifn-γ, which is a predisposing factor of chronicity of hbv infection; fulminant hepatitis patients with poor prognosis had high frequency of occurrence of - c, - a and tnf-βb allele in tnf-α gene promoter region; snp in il- gene promoter region was related with progression of chronic hbv infection; the frequency of haplotype expressed by down-regulated il- in the il- gene promoter region in patients with fulminant hepatitis was higher than the controls, while the frequency of haplotype gene occurrence by up-regulated il- expression was even lower. yan et al. also revealed the relationship between polymorphism of il- gene promoter in th immuno response pathway and chronic severe-type hepatitis, which provided new evidence on natural selection theory of il- promoter and sirs pathophysiology theory of acute liver failure. in a study of human fibrinogen-like protein (hfg ) gene regulation mechanism and network, han et al. observed that hbc protein and hbx protein all had the function of hfg activation, while hbs protein cannot activate the gene. a series of promoter deletion experiments demonstrated that the regulation sequence of activating hfg gene existed between the sits of hfgl gene promoter − ~ − , transcription factor c-ets- can bind with cis-acting element on hfg gene promoter, then activate the expression of the gene under the action of that viral protein; the phosphorylation level of p-jnk and p-erk was enhanced in patients with severe hepatitis b than healthy controls, which indicated jnk and erk signal pathways were activated. some studies in vitro revealed that jnk and erk signal pathways were activated respectively under the effect of viral protein hbx and hbc, and c-ets- expression and transposition were correlated with the activity of jnk and erk. all the studies mentioned above indicated that viral protein hbc and hbx can activate jnk pathway and erk pathway respectively, further activate transcription factor c-ets- , shift into the nuclear, and finally up-regulate the expression of hfg gene by binding with cis-acting element of hfg gene promoter. tnf-α is an important proinflammatory factor induced during liver failure. mfg /prothrombinase plays an important role on mouse fulminant hepatitis and acute on chronic liver failure. gao et al. constructed eukaryotic expression vector of mfg gene and tnfr gene, green color fluorescence fusion protein and its shrna interfere plasmid. it was more effective to improve the survival rate of mouse with severe type hepatitis using combination of fg and tnfr genes compared with single gene intervention, and improve serology and pathological changes of liver, which indicated that fg and tnfr genes might produce synergistic effect during the progression of severe-type hepatitis. hbv infection is a necessary condition and cause of occurrence and progress of severe-type hepatitis, while hbv gene transcription and replication are a key step of the hbv life cycle. beginning from the new point of genetic transcription, further exploring the effect and mechanism of acute exacerbation of hepatitis b on hbv genetic transcription and regulation, will provide important clue of host transcription factor, which can be useful to predict and monitor the occurrence, development of severe-type hepatitis, and to provide new targets for effective methods of treatment of severe-type hepatitis. genome-wide association study (gwas) has been available since , and have become the main aspect of complicated genome association study. the strategy does not need to select candidate genes, but to make genome-wide associations and analysis by selecting directly ten thousand single nucleotide polymorphism (snp) sites and copy number variation (snv) sites over the total genome. compared with the strategy of a candidate gene, gwas was a significant improvement in statistical efficacy, and also avoided the bias of group stratification and randomness of gene selection. in recent years, some studies on the aspects of viral hepatitis and hbv related hepatocyte carcinoma has gained great breakthrough using these approaches. several independent and large sample gwas in usa, europe and japan demonstrated that only rs site near the il- b gene had relationship with curative effect of interferon in the study on genetic correlation of ifn response in patients with hepatitis c (with p value of − ). guo et al. observed that gene variation of hlp-dp gene can play great influence on clinical severity of persistent chronic hbv carriers. karlsen et al. also reported the relation between hla-ii gene and hbv infection. he fc and zhou gq made gwas of hbv related hepatoma, and they discovered a related site p . , where one of the three genes (kif b, ube b, pgd) might be predisposing gene of hbv related hepatoma. the studies on genetic predisposition of severe-type hepatitis b are relatively less. only a minority of studies have examined a candidate gene-disease associated study strategy, and their study populations were all from asia. recently, under the support of the national program and key state science and technology project of infectious disease, chinese experts have taken affymetrix snp . array (including , snp sites and , cnv sites in the range of human total genome-wide) to make gwas in severe-type patients with hepatitis b and asymptomatic carriers. the project is now being analyzed, expecting to explore common genetic variance sites influencing severe-type hepatitis b under the point of host total genome. epigenetics mainly studies the change of herediable gene expression with no change of dna sequence. currently, epigenetic mutation mainly includes dna methylation, microrna (mirna) and chromatin remodeling. several functional studies also demonstrated that mirna participated and regulated the expression of multiple inflammatory signal factors. it was found that mir- and mir- might be linked with liver inflammatory activity of viral hepatitis. mir- mainly participated in regulating maturation of b lymphocytes, and also regulate the differentiation of th and th cells. mir- located in human x chromosome, and highly expressed specifically in granulocyte series cells. johnnidis, et al. observed the granular leukocytes increased twice in mir- gene knock out mouse, and these leukocytes were more sensitive when treated with antigenic stimulation outside (especial fungi); compared with mir- gene non-knock out mouse, the lung inflammation of mir- gene knock out mouse was more obvious, and the tissue injury induced by exdotoxin stimulation even more serious. the latest studies have discovered seven susceptible molecules correlated with acute exacerbation of hepatitis b: mir- a (down-regulation in severe-type twins patients with hepatitis b), mir- a (up-regulation in severe-type patients with hepatitis b), mir- (up-regulation in severe-type patients with hepatitis b), mir- (providing early warning signal on acute exacerbation of hepatitis b and disease severity), mir- (has obvious decline tendency with the development of liver failure, and can be considered as biomarker for predicting clinical severity and acute exacerbation of hepatitis b), mir- (its expression decreases gradually accompanied with viral clearance, can be considered a biomarker of turnover of acute exacerbation of hepatitis b, and provide early warning signal on acute exacerbation of hepatitis b and treatment), mir- (down-regulation has predictive value to liver inflammation). it has been finally shown that detection of specific mirna correlates with liver inflammation, by using mirna array technique in severe-type patients, can provide novel target on early prediction of severe-type hepatitis. qi zx, et al. observed the difference of th and th cells chromatinization status in il- gene promoter region, which interfered with the binding of promoter and transcription factors, and influenced gene transcription of il- . the distribution of methylation in patients with liver failure showed obvious differences between chb patients and healthy controls; concentrations of serum il- were negatively related with promoter methylation status, which indicated the methylation of il- gene promoter region might involve in the pathogenesis of liver failure, and it is also a reason of il- change. furthermore, some studies revealed that methylation of glutathione-s-transferase p promoter region can promote acute exacerbation of hepatitis b. of hepatitis b toll-like receptors (tlrs) mediated signal transduction pathway includes two forms: myeloid differentiation factor- (myd ) dependent form and myd independent form. tlr , tlr and tlr mediated signal pathway belongs to myd dependent form pathway; tlr mediated signal pathway belongs to myd independent form or trif independent form signal pathway. in the myd independent form pathway, tlrs recognized ligand, then activate nf-κb and mapk, induce release of multiple cytokines, up-regulate costimulatory molecules such as cd , cd , et al., then finally activate specific immune system. tlrs and tlr in particular, play important roles on the mechanism of acute exacerbation of hepatitis b, which can better predict tendency of the disease, and can be considered as indicators for evaluating prognosis of severetype hepatitis b. tlr is a key receptor in endotoxin transmembrane signal transduction; it is also a rate limiting factor in lps transmembrane signal transduction of mononuclear cell and macrophage. some studies demonstrated that the expression of tlr mrna in severe-type patients with viral hepatitis was higher than the healthy controls; and it is higher during the aggressive stage than the critical stage in the nonsurvivors and it is lower during improvement than the critical stage in the survivors. furthermore, expression of tlr mrna is positively correlated with the levels of endotoxin. deng m, et al. observed that the severe-type patients with viral hepatitis had tendency to endotoxemia, with endotoxin binding with tlr , then transmembrane signal activation of nf-κb through intracellular structure of the tlr , further induced release of inflammatory factors, such as tnf-α and il- , and produce secondary intrahepatic microcirculation disturbances. tlr is a pattern recognition receptor with extensive pathogen recognition abilities. tlr can recognize cell walls from multiple bacteria such as gram-positive bacteria, gram-negative bacteria, fungi, spirochaetes, mycobacterium tuberculosis and mycoplasma, and play important roles on acute and chronic infection. yan cg, et al. observed the expression of tlr of mouse with fulminant liver failure induced by d-gal/lps. they observed the high and persistent expression of tlr mrna, and accompanied with high expression of tnf-α, which indicated that tlr can up-regulate expression of downstream inflammatory response genes and release of cytokines, to involve in acute liver failure induced by d-gal/lps. metabolomics is a new technology, which studies various changes of endogenous metabolic products and biologic conditions in humans by observing biosystem changes qualitatively and quantitatively under various stimulations and changes of internal and external environment. the study object is the micromolecule compound with relative molecular mass < in the metabolic network. at present, the major techniques include nuclear magnetic resonance spectrum (nmr), gas chromatogram (gc), liquid chromatography (lc), capillary electrophoresis (ce), mass spectroscopy (ms), infrared spectrum and ultraviolet spectra. of them, nmr, gc-mc and lc-mc are used more extensively. yang et al. investigated the serological profile in acute hepatitis b patients with sudden aggravation of liver function by hplc-ms and pls analytical techniques. they observed the changes in individual atoms in lysophosphatidyl choline (lpc) and gcdca, which can predict early disease aggravation. feng b, et al. analysed the metabolic product in serum of rats with fulminant liver failure by gc-mc and pca software, and observed high content of -hydroxyindole acetic acid, glucose, β-hydroxybutyric acid and phosphate, which indicated the changes of these substances might become potential biomarkers of fulminant liver failure. yu, et al. set up a research platform based upon liver failure metabolomics by using gas chromatographic mass spectrometry (gcms) and super-high performance liquid chromatogram mass spectrometry technology, constructed a model for evaluating clinical severity of liver failure, and constructed serum specific metabolism spectrum by partial least squares discriminant analysis, which can be used to predict the prognosis, with sensitivity of . %. mao et al. also derived similar results with a high positive diagnostic rate of . % for liver failure, and also found that the changes of climax concentration of plasma citrate had potential diagnostic significance. li lj, et al. pointed out the low level of lysolecithin, high level of fatty amide and nonelevation of bile acid by using metabolomics were risk factors for predicting poor prognosis in liver failure patients with pretreatment and post-treatment by artificial liver support systems. by observing the trend changes of serum metabolic spectrum in patients with pretreatment and post-treatment with an artificial liver, we can predict the prognosis and assess curative effect of artificial liver. electrolyte disturbances were usually complicated in patients with liver failure because the patients typically have low renal blood flow and glomerular filtration rate (gfr). a majority of patients manifest hypokalemic, hyponatremia, hypomagnesiumemia and hypocalcemia. the occurrence of hyponatremia and its severity are positively related with prognosis in patient with liver failure. severe hyponatremia can cause acute low sodium syndrome and encephalopathy; and hyponatremia can also cause renal injury and promote or aggravate development of hepatic encephalopathy and hepatorenal syndrome (hrs), and increase mortality. some studies indicated that the mortality of the patients with severe hyponatremia (< mmol/l) is extremely high and up to . %. in patients with acute liver failure, hypochloraemia can be caused by insufficient intake of chlorine, vomiting, large excretion of aldosterone and acidosis, while water intake insufficiency, renal failure, renal tubular acidosis and potassium chloride overdose can cause hyperchloraemia inversely. furthermore, hypophosphatemia is more readily detected than hypocalcemia in most patients. acid base disorders (abd) are very common in patients with acute liver failure, especially alkalemia. li xm, et al. presumed that arterial carbon dioxide pressure depression and respiratory alkalosis are frequent manifestations of acid base disorders. abd is not related with basic pathological changes of severe-type hepatitis, whilst blood ph value is an important factor influencing the survival outcome of severe-type patients with hepatitis. in the latest years, some scholars think that pre-estimation of compensatory formula (pcf) for abd has practical value on differential diagnosis of partial simple and duality abd. partial patients with acute liver failure complicated by abd can be diagnosed by anion gap (ag), potential hco −· and cl − . elevation of ag is a reliable indicator of appearing potential metabolic acidosis, and is common in patients with hepatic encephalopathy, lactic acidosis caused by hypoxemia. during hepatorenal syndrome since reduction of acidum excretion of kidney ketoacidosis may appear. potential hco −· is the hco −· value exclusive of the masking hco −· by high ag metabolic acidosis, which can raise the existence of ag metabolic acidosis and metabolic alkalosis with triplicity abd. a mixed metabolic acidosis can be discerned by combination of ag and blood ci. series of primary abd can overlap, even to develop duplex and triplication abd. for example, if the respiratory alkalosis prolongs, accompanied with increasing of potassium excretion by renal, and with iatrogenic factors to develop metabolic alkalosis, and further develop multiple complications combined with metabolic acidosis, which finally develop triplicated abd. triplication abd is usually the end stage of acute liver failure, with worst prognosis. so, prevention and active treatment of abd is an important parameter for rescuing patients with acute liver failure. liver biopsy is a good method to acquire pathologic changes of liver in multiple liver diseases including liver failure, which have important value on directly evaluating the severity of liver damage. liver biopsy is generally divided into percutaneous biopsy, transvenous biopsy, surgical/laparoscopic biopsy and plugged biopsy. of them, percutaneous biopsy is safe and simple, without special instrument or equipment, and being used extensively. transvenous biopsy is more suitable to the patients with large amount of ascites, clotting dysfunction, diminution of liver volume and increasing of liver hardness because of cirrhosis, difficulty to determine hypochondria because of obvious obesity, and with high hepatic vein pressure. the contraindication of liver biopsy are as the follows: ( ) excessively prolonged pt, excessive declining of pta, which might cause haemostasis difficult even mild injury; ( ) obvious cavity bleeding or large area of petechia; ( ) patients with unconsciousness, who might not be able to fit the operation; ( ) medium dose ascites, especially patients complicated by abdominal infection; ( ) patients with obvious pleural effusion and severe heart and lung disease. it has been proved that liver biopsy is safe to a great extent under careful preparation, attentive operation, even in the liver failure patients with obvious clotting dysfunction. what we need to point out is that although liver biopsy has important value on recognizing liver tissue degeneration, necrosis and degree of inflammatory infiltration, the pathologic change of the biopsy tissue might not be able to reflect entire pathologic change of the liver because of the limited liver tissue obtained. so, it is very important for clinicians to collect and combine various forms of clinical data, laboratory and pathogenetic results from the patients, for getting an accurate judgment. the incidence of cerebral edema in severe-type patients is high, with ratio of to %, and a quarter of them can appear cerebral hernia with poor prognosis. so, measurement of intracranial pressure plays important role on diagnosis and treatment of cerebral edema. traditional lumbar puncture manometry can measure intracranial pressure only one time; it cannot be observed that the changes of intracranial pressure dynamically and exactly. on the other hand, lumbar puncture on patients with acute intracranial hypertension might cause or aggravate cerebral hernia. furthermore, under the condition of cerebral hernia, cranial cavity and spinal cord cavity can not intercross, so the pressure detected by lumbar puncture cannot represent actual intracal pressure. so, persistent detection of intracranial pressure retrieves shortage of lumbar puncture, and cerebral ventricle catheterization is still an extensively used method, which is considered as gold standard of intracranial pressure monitoring by clinicians. intracranial hypertension is defined as persistent elevation of intracranial pressure with levels above mmhg. according to the difference of intracranial pressure, intracranial pressure can be divided into four stages: ( ) normal: ~ mmhg; ( ) mild: ~ mmhg; ( ) moderate: ~ mmhg; ( ) severe: above mmhg. if intracranial pressure is close to mean arterial pressure (map), which illustrates almost no brain perfusion, with nearly close to brain death. currently, mmhg is defined as the critical value of applying treatment of anti-intracranial hypertension. complications of intracranial pressure measurement include infection, intracranial hemorrhage, iatrogenic acute intracranial hypertension and brain parenchyma injury. although laboratory parameters can reflect pathological changes and liver functions during the clinical course of severe-type hepatitis and acute exacerbation of hepatitis b sensitively and in time, and can provide detailed reference data for clinical typing, grading and curative effect evaluation, in total, the extensive and large numbers of indicators listed above are still under study and experimental evaluation, and their availability and utility need to be checked by more clinical practice. until now, laboratory parameters have been extensively used and applied clinically but are still limited. the laboratory parameters conventionally tested in the majority of hospitals are mainly pta, inr, serum bilirubin, alt/ast, pre-protein and blood ammonia. furthermore, some studies also reveal that serum afp, serum sodium and phosphate are closely related with prognosis of liver failure. although some indicators such as arterial blood lactic acid, pct, nagl and inos are closely related with severe-type hepatitis or liver failure, they also score as abnormal in other severe diseases or conditions such as septic shock and mods, so these parameters are not specific for severe-type hepatitis b and liver failure. it is the same on the indicators related with immunity or inflammatory cell or factors, with high sensitivity, while without specificity. other indictors related with heredity, metabolomics, genomics, proteomics and glycomics are still in research, or needing expensive instruments, and still difficult to the routine clinical practice in the short term. what we need to point out is that the various kinds of prognosis scoring systems and mathematical models constructed and tested in the latest years, such as royal school of medicine standard in united kingdom, model for end-stage liver disease (meld) and child-pugh scores, have higher accuracy and utility on predicting prognosis of severe-type hepatitis and liver failure, although some of them still need additional supplement and improvement in the future. because of diversity and individualization for particular causative factors, clinical types, clinical course, complications and clinical treatments, until now, there are still many challenges reflecting prognosis of liver failure. it is believed that more and more novel biomarkers will come into the clinic in the near future, and with development of studies of mechanism and clinical characteristics on acute exacerbation of hepatitis b, therapeutic efficacy of severe-type hepatitis and liver failure will be improved. pathogenesis of aechb is generally considered to include viral factors (hbv genotype, viral replication and viral mutation, etc.), host factors (host genetic characteristics, immune injury, cell apoptosis and necrosis) and interaction between these two aspects. currently, there are at least ten different hbv genotypes and several subtypes distributed all over the world (see table . ) based on the differences of whole genome sequences > % for the major genotypes or - % at the sub-genotype level. genotype a is mainly distributed in northern europe (a ), west africa (a ), and sub-saharan africa (a ). in asia, genotype b and c are most common. genotype b have six subtypes (b -b ), in which, b was found in japan, b ~ b were found in east asia, and b was found mainly in the arctic regions, such as alaska, northern canada and greenland. genotypes b -b are also regarded as recombinants with genotype c. genotype c, including five subtypes (c ~ c ), is mainly distributed in east asia and southeast asia. genotype d, including subtypes d ~ d , prevails in africa, europe, mediterranean and india. genotype e is only found in west africa. genotype f, having four subtypes, is found in central and south america. genotype g has been reported popular in france, germany and the united states. genotype h is found in central america [ ] [ ] [ ] . genotype i was recently newly found in vietnam and laos, but this new genotype is under controversial [ ] . the newly found genotype j in japan has a close relationship with the orangutan's genotype and human genotype c. population migration, promotion of antiviral therapy and host immune selection pressures result in increased risk of hbv gene recombination or mutation [ ] . with the development of genetic testing methods, even more new genotypes could still discovered. due to the distribution differences of hbv genotypes, the study on the relationship between hbv genotypes and severe hepatitis b is quite limited. comparisons have only been conducted in a few genotypes. a study from united states on patients with hbv related acute liver failure suggested that outcomes of these patients were not associated with genotypes [ ] . a multicenter study from japan involving patients with acute hbv infection has compared genotypes (ae [a ],ba [b - ],bj [b ],ce [c ],cs [c ],dandg). multi-factor regression analysis indicated that subtype bj(b ) is one of the independent predictors for fulminant hepatitis. subtype ae(a ) is more related to hbv persistence but not self-limiting hepatitis b [ ] . another multicenter study from japan showed that patients with genotype c accounted for and % in patients with acute-on-chronic liver failure and acute liver failure, respectively. these rates are much higher than that in patients with chronic infection, suggesting that patients with genotype c are more likely to suffer from fulminant liver failure [ ] . a study from china included hbv carriers, patients with chronic hepatitis b, patients with aclf, hbv related liver cirrhosis and patients with hbv related hcc. data showed that genotype b ( . %) and c ( . %) were the main genotypes in these patients. compared with genotype b, genotype c was seen more frequently in those with severe liver diseases, was accompanied with high levels of hbv replication, indicating that genotype c is associated with high hbv replication and severe liver disease [ ] . however, results from another study showed no difference in genotype composition among patients with chronic hepatitis b and those with chronic severe hepatitis [ ] . in a study involving hbv-infected pediatric patients, in which patients had been treated with nucleos(t)ide analogues, genotype c and b were found to be the most prevalent subtypes ( . and . %). compared with genotype b , genotype c is more likely to cause severe hepatitis in hbeag positive pediatric patients [ ] . the association between various genotypes and the pathogenesis of severe hepatitis needs further studies. hbv uses reverse transcription to copy its dna genome and lack of proof-reading capability permits the emergence of mutations in the genome. every day, approximately viral particles are produced and released to maintain a stable level of virus in blood. the average mismatch rate of hbv polymerase is from : to : , potentially resulting in a large amount of mutants in the circulation [ ] [ ] [ ] [ ] . for single individuals infected with hbv, hbv genome mutation either naturally occurs naturally or is selected out by antiviral drugs or the change of internal host environment. the probability of hbv mutations varies in different regions of the whole genome. generally, mutations are more likely to occur in the basal core promoter (bcp), pre-c region and neutralization determinants of the viral envelope, but they can also be found in other regions. some of these mutations have important clinical significance, but most of them are silent mutation without biological significance. pre-c region encoding hbeag, is composed of amino acids. the most common mutation is a guanine (g) to adenine (a) substitution at nucleotide , which creates a premature stop codon at codon , and prevents the translation of the hbeag [ ] . although synthesis of hbeag is inhibited, the hbv replication still continues, manifesting as hbeag negative hbv infection. hbeag expression is not necessary for viral replication, its role in the hbv life cycle remains unclear. in the immune system, hbeag may act as bait, which induces immune tolerance, especially in the newborn babies whose mothers have high level viremia. the hbeag-induced immune tolerance can prevent the attacks on the virus-infected hepatocytes by ctl on hbcag, thus the hbv-infected hepatocytes are not able to be cleared. the hindered synthesis of hbeag may facilitate the ctl to damage infected liver cells, which might be one of the mechanisms of severe hepatitis. it is reported in japan that patients, especially children, infected with this mutant, are more likely to suffer from severe hepatitis. other pre-c mutations include point mutations generating other termination codons, for example g a generating uga codons. point mutations may change the initiation codon of p or the specific amino acid for cleavage and insertion of key signal peptide, particularly between and . all of these mutations can affect the hbeag production. the pre-c mutation can reduce hbeag expression, increase hbv replication and aggravate liver damage [ ] . a number of studies have suggested the association of pre-c mutation and development of severe hepatitis. the hbcag encoded by c region, contains a t-cell-dependent/independent epitopes and induces the host humoral and cellular immune responses. the c gene mutation may cause deletion of the cell surface antigen, and consequently the lack of humoral immune response by the host against hbv. however, the cytotoxicity of ctls was not affected resulting in potentially massive necrosis of liver cells and eventually leads to severe hepatitis. core promoter directly activates pgrna transcription, and plays a central role in hbv replication. core promoter is composed of basic core promoter (bcp) and its upstream regulatory elements. the bcp region partly overlaps with the 'end of x gene and the ' end of pre-c gene and can independently start the transcription of pre-mrna and pgrna. the core promoter mutation, which is associated with nt - that are at the upstream of the starting point of pre-c mrna, reduces the synthesis of hbeag, but has no effect on hbcag. the development of severe hepatitis is often accompanied with hbv core promoter mutation, especially the , double set of mutations [ ] . other common mutations in the core promoter region of patients with severe hepatitis include nt c-t, nt t-a and cluster mutations, including nucleotide insertion, deletion and substitution. the bcp mutations can induce changes of two codons (l m and v i) in x protein, and generate the hnf (hepatocyte nuclear factor ) binding sites. insertion of bases into the core promoter produces a new binding site of hnf , which can enhance viral replication and lead to severe hepatitis [ ] . in-vitro studies have confirmed that bcp trans-activating transcription causes x protein replacement, which downregulates the transcription of pre-c region and pgrna [ ] . however, the double-mutant can upregulate the transcription of pgrna, increase hbcab production, thereby enhancing viral replication. previous studies have shown that a t and g a mutation are more prevalent in hbv genotype c, which partially explains the stronger pathogenicity of genotype c than genotype b. recent studies have shown that a t and g a mutations in hbv genotype b may be associated with severe hepatitis, but in hbv-infected pediatric patients, a t and g a mutations show no significant difference in genotype b and c. overall though, compared with wildtype hbv, bcp double mutation is more commonly associated with severe liver diseases, especially liver cirrhosis and hcc [ ] . the mutations in pre c/bcp region may alter the biological characteristics of the virus, and induce the development of severe hepatitis through impacts on host immune responses, being more vigorous in hbeag-negative chb [ ] . however, the biological significance of mutations in different sites or forms, the dynamic interaction between virus mutation and host immunity, the influence of different genotypes and viral quasispecies on mutation are still not fully elucidated. immune evasion or vaccine failure related pre-s point mutation or deletion mutation does not affect the viral replication. the pre-s , s recombination, including deletion mutation and promoter mutation, have been regularly found in patients either with chronic or fulminant hepatitis. these mutations frequently occur after hbeag seroconversion or interferon treatment, suggesting the host immune selective pressure during their selection. the pre-s region mutations may play a role in hbv persistent infection, and may also cause liver damage. it has been reported that the pre-s mutation is related to fulminant hepatitis, and the pre-s mutation is a strong risk factor for the development of hbv-related liver cancer [ , ] , presumably as a result of an accumulation of viral envelope proteins inside the cell.mutations of the surface antigen protein, particularly aa mutation (sg r), result in conformational change of the major antigen epitope 'a'. this change disables the immunological recognition and surveillance of the host immune system for the mutant can also result in failure of the clinical vaccination and might be one of the precipitations for the exacerbation of hepatitis b [ ] . the p gene mutation in key catalytic domains indicates the hbv resistance against nucleos(t)ide analogues (na). the current five nas in clinical application include lamivudine, adefovir, telbivudine, entecavir and tenofovir. the clinically extensive application of nas leads to rapid selective drug resistance. the selection of drugresistant mutation depends on the following factors: ( ) the long half-life of hepatocytes and intrahepatic cccdna; ( ) the capacity of hbv replication and mutation; ( ) antiviral drug pressure; ( ) genetic barrier to resistance. for example, the lamivudine resistance is closely associated with the hbv reverse transcriptase gene ymdd motif mutation, presenting as rt m i and rt m v mutation, with or without rt l m mutation. the replication capacity of rt m i/v mutants is weaker than the wild strains in the absence of drug. the rtl m mutation can restore the hbv replication capability. in addition, the single or combined mutation of rt l i, rt l m, rt f l, rt v l, rt a v and rt v i may compensatorily restore the replication capability of rtm i/v mutant [ ] . the resistance rate is up to % after -years of lamivudine therapy, and more than % after -year mono-therapy. the -year resistance rate of telbivudine is about %. the rtn t site mutation (threonine substitute asparagine) is mainly seen in adefovir resistance, and the -year resistance rate is about %. the rta t/v (valine/threonine substitution alanine) site mutation is found in all the above three antiviral drugs. entecavir resistance mutations include and substitutions, combined with substitutions at codons , and . the -year resistant rate in patients initially treated with entecavir is less than %. for patients that have been previously treated with lamivudine, the resistance rate of entecavir increased significantly. so far, there have been no reports on the primary drug resistance for tenofovir mono-therapy. the rta t mutation was found in the combination therapy of tenofovir and lamivudine [ ] . the entire s gene is included in the p gene, and the rt region overlaps with s gene, thus the rt mutation may cause the s gene mutation. double mutations in these two regions can change the viral replication capacity. the hbv drug-resistance mutation occurs in patients with chronic hepatitis b may reduce the hbeag seroconversion rate, reverse the histological improvement, increase the disease progression rate, aggravate liver cirrhosis, and increase the death risk of liver transplant patients. rt mutations may also cause the s protein epitope changes and affect the hbs antibody and the function of ctl, suggesting its role in the development of liver failure [ , ] . as salvage therapy for lamivudine resistance, lamivudine combined with adefovir dipivoxil has higher rate of viral suppression and lower rate of adefovir resistance compared with switching to adefovir dipivoxil monotherapy [ , ] . tenofovir is a potent antiviral drug for lamivudine-resistance salvage therapy, and showed a better effect than switching to adefovir dipivoxil monotherapy [ ] . in contrast, switching to entecavir is not an optimal choice for lamivudine-resistance [ ] . telbivudine resistance is associated with the rtm i mutation, and has crossresistance with lamivudine. therefore, telbivudine could not be an alternative for lamivudine-resistance [ ] . treatment for telbivudine resistance is similar to that for lamivudine resistance [ ] . treatment for adefovir-resistance is determined by the virus mutation types and antiviral medication history [ , ] . lamivudine has been proved to be effective on inhibiting rtn t adefovir resistance mutations [ ] . in vitro data has also suggested the effectiveness of telbivudine. additionally, entecavir might be a reasonable choice for rtn t mutants. patients with rtn t mutation are suggested to ( ) switch to or add entecavir; or ( ) add lamivudine or telbivudine; or ( ) switch to tenofovir. compared with that on hbv wild strain, lamivudine becomes less effective on a v adefovir resistant strain. in vitro studies show that tenofovir has reduced sensitivity to the rta t mutation. clinically, entecavir and tenofovir can effectively inhibit the replication of a t adefovir resistant mutants [ ] . patients with rta t mutation are suggested to ( ) switch to or add entecavir; or ( ) switch to tenofovir. under this circumstance, lamivudine should not be suggested in case it increases the risk of cross-resistance [ , ] . currently, there has been no data from large sample clinical trials that can guide the treatment for entecavir resistance. in-vitro studies and case reports suggested that adefovir and tenofovir are effective for entecavir-resistant patients. based on expert opinions, patients with entecavir resistance are recommended to add tenofovir or adefovir [ ] [ ] [ ] . in summary, the virus mutation in above regions may be associated with the pathogenesis of severe hepatitis. however, the severity of hepatitis depends on key factors of virus and host. the same mutant may lead to different clinical outcomes in different hosts. thus except for virus mutation, factors including host immune status, cytokines and hla might also account for the development of severe hepatitis. tests for hbv infection hbv surface antigen/pre-s protein/pre-s protein hbsag is the major coat protein of hbv with antigenicity but not infectivity. in a broad sense, hbsag contains the major protein, middle protein and large protein. narrowly, hbsag simply refers to the major protein, which appears earliest and has the highest titer. thus it is considered as an important marker for early diagnosis of hepatitis b. for typical acute hepatitis b, hbsag appears during the incubation period, followed by the clinical symptoms and abnormal liver function in - weeks. hbsag stays in the blood for - months, and disappears in the recovery period. persistence of hbsag more than months indicates the development of chronic hepatitis. hbsag can also be detected in hbv carriers and patients with hbv-related liver cirrhosis or liver cancer. a rapid reduction of quantitative hbsag within months can predict the efficacy of antiviral drugs, but no changes in the quantitative hbsag level after months is not considered as a good predictor [ , ] . pre-s protein, which appears early and is significantly associated with hbeag and hbv dna, can be used as a marker of acute hepatitis b early in infection. the pre-s protein has a strong immunogenicity, and includes the important site where hbv attaches to and invade the hepatocytes, the sodium taurocholate co-transporting peptide (ntcp). it is also a reliable reflection of hbv replication level. the synergy from pre-s protein is also important for hbv invasion. most patients with acute exacerbation of chronic hepatitis, or chronic active hepatitis, or acute hepatitis developing to chronic hepatitis have persistent pre-s protein expression in serum. therefore, serum pre-s protein can be used to estimate the activity and infectivity of hbv in chronic patients [ ] . pre-s and pre-s protein, which can induce and regulate humoral and cellular immune response of the host, provide important immune defense for eliminating virus in blood circulation and preventing healthy liver cells being infected. hbsab, which is a protective antibody, can eliminate the virus and prevent hbv infection. hbsab appears in the late stage of acute infection, just before hbsag becomes negative, and will gradually rise to the peak levels in - months. this antibody can last for a long time, but the titers will gradually decline after years. a small number of cases do not produce hbsab after hbsag becomes negative. in acute hepatitis b infection, appearance of hbsab suggests recovery of the disease. patients with severe hepatitis often present with high titers of hbsab, which forms the immune complexes with hbsag, which can induce flares of hepatitis that lead to liver cell necrosis. after the hepatitis b vaccination, hbsab (> iu/l) means the successful vaccination and development of immunity. in the blood, hbcag is mainly located in the core of the dane particles or virions. the only small amount of free hbcag is also combined by high titers of hbsab and presents as immune complexes. thus, it cannot be detected unless treated by detergent. hbcag on the surface of hepatocytes is considered to be the main target antigen of the host ctls. hbcag is a direct evidence of hbv infection and replication, and also a marker for evaluating the efficacy of antiviral drugs. hbcag is strongly immunogenic, so that hbcab can be detected in most patients with hbv infection. hbcab often emerges in the early stage after infection, is present in high titer in blood and can persist for a very long time. titer of hbcab above : , together with abnormal alt level, can be used for the diagnosis of hepatitis b infection. for occult hepatitis b, high titer of hbcab is also valuable for the diagnosis. hbcab consists of igm and igg antibodies. anti-hbc-igm, which suggests hbvresulted liver damage, is the main evidence for the diagnosis of acute hepatitis b. it may become positive during the active phase of chronic hepatitis b and turn negative during remission. it also appears during the flares of chronic hepatitis b, mostly in a week after infection, and disappears within months. anti-hbc-igg appears late but is sustained for many years or even a lifetime. in patients with acute hepatitis b, the titer of anti-hbc-igm is higher than anti-hbc-igg, while in those with chronic hepatitis b the situation is opposite. both antibodies show high titers in fulminant hepatitis. hbeag is a soluble antigen, which appears later than hbsag. sustained expression of hbeag suggests persistence of hbv infection. in patients with chronic hepatitis b, hbeag acts as an important immune tolerance factor leading to a low immune response to hbv infection. it is a valuable marker for evaluating the efficacy of antiviral drugs. seroconversion refers to the loss of hbeag and development of anti-hbe. approximate - % patients have spontaneous seroconversion every year. studies have shown that spontaneous seroconversion occurs earlier in patients with genotype a, b, d and f than those with genotype c. appearance of hbeab demonstrates the decrease or termination of viral replication and low infectivity. recent studies showed that, after year since the spontaneous hbeag seroconversion, viral load more than iu/ml increased the incidence of fulminant hepatitis. for hbv chronic carriers and patients with hcc, hbeab does not mean the recovery, or elimination. in contrast, hbv dna integration is often found in these patients. x protein is capable of transactivating the expression of numerous cellular and viral genes, and is vital for virus replication. x protein can be detected in some patients with chronic hepatitis, so it is used as an auxiliary diagnostic marker of hbv infection [ ] . x protein plays a central role in hbv-related hcc progression and stimulation. thus, follow-up is necessary for patients active and persistent hbv replication. serum hbv dna is the direct evidence of active hbv infection, reflecting the level of viral replication and infectivity. the quantitative detection for viral genes is a very important marker for treatment decision, efficacy prediction and observation. long-term high load of hbv dna is an independent risk factor for predicting the development of liver cirrhosis and hcc. numerous studies have shown that viral load is the most reliable marker to predict the development of hcc [ ] . the differences of hbv whole genome sequence are approximately - %. the diverse variants that are genetically linked through mutation are known as quasispecies. quasispecies contain a large number of mutated genes serving as a reservoir for viral selection under the pressure of immune response and antiviral treatment. when changes occur in the environmental conditions, the quasispecies structure responds by rebalancing its composition. the predominant sequence may shift by selection of a variant that is better adapted to the new environment, in the classic darwinian process of survival of the fittest [ ] . this feature gives the virus strong adaptability, and makes it difficult to prevent and control. study on the relationship between quasispecies and different clinical outcomes will provide valuable information for exploring anti-hbv treatment strategies. . quasispecies evolution under host immune pressure. in chronic hbv infection transmitted via perinatal transmission, the different immune phases of chronic hbv infection confer different environments on hbv quasispecies. thus, the characteristics of hbv quasispecies may differ. a preliminary study on the differences of full-length hbv quasispecies between mothers and their progeny showed that, after years of evolution, the dominant sequence of hbv quasispecies became different between mothers and daughters. the characteristics of hbv quasispecies in various gene regions are different in mothers and daughters with different treatment responses or disease status. among these genes, the prec/c gene had the highest substitution rate [ ] . under antiviral drug selection pressure, hbv mutants are selected from the preexisting pool of quasispecies and over time become the dominant species [ ] . the probability of resistant mutations depends on the effectiveness of antiviral drugs. low potent drugs have almost no selective pressure on the virus, thus lead to low probability of viral resistance; on the contrary, drugs that completely inhibit viral replication also rarely result in resistance. only medium potent drugs have the highest rates of drug resistance. a study showed that during the -week lamivudine therapy, distinct patterns of quasispecies evolution are found between responders and non-responders; the structures of viral quasispecies tended to be simpler in responders, but more complicated (higher diversity) in non-responders. similar phenomenon was also observed during entecavir therapy. another study detected the full length sequence of resistant virus in lamivudine and adefovir sequential therapy, and found that variation of nucleotide or amino acid sequence usually occurs in hbv hbsag or rt region. using single strand conformation polymorphism (sscp) and dna sequence analysis, researchers found that the complexity of hbv quasispecies in patients with cirrhosis was more than those in patients with chronic hepatitis b, suggesting that complexity of hbv quasispecies is associated with disease status [ ] . researchers from china had also used the same methods to analyze the difference of quasispecies complexity in s region among patients with chronic severe hepatitis b, patients with chronic hepatitis b and hbv carriers. it is found that the quasispecies complexity in the s region increases along with disease progression in chronic hbv infection. analysis on quasispecies in acute hepatitis b, chronic hbv carriers, chronic hepatitis b and chronic severe hepatitis by full-length hbv genomic clone and bioinformatics methods also discovered the positive correlation between hbv quasispecies complexity and disease severity [ ] . on one hand, complex evolution of quasispecies may lead to persistent infection and continuous liver damage, and increase opportunities for the emergence of new hbv variants. on the other hand, enhanced virulence of mutated virus and change of antigen epitope may cause excessive immune response and severe liver damage. however, correlation between hbv quasispecies complexity and disease severity still needs dynamic large sample research to confirm [ ] . the dynamic change of quasispecies during na antiviral therapy may be related to the antiviral efficacy and drug resistance. results from a study on patients receiving lamivudine for weeks suggested that the baseline quasispecies heterogeneity is not associated with antiviral efficacy, and the changes of quasispecies complexity at an early stage may predict antiviral efficacy and drug resistance more accurately than the change of hbv dna level during lamivudine therapy. another study on dynamic changes of quasispecies in patients receiving entecavir antiviral therapy suggested that, compared to the partial responders, quasispecies complexity is reduced but dispersion is increased in complete responders after weeks of treatment [ ] . in these two studies, the quasispecies dispersion decreased in lamivudine responders but increased in entecavir responders after weeks of treatment. this might be because entecavir has stronger antiviral effect than lamivudine, thus generates more selection pressure. in addition, entecavir can still induce complete response even when some mutations occur since it has a higher drug resistance barrier. therefore, the early changes in hbv quasispecies complexity may act as a predictor of sustained antiviral effect of nucleos(t)ide analogues. the resistant strains typically already exist before antiviral therapy, and become the predominant strains under selection pressure of antiviral drugs. a study showed that adefovir treatment for weeks in patients with chronic hepatitis b selected resistant virus strains [ ] . study on gene heterogeneity of hbv reverse transcriptase suggested that lamivudine monotherapy is liable to induce the quasispecies that affect response rate of salvage therapy with adefovir for virologic breakthrough in lamivudine-treated patients, and reduce the sensitivity to other nucleos(t)ide analogues [ ] . under different drug selection pressure, non-responders have similar quasispecies evolution patterns, suggesting that this pattern may be associated with viral resistance mechanisms. from the perspective of quasispecies, drug selection pressure changes the relative ratio of viral populations, and leads to population drift. dna sequence analysis is the most direct and reliable method to detect gene mutations. it is also the gold standard to detect nucleic acid sequence mutation. however, the high cost of this method prevents its application in large sample research. dna sequencing, which can be divided into direct sequencing and cloning sequencing, is built on the basis of high-resolution denaturing polyacrylamide gel electrophoresis. direct sequencing detects the nucleotide sequence of dominant strains; clone sequencing method can find out changes of nucleotide in other strains. rflp is a technique that applies to detect variations in homologous dna sequences. it refers to a difference between samples of homologous dna molecules from differing locations of restriction enzyme sites, which may be naturally formed or brought in by pcr mismatch. the dna sample is broken into pieces and digested by restriction enzymes and the resulting restriction fragments are separated according to their lengths by gel electrophoresis. mismatched pcr is a modified pcr, which changes one or a few nucleotide bases in designed pcr primers to make the synthetic dna meet special requirements. here, a restriction enzyme recognition sequence is introduced into the pcr amplified fragment in order to change the target dna restriction map and distinguish the mutants and non-mutants. nucleic acid hybridisation is the pairing of complementary single-stranded nucleic acids (dna or rna) to produce dna-dna or dna-rna hybrids. when the target dna obtained by pcr amplification combines with the probe labeled by radioactive or non-radioactive labels, any mismatch between the probe and target dna can be detected. this helps to distinguish the wild and mutant strains. nucleic acid hybridization applies to high frequency point mutation and is suitable for large sample detection, but the high requirement for hybridization temperature makes it difficult to popularize. the principle of sscp is based on conformational difference of single-stranded nucleotide sequences of identical length. this property allows sequences to be distinguished by means of gel electrophoresis so as to determine whether mutations exist. it applies to the single base substitution and screening of dna fragment mutation. however, sscp is neither stable nor practical [ , ] . primer extension starts from the ′ end in pcr amplification, and only succeeds when the ′ end of the primer is an exact match to the template dna. based on this phenomenon, the primer with ′ end containing mutated bases is used to detect the mutation of target dna. the ′ base-specific pcr technology is simple but with low sensitivity, and the results are prone to be false-negative. the incomplete block of pcr amplification also leads to false-positive results [ ] . melting curve analysis is an evaluation of the dissociation-characteristics of doublestranded dna during heating, the temperature at which % of dna is denatured is referred to the melting point [ ] . in chronic hbv infection, the peak numbers of dna melting curve in patients with moderate and severe hepatitis are significantly more than those in hbv carriers and mild hepatitis; the peak number of melting curve in patients with severe hepatitis is significantly more than that in moderate hepatitis. the melt-curve analysis is less sensitive than sscp, but is more accurate on analyzing genetic variation. the strong operability and high cost-effective make it a preferable method for genetic variation analysis. the high demand for low-cost sequencing has caused the development of highthroughput sequencing-the next-generation sequencing, which includes massively parallel signature sequencing (mpss), solexa sequencing, solid sequencing, pyrosequencing, heliscope single molecule sequencing, etc. these methods apply to genome sequencing, genome resequencing, rna-sequencing, chip-sequencing and epigenome characterization [ ] [ ] [ ] . current dna sequencing methods under development include microscopy-based techniques, macromolecule and nanotechnology that can distinguish the base signal and directly read the sequence without the use of biological or chemical reagent. the third-generation sequencing methods include: ( ) non-optical microscope imaging: the dna sequence can be read out if the resolution of image is high enough to differentiate the four kinds of bases on dna when visualizing the spatial linear arrangement of nucleotides. this idea is based on non-optical microscope at the atomic level, for instance, scanning tunneling microscopy (scanning tunneling microscope, stm) [ ] . ( ) nanopore dna sequencing: it is based on the readout of electrical signals occurring at the single stranded dna or rna molecules passing by alpha-hemolysin pores covalently bound with cyclodextrin [ ] [ ] [ ] . those methods still need further validation and improvement. the pathogenesis of hbv infection is determined by the interplay between both virus and host. different outcomes after infection are related to different host immune responses and viral mutations. however, the biological significance of viral mutation has not been fully elucidated because of: ( ) the limited samples and lack of comparison between different groups; ( ) the overlap of each hbv genomic coding regions; ( ) the limitation of detection technology. with the rapid development of detection technology, the large sample, long-term, multi-level studies will help to understand more about the host-virus interaction and potential mechanisms. zhi the indications for liver transplantation are changing over time. before , the major indication for liver transplantation was primary malignancy of the liver, especially hepatocellular carcinoma (hcc) which significantly influenced the therapeutic efficacy of liver transplantation and postoperative survival. currently, not only are acute or chronic liver diseases nonresponsive to other medical treatment and surgery now the major indication for liver transplantation but also liver diseases that markedly affect quality of life. the major indications for liver transplantation are shown in table . . viral hepatitis has and continues to be a major public health problem in china. it is the most common liver disease and most common cause of liver failure. the proportion of patients with hepatitis b-induced liver failure among patients receiving liver transplantation in china is significantly higher than in other countries. hepatitis b has diverse clinical manifestations and may progress to chronic hepatitis, liver failure (including acute liver failure, acute on chronic liver failure, and chronic liver failure), hepatic cirrhosis (compensated and decompensated), and even hepatitis b-related liver tumors. whether liver transplantation is necessary for patients with hbv infection and the timing of transplantation must be carefully considered. early liver transplantation may increase patient risk and be an economic burden because patients could recover and even survive for a long time in the absence of liver transplantation. however, presently it is difficult to predict patient outcome to hbv infection. in contrast, if liver transplantation is performed in the late stages of disease, numerous complications of hepatitis b-induced liver dysfunction may either increase the risk of transplant surgery resulting in a poor prognosis. thus, for patients with severe hepatitis b, the indications for and the timing of liver transplantation are crucial and should be carefully evaluated. in general, the following conditions are indications for liver transplantation in patients with chronic hepatitis b: . obvious manifestations of liver failure including sustained elevation of serum bilirubin to > mg/dl; prothrombin time > s longer than the reference range; plasma albumin < . g/dl; and liver failure which is nonresponsive to active and/or symptomatic therapy (such as infusion of fresh plasma and albumin) or if the patient continues to deteriorate clinically despite optimal medical therapy. . when there are complications related to either liver failure or portal hypertension such as the presence of severe hepatic encephalopathy, disturbances of coagulation function, refractory bleeding due to rupture of esophageal or gastric varices, refractory ascites, repeated episodes of spontaneous bacterial peritonitis, or the development of hepatorenal syndrome. . when hepatitis b influences the quality of life including the development of severe lethargy, uncontrollable itching, metabolic bone diseases or the development of bacterial cholangitis and . the development of hepatocellular carcinoma. although there are some well defined indications for liver transplantation, the ultimate determination of the timing and specific indications for liver transplantation remains a challenge in clinical practice for hepatitis b patients with liver failure. the introduction of the model of end stage liver diseases (meld) and some derivative scoring systems are now frequently used to determine whether a patient should be listed for transplantation and the urgency of liver transplantation. in , the mayo clinic proposed that meld should replace the child-pugh grading system for the determination of urgency of liver transplantation. meld is calculated using the following calculation: meld = . × log e (creatinine [mg/dl]) + . × log e (bilirubin [mg/ dl]) + . × log (inr) + . × (causes: for biliary and alcoholic; for others). meld was originally used for the evaluation of prognosis of hepatic cirrhosis patients receiving transjugular intrahepatic portosystemic shunt. as described above, the meld score is determined on the basis of total bilirubin, international standardization of bleeding time, serum creatinine, and etiology. compared to the child-pugh grading system, meld employs objective parameters, which are helpful for the comparisons of patients from different centers. while the meld score changes with the alteration of the liver disease, the child-pugh grade has only three levels and is unable to meet the requirements of accurate and objective evaluation. saab et al. investigated the prognosis of patients receiving liver transplantation and found that the -year survival rate was , , , , and % in patients with preoperative meld scores of ≤ , - , - , - , and ≥ , respectively. however a higher meld score negatively affected the -year survival rate. for example patients with a meld score ≤ had a year survival rate of whereas patient survival was reduced to % in patients with a meld score > . despite the benefits and the widespread application of meld in clinical practice, there remain some imperfections in the evaluation of timing of liver transplantation and the assessment of prognosis and therapeutic efficacy. one of the major imperfections is the failure to consider complications such as infection, hepatic encephalopathy, hepatorenal syndrome, and disturbances in fluid and electrolytes which may significantly influence the prognosis and timing of liver transplantation but are not included in the meld scoring system. hence inclusion of sodium (na) in the meld scoring system: meld − na [meld + . × ( − na)], imeld [meld + ( . × age) − ( . + na) + ]; and meso [meld/na (mmol/l)] × has improved outcomes of patients requiring liver transplantation. those scoring systems, however, also fail to consider other complications. including the development of hepatic encephalopathy or ascites and therefore, their applicability is limited in china. in china, liver transplantation was initiated relatively late compared with other countries; regulations regarding liver transplantation remain imperfect; and smooth communication among transplantation centers in different regions of the country are lacking. these drawbacks markedly influence the timely and fair distribution of donor livers. determination of waiting times for transplantation is not scientific. therefore, the comprehensive evaluation of a patient's condition of hepatitis b-induced liver failure, determination of the timing of liver transplantation, and optimization of the rational and fair distribution of donor livers needs to be carefully considered by chinese clinicians in the field of hepatology going forward if improvements are to occur. there are currently additional scoring systems which have been used by chinese clinicians. one of these was developed by professor ke wm in the department of infectious diseases of the affiliated third hospital of sun yat-sen university. in that system, hepatic encephalopathy, serum creatinine, prothrombin activity, serum total bilirubin, liver size (determined by ultrasonography), amount of ascitic and pleural fluid (determined by ultrasonography), and infection (peripheral white blood cell count, proportion of neutrophils, and inflammatory findings from thoracic imaging examinations) are taken into account and objectively and conveniently scored on a scale of - according to their severities as described in tables . , . , and . . [ ] these newer scoring systems and the meld scoring system can favorably predict the mortality of acute on chronic liver failure patients with hepatitis b. the area under receiver operator curves of scores determined with a new scoring system and meld scoring system was . [ % confidence interval (ci), . - . ] and . ( % ci, . - . ), respectively. there was no overlap in % cis between the two, and they were significantly different (p < . ) as illustrated in figs. . , . , and . ). wenzhou medical college in china subsequently proposed a scoring system in which the total score is calculated using the following equation: x = . + . × hepatorenal syndrome (hrs) + . × lc − . × hepatitis b e antigen (hbeag) − . × alb − . × pta. that scoring system has been used in several centers for liver diseases, and its effectiveness and accuracy have now been confirmed in these centers. in summary, to establish a new scoring system on the basis of china's national status of liver disease and to further validate this system, large multicentered studies with a large number of patients is crucial before they are adopted in china. it is important that any new system developed under these conditions be subjected to rigorous study, standardization and scientific validation. for liver transplantations in patients with hepatitis b-induced liver failure, perioperative therapy is crucial, impacting the recurrence of hepatitis b virus reinfection following liver transplantation. in fact, perioperative therapy can make a major fig. . receiver operator curve of a new scoring system and meld scoring system difference in patients with hepatitis b compared to patients with other liver diseases (e.g., tumor recurrence). it is well appreciated that antiviral therapy is necessary in hepatitis b virus patients as discussed below. the guideline for the prevention and treatment of chronic hepatitis b in china ( ) recommends that ( ) for patients with hepatitis b planning to receive liver transplantation, oral lamivudine be administered within - months before liver transplantation when hepatitis b virus dna is detectable ( mg q h). hepatitis b immune globulin (hbig) should be administered during the anhepatic stage in surgery and long-term use of lamivudine and low-dose hbig ( iu q h for the first week postsurgical, iu q week, then iu q month). the dose of hbig and interval between two treatments [generally, trough hepatitis b surface antibodies (anti-hbs) are > - miu/ml and anti-hbs is better if > miu/ml within months of surgery) should be determined according to the anti-hb levels. for patients nonresponsive to lamivudine, other nucleos(t)ide analogues effective for resistance mutation should be used and for patients with a low risk for recurrence of hbv infection (i.e., hbv dna negative before liver transplantation and absence of hbv infection recurrence within years after liver transplantation), lamivudine plus adefovir should be considered for the prevention of hbv infection recurrence. while patients are waiting for liver transplantation, an artificial liver support system (alss) may be of use as a bridge to transplantation. liver failure may significantly compromise the detoxication, synthesis, and metabolism activities, resulting in a significant accumulation of toxins and deficiency of some important factors (such as coagulation factors). unfortunately, some patients die while waiting for either their liver function to improve or for liver transplantation. alss have been generally used to partially substitute the liver's normal activities, such as clearing some toxins and supplement some missing factors, which is helpful for life maintenance while awaiting subsequent liver transplantation or spontaneous recovery. thus, for patients with liver failure secondary to hepatitis b, alss maybe an important therapeutic strategy while patients are waiting for liver transplantation. alss can be classified as a mechanical artificial liver, biological artificial liver, or mixed artificial liver. mechanical alsss mainly utilizes nonbiological materials to clear toxins in the body and supplement some missing factors. biological alsss use biological materials to substitute the liver's activities. the core feature of the biological alss systems is to simulate hepatocyte function. however, the source and biosafety, as well as their location (bioreactor), are important factors limiting the development of biological alsss. finally, mixed alsss employ the hemodiafiltration, plasma exchange, and hemoperfusion that are able to detoxify substances (nonbiological alss) and human or porcine "hepatocytes" in the bioreactor. currently, nonbiological alsss are the most widely used in clinical practice, and biological and mixed alsss are still undergoing investigation and have not been widely applied in clinical practice. in addition to its use before liver transplantation, alss post liver transplantation may be used to correct ongoing renal failure, brain edema, severe water and electrolyte disturbances, and severe infections. another factor to consider is that liver donors are rare. as a result, the inability to perform liver transplantation in a timely fashion results in reduced survival rates. under those conditions, pre transplant complications including multi organ failure may persist. in such cases, alss therapy may prove to be beneficial. for patients with hepatitis b-related liver failure, perioperative therapies are more important than in patients receiving elective liver transplantation (such as liver tumor patients without liver failure). liver failure causes a variety of complications that directly contribute to transplantation failure and a high-risk status after surgery. clinicians need to address problems such as portal hypertension, upper gastrointestinal bleeding, severe jaundice, ascites, spontaneous peritonitis, hepatic encephalopathy, hepatopulmonary syndrome, portal pulmonary hypertension, kidney dysfunction, hepatorenal syndrome (among others) through active treatment/management in specialized liver units. preserving liver function and maintaining a normal physiological status have been shown to reduce the risk of therapeutic failure in patients receiving liver transplantation due to hepatitis b-related liver failure. diagnostic and treatment guidelines for liver failure the clinical implications of hepatitis b virus genotype: recent advances new complex recombinant genotype of hepatitis b virus identified in vietnam possible new hepatitis b virus genotype when should "i" consider a new hepatitis b virus genotype? a genetic variant of hepatitis b virus divergent from known human and ape genotypes isolated from a japanese patient and provisionally assigned to new genotype clinical outcome and virological characteristics of hepatitis b-related acute liver failure in the united states influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis b virus infection mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis b virus infection in japan profile, spectrum and significance of hepatitis b virus genotypes in chronic hbv-infected patients in yunnan, china. hepatobiliary pancreat dis int precore/core promoter mutations and genotypes of hepatitis b virus in chronic hepatitis b patients with fulminant or subfulminant hepatitis virologic and clinical characteristics of hbv genotypes/ subgenotypes in chinese pediatric patients with chb quasispecies and its impact on viral hepatitis hepatitis b virus: molecular virology and common mutants a function of the hepatitis b virus precore protein is to regulate the immune response to the core antigen cytoplasmic expression of hepatitis b core antigen in chronic hepatitis b virus infection: role of precore stop mutants different hepatitis b virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis b e antigen seroconversion hepatitis b virus e antigen variants two core promoter mutations identified in a hepatitis b virus strain associated with fulminant hepatitis result in enhanced viral replication type, prevalence, and significance of core promoter/ enhancer ii mutations in hepatitis b viruses from immunosuppressed patients with severe liver disease probable implication of mutations of the x open reading frame in the onset of fulminant hepatitis b association between the various mutations in viral core promoter region to different stages of hepatitis b, ranging of asymptomatic carrier state to hepatocellular carcinoma number of mutations within ctl-defined epitopes of the hepatitis b virus (hbv) core region is associated with hbv disease progression pre-s defective hepatitis b virus infection in patients with fulminant hepatitis associations between hepatitis b virus mutations and the risk of hepatocellular carcinoma: a meta-analysis potential threat of drug-resistant and vaccine-escape hbv mutants to public health early changes of hepatitis b virus quasispecies during lamivudine treatment and the correlation with antiviral efficacy hepatitis b virus variant with the a t substitution within reverse transcriptase before and under adefovir and tenofovir therapy restoration of replication phenotype of lamivudine-resistant hepatitis b virus mutants by compensatory changes in the "fingers" subdomain of the viral polymerase selected as a consequence of mutations in the overlapping s gene lamivudine resistance and other mutations in the polymerase and surface antigen genes of hepatitis b virus associated with a fatal hepatic failure case adefovir rapidly suppresses hepatitis b in hbeag-negative patients developing genotypic resistance to lamivudine adefovir dipivoxil monotherapy and combination therapy with lamivudine for the treatment of chronic hepatitis b in an asian population comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis b virus infection two-year assessment of entecavir resistance in lamivudine-refractory hepatitis b virus patients reveals different clinical outcomes depending on the resistance substitutions present telbivudine, a nucleoside analog inhibitor of hbv polymerase, has a different in vitro cross-resistance profile than the nucleotide analog inhibitors adefovir and tenofovir management of treatment failure in chronic hepatitis b resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the hbv polymerase selection of a hepatitis b virus strain resistant to adefovir in a liver transplantation patient susceptibility to antivirals of a human hbv strain with mutations conferring resistance to both lamivudine and adefovir impact of hepatitis b virus rta v/t mutants on hepatitis b treatment failure management of drug-resistant chronic hepatitis b treatment of patients with lamivudine-resistant and adefovir dipivoxil-resistant chronic hepatitis b virus infection: is tenofovir the answer? successful treatment of an entecavir-resistant hepatitis b virus variant how to diagnose and treat hepatitis b virus antiviral drug resistance in the liver transplant setting prevention and management of drug resistance for antihepatitis b treatment is there an association between the measurement of qualitative hbsag and virologic response in chronic hbv infection serum hepatitis b surface antigen quantitation can reflect hepatitis b virus in the liver and predict treatment response serological and molecular diagnosis hbv induced hcc: major risk factors from genetic to molecular level new insight in the pathobiology of hepatitis b virus infection quasispecies structure, cornerstone of hepatitis b virus infection: mass sequencing approach clinical implications of evolutionary patterns of homologous, full-length hepatitis b virus quasispecies in different hosts after perinatal infection hepatitis b virus mutations associated with antiviral therapy hepatitis b virus s gene mutants in a patient with chronic active hepatitis with circulating anti-hbs antibodies hepatitis b virus genomes of chronic hepatitis patients do not contain specific mutations related to acute exacerbation molecular virology and the development of resistant mutants: implications for therapy evolutionary patterns of hepatitis b virus quasispecies under different selective pressures: correlation with antiviral efficacy complex dynamics of hepatitis b virus resistance to adefovir emergence of hepatitis b virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment optimization of nonradioisotopic single strand conformation polymorphism analysis with a conventional minislab gel electrophoresis apparatus evaluation of the genetic variability of orchid fleck virus by single-strand conformational polymorphism analysis and nucleotide sequencing of a fragment from the nucleocapsid gene an improved allele-specific pcr primer design method for snp marker analysis and its application product differentiation by analysis of dna melting curves during the polymerase chain reaction next-generation sequencing in aging research: emerging applications, problems, pitfalls and possible solution next-generation dna sequencing methods applications of next-generation sequencing technologies to diagnostic virology fast dna sequencing via transverse electronic transport single-nucleotide discrimination in immobilized dna oligonucleotides with a biological nanopore rapid sequencing of individual dna molecules in graphene nanogaps detecting single stranded dna with a solid state nanopore peri-operative therapies of patients receiving liver transplantation due to severe hepatitis establishment of a scoring system for evaluating the severity of hepatitis b patients with acute-on-chronic liver failure key: cord- - kqx arn authors: rueda, mario; lipsett, pamela a. title: hepatic failure date: - - journal: principles of adult surgical critical care doi: . / - - - - _ sha: doc_id: cord_uid: kqx arn the progression of liver disease can cause several physiologic derangements that may precipitate hepatic failure and require admission to an intensive care unit. the underlying pathology may be acute, acute-on chronic, or chronic in nature. liver failure may manifest with a variety of clinical signs and symptoms that need prompt attention. the compromised synthetic and metabolic activity of the failing liver affects all organ systems, from neurologic to integumentary. supportive care and specific therapies should be instituted in order to improve outcome and minimize time of recovery. in this chapter we will discuss the definition, clinical manifestations, workup, and management of acute and chronic liver failure and the general principles of treatment of these patients. management of liver failure secondary to certain common etiologies will also be presented. finally, liver transplantation and alternative therapies will also be discussed. accepted theories that revolve around impaired detoxification of substances normally cleared by the liver. • ammonia • the metabolism of nitrogen-containing compounds in the gastrointestinal system results in the production of ammonia. in its normal state, the liver converts this neurotoxic product into glutamine and urea. impaired liver function results in elevated blood ammonia. astrocytes contain the enzyme glutamine synthetase in their endoplasmic reticulum as a means of handling excessive ammonia. accumulation of glutamine within the astrocytes results in cell swelling which leads to a series of events that result in a neuroinhibitory state [ ] . • false neurotransmitters • the failing liver results in the production of false neurotransmitters. these molecules may interfere with normal brain functioning and have a net inhibitory effect [ ] . • amino acid imbalance • patients with hepatic failure have decreased plasma levels of the branched-chain amino acids (bcaa) valine, leucine, and isoleucine while experiencing increased levels of aromatic amino acids (aaa) phenylalanine, tryptophan, and tyrosine. this is thought to be related to increased muscle catabolism and therefore increased bcaa metabolism as well as decreased breakdown of aaa by the compromised liver. the end result is an imbalance that leads to an increased influx of aaa in the brain which has an inhibitory effect in the nervous system [ ] . • gaba receptor • thought to be mediated by inflammatory cells, neurosteroids are produced by myelinated glial cells. this results in positive modulation of gaba receptors that in turn enhance the inhibitory tone [ ] . besides the astrocyte swelling that is seen with the accumulation of glutamine explained above, overall neurologic dysfunction results in loss of autoregulation of intracranial pressure as well as reduced cerebral blood flow. the result of these changes may result in further neurologic derangement and compromise [ ] . besides hepatic encephalopathy, patients with alf can also present with cerebral edema. there is an overlap with the clinical features that are seen with encephalopathy and include nausea, vomiting, headache, and agitation. in advanced cases which can progress to brain herniation, hypertension, bradycardia, changes in pupillary exam or reflexes, as well as respiratory depression can be seen [ ] . patients with alf may present with nonspecific respiratory symptoms including dyspnea on exertion, orthopnea, anxiety, and air hunger. the affecting processes involved are very broad and can range from a simple pleural effusion to acute respiratory distress syndrome (ards) [ ] . the spectrum of respiratory pathology that is seen can be grouped in to two major categories: infectious and noninfectious (table . ) . pulmonary edema can be of cardiogenic or noncardiogenic etiology. the prevalence of pulmonary edema appears to be higher in those patients with cerebral edema, suggesting the accumulation of osmotic substances within the lung parenchyma and outside the vasculature [ ] . molecular imbalance and injury to endothelial cells, accompanied by a decrease in oncotic pressure, may play a role in the development of this disease. hepatopulmonary syndrome can be seen in both alf and chronic liver failure. it is thought to arise from microscopic shunting from arteriovenous dilations that occur in the pulmonary vasculature [ ] . the precise mechanism is unknown; however, it is thought that the elevated levels of nitric oxide seen in patients with liver failure may mediate the abnormal vasodilation that occurs in the pulmonary parenchyma. the result is an overperfusion with maintenance of ventilation; a vq mismatch occurs that ultimately leads to hypoxemia [ ] . as part of the pathophysiology associated with alf, there is low systemic vascular resistance and a hyperdynamic circulation with elevated cardiac output. the pathophysiology is multifactorial but vasoactive substances are thought to mediate the process [ ] . while the underlying pathophysiology may differ, hemodynamic variables appear very similar to those seen in sepsis and septic shock. in the failing liver, there is an increase in splanchnic blood pooling that is associated with the increased resistance of flow through the liver. this results in increased shear stress in the splanchnic circulation that causes upregulation of endothelial nitric oxide synthase (enos) and ultimately nitric oxide (no) production [ , ] . there is further systemic vasodilation causing a low effective circulating volume and relative hypotension despite an overall elevated intravascular volume. the systemic baroreceptors are unloaded and there is a compensatory increase in cardiac output as well as activation of the renin-angiotensinaldosterone system (raas) that may ultimately affect the renal system ( fig. . ) [ ] . patients with alf usually present with varying degrees of coagulopathy. as the liver fails, there is decrease in the synthesis of factors involved in both coagulation and anticoagulation, specifically fibrinogen, prothrombin, protein c, protein s, and factors v, vii, viii, ix, x, and xi. the end result is an increased in prothrombin and activated partial thromboplastin times as well as elevation of inr [ ] . overt bleeding is not typically seen, as there is a decrease in both coagulation and anticoagulation factors. however, mucosal bleeding from the oropharynx or the gastrointestinal mucosa can be frequently seen. this is compounded by the underlying platelet dysfunction that can occur in patients with liver failure. right upper quadrant pain, gastrointestinal bleeding, ascites, nausea, and vomiting can be seen in patients with alf. these symptoms are nonspecific and can be multifactorial. patients with acute viral or autoimmune hepatitis may experience liver parenchyma inflammation as part of the normal response to infection. this leads to an increase in the overall volume of the liver. the liver capsule may be unable to accommodate acute volume changes, and stretching of it results in activation of pain receptors and right upper quadrant pain. discomfort in this area can also be related to direct trauma causing bleeding. abdominal distention may be associated with ascites. the neurohumoral alterations are seen with alf leading to excessive sodium retention and ultimately plasma volume expansion. this, combined with a decrease in the overall circulating proteins due to compromised liver function, leads to overflow of fluid into the peritoneal cavity [ ] . tense ascites can result in compromise of respiratory, renal, and cardiovascular function due to direct compression of the diaphragm and vasculature. as part of its normal physiologic function, the liver is responsible for gluconeogenesis as well as glycogen storage. as liver function worsens, these two key metabolic functions are compromised. in up to % of patients, hypoglycemia is seen and treatment is warranted [ ] . compromised flow through the liver secondary to fibrosis or intrinsic disease acute kidney injury can be present in - % of patients with alf [ , ] . the etiology can be variable: prerenal azotemia, drug toxicity, and acute tubular necrosis have all been implicated. hepatorenal syndrome, especially type , has also been associated with the progression of this disease. acute kidney injury can be divided into oliguric vs. anuric failure, with the latter making fluid management difficult in the critical care setting [ ] . accompanying this derangement we can also see electrolyte disturbances: hyperkalemia, hyperphosphatemia, hypophosphatemia, hypercalcemia, and hypomagnesaemia that can lead to secondary arrhythmias and mental status changes [ ] . lactic acidosis can be seen in patients with alf. the accumulation of tissue lactate is multifactorial. the effective blood pressure is usually lower in those patients with liver failure. this causes a generalized tissue hypoxia that leads to the production of lactate. the compromised liver is unable to uptake and process the lactate, leading to its accumulation [ ] [ ] [ ] . in addition, acute kidney injury can further contribute to the underlying acidosis due to failure of fixed acid clearance [ ] . kupffer cells can be found around the hepatic sinusoids. because of their location, they are constantly exposed to gut bacteria and endotoxins. they play a key role in clearing these pathogens and in maintaining normal homeostasis. in patients with liver failure, their function is impaired, and there is an increased susceptibility to develop gram-positive and gram-negative bacterial infections as well as possible fungal and viral infections [ ] . hepatic encephalopathy has been linked to an increased incidence of infection [ ] . although the mechanism behind this has not been clearly elucidated, it is thought that cns depression alters the immune system modulation. in alf, there is also a change in the production as well as clearance of different cytokines in patients with liver failure and compromised neutrophil function. these problems will lead to decreased bacterial opsonization and clearance. these alterations ultimately contribute to the immunologic impairment [ ] [ ] [ ] . up to three quarters of patients with alf will develop a bacterial infection. the organisms that are most commonly seen include gram-negative-bacteria, streptococcus, staphylococcus, and candida. they may develop a systemic inflammatory response syndrome (sirs) that will be undistinguishable from noninfectious conditions including necrotic hepatocytes from the failing liver [ ] [ ] [ ] . jaundice and pruritus are common complaints of patients with alf. although not specific to liver failure, the presence of both symptoms should raise suspicion of compromised excretion of bilirubin by hepatocyte failure. a normal by-product of the metabolism of heme, bilirubin is usually excreted in bile and urine. the liver is responsible for conjugating glucuronic acid with bilirubin in order to make a soluble compound. as a result, conjugated bilirubin passes into the colon and is eventually eliminated. in the failing liver, there is a severe compromise of the ability to metabolize and excrete bilirubin secondary to the undergoing cell necrosis. there is buildup of unconjugated bilirubin in the blood resulting in eventual deposition of these molecules in mucous membranes, skin, and conjunctiva, what is known as jaundice [ ] . because of the yellow color of the pigment, the physical appearance of the patient changes, directly correlating with bilirubin levels. besides bilirubin, there is also accumulation and deposition of bile acids in the skin. this has been associated with pruritus. other mechanisms that may explain this symptom include the endogenous opioids theory which proposes that the liver failure patient has elevated opioid levels secondary to decrease clearance and metabolism. these molecules activate the mu opioid receptor which may produce pruritus [ ] [ ] [ ] . as explained throughout this chapter, the management strategies for patients with alf are different from those of patients that have chronic liver failure with an acute decompensation. it is imperative to determine what form of failure the patient is experiencing. for those with alf, early recognition and transfer to a transplant center will improve outcomes and mortality. on initial presentation, a patient's mental status will be affected to different degrees; however it may deteriorate further. getting a thorough history during the first encounter is therefore important as it can elucidate the possible cause of the acute failure. the intensivist should review all medications that the patient ingested in the last days. specific questions about ingestion of acetaminophen should be asked. dietary intake should also be explored, playing close attention to any exposure to mushrooms. exact time of ingestion is key in order to determine treatment and further steps in management. social history should also be reviewed in detail. recent travel to viral hepatitis endemic areas as well as contact with other patients that have required hospital visits should be evaluated. focus on alcohol and drug use, sexual behaviors, and vaccination status can help determine the causative mechanism for the liver failure. past medical history plays a key role in determining if the patient has chronic liver disease or if they are experiencing an acute failure. a history of hepatitis, ascites, jaundice, asterixis, and gynecomastia and family history of a metabolic disorder favor chronic liver disease with an acute exacerbation. history of malignancy and lack of screening for colorectal cancer should also make the intensivist suspicious for metastatic malignancy. physical exam may disclose important findings that can elicit cause. an effort to identify the clinical manifestations described previously should be done. laboratory values that should be routinely obtained are listed in table . . when testing for hepatitis b, it is important to evaluate for immunity (hepatitis b surface antibody), infectivity (hepatitis b e antigen), and the presence of an acute infection (hepatitis b core antibody igm). although hepatitis c can cause alf, it is usually associated with chronic liver failure [ ] . bun and co can usually be lower than reference values in patients with alf. this is secondary to poor muscle mass as well as a respiratory alkalosis experienced by these patients. presentation with concomitant renal failure will alter most serum electrolytes. elevation of liver enzymes can be indicative of acute hepatitis and alf. however, values that are within reference range may be markers of poor prognosis as it may be reflective of decreased effective liver mass [ , ] . workup should be started on presentation, even if patient is going to be transferred to a liver center. early identification of the etiology and early treatment can significantly improve outcome. it can also identify those patients that will need liver transplantation in order to treat their disorder. if during the history and physical assessment a cause can be clearly identified, treatment should be started empirically. waiting for laboratory values can be detrimental and result in further deterioration of the patient. consultation with hepatology/gastroenterology, transplant surgery, and the intensivist should be done upon determination of liver failure of any cause. the development of alf has very different etiologies as well as presentations. as such, the management may differ from patient to patient. identification of the causative agent and treatment of it is important. however, supportive care in the intensive care unit is critical for ensuring a positive outcome. patients that have evidence of encephalopathy will require intensive care unit (icu) admission and management while those with no neurologic derangement can be followed on a regular ward with close monitoring. patients should have frequent checks of their coagulation parameters, arterial blood gases, complete blood counts, metabolic panels, serum aminotransferases, alkaline phosphatase, and bilirubin levels. derangements warrant further investigation. hemodynamic monitoring, precise fluid management, and monitoring for infections are all essential. the grade of hepatic encephalopathy guides the management and treatment of the neurologic system in alf. this is because intracranial hypertension (ich) and cerebral edema characterize the severity of patient presentation. those with mild forms (grades i and ii) very rarely develop these devastating complications while - % of patients with grade iii and - % of those with grade iv present with ich [ ] . for those patients with grades i and ii, frequent neurologic assessments should be performed to follow possible neurological progression. maintaining the patient in a quiet environment helps minimize agitation. sedation should be minimized; however, if needed minimal doses of short-acting benzodiazepines should be used [ ] . for patients who present with or develop grade iii and iv neurological symptoms, securing an airway should be the first treatment strategy followed by mechanical ventilation. for sedation, propofol should be used since there is evidence that it decreases cerebral blood flow and allows for frequent ongoing neurological assessment [ ] . intracranial pressure (icp) monitoring devices are used in some icus in patients with alf and grade iii or grade iv encephalopathy [ ] . the main reason for its use is the early identification of ich and subsequent treatment. also, not all patients present with cushing's trial of systemic hypertension, bradycardia, and irregular respirations. several trials have shown that icp monitoring can be performed safely and successfully be used to manage ich [ ] [ ] [ ] . however, no trial has demonstrated a survival benefit. bleeding has been associated with the placement of monitors; however, recent literature reports that there is a decrease prevalence of this particular complication. the incidence of bleeding after placement of icp monitor device has been less than % [ ] . ct scan of the brain should be considered in those patients with an acute mental status change and those with coagulopathy in order to rule out intracranial bleed. this imaging modality does not diagnose cerebral edema or ich in all patients, and therefore, it is not needed in every case of encephalopathy. patients at risk of encephalopathy should also have the head of their bed elevated at ° [ ] , minimize et suctioning, and minimize pain as these factors can lead to ich [ ] . for those patients with elevated ammonia levels (greater than ug/dl) and alf, administration of lactulose can lower the incidence of cerebral edema and decrease mortality [ ] . prior to prescribing this drug, the route of drug administration must be considered as the patient's ability to tolerate po intake may be compromised. other compounds studied include l-ornithine l-aspartate but have failed to demonstrate any survival improvement [ ] . phenytoin has been proposed as a possible prophylactic measure to prevent cerebral edema. an initial study that involved evaluation of brain at autopsy showed that patients who were treated with prophylactic phenytoin had a decrease in cerebral edema [ ] . follow-up trials were unable to replicate these results and more importantly, there was no survival improvement when this agent was used prophylactically [ ] . the administration of intravenous mannitol has been shown to transiently decrease cerebral edema and may be helpful in cases in which ich is < mmhg [ ] . a dose of . - g/kg may be beneficial and it may be repeated if serum osmolality is below mosm/l. the use of hypertonic saline has also been suggested. there is a lower incidence of ich in patients with alf that are treated with hypertonic if it is used to achieve a serum sodium level between and meq/l [ ] . use of hypertonic saline can be limited by renal failure. a newer treatment technique that has been proposed to prevent ich is hypothermia. it is thought to mediate this benefit by preventing hyperemia [ ] . concerns regarding the use of hypothermia in the treatment of alf include worsening coagulopathy and compromise of hepatocyte recovery [ ] . hyperventilation and use of corticosteroids have been proposed as a management option to reduce icp. the former may achieve this goal via vasoconstriction. however, trials suggest that although there is a delay in the onset of cerebral herniation, there is no reduction in the incidence of cerebral edema and no survival benefit [ ] . hyperventilation should only be used after all other resources have failed. while hypoxemia in patients with alf arises from many causes, it is treated with supplemental oxygen. if the patient has grade iii or iv hepatic encephalopathy, a definite airway should be established. during intubation, cis-atracurium is the agent of choice since it does not increase icp [ ] . pleural effusions can be observed and may or may not be contributing to hypoxemia or other respiratory problems. the use of diuretics should be carefully considered as these patients are usually in a very delicate hemodynamic state. overuse of diuretics can precipitate renal failure [ ] . hepatopulmonary syndrome (hps) has been traditionally resistant to medical therapies [ ] . oxygen supplementation for hypoxemia is recommended. transjugular intrahepatic portosystemic shunt (tips) has been reported to improve hps; however, it is not currently recommended as its outcomes are variable [ , ] . liver transplantation is the only therapy that has been shown to improve oxygenation and decrease oxygen requirement [ ] . the diagnosis of hps should prompt immediate referral to a transplant center. decreases in blood pressure lead to compromised renal and brain perfusion. it is imperative to be attentive to blood pressure and heart rate values in order to ensure adequate hemodynamics and, most importantly, adequate perfusion. patients with alf should be resuscitated initially with crystalloid before considering vasoactive agents. the generally accepted goal mean arterial pressure is mmhg [ ] . if after adequate volume resuscitation the patient is still hypotensive and not meeting blood pressure goals, vasopressors should be considered. norepinephrine should be initiated and titrated to effect [ ] . for resistant hypotension consideration to vasopressin should be given, although it should be used with caution as it has been associated with cerebral vasodilation and increased ich [ , ] . terlipressin has also been suggested as adjuvant treatment but it is currently not available in the united states [ ] . other causes of hypotension resistant to vasopressor therapy should also be entertained including adrenal failure and severe acidosis. during liver transplantation, ich and hemodynamics improve immediately after hepatectomy, probably secondary to removal of vasoactive cytokines. hepatectomy can improve these derangements for up to h [ ] . hepatectomy is currently recommended only as a last resort and when a liver graft in the process of being delivered to the transplant institution [ ] . despite the derangements of coagulation laboratories in patients with alf, their coagulation status remains in equilibrium and overall hemostasis. in the absence of bleeding, no correction of laboratory parameters should be performed [ ] . transfusion should be discouraged because treatment with ffp may precipitate pulmonary problems including hypoxia, and transfusion also prevents the use of inr as a marker of hepatocyte recovery [ ] . if an invasive procedure is planned or if there is evidence of significant bleeding, correction of coagulopathy should be done. ffp can be used for this purpose; however, careful volume management should also be achieved. the use of plasmapheresis and recombinant activated factor vii (rfviia) can help in the correction of coagulopathy. rfviia has been proposed as it effectively corrects derangements without volume overload [ ] . however, administration does carry the risk of myocardial infarction and portal vein thrombosis [ ] . alf has also been associated with vitamin k deficiency and it should be administered routinely in these patients [ ] . thrombocytopenia has also been reported in patients with alf. platelets should not be administered in the absence of bleeding. if the patient has platelet counts that are greater than , /mm , no prophylactic transfusion should be given [ ] . if an invasive procedure is planned, platelets between , /mm and , /mm have been proposed, and in those bleeding, the intensivist should consider transfusion if platelets drop below , /mm [ , ] . bleeding from intestinal mucosa is rare but has been reported in patients with alf. histamine- receptor blockers have been used in critically ill patients as prophylaxis of gastrointestinal (gi) bleeding with great success [ ] . also, proton pump inhibitors (ppi) have contributed to the reduced incidence of upper gi bleeding in patients with liver dysfunction [ ] . it is therefore recommended that alf patients are started on prophylaxis while in the icu. nutrition can be compromised in patients with alf; therefore, enteral feedings should be started early unless there are contraindications. there is no evidence that using branched-chain amino acid formulas has benefits over other enteral tube feeds [ ] . protein supplementation should not be restricted but rather limited to g per day in most patients. if gastrointestinal feeding is contraindicated, parenteral nutrition may be considered. there is also evidence that the risk of gi bleeding is reduced in patients that are on enteral feeding [ ] . hypoglycemia should be actively treated in patients with alf. the intensivist should consider adding dextrose to crystalloids in the form of d . if hypoglycemia is severe, central replacement with d concentration should be used. frequent glucose checks should be performed in order to assess the response to glucose administration. improvement and eventually weaning can be achieved in those patients that experience hepatocyte recovery. right upper quadrant pain can be treated with narcotics. judicious doses should be used as metabolism of medications can be compromised with the failing liver [ ] . the management of ascites will be discussed with chronic liver failure. close urine output monitoring is paramount in patients with alf. hemodynamic changes and alterations in the cardiovascular system make the kidneys susceptible to injury. insertion of a urinary catheter should be performed upon determination of hepatic failure. besides serum electrolytes, measurement of urinary sodium and creatinine is necessary. high or normal urine sodium may indicate the presence of acute tubular necrosis, while a low urine sodium may indicate prerenal azotemia or hepatorenal syndrome. several electrolyte derangements may occur and correction should be attempted. accumulation of lactate may result from tissue hypoxia and combined with renal failure may cause life-threatening acidosis. renal replacement therapy may be necessary in these patients. when indicated, continuous dialysis should be used as studies have shown that it provides cardiovascular as well as intracranial pressure stability when compared to intermittent dialysis [ ] . the development of an infection in a patient with alf has been associated with worsening encephalopathy and cerebral edema. also, the presence of bacterial or fungal infections may compromise any attempts at performing a liver transplantation. because of the impact that it has, prophylactic antimicrobials have been proposed as a prevention strategy for these patients [ ] . prophylactic antibiotics have been used and shown to decrease the incidence of infections in patients with alf. in a prospective control trial by rolando n et al., patients with fulminant liver failure were randomized to receive either selective parenteral and enteral antimicrobials vs. no treatment until clinically indicated. patients were included in this study. thirty-four percent of those patients randomized to receive prophylactic antibiotics developed an infection compared to % of those that were treated when clinically indicated (p < . ). however, this did not translate into a survival benefit [ ] . it is currently recommended that if no prophylactic antibiotics are used, periodic sputum, urine, and blood cultures are performed to determine if there are bacterial infections [ ] . the use of antifungals has also been studied [ ] . it is routine practice of the authors to use prophylactic enteric fluconazole in patients that are expected to be in the icu for more than days, given that there is a decrease in fungal infections in high-risk critically ill surgical patients [ ] . it is paramount to perform an infectious workup to any patient with liver failure that develops a change in mental status as it may be a change precipitated by infection. the most common cause of alf in the united states is acetaminophen (paracetamol) toxicity [ ] . over-the-counter availability and the fact that it can be found in combination with other medications make it the cause of voluntary or involuntary overdoses that compromise liver function and may result in fulminant liver failure. acetaminophen is usually taken orally and absorbed via the gastrointestinal system. its half-life is usually - h with one exception being extended release preparations in which it is increased to more than h. total doses should not exceed g per day. ingesting doses less than . g per day is unlikely to result in acute toxicity; however, it can vary depending on underlying liver function [ ] . the metabolism of acetaminophen is performed in the liver. most of the compound, approximately %, is conjugated with sulfate or glucuronide and excreted in the urine. five percent of the remaining medication is excreted unchanged in the urine. the remaining acetaminophen is subject to metabolism by the cytochrome p pathway. it is converted into n-acetyl-p-benzoquinoneimine (napqi), a highly reactive and toxic compound that is immediately conjugated with hepatic glutathione and excreted in the urine. when glutathione levels drop below % physiologic levels, napqi forms covalent bonds via cysteine groups with hepatic molecules and proteins, leading to irreversible hepatocyte damage. a decrease in glutathione levels, enhanced cytochrome p activity secondary to medication use, acetaminophen overdose, or decreased liver function from chronic disease make patients more susceptible to developing toxicity. the clinical presentation of acetaminophen toxicity can be divided into four different stages (table . ). stage i includes a series of nonspecific gi symptoms that start shortly after ingestion. no liver abnormality can be seen. during stage ii, there is usually transaminitis with a high ast/alt ratio. stage iii is characterized by the clinical evidence of liver failure and, in some patients, renal failure. mortality is higher at this stage. those patients that survive this stage progress to stage iv in which there is normalization of most of their lab derangements. because patients may not show symptoms up to h after ingestion, it is very important to obtain a detailed history. standard workup should be initiated as discussed previously. contacting poison control will help coordinate efforts to treat and eventually transfer patient to a liver center [ ] . in order to determine the severity of the poisoning, a serum acetaminophen concentration ( h post ingestion or later) should be plotted against time on the modified rumack-matthew nomogram (fig. . ) [ , ] . patients with acetaminophen levels below the treatment line can be discharged home after psychiatric and social evaluation. all other patients should be admitted to the intensive care unit [ ] . for those patients that ingested a single dose of acetaminophen of more than . g less than h prior to presentation, administration of activated charcoal should be considered. review of several small studies demonstrated that activated charcoal was the best available option to reduce absorption [ ] [ ] [ ] . also, there is a decreased risk of developing liver injury if charcoal is given prior to other forms of treatment [ ] . if patient has an unstable airway, charcoal should not be administered until the airway is controlled. the antidote of choice for acetaminophen toxicity is n-acetylcysteine (nac). the exact mechanism of action is unclear; however, it appears to restore glutathione levels [ , ] . indications for administration include a serum acetaminophen level above the treatment line, ingestion of more than . g, serum acetaminophen level > mcg/ml if time of ingestion is unknown, evidence of liver injury, and a history of acetaminophen ingestion regardless of time of ingestion [ ] [ ] [ ] . oral and iv administration of nac have been studied and both appear effective [ ] . the main factor determining the mode of treatment should be the mental status of the patient. if the patient is confused or has evidence of encephalopathy, oral administration should be avoided. if the oral protocol is used, a loading dose of mg/kg should be given followed by doses of mg/kg given every h. if iv nac is used, a loading dose of mg/kg is given over h. a second dose of mg/kg is then given over h and finally a third dose of mg/kg is given over h. an alternative to nac is hemodialysis. this method effectively removes acetaminophen [ ] . however, because of the effectiveness of nac, it should be reserved for cases in which the antidote is not available. acetaminophen toxicity is best managed in a multidisciplinary setting with assistance from hepatology and surgery teams. ingestion of poisonous mushrooms can lead to lethal emergencies including alf. amanita phalloides, amanita bisporigera, amanita verna, and other mushroom species may cause alf. these mushrooms do not express repulsive smells or tastes, and they can be found throughout midsummer in moist oak forests. alpha-amanitin is the amatoxin responsible for liver failure. after gastrointestinal absorption, enterohepatic circulation is responsible for transportation into the liver, where via active transport it concentrates in hepatocytes. the toxin will bind to rna polymerase and inhibit protein synthesis, ultimately leading to apoptosis [ ] . the clinical presentation of patients that ingest amatoxin includes an initial asymptomatic period of a few hours. this is followed by gastrointestinal symptoms that include abdominal pain, nausea, vomiting, and diarrhea that can be bloody. liver enzymes will be elevated and will continue to increase. one to two days after ingestion, the second phase of the presentation begins with an apparent recovery with continuing elevation of ast and alt. in severe poisonings, coagulopathy and possible dic and renal failure may ensue. the last phase includes alf and typically starts days after ingestion. hypoglycemia and multi-organ failure can be seen. workup of a patient with suspected amanita ingestion should proceed as indicated earlier in this chapter. detection of amatoxin can be performed in urine samples using enzyme-linked immunoassay (elisa); this test is not readily available in all institutions and awaiting results should not preclude supportive treatment [ ] . supportive treatment should be started immediately after presentation. in addition, an effort to minimize toxin absorption should be attempted. activated charcoal can bind amatoxin, and if given in repeated doses, it can reduce mortality significantly by increasing elimination via gastrointestinal tract [ ] . medications that can inhibit uptake of this toxin have also been described. these include penicillin g and silymarin. the former is given as a continuous infusion and has been show to decrease mortality [ , ] . the latter is a more potent inhibitor and is available in iv and po formats. silymarin has been shown to minimize damage to hepatocytes [ , , ] . nac has also been used in the treatment of amatoxin intoxication. mortality appears to improve with implementation of protocols very similar to those of acetaminophen toxicity [ , ] . wilson's disease poses a different presentation from frank alf. it normally occurs in the background of chronic liver disease that has been unrecognized. treatment varies when presentation of this disease is acute, and this will be the focus of this section. a genetically recessive disease, it is estimated that - % of alf cases are related to wilson's disease [ ] . the majority of copper that is ingested is transported into the liver where it is incorporated into enzymes and copper-binding proteins (ceruloplasmin). excess copper is combined with apometallothionein and excreted into bile. in wilson's disease, the incorporation into ceruloplasmin is compromised and copper is accumulated in the liver. as the disease progresses, other organs are affected. besides parkinsonian movements and tremors, kayser-fleischer rings, psychiatric alterations, and renal problems, wilson's disease will present with liver disease: cirrhosis, chronic failure without cirrhosis, and acute liver failure. laboratory workup should include serum ceruloplasmin, which is usually low, as well as serum copper level (above mcg/dl) [ ] . in patients with evidence of alf, low transaminases, low alkaline phosphatase, hypokalemia, glycosuria, hypophosphatemia, and renal tubular acidosis, the diagnosis of wilson's disease should be considered. in patients with acute failure, the aim should be to remove copper. hemodialysis and peritoneal dialysis can successfully achieve this goal [ ] . albumin dialysis and the molecular absorbent recirculating system (mars) device have also been used with promising results [ , ] . penicillamine, zinc, and other medications used for treatment of wilson's disease do not play a role in alf. the development of alf from viral hepatitis may occur after acute infection; ostapowicz et al. estimated that the etiology of % of those patients that were diagnosed with alf was viral hepatitis [ ] . most of the clinical deteriorations that are seen in patients with this etiology of disease are related to chronic liver infection. alf is more common with hepatitis b but it can also present in patients with hepatitis a, c, and e [ ] . presentation of viral hepatitis is described in four phases. phase is characterized by lack of symptoms but changes in laboratory studies that may be suggestive of viral hepatitis. phase marks the development of symptoms that include nausea, vomiting, abdominal pain, arthralgias, and possible fevers. the next phase includes clinical characteristics of alf including right upper quadrant pain, becoming icteric, and possible coagulopathy. the last phase, , leads to the normalization of laboratory values and resolution of symptoms. diagnosis of viral hepatitis relies on serum laboratories. hepatitis b has several important antigens and antibodies. hepatitis b surface antigen (hbsag) is usually found in patients with acute infection. a second antigen, associated with infectivity, is hepatitis b e antigen. the first antibody that can be detected in patients acutely infected and that indicates acute presentation of disease is igm anti-hbcag. resolution of acute infection and recovery results in igg antibodies against this antigen. finally, anti-hbsag appears in the serum several months after infection, indicating resolution. they will also be found in patients with hepatitis b vaccine. igg anti-hepatitis c virus has been used to diagnose exposure to this viral infection. it can usually be found in the serum several months after an acute infection and contrary to anti-hbsag, it does not confer immunity to hepatitis c. use of elisa and riba testing for diagnosis has fallen out of favor. hcv rna pcr assays were developed in order to detect the presence of the virus. it has been successful in not only establishing the diagnosis but also the presence of an acute infection. treatment of acute hepatitis a is limited to supportive care as there are no medications that improve outcome. hepatitis b treatment usually follows the same principles as most antiviral therapy is directed toward treatment of chronic disease. however, recent studies have suggested that acute hepatitis b may benefit from administration of lamivudine [ ] . finally, acute hepatitis c has been treated with ifn therapy with resolution of hcv rna after several months of treatment [ ] . low perfusion pressure to the liver may result in clinical manifestations of alf known as ischemic or hypoxic hepatitis. it is an uncommon cause of liver failure, with a prevalence of per , hospital admissions [ ] . this can be a direct consequence of global hypoperfusion, hemodynamic instability, direct vascular occlusion during surgical procedures, hepatic artery disease (occlusion, dissection, thrombosis) in patients with portal vein thrombosis, or hepatic sickle cell crisis [ ] . hepatocytes in zone become ischemic and eventually necrotic leading to liver insufficiency. prognosis of ischemic hepatitis is poor. raurich et al. described an in-hospital mortality of . % in all patients that were diagnosed with this disease process. in those patients with concomitant septic shock and those that experienced cardiac arrest, mortality rates were higher, at . % and . %, respectively. risk factors for mortality included an elevated inr, need for renal replacement therapy, and diagnosis of septic shock. non-survivors were more likely to be on vasopressors and to require mechanical ventilation [ ] . patients with hepatitis secondary to shock present with several symptoms related to their hemodynamic instability including altered mental status, respiratory distress, severe hypotension, and renal failure. patients with a history of cardiac compromise may present with nausea, vomiting, right upper quadrant pain, and malaise. up to % of patients with septic shock will also have ischemic hepatitis, presenting with fevers and severe hypotension [ ] . laboratory examination reveals elevated aminotransferase levels, usually above , iu/l. the ratio of serum alanine aminotransferase to ldh less than . suggests ischemic hepatitis [ ] . if hypoperfusion is chronic in nature, synthetic function may be preserved and coagulation studies may be normal; however, in acute cases, there is severe derangements that continue to progress with time. if ischemic hepatitis is suspected, a right upper quadrant ultrasound with doppler should be immediately performed as it may reveal the etiology of the insufficiency. there is no specific treatment for ischemic hepatitis. management is centered around restoring cardiac output and reestablishing hepatic perfusion. appropriate resuscitation is necessary. excessive fluid administration may lead to vascular congestion which can in turn compromise perfusion of hepatocytes and aggravate the presentation. judicious use of diuretics should be exercised as diuresis may exacerbate hypoperfusion and therefore liver failure. intensivists should rule out ischemic hepatitis in any patient that presents with septic shock and has elevated aminotransferases [ ] . prompt recognition of hypoperfusion state may lead to early intervention and possible better outcomes. continuous hepatic injury that persists for more than months is considered chronic liver disease (cld). the liver parenchyma suffers continuous inflammation and potential destruction. the hepatic insult does not only result in damage but also in attempts of repair. ultimately this leads to a broad spectrum of clinical manifestations including fibrosis, cirrhosis, and hepatocellular carcinoma. these changes are accompanied by alterations in serum liver function tests and can include physical exam finding suggestive of physiologic alterations. in the united states, the most common causes of cirrhosis leading to liver transplantation are alcoholic liver disease, chronic viral hepatitis, and nonalcoholic liver disease (table . ) [ ] . this last etiology has increased significantly in incidence. most patients are generally asymptomatic until decompensation occurs, making the calculation of prevalence difficult. approximately , deaths in where associated with cld [ ] . patients with cld may present with compensated or uncompensated hepatic failure. the former may be asymptomatic prior to evaluation, but patients usually report nonspecific symptoms such as weight change, fatigue, and lack of appetite. those patients with an acute decompensation may show signs of active bleeding, confusion, and skin changes. because of the broad spectrum of the disease, presentation will vary between different patients. due to similar underlying pathophysiology, symptoms and findings may be similar to those described previously during the acute liver failure presentation. patients with cld may present with varying degrees of hepatic encephalopathy. classification and underlying pathophysiology are similar to those described previously in the alf section. an acute exacerbation with an underlying chronic liver dysfunction can cause rapid progression from confusion to coma. shortness of breath, dyspnea, and other nonspecific respiratory symptoms may also be reported. as with acute dysfunction, the etiology may be of infectious, metabolic, or of cardiac etiology. hepatopulmonary syndrome can also play a role in underlying hypoxemia [ ] . the mechanisms that lead to the respiratory derangements in cld are similar to those described in acute liver compromise. figure . explains the molecular mechanism behind the underlying decreased effective perfusion pressure seen in patients with liver failure. as a result, patients will have a lower than baseline blood pressure, with some of them transitioning from hypertensive to normotensive. the cardiac output in patients with liver disease is usually high; however it is important to understand that myocardial cells are actually depressed from exposure to the changes in cytokines and other molecules. there is a slightly elevated heart rate that compensates for the depression and overall results in increase cardiac output, in a normal-sized man, often in the range of - l/min [ ] . patients with cld may present with anemia, leukopenia, thrombocytopenia, and coagulopathy [ ] . the pathophysiology behind anemia is multifactorial, and it may include episodes of gastrointestinal bleeding associated with portal hypertension and coagulopathy. there may also be nutritional deficiencies such as folate deficiency that can lead to compromised production of red cells and vitamin k deficiency that can lead to decreased production of coagulation factors [ ] . aplastic anemia, hypersplenism, and hemolysis may contribute to the anemia experienced by patients with chronic failure [ ] . thrombocytopenia is associated with portal hypertension: an enlarged spleen can sequester the majority of the circulating platelet mass and lead to a decrease platelet count. it has also been described that patients with liver disease have decreased levels of thrombopoietin that will also lead to thrombocytopenia [ ] . patients experiencing cld can present with abdominal distention and pain, anorexia, nausea, and vomiting. physical exam may also show ascites, hypogonadism, hypersplenism, and evidence of gastrointestinal (gi) bleeding such as hematemesis, hematochezia, and melena. gi bleeding can be the result of mucosal injury and thrombocytopenia or a more severe and life-threatening event such as variceal hemorrhage. an umbilical hernia may be seen when ascites becomes prominent. for those patients with cld, there are significant changes in the hemodynamics of the portal vein. the hepatic microcirculation, sinusoids, undergoes constriction secondary to architectural changes that compromise the lumen of these systems. furthermore, there is active contraction of myofibroblasts and active smooth muscle secondary to cytokine changes (increased levels of intrahepatic et- ) that cause even more restriction in the radius of these sinusoids [ , ] . these changes lead to an increase in portal pressure. a second factor that impacts the pressure of the portal vein is the increased in blood flow in the portal vein. as shown in fig. . , there is a splanchnic arteriolar vasodilation that leads to increase venous outflow and, therefore, increased flow that results in further increases of portal pressure and eventually portal hypertension (pht) [ ] . the elevated blood pressure and flow are partially relieved by decompressing the inflow into the portal vein into systemic collaterals. the esophageal submucosal veins are a preferred method of decompression and may result in esophageal varices. as flow increases so does the vessel radius [ ] . this ultimately leads to an increase in wall tension that may end up in rupture and variceal bleeding [ , ] . ascites is also closely related to pht. in fact, patients without evidence of pht do not develop ascites even in the presence of cirrhosis. the threshold for formation of ascites appears to be mmhg at the level of the portal vein [ ] . as a response to this increase in pressure, there is splanchnic vasodilation leading to a decrease in effective arterial blood volume that is mediated by several molecules including nitric oxide (no). there is subsequently an activation of the renin-angiotensin-aldosterone system that increases renal sodium retention and plasma expansion that ultimately leads to accumulation of fluid in the peritoneal cavity [ ] . the low levels of circulating protein secondary to liver compromise may also favor the formation of ascites. on physical exam, we can find evidence of pht by placing a stethoscope over the epigastrium. if there are collateral connections between the portal system and the umbilical vein, a murmur can be auscultated. this finding is known as cruveilhier-baumgarten murmur. dizziness, diaphoresis, and overall malaise may be reflective of underlying hypoglycemia. patients with cld undergoing an acute exacerbation may see decreased levels of circulating glucose with corresponding changes in neurologic exam. male and female patients with cld can report abnormalities related to infertility, impotence, and in the case of women chronic anovulation. physical exam may show evidence of testicular atrophy in men, while ultrasound and other imaging may show atrophic ovaries and uterus. there are several possible mechanisms that explain these findings. the increased levels of follicle-stimulating hormone (fsh) and luteinizing hormone (lh) observed in some patients suggest the primary dysfunction of the testicles or ovaries. an alternative mechanism suggests suppression of the hypothalamicpituitary function. the dysfunction may be secondary to decreased clearance of estrogen, testosterone, prolactin, and other substances [ , ] . male patients with cld may complain of loss of male pattern pubic hair, chest and axillary hair loss, and gynecomastia. this finding is thought to be related to an overall increase in estradiol: the adrenal glands produce and increase quantities of androstenedione that undergoes aromatization into estrone and eventually to estradiol [ ] . similar to patients with alf, patients with cld can present with renal pathology. these may manifest as decreased urine output, arrhythmias, generalized body edema, and overall malaise. most of the changes are associated with the underlying liver dysfunction. in hospitalized patients with cld, it is estimated that approximately % of them will develop hepatorenal syndrome (hrs). the pathophysiology of hrs follows the development of pht. as explained in fig. . , there is dilation of the splanchnic circulation, leading to a decrease in perfusion pressure. the response is cardiac compensation as well as activation of the renin-angiotensin-aldosterone system. there is also vasoconstriction mediated by the sympathetic nervous system. these changes ultimately lead to low renal perfusion and a significant decrease of the glomerular filtration rate [ ] . electrolyte abnormalities can accompany the changes that are seen on the renal system. hyperkalemia, hyperphosphatemia, and hyponatremia can be detected in serum electrolytes. symptoms may be variable and depend not only on severity of derangement but acuity. dizziness, weakness, and palpitations may be reflections of these abnormalities. cld leads to acquired immune deficiency and makes these patients prone to developing infections. the mechanism by which the immune response is compromised includes the deficiency of serum complement [ ] as well as the compromised activity and function of phagocytes such as macrophages, pmns, and kupffer cells [ , ] . certainly, the presence of fevers should make the intensivist suspicious for an infectious process and further investigation is warranted in order to determine additional symptoms that may guide further treatment. however, patients who present with decompensated liver failure may have an infection causing the decompensation. thus, suspicion for the presence of infection should be high, and the threshold for obtaining cultures is low in any patient with liver failure who is acutely ill. abdominal pain that worsens and fevers should raise the suspicion for spontaneous bacterial peritonitis (sbp) in those patients with evidence of ascites. up to % of these patients may develop sbp [ ] . patients with cirrhosis have an increased intestinal permeability as well as altered intestinal motility. this may lead to the bacterial overgrowth and infection of ascites [ ] . the most common organism seen is escherichia coli; however, other organisms have also been described [ ] . typically sbp is monomicrobial and a polymicrobial infection should prompt consideration of a perforated viscous. similar to alf, skin and urine color can change in patients with cld. the increase in bilirubin secondary to compromised liver function leads to the accumulation in the skin leading to jaundice as well as dark appearance of urine. these changes are usually undetectable if the serum bilirubin is less than mg/dl. another change that can be appreciated in the skin of patients with cld includes palmar erythema. it is thought to be the consequence of altered sex hormone metabolism which may lead to capillary vasodilation [ ] . careful examination of the skin can also reveal vascular lesions characterized by the presence of a central arteriole with surrounding smaller vessels. these are called spider angiomata and their appearance is related to an increase in estradiol levels. the number as well as size of these lesions is related to the severity of liver disease although they are not specific for it [ ] . as an additional route to decompress the portal vein during pht, the umbilical vein may open leading to shunting into abdominal wall veins. these vessels engorge significantly making them very easy to identify during physical exam. this finding is known as caput medusa. initial workup and management of patients with cld should begin with a thorough history. onset of symptoms and identification of disease progression helps determine the pathophysiologic manifestations of the disease. previous medical diagnosis including viral hepatitis should be assessed. a thorough review of all medications that the patient takes can help identify potential additional mechanisms of liver injury. hospitalizations and transfusions should be reviewed. social history including exposure to high-risk behaviors such as intravenous drug use and alcohol abuse should be performed. family history of liver disease and personal history of malignancy (including oncologic treatment and surveillance studies) also play a key role in the development of disease and should be explored. a complete physical exam should be performed and an attempt to determine if any of the clinical manifestation discussed previously are present. the exam should include neurologic, rectal, and skin exam. assessment of vital signs in order to identify possible hypotension, hypoxemia, as well as end-organ perfusion should be performed. there is no serologic test that can diagnose cld accurately. laboratory abnormalities that are identified could be related to alf or another etiology with some degree of liver dysfunction. besides serologic tests, evaluation of the degree of liver fibrosis and additional characteristics of cld can be investigated with radiologic studies. the initial serologic studies that are performed as well as initial management are similar to those described in table . in the alf section. in addition, studies from ascitic fluid should also be performed when it is desired to identify etiology of fluid and possibility of infection. after paracentesis with removal of ml of ascites in a sterile fashion, the intensivist should send the fluid for cell count, cytology, albumin, total protein, triglycerides, amylase, adenosine deaminase, as well as culture [ ] . this should be accompanied by a serum albumin in order to calculate the serum-ascites albumin gradient (saag). this is done by subtracting the albumin in the ascitic fluid from the serum value. based on such studies, the etiology of ascites can be determined (table . ) . imaging studies that are routinely used include ultrasonography (us), ct scan, and magnetic resonance imaging (mri). us can help identify morphologic changes such as nodularity. with doppler us, patterns of flow as well as possible occlusions can be identified. ct and mri are able to identify nodularity and changes in volume of liver mass (hypertrophy or atrophy) as well as assess the portal vasculature [ ] . evaluation of collateral circulation, varices, and tumors can also be performed. since us does not use contrast, this can be very helpful in those patients with renal compromise [ , ] . if after a thorough workup, the diagnosis of cld cannot safely be established, liver biopsy should be considered. identifying changes consistent with cld may be very beneficial as it may prevent delays in therapy and potential worsening of the patient [ ] [ ] [ ] . surgery and interventional radiology teams should be involved in order to determine the safest and least invasive method that can render a diagnosis. suspicious findings for cld should prompt consultation with hepatology/gastroenterology and transplant surgery in order to determine if the patient will benefit from additional therapies and workup including possible transplantation. evidence of encephalopathy, compromised ventilation, hypotension, hypoperfusion, active bleeding, sepsis, and sbp should prompt admission to the icu. consideration of additional hemodynamic monitors such as an arterial line and central access may be considered in every patient. a foley catheter should be placed in all patients with hemodynamic instability or with poor renal function but avoided in those with anuria to prevent a urinary tract infection. it is also helpful to classify the severity of liver disease. the child-turcotte pugh (ctp) classification divides patients into three groups based on serum labs and clinical presentation. it can help in determining possible surgical treatments or additional therapies [ , ] . this specific scoring system is presented in table . . another classification system that is used for the allocation of organs in the unites states is the model for end-stage liver disease (meld). it consists of a formula that will assign a score to a patient and that accurately predicts mortality within months. the formula is based on three laboratory values (bilirubin, inr, and creatinine) and it is modified by etiology. the formula is shown below [ ] : if the disease process is alcohol, is assigned to etiology. if the liver failure is secondary to a cholestatic process, is assigned instead. several factors can modify the calculated meld score for allocation purposes, and these include dialysis and the presence of hepatocellular carcinoma. the ctp and meld system have been compared in several studies in order to determine which provides a better answer to prognosis for patients. although some studies show superiorities of meld, others show no difference and good predictions with both systems [ ] [ ] [ ] [ ] . a systematic review, suggested that the meld was better for predicting -month mortality but otherwise the systems were similar [ ] . because of its use with united network for organ sharing (unos) lists for allocation of organs, meld has become more popular. hepatic encephalopathy (he) is a diagnosis of exclusion, and therefore, an effort to identify other etiologies of altered mental status should be performed. it is also necessary to determine the precipitating event leading to the neurologic derangement which includes bleeding, renal failure, electrolyte abnormalities, changes in diet, and changes in medication [ ] . treatment principles are similar to those described in the alf section. they should be based on supportive care, attempts to correct precipitating factors, minimizing gi nitrogen intake, and establishment of therapy. admission to an icu is important as patients with he need constant neurologic assessments for progression or resolution. for grade iii and grade iv he, establishment of definite airway should be the first step in management. laboratory studies are key in order to identify possible precipitating events. a decrease in nitrogen production as well as nitrogen delivery should be attempted with medication. the most common therapy used is lactulose, which reduces the absorption of ammonia. twenty-five milliliter should be given twice a day and should be titrated to achieve two soft bowel movements [ ] . rifaximin has also been used as an add-on therapy to lactulose. it is an antibiotic with activity against grampositive and gram-negative aerobes and anaerobes. the usual dose is mg three times a day. trials have shown benefit in the treatment of he when rifaximin is used in addition to lactulose [ ] . another antibiotic that has been use is neomycin. this alternative treatment has been used for the treatment of overt hepatic encephalopathy [ ] . however, because it has been associated with complications such as ototoxicity and nephrotoxicity, neomycin is used less commonly today [ ] . an assessment of nitrogen intake by assessing a patient's diet is also very important. if a patient's he is unresponsive to the therapies described above, oral branched-chain amino acids (bcaa) should be considered in an attempt to reduce the hepatically metabolized nitrogen load. a recent metaanalysis showed that bcaa-enriched formulations may be beneficial in some patients with he and cld [ ] . the daily protein intake should be . - . g/kg/day as severe restriction may be detrimental in the catabolic state of cld [ ] . the first step in management of a patient with cld and ascites should be sodium restriction to no more than , mg per day [ ] . this should also be accompanied by oral spironolactone and possibly furosemide in order to perform natriuresis while maintaining normokalemia. spironolactone inhibits sodium reabsorption in the distal tubule and collecting ducts but it can lead to gynecomastia and hyperkalemia. furosemide is a loop diuretic and inhibits the luminal na-k- cl symporter causing natriuresis and also hypokalemia when used alone. combination therapy has been used more effectively in achieving sustained results. if the serum sodium is less than mmol/l, fluid restriction to no more than . l per day should also be done [ ] . for those patients that are not responsive to diuretic therapy, serial paracenteses can be performed in order to relieve symptoms [ ] . in carefully selected patients, transjugular intrahepatic portosystemic shunt (tips) should be considered. trials have demonstrated that there is better control of ascites and overall survival with this procedure; however, there is worsening hepatic encephalopathy [ ] . referral to a transplant center should be done for patients with refractory ascites. tense ascites with respiratory compromise and abdominal discomfort can also be the initial presentation of patients with cld. prior to sodium restriction, paracentesis should be performed. for large volume (> l) removal, albumin replacement should be done [ ] . replacement of - g of albumin per l of fluid removed has been shown to improve survival [ ] . replacement after paracentesis has remained a controversial topic. in one study performed by gines et al., patients with tense ascites were randomized to receive albumin or no replacement. those that did not receive albumin had more changes in serum electrolytes, plasma renin, and creatinine but had no survival advantage [ ] . there has been no study up to date demonstrating decreased survival in patients without replacement when compared to albumin [ ] . in a meta-analysis by bernardi et al., , patients from trials were analyzed. albumin was shown to be superior to other plasma expanders, with an infusion between and g of albumin per liter removed [ ] . angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aspirin, and nonsteroidal anti-inflammatory agents should be avoided in patients with cld and ascites: prostaglandin inhibition can severely affect renal hemodynamics as well as natriuresis. it is important to evaluate patients with ascites for ventral and umbilical hernias. for those patients with ascites, hernia repair should only be attempted after medical treatment of ascites. for those with refractory ascites, repair should be deferred until after liver transplantation. if the patient has an incarcerated or strangulated hernia, emergency repair is warranted, but special attention to the ascites postoperatively must be made. the diagnosis of spontaneous bacterial peritonitis (sbp) is established with studies sent from ascitic fluid revealing one of the following three findings: . leukocyte count of more than per mm . polymorphonuclear count of more than per mm the causative organism is usually a gram-negative enteric bacteria; if more than one organism is identified, secondary peritonitis should be considered. escherichia coli and klebsiella are responsible for more than % of the cases [ ] . therapy is tailored based on the most likely causative agent. if the patient has not been on empiric antibiotics prior to presentation, an intravenous third-generation cephalosporin should be started, preferably cefotaxime g every h. if the patient has been exposed prior to this medication, coverage should be based on hospital antibiogram [ ] . therapy should be started if there is a high suspicion for infection while cultures are pending. the recurrence rate of sbp can be as high as % and therefore prophylaxis is advocated. long-term antibiotic therapy, norfloxacin mg daily, is recommended [ ] . trimethoprim/sulfamethoxazole can be used as a secondline agent for those patients with sensitivities [ ] . the presence of esophageal varices in patients with cld warrants prophylactic therapy. the most effective medication has been propranolol that inhibits stimulation of the beta- venodilator receptors seen in varices. it should be started at low doses, mg orally twice a day, and titrated to reduction of pulse rate by %. if patients cannot take propranolol, isosorbide mononitrate can be used. if the patient is unable to tolerate medical therapy, esophagogastroduodenoscopy (egd) and variceal banding should be performed [ ] . three principles govern the management of an acute variceal bleed: stabilization and resuscitation, identification and treatment of bleeding, and prevention of recurrence. if a patient presents with evidence of gi bleeding, immediate type and cross should be performed, and if needed, transfusion of untyped and uncrossed blood should begin. waiting for laboratory values to show anemia may worsen the overall clinical condition of the patient. upper gi bleeding in a patient with presumed cld prompts urgent endoscopy to identify possible bleeding esophageal or gastric varices. if during endoscopy, no varices are seen, repeat evaluation should be done in years. if varices are identified but not bleeding, follow-up endoscopy should be done after year. if active bleeding is encountered and it appears to involve esophageal varices, an attempt at controlling the bleeding varices should be done. banding followed by sclerotherapy are the two most common methods of achieving control. if after appropriate attempts bleeding does not stop, a sengstaken-blakemore tube should be inserted. tips and surgical shunts should be considered if all previous methods fail. tips has shown improved outcomes [ ] ; however, it is associated with he [ ] . surgical shunts carry a high morbidity and should be considered a last resort. cld patients with gi bleeding are at risk of developing bacterial infections. some advocate the use of ceftriaxone for days while patients are gi bleeding [ , ] . if the patient stabilizes and tolerates oral intake, changing to norfloxacin is reasonable. the diagnostic criteria for hepatorenal syndrome (hrs) are shown in table . . hrs is a diagnosis of exclusion and it is important to rule out other etiologies including prerenal azotemia, intrinsic renal disease, and post renal failure. in order to diagnose hrs, all major criteria in table . must be met. minor criteria are not required; however, they provide supportive evidence that the pathophysiology is consistent with hrs. identification of precipitating event is also instrumental in the management of hrs as additional therapy can be instituted. when performing large volume (> l) paracentesis, it is recommended to replace volume with albumin (see ascites section above) as this procedure may lead to hrs. evaluation for possible sbp as well as workup for gi bleeding should be considered as they are well-established risk factors for the development of this syndrome. there are two manifestations of hrs: type i and type ii. the former shows a rapid decline in renal function with either an initial creatinine of greater than . mg/dl or a % reduction in the creatinine clearance. type ii usually leads to moderate renal failure that progresses slowly and is manifested as diuretic-resistant ascites [ ] . liver transplantation is the preferred treatment for patients with hrs. any patient with evidence of this syndrome should be referred to a liver transplantation center in order to be listed for transplantation [ ] . bridging with pharmacotherapy is necessary in most patients as there is rapid decompensation, especially in those with type i hrs. the basic principle behind the management of hrs is reversal of renal vasoconstriction and splanchnic vasodilation. dopamine, fenoldopam, and prostaglandins have been used in an attempt to cause direct renal vasodilation [ ] . results of several trials have not favored any of these agents as none have improved outcome [ ] [ ] [ ] . splanchnic vasoconstriction, in an attempt to reduce portal blood flow and decrease pressure, has been attempted with vasopressin, ornipressin, terlipressin, norepinephrine, and midodrine [ ] . ornipressin, with some promising results, resulted in an increase rate of ischemic events [ ] . terlipressin in combination with albumin has shown the most promising results, with improvements in renal function although its use has not been approved in the united states [ ] . norepinephrine and vasopressin have been used with improvement of renal function and successful bridging to transplantation [ ] . hemodialysis may be required in the treatment of these patients, especially those with type disease. those patients that are hospitalized in an icu should receive continuous dialysis rather than intermittent as it minimizes changes of abrupt hemodynamic changes and further compromise of these frail patients [ ] . patients with alf and cld may benefit from liver transplantation. this therapeutic option should be considered when medical therapy has failed and when there is progression of disease. referral to transplant center should occur once the patient has experienced ascites, variceal hemorrhage, hrs, and he. consultation with hepatology and transplant surgery teams ensures early consideration for transplantation. table . presents poor prognostic factors from the king's college criteria that may suggest that the need for transplantation is increased. prior to transplantation, a thorough evaluation is performed on patients regardless of etiology. this includes assessment of cardiac function, possible occult malignancy, identification of infection, contraindications to chronic steroid therapy, and appropriate social support. the rapidly progressive nature of alf designates that these patients are currently listed as status by the united network for organ sharing (unos) [ ] . approximately table . criteria for diagnosis of hepatorenal syndrome chronic or acute liver disease with advanced hepatic failure and portal hypertension low glomerular filtration rate serum creatinine > . mg/dl or h creatinine clearance < ml/min absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs absence of gi fluid losses absence of renal fluid losses in response to diuretic therapy no sustained improvement in renal function after diuretic withdrawal and expansion of plasma volume with . l of plasma expander proteinuria < mg/day no obstructive uropathy, parenchymal renal disease, microhematuria minor criteria urine volume < ml/day urine sodium < meq/l urine osmolality greater than plasma osmolality urine rbcs < /high-power field serum sodium concentration < meq/l non-acetaminophen inr greater than . or three of the following five criteria: patient age of less than or greater than serum bilirubin of greater than μmol per liter time from onset of jaundice to the development of coma of greater than days inr greater than . drug toxicity, regardless of etiology of alf acetaminophen arterial ph < . inr greater than . creatinine greater than μmol per liter encephalopathy (grade iii or iv) % of patients with alf will undergo liver transplantation, % of them will improve with supportive care, and % will not survive their presentation; of those that have a liver transplant performed, the -year survival is approximately % [ ] . patients with failure secondary to viral hepatitis usually have better outcomes than those with drug reactions or metabolic causes. also, patients with alf have worst outcomes when compared with patients with cld. the -year survival for patients with cld that undergo liver transplantation is % [ ] . timing is not standard and is usually dependent on severity of meld. living donors have been used secondary to decrease in organ availability and it has been successful. this therapy has not been studied in patients with alf. liver replacement therapies (lrt), also known as liver dialysis, have been studied and used as a bridging therapy to transplant [ ] [ ] [ ] [ ] . several methods have been developed and they can be grouped into artificial and bioartificial devices. regardless of the mode of action, they attempt to clear toxins that are free and protein bound, as well as to regenerate or replace proteins that are affected by the liver failure process. among the artificial methods, the most studied is the molecular adsorbent recirculation system (mars). it effectively clears several toxic compounds and causes a dramatic improvement in serum laboratories and in some symptoms such as pruritus [ ] . unfortunately, this has not translated into clinical benefits [ ] . biologic methods include devices with porcine hepatocytes and with human hepatoblastoma cells [ , [ ] [ ] [ ] . their theoretical advantage is the production of 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authors: akgul, ahmet; turkyilmaz, saygin; turkyilmaz, gulsum; toz, hasan title: acute aortic dissection surgery in patient with covid- date: - - journal: ann thorac surg doi: . /j.athoracsur. . . sha: doc_id: cord_uid: d s oe abstract acute aortic dissection is one of the most common life-threatening disease which affects aortic vessel. we present a case of acute stanford type a aortic dissection in a patient with covid- under treatment of ace inhibitors. a -year-old female complaining of acute chest pain and dyspnea admitted to the emergency clinic of our hospital on may , . she had history of diabetes and hypertension. this is one of the first acute aortic surgery case among patients with covid- . acute aortic dissection is one of the most common life-threatening disease which affects aortic vessel. we present a case of acute stanford type a aortic dissection in a patient with covid- under treatment of ace inhibitors. a -year-old female complaining of acute chest pain and dyspnea admitted to the emergency clinic of our hospital on may , . she had history of diabetes and hypertension. this is one of the first acute aortic surgery case among patients with covid- . covid- has proven to be one of the worst pandemic in modern times in terms of both mortality and morbidity after being detected in the republic of china on december , . after the first confirmed case in turkey was detected on march , ; the number of confirmed cases has increased so far [ ] . although there are an increasing number of reports regarding the effects of coronavirus on cardiovascular system, acute dissection of the aorta among patients with covid- has not been presented. a -year-old female referred to our institution with a chest pain and shortness of breath. the patient's family reported a history of hypertension and diabetes. upon admission, the physical examination showed pulseless right femoral artery, an arterial pressure of / mmhg, and a pulse rate of beats/min. pulmonary rales were audible at the bases of both lungs, and an aortic diastolic murmur was detected during cardiac auscultation. electrocardiography revealed pulmonary hypertension. transthoracic echocardiography showed mild aortic insufficiency with % of ejection fraction. computed tomography revealed type a aortic dissection flap extending through right common iliac artery, and ground-glass opacities in both lungs with nodular infiltration in right apex (figure ). at surgery, because of the dissection that extended to right femoral artery, we decided to establish cardiopulmonary bypass through the left femoral artery. transesophageal echocardiography was performed, which revealed intact aortic valves without insufficiency. a midline sternotomy was performed and a cross-clamp was placed on the intact aorta to ensure cardiac arrest with the administration of del nido cardioplegia solution through coronary ostiums after aortotomy, which exposed marked thickening of the aortic wall. proximally, the aorta was completely transected at a level just above the aortic commissures and distally, just before the innominate artery. a mm dacron graft (intervascular sa, la ciotat cedex, france) was placed. individual teflon pledgeted sutures were used for distal anastomosis in order to affix the dissection flap to the aortic wall. the crossclamp was removed and deairing maneuvers were applied. cardiopulmonary bypass (cpb) was concluded without any complication, and the femoral cannula was removed after protamine administration. (cpb time was min, aortic crossclamp time was min). despite repairs and protamine administration, the bleeding through distal anastomosis line did not cease. therefore, bioglue ® surgical adhesive (cryolife international, inc.;kennesaw, ga) was applied to the bleeding zones. the patient had an excellent pulse in her right femoral artery after the operation. and/or dissections when compared with patients having non-aids chronic cardiovascular diseases as arterial hypertension [ ] . reports are presented to evaluate the possibility of "similarity" of virulence as well as its' therapy of hiv and sars-cov- and their infections [ ] . during aortotomy, in our case, we evaluated the aorta, which revealed pronounced thickening of the wall (as seen in inflammatory aortopathies [ ] ) when compared with our experience in previous aortic dissection published [ ] and/or unpublished cases. another challenge in surgery for inflammatory aortopathy remains in the suture line where, in acute phase, bleeding might be occur (as seen in our present case) and/or in chronic phase, formation of aneurysm may be seen. this inflammation may be due to sars-cov- viremia. preoperative measurement of c-reactive protein and erythrocyte sedimentation rate were high in our patient and immunosuppressive therapy was started just after surgery. another important point in our case was the use of ace inhibitory drugs for the treatment hypertension. sars-cov binds to the angiotensin-converting enzyme (ace) which is also present on endothelial cells and ace inhibitory drugs are presented to have beneficial effects on the covid- process [ ] . despite the hypothetical concerns on the use of raas inhibitors which alter ace expression, the maintenance of hypertension treatment by raas inhibitors is recommended due its beneficial effect on raas activation, however, our present case did not show any beneficial performance despite usage of raas inhibitors for years, which may be due to raas activation may not efficiently achieved without local/systemic mast cell stabilizers as pro-inflammatory and pro-fibrotic cytokines as well as proteases as renin are highly released by local mast cells [ , ] . additionally, one of the important issue in patients with covid- is the elevated risk of thrombosis which necessitates anti-coagulation therapy during hospitalization. low molecular weight heparin was used for anticoagulation in our patient during hospital stay, and clopidogrel was preferred for profilactic antiaggregant agent during followup. predicting the progress of covid- : the case for turkey many different patterns under a common flag: aortic pathology in hiv-a review of case reports in literature repurposing antiviral protease inhibitors using extracellular vesicles for potential therapy of covid- . viruses behçet's inflammatory vessels for cannulation in inflammatory aortic repair repair of the aortic arch with left unilateral selective cerebral perfusion potential harmful effects of discontinuing aceinhibitors and arbs in covid- patients role of mast cells and their mediators in failing myocardium under mechanical ventricular support renin: at the heart of the mast cell. immunol rev figure : computed tomography of the patient. pane a, b and d show type a aortic dissection flap panel c shows ground-glass opacities in both lungs with nodular infiltration in right apex key: cord- - esrg jw authors: tam, clarence c.; offeddu, vittoria; anderson, kathryn b.; weg, alden l.; macareo, louis r.; ellison, damon w.; rangsin, ram; fernandez, stefan; gibbons, robert v.; yoon, in-kyu; simasathien, sriluck title: association between semi-quantitative microbial load and respiratory symptoms among thai military recruits: a prospective cohort study date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: esrg jw background: multiplex real-time polymerase chain reaction assays have improved diagnostic sensitivity for a wide range of pathogens. however, co-detection of multiple agents and bacterial colonization make it difficult to distinguish between asymptomatic infection or illness aetiology. we assessed whether semi-quantitative microbial load data can differentiate between symptomatic and asymptomatic states for common respiratory pathogens. methods: we obtained throat and nasal swab samples from military trainees at two thai army barracks. specimens were collected at the start and end of -week training periods (non-acute samples), and from individuals who developed upper respiratory tract infection during training (acute samples). we analysed the samples using a commercial multiplex respiratory panel comprising bacterial, viral and fungal targets. we used random effects tobit models to compare cycle threshold (ct) value distributions from non-acute and acute samples. results: we analysed non-acute and acute swab samples from participants. haemophilus influenzae type b was the most commonly detected microbe ( . % of non-acute and . % of acute samples). in acute samples, nine specific microbe pairs were detected more frequently than expected by chance. regression models indicated significantly lower microbial load in non-acute relative to acute samples for h. influenzae non-type b, streptococcus pneumoniae and rhinovirus, although it was not possible to identify a ct-value threshold indicating causal etiology for any of these organisms. conclusions: semi-quantitative measures of microbial concentration did not reliably differentiate between illness and asymptomatic colonization, suggesting that clinical symptoms may not always be directly related to microbial load for common respiratory infections. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. multiplex polymerase chain reaction (pcr)-based diagnostic techniques allow rapid, simultaneous identification of a broad range of respiratory pathogens [ ] . compared to classical microbiological diagnostic methods, pcr-based assays offer higher sensitivity, specificity, and reproducibility [ ] . however, the high sensitivity of multiplex pcr diagnostics does not directly translate into clinical utility, because such assays do not distinguish between viable and dead organisms, or acute infection and asymptomatic colonisation [ ] . in the clinical setting, the etiological agent is seldom identified and unspecific respiratory symptoms are often treated empirically [ ] . although the quantification of microbial load may vary depending on the presence of co-infections, specimen type, sampling technique, or timing of sampling, quantitative or semi-quantitative microbial load data from real-time pcr assays may help define organism densities that are consistent with colonization or infection and distinguish between symptomatic and asymptomatic states [ ] . in this study, we assessed whether semi-quantitative microbial load availab from real-time pcr assays can differentiate between symptomatic and asymptomatic states for common respiratory agents in a cohort of basic military trainees at two royal thai army barracks. details of the study setting and procedures have been described previously [ ] . briefly, participants were recruited from six consecutive cohorts of basic military trainees at two royal thai army barracks between may and july . trainees entered the camps for a -week training period at the start of may and november each year. individuals aged ≥ years entering one of the two army barracks involved in the study were eligible for enrolment. suspected tuberculosis cases or individuals with immune deficiencies, such as acquired immune deficiency syndrome, leukemia or lymphoma, were excluded. throat and anterior nasal swab samples were collected using stiff synthetic swabs by trained study staff at the start and end of each training period (non-acute samples) and were placed in viral transport media (universal transport medium c ; copan diagnostics) and stored at − °c until time of transfer to the armed forces research institute of medical sciences for further testing. in addition, enrolled participants were asked to consult the camp's medical unit if they experienced respiratory symptoms during the training period. medical staff took a history, conducted a medical exam, and recorded symptoms of upper respiratory illness (uri) or influenza-like illness (ili). uri was defined as an illness with at least two of the following: (i) runny nose or sneezing; (ii) nasal congestion; (iii) sore throat, hoarseness or difficulty swallowing; (iv) cough; (v) swollen or tender glands in the neck; and (vi) fever (oral temperature > °c). ili was defined as a respiratory illness with acute onset presenting with fever and cough or sore throat. throat and nasal swab samples were collected on average . days after symptom onset from individuals who developed uri or ili during the -week follow-up (acute samples). specimens from two of the six cohorts (total number of individuals = ) were tested using a commercial multiplex real-time pcr assay comprising bacterial, viral and fungal targets according to the manufacturer's instructions (ftd kit, fast track diagnostics, esch-sur-alzette, luxembourg). these two cohorts were selected because they underwent concurrent routine environmental sampling of air and surfaces within the barracks, which were then similarly tested using the ftd kit (data not shown). multiplex testing of specimens from the remaining cohorts was not done due to resource constraints. a cycle threshold (ct) value below the detection limit of the assay (< ) was considered a positive result. non-acute samples collected at the end of the training period from participants who experienced an acute episode during follow-up were excluded from the analysis, as the ct-value might reflect post-infectious shedding. we used the mcnemar test to determine whether target-specific frequencies were significantly different in non-acute baseline samples and acute samples. in addition, we computed the chi-square (χ ) or fisher's exact test (for expected values < ) to assess whether co-detection of specific microbe pairs occurred more frequently than expected by chance in non-acute baseline or acute samples. to account for data censoring at ct-value = , random effects tobit regression models were used to compare ct-value distributions from non-acute and acute samples, or ct-value distributions from samples containing a single or multiple organisms. in addition, we used the kruskal-wallis test to compare the median delay between illness onset and sample collection between samples containing one or multiple organisms. all analyses were conducted using stata software (stata corporation). the study was approved by the institutional review boards of the royal thai army in bangkok, thailand, the walter reed army institute of research and the london school of hygiene & tropical medicine. all participants provided written informed consent. the investigators have adhered to the policies for protection of human subjects as prescribed in army regulation - . we analyzed a total of non-acute swab samples collected from recruits at the start (n = ) or end (n = ) of the training period, and acute specimens from individuals who developed one or more uri episodes during follow-up. of targets contained in the respiratory panel, were detected in at least one specimen (table ) . viruses were detected in . % ( / ) and bacteria in . % ( / ) of non-acute samples. among acute samples, viruses were detected in . % ( / ) and bacteria in . % ( / ) of specimens. haemophilus influenzae type b (hi-b) was the most commonly detected microbe ( . % of non-acute and . % of acute samples). other frequently detected bacteria included non-type b haemophilus influenzae (hi-nonb), streptococcus pneumoniae, and klebsiella pneumoniae (table ) . rhinovirus was the most prevalent virus, detected in . % of non-acute and . % of acute samples. all other viruses were detected in < % of collected specimens (table ) . hi-nonb, rhinovirus, and coronavirus were detected significantly less frequently in non-acute samples collected at the start of the training period than acute samples (p-values < . ) ( table ) . influenza b was identified in none of the non-acute, but . % of acute specimens. multiple microbes were detected in . % ( / ) of non-acute samples collected at the start of the training period. co-detection of multiple organisms was significantly higher in both non-acute samples taken at the end of the training period ( . %) and acute specimens ( . %) (p-values < . ; table ). among acute samples, specific organism pairs were co-detected more frequently than expected by chance (p-values < . ) ( were found in < % of acute specimens (table ) . no microbe pair occurred more frequently than expected by chance among non-acute baseline samples. overall, there was a substantial overlap in ct-value distributions from non-acute samples collected at the start or end of the training period and acute samples collected from symptomatic individuals during follow-up (fig. ) . this was the case even when considering only samples where a single organism was identified (fig. ) . for hi-nonb and s. pneumoniae, our tobit regression models indicated significantly lower microbial load in non-acute baseline compared to acute samples (p-values < . ) ( table ). for hi-nonb, a coefficient of . represents a . higher average ct-value in non-acute baseline samples compared to acute specimens, which corresponds to an approximately -fold lower microbial load in non-acute compared to acute samples. for s. pneumoniae, the average microbial load was . -fold lower in non-acute baseline samples compared to acute specimens. our analysis also indicated a significantly lower average rhinovirus load in non-acute samples collected either at the start or at the end of the training period compared to acute samples (p-values < . ) ( table ). this was in contrast with hi-b, for which regression analysis indicated a . -fold higher average microbial load in non-acute baseline samples compared to acute samples (p-value < . ) ( table ). for hi-non b and s. pneumoniae, there was a . -fold or . -fold increase in average microbial load in non-acute samples collected at the end of follow-up compared to acute samples collected during an uri episode, respectively (p-values ≤ . ). there was no significant difference in delay between symptom onset and specimen collection in acute samples containing one (median delay: days; interquartile range (iqr): - ) or more (median delay: days; iqr: - ) organisms (p-value = . ). six acute specimens were negative for all agents tested (median delay: . days; iqr: - ). thus, sampling delay is unlikely to account for any observed differences in ct-value distributions. we analyzed the patterns of infection with common respiratory agents in a well-defined population of military recruits. the use of highly sensitive multiplex pcr diagnostics allowed an accurate characterization of the spectrum of organisms contained in non-acute and acute samples. the data indicate co-circulation of several different viral agents, and high frequency of bacterial colonization in both non-acute and acute samples. up to one third of respiratory illness cases among army personnel are reportedly caused by viral or bacterial infections [ ] . the gathering of individuals from diverse geographic locations and the crowded living conditions increase the risk of microbe transmission in these settings [ ] . illnesses are usually self-limiting, although the emergence of highly virulent strains can lead to high morbidity and mortality [ ] . streptococcus bacteria, adenoviruses, coronaviruses and influenza are among the most widely distributed microbes in the military environment, and are implicated in > % of febrile illness cases reported at military medical facilities [ ] . we identified each of these organisms in one or more samples. for most of these microbes, overall detection frequencies were comparable in non-acute and acute samples, although influenza b and coronavirus were more commonly identified among acute specimens. other infectious agents commonly circulating among military personnel include h. influenzae, rhinovirus, and, to a lesser extent, parainfluenza, rsv, and l. pneumophila, although their presence does not necessarily imply the occurrence of clinical symptoms [ ] [ ] [ ] . h. influenzae and rhinoviruses were the most frequently detected organisms in our population in both non-acute and acute samples. we detected parainfluenza and l. pneumophila, but we did not find rsv in any of our samples. for individuals developing uri during follow-up, illness etiology could not be unequivocally determined. among acute samples, hi-b was the most frequently detected organism. it was the sole agent identified in % of acute specimens, while it was co-detected with other microbes in > % of acute samples. however, colonisation with hi-b was also common among non-acute baseline samples, where it was detected alone or in combination with other microbes in . % and . % of specimens, respectively. for organisms rarely detected among asymptomatic individuals but frequently found in acute samples, a causal association may be more likely. for instance, influenza b was detected in none of the non-acute, but . % of acute samples. similarly, the proportion of both hi-nonb-and rhinovirus-positive samples was significantly lower among non-acute specimens collected at baseline compared to acute samples. however, > % of acute samples positive for hi-non b, rhinovirus or influenza b were also positive for one or more additional microbe, so that a causal table ) association could not be determined. some agents, such as hi-non b or adenovirus, were most frequently detected in non-acute samples collected at the end of follow-up, possibly indicating post-infectious shedding or persistent infection at sub-clinical levels. in the clinical setting, overlapping clinical presentations and poor capabilities to determine the etiology of respiratory illnesses often lead to inappropriate treatment with broad-spectrum antibiotics [ ] . this might occur even more frequently in the military setting, where molecular diagnostic tools are usually inaccessible [ ] . since a considerable fraction of respiratory illnesses is caused by viruses, the unsubstantiated use of antibiotics is particularly problematic, because it can lead to negative health outcomes and promote the development of antimicrobial resistance [ ] . studies evaluating the impact of multiplex diagnostic procedures on patient management report inconsistent results. in the outpatient setting, access to rapid molecular diagnostic tools for respiratory pathogens significantly reduced antibiotic a b fig. cycle threshold value distribution in non-acute and acute samples. ct-value distribution for selected a bacteria and b viruses detected in non-acute samples collected at the start or end of the training period (orange bars) or acute samples from individuals experiencing an upper respiratory tract infection during follow-up (blue bars). a ct-value of < was considered a positive result prescription rates for patients presenting with respiratory illness [ ] . however, these findings were not confirmed in the hospital setting. pcr-based testing failed to reduce hospital admissions and duration of hospital stay in patients with acute respiratory infection [ , ] . although molecular diagnostic tools may help to differentiate bacterial and viral respiratory agents, it is unlikely that antibacterial treatment would be terminated based on the mere presence of viral agents in an acute respiratory sample, especially considering the high rates of bacterial co-infection [ ] . quantitative or semi-quantitative diagnostic tools can potentially help define clinically significant pathogen densities, and have proven highly valuable to understand the dynamics of diarrheal disease [ ] and to improve the management of gastrointestinal illnesses [ ] . among acute diarrhea patients, quantitative amplification of norovirus rna from fecal samples can help determine pathogen load thresholds that effectively distinguish between causal association and sub-pathogenic carriage [ ] . similarly, rotavirus load correlates with disease severity among children with gastroenteritis [ ] . because of the crucial role of microbial replication in viral pathogenesis, the value of pathogen load quantitation could be most clearly established for gastrointestinal illnesses of viral etiology, although some evidence is available for bacterial infections as well. for instance, microbial load of enteropathogenic e. coli is significantly higher among children with diarrhea compared to control subjects, especially when enteropathogenic e. coli is the sole agent identified [ ] . in this study, tobit regression indicated significantly lower microbial load in non-acute relative to acute samples for rhinovirus, hi-nonb, and s. pneumoniae. however, due to a substantial overlap in ct-value distributions, it was not possible to identify a ct-value threshold indicating causality for any of these organisms. previous studies assessing the association of viral load with clinical symptoms of respiratory infections reported similar findings. mean viral load for rhinovirus and six additional viruses was significantly higher in upper respiratory tract aspirates from children with pneumonia compared to healthy controls, but the overlap in viral load distribution was substantial [ ] . in pediatric patients, high rhinovirus load was associated with the presence of lower respiratory tract symptoms [ , ] , but a threshold for clinical relevance could only be determined if rhinovirus was the sole agent identified [ ] . additional studies reported a correlation between microbial load and occurrence or severity of respiratory symptoms for rsv [ ] , bocavirus [ ] , and human metapneumovirus (hmpv) [ , ] , although these findings were inconsistent [ , ] or conditional on the presence of the virus as a single microbe [ ] . we did not detect any significant association between microbial load and clinical manifestations for viruses other than rhinovirus. for both h. influenzae and streptococcus species, previous studies reported a significant correlation of bacterial densities with clinical manifestations of disease [ ] . in young patients with acute respiratory tract infection, s. pneumoniae load fluctuated with symptom incidence and resolution [ ] . among children hospitalized with pneumonia, median nasopharyngeal s. pneumoniae load was substantially higher compared to healthy controls [ ] . pneumococcal density was also associated with severity of symptoms [ ] and increased duration of children's hospital stay [ ] . similar associations were observed in pneumonic adults, although the correlation was not significant in this population [ ] . the association between microbial load and clinical manifestations may depend on specific pathogen-host interactions. if pathogenesis is primarily related to microbial replication, a stronger correlation between microbial load and illness magnitude may be observed [ ] . if clinical manifestations are largely attributable to host immune defences or bacterial toxins, the correlation with microbial load may not be obvious [ ] . temporal variations in microbial load may also play an important role if the quantity of nucleic acid is significantly more abundant at the time and location of pathology [ , ] . in acute respiratory illness patients, high bacterial colonization densities are often associated with the presence of viral co-infections [ ] , and clinical manifestations may vary depending on specific co-infection patterns [ ] . the ecology of respiratory pathogens is also likely to be influenced by the living conditions in military settings. mixing of individuals from diverse backgrounds living in close-quarters with high levels of inter-personal contact increases the potential for introduction and spread of multiple microbes in this population, which could account for the broad range of organisms and co-detections in this study. we analysed both non-acute and acute samples from a closely monitored population in a semi-closed, longitudinal setting. the study population was well-defined and relatively homogeneous with regards to demographics and living conditions. however, our findings may not be applicable to populations with different socio-demographic characteristics and populations outside the military environment, such as cohorts of children among whom the impact of respiratory infections may be greater. the frequent co-detection of multiple respiratory agents and the failure to distinguish between viable and dead organisms, or microbes that colonize the host at sub-pathogenic levels, may prevent the unambiguous interpretation of test results [ ] . a positive result may indicate illness aetiology, asymptomatic colonisation, post-infectious shedding, or an incipient infection. therefore, ct-values may not always be a reliable surrogate for infectious load. samples from only two out of six cohorts were tested by real-time pcr. although there might be bias from seasonal effects, these are usually less pronounced in the tropics. given the relatively low frequencies of viral detection, a larger sample size and a longer follow-up may have captured a more precise picture of infection patterns in this population. this study was also limited to the detection of organisms contained in the respiratory panel. we cannot exclude the presence of additional organisms in our specimens. in addition, the data were obtained from throat and nasal swab samples, but our findings may not apply to nasopharyngeal or sputum specimens. finally, the quality and quantity of material obtained through nose and throat swabs may differ significantly among subjects, and the success of pcr-based methods also depends on the availability of intact genome sequences and the absence of random mutations. overall, the multiplex respiratory panel provided a comprehensive characterization of the microbe spectrum contained in non-acute and acute respiratory samples collected among recruits. however, semi-quantitative assessment of microbial load could not reliably distinguish between symptomatic and asymptomatic samples. more research is warranted to compare new multiplex diagnostic techniques with traditional methods and evaluate their potential with regards to diagnostic accuracy [ ] and clinical utility [ , ] in the context of respiratory infections. additional file : dataset. title of data: semi-quantitative microbial load in throat and nasal swab samples from thai army recruits. description of data: semi-quantitative microbial load in non-acute and acute throat and nasal swab samples from thai army recruits, determined using a commercial multiplex real-time pcr assay comprising bacterial, viral and fungal targets; includes names, labels, and coding for individual variables. (xls kb) abbreviations pcr: polymerase chain reactionuriupper respiratory illnessiliinfluenza-like illnessftdfast track diagnosticsctcycle thresholdhi-bhaemophilus influenzae type bhi-nonbnon-type b haemophilus influenzaeiqrinterquartile rangehmpvhuman metapneumovirus we are grateful to the participants of this study, the royal thai army, and the clinical, laboratory and administrative personnel at afrims. material has been reviewed by the walter reed army institute of research. there is no objection to its presentation and/or publication. the opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the department of the army or the department of defense. this work was supported by the united states department of defense -global emerging infectious disease surveillance (dod -geis), protocol a. the datasets analysed for the current study are available as additional file in this publication. author's contributions cct conceived the idea for this paper, vo conducted the analysis and wrote the manuscript. ka, aw, lm, de, rr, and ss participated in project oversight. sf, rg, rr, ss, and iy participated in the design of the study. all authors contributed to drafting the manuscript and approved the final submission. the study was approved by the institutional review boards of the royal thai army in bangkok, thailand, the walter reed army institute of research and the london school of hygiene & tropical medicine. all participants provided written informed consent. the investigators have adhered to the policies for protection of human subjects as prescribed in army regulation - . not applicable. cct is associate editor for bmc infectious diseases, research area viral diseases. all other authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. author details saw 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community-acquired pneumonia dna bacterial load in children and adolescents with pneumococcal pneumonia and empyema comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia new concepts in diagnostics for infectious diarrhea high nasopharyngeal pneumococcal density, increased by viral coinfection, is associated with invasive pneumococcal pneumonia clinical characteristics of children with lower respiratory tract infections are dependent on the carriage of specific pathogens in the nasopharynx development of two real-time multiplex pcr assays for the detection and quantification of eight key bacterial pathogens in lower respiratory tract infections key: cord- - yfs ve authors: flores, carlos; del mar pino-yanes, maria; villar, jesús title: a quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury date: - - journal: crit care doi: . /cc sha: doc_id: cord_uid: yfs ve introduction: clinical observations and animal models provide evidence that the development of acute lung injury (ali), a phenomenon of acute diffuse lung inflammation in critically ill patients, is influenced by genetic factors. association studies are the main tool for exploring common genetic variations underlying ali susceptibility and/or outcome. we aimed to assess the quality of positive genetic association studies with ali susceptibility and/or outcome in adults in order to highlight their consistency and major limitations. methods: we conducted a broad pubmed literature search from to june for original articles in english supporting a positive association (p ≤ . ) of genetic variants contributing to all-cause ali susceptibility and/or outcome. studies were evaluated based on current recommendations using a -point quality scoring system derived from criteria, and the gene was considered as the unit of replication. genes were also categorized according to biological processes using the gene ontology. results: our search identified a total of studies reporting positive findings for genes involved mainly in the response to external stimulus and cell signal transduction. the genes encoding for interleukin- , mannose-binding lectin, surfactant protein b, and angiotensin-converting enzyme were the most replicated across the studies. on average, the studies had an intermediate quality score (median of . and interquartile range of . to . ). conclusions: although the quality of association studies seems to have improved over the years, more and better designed studies, including the replication of previous findings, with larger sample sizes extended to population groups other than those of european descent, are needed for identifying firm genetic modifiers of ali. critical illness in adults often is followed by acute lung injury (ali). ali and its most severe form, the acute respiratory distress syndrome (ards), are currently defined as a phenomenon of acute diffuse lung inflammation pathologically characterized by an acute onset of non-cardiogenic pulmonary edema resulting from increased capillary-alveolar permeability. both are clinically manifested by hypoxemia under mechanical ventilation (arterial partial pressure of oxygen/fraction of inspired oxygen [pao /fio ] of less than or equal to mm hg for ali and pao /fio of less than or equal to mm hg for ards), diffuse bilateral pulmonary infiltrates on chest radi-ographs, and reduced lung compliance [ ] . pneumonia and sepsis are the main and most common risk conditions associated with the development of both disorders [ ] . ali and ards remain a major health problem worldwide: it has been estimated that each year in the us there are , cases of ali, which are associated with , deaths and . million hospital days [ ] . our understanding of the pathogenesis of ali and ards has improved in recent years with the appreciation that inflammation is a fundamental component of the pathophysiology of these two clinical manifestations of the same syndrome. ali: acute lung injury; ards: acute respiratory distress syndrome; ci: confidence interval; fio : fraction of inspired oxygen; il- : interleukin- ; iqr: interquartile range; ld: linkage disequilibrium; ncbi: national center for biotechnology information; pao : arterial partial pressure of oxygen. clinicians have long recognized that all critically ill patients with ali are not alike. it is becoming apparent that the diversity of clinical manifestations and the response to treatment and outcome among patients with the same disease process are influenced by genetic factors [ ] [ ] [ ] . the first piece of evidence supporting a role for genetic differences in infection risk and outcome came from an epidemiological study reporting a strong association between death from infection in adoptees and their biological, but not adoptive, parents [ ] . for ali, this is further strengthened by the mortality rate disparities across the different ethnic groups in the us [ ] . in addition, ali models in inbred rodents have demonstrated differences for susceptibility and severity traits, allowing the identification of several loci and pinpointing the multigenic nature of the condition [ ] [ ] [ ] . in our attempt to better define patients at risk, recent trends have turned our attention to the search for common genetic variation underlying ali susceptibility and/or outcome. based on the extensive evidence that common genetic variation with modest effects underlies susceptibility to common complex diseases [ ] and on the impossibility of linkage analysis to detect such signals [ ] , association studies have constituted the main tool for improving our understanding of the genetic factors affecting ali susceptibility and outcome. association studies compare two groups of samples (cases and controls) for statistical differences in the frequency of variants at one or more sites of the genome. although the international hapmap project and the development of genotyping technologies have made possible the testing of more than one million of these variants in a single experiment [ ] , they have been available for a short period of time [ ] . thus, currently, association studies in ali have exclusively used a candidate gene approach, in which one or several genes -known to be etiologically involved in the disease -are studied for relevant variant sites. in general, the inconsistency of findings across association studies [ ] -partially attributed to inappropriate designs, implementations, and/or interpretations of studieshas motivated the formulation of standards to improve their quality and to help perform meta-analysis [ ] under the premise that the replication of previous findings most likely reflects interesting biological processes rather than methodological quirks. here, we aimed to examine studies reporting positive findings with all-cause ali susceptibility and/or outcome in adults in order to evaluate their relative merits and caveats based on actual recommendations. we conducted a broad pubmed literature search from to june for original articles by querying for 'polymorphism and acute lung injury' and 'polymorphism and ards'. the retrieved references were then manually curated, and those reporting genetic association studies and published in english were sought. studies were considered if a positive association (p ≤ . ) was reported with either susceptibility or outcomes of all-cause ali or ards. since the current tendency to perform association analysis at the individual variant level may be problematic (for example, there may be important differences in allele frequency or linkage disequilibrium [ld] structure across different populations), we instead considered the gene as the unit of replication [ ] . the gene ontology was used to categorize associated genes according to biological processes [ ] . among reports with positive associations, study qualityrather than significance value -was reviewed based on current recommendations. since performing a checklist of all issues to consider in association studies would require more than a single article, we have focused on the most relevant criteria from a checklist suggested recently [ ] . all together, criteria were considered and each of them was scored as if present or if absent. scoring was performed independently by two authors. studies were divided into case-control or cohort studies based on the design in which the authors reported the positive association. if a case-control study reported a positive association with an outcome in the case series, the positive finding of the study was also considered as found in a cohort design. a final quality score was obtained by adding up scores from all criteria (see below). a reported association could have a maximum score of points for casecontrol studies if more than one polymorphism was analyzed, a maximum of points if reporting a case-control study for a single polymorphism (multiple testing adjustment not needed) or for a cohort with more than one polymorphism analyzed (definition of the control group not needed), or a maximum of points for cohorts analyzing a single locus (definition of the control group and the multiple testing adjustment are not needed). to facilitate comparison across study designs, scores were then transformed to a -to -point scale. criteria that were evaluated in relation to the study design included power calculation, characterization of cases and controls or the cohort, and whether the study considered common gene-wide variation. power calculation was scored as present only if it was explored prospectively or retrospectively as part of the original study. controls were considered to be adequate if obtained from the same population as cases and described in such a way that could be replicated. this criterion was not scored in the cohort studies. adequacy of case groups was considered if demographical and clinical data were reported in sufficient detail in the text and/or a table. mentioning accepted international guidelines for phenotype definition [ ] as the sole description of cases was not considered to be acceptable. to cover the adequacy of exploring gene-wide variation in the association, ld must have been explored for polymorphism selection and/or for the interpretation of results. to evaluate study reproducibility, unambiguous identification of polymorphisms by means of national center for biotechnology information (ncbi) reference numbers or flanking sequences was scored as present. the sole description of amplification primer pairs and/or a reference to a previous publication that reported the assay was not considered to be acceptable. the three other criteria evaluated as part of study reproducibility relate to genotyping quality control measures. duplicate genotyping of a portion of individuals by means of the same or alternative genotyping techniques to calculate an error rate was considered to be adequate and scored as present. testing of hardy-weinberg equilibrium was scored as present even when significant p values were reported for any of the groups as long as a duplicate genotyping was performed. finally, adequate studies performed an interpretation of results blind to the clinical status of samples. to evaluate the statistical analyses, we considered the presence of multiple testing adjustments to be adequate. however, note that this category was not scored if a single polymorphism was assessed since we did not consider an adjustment for the multiple explored phenotypes or outcomes for the adequacy of the study to be necessary. three other categories scored as adequate included an evaluation of other recorded risk factors by means of regression models, reporting major findings in terms of risks (as hazard or odds ratios) and their % confidence intervals (cis), and an empirical assessment or adjustment for population stratification by means of an independent set of polymorphic markers. finally, we scored as adequate additional support from studies performing a validation in at least a second independent sample as part of the original study. studies designed to confirm previously associated polymorphisms were not considered to be acceptable for this category. studies that also included experiments providing evidence of functionality for associated variant(s) were scored as adequate. the sole reference to previous publication(s) providing the functional evidence of the associated polymorphism was scored as absent. searching for 'polymorphism and acute lung injury' or 'polymorphism and ards', we retrieved and original articles, respectively. this allowed us to identify a total of articles [ - ] on genes that showed a positive association with susceptibility and/or outcomes of all-cause ali or ards in at least one study (table ) . although we used broad terms for this search, the possibility for missing additional studies with positive findings might still exist. nevertheless, a complementary search querying for the disease name in the hugenet navigator [ ] gave completely overlapping results, showing studies for additional genes, albeit reporting negative findings. most studies ( . %) were carried out exclusively in populations of european descent (defined as 'whites' or caucasians). a minority of studies were performed in east asians ( %) and the remaining . % of studies included populations of both european and african descent. among the genes that showed a positive association in at least one study, four genes were replicated in at least a second article, three genes were replicated in at least three studies, and one gene was replicated in four studies (figure ). since with only two exceptions [ , ] none of these studies attempted to validate the association results in an independent sample, all studies were counted as a single contribution for the purpose of this assessment. ontology analysis of these genes showed that the majority of them were involved in the response to external stimulus ( . %) and cellular signal transduction ( %). there was also a prominent representation of genes implicated in cell proliferation ( . %), inflammatory response ( . %), immune response ( %), and chemotaxis ( %). seventeen studies ( . %) reported positive findings using a case-control design and ( . %) using a cohort. median sample sizes among studies were of cases (interquartile range [iqr]: to ) and controls (iqr: to ), whereas the median sample size for cohort studies was patients (iqr: to ). overall median quality score was . (iqr: . to . ) and maximum and minimum scores were . and . , respectively. when studies were classified by design, the median quality score in case-controlled studies ( . ; iqr: . to . ) was significantly higher than in cohort studies ( . ; iqr: . to ) (p = . , mann-whitney u test). when studies were explored by the year of publication, there was an improvement trend of association studies over time (spearman rho = . , p = . ), but this was due mostly to case-controlled studies (spearman rho = . , p = . ) since no significant trend was observed for cohort studies (spearman rho = . , p = . ). genes that showed positive association with either susceptibility and/ or outcome with all-cause acute lung injury or acute respiratory distress syndrome genes that showed positive association with either susceptibility and/ or outcome with all-cause acute lung injury or acute respiratory distress syndrome. ace, angiotensin-converting enzyme; cxcl , chemokine cxc motif ligand ; f , coagulation factor v; il- , interleukin- ; il- , interleukin- ; mbl , mannose-binding lectin- ; mif, macrophage migration inhibitory factor; mylk, myosin light-chain kinase; nfkb , nuclear factor kappa light polypeptide gene enhancer in b cells; nfk-bia, nuclear factor kappa light polypeptide gene enhancer in b cells inhibitor alpha; nrf , nuclear factor erythroid-derived factor; pbef, pre-b cell-enhancing factor; plau, plasminogen activator urokinase; sftpb, surfactant pulmonary-associated protein b; tnf, tumor necrosis factor; vegf, vascular endothelial growth factor. almost two thirds of the studies ( . %) did not explore their power to detect positive findings. nearly all studies ( %) fulfilled the internationally accepted definition criteria for ali and ards [ ] , and most studies ( . %) appropriately described demographical and clinical data from cases ( figure ). more heterogeneity was found for the criteria to select a control group: although most studies used healthy subjects or population-based controls ( %), a great proportion of studies preferred icu patients as controls ( %). in any case, . % of studies fulfilled the required criteria to have an adequate control group. most studies ( . %) analyzed a few variants per gene ( . % analyzed a single variant with anticipated functionality) without providing appropriate coverage or discussion to other untyped common variation by means of ld-based methods. in almost half of the studies ( . %), we were not able to identify the associated polymorphism(s) in ncbi databases straightforwardly and unambiguously since flanking sequences or genetic reference numbers were lacking. less than half of the studies reported genotyping error checks ( . %) or a blinding strategy ( . %) to avoid biased results ( figure ). however, hardy-weinberg equilibrium was assessed separately in cases and controls or in the cohort in . % of studies. remarkably, three of these studies reported a positive finding for polymorphisms that nominally deviated from hardy-weinberg expectations in control samples. adjustments for multiple testing were lacking in most studies since only . % of them made adjustments during statistical interpretation. conversely, regression analyses to adjust for covariates were used in a high proportion of studies ( . %). likewise, the magnitude of effects has been appropriately reported in terms of hazard or odds ratios and their % cis in most studies ( . %). by contrast, adjustments for the underlying population stratification were nearly absent as part of the statistical toolbox of the studies ( . %). as few as studies ( . %) supported the association in an independent validation sample [ , ] . only of studies ( . %) explored functional significance of variants associated with disease, either by evaluating the functionality of the associated polymorphism using gene reporter assays [ , ] or by its correlation with serum protein levels [ , , , ] . this quality assessment of genetic association studies with positive findings in susceptibility or outcome of ali and ards identified a total of articles and genes. due to our limited knowledge of the pathogenesis of these conditions and given that it is likely that many common genes and pathways contribute to the onset, course, or severity of these two forms of the same disease process, for the purpose of genetic susceptibility and outcome in this systematic review, we considered ali and ards as a single entity. the top gene ontologies represented in current association studies fit within the major biological processes underlying ali development on the basis of different microarray experiments among several studies using diverse animal models of the disease and cellular models of stretch-induced injury [ ] . overall, the paucity and quality of association data in ali/ ards call for more and better designed studies with larger sample sizes with unambiguous identification of the studied variants and procedures that allow monitoring of genotyping quality for a consistent replication and with better statistical a names are those originally reported in the corresponding reference. ins/del, insertion-deletion polymorphism. ace, angiotensin-converting enzyme; ali, acute lung injury; ards, acute respiratory distress syndrome; cap, community-acquired pneumonia; cxcl , chemokine cxc motif ligand ; f , coagulation factor v; il- , interleukin- ; il- , interleukin- ; mbl , mannose-binding lectin- ; mif, macrophage migration inhibitory factor; mv, mechanical ventilation; mylk, myosin light-chain kinase; nfkb , nuclear factor kappa light polypeptide gene enhancer in b cells; nfkbia, nuclear factor kappa light polypeptide gene enhancer in b cells inhibitor alpha; nrf , nuclear factor erythroid-derived factor; pbef, pre-b cell-enhancing factor; plau, plasminogen activator urokinase; sars, severe acute respiratory syndrome; sftpb, surfactant pulmonaryassociated protein b; sirs, systemic inflammatory response syndrome; snp, single-nucleotide polymorphism; tnf, tumor necrosis factor; tr, tandem repeat (polymorphism); vegf, vascular endothelial growth factor. positive genetic association studies with acute lung injury/acute respiratory distress syndrome susceptibility and/or outcome (by year of publication) percentage of studies scored as adequate for criteria (x-axis) used for the quality assessment of genetic association studies supporting susceptibility and/or outcome in acute lung injury percentage of studies scored as adequate for criteria (x-axis) used for the quality assessment of genetic association studies supporting susceptibility and/or outcome in acute lung injury. ld, linkage disequilibrium; pop. stratification adjust., population stratification adjustment. analyses. some of the reported associations, mostly in populations of european descent, have already set the bar high in the field with 'high-quality' studies, either with well-powered studies [ , ] or with a functional correlation of the associated polymorphism [ ] . however, most of those association studies examining the functional effects of polymorphisms have reported the plasma levels of the gene product (protein) at one time point during the development or evolution of the disease process, so the role of those protein levels in the natural history of ali or ards remains to be defined. additionally, positive association studies on ali/ards have focused essentially on exploring genetic risk effects of candidate gene variants in european populations. thus, future studies must try to fill this gap by extending the association analysis to other populations that might give us an overall picture of cosmopolitan and population-specific genetic risks. this also requires authors to give a more appropriate interpretation of results in light of power estimates since genetic effects are expected to be weak and sample sizes will rarely increase to the extent considered necessary [ ] . the current evidence also encourages more replication studies, especially of those genes that have been positively associated in at least two studies [ ] . a strong candidate would be the gene encoding the pro-inflammatory cytokine interleukin- (il- ). extensive cross-species gene expression pattern comparisons in experimental models of ali have shown that il- is highly upregulated [ ] and at increased circulating concentrations in ali patients [ ] . however, undisputed evidence supporting the association of il- gene variants with ali/ards susceptibility or outcome is still lacking, even though positive results have been found in four studies. one of the major reasons is that the predicated association has been explored in a single polymorphism of the il- gene (g/c at position - from the transcription start site). association studies using a gene-wide coverage of common variation may reveal more robust patterns of variation associated with the disease [ , ] . in this sense, a (nearly) full coverage of common variation of the candidate gene in association studies of ali is especially important since no association is yet definitive and our understanding of the functional elements of our genome is incomplete [ ] . classification and characterization of ali/ards across reviewed studies were highly concordant. however, another face of the problem is that ali/ards is still ill defined and the problem is further confounded by the diversity of etiological mechanisms such as sepsis, pneumonia, trauma, and massive transfusion that predispose patients to the condition. furthermore, it has been recently shown that patients meeting current american-european consensus conference ards criteria may have highly variable levels of lung injury and outcomes [ ] . we believe that the development of novel diagnostic tools to precisely characterize the ali and ards phenotypes or the risk factors underlying disease development might result in associations that are more reproducible. as a result of the progress of our understanding of this disease and the use of high-throughput methodologies [ ] , it is expected that robust well-replicated associations between genetic polymorphisms and ali/ards susceptibility and outcome will become a reality in the near future. to reach this point, guidelines to report genotype data fulfilling minimum quality standards need to be implemented to improve our understanding of the genetic architecture of this disease. in addition, statistical methodologies such as multiple testing and population stratification adjustments, which to date have been almost completely absent in these studies, need to be routinely employed as well. since all studied candidate genes await validation in independent studies using larger samples, the search for genetic variants determining susceptibility and outcome in ali or ards still needs to grow and continue improving for the identification of true associations between genotype and clinical outcomes important in the care of ali/ards patients. integration of data across studies (for example, gene expression profiling, association studies, and proteomics) may reveal novel insights into ali development which may allow us to identify cellular pathways specific to the disease. this knowledge will speed up the development of better and increasingly efficient tailored therapies for ali/ards patients admitted to the intensive care unit. tions, mechanisms, relevant outcomes and clinical trial coordination the help network: an early peep/fio trial identifies different degrees of lung injury in patients with acute respiratory distress syndrome incidence and outcomes of acute lung injury understanding genetic predisposition to sepsis injury research in the genomic era. lancet genetic determinants of phenotypic diversity in humans genetic and environmental influences on premature death in adult adoptees race and gender differences in acute respiratory distress syndrome deaths in the united states: an analysis of multiple-cause mortality data ( - ) genetic analysis of ozone-induced acute lung injury in sensitive and resistant strains of mice use of consomic rats for genomic insights into ventilator-associated lung injury reciprocal congenic lines of mice capture the aliq effect on acute lung injury survival time genetic association studies the future of genetic studies of complex human diseases the international hapmap consortium: a second generation human haplotype map of over . million snps what can genome-wide association studies tell us about the genetics of common disease? what makes a good genetic association study? meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease the future of association studies: genebased analysis and replication gene ontology: tool for the unification of biology. the gene ontology consortium working group on replication in association studies: replicating genotype-phenotype associations polymorphisms of human sp-a, sp-b, and sp-d genes: association of sp-b thr ile with ards genetic polymorphisms associated with susceptibility and outcome in ards angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome association between surfactant protein b + polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia polymorphism in the surfactant protein-b gene, and the risk of direct pulmonary injury and ards pre-b-cell colony-enhancing factor as a potential novel biomarker in acute lung injury mannose-binding lectin in severe acute respiratory syndrome coronavirus infection the association of interleukin haplotype clades with mortality in critically ill adults functional genomic insights into acute lung injury: role of ventilators and mechanical stress and tnfb polymorphisms in acute respiratory distress syndrome vascular endothelial growth factor gene polymorphism and acute respiratory distress syndrome novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury interleukin- polymorphism in position - and acute respiratory distress syndrome polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations pre-bcell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome functional polymorphisms in the transcription factor nrf in humans increase the risk of acute lung injury a cxcl polymorphism is associated with better outcomes in patients with severe sepsis polymorphisms in the mannose binding lectin- gene and acute respiratory distress syndrome ace i/d but not agt (- )a/g polymorphism is a risk factor for mortality in ards inhibitor kappab-alpha haplotype gtc is associated with susceptibility to acute respiratory distress syndrome in caucasians insertion/deletion polymorphism in the promoter of nfkb influences severity but not mortality of acute respiratory distress syndrome genotypes and haplotypes of the vegf gene are associated with higher mortality and lower vegf plasma levels in patients with ards association between urokinase haplotypes and outcome from infection-associated acute lung injury variation in the mylk gene is associated with development of acute lung injury after major trauma mannose-binding lectin and mannose-binding lectinassociated serine protease in susceptibility, severity, and outcome of pneumonia in adults an il gene-wide haplotype is associated with susceptibility to acute lung injury the - interleukin- polymorphism is associated with acute respiratory failure after major trauma: a prospective cohort study factor v leiden mutation is associated with improved -day survival in patients with acute respiratory distress syndrome a navigator for human genome epidemiology microarray-based analysis of ventilator-induced lung injury the complex interplay among factors that influence allelic association angiotensin-converting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome orthologous gene-expression profiling in multi-species models: search for candidate genes persistent elevation of inflammatory cytokines predicts a poor outcome in ards. plasma il- beta and il- levels are consistent and efficient predictors of outcome over time encode project consortium: identification and analysis of functional elements in % of the human genome by the encode pilot project highly parallel genomic assays this work was supported in part by ministerio de ciencia (spain) (saf / ) and funcis ( / ). cf was supported by a specific agreement between instituto de salud carlos iii and funcis (emer / ) under the encyt framework. the authors declare that they have no competing interests. all authors contributed equally in the assessment design and the literature search and read and approved the final manuscript. • current evidence suggests that acute lung injury (ali) and its most severe form, the acute respiratory distress syndrome, are influenced by genetic factors.• association studies, the main tool for the exploration of common genetic variation underlying ali, have thus far reported a total of genes associated with ali susceptibility and/or outcome.• these genes are involved mainly in the response to external stimulus and cell signal transduction.• more studies with improved designs, as well as replication of previous findings with larger sample sizes, are needed to definitely identify genetic factors predisposing patients to ali. key: cord- -cuvfy pj authors: baselga, eulalia; torrelo, antonio title: inflammatory and purpuric eruptions date: - - journal: neonatal dermatology doi: . /b - - - - . - sha: doc_id: cord_uid: cuvfy pj nan infl ammatory and purpuric eruptions this group of eruptions is composed of lesions of variable morphology and diverse etiology. however, all have erythema as a common feature, a refl ection of their infl ammatory nature. several disorders appear to represent hypersensitivity reactions, but for most the etiologic agents are unknown. the differential diagnosis of purpura is extensive in neonates, and includes hematological disorders, infections, trauma, and iatrogenic disorders. annular erythema is a descriptive term that encompasses several entities of unknown etiology characterized by circinate polycyclic lesions that extend peripherally from a central focus. , because of subtle differences in clinical features, age of onset, duration of individual lesions, and total duration of the eruptions, a variety of descriptive terms have been coined for these disorders (table - ) . for prognostic reasons, it is useful to subdivide annular erythemas into transient and persistent forms. transient forms include annular erythema of infancy and the less well-established entity erythema gyratum atrophicans transient neonatale. persistent annular erythemas include erythema annulare centrifugum, familial annular erythema, and erythema gyratum perstans. other annular erythemas known to be a manifestation of well-defi ned diseases (e.g. neonatal lupus) or with distinctive clinical or histologic features (e.g. erythema multiforme, erythema chronicum migrans, erythema marginatum rheumaticum, and erythema gyratum repens) are not considered under this heading. annular erythema of infancy is a benign disease of early infancy characterized by urticarial papules that enlarge peripherally, forming - cm rings or arcs with fi rm, raised, cord-like or urticarial borders. [ ] [ ] [ ] adjacent lesions become confl uent, forming arcuate and polycyclic lesions ( fig. - ) . neither vesiculation nor scaling is present at the border. the eruption is asymptomatic. individual lesions resolve spontaneously without a trace within several days, but new lesions continue to appear in a cyclical fashion until complete resolution within the fi rst year of life. a few cases lasting for years have been described. [ ] [ ] [ ] the cause of annular erythema is unknown, and there are no associated systemic fi ndings. histologic studies reveal a superfi cial and deep, dense, perivascular infi ltrate of mononuclear cells and eosinophils. no fl ame fi gures are observed. the epidermis is normal or mildly spongiotic. laboratory studies are normal. peripheral eosinophilia does not accompany tissue eosinophilia. immunoglobulin levels, including ige levels, are normal. the differential diagnosis should include other annular lesions of infancy (see the following discussion). no treatment is warranted because of the self-limited nature of the eruption. erythema gyratum atrophicans transiens neonatale is a less well-defi ned entity, characterized clinically by annular plaques with an erythematous border and an atrophic center. the lesions appear in the newborn period and resolve within the fi rst year of life. histologic fi ndings include epidermal atrophy and a mild perivascular mononuclear infi ltrate. immunofl uorescence studies reveal granular deposits of igg, c , and c at the dermoepidermal junction and around capillaries. erythema gyratum atrophicans transiens neonatale possibly represents a variant of neonatal lupus erythematosus. erythema annulare centrifugum is a more persistent type of annular erythema that usually affects adults, but may also occur in children and rarely in newborns. , [ ] [ ] [ ] [ ] the lesions are clinically somewhat similar to those of annular erythema of infancy, but scaling or vesiculation is seen at the border. the scales lag behind the advancing border, which, in contrast to annular erythema of infancy, is not indurated. individual lesions resolve spontaneously after a few weeks, but new plaques continue to develop for years, or may be a lifelong condition. there is no associated pruritus. erythema gyratum perstans falls within the spectrum of erythema annulare centrifugum. [ ] [ ] [ ] some authors defend the distinctness of erythema gyratum perstans and consider distinctive features of this disorder to be its early onset, a duration of more than years, the presence of slight to severe pruritus, and especially the presence of vesiculation. erythema annulare centrifugum is thought to represent a hypersensitivity reaction to several trigger factors, including infectious agents (candida, , epstein-barr virus, and ascaris ), drugs or foods, , and neoplasia, especially in adults. intradermal injection of candidin or trichophytin may reproduce the clinical lesions. histologic features consist of a dense, superfi cial, perivascular mononuclear infi ltrate. parakeratosis or epidermal spongiosis may be present. no therapy has been successful in all cases. treatment agents include oral nystatin, oral amphotericin b, topical antifungals, antihistamines, disodium cromoglycate, and interferon-α. familial cases of annular erythema with autosomal dominant inheritance have been described. , the onset is in early infancy. scaling, vesiculation, and pruritus may be more common than in erythema annular centrifugum. lesions resolve with residual hyperpigmentation. chronicity is the rule. geographic tongue may be associated. differential diagnosis includes other eruptions with ringlike lesions, such as neonatal lupus, erythema multiforme, urticaria, urticarial lesions of pemphigoid, fungal infections, erythema chronicum migrans, and congenital lyme disease. , , serum antibody determinations (antinuclear, ss-a, and ss-b) are recommended to exclude neonatal lupus. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] neonatal lupus erythematosus (nle) is a disease of newborns caused by maternally transmitted autoantibodies. the major manifestations are dermatologic and cardiac. skin fi ndings are transient. cardiac disease, which is responsible for the morbidity and mortality of nle, begins in utero and affects the cardiac conduction system permanently. other fi ndings include hepatic and hematologic abnormalities. mothers of infants with neonatal lupus have anti-ro/ss-a autoantibodies in % of cases. anti-la/ss-b and anti-u rnp autoantibodies have also been implicated in the pathogenesis of nle in a minority of patients. , fifty per cent of infants with nle have skin lesions, and congenital heart block is present in about %. , lesions commonly develop at a few weeks of age but may be apparent at birth, which suggests that ultraviolet (uv) radiation is not essential for the development of skin lesions in nle. clinically, skin lesions are analogous to those of subacute cutaneous lupus in its two variants: papulosquamous and annular. papulosquamous lesions are more common and are characterized by erythematous, nonindurated scaly plaques ( fig. - ). sometimes the skin lesions have an atrophic appearance ( fig. - ). ulcerations may be present. in contrast to discoid lupus, scarring and follicular plugging are absent. the annular variant, which occurs almost exclusively in japan, consists of annular, more infl ammatory plaques. lupus profundus and generalized poikiloderma with erosions and patchy alopecia are rare manifestations. , nle lesions may be widespread but are most common on the face and scalp, predominantly affecting the periorbital and malar areas and often causing a 'raccoon eyes' appearance . the eruption is frequently precipitated or aggravated by sun exposure. sun exposure is not strictly required, however, as the lesions may occur in sun-protected areas such as the diaper region, palms, and soles. , , skin lesions are transient and cease to appear around the age of months, after the disappearance of maternal antibodies. transient hypopigmentation and epidermal atrophy may result ( fig. - ) . telangiectasia is a more permanent sequela. telangiectasia also may be an initial sign of nle, occurring without preceding identifi able infl ammatory lesions; features of cutis marmorata telangiectatica congenita have been observed. , a case of nle with a serological profi le consis-tent with drug-induced lupus has been described in a newborn whose mother was treated with α-interferon during pregnancy. the most signifi cant manifestation is isolated complete congenital heart block. more than % of such cases are due to nle. most patients have third-degree block, but progression from a second-degree block has been reported. heart block can often be detected as early as weeks of gestation. transient liver disease, manifesting as hepatomegaly (with a picture of cholestasis) or elevation of liver enzymes, , [ ] [ ] [ ] and thrombocytopenia or other isolated cytopenias, may occur. petechiae and purpura have been described as presenting signs of nle. less common fi ndings include thrombosis associated with anticardiolipin antibodies, hypocalcemia, spastic paraparesis, pneumonitis, and transient myasthenia gravis. [ ] [ ] [ ] central nervous system (cns) involvement has been reported in of consecutive infants with nle, in the form of ultrasound and ct scan abnormalities which did not result in clinical neurological manifestations. such cns involvement in nle is probably a transient phenomenon. between % and % of mothers of infants with nle have a connective tissue disease, most commonly sle or sjögren syndrome. most, however, are asymptomatic. the risk for developing overt connective tissue disease in these mothers is highly debated, with estimates ranging from % to more than %. , [ ] [ ] [ ] [ ] [ ] [ ] it is universally agreed that placentally transmitted maternal igg autoantibodies are necessary for the pathogenesis of nle, but not suffi cient. the most commonly implicated autoantibodies have been anti-ro/ss-a and anti-la/ss-b. more than % of nle infants have anti-ro antibody, and - % have anti-la antibodies. a small subset of affected infants do not have detectable anti-ro or anti-la antibodies, but instead have anti-u rnp. , mothers with high titers of anti-ro and anti-la antibodies are at greater risk of delivering an infant with nle. despite initial observations based on immunoblot or elisa testing that anti- kda ro antibodies conferred a higher risk of nle than anti- kda ro antibodies, more precise testing with line immunoassay has revealed that antibodies to kda ro are signifi cantly more sensitive than antibodies to kda ro and kda la. furthermore, comparing mothers of children with nle with rash alone or with congenital heart block, there is no signifi cant difference in the prevalence of any of the three antibodies between the two groups. however, signifi cantly more symptomatic mothers of children with congenital heart block have anti-la antibodies than do disease-matched mothers with unaffected children. moreover, the mean level of anti-la seems to be higher in mothers of infants with congenital heart block than in mothers of children with cutaneous nle. it is not clear why only less than % of mothers with anti-ro and anti-la antibodies give birth to affected children and why mothers of affected infants are often asymptomatic despite having the same antibodies. furthermore, fraternal twins are often discordant for nle, and nle does not occur in every pregnancy. genetic factors may be important for the development of nle in children with maternal lupus antibodies. a link has been suggested between nle rash and the allele hla-drb * , as well as a - a polymorphism in the tnf-α gene. alternatively, maternal and/or sibling microchimerism may play an additional role, as levels of microchimerism have been reported to correlate with nle disease activity. serologic studies for autoantibodies in the mother and infant demonstrate anti-ro, anti-la, and/or anti-u rnp antibodies. anti-ndna, anticardiolipin antibodies, antinuclear antibody, and rheumatoid factor may also be present. anti-sm antibody, highly specifi c for systemic lupus erythematosus, is not found in nle. the maternal antibody titer is usually higher than the infant titer, which may even be negative if only immunodiffusion techniques are used. more sensitive methods, such as elisa, immunoblotting, or line immunoassay, should be used in such instances. skin biopsy, which is usually not necessary for diagnosis, shows changes characteristic of lupus erythematosus, that is, epidermal atrophy and vacuolization of the basal layer with a sparse lymphohistiocytic infi ltrate at the dermoepidermal junction and in a periappendageal distribution. in many instances, histopathological features in children with nle rash are subtle. direct immunofl uorescence is positive in % of cases, demonstrating granular deposits of igg, c , and igm at the dermoepidermal junction. histopathologic examination of the heart shows replacement of the atrioventricular node by fi brosis or fatty tissue. endomyocardial fi broelastosis and patent ductus arteriosus may also be seen, , as well as deposits of igg and complement. the differential diagnosis includes congenital rubella, cytomegalovirus infection, annular erythema of infancy, tinea corporis, and seborrheic dermatitis. congenital syphilis should also be considered, but mucosal lesions are not a feature of nle. false positive serologic tests for syphilis may occur in nle. telangiectasia and photosensitivity may suggest bloom syndrome or rothmund-thomson syndrome. serologic studies for autoantibodies in both infant and mother help to confi rm the diagnosis. skin biopsy for histologic and direct immunofl uorescence studies is seldom necessary. neonates with suspected nle should receive a complete physical examination, electrocardiogram, complete blood count with platelet count, and liver function tests (box - ). skin lesions are transient. treatment of skin disease consists of sun protection and the application of topical steroids. pulsed dye laser therapy may be considered for residual telangiectasia. congenital heart block is permanent. half of newborns with complete congenital heart block require implantation of a pacemaker in the neonatal period. mortality from complete congenital heart block in the neonatal period is %; another - % die of pacemaker complications. , late-onset cardiomyopathy may develop in a few infants. [ ] [ ] [ ] for mothers with anti-ro or anti-la antibodies, the risk of delivering an infant with nle is - %, depending on whether they have asymptomatic or symptomatic sle. , the risk of recurrence of congenital heart block in subsequent pregnancies may be as high as %. such pregnancies should be closely monitored, with repeated fetal echocardiograms. if signs of intrauterine congestive heart failure are detected dexamethasone or plasmapheresis, or both, have been given. , [ ] [ ] [ ] [ ] although nle is usually self-limited, sle or other rheumatologic/autoimmune diseases may develop later in life in a small subset of patients. , , the exact risk is unknown. [ ] [ ] [ ] [ ] cutaneous drug reactions are extremely rare in the neonatal period because the ability to generate a drug-induced immune response appears to be lower in infants. [ ] [ ] [ ] furthermore, most drug reactions require time for sensitization, which may range from to weeks or more, as well as re-exposure to the causative drug. finally, newborns and young infants are less exposed to drugs than adults. cutaneous adverse reactions to drugs may be classifi ed according to the clinical characteristics of the eruption (box - ). whenever a suspect eruption is observed, a detailed history of medications should be obtained, including drugs administered to the mother, which may be present in breast milk. morbilliform ( fig. - ) or maculo-papular eruptions (fig. - ) are the most frequent type of drug reaction in neonates, and antibiotics are commonly implicated ( fig. - ) . distinguishing a drug eruption from a viral exanthem is often diffi cult. emla cream, a local anesthetic that may be used with great frequency in neonatal units, has been noted to produce a localized purpuric eruption. , this type of reaction is seen preferentially in neonates, and subsequent applications of the cream do not always reproduce the purpuric lesions. methemoglobinemia is another complication of emla use in this age group. emla cream should therefore be used with caution in infants who are taking methemoglobin-inducing medications such as sulfonamides, acetaminophen, nitroglycerin, nitroprusside, and phenytoin, and particularly in those with a history of methemoglobinemia. vancomycin, an antibiotic frequently administered to premature newborn infants for staphylococcus epidermidis nosocomial infections, may produce shock and rash in newborns (red-baby syndrome). [ ] [ ] [ ] this reaction is characterized by the appearance of an intense, macular, erythematous eruption on the neck, face, and upper trunk shortly after the infusion is completed. it may be accompanied by hypotension and shock. the reaction resolves rapidly in a matter of hours. it is frequently associated with rapid infusion; however, lengthening the infusion to more than hour does not completely eliminate the risk. newborns with aids have an increased susceptibility to drug reactions. , reactions to trimethroprim/sulfamethoxazole in patients with hiv infections can be severe and life-threatening. fixed drug reactions of the scrotum and penis, with erythema and edema resulting from hydroxyzine hydrochloride, have been described in early infancy. however, hydroxyzine hydrochloride is administered infrequently in the neonatal period because of the risk of antimuscarinic effects, such as restlessness and excitation. serum sickness-like reaction is a type of drug reaction that occurs predominantly in children and has been reported in infants months of age. it is characterized by fever, an urticarial eruption, and arthralgias. lymphadenopathy may be present. in contrast to true serum sickness, there are no immune complexes, vasculitis, or renal impairment. the most commonly implicated drug has been cefaclor. [ ] [ ] [ ] this type of reaction may be seen in infants with an unknown or presumably viral etiology ( fig. - ) hypersensitivity syndrome reaction is a serious drug reaction characterized by fever, skin rash, lymphadenopathy, and internal organ involvement, especially of the liver. , the most commonly implicated drugs are anticonvulsants, and therefore it is not rare in children. a fatal case in a -monthold infant has been reported, as well as a case in a premature infant. , toxic epidermal necrolysis (ten) is extremely rare in newborns. cases of ten in newborns have been related to antibiotics and phenobarbital. all cases described so far proved fatal. vegetant bromoderma is a reaction to bromides characterized by coalescing papules and pustules which form vegetant infl ammatory or pseudotumoral lesions. it usually affects the scalp, face, and legs. most cases of vegetant bromoderma have been described in infants after the ingestion of syrups and solutions containing bromide, which has sedative and expectorant properties, or the spasmolytic agent scopolamine bromide. the eruption ceases after withdrawal of bromide. the risk of systemic intoxication, known as bromism, makes it advisable to avoid bromide use in newborns and infants. other anectodal reports of toxicoderma in very young infants or newborns have been described, such as a papular eruption from g-csf for collection of stem cells (fig. - ) , a lichenoid reaction to ursodeoxycholic acid for neonatal hepatitis, and a maculopapular rash from diazoxide used for neonatal hyperglycemia (see fig. - ). urticaria (hives) occurs frequently in childhood but is uncommon in children younger than months and even rarer in the neonatal period. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] urticaria is usually sporadic; however, familial forms with autosomal dominant inheritance have been described for many of the physical urticarias, such as dermographism, heat urticaria, cold urticaria, and vibratory urticaria. urticaria can be divided into acute (lasting less than weeks) and chronic (lasting more than weeks) types. nevertheless, this arbitrary division has prognostic and etiopathogenic signifi cance. in infants, chronic urticaria is very rare. , physical urticarias represent a special subgroup of urticaria in which wheals are elicited by different types of physical stimuli. these include dermographism, cold, pressure, cholinergic, aquagenic, vibratory, and solar urticaria. urticaria is characterized by transient edematous pruritic wheals ( fig. - ). by defi nition, individual lesions last less than hours. hives may occur on the skin and mucous membranes. angioedema or giant urticaria is a closely related entity in which there is swelling of the deep subcutaneous tissues and diffuse swelling of the eyelids, genitalia, lips, and tongue. it may be seen alone, or more often in association with 'common' urticaria. urticaria in children has certain characteristic features. the hives tend to coalesce, forming bizarre polycyclic, serpiginous, or annular shapes (fi gurative urticaria, fig. - ; or annular urticaria, fig. - ), and may become hemorrhagic. , edema is often pronounced and painful. these features confer a dramatic appearance to the eruption. in children the itching may be absent. urticaria may be more common and recurrent in atopic patients. , acute urticaria may be accompanied by signs of anaphylactic shock. in cases of angioedema, abdominal pain, diarrhea, vomiting, respiratory compromise, and joint pain may occur. , urticaria develops as a result of an increased permeability of capillaries and small venules, which leads to leakage of fl uid into the extravascular space. mast cell activation and subsequent mediator release are responsible for these changes. histamine is the best-known mediator. many triggers (secretagogues) initiate mast cell degranulation through receptors on mast cell membranes, either via an ige-dependent mechanism or through complement activation (immunologic secretagogues) or by acting directly without the need for receptors (nonimmunologic secretagogues). the most common provocative agents in children are drugs, foods, and infections, which account for % of the cases of acute urticaria. , , antipyretics (primarily aspirin) and antibiotics (amoxicillin, macrolides, and oral cephalosporins) are the most frequently incriminated drugs. food-related urticaria is associated with atopy. cow's milk allergy is one of the main causes of urticaria in infants, being present in - % of cases of cow's milk intolerance. , , the diagnosis of urticaria is made on clinical grounds. histopathologic examination of a skin biopsy specimen shows vascular dilation, edema, and a perivascular infl ammatory infi ltrate composed of lymphohistiocytic cells, polymorphonuclear cells, and more specifi cally eosinophils. neutrophils may predominate. laboratory tests are not usually necessary for the evaluation of acute urticaria. ige levels can be elevated in some patients. an exhaustive search for an underlying cause not elicited by history alone is not warranted. an erythrocyte sedimentation rate may suffi ce as a screening test in cases of chronic urticaria because it is usually elevated in diseases associated with chronic urticaria (e.g. collagen vascular diseases). in - % of patients no cause is identifi ed. intradermal skin tests to discover suspected allergens are not reliable. urticaria in infants is often misdiagnosed as erythema multiforme, acute hemorrhagic edema, annular erythema of infancy, or kawasaki disease. in an infant with urticaria and dermographism the possibility of diffuse cutaneous mastocytosis without visible cutaneous lesions should also be considered. nomid/cinca (see below) should be considered in young infant with urticaria. the predominance of neutrophils in skin biopsies of children with nomid may help in the differential diagnosis, although it is not % specifi c. in case of doubt, genetic testic for nomid is now available. despite its alarming symptoms, urticaria in early infancy is usually benign. exceptions are chronic infantile neurological cutaneous and articular syndrome (cinca) (see below) and the inherited physical urticarias, which may have a lifelong course. if medication is required, antihistamines such as diphenhydramine or hydroxyzine are the mainstay of therapy. however, newborns have an increased susceptibility to antimuscarinic side effects, such as central nervous system (cns) excitation causing convulsions. systemic corticosteroids should be reserved for cases of intractable urticaria. autosomal dominant variants have been described for many of the physical urticarias. although rare, these familial cases begin early in life, even immediately after birth, and have a lifelong course, usually with increased severity. the exact pathogenic mechanism for many of the physical urticarias is unknown. familial cold urticaria (fcu) is an autosomal dominant disorder characterized by the development of burning wheals, and frequently pain and swelling of joints, stiffness, chills, and even fever after exposure to cold, especially in combination with damp and windy weather. [ ] [ ] [ ] [ ] the skin lesions appear on exposed areas and generalize afterwards. leukocytosis may be present during the attacks. the reaction may be delayed for up to hours after cold challenge. in contrast to acquired cold urticaria, the reaction cannot be elicited by an ice cube test: rather, the patient must be subjected to cold environmental temperatures or cold water immersion. on skin biopsy a neutrophilic infi ltrate predominates. the symptoms tend to improve with age. responses to h and h blockers and ketotifen are poor. stanozolol has been of limited benefi t. fcu has also been described along with amyloidosis and deafness as muckle-wells syndrome (mws). it has been recently demonstrated that both fcu and mws are due to mutations in the cias (cryopyrin) gene: in fact they are the same disorder and may share exactly the same genetic mutation. fcu and mws are also allelic diseases with cinca syndrome (see below), which is also due to cias gene mutations. familial dermographism (autosomal dominant) has been described in a single large family. in neonates dermographism can also be a manifestation of 'silent' diffuse cutaneous mastocytosis. , vibratory urticaria is an autosomal dominant physical urticaria in which wheals develop after repetitive vibratory stimulation or stretching. , the need for repetitive trauma differentiates it from dermographism. familial aquagenic urticaria and familial heat urticaria usually have onset in childhood. [ ] [ ] [ ] chronic infantile neurological cutaneous and articular syndrome (cinca) [ ] [ ] [ ] [ ] cinca syndrome, also known as neonatal onset multisystemic infl ammatory disease (nomid), is a chronic systemic infl ammatory disease of neonatal onset characterized by skin rash, arthropathy, and cns manifestations. cutaneous fi ndings are the presenting signs. the disease follows a chronic course with acute febrile exacerbations, lymph node enlargement, and hepatosplenomegaly. two-thirds of patients are born prematurely. a skin eruption is usually the fi rst manifestation of the disease and is present at birth or develops during the fi rst months of life. it is characterized by generalized, evanescent, urticarial macules and papules that migrate over the course of a single day and wax and wane in intensity ( fig. - ) . the rash is persistent, although recrudescence of the skin lesions is noted at fl are-ups. the lesions may be pruritic, especially after sun exposure, but are usually asymptomatic. , geographic tongue and oral ulcers have been noted in a single patient. symmetric or asymmetric arthropathy is another constant fi nding and is severe in half of patients. it is often absent in the fi rst few weeks of life, but usually develops during the fi rst year. , the severity of the arthropathy correlates with an early onset of joint symptoms. the knees are most frequently affected, followed by the ankles and feet, elbows, wrists, and hands. joint swelling and pain are more severe during febrile fl are-ups. on palpation, a bony consistency is characteristic as a result of epiphyseal and growth cartilage involvement and overgrowth of the patellae. joint contractures and severe deformities result. neurologic signs and symptoms such as headache, vomiting, and seizures develop at a variable age. intellectual impairment is also common. both spasticity and hypotonia have been described. eye involvement is an inconstant fi nding. papilledema with or without optic nerve atrophy is the most common feature. other ocular manifestations include uveitis, keratitis, conjunctivitis, and chorioretinitis. these changes may lead to complete blindness in adulthood. progressive sensorineural hearing loss and hoarseness are also common. affected children have a characteristic phenotype. there is progressive growth retardation and increased head circumference with frontal bossing. fontanel closure is retarded. icterus may be present in the neonatal period, especially in patients with severe arthropathy. mutations in the cias gene have been identifi ed in % of patients with cinca syndrome. , cias encodes a protein called cryopyrin, which is involved in the regulation of apoptosis and the infl ammatory signaling pathway. it is proposed that familial cold urticaria and cinca represent extreme groups of the same disease, defi ned by the magnitude of phenotypic expression. considerable clinical overlapping exists between these disorders. nonspecifi c fi ndings typical of a chronic infl ammatory process include microcytic anemia; leukocytosis with high neutrophil and eosinophil counts, elevated platelet counts, sedimentation rates, and acute-phase reactants; and polyclonal hyperglobulinemia g, a, or m. rheumatoid factor and antinuclear antibodies are usually absent. liver enzymes may be mildly elevated. csf examination shows pleocytosis and high protein levels. radiologic studies of the affected joints show irregularly enlarged, bizarre, spiculated epiphyses with a grossly coarsened trabecular appearance. , there is periosteal new bone formation, and growth cartilage abnormalities are frequent. with time, there is bowing deformity of long bones and shortening of diaphyseal length. ct scans of the head have demonstrated hydrocephalus and cerebral atrophy. histopathologic examination of the skin reveals interstitial and perivascular neutrophilia. , neutrophilic eccrine hidradenitis has been described. biopsies of lymph nodes, liver, and synovium show nonspecifi c signs of chronic infl ammation. nomid must be differentiated from systemic onset juvenile arthritis. the main differences are its neonatal onset, persistent rash, the short duration of bouts of fever, absence of morning stiffness, and central nervous system involvement. the arthropathy is more deforming, and the radiographic fi ndings of enlarged and disorganized epiphyses are distinctive. in addition, the response to nsaids is poor. urticaria should also be considered and the predominance of eosinophils in skin biopsy may be a relative clue. the disease follows a chronic course with acute febrile exacerbations. occasionally it causes death in the fi rst or second decade. nonsteroidal anti-infl ammatory drugs may be effective for pain relief but do not alter the course of the disease. prednisone has been palliative in doses ranging from . to . mg/kg/day. chlorambucil and penicillamine have been tried, with limited success. , thalidomide has shown benefi cial effects in a single patient. other choices include methotrexate, the recombinant human il- receptor antagonist anakinra, [ ] [ ] [ ] [ ] and the anti-tnf-α agent etanercept. erythema multiforme (em) is an acute, self-limited disorder of skin and mucous membranes. [ ] [ ] [ ] it has been considered a spectrum of disorders, designated em minor, consisting of skin involvement only or of both the skin and the mouth, and as em major (stevens-johnson syndrome; sjs), which involves at least two mucous membranes with variable cutaneous lesions. some authors include toxic epidermal necrolysis within this spectrum as a severe form of sjs. recent evidence suggests that em and sjs have distinct clinical features and different precipitating factors, so perhaps the terms em major and em minor are best avoided. , em is a common disease in children but extremely unusual in the neonatal period. , , [ ] [ ] [ ] [ ] toxic epidermal necrolysis is discussed in chapter . the prototypic lesion of em is a - cm erythematous, edematous papule that develops a dusky vesicular, purpuric, or necrotic center. a raised edematous ring of pallor surrounded by an erythematous outer ring is often present. these concentric color changes produce the typical target, or iris, lesion. in many cases only two zones are seen, with a single ring around the central papule (atypical target lesions). the lesions are distributed symmetrically and acrally on the extensor surface of the extremities. they may extend to the trunk, fl exural surfaces, palms, and soles. in children, lesions on the face and ears are common, but are rare on the scalp (fig. - ). in sjs, the lesions are more centrally located, predominating on the trunk. the targets are atypical and are usually fl at. individual lesions tend to coalesce in large patches. areas of epidermal detachment may occur, but usually affect less than % of the body surface area. mucosal lesions occur frequently in em and are requisite for a diagnosis of sjs. mucous membrane involvement is characterized by erythema or blisters that rapidly evolve to confl uent erosions with pseudomembrane formation. the oral mucosa and conjunctiva are most commonly involved, but genital, anal, pharyngeal, and upper respiratory tract involvement may be seen. the number of mucous membranes involved has been considered one of the main distinguishing features of em and sjs. mild, nonspecifi c, prodromal symptoms of cough, rhinitis, and low-grade fever are occasionally present in em. fever, arthralgias, and prostration are common in sjs. em has been considered a hypersensitivity phenomenon to multiple precipitating factors such as infectious agents or drugs. three etiologic factors have been well documented: herpes simplex for erythema multiforme, and mycoplasma infections and drugs for sjs. herpes simplex (hsv- or hsv- ) is considered to be responsible for more than % of em in children, even if clinical infection is inapparent. hsvassociated em follows the lesions of herpes by - weeks and is often recurrent. however, not every episode of recurrent herpes is followed by em. hsv-specifi c dna has been detected by polymerase chain reaction and in situ hybridization in lesional skin from a large number of children with em, whether 'idiopathic' or clearly hsv related. erythema multiforme fig. - target lesions of erythema multiforme in a newborn. cow's milk intolerance has been described as a cause of erythema multiforme in a neonate. drugs are the most common cause of sjs. sulfonamides, phenylbutazone, diphenylhydantoin, and penicillin derivatives are most frequently implicated. vaccinations were the only known possible causative agents in a newborn and two infants with erythema multiforme. , in cases of extensive involvement an elevated sedimentation rate, leukocytosis, and mild elevation of transaminases may be seen. electrolyte imbalance and hypoproteinemia may be encountered in sjs. eosinophilia may be seen in drug-related cases. histopathologic examination of early lesions reveals a lymphocytic band-like infi ltrate at the dermoepidermal junction, with exocytosis and individual necrotic keratinocytes in close proximity to lymphocytes ('satellite cell necrosis'). there is vacuolization of the basal layer with focal cleft formation at the dermoepidermal junction. the upper dermis is edematous. over time, more extensive confl uent necrosis of the epidermis supervenes, resulting in subepidermal blister formation. in em a lichenoid infi ltrate predominates, whereas in sjs epidermal necrosis predominates. in typical cases em or sjs is rarely confused with other entities. urticarial vasculitis may be considered in some cases. kawasaki disease may produce target-like lesions; however, associated fi ndings should allow differentiation. serum sickness-like reactions often associated with the use of cefaclor or other antibiotics, or even without any known etiology, can also produce targetoid lesions (see fig. - ). erythema multiforme is usually self-limited. individual lesions heal in - weeks, with residual hyperpigmentation. conservative supportive care is the preferred form of treatment. possible underlying causes should be sought. treatment of underlying infection and discontinuation of nonessential drugs are indicated. corticosteroids are unnecessary and may even worsen a concurrent infection. , in hsv-associated em, early intervention or even prophylactic treatment with oral aciclovir may be benefi cial. sjs has a less favorable prognosis, with a mortality rate of - % if left untreated. the use of corticosteroids in sjs is more controversial. , , , no controlled study has proved their effi cacy, and in some studies patients treated with corticosteroids have had a worse prognosis. corticosteroids may predispose to secondary infection while suppressing the signs of sepsis. supportive care is extremely important. sweet syndrome, or acute febrile neutrophilic dermatosis, is a benign disease characterized by tender, raised erythematous plaques, fever, peripheral leukocytosis, histologic fi ndings of a dense dermal infi ltrate of polymorphonuclear leukocytes, and a rapid response to systemic corticosteroids. [ ] [ ] [ ] [ ] [ ] only a few pediatric cases have been reported, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the youngest being weeks of age. two brothers with sweet syndrome starting at weeks of life have been reported. the lesions of sweet syndrome have an acute, explosive onset and are characterized by indurated, tender, erythematous plaques or nodules that vary in size from . to cm ( fig. - ). tiny pustules may appear at a later stage. the borders may be raised, mammillated, or even vesicular. some of the lesions may show central clearing, forming annular or gyrate plaques ( fig. - ) . the lesions are usually multiple and distributed over the face and extremities or, more rarely, the trunk. without treatment, they tend to heal spontaneously within a few months. in some patients, especially children, the lesions heal with areas of secondary cutis laxa, also known as marshall syndrome. , , a high, spiking fever is characteristic but may be absent in up to % of patients. arthralgias or asymmetric arthritis may be associated, and conjunctivitis or iridocyclitis may be seen in one-third of patients. renal involvement manifesting as proteinuria or hematuria, as well as lung involvement with infi ltrates visible on chest radiographs, has also been described. central nervous system involvement may occur in rare instances and manifest as headaches, convulsions, or disturbance of consciousness. cerebrospinal fl uid pleocytosis with lymphocyte predominance is usually found in such cases. the pathogenesis is unknown. many of the patients reported have had a preceding respiratory tract infection or elevated antistreptolysin o titers. ten per cent of the cases have been seen in the setting of a variety of hematologic malignancies, particularly acute myeloid and myelomonocytic leukemias. sweet syndrome has also been associated with solid tumors, infl ammatory bowel disease, connective tissue diseases, and chronic granulomatous disease, or it may occur as an adverse reaction to drugs, [ ] [ ] [ ] particularly granulocyte colonystimulating factor or after vaccination. because of these associations and the rapid response to systemic corticosteroids, sweet syndrome is thought to represent a hypersensitivity reaction to infectious agents or tumoral antigens. an elevated erythrocyte sedimentation rate and peripheral leukocytosis are frequent accompanying abnormalities. eosinophilia, microcytic anemia, mild elevation of liver enzymes, and urinalysis abnormalities may be present occasionally. antineutrophil cytoplasmic antibodies have been detected in some cases. α -antitrypsin defi ciency has been documented in one case of marshall syndrome. the histopathologic fi ndings are diagnostic. there is a dense perivascular infi ltrate composed almost entirely of neutrophils. the dermis appears edematous, and subepidermal blisters may form. spongiosis, exocytosis, and intraepidermal vesiculation may be seen. there is endothelial swelling and nuclear dust, but true vasculitis is characteristically absent. the lesions of sweet syndrome may initially resemble those of em or acute hemorrhagic edema. lesions on the lower extremities may resemble those of erythema nodosum, but lesions more characteristic of sweet syndrome are usually present in other locations. sweet syndrome is a benign disease but may be a marker of malignancy. if left untreated it resolves spontaneously over weeks to months. recurrences are common. marshall syndrome may have a poorer prognosis, with the development of elastolysis in the lungs or cardiovascular involvement. oral corticosteroids are the treatment of choice and usually elicit a prompt response. potassium iodide administration has been successful in a few cases, as have colchicine, dapsone, clofazimine, and intravenous immunoglobulin. kawasaki disease is an acute systemic vasculitis involving small and medium-sized muscular arteries, especially the coronary arteries, of young children. in the past, many cases were called infantile polyarteritis nodosa. the disease is characterized by fever lasting at least days, nonpurulent conjunctivitis, a polymorphous exanthem, erythema and swelling of the hands and feet, infl ammatory changes of the lips and oral cavity, and acute nonpurulent cervical adenopathy. [ ] [ ] [ ] [ ] coronary artery aneurysms or ectasia develop in - % of untreated children and may lead to ischemic heart disease or sudden death. kawasaki disease occurs predominantly in children under and has a peak incidence between and months. [ ] [ ] [ ] it is infrequent before months of age, although it has been reported in patients less than weeks of age [ ] [ ] [ ] boys are affected . times as often as girls. kawasaki disease is an endemic disease with epidemic and geographic clustering. there is seasonal predominance in late winter and spring, although this may differ in different countries. , it is most common in japan, with an annual incidence of cases per children under , and is steadily increasing. , familial cases in household contacts have been described. the recurrence rate is %, with some patients having two or more recurrences. , the skin is involved in % of patients. the fi rst sign often consists of diffuse erythema and painful induration of the hands and feet. between and weeks after disease onset the eruption characteristically begins to desquamate beneath the distal nail plates, and peeling may extend to involve the entire palm and sole. horizontal depressions in the nail plates (beau's lines) usually result. a polymorphous exanthem on the trunk and proximal extremities usually appears within days of onset of fever ( fig. - ). it is a nonspecifi c, diffuse maculopapular or kawasaki disease fig. - morbiliform eruption in an infant with kawasaki disease. morbilliform eruption, but may be urticarial, scarlatiniform, targetoid, or even pustular. bullous or vesicular eruptions have not been described. the rash is usually in the perineum, which is a distinctive feature at this early stage, and it desquamates within hours, preceding fi nger-tip and toe-tip desquamation (fig. - ) . plaque-type, guttate, and pustular psoriasis have been described, either during the acute or the convalescent phase of the disease, which supports a superantigenmediated etiology. [ ] [ ] [ ] [ ] changes in the lips and oral mucosa include erythema, swelling and fi ssuring of the lips, strawberry tongue, and erythema of the oropharynx. oral ulcerations and pharyngeal exudates are not seen. intermittent acrocyanosis has been observed in infants younger than months of age, as well as peripheral gangrene. infl ammatory changes with necrosis at the site of a previous bcg inoculation have been reported. [ ] [ ] [ ] [ ] extracutaneous findings , , , prolonged fever for at least days is the cardinal and initial feature of the disease. it begins abruptly and is high, with peak temperatures generally > °c ( °f) and in many cases > °c ( °f), with several spikes each day (remittent fever). in the absence of appropriate therapy, fever persists for a mean of days, but it may continue for - weeks and, rarely, even longer. bilateral nonexudative conjunctival injection, involving mainly the bulbar conjunctivae, begins shortly after disease onset and may already be resolved at time of fi rst consultation. anterior uveitis is frequently noted on slit-lamp examination but is rarely symptomatic. cervical lymphadenopathy is the least common diagnostic sign, with a prevalence of approximately %. it is usually unilateral, and confi ned to the anterior cervical triangle. the lymph nodes are often fi rm, nonfl uctuant, and only slightly tender. cardiac conditions are the main cause of long-term morbidity and mortality. the pericardium, myocardium, endocardium, and coronary arteries may all be involved. myocarditis may manifest in the acute phase, and arrhythmias due to ischemia, congestive heart failure, and valvular involvement, usually mitral, may occur. occasionally there may low cardiac output syndrome or shock. cardiac auscultation of the infant or child with kawasaki disease in the acute phase often reveals a hyperdynamic precordium, tachycardia, a gallop rhythm, and an innocent fl ow murmur. a pansystolic regurgitant murmur may be heard in children with signifi cant mitral regurgitation. electrocardiography may show arrhythmia, prolonged pr interval, or nonspecifi c st and t-wave changes. pericardial effusion may be detected by an echocardiogram in % of patients. without treatment, coronary artery aneurysms develop in % and are most commonly detected days to weeks after onset. risk factors for the development of coronary aneurysms include age younger than year, male gender, fever for more than weeks, recurrent fever, and delayed treatment. aneurysms may also develop in systemic medium-sized arteries and result in peripheral gangrene. polyarticular arthritis and arthralgias may occur in the fi rst weeks of the illness. it affects small as well as large joints. irritability is usually prominent. lethargy and other signs of aseptic meningitis may be present. abdominal symptoms such as vomiting, diarrhea, and pain are common. in rare instances acute abdominal pain, mimicking a surgical abdomen, may herald the onset of the disease. mild hepatitis occurs frequently, as does acute distension of the gallbladder (hydrops). transient unilateral peripheral facial nerve palsy occurs rarely. respiratory symptoms due to pulmonary nodules, infi ltrates, or pleural effusion may also be observed. [ ] [ ] [ ] rare fi ndings include testicular swelling, hemophagocytic syndrome, and transient high-frequency sensorineural hearing loss ( - db). [ ] [ ] [ ] epidemiologic and clinical data suggest that kawasaki disease has features of infectious disease in an immunologically susceptible host and of an immune-mediated vasculitis. many etiologic agents, ranging from bacteria such as propionibacterium, staphylococcus, streptocuccus, chlamydia and yersinia to viruses such as epstein-barr, parvovirus, adenoviruses, retroviruses, and a novel human coronavirus, have been linked to kawasaki disease in different geographic outbreaks, but none has been consistently demonstrated. much of the continuing debate in the literature concerns whether kawasaki disease is caused by a superantigen or a conventional antigen. , evidence of a superantigen-mediated disease process includes the identifi cation of superantigen-producing organisms, isolation of bacterial superantigens, or fi nding the hallmark of superantigen activation in affected children, such as selective expansion of vβ and vβ t-cell receptor families. however, the immune response in kawasaki disease is oligoclonal (antigen driven, i.e. similar to a response to a conventional antigen) rather than polyclonal (as found typically in superantigen-driven responses), and immunoglobulin a (iga) plasma cells play a central role. , regardless of the cause, evidence points to a generalized immune activation with production of various proinfl ammatory cytokines and endothelial cell activation which lead to coronary artery alteration. [ ] [ ] [ ] [ ] the most studied cytokine has been tnf-α, which is usually elevated in children with kawasaki disease. enzymes, including matrix metalloproteinases that are capable of damaging arterial wall integrity, may also be important in the development of aneurysmal dilatation. various chemotactins that attract neutrophils and monocytes to coronary arteries may also play an important role. host genetic determinants play a role in both susceptibility and coronary artery outcome in kawasaki disease. the fig. - early perineal desquamative eruption of kawasaki disease. incidence rate in siblings is times the population incidence. , , the risk of occurrence in twins is higher than in ordinary siblings. parents who had kawasaki disease in childhood are more likely to have affected children, and children with recurrent disease. in the acute phase, laboratory studies show leukocytosis (> /mm ) with a left shift, normochromic normocytic anemia, increased sedimentation rate and other acute-phase reactants, depressed albumin, and elevated igm and ige levels. the degree of elevation of esr and c-reactive protein may show discrepancy, and both should be measured. furthermore, elevation of esr can be caused by ivig therapy and therefore can not be the sole determinant of the degree of infl ammatory activity. plasma lipids are altered in the acute stage, with depressed plasma cholesterol and hdl. , there may be mild elevation of transaminases and polyclonal hypergammaglobulinemia. in the subacute stage, in the second and third weeks of illness, there is a marked and almost universal thrombocytosis, which returns to normal in - weeks. thrombocytopenia is rarely seen in the acute stage and may be a sign of disseminated intravascular coagulation. antineutrophil cytoplasmic antibodies may be detectable as a nonspecifi c epiphenomenon. there may be sterile pyuria with mild proteinuria. cerebrospinal fl uid shows a mononuclear pleocytosis with normal protein and glucose levels. skin biopsy fi ndings are not specifi c. there is edema in the papillary dermis, with a mild perivascular mononuclear cell infi ltrate. vasculitis of medium and large arteries is observed. there is no single diagnostic test for kawasaki disease and therefore clinical criteria have been established to guide treatment decisions (box - ) . the classic diagnosis has been based on the presence of days of fever and four of the fi ve principal clinical features. clinical features usually appear sequentially and are not all present at a single point in time, therefore watchful waiting is sometimes necessary before a diagnosis can be made. to avoid holding treatment until more than four clinical criteria are met, and the recognition that many patients with 'incomplete' kawasaki still develop coronary artery disease, one may diagnose and treat kawasaki on day of illness in the presence of four principal criteria. , also, the diagnosis can be made in patients with fever for days and fewer than four principal features when coronary artery disease is detected by two-dimensional echocardiography ( de) or coronary angiography. kawasaki disease should be considered in the differential diagnosis of a young child, specially under year of age, with unexplained fever for days that is associated with any of the principal clinical features of this disease, or even in the presence of other clinical and laboratory fi ndings that are not classic criteria but which are commonly encountered in this disease (box - ). for example, an elevated crp or esr and elevated platelet count after days of illness are uncommon in viral infections but are universally seen in children with kawasaki disease. echocardiography may be useful in evaluating 'incomplete kawasaki disease' and should be considered in any infant under months with fever of more than days' duration, laboratory evidence of systemic infl ammation, and no other explanation for the febrile illness. although aneurysms rarely form before day of illness there may be signs of coronary arteritis, decreased contractibility, mitral regurgitation, and pericardial effusion. with all these considerations a new algorithm has been proposed to help in deciding which patient with incomplete kawasaki disease should undergo echocardiography or receive ivig treatment (fig. - ) . the morbidity and mortality of kawasaki disease depend primarily on coronary artery lesions. [ ] [ ] [ ] [ ] [ ] coronary artery aneurysms or ectasia develop in - % of untreated children and may lead to ischemic heart disease or sudden death. with early treatment the risk is reduced to around - %. , small aneurysms resolve completely within the fi rst years after disease onset in - % of these patients. however, coronary aneurysms, especially if giant (> mm), may persist and be complicated by thrombotic occlusion or the development of stenosis at the outlet of the aneurysm. stenotic lesions as well as early coronary atherosclerosis may develop gradually over several years, so long-term follow-up is warranted. , , , several scoring systems have been developed to predict risk for coronary artery aneurisms. the harada score is one that is used in japan. sometimes kawasaki disease may be 'atypical,' presenting at onset with clinical features that are not generally seen, such as acute abdominal pain, renal impairment, meningeal irritation, pneumonia, or retropharyngeal abscess. many diseases mimic kawasaki disease, including viral infections, streptococcal infection, juvenile rheumatoid arthritis, erythema multiforme, staphylococcal scalded skin syndrome, toxic shock syndrome, drug hypersensitivity reactions, rocky mountain spotted fever, leptospirosis, mercury hypersensitivity reaction (acrodynia), and bacterial cervical adenitis. low white blood cell count, lymphocytosis and low platelet count may be useful in suggesting a viral infection instead of kawasaki disease. because the major sequelae of kawasaki disease are related to coronary artery systems, cardiac imaging is critical in the evaluation of all patients with suspected kawasaki disease, and serial echocardiograms are recommended. echocardiography should focus on coronary artery visualization and measurement, but also on left ventricle contractibility, valve function, the presence of pericardial effusion, and measurement of the aortic root. an initial examination should be performed as soon as the diagnosis is suspected and is useful as a baseline for follow-up. thereafter, for uncomplicated cases it should be repeated at weeks and at - weeks after disease onset. for those who develop coronary artery aneurysms or other cardiac abnormalities more frequent evaluation is recommended. other noninvasive imaging modalities, such as mri, mra, and ultrafast ct, as well as cardiac stress testing, are being evaluated in the management of kawasaki disease. until the aneurysm resolves a stress test may be needed to guide recommendations for physical activity and the need for angiography. treatment in the acute phase of the disease is directed to reducing infl ammation in the coronary artery wall and preventing coronary thrombosis, whereas long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction. intravenous γglobulin (ivig) combined with high-dose aspirin is the treatment of choice in the acute phase of the disease. aspirin alone does not appear to reduce the frequency of the development of coronary abnormalities, but together with ivig it has an additive anti-infl ammatory effect. in the acute stage aspirin is given in doses of - mg/kg divided into four. the duration of high-dose aspirin varies in different centers. in many institutions the dose is reduced after the child has been afebrile for - hours. others continue until day of illness and > - hours after fever cessation. following this acute phase low-dose aspirin ( - mg/kg) is given as an antiplatelet agent until there is no evidence of coronary changes at - weeks from disease onset. for patients who develop coronary abnormalities, low-dose aspirin is continued until regression of coronary artery aneurysms, but some clinicians continue indefi nitely. ibuprofen should be avoided in children taking aspirin for its antiplatelet effect because it antagonizes platelet inhibition. ivig has been shown to reduce the incidence of coronary artery aneurisms from % to - %. [ ] [ ] [ ] [ ] a single dose of mg/kg has been shown to be superior than lower doses for consecutive days. , ivig should be started early, within days of disease onset and preferably within days. treatment before day does not appear to prevent cardiac sequelae and may be associated with an increased need for ivig retreatment. , treatment after day should be considered if there are still signs of ongoing infl ammation (elevated esr or crp) or persistent fever. not all patients respond to a single dose of ivig and may have persistent or recrudescent fever hours after completion of the initial treatment, and require a second dose. it has been observed that those children who received ivig very early in the illness are more prone to require a second infusion. vaccination with live or other vaccines should be deferred for at least months after high-dose ivig treatment, both to ensure correct immunization and to avoid fl ares of kawasaki disease. the usefulness of steroids in combination with ivig in the initial therapy of kawasaki disease is not well established. steroids shorten the duration of fever and lower esr and crp, but do not seem to infl uence the coronary outcome. , steroids have also been used for ivig treatment failures, but their role in preventing or reversing coronary anomalies is uncertain. it has been recommended to restrict their use in children who have persistent fever after two infusions of ivig. the most common regimen is intravenous pulse methylprednisolone, mg/kg for - days. because of its inhibition of tnf-α messenger rna transcription, pentoxifylline may have a theoretical benefi t in the initial treatment of kawasaki disease, although there are only small clinical trials reported. the role of tnf-α antagonists such as infl iximab; abciximab, a platelet glycoprotein iib/iia receptor inhibitor; plasma exchange; and cytotoxic agents for patients with refractory kawasaki disease, remains uncertain. , acute hemorrhagic edema (ahe), purpura en cockade, or finkelstein disease, is an acute, benign leukocytoclastic vasculitis of limited skin involvement occurring in children under years of age. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ahe has been considered an infantile variant of henoch-schönlein purpura; however, because of clinical and prognostic differences it is sometimes regarded as a separate entity. the disease is characterized by the abrupt onset of fever; tender edema of the face, eyelids, ears, scrotum, and acral extremities; and ecchymotic purpura on the face and extremities. the trunk is usually spared. individual lesions often have a darker center and expand centrifugally, giving them a cockade or target-like confi guration. lesions range in size from . to . cm and may become confl uent, forming polycyclic, annular plaques ( fig. - ). necrotic , and bullous lesions may be seen. , petechiae in the mucous membranes have also been described. except for fever, there are no associated manifestations. in many patients there is a preceding upper respiratory tract infection. the dramatic cutaneous fi ndings contrast with the general wellbeing of the patient. acute hemorrhagic edema fig. - acute hemorrhagic edema. the cause of ahe is unknown. it is thought to represent an immune complex-mediated disease precipitated by a preceding infection, particularly an upper respiratory tract infection, drug intake, or immunization. staphylococci and streptococcus spp. and viruses (adenoviruses, rotavirus) have been implicated most commonly. leukocytosis (both lymphocytic and granulocytic), thrombocytosis, eosinophilia, and an elevated esr may be present. urinalysis, tests for occult blood in the stool, immunoglobulin, and complement levels are usually normal or negative. circulating immunocomplexes may occasionally be found. histopathologic examination of skin biopsy specimens demonstrates a small vessel leukocytoclastic vasculitis. direct immunofl uorescence shows deposition of c and fi brinogen in the vessel wall. igm, igg, iga, and ige deposition has also been noted in up to one-third of cases. , [ ] [ ] [ ] the differential diagnosis includes henoch-schönlein purpura, child abuse, meningococcemia and other infectious purpuras, erythema multiforme, kawasaki disease, and sweet syndrome. , distinction from henoch-schönlein purpura may be impossible (table - ). perivascular deposits of iga are not useful for differentiation because they may be present in both entities. the prognosis is excellent. the eruption resolves spontaneously without sequelae in - weeks. treatment with corticosteroids is not necessary and may lead to complications and worsen the prognosis. exacerbations may be observed during the clinical evolution, with new crops of lesions and fever, , but true recurrences weeks or months after the fi rst episode are rare. , there has been a single report of a fatal ileoileal intussusception in an infant with cutaneous lesions otherwise typical for ahe. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the porphyrias are a group of diseases characterized by abnormalities of porphyrin-heme metabolism. each type results from defi cient activity of one of the enzymes of the heme biosynthetic pathway, which leads to an accumulation of heme precursors within plasma, red blood cells, urine, and feces. the genes for these enzymes have been characterized. , , porphyrias are mainly inherited in an autosomal dominant manner with incomplete penetrance, but autosomal recessive and more complex patterns of inheritance are also possible. porphyrias are classifi ed as hepatic or erythropoietic, according to the organ site in which the underlying defect of heme synthesis is predominantly expressed (see table - ). cutaneous manifestations in porphyrias may be classifi ed as acute photosensitivity with burning pain, edema, and erythema shortly after sun exposure, or delayed photosensitivity manifesting as skin fragility, subepidermal blisters, milia, disorders of pigmentation, and sclerodermoid signs. hepatic porphyrias usually manifest acute neurovisceral attacks and delayed photosensitivity, and rarely present before puberty except from the homozygous variants. elevated porphyrins may be detected in the stool or urine. erythropoietic porphyrias are characterized by acute cutaneous photosensitivity from early childhood. the more delayed photosensitivity, although less characteristic of this type of porphyria, may be also present. erythrocyte and plasma porphyrin levels are elevated in erythropoietic porphyrias. photosensitivity in porphyrias is maximum for ultraviolet wavelengths between and nm ('soret band'), the spectrum of maximum absorption of porphyrins. the pathophysiologic mechanisms involved in the cutaneous manifestations of the porphyrias are multiple and involve the creation of reactive oxygen specimens. [ ] [ ] [ ] childhood porphyrias are relative uncommon and their exact incidence is unknown. only those porphyrias manifesting early in infancy are reviewed here. congenital erythropoietic porphyria (cep), also called günther disease, is a rare autosomal recessive disorder caused by deficient activity of uroporphyrinogen iii (urogen iii) synthase which leads to nonenzymatic conversion of hydroxymethylbilane to uroporphyrinogen i, a nonphysiologic substrate that is converted to coproporphyrinogen i; these porphyrinogen i isomers are then oxidized to uroporphyrin i (uro-i) and coproporphyrin i (copro-i), which are phototoxic compounds. elevated levels of uro-i and copro-i in erythrocytes result in massive hemolysis, and the released porphyrins accumulate in peripheral blood, skin, bone, and teeth and are excreted in large amounts in the urine and feces. , , cep presents with severe photosensitivity from birth or early infancy with formation of vesicles and bullae on areas exposed to sun, phototherapy devices, or even ambient lighting. there is also marked skin fragility. as a result of the phototoxic injury and the increased skin fragility, there are severe mutilations, mainly of the fi ngers, hands, and face, particularly the nose and ears, but also in sun-protected areas. hypertrichosis of the face and extremities, scarring alopecia of the scalp and eyebrows, and pigmentary changes (hyperpig- histologic examination of skin biopsy specimens from blisters reveals subepidermal cleavage (within the lamina lucida) and minimal infl ammatory infi ltrate. perivascular accumulation of pas-positive, diastase-resistant, homogeneous hyaline material (porphyrins) may be seen, which is best viewed with fl uorescence microscopy. see table - for porphyrin excretion profi le. measurement of uro iii synthase activity is available. prenatal diagnosis from amniotic fl uid is possible by either measurement of uroproporphyrin i or direct gene mutation analysis. [ ] [ ] [ ] [ ] other photosensitivity diseases presenting early in life (box - ) or diseases manifesting with blisters, such as epidermolysis bullosa and bullous pemphigoid, should be considered. determination of porphyrins is diagnostic and allows differentiation from other porphyrias presenting early in life with photosensitivity. the clinical severity of cep is highly variable, ranging from hydrops fetalis, hepatosplenomegaly, and severe anemia in utero to adult-onset disease with only cutaneous manifestations. in most cases, however, patients survive well into adulthood, albeit with severe mutilations or major disfi gurement. mentation and hypopigmentation) are also common. over time, severe facial mutilation results, with destruction of nasal and auricular cartilages, ectropion, and eclabium, as well as shortening and contraction of the fi ngers. milder phenotypes may have onset later in childhood. the accumulation of porphyrins in deciduous and permanent teeth produces red discoloration (erythrodontia) and reddish fl uorescence on wood's light examination, which is pathognomonic. the urine is also reddish, which causes pink discoloration of the diapers that fl uoresces -an early bed-side diagnostic sign. porphyrins accumulate in the amniotic fl uid and brownish amniotic fl uid may be observed. severe hemolytic anemia and secondary splenomegaly occur. anemia may be so severe as to lead to hydrops fetalis and death in utero. patients with late-onset disease may not develop hemolytic anemia but only thrombocytopenia and myelodysplasia. ocular changes include ectropion, photophobia, and keratoconjunctivitis. other manifestations include osteodystrophy with increased bone fragility, and porphyrin-rich gallstones. the gene for urogen iii synthase is localized on chromosome . several mutations have been identifi ed, protection from sun exposure is essential. chemical sunscreens do not achieve good protection against soret band radiation, so protective clothing and physical sunblocks are necessary. long-wavelength, uv-absorbing fi lms are encouraged on car windows and windows at home. children with the severe phenotypes and severe hemolysis benefi t from repeated erythrocyte transfusions and hydroxyurea to suppress erythropoiesis. hematocrits should be maintained above %, with appropriate iron chelation. the effi cacy or repeated erythrocyte transfusion may decrease at puberty. subsequent splenectomy is often needed to control hemolytic anemia. , activated charcoal, [ ] [ ] [ ] [ ] and β-carotene , have been used, with inconsistent results. bone marrow transplantation or stem cells from cord blood offer the possibility of correcting enzyme activity. [ ] [ ] [ ] [ ] [ ] replacement gene therapy has been accomplished in vitro. , erythropoietic protoporphyria , , erythropoietic protoporphyria (epp) is the most common form of cutaneous porphyria apart from porphyria cutanea tarda (pct). epp is caused by defi cient activity of ferrochelatase, leading to the accumulation of protoporphyrin in erythrocytes, plasma, and feces. clinical symptoms typically begin in infancy or early childhood, with a peak incidence between and years of age. epp is usually inherited as an autosomal dominant condition, but most individuals who are heterozygous for the inherited mutations are asymptomatic, because of halfnormal ferrochelatase activity for protoporphyrin to accu-mulate suffi ciently to cause photosensitivity, a reduction of enzymatic activity to below a critical threshold of about % of normal is required. some families may have autosomal recessive inheritance. [ ] [ ] [ ] clinical manifestations are those of an acute phototoxic reaction, which triggers an episode of crying within minutes of sunlight exposure due to burning pain or stinging sensations on exposed areas (the face and the dorsal aspect of hands). some patients are photosensitive to fl uorescent lighting. erythema, edema, and urticarial lesions occur, but vesicles and bullae are rare (fig. - ) . fine petechiae may occur on sunexposed areas after prolonged exposure. some patients have only subjective symptoms. with chronic exposure there is characteristic thickening and wrinkling of the knuckle pads, furrowing around the mouth (pseudorhagades), and shallow elliptical scars on the nose, cheeks, and forehead. hemolytic anemia is absent, but in some patients a mild hypochromic, microcytic anemia may occur. protoporphyrinrich gallstones may develop in childhood. fatal liver failure resulting from the progressive accumulation of protoporphyrin in hepatocytes is a possible outcome in about . % of patients, altering the prognosis for an otherwise clinically benign disorder. recessive inheritance may predispose to severe liver disease. families. , in most symptomatic patients inheritance of a second mutation is needed in order to reduce the enzymatic activity to a critical threshold where clinical symptoms are caused. autosomal recessive inheritance has been demonstrated in % of patients with epp. histopathologic examination of skin biopsy specimens of sunexposed areas shows marked concentric deposits of a hyaline material around dermal blood vessels. this material is pas positive and diastase resistant. patients with epp should undergo frequent liver function tests, and those with persistent abnormalities should have a liver biopsy. children with high erythrocyte protoporphyrins should have periodic determination of blood, urinary, and fecal porphyrins because increased excretion of copropophyrins, high erythrocyte protoporphyrins and reduced excretion of faecal protoporhyrins can predict liver failure. the diagnosis of epp is established by detecting elevated levels of protoporphyrin in erythrocytes, plasma, and feces. in addition, fecal and erythrocyte coproporphyrins may be increased. a rapid microfl uorometric assay for free erythrocyte protoporphyrins and examination of a blood smear for fl uorescent erythrocytes may also be used as screening tests. the differential diagnosis includes other types of porphyria, but causes of immediate photosensitivity such as pmle or solar urticaria do not occur in infants. the mainstay of treatment for erythropoietic protoporphyria is sun avoidance and the use of physical sunscreens. , topical dihydroxyacetone may be helpful in some patients by producing brown pigment. oral administration of βcarotene ( - mg/day for children) has been shown in uncontrolled studies to increase tolerance to sun exposure because it quenches the formation of free radicals. , , narrowband ultraviolet b phototherapy has been proposed, as this wavelength does not cause photosensitivity. desensitization with puva therapy has also been used. oral iron, intravenous hematin, transfusion therapy, and a highcarbohydrate diet have been used to prevent protoporphyrin accumulation in the liver by reducing protoporphyrin production, but their effi cacy is unproven. cholestyramine or activated charcoal have been used to interrupt the enterohepatic circulation of protoporphirins. avoidance of alcohol and drugs that interfere with hepatic excretory function is also essential. liver transplantation has been performed in a few patients with liver failure, although the enzymatic defect is not thereby corrected and hence the long-term outcome is poor. [ ] [ ] [ ] [ ] modifi cation of the lighting in the operating room is necessary to avoid photoxicity to exposed organs. hepatoerythropoietic porphyria (hep) is an extremely rare disorder caused by a marked defi ciency of uroporphyrinogen decarboxylase due to a homozygous state. [ ] [ ] [ ] [ ] clinical manifestations begin in infancy, or more commonly in early childhood, and resemble both porphyria cutanea tarda and günter disease. the disease usually presents with darkening of the urine and delayed-type cutaneous photosensitivity, with vesicles, skin fragility, milia, and scarring. with time, hypertrichosis, sclerodermoid changes, and mutilation similar to the manifestations of günter disease become apparent. anemia, hepatosplenomegaly, and abnormalities of liver function of varying degrees may also occur, but are less common than in congenital erythropoietic porphyria. the porphyrin excr etion pattern resembles that of porphyria cutanea tarda (pct), with elevated urinary uroporphyrins and -carboxylated porphyrins, and a smaller elevation of coproporphyrins, -and -carboxylated porphyrins. increased isocoproporphyrins in feces are characteristic. unlike in pct, erythrocyte proto is increased. treatment is directed to sun protection. hypertrichosis in hepatoerythropoietic porphyria has been treated successfully with high-intensity pulses of noncoherent light. other porphyrias with onset of symptoms in infancy or early childhood include homozygous variants of aminolevulinate dehydratase (alad) defi ciency, homozygous coproporphyria (harderoporphyria), homozygous variegate porphyria, and homozygous acute intermittent porphyria. alad defi ciency porphyria is rare (fewer than patients reported) and usually manifests later in childhood or adulthood, but neonatal onset has been reported. clinical manifestations from birth are recurrent attacks of pain, vomiting, hyponatremia, and symptoms of polyneuropathy affecting motor functions, including respiration. raised levels of aminolevulinic acid and coproporphyrin in urine are found. very low erythrocyte aminolevulinate dehydratase activity is diagnostic. liver transplantation in patients with neonatal onset has little effect. in harderoporphyria, neonatal jaundice, hemolytic anemia, and hepatosplenomegaly dominate the clinical picture. [ ] [ ] [ ] [ ] blisters may occur during phototherapy for neonatal jaundice. diagnosis depends on detecting very low coproporphyrinogen oxidase activity, elevated coproporphyrin in urine, markedly homozygous variegate porphyria may present shortly after birth with marked photosensitivity or, more commonly, with erosions, blisters, and milia following minor trauma in sunexposed areas. [ ] [ ] [ ] acute attacks are absent, but mental and growth retardation, seizures, nystagmus, and clinodactyly have been described. homozygous variant of acute intermittent porphyria may present early in life with ataxia, mental retardation, convulsions, cataracts, and hepatosplenomegaly, but acute attacks typical of acute intermittent porphyria do not occur in these children. [ ] [ ] [ ] [ ] there are no cutaneous manifestations. markedly increased porphobilinogen and alad in urine are found and are responsible for the orange urine. [ ] [ ] [ ] [ ] transient increases in porphyrin levels have been described in neonates with hemolytic disease of the newborn and in a neonate with severe liver failure due to tyrosinemia type . these infants develop erythema, violaceous discoloration, purpura, erosions, and blisters in areas exposed to phototherapy, with sharp demarcation at photoprotected sites. sensitivity to sunlight may occur. elevated levels of plasma/urine porphyrins (mainly coproporphyrin) and/or erythrocyte protoporphyrin are found, which normalize spontaneously during the fi rst few months. the cause of transient porphyrinemia is unclear but is probably due to cholestasis. other factors likely to be involved include blood transfusions and drug use. purpura in the neonate is almost always an emergency and should prompt an immediate search for an underlying disorder. apart from trauma, purpura in the newborn may be due to coagulation defects, platelet abnormalities, or infections (see . extramedullary erythropoiesis also causes purpuric lesions by a different mechanism. in the evaluation of a neonate with purpura it is important to obtain a maternal and familial history of bleeding diathesis and thromboembolic phenomena, drug intake, and symptoms of infectious diseases. a general physical examination and workup for sepsis is warranted. laboratory studies should include hemoglobin and hematocrit values, platelet count, white blood count, coagulation studies, and torch serologies. persistence of the erythropoietic activity of fetal dermal mesenchyme into the newborn period produces a characteristic purpuric eruption for which the term blueberry muffi n baby was coined. the eruption, fi rst observed in newborns with congenital rubella (fig. - ) , may be the result of other intrauterine infections (fig. - ) and hematologic dyscrasias. [ ] [ ] [ ] a blueberry muffi n-like eruption may also represent metastatic infi ltration of the dermis by congenital malignancies, without true extramedullary erythropoiesis (fig. - ). the cutaneous lesions of blueberry muffi n babies consist of dark blue or magenta, nonblanchable, round to oval papules ranging in size from to mm and have a generalized distribution, with emphasis on the head, neck, and trunk ( fig. - ). the papules are fi rm to palpation, with an infi ltrative quality that distinguishes them from petechiae and purpura, which often coexist in the same patient. these lesions evolve into dark purple to brown macules and involute spontaneously within - weeks. blueberry muffi n lesions caused by infi ltrative processes are usually larger, more nodular, less hemorrhagic, fewer in number, and fi rmer to palpation. accompanying abnormalities vary with the underlying cause. in the prevaccination era rubella was the most common cause of dermal erythropoiesis, but now congenital cytomegalovirus (cmv) infection is the major cause. , dermal erythropoiesis has been associated with other intrauterine infections, such as coxsackie b and parvovirus b , as well as hematologic dyscrasias such as rh incompatibility (fig. - ) , , maternofetal abo incompatibility, spherocytosis, and the twin transfusion syndrome , (box - ) . in rare instances it may occur in otherwise healthy newborns. , histopathologic examination demonstrates poorly circumscribed collections of nucleated and nonnucleated red blood cells, predominantly confi ned to the reticular dermis and extending to the subcutaneous tissue. [ ] [ ] [ ] occasionally a few myeloid precursors may be interspersed. laboratory fi ndings depend on the underlying cause. in the evaluation of a blueberry muffi n baby the following tests are indicated: peripheral blood count, hemoglobin level, torch serologies, viral cultures, and a coombs' test. skin biopsy is not always necessary for diagnosis, but may be helpful if an infi ltrative process is suspected. the differential diagnosis includes other causes of neonatal purpura, such as coagulation defects, platelet abnormalities, and infections. neoplastic diseases that produce infi ltrative metastases in the neonatal period, such as neuroblastomas, [ ] [ ] [ ] rhabdomyosarcomas, the lesions of true dermal erythropoiesis fade and resolve spontaneously - weeks after birth. treatment is directed at the underlying condition. neonatal purpura fulminans is a rare condition characterized by massive and progressive hemorrhagic necrosis of the skin accompanied by thrombosis of the cutaneous vasculature in the neonatal period. [ ] [ ] [ ] [ ] [ ] [ ] occasionally larger vessels and other organs are involved. the primary pathologic event is widespread thrombosis, which is responsible for a hematologic picture of disseminated intravascular coagulation (dic). in neonates, purpura fulminans is usually the result of inherited thrombophilic disorders that are attributable to protein c deficiency, protein s defi ciency, or resistance to activated protein c due to factor v mutations. neonatal purpura fulminans manifests - hours after birth. in rare instances, delayed onset of up to - months of age has been described. cutaneous lesions consist of extensive ecchymoses in a diffuse and often symmetric distribution that rapidly evolve into hemorrhagic bullae and purple-black necrotic skin lesions, which ultimately form a thick eschar ( fig. - ). the initial ecchymotic areas are sharply defi ned from the surrounding skin and usually have a red, advancing infl ammatory rim. they are most common at sites of trauma or pressure, the buttocks, extremities, trunk, and scalp. mucous membranes may rarely be involved. if treatment is instituted in the fi rst - hours, before necrosis ensues, the initial lesions may be reversible. other organs may be affected by the microvascular thrombosis, most commonly the cns and eye, but also the kidney and gastrointestinal tract. cavernous sinus involvement, which may occur in utero, can result in hydrocephalus, seizures, intracerebral hemorrhage, and mental retardation. , , microphthalmia, cataracts, and blindness due to vitreous or retinal hemorrhage may be seen. , deep venous thrombosis and pulmonary embolism have also been described. purpura fulminans in the neonatal period is almost always caused by inherited thrombophilic states such as homozygous protein c and s defi ciency or resistance to activated protein c. severe bacterial infection associated with dic can also induce purpura fulminans in the neonate, although it is more common in infancy or early childhood. , proteins c and s are vitamin k-dependent glycoproteins with antithrombotic properties. , protein c defi ciency is an autosomal dominant disease with incomplete penetrance. homozygous or compound heterozygous patients have a severe clinical phenotype and usually present with neonatal purpura fulminans, although they may be asymptomatic or present later in life with recurrent thrombosis. , protein s defi ciency is also transmitted as an autosomal dominant trait with incomplete penetrance. homozygous patients may develop neonatal purpura fulminans, although the risk is lower than in patients with homozygous protein c defi ciency. , neonatal purpura fulminans may also be caused by activated protein c resistance due to a mutation in the factor v gene. , resistance to activated protein c may coexist with protein s and protein c defi ciencies, becoming an additional genetic risk factor for purpura fulminans or thromboembolic complications, and explaining in part the incomplete clinical penetrance of inherited thrombophilic disorders. blood coagulation studies demonstrate evidence of dic, including prolonged prothrombin and partial thromboplastin times, increased fi brin split products, reduced fi brinogen, and reduced platelets. microangiopathic hemolytic anemia may occur. biopsy of the early skin lesions demonstrates occlusion of dermal blood vessels by microthrombi. hemorrhage and dermal necrosis are present in the more advanced stages. necrosis of the overlying epidermis with subepidermal hemorrhagic bullae occurs in later phases. secondary fi brinoid necrosis of dermal vessel walls may be present in the necrotic areas, but primary vasculitis is absent. , a defi nitive diagnosis of protein c and s defi ciency is established by measurements of protein c and s levels. protein c defi ciencies can be identifi ed by immunoenzymatic assays measuring the actual concentration of the protein in plasma, and two functional assays measuring the enzymatic activity and the anticoagulant activity. these tests distinguish two types of protein c defi ciency. in type i, which is the most common, reduced synthesis of the normal protein leads to a low plasma concentration in all three assays. in type ii, a qualitative defi ciency, levels are normal but functional assays are abnormal. for protein s defi ciency, functional and immunoenzymatic assays are available, and both the free form and the inactive form that circulates bound to c b-binding protein have to be measured. type i defi ciency is characterized by low total and free protein s, type ii by normal free protein s and low activity, and type iii by low free protein levels with normal total levels. interpreting the results of the assays may be diffi cult because protein c and s levels are physiologically reduced in the neonatal period, and may be undetectable in sick newborns with liver disease, respiratory distress syndrome, dic, or sepsis. , , , , a complete sepsis workup is therefore recommended in any case of neonatal purpura fulminans. serial determination of protein levels in patients and other family members is necessary to exclude a transient defi ciency and confi rm true congenital defi ciency. the cutaneous lesions of purpura fulminans are very characteristic and rarely mistaken for any other condition. other causes of purpuric eruptions in the newborn may be considered (see . without treatment, neonatal purpura fulminans is often fatal. if the diagnosis is suspected, therapy should be initiated immediately without waiting for the results of protein c and s measurements. prompt treatment may completely reverse early skin lesions. initial therapy consists of the administration of fresh frozen plasma ( - ml/kg/ h) or prothrombin complex concentrate, sources of protein c, protein s, and activated protein c. , a protein c concentrate has been developed that has the advantage of avoiding blood volume overload and does not carry the risk of transmission of viral fig. - neonatal purpura fulminans due to protein c defi ciency. ment therapy to avoid coumarin-induced skin necrosis. experience with long-term treatment using protein c infusions is limited. there are few case reports of a successful liver transplant for homozygous protein c defi ciency. , this benign, transient purpura in transfused neonates who undergo phototherapy is characterized by raspberry-colored, nonblanching lesions at exposed sites, sparing sites that are protected from lights (e.g. leads and temperature probes). , the eruption develops after - days of phototherapy and clears spontaneously after discontinuation of light therapy. histologically there is extravasation of red blood cells in the dermis without epidermal damage. the pathogenesis of this disease is unknown, although transient porphyrinemia has been detected in some patients. , the purpuric nature of the eruption and the absence of 'sunburn cells' differentiate this eruption from 'sunburn' caused by exposure to uva from fl uorescent lamps. congenital erythropoietic porphyria and transient elevated porphyrin levels in neonates with hemolytic disease may also cause photosensitivity. drug-induced phototoxicity in neonates who have received photosensitizing chemicals such as fl uorescein dye, furosemide or methyleneblue must be considered. [ ] [ ] [ ] [ ] diseases. , protein s concentrate is not yet available for clinical use. replacement therapy should be continued until all lesions have healed, usually after - weeks. long-term treatment involves careful administration of oral anticoagulants, starting at very low doses and with protective replace- the annular erythemas persistent' annular erythema of infancy an annular erythema of infancy annular erythema of infancy annular erythema of infancy congenital annular erythema persisting in a -year-old girl persistent annular erythema of infancy erythema annulare centrifugum: report of a case with neonatal onset erythema gyratum atrophicans transiens neonatale erythema gyratum atrophicans transiens neonatale: a variant of cutaneous neonatal lupus erythematosus reactive erythemas: erythema annulare centrifugum and erythema gyratum repens erytheme annulaire centrifuge de darier à debut neonatal avec ans de suivi. effi cacité de l'interféron et role de cytokines erythema 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manifested by massive venous thrombosis in the newborn severe homozygous protein c defi ciency severe acquired neonatal purpura fulminans causes of purpura fulminans protein c pathway in infants and children protein c and protein s defi ciencies late-onset homozygous protein c defi ciency asymptomatic homozygous protein c defi ciency homozygous protein s defi ciency due to a one base pair deletion that leads to a stop codon in exon iii of the protein s gene the discovery of activated protein c resistance blood coagulation and its regulation by anticoagulant pathways: genetic pathogenesis of bleeding and thrombotic diseases dermatopathology of skin necrosis associated with purpura fulminans neonatal purpura fulminans and transient protein c defi ciency homozygous protein c defi ciency -management with protein c concentrate replacement therapy with a monoclonal antibody purifi ed protein c concentrate in newborns with severe congenital protein c defi ciency en bloc heterotopic auxiliary liver and bilateral renal transplant in a patient with homozygous protein c defi ciency successful treatment of homozygous protein c defi ciency by hepatic transplantation transient erythroporphyria of infancy ultraviolet light burn: a cutaneous complication of visible light phototherapy of neonatal jaundice methylene-blue-induced hyperbilirubinemia and phototoxicity in a neonate methylene blue-induced phototoxicity: an unrecognized complication fluorescein phototoxicity in a premature infant phototoxic blisters from high frusemide dosage key: cord- - bvju g authors: gonzales, ralph; bartlett, john g.; besser, richard e.; cooper, richelle j.; hickner, john m.; hoffman, jerome r.; sande, merle a. title: principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background date: - - journal: annals of emergency medicine doi: . /s - ( ) - sha: doc_id: cord_uid: bvju g abstract the following principles of appropriate antibiotic use for adults with acute bronchitis apply to immunocompetent adults without complicating comorbid conditions, such as chronic lung or heart disease. . the evaluation of adults with an acute cough illness or a presumptive diagnosis of uncomplicated acute bronchitis should focus on ruling out serious illness, particularly pneumonia. in healthy, nonelderly adults, pneumonia is uncommon in the absence of vital sign abnormalities or asymmetrical lung sounds, and chest radiography is usually not indicated. in patients with cough lasting weeks or longer, chest radiography may be warranted in the absence of other known causes. . routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough. if pertussis infection is suspected (an unusual circumstance), a diagnostic test should be performed and antimicrobial therapy initiated. . patient satisfaction with care for acute bronchitis depends most on physician–patient communication rather than on antibiotic treatment. [gonzales r, bartlett jg, besser re, cooper rj, hickner jm, hoffman jr, sande ma. principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. ann emerg med. june ; : - .] the following principles of appropriate antibiotic use for adults with acute bronchitis apply to immunocompetent adults without complicating comorbid conditions, such as chronic lung or heart disease. . the evaluation of adults with an acute cough illness or a presumptive diagnosis of uncomplicated acute bronchitis should focus on ruling out serious illness, particularly pneumonia. in healthy, nonelderly adults, pneumonia is uncommon in the absence of vital sign abnormalities or asymmetrical lung sounds, and chest radiography is usually not indicated. in patients with cough lasting weeks or longer, chest radiography may be warranted in the absence of other known causes. . routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough. if pertussis infection is suspected (an unusual circumstance), a diagnostic test should be performed and antimicrobial therapy initiated. . patient satisfaction with care for acute bronchitis depends most on physician-patient communication rather than on antibiotic treatment. the term "acute bronchitis" usually designates an acute respiratory tract infection in which cough, with or without phlegm, is a predominant feature. , in the united states, about % of adults self-report an episode of acute bronchitis each year, and up to % of these persons seek medical attention. [ ] [ ] [ ] in , adults in the united states made more than million office visits for bronchitis. as a result, acute bronchitis consistently ranks among the conditions that account for most ambulatory office visits to u.s. physicians. [ ] [ ] [ ] [ ] [ ] [ ] most cases of acute bronchitis occur in otherwise healthy adults, in whom this acute cough illness can be called "uncomplicated acute bronchitis"; these principles are intended to apply to such patients. the evaluation and management of acute cough illness in patients with underlying chronic obstructive pulmonary disease, congestive heart failure, or immunosuppression must be tailored in light of the patient's comorbid condition and is outside the scope of this discussion. the background of, rationale for, and methods used to develop these principles are published separately. p r i n c i p l e s principle . the evaluation of adults with an acute cough, illness, or a presumptive diagnosis of uncomplicated acute bronchitis should focus on ruling out serious illness, particularly pneumonia. college of chest physicians defines acute cough illness, in contrast to chronic or persistent cough, as lasting less than weeks. acute upper respiratory tract infection accounted for approximately % of primary diagnoses in adults presenting for an ambulatory office visit with a chief symptom of cough. asthma and pneumonia were the next most common diagnoses, assigned to % and % of patients, respectively. the predominance of cough and accompanying clinical features suggestive of an acute upper respiratory tract infection, such as sore throat or rhinorrhea, is usually used to distinguish bronchitis from other acute upper respiratory tract infections. as one might expect, clinicians are inconsistent in assigning each diagnosis. for example, some clinicians diagnose acute bronchitis only when productive cough is present; others insist on the presence of purulent sputum. . previously undiagnosed asthma is a consideration in patients presenting with an acute cough illness. however, in the setting of acute cough ( < to weeks' duration), the diagnosis of asthma is difficult to establish because many patients with acute bronchitis will have transient bronchial hyperresponsiveness (and abnormal results on spirometry). no guidelines have been established for distinguishing transient from chronic bronchial hyperresponsiveness, and long-term follow-up studies suggest that abnormalities on pulmonary function testing in patients with uncomplicated acute bronchitis typically resolve after to weeks, although they may last as long as months. [ ] [ ] [ ] the diagnosis of cough-variant asthma, in contrast, is generally reserved for patients with persistent cough ( > to weeks' duration), lack of wheezing, and (usually) normal results on pulmonary function tests. , cough-variant asthma should be suspected in adults with persistent cough that worsens at night or after exposure to cold or exercise; the diagnosis relies on improvement of symptoms with bronchodilator treatment or a positive result on a methacholine challenge test. therefore, in the absence of severe airflow obstruction, it is prudent to limit evaluation for possible chronic asthma or cough-variant asthma to patients with cough illness lasting longer than weeks. when evaluating an otherwise healthy adult with uncomplicated acute cough illness, the primary diagnostic objective should be to exclude the presence of pneumonia. four prospective studies ( to ) examined the accuracy of patient history and physical examination for diagnosing radiographic pneumonia in adults with acute respiratory illness in outpatient and emergency department settings, and a clinical decision tool to determine the need for radiography was developed. - a subsequent validation study done by an independent group of investigators found that the specificity (about %) but not the sensitivity (about %) of these prediction rules for detecting radiographic pneumonia exceeded that of physician judgment (specificity, %). an evidence-and quality-based review of these studies concluded that the absence of abnormalities in vital signs (heart rate ≥ beats/min, respiratory rate ≥ breaths/ min, or oral temperature ≥ °c) and chest examination (focal consolidation-for example, rales, egophony, or fremitus) sufficiently reduces the likelihood of pneumonia to the point where further diagnostic testing is usually not necessary [a]. (letters in square brackets are evidence ratings. see the background document in this issue for explanation.) notably absent from all of the rules is the presence of purulent sputum. many patients and physicians seem to believe that purulent sputum signifies that a bacterial infection is present and antibiotic therapy is indicated. [ ] [ ] [ ] purulence primarily occurs when inflammatory cells or sloughed mucosal epithelial cells are present, and it can result from either viral or bacterial infection. , . specific patient and epidemiologic circumstances should be taken into account before this recommendation is applied. although all of the studies on which this recommendation is based included elderly persons and patients with chronic lung disease, subgroup analyses serology, or polymerase chain reaction. specific viruses most frequently associated with acute bronchitis include those that produce primarily lower respiratory tract disease (influenza b, influenza a, parainfluenza , and respiratory syncytial virus), as well as viruses that more commonly produce upper respiratory tract symptoms (corona virus, adenovirus, and rhinoviruses). unless bacterial superinfection is present (defined as pneumonia with an infiltrate on chest radiography), antibiotic treatment does not affect the clinical course of viral respiratory infections. to date, only bordetella pertussis, mycoplasma pneumoniae, and c. pneumoniae (twar) have been established as nonviral causes of uncomplicated acute bronchitis in adults. as a group, these agents are associated with % to % of all cases of uncomplicated acute bronchitis in adults. they are recovered more frequently ( % to % of cases) in studies of adults with chronic or persistent cough. [ ] [ ] [ ] the diagnoses in these studies are frequently based on serologic conversion, an event that can also occur in asymptomatic persons and may not be related to the clinical illness in question. more recent studies using polymerase chain reaction have reported similar frequencies of recovery of these agents in adults with acute bronchitis. no evidence indicates that streptococcus pneumoniae, haemophilus influenzae, or moraxella catarrhalis produces acute bronchitis in adults without underlying lung disease. studies reporting an association between these encapsulated bacteria and acute bronchitis have failed to distinguish between colonization and acute infection. since gram stain and culture of sputum do not reliably detect m. pneumoniae, c. pneumoniae, or b. pertussis, these tests are not recommended in the evaluation of patients with uncomplicated acute bronchitis. on the basis of the microbiology of acute bronchitis, it should not be surprising that randomized, placebocontrolled trials have failed to support a role for antibiotic treatment of uncomplicated acute bronchitis (table) . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] by the mid- s, published reviews of randomized, placebo-controlled trials , had concluded that routine antibiotic treatment of acute bronchitis does not have a consistent impact on duration or severity of illness or on potential complications, such as development of pneumonia. consistent with these conclusions, the u.s. food and drug administration removed uncomplicated acute bronchitis (or "secondary bacterial infections of acute bronchitis") as an indication for randomized, controlled trials of antimicrobial therapy in . since then, three were not performed; a high index of suspicion for pneumonia therefore remains warranted in these patient groups, given the increased likelihood for atypical disease presentation. , conversely, even when vital sign abnormalities are detected in the absence of chest auscultatory findings, chest radiography may not be indicated in patients with other clinical features consistent with a viral illness (such as influenza, parainfluenza, or respiratory syncytial virus) or features that are inconsistent with pneumonia (such as streptococcal pharyngitis or chronic sinusitis). cough lasting longer than weeks exceeds the case definition for acute bronchitis; such patients should be considered to have persistent cough or chronic cough illness. irwin and colleagues have developed a welldefined approach to the adult with persistent cough [d]. the vast majority of cases ( ≥ %) of uncomplicated acute bronchitis have a nonbacterial cause. we reviewed the medline database ( to october ) by using medical subject headings and keyword searches that included microbiology and bronchitis and analyzed references from review articles and chapters in textbooks on infectious disease to identify studies of the microbiology of acute bronchitis. we excluded studies involving patients with chronic lung disease, malignant conditions, or immunosuppression, as well as those conducted during confirmed outbreaks of a pathogen (for example, a chlamydia pneumoniae outbreak at a single university). we limited our selection to english-language studies of consecutive, unselected adolescents or adults enrolled in nonreferral, ambulatory settings. in the mid- s, it was established that a specific species of c. pneumoniae (twar) could cause uncomplicated acute bronchitis. therefore, estimates of the proportion of cases with a potential bacterial cause are limited to studies published since this discovery. , . as in community-acquired pneumonia, microbiological study of uncomplicated acute bronchitis identifies a pathogen in the minority of cases, ranging from % to %. , [ ] [ ] [ ] [ ] this variability is most likely due to the epidemic nature of agents that produce uncomplicated acute bronchitis and limitations in viral and bacterial identification techniques. noninfectious causes of uncomplicated acute bronchitis, such as occult asthma exacerbation or toxic fume inhalation, should also be considered, although the prevalence of these conditions in adults with acute cough illness has not been well studied. in epidemiologic studies, respiratory viruses, particularly influenza, appear to cause the large majority of cases of uncomplicated acute bronchitis according to culture, antibody ( ) productive cough of any times daily for days group (n = ) vs. . in antibiotic group (n = ) (p < . ); duration proportion of patients with congestion at day , % vs. %; proportion of patients taking cough or cold medicines at day , % vs. % (p < . ); no difference between groups for day cough, night cough, productive cough, sore throat, feeling poor or unable to work or carry out daily routine at day ; no differences among smokers scherl et al, kentucky persons > years of age with doxycycline, mg twice mean (± sd) duration of cough, . ± . days in placebo ( ) self-described cough daily on day , then mg/d group vs. . ± . days in antibiotic group; mean duration producing purulent sputum for days of sputum, to decrease shedding of the pathogen and spread of disease, since antibiotic treatment does not appear to hasten resolution of symptoms if it is initiated to days after onset of illness. [ ] [ ] [ ] because of the public health implications of pertussis, antibiotic treatment of suspected pertussis should always be accompanied by a diagnostic test. diagnostic tests for pertussis are not routinely available; one could inquire at local or state health departments or academic medical centers for further assistance. because influenza is the most common pathogen isolated in patients with uncomplicated acute bronchitis, it is worthwhile discussing recent advances in diagnosis and treatment of influenza. although amantadine and rimantidine have been available for more than years, , the recent development and direct-to-consumer marketing of neuraminidase inhibitor therapy has generated immense public and physician interest in pharmacologic treatment of influenza. a cochrane collaborationsponsored systematic review of neuraminidase inhibitors for the treatment of influenza in healthy adults was recently performed. inhaled (zanamivir) and oral (oseltamivir) formulations of neuraminidase inhibitors have demonstrated some efficacy in reducing illness duration [ ] [ ] [ ] in adults with naturally acquired influenza a and b if treatment begins within hours of symptom onset. the major clinical advantage of neuraminidase inhibitor therapy relates to activity against influenza a and b; amantadine and rimantidine, in contrast, have activity only against influenza a. the relative proportion of cases due to each type of influenza varies substantially from year to year. in the - influenza season, % of influenza cases from surveillance facilities in the united states were due to influenza a. all drugs appear to have a similar impact on influenzal illness: about less day of illness, and about a half-day quicker return to normal activities. on the basis of the cochrane collaboration's calculations, adverse effects are modestly more frequent with rimantadine (in about % of patients; most cases are related to the central nervous system) than oral neuraminidase inhibitor (in about % of patients; most cases are gastrointestinal) or placebo (in about % of patients). neuraminadase inhibitors are likely to be much more costly to health plans and patients than rimantadine, although formularies are likely to vary considerably. for any of these antiviral agents to be effective, influenza must be diagnosed and therapy initiated within hours (preferably < hours) of symptom onset. during documented influenza outbreaks, the positive predictive value of clinical diagnosis based on clinician judgment appears meta-analyses have also been published. [ ] [ ] [ ] these meta-analyses are plagued by lack of uniformity in outcome measures used in each of the randomized, placebocontrolled trials and by inclusion of poor-quality studies. in one of the meta-analyses, no statistically significant benefit of antibiotic treatment was observed when cough duration was treated as a continuous variable. however, when cough was treated as a dichotomous variable (proportion of patients with cough at a follow-up visit), the investigators reported a significant difference (relative risk, . [ % ci, . to . ]). another meta-analysis transformed heterogenous outcome measures to calculate a "standardized effect size" and reported that antibiotic therapy decreases the duration of cough and sputum by . day (over a -day period). the third meta-analysis excluded three trials that were included in the previous meta-analyses on the basis of poor quality or lack of information on loss to follow-up , ; those investigators reported no benefit of antibiotic treatment on cough duration. all three meta-analyses reported no impact of antibiotic treatment on duration of illness, limitation of activity, or loss of work, and all concluded that routine antibiotic treatment of acute bronchitis in adults is not justified. identification of cases of bacterial or mycoplasmaassociated bronchitis might seem to be a reasonable strategy for selecting patients in whom antimicrobial therapy would be beneficial. however, studies to date have been unable to distinguish bacterial bronchitis from viral bronchitis on clinical grounds. furthermore, the single randomized, placebo-controlled trial in which subgroup analysis of patients with probable mycoplasma infection (based on a single rapid serology test) was done did not find a consistent benefit of antibiotic treatment. however, the sample was fairly small ( and patients in the placebo and treatment groups, respectively). . the one uncommon circumstance for which evidence supports antibiotic treatment of patients with uncomplicated acute bronchitis is suspicion of pertussis. selected studies have recovered pertussis in up to % to % of patients with cough lasting longer than to weeks. , unfortunately, no clinical features allow clinicians to distinguish adults with persistent cough due to pertussis, primarily because pertussis in adults with previous immunity does not lead to the classic features of whooping cough seen in patients (usually children) with primary infection. therefore, clinicians should limit suspicion and treatment of adult pertussis to adults with a high probability of exposure to pertussis-for example, during documented outbreaks. antimicrobial therapy for suspected pertussis in adults is recommended primarily to be good and to perform as well as available rapid diagnostic tests for influenza; reported sensitivities of these tests range from % to %. [ ] [ ] [ ] reports from the management of influenza in the southern hemisphere trialists study, which evaluated neuraminidase treatment of community-acquired influenza, suggest that clinical diagnosis or suspicion of influenza is correct approximately % of the time during documented influenza outbreaks. although this study was not adequately designed to evaluate the true sensitivity or specificity of clinical diagnosis, which would have required measuring the rate of influenza infection in patients in whom it was not suspected, the findings probably accurately reflect clinical practice. accurate clinical diagnosis of influenza outside the annual outbreak period is more difficult. as a result, diagnostic testing for influenza outside outbreaks, when suspected, may be considered for epidemiologic purposes. what symptomatic therapy should we offer patients seeking care for uncomplicated acute bronchitis? the first task is to identify which symptoms are most bothersome to the patient. in most cases, cough is the major symptom for which patients seek relief. randomized, controlled trials have demonstrated a consistent benefit of therapy with albuterol versus placebo for uncomplicated acute bronchitis in reducing the duration and severity of cough (in one study, the "placebo" was erythromycin). [ ] [ ] [ ] approximately % fewer patients report the presence of cough after days of treatment. the efficacy of bronchodilators in patients with uncomplicated acute bronchitis makes sense given the frequent finding of bronchial hyperresponsiveness in these patients. the randomized, placebo-controlled trials of albuterol have reported mixed results in identification of subsets of patients most likely to benefit from treatment; therefore, treatment should be individualized in patients without clinical evidence of bronchial hyperresponsiveness (such as wheezing or bothersome cough). . the literature evaluating the efficacy of antitussive treatments is problematic because treatment benefit appears to depend on the cause of the cough illness. acute or early cough due to colds or other viral upper respiratory tract infections does not appear to respond to dextromethorphan or codeine, whereas chronic cough (duration > weeks), cough associated with underlying lung disease, or experimentally induced cough seems to respond to these two agents. in patients with uncomplicated acute bronchitis (in whom the average duration of cough is to weeks), preparations containing dex-tromethorphan or codeine probably have a modest effect on severity and duration of cough. although evidence from randomized, placebo-controlled trials is lacking, other low-cost and low-risk actions, such as elimination of environmental cough triggers (for example, dust and dander) and vaporized air treatments (particularly in low-humidity environments, such as high altitude) are also reasonable options, given the underlying pathophysiology of uncomplicated acute bronchitis. principle . patient satisfaction with care for acute bronchitis depends most on physician-patient communication rather than whether an antibiotic is prescribed [b] . . clinicians caring for patients with uncomplicated acute bronchitis should be encouraged to discuss the lack of benefit of antibiotic treatment for uncomplicated acute bronchitis and stop prescribing antibiotics for this condition as a standard of practice. patients frequently expect to receive antibiotics for uncomplicated acute bronchitis , ; however, this expectation appears to derive from previous receipt of antibiotics for uncomplicated acute bronchitis. mounting evidence indicates that patient satisfaction with the office encounter for uncomplicated acute bronchitis does not depend on receipt of antibiotic therapy but instead is related to the patient-centered quality of the encounter (for example, believing that the provider spent enough time and explained the illness and treatment plan). a combined patient and physician educational intervention that reduced antibiotic use for acute bronchitis did not lead to greater utilization of services (such as nonantibiotic prescriptions or return visits), greater patient dissatisfaction, or longer duration of illness. a recommended outline for discussing the management of acute bronchitis with patients includes the following steps. . provide realistic expectations for the duration of the patient' s cough, which will typically last to days after the office visit. . refer to the cough illness as a "chest cold" rather than bronchitis. in a study of members of a commercial managed care organization' s health plan, use of the term "chest cold" was associated with much less frequent belief that antibiotic therapy was necessary to get better. . personalize the risk of unnecessary antibiotic use. inform patients that previous antibiotic use increases their likelihood of carriage of and infection with antibioticresistant bacteria, that antibiotics commonly have side effects (gastrointestinal symptoms or alterations in taste, for example), and that rare but serious adverse reactions may occur, such as anaphylaxis. . explain to patients why we need to be more selective in treating only those conditions for which a major clinical benefit of antibiotics has been proven-tell them that the current 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impact of a multidimensional intervention on the treatment of uncomplicated acute bronchitis in adults reducing antibiotic use in ambulatory practice: impact on patient-centered outcomes key: cord- -bc hr fr authors: sirpilla, olivia; bauss, jacob; gupta, ruchir; underwood, adam; qutob, dinah; freeland, tom; bupp, caleb; carcillo, joseph; hartog, nicholas; rajasekaran, surender; prokop, jeremy w. title: sars-cov- -encoded proteome and human genetics: from interaction-based to ribosomal biology impact on disease and risk processes date: - - journal: j proteome res doi: . /acs.jproteome. c sha: doc_id: cord_uid: bc hr fr [image: see text] sars-cov- (covid- ) has infected millions of people worldwide, with lethality in hundreds of thousands. the rapid publication of information, both regarding the clinical course and the viral biology, has yielded incredible knowledge of the virus. in this review, we address the insights gained for the sars-cov- proteome, which we have integrated into the viral integrated structural evolution dynamic database, a publicly available resource. integrating evolutionary, structural, and interaction data with human proteins, we present how the sars-cov- proteome interacts with human disorders and risk factors ranging from cytokine storm, hyperferritinemic septic, coagulopathic, cardiac, immune, and rare disease-based genetics. the most noteworthy human genetic potential of sars-cov- is that of the nucleocapsid protein, where it is known to contribute to the inhibition of the biological process known as nonsense-mediated decay. this inhibition has the potential to not only regulate about % of all biological transcripts through altered ribosomal biology but also associate with viral-induced genetics, where suppressed human variants are activated to drive dominant, negative outcomes within cells. as we understand more of the dynamic and complex biological pathways that the proteome of sars-cov- utilizes for entry into cells, for replication, and for release from human cells, we can understand more risk factors for severe/lethal outcomes in patients and novel pharmaceutical interventions that may mitigate future pandemics. the sars-cov- (covid- ) pandemic has impacted every component of life, including research and medicine. in just a few months from the onset of infections to writing of this review, papers/objects have been published on sars-cov- ( figure ). this body of literature primarily focuses on infectious diseases, the respiratory system, public environmental occupational health, biochemistry molecular biology, virology, immunology, pharmacology, microbiology, and healthcare science services, to name a few fields ( figure a ). title extraction of these papers reveals mainly clinically connected terms ( figure b) . the extensive infectious disease and clinical base of this literature has yielded knowledge of viral entry, replication, immune response, and transmission. however, in a short window of time, biochemical and molecular biology insights into sars-cov- have yielded a smaller body of literature that continues to grow ( out of the items), taking more time for data generation than clinical descriptions. of these biochemistry/molecular biology items, are primary articles ( figure c ). title and abstract word extraction from these biochemistry/molecular biology items, followed by counting mentions of all human ( ) or sars-cov- proteins, shows a heavy focus on ace and spike (s) proteins ( figure d ). the virus primarily enters cells through the interaction of the sars-cov- surface glycoprotein, spike (s), interacting with the human encoded ace , similar to that of the sars virus. , from the abstract/title terms, we identified / usages of ace and / of spike. other human proteins with repeated mentions include tmprss ( titles/ abstract), ace ( / ), furin ( / ), dpp ( / ), and c ( / ). additional sars-cov- proteins with mentions include nsp (rna-directed rna polymerase, / ), nucleocapsid (n, / ), membrane (m, / ), envelope (e, / ), nsp ( clpro/mpro, / ), nsp ( / ), nsp ( ′-o-methyltransferase, / ), orf ( / ), nsp ( / ), nsp (guanine-n methyltransferase, / ), nsp (papain-like protease, / ), and nsp (uridylate-specific endoribonuclease, / ). only nsp and nsp for sars-cov- have no mentions within any of these titles or abstracts for biochemical linked papers on sars-cov- . overall this suggests a few papers specifically related to sars-cov- proteins have been published; however, a large body of literature exists for the original sars and other coronaviruses that can give interpretation of the diverse functions performed by the viral-coded proteins and how they interact with human biology. the advancement of knowledge of the sars-cov- proteome has been slower than clinical insights due to the need for experimental work that is slow and that is being hampered by social isolation. the base-pair single-stranded rna genome of sars-cov- (ncbi nc_ . ) has a base-pair ′ utr, multiple protein-coding segments, and a base-pair ′ utr. sars-cov- has a % genomic similarity with sars-cov, a known human pathogen, with both known to enter cells through the binding of human ace . , in addition to sars-cov and sars-cov- , five other coronaviruses are capable of human-to-human transmission and infection (hku , nl , oc , e, and mers-cov). hundreds of coronaviridae family member genomes have been sequenced in human and other vertebrate hosts, , and many structures have been solved for coronaviridae species proteins, allowing for systematic assessments of the knowledge base. our group implemented a sequence-to-structure-to-function analysis , to understand sars-cov- proteins, developing a robust understanding of protein conservation, structure, and molecular dynamics. the data generated for each protein was then developed into the viral integrated structural evolution dynamic database (vistedd), a publicly released database of multiple tools for the virus. the database can be accessed at https://prokoplab.com/vistedd/. these tools consist of educational resources for the proteins coded by sars-cov- (molecular videos, d protein model prints, amino acid details of conservation, and dynamics), the mapping of critical sites to each protein, and the insights into how sars-cov- interacts with human proteins. generating this database has given our team a diverse understanding of sars-cov- , particularly for host protein interactions of each of the viral proteins. multiple studies have begun building systemic insights for sars-cov- infections. multiple groups have performed systematic data assessment of ace expression and protein staining, suggesting the physiological cell types that can be targeted by the virus. they have shown expression in many tissues throughout humans, with expression within the lung found on the apical surface of polarized bronchial secretory epithelia cells. − once the virus enters the cells, it results in the alteration of broad biological pathways, including translation, splicing, protein homeostasis, and nucleic acid metabolism. epithelial organoid cultures exposed to the virus produce a robust change in rna expression patterns for cytokine and interferon intracellular immune responses that give rise to tissue signals. single cell profiling within the lungs of patients shows the intracellular cytokine/interferon response results in the recruitment of macrophages in severe cases and t-cells in moderate cases, with a high potential for therapeutic intervention. , over activation of the cytokine/interferon response is connected to poor outcomes within patients, correlating with macrophage activation syndrome. additional adverse outcomes for the activation of apoptosis within lymphocytes have been observed and may contribute to the noted lymphopenia. proteomics and metabolomics of patient sera show the same macrophage dysfunction, while also elucidating platelet and complement dysregulation with the identification of severity classifiers. − in totality, the physiological response to the virus is likely mediated by a combination of immune system activation and the direct human interaction partners, altering cellular processes. an understanding of these detailed biological interactions can shed light on potential therapeutic opportunities while building a fundamental knowledge of viral biology. to date, few studies have been performed that systematically look at mapping how the sars or coronavirus proteins physically interact with human proteins. structural level insights for coronavirus proteins are surprisingly deficient of human interaction partners. a few of these proteins have been targeted for interaction assessments, such as the nucleocapsid protein , (shown below). it has been speculated that the understanding of virus−host interactions represents a major untapped potential of viral inhibitors. a review highlights the literature of viral−host interactions for coronaviruses, focused on synergizing the knowledge of independent experiments for virus receptors, translation, membrane dynamics, immune regulation, cell cycle control, and replication. the more recent work by gordon et al. covering the systematic affinity purification of different sars-cov- proteins within human cells has elucidated many mechanisms and drug compounds for the regulation of viral processes. bringing this data together with our vistedd tools, we provide a current snapshot of sars-cov- viral proteins ( figure ). orf ab is a large protein that is proteolytically cleaved to produce different proteins, many involved in rna replication. the nmr structure of gdt has been solved, and sequences have been identified by basic local alignment search tool (blast). nsp interacts with proteins of the alpha dna polymerase ( figure ) and is involved in regulating endonucleolytic rna cleavage of mrna, allowing the virus to enrich viral rna within a cell. , nsp has been shown to interact with ribosomal subunits, resulting in the inhibition of translation, ′ mrna capping changes, and mrna destabilization. − from a sars-cov yeast two hybrid screen, nsp was identified to interact with immunophilins, showing that it alters the intracellular immune response. expression of nsp drives changes in interferon signaling. these processes make nsp a potential virulence factor. − see prokoplab.com/ nsp for additional information. the protein has no solved protein structure, with itassergenerated predictions that are mostly ( %) coiled, and sequences have been identified by blast. all of the protein interaction partners are acetylated ( figure ). the protein has been suggested to be dispensable to viral replication but does impact rates of replication. see prokoplab.com/nsp for additional information. the protein has hundreds of solved x-ray crystal structures with a c zinc finger, and sequences have been identified by blast. the papain-like proteinase cleaves the first four nsp proteins, where inhibition can block viral replication. the proteinase can cleave proteins and has been shown to have deubiquitinase activity. − this deubiquitinase function has been linked to the regulation of immune system cytokine response, , specifically the type-i interferon signaling pathway, and has connection to virulence. see prokoplab. com/papain_like_proteinase for additional information. the protein has no solved protein structure, with itassergenerated predictions that are mostly ( %) coiled, and sequences have been identified by blast. nsp interacts with several proteins involved in mitochondrial import for inner membrane insertion (figure ). nsp and nsp interact and form within the membrane and are involved in transcription complex assembly anchoring. , the complex is involved in the double membrane secretory vesicle formation , in the endoplasmic reticulum, conferring with human protein interaction partners. see prokoplab.com/nsp for additional information. nsp has hundreds of solved x-ray crystal structures, with the protein found in a dimer form with a cysteine protease function, , and sequences have been identified by blast. the enzyme cleaves most of the proteins of the larger rep protein with a highly conserved specificity, where inhibition is one of the most studied interventions. − see prokoplab.com/ c-like_proteinase for additional information. the protein has no solved protein structure, with itassergenerated predictions that are mostly ( %) coiled, and sequences have been identified by blast. nsp interacts with multiple proteins involved in atp hydrolysis-coupled cation transmembrane transport ( figure ). the protein is likely transmembrane-localized, along with nsp /nsp , and is involved in autophagosome formations. − the few papers discussing nsp suggest a major future area of understanding and pharmaceutical intervention potential. see prokoplab. com/nsp for additional information. there are several solved structures for nsp that interact with nsp /nsp ( nur, ahm, and ub ), − and sequences have been identified by blast. the nsp protein interacts with multiple small gtpases of the ras complex, many of which are prenylation-regulated ( figure ). the nsp /nsp /nsp complex is a viral rna-directed rna polymerase unit, where nsp is enhanced through the binding of nsp /nsp . see prokoplab.com/nsp for additional information. there are several solved structures for nsp that interact with nsp /nsp ( nur and ub ), − and sequences have been identified by blast. the nsp protein interacts with proteins involved in translation, snrna ′-end processing, s rna binding, and ribonucleoproteins ( figure ). in addition to the information provided for nsp , nsp has been suggested to also interact with the orf protein. see prokoplab.com/nsp for additional information. nsp has many known protein structures, with the protein requiring dimerization to function, and sequences have been identified by blast. nsp interacts with multiple proteins of structural constituents of the nuclear pore ( figure ). nsp and nsp interact with the nuclear factor-κb repressing factor (nkrf) and may cause an interleukin (il)- /il- -mediated chemotaxis of neutrophils and an overexuberant host inflammatory response. nsp is involved in viral rna synthesis and rna binding, which likely evolved from a protease. , see prokoplab.com/nsp for additional information. nsp has many known protein structures, including those interacting with nsp and nsp , and contains two zinc binding motifs; sequences have been identified by blast. nsp stimulates nsp ′− ′ exoribonuclease/ mismatch excision , and nsp ′-o-methyltransferase activities. , the interface of interaction with nsp and nsp overlaps, suggesting a dynamic regulation process that may involve the linkage of functions through a spherical dodecameric structure. a peptide-based inhibition of the nsp interaction has been proposed as a potential viral regulator. see prokoplab.com/nsp for additional information. nsp is a little-known small . kda peptide with few interaction partners. nsp has multiple known protein structures with a zinc active site and a structure that interacts with nsp /nsp , − and sequences have been identified by blast. nsp is involved in the replication of plus-strand rna through complement strand synthesis and then viral rna synthesis. the enzyme is highly targeted for therapeutic inhibition of viruses. it is also known as rdrp and is the target of the drug remdesivir. see prokoplab.com/rna-directed_rna_polymerase for additional information. nsp has multiple known protein structures with a zinc active site, and sequences have been identified by blast. nsp interacts with multiple proteins involved in the centrosome−golgi apparatus and centrosome ( figure ) and has a rna and a dna duplex-unwinding ability to separate strands with ′ to ′ polarity. − see prokoplab.com/helicase for additional information. nsp has multiple known protein structures with a zinc active site, and sequences have been identified by blast. nsp has an s-adenosyl-l-methionine (sam)-binding pocket and an exoribonuclease function that is involved in rna capping, − and it interacts with nsp and is known to interact with the human ddx rna helicase to enhance the virus replication. see prokoplab.com/guanine-n _ methyltransferase for additional information. nsp has multiple known protein structures, and sequences have been identified by blast. nsp is a mn +dependent toric monomer to the hexamer enzyme involved in uridylate-specific cleavage , that may be regulated by nsp / nsp , and it interacts with the retinoblastoma protein to impact the cell cycle and is also known as nendou. see prokoplab.com/uridylate-specific_endoribonuclease for additional information. nsp has multiple known protein structures with na, mg, and s-adenosyl-l-methionine (sam), and sequences have been identified by blast. nsp is an sam-based enzyme for the methylation of ribose ′-oh in viral rna capping , and interacts with nsp . the protein is a critical component in the inhibition of the host type-i interferon response and is also known as ′-o-mtase. see prokoplab.com/ -omethyltransferase for additional information. the spike surface glycoprotein has multiple known protein structures that are heavily glycosylated and form a trimer complex , and is a known structure of the interaction with the dimer of heterodimers ace /slc a ( m ); sequences have been identified by blast. s is a class-i viral fusion protein and drives the specificity of cell targets through the interaction with ace to enter human cells. , following binding to the receptor, s undergoes a conformational change to allow viral entry. for the protein to function correctly, it must be proteolytically cleaved by trypsin and, upon cell-binding proteases such as tmprss , elevate entry through the mediating tropism. s is of interest to the development of immunizations and rapid detection of coronaviruses, as its surface is exposed. , see prokoplab. com/spike for additional information. orf a has no solved protein structure, with itassergenerated predictions, and sequences have been identified by blast. orf a is a three transmembrane helix protein where the extracellular component localizes the protein to the golgi apparatus with a caveolin- binding potential and is involved in the formation of viral particles. , orf a has been shown to impact the cell cycle. see prokoplab.com/ a for additional information. the envelope protein (e) has no solved protein structure, with itasser-generated predictions, and sequences have been identified by blast. e is required for viral particle formation with transmembrane helix-forming pentameric αhelical bundles with channel activity that can contribute to the membrane permeability. see prokoplab.com/e for additional information. the membrane protein (m) has no solved protein structure, with itasser-generated predictions, and sequences have been identified by blast. m has human interaction partners that are involved in the mitochondrial matrix ( figure ) and is a critical component of viral membranes that are involved in viral budding. see prokoplab.com/m for additional information. orf has no solved protein structure, with itassergenerated predictions, and sequences have been identified by blast. two of the interaction partners are involved in the transcription-dependent tethering of rna polymerase ( figure ). orf can function toward the inhibition of beta interferons through the regulation of the signal transducer and activator of transcription (stat ) and endoplasmic reticulum (er) stress and can interact with nsp . see prokoplab.com/orf for additional information. orf a has multiple known protein structures, and sequences have been identified by blast. orf a has protein interaction partners involved in ribosomal large subunit biogenesis ( figure ) and localizes to the er and golgi network. it can regulate the cell cycle in g /g progression. see prokoplab.com/ a for additional information. orf has no solved protein structure, with itassergenerated predictions, and sequences have been identified by blast. orf has multiple interaction partners involved in the er lumen (figure ) and is a protein shared with sarsr-batcov, with a high positive selection. see prokoplab.com/ orf for additional information. the nucleocapsid protein (n) has multiple known protein structures, and sequences have been identified by blast. n has protein interaction partners involved in mrna binding, the ribonucleoprotein complex, and the mrna surveillance pathway (figure ) and is critical for the viral replication in multiple processes, including viral rna stability, replication, and packaging. the protein is modified within the cell, including phosphorylation and adpribosylation. , the protein consists of three domains, with the n-terminal domain involved in rna binding, the internal dynamic multimer structured unit, and the c-terminal domain, an acidic dimerization region. − the protein can interact with rna by serving as a rna chaperone while also interacting with the m protein and human hnrnpa through the internal multimerization domain. , see prokoplab.com/n for additional information. orf has no solved protein structure, with itassergenerated predictions, and is unique to sars-cov- . very little is known of its molecular function or cellular expression. see prokoplab.com/orf for additional information. ■ sars-cov- risk factors and genetics based on human protein interactions sars-cov- infection exhibits more adverse effects and outcomes in those with other comorbidities, including hypertension, diabetes mellitus, and coronary heart disease. the other risk factors for mortality include older age, elevated d-dimer levels, and a higher sequential organ failure assessment (sofa) score. the mortality associated with sars-cov- infection is tied to the patient's progression to multiorgan dysfunction. the elderly are particularly susceptible to severe sars-cov- infection, which is most likely due to the immunosuppression and underlying comorbidities associated with advanced age. advanced age has been shown to have a depressive effect on both the innate and the adaptive immune system, known as immunosenescence. this is associated with decreased phagocytosis and the bactericidal effects of neutrophils and is also associated with the downregulation of cytokine signaling , and innate immune receptors. with sars-cov- infection, emphasis is placed on the adaptive immune system to aid in clearing virally infected cells. the elderly population has been shown to have a shift toward inhibitory pathways, particularly in cd + t cells and to a lesser degree in cd + t cells, which may play a role in allowing disseminated viral spread. this reduction of t cell activity is also joined by the involution of the thymus with age, leading to less naive t cell output, which further depresses immune functions. these accumulative effects on the immune system render the elderly population particularly susceptible to dispersed viral infection at baseline levels, which may ultimately result in viral sepsis. with the immunosenescence and increased prevalence of comorbidities associated with older age, it makes sense that this population is being hit the hardest by sars-cov- ; however, many younger adults who lack the above immunosenescence have also been killed from the infection, some of whom displayed no prior medical history. this aspect points to the idea that genetics may play a role in determining the severity of sars-cov- infection. the immune response to sars-cov- infection in severe cases characteristically induces lymphopenia, particularly of cd- + t cells, and increases il- , il- , il- , and interferon (ifn)-γ levels. this work is backed by multiple proteomic studies identifying biomarkers of severity that connect to the immune system. , the cytokine storm induced by sars-cov- is not a new phenomenon and has been demonstrated in the pathogenesis of other novel human coronaviruses, including mers and sars-cov- . similar consequences in severe coronavirus infections appear to stem from the cytokine storm of proinflammatory chemokines and cytokines, eventually resulting in acute respiratory distress syndrome (ards) and multiorgan dysfunction. a previous study on sepsis and cytokine storm indicates the presence of genetic variants in multiple pathways that have a polygenetic contribution. in many patients with sars-cov- that have severe infection, the identification of hyperferritinemic sepsis often occurs. fever developed at day , sepsis developed at day , admission to the intensive care unit occurred at day (for acute respiratory distress syndrome), and death occurred at day . critically ill patients, defined as those with septic shock, multiple organ dysfunction/failure, and/or respiratory failure, accounted for approximately % of the study population, yet the study population displayed a case fatality rate of . % in early reports from wuhan, china. hyperferritinemia on day and day predicts mortality long before the development of sepsis and intensive care unit admission. hyperferritinemia has been suggested to have genetic associations through pathogenic variants in genes targetable by il rap and anti-c antibodies. type- interferonopathies, like heterozygous null variants in irf , have been shown to result in severe manifestations of seasonal influenza virus. similar monogenetic variants likely exist that lead to the individual risk of severe disease onset from sars-cov- in previously healthy patients. much of the genetics around the immune activation leading to a cytokine storm and hyperferritinemic sepsis remains poorly defined and requires future initiatives and cohorts to define these genetic contributions adequately. initial sars-cov- infection is commonly associated with fever, cough, malaise, and fatigue. in more severe cases, disseminated intravascular coagulation has been noted with elevated d-dimer levels in the serum of severe covid- patients, placing them into thromboembolic risk. recent recommendations have been made to utilize thromboprophylaxis or full-anticoagulation therapy for patients in the thromboembolic risk category. a specific protein−protein interaction was discovered between sars-cov- 's orf and the tissue plasminogen activator (tpa) protein of hosts. the tpa, which is encoded by the plat gene, plays a crucial role in thrombolysis by catalyzing the conversion of plasminogen to plasmin, the major enzyme involved in lysis of blood clots. increased the activity of tpa can lead to excessive bleeding, whereas decreased activity is associated with thromboembolus formation, increasing the chances of pulmonary embolism, stroke, and myocardial infarction. the extent to which orf interacts with tpa is not well understood, but its involvement may render a patient at risk for thromboembolism, as has been seen in the clinical setting. in a study by ladenvall et al., it was found that the discovered eight single nucleotide polymorphisms and the alu insertion polymorphism at the plat locus were not significant contributors to plasma tpa levels. this finding indicates that inherited variants of the plat gene may not be directly involved with the coagulopathy in sars-cov- patients; however, the polymorphisms may render the host's tpa protein to a tighter binding by orf , yielding greater repression during infection, placing the patient at higher risk for thromboembolism. it has also been shown that sepsis involves upregulation of platelet adhesion molecules and increased circulation of platelet−leukocyte aggregates. this may point toward more of an immune-system-catalyzed coagulopathy, resulting in the presentation of strokes, pulmonary embolisms, myocardial infarctions, and microvascular injury, which impact severe sars-cov- patients. as coagulopathy has mainly been investigated in both viral and bacterial sepsis, there may be a dual effect of both the immune-mediated response and the protein−protein interaction of orf with the host tpa in cases of sars-cov- infection. further investigation is warranted to determine the extent of the interaction of orf with the host tpa to determine if it plays into the pathogenesis of sars-cov- -related coagulopathy. sars-cov- has been associated with cardiac dysfunction, including myocardial infarction and heart failure. the underlying mechanisms for cardiac injury currently being hypothesized are indirect cardiac injury from the cytokine storm and inflammatory response, severe hypoxia as a result of ards, and direct viral invasion of cardiomyocytes. interestingly, ace , the host receptor for sars-cov- , is expressed in the heart, indicating direct viral invasion could be a potential cause of myocardial dysfunction. sars-cov- 's nonstructural protein (nsp ) was found to interact with the e -ubiquitin ligase mindbomb homologue (mib ). this ubiquitin ligase is a positive regulator of the delta-mediated notch signaling pathway, which is involved in multiple processes during cardiac development. mutations in the mib have been associated with left ventricular noncompaction (lvnc) characterized by left ventricular trabeculations and reductions in cardiac systolic function. lvnc can range from being asymptomatic to presenting heart failure, depending on the extent the mutation has on the notch pathway. the prevalence of lvnc in the general population is estimated to be around / to / . patients with the asymptomatic form of lvnc may be at higher risk for exacerbation of cardiac dysfunction following sars-cov- due to involvement of this pathway, especially if they are unaware that they have this mutation. this may play a role in the cardiac dysfunction seen in younger sars-cov- patients who lack underlying comorbidities. aside from cardiac development, the notch pathway has also been implemented in cardiac repair, which was demonstrated in rat models where the notch and notch pathways were upregulated, thereby reducing postmyocardial infarctions in the setting of heart failure. the mechanism behind the repair process is still under investigation; however, the disruption of the notch signaling pathway by the interaction of nsp with mib may prove to play a role in the cardiac involvement of sars-cov- infection. furthermore, although vertical transmission of sars-cov- has not been seen, neonates who have tested positive for the infection may need to have their cardiac function assessed over time due to mib 's role in cardiogenesis and repair. while we present a detailed assessment of two interaction partners' connections to pathology and risk factors, many more likely exist. we postulate that if function of any protein diverges from normal biology to contribute to sars-cov- biology, it could result in a similar disease state within the cell as a loss of function or deleterious genetic mutation. thus, to journal of proteome research pubs.acs.org/jpr reviews understand the sars-cov- -connected diseases through the human protein interactions, we assessed clinvar, a database of clinically identified variants. a query of the sars-cov- human interaction partners through clinvar reveals protein-based variants within the list ( figure a ). in total, of the queried genes have a clinvar submission. of these clinvar-connected genes, there are a total of that have a clinical annotation of pathogenic (pathogenic or likely pathogenic), with a total of different variants ( figure b ). the gene with the most pathogenic variants is fbn , which is known to interact with sars-cov- nsp and is involved in autosomal dominant familial thoracic aortic aneurysms and aortic dissections and marfan syndrome. a further analysis of clinical disorders connected with those genes with or more pathogenic-associated variants, excluding fbn (pkp , acadm, ppt , wfs , col a , pcnt, fbn , bcs l, ngly , cyb r , acad , neu , gnb , nars , tcf , npc , pigo, cdk rap , cenpf, ggcx, fkbp , tbk , fbln , exosc , por, gpaa , and rhoa), reveals a high connection to cardiac, neurological, diabetic, and syndromic biology. the sars-cov- orf has the most genes connected by interactions to pathogenic clinvar returns from queried genes, followed by protein m, nsp , nsp , and orf c ( figure c ). orf is connected to genes associated to human genetic diseases (col a , ngly , neu , npc , fkbp , dnmt , plod , smoc , il ra, adam , sil , lox, pofut , tor a, hyou , edem , emc , and hs st ), with significant enrichment of these genes to protein folding (false discovery rate (fdr) = . ) and endoplasmic reticulum lumen (fdr = . × − ). while only associated with pathogenic interaction partners, the nucleocapsid (n) protein has interesting disease genetics based on previous observations of a process known as viral-induced genetics. the nucleocapsid (n) protein has the potential to impact and change cellular landscapes through the direct regulation of ribosomal biology. the protein−protein interaction map by gordon et al. supports the hypothesis that sars-cov- n proteins interact with multiple mrna-binding proteins and ribonucleoprotein complex proteins ( figure ). in multiple viruses, proteins have been shown to interact with these complexes to regulate a process known as nonsense-mediated decay (nmd). nmd is a cellular process involved in the removal of mrna that does not conform to the bulk of cellular mrna, where proteins accumulate on the transcript and direct the cellular degradation of the mrna. the process is primarily used within cells to degrade mrna molecules with nonsense and frameshift genetic variants and those with improper splicing to prevent the cell from producing truncated proteins that can drive dominant-negative or deleterious gain of function outcomes. viral rna is usually suppressed and degraded within cells through nmd, acting as a cellular immune system process. − thus, an evolutionary arms race has arisen where a virus can propagate more efficiently if it has a protein that can suppress nmd, keeping its rna levels elevated. − multiple lines of evidence for both sars-cov- and sars-cov suggested that the n protein is used to suppress nmd and evade cellular immune processes. nearly all of the coronaviruses and the larger nidovirales order genomes contain the n protein, which has been shown to interact with multiple ribosomal proteins, including crucial nmd factors. directly inhibited by nmd, with the n protein expression blocking this inhibition. positive-sense single-stranded rna viruses, including coronaviruses, are likely targets of nmd due to their many overlapping reading frames, retained introns, and long ′ utrs present within the cytoplasm of human cells. the n protein interacts with three proteins annotated to the mrna surveillance pathway (upf , pabpc , and pabpc ) and several proteins involved in mrna binding and the ribonucleoprotein complex that are all known to have cellular interactions (figure ). while the fine details of the n protein interaction on the factors are poorly understood, the three mrna surveillance genes are well-connected to nmd biology. pabpc is known to be critical for nmd, with its removal suppressing nmd. , from plants to humans, upf is considered a key regulator of nmd through its recruitment of multiple proteins to rna. − the regulation switch of upf is known to be regulated/activated through phosphorylation at various sites to allow its protein interactions, − while the n protein has been shown in multiple viral species to be phosphorylated − and likely dynamic in modifications throughout the rna replication and viral lifecycle. , these phosphorylation switches and the interaction of n to nmd proteins are potential sites of pharmaceutical or biological regulation that have been undervalued to this point. other notable interactions of the n protein are ras gtpaseactivating protein-binding protein homologues (g bp / ) and casein kinase alpha (csnk a ), suggesting the regulation of stress granule formation. nmd is found at the intersection of a variety of cellular pathways beyond mrna surveillance and viral control. notably, it is closely associated with the integrated stress response requiring translation initiation factor eif s for function. cellular stresses such as hypoxia and er stress lead to the inhibition of nmd via phosphorylation of eif s . this phosphorylation typically induces stress granule formation as well, which has been cited to aid viral replication in some cases and weaken them in others. when g bp is depleted within cells, there is a significant impairment of the replication for coronaviruses and respiratory syncytial viruses (rsvs). , multiple viruses have been shown to regulate phosphorylation of eif s at varying time points of infection with connection into nmd regulation. stress granule formation can enhance nmd inhibition, such as hypoxic conditions modulating upf and eif s . , the interaction of sars-cov- n protein human interactors promotes the inhibition of nmd and enhancement of both viral replication and truncated host polypeptides that can enhance viral pathogenicity (figure ) . the regulation of nmd by viral proteins is crucial for allowing the viral rna to survive, but nmd processes within cells also regulate multiple endogenous transcripts, several in normal biology, and some based on genetic disease regulation. many genes, including isoforms with early truncation (frameshifts and nonsense codons) and genes involved in amino acid homeostasis, tumorigenesis, and cell cycle control, are activated when nmd is inhibited within a cell. − in total, this amounts to about % of transcripts within a cell that are regulated by nmd processes and could be altered within the cell by sars-cov- . on top of this, most individuals contain at least one gene where a nonsense or frameshift variant within the genome is being suppressed, being either inherited or somatic. assessments of human genomes reveal that every person has at least one variant regulated by nmd. recently, our group has shown a complex involvement of this regulation with rare human variants, driving adverse outcomes through a process we have termed viral-induced genetics (vig). in a patient with an epstein−barr virus (ebv) infection, they had an adverse immune response of classical hyperferritinemic sepsis like that of severe sars-cov- patients. this individual has both whole-exome sequencing in addition to multiple bloodbased rnaseq experiments performed throughout their clinical course. sequencing revealed a heterozygous splicing variant in the gene rnaseh b, which is associated with recessive aicardi−goutieres syndrome and has been connected to type-i ifn-mediated autoimmune disease. , rnaseq of the patient, when healthy, showed that the splicing variant was present at very low levels, suggesting that the copy was being inhibited through nmd. while the patient was healthy for years of life, the ebv was shown by rnaseq to inhibit nmd, resulting in the presence of the splice variant, which resulted in a dominant-negative rnaseh b protein that drove cell dysfunction. this suggests that many human variants within genes connected to the immune system and viral response, which are usually suppressed by nmd and result in no cellular dysfunction, are activated by the virus through the inhibition of nmd and can give rise to severe viral outcomes. just like in a computer virus, the antivirus of the computer is often targeted. when additional computer code contains a risk to system failure that is inhibited by the antivirus, if the antivirus is shut down, the other system vulnerabilities become present and often contribute to the computer failure. the full extent of these variants and the disease process remain to be elucidated but is a promising avenue for exploration of viral-induced outcomes in sars-cov- . the sars-cov- pandemic represents a unique challenge to scientists. unlike previous pandemics, our knowledge of the genome and its coded proteins was gleaned within weeks of the outbreak, now with thousands of sequences within a short window. this level of insight has allowed for a pivot to a more robust insight into the viral proteome and how it interacts with host proteins. the advancement of protein-based bioinformatics and previous coronavirus research studies have proved useful in defining the function of each protein coded by the virus. here, we show how many of these viral proteins interact with human proteins connected to biological pathways and disease connections, including numerous risk factors from immune to cardiovascular systems. most notably, we highlight literature on the role of the viral nucleocapsid (n) protein in nmd regulation, where the inhibition of nmd allows for viral rna stability while simultaneously activating genetics of cellular processes and viral-induced genetics. while we have seen thousands of publications on sars-cov- and other coronaviruses, the details of a proteome-wide knowledge base of sars-cov- -coded proteins limit our ability to expand into the incredible potential of preventing and mitigating the current pandemic and future pandemics with a larger therapeutic toolset. characterization of coding/noncoding variants for shroom in patients with ckd molecular modeling in the age of clinical genomics, the enterprise of the next generation sars-cov- (covid- ) structural and evolutionary dynamicome: insights into functional evolution and human genomics expression of the sars-cov- cell receptor gene ace in a wide variety of human tissues ace receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia receptor ace and tmprss are primarily expressed in bronchial transient secretory cells hca lung biological network. sars-cov- entry factors are highly expressed in nasal epithelial cells together with innate immune genes proteomics of sars-cov- -infected host cells reveals therapy targets single-cell landscape of bronchoalveolar immune cells in patients with covid- eils, r. covid- severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis imbalanced host response to sars-cov- drives development of covid- transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in covid- patients proteomic and metabolomic characterization of covid- proteomic fingerprints for potential application to early diagnosis of severe acute respiratory syndrome the sars coronavirus nucleocapsid protein-forms and functions nucleocapsid phosphorylation and rna helicase ddx recruitment enables coronavirus transition from discontinuous to continuous transcription virus-host interactomes-antiviral drug discovery host factors in coronavirus replication novel beta-barrel fold in the nuclear magnetic resonance structure of the replicase nonstructural protein from the severe acute respiratory syndrome coronavirus sars coronavirus nsp protein induces template-dependent endonucleolytic cleavage of mrnas: viral mrnas are resistant to nsp -induced rna cleavage suppression of host gene expression by nsp proteins of group bat coronaviruses a two-pronged strategy to suppress host protein synthesis by sars coronavirus nsp protein severe acute respiratory syndrome coronavirus protein nsp is a novel eukaryotic translation inhibitor that represses multiple steps of translation initiation severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp and rational design of an attenuated strain unique sars-cov protein nsp : bioinformatics, biochemistry and potential effects on virulence coronavirus nonstructural protein : common and distinct functions in the regulation of host and viral gene expression protein structure and sequence reanalysis of -ncov genome refutes snakes as its intermediate host and the unique similarity between its spike protein insertions and hiv- the nsp proteins of mouse hepatitis virus and sars coronavirus are dispensable for viral replication identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity a noncovalent class of papain-like protease/deubiquitinase inhibitors blocks sars virus replication deubiquitinating activity of the sars-cov papainlike protease the papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme sars coronavirus papain-like protease inhibits the tlr signaling pathway through removing lys -linked polyubiquitination of traf and traf coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of sting-mediated signaling sars coronavirus papain-like protease inhibits the type i interferon signaling pathway through interaction with the sting-traf -tbk complex the papain-like protease determines a virulence trait that varies among members of the sars-coronavirus species structure and cleavage specificity of the chymotrypsin-like serine protease ( clsp/nsp ) of porcine reproductive and respiratory syndrome virus (prrsv) mutation in murine coronavirus replication protein nsp alters assembly of double membrane vesicles localization and membrane topology of coronavirus nonstructural protein : involvement of the early secretory pathway in replication replication is supported by a reticulovesicular network of modified endoplasmic reticulum c-like proteinase from sars coronavirus catalyzes substrate hydrolysis by a general base mechanism dissection study on the severe acute respiratory syndrome c-like protease reveals the critical role of the extra domain in dimerization of the enzyme: defining the extra domain as a new target for design of highly specific protease inhibitors coronavirus main proteinase ( clpro) structure: basis for design of anti-sars drugs biosynthesis, purification, and substrate specificity of severe acute respiratory syndrome coronavirus c-like proteinase the substrate specificity of sars coronavirus c-like proteinase topology and membrane anchoring of the coronavirus replication complex: not all hydrophobic domains of nsp and nsp are membrane spanning coronavirus nsp proteins generate autophagosomes from the endoplasmic reticulum via an omegasome intermediate evolutionary analysis of sars-cov- : how mutation of non-structural protein could affect viral autophagy coronavirus nsp restricts autophagosome expansion structure of the sars-cov nsp polymerase bound to nsp and nsp co-factors insights into sars-cov transcription and replication from the structure of the nsp -nsp hexadecamer nonstructural proteins and of feline coronavirus form a : heterotrimer that exhibits primer-independent rna polymerase activity the sars-coronavirus nsp +nsp complex is a unique multimeric rna polymerase capable of both de novo initiation and primer extension the nonstructural protein (nsp ) of the sars coronavirus interacts with its orf accessory protein severe acute respiratory syndrome coronavirus nsp dimerization is essential for efficient viral growth virus-host interactome and proteomic survey of pmbcs from covid- patients reveal potential virulence factors influencing sars-cov- the nsp replicase protein of sars-coronavirus, structure and functional insights the severe acute respiratory syndrome-coronavirus replicative protein nsp is a single-stranded rna-binding subunit unique in the rna virus world crystal structure of nonstructural protein from the severe acute respiratory syndrome coronavirus reveals a novel fold with two zinc-binding motifs rna ′-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp / nsp exoribonuclease complex structural basis and functional analysis of the sars coronavirus nsp -nsp complex in vitro reconstitution of sars-coronavirus mrna cap methylation crystal structure and functional analysis of the sars-coronavirus rna cap ′-o-methyltransferase nsp /nsp complex coronavirus nsp , a critical co-factor for activation of multiple replicative enzymes dodecamer structure of severe acute respiratory syndrome coronavirus nonstructural protein nsp coronavirus nsp /nsp methyltransferase can be targeted by nsp -derived peptide in vitro and in vivo to reduce replication and pathogenesis molecular anatomy of viral rna-directed rna polymerases multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase the severe acute respiratory syndrome (sars) coronavirus ntpase/helicase belongs to a distinct class of ′ to ′ viral helicases the human coronavirus e superfamily helicase has rna and dna duplex-unwinding activities with ′-to- ′ polarity structure-function analysis of severe acute respiratory syndrome coronavirus rna cap guanine-n -methyltransferase functional screen reveals sars coronavirus nonstructural protein nsp as a novel cap n methyltransferase characterization of the guanine-n methyltransferase activity of coronavirus nsp on nucleotide gtp the cellular rna helicase ddx interacts with coronavirus nonstructural protein and enhances viral replication crystal structure and mechanistic determinants of sars coronavirus nonstructural protein define an endoribonuclease family crystal structure of a monomeric form of severe acute respiratory syndrome coronavirus endonuclease nsp suggests a role for hexamerization as an allosteric switch structural and biochemical characterization of endoribonuclease nsp encoded by middle east respiratory syndrome coronavirus binding of the methyl donor s-adenosyl-l-methionine to middle east respiratory syndrome coronavirus ′-o-methyltransferase nsp promotes recruitment of the allosteric activator nsp coronavirus nonstructural protein is a cap- binding enzyme possessing (nucleoside- ′o)-methyltransferase activity ribose ′-o-methylation provides a molecular signature for the distinction of self and non-self mrna dependent on the rna sensor mda assembly of coronavirus spike protein into trimers and its role in epitope expression cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer the coronavirus spike protein is a class i virus fusion protein: structural and functional characterization of the fusion core complex coronavirus spike proteins in viral entry and pathogenesis structure of sars coronavirus spike receptor-binding domain complexed with receptor characterization of severe acute respiratory syndrome-associated coronavirus (sars-cov) spike glycoprotein-mediated viral entry mechanisms of coronavirus cell entry mediated by the viral spike protein severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice potent binding of novel coronavirus spike protein by a sars coronavirus-specific human monoclonal antibody severe acute respiratory syndrome coronavirus orf a protein interacts with caveolin severe acute respiratory syndrome coronavirus a protein is a viral structural protein the severe acute respiratory syndrome coronavirus a is a novel structural protein g phase cell cycle arrest induced by sars-cov a protein via the cyclin d /prb pathway nucleocapsid-independent assembly of coronavirus-like particles by co-expression of viral envelope protein genes structure and inhibition of the sars coronavirus envelope protein ion channel expression of sars-coronavirus envelope protein in escherichia coli cells alters membrane permeability coronavirus particle assembly: primary structure requirements of the membrane protein severe acute respiratory syndrome coronavirus open reading frame (orf) b, orf , and nucleocapsid proteins function as interferon antagonists severe acute respiratory syndrome coronavirus orf antagonizes stat function by sequestering nuclear import factors on the rough endoplasmic reticulum/golgi membrane orf- , induces caspase- mediated, er stress and jnk-dependent apoptosis structure and intracellular targeting of the sars-coronavirus orf a accessory protein sars coronavirus a protein blocks cell cycle progression at g /g phase via the cyclin d /prb pathway severe acute respiratory syndrome (sars) coronavirus orf protein is acquired from sars-related coronavirus from greater horseshoe bats through recombination selective replication of coronavirus genomes that express nucleocapsid protein the coronavirus nucleocapsid is a multifunctional protein the severe acute respiratory syndrome coronavirus nucleocapsid protein is phosphorylated and localizes in the cytoplasm by − - -mediated translocation sequence comparison of the n genes of five strains of the coronavirus mouse hepatitis virus suggests a three domain structure for the nucleocapsid protein the nucleocapsid protein of coronavirus infectious bronchitis virus: crystal structure of its n-terminal domain and multimerization properties modular organization of sars coronavirus nucleocapsid protein coronavirus nucleocapsid protein is an rna chaperone characterization of protein-protein interactions between the nucleocapsid protein and membrane protein of the sars coronavirus the sars-cov nucleocapsid protein: a protein with multifarious activities clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study effect of age on human neutrophil function innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans altered cytokine production in the elderly cutting edge: impaired toll-like receptor expression and function in aging signaling pathways in aged t cells -a reflection of t cell differentiation the effect of age on thymic function human coronavirus infections: causes and consequences of cytokine storm and immunopathology molecular immune pathogenesis and diagnosis of covid- understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (genims) study adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation understanding human autoimmunity and autoinflammation through transcriptomics covid- ) in china: a systematic review and meta-analysis changes in blood coagulation in patients with severe coronavirus disease (covid- ): a meta-analysis thromboembolic risk and anticoagulant therapy in covid- patients: emerging evidence and call for action tissue plasminogen activator genetic variation at the human tissue-type plasminogen activator (tpa) locus: haplotypes and analysis of association to plasma levels of tpa the coagulopathy of acute sepsis covid- presenting as stroke pulmonary embolism in patients with covid- : time to change the paradigm of computed tomography covid- and the cardiovascular system: implications for risk assessment complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases novel coronavirus outbreak research team. epidemiologic features and clinical course of patients infected with sars-cov- in the cardiovascular burden of coronavirus disease (covid- ) with a focus on congenital heart disease associated with acute respiratory distress syndrome receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus notch signaling in cardiac development and disease mutations in the notch pathway regulator mib cause left ventricular noncompaction cardiomyopathy activation of notch signaling in cardiomyocytes during post-infarction remodeling vertical transmission of coronavirus disease (covid- ) from infected pregnant mothers to neonates: a review viral-induced genetics revealed by multi-dimensional precision medicine transcriptional workflow applicable to covid- nucleocapsid protein recruitment to replication-transcription complexes plays a crucial role in coronaviral life cycle interplay between coronavirus, a cytoplasmic rna virus, and nonsense-mediated mrna decay pathway nonsense-mediated mrna decay (nmd) mechanisms the nonsense-mediated decay rna surveillance pathway the host nonsense-mediated mrna decay pathway restricts mammalian rna virus replication nonsense-mediated mrna decay: novel mechanistic insights and biological impact beyond quality control: the role of nonsense-mediated mrna decay (nmd) in a combined proteomics/genomics approach links hepatitis c virus infection with nonsense-mediated mrna decay virus escape and manipulation of cellular nonsense-mediated mrna decay rna virus evasion of nonsense-mediated decay how retroviruses escape the nonsense-mediated mrna decay an interactome map of the nucleocapsid protein from a highly pathogenic north american porcine reproductive and respiratory syndrome virus strain generated using silac-based quantitative proteomics function of a retrotransposon nucleocapsid protein the cellular interactome of the coronavirus infectious bronchitis virus nucleocapsid protein and functional implications for virus biology interaction of pabpc with the translation initiation complex is critical to the nmd resistance of aug-proximal nonsense mutations a conserved role for cytoplasmic poly(a)-binding protein (pabpc ) in nonsense-mediated mrna decay upf is required for nonsense-mediated mrna decay (nmd) and rnai in arabidopsis mammalian staufen recruits upf to specific mrna ′utrs so as to elicit mrna decay nmd factors upf and upf bridge upf to the exon junction complex and stimulate its rna helicase activity interactions between upf , erfs, pabp and the exon junction complex suggest an integrated model for mammalian nmd pathways upf phosphorylations create binding platforms for smg- and smg- :smg- during nmd binding of a novel smg- -upf -erf -erf complex (surf) to the exon junction complex triggers upf phosphorylation and nonsense-mediated mrna decay a post-translational regulatory switch on upf controls targeted mrna degradation phosphorylation of the porcine reproductive and respiratory syndrome virus nucleocapsid protein phosphorylation and subcellular localization of transmissible gastroenteritis virus nucleocapsid protein in infected cells severe acute respiratory syndrome coronavirus nucleocapsid protein expressed by an adenovirus vector is phosphorylated and immunogenic in mice phosphorylation of the mouse hepatitis virus nucleocapsid protein effects of phosphorylation of avian retrovirus nucleocapsid protein pp on binding of viral rna regulation of hepadnavirus reverse transcription by dynamic nucleocapsid phosphorylation nonsense-mediated mrna decay at the crossroads of many cellular pathways valiente-echeverría, f. strategies for success. viral infections and membraneless organelles innate immune evasion by human respiratory rna viruses mouse hepatitis coronavirus replication induces host translational shutoff and mrna decay, with concomitant formation of stress granules and processing bodies hypoxic inhibition of nonsense-mediated rna decay regulates gene expression and the integrated stress response possible roles in the control of translation and mrna degradation. cold spring harbor perspect nonsense surveillance regulates expression of diverse classes of mammalian transcripts and mutes genomic noise nonsense-mediated rna decay regulation by cellular stress: implications for tumorigenesis nonsense-mediated mrna decay factors act in concert to regulate common mrna targets nonsense-mediated mrna decay in health and disease the rules and impact of nonsense-mediated mrna decay in human cancers a novel rnaseh b splice site mutation responsible for aicardi-goutieres syndrome in the faroe islands genetically defined autoinflammatory diseases rare adar and rnaseh b variants and a type i interferon signature in glioma and prostate carcinoma risk and tumorigenesis key: cord- -uxxrpfl authors: resta-lenert, silvia title: diarrhea, infectious date: - - journal: encyclopedia of gastroenterology doi: . /b - - - / - sha: doc_id: cord_uid: uxxrpfl nan diarrheal diseases are a major cause of morbidity and mortality around the world, especially in developing countries where children suffer the greatest brunt of infectious diarrhea, malnutrition, and death. annually, approximately million children and infants die worldwide due to diarrheal diseases. in north america, the rate per year is still . diarrheal episodes per child, and in special circumstances (daycare centers, institutions), the incidence is as high as episodes per year. fourteen hospital admissions per children younger than months, per year, result from acute diarrhea. among the adult population, most patients developing acute diarrhea are managed as outpatients or will not seek medical attention. however, . million hospital admissions per year, or . % of all adult hospital admissions annually, are due to diarrhea. in developing countries, inadequate water supply, inef®cient or nonexistent sewage removal systems, chronic malnutrition, and lack of access to oral rehydration are responsible for the high incidence of infectious diarrheal diseases. in the industrialized world, acute diarrhea is still one of the most frequent diagnoses in general practice and children, elderly, and immunocompromised patients are the most vulnerable individuals and account for the majority of these cases. regardless of the etiology, diarrhea is de®ned clinically as the occurrence of three or more episodes of loose stool or any loose stool with blood during a h time period. symptoms lasting less than days represent acute diarrhea, whereas persistent diarrhea lasts more than days but less than weeks, and chronic diarrhea is de®ned by a duration of symptoms greater than weeks. infectious diarrheas are miserable illnesses of overwhelming impact on the general survival of entire populations. throughout history, thousands-strong armies have been defeated by raging diarrheal diseases: from the greeks and macedons under alexander (tucidides), to the romans in the campaigns against the gauls ( julius caesar), to the hundred years war in th century europe, to napoleon, the civil war in america, world war ii, and the vietnam war. scores of previously healthy men suffered and died from the scourge of diarrhea and dysentery in all of these con¯icts. twenty years ago, million to billion episodes of infectious diarrhea and nearly million deaths occurred per year worldwide, primarily in developing countries. ten years later, survival had improved, but the incidence was virtually unchanged despite greater knowledge of the pathophysiology of diarrhea and greater intervention by the world health organization (who). approximately million episodes of acute diarrhea occur in the united states yearly, with an incidence of . to . diarrheal episodes per person-year. medical costs/analyses show that . million americans sought physician care for diarrhea yearly and , required hospitalization. hospitalization and medical costs approached $ million, whereas lost productivity totaled $ million. approximately another million people sought physician care but were not hospitalized. these patients incurred $ million in medical costs and $ billion in loss of work hours. an estimated million cases occurred in people who did not seek physician care, costing nearly $ billion in lost productivity. approximately % of all these cases were presumably of infectious origin. thus, the total cost estimate for diarrheal diseases exceeds $ billion annually in the united states alone. although the elderly have an increased risk for death from diarrhea, death from diarrhea is rare among young children in industrialized countries. in fact, of all pediatric admissions for diarrhea, . % resulted in death, compared with % in patients older than age . increased age was the most important risk factor for death with an odds ratio of . ( % con®dence interval, . to . ) for age or older versus children b years. the national mortality ®gures for the -year period À in the united states show % of diarrheal deaths occurring in individuals older than age . acute infectious diarrhea is transmitted mostly through the fecalÀoral route and by ingestion of contaminated water and food. infection via the fecalÀoral route occurs by direct contact with index cases, especially under conditions of crowding, such as daycare centers or nursing homes. waterborne and foodborne outbreaks are another important source of disease transmission and result from general and/or individual failures in proper standards for the safe handling of foods. in most developing nations, acute diarrhea is endemic due to poor sanitation. furthermore, epidemics of signi®cant proportions often result from natural disasters in areas where water and food supplies are already chronically jeopardized. in some areas of the world, such as asia, africa, and latin america, certain infectious diarrheas (e.g., cholera) have become ongoing pandemics lasting several decades, notwithstanding who efforts at eradication. in most parts of the world, a de®nite seasonality is recognized in the incidence of acute diarrhea. in industrialized nations, the highest incidence of hospital admissions for diarrhea occurs in august and september and in the winter months. in developing nations with warmer climates and endemic conditions, variations in incidence occur from year to year in relation to precipitation indices and crop failures. infectious diarrheas may be classi®ed according to various criteria: duration, underlying mechanism, clinical presentation, etiology, and history. table i summarizes the various criteria for classifying diarrheas in general and infectious diarrheas in particular. in this section, infectious diarrheas are described according to the duration of the main gastrointestinal symptom. acute diarrheas last, by de®nition, less than days and the majority are due to infectious agents. most of these infections are self-limited and generally do not require medical intervention, unless severe dehydration and toxicity develop. however, immunocompromised patients, the elderly, and the very young may develop complications from enteric pathogens that warrant prompt and decisive medical intervention. a list of the major organisms involved in the etiology of acute infectious diarrheas is presented in table ii . not listed is a type of acute enteritis, waterborne and of presumed infectious origin, that has been responsible for several outbreaks of traveler's diarrhea, known as brainerd diarrhea. the etiologic agent of this disease still escapes de®nition. many of the acute infectious diarrheas observed worldwide are diagnosed in the course of local or epidemic outbreaks. three major situations may be encountered: ( ) waterborne infections; ( ) food-borne diarrhea; and ( ) traveler's diarrhea. whereas foodborne diarrhea is often associated with residual microbial toxins, waterborne and traveler's diarrheas are more often caused by active infection via the fecalÀoral route. table iii summarizes the most common causes in these epidemiological situations. a successful enteric pathogen possesses well-developed abilities to colonize, grow, and compete for nutrients in a crowded environment and to interact effectively with the host's enterocytes, inducing changes in the balance between absorption and secretion of water and electrolytes. in most gut infections, a pathogen enters via the oral route and colonizes an area of the ]. in addition to direct effects by microorganisms and their products, enteropathogens induce intestinal damage indirectly via the mucosal in¯ammatory response, which involves secretion of various powerful mediators of secretion and apoptosis. a summary of the current knowledge about the pathogenesis of the most common acute infectious diarrheal syndromes is shown in fig. . on the basis of these three mechanisms, acute infections present as watery, nonin¯ammatory diarrheal syndromes or in¯ammatory diarrheal syndromes. the majority of watery, nonin¯ammatory diarrhea cases are self-limited diseases characterized by low-grade fever, nausea, vomiting, large-volume diarrhea, and the absence of blood and leukocytes in the stools. this presentation is typically reported in patients infected with enterotoxigenic escherichia coli, v. cholerae, clostridial and staphylococcal food poisoning, rotavirus, norwalk virus agent, giardia lamblia, and cryptosporidium. on the other hand, the in¯ammatory diarrheal syndrome is characterized by frequent, small-volume stools that may contain blood and leukocytes, tenesmus, fever, and severe abdominal pain. the most common microorganisms causing this syndrome include salmonella, shigella, campylobacter, enterohemorrhagic e. coli, eiec, clostridium dif®cile, entamoeba histolytica, and yersinia. table iv describes the basic biologic, pathophysiologic, and clinical characteristics pertinent to the most common enteric pathogens. persistent diarrhea is emerging as a major world health problem. children are more likely to develop persistent diarrhea and suffer malnutrition, wasting, and immunocompromise as a consequence. persistent diarrhea is de®ned by looseÀsoft stools occurring at increased frequency and lasting for more than postinfectious persistent diarrhea is a poorly de®ned syndrome that occurs as a sequela of an acute episode with de®nite infectious etiology. patients may develop mild to severe degrees of malabsorption, from lactose intolerance to inability to absorb proteins, fat, and sugars, as well as permanent blunting of villi as assessed by histopathology. the condition is characterized by watery, malodorous stools and progressive wasting. chronic infectious diarrhea occurs mostly in immunocompromised patients. after an acute infectious episode, patients sometimes develop chronic symptoms that are independent of the etiologic agents of acute diarrhea (irritable bowel syndrome with diarrhea, or, occasionally, ulcerative colitis). table vi lists the most common agents isolated from cases of chronic infectious diarrhea. by de®nition, chronic diarrhea lasts more than weeks and patients developing this syndrome quite often are hospitalized and have undergone antibiotic therapy for other reasons. elderly, human immunode-®ciency virus (hiv)/acquired immunode®ciency syndrome (aids), transplant, and cancer patients are easy targets for reinfections or reactivation of only partially subdued infectious organisms. in addition to the causes listed above, bacterial overgrowth can occur in areas of bowel stasis or impaired bowel motility. postsurgery patients, diabetics, posttrauma patients, and intensive care patients are more likely targets of chronic infectious diarrheas from bacterial overgrowth. infectious diarrhea causes high morbidity and mortality among the aging population worldwide. multiorgan complications from an acute episode of infectious diarrhea are also more frequent among the elderly. life expectancy in the united states has risen from an average of years in the th century to years at present. by the year , % of the u.s. population will be older than age . gastrointestinal physiology and gut colonization change constantly with aging and contribute in a signi®cant way to increasing the susceptibility of elderly people to enteric infections. furthermore, the gastric acid barrier in the elderly is impaired. the most frequently isolated organisms and most deadly in elderly patients with diarrhea are c. dif®cile, salmonella, and toxigenic e. coli. these three agents top the list of figure infectious diarrhea: mechanisms of action of major enteric bacteria and viruses. enteric pathogens can induce intestinal injury with consequent diarrhea in three ways: ( ) by producing enterotoxins that interact with receptors located on the gut epithelial cells and evoke anion secretion, such as v. cholera, epec, eaec, stec, c. dif®cile, and s. aureus (a); ( ) by invading the gut epithelium and m cells, thus altering the cell cytoskeleton and activating intracellular pathways through virulence factors. organisms that lead to diarrhea through these mechanisms include eiec, shigella, epec, salmonella, and rotaviruses (b); ( ) by invading mucosal macrophages and inducing in¯ammatory responses leading to intestinal epithelial damage and anion secretion. campylobacter and yersinia use this mechanism (b). outbreaks in long-term and short-term care facilities and salmonella by itself accounts for more than % of cases and more than % of deaths in food-borne outbreaks in nursing homes. more than % of hiv/aids patients in the united states experience infectious diarrhea and this estimate may approach % in developing countries where the hiv epidemic is currently raging unchecked. these patients are more likely to develop persistent or chronic diarrhea after an acute episode because of their impaired immunity, with a signi®cant increase in morbidity and mortality. table vii lists the most common causes of infectious diarrhea in aids patients. the american gastroenterological association (aga) has published a set of general guidelines for the management of chronic diarrhea in aids patients. at least three sets of stool samples should be secured for common enteric bacteria and parasites, including microsporidia, cryptosporidia, and c. dif®cile. febrile patients with diarrhea should have blood cultures for common enteric bacteria. patients with cd lymphocyte counts of cells/mm are at high risk for disseminated mycobacterial infection. the most important ®nding in patients presenting with acute diarrhea is the degree of volume depletion, i.e., dehydration. postural changes in blood pressure are a reliable sign of dehydration. fever, abdominal tenderness, increased bowel sounds, or blood on rectal examination should alert the physician to acute infectious diarrhea. microscopic examination of a stool sample or rectal swab is a traditional and helpful tool in the rapid, bedside investigation of diarrheal illness. the specimen is placed on a glass slide and mixed thoroughly with two drops of methylene blue. the presence of ova, cysts, and/or leukocytes may point directly to a diagnosis. the aga guidelines on managing acute diarrhea indicates empiric antimicrobial therapy in the case of positive fecal leukocytes in a febrile patients. endoscopy has limited utility in the investigation of acute infectious diarrhea and is not cost-effective. it may have a place, however, in cases of persistent or chronic diarrhea. preventative measures against infectious diarrhea must include improvements in sanitation (water supply, sewer systems, housing), education of the general population and, where applicable, vaccination campaigns. unfortunately, no effective vaccines are available for the organisms that cause infectious diarrheas, with the exception of typhoid fever. treatment most acute diarrheal illnesses are self-limited and no speci®c therapy is required. water and electrolyte loss can be prevented or treated with oral¯uidÀelectrolyte solutions. intravenous salineÀglucose solutions are recommended in cases of moderate to severe dehydration. glucose in the intestinal lumen facilitates the absorption of sodium and the cotransport mechanism for these solutes appears to be unhampered by infection with microorganisms or by their toxins. antimotility therapy should be reserved for severe cases and chronic diarrheas and avoided in infants and children. antibiotic or antiviral treatment should be considered in moderate to severe cases in which a microbiological diagnosis is obtained or strongly see also the following articles aids, gastrointestinal manifestations of anti-diarrheal drugs campylobacter cholera cryptosporidium cytomegalovirus diarrhea foodborne diseases food poisoning food safety giardiasis rotavirus salmonella shigella traveler's diarrhea further reading anonymous epidemiology of clostridium dif®cile-associated infections ef®cacy and tolerability of racecadotril in acute diarrhea in children practice guidelines for the management of infectious diarrhea principles and practice of infectious diseases microbes and microbial toxins: paradigms for microbialÀmucosal interactions. viii. pathological consequences of rotaviral infection and its enterotoxin traveler's diarrhea due to intestinal protozoa the role of antibiotics in the treatment of infectious diarrhea infectious diarrhea in children pathogenesis of infectious diarrhea key: cord- - ebo cy authors: nan title: lungenversagen date: journal: chirurgische intensivmedizin doi: . / - - - - _ sha: doc_id: cord_uid: ebo cy das akute lungenversagen ist eine schwere diffuse entzündliche erkrankung der lunge. nach der „american-european consensus conference“ (bernard et al., ) wird zwischen einem ards — acute respiratory distress syndrom und einem ali — acute lung injury unterschieden. das ausmaß der respiratorischen insuffizienz wird nach der höhe des scores definiert. score ist die gesamtsumme der einzelwerte dividiert durch score: kein lungenversagen , - , leichtes lungenverasgen > , schweres lungenversagen multiple pathomechanismen (tabelle ) sind verantwortlich für schwerwiegende morphologische (lorraine et al., ) und funktionelle lungenveränderungen, sodass eine ausreichende oxygenierung der patienten mittels konventioneller beatmung oft nicht mehr möglich ist. in der frühphase des ards findet sich eine massive ansammlung neutrophiler granulozyten in der lunge sowie deren migration durch die gefäßwand. sie setzen eine reihe von endothelschädigenden und den pulmonal-vasku-lären gefäßwiderstand erhöhende substanzen frei (abb. ), die den ausgangspunkt für eine weitere kaskadenartige aktivierung verschiedener mediatorsysteme darstellen. (freisetzung freier radikale, elastase, aktivierung der phospholipase, aktivierung des kallikreinsystems, freisetzung von zytokinen: tnf, interleukin - , , - , - , - , - ; platelet activating factor (paf), komplement-komponente (c a), adhäsionsmoleküle. des weiteren spielt jedoch auch die freisetzung chemotaktischer moleküle, der chemokine ein wichtige rolle (puneet et al., ) . es kommt zunächst einerseits zu einer erhöhung der permeabilität der gefäßwand mit interstitieller Ödembildung und anderseits zu einer permeabilitätsstörung der alveolarwand, hervorgerufen durch membranfragmentationen der endothelzellen und eine degeneration der alveolären epithelzellen (typ-i-pneumozyten) mit ablösung von der basalmembran. sie machen % der alveolären fläche aus und sind vulnerabel als die typ ii zellen, die % der alveolarfläche ausmachen. dadurch wird die entstehung eines proteinreichen interstitiellen und intraalveolären Ödems (patroniti et al., ) ausgelöst, wodurch wiederum der gasaustausch erheblich erschwert wird. das zunehmende gewicht der lunge, bedingt durch das zunehmende Ödem, führt zu einem kollaps von lungenabschnitten entlang eines vertikalen gradienten verursacht durch hydrostatische kräfte, die kompressionsatelektasen erzeugen. diese veränderungen treten bevorzugt in abhängigen lungenabschnitten auf. die in der computertomographie sichtbaren dichteänderungen stellen eine kombination von atelektasen, Ödem, konsolidation oder eine kombination dieser drei formen dar. die schädigung der alveolarepithelien führt weiters zu einer abnahme der surfaktantproduktion und fördert damit die bildung von atelektasen. so kommt es zu einer zunahme des intrapulmonalen shunts und des totraumquotienten. der zusätzliche funktionsverlust des surfactant ist auf die anwesenheit funktioneller inhibitoren, seine abnorme zusammensetzung und die proteolytische störung der einzelkomponenten zurückzuführen. bei längerem bestehen des krankheitsbildes kommt es zur fibrosierung und proliferation der typ-ii-pneumozyten. durch die abnahme der compliance der lunge steigt das risiko für die entstehung eines barotraumas. im gegensatz zu der noch bis vor einiger zeit bestehenden meinung, dass die rückbildung eines alveolaren Ödems alleinig als ergebnis aus der druckdif-ferenz zwischen hydrostatischem und osmotischem druck (starling-kräfte) resultiert, zeigen nun neuere studien, dass die beseitigung eines alveolären Ödems durch einen aktiven natrium-chlorid transport durch das pulmonale epithel, einschließlich der alveolären epithelzellen vom typ i und typ ii als auch der distalen epithelzellen des atemweges reguliert wird , verghese et al., , ware et al., . so erfolgt durch eine na + , k + -at-pase eine aktive förderung von na + von der basolateralen oberfläche in das interstitium (matthay et al., ) . so zeigt es sich, dass bei einer akuten lungenschädigung die alveoläre flüssigkeitsclearance geringer ist als bei einem kardial bedingten hydrostatischem lungenödem. erste medikamentöse therapieansätze zeigen, dass unter einer -adrenergen agonisten (z. b. isoproterenol) bzw. epithelialer wachstumsfaktoren-applikation möglicherweise die alveoläre flüssigkeitsclearance gesteigert werden kann (sartori et al., bei patienten mit ali/ards kann das auftreten apoptotischer vorgänge an pulmonalen epithelialen zellen (song y et al., , li et al., , martin et al., (abraham, ) derselben, sodass es zur aufrechterhaltung eines von leukozyten geführten inflammatorischen prozesses kommt, der typisch für eine akute lungenschädigung ist (wang et al., , yum et al., die verminderte apoptose der neutrophilen ist bedingt durch: . verhinderung einer zytochrom c freisetzung aus den mitochondrien, . hemmung der aktivierung des proapoptotischen protein bad, . gesteigerte transkription des antiapoptotischen protein mci- und bci- , welches die protease caspase- hemmt und unter aktivierung von nf-kb eine gesteigerte transkription antiapoptotischer gene induziert. anschließend an diese zone findet sich meist ein dorsobasal lokalisierter erguss unterschiedlichen ausmaßes. computertomographischen untersuchungen (puybasset et al., , peseti et al., , pelosi et al., der lunge an patienten mit ali zeigen, dass hyperdensitäten entlang eines anteriorposterior gradienten als auch gleichzeitig entlang eines zephalokaudalen gradienten feststellbar sind. diese hyperdensitäten entsprechen nonaerated-nichtbelüfteten lungenarealen, welche sich von aerated lungenarealen unterscheiden lassen. nonaerated lungenareale sind bevorzugt in zwerchfellnahen lungenabschnitten zu finden. bei anwendung eines peep findet sich ein alveoläres rekruitment mehr in den nondependend als in den dependend lungenregionen und mehr in den zephalen als in den kaudalen regionen. wenn jedoch der zur verwendung kommende peep ausreichend hoch ist um in den dorsalen regionen und den unteren lungenabschnitten alveolen zu rekrutieren, dann kommt es zu einer Überdehnung der oberen lungenabschnitte. Überdehnung der lunge (quadri et al., ) auch als atelektrauma (uhlig et al., ) (ranieri et al., , lorraine et al., . konzepte der beatmung von patienten mit ards beinhalten die anwendung von spontanatmungsverfahren (putensen et al., ) (kuhlen et al., , luce , wobei keiner beatmungstechnik ein entscheidender vorteil eingeräumt werden kann, jedoch müssen gleichzeitig respiratoreinstellungen angestrebt werden, welche eine protektive beatmung ermöglichen (malarkkan et al., , eisner et al., . (gattinoni et al., , amato et al., , adams et al., , malarkkan et al., , bhattacharya die anwendung eines peep ist eine unumstrittene maßnahme bei jeder form einer respiratorischen insuffizienz (gattinoni et al., , medoff et al., , durante et al., . diskussionspunkte sind die höhe des verwendenen peep und die klinische umsetzung eines best-peep. ist das lungenvolumen, bei dem es während der exspiration zu einem verschluss der kleinen atemwege kommt. ist die summe aus verschlussvolumen und residualvolumen. Überschreitet die verschlusskapazität die frc, dann tritt endexspiratorisch ein verschluss basaler luftwege auf. der verschluss der kleinen atemwege tritt vor allem in den abhängigen dorsobasalen lungenabschnitten auf, wo der extraluminale gravitations-bedingte gewebsdruck größer ist als der endobronchiale intrapulmonale atemwegsdruck. (neumann et al., ) darauf hin, dass zur vermeidung eines kollapses von alveolen (ohne extrinsischen peep) eine exspirationszeit von weniger als , sec notwendig wäre. bei länger bestehender exspirationszeit kommt es trotz peep-anwendung bis zu einer höhe von cm h₂o zur ausbildung von atelektasen. erst bei einem peep von cm h₂o kann der exspiratorische alveolenkollaps vermieden werden. resultierend aus den experimentellen ergebnissen bedeutet die wertigkeit der zeitkonstante in der klinischen anwendung, dass prinzipiell eine regelmäßige adaptation des respirators an die gegebene lungensituation (compliance, resistance) notwendig ist um z. b. durch adaptation der exspirationszeit des respirators an die exspiratorische zeitkonstante die entwicklung eines inadvertent peep vermeiden zu können. bei Übertragung der experimentellen ergebnisse auf patienten mit schwerer respiratorischer insuffizienz wäre jedoch bezogen auf die respiratortherapie unter anwendung einer sehr kurzen exspirationszeit mit der entwicklung eines erhöhten intrinsischen peep und auch des mittleren atemwegsdruckes zu rechnen. hingegen konnte gezeigt werden, dass bei patienten mit ards eine kinetische therapie in form der bauchlage eine signifikante reduktion der exspiratorischen zeitkonstante (vieillard- baron et al., ) in der akutphase des lungenversagens sind ein beträchtlicher teil von lungenarealen bedingt durch einen kollaps von alveolen nicht belüftet. ziel eines open-lung-konzeptes (lachmann, ; blanch et al., , lim et al., , haitsma, ist es eine eröffnung von kollabierten alveolen bzw. rasche rekrutierung von konsolidierten lungenarealen unter kurzfristiger anwendung hoher inspirationsdrücke ( - mbar) zu erzielen und dann durch entsprechend hohe peep-werte ein offenhalten der alveolen zu garantieren (abb. ). dazu ist es notwendig, dass der inspiratorische plateaudruck den alveolar-Öffnungsdruck übersteigt und dann der peep über dem alveolarverschlussdruck liegt. ausgehend von dem hier beschriebenen grundkonzept gibt es inzwischen unterschiedlichst angewandte modifikationen (methoden) von rekrutierungsverfahren. wird der peep schrittweise auf - cm h₂o erhöht. damit sollen alle während der sich anschließenden inspiratorischen druckerhöhung rekrutierten alveolen offengehalten werden. . nun wird schrittweise der atemwegsspitzendruck auf - - mbar über atemzüge erhöht, womit ein kritischer wert des Öffnungsdrucks erreicht wird. diese hohen inspiratorischen druckwerte werden als notwendig angesehen, um einerseits die adhäsivkräfte kollabierter alveolen (böhm et al., ) , anderseits auch die kapillarkräfte in den flüssigkeitsgefüllten atemwegen überwinden zu können. als parameter der erreichung des Öffnungsdrucks ist das arterielle po₂ anzusehen, welches sich in einer deutlichen erhöhung zeigt. bei optimaler rekrutierung von alveolen führen nun weitere drucksteigerungen zu keiner erhöhung des pao₂. sind alle rekrutierten alveolen offen, dann ist ein derart hoher atemwegsspitzendruck für deren beatmung nicht mehr notwendig. resultierend aus dem zusammenwirken von surfactant und dem "la place gesetz" ist der notwendige innendruck in der alveole nach ihrer eröffnung geringer als vor ihrer eröffnung. es muss nun der verschlussdruck der lunge ermittelt werden, indem der atemwegsspitzendruck schrittweise gesenkt wird. kommt es zu einem pao₂-abfall, dann ist er durch einen kollaps von alveolen bedingt und somit ist der kritische verschlussdruck der alveolen festgestellt. die sich nun entwickelnden atelektatischen lungenareale müssen erneut eröffnet werden. die zuvor bestimmten eröffnungsdrucke sind bekannt. durch eine kurze beatmungsdauer mit diesen bekannten drücken, über einen zeitraum von sekunden, wird die lunge erneut eröffnet. anschließend kann der atemwegsspitzendruck soweit gesenkt werden, dass ein druck verwendet wird, der cm h₂o über dem bekannten verschlussdruck liegt. eine permissive hyperkapnie wird als teil einer lungenprotektiven maßnahme bei einem akuten lungenversagen angesehen (carvalho et al., nachdem no lange zeit als schadstoff angesehen wurde, gelang erst und im rahmen dreier studien der nachweis, dass der endothelium-derived relaxin factor (edrf), entdeckt von furchgott und zawadzki, ident mit no ist (ignarro et al., ; palmer et al., ; furchgott, ) die hochfrequenzbatmung ist eine form der künstlichen beatmung, bei der kleine tidalvolumina mit einer supraphysiologischen frequenz appliziert werden. verschiedenste typen der hochfrequenzbeatmung sind in den letzten jahren entwickelt und angewendet worden worden (froese et al., ) . von den zahlreichen möglichen anwendbaren hochfrequenzbeatmungsformen wie: hfp-high-frequency pulsation, fdv-forcierte diffusionsventilation (baum et al., ) , hfjv-high frequency jet oscillation haben sich im klinisch anwendbaren bereich jedoch techniken wie die hfpp-high-frequency positive-pressure ventilation, hfj-high frequency jet- chang ( ) beschreibt in einer Übersichtsarbeit mehrere mechanismen des gasaustausches, die vor allem bei der hochfrequenzoszillation von bedeutung sind. (shimaoku et al., ) . erste klinische ergebnisse zeigen, dass es möglicherweise unter hochfrequenter beatmung zu einem rascheren rekruitment von dependend lungenarealen kommt, ohne dass es gleichzeitig zu einer massiven Überdehnung von non-dependend lungenarealen kommt. denkbar ist, dass der unter hochfrequenzbeatmung oft zu beobachtende bessere gasaustausch nicht so sehr über mechanismen einer gesteigerten diffusion zu erklären ist, sondern durch pulsatile mechanismen, die zu einer rascheren rekrutierung von lungengewebe führen. . des weiteren kann diese jet-ventilationstechnik mit no-applikationsgeräten kombiniert werden, wobei eine exakte no-dosierung gewährleistet ist . meist kommt sie erst dann zu einsatz, wenn eine konventionelle beatmung versagt. in der literatur handelt es sich daher meist um fallberichte oder nicht randomisierte kleinstudien. jedoch zeigt es sich, dass die angewandten techniken, wenn oft auch aufwendig, sicher in der anwendung sind und oft eine verbesserung der oxygenierung ermöglichen. durch die verwendung eines konventionellen beatmungsteiles (abb. ) mit niedriger beatmungsfrequenz mit konventionellem peep, jedoch mit größerem vtid, ist eine ausreichende co₂-elimination gewährleistet. Überlagert wird dem konventionellen teil eine hochfrequente beatmungsform (tabelle ). die oxygenierung wird bevorzugt durch den hochfrequenten pulsatilen teil der beatmung verbessert. so wurden konventionelle beatmungstechniken mit unterschiedlichen hochfrequenten beatmungstechniken kombiniert. die jet-gasapplikation erfolgt bei einer kombinierten jet-ventilation (chfjv) (abb. ): abb. . darstellung des hochfrequenten jet-gas-impuls-volumens unter variabler jetfrequenz bei konstantem trachealdruck von mbar. bei anwendung einer hohen jet-frequenz (links) ist das tidalvolumen des jet-gasimpulses niedrig. je niedriger die jet-frequenz (rechts), desto höher ist das jet-impuls-gasvolumen ein suffiziente anfeuchtung und erwärmung des atemgases ist für eine maschinelle beatmung von wesentlicher bedeutung. als zielwerte werden eine temperatur von grad und eine relative feuchtigkeit von % angesehen (roth, ) . als optimaler feuchtigkeitsgehalt der inspirationsluft werden werte bis mg/l angesehen (williams et al., , christiansen et al., . (perkins gd et al., ) im entzündungsgeschehen bei einem ards (verminderung der sequestration von neutrophilen, beschleunigung der alveolären flüssigkeitsclearance, erhöhung der sekretion von surfactant) zugeschrieben. dennoch liegt auch eine beschreibung über die entwicklung eines lungenödems (russi et al., ) unter der kontinuierlichen therapie einer tokolyse mit -mimetica vor. bei patienten mit ards konnte abnahme von atemwegsspitzendruck, plateaudruck sowie des atemwegswiderstandes erzielt werden (morina et al., ) . antiphlogistica ist ein inhalatives glukokortikoid, lokaler entzündungshemmender effekt dosierung × atemhub bei der jet-ventilation sollte nach stunden eine kontrolle der trachealschleimhaut durchgeführt werden, um frühzeitig schleimhautveränderungen, die durch eine zu geringe befeuchtung bedingt sind, zu verhindern. danach weitere kontrollen der befeuchtung durch bronchoskopien in größeren zeitabständen. bei der jet-ventilation werden kleine gasvolumina mit hoher frequenz von einer düse über den endotrachealtubus in die trachea appliziert. wird nur --ein einzelimpuls des jet-gas-volumens abgegeben, dann gelangt das gasvolumen höchstens einige trachealdurchmesser in die trachea; aber durch die periodische kontinuierliche abgabe eine jet-impulses mit hoher frequenz wird das gasvolumen kontinuierlich bis in die alveolen transportiert. dieser gastransport ist begleitet von einer interaktion zwischen konvektion und molekularer diffusion innerhalb der atemwege. der konvektive teil des gasbewegung setzt sich aus zwei teilen zusammen: so besteht erstens ein turbulent konvektiver gasaustausch mit der atmosphäre verursacht durch den jet in der trachea und zweitens eine konvektive strömungsbewegung entlang der atemwege gesteuert durch eine interaktion zwischen dem jet und einer expandierenden und kontrahierenden bewegung der atemwege, verursacht durch die compliance der lunge (scherer et al., ) . in den peripheren atemwegen besteht ein pulsierender bidirektionaler koaxialer gasfluss sowie eine verstärkte konvektive dispersion die so genannte "augmented diffusion", die um ein vielfaches größer ist als die normale molekulare diffusion. unter anwendung der superponierten hochfrequenz-jet-ventilation dürfte neben gesteigerten gasaustauschmechanismen jedoch ein rasches rekruitment von minderbelüfteten abhängigen lungeanarealen ursächlich an der oft feststellbaren raschen verbesserung des pulmonalen gasaustausches beteiligt sein, wie es mittels einer computertomographischer studie (kraincuk, ) gezeigt werden konnte. wobei der pulsatilen gasbewegung offensichtlich eine wichtige rolle zuzukommen scheint. die hochfrequenzoszillation unterscheidet sich von der hochfrequenz-jet-ventilation, dass sowohl neben der inspiration auch die exspiration aktiv ist, die tidalvolumina kleiner sind als bei einer combined hfjv (meist unter ml), der möglich anwendbare frequenzbereich erstreckt sich bis hz (meist liegt er bei hz ähnlich der jet-ventilation). kolla et al., ; lewandowski et al., ) größere patientenzahlen mit einer Überlebensrate von über % aufwiesen, des weiteren schwere bakterielle als auch virale pneumonien (vida et al., ) als auch sekundäre lungenschädigungen, die nach einem trauma, einer pankreatitis, nach systemischer erkrankung mit lungenbeteiligung (loscar et al., ) nach einer chemischen pneumonitis sowie einer sepsis auftreten können. zur anwendung kommt sie auch bei transplantations-empfängern unmittelbar postoperativ nach einer lungentransplantation als auch nach herzchirurgischen eingriffen. ebenso ist der frühzeitige beginn mit anschließenden mobilem inter-hospitalen transfer an ein ecmo zentrum beschrieben linden, ) . die anwendung extrakoproraler oxygenierungsverfahren stellt eine notwendige therapieoption (kopp et al., , henzler et al., bei schwerster respiratorischer insuffizienz dar, die mit der laufenden weiterentwicklung (bartlett, , bensberg et al., einschließlich der entwicklung kleinerer und einfacherer systeme den einsatzbereich erweitert. betreffend die gesundheitsbezogene lebensqualität (stoll et al., ) bei einer zunahme des herzzeitvolumens steigt der mikrovaskuläre druck, gleichzeitig kommt es zu einer rekrutierung von bis dahin nicht oder kaum perfundierten gefäßen. damit kommt es zu einer zunahme von kapillaroberfläche über die flüssigkeit filtriert wird. das so genannte permeabilitäts-oberflächenprodukt steigt. bei einem anstieg des hzv kommt es somit durch rekrutierung von gefäßen und der damit einhergehenden vergrößerung des gefäßquerschnittes zu einem abfall des postkapillären gefäßwiderstandes der gesamten lunge, wobei dennoch die transvaskuläre flüssigkeitsfiltration zunehmen kann. akutes nierenversagen durch eine extreme hypovolämie splanchnikusischämie vermeidung einer extremen hypovolämie: akutes nierenversagen splanchnikusischämie hypovolämie bedingt eine freisetzung vasoaktiver mediatoren. im tierexperiment führt volumenmangel zu translokation von bakterien und endotoxinfreisetzung aus dem darmlumen in den intravasalraum und zu gesteigerter freisetzung von tnf-. die kinetische therapie ist eine lagerungstherapie mit dem ziel einer verbesserung der lungenfunktion und damit des pulmonalen gasaustausches. zahlreiche arbeiten beweisen die effektivität dieser maßnahmen (langer et al., , hörman et al., , lamm et al., , stiletto et al., , koutsoukou, (spragg rg et al., ) nur eine kurzfristige besserung des gasaustausches innerhalb der ersten stunden nach seiner verabreichung sowie keine verbesserung des outcome. die problematik liegt in der notwendigen schwierigen zerstäubung einer fetthaltigen lösung, der platzierung in der gesunden lunge, der inaktivierung in geschädigten -----alveolen (baudouin sv ) , der hohen dosierung beim erwachsenen und der damit verbundenen hohen kosten der jeweiligen präparate, die eine routinemäßge applikation derzeit nicht rechtfertigen, obwohl kleine studien auf die positiven effekte hinweisen (seeger et al., , günther et al., , von kaam et al., , calkovska et al., . 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therapie zur therapie und prophylaxe der posttraumatischen lungeninsuffizienz. ergebnisse einer prospektiven studie an polytraumatisierten gesundheitsbezogene lebensqualität; langzeitüberleben der erwachsenen patienten mit ards nach extracorporaler mmbranoxygenation (ecmo) mechanotransduction in the lung ventilation-induced lung injury and mechanotransduction: stretching it too far high-frequency percussive ventilation improves oxygenation in patients with ards alveolar epithelial fluid transport and the resolution of clinically severe hydrostatic pulmonary edema prolonged ecmo support for virus-induced cardiorespiratory failure early after cardiac surgery prone position improves mechanics and alveolar ventilation in acute respiratory distress syndrome response to exogenous surfactant is different during open lung and conventional ventilation alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome the acute respiratory distress syndrome fas-induced apoptosis epithelial cells requires ang ii generation and receptor interaction pathophysiologie und aktuelle medikamentöse therapiekonzepte relationship between the humidity and temperature of inspired gas and the function of the airway mucosa high-frequency jet ventilation produces auto-peep involvement of phosphoinositide -kinases in neurtophil activation and the development of acute lung injury arteriovenous carbon dioxide removal: development and impact on ventilator management and survival during severe respiratory failure key: cord- -i cy authors: suzumoto, masaki; hotomi, muneki; billal, dewan s.; fujihara, keiji; harabuchi, yasuaki; yamanaka, noboru title: a scoring system for management of acute pharyngo-tonsillitis in adults date: - - journal: auris nasus larynx doi: . /j.anl. . . sha: doc_id: cord_uid: i cy objectives: the aim of this study was to develop and evaluate a scoring system for the management of acute pharyngo-tonsillitis. methods: we conducted a prospective study between may and june . patients with acute pharyngo-tonsillitis were evaluated for causative pathogens and were assessed clinical symptoms and pharyngo-tonsillar finding by a clinical scoring system. results: a total adult patients were enrolled in this study. streptococcus pyogenes were identified at . %. thirty-one viruses were also identified by pcr. they were adenovirus ( . %), influenza virus ( . %), rs virus ( . %), and human metapneumovirus ( . %). numbers of total white blood cells and levels of c-reactive protein showed a significant positive correlation with clinical scores (p < . ) and were also higher in cases with s. pyogenes. the clinical scores rapidly improved after the antimicrobial treatments in moderate cases and severe cases. conclusion: the current study strongly suggested that the clinical scoring system reflected disease severity well and would be very useful for evaluating clinical course and decision making for the antimicrobial treatment of acute pharyngo-tonisllitis. sore throat is one of the commonest respiratory symptoms in general practice and the vast majority of adults presenting sore throat have acute pharyngitis. acute tonsillitis also accompanies acute pharyngitis and is obvious from typical appearances of tonsils as crypts studded with purulent material or purulent exudations covering palatine tonsils [ , ] . the management of acute pharyngo-tonsillitis is an important issue for quality of care because this infectious disease is frequent in outpatients setting. most of cases are caused by viral infections and are self-limiting by only symptomatic treatments. approximately - % of cases in adults are caused by streptococcus pyogenes (s. pyogenes) and prescribed antimicrobial agents [ , , , , [ ] [ ] [ ] . in contrast to the rationale of managements for pharyngotonsillitis, antibiotics are actually prescribed to a majority of adult patients at approximately % [ , ] . the best way to manage adult patients with pharyngo-tonsillitis has still been controversial among countries [ , , [ ] [ ] [ ] ] . optimal management depends on both the clinical likelihood of infections with s. pyogenes and the relative importance assigned to the criteria to avoid over-use and/or under-use of antibiotics with preventing complications. it is important to develop a clinical scoring system easy to use and to assess accurate clinical features of acute pharyngo-tonsillitis with special emphasis on infections with s. pyogenes in adults [ , ] . we organized a nationwide prospective surveillance study group (pharyngo-tonsillitis study group: phatons) in japan during [ ] [ ] pharyngo-tonsillitis in comparison with clinical features. an appropriate scoring system was also developed and applied for evaluating severities and clinical course of acute pharyngo-tonsillitis. adult outpatients with acute pharyngo-tonsillitis between ages of and years old, irrespective of gender, were eligible and were enrolled in this prospective study. the diagnostic criteria for acute pharyngo-tonsillitis included sore throat, histories of fever, erythema of pharyngotonsillar mucosa, and, if any, tonsillar exudates. exclusion criteria included cases with complications that reduce antimicrobial treatments, antibiotics in preceding month, pregnancy, and immune deficiency including immunosuppressive medications. we designed the study as a prospective trial organized by a nationwide study groups (pharyngo-tonsillitis study group: phatons) during may -june . adult patients with pharyngo-tonsillitis were prospectively enrolled in this study. the severity and clinical courses of the disease were evaluated by a clinical scoring system (table ) . swabs from tonsillar crypts for identifying pathogens and blood examinations were performed at the first visit (day ). the patients were treated with or without antibiotics according to the severity of illness. briefly, the mild cases were treated with oral antibiotics or symptomatic management without antibiotics, the moderate cases were treated with oral antibiotics, and the severe cases were treated with oral or parenteral antibiotics. for the evaluation of relationship between doctors' habit of using and selecting antimicrobial agents and the severity of illness, antimicrobial agents were selected and used by physician's own decision. informed consent approved by the institutional review broad was obtained from the patients at the time of enrollment in the study. we assessed the severity and clinical course of the disease using a scoring system consisting of symptoms and pharyngo-tonsillar findings (table ) . we evaluated difficulties in a daily life, sore throat, and fever as symptoms and scored erythema and swelling of pharyngo-tonsillar mucosa and the presence of exudates or plugs in tonsils grading from (none) to (marked). severities of the disease were classified into three groups according to total scores. patients with total scores ! , - , and were assigned into severe group, moderate group and mild group, respectively. standard laboratory methods were performed to identify pathogenic bacteria according to the manual of clinical microbiology ( th edition). briefly, swabs from tonsillar crypts were cultured on sheep blood agar, chocolate agar and macconkey agar plates overnight at c in % co . haemophilus influenzae (h. influenzae) were determined by growth in chocolate but not in blood agar plates, catalase test, and requirement of x and v factor. haemophilus haemolyticus (h. haemolyticus) were differentiated from h. influenzae by haemolysis on blood agar plates. streptococcus pneumoniae (s. pneumoniae) were identified by optochin susceptibility and bile solubility. s. pyogenes were confirmed by latex agglutination with commercially available latex reagen (biomerieux, marcy l'etoile, france) and bacitracin susceptibility. suspected staphylococcus aureus (s. aureus) were identified by use of dnase testing and a staphaurex latex test (remel, lenexa, usa). the growth of bacteria was graded from to + . we applied pcr to identify adenovirus and rt-pcr to identify human metapneumo virus (hmpv), influenza virus a and b, and respiratory syncytial (rs) virus a and b. swabs from tonsillar crypts were suspended into minimum essential medium (mem) with penicillin and streptomycin. nucleic acid including rna and dna were purified using high pure viral nucleic acid purification kit (roche, basel, switzerland). the final amplified products were separated by electrophoresis on % agarose gels and visualized by ethidium bromide. statistical analysis of data was performed using nonparametric test. comparisons between two groups were assessed by tukey-kramer analysis. comparisons of clinical outcomes of the disease were assessed by wilcoxon signed-rank test. correlation between clinical scores and numbers of wbc or levels of crp were assessed pearson regression analysis. statistical tests were based on a level of significance of p-value less than . . calculations were performed using the statistical software package jmp . . (sas institute, inc., cary, nc, usa). a total adult patients with pharyngo-tonsillitis were enrolled in this study. during a study patients were dropped out for incomplete follow-up and patients ( . %) were finally evaluated for causative pathogens and clinical outcomes of the disease. they were males and females, ranging in ages between and years old (mean . years old). acute pharyngitis is a painful inflammation of the mucosa of the pharynx. acute pharyngitis includes a sore throat and is characterize by signs of erythema of pharyngeal mucosa. acute tonsillitis is an infectious inflammation of the pharyngeal tonsils. acute tonsillitis accompanying acute pharyngitis includes a severe sore throat, painful and difficult swallowing, fever and chills and is characterize by signs of red, swollen tonsils which have a purulent exudative coating of white pus. the characteristics of illness in this study were classified in cases with acute tonsillitis and cases with acute pharyngitis (table ) . a total pathogenic bacteria were identified in ( . %) out of a total patients. the organisms were s. pyogenes ( isolates, . %), hemolytic streptococci ( isolates, . %), h. influenzae ( isolates, . %), h. haemolyticus ( isolates, . %), s. aureus ( isolates, . %), s. pneumoniae ( isolates, . %), m. catarrhalis ( isolates, . %), and others ( isolates, . %) ( table ). there were no significant differences in distribution of bacteria between acute tonsillitis and pharyngitis. thirty-one viruses were identified by pcr. they were adenovirus ( out of cases, . %), influenza virus ( out of cases, . %), rs virus ( out of cases, . %), and hmpv ( out of cases, . %) ( table ) . among cases in which both bacterial culture and virus pcr were performed, bacteria alone were identified in cases ( . %), virus alone were identified in cases ( . %), both bacteria and virus were identified in cases ( . %). in cases ( . %) neither bacteria nor virus was identified. both severities of disease and inflammatory parameters were compared with pathogens. although s. pyogenes together with hemolytic streptococci, h. influenzae, h. haemolyticus, s. aureus, s. pneumoniae, m. catarrhalis were frequently identified among patients with acute pharyngotonsillitis, the clinical scores were not different among those (fig. a) . on the other hands, the numbers of total wbc at the first visit were significantly higher in cases with s. pyogenes than cases with other pathogens (fig. b) . the levels of crp were significantly higher in cases with s. pyogenes than in cases with s. aureus and m. catarrhalis ( p < . ) (fig. c) . patients were classified into ( . %) mild cases, ( . %) moderate cases, and ( . %) severe cases according to the criteria by clinical scores. the ratio of acute tonsillitis and pharyngitis according to the severities were . % and . % in mild cases, . % and . % in moderate cases, and . % and . % in sever cases, respectively. total numbers of wbc at the first visit showed a positive correlation with clinical scores (r = . , p < . ) (fig. ) . the mean ae s.d. of wbc in mild cases, moderate cases, and severe cases were ae cells/mm , ae cells/mm , and , ae cells/mm , respectively. the levels of crp at the first visit were also showed a positive correlation with clinical scores (r = . , p < . ) (fig. ) . the mean ae s.d. of crp in mild cases, moderate cases, and severe cases were . ae . mg/dl, . ae . mg/dl, and . ae . mg/dl, respectively. the frequencies of isolations of pathogenic microorganisms did not differ regarding the severities of the disease. the clinical outcomes were evaluated by a scoring system according to the severities of the disease (fig. a and b) . in mild cases, ( . %) patients followed up without antibiotics and improved scores gradually whereas ( . %) patients were treated with oral antibiotics (ampc: . %, lvfx: . %, cfpn: . %). in moderate cases, ( . %) patients were treated with antibiotics and patients ( . %) were treated with ampc ( patients, . %) or lvfx ( patients, . %). all severe cases were treated with antibiotics. seven patients ( . %) were treated with ampc and patients ( . %) were treated with lvfx. in the severe cases, patients ( . %) were treated with parenteral antibiotics. among those patients, patients ( . %) were treated with ctrx. the clinical scores of moderate and severe cases were significantly improved after antimicrobial treatments ( p < . ). because of a wide range of illness with sore throat, diagnosis of acute pharyngitis is still troublesome for primary care physicians. in the current study, we defined causative pathogens and the severity of acute pharyngo- tonsillitis by a clinical scoring system in adult patients. most of acute pharyngo-tonsillitis were reported to be caused by viruses such as adenovirus, rhinovirus, corona virus, parainfluenza virus, coxackie virus, influenza virus, herpes virus, and cytomegalovirus and were considered to be selflimiting [ , ] . in this study, the frequencies of viruses in adult acute pharyngo-tonsillitis were lower rather than those reported in children, when we applied pcr/rt-pcr to identify four important viruses such as rs virus, adenovirus, influenza virus, and hmpv from pharyngeal swab. the implication of viral infections might be low in adult acute pharyngo-tonsillitis [ , ] . bacteria were identified in . % of patients studied herein. s. pyogenes that had been reported as an important causative pathogen responsible for acute pharyngo-tonsillitis were identified at . % [ , , ] . other hemolytic streptococci were also frequently identified from the patients with acute pharyngotonsillitis. however, the pathogenic roles of group c or g streptococci in the upper respiratory tract infections have not been completely studied. the haemophilus spp. and staphylococcus spp. are more controversial. isolation of s. pyogenes was closely related with the high value of inflammatory parameters such as white blood cells and creactive protein compared to isolation of other pathogens. determinations of infections due to s. pyogenes have been an important issue for studying acute pharyngotonsillitis [ , , , ] . several clinical findings have the discriminative value in distinguishing s. pyogenes from other causes of acute pharyngo-tonsillitis. the ability of experienced physicians to predict positive throat cultures of s. pyogenes is moderate with estimated sensitivity and specificity ranging from to % and to %, respectively. in an attempt to improve clinical sensitivity and specificity, investigators have developed clinical decision rules based on constellation of physical signs and symptoms [ , , ] . the centor score has been the most reliable predictors for estimating the likelihood of infections of s. pyogenes in a patients presenting with a sore throat [ ] . the score is calculated by determining how many of the following four clinical features are present: history of fever, tonsillar exudates, anterior cervical adenopathy, and absence of cough. at the usual clinical setting, the majority of primary care physicians prescribe antimicrobial agents and pain-killers based on the severity of illness [ ] . although the center score is useful to infer s. pyogenes, the score is not valuable for diagnosis of the severity of the illness. a rapid antigen detection kit for s. pyogenes using a latex agglutination method also applied to determine infections with s. pyogenes. the test showed negative predicting value at % and relatively lower positive predicting value at % [ ] . there has been a general consensus that negative rapid antigen tests for s. pyogenes should be confirmed by the culture test [ ] . however, recent guidelines have suggested that confirmation of negative rapid antigen test results for s. pyogenes in adults is either not necessary at all or only if the sensitivity of the rapid antigen test is < % [ , ] . the rapid antigen tests has the lower sensitivity compared to a well-performed culture. therefore, the importance of rapid identification of s. pyogenes is still controversial. we applied a scoring system based on symptoms and clinical findings to diagnose the severity of acute pharyngotonsillitis in this study. the scoring system reflected severities of the illness correlated well with numbers of wbc and levels of crp. although we could not found any correlations between identification of s. pyogenes and severity of the disease, identification of s. pyogenes clearly correlated with numbers of wbc and levels of crp. regarding to antibiotic treatment, it is important to discriminate causative agents such as bacterial and/or virus infection in acute pharyngo-tonsillitis. however, it is sometimes difficult to discriminate them in the usual clinical setting. the current study was also designed to evaluate correlation among clinical parameters such as clinical scores, wbc, and crp. viruses were identified in only ( . %) patients and there were no correlation between identification of viruses and numbers of wbc or levels of crp. in contrast, the numbers of total wbc and the levels of crp at the first visit were significantly higher in cases with s. pyogenes indicationg the importance of s. pyogenes as the causative pathogen for acute pharyngotonsillitis. thus, the clinical scoring system together with blood test could discriminate the possible bacterial infections from virus infections. we further confirmed the usefulness of the clinical scoring system to evaluate the efficacy of antimicrobial treatments on acute pharyngo-tonsillitis. the study on the difference of treatment outcomes among various age groups reported that group a b-hemolytic streptococcus required antibiotic therapy [ , ] . in this study, a marked reduction of clinical scores after antimicrobial treatments in severe and moderate cases indicated high efficacy of them for the illness with higher severity. on the other hand, mild cases showed decrease of scores regardless of antimicrobial treatments. thus, the current study strongly suggested that the clinical scoring system reflected disease severity well and would be very useful for evaluating clinical course and decision making for the antimicrobial treatment of acute pharyngo-tonisllitis. practice guidelines for the diagnosis and management of group a streptococcal pharyngitis diagnosis and management of group a streptococcal pharyngitis: a practice guideline. infectious disease society of america appropriate use of antibiotics: pharyngitis diagnosis of strep throat in adults: are clinical criteria really good enough? acute pharyngitis roles of the microbiology laboratory in diagnosis and management of pharyngitis a simple scorecard for the tentative diagnosis of streptococcal pharyngitis understanding the culture of prescribing: qualitative study of general practioners' and patients' perceptions of antibiotics for sore throat the diagnosis of strep throat in adults in the emergency room principles of appropriate antibiotic use for acute pharyngitis in adults: background do patients with sore throat benefit from penicillin? a randomized double-blind placebocontrolled clinical trial with penicillin v in general practice effect of penicillin on the clinical course of streptococcal pharyngitis in general practice a scoring system for predicting group a streptococcal throat infection the rational clinical examination. does this patient have strep throat role of beta-hemolytic group c streptococci in pharyngitis: incidence and biochemical characteristics of streptococcus equisimilis and streptococcus anginosus in patients and healthy controls principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: background, specific aims, and methods the prevalence of bhaemolytic streptococci in throat specimens from healthy children and adults, implications for the clinical value of throat cultures a randomized controlled trial of antibiotics on symptom resolution in patients presenting to their general practitioner with a sore throat pharyngitis in adults: the presence and coexistence of viruses and bacterial organisms susceptibility of group a beta-hemolytic streptococci to thirteen antibiotics: examination of strains isolated in the united states between detection of group a streptococci in the laboratory or physician's office. culture vs antibody methods suitability of throat culture procedures for detection of group a streptococci and as reference standards for evaluation of streptococcal antigen detection kits streptococcal pharyngitis. placebo-controlled double-blind evaluation of clinical response to penicillin therapy antibiotic treatment of adults with sore throat by community primary care physicians: a national survey clinical and psychosocial predictors of illness duration from randomized controlled trial of prescribing strategies for sore throat reattendance and complications in a randomized trial of prescribing strategies for sore throat; the medicalizing effect of prescribing antibiotics open randomized trial of prescribing strategies in managing sore throat sore throat management in general practice molecular assays for detection of human metapneumovirus a clinical score to reduce unnecessary antibiotic use in patients with sore throat role of metapneumovirus in viral respiratory infections in young children the accuracy of experienced physicians' probability estimates for patients with sore throat. implications for decision making optimal management of adults with pharyngitis-a multi-criteria decision analysis principles of appropriate antibiotic use for acute pharyngitis in adults diagnosis of pharyngitis: clinical and epidemiological features perplexity and precision in the diagnosis of streptococcal pharyngitis use of a high-sensitivity rapid strep test without culture confirmation of negative results: years' experience we greatly thank to prof. edward l. kaplan, m.d. (department of pediatrics, the university of minneapolis, usa) for his suggestion to this paper. these works were organized by a nationwide surveillance group for adult acute pharyngo-tonisllitis (pharyngo-tonsillitis study group: phatons). we greatly thank to all members of phatons. we also express our hearty thanks to miss yuki tatsumi for her technical assistances. this study was supported for funding by daiichi pharmaceutical co., ltd. (presently daiichi-sankyo, post-merger). key: cord- -sewfb q authors: kang, xixiong; xu, yang; wu, xiaoyi; liang, yong; wang, chen; guo, junhua; wang, yajie; chen, maohua; wu, da; wang, youchun; bi, shengli; qiu, yan; lu, peng; cheng, jing; xiao, bai; hu, liangping; gao, xing; liu, jingzhong; wang, yiping; song, yingzhao; zhang, liqun; suo, fengshuang; chen, tongyan; huang, zeyu; zhao, yunzhuan; lu, hong; pan, chunqin; tang, hong title: proteomic fingerprints for potential application to early diagnosis of severe acute respiratory syndrome date: - - journal: clin chem doi: . /clinchem. . sha: doc_id: cord_uid: sewfb q background: definitive early-stage diagnosis of severe acute respiratory syndrome (sars) is important despite the number of laboratory tests that have been developed to complement clinical features and epidemiologic data in case definition. pathologic changes in response to viral infection might be reflected in proteomic patterns in sera of sars patients. methods: we developed a mass spectrometric decision tree classification algorithm using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. serum samples were grouped into acute sars (n = ; < days after onset of fever) and non-sars [n = ; fever and influenza a (n = ), pneumonia (n = ); lung cancer (n = ); and healthy controls (n = )] cohorts. diluted samples were applied to wcx- proteinchip arrays (ciphergen), and the bound proteins were assessed on a proteinchip reader (model pbs ii). bioinformatic calculations were performed with biomarker wizard software . . (ciphergen). results: the discriminatory classifier with a panel of four biomarkers determined in the training set could precisely detect of (sensitivity, . %) acute sars and of (specificity, . %) non-sars samples. more importantly, this classifier accurately distinguished acute sars from fever and influenza with % specificity ( of ). conclusions: this method is suitable for preliminary assessment of sars and could potentially serve as a useful tool for early diagnosis. causative agent for sars ( , ) . rapid progress has also been made in the determination of its genome sequences ( - ) and the molecular evolution of the coronavirus ( ) . identification of angiotensin-converting enzyme as the viral receptor provided further information toward deciphering its molecular mechanisms of infection ( ) . despite such advances in virologic studies, early diagnosis of sars has been based primarily on the clinical definitions released by who and cdc ( , ) , which can be confusing or contradictory ( ) . available serologic tests cannot guarantee an early diagnosis ( ) , and pcrbased molecular detection of the viral rna suffers from unsatisfactory sensitivity and specificity ( , ( ) ( ) ( ) . in the last year, failure to develop diagnostic tests for sars, especially in the acute phase, severely impacted specific prevention and treatment measures for sars. there is a need to establish a reliable diagnostic methodology for sars-cov, in particular, to distinguish the similar clinical manifestations of sars and other respiratory tract infections. this urgency is reinforced by the first sars case not linked to laboratory contamination, which occurred in guangdong, china this year ( ) . proteomic analysis has provided a unique tool for the identification of diagnostic biomarkers, evaluation of disease progression, and drug development ( , ) . surfaceenhanced laser desorption/ionization time-of-flight mass spectrometry (seldi-tof ms) enables rapid, reproducible protein/peptide profiling of multiple disease-specific biomarkers directly from crude samples (e.g., tissue cell lysates or body fluids) ( , ) . small amounts of sample can be applied directly to a biochip coated with specific chemical matrices (e.g., hydrophobic, cationic, or anionic) or specific biochemical materials such as dna fragments or purified proteins. the bound proteins/peptides can then be analyzed by ms to obtain the protein fingerprints, or even amino acid sequence determinants, when interfaced to a mass spectrometric microsequencing device. analogous to the proteomic detection of various cancers ( , ) , we used a weakly cationic proteinchip (wcx chip surface) to retrospectively analyze sars sera to determine whether there are distinct and reproducible protein fingerprints potentially applicable to the diagnosis of sars. we established a decision tree algorithm consisting of four unique biomarkers for acute sars in the training set and subsequently validated the accuracy of this classifier by use of a completely blinded test set. more than serum specimens from suspected/probable sars patients admitted to major hospitals in the beijing area between april and june , , were eligible for inclusion. the serum procurement, data management, and blood collection protocols were approved by the beijing sars-control working group and were in accordance with who biosafety guidelines ( ) . among the retrospective samples, only were selected from probable patients whose blood samples were collected with onset of fever within days at the time of admission (acute sars patients; table ). probable cases were based on the eligibility criteria set forth by who ( ) . these cases had also radiographic evidence of infiltrates consistent with pneumonia or respiratory distress syndrome on chest x-ray. the paired convalescent serum samples from the sars cohort tested positive for igm seroconversion by the ifa method (beijing genomics institute), and four samples also tested positive in a dna array test using nasopharyngeal samples. the non-sars control se- the patients and serum samples were then divided into two groups: one for the "training" set and the other for the blinded "test" set (tables and ). sars and non-sars control sera were all stored at Ϫ °c in -l aliquots. before each round of mass spectrometric assays, we routinely performed quality control of serum samples by the appearance and peak intensity of m/z . (fig. a ). because the peak intensity of m/z . remained relatively constant among spectra from different assays and different instruments, it was also used for normalization between each round of analyses. three different chip chemistries (hydrophobic, anionic, and cationic) were first evaluated to determine which affinity chemistry gave the best serum profiles in terms of the number and resolution of proteins. the weakly cationic exchange chip (wcx) gave the best results with mass spectra from to kda. the wcx chips in an -well bioprocessor format (ciphergen) were chosen to allow a larger volume of serum for the chip array. the bioprocessor was pretreated with l of mmol/l sodium acetate (ph ) on a platform shaker at rpm for min. the excess sodium acetate was removed by inverting the bioprocessor on a paper towel. this process was repeated twice. the serum samples were thawed on ice in a biosafety level ii cabinet, and l of each sample was mixed with l of u buffer ( mol/l urea, g/l chaps in phosphate-buffered saline) in a . -ml eppendorf tube and vortex-mixed at °c for min. we then added l of u buffer [u buffer diluted by ninefold ( ml of u buffer plus ml of tris-hcl) with mmol/l tris-hcl (ph )] to the serum/urea mixture, vortex-mixed it for min, and stopped the reaction by addition of l of sodium acetate on ice. we applied l of the serum/urea sample to each well, and the bioprocessor was sealed and shaken on a platform shaker at rpm for min. the excess serum/urea solution was discarded, and the bioprocessor was washed three times with mmol/l sodium acetate as described above. the chips were removed from the bioprocessor, washed twice with deionized water, and air-dried. subsequently . l of eam sinapinic acid saturated in ml/l acetonitrile- g/l trifluoroacetic acid was added to each well. after air-drying, the sinapinic acid application was repeated. chips were then placed in the protein biological system ii (pbs ii) mass spectrometer reader (ciphergen), and tof spectra were generated by an average of laser shots collected in the positive mode. the settings for low-energy readings were set with a high mass of kda and were optimized from to kda at a laser intensity of , detector sensitivity of , and a focus by optimization center. high-energy readings were set with a high mass of kda and were optimized from to kda at a laser intensity of and a detector sensitivity of . mass accuracy was calibrated externally by use of the all-in-one peptide molecular mass calibrator (ciphergen). sera from a healthy control were individually applied to seven bait surfaces of eight wcx chips and run during -day intervals for analysis of within-run reproducibility. in parallel, samples ( from sars patients, from patients with fever, from patients with pneumonia, and from health controls) were applied in duplicate to a single chip and run on two different instruments (pbs ii and pbs iic; ciphergen) for between-run analysis of instrument drift. to avoid the possibility that placement or run order of samples would affect assay accuracy, samples were loaded on chips in a rotational fashion. in in the pericardium (n ϭ ), upper right clavicle (n ϭ ), lymph nodes (n ϭ ), liver (n ϭ ), and brain (n ϭ ); accompanying hydrothorax was also observed in nine patients. brief, sample was spotted on the -well directional chip (wells a to h) in duplicate in wells a and b and then in wells g and h of the second chip. samples , , and were loaded on chips in the same rotation order. we also randomized the order of chip placement in the spectrometer to minimize bias from run order. spectra were collected for each sample and analyzed independently using the classification algorithm established in the training step. the peak at m/z . in the quality-control serum was adjusted to have an intensity of - for both the pbs ii and pbs iic. the peak intensity of m/z . in the quality-control serum was used to normalize instrument resolution between the pbs ii and pbs iic. we normalized spectra using total ion current with an identical normalization coefficient and a low mass cutoff Ͻ da. if the factor was Ͻ . or Ͼ . after normalization to total ion current for the peak at m/z , repeated runs would be performed. no outlier was rejected in the test. the "root" biomarker, m/z , yielded the lowest and similar p value in both the pbs ii and pbs iic. peak detection was performed with biomarker wizard software . . (ciphergen). the m/z ratios between and were selected for analysis because this range contained the majority of the resolved protein and peptides. the m/z range between and was eliminated from analysis to avoid interference from adducts, artifacts of the energy-absorbing molecules, and other possible chemical contaminants. peak detection involved baseline subtraction, mass normalization using a common calibrant peak (m/z . ), and normalization to the total ion current intensity with a minimum m/z of , using an external normalization coefficient of . (normalization factor for individual spectrum ϭ . /average ion current for each spectrum) for spectra obtained at different times or locations. the settings used for autodetect peaks to cluster in the first pass were a signal-to-noise ratio of and a minimum peak threshold of % of all spectra. the peak clusters were completed by second-pass peak detection using a signal-to-noise ratio of and . % of mass for the cluster window. an average of peaks was detected in each spectrum. the mass range from to kda was analyzed in parallel. analytical procedure data analysis.the data analysis process used in this study involved three stages: (a) peak detection and alignment; (b) selection of peaks with the highest discriminatory power; and (c) data analysis using a decision tree algorithm. a random sampling (acute sars, fever, pneumonia, lung cancer, and healthy) with two strata (acute sars and non-sars) was used to separate the entire data set into training and test data sets. the training data set consisted of seldi spectra from acute sars and non-sars serum samples. the validity and accuracy of the classification algorithm were then challenged with a blinded test data set consisting of acute sars and non-sars samples. decision tree classification. construction of the decision tree classification algorithm was performed as described previously ( ) with modifications based on the biomarker patterns software (ciphergen). classification trees were split into two branches or nodes, using one rule at a time. we set target the variable level at and the minimum value at , and the decision was made based on the presence or absence and the intensity of one peak, using the gini or twoing method, favoring even splits from . to . and varied by . each time, and with v-fold cross-validation from to changed by for the growth of trees. the lowest cost tree (value ϭ . ; gini ϭ . ; v-fold ϭ ) was selected for the final test. to identify the serum biomarkers that could distinguish sars from non-sars samples, we used a training set of specimens ( sars acute and controls; tables and ) and constructed the decision tree classification algorithm using peaks [ peaks ϫ ( ϩ ) spectra] of statistical significance identified in the low energy readings (see materials and methods). the classification algorithm used four peaks between and kda (m/z . , . , . , and . ) and generated five terminal nodes (fig. ) . these discriminatory peaks efficiently split sars specimens into terminal nodes and and non-sars samples into terminal nodes , , and . each mass peak showed a mean intensity ratio of sars vs non-sars Ͼ and a p value close to (table ) . notably, the protein or peptide with masses at . , . , and . da was up-regulated in patients with acute sars, whereas that of a mass at . da was down-regulated compared with healthy controls or patients with respiratory tract infections. a representative spectrum of a sars specimen aligned with that of a healthy control ( fig. a) showed the four fingerprints in node required for pattern recognition in the classifier. the unique presence of the root biomarker, m/z . , is demonstrated in the alignment of representative spectra of samples from patients with acute sars ( , , , and days after the onset of fever; from terminal node ) and those from healthy controls and patients with fever and influenza or pneumonia (fig. b) . this decision algorithm correctly classified of ( %) of the acute sars samples and of ( . %) of the non-sars controls in the training set ( table ) . the above classifier used only those masses in the low-energy readings (m/z Ͻ ). to exhaust all meaningful serum biomarkers, we expanded the analysis of the same training samples in the high-energy setting (m/z combine two energy settings for analysis, we reasoned that the decision tree generated with only low-energy readings (fig. ) would be more sensitive ( %) and more convenient for a clinical application. to determine the reproducibility of seldi spectra, mass location, and intensity from array to array on a single chip (intraassay) and between instruments (interassay), we first spotted the serum from a healthy control on seven baits in a single chip and collected seven independent spectra over a time span of days (fig. a) . we then selected seven proteins in the range of - kda (m/z . , . , . , . , . , . , and . ; black arrows in fig. a ) to calculate the intraassay cv. these peaks were selected because they were in the proximity of the four biomarkers with comparable current intensities. the interassay experiments were similar except that sera from healthy controls and from patients with high fever, pneumonia, and sars were applied to a single chip, and the independent spectra were collected from two different instruments (pbs ii and pbs iic; fig. , b and c). the mean intra-and interassay cvs for peak location were . % and . %, respectively. we considered masses with accuracies within . % between spectra to be the same. the mean intra-and interassay cvs for the normalized intensity were % and %, respectively. cv calculations using lower intensity peaks (fig. a, gray arrowheads) , on the other hand, yielded results similar to those obtained with the seven high-intensity peaks (peak location, intra-and interassay cvs both . %; peak intensity, intraassay cv ϭ % and interassay cv ϭ %). analysis of spectra from the completely blinded test set ( acute sars and controls; tables and ) accurately classified of ( . %) sars specimens and accurately classified of ( . %) of the controls as non-sars (table ). more important was that the classification algorithm successfully distinguished acute sars from fever and influenza, with a sensitivity and specificity reaching . % ( of ) and % ( of ; of with influenza), respectively. interestingly, when we tested the classifier using an additional control population of samples from patients in the beijing area with measles after july , , who had no history of close contact with sars patients and had not visited those hospitals treating sars patients, the classifier had a specificity of % ( % confidence interval, - %; data not shown). several laboratory tests, based on either viral rna ( , , ) or serology ( , ) , have been developed to complement clinical characteristics and epidemiologic data in the identification of sars, but early detection of sars with sufficiently high sensitivity and specificity has not been achieved. the identification of proteins/peptides of pathophysi- fig. . intra-and interassay reproducibility. (a), example of intraassay reproducibility of mass spectra and tree decision classification. serum from an unaffected healthy control was individually applied to seven bait surfaces on eight chips, and seven randomly selected peaks (arrows) in each spectrum over a course of days were used as surrogate markers for calculation of cv. the reproducibility of seldi spectra, mass location, and intensity from spectrum to spectrum was determined accordingly. ologic significance (phenomic fingerprints) in crude biological and clinical samples by seldi-tof ms has been demonstrated in various cancer studies ( ) . using a similar profiling strategy, we have established a classification algorithm that delineates probable sars patients as early as day after self-described onset of symptoms from healthy individuals and from patients with respiratory tract infections in the training set (sensitivity ϭ %; specificity ϭ . %). when applied to the blinded test set, this discriminatory profiling method precisely classified . % of patients with acute sars and . % of non-sars patients. more strikingly, our classifier was able to discriminate sars-cov infection from bacterial (mycoplasma, tuberculosis) and other local (influenza) or systemic (measles) viral infections of the respiratory tract with a specificity reaching %. this was attributable to the inclusion of corresponding inflammatory control samples in the training set and optimization of the classification algorithm. the biomarkers identified in the acute phase of sars seemed to remain throughout the convalescent phase of the disease because when we applied the identical tree classification to samples from patients in whom onset of fever had been Ͼ , , , and Ͼ weeks previously, we could detect sars with sensitivities and specificities reaching . % and . %, . % and . %, . % and . %, and . % and . %, respectively (data not shown). one intriguing observation was that sars patients clustering in terminal node all demonstrated moderate clinical features, whereas those in node were severe cases. we are investigating the correlation between this proteomic pattern and the pathology of sars. these results represent, to the best of our knowledge, the most accurate laboratory technique for early detection of sars: pcr-based assays have a maximum sensitivity of % when used to test nasopharyngeal aspirates or plasma specimens ( , ) . the proteomic method described here also has advantages over pcr-based assays in that it does not require bsl- containment and it can detect sars in serum samples. this is a critical alternative to pcr-based tests, which are challenged by low viral loads in nasopharyngeal aspirates and throat swab specimens in the acute phase of sars. instead of traditional chromatographic fractionation of samples, we directly spotted the crude serum on the wcx chips. by doing this we avoided the unnecessarily biased depletion of thousands of proteins and/or peptides associated with human serum albumin before ms analysis. processing of samples and generation of the diagnostic mass spectra by our method required only a small amount of serum ( l vs several milliliters needed for pcr methods) and took Ͻ h. high-throughput proteomic screening for sars in a -well format is also feasible. we adhered to the who case definition and eligibility criteria for sars and avoided using samples from non-sars controls from hospitals where sars patients had been admitted because these persons might have a history of close contact with sars patients or had been inside those sars hospitals. we further emphasized this point by sampling control sera from a nonepidemic region of the country. although the possibility might exist that the difference in serum fingerprints would reflect differences among sars and non-sars hospitals, the fact that all sars cases from different hospitals fit into the single classification algorithm would likely rule out such a concern. more importantly, severe and mild cases of sars from different hospitals, which had been completely randomized in the experimental analysis, fell into distinct nodes of the tree classification, strongly indicating that the biomarkers we have identified were specific to sars and not the sites at which blood samples were collected. we further minimized the potential sampling bias by simultaneously using four biomarkers instead of one (e.g., m/z . ), which nevertheless could sufficiently delineate sars from non-sars (sensitivity ϭ . %; specificity ϭ . %; data not shown). all sars and non-sars samples were from patients with the same ethnic background. sars and non-sars control sera collected at different times were all freshly aliquoted and properly stored at Ϫ °c. the differential protein pattern as the discriminator between sars and non-sars is independent of protein identities. the origins and full identities of the discriminating biomarkers are under investigation. to know their identities for the purpose of differential diagnosis is not absolutely required, as shown by numerous studies showing diagnosis of cancers by seldi methods. however, to characterize these peaks would certainly help in understanding the biological roles of these peptide/proteins and could potentially lead to the discovery of more direct diagnostic tools and novel therapeutic targets for sars-cov. cumulative number of reported probable cases of sars epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong identification of a novel coronavirus in patients with severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome identification of severe acute respiratory syndrome in canada coronavirus as a possible cause of severe acute respiratory syndrome newly discovered coronavirus as the primary cause of severe acute respiratory syndrome koch's postulates fulfilled for sars virus characterization of a novel coronavirus associated with severe acute respiratory syndrome the genome sequence of the sars-associated coronavirus comparative full-length genome sequence analysis of sars coronavirus isolates and common mutations associated with putative origins of infection sars-beginning to understand a new virus angiotensin-converting enzyme is a functional receptor for the sars coronavirus updated interim u.s. case definition of severe acute respiratory syndrome (sars) case definitions for surveillance of severe acute respiratory syndrome (sars) clinical presentations and outcome of severe acute respiratory syndrome in children clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study quantitative analysis and prognostic implication of sars coronavirus rna in the plasma and serum of patients with severe acute respiratory syndrome rapid diagnosis of a coronavirus associated with severe acute respiratory syndrome (sars) laboratory confirmation of a sars case in southern china disease proteomics biomedical informatics for proteomics clinical proteomics translating benchside promise to bedside reality seldi proteinchip ms: a platform for biomarker discovery and cancer diagnosis use of proteomic patterns in serum to identify ovarian cancer serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men who biosafety guidelines for handling of sars specimens proteomic applications for the early detection of cancer detection of sars coronavirus in plasma by real-time rt-pcr crouching tiger, hidden dragon: the laboratory diagnosis of severe acute respiratory syndrome key: cord- -p c fneh authors: bosma, karen j.; taneja, ravi; lewis, james f. title: pharmacotherapy for prevention and treatment of acute respiratory distress syndrome: current and experimental approaches date: - - journal: drugs doi: . / - - sha: doc_id: cord_uid: p c fneh the acute respiratory distress syndrome (ards) arises from direct and indirect injury to the lungs and results in a life-threatening form of respiratory failure in a heterogeneous, critically ill patient population. critical care technologies used to support patients with ards, including strategies for mechanical ventilation, have resulted in improved outcomes in the last decade. however, there is still a need for effective pharmacotherapies to treat ards, as mortality rates remain high. to date, no single pharmacotherapy has proven effective in decreasing mortality in adult patients with ards, although exogenous surfactant replacement has been shown to reduce mortality in the paediatric population with ards from direct causes. several promising therapies are currently being investigated in preclinical and clinical trials for treatment of ards in its acute and subacute, exudative phases. these include exogenous surfactant therapy, β( )-adrenergic receptor agonists, antioxidants, immunomodulating agents and hmg-coa reductase inhibitors (statins). recent research has also focused on prevention of acute lung injury and acute respiratory distress in patients at risk. drugs such as captopril, rosiglitazone and incyclinide (col- ), a tetracycline derivative, have shown promising results in animal models, but have not yet been tested clinically. further research is needed to discover therapies to treat ards in its late, fibroproliferative phase. given the vast number of negative clinical trials to date, it is unlikely that a single pharmacotherapy will effectively treat all patients with ards from differing causes. future randomized controlled trials should target specific, more homogeneous subgroups of patients for single or combination therapy. the acute respiratory distress syndrome (ards) arises from direct and indirect injury to the lungs and results in a life-threatening form of respiratory failure in a heterogeneous, critically ill patient population. critical care technologies used to support patients with ards, including strategies for mechanical ventilation, have resulted in improved outcomes in the last decade. however, there is still a need for effective pharmacotherapies to treat ards, as mortality rates remain high. to date, no single pharmacotherapy has proven effective in decreasing mortality in adult patients with ards, although exogenous surfactant replacement has been shown to reduce mortality in the paediatric population with ards from direct causes. several promising therapies are currently being investigated in preclinical and clinical trials for treatment of ards in its acute and subacute, exudative phases. these include exogenous surfactant therapy, b -adrenergic receptor agonists, antioxidants, immunomodulating agents and hmg-coa reductase inhibitors (statins). recent research has also focused on prevention of acute lung injury and acute respiratory distress in patients at risk. drugs such as captopril, rosiglitazone and incyclinide (col- ), a tetracycline derivative, have shown promising results in animal models, but have not yet been tested clinically. further research is needed to discover therapies to treat ards in its late, fibroproliferative phase. given the vast number of negative clinical trials to date, it is unlikely that a single pharmacotherapy will effectively treat all patients with ards from differing causes. future randomized controlled trials should target specific, more homogeneous subgroups of patients for single or combination therapy. acute lung injury (ali) and the acute respiratory distress syndrome (ards) arise from direct or indirect injury to the lungs, and results in a life-threatening form of respiratory failure. ali/ards is both common and serious: . - . % of patients admitted to an intensive care unit (icu) will be diagnosed with ali or ards, [ ] [ ] [ ] and approximately one-quarter to one-half of these patients will succumb to this disease process. [ , [ ] [ ] [ ] over the past years, ards has been the focus of extensive basic science and clinical research, although no single pharmacotherapy has been shown to reduce mortality in a large, randomized, controlled, multicentre trial of adult patients. the reasons for this are manifold, and include issues of dosing, route of administration and timing of the various interventions tested. more importantly, however, may be the nature of the disorder itself: the diagnosis of ards envelops a heterogeneous group of patients with varying causes and pathophysiological mechanisms at work. the notion that a therapeutic agent that can successfully alter a single biological target in an animal model of ali will reduce mortality in all patients with ards may be unrealistic. nonetheless, there is reason for hope on the scientific horizon. recent advances have been made in our understanding of the pathophysiological mechanisms underlying ali/ards, leading to the identification of potential novel targets for pharmacological intervention. some therapies are best aimed at preventing the development of ards, while others treat the syndrome as it unfolds or aid in its resolution. the challenge lays in identifying the subgroup of patients most likely to benefit from such focused therapy. this paper reviews the current experimental and existing approaches to managing ards, highlighting the pathophysiological basis for their use and potential for future clinical development. ali may occur following a direct insult to the pulmonary system such as aspiration of gastric contents, bacterial pneumonia or viral pneumonitis (e.g. h n influenza virus), or an indirect insult such as the systemic inflammatory response associated with pancreatitis, sepsis or multiple trauma. table i shows common direct and indirect causes of ali/ards. whether this 'first hit' to the lung is direct or indirect, a pulmonary inflammatory response may occur, which often is adaptive and self-limited. however, when coupled with repeated 'hits' to the lung from insults such as injurious mechanical ventilation or other secondary processes such as hypotension, a cycle of intense inflammation and worsening pulmonary injury ensues. the 'multiple hit' theory of ards progression also provides a framework for studying the disease process (figure ). clinically, ali manifests as bilateral airspace disease observed on chest radiograph and hypoxaemia, such that the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (pao /fio ) is greatly reduced. according to the american european consensus conference (aecc) definition, a chest radiograph consistent with pulmonary oedema and a pao /fio ratio < is sufficient to diagnose ali in the setting of an inciting pulmonary insult and the absence of congestive heart failure. the aforementioned criteria but with a pao /fio ratio < is classified as ards. [ ] although differentiated by the aecc definition, ali and ards are often grouped together for the purpose of clinical trial enrolment and are treated as a single entity throughout this review. although not all patients follow the same clinical course, progression of ali/ards may be considered along a pathophysiological timeline of early, mid and late phases, with considerable overlap between these phases. table ii summarizes the pathogenetic mechanisms at work during each phase, linking each biological pathway to a potential drug therapy. a general overview of the pathophysiology of ards is provided here, with more detailed descriptions of the specific biologic pathways discussed in sections . - . as they pertain to each potential pharmacological therapy. the early phase, within the first hours of the inciting lung injury, is characterized by inflammatory damage to the alveolar-capillary barrier. this results in increased vascular permeability, leading to interstitial and alveolar oedema as proteinaceous fluid fills the alveolar space. this inflammation-induced pulmonary oedema disrupts normal gas exchange and increases the work of breathing, leading to respiratory failure and the need for mechanical ventilation. mechanical ventilation itself may cause secondary insult to the already inflamed oedematous alveoli. during each tidal breath induced by mechanical ventilation, unstable alveoli undergo cyclical collapse and shearing open, termed 'atelectrauma'. furthermore, the non-collapsed alveolar units may receive a greater proportion of the delivered tidal volume, leading to damage due to overdistention or 'volutrauma'. further breakdown of the endothelial-epithelial barrier may occur with atelectrauma and volutrauma, along with the release of local proinflammatory mediators which further b see text for details. aa = arachidonic acid; arb = angiotensin receptor antagonist (blocker); fa = fatty acid; gm-csf = granulocyte macrophage colonystimulating factor; hne = human neutrophil elastase; icam- = intercellular adhesion molecule- ; il- = interleukin- ; mmps = matrix metalloproteinases; nf-kb = nuclear factor-kb; paf = platelet-activating factor; ppar-g = peroxisome proliferator activated receptor-g; rhpaf = recombinant human paf; tnfa = tumour necrosis factor-a. propagate this cycle of ventilator-exacerbated lung injury. [ ] as inflammation ensues, neutrophils are recruited to the lung. damaged endothelial cells exhibit increased activity of the transcription factor nuclear factor-kb (nf-kb), which upregulates the surface expression of intercellular adhesion molecule (icam)- . icam- mediates leukocyte adhesion and migration across the endothelium to the alveolar epithelium. activated neutrophils release proteases, such as matrix metalloproteinases (mmp) and neutrophil elastase (ne), which further damage the alveolarcapillary membrane. [ ] activated neutrophils also contain high levels of arachidonic acid, [ ] which is metabolized into leukotrienes, prostaglandins and thromboxanes. leukotrienes attract more neutrophils, prostaglandins are proinflammatory mediators, and thromboxanes play a role in vasoconstriction and platelet and leukocyte aggregation. neutrophil recruitment and activation may be an adaptive physiological response to injury, or may incite a vicious cycle of inflammation and further damage. [ ] at this stage, patients may recover from the initial insult, with clearance of the pulmonary oedema and restoration of the barrier between capillary endothelial and alveolar epithelial cells, or may progress to the exudative or mid phase of ards. it is not fully understood why two patients exposed to the same insult may have completely different clinical courses; however, genetic factors, [ ] co-morbid illnesses such as diabetes mellitus and alcohol addiction, [ ] nutritional status, medications and exposure to further insults are all likely to play a role. understanding the host and environmental factors that place a patient at high risk of progressing to the exudative phase of ards will facilitate identification of targets for earlier intervention. the exudative or subacute phase typically occurs over the - days following the initial insult. pathologically, this mid phase is characterized by formation of intra-alveolar hyaline membranes rich in plasma proteins, fibrin and cellular debris. [ ] a biopsy of the lungs at this stage will show diffuse alveolar damage and, clinically, the lungs have poor compliance with ongoing gas exchange problems including hypoxaemia and elevated dead space fraction. the inflammatory milieu within the alveoli, coupled with the cyclical opening, stretching and collapsing of alveoli via mechanical ventilation, initiates a number of pathogenic pathways in concert or in series. these include disruption of surfactant function and metabolism, ongoing neutrophil recruitment and activation, along with increased expression and release of inflammatory mediators, imbalance of oxidant and antioxidant activity, and activation of complement and coagulation cascades. each of these pathways is further discussed to provide context for the drugs or therapies aimed at ameliorating these various mechanisms (see section ). interestingly, only a minority of patients will succumb to severe hypoxaemia or hypercarbia, as the major source of mortality is not the pulmonary injury per se, but rather the occurrence of multiple organ failure. in this setting, the injured lung may represent a rich source of inflammatory mediators that could contribute to the development of multi-organ failure. for example, stress failure and necrosis of the endothelial-epithelial barrier may allow various inflammatory mediators, bacteria and endotoxins to quickly spread from the lungs into the systemic circulation. indeed, it is this de-compartmentalization of inflammatory mediators from the lungs into the circulation that is felt to lead to cell apoptosis in distal organs, [ ] and ultimately multiple organ dysfunction syndrome (mods) [ figure ]. [ ] once mods develops, disease is often irreversible and mortality may increase significantly to - %, the latter occurring when three or more organs are involved for a period of more than days. [ ] [ ] [ ] thus, a key to developing novel therapies that will reduce mortality in ards will be identification of the cellular and molecular mechanisms by which ards leads to mods. survivors of the first week of ali/ards may enter the late phase of the disorder, known as the fibroproliferative phase. during days - , the exudates and hyaline membranes become organized, and fibrosis may become apparent. type ii alveolar cells proliferate and line the alveolar walls, fibroblasts migrate and differentiate into myofibroblasts in the interstitial and alveolar spaces, and a collagen-rich extracellular matrix is laid down in the interstitium. [ ] alveoli may be destroyed, pulmonary vascular area may be reduced and chronic inflammation is generally present. patients in the fibroproliferative phase of ards may slowly recover, or may fail to wean from mechanical ventilation and succumb to complications of a lengthy critical illness or pre-existing co-morbid illnesses. pharmaceutical interventions for late ards must interrupt the fibrosing alveolitis and aid in resolution, remodelling and repair of injured lungs. [ ] often, therapies that might be beneficial during the early phase of lung injury are started too late in the course of the disease, when fibrosis is already established, muting their potential efficacy. when tested specifically for the late fibroproliferative phase of ards, anti-inflammatory therapies have yielded disappointing results. basic science research examining mechanisms of idiopathic pulmonary fibrosis may illuminate therapeutic pathways for fibroproliferative ards, but further work is required in this area. although no pharmacological therapies have been proven to reduce mortality in large, randomized controlled trials (rcts) involving adult patients, it appears that improvements in supportive care have reduced mortality to some extent. for example, mortality estimates ranged progression of acute respiratory distress syndrome (ards) to multi-organ failure (mof). initially, inflammatory damage to the alveolar-capillary barrier results in increased vascular permeability, leading to interstitial and alveolar oedema as proteinaceous fluid fills the alveolar space. there, the proteinaceous fluid interferes with the function and metabolism of the endogenous surfactant system. coupled with this, neutrophils that infiltrate lungs are subsequently activated and represent an important source of inflammatory mediators and oxygen free radicals, inducing further epithelial and endothelial cell damage and an altered host immune response. newly secreted mediators and/or spillover of inflammatory mediators from the lung into the systemic circulation ultimately contribute to the development of mof. inflammatory mediators released from organs such as the liver, heart and kidney return to the lung via the systemic circulation and may contribute to further pulmonary inflammation. thus, each new insult to the pulmonary system accelerates the acute lung injury cycle (reproduced from bosma et al. [ ] [ ], with permission). from % to % as reported in the literature in the s and early s [ ] [ ] [ ] [ ] to more recent estimates of - % in observational epidemiological studies [ , ] and - % in large clinical trials. [ , ] although this mortality reduction may in part reflect differences in diagnostic criteria used post publication of the aecc definition, undoubtedly the largest impact has been the move to more 'protective' strategies of mechanical ventilation. in , the national institutes of healthsponsored ards network (ardsnet) trial involving low tidal volume ventilation was published, and now constitutes the standard of care for patients with ali and ards. this trial compared a traditional tidal volume of ml/kg with a lower tidal volume of ml/kg in patients and reported a mortality reduction from % in the control arm to % in the treatment arm. [ ] these results definitively ended the debate fuelled by three previous inconclusive smaller trials regarding lower versus conventional tidal volumes. in terms of furthering ali/ards research, several lessons have been learned from this landmark study. first, ardsnet was set up to conduct well designed, large, phase iii studies with a concerted effort to optimize patient enrolment through involvement of many centres in an organized and cohesive group. [ ] this enabled a study sufficiently powered to realize a mortality difference to be conducted within a reasonable timeframe, and pointed the way for other similarly structured ards research networks to become established. second, the treatment arm was associated with lower oxygenation values than the conventional arm, highlighting the potential danger of relying on oxygenation or other physiological parameters as surrogates for mortality. third, this study demonstrated that a nonpharmacological intervention could alter mortality, indicating that future rcts need to be carefully standardized in all aspects of supportive care in both treatment and control arms. one potential caveat ensuing from this study has been the assumption that any additional proven therapy would reduce mortality across a population as heterogeneous and diverse as that enrolled in the ardsnet low tidal volume trial. this approach may be misguided, as subsequent studies have demonstrated differences between patients with direct and indirect causes of ali/ards in responsiveness to specific therapies. [ , ] research is ongoing to determine whether newer modes of mechanical ventilation, such as high-frequency oscillation (hfo), can further improve outcomes in ards relative to the ardsnet low tidal volume strategy. [ ] in addition, other aspects of supportive care have been evaluated in large clinical trials, some conducted by ardsnet, and have proven effective in reducing morbidity associated with critical illness. these include cautious fluid management, [ , ] adequate nutrition, [ ] prevention of ventilator associated pneumonia, [ ] [ ] [ ] [ ] prophylaxis for deep venous thrombosis [ ] and gastric ulcers, [ ] weaning of sedation and mechanical ventilation as early as possible, [ ] and physiotherapy and rehabilitation. [ ] a recent review of all patients enrolled in ardsnet studies between and showed that these advancements in critical care (aside from lower tidal volume ventilation) are likely responsible for the improved survival in ali/ards patients in clinical trials noted over the last decade. [ ] additional modalities used as 'rescue therapies' for the ards patient at risk of succumbing to severe hypoxaemia or respiratory acidosis have also been tested, including nitric oxide, prone positioning, hfo and extracorporeal membrane oxygenation (ecmo). nitric oxide [ ] and prone positioning [ , ] have not been shown to reduce mortality or duration of mechanical ventilation in patients with ali/ards, and are therefore not recommended for routine use. however, combined together, these therapies may provide a sustained improvement in oxygenation for patients with severe hypoxaemia and a mortality benefit for patients who are failing conventional mechanical ventilation strategies. [ ] [ ] [ ] a clinical trial of hfo for routine care of patients with ards is currently underway, but existing evidence supports its use as salvage therapy if instituted early for patients failing conventional ventilation, [ ] and may have additive benefits when combined with nitric oxide and prone positioning. [ ] finally, ecmo has recently been studied in the cesar trial (see table iii for a list of trial acronyms). [ ] this study showed that transferring adult patients with severe but potentially reversible respiratory failure, whose murray score exceeds . or who have a ph of < . on optimum conventional management, to a centre with an ecmo-based management protocol, significantly improved survival without severe disability. recent evidence suggests ecmo is also useful for rescue therapy for adults with severe ards due to h n -influenza a virus infection. [ ] pharmacological treatments for ali/ards may be employed prior to the onset of ards or in the early, mid or late phases of ards (table iv) . accordingly, their purpose may be to prevent ali in those at risk, mitigate the pathogenic mechanisms responsible for the cycle of lung injury and systemic inflammation in established ards, or aid in lung healing and repair. some therapies, such as corticosteroids, have been studied for prevention of ards, treatment of early ards and treatment of late ards, and are discussed within each context. the concept that ards may be prevented in those at high risk after an inciting insult is not new, but is one that is garnering greater attention in the scientific literature in recent years. since no pharmacological agent has proven effective in treating established ards in adults, attention has turned to prophylactic treatment to prevent the development of ards in those at highest risk. of course, any pharmacotherapy that is initiated prior to the diagnosis of disease must have a very high benefit to risk ratio and be cost effective. as such, it should have the following attributes: (i) be low risk, without serious adverse effects; (ii) be easily and widely applicable; and (iii) be relatively inexpensive. drug classes studied for ards prevention include imidazoles (e.g. ketoconazole), ace inhibitors, thiazolidinediones (e.g. rosiglitazone), chemically modified tetracycline derivatives, antioxidants, and corticosteroids and other immunomodulating agents. over years ago, the first clinical trial examining prophylactic use of ketoconazole to prevent ards in patients at risk was published. [ ] the rationale for using ketoconazole, an antifungal drug with anti-inflammatory properties, was as follows. as mentioned in section , patients with ards have increased levels of arachidonic acid metabolites in their bronchoalveolar fluid. [ , ] metabolism of arachidonic acid leads to the production of leukotrienes, prostaglandins and thromboxanes. thromboxane a is a potent vasoconstrictor, and is involved with platelet and leukocyte aggregation, while leukotrienes act as powerful chemokines to attract neutrophils. ketoconazole is an antifungal agent of the imidazole class which selectively blocks thromboxane synthetase. ketoconazole also inhibits -lipoxygenase, the enzyme necessary to generate leukotrienes, and inhibits procoagulant activity. [ ] in addition to showing promise in preclinical animal studies, when given prophylactically to patients at risk of developing ards, ketoconazole has been shown to reduce the incidence of severe ards in three small trials. a study of patients admitted to a surgical icu showed that in the group treated prophylactically with oral ketoconazole mg/day, of patients ( %) ultimately developed ards, whereas of ( %) patients in the control group developed ards (p < . ). [ ] similar results followed in a study of patients with septic shock admitted to a surgical icu, where the incidence of ards in the group treated with ketoconazole mg/day was % ( of patients) compared with % ( of patients) in the control group (p = . ), and mortality was % versus %, respectively (p = . ). [ ] although both of these studies were conducted prior to the aecc definition, ards was strictly defined in the aforementioned studies, including a pao /fio ratio < or intrapulmonary shunt > % in patients requiring mechanical ventilation and who had diffuse infiltrates on chest radiograph without clinical evidence of heart failure as pulmonary arterial occlusion pressures were < mmhg. building on the results of these two studies, sinuff and colleagues [ ] developed practice guidelines for prophylactic ketoconazole use, and tested the implementation and efficacy of these guidelines in two icus (one control and one active comparator). they reported a significantly decreased incidence of ards in the icu population receiving ketoconazole prophylaxis, although mortality was equivalent within the two units. [ ] in , ardsnet published the karma study evaluating oral ketoconazole versus placebo for patients within hours of an established diagnosis of ali or ards according to the aecc definition. [ ] the study was stopped early after enrolment of patients for failing to show a difference in mortality or ventilator-free days. of note, this study was designed to look at early treatment of ali/ards rather than prevention of ards in patients at risk, and therefore did not necessarily negate the findings of the three previous smaller studies. furthermore, a problem identified in the karma study was that even though blood ketoconazole concentrations were adequate, urinary metabolites of thromboxane were not affected, raising the possibility that the proper dose to achieve an anti-inflammatory effect was not given. however, since the karma f mortality reduction in subgroup of patients with ards, septic shock and relative adrenal insufficiency. g no mortality reduction in larger study, n = (lasrs). il- = interleukin- ; ma = meta-analysis; mc = multicentre; ppar-c = peroxisome proliferator activated receptor-g; rhpaf = recombinant human platelet-activating factor; rsp-c = recombinant surfactant protein-c; sc = single-centre. study showed no difference in mortality, widely considered the most important endpoint to achieve, further research on ketoconazole for ali/ards ceased. [ ] additionally, ketoconazole has numerous drug interactions and requires an acidic milieu to be absorbed via the enteral route, making routine use in the icu complicated. further research should examine whether other drugs in the imidazole class given intravenously have similar anti-inflammatory properties, and also establish the inflammatory dose-response curve for ali/ards. in addition, although the concept that prevention of ards will definitely lead to decreased mortality is intuitive, this still has to be proven in large multicentre clinical trials. the authors are unaware of any studies being conducted in this area presently. angiotensin-converting enzyme (ace) is produced in the lungs and is responsible for converting angiotensin i into angiotensin ii, a peptide active in vasoconstriction and sodiumfluid balance to maintain blood pressure homeostasis. ace inhibitors and angiotensin ii receptor antagonists (blockers; arbs) are classes of drugs commonly used to treat hypertension, and prevent progression of diabetic nephropathy in patients with diabetes. ace inhibitors also help to preserve vascular structure and function, by exerting a protective effect on endothelial cells. endothelial cell damage is the catalyst for the inflammatory and coagulation cascades activated in ali/ards. thus, the protection of endothelial cells offered by ace inhibitors may have a beneficial role in ards. [ ] studies in transgenic mice have shown that ace, angiotensin ii and angiotensin ii receptor type a may promote lung injury, whereas ace , a close homologue of ace, and angiotensin ii receptor type may protect against severe lung dysfunction in models of ards. [ ] the ace inhibitor captopril has been shown to prevent severe lung injury in an oleic acid-induced model in rats. in this model, captopril reduced expression of icam- in lung tissue, indicating a protective effect on endothelial cells, diminished activity of tissue plasminogen activator, involved in coagulation, and blocked nf-kb, the major signal transduction pathway that regulates the expression of multiple early-response genes related to inflammation. [ ] in humans, two small cohort studies have demonstrated that polymorphism of the ace gene increases susceptibility to the development of ards and its outcome. [ , ] two additional studies, published only in abstract form to date, have examined the association between ace inhibitor use and ards. a retrospective cohort study of adult critically ill patients found that . % of patients developed ards after hospital admission, and that preexisting, long-term use of an ace inhibitor or arb was associated with decreased risk of ards development, after adjusting for predisposing conditions (odds ratio [or] . ; % ci . , . ; p = . ). [ ] the second abstract, a case-control study nested within a prospective cohort of critically ill patients at risk for ards, reported that patients on ace inhibitors had a lower prevalence of respiratory failure on admission to icu, but not lower incidence of ards after adjusting for confounders on multivariate analysis. however, among patients who developed ards, ace inhibitor use was associated with lower mortality (adjusted hazard ratio . ; % ci . , . ). [ ] the associations observed in these clinical studies is consistent with preclinical animal data, but requires further research prior to being applicable clinically. [ ] peroxisome proliferator activated receptors (ppars) are ligand-activated transcription factors related to thyroid hormone, steroid and retinoid receptors. [ ] there are three isoforms: ppar-g, ppar-a and ppar-b/d. ppar-g plays a central role in glucose homeostasis. thiazolidinediones, a class of oral antidiabetic drugs, are synthetic ligands for ppar-g. synthetic ppar-g agonists also have anti-inflammatory properties, inhibiting proinflammatory cytokine production and macrophage activation in vitro. [ , ] this action is mediated in part by antagonizing the activity of transcription factor nf-kb. when activated, nf-kb induces overexpression of inflammatory cytokines such as tumour necrosis factor (tnf)-a, which in turn induces upregulation of icam- expression, as well as recruitment and activation of immune cells. icam- , expressed on the surface of endothelial cells, mediates leukocyte adhesion and migration through endothelium into tissues. the anti-inflammatory properties of thiazolidinediones have been demonstrated in vivo in murine models of inflammatory bowel disease [ ] and rheumatoid arthritis. [ ] rosiglitazone is the most potent selective ppar-g of the thiazolidinediones. prophylactic administration of rosiglitazone has been shown to attenuate ali in an animal model of pancreatitis-associated ali. [ ] in this study, rosiglitazone was dissolved and given intravenously to rats minutes prior to induction of acute pancreatitis by sodium taurocholate. compared with control group rats with acute pancreatitis and its associated lung injury, prophylactic administration of rosiglitazone resulted in a significantly lower histological pulmonary injury score, reduced pulmonary expression of tnfa and icam- messenger rna, and decreased lung tissue myeloperoxidase activity, a measure of neutrophil infiltration in the lung. [ ] this suggests that prophylactic rosiglitazone mitigates the ali associated with acute pancreatitis by its anti-inflammatory effect. unfortunately, the safety of rosiglitazone has recently been questioned due to its augmentation of sodium and water retention, leading to increased incidence of congestive heart failure in diabetic patients placed on this drug long-term. [ , ] thus, further animal studies are needed to confirm the effects of rosiglitazone in acute pancreatitis and evaluate potential complications related to its use, prior to proceeding to human studies. during the early phase of lung injury, neutrophils are recruited into the pulmonary vasculature and activated to release proteases, such as mmps and ne, which damage the alveolarcapillary membrane, [ ] resulting in further release of inflammatory mediators. a single laboratory in the state university of new york (new york, ny, usa) has demonstrated in various animal models that blocking the proteases ne, mmp- and mmp- with a unique modified tetracycline can prevent the increased pulmonary vascular permeability that ultimately leads to ards. the same group has developed a 'two-hit' porcine model of sepsis plus gut ischaemiareperfusion injury that parallels the insidious onset of sepsis-induced ards in humans. in this model, anaesthetized yorkshire pigs undergo cross-clamping of the superior mesenteric artery for minutes to induce intestinal ischaemia, followed by intraperitoneal placement of a faecal blood clot. pigs are then awakened, extubated and taken to an animal icu for hours of continuous observation, where they receive intravenous fluids, broad-spectrum antibacterials and pain control medications. when the pao /fio ratio falls below , pigs are anaesthetized and placed back on mechanical ventilation with tidal volumes of ml/kg. in this model, they demonstrated that prophylactic administration of a synthetic, nonantimicrobial derivative of tetracycline called incyclinide (col- ; collagenex pharmaceuticals), prevented the development of both ards and septic shock. [ ] incyclinide has not yet been tested in any human studies of ards prevention; however, the complex model developed by this group contains all the elements of a clinically relevant animal model and, therefore, these results show potential for phase ii studies. oxidative stress is associated with development of ards and mods via direct tissue injury. nathens and colleagues [ ] examined the effect of antioxidant supplementation using atocopherol and ascorbic acid in critically ill surgical patients. in a prospective rct of surgical icu patients (mainly victims of trauma), they found antioxidants did not reduce the risk of developing ards, but did decrease the risk of developing mods, and shortened duration of mechanical ventilation and length of icu stay. [ ] antioxidants supplementation and nutritional strategies are now being studied for critically ill patients with early signs of mods, [ ] but not specifically for ards prevention. antioxidants and nutrition have also been studied for treatment of ards, and are further discussed in this context in section . . . given that excessive and protracted inflammation is the overriding principle responsible for the various pathophysiological mechanisms leading to ards, broad and potent anti-inflammatory drugs, such as corticosteroids, would seem to be a rational choice for prevention. four rcts, published between and , have examined the use of corticosteroids to prevent the onset of ards in patients at risk. a recent meta-analysis of these studies demonstrated that preventive corticosteroids may actually increase the risk of developing ards in critically ill adults. [ ] furthermore, the meta-analysis suggested a weakly increased risk of death associated with preventive corticosteroid therapy in those patients who ultimately developed ards. thus, corticosteroid therapy is not recommended for preventing ards in those at risk. corticosteroid therapy has also been extensively studied for the treatment of established disease in the early and late phases, and is discussed further in these contexts (see the corticosteroids subsection of section . . and section . . ). platelet-activating factor (paf) is a potent proinflammatory mediator that is degraded by the enzyme paf acetylhydrolase. recombinant human paf acetylhydrolase (rhpaf-ah; epafipase) was studied in a phase iib rct to prevent ards in septic patients. [ ] patients with severe sepsis were randomized to receive rhpaf-ah mg/kg, rhpaf-ah mg/kg or placebo. the incidence of ards was not different amongst the three groups, but -day all-cause mortality was significantly decreased in the mg/kg treatment group compared with placebo ( % vs %; p = . ). therefore, although rhpaf-ah does not appear to be an effective prophylactic treatment for ards, it may hold promise for treatment of severe sepsis. the majority of research to date has focused on treating ards once the diagnosis is established. although many studies are designed to treat 'early ards', with randomization occurring within hours of diagnosis, these studies also likely capture many patients in the exudative phase of ards with intra-alveolar hyaline membranes and histological diffuse alveolar damage at the time of enrolment. this problem arises in part because the diagnostic criteria for ards are subjective and lack sensitivity and specificity when compared with pathological diagnosis. [ ] thus, timing an intervention at a certain point after 'diagnosis' could result in the patient receiving treatment in the early, mid or even late pathophysiological stage of ali/ards. some more recent studies are now targeting time after intubation rather than time after diagnosis to achieve more uniform timing of intervention. however, since the acute and exudative phases occur along a continuum and are not generally distinguished clinically, therapies targeting these phases will be considered concomitantly. therapies currently under investigation for early and/or exudative ards include those targeting the disrupted surfactant system, oxidative stress and antioxidant activity, neutrophil recruitment and activation, expression and release of inflammatory mediators, activation of the coagulation cascade, and microvascular injury and leak. treatment of the overall inflammatory response with agents such as corticosteroids has also been studied and is discussed. finally, the only drugs specifically targeting resolution of the alveolar oedema of the acute phase are b -adrenergic receptor agonists (b -agonists). clearance of alveolar oedema depends on the balance between oedema formation and reabsorption. the rate of fluid reabsorption depends on the active transport of sodium and electrolytes; water follows in the direction of the transported electrolytes. the active transport of salt and water occurs via epithelial sodium channels induced via na + /k + adenosine triphosphatase (atpase). [ ] b -agonists are thought to increase alveolar fluid clearance via two possible mechanisms: (i) increasing the levels of intracellular cyclic adenosine monophosphate, which in turn upregulates na + /k + atpase, causing increased sodium transport across alveolar type ii cells; and (ii) reducing alveolar-capillary permeability, thereby decreasing oedema formation. preliminary animal and ex vivo studies demonstrated the potential of b -agonists to accelerate the rate of alveolar fluid clearance. [ , ] a small, single-centre rct randomized patients with ali/ards to receive intravenous salbutamol (albuterol) mg/kg/h or placebo for days. [ ] the primary endpoint of balti- was extravascular lung water measured by the singleindicator transpulmonary thermodilution system (picco Ò ; pulsion medical systems) at day . patients in the salbutamol group had lower extravascular lung water and plateau pressures, although oxygenation did not differ between the treatment and placebo groups. this latter finding was perhaps due to the vasodilatory effects of b -agonists contributing to shunting of oxygen in the capillary bed. there was no difference in -day mortality or ventilator-free days, although the study was not sufficiently powered to detect a difference in these endpoints. [ ] funded by the medical research council, the same investigators in the uk are now conducting balti- , using the same intravenous salbutamol protocol as in balti- , but powered to detect clinically important outcomes. [ ] it will be interesting to determine if the physiological benefits observed in balti- confer a reduction in -day allcause mortality in balti- . aerosolized b -agonists have fewer systemic adverse effects than intravenous preparations. the national heart, lung and blood institute (nhlbi), in conjunction with ardsnet, conducted a study of an aerosolized b -agonist, the alta study. [ ] the study was stopped for futility at the first interim analysis after enrolling patients. [ ] there was no difference in the primary outcome of ventilator-free days to day . this study may have been negative for the following reasons: (i) delivery of nebulized drug to lung injury sites may have been suboptimal, as was the case with aerosolized surfactant; and/or (ii) less severely ill patients with ali (rather than ards with more severe hypoxaemia) may retain adequate alveolar fluid clearance without the need for upregulation with b -agonists. sixty-day mortality in the alta study was . % compared with a -day mortality of % in the severely ill group of patients who received physiological benefit from intravenous salbutamol in balti- . [ ] exogenous surfactant administration has been very successful in treating and preventing neonatal respiratory distress syndrome (nrds). given the physiological and pathological similarities between nrds and ards, exogenous surfactant therapy has been under investigation for treatment of ali/ards for over a decade. although clinical trial results have been largely disappointing, recent studies show promise. the strong scientific rationale for targeting the disrupted surfactant system, as well as lessons learnt from previous trials, therefore merit further attention. endogenous surfactant is composed of % lipids (mainly phosphatidylcholine and phosphatidylglycerol) and % proteins. the role of endogenous surfactant in the healthy lung is to decrease surface tension and thereby prevent alveolar collapse. in addition, surfactant plays a role in suppressing inflammation and scavenging free oxygen radicals. four apoproteins have been identified, termed surfactant protein (sp)-a, -b, -c and -d. whereas the presence of either or both of the hydrophobic surfactant proteins sp-b and -c are important for the biophysical function of surfactant, the hydrophilic proteins sp-a and -d perform the various host defence roles, including modulation of leukocytes, enhancement of the function of phagocytic cells [ ] and regulation of the host's immune system. [ , ] in ali, disruption of the endogenous surfactant system occurs by a number of mechanisms: injury to alveolar type ii cells results in abnormal synthesis and secretion of surfactant, serum proteins that leak into the airspace interfere with surfactant function, serine endopeptidase and phospholipase a cause degradation of surfactant, and, finally, mechanical ventilation, particularly with high tidal volumes, causes conversion of functional surfactant aggregate forms into dysfunctional forms. without optimal surfactant function, there is high surface tension at the alveolar surface in a non-uniform pattern within the lung leading to alveolar instability and collapse. the presence of bacteria within the airspace may also release and activate endotoxins, a process that is augmented in the presence of an abnormal surfactant system. based on the functional importance of the endogenous surfactant system in the normal lung and, more importantly, the consequences of an altered surfactant system in ali/ards, there is good rationale to consider exogenous surfactant administration as a therapeutic intervention in these patients. [ ] in , a phase iii, double-blind rct tested an aerosolized, synthetic surfactant called exosurf Ò (glaxo wellcome) in patients with sepsis-induced ards. [ ] this study showed no significant difference in overall survival, duration of mechanical ventilation or oxygenation between the treatment groups and standard care. it was postulated that this lack of efficacy was due to a low level of alveolar deposition of the aerosolized preparation and/or due to the absence of surfactant proteins in the preparation. [ ] currently, this surfactant preparation is not being evaluated for patients with ali/ards and is no longer marketed in the us. shortly afterwards, a smaller, open-label phase ii clinical trial evaluated tracheal instillation of a liquid bolus of the natural bovine extract surfactant, survanta Ò (ross laboratories), in patients with severe ards. [ ] there was a trend toward decreased mortality in the group of patients receiving up to four doses of phospholipids mg/kg surfactant compared with the patients in the control group ( . % vs . %; p = . ), and no safety concerns were identified. however, survanta Ò contains only very small amounts of sp-b. coupled with concerns regarding resource limitations, no further clinical trials of this exogenous surfactant preparation for adults with ards have been performed. recognizing the importance of surfactantspecific proteins brought progress to clinical surfactant research. in , results were published for two phase iii clinical trials evaluating effect of a liquid, recombinant sp-c (rsp-c) surfactant, venticute Ò (nycomed), instilled intratracheally in patients with established ards. [ ] the two studies enrolled a total of patients within hours of diagnosis of ards and were powered to show a difference in ventilator-free days. although oxygenation was significantly better during the -hour treatment period in the surfactant group, there were no significant differences noted in the number of ventilator-free days or in -day survival. [ ] a post hoc analysis demonstrated that patients with 'direct' causes of ards (i.e. pneumonia, witnessed aspiration of gastric contents or both) had a mortality benefit with surfactant treatment compared with standard care. a followup meta-analysis pooling results of five multicentre studies of rsp-c confirmed this finding: the subgroup of patients with severe ards due to pneumonia or aspiration had decreased mortality when treated with rsp-c ( . % vs . % in the usual care group; p = . ). [ ] subsequently, a prospective phase iii rct evaluating effect of venticute Ò in patients with pneumonia or aspiration of gastric contents was conducted. the study was terminated at patients due to futility. neither these results nor the potential reasons for futility have been published to date. [ ] calfactant (infasurf Ò , ony inc.) is a modified natural surfactant produced by extracting the phospholipids, neutral lipids and surfactantspecific proteins sp-b and sp-c from newborn calf lungs. in in vivo animal lung studies, calfactant has shown greater surface activity than exosurf Ò and survanta Ò , [ ] [ ] [ ] [ ] and the highest level of resistance to inactivation due to its high ratio of protein sp-b to phospholipids. [ ] [ ] [ ] from to , calfactant was used in a multicentre study of ali/ards in the paediatric population week (full-term infants) to years of age. overall, calfactant significantly improved oxygenation and reduced mortality ( % vs %; p = . ), although the greatest impact was observed in the subgroup of patients with direct ali/ards while calfactant had little effect in patients with indirect ali or ards. [ ] indeed, calfactant is the first and only pharmacological agent to demonstrate a mortality benefit for treatment of ali/ards. it is of note, however, that this study differs from other adult studies in that the majority of paediatric patients had direct causes of ards and the most common cause of death was respiratory failure, whereas adult studies have included a larger proportion of patients with indirect causes, such as sepsis, wherein the most common cause of death is multi-organ failure. based on those encouraging results, pneuma pharmaceuticals began conducting a large phase iii multicentre rct of calfactant for direct ards (origin of ards must be infectious pneumonia, aspiration, near drowning, smoke inhalation without pulmonary burn or inhaled industrial gas) in adults and children. a total of patients in two consecutive studies of patients under and over years of age was planned. however, after the first interim analysis in january , the paediatric arm of the study was stopped for futility due to an unexpectedly low mortality rate. recruitment in the adult arm (ages - years) is continuing as the interim analysis did not reveal futility or any safety concerns (wilson d, university of virginia health sciences center, charlottesville, va, usa, personal communication). [ ] since reactive oxygen species also contribute to the tissue damage incurred in ali, antioxidant therapies have also been investigated as therapeutic options for established disease. n-acetylcysteine (nac) is a commercially available antioxidant approved for the treatment of paracetamol (acetaminophen) toxicity. nac is a precursor for glutathione, an antioxidant present in normal lungs and deficient in bronchoalveolar lavage fluid from ali/ards patients. additionally, because of its thiol group, nac can scavenge reactive oxygen species such as hydrogen peroxide and superoxide anion. in an rct of patients, nac and oxothiazolidine carboxylate (procysteine Ò , clintec technologies inc.), another glutathione precursor, were studied for their combined effect in ali/ards but failed to reduce mortality compared with placebo, [ ] negating promising results of three prior small studies. [ ] [ ] [ ] interestingly, recent evidence suggests that genetic diversity may explain variable responsiveness to nac. glutathione-s-transferases (gsts) are enzymes from a complex, multigene family with important roles in oxidative stress pathways. a study by moradi and co-workers [ ] demonstrated that deletion of specific gst gene polymorphisms correlated with mortality and that treatment with nac significantly lowered mortality in these subgroups of patients. these results suggest that patients with gst gene deletions are more vulnerable to oxidative stress contributing to ards and may be in greater need of antioxidant therapy. [ ] antioxidant supplementation to enteral nutrition rich in omega- fatty acids has also been investigated for patients with ali/ards. while the rationale for nutritional antioxidants such as vitamins e and c is to reduce the oxidative stress present in ali, the purpose of the omega- fatty acids is to reduce production of proinflammatory mediators. eicosanoids, such as prostaglandins, thromboxanes and leukotrienes, derived from omega- fatty acids are generally much less proinflammatory than those derived from omega- fatty acids. since omega- fatty acids compete with omega- fatty acids for the same rate-limiting enzymes in the production of eicosanoids, diets with a high proportion of omega- fats are thought to be proinflammatory and prothrombotic. examples of polyunsaturated omega- fatty acids are a-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. [ ] a phase ii study enrolling patients with ali compared an antioxidant enteral feeding formula containing eicosapentaenoic acid, g-linolenic acid and antioxidant vitamins with placebo, and observed improved oxygenation, reduced pulmonary inflammation, fewer days of mechanical ventilation and fewer non-pulmonary organ failures in the treatment arm, although there was no difference in mortality between this approach and the control group. [ ] ardsnet proceeded to conduct the omega study, a phase iii study examining efficacy of omega- and antioxidant supplementation to enteral nutrition. the study was stopped for futility, but results have not yet been published. [ , ] several therapies aimed at modulating neutrophil activity have been studied. to understand why previous clinical trials have been negative and highlight potential targets for novel therapies, it is important to understand the role of neutrophils in propagating lung injury and mods. polymorphonuclear neutrophils (pmns) form the first line of defence against invading pathogens, and neutropenia or defective neutrophil function predisposes the host to increased morbidity. extensive clinical and experimental data support the role of the activated neutrophil in the pathogenesis of organ injury in sepsis. the lung is particularly vulnerable. postmortem studies of patients with ards show massive pulmonary accumulation of neutrophils, with the highest counts in non-survivors. [ ] the pathological impact of neutrophils may be due to their activation, transmigration or delayed apoptosis. however, neutrophil-independent mechanisms of ali must also exist, since ards has been described in neutropenic patients. neutrophil kinetics in the pulmonary circulation differ substantially from that of microvascular beds in the systemic circulation. the pulmonary circulation harbours a large intravascular reservoir of leukocytes, mainly neutrophils, referred to as the 'marginated pool'. [ ] this marginated pool may equal or even exceed the pool of circulating neutrophils and exchanges with the latter as an ongoing phenomenon. thus, it is important to appreciate that circulating neutrophils, when isolated for experimental analysis, may not represent the characteristics of the entire population of neutrophils in the bloodstream. intravital microscopic studies have revealed that, in contrast to the systemic circulation where neutrophil sequestration is almost exclusively confined to the venular compartment, the major site of neutrophil retention in the lung is the alveolar capillary bed. [ ] neutrophil activation can also lead to cytoskeletal changes that reduce cell deformability and slow their transit time through the alveolar capillaries. since one of the earliest manifestations of ards is accumulation of large numbers of neutrophils in the alveolar capillaries, it is possible that the accumulation of neutrophils may initiate selective capillary blockade and arteriovenous shunting leading to hypoxia seen in ards. activated neutrophils also produce human ne (hne), a protease capable of producing tissue damage by means of its degradation of elastin, fibronectin, laminin, collagen and proteoglycans. normally, protease inhibitors impede ne, but in the setting of an overwhelming inflammatory response, neutrophils generate reactive oxidants that inactivate endogenous protease inhibitors, leaving the activity of hne unchecked. this may lead to increased pulmonary inflammation and endothelial cell permeability. [ ] sivelestat (elaspol Ò , ono pharmaceuticals) is a competitive inhibitor of ne. it was launched in japan after a phase iii study demonstrated reduced icu stay and improved pulmonary function in patients with ali associated with the systemic inflammatory response syndrome (sirs). [ ] however, the strive study [ ] was terminated early after randomizing patients from sites in six countries, when the data and safety monitoring board found a trend to increased mortality at days. final analysis revealed no difference in -day all-cause mortality ( % in both groups) or number of ventilator-free days between the treatment group and controls. epi-hne- or depelestat (debiopharm s.a.) is another hne inhibitor currently under development for treatment of inflammatory pulmonary diseases, including ali. in a repeated lung injury rat model depelestat administration afforded a significant protective effect on lung compliance and alveolar inflammation at day compared with the control group. [ ] a phase ii study examining safety and efficacy of intravenous depelestat for patients with ards has been completed, but results have not yet been published. [ ] neutrophil transmigration neutrophil margination allows for a molecular interaction between the cell surfaces of the neutrophil and endothelial cell to occur. subsequently, as a consequence of cell surface integrins and their ligands, neutrophils undergo adhesion with endothelial cells. following adherence, neutrophils must pass through the endothelial monolayer, interstitial tissue and alveolar epithelium to reach the alveolar space. passage of large numbers of activated neutrophils can cause epithelial damage, sloughing and increased permeability both due to mechanical force exerted by neutrophil pseudopodia as well as due to release of toxic substances such as proteinases (e.g. elastases, cationic peptides, defensins, oxidants and mmps). [ ] while there are conflicting reports on the effects of elastase on increased epithelial permeability, cationic peptides such as defensins can cause both epithelial and endothelial cell injury. defensin levels have been found to be greatly elevated in patients with ards and their levels correlate with the severity of lung injury. [ ] neutralizing its effects could be important in the management of ards. ongoing research is examining if defensins can be used to identify patients with ali at an early stage. [ ] delayed apoptosis of neutrophils once egressed into the extravascular space, neutrophils cannot return to the circulation and their elimination is dependant upon their clearance by apoptosis and subsequent recognition and elimination by macrophages and other phagocytic cells. normally, neutrophils are terminally differentiated cells with a terminal half-life of - hours in vivo. upon completion of their lifespan, neutrophils institute a programme of cell death known as 'apoptosis' and are then removed from the circulation by the liver and spleen. apoptosis, as opposed to necrosis, is believed to be crucial for resolution of inflammation as it does not result in loss of cell membrane integrity and bystander tissue damage by release of intracellular enzymes, proteases and reactive oxygen species. [ ] expression of neutrophil apoptosis is delayed in ards. [ ] this is not an unexpected finding, especially since pmn apoptosis is delayed in other critically ill patients with sepsis, trauma and burns. [ , ] apoptosis of neutrophils may be an important consequence in determining the extent of lung injury. for example, it has been shown that the induction of neutrophil apoptosis by the administration of dead escherichia coli prior to reperfusion resulted in significant improvement in lung injury. [ ] induction of neutrophil apoptosis in the alveolar space has the potential for resolution of inflammation in ards, and can be carried out in a number of ways that could include multiple strategies such as ligation of fas, activation of proapoptotic caspases and modulation of mitogen-activated protein kinases or transcription factors such as nf-kb. hastening neutrophil apoptosis in the alveolar space may also decrease the probability of secondary necrosis and further tissue damage in ards. it is intriguing that no significant differences were found between the expression of neutrophil apoptosis in patients at risk and those with established ards, nor did the extent of apoptotic inhibition correlate with overall outcome in ards. [ ] therefore, while it is well established that ards is associated with accumulation of large numbers of neutrophils in alveolar spaces, their contribution to the severity of ards in humans remains uncertain. in summary, targeting neutrophil responses in ards may have therapeutic potential. however, as has been learnt from various ali and sepsis trials in the past, simple strategies to control dysregulated neutrophil behaviour may not be effective. rather, key stages of neutrophil function and kinetics may need to be identified in different clinical phases of ards, and selective immunomodulation strategies may need to be identified for individual patients. in addition to modulation of neutrophil function, there are other facets of the immune and inflammatory response currently under investigation as potential therapeutic targets for treatment of ards. these include modulation of macrophage activity with granulocyte macrophage colony-stimulating factor (gm-csf), inhibition of inflammatory mediators and broad suppression of the inflammatory response with corticosteroids. although most prostaglandins are proinflammatory mediators, prostaglandin e (pge ) has potential beneficial effects in ali, specifically due to its ability to modulate neutrophil activation. however, exogenous pge is associated with several adverse effects and patient intolerance due to haemodynamic instability has been observed. tlc-c- (ventusÔ; the liposome company) is a liposomal dispersion of pge . the development of pge in liposomal form may potentiate its role in neutrophil downregulation, improve peripheral delivery of the drug to the lung and decrease systemic adverse effects, thus providing a good rationale for testing in humans. [ ] a phase iii trial of patients with ards randomized to intravenous tlc-c- at escalating doses for days versus placebo found no difference in duration of mechanical ventilation or -day mortality between the treatment and control groups, although treatment was associated with accelerated improvement in oxygenation. [ ] however, more than % of patients required a dose reduction due to hypotension or hypoxaemia. interestingly, those patients who tolerated and received at least % of the full dose had a shorter duration of mechanical ventilation. a subsequent multicentre phase iii trial of tlc-c- in ards patients [ ] demonstrated no differences in time to liberation from the ventilator or -day mortality; the trend to shorter duration of hypoxaemia in the treatment group failed to reach statistical significance. gm-csf has been shown to stimulate phagocytosis and oxidative functions of host defence neutrophils, monocytes and macrophages. [ ] in addition to its systemic actions, gm-csf may also influence pulmonary host defence by modulating alveolar macrophage function and surfactant metabolism. as noted, apoptosis of neutrophils is an important mechanism by which these cells are cleared from inflamed lung regions, thereby facilitating resolution of inflammation. although both granulocyte colony-stimulating factor and gm-csf are thought to inhibit neutrophil apoptosis, in animal models of lung injury, gm-csf has been shown to help restore capillary barrier integrity, [ ] preserve alveolar epithelial function and improve alveolar fluid clearance. [ ] a pilot study of patients with ards undergoing serial bronchoalveolar lavage found that patients who survived ards had higher concentrations of gm-csf in the bronchoalveolar lavage fluid on day than patients who died. [ ] the authors speculated that gm-csf might improve survival by prolonging the neutrophil lifespan in the alveoli and/or inducing proliferation of alveolar macrophages, thereby improving host defence and reducing infectious complications in this setting. in a phase ii trial, molgramostim (schering-plough), a recombinant human gm-csf, was given intravenously at a low dose ( mg/kg) for days to ten patients with severe sepsis and sepsis-related pulmonary dysfunction (defined as a pao /fio ratio of < with a pulmonary infiltrate on chest radiograph). [ ] the primary outcome was -day survival, and secondary outcomes included oxygenation, occurrence of ards and degree of organ dysfunction at day . there was no difference in -day survival between the treatment and placebo groups, but oxygenation improved in the gm-csf group. ards was present in four of ten patients in the gm-csf group on study entry, but resolved in two of these patients by day , whereas in the placebo group ards was present in three patients on study entry and five patients on day . organ dysfunction was similar between the two groups, with no change between study entry and day . from july to july , the nhlbi enrolled patients who had been diagnosed with ali/ards for at least days into a phase ii rct of recombinant gm-csf (sargramostim [leukine Ò ], genzyme corporation) versus placebo. [ ] the primary outcome was the number of ventilator-free days during days - . secondary outcomes included measures of lung epithelial cell integrity, alveolar macrophage function, changes in severity of respiratory gas exchange, non-respiratory organ failure and incidence of ventilator-associated pneumonia. this study has been completed, but results have not yet been published. [ ] cytokine inhibitors cytokines are glycoproteins that act as messengers to cell surface receptors to promote or diminish the inflammatory cascade. specific cytokines are observed in high amounts in the bronchoalveolar lavage fluid of patients with ards, and are thought to play an important role in propagating lung injury. unsaturated phosphatidic acid plays an important role in intracellular signalling leading to neutrophil accumulation within the lungs, as well as proinflammatory cytokine expression and cell membrane oxidation, all of which leads to lung tissue damage. [ ] lisofylline (cell therapeutics) is a cytokine inhibitor that impedes synthesis of phosphatidic acid- a and, therefore, was thought to hold potential for treatment of ards. however, ardsnet stopped a phase ii/iii trial, the larma study, for futility after the first interim analysis failed to demonstrate any difference in -day mortality, ventilator-free days, organ failures or levels of circulating free fatty acids. [ ] interleukin (il)- is another potent chemoattractant for neutrophils, observed in high levels in patients with early ards [ ] and associated with increased mortality. [ ] anti-il- monoclonal antibody has been shown to reduce pulmonary oedema and neutrophil accumulation in animal models of ards [ , ] but has not yet been tested in humans. finally, tnfa has long been recognized as an important proinflammatory cytokine in ards, but more recent evidence suggests that it actually plays a dichotomous role in both contributing to permeability oedema but also increasing alveolar fluid clearance capacity. monoclonal anti-tnfa antibodies have been tested in patients with sepsis with disappointing results. [ ] given its dual role in alveolar oedema formation and resorbtion, a more sophisticated approach than simply blocking all tnfa activity is likely to be required in ards. studies examining the efficacy of corticosteroids for acute exudative ards have shown conflicting results. in , bernard et al. [ ] published results of a study of patients with ards randomized to high-dose pulse methylprednisolone ( mg/kg every hours for hours) or placebo. there was no difference in -day mortality ( % vs %; p = nonsignificant) but the confidence intervals were wide, suggesting that the study may have been underpowered to detect a small difference in a population with heterogenous outcomes. in , meduri and colleagues [ ] published their results of patients with severe early ards (< hours) from five hospitals randomized to methylprednisolone mg/kg/day for days versus placebo. they found corticosteroids significantly reduced icu mortality ( % vs %; p = . ), duration of mechanical ventilation and length of icu stay. [ ] annane et al. [ ] published a post hoc analysis of ards patients enrolled in an rct of low-dose corticosteroids in septic shock. patients in the treatment group received hydrocortisone mg every hours plus fludrocortisone mg/day for days. although there was no mortality difference for ards patients overall, ards patients with relative adrenal insufficiency and septic shock had significantly reduced mortality when treated with low-dose hydrocortisone ( % vs % in the placebo group; p = . ). [ ] the use of corticosteroids for acute exudative ards remains controversial, although the evidence is more definitive for corticosteroid treatment initiated late for fibroproliferative ards (see section . . ). a study examining low doses of corticosteroids as adjuvant therapy for lung injury associated with h n influenza virus (cortiflu) is planned. [ ] . . activated protein c microvascular injury and coagulation play critical roles in the pathogenesis of ali. plasma protein c levels are decreased in patients with ali, and are associated with higher mortality and fewer ventilator-free days. [ ] recombinant human activated protein c (rhapc; drotrecogin alfa; eli lilly) was tested in a phase iii clinical trial of patients and demonstrated a significant mortality reduction from % to % in patients with severe sepsis. [ ] a phase ii study was sponsored by the nhlbi to determine if drotrecogin alfa increased ventilator-free days in patients with ali (patients with severe sepsis were excluded). the study was terminated by the data safety monitoring board. although drotrecogin alfa significantly increased plasma protein c levels and decreased pulmonary dead space fraction, there was no significant difference in the number of ventilator-free days or in -day mortality ( of vs of patients, respectively; p = . ). [ ] . . hmg-coa reductase inhibitors (statins) hmg-coa reductase inhibitors, commonly known as statins, have recently been proposed as a treatment for ali/ards. the rationale for this is based on animal models suggesting that statins can attenuate organ dysfunction by reducing vascular leak and inflammation. [ ] a prospective cohort study in ireland showed a nonsignificant trend towards lower odds of death in ards patients receiving a statin during their icu admission (or . , % ci . , . ; p = . ). [ ] however, a recently published retrospective cohort study from the mayo clinic (rochester, mn, usa) showed no difference in mortality or organ dysfunction in ards patients treated with statins. [ ] stip is currently enrolling patients admitted to an icu with respiratory distress and a pao /fio ratio < due to the h n pandemic strain of influenza. [ ] patients in this trial will be randomized to receive rosuvastatin mg/day or placebo for days. since this is a specific subpopulation of patients with ali, findings from this study may not be generalizable to other ali subgroups. the sails trial (also rosuvastatin mg/day vs placebo) is also planned but not yet open for recruitment. [ ] patients who survive the early and exudative phases of ards generally enter a period from week to consisting of fibroproliferation and organization of exudative debris within the airspace. this fibroproliferative relatively 'late' phase either slowly resolves or progresses to fibrosis. during this phase, patients are at risk of dying from other complications such as mods, or may fail to wean from mechanical ventilation due to severely impaired respiratory muscle and lung function. those who successfully wean off mechanical ventilation may have residual pulmonary fibrosis and reduced exercise capacity. for resolution to occur, removal of inflammatory cells, cellular debris, and soluble and insoluble proteins needs to take place. as noted in section . . , apoptosis of neutrophils facilitates resolution of inflammation. monocyte and macrophage phagocytic clearance of apoptotic cells appears to be an important mechanism by which neutrophils are cleared from inflamed lung regions. soluble proteins are likely to be primarily removed via paracellular diffusion, but removal of insoluble proteins appears to depend on the function of alveolar macrophages. mechanisms involved in remodelling of hyaline membranes and restoration of a functional alveolar-capillary barrier are incompletely understood at present, but therapeutic interventions aimed at modulation of phagocytosis/apoptosis are being evaluated. to date, far less research has targeted this later phase of the disease, as most trials have focused on earlier preventative processes. fibroproliferative ards is characterized by ongoing inflammation. in addition to being tested for prevention of ards, and treatment of the early and mid exudative phases, corticosteroids have also been tested for efficacy in reversing the fibrosing alveolitis of the late phase of ards. a study by meduri and colleagues [ ] examined the effect of prolonged methylprednisolone therapy ( mg/kg/day for days) on patients with severe ards that was unresolved after days of respiratory failure. although this study demonstrated a significant hospital mortality benefit ( of patients [ %] in the corticosteroid group died vs of [ %] in the placebo group), the significance of these findings was controversial for two reasons: the calculated sample size to demonstrate a % absolute difference in mortality was patients but the study was terminated early after enrolment of patients, and the mortality in the placebo group was slightly higher than anticipated. [ ] to shed further light on this issue, ardsnet specifically designed a study to focus on the late fibrotic stage of the disease, called lasrs. [ ] this study examined the role of corticosteroids in patients in the late phase (> days from onset) of persistent ards. methylprednisolone, dosed at mg/kg/day for days followed by tapering doses until day , was compared with placebo. there was no difference in -or -day mortality rates. methylprednisolone improved oxygenation, respiratory system compliance and blood pressure, resulting in an increased number of ventilator-free and shock-free days; however, a higher rate of neuromuscular weakness and, if initiated more than days after the onset of ards, a significant increased mortality was observed in the methylprednisolone group. therefore, despite the improvement in cardiopulmonary physiology, methylprednisolone does not improve overall mortality in ards and is not recommended for treatment of late ards. given these results, the convincing lack of efficacy for prevention of ali prior to diagnosis and the lack of evidence of benefit in the early phase, corticosteroids cannot be recommended for routine treatment of ali/ards at any stage, at this time. furthermore, it may prove to be exceedingly difficult to determine which individual patient might benefit from corticosteroids and at what specific point to intervene. clearly, the current status of treatment options for patients with ali/ards is suboptimal. at this time, the clinical management of patients with ali/ards involves supportive therapy only. this primarily includes low stretch or 'lung protective' mechanical ventilation, conservative fluid management and adequate nutritional support. although the term 'supportive' may sound somewhat discouraging, these are important observations, not only because they impact on the outcome of patients with ali/ards but also because they should be embraced and implemented as 'standard care' for this patient population. furthermore, any new therapy being tested should be compared with optimal 'standard care'. other methods proposed to offer greater protection to the lungs while providing mechanical support to respiration include hfo and ecmo. studies into these modes are ongoing. although supportive therapies have reduced mortality, there is still significant need for improvements. previous studies have provided important insight into the pathophysiology of ali/ards. research is ongoing into therapies to prevent ali/ards in those at risk, treat it early in its course or aid in its resolution. each of these goals is associated with specific challenges. demonstrating that a prophylactic intervention reduces mortality, morbidity and is cost effective is challenging at best. this is most likely to occur when the risk of acquiring the disease is high, the outcome of the disease is uniformly devastating and treatment for the disease is nonexistent. for some critically ill patients at risk for ards, this may be the case. however, the diagnosis of ali/ards encompasses a very heterogeneous population, with incompletely understood risk factors and non-uniform, diverse outcomes. the greatest likelihood of success for prophylactic therapy will come when we have further delineated the subgroups at highest risk of dying from ali/ards and have accurate diagnostic tests to identify these patients. for ali/ards, specifically targeting the pathogenic mechanisms responsible for the increased risk of death in these patient subgroups would theoretically be high yield. basic science research identifying genetic polymorphisms of patients with highest mortality or greatest need for specific therapies shows great promise in this regard, but is not yet clinically applicable. until then, validating biomarkers and clinical indicators for poor prognosis in ali/ards should remain a primary research goal. finding therapies to treat ards in its late fibroproliferative phase is also in great need. too often patients survive the early and mid phase of ards only to succumb to complications in the late phase or undergo withdrawal of life support as they are unable to be weaned from mechanical ventilation. research into mechanisms of idiopathic pulmonary fibrosis may help identify common pathways to target for therapy. to date, the majority of research has focused on treating ali/ards in its earlier stages, in the hope that the disease process may be reversed prior to the patient entering the fibroproliferative phase. progress in finding therapies to treat established ards has been slow and hampered by a long series of negative clinical trials. however, there are several lessons to be learned from these rcts. first, a 'one-size-fits-all' approach has not worked for pharmacotherapy for ards. in this sense, the syndrome of ali/ards may be likened to cancer. cancer as a broad term signifies the uncontrolled replication of abnormal cells, but there are specific chemotherapeutic treatments for specific types of cancer, depending on its origin. some treatments may be effective for more than one type of cancer, but not for other types, and the magnitude of the benefit might vary according to the type and stage of disease. oncologists would not design a trial enrolling all patients with differing types of cancer and expect to find a single drug that shows a survival benefit. yet, that is what has been attempted with several large ards trials. recent studies have demonstrated that direct ards is likely to respond differently than indirect ards, and in fact within these broad categories, pathogenesis may differ. therefore, different therapies may need to be developed for specific aetiologies such as sepsis-related ards, sirs-related ards and various direct causes of ards. second, a well designed negative rct does not necessarily mean that the therapy tested should be abandoned. it means that the therapy is likely to not be appropriate for widespread application. however, just because a drug does not work for every ards patient does not necessarily mean it should not be used for anyone with ards. for example, there is no evidence for treating all patients with acute ards with corticosteroids, but there is evidence that treating ards patients with relative adrenal insufficiency and septic shock with low doses of hydrocortisone is likely to be beneficial. similarly, nitric oxide should not routinely be applied to all patients with ali/ards, but may be useful in refractory hypoxaemia, particularly in conjunction with other ventilation rescue strategies. third, a negative rct should potentially lead to further research so that we can gain further insight as to why the therapy failed to yield a clinical benefit. thomas edison, when asked why he pursued his quest to invent a functional and practical light bulb after innumerable failed attempts, is reported to have replied, ''i have not failed. i've just found ways that won't work''. ards research should take us from bench to bedside and back to the bench again. basic science can help us understand basic mechanisms of disease, discover why a therapy failed, then provide new ideas to apply to the clinical realm. rcts are necessary to prove benefit and quantify risk prior to changing clinical practice. since we are in urgent need of therapies to treat ali/ ards, it is necessary that rcts continue to advance our clinical care. however, these rcts need to be well founded in basic biology and physiology research, and focused on specific hypotheses regarding mechanisms of disease. continuing to conduct large clinical trials on heterogeneous patients with ali/ards from multiple aetiologies will not only prove ineffective but also add enormous cost to the healthcare system. the most significant and promising finding from an rct to date is that calfactant, the natural bovine surfactant rich in sp-b and -c, reduces mortality in ali from % in the control arm to % in the paediatric population. indeed, calfactant is the first and only pharmacological agent to demonstrate a mortality benefit for treatment of ali/ards. the ongoing cards study will 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directly relevant to the content of this review. key: cord- -j x ke authors: alcaide, maria l.; bisno, alan l. title: pharyngitis and epiglottitis date: - - journal: infect dis clin north am doi: . /j.idc. . . sha: doc_id: cord_uid: j x ke acute pharyngitis is one of the most common illnesses for which patients visit primary care physicians. most cases are of viral origin, and with few exceptions these illnesses are both benign and self-limited. the most important bacterial cause is the beta-hemolytic group a streptococcus. there are other uncommon or rare types of pharyngitis. for some of these treatment is required or available, and some may be life threatening. among those discussed in this article are diphtheria, gonorrhea, hiv infection, peritonsillar abscess, and epiglottitis. sore throat accounts for % to % of all patient visits to office-based primary care practitioners, hospital outpatient departments, and emergency departments in the united states [ ] . data from the national medical care survey indicate approximately . million annual visits for children [ ] and . such visits for adults [ ] . thus, familiarity with the principles of diagnosis and management of this disorder is essential for primary care physicians seeing patients of all ages. the hallmarks of acute pharyngitis are sore throat of varying degrees of clinical severity, pharyngeal erythema, and fever. most cases of pharyngitis are of viral origin, and with few exceptions these illnesses are both benign and self-limited. a large proportion of cases of pharyngitis is associated with rhinovirus [ ] and coronavirus colds or with influenza. the most important cause of bacterial pharyngitis is the beta-hemolytic group a streptococcus (streptococcus pyogenes, gas). there are other uncommon or rare types of pharyngitis, and for some of these treatment is also required or available. the recognized microbial causes of pharyngitis are listed in table , which shows the syndromes of respiratory illness caused by the various agents [ ] [ ] [ ] [ ] [ ] [ ] . it still is not possible to determine the cause in a sizable proportion of cases. a major task of the primary care physician is to identify those patients with acute pharyngitis who require specific antimicrobial therapy and to avoid unnecessary and potentially deleterious treatment in the great majority who suffer from a benign, self-limited, usually viral infection. in most cases this distinction can be made easily by attention to the epidemiologic setting, history, and physical findings augmented by performance of a few simple and readily available laboratory studies. the results of epidemiologic investigations are influenced by the season of the year, the age of the population, the severity of illness, and the diagnostic methods used to detect cases. most cases of pharyngitis occur during the colder months of the year, during the respiratory disease season. viral agents such as rhinoviruses tend to have annual periods of peak prevalence in the fall and spring; coronaviruses have been found most often in the winter. influenza appears in epidemics, which in the united states usually occur between december and april. in military recruits, adenoviruses cause the syndrome of acute respiratory disease during the colder months. in civilians, acute respiratory disease occurs in the winter, and epidemics of pharyngoconjunctival fever occur in the summer. streptococcal pharyngitis occurs during the respiratory disease season, with peak rates of infection in winter and early spring. spread among family members in the home is a prominent feature of the epidemiologic behavior of most of these agents, with children being the major reservoir of infection [ ] . as shown in table , a number of bacteria may cause acute pharyngitis, but most of these are rare or unusual causes of the syndrome. moreover, the benefit of antimicrobial therapy for some of these agents (ie, arcanobacterium haemolyticum, non-group a beta hemolytic streptococci) is unclear. thus, gas is the only commonly occurring cause of sore throat for which antimicrobial therapy is definitely indicated. gas is estimated to be the cause of % to % of cases of acute tonsillopharyngitis occurring during the cooler months of the year in schoolaged children [ ] and of approximately % of cases in adults [ , ] , but there is considerable variability from study to study [ ] . nationally, however, approximately % of children [ ] and % of adults [ ] who have sore throat receive antimicrobial agents, and a substantial proportion receives antimicrobial agents not recommended as treatments of choice for gas pharyngitis. the following discussion provides recommendations by which such unnecessary and/or inappropriate therapy may be minimized. the characteristic clinical findings are summarized in table . the presence of marked odynophagia, exudative tonsillopharyngitis ( fig. ) , anterior cervical adenitis, fever, and leukocytosis is highly suggestive of gas pharyngitis. none of the signs and symptoms listed in the table is specific for ''strep throat,'' however. moreover, patients vary widely in the severity of their symptoms. many cases are milder and nonexudative. only approximately half of children presenting with sore throats and positive throat cultures have tonsillar or pharyngeal exudates [ ] . patients who have had a tonsillectomy may have milder symptoms. children less than years of age may have coryza and crusting of the nares; exudative pharyngitis caused by gas is rare in this age group. on the other hand, the presence of cough, coryza (in children older than years), hoarseness, diarrhea, conjunctivitis, and/or anterior stomatitis is highly indicative of viral rather than streptococcal infection. scarlet fever results from infection with a streptococcal strain that elaborates streptococcal pyrogenic exotoxins (erythrogenic toxins) to which the patient is not immune. although this disease usually is associated with pharyngeal infections, it may follow streptococcal infections at other sites such as wound infections or puerperal sepsis. nowadays, the clinical syndrome is similar in most respects to that associated with nontoxigenic strains, save for the scarlatinal rash. the latter must be differentiated from those of viral exanthems, drug eruptions, staphylococcal and streptococcal toxic shock syndrome, and kawasaki disease. when confronted with a patient who has acute pharyngitis, the clinician must decide whether the likelihood of gas infection is high enough to warrant a confirmatory diagnostic test. patients lacking the suggestive clinical and epidemiologic findings or manifesting signs and symptoms indicative of viral pharyngitis (see table ) need not be tested or treated with antimicrobial agents. attempts have been made to incorporate clinical and epidemiologic features of acute pharyngitis into scoring systems that attempt to predict the probability that a particular illness is caused by gas [ , [ ] [ ] [ ] [ ] . these clinical scoring systems are helpful in identifying patients at such low risk of streptococcal infection that further testing is usually unnecessary. selective use of diagnostic studies for gas will increase the proportion of positive test results and also the percentage of patients with positive tests who are truly infected rather than merely streptococcal carriers. the signs and symptoms of streptococcal and nonstreptococcal pharyngitis overlap too broadly, however, to allow the requisite diagnostic precision on clinical grounds alone. although some have suggested otherwise [ , ] , empiric antimicrobial treatment based on clinical and epidemiologic grounds alone has been found suboptimal in cost effectiveness [ ] and by prospective analyses [ ] . therefore, if the clinician is unable to rule out strep throat on clinical and epidemiologic grounds, further testing is required (see later discussion) [ ] . a properly performed and interpreted throat culture is the gold standard for the diagnosis of gas pharyngitis. it has a sensitivity of % or higher, as judged by studies employing duplicate throat cultures. obtaining definitive results of the throat culture takes to hours. in the minority of patients who are severely ill or toxic at presentation and in whom clinical and epidemiologic evidence leads to a high index of suspicion, oral antimicrobial therapy may be initiated while awaiting the results of the throat culture. if oral therapy is prescribed, the throat culture serves as a guide to the necessity of completion of a full antimicrobial course or, alternatively, of recalling the patient for an injection of penicillin g benzathine. early initiation of antimicrobial therapy results in faster resolution of the signs and symptoms, but two facts should be kept in mind. first, gas pharyngitis usually is a self-limited disease; fever and constitutional symptoms are markedly diminished within or days after onset even without antimicrobial therapy. thus, antimicrobial therapy initiated within the first hours of onset will hasten symptomatic improvement only modestly. second, it has been shown that therapy can be postponed safely up to days after the onset of symptoms and still prevent the occurrence of the major nonsuppurative sequela, acute rheumatic fever [ ] . the issues alluded to in the previous discussion may be obviated in part by the use of rapid antigen detection tests (radt), which can confirm the presence of gas carbohydrate antigen on a throat swab in a matter of minutes. currently available commercial test kits yield results that are highly specific for the presence of gas. thus, a positive radt can be considered equivalent to a positive throat culture, and therapy may be initiated without further microbiologic confirmation. unfortunately, the sensitivity of most of these tests ranges between % and % when compared with the blood agar plate culture [ ] . for this reason it is necessary to back up negative radts with a conventional throat culture. one possible exception to the need for such backup relates to adults, in whom the prevalence of gas pharyngitis is relatively low and the risk of a first attack of acute rheumatic fever in north america is minimal [ , ] . a positive radt or throat culture does not differentiate between the presence of acute streptococcal infection and chronic gas carriage [ ] . in the appropriate clinical setting, however, a positive test should be considered as confirmatory of strep throat. follow-up throat cultures are not indicated routinely for asymptomatic patients who have received a complete course of therapy for gas pharyngitis, because most such patients are streptococcal carriers. exceptions include patients who have a history of rheumatic fever, patients who develop acute pharyngitis during outbreaks of either acute rheumatic fever or poststreptococcal acute glomerulonephritis, and outbreaks of gas pharyngitis in closed or semiclosed communities. follow-up throat cultures also may be indicated when ''ping-pong'' spread of gas has been occurring within a family. treatment of gas pharyngitis is recommended to prevent acute rheumatic fever, prevent suppurative complications [ ] , shorten the clinical course (although only modestly) [ ] , and reduce transmission of the infection in family and school units. there is no definitive evidence that such therapy can prevent acute glomerulonephritis. a number of antibiotics have been shown to be effective in therapy of gas pharyngitis. these include penicillin and its congeners (such as ampicillin and amoxicillin), numerous cephalosporins, macrolides, and clindamycin. penicillin, however, remains the treatment of choice because of its proven efficacy, safety, narrow spectrum, and low cost. amoxicillin often is used in place of oral penicillin v in young children; the efficacy appears equal, and this choice is related primarily to superior palatability of the suspension. erythromycin is a suitable alternative for patients allergic to penicillin, although increases in gas resistance to this agent have been reported in certain localized areas of the united states. first-generation cephalosporins also are acceptable for penicillin-allergic patients who do not manifest immediate-type hypersensitivity to beta-lactam antibiotics. there is debate regarding the relative efficacy of cephalosporins vis-a-vis penicillin [ ] in eradicating gas from the pharynx and about the utility of shorter courses of certain antimicrobial agents in treating strep throat. for a further discussion of this topic, the reader is referred to the infectious diseases society of america (idsa) practice guideline [ ] . penicillin, however, remains the preferred therapy according to guidelines published by the american heart association [ ] , american academy of pediatrics [ ] , and idsa (table ) [ ] . the idsa guideline also offers guidance in management of patients who have recurrent episodes of culture-or radtpositive acute gas pharyngitis. preliminary investigations have demonstrated that once-daily amoxicillin therapy is effective in the treatment of group a beta hemolytic streptococcus pharyngitis [ ] [ ] [ ] . in the most careful of these studies, feder and colleagues [ ] randomly assigned children to receive amoxicillin, mg once daily, or penicillin v, mg three times daily. compliance was monitored by urine antimicrobial activity, and serotyping was performed to distinguish treatment failures from new acquisitions. the two regimens a although shorter courses of azithromycin and some cephalosporins have been reported to be effective for treating group a streptococcal upper respiratory tract infections, evidence is not sufficient to recommend these shorter courses for routine therapy at this time. b amoxicillin often is used in place of oral penicillin v for young children; efficacy seems to be equal. the choice is related primarily to acceptance of the taste of the suspension. c for patients who weigh ! kg. d dose should be determined on basis of the benzathine component. for example, mixtures of  u of benzathine penicillin g and  u of procaine penicillin g contain less benzathine penicillin g than is recommended for treatment of adolescents or adults. e available as stearate, ethyl succinate, estolate, or base. cholestatic hepatitis, rarely, may occur in patients, primarily adults, receiving erythromycin estolate; the incidence is greater among pregnant women, who should not receive this formulation. f these agents should not be used to treat patients with immediate-type hypersensitivity to beta-lactam antibiotics. were equally effective in eradicating gas from the pharynx. if additional investigations confirm these results, once-daily amoxicillin therapy, because of its low cost and relatively narrow spectrum, could become an alternative regimen for the treatment of group a beta-hemolytic streptococcal pharyngitis. suppurative complications of gas pharyngitis include peritonsillar infection, retropharyngeal abscess, cervical lymphadenitis, mastoiditis, lemierre syndrome, sinusitis, and otitis media. such complications have become relatively rare since the advent of effective chemotherapy. peritonsillar infection may take the form of cellulitis or abscess (quinsy) and is the most common form of deep oropharyngeal infection. although peritonsillar abscesses may occur as complications of gas pharyngitis, the abscesses themselves frequently contain a variety of other oral flora including anaerobes, with or without gas [ ] [ ] [ ] . they occur more frequently in adolescents and adults than in young children. pharyngeal pain is usually severe, and dysphagia is common. on examination, there is inflammation and swelling of the peritonsillar area with medial displacement of the tonsil, and patients speak with a ''hot potato'' voice. trismus may be present. peritonsillar cellulitis may be treated with antibiotics alone, but abscesses require drainage by direct aspiration or by incision and drainage. given the polymicrobial nature of these infections, parenteral antibiotics such as clindamycin, penicillin with metronidazole, or ampicillin-sulbactam are frequently employed. their superiority over penicillin has not been demonstrated definitively, however. lemierre syndrome (postanginal septicemia) is caused by an acute oropharyngeal infection with secondary septic thrombophlebitis of the internal jugular vein and, often, bacteremic spread to lungs or elsewhere [ ] . the most common causative organism is fusobacterium necrophorum. the clinical findings include acute presentation with fever, swelling and tenderness at the angle of the jaw, and neck rigidity. dysphagia and dysphonia can occur. the peritonsillar area is inflamed only early in the disease. emergency medical treatment with intravenous antibiotics such as clindamycin, penicillin with metronidazole or ampicillin-sulbactam is usually sufficient, but at times ligation of the internal jugular vein is required. acute rheumatic fever and poststreptococcal acute glomerulonephritis are the delayed nonsuppurative sequelae of gas pharyngitis. although the former occurs only after gas upper respiratory infection, the latter may occur after infection of the throat or skin (streptococcal pyoderma). discussion of these entities is beyond the scope of this article. non-group a beta-hemolytic streptococci are classified biochemically by species. for clinical purposes, however, they usually are identified by their expression of the lancefield cell-wall antigens. certain of these strains clearly are capable of causing acute pharyngitis when ingested in high inocula. streptococci of serogroup g have been linked to common-source outbreaks of pharyngitis, usually related to a food product. one unusual species of group c organisms, streptococcus equi subspecies zooepidemicus, has given rise to common-source epidemics of pharyngitis, usually caused by consumption of unpasteurized dairy products. several of these outbreaks have been associated with poststreptococcal acute glomerulonephritis [ ] . groups c and g streptococci are common commensals of the human pharynx. they form large colonies similar to those of gas and belong to the species streptococcus dysgalactiae subspecies equisimilis. physicians who do not back up negative radts with throat cultures will not identify these organisms. the extent to which they cause sporadically occurring episodes of true acute pharyngitis is unclear, but several careful studies suggest that group c streptococci may cause episodes of pharyngitis that mimic gas infection [ , ] . moreover, a community-wide outbreak of group g streptococcal pharyngitis occurred in connecticut during the winter of - [ ] . because of the difficulty in differentiating benign colonization from true infection with groups c or g streptococci, the benefit, if any, of antimicrobial therapy in sporadically occurring cases is unknown. should therapy be elected, agents listed in table would be appropriate, but probably for a shorter duration, because non-group a streptococci never have been shown to cause acute rheumatic fever. arcanobacterium haemolyticum. arcanobacterium (formerly corynebacterium) haemolyticum is a gram-positive bacillus that is a relatively uncommon cause of acute pharyngitis and tonsillitis. symptomatic infection with this organism closely mimics acute streptococcal pharyngitis. rarely, a haemolyticum produces a membranous pharyngitis that can be confused with diphtheria. two features of pharyngeal infection with this organism are notable. it has a predilection for adolescents and young adults, and it frequently provokes a generalized rash that may resemble that of scarlet fever [ ] [ ] [ ] . the organism is detected more readily on human-than sheep-blood agar plates and thus may not be identified in the routine throat culture. thus, the clinician should suspect a haemolyticum infection in a teenager or young adult who has an acute pharyngitis and scarlatiniform rash but a negative culture or radt for gas. should antimicrobial therapy of a patient who has a haemolyticum pharyngitis be elected, a macrolide or, alternatively, a betalactam antimicrobial agent may be prescribed. neisseria gonorrhoeae. neisseria gonorrhoeae is an uncommon, sexually transmitted cause of acute pharyngitis seen in persons who practice receptive oral sex. the risk of acquisition by this means is highest in men who have sex with men (msm). rates of pharyngeal gonorrhea in msm have been reported as being as high as %. a recent study in san francisco found n gonorrhoeae in the pharynx of . % of msm and concluded that the pharynx was the most common site of infection in this population [ ] . because of this high prevalence, the united states centers for disease control and prevention (cdc) guidelines for sexually transmitted diseases recommend a yearly pharyngeal test for n gonorrhoeae in msm who receive oral intercourse [ ] . although the presence of gonorrhea in the pharynx is common, the occurrence of symptomatic pharyngitis is rare. in the abovementioned san francisco study, there was no association between the presence of n gonorrhoeae and pharyngeal symptoms. when symptomatic oral infection does occur, pharyngitis and tonsillitis are the most common manifestations. sore throat with an erythematous pharynx, bilateral tonsillar enlargement, at times with grayish-yellowish exudate, and occasionally with cervical lymphadenopathy have been reported [ ] . gingivitis and glossitis also have been described. the diagnosis should be confirmed by culture on thayer-martin medium. currently, ceftriaxone ( mg in a singular intramuscular dose) is the only cdc recommended therapy for uncomplicated pharyngeal gonorrhea. concomitant therapy for chlamydia is recommended if this infection has not been ruled out. corynebacterium diphtheriae. pharyngeal diphtheria is caused by corynebacterium diphtheriae. humans are the only reservoir of the organism. asymptomatic carriers account for % to % of the population in endemic areas, and transmission occurs through respiratory secretions. although diphtheria has become extremely rare in the united states and other developed countries with effective childhood immunization programs, there are reasons for the primary care physician and infectious disease specialist to be familiar with this disease. first, there have been a few indigenous cases in the united states in the last years in unimmunized or underimmunized individuals in the lower socioeconomic groups [ ] . second, a large proportion of adults in north america and western europe lack protective serum levels of antitoxic immunity and are at risk for acquiring the infection when traveling to endemic areas. in , a fatal case occurred in a pennsylvania resident who traveled to haiti to assist in building a church [ ] . epidemics of diphtheria involving thousands of cases occurred in the s among residents of the newly independent countries of the former soviet union. third, early diagnosis and treatment are important predictors of ultimate prognosis. respiratory diphtheria is typically caused by toxin-producing (''toxigenic'') strains of c diphtheriae and rarely by toxigenic strains of corynebacterium ulcerans. the main pathogenic factor is an exotoxin capable of producing a severe local reaction of the respiratory mucosa with the formation of a dense necrotic coagulum and pseudomembranes. these pseudomembranes can lead to airway obstruction resulting in suffocation and death. the toxin is also responsible for severe cardiac and neurologic complications [ ] . the incubation period of to days is followed by malaise, sore throat, and low-grade fever. the most notable physical finding is the grayish-brown diphtheritic pseudomembrane that may involve one or both tonsils or may extend widely to involve the nares, uvula, soft palate, pharynx, larynx, and tracheobronchial tree. it is firmly adherent to the mucosa, and its removal provokes bleeding. in severe cases, there is swelling of the soft tissues of the neck (''bull neck''), cervical adenopathy, profound malaise, prostration, and stridor. cardiac complications manifested as myocarditis with cardiac dysfunction occur in % to % of cases, usually when the pharyngeal manifestations are improving. neurologic complications can occur also and are related directly to the severity of the primary infection, the immunization history, and the time between the onset of symptoms and institution of treatment. the diagnosis of diphtheria requires a high index of suspicion and specific laboratory techniques. diagnosis should be suspected on epidemiologic grounds and in the presence of pharyngitis with pseudomembranes, especially if extending to the uvula and soft palate and bleeding when dislodged. plating on loeffler's or tindale's selective media can identify black colonies with metachromatic granules, but definitive diagnosis requires demonstration of toxin production by immunoprecipitation, polymerase chain reaction (pcr), or immunochromatography. because successful treatment is inversely related to the duration of the disease, therapy should be started once the diagnosis seems likely on clinical grounds and while awaiting laboratory confirmation. treatment of diphtheria includes diphtheria antitoxin and antibiotics. equine diphtheria antitoxin is only available through the national immunization program of the cdc. the therapeutic dose and mode of administration are recommended by the american academy of pediatrics according to the duration and extension of the disease [ ] . antibiotics are effective in decreasing local infection, decreasing toxin production, and decreasing spread. intramuscular penicillin g, switched to oral penicillin v once the patient is able to swallow, and erythromycin are the antibiotics of choice. respiratory diphtheria (in contrast to cutaneous diphtheria) does not induce protective immunity, so diphtheria toxoid should be administered to patients during convalescence. prevention of transmission is crucial and is accomplished by strict isolation. close contacts should be cultured and started on prophylactic antibiotics while awaiting culture results; if not fully immunized, they should receive diptheria toxoid. both penicillin and erythromycin are efficacious in eradicating the carrier state, but erythromycin has been shown to be superior in some reports. c ulcerans is an animal pathogen that causes bovine mastitis but can be transmitted to humans through the consumption of raw milk. it can produce diphtheritic toxin and a clinical disease undistinguishable from c diphtheriae. mycoplasma pneumoniae and chlamydophila pneumoniae are known causes of lower respiratory tract infections; they also can be found in the throats of patients who have symptomatic pharyngitis and of asymptomatic carriers. although these agents probably cause some cases of acute pharyngitis, either as primary pathogens or copathogens, the frequency with which this occurs is still unclear. the pharyngeal manifestations that have been described include erythema, tonsillar enlargement, and, less often, exudate with cervical lymphadenopathy. in a recent italian study, children who had acute tonsillopharyngitis were tested for m pneumoniae and c pneumoniae with acute-and convalescent-phase titers and pcr on nasopharyngeal aspirates. thirty-six of the children ( %) had serologically confirmed acute m pneumoniae infection, and ( . %) had serologically confirmed c pneumoniae infection. five of the latter also had a positive nasopharyngeal pcr for this organism [ ] . the children were assigned randomly to receive azithromycin plus symptomatic treatment or symptomatic treatment alone and were followed for months. in the short term, there was no difference in the outcomes of children with or without atypical infection. a significantly decreased rate of recurrent upper and lower respiratory infections occurred in patients with atypical infections who were randomized to azithromycin, however. these results require confirmation. infectious mononucleosis clinical manifestations. infectious mononucleosis (im) or ''glandular fever'' is caused by the epstein-barr virus (ebv). the virus is present in the oropharyngeal secretions of patients who have im and is spread by personto-person contact. infection with ebv is frequent in childhood but usually is asymptomatic. clinical manifestations are more common when the infection is acquired in adolescence or young adulthood. thus, most cases of im occur between ages and years. symptoms develop after an incubation period of to weeks. following a -to -day prodromal period of chills, sweats, feverishness, and malaise, the disease presents with the classic triad of severe sore throat accompanied by fever as high as c to c and lymphadenopathy. pharyngitis with associated tonsillitis occurs in % to % of the patients. tonsillar exudates are present in approximately one third of cases, and palatal petechiae may also be present lymphadenopathy is bilateral, particularly posterior cervical, but can involve axillary and inguinal areas. about % of patients have a rash of variable morphology, but administration of ampicillin or amoxicillin provokes a pruritic maculopapular eruption in % of patients. hepatomegaly is present in % to % of patients who have im, and splenomegaly occurs in almost half of the patients. this classic clinical presentation of im occurs in most of the children and young adults. older adults may not exhibit pharyngitis or lymphadenopathy, and disease can be manifested only with fever and more prominent hepatic abnormalities (typhoidal presentation) [ ] . ebv infection can be complicated by a variety of neurologic and oncologic conditions that are beyond the scope of this article. the hematologic findings include leukocytosis with % to % lymphocytosis and thrombocytopenia that usually is mild but occasionally may be severe. the lymphocytosis usually is found at presentation and peaks to weeks after onset of the disease. the presence of more than % atypical lymphocytes in peripheral blood is one of the characteristic features of im and supports the diagnosis. the differential diagnosis at initial presentation includes gas pharyngitis, other respiratory viral infections (see table ), cytomegalovirus infection, and, if suggested by epidemiologic history, the acute retroviral syndrome (see later discussion). rarely, entities such as toxoplasmosis, hepatitis a, human herpesvirus , and rubella must be considered. in most cases, the diagnosis is readily confirmed if suspected. initial diagnostic studies should include throat culture or radt for gas and a serologic test for the presence of heterophile antibodies. the latter are antibodies directed against antigens in erythrocytes from different animal species. they are present in approximately % of affected adolescents and adults within the first to weeks of illness and may persist for up to year. spot and slide tests that use horse or purified bovine erythrocytes and allow rapid screening are commercially available. when combined with a compatible clinical presentation, a positive rapid test for heterophile antibodies can be considered diagnostic of im. false-negative tests can occur in up to % of patients, however, especially in children and older adults and in the early stages of the disease. approximately % of patients who have a classic mononucleosis syndrome have negative tests for heterophile antibodies. in such patients, ebv-specific antibodies should be assayed. the most useful of these for general clinical purposes is the igm antibody to viral capsid antigen. this test is present at clinical presentation and persists for to weeks. antibody to epstein-barr nuclear antigen first appears to weeks after onset and persists for life [ ] . many patients who have heterophile-negative im are found by the aforementioned tests to be infected with ebv. in the majority of the remainder, serologic studies confirm infection with cytomegalovirus, which can produce a syndrome closely mimicking that induced by ebv. im is predominantly a self-limited disease, and studies have failed to detect any benefit of using antiviral agents. most symptoms resolve within weeks of onset. physical activity is tailored to patient tolerance. because of the risk of splenic rupture, contact sports and heavy lifting should be avoided until the spleen returns to normal size, usually in approximately to weeks. the use of corticosteroids has been studied in clinical trials, but no clear benefit has been demonstrated [ , ] . steroids, however, may be useful in the management of severe complications such as airway obstruction, hemolytic anemia, severe thrombocytopenia, and aplastic anemia. within days to weeks after initial infection with hiv type , % to % of patients develop a constellation of symptoms known as the ''acute retroviral syndrome.'' fever, sore throat, lymphadenopathy, maculopapular rash, myalgia, arthralgias, and mucocutaneous ulcerations are the landmarks of the syndrome [ ] [ ] [ ] [ ] . a nonexudative pharyngitis is present in % to % of patients. other oropharyngeal findings include ulcers and thrush. oral ulcers, which occur in % to % of the patients, appear in the first days of the illness and last for approximately week. their distribution is usually in the inner lips and in the floor of the mouth, but tonsils, soft palate, and uvula also can be involved. fever occurs in almost % of patients who have acute retroviral syndrome, and it is usually high. lymphadenopathy occurs in % to % of the patients, is nontender, usually develops after week of illness, and involves cervical, axillary, and inguinal regions. skin rash, which occurs in % to % of patients, usually is maculopapular, disseminated, and almost invariably involves the neck and upper trunk. the rash usually spares the distal extremities, although palms and soles can be affected. the clinical findings of fever, pharyngitis, and lymphadenopathy may simulate im. atypical lymphocytosis, although infrequent, also could lead to a misdiagnosis of mononucleosis. acute retroviral syndrome can be differentiated from mononucleosis, however, by its more acute onset, the absence of exudate or prominent tonsillar hypertrophy, the frequent occurrence of rash (rare in mononucleosis except after treatment with ampicillin or amoxicillin), and the presence of oral ulcerations (table ) [ ] . it is important for the clinician to recognize that the elisa commonly used to diagnose hiv- infection are negative in the first to weeks after infection and therefore are not useful in this setting. tests for p antigen or, preferably, quantitative assays for plasma hiv rna by branched chain dna or pcr should be performed. the viral load can be anticipated to be very high during this acute phase of infection. an hiv antibody test always should be performed later in time to confirm the diagnosis. treatment of acute retroviral syndrome with highly active antiretroviral medication has been controversial, current recommendations consider the use of antiretroviral medications in the setting of acute hiv infection to be optional [ ] . potential benefits of antiretroviral therapy in acute hiv would be to decrease the severity of acute disease and to decrease viral replication. studies have demonstrated improvement of laboratory markers of disease progression when highly active antiretroviral therapy is used in acute hiv infection [ , ] . these results would suggest a decrease in progression and transmission of the disease. treating acute hiv infection, however, also can have potential risks, including known side effects to medications, possible development of resistance, and adverse effects on quality of life. if the patient and clinician elect to start antiretroviral medications, the goal should be suppression of viral replication. whereas most respiratory viruses can cause symptoms indistinguishable from the common cold or acute pharyngitis, some viruses may produce more distinctive clinical syndromes. adenovirus. adenovirus is a common cause of viral pharyngitis. it is manifested clinically as an upper respiratory infection with fever, cough, rhinorrhea, and sore throat, usually more pronounced than in the common cold. the pharynx is erythematous and frequently may have exudates that mimic streptococcal pharyngitis [ ] . a distinctive syndrome associated with adenovirus infection in children is pharyngoconjunctival fever. the disease occurs in outbreaks and is characterized by conjunctivitis, pharyngitis, rhinitis, cervical adenitis, and high fever. although adenoviral infections commonly occur in winter months, pharyngoconjuntival fever has been implicated in outbreaks in summer camps [ ] and associated with contaminated swimming pools and ponds. several types of adenovirus also have been implicated in outbreaks of influenza-like illnesses with sore throat, rhinorrhea, and tracheobronchitis, known as acute respiratory disease of army recruits [ , ] . these infections are self limited, and symptomatic treatment alone is recommended. coxsackie virus. most enteroviral infections occur in the summer and fall and present as febrile illnesses with sore throat, cough, or coryza. distinctive manifestations of enteroviral infection are herpangina and hand-footand-mouth disease. herpangina most often is caused by coxsackie a and is most frequent in infants or young children. it usually presents acutely with fever, sore throat, odynophagia, diffuse pharyngeal erythema, and a vesicular enanthem. headache and vomiting can be preceding symptoms. the oral lesions consist of -to -mm gray-white papulovesicles that progress to ulcers on an erythematous base and may be present on the soft palate, uvula, and anterior tonsillar pillars [ ] . they are moderately painful and usually number less than a dozen. hand-foot-and-mouth disease also is caused by coxsackie a. it is characterized by a febrile vesicular stomatitis with associated exanthema. the oral findings include small, painful vesicles in the buccal mucosa and tongue that can coalesce and form ulcerative bullae. the lesions are similar to those seen in herpangina, but there is an associated peripheral rash involving hands and feet that can extend proximally. these coxsackie diseases are self limited, and treatment is symptomatic. herpes simplex virus. several studies have documented primary human herpes simplex (hsv) type infection as a cause of pharyngitis in college students [ , ] . hsv occasionally can cause a similar illness as a consequence of oral-genital contact [ ] . this form of pharyngitis represents primary infection in immunocompetent patients but can occur as a reactivation of latent virus in immunocompromised hosts. although the characteristic presentation consists of small vesicles and ulcerations in the posterior pharynx and tonsils, hsv also may produce pharyngeal erythema and exudates at times indistinguishable from strep throat. lesions may extend to the palate, gingiva, tongue, lip, and face. general symptoms include fever, malaise, inability to eat, and cervical lymphadenopathy. treatment of hsv oral infection with antiherpetic medication is efficacious in reducing the duration of signs and symptoms as well as viral shedding. acyclovir, valcyclovir, and famciclovir are all useful in treating hsv infection. acetaminophen or nonsteroidal anti-inflammatory drugs are effective analgesics and antipyretics. treatment should be started as soon as symptoms develop and is useful in both viral and bacterial diseases. oral hydration and gargles with salt water may help alleviate the pharyngeal complaints. oral cough suppressants, decongestants, and antihistamines are helpful, depending on the symptoms present. lozenges containing local anesthetics are widely available over the counter and seem to provide temporary relief of sore throat [ , ] . several authors have reported that adjuvant therapy with dexamethasone decreases the duration of throat pain in patients who have severe odynophagia [ ] [ ] [ ] . the regimens used and the magnitude of the effect varied among the studies. no adverse effects have been reported, but duration of follow-up often has been limited. one randomized, double-blind, placebo-controlled trial of adjuvant dexamethasone therapy in children found efficacy only in patients who had radt-positive pharyngitis, and the benefit was judged to be only ''of marginal clinical importance'' [ ] . the authors do not recommend use of corticosteroids in the therapy of gas pharyngitis. acute epiglottitis or supraglottitis is an inflammatory process of the epiglottis and adjacent structures that can lead to life-threatening acute respiratory obstruction. in the past, epiglottitis occurred most frequently in children between and years of age and was associated mainly with haemophilus influenzae type b (hib) infection. since the initiation of the childhood vaccination programs, epiglottitis caused by this organism is much less common. nevertheless, there are still cases of hib epiglottitis in both immunized and nonimmunized children, and the possibility of an infection with this pathogen cannot be excluded completely in vaccinated patients [ , ] . bacteria associated with epiglottitis nowadays include streptococcus pneumoniae, staphylococcus aureus, and beta hemolytic streptococci. multiple agents including other bacteria, viruses, and fungi have been implicated in rare cases. the typical presentation in children includes fever, irritability, sore throat, and rapidly progressive stridor with respiratory distress. the affected child adopts a forward-leaning position, drooling oral secretions while trying to breathe. adults usually present with sore throat and a milder disease, although airway compromise can occur also. physical examination of patients suspected of having epiglottitis requires careful inspection of the oropharyngeal and suprapharyngeal area. the diagnosis requires direct visualization of an erythematous and swollen epiglottis under laryngoscopy. because of the risk of airway obstruction, this procedure should be performed in children only when skilled personnel and equipment to secure the airway are available [ ] . once the airway has been secured, culture of the surface of the epiglottis along with blood cultures should be obtained to guide antibiotic therapy. management focuses on two important aspects: close monitoring of the airway with intubation if necessary and treatment with intravenous antibiotics. because of the aforementioned possibility of failure of vaccination, antibiotics should be directed against hib in every patient regardless of immunization status. cefotaxime, ceftriaxone, or ampicillin/sulbactam are appropriate choices. steroids are used commonly in the management of acute epiglottitis although no randomized trial has been done to support this practice. when a case of hib epiglottitis is diagnosed, the american academy of pediatrics recommends that postexposure prophylaxis with rifampin be given to household contacts when there is at least one child in the household younger than years of age, a child in the household younger than months of age who has not received the primary series of hib vaccine, or an immunosuppressed child, regardless of that child's hib immunization status [ ] . acute pharyngitis is an extremely common disorder that usually runs a benign course. in almost all cases, the primary care physician must discriminate between a viral sore throat, which requires only symptomatic management, and gas pharyngitis, which requires specific antimicrobial therapy. this distinction is important so that gas pharyngitis can be treated appropriately to minimize the risk of suppurative and nonsuppurative complications. equally important is minimizing unnecessary and potentially deleterious overtreatment of viral infections with antimicrobial agents. this article has outlined the epidemiologic, clinical, and laboratory findings that assist in decision making. the clinician also must be alert to the occurrence of rare but serious upper respiratory infections that may be life threatening and require special forms of therapy (eg, diphtheria, parapharyngeal suppurative processes, acute epiglottitis). principles of appropriate antibiotic use of acute pharyngitis in adults antibiotic treatment of children with sore throat antibiotic treatment of adults with sore throat by community primary care physicians: a national survey clinical significance and pathogenesis of viral respiratory infections a collaborative study of the aetiology of acute respiratory infection in britain - . a report of the medical research council working party on acute respiratory virus infections virology of middle ear virologic studies of acute respiratory disease in young adults. iv. virus isolations during four years of surveillance acute respiratory illness in an american community. the tecumseh study acute pharyngitis and tonsillitis in university of wisconsin students group a streptococci, mycoplasmas, and viruses associated with acute pharyngitis principles and practice of infectious diseases diagnosis of streptococcal pharyngitis: differentiation of active infection from the carrier state in the symptomatic child a clinical score to reduce unnecessary antibiotic use in patients with sore throat the prediction of streptococcal pharyngitis in adults group a streptococcal pharyngitis in adults the diagnosis of strep throat in adults in the emergency room a streptococcal score card revisited empirical validation of guidelines for the management of pharyngitis in children and adults streptococcal pharyngitis: evaluation of clinical syndromes in diagnosis principles of appropriate antibiotic use for acute pharyngitis in adults: background a cost-effectiveness analysis of diagnosis and management of adults with pharyngitis diagnosing strep throat in the adult patient: do clinical criteria really suffice? the role of streptococcus in the pathogenesis of rheumatic fever rapid diagnosis of pharyngitis caused by group a streptococci practice guidelines for the diagnosis and management of group a streptococcal pharyngitis management of acute pharyngitis in adults: reliability of rapid streptococcal tests and clinical findings treatment failures and carriers: perception or problems? antibiotics for sore throat are cephalosporins superior to penicillin for treatment of acute streptococcal pharyngitis? treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. committee on rheumatic fever, endocarditis, and kawasaki disease of the council on cardiovascular disease in the young, the american heart association committee on infectious diseases. group a streptococcal infections once-daily therapy for streptococcal pharyngitis with amoxicillin randomized, single-blinded comparative study of the efficacy of amoxicillin ( mg/kg/day) versus standard-dose penicillin v in the treatment of group a streptococcal pharyngitis in children treatment of streptococcal pharyngitis with amoxycillin once a day microbiology and management of peritonsillar, retropharyngeal, and parapharyngeal abscesses peritonsillitis: abscess of cellulitis? the microbiology of peritonsillar sepsis the evolution of lemierre syndrome: report of cases and review of the literature group c and group g streptococcal infections: epidemiologic and clinical aspects epidemiologic evidence for lancefield group c beta-hemolytic streptococci as a cause of exudative pharyngitis in college students clinical and microbiological evidence for endemic pharyngitis among adults due to group c streptococci community-wide outbreak of group g streptococcal pharyngitis arcanobacterium haemolyticum in children with presumed streptococcal pharyngotonsillitis or scarlet fever incidence and pathogenicity of arcanobacterium haemolyticum during a -year study in ottawa corynebacterium hemolyticum as a cause of pharyngitis and scarlatiniform rash in young adults prevalence and incidence of pharyngeal gonorrhea in a longitudinal sample of men who have sex with men: the explore study sexually transmitted diseases treatment guidelines gonococcal tonsillar infection-a case report and literature review status report on the childhood immunization initiative: reported cases of selected vaccine-preventable diseases-united states fatal respiratory diphtheria in a u.s. traveler to haiti-pennsylvania principles and practice of infectious diseases red book: report of the committee on infectious diseases. elk grove (il): american academy of pediatrics acute tonsillopharyngitis associated with atypical bacterial infection in children: natural history and impact of macrolide therapy infectious mononucleosis in middle age epstein-barr virus (infectious mononucleosis) epstein-barr virus infections: biology, pathogenesis, and management steroids for symptom control in infectious mononucleosis acute human immunodeficiency virus type infection acute aids retrovirus infection. definition of a clinical illness associated with seroconversion primary hiv infection clinical presentations and virologic characteristics of primary human immunodeficiency virus type- infection in a university hospital in taiwan clinical picture of hiv infection presenting as a glandular-fever-like illness is antiretroviral treatment of primary hiv infection clinically justified on the basis of current evidence? highly active antiretroviral treatment initiated early in the course of symptomatic primary hiv- infection: results of the anrs trial effect of combination antiretroviral therapy on t-cell immunity in acute human immunodeficiency virus type infection clinical presentation and characteristics of pharyngeal adenovirus infections outbreak of pharyngoconjunctival fever at a summer camp-north carolina large, persistent epidemic of adenovirus type -associated acute respiratory disease in u.s. army trainees large epidemic of adenovirus type infection among military trainees: epidemiological, clinical, and laboratory studies viral exanthems pharyngitis associated with herpes simplex virus in college students acute respiratory disease of university students with special reference to the etiologic role of herpesvirus hominis acute pharyngotonsillitis caused by herpesvirus type efficacy and tolerability of ambroxol hydrochloride lozenges in sore throat. randomised, double-blind, placebo-controlled trials regarding the local anaesthetic properties demonstration of dose response of flurbiprofen lozenges with the sore throat pain model efficacy of single-dose dexamethasone as adjuvant therapy for acute pharyngitis effectiveness of oral dexamethasone in the treatment of moderate to severe pharyngitis in children a pilot study of versus days of dexamethasone as add-on therapy in children with streptococcal pharyngitis oral dexamethasone for the treatment of pain in children with acute pharyngitis: a randomized, double-blind, placebo-controlled trial epiglottitis and haemophilus influenzae immunization: the pittsburgh experience-a five-year review paediatric acute epiglottitis: not a disappearing entity airway infectious disease emergencies red book: report of the committee on infectious diseases key: cord- -znnlyz y authors: lim, peter a.c. title: transverse myelitis date: - - journal: essentials of physical medicine and rehabilitation doi: . /b - - - - . - sha: doc_id: cord_uid: znnlyz y transverse myelitis (tm) is an inflammatory condition across the spinal cord, along one or more levels and in the absence of compression. idiopathic acute tm is rare and with improvements in diagnostic tools and longer follow-up, the etiology which may include post-infectious, multiple sclerosis, or neuromyelitis optica often becomes clearer. the patient may present acutely with weakness, sensory impairments, or bowel and bladder changes. a careful history, physical examination, and appropriate diagnostic studies including blood tests and an mri scan may help determine the diagnosis and etiology. following the acute management, which may include use of steroids, immunosuppressive drugs, and plasma exchange, a comprehensive medical rehabilitation program is important to optimize recovery from the resultant impairments and disabilities and manage associated complications. complications such as paralysis, autonomic dysfunction, neuropathic and musculoskeletal pain, spasticity, contractures, neurogenic bladder and bowels, skin breakdown, and psychological issues will benefit from the expertise of the physiatrist. rehabilitation will include functional restoration with therapy as well as compensation of residual impairment with mobility and various other assistive devices. to maximum weakness in idiopathic tm has been reported to range from hours to days, with a mean of days. subacute presentations, progressing over days to weeks and ascending, are associated with a good to fair prognosis. acute and catastrophic presentations with back pain have a poorer outcome. recovery is often related to the clinical presentation and may or may not be complete. in general, one third of patients with acute tm make a good recovery, another third have fair recovery, and the rest either fail to improve or die. , , in idiopathic tm treated with methylprednisolone using the medical research council (mrc) scale for muscle strength, . % were reported to have complete recovery or minimal residual deficit (mrc - ), % had partial recovery (mrc ), and . % had severe disability or absent recovery (mrc - ). factors associated with poor outcomes include severe initial symptoms with spinal shock, delayed presentation to the hospital after maximum deficits have already occurred, development of syringomyelia, and extensive mri lesions. , if no recovery has occurred by to months, complete recovery is less likely. , patients with tm may present in the ambulatory clinic, urgent care center, or hospital setting with complaints of weakness of the limbs, sensory impairments, pain, and difficulties with the bowel and bladder. weakness may affect only the lower limbs or all four limbs with varying severity. it may be complete, incomplete, or may present as one of the spinal cord syndromes. the clinical spinal level usually corresponds to the lesion, but lower limb findings do not preclude a lesion at the cervical level. sensory complaints may include hypersensitivity, numbness, tingling, coldness, burning, or as a circumferential constriction. pain is a common symptom in one third to one half of patients and may be central or localized, aching or radicular in character. bowel frequency or constipation may occur, and bladder symptoms include increased frequency, retention, and incontinence. , , the history, including past medical, family, and detailed social, may reveal symptoms of recent infection, immunocompromised or autoimmune condition, space-occupying lesion, demyelinating disease, travel, vaccination, trauma, sexual exposure, animal, insect or tick bites. whether vaccination triggers tm has been debated. there were only seven cases of tm and eight of acute disseminated encephalomyelitis (adem) in the primary vaccination exposure window of to days prior to onset, after million doses within a healthcare network. the incidences were both nonstatistically significant except adem with tdap (tetanus, diphtheria, and pertussis) vaccine at p = . (translating into . cases per million doses). a careful review may yield systemic symptoms, including the upper respiratory tract with cough and difficulty in breathing, chest pain, rashes, joint aches, muscle pain, vision changes, nausea, diarrhea, constipation, and problems with urinary function. particular attention should be paid to details pointing toward potentially treatable or reversible conditions responsive to antimicrobials or surgical decompression. there may be a history of invasive spinal intervention for pain management, and tm relating to the infected catheter tip of an intrathecal morphine pump for chronic pain has been reported. the physical examination should be broadly systemic as well as focused on neurological findings such as motor weakness, changes in sensation (pinprick, light touch, vibration, position sense, or temperature), tone, muscle stretch reflexes, coordination, and bowel and bladder functioning. changes affecting the brain, such as cognitive dysfunction and cranial nerve and visual abnormalities, are generally not seen with idiopathic tm. fever, tachycardia, and tachypnea may indicate an infectious etiology. infections, autoimmune, and other conditions that cause acute inflammation of the spinal cord may also manifest in the other body systems. respiratory, cardiovascular, gastrointestinal, and genitourinary tracts as well as the musculoskeletal and integumentary systems should be assessed accordingly. the findings will assist in determining the level of spinal involvement, guide diagnostic testing, and help rule out other diagnoses. the physiatrist is likely to encounter the patient as a consultation for rehabilitation assessment and management, or referral for a specific problem, such as spasticity or pain intervention. the functional limitations in a patient with tm usually depend on the level of spinal cord involvement and corresponding muscles affected. debilitation and deconditioning from associated illnesses and prolonged recumbency will also affect function secondarily. the functional capability review according to spinal level may be influenced by whether the cord injury is unilateral or bilateral and the degree of completeness. high cervical lesions result in tetraplegia with sensory impairment and also affect the phrenic nerve (c -c ) with diaphragmatic paralysis requiring mechanical ventilation. a patient with c innervation preserved may or may not have respiratory difficulties but will be dependent for most self-care activities. using appropriate technology and devices, whether customized or commercially available, the patient may be able to control the home environment, summon assistance, direct their care, and mobilize in an electric wheelchair with a chin control or a sip-and-puff interface. a patient with c level may be able to self-feed and perform personal grooming with equipment such as a universal cuff for the hand allowing attachment of tools (e.g., fork, spoon, or comb). the patient can independently use a powered wheelchair and propel a lightweight manual wheelchair with hand rim projections ("quad knobs") for limited distances over level ground. c innervation allows independence with upper extremity dressing, bathing with equipment, and functional propulsion of a manual wheelchair indoors. the patient with superior balance and motor control could theoretically perform independent or supervised transfers with a sliding board, and self-catheterize with appropriate assistive devices. driving a specially adapted automatic transmission vehicle with powered steering, hand-controlled accelerator and brake can be achieved with c -c preservation. a c level allows independence in all self-care activities with equipment, independent transfers with ability to push off using intact elbow extensor muscles, and the patient may be able to live alone. a patient with c and t innervation will have improved manual strength and dexterity for self-care, is independent with a manual wheelchair, and should be able to self-catheterize. preservation of upper thoracic innervation allows a greater degree of trunk control, increasing stability during use and propulsion of a manual wheelchair. it also adds to ease and independence with bladder and bowel self-management. with bracing of the hips, knees, and ankles (kafo or knee-ankle-foot orthoses), minimal ambulation can be attempted, although mainly for training and exercise purposes than truly functional. independent ambulation, even with bracing and bilateral axillary or forearm crutches, is usually not realistic unless the patient has preservation of some upper lumbar innervation. further preservation of lumbar and sacral innervation will increase ease of ambulation with better trunk and pelvic control. the patient with incomplete spinal injury is less predictable, and functional abilities will largely depend on the degree and nature of neurologic preservation. with increasingly greater resolutions and techniques such as t -weighted fast spin-echo and short-tau inversion recovery (stir) to enhance or suppress the appearance of fat and tissues of different densities, the best tool when tm is suspected is mri. mri not only allows visualization of the lesion but also rules out treatable causes, such as tumor, abscess, and other lesions causing compressive myelopathy. contrast material can be given to highlight lesions, and myelography may rarely be considered if mri is not available. mri scans show features that help differentiate tm from disorders such as multiple sclerosis (figs. . and . ). the lesion in tm tends to affect the central region of the cord and involve more than two thirds of the cord diameter, whereas in multiple sclerosis it is usually more peripheral and involves less than half of the cord diameter. tm is more often associated with high signal intensity on t -weighted images extending longitudinally over more segments. , the number of segments involved may be from or up to , and the entire cord or sometimes only the medulla may be affected. , , , the lesion in tm at times resembles a spinal cord tumor and biopsy may even be attempted during investigation. , , mri of the brain with contrast enhancement is often performed to help determine whether the mri findings point toward multiple sclerosis rather than "idiopathic" tm. in idiopathic partial tm, a study that does not show brain lesions translates to the likelihood of evolving multiple sclerosis at % to %. when brain lesions such as white matter plaques (especially periventricular) are seen, the chance for development of multiple sclerosis increases to % to %. asymmetric motor or sensory symptoms and absence of peripheral nervous system involvement at presentation suggest acute myelopathic multiple sclerosis, whereas symmetric symptoms and peripheral nervous system involvement suggest acute tm. , immunoglobulin g antibodies may be useful for determining neuromyelitis optica (devic's disease) as the etiology in patients with acute complete tm. longitudinally extensive tm spanning three or more vertebral segments is an important feature and detection of anti-aquaporin -specific antibodies (anti-aqp , aq p-ab, or nmo-igg) is useful to determine both increased risk for recurrence and conversion to neuromyelitis optica. , other tests include the usual blood counts and chemistry, tests for autoimmune conditions, such as antinuclear antibodies, anti-double-stranded dna antibodies, anti-sm antibodies, erythrocyte sedimentation rate, ss-a antibody for sjögren disease, immunoglobulin levels, and vdrl. vitamin b enteric cytopathic human orphan virus may be elevated. the polymerase chain reaction (pcr) technique is useful for amplifying minute quantities of dna or rna. it was used in a recent case report on acute myelitis caused by zika virus infection, which responded well to high-dose prednisolone. a lumbar puncture allows assessment of cerebrospinal fluid pressure, and samples for cell count, determination of protein and glucose concentrations, measurement of immunoglobulins, and protein electrophoresis. oligoclonal bands detected in cerebrospinal fluid are useful in making a diagnosis. in one report, they were present in three of five patients with multiple sclerosis-associated tm, but in none of four patients with parainfectious tm. nerve conduction studies (ncs), electromyography (emg), as well as somatosensory and motor evoked potentials may be useful for establishing diagnosis and monitoring progress. , urinary system evaluation including cystourethrography, cystoscopy, a baseline renal ultrasound, and urodynamic studies with or without video, have been recommended because of the very high rates of persistent long-term bladder dysfunction. , bowel evaluation may require radiography, computed tomography (ct), and mri scans with or without contrast, or colonoscopy to rule out obstruction. in , the tm consortium working group proposed the criteria in table . for the diagnosis of idiopathic acute tm. a comparison by de seze of the clinical findings, mri results, laboratory profiles, and outcomes of patients with acute myelopathy according to etiology is presented in although the physiatrist may manage stable long-standing tm on an outpatient basis, hospitalization may be necessary during the initial presentation to monitor vital signs, manage respiratory difficulties, bowel or bladder complications, and carry out diagnostic investigations. , abnormalities of vital signs such as tachypnea or tachycardia may suggest impaired oxygenation or blood flow to be managed urgently. the ability to provide antiviral or antibacterial agents and surgical intervention may also be critical when a specific cause has been identified. several anti-inflammatory drugs have been tried for tm without clear success. although there is insufficient evidence for corticosteroid efficacy, intravenous methylprednisolone is often used to prevent further damage to the spinal cord as a result of swelling. , , during the acute phase, it may lead to faster recovery and less disability, and is well tolerated. cyclophosphamide exerts an immunosuppressive and immunomodulatory effect through suppression of cell-mediated and humoral immunity (on the t cells and b cells). cyclophosphamide together with methylprednisolone may help in lupus-related tm. , however, there appears to be an absence of any beneficial effect of immunosuppressive drugs (cyclophosphamide, azathioprine, intravenous immune globulin) in patients with idiopathic acute tm. , plasma exchange to remove autoreactive antibodies and other toxic molecules from plasma may be effective with a good clinical response, especially within days of onset and when nonresponsive to highdose corticosteroids. , the monoclonal antibody rituximab can be effective in decreasing relapses in tm due to nmo. the management of any spinal cord injury will include rehabilitation, and the more severely affected cases of tm will require a comprehensive multidisciplinary rehabilitation program led by a physiatrist. physical and occupational therapists on the team can work with strengthening, endurance, balance, coordination, joint range of motion, reconditioning, mobility, and independence with activities of daily living. the goal is one of optimal functioning and independence in the activities of daily living and mobility for the patient. functional independence measure and the modified barthel index are among the more widely used outcome measures during the rehabilitation process. assessment for appropriate equipment, such as a wellfitting wheelchair and other assistive and walking devices, is needed. gait efficiency, stability, and overall mobility can be improved with bracing devices such as an ankle-foot orthosis or kafo. education of the patient and family about the disease, resultant impairments, potential complications, rehabilitation plans and prognosis is important. the psychological state of the patient should not be neglected, and there should be monitoring for depression and medications initiated if necessary. sexual functioning is often affected, and education and counseling, with or without intervention, may be appropriate early. discharge planning needs and issues potentially affecting the patient's community reintegration, including vocational and recreational, should be assessed. recovery to some extent is expected in tm, but it is important to minimize the effects of even temporary impairments and immobility. all muscles and joints should be kept as active as possible, and daily exercises to preserve range of motion of the joints will help prevent contractures and keep joints flexible. progressive resistive exercises and possibly functional electrical stimulation (fes), also known as neuromuscular electrical stimulation, help maintain strength and decrease muscle atrophy. exercises for inspiratory muscles should be included and use of an incentive spirometer as needed. rarely, glossopharyngeal breathing may need to be taught and electrical stimulation of the phrenic nerve diaphragm considered in the high cervical cord patient not showing recovery. spasticity (see chapter ) is a possible complication and regular stretching with use of antispasticity medications such as baclofen, diazepam, gabapentin, and tizanidine, can minimize and decrease development of joint contractures. if pain is present, appropriate medications, thermal (heat, cold), and electrical modalities including transcutaneous electrical stimulation may be helpful. antiepileptic drugs such as gabapentin, pregabalin, and carbamazepine, may be prescribed as they have good efficacy for neuropathic pain. amitriptyline may also be useful, although caution is advised with its strong anticholinergic effects. thorough checks of the skin on a daily basis can help avoid pressure sores and associated infections. insensate areas, particularly over bony prominences, should be relieved with special cushions and mattresses such as eggcrate foam and alternating pressure overlays, and pressurerelieving ankle-foot orthoses (prafo) may be helpful. the many varieties of hydrophilic and antimicrobial wound dressings currently available promote faster healing of skin breakdown. bladder (see chapter ) and bowel (see chapter ) functioning should be assessed, and a bedside ultrasound for post-void residual urine volume is a simple informative procedure, as is a rectal examination. a program may be needed to avert a neglected neurogenic bowel or bladder leading to stool impaction and hydroureter or hydronephrosis. an indwelling catheter can initially be used for bladder drainage but intermittent catheterization, independently or otherwise, should be instituted whenever possible. longterm follow-up of to years in pediatric patients with tm has shown that residual bladder dysfunction is common even with improvement of paraparesis and lack of urologic symptoms. in one study, % had persistent bladder dysfunction and % had persistent bowel dysfunction. , a bowel program includes adequate fluids, proper diet, activity, and scheduled bowel movements. upper motor neuron bowels may need a stool softener (e.g., docusate), osmotic laxative (lactulose), or stimulant laxative (senna or bisacodyl) for evacuation. digital stimulation of the rectum is often effective and needs to be taught. with areflexic lower motor neuron bowels, use of bulk laxatives like psyllium or methylcellulose to produce formed stools may help during digital manual evacuation. bowel evacuation is often done on a daily basis in the hospital, but frequency can be extended to every or days once an individual returns home. the patient requiring a wheelchair, walker, crutches, or cane will need training, including maneuvering over steps and curbs. if transfers and ambulation require assistance, the training should also include family members or assistants. for patients with tm at the cervical level especially, various types of equipment and orthoses can be provided to help with self-care activities. proper bathroom equipment and modifications, such as a tub bench, commode, handheld shower, raised toilet seat, and grab bars, may make the difference between dependence and independence. selection of appropriate assistive devices helps maximize function. some of this equipment can be fairly expensive; hence, timing of purchases must be carefully considered, as they may not be required soon after. despite a reasonable prognosis for eventual recovery, complacency is to be avoided as it may result in unnecessary secondary complications. renal ultrasound and urodynamic evaluations are relatively routine procedures to assess and monitor bladder dysfunction. electrodiagnosis including ncs and emg are useful for diagnosis and for monitoring recovery. intramuscular botulinum toxin injections are very effective in the management of spasticity and commonly performed by the physiatrist, as are the alternatives of alcohol or phenol nerve and motor point blocks for spastic limb muscles. an intrathecal baclofen pump may be effective in intractable cases and allows much smaller doses and concomitantly fewer side effects. many physiatrists are able to manage the settings and refilling of these pumps. intractable neuropathic pain may respond to an intrathecal morphine pump, which will also require management. the field of rehabilitation uses a plethora of devices and technology during the process of restoring or compensating for the impairments and disabilities resulting from conditions such as tm. some individuals receive fes systems to help maintain fitness and muscle bulk or improve and restore function. fes for the forearm and arm muscles is a routinely employed technique with many devices commercially available. exercise bicycles for the lower as well as upper limbs (e.g., ergys [therapeutic alliances, inc.], rt -s [restorative therapies, inc.]) have also long been used, although are not cheap and have a risk for osteoporotic fractures. from simple body weight-support suspension devices, stationary and mobile, allowing for safer ambulation training, to motorized treadmills allowing flexibility in intensity, velocity, and effort, multiple devices from various manufacturers are available. robotic wheelchairs are ubiquitous equipment, available as either manual, powered, or hybrid, with an almost infinite offering of choices for size, weight, purpose, and even color. control of the wheelchair can be achieved by hand, chin, or other head part, and by voice activation. other than locomotion, there are also wheelchairs available for standing purposes, whether for activities at an erect level, or for weight-bearing exercise. braces or orthotics have also undergone much development and come with different materials, rigidity or flexibility, weight, and functional goals including for support, pressure relief, positioning, or protection. powered exoskeleton systems are currently of interest with systems to assist standing and ambulation such as the rewalk . (rewalk robotics inc.), hybrid assistive limb or hal (cyberdyne inc.), rex (rex bionics), ekso gt (ekso bionics), and indego (parker hannifin corp). at this time, they are mainly for training and exercise, and limited by the individual's abilities, terrain, device battery, and need for safety supervision including skin breakdown, falls, and equipment failure. the next wave for independent mobility in patients with handicaps could well be that of self-driving or autonomous cars undergoing trials by the major automobile companies and various research laboratories. environmental control units or multiple devices within a smart home controlled using simple touch-pad, infrared or motion-sensitive, and voice-activated mechanisms including automatic doors, curtains, and various electronics such as the television and personal computer, are now commercially available, easy to control, and importantly becoming increasingly affordable. apps (applications) that allow easy communication, videophone interactions, and ready access to the internet are already built-in for many smart phones. intelligent voicecontrolled personal assistants include the apple siri, google assistant, amazon alexa, microsoft cortana, and samsung bixby. there is no specific curative surgical procedure for tm. however, lesions such as abscesses, herniated disks, spinal stenosis, and tumors may need surgery as soon as possible to relieve pressure and prevent further damage to the cord. timely management of compressive lesions may reverse or at least halt further neurologic injury to the cord. pressure sores may require sharp débridement on the unit to remove dead or infected tissue and other debris to accelerate healing. tendon transfers may be considered at a later stage to increase an individual's functioning. nerve transfer in patients with permanent upper limb deficits may be considered to restore or to improve ability to voluntarily activate a muscle. in one case report, a child with tm who underwent multiple fascicle transfers from median and ulnar nerves to the musculocutaneous nerve, spinal accessory to suprascapular nerve, and medial cord to axillary nerve, had excellent recovery of elbow flexion. potential complications from the spinal cord dysfunction of tm are numerous and may require medical or surgical intervention. they include orthostatic hypotension, impaired thermoregulation, autonomic dysreflexia, lung and urinary tract infections, ileus and constipation, electrolyte imbalances, skin breakdown, spasticity and contractures, musculoskeletal and neuropathic pain, injury (including fractures) to bones, muscles and joints due to sensory impairments, heterotopic ossification, osteoporosis, kidney stones, depression, and anxiety. there may be respiratory muscle weakness depending on the level of spinal cord involved, and when severe, mechanical ventilation assistance may be required. the risk of bronchopneumonia and sleep apnea is compounded by any sedating medications or respirationdepressing medications. spasticity and joint contractures are common complications with spinal cord injury and management may be straightforward or extremely difficult, requiring several interventions simultaneously. heterotopic ossification (see chapter ) may develop around a joint, especially the elbow, knee, and hip. gastrointestinal complications include gaseous distension, regurgitation, indigestion, and chronic constipation. urinary tract infections and urosepsis are also common with a neurogenic bladder, as both retained urine and bladder instrumentation increase infection risk. autonomic dysreflexia/hyperreflexia may occur, especially for lesions above t . pain is a very frequent complaint and may arise from musculoskeletal sources or be neuropathic in nature. pain management may include medications such as analgesics, nonsteroidal anti-inflammatory drugs, short courses of cyclooxygenase- inhibitors, various anticonvulsants, and tricyclic antidepressants. overuse syndromes often occur because muscles and joints are overstressed during functional compensation for weakness or even during the process of rehabilitation training. shoulder pain is a common phenomenon with causes including tendinitis, rotator cuff injury, impingement syndromes, contractures, and inflammatory or degenerative arthritis. steroid and local anesthetic injections in the joint may sometimes be needed, but topical anti-inflammatory drugs, heat, cold, and other modalities, with proper transfer techniques or specific adaptive equipment such as sliding board, are often helpful. a common complication is ischemic breakdown of the skin if pressure relief is not regularly performed. awareness and monitoring for deep venous thrombosis and pulmonary embolism should be routine. prolonged pressure on a peripheral nerve can also cause dysesthesias, pain, or weakness. there may be sexuality, reproduction, and fertility concerns, particularly in younger as well as sexually active patients. the concerns and possible solutions should be discussed, addressed, or referred to a specialist as appropriate. depression and anxiety are not uncommon and usually respond to supportive counseling, but may need antidepressants such as the selective serotonin reuptake inhibitor or the serotonin-norepinephrine reuptake inhibitor drugs. treatment complications may occur because of the medications and equipment required to manage the disease and its complications. strictures or tracheal irritation can result from tracheostomy tubes, lung infections are common in this population, and the ventilators may break down, resulting in an emergency situation. high-dose corticosteroids frequently used for treatment of inflammation in the spinal cord may result in peptic ulcer disease or gastrointestinal bleeding. thromboembolism prophylaxis and anticoagulant treatment in the event of this happening may result in serious bleeding complications. skin breakdown may result at contact and pressure areas with devices or dressings used. frequent catheterization results in increased risk for urinary tract infections and accidental creation of false passages in the urethra with development of strictures. if bowel programs are not well managed or carried out gently, there may be discomfort, pain, and anorectal injuries. transverse myelitis consortium working group. proposed diagnostic criteria and nosology of acute transverse myelitis transverse myelitis fact sheet transverse myelitis: retrospective analysis of cases, with differentiation of cases associated with multiple sclerosis and parainfectious events acute transverse myelitis: incidence and etiological considerations idiopathic acute transverse myelitis: application of the recent diagnostic criteria long-term follow-up of acute partial transverse myelitis acute myelopathies: clinical, laboratory and outcome profiles in cases analysis of prognostic factors associated with longitudinally extensive transverse myelitis the clinical course of idiopathic acute transverse myelitis in patients from rio de janeiro a retrospective cohort study of years follow-up evidence-based guideline: clinical evaluation and treatment of transverse myelitis: report of the therapeutics and technology assessment subcommittee of the american academy of neurology idiopathic transverse myelitis: an experience in a tertiary care setup the prognosis of acute and subacute transverse myelopathy based on early signs and symptoms acute demyelinating events following vaccines: a case-centered analysis transverse myelitis associated with acinetobacter baumanii intrathecal pump catheter-related infection acute transverse myelitis: mr characteristics magnetic resonance imaging findings in cases of myelitis: comparison between patients with and without multiple sclerosis idiopathic transverse myelitis mimicking an intramedullary spinal cord tumor sjögren's syndrome with acute transverse myelopathy as the initial manifestation transverse myelopathy in systemic lupus erythematosus: an analysis of cases and review of the literature idiopathic transverse myelitis and neuromyelitis optica: clinical profiles, pathophysiology and therapeutic choices transverse myelitis. comparison of spinal cord presentations of multiple sclerosis discriminatory features of acute transverse myelitis: a retrospective analysis of patients distinct features between longitudinally extensive transverse myelitis presenting with and without anti-aquaporin antibodies acute myelitis due to zika virus infection clinical and evoked potential changes in acute transverse myelitis following methyl prednisolone residual bladder dysfunction to years after acute transverse myelitis transverse myelitis in children: long-term urological outcomes involvement of the entire spinal cord and medulla oblongata in acute catastrophic-onset transverse myelitis in sle neuromuscular electrical stimulation for muscle weakness in adults with advanced disease point: should phrenic nerve stimulation be the treatment of choice for spinal cord injury? effective management of intractable neuropathic pain using an intrathecal morphine pump in a patient with acute transverse myelitis effects of locomotor training after incomplete spinal cord injury: a systematic review robot-assisted gait training (lokomat) improves walking function and activity in people with spinal cord injury: a systematic review powered exoskeletons for walking assistance in persons with central nervous system injuries: a narrative review nerve transfers for restoration of upper extremity motor function in a child with upper extremity deficits due to transverse myelitis: case report key: cord- - igk jmn authors: yang, xiaopeng; tian, shasha; guo, hui title: acute kidney injury and renal replacement therapy in covid- patients: a systematic review and meta-analysis date: - - journal: int immunopharmacol doi: . /j.intimp. . sha: doc_id: cord_uid: igk jmn purpose reported rates of acute kidney injury (aki) have varied significantly among studies of coronavirus disease (covid- ) published to date. the present meta-analysis was conducted to gain clarity regarding aki incidence and renal replacement therapy (rrt) use in covid- patients. methods the pubmed, embase, web of science, medrxiv, and biorxiv databases were systematically searched for covid- -related case reports published through july . pooled analyses were conducted using r. results the pooled incidence of aki in studies including patients was . % ( % ci . %- . %), with higher rates of . % in transplant patients ( % ci . %- . %), . % in icu patients ( % ci . %- . %) and . % among deceased patients ( % ci . %- . %). rrt usage was reported in studies of patients, with an overall pooled use of . % ( % ci . %- . %), with higher rates of . % in transplant patients ( %ci . %- . %) and . % in icu patients ( % ci . %- . %). conclusion aki and rrt use among covid- patients represent a major public health concern, and early and appropriate intervention should be called upon to improve the prognosis of patients suffering from aki. within the past two decades, two previously unknown coronaviruses known as severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov) have caused serious epidemic outbreaks associated with high mortality rates [ , ] . a new form of pneumonia associated with a novel coronavirus emerged in late in wuhan, china [ ] , and rapidly began spreading between humans after initial local spread in a seafood market. the disease caused by this novel sars-related coronavirus (sars-cov- ), which was designated coronavirus disease (covid- ), was declared a global pandemic by the world health organization in march . as of july , , over million covid- cases and , deaths associated with this virus had been reported [ ] . early symptoms of covid- include fever, a dry cough, and dyspnea [ ] . the disease can progress rapidly and can cause high rates of mortality or severe life-threatening organ damage in some patients. one retrospective analysis of sars patients found that while acute kidney injury (aki) was uncommon among these patients ( cases), its incidence was associated with a . % mortality rate [ ] . a male patient that died of acute pneumonia and renal failure in saudi arabia in was the first patient from whom mers-cov was isolated [ ] , underscoring the potential for severe renal damage associated with these viruses. xu et al. [ ] determined that sars-cov and sars-cov- are highly homologous, and computational models revealed that sars-cov- exhibits a strong affinity for human angiotensin-converting enzyme (ace ). there is evidence to suggest that covid- infection has the potential to induce kidney damage in infected patients. for example, li et al. [ ] found that blood urea nitrogen was elevated in . % ( / ) of analyzed covid- patients, while creatinine levels were elevated in . % ( / ) of these patients. these same patients also frequently exhibited proteinuria ( . %; / ) and hematuria ( . %; / ), and most exhibited abnormal renal radiographic findings consistent with edema and inflammation. aki incidence in covid- patients has also been found to be an independent predictor of poor prognosis and elevated mortality rates [ the preferred reporting items for systematic reviews and meta-analyses (prisma) statement and meta-analysis of observational studies in epidemiology (moose) guidelines were used to guide the conceptualization and execution of this meta-analysis [ , ] . the pubmed, embase, web of science, medrxiv, and biorxiv databases were systematically searched for relevant studies published as of july , without any language restrictions, using the following search terms: "covid- ", " -ncov", "sara-cov- ", "novel coronavirus" "acute kidney injury", and "acute renal failure". the search strategy was presented in online appendix . covid- -related reports in relevant literature reviews and the references of included studies were also searched to identify other relevant analyses. studies eligible for inclusion in this meta-analysis were: ( ) observational studies reporting rates of aki and rrt use in covid- patients; ( ) published studies that met with relevant requirements, regardless of whether or not aki definition was mentioned; and ( ) pre-print articles that included an explicit definition of aki. studies were excluded from this analysis if they were abstracts, editorials, reviews, letters, conference abstracts, or commentaries. for any studies reporting on patient populations within the same hospital during overlapping time periods, only the study with the most comprehensive dataset was included in this analysis. two investigators (xpy and sst) independently reviewed studies, extracted data, and assessed study quality. any discrepancies were resolved by a third investigator (hg). data extracted from each study included study design, study title, first author, year of publication, country, patient information, aki incidence, and rates of rrt use. observational study quality was evaluated using the newcastle-ottawa scale. primary study outcomes included aki incidence among total covid- patients, among covid- patients admitted to the intensive care unit (icu), and among deceased covid- patients. secondary outcomes included rrt use in total covid- patients and among covid- patients admitted to the icu. the "meta" package for r (v. . . ) was used to conduct the present meta-analysis when there are five or more studies reporting the same outcome with the same definition. the normality of data distributions was assessed, and data were used in their raw form when normally distributed, whereas they were otherwise subjected to logit transformation. freeman-tukey double arcsine transformation was conducted for variables for which many values were either or in order to facilitate variance stabilization. a continuous correction of . was used for studies with rates of . corresponding % confidence intervals (cis) were computed for all pooled result analyses. the i statistic was used to assess heterogeneity among studies. when i ＞ %, a random-effects model was used for analyses, whereas a fixed-effects model was otherwise used. potential sources of heterogeneity were identified through sensitivity and subgroup analyses. the prisma flow diagram was shown in fig. . our search strategy identified potentially studies, of which were not peer-reviewed and failed to define aki, failed to report aki or rrt outcomes in patients, with wrong design and utilized data from the same source. the remaining studies of patients were included in the present meta-analysis [ , . individual studies incorporated - patients, with average patient ages ranging from to . years ( table ) . the newcastle-ottawa scale was used to assess the quality of these included studies (table ). studies came from china (n= ), the usa (n= ), italy (n= ), the uk (n= ), spain (n= ), kuwait (n= ), france (n= ), germany (n= ), canada (n= ), thailand (n= ), india (n= ), poland (n= ) and turkey (n= ). one study included data from countries. all studies were observational in nature, including retrospective studies and prospective studies. of these studies, were multi-center analyses. incidence of aki among covid- patients was reported in of the included studies. of the patients included in these studies, developed aki, with a pooled aki incidence rate of . % among covid- patients ( % ci . %- . %, i = %) (fig. a) . in an effort to identify sources of heterogeneity among included studies, a sensitivity analysis was conducted which failed to identify the drivers of such heterogeneity. as aki incidence was highest among kidney transplant recipients, we additionally conducted a subgroup analysis, which revealed that the incidence of aki among transplant patients was . % ( % ci . %- . %, i = %), whereas among non-transplant patients this incidence rate was . % ( % ci . %- . %, i = %) (fig b) . of three continents were included in our study: asia, north america and europe, and we conducted a subgroup analysis according to different continents, the aki (fig d) (fig e) . in total, studies reported on aki incidence among icu patients. overall, aki occurred in / patients admitted to the icu for an overall pooled incidence rate of . % ( % ci . %- . %, i = %) (fig f) . a total of studies reported on aki incidence among deceased patients, of whom / exhibited signs of aki for an incidence rate of . % ( % ci . %- . %, i = %) (fig g) data pertaining to the use of rrt among covid- patients was reported in of the studies included in the present meta-analysis. in total, rrt was used to treat out of covid- patients in these studies, for a pooled application rate of . % ( % ci . %- . %, i = %) (fig a) . sensitivity analyses did not result in any meaningful changes in the high heterogeneity observed among the included studies. subgroup analyses revealed that rrt was used in . % of transplant patients ( % ci . %- . %, i = %) and in . % of non-transplant patients ( % ci . %- . %, fig b) . in total, studies reported on rrt use among covid- patients admitted to the icu. overall, rrt use was reported for / of these patients for a pooled incidence rate of . % ( % ci . %- . %, i = %) (fig c) . we found that rates of aki ( . %) and rrt use ( . %) were high among covid- patients, the aki incidence was lower in asia ( . %) compared to europe ( . %) and north america ( . %). we also found that patients admitted to the icu exhibited very high rates of aki ( . %) and rrt use ( . %). this meta-analysis also reported the rates of aki ( . %) and rrt use ( . %) among kidney transplant patients. while we were unable to specifically establish rates of mortality among aki patients, we did determine that aki was common among patients that died of covid- ( . %). aki development in covid- patients may be driven by several mechanisms. for one, the virus may directly infect and damage renal cells. sars-cov- utilizes ace as a cell entry receptor [ ] , and in humans, ace is expressed on proximal tubular cells and podocytes [ , ] . week between virus detection in the blood and aki, suggesting that direct renal infection may be a key process driving the incidence of this dangerous condition [ , , , ] . another study found that sars-cov- may also be able to enter target cells using cd , which is highly expressed in the kidneys, as a cell surface receptor [ , ] . in critically ill patients, sepsis is also thought to be the primary driver of aki incidence [ ] , and is common in deceased covid- patients [ , ] . indeed, up to % of severe hospitalized covid- patients develop viral sepsis and acute respiratory distress syndrome (ards) [ ] . in individuals suffering from sepsis, hypoxia-related acute tubular necrosis (atn) and severe hyperinflammation can drive aki development [ ] . such hyperinflammation is closely associated with cytokine release syndrome (crs), which results in intrarenal inflammation and increased vascular permeability [ ] . crs has frequently been detected among covid- patients, with particularly elevated levels of il- having bene detected in affected individuals [ , ] . organ crosstalk may also govern aki pathogenesis. indeed, ards and associated hypoxemia, inflammation, and the need for mechanical ventilation can result in the degradation of kidney hemodynamics and functionality [ ] . annat et al [ ] found that continuous positive pressure ventilation (cppv) was sufficient to decrease urine output, glomerular filtration rate (gfr), and renal blood flow (rbf), potentially resulting in aki. drug-or hyperventilation-related rhabdomyolysis can also result in tubular toxicity, and analyses of covid- patient renal histopathology have suggested that rhabdomyolysis may be a disease-related complication as evidenced by the presence of pigmented casts within tubules and increased levels of creatine phosphokinase [ ] . ultimately, a number of pathogenic factors are likely to contribute to the incidence and severity of aki in individuals suffering from covid- . there are multiple limitations to the present study. for one, some of these outcomes were associated with high heterogeneity that may be attributable to the diverse covid- incidence rates and treatment approaches in different countries, as well as to differences in study design and mutation-related changes in viral virulence. in addition, the definition of aki was not always clear as it was generally not the main study outcome. as such, only pre-print studies that explicitly define aki and published studies were included in this analysis. furthermore, the majority of the studies included in this meta-analysis were conducted in china, and their applicability to other regions remains to be established. in summary, aki frequently occurs among patients suffering from covid- and is most common among severely ill patients and among those that ultimately succumb to this disease. it is thus essential that the incidence of aki be identified as quickly as possible in these patients so that rrt and other treatments can be initiated as appropriate in an effort. we believe that the present study will underscore the severity of aki rates among covid- patients, while emphasizing the need for further clinical studies of this severe complication. none. all authors declare that there are no conflicts of interest. 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( ) ( -ncov disease or -ncov infection or covid or covid or covid or ncov disease or ncov infection or novel coronavirus disease or novel coronavirus infection or novel coronavirus disease or novel coronavirus infection or wuhan coronavirus disease or wuhan coronavirus infection). ab, ti. ( ) kidney injury or acute kidney insufficiency or acute renal failure or acute renal insufficiency or kidney acute failure or kidney failure, acute or kidney insufficiency, acute or renal insufficiency, acute). ab, ti novel coronavirus pneumonia) or ts=(sars-cov- ) or ts=(severe acute respiratory syndrome coronavirus ) or ts=(covid- ) or ts=(coronavirus disease ) or ts=(sars-cov- infection) or ts=(covid- virus infection) or ts=( -ncov infection) or ts= acute) or ts=(acute renal injury) or ts=(acute renal injuries) or ts=(renal injuries, acute) or ts=(renal injury, acute) or ts=(kidney failure, acute) or ts=(acute kidney failures) or ts=(kidney failures, acute) or ts=(acute renal failure) or ts=(acute renal failures) or ts=(renal failures, acute) or ts=(renal failure, acute) or ts=(acute kidney failure). ( ) biorxiv database: medrxiv and biorxiv key: cord- -bhrrb s authors: nan title: medical sequelae of covid- date: - - journal: bull acad natl med doi: . /j.banm. . . sha: doc_id: cord_uid: bhrrb s nan the most severely affected patients, the medical sequelae are a real threat whose importance remains poorly assessed [ ] . caregivers and patients will also face psychic medical sequelae that should not be underestimated. the medical sequelae of covid- can be separated into two groups. the first group includes those following the organ damage in the acute phase, which are not or only slightly reversible. the second includes complex poorly qualified disorders occurring a few weeks after recovery, the origin and fate of which remain unknown. because of the spread of the pandemic, even a small percentage of medical sequelae represent a nationwide public health problem. the lung is the most frequently affected organ in the acute phase of the disease, and epidemics due to other coronaviruses such as sars-cov and mer-cov have shown that pulmonary fibrosis can persist after the initial infection. interstitial pulmonary fibrosis is a frequent consequence of respiratory distress observed in the acute phase of the disease. it may also result from an acute phase that appeared to be mild. it is mainly attributed to the increased produc-doi of original article:https://doi.org/ . /j.banm. . . . ଝ position statement of the national academy of medicine, july q th . tion of pro-inflammatory cytokines, an indirect consequence of the viral infection. other factors may be involved, such as airway hyper pressure following artificial ventilation and anoxia due to an imbalance between oxygen requirements and oxygen supply. fibrosis is characterized by a progressive decline in respiratory function, an extension of the lesions visible on the chest tomography, an increased susceptibility to respiratory infections. even a low degree of residual fibrosis can increase mortality in the elderly. inflammatory myocarditis proven by elevation of troponin and ''b-type natriuretic peptide'' (bnp) is frequently found in patients treated in intensive care units and may lead to left ventricular failure. myocardial infarction may occur in connection with plaque rupture promoted by infection or prolonged anoxia. right ventricular failure secondary to pulmonary arterial hypertension resulting from respiratory fibrosis and/or acute pulmonary embolisms is also possible. arrythmia is sometimes observed, including extrasystoles, q ventricular tachyarrhythmia and atrial fibrillation. heart failure, myocardial necrosis, and arrythmia persist after the acute phase and require a prolonged monitoring and an appropriate treatment. proteinuria, microscopic hematuria, and moderate elevation of plasma creatinine are common in the acute phase, https://doi.org/ . /j.banm. . . - / indicative of renal impairment. since creatinine measurement is a marker of decreased glomerular filtration rather than tubular injury, more specific markers such as ''kidney injury molecule- '' (kim- ) and ''neutrophil gelatinase associated lipocain'' (ngal) should be used. reversible acute renal failure related to fluid and electrolyte disorders has been observed. direct virus-related damage results in inconsistently reversible tubular epithelial cell necrosis leading to chronic end-stage renal disease. as the progression to chronic renal failure is always silent, patients with this disease should be monitored over a long period of time. brain damage may be directly related to the virus or more often the consequence of prolonged anoxia in patients on artificial ventilation, strokes, or an autoimmune syndrome such as an acute disseminated encephalomyelitis which, if accompanied by peripheral disorders and affecting the diaphragm, can aggravate respiratory disorders. brain stem damage has also been described contributing to breathing difficulties. sarcopenia is almost constant in patients who are immobilized for several weeks in intensive care units, requiring prolonged rehabilitation during convalescence. patients apparently recovering from the acute episode have been found to require prolonged convalescence or to complain of new symptoms after a period of remission. the initial infection was often short and healed spontaneously. negative virus tests rule out a reinfection and the presence of igg specific for sars-cov- confirms the previous infection. the disorders complained of by these subjects are general discomfort or sometimes, attacks of tachycardia, muscular pain, arthralgia, fatigue at the slightest muscular or intellectual effort, memory loss. the clinical examination remains negative except often a loss of weight indicating undernutrition. these disorders are most often episodic, but are sometimes prolonged. treatment is difficult, apart from the prescription of paracetamol, psychological support and correction of any undernutrition by a dietician. it is difficult to distinguish between the consequences of covid- or other causes, as is the case in the post-borreliosis syndrome of lyme disease. psychic after-effects are to be feared in patients, caregivers and victims of confinement. those coming out of intensive care units with assisted ventilation and deep sedation, and then from a long convalescence, are intensely marked. in addition to the functional recovery of the affected organs, they need psychological support to enable them to return to work and a normal social life. those who have recovered spontaneously also sometimes need this support, when they suffer from the various and poorly qualified disorders considered above. whether they work in hospitals or residential institutions for the elderly dependent persons, whether they are doctors, nurses, orderlies, stretcher bearers, manipulators. . ., this staff has been subjected to extended work schedules associated with increased responsibilities, given the worrisome condition of the patients treated, leading to fatigue, anxiety and lack of sleep. even if most of these symptoms disappear with the return to their usual activity and the possibility of leave, some of them remain tired, anxious and insomniac, what requires follow-up and psychological support. although the entire population was subject to the rules of containment limiting leaving the home and social contact, some groups were particularly affected: children and young adults with disabilities who left their host institution; children deprived of school and of any contact with their pals; students who returned to their parents' homes and whose studies were interrupted. while these disorders are often spontaneously self-resolving, some may require psychological help. to treat the medical sequelae, within the limits of our current knowledge, the french national academy of medicine recommends: • the resumption of a physical activity as soon as possible, of which walking is the easiest; • vigilance as to the functional quality of the organs most often affected (heart, brain, muscles and lungs); • monitoring the long-term evolution of these after-effects by assembling a cohort of patients in a longitudinal study lasting several years; • measures concerning the organisation of work in hospitals and residential institutions for the elderly dependent persons (recruitment of nursing staff, increase of remuneration), to reduce the risk of ''burn out'' and the psychological tensions linked to an excessive work; • helping the parents of disabled children who, in the event of a new containment, would have to replace the host institutions. the authors declare that they have no competing interest. q les phases de l'épidémie covid- : critères, défis et enjeux pour le futur. prérapport de l'académie nationale de médecine pulmonary fibrosis and covid- : the potential role for antifibrotic therapy cardiovascular disease in the post-covid- era. the impending tsunami is the kidney a target of sars-cov- ? neurologie et covid- follow-up studies in covid- recovered patients -is it mandatory? psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the covid- pandemic key: cord- -qwh inx authors: mendoza, jose luis accini; estrada, victor hugo nieto; lópez, nelly beltrán; bolaños, elisabeth ramos; franco, daniel molano; castell, carmelo dueñas; moreno, albert alexander valencia; amaya, iván camilo alarcón; flórez, john serna; valencia, bladimir alejandro gil; camilo pizarro, g; polo, yulieth maría zabaleta; meza, carmen lucia chica title: actualizacion de la declaraciÓn de consenso en medicina critica para la atenciÓn multidisciplinaria del paciente con sospecha o confirmaciÓn diagnÓstica de covid- date: - - journal: nan doi: . /j.acci. . . sha: doc_id: cord_uid: qwh inx antecedentes y objetivos: la enfermedad por coronavirus de (covid- ) es una enfermedad ocasionada por el nuevo coronavirus del síndrome respiratorio agudo grave (sars-cov- ). se identificó por primera vez en diciembre de en la ciudad de wuhan, en los meses siguientes se expandió rápidamente a todos los continentes y la organización mundial de la salud (oms), la reconoció como una pandemia global el de marzo de . la mayoría de los individuos son asintomáticos pero una baja proporción ingresan a cuidados intensivos con una alta morbilidad y mortalidad. este consenso tiene como objetivo actualizar la declaratoria inicial emitida por la asociación colombiana de medicina crítica (amci) para el manejo del paciente críticamente enfermo con covid- dentro de las áreas críticas de las instituciones de salud. métodos: este estudio utilizó dos técnicas de consenso formal para construir las recomendaciones finales: delphi modificada y grupos nominales. se construyeron preguntas por la estrategia pico. grupos nominales desarrollaron recomendaciones para cada unidad temática. el producto del consenso fue evaluado y calificado en una ronda delphi y se discutió de forma virtual por los relatores de cada núcleo y los representantes de sociedades médicas científicas afines al manejo del paciente con coid- . resultados: expertos nacionales participaron en la actualización del consenso amci, especialistas en medicina critica y cuidados intensivos, nefrología, neurología, neumología, bioeticistas, medicina interna, anestesia, cirugía general, cirugía de cabeza y cuello, cuidados paliativos, enfermeras especialistas en medicina crítica, terapeutas respiratorias especialistas en medicina crítica y fisioterapia, con experiencia clínica en la atención del paciente críticamente enfermo. la declaratoria emite recomendaciones en los ámbitos más relevantes para la atención en salud de los casos de covid- al interior de las unidades de cuidados intensivos en el contexto nacional de colombia. conclusiones: un grupo significativo multidisciplinario de profesionales expertos en medicina crítica emiten mediante técnicas de consenso formal recomendaciones sobre la mejor práctica para la atención del paciente críticamente enfermo con covid- . las recomendaciones deben ser adaptadas a las condiciones específicas, administrativas y estructurales de las distintas unidades de cuidados intensivos del país. background and objectives: the coronavirus disease (covid- ) is caused by the new severe acute respiratory syndrome coronavirus (sars-cov- ). it was first identified in december in wuhan, china. in the following months it spread quickly to all continents and was recognised as a global pandemic by the world health organization (who) on march th, . most cases of infection remain asymptomatic, while a low proportion require intensive care, experiencing high morbidity and mortality. this consensus aims to update the initial statement issued by the colombian association of critical medicine (amci) for the management of the critically ill patient with covid- within the critical areas of health institutions. methods: this study used two formal consensus techniques to construct the final recommendations: modified delphi and nominal groups. questions were constructed using the pico strategy. recommendations for each thematic unit were developed by nominal groups. the consensus product was evaluated and qualified in a delphi round, and was discussed virtually by the speaker of each nucleus, as well as the representatives of scientific medical societies related to the management of the patient with covid- . results: a total of national experts participated in the update of the amci consensus, all specialists in critical and intensive care medicine, nephrologists, neurologists, chest physician, bioethicists, internal medicine specialists, anaesthetists, general surgeons, head and neck surgery, palliative care, nurses specialised in critical medicine, respiratory therapists specialised in critical medicine and physiotherapy, with clinical experience in the care of critically ill patients. this update issues recommendations in the most relevant areas for health care of covid- patients within the intensive care units, contextualised for colombia. conclusions: a significant multidisciplinary group of professionals, who are experts in critical medicine, reviewed and issued recommendations on best practice for the care of critically ill patients with covid- through formal consensus techniques. recommendations must be adapted to the specific, administrative, and structural conditions of the different intensive care units in the country. para la actualización de la declaratoria se utilizaron dos técnicas para el desarrollo de consensos de tipo formal, técnica delphi modificada y grupos nominales. un consenso formal permite integrar las opiniones de un colectivo de expertos que están expuestos a un tema específico (experto afectado) con la mejor evidencia científica disponible, utilizando técnicas que permitan reducir los sesgos de subjetividad. la técnica delphi es una metodología que plantea enviar cuestionarios a un grupo de expertos, para que califiquen una serie de recomendaciones en rondas reiteradas con retroalimentación de los resultados y respuestas anónimas, la técnica delphi empleada fue modificada, variante a la versión original propuesta por la corporación rand en , pero se mantuvo las ventajas de la técnica, la iteración y retroalimentación para reflexión de las propias opiniones. los grupos nominales es una técnica que reúne a un grupo de expertos bajo la coordinación de un facilitador para evaluar y calificar información o preguntas ( , ) . para la actualización se convocó grupos nominales con expertos multidisciplinarios cada uno con un líder o jefe de núcleo. los grupos construyeron las preguntas por metodología pico y desarrollaron progresivamente las recomendaciones hasta las versiones finales. el proyecto se desarrolló en fases, fase : formulación del problema y socialización; fase : elaboración de las preguntas, fase : formulación de las recomendaciones y ronda de calificación. las estrategias de búsqueda se desarrollaron en bases de datos especializadas (medline, embase, lilacs, central), en las circunstancias donde no se encontró evidencia directa, se utilizó y se adaptó evidencia indirecta del tópico relevante en el paciente críticamente enfermo general. expertos con un promedio de años de experiencia en la atención del paciente crítico evaluaron y calificación las recomendaciones en la metodología delphi mediante un cuestionario distribuido por medio de correo electrónico, respetando la política de privacidad de datos vigente. recomendaciÓn se recomienda que los prestadores de servicios de acuerdo con su infraestructura física y la disponibilidad de recursos (tecnológico, humano, de interdependencia y apoyo) definan su modelo de atención para pacientes con covid- en estado crítico basado en principios de factibilidad, efectividad, seguridad y la relación entre la demanda (momento epidemiológico) y capacidad/capacidades de respuesta:  modelo . atención de pacientes con sospecha o confirmación diagnóstica covid- . este enfoque permite concentrar, optimizar y racionalizar recursos y reducir el riesgo potencial de contagio al equipo de atención, de apoyo y de pacientes.  modelo . atención mixta, de pacientes con y sin diagnóstico de covid- , en escenarios que cuentan con unidades de aislamiento normatizados (presión negativa y > -renovaciones completas de aire por hora) soportado en el documento institucional de gestión organizacional y operativo del servicio de cuidados intensivos, descrito en los procesos prioritarios. amci ® menos accidentalidad y violencia). la reducción de procedimientos quirúrgicos complejos electivos es una opción razonable condicionado a las posibilidades del paciente. sin embargo, situaciones como la progresión y descompensación de las patologías crónicas asociadas a las medidas de restricción social puede plantear un efecto bumerang con mayor demanda de camas de uci. con base en las predicciones simuladas de las tasas esperadas de ingreso a uci de pacientes con covid- contrastado con el déficit de servicios y camas de cuidados críticos en el país a partir de la capacidad instalada se han planteado fases de desarrollo cuyas características en términos de servicios, recursos y cronología se aprecian en la ilustración y .  fase (para el gobierno nacional: ampliación de la capacidad instalada*). parte de la liberación de camas de cuidados intensivos destinadas para atención covid- bajo el modelo y/o . la liberación de camas y servicios con mínima adaptación es la fase más inmediata y resolutiva que debe acogerse a la exigencia normativa (resolución de ), en la que se espera menos mortalidad, morbilidad y tasa de complicaciones asociados con la atención de pacientes con covid- en estado crítico.  fase (optimización para el gobierno nacional*) representan el reordenamiento de las camas de cuidados intermedios adultos en camas de cuidados intensivos y de hospitalización en intermedio. de adultos. el gobierno nacional toma en cuenta la ampliación de la capacidad instalada hospitalaria descrita en el plan territorial. para esta fase se necesitan equipos de ventilación mecánica (excluidos por la norma de estos servicios), monitoreo básico y avanzado y un número mayor de talento humano multidisciplinario competente. amci ® acuerdo con las etapas ( - ) y los perfiles requeridos priorizados como primera, segunda y tercera línea de respuesta*. en la ilustración podemos observar que avanzar de las fases a se va a necesitar mayor intervención en términos de organización, planeación operativa, formación por competencias y apoyo por telesalud (teleapoyo o teleexperticia). el personal no especializado o especializado de servicios hospitalarios diferente a urgencia, quirófano o uci pueden constituir grupos de apoyo para la gestión administrativa y de índole humanitaria (líneas de respuesta) la integración de estos requerimientos adaptativos se ha puesto de manifiesto en la experiencia del centro médico new york -presbyterian weill en la ciudad de nueva york, en donde la demanda de camas de unidades de cuidados intensivos (uci) y ventilación mecánica excedió su capacidad.( ) se recurrió a los quirófanos y de recuperación las cuales no estaban en uso porque los procedimientos electivos habían sido pospuestos. se hicieron adecuaciones físicas para garantizar la vigilancia continua de los pacientes y la seguridad del equipo de atención. se capacito a todo el personal de cuidado perioperatorio disponible y fueron distribuidos en las áreas recién configuradas. las enfermeras familiarizadas con las máquinas de anestesia asumieron como terapeutas respiratorios y los intensivistas de anestesia supervisaban estas unidades. recomendaciÓn se recomienda la adopción de un modelo simulado de predicción (basado en el cociente de fatalidad, tasa de ingreso a uci y el número de reproducción ro) para proyectar, de manera anticipada las necesidades de recurso físico, tecnológico y humano de cuidados críticos en fase de preparación de la pandemia por covid- . las tomas de decisiones relacionadas con el fortalecimiento de la capacidad/capacidades de la oferta de cuidados críticos (habilitadas o adaptadas) pueden deducirse mediante la aplicación de modelos matemáticos que intentan, desde la dinámica epidemiológica, establecer el efecto simulado de las medidas de mitigación o supresión adoptadas sobre la tasa de contagio a través del tiempo. con ello se busca planear el uso de recursos e implementar acciones de prevención y de distanciamiento social más eficientes, así como establecer las necesidades en materia de cama de cuidados críticos (intensivos e intermedios) habilitadas o adaptadas en áreas de expansión y con ello los recursos resolutivos como tecnologías, interdependencias y talento humano capacitado. la capacidad predictiva del modelo resulta de establecer: la información en términos de casos proyectados (población susceptible), el modelo de transmisión, el impacto de las amci ® intervenciones no farmacológicas (mitigación y supresión) para lograr disminuir el número de reproducción r (tasa de contagio), la distribución de la gravedad de la enfermedad y con ello el porcentaje esperado de casos críticos el decreto del . . ( ) , por el cual se declara un estado de emergencia económica, social y ecológica en todo el territorio nacional proyectó para una tasa de contagio de . y cerca de millones de casos, la ocurrencia de mil casos de pacientes con covid- en estado crítico ( . %) y la necesidad de incrementar las camas de cuidados intensivos en un % que con una estancia promedio de días tendría un costo de mil millones de pesos. colombia cuenta con cerca de camas de cuidados intensivos ( / parte son intermedio) de las cuales el % podría ser utilizada para la atención de pacientes covid- ( ). con base en el modelo matemático ha proyectado la necesidad de camas de uci indicando por deducción la necesidad de camas a partir de un plan adaptativo de expansión y extensión. colombia reporta a la fecha actual , casos confirmados y nuevos casos de covid- confirmados y cerca del % ocupan una cama de cuidados intensivos (esta cifra es mayor si se tomaran en cuenta los casos sospechosos). de este modo, los modelos matemáticos permiten predecir el comportamiento epidemiológico de la enfermedad y con esto anticiparse a proyectar el plan de fortalecimiento hospitalario (incluyendo camas, tecnologías, talento humano) y los recursos financieros para respaldar la expansión del cuidado críticos. estos modelos deben ser predictivos y no reactivos al comportamiento epidemiológico de la enfermedad y solo debe des escalarse hasta después de reducirse a menos de . el índice ro. ( - ) recomendaciÓn se sugiere la implementación de una estrategia de telesalud (teleapoyo o teleexperticia) en el marco de la pandemia covid- , cuando no se cuente con un intensivista presencial, que, mediante una tecnología adecuada complemente la atención en las áreas de cuidados críticos realizado por personal capacitado. aún cuando es considerada ventajosa sus implicaciones en términos de resultados clínicos, económicos y de riesgos legales no se ha demostrado. en situaciones donde se declara una pandemia los sistemas de salud pueden tener dificultades para hacer frente a una demanda exponencial y fuera de control. esto puede ser así en el marco pandemia covid- que prevé un % de pacientes en condición crítica y que amerita reorganización y/o adaptación de su capacidad de respuesta. incrementar la disponibilidad de camas y servicios de cuidados críticos mediante una estrategia de expansión supone retos asociados a la insuficiencia que se puede presentar en talento humano especializado específicamente de especialistas en medicina crítica y cuidado amci ® intensivo, escenario que se puede complicar en la medida que intensivistas sean separados o aislados en el curso de la epidemia. en este contexto se hace necesaria la implementación de modelos ágiles de telesalud (ts) para el acompañamiento de las unidades de cuidado crítico en expansión y de instituciones prestadoras de servicios de salud de baja y mediana complejidad para la regulación con los equipos de referencia y contrarreferencia de pacientes que pueden necesitar atención en cuidados intensivos. ( ) ( ) ( ) ( ) ( ) ( ) el decreto ley de ( ) plantea la adopción de medidas en el sector salud para garantizar la prestación de los servicios de salud y para facilitar la implementación de modelos de atención que incluyan la telesalud y la prestación de los servicios en la modalidad de telemedicina se determinan algunas medidas temporales para: i) adecuar temporalmente un lugar no destinado a la prestación de servicios de salud, intra o extra mural. ii) prestar servicios en modalidades o complejidades diferentes a las habilitadas dentro de las cuales puede estar la telemedicina iii) prestar servicios de salud no habilitados. en este decreto también se establecen condiciones temporales para la implementación de plataformas tecnológicas para la telesalud. en complemento, la resolución de ( ) (estándares de habilitación) plantea la modalidad de la telemedicina (prestador remisor-prestador de referencia) para las unidades de cuidado intermedio e intensivo. la telesalud se puede prestar de dos maneras: teleapoyo y teleexperticia. tabla . teleapoyo (ta) soporte solicitado por un profesional de la salud a otro profesional de la salud a través de tic siendo responsable de la conducta quién solicita el apoyo. no requiere habilitación y por tanto no requiere autorización transitoria relación a distancia con comunicación sincrónica o asincrónica utilizando tic entre dos profesionales de la salud, uno de los cuales atiende presencialmente al usuario y otro atiende a distancia. el primero es responsable de las decisiones/recomendaciones entregadas al paciente y el segundo es responsable de la calidad de la opinión que entrega y debe especificar las condiciones en las que se da dicha opinión, lo cual debe consignarse en la historia clínica. requiere autorización transitoria (decreto ) ( ) la telesalud y la prestación de servicios de salud en esta modalidad son estrategias seguras y efectivas para guiar, a distancia, el diagnóstico y el tratamiento del paciente hospitalizado y en estado crítico. sus ventajas generales se presentan en la tabla . asociaciÓn colombiana de medicina crÍtica y cuidados intensivos. amci ® tabla . ventajas generales de la telesalud decreto legislativo de .  facilita la viabilidad de aplicación modelos organizativos que favorecen la continuidad y la integridad asistencial y la atención centrada al entorno del paciente, aplicando conceptos de globalidad e interoperabilidad a las organizaciones sanitarias, dando lugar a nuevas formas de organización y trabajo en red.  mejora de la calidad asistencial, ya que facilitan el acceso y la disponibilidad de servicios asistenciales en condiciones de calidad.  mejora calidad de vida del paciente por la disminución de desplazamientos para la atención ya que permite la atención o monitorización remota con tic en su domicilio.  mejora la oportunidad y la resolutividad de la atención.  facilita la equidad en el acceso a los servicios de salud independientemente de la localización geográfica (acerca la atención especializada a toda la población).  mejora la atención integral y seguimiento tanto de los pacientes crónicos, como los de las enfermedades de baja prevalencia.  reduce los tiempos de espera (tanto en la realización del diagnóstico como en el tratamiento), evitando complicaciones por no atención oportuna.  posibilita realizar atención remota de mediana y alta complejidad en la baja complejidad, reduciendo el número de remisiones.  disminuye la posibilidad de infección cruzada entre usuarios de los servicios de salud y el personal de salud.  incide en la formación y competencia del talento humano en salud.  facilita la educación de pacientes en medicina preventiva y salud pública.  descongestiona servicios de urgencias y consulta externa.  contribuye a la reducción de movilidad de personas en la ciudad.  responde a las necesidades inmediatas en salud de la comunidad.  es un medio de racionalización de costos en salud. puede abarcar otros servicios de gestión administrativa como entrega de fórmulas o facturación. amci ® se recomienda la implementación de un modelo de cuidados críticos covid- liderado por intensivistas, en áreas habilitadas o adaptadas, con el beneficio preponderante de disminuir la mortalidad, tiempo de estancia y optimización de recursos. se recomienda una cobertura por intensivistas de al menos horas diarias y un cociente intensivista/paciente cercano a intensivista por cada - pacientes, basado en la alta complejidad de la enfermedad critica covid- con un alto porcentaje de pacientes en ventilación mecánica, largos tiempos de estancia y alto riesgo de mortalidad. fuerte a favor fundamento un intensivista es un profesional médico capacitado en medicina crítica y de cuidados intensivos conforme a los estándares establecidos por una institución de educación superior debidamente reconocida ante el ministerio de salud. este especialista debe liderar y tomar todas las decisiones con respecto al cuidado de los pacientes críticos, incluyendo admisiones y egresos, qué médicos consultar, estándares de atención, gestión de la calidad y seguridad, gestión humana y ética, interacción con la familia e implementación de un programa de investigación y de formación continua para mejorar capacidades y competencias del equipo de atención, control de conflictos, entre otras.( ) existe una enorme validez conceptual y una preponderancia de evidencia que sugiere que ser atendido por un especialista en cuidados críticos (intensivista) es "bueno" para los pacientes de la uci. la mayoría de los estudios demuestran el impacto positivo de un uci dirigida por intensivistas los modelos de personal médico de la uci más ampliamente estudiados difieren en el nivel al cual los intensivistas están involucrados en el manejo de los pacientes. las uci de alta intensidad son aquellas donde un intensivista de tiempo completo u obligatorio maneja a la mayoría de los pacientes diariamente. las uci de baja intensidad no tienen participación intensivista u ofrecen consultas intensivistas electivas. un metaanálisis mostró que un modelo de alta intensidad en comparación con uno de baja intensidad estuvo asociado con una menor mortalidad en la uci, menor mortalidad hospitalaria, y una reducción significativa en la duración de la estancia hospitalaria. un modelo de alta intensidad por la noche se asoció con menor mortalidad solo cuando durante el día era de baja intensidad. ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) asociaciÓn amci ® forzosa" por condición de riesgo siempre en consonancia con los términos establecidos en el decreto ley de ( ). según la normatividad vigente todo miembro del equipo de atención, especialista no intensivista o no especialista (enfermeras, fisioterapeutas/terapeutas respiratorias) y auxiliares de enfermería deben tener constancia de asistencia a acciones de formación continua y/o capacitación en atención covid- en cuidados críticos las cual puede ser parte de un programa institucional de capacitación liderado por el intensivista coordinador o titular del servicio o a partir de cursos respaldados por instituciones académicas acreditadas o los ofrecidos por la asociación colombiana de medicina crítica y cuidados intensivos (amci). las tablas y nos muestra como dentro de este proceso adaptativo por estado de emergencia y atribuido a un desequilibrio entre la oferta y la demanda, otras especialidades, profesionales de la salud y personal en formación pueden hacer parte de los equipos de atención bajo las siguientes premisas: . la supervisión, coordinación y liderazgo del intensivista es necesaria y . el intensivista establece los roles y competencias del th no intensivista y no normatizado, de acuerdo a sus perfiles, y delegada acciones asistenciales (vía aérea, accesos vasculares, reanimación cardiopulmonar, pronación), administrativas (ordenes médicas, notas clínicas) o de naturaleza humanitaria (comunicación con la familia, apoyo emocional al th, etc.). es necesario considerar los roles de las especialidades que formarán parte de la gestión asistencial y/o administrativa de pacientes con covid- en áreas críticas habilitadas o adaptadas de manera transitoria en colombia tabla . integridad de interdependencia (norma / ) integralidad e interdependencia (adaptiva) gfa integridad de interdependencia (norma / ) integralidad e interdependencia (norma / ) integridad de interdependencia (norma / ) obligatorio en gestión asistencial integralidad e interdependencia(norma / ) obligatorio gestión asistencial apoyo a tomas de decisiones(gfa) apoyo a tomas de decisiones (gfa) a:formacion continua + covid- (curso virtual); b: requiere capacitación covid- (curso virtual); c: gfa: grupo focal asistencial, sistema alerta-acción, rcp, pronación, accesos vasculares, ingreso a uci. d: gfad: grupo focal administrativo: consentimiento, notas de evolución. ts: telesalud. se recomienda la aplicación de la escala news- por parte de un equipo de respuesta rápida, para establecer el lugar de atención de pacientes con diagnóstico definitivo o sospecha de infección por covid- que encuentran en los servicios de urgencias o de hospitalización. se recomiendan escalas como el qsofa y el curb- para apoyar la decisión tomada con base en la escala news- . sin embargo, un qsofa mayor o igual a puntos (mínimo / ) y un crb- mayor o igual puntos tienen baja sensibilidad (alta incidencia de falsos negativos) para identificar pacientes que puedan requerir ingreso a uci. se recomienda el score de riesgo covid- -gram para identificar el riesgo de desarrollar un estado de la enfermedad crítico en pacientes con covid- y como herramienta complementaria a la escala news- en escenarios de alta demanda y escasez de recursos, de manera que la decisión de ingreso a uci se haga sobre aquellos pacientes que realmente se beneficiarán de la misma en términos de vidas salvadas y número de años salvados. la escala news fue construida y validada en paciente con infección por el virus de la influenza a/h n y se recomienda como una herramienta objetiva para decidir nivel de atención, incluyendo ingreso a uci o situaciones terminales que requieren acompañamiento familiar y medidas de cuidado paliativo. esta escala incluye variables fisiológicas que son: frecuencia respiratoria, saturación arterial de oxígeno (spo ), uso de oxígeno suplementario, presión arterial sistólica, frecuencia cardiaca (pulso), temperatura y nivel de conciencia. es de mencionar que esta escala no contempla la edad del paciente. en un reporte del acute medicine task force of the royal college, london, uk, recomendó la utilización de la escala news en los servicios de urgencias ( ) . un estudio que evaluó una base de datos con . signos vitales obtenidos de . pacientes demostró que esta escala tiene una buena capacidad para discriminar pacientes en riesgo para un desenlace combinado de paro cardiaco, ingreso no anticipado a uci o muerte dentro de las primeras horas de atención; de esta manera genera una gran oportunidad para el establecimiento temprano de una intervención clínica que cambie el pronóstico del paciente ( ) . la escala news- tampoco contempla la edad, pero sí incluye la presencia de hipercapnia bajo diferentes niveles de spo y oxígeno suplementario. esta escala es la que ha sido estudiada como herramienta para identificar pacientes en riesgo de desarrollar un estado de enfermedad crítica por covid- con un valor ≥ puntos ( / ) ( ) . con base en la escala news- se establece el grado de riesgo, el tipo de alerta, y la intensidad de monitoreo requerido; y de acuerdo con el puntaje arrojado, se define claramente el nivel de atención que requiere el paciente con diagnóstico de infección por covid- , incluso ingreso a uci (tabla ). esto se establece a través de una escala de puntuación así: -score puntos: manejo domiciliario bajo aislamiento y signos de alarma. -score punto: manejo domiciliario y seguimiento clínico en casa. -score - puntos: manejo en salas de hospitalización. -score - puntos: manejo en uci, área covid- . -score ≥ puntos sin condición extremadamente grave o irreversible y con alta posibilidad de recuperación: traslado a uci, área covid- . amci ® -score ≥ puntos con condición extremadamente grave y con datos de irreversibilidad o enfermedad terminal: no ingresa a uci y se traslada a salas de hospitalización con acompañamiento familiar y consulta a experto en bioética y cuidados paliativos. la ilustración establece un flujograma de conductas basado en el puntaje del news- . tabla . news- score. el qsofa con un valor ≥ puntos es otra herramienta recomendada para decidir qué pacientes que ingresan a uci. esta herramienta fue recomendada por la tercera definición de consenso (sepsis- ) para identificar pacientes con alto riesgo de muerte o estadía prolongada en uci entre aquellos con sospecha de infección ( ) . en este score, un punto es asignado para variables así: frecuencia respiratoria ≥ /min, presión arterial sistólica ≤ mmhg y escala de coma de glasgow (ecg) < . el score curb- y su versión simplificada, el crb- se utilizan para evaluar la severidad de enfermedad en personas hospitalizadas con neumonía adquirida en comunidad (nac). ambos scores han sido adoptados por la sociedad británica de tórax para predecir la necesidad de soporte respiratorio o vasopresor intensivo (srvi) en pacientes con covid- ( ) . el score crb- asigna un punto para variables así: confusión de reciente inicio, frecuencia respiratoria ≥ /min, presión arterial sistólica < mmhg o presión arterial diastólica ≤ mmhg y edad ≥ años. pacientes con un score ≥ puntos necesitan hospitalización ( ) . en un estudio clínico observacional realizado sobre los primeros pacientes ingresados en un hospital de noruega con diagnóstico confirmado de covid- , se evaluó la utilización de sistemas de score clínicos al momento del ingreso: news- , qsofa, crb- y sirs, con los puntos de corte previamente mencionados ( ) . la enfermedad se clasificó como enfermedad severa y enfermedad crítica. solo pacientes ( %) se clasificaron como enfermedad crítica. al evaluar los scores con sus puntos de corte, pacientes presentaron un qsofa ≥ [ con enfermedad severa ( %) y con enfermedad crítica ( %)], solo pacientes presentaron un crb- ≥ [ con enfermedad severa ( %) y con enfermedad crítica ( %)] y pacientes presentaron un news- ≥ [( con enfermedad severa ( %) y con enfermedad crítica ( %)]. la mediana del score news- para pacientes con enfermedad severa fue de . [riq: - ] vs . [riq: . - ] para pacientes con enfermedad crítica. los autores concluyen que el qsofa y el crb- se comportan similar y con una baja capacidad para la identificación de enfermedad crónica en pacientes con covid- ; por otro lado, los datos indican que el news- podría ser una herramienta más útil para identificar pacientes con riesgo de un curso más agresivo de la enfermedad ( % vs. %) ( ) . amci ® un estudio de cohorte retrospectivo realizado en un hospital en liverpool (uk), el puntaje qsofa se comportó como el más específico ( %; % ic: % - %) pero el menos sensible ( %; % ic: % - %) en comparación al puntaje sirs y la escala news como predictor de mortalidad hospitalaria en un grupo de paciente admitidos por sepsis al servicio de emergencias ( ) . otro estudio retrospectivo de un único centro comparó el rendimiento de sistemas de score, qsofa, curb- y crb- para predecir la necesidad de soporte vasopresor o respiratorio intensivo (svri) en pacientes ingresados con diagnóstico confirmado de covid- a un hospital de wuhan (china) ( ) . un total de pacientes ( . %) necesitaron svri durante su estadía en el hospital. la tasa de mortalidad hospitalaria en esta cohorte fue de pacientes ( . %). se evalúo el rendimiento de las escalas con análisis de curva roc (auc), puntos de corte óptimo, sensibilidad, especificidad y valores predictivos. el punto de corte óptimo del crb- para predicción de srvi fue de puntos, con una sensibilidad del % y una especificidad del . %. el valor auc del score crb- para predecir la necesidad de svri fue significativamente más alto que el del qsofa ( . ± . vs. . ± . , p= . ). los valores de auc fueron similares entre crb- y curb- para predecir svri ( . ± . vs. . ± . , p= . ). los autores concluyen que el crb- podría ser mejor que el qsofa para identificar paciente con covid- en riesgo de necesitar svri. su et al consideran que fue la inclusión de la edad ≥ años dentro del score crb- lo que le dio un mayor grado de superioridad sobre el qsofa ( ) . el crb- puede ser una herramienta de puntuación útil para covid- debido a su simplicidad en la aplicación, especialmente en emergencias y condiciones de escasez de recursos. finalmente, el score de riesgo covid- -gram fue descrito por un grupo de investigadores en covid- quienes reunieron datos de pacientes en hospitales en china ( ) . esta fue una cohorte retrospectiva multicéntrico en la que se recogieron un total de variables entre demográficas, médicas, clínicas (signos y síntomas), imagenológicas y de resultados de laboratorios. utilizando la metodología de regresión lasso (least absolute shrinkage and selection operator) construyen un modelo de regresión multivariable resultando en un score de riesgo predictivo para desarrollar enfermedad critica en pacientes con covid- confirmado al momento de la admisión. de las variables iniciales fueron predictores independientes estadísticamente significativos para el desarrollo de enfermedad crítica. estas variables fueron: anormalidad en los rx tx (or: . ; %ic: . - . recomendaciÓn se recomienda la aplicación de un algoritmo basado en una evaluación dinámica del score news que involucre una escala de evaluación funcional, para priorizar el ingreso a uci con transparencia científica y ética con equidad social, y de ser posible respaldado por un comité de priorización clínica (cpc) integrado por expertos de cuidado intensivo y un representante del comité de ética hospitalaria durante la pandemia por covid- . se recomienda un modelo determinado por prioridades para definir criterios de ingreso a uci, permite establecer rápidamente qué pacientes se benefician de ingreso uci y qué pacientes deben permanecer en servicios de hospitalización, o con acompañamiento familiar y cuales con medidas de cuidado paliativo. fuerte a favor page amci ® fundamento la pandemia covid- nos ha enseñado que la disponibilidad de camas de uci puede ser insuficiente y el plan estratégico diseñado para ampliar la capacidad de respuesta debe ir de la mano con la implementación rigurosa de un protocolo de triaje y de priorización de ingreso a cuidados intensivos, como medida extraordinaria para optimizar los recursos, mitigar y controlar los efectos de la pandemia sobre el balance oferta (efectiva y resolutiva) y la demanda. los protocolos de triaje y priorización están diseñados para asignar los limitados recursos de una manera justa y transparente donde, por definición, algunas personas serán excluidas del acceso a la atención orientado a aumentar la disponibilidad de camas de cuidados intensivos. sin embargo, es necesario enfatizar que la disponibilidad de camas no es un fin en sí mismo. la intención implícita y explícita de los protocolos de clasificación debiera ser el «bien público» de maximizar la supervivencia de la población. pero es incorrecto suponer que este bien público se logra al maximizar la supervivencia entre los que reciben cuidados intensivos. si bien muchos protocolos de triaje reconocen esto al tratar de excluir a los pacientes que no lo necesitan absolutamente (el «demasiado sanos») y los que tienen menos probabilidades de beneficiarse (él «demasiado enfermo»), no prestan suficiente atención a las diferencias entre grupos en términos de la duración de los cuidados intensivos necesarios para lograr resultados. si el objetivo del triage es mejorar la supervivencia de la población con un recurso escaso, entonces el recurso escaso no son camas, sino días de cama; no son ventiladores, sino tiempo de ventilación. de ello se deduce que el triaje no será efectivo si en la valoración, no se discrimina adecuadamente y se considera de manera equívoca que la gran mayoría de las personas que requieren cuidados intensivos tienen una probabilidad similar de supervivencia y una duración de estadía anticipada similar. ( ) de este modo, el ingreso a uci debe acogerse a los criterios habituales, científicos y éticos, bajo el rigor de "idoneidad clínica" tomando en cuenta parámetros como la gravedad de la enfermedad, la presencia de comorbilidades (severidad, clase funcional), potencial de recuperabilidad, deseo del paciente (o la familia), de equidad distributiva y el uso de las escalas validadas de severidad y de predicción de ingreso a cuidados intensivos. los pacientes con covid- tienden a progresar después del inicio de los síntomas dentro de los a días a una forma grave con síndrome de dificultad respiratoria aguda (sdra) o falla multiorgánica órgano. la identificación temprana y simple de pacientes que requieren respiración intensiva o el soporte vasopresor sería de gran valor durante el brote covid- . ( ) ( ) ( ) ( ) la implementación de un algoritmo "dinámico" que vincule uno o más de las escalas fisiológicas (news con o sin qsofa y/o crb- ≥ ), una escala de predicción de ingreso a uci (covid- -gram) y un puntaje de fragilidad (vipi) puede informarnos sobre el estado actual y evolutivo de la enfermedad y a priorizar el ingreso de pacientes a uci permitiendo un uso óptimo de los recursos y tomar decisiones éticas, transparentes y centradas en la dignidad de los pacientes y el bien público ilustración - . se recomienda no usar escalas de severidad de enfermedad (criterios objetivos) para definir el traslado de pacientes de uci hacia un nivel de menos complejidad de atención, ya que estas escalas no han sido validadas para este uso. se recomienda en la atención por covid- en cuidados intensivos utilizar los mismos criterios de egreso que se emplean para el traslado desde uci hacia una unidad de menor complejidad de pacientes sin infección por covid- . se recomienda contar con áreas de bajo nivel de complejidad asignadas solo a la atención de paciente con infección por covid- , las cuales serán las áreas hacia donde se realiza el de-escalamiento gradual de los pacientes basado en su evolución clínica. cuando se habla de criterios objetivos, se hace referencia a escalas de severidad de enfermedad que ayuden a tomar decisiones más racionales y no basadas en consideraciones tradicionales de resolución de cuadros clínicos. no hay una recomendación definida sobre el uso de escalas de severidad de enfermedad para definir el de-escalamiento de la atención para pacientes críticos. los sistemas de evaluación de severidad de enfermedad generales y específicos pueden identificar una población específica de pacientes en alto riesgo de deterioro clínico luego del traslado fuera de la uci( ); sin embargo, su valor para evaluar que tan preparado está un paciente individual para ser trasladado a un nivel inferior de cuidado no ha sido evaluado( ). los criterios que recomienda el colegio americano de cuidado intensivo( ) para definir el traslado desde uci a un nivel de menor complejidad (unidad de cuidados intermedios o sala de hospitalización) se basan en principios:  cuando el estado fisiológico del paciente se ha estabilizado y ya no es necesario monitoreo y tratamiento en uci.  cuando el paciente cumpla con los criterios de admisión del nivel de menor complejidad, teniendo en cuenta la disponibilidad actual del recurso, el pronóstico del paciente y la presencia de intervenciones activas en curso. específicamente para los pacientes con alto riesgo de muerte y reingreso a uci en quienes se decide no hacer intervenciones adicionales (alta severidad de enfermedad, inestabilidad fisiológica, soporte orgánico), el colegio americano de cuidado intensivo( ) siguiere pasarlos a una unidad de menor nivel de atención o a un hospital de cuidado agudo de largo plazo; siempre con un formato escrito donde se deje claro la decisión para reducir la tasa de reingreso a uci( ). específicamente en situaciones de pandemia y escasez de recursos, la sociedad española de medicina intensiva, crítica y unidades coronarias (semicyuc) recomienda la realización de la escala sofa al menos cada horas para identificar pacientes con evolución tórpida y progresiva a un fallo multiorgánico luego de la iniciación de tratamientos de soporte vital. esto permitirá la adecuación y reorientación de medidas terapéuticas a un objetivo más paliativo, incluyendo la transferencia del paciente a un nivel más bajo de complejidad y la consulta al servicio de cuidado paliativo para que brinde la atención respectiva( ). finalmente, se debe mencionar que no se ha establecido una diferencia en los criterios de egreso de pacientes con covid- para su traslado desde uci hacia una unidad de menos complejidad, con respecto a los utilizados para pacientes sin infección por covid- ( ). todo paciente hospitalizado en uci sea covid- o no, debe ser valorado diariamente para establecer en qué momento su condición clínica permite que sea trasladado fuera de la uci hacia una unidad de menor complejidad. en caso de tratarse de pacientes con sospecha o diagnóstico de covid- , este traslado puede hacerse a una unidad de cuidados intermedios dispuesta como área covid- o una sala de hospitalización con igual asignación( ); esto es lo que se conoce como de-escalamiento gradual de la atención hasta el final egreso del paciente a casa. se recomienda para pacientes con covid- que evolucionan hacia la mejoría, utilizar los criterios clásicos de de-escalamiento del nivel de atención (unidad de cuidados intermedios o sala de hospitalización) que propone el colegio americano de cuidado intensivo( ) . se recomienda aplicar la escala sofa al menos cada horas sumado al criterio de fragilidad y años de vida saludables salvados estos criterios podrían ser válidos en pacientes con fallo terapéutico a las medidas óptimas y orientar decisiones de deescalamiento de medidas y de nivel de complejidad de atención cuando la demanda potencial supera la oferta (capacidad y capacidades), estas decisiones deben ser tomadas idealmente en junta médica. amci ® se recomienda generar procesos administrativos más eficientes para el traslado de pacientes fuera de la uci hacia niveles de menor complejidad, estos ayudarán a liberar recursos para otros pacientes. se recomienda no utilizar el resultado de la rt-pcr positiva para decidir el egreso de la unidad de cuidados intensivos. la literatura no ha definido unos criterios de flexibilidad en uci para el traslado de pacientes con sospecha o diagnóstico confirmado de covid- ; y los criterios que definen la posibilidad de egreso de uci y que aplican a todos los pacientes, incluso aquellos ingresados por una condición crítica en relación con infección por covid- , están claramente definidos por el colegio americano de cuidado intensivo en su documento-guía del .( ). los principios fundamentales han sido revisados en los fundamentos de la pregunta . es importante implementar una estrategia de identificación temprana para aquellos pacientes con soporte vital avanzado que evolucionan progresivamente a fallo multiorgánico y pocas probabilidades de recuperación; el de-escalamiento de medidas y su posterior traslado fuera de la uci, liberará espacio para otros pacientes en situaciones de desborde de la demanda. la sociedad española de medicina intensiva, crítica y unidades coronarias (semicyuc) recomienda que en caso de complicaciones o que se prevea una mala evolución tanto clínica como funcional, se plantee el retiro terapéutico por futilidad y se inicie un manejo con medidas de soporte paliativo, tal como ha sido considerado en los fundamentos de la pregunta ( ) . para el grupo español es claro que, adecuar procesos administrativos más eficientes para traslado de pacientes fuera de la uci a los usualmente utilizados en condiciones normales de práctica clínica, ayudaría a ser más eficientes en la gestión de la demanda ( ) . finalmente, la persistencia de una rt-pcr positiva no es una contraindicación para el traslado del paciente fuera de la uci siempre y cuando se aseguren condiciones de aislamiento por contacto y aerosol en aquellas áreas de menor complejidad de atención; estas incluyen zonas de expansión o área del hospital específicamente acondicionadas para el manejo de pacientes estables o pacientes con limitación de esfuerzo y manejo paliativo de su condición ( ). recomendaciÓn se recomienda que la disposición final de cadáveres de personas con sospecha o diagnóstico de covid- se haga preferiblemente por cremación. en tal caso, las cenizas pueden ser objeto de manipulación sin que suponga ningún riesgo. amci ® se recomienda que la disposición final del cadáver se haga por inhumación en sepultura o bóveda individualizada cuando no se cuente con instalaciones para cremación en el territorio donde ocurrió el deceso o la disponibilidad de esta tecnología desborda la capacidad económica de las personas. se recomienda realizar siempre el aislamiento del cadáver en el lugar del deceso, siguiendo las recomendaciones del ministerio de salud y la protección social (msps). se recomienda que en los casos que se requiera necropsia médico legal y estuviese indicada la cremación, esta deberá contar con la orden del fiscal del caso. se recomienda que la institución establezca en sus procesos prioritarios un protocolo humanizado de despedida bajo estrictos criterios de bioseguridad. no existe una evidencia fuerte que recomiende hacer una disposición de cadáveres de pacientes fallecidos con sospecha o diagnóstico confirmado de covid- con un acto de cremación o con inhumación y sepultura en féretro; sin embargo, siempre y cuando la manipulación y manejo del cadáver hasta su disposición final se haga manteniendo todas las medidas de precaución para evitar la diseminación del virus y siguiendo la normatividad legal vigente, ambas formas son aceptadas. la infección por covid- es una enfermedad con gran variabilidad en presentación clínica, alta tasa de contagio y para la cual no existe en el momento un tratamiento definido. el riesgo de contagio al personal que ejecuta autopsias o procedimientos de tanatopraxia y la probabilidad de diseminación de la enfermedad por la manipulación de cadáveres no se conoce, pero se considera que puede ser alto, teniendo en cuenta que, en ausencia de la aplicación de un método de diagnóstico masivo, todo caso debe considerarse potencialmente positivo. por tanto, el manejo de cuerpos de personas fallecidas con diagnóstico confirmado, sospechoso o probable de sars-cov- (covid- ), debe realizarse con la mínima manipulación posible( ). el cadáver debe ser transferido lo antes posible al depósito y entregado al servicio funerario antes de horas luego del fallecimiento( ). el transporte, la cremación o inhumación, según sea el caso, se efectuará en el menor tiempo posible, con el fin de prevenir la exposición de los trabajadores y comunidad general al virus sars-cov- (covid- ). se debe evitar la realización de rituales fúnebres que conlleven reuniones o aglomeraciones de personas( ). el alistamiento del cadáver será realizado en el ámbito hospitalario del mismo sitio del deceso. las personas que accedan a la habitación donde se encuentre el cadáver, deben tomar las precauciones de transmisión por contacto y gotas, y para ello deben contar con todos los elementos de protección personal (epp) y seguir los procedimientos de amci ® bioseguridad de acuerdo con lo establecido en el protocolo del msps.( ) para hacer el alistamiento del cadáver, se debe cubrir todos los orificios naturales con algodón impregnado de solución desinfectante y se deberá envolver en su totalidad sin retirar catéteres, sondas o tubos que puedan contener los fluidos del cadáver, en tela antifluido o sábana; luego se deberá envolver en dos bolsas plásticas biodegradables que cumplan con las características técnico-sanitarias de impermeabilidad y resistencia a la presión de gases en su interior( ). se debe rociar el interior y el exterior de ambas bolsas con solución desinfectante de hipoclorito sódico que contenga . ppm de cloro activo( ) (exceptuando los casos asociados de covid- y muerte violenta). una vez el cadáver esté adecuadamente dispuesto en las bolsas, se podrá movilizar sin riesgo hacia el depósito de cadáveres siguiendo la ruta intrahospitalaria dispuesta para este traslado. luego el cadáver podrá será entregado al personal del servicio funerario para su depósito en ataúd o contenedor de cremación o inhumación y posterior traslado al sitio de destino final (horno crematorio y/o cementerio), luego de completar toda la documentación necesaria. cuando deba practicarse necropsia médico legal, el cuerpo será entregado a los servidores del sistema judicial quienes asumirán la custodia( ). si se han seguido correctamente todas estas indicaciones, se asume que no hay ninguna diferencia entre disponer del cuerpo enviándolo al crematorio o colocarlo en ataúd para llevarlo al tanatorio y realizar el entierro. si se opta por lo primero, las cenizas pueden ser objeto de manipulación sin que supongan ningún riesgo.( ) se recomienda que el trabajador de la salud conozca a través de la institución donde labora, los riesgos éticos, de salud y seguridad a que se expone por la atención en el paciente covid- , evitando así conflictos e incertidumbres que afecten la atención. se recomienda que las instituciones prestadoras de salud a través de los líderes de atención médica, guíen y orienten a los trabajadores, para ofrecer una mejor atención médica y menor daño emocional durante la pandemia. se recomienda dar a conocer las directrices institucionales sobre el nivel de atención (uci vs. sala médica); inicio del tratamiento de soporte vital (incluyendo rcp y soporte de ventilación); retirada del tratamiento de soporte vital; y derivación a cuidados paliativos (centrados en la comodidad) en la atención médica de los pacientes durante la pandemia, esto genera una atención caracterizada por alivio del sufrimiento, no abandono, respeto a amci ® los derechos y preferencias de los pacientes, igualdad moral de las personas y la equidad en la distribución de riesgos y beneficios en la sociedad. el apoyo de la práctica ética es necesario integrarlo al cuidado de la salud y al bienestar de la fuerza laboral del cuidado en salud. reconociendo los desafíos especiales a que se enfrentan al responder al covid- . esto forma parte del liderazgo en la atención médica y del servicio del deber cívico. berlinger n. el de abril del . en su artículo "respondiendo a covid- como un desafío regional de salud pública pautas preliminares para la colaboración regional que involucra hospitales". refiere que los trabajadores del equipo médico tienen el deber de conocer la gestión asistencial de los "desafíos éticos" previsibles durante la emergencia de salud pública (pandemia covid- ). que los desafíos éticos surgen cuando existe incertidumbre acerca de cómo "hacer lo correcto" es cuando los deberes o valores en los trabajadores entran en conflicto. estos desafíos afectan a la fuerza laboral (carga moral y emocional ante una decisión no prevista) en la atención médica. así como la operatividad en la atención médica (falta de epp y recursos que pueden limitar el buen desempeño por temor a infectarse).( ) los líderes de atención médica tienen el deber de guiar a los trabajadores de atención médica que experimentan condiciones laborales exigentes, mayor riesgo de daños ocupacionales, incertidumbre ética y angustia moral durante una emergencia de salud pública.( ) chih chen a, t. el de abril del . en su editorial ¿cómo deben prepararse los sistemas de salud para la evolución de la pandemia de covid- ? sugiere un apoyo emocional adecuado para el personal y horas razonables de exposición al riesgo para evitar el agotamiento, ya que los profesionales de la salud luchan por cuidar a los pacientes y proteger sus vidas y sus familias. se refiere que a medida que aumenta el número de casos, los médicos y los trabajadores de la salud en la primera línea deben reducir al mínimo su carga de trabajo clínico. las instituciones de atención médica deben reasignar al personal realizar tareas no clínicas, incluidos el papeleo y la recopilación de datos, tanto como sea posible. los hospitales deben tomarse su tiempo para capacitar al personal para implementar eficazmente las precauciones de contacto y los procesos de flujo. ( ) jick j.l. el de marzo del . en relación con la obligación de planificar la atención médica, considera que: los líderes de atención médica tienen el deber de planificar la gestión de los desafíos éticos previsibles durante una emergencia de salud pública. la planificación de los desafíos éticos previsibles incluye la identificación de posibles decisiones de triage, herramientas y procesos. en una emergencia de salud pública que presenta una enfermedad respiratoria grave, es posible que se deban tomar decisiones de clasificación sobre el nivel de atención (uci vs. sala médica); inicio del tratamiento de soporte vital (incluyendo rcp y soporte de ventilación); retirada del tratamiento de soporte vital; y derivación a cuidados paliativos (centrados en la comodidad) si el tratamiento de soporte vital no se iniciará o se suspenderá. es posible que también se deban tomar decisiones de clasificación en relación con la escasez de personal, espacio y suministros. el deber de cuidado fundamental requiere fidelidad al paciente (no abandono como una obligación ética y legal), alivio del sufrimiento y respeto a los derechos y preferencias de los amci ® pacientes. el deber de cuidado y sus ramificaciones son el enfoque principal de la ética clínica, a través de los servicios de consulta de ética clínica a pie de cama, el desarrollo de políticas institucionales y la educación y capacitación en ética para los médicos. deberes de promover la igualdad moral de las personas y la equidad (justicia en relación con la necesidad) en la distribución de riesgos y beneficios en la sociedad. estos deberes generan deberes subsidiarios para promover la seguridad pública, proteger la salud de la comunidad y asignar de manera justa recursos limitados, entre otras actividades. estos deberes y sus ramificaciones son el foco principal de la ética de la salud pública. no se puede emitir una recomendación a favor o en contra acerca del uso de los medicamentos y dispositivos "prototipos" utilizados en el manejo del covid- denominados de uso compasivo o fuera de etiqueta, se considera sin embargo que no pueden ser utilizados por fuera de ensayos clínicos o protocolos institucionales estandarizados de evaluación del perfil de riesgo/beneficio y bajo la aplicación de consentimiento informado. se entiende como uso compasivo la utilización, en pacientes aislados y al margen de un ensayo clínico. dichos medicamentos experimentales no han sido aprobados aún por la fda, ( ) y no se ha demostrado su seguridad y eficacia. es importante recordar que el medicamento médico puede tener efectos secundarios inesperados y graves, y que los pacientes deben considerar los posibles riesgos cuando procuran acceder a un producto médico experimental. hay que tener en cuenta que, para utilizar un medicamento bajo las condiciones de uso compasivo, se requerirá el consentimiento informado por escrito del paciente o de su representante legal, un informe clínico en el que el médico justifique la necesidad de dicho tratamiento. la regulación de la utilización de medicamentos por la vía del uso compasivo se ha realizado dentro de un texto legal sobre la realización de ensayos clínicos. una interpretación común del uso no indicado en la etiqueta y el uso compasivo de medicamentos es que, si el paciente murió, murió de la enfermedad, pero si el paciente sobrevivió, sobrevivió debido al medicamento administrado. recomendaciÓn se recomienda en la comunicación inicial con los familiares del paciente adulto con sospecha o diagnóstico de covid- críticamente enfermo incluir de forma clara y transparente los aspectos relacionados con el derecho al final de la vida que incluye: proporcionalidad en el tratamiento, adecuación del esfuerzo terapéutico, documento de voluntad anticipada, adecuación del esfuerzo terapéutico y la atención paliativa. situaciones estas que se pueden presentar durante la evolución hospitalaria y que requieren de una decisión conjunta entre el médico y el familiar del paciente. se recomienda dar una información específica, y adecuada a los familiares del paciente con sospecha o diagnóstico de covid- , para que firmen el consentimiento informado, generando esta información confianza y comprensión en el familiar. la información del consentimiento que recibe el familiar debe constar dentro de la historia clínica. fundamento el ministerio de salud y protección social del de marzo del a través del documento de "recomendaciones generales para la toma de decisiones éticas en los servicios de salud durante la pandemia covid- ". ante la posible circunstancia de pacientes sin capacidad para la toma de decisiones, por deterioro del estado general o requerimiento de aislamiento, en el cual no se puede contactar a su representante, conduzca la toma de decisiones teniendo en cuenta la prioridad de no hacer daño y la modificación en las condiciones de disponibilidad de los recursos en caso de presentarse deterioro. recuerde que esta situación debe preverse y debe ser informada a los representantes desde la admisión del paciente". durante toda la atención debe darse información sobre la posibilidad de que se presenten limitaciones de acceso a los soportes necesarios incluido al personal de salud , lo anterior puede limitar los derechos individuales o preferencias, esto debe ser informado al paciente y su familia, para que les permita entender que bajo la emergencia, puede presentarse una circunstancia que en condiciones habituales pudiera ser reversible de ser tratada pero en el contexto actual los recursos pueden verse trágicamente limitados, sin que esto implique abandono en el cuidado. el documento se refiere a la información que debe recibir el paciente o su familiar sustituto durante su evolución o fallecimiento. ( )la información durante la evolución también debe incluir: la información sobre el ejercicio de derechos al final de la vida incluyendo la adecuación de los esfuerzos terapéuticos y la suscripción de documentos de voluntad anticipada la consulta y revisión de existencia de este en todos los casos. se recomienda tener un consentimiento informado al ingreso hospitalario del paciente covid- , se deben tener en cuenta las circunstancias del paciente al ingreso hospitalario, si la capacidad para la toma de decisiones está limitada por su estado clínico o incapacidad mental. de ser estas las circunstancias se dará la información al familiar en primera línea de consanguinidad quien asume por el paciente el consentimiento de la información (consentimiento sustituto). se recomienda tener el consentimiento informado en situaciones de excepción o urgencia ante la pandemia por covid- , debe ser universal, en el que se informe el ingreso a la uci, o a cualquier otra área hospitalaria, realización de procedimientos, administración de tratamientos, posibles riesgos, beneficios durante su hospitalización. con esto se respeta el derecho a la autonomía personal en el paciente competente. en caso contrario el familiar tomará la información y asume el consentimiento a la información dada. es importante que el familiar esté informado de las decisiones que se vayan tomando durante la evolución hospitalaria (realización de procedimientos, inicios o cambios de tratamientos, movilización dentro del área hospitalaria. etc.) fuerte a favor fundamento el ministerio de salud y protección social, el de marzo del ha elaborado un formato de "consentimiento informado para acompañante de casos probable/confirmado de covid- ". en que se expresa: "que de manera detallada se me ha suministrado información completa, suficiente, con un lenguaje sencillo y claro. el profesional de la salud me ha explicado la naturaleza de la enfermedad, acerca del significado de caso sospechoso o confirmado del coronavirus covid- en cuanto a su presentación clínica, modo de contagio, medidas para contenerla, posibilidad de sufrir la enfermedad, complicaciones o muerte, mientras permanezca como acompañante del paciente". este documento se firma al ingreso por el acompañante o familiar quien asume las decisiones durante su estancia hospitalaria. ( ) el consentimiento informado en los pacientes covid- será un consentimiento sustituto para su ingreso a la uci y para los procedimientos que en la uci se realicen (colocación de tubo orotraqueal, diálisis, colocación de catéteres, reanimación cardiopulmonar, ecmo, etc.). previa información y autorización del familiar. en circunstancias normales el consentimiento debe ser firmado por el paciente quien en su autonomía acepta la información sobre su manejo y tratamiento. feld ad. recomendaciÓn se sugiere ante la pandemia del covid- , si es posible, que el grupo de expertos en bioética y/o comité de ética institucional sean consultados y estén informados por el médico responsable para la orientación o consejo en la toma de directrices ante decisiones difíciles. se sugiere en lo posible que el médico tratante no asuma solo la responsabilidad moral de la decisión y que la decisión sea institucional y documentada en la historia clínica e informada a los familiares. en caso de no contar con un comité de bioética y/o ética hospitalaria el médico responsable podrá tomar la decisión fundamentada en principios éticos y derechos del paciente o convocar a una junta médica u otro comité relacionado con su dilema o consultar un apoyo externo en bioética. débil a favor fundamento el ministerio de salud y protección social. ( ) el de marzo del en el documento "recomendaciones generales para la toma de decisiones éticas en los servicios de salud durante la pandemia covid- establece: "que en caso de que la institución cuente con un comité de bioética y/o Ética, con el servicio de bioética o Ética clínica, o consultoría clínico-ética, se debe definir una ruta de consulta para los casos que de forma concreta puedan superar las recomendaciones generales. de igual forma establece que en las circunstancias actuales que se viven el actuar ético es parte integral del profesionalismo del cuidado. teniendo en cuenta que los profesionales de la medicina serán los llamados a tomar decisiones de alto estrés moral, al tener que adherirse y promover conductas concretas basados en las circunstancias que les rodean para dar o retirar tratamientos de las personas infectadas, quienes esperan confirmación del diagnóstico y de las personas que acuden a la atención en salud por razones diferentes a la infección por covid- . partiendo de lo antes referenciado, se recomienda que las acciones emprendidas, busquen siempre poder responder a: a. no hacer daño b. beneficiar c. actuar con justicia sobre la persona en el contexto de la emergencia frente a la justicia sanitaria de la población d. mantener la integridad profesional" el comité de bioética y/o comité de ética institucional en tiempos normales o en tiempos de pandemia deberá mantener actualizadas las directrices de toma de decisiones. que apoyaran al médico responsable en la decisión. de no contar el médico con dicho comité o directrices institucionales y deba tomar una decisión que no permite interconsultar, deberá justificar en la historia clínica fundamentado en los principios éticos y derechos del paciente las razones que lo llevaron a tomar la decisión e informar y dialogar con los familiares del hecho. esto es importante que siempre quede documentado en la historia clínica la acción moral y ética de la decisión y el diálogo con la familia. en caso de que el médico responsable no cuente con un comité de bioética y/o comité de ética institucional, ni con el apoyo externo de expertos en bioética. y no quiera tomar la amci ® decisión a título personal podrá consultar a otro médico de la institución su decisión y entre ambos definir la acción a seguir. esta decisión conjunta debe ser documentada en la historia clínica e informada al grupo de trabajo y a los familiares como junta médica. si los familiares después de recibir la información no quedan satisfechos ellos tienen el derecho a la segunda opinión. los comités de bioética y/o comités de ética hospitalaria son entes administrativos, consultores, orientadores, asesores y consejeros de las situaciones que tienen que ver con el respeto y cumplimiento de los principios éticos, deberes y derechos de los pacientes, sus recomendaciones no son vinculantes, apoyan y orientan la decisión médica. aconsejando la mejor decisión ante una situación que genera un dilema moral o ético en el médico responsable. las decisiones médicas son tomadas por el consultor en bioética, quien es médico. los comités institucionales fuera de un comité de bioética y/o ética que podría dar apoyo al médico responsable y que serían otras instancias consultivas serian el comité de humanización, comité de historias clínicas, comité de bioseguridad, comité de infectología, comité de mortalidad hospitalaria, comité de paliativos o un comité de gerencia. pues todos los mencionados tiene que ver con el bienestar del paciente y la seguridad del médico ante una decisión. las decisiones especiales deben ser tomadas inicialmente a través de la realización de un comité (pueden ser los mencionados), en su defecto una junta médica. una vez se tenga la decisión esta debe ser consultada a la familia como una decisión institucional respaldada por el comité o junta médica realizada. se recomienda que todo ensayo clínico que se realice en la institución debe ser presentado, revisado y aceptado por un comité de investigación local o un comité de investigación externo nacional o internacional. se recomienda que todo paciente que se incluya en un ensayo clínico debe contar con un consentimiento informado el cual garantiza la aceptación voluntaria a participar y la comprensión de los objetivos, riesgos, beneficios, derechos y responsabilidades que tiene dentro de la investigación. se recomienda el consentimiento informado en todo ensayo clínico, el cual debe ser debe ser individual en tiempos de normalidad como en tiempos de pandemia por covid- . solo el comité de ética en investigación podrá establecer en tiempos de normalidad o de pandemia las condiciones de dispensa o excepción al requisito de obtener el consentimiento informado. refiere que el consentimiento informado tiene sus raíces en el código de núremberg de y la declaración de helsinki de y ahora es un principio rector para la conducta en la investigación médica. en el consentimiento informado para investigaciones clínicas es claro que los participantes deben entender ampliamente los componentes del consentimiento. ( ) thanh tam, n. et al. el de enero . mediante una revisión sistemática de pubmed, scopus y google scholar y revisando manualmente las listas de referencias para publicaciones hasta octubre de . realizó un metaanálisis de los resultados del estudio utilizando un modelo de efectos aleatorios para tener en cuenta la heterogeneidad. evaluó la proporción de participantes en ensayos clínicos que entienden los diferentes componentes del consentimiento informado. encontrando que los participantes en ensayos clínicos deben comprender los componentes fundamentales del consentimiento informado como: la naturaleza y los beneficios del estudio, la libertad de retirarse en cualquier momento y la naturaleza voluntaria de la participación, así como la comprensión de otros componentes, como la aleatorización y el placebo. la proporción de participantes en ensayos clínicos que comprendieron diferentes componentes del consentimiento informado varió de . % a . %. esto asegura que la toma de decisiones de los participantes es significativa y que sus intereses están protegidos. ( ) la red de américa latina y el caribe de cnb-unesco, ( de marzo de ) que agrupa a las comisiones y consejos nacionales de bioética cuya finalidad es la de asesorar sobre los problemas éticos relativos a las ciencias de la vida y la salud humana expresa su preocupación ante la realización de investigaciones biomédicas en relación con la pandemia de enfermedad infecciosa por coronavirus covid- . reconociendo lo siguiente en relación con el consentimiento informado: que la investigación con seres humanos durante las emergencias debe contar con garantías éticas mayores, no menores, que en las situaciones ordinarias. que en situación de excepción o emergencia los participantes deben seleccionarse en forma justa y proporcionar una justificación adecuada cuando se escogen o excluyen determinadas poblaciones, distribuyendo en forma equitativa las posibles cargas y beneficios de participar en esa investigación. "que se debe obtener el consentimiento informado individual de los participantes incluso en una situación de excepción o alarma, a menos que se cumplan las condiciones para la dispensa del consentimiento informado. las cuales el comité de revisión ética solo puede decidir dar la dispensa al requisito de obtener consentimiento informado: a) si no es factible obtenerlo; y si además los estudios: b) tienen un importante valor social y científico, c) solo suponen riesgos mínimos para los participantes, d) no implican agravio comparativo con otros grupos en situación o no de vulnerabilidad; y si e) se garantiza que no se privará a la población investigada de acceder en forma preferencial al beneficio derivado. de otorgarse un consentimiento informado amplio, éste debería ser única y exclusivamente para los procesos asociados con covid- ".( ) amci ® se recomienda considerar la transición del cuidado intensivo al cuidado paliativo en todo paciente con sospecha o diagnóstico de covid- sin mejoría a pesar de las intervenciones óptimas, con empeoramiento progresivo de su pronóstico vital y ante un evidente deterioro; aplicando medidas generales en control de síntomas ( manejo de secreciones -tratamiento del dolor -tratamiento de la disnea -sedación paliativa), así como apoyo espiritual, siempre acompañando al paciente y nunca abandonarlo en el final de la vida. fuerte a favor fundamento la sociedad española de anestesiología, reanimación y terapéutica del dolor en su documento: "marco Ético pandemia covid- " madrid, de marzo de refiere: la sedación paliativa en pacientes hipóxicos con progresión de la enfermedad no subsidiaria de tratamiento debe considerarse como una expresión de buena práctica clínica y debe seguir las recomendaciones existentes. si se prevé un período agónico no corto, se debe proporcionar una transferencia a un entorno no intensivo.( ) se recomienda la utilización de guías establecidas previamente a la pandemia por el ministerio de salud y sociedades científicas para orientar las decisiones que se tomen al final de la vida en pacientes con sospecha o diagnóstico de covid- . estas guías deben ser divulgadas al equipo de atención y aplicadas en los pacientes en casos de: adecuación del esfuerzo terapéutico (aet), orden de no reanimar (onr), consentimiento sustituto, voluntades anticipadas, cuidados paliativos. se recomienda fundamentar las decisiones del final de la vida individualizadas a cada paciente y a cada situación sin llegar a tomar decisiones apresuradas sin fundamento científico o ético, solicitando de ser posible una valoración por medicina paliativa para el manejo de síntomas. se recomienda indagar durante la hospitalización de todo paciente con sospecha o diagnóstico de covid- , si en tiempos de salud hizo válida su autonomía y realizó un documento de voluntad anticipada, teniendo en cuenta que esta será equivalente al consentimiento informado. amci ® terapéuticos y la suscripción de documentos de voluntad anticipada.( ) el inicio de sedación paliativa con reubicación del pacientede ser necesario el des escalonamiento por deterioro clínico. en situación de pandemia covid- cuando se refiere a situaciones del final de la vida se relaciona a la adecuación del esfuerzo terapéutico, la sedación paliativa la cual será la maniobra terapéutica que se utilizará en pacientes no recuperables y que no son candidatos a cuidados intensivos por covid- ,( ) que evolucionan desfavorablemente y tienen mal pronóstico a corto plazo, así como la disnea refractaria y la limitación del esfuerzo terapéutico. el delirium o síndrome confusional por fallo cerebral agudo, es un problema habitual en situaciones de alteración orgánica severa, y ha sido descrito como uno de los síntomas neurológicos presente en los pacientes que sufren infección por el covid- ( ). wilson c. de abril del . en su artículo "la crisis golpea al final de la vida" se refiere a que el brote de coronavirus está obligando a las personas a enfrentar dilemas en torno a la cantidad de atención médica que se debe brindar al final de la vida y apresurar decisiones controvertidas sobre rechazar ciertos tratamientos. dicen los expertos que esto ha alentado a más personas a tomar decisiones de tratamiento anticipadas relacionadas con la rcp y la ventilación,( ) haesen s. el de mayo de . en su artículo "dirigir a los ciudadanos a crear directivas anticipadas" las voluntades o directrices anticipadas son para las personas que quieran asumir plenamente su papel de ciudadanos responsables tomando decisiones proactivas. la decisión de redactar directivas anticipadas marca un cambio del enfoque actual de "aceptación" a un escenario de "exclusión voluntaria".( )al emitir una directiva de tratamiento anticipado, una persona autónoma puede expresar formalmente qué tipo de tratamiento desea y no desea recibir en caso de que se enferme o se lastime y no pueda decidir de manera autónoma sobre su tratamiento. ( ) ministerio de salud y protección social en su documento de voluntades anticipadas que es el documento en el que toda persona capaz, sana o en estado de enfermedad, en pleno uso de sus facultades legales y mentales y como previsión de no poder tomar decisiones en el futuro, declara, de forma libre, consciente e informada su voluntad sobre las preferencias al final de la vida que sean relevantes para su marco de valores personales.( ) se recomienda que el paciente crítico con covid- que no es candidato para ingresar o continuar recibiendo cuidados intensivos y que presente deterioro rápido con mal pronóstico a corto plazo, se le brinde una adecuación del esfuerzo terapéutico orientada a acompañamiento al final de la vida, alivio del sufrimiento y control de síntomas. dependiendo de la disponibilidad de recursos se sugiere dentro del plan de atención hospitalaria contar con un área destinada a la atención del final de vida con el recurso físico, humano y de procesos necesario. marzo del . refiere: en situación de adecuación terapéutica, retirada de medidas y/o mala evolución es adecuado derivar al paciente a un área de menor complejidad para establecer el plan de cuidados paliativos. consultar al servicio de cuidados paliativos para procurar la continuidad de cuidados de los pacientes en los que se haya acordado la limitación de tratamientos y aliviar su sufrimiento, incluyendo la sedación paliativa en los casos en los que sea precisa.( ) schmidhauser tf. el de abril . considera en su publicación que: los cuidados paliativos durante la pandemia de covid- deben adaptarse a un estilo de" cuidados paliativos de emergencia" ya que los pacientes pueden deteriorarse rápidamente y requieren decisiones rápidas y planes de tratamiento claros. estos deben ser seguidos fácilmente por los miembros del personal de salud que atienden a estos pacientes. además, los cuidados paliativos deben estar a la vanguardia para ayudar a tomar las mejores decisiones, atender a las familias y ofrecer apoyo espiritual.( ) se recomienda como estrategia de protección personal en las unidades de cuidado intensivo sin presión negativa y cubículos abiertos utilizar de forma continua el respirador n o fpp , adicional a otros elementos de protección para prevención del contagio por covid- . la atención segura en áreas crítica para todas las modalidades de atención se fortalece a través de las medidas de precauciones estándar en el manejo de todos los pacientes, establecidos en el "manual de medidas básicas para control de infecciones en prestador servicios de salud" ley de , por la cual se dictan medidas sanitarias. resolución de , numeral y numeral . epp. el respirador, n o fpp , puede utilizarse de manera continua por a horas, o desecharlo antes si está visiblemente contaminada o si está húmeda. luego de colocar la n se debe verificar prueba de ajuste antes de ingresar a la unidad para atención de pacientes con covid- de la siguiente manera: mascarillas sin válvula de exhalación: cubra la totalidad de la mascarilla con ambas manos y exhale con fuerza. si nota fugas de aire por sus bordes, reajuste la posición del respirador. mascarillas con válvula de exhalación: cubra el respirador con ambas manos e inhale con energía. deberá sentir una presión negativa dentro de la mascarilla. si detecta alguna pérdida de presión o entrada de aire, reajuste la posición del respirador. no se puede emitir una recomendación a favor o en contra acerca de la efectividad de bioseguridad del uso extendido, continuo o intermitente de los respiradores n ó ffp . sin embargo, se considera que puede ser una alternativa, bajo la adopción de un protocolo riguroso, cuando se debe optimizar el uso de los epp en el contexto de un acceso limitado. el reúso no está permitido en colombia. la duración máxima del uso continuo de la n es de a horas, siguiendo las recomendaciones del manual de medidas básicas para control de infecciones en ips de minsalud. pero en la vida real, ningún trabajador tolera a horas continuas con un respirador. por esto, su uso continuo en el sitio de trabajo dependerá de la necesidad de pausar para comer, para ir al baño, etc. en este caso, se guardará en una bolsa de papel para su nueva colocación, si tiene menos de horas, o desechará si está visiblemente contaminada o se torna húmeda. el reúso de la n dependerá de la casa del fabricante, de si contiene o no celulosa en su estructura del respirador. por ejemplo, la recomendación de desinfección para los respiradores sin celulosa es con peróxido de hidrógeno vaporizado al % por minutos (tabla y ). los respiradores n de uso industrial tienen mayor contenido de celulosa que los de uso médico por lo tanto para procesos de esterilización, solo los n de uso médico podrán ser esterilizados mediante de peróxido de hidrógeno vaporizado (sterrad®) ( - ) . ¿existe superioridad en términos de protección personal para el personal sanitario y de apoyo dentro de las unidades de cuidados intensivos con la utilización del overol frente a la bata manga larga con antifluido durante la atención del paciente con covid- ? no se puede emitir una recomendación a favor o en contra si los overoles ofrecen mayor protección por cobertura corporal frente a otros elementos como vestidos largos, batas y delantales. resulta intuitivo que su uso genera una mayor protección en especial en servicios cohortizados. sin embargo, su uso está asociado con una mayor dificultad para su colocación y retiro, lo que puede potencializar el contagio del usuario, la utilización debe hacerse bajo un protocolo supervisado y chequeado. las batas modificadas para ajustarse firmemente en el cuello pueden reducir la contaminación. en estudios ya descritos el uso de un respirador eléctrico purificador de aire con overol puede proteger contra el riesgo de contaminación mejor que una máscara n y una bata con un rr: . , intervalo de confianza (ic) del %: . a . pero fue más difícil su retiro con rr . , ic del % . a . . en un eca ( participantes), las personas con una bata larga tenían menos contaminación que aquellas con un overol. las batas pueden proteger mejor contra la contaminación que los delantales.( - ) los epp como batas y overoles deberían estar hechos de un material que cumpla con los requisitos mínimos de la asociación americana de químicos textiles:  tipo a: buena repelencia al agua, resistente a la penetración, pero mala permeabilidad al aire.  tipo b: buena repelencia al agua, buena permeabilidad al aire, pero poca resistencia a la penetración del agua.  tipo c: bata quirúrgica que tiene poca repelencia al agua y resistencia a la penetración de agua.  tipo d: hecho de fibras de polietileno de alta densidad, tela no tejida (tyvek®), tiene buena repelencia y resistencia al agua, mala permeabilidad al aire. no se puede emitir una recomendación a favor o en contra para el uso de respiradores elastoméricos como elementos de protección personal dentro de las unidades de cuidados amci ® intensivos. no hay evidencia que soporte la superioridad de los respiradores elastoméricos frente a los n , son más costosos, difíciles de utilizar y pueden implicar algún riesgo para el paciente. por tanto, su uso sólo debería considerarse frente a un desabastecimiento de los n y bajo la adopción de un protocolo institucional riguroso y bajo chequeo. los respiradores elastoméricos son respiradores ajustados a media cara o cara completa, esta última otorga protección ocular. su filtración está determinada por el filtro que se utilice, estos van desde partículas de nivel n a p . están hechos de material sintético o de goma que les permite desinfectarse, limpiarse y reutilizarse repetidamente. están equipados con cartuchos de filtro reemplazables. al igual que los respiradores n , los respiradores elastoméricos requiere entrenamiento adecuado para su correcta colocación y retiro. por eso es muy importante revisar el manual del usuario antes de su uso. los respiradores elastoméricos no deberían utilizarse en entornos quirúrgicos, debido al riesgo potencial de contaminación del campo quirúrgico, con el aire que sale de la válvula de exhalación. como recomendación de buena práctica, aprobado por la fda, debe colocarse una máscara quirúrgica encima de la válvula de exhalación para evitar este riesgo. solo se debe permitir el uso del respirador elastoméricos por clínica para evitar infecciones cruzadas, esto permitirá una protección esencial contra agentes infecciosos y la auto contaminación. aunque los cartuchos de filtro son finalmente desechables, están destinados a ser reutilizados hasta que ya no se puede respirar o se vuelven visiblemente sucio. generalmente se recomienda, en la mayoría de los casos, hacer recambios cada días. deben tener procedimientos de limpieza/desinfección actualizados y aprobados por su manufacturador.( , - ) recomendaciÓn se recomienda realizar la limpieza y desinfección de equipos biomédicos y de superficies las veces que sean necesarias y en el momento de egreso del paciente siguiendo los protocolos de cada institución. el desinfectante para este proceso debe ser de nivel intermedio o alto para superficies y equipos biomédicos y cumplir con las recomendaciones del fabricante según lo aprobado en el registro sanitario. fuerte a favor fundamento para la desinfección de las superficies ambientales hospitalarias y domiciliarias, la oms recomienda emplear un desinfectante que sea efectivo contra virus cubiertos (el coronavirus pertenece a esta categoría), específicamente, recomienda emplear alcohol etílico para la desinfección de algunos equipos biomédicos reusables (p. ej.: termómetros) y para las superficies, el hipoclorito de sodio o precursores de sodio como el dicloroisocianurato de sodio (nadcc) que tiene la ventaja de la estabilidad, la facilidad en la dilución y que no es corrosivo.( ) (tabla ). page se recomienda que el ingreso de un paciente a uci debe hacerse bajo un procedimiento estandarizado que incluya la coordinación y comunicación de los servicios vinculados, adecuación de la unidad de atención a las necesidades del paciente y la garantía de la bioseguridad del equipo multidisciplinario. se recomienda que cada institución establezca en sus procesos prioritarios el circuito del traslado que incluye el itinerario del traslado, el uso de ascensor, el número y la organización de los intervinientes sanitarios y no sanitarios (celadores, seguridad, limpieza), las medidas de protección empleadas por los mismos (epp, limpieza) y los recursos materiales necesarios durante el traslado. el traslado de pacientes con casos sospechosos o confirmados de covid- se puede presentar entre servicios a nivel hospitalario o entre instituciones con diferentes niveles de atención y deben tenerse las precauciones universales de un traslado seguro. una posición responsable es evitar el traslado de estos pacientes el máximo posible, a menos que sea imprescindible, teniendo en cuenta el riesgo/beneficio. considerar evitar traslados interinstitucionales solo por temas administrativos. el personal sanitario que realice el traslado debe contar con todos los epp, considerando este traslado como de alto riesgo de transmisión vírica. se debe utilizar mascarilla quirúrgica o n- , de acuerdo con el riesgo amci ® de aerosolización. hasta que la rt-pcr para sars-cov- este negativo se podrían retomar las prácticas habituales de traslado de los pacientes . ( ) ( ) ( ) capítulo . abordaje diagnóstico y covid- se recomienda en pacientes con diagnóstico o sospecha de infección por sars-cov- clasificar la enfermedad en leve, severo o paciente crítico, teniendo en cuenta los criterios de la clasificación por las fases y estadios de la enfermedad. se recomienda en pacientes con diagnóstico o sospecha de infección por sars-cov- , clasificados como críticos y que requieren de intubación orotraqueal realizar la clasificación por fenotipos ( o ), con el fin de proyectar una estrategia de ventilación mecánica. el covid- , es una enfermedad con una presentación clínica diversa, desde formas leves hasta presentaciones graves que incluyen el sdra, la mediana del período de incubación desde la exposición hasta el inicio de los síntomas es de aproximadamente a días, y el . % de los pacientes sintomáticos tendrán síntomas dentro de los . días después de la infección ( ) , que incluye fiebre, tos, disfagia, malestar general, mialgias, anorexia, náuseas, diarrea, anosmia y ageusia; la disnea se presentó entre los y días ( ) y puede representar progresión a covid- severo, que se manifiesta con hipoxemia, disfunción orgánica múltiple, documentación de arritmias cardíacas, rabdomiólisis, coagulopatía y choque ( ) . dentro del espectro de enfermedad, siddiki et al, proponen un enfoque estructurado por fases expresados en tres estadios (historia natural de la enfermedad), siendo el primero donde la patogenicidad viral es dominante, se incluye el periodo de incubación, síntomas leves, con multiplicación del sars-cov- centrándose principalmente en el sistema respiratorio gracias a la unión del virus con el receptor de la enzima convertidora de angiotensina (ace ), el hemograma puede revelar linfopenia y neutrofilia sin otras anormalidades significativas. el estadio es la enfermedad pulmonar establecida, neumonía viral, tos, fiebre con progresión en algunos casos a hipoxia con trastorno de los índices de oxigenación (pao /fio menor mmhg), hallazgos en imágenes de tórax (radiografía y/o tomografía) de infiltrados alveolares o vidrio esmerilado, mayor linfopenia y elevación de transaminasas ( a: sin hipoxemia, b: con hipoxemia). el estadio o fase de híper inflamación sistémica extrapulmonar se caracteriza por elevación de biomarcadores inflamatorios y estado protrombótico (il - , il- , il- , ftn -α, proteína c reactiva, ferritina y el dímero d), con presencia en las formas más graves de disfunción orgánica múltiple, lesión miocárdica (troponina y péptido natriurético de tipo b elevados), con fenómenos trombóticos, progresión a sdra y choque ( ) . amci ® la neumonía por sars-cov- , se característica por disociación entre la severidad de la hipoxemia y el mantenimiento relativamente bueno de la mecánica respiratoria, con compliance del sistema respiratorio en promedio de ml / cmh o; gattinoni, marini et al, proponen dos fenotipos de presentación de la insuficiencia respiratoria; el primero (tipo ) con una mecánica pulmonar adecuada, con baja probabilidad de reclutabilidad y con hipoxemia, relacionado al desbalance entre la perfusión y la ventilación; el segundo (tipo ) más acorde a las definiciones de sdra (csdra "covid- patient with sdra"), con una compliance pulmonar baja y reclutabilidad potencial( , ) ( ). se propone la siguiente clasificación clínica del covid- . ( , , y pacientes críticos de %, con tasa global de mortalidad de , %, siendo mayor entre los pacientes de a años con % y entre los mayores de años con . %, dentro del grupo de pacientes clasificado como crítico la mortalidad descrita fue del %( ). recomendaciÓn se recomienda en cuidado intensivo, realizar el diagnóstico de covid- del paciente sospechoso por medio de rt-pcr conociendo su alta especificidad, su variabilidad en relación con el tiempo y pérdida de rendimiento diagnóstico luego de la primera semana de inicio de los síntomas. se recomienda tomar la primera muestra para rt-pcr de hisopo nasofaríngeo o de cornete medio sobre hisopado oro faríngeo o de saliva, de ser negativo se puede repetir la prueba de a horas preferiblemente de tracto respiratorio inferior, esputo no inducido o en aspirado traqueal en paciente intubado. se recomienda el uso conjunto de rt-pcr e igm por elisa en pacientes con sospecha de covid- , primera rt-pcr negativa, que se encuentren entre la segunda y tercera semana desde el inicio de los síntomas, con el objetivo de mejorar la sensibilidad en la identificación de infección por sars-cov- . en cuidado intensivo, el diagnóstico de covid- se fundamenta con base en la presentación clínica compatible y factores epidemiológicos asociados con probabilidad de infección; el diagnóstico definitivo se realiza con pruebas de amplificación de ácido nucleico del virus (naat), la detección del genoma viral del sars-cov- se realiza por medio de reacción en cadena de la polimerasa por transcriptasa reversa (rt-pcr) dado a su especificidad del % ( , ) ; por lo cual todo paciente que cumple con la definición de caso sospechoso se le debe realizar rt-pcr, sars-cov- independientemente de si se encuentra otro patógeno respiratorio ( ) . las muestras para el diagnóstico por rt pcr se recolecta de las vías respiratorias superiores, nasofaringe, cornete medio u orofaringe; todos con alta especificidad. sin embargo, se sugiere recolectar los hisopos nasofaríngeos o de cornete medio por tener mayor sensibilidad ( ( / ) . en pacientes con neumonía severa a quienes se le realizó lavado broncoalveolar (bal) y rt-pcr entre los días y el % de las muestras fueron positivos, en pacientes no intubados con esputo no inducido el % de las muestras fueron positivas ( , ). wang et al, en un estudio de pacientes con covid- , las rt-pcr con tasas positivas más altas fue en muestras extraídas por bal ( %; de muestras) y esputo % ( de muestras) ( ) . para la detección del sars-cov- por rt-pcr en pacientes en cuidado intensivo, teniendo en cuenta la rigurosidad de aspectos de bioseguridad y aerosolización, se debe tomar la primera muestras en nasofaringe o cornete medio, si esta prueba es negativa se puede repetir en a horas, si este es el caso o existe más de días desde el inicio de los síntomas se prefiere una muestra del tracto respiratorio inferior, por esputo no inducido por personal de salud o por aspirado traqueal en pacientes intubados ( , ), aunque el rendimiento diagnóstico del bal es alto por lo general, se debe evitar la broncoscopia para minimizar la exposición de los trabajadores de la salud ( ) . la probabilidad de detección del arn de sars-cov- puede variar según la fase de la enfermedad, si bien una rt-pcr positiva confirma el diagnóstico de covid- , los reportes falsos negativos y la sensibilidad se ve influenciado por el tiempo desde la exposición e inicio de síntomas. kucirka et al, en un análisis de siete estudios evaluaron el rendimiento diagnóstico de la rt-pcr en relación con el tiempo desde el inicio de los síntomas o la exposición, con resultados expresados en tasa estimada de falsos negativos, siendo del % el día de la exposición, del % el día (estimado como primer día de síntomas, ic: % a %), % en el día (día desde el inicio de síntomas, ic: % a %) luego comenzó a aumentar nuevamente de % en el día (ic: a %) a % en el día (ic: a %) ( ) . la precisión y los valores predictivos de rt-pcr para sars-cov- no se han evaluado sistemáticamente, la sensibilidad de las pruebas moleculares está influenciada por múltiples factores como sitio y calidad de la muestra, técnica de procesamiento; probablemente las menores tasas de falsos negativos (sensibilidad entre y %) está entre el día y luego de inicio de los síntomas ( ) . a partir de aquí el rendimiento diagnóstico disminuye, por lo tanto, es importante que el intensivista valore estas consideraciones en el momento de tomar conductas, en cuanto tipo de aislamiento, tratamiento y pronóstico. amci ® las pruebas serológicas detectan anticuerpos contra el sars-cov- y ayudan a identificar pacientes que han tenido la enfermedad y algunos con la enfermedad activa, la seroconversión se ha descrito entre el día y , sin embargo, hay incertidumbre en la incidencia de la seroconversión ( ) . estas pruebas se usan principalmente en tamizaje poblacional y estudios de seroprevalencia; en cuidado intensivo el análisis de la igm por elisa contribuye a la detección de pacientes con infección reciente, además con el análisis conjunto con la igg se clasifica el estado de infección en agudo o convaleciente. las pruebas serológicas se realizan por diferentes técnicas como la inmunocromatográfica de flujo lateral, la inmunofluorescencia indirecta (ifi) y el ensayo de inmunoadsorción ligado a enzima (elisa) ( , ) . las pruebas serológicas no deben usarse como la única prueba para diagnosticar o excluir la infección activa por sars-cov- . la sensibilidad y la especificidad de muchas de estas pruebas serológicas son inciertas, así como su valor predictivo positivo. los anticuerpos detectables generalmente tardan varios días en desarrollarse. guo et al, documenta niveles de anticuerpos por elisa, con una mediana de detección de anticuerpos igm e iga de días (iqr, - ) y de igg de días (iqr, - ) después del inicio de los síntomas, con una probabilidad de resultados positivos de . %, . % y . % respectivamente; es probable que el rendimiento diagnóstico de igm por elisa sea mayor que la de rt-pcr después del quinto día luego de inicio de síntomas; cuando se combinan estas técnicas (elisa igm con rt-pcr) la tasa de detección positiva es del . % ( ) . zaho et al, en un estudio de pacientes con covid- , donde el , % estaba en condición crítica, la mediana del tiempo desde el inicio de los síntomas hasta la detección de anticuerpos (técnica elisa) fue de días para igm y días para igg; dentro de los primeros días desde el inicio de los síntomas solo el . % tenía anticuerpos detectables, entre los días a la sensibilidad de igm fue . % e igg de . %, luego de los días la sensibilidad igm e igg fue de . % y . % respectivamente; el uso combinado de rt-pcr y elisa igm presentó una sensibilidad del % entre los días a y del % entre los días a . ( ) la rt-pcr tiene especificidad del %, con adecuado rendimiento diagnóstico entre los días y luego del inicio de los síntomas con sensibilidad que varía entre el y %, con presencia ascendente de falsos negativos luego del día , por lo cual el diagnóstico debe tener consistencias epidemiológicas y clínicas (síntomas y hallazgos radiológicos compatibles con covid- ) donde una rt pcr negativa no excluye la enfermedad; la precisión y el tiempo para la detección de anticuerpos varían con la técnica utilizada, su uso es limitado en cuidado intensivo, sin embargo su identificación por técnica elisa en conjunto con rt-pcr mejora la sensibilidad y la probabilidad de falsos negativos, especialmente entre los días y desde el inicio de síntomas. faltan estudios que evalúen el rendimiento diagnóstico de las diferentes pruebas. amci ® se recomienda la medición de marcadores de severidad al ingreso a uci del paciente críticamente enfermo por covid- (hemograma, transaminasas, ldh, ferritina, troponina, dímero d y pcr) los cuales se han asociado con peor pronóstico en la enfermedad por covid- , logrando ofrecer intervenciones más tempranas. se recomienda no utilizar una periodicidad de rutina para la medición de seguimiento de biomarcadores de severidad en el paciente con sospecha o diagnóstico de covid- . en un estudio cohorte retrospectivo que evaluó pacientes diagnosticados con covid- desde el de enero de hasta el de marzo de , fang liu y colaboradores encontraron correlación en la elevación de il- y pcr con la gravedad clínica, lo que sugiere podrían usarse como factores independientes para predecir la severidad del cuadro, los pacientes con il- > . pg./ml o pcr> . mg/l tenían más probabilidades de tener complicaciones graves ( ) , así mismo en otro estudio multicéntrico retrospectivo de pacientes infectados se identificó resultados de laboratorio con diferencias significativas con elevación de glóbulos blancos, valores absolutos de linfocitos, plaquetas, albúmina, bilirrubinas, función renal, transaminasas, troponina, proteína c reactiva e interleucina (il ) en el grupo con desenlace de mortalidad contra los dados de alta ( ) . entre otros marcadores la troponina como lesión cardiaca (elevación de troponina por encima del percentil límite de referencia superior) se ha reportado en % a % de los pacientes con covid- en wuhan, china, en dos estudios retrospectivos por xiabo yang y colaboradores ( , ) . en una revisión sistemática de mayo , kermali m. y colaboradores exponen que existe evidencia a favor de los valores bajos de linfocitos y plaquetas y valores elevados de los biomarcadores il- , pcr, troponina, ldh, ferritina, proteína amiloidea a y dímero d, pueden relacionarse con la gravedad de la infección por covid- y su fuerte asociación con la mortalidad ( ) . estos resultados pueden usarse como un complemento en la práctica clínica para guiar a los médicos a identificar pacientes con mal pronóstico y la rápida implementación de medidas de soporte, monitorización y reanimación en la evolución de los pacientes críticos en la unidad de cuidados intensivos. solo en estudio, karmali et al, en , determinan en promedio entre a horas, la periodicidad en el seguimiento de estos, sin embargo, no se discrimina entre pacientes críticos y no críticos. consideramos que el seguimiento de estas pruebas debe estar ajustado al juicio clínico del médico intensivista tratante, según la evolución de los pacientes. se muestran el comportamiento de los biomarcadores mas frecuentes en la tabla . tabla . biomarcadores en pacientes críticos con sospecha o diagnóstico de covid- . tendencia de biomarcador en relación con la gravedad covid- pcr aumentada recomendaciÓn se recomienda la no medición de marcadores de inflamación o de severidad de forma rutinaria solo con el objetivo de iniciar un tratamiento específico o algoritmos terapéuticos en la enfermedad por covid- en pacientes críticos. el síndrome de liberación de citocinas o denominado "tormenta de citocinas" parece asociarse en pacientes con afecciones graves por covid- . la citocina proinflamatoria il- es la citocina mejor documentada en covid- correlacionada con la gravedad, el estado crítico del paciente, la carga viral y el pronóstico ( , , ) . se han descrito mayores niveles de citoquinas proinflamatorias (il- , il- , il- , factor estimulante de colonias de granulocitos, factor de necrosis tumoral e interferón gamma) asociadas a compromiso pulmonar severo en pacientes con infección por coronavirus, determinado por la rápida replicación del virus, infiltración masiva de células inflamatorias y trastorno severo de la inflamación ( , ) . igualmente, está asociada la presencia de linfopenia como biomarcador de mal pronóstico para covid- ( ) . hallazgos similares se encontraron en la pandemia de influenza a (h n ) de sin ser especificó su valor ( ) . las manifestaciones clínicas de la tormenta de citocinas incluyen síndrome de respuesta inflamatoria sistémica, hipotensión, síndrome de fuga capilar, insuficiencia renal, sdra, miocarditis, entre otras ( ) , algunos autores han determinado este cuadro como un síndrome de linfohistiocitosis hemofagocitica secundaria. es razonable pensar que, en pacientes con sospecha de tormenta de citocinas basado en los hallazgos de laboratorio, el manejo con inmunomoduladores puede resultar beneficioso, sin embargo, los resultados del manejo de la hiperinflación basado en pruebas diagnósticas han tenido resultados encontrados en pacientes con covid- . el uso de esteroides, inmunoglobulina endovenosa, inhibidores del receptor de citoquinas (tocilizumab) o inhibidores de janus kinasa, han disminuido los valores de los biomarcadores, días de hospitalización ( ) o necesidad de fracciones elevadas de oxígeno ( ) , sin embargo no han demostrado beneficio sobre la mortalidad y en algunos casos, si un aumento en la incidencia de infecciones bacterianas o fúngicas sobreagregadas ( ) . se recomienda realizar radiografía simple de tórax para todos los pacientes con sospecha o diagnóstico de covid- en uci. se recomienda realizar tac de tórax según disponibilidad de tecnología institucional, ante la incertidumbre diagnostica, teniendo en cuenta las condiciones clínicas, la tolerancia del paciente al traslado y los protocolos administrativos de seguridad. fuerte a favor fundamento se reconoce como el gold estándar diagnóstico de infección pulmonar por covid- a los estudios moleculares, sin embargo, estos presentan limitaciones: a) contaminación de las muestras b) errores en la técnica de la toma, c) muestra insuficiente para ampliación genética favoreciendo falsos negativos d) demora de reporte de los resultados. por lo anterior, se recomienda imágenes diagnósticas en la aproximación de paciente con sospechas de infección pulmonar por covid- ( , ) .  radiografía simple de tórax: ventajas: mayor accesibilidad que la tac de tórax y realización de la prueba a la cabecera del enfermo desventaja: baja sensibilidad en estadio temprano, después del día de inicio de los síntomas presenta aumento en el rendimiento diagnóstico  tac de tórax: ventaja: es ampliamente recomendada. alta sensibilidad en estadios tempranos. permite describir extensión, distribución, localización, densidades parenquimatosas, aplicables en clasificaciones y puntajes diagnósticos, pronósticos y de seguimiento en permanente evolución y mejoría. algunas asociaciones referentes como asociación china de radiología, en su recomendación de expertos propone clasificación tomografía en estadios temprana avanzada severo disipación desventaja: traslado del paciente hasta el tomógrafo (no todos los enfermos toleran el transporte) y tecnología no disponible en todos los niveles de atención page no se puede emitir una recomendación a favor o en contra para el uso de ecografía pulmonar a la cabecera del paciente crítico como herramienta diagnóstica o de pronóstico en con covid- . se puede considerar como una alternativa para la valoración imagenológica pulmonar en el paciente crítico con covid- cuando las condiciones del paciente no permitan su traslado. no se sugiere la utilización de la ecografía pulmonar para el seguimiento de lesiones pulmonares agudas en el enfoque del paciente crítico con covid- . puede utilizarse para determinar complicaciones asociadas a la enfermedad o en la inserción de dispositivos invasivos. en general los estudios de imágenes no representan un papel concluyente para el diagnóstico de covid- . la ultrasonografía en específico requiere estudios de validación, un programa de entrenamiento es operador dependiente, y se le atribuido limitaciones en la capacidad de discriminación en la cronicidad de las lesiones pulmonares. la ultrasonografía pulmonar puede servir como herramienta a la cabecera del paciente para mejorar la evaluación del compromiso pulmonar y reducir el uso de radiografías de tórax y tomografía computarizada ( ) , sin embargo no debe usarse para el diagnóstico inicial, pues éste se compone de criterios clínicos, radiográficos y microbiológicos que actualmente son el estándar de oro; la ecografía no los reemplaza debido a la baja especificidad en relación con el virus, se sugiere su uso como complemento en la valoración diaria del paciente, ojalá realizada por el mismo observador. la ecografía pulmonar es altamente sensible y puede revisar de forma rápida y precisa la condición pulmonar, creando un potencial para evaluar los cambios o la resolución con el tiempo, especialmente en la uci, escenario en el que cada vez se usa más para la detección de múltiples patologías pulmonares que se pueden demostrar junto con covid- , sin embargo, hasta la fecha no hay hallazgos específicos, ni patognomónicos que se relacionen con covid- en el examen ecográfico del paciente ( ) . la adopción de ultrasonido pulmonar puede reducir la necesidad de exposición a la radiación ionizante y, a su vez, reducir la cantidad de radiografías necesarias para la evaluación rutinaria del paciente, disminuyendo también la exposición de personal asistencial adicional como el uso de elementos de protección personal ( ) . es bien conocido el beneficio de la ecografía durante y después de la colocación de accesos venosos centrales para establecer la presencia o no de complicaciones inmediatas como neumotórax. a la fecha no hay publicaciones acerca de la utilidad del ultrasonido como herramienta para establecer pronóstico. se necesitan más estudios para evaluar la utilidad de la ecografía pulmonar en el diagnóstico y manejo de covid- ( ) . se recomienda no establecer un punto de corte en el valor de dímero d para el inicio rutinario de anticoagulación plena en el contexto de infección por covid- . se recomienda la administración de profilaxis antitrombótica según protocolo institucional independiente de niveles de dímero d en el paciente críticamente enfermo por covid- . los fenómenos inflamatorios inherentes a procesos infecciosos son considerados desde décadas previas, factores protrombóticos, no siendo una excepción la infección por covid- . en algunas publicaciones se hallan asociaciones con desenlaces cardiovasculares negativos ( ) y sugieren asociación entre niveles elevados de dímero d ( marcador de estado de trombosis ) y riesgo de embolismo pulmonar con or crecientes or de . a los días hasta . a los días de seguimiento ( ) . de igual manera, zhou et al, reportan asociación de dímero d mayor a mcg/ml y mortalidad ( ) sin embargo los estudios presentan limitaciones en su diseño, a pesar de ello algunos autores proponen anticoagulación como factor de protección en mortalidad sin precisar precisión en la dosis, tipo de heparina y selección de enfermos ( ) . finalmente la european heart journal en su entrega de farmacología cardiovascular desarrolla una propuesta en la cual combina un puntaje previo de riesgo de cid en uci a niveles de fibrinógeno; esta pudiera ser una herramienta para selección de pacientes a recibir anticoagulación sin embargo aún está en proceso de validación ( ) . por estos motivos, hasta el momento, no se tiene suficiente cuerpo de evidencia que permita hacer una recomendación basado en los niveles de dímero d como variable aislada para administración de anticoagulación terapéutica. se recomienda no utilizar de rutina la procalcitonina en un algoritmo diagnóstico, para diferenciar entre neumonía viral vs bacteriana o confirmar la presencia de una sobreinfección bacteriana en el paciente con sospecha o diagnóstico de covid- . se recomienda no medir de forma rutinaria la procalcitonina en pacientes con sospecha o diagnóstico de covid- como factor pronóstico. la procalcitonina es un biomarcador que ha sido incluido en algoritmos de diagnóstico y pronóstico durante los últimos años. schuetz et al, en , concluyen en una revisión sistemática de estudios, que la procalcitonina es segura dentro de un algoritmo, para guiar a los médicos tratantes entre iniciar o suspender antibióticos en neumonía adquirida en la comunidad; sin embargo en una revisión sistemática más reciente, kamat et al, reportaron una sensibilidad % [ic % %- %; i = . %], especificidad % [ % ic, %- %; i = , %]) para el inicio de tratamiento antibiótico para neumonía bacteriana, lo cual nos determina que la prueba es inespecífica para diferenciar entre infecciones virales vs bacterianas. en neumonía por sars-cov- , se han publicado algunos artículos evaluando el uso de la procalcitonina como prueba asociada al pronóstico de los pacientes. liu et al encontraron que la procalcitonina se asoció a mayor severidad de los cuadros de neumonía. hr, . ; % ci, . - . ; p= . . en este estudio también se tuvo un resultado similar con la proteína c reactiva y la il- . plebani et al, publican un metaanálisis, donde sugiere que los niveles elevados de procalcitonina se asocian a mayor severidad de la infección. (or, . ; % ci, . - . ). es importante mencionar, que en estos estudios se evaluaron otros biomarcadores de inflamación como interleucina , proteína c reactiva y ferritina; presentando todos ellos, aumento en sus valores y asociándose a severidad de la enfermedad; por tanto, se considera que, en particular, la procalcitonina elevada, no representa una diferencia en el pronóstico, comparado con otros biomarcadores de inflamación. hasta el momento no se han publicado estudios en infección por sars-cov- donde se evalué el papel de prueba diagnóstica para confirmar sobreinfección bacteriana o diferenciar entre neumonía viral vs bacteriana. ( , ( ) ( ) ( ) se recomienda no usar de forma rutinaria el uso de pruebas clínicas de laboratorios clínicos para determinar la resolución de la enfermedad crítica por covid- . se recomienda considerar la ausencia de dificultad respiratoria y fiebre por más de horas, requerimiento de oxígeno a baja concentración y bajo flujo, como indicadores clínicos de resolución de la fase crítica de la enfermedad por covid- . se recomienda no utilizar de forma rutinaria el uso de pruebas microbiológicas de erradicación viral, para determinar la resolución de la enfermedad en pacientes en uci con covid- . amci ® enfermedad está asociado tanto a la carga viral como a la respuesta hiperinflamatoria del huésped a la infección viral. en cuanto a la carga viral, en pacientes que tienen un curso leve de infección, el pico de la carga viral en muestras nasales y orofaríngeas ocurre durante los primeros - días tras el inicio de síntomas y prácticamente desaparece al día , mientras que en los que cursan con neumonía severa en uci, la carga viral es veces mayor y puede persistir la excreción viral hasta el día a ( ) . por esta razón, consideramos que en los pacientes en uci no es necesario confirmar la erradicación del virus o su negativización en muestra respiratorias, orina o heces, para determinar la mejoría clínica, curación o para el egreso del paciente crítico ( ) . en el contexto clínico, el pronóstico se ha asociado a la presencia de marcadores bioquímicos elevados, sin embargo, no existe evidencia que el seguimiento con estos marcadores iniciales de inflamación determine el momento exacto de la resolución de la enfermedad. varias organizaciones internacionales como el cdc de usa y el european centre for disease prevention and control ( mar ) ( , ), national centre for infectious diseases (ncid) singapore ( ), world health organization ( de marzo de )( ), han establecido criterios para resolución clínica y egreso hospitalario de los pacientes. estos criterios incluyen: ausencia de fiebre mayor a horas sin antipiréticos, mejoría de los síntomas respiratorios, ausencia de requerimiento de hospitalización por otras patologías, el resultado de dos ( ) rt-pcr para sars-cov- negativas, con intervalo de muestra mayor a horas. la utilidad de dichos criterios no ha sido evaluada en pacientes en cuidado intensivo. en uci, huang et al ( ) , describieron en pacientes a quienes se dio egreso, la ausencia de fiebre por días, mejoría radiológica y evidencia de erradicación viral, como criterios de alta. sin embargo, consideramos que deben primar los criterios clínicos sobre los paraclínicos, en el momento de definir el egreso de un paciente de cuidado intensivo, teniendo como principal indicador la ausencia de dificultad respiratoria y la mejoría en los índices de oxigenación, con requerimiento de oxígeno suplementario a bajos flujos y concentración ( ) . se recomienda la cánula de alto flujo, donde esté disponible, en pacientes con covid- a nivel del mar con hipoxemia leve (pao /fio < y > o sao /fio < y> ). en alturas superiores a los mts por encima del nivel del mar esta terapia se puede considerar en pacientes que no tengan hipoxemia severa (pafi< ). amci ® se recomienda en pacientes críticos por covid- el uso de la cánula de alto flujo en salas de presión negativa, donde estén disponibles, que garanticen la seguridad del recurso humano. si no se dispone de habitación con presión negativa se puede optar por habitación individual cerrada. se debe contar con todo el equipo de protección personal necesario para el personal sanitario y de apoyo. se recomienda colocar mascarilla quirúrgica por encima de la cánula nasal en el paciente con sospecha o diagnóstico de covid- y mantener una distancia mínima de metros con otros pacientes. se recomienda la intubación inmediata en pacientes críticamente enfermos con sospecha o diagnóstico covid- con índice de rox ([spo /fio ] / frecuencia respiratoria) < a las horas de iniciada la oxigenación con cánula de alto flujo teniendo en cuenta que el retraso en la intubación aumenta la mortalidad. se recomienda considerar la cánula de alto flujo en caso de agotamiento de ventiladores mecánicos. la cánula de alto flujo ofrece flujos de hasta litros/minuto, que aportan una fracción inspirada de oxígeno (fio ) constante que reduce el espacio muerto y produce una presión positiva que genera reclutamiento alveolar y puede redistribuir el líquido alveolar ( ) ( ) ( ) . se ha reportado que al generar aerosoles, aumenta el riesgo de contagio para el personal de salud ( , ( ) ( ) ( ) . hasta el punto de que se ha recomendado su uso en salas con presión negativa ( ) . recientes publicaciones han establecido que la cánula de alto flujo genera una corta distancia de dispersión de aerosoles con lo cual las medidas de distanciamiento, un adecuado equipo de protección personal y donde estén disponibles, realizarla en salas de presión negativa darían seguridad al uso de la cánula de alto flujo ( , ) . a pesar de que la experiencia en la actual pandemia ha sido escasa, basada en series de casos, estudios retrospectivos y de metodología limitada, ha resultado ser promisoria en cuanto a la mejoría en la oxigenación y la tolerancia por el paciente ( , , , , , ( ) ( ) ( ) ( ) ( ) . sin embargo, hasta el momento no se ha establecido que la cánula de alto flujo evite la intubación. la caf podría convertirse en un alto riesgo de mortalidad al prolongar la decisión de intubación y al favorecer la lesión pulmonar autoinducida (p-sili) por aumento del esfuerzo inspiratorio. por todo ello es necesario un estricto y estrecho monitoreo del paciente durante una o dos horas para definir si ha habido mejoría o no mientras se realizan estudios que demuestren que evita la intubación y genera desenlaces clínicos importantes como menor estancia en uci, menor estancia hospitalaria y menos días de ventilación mecánica. la terapia de oxígeno de caf podría ser considerada para pacientes atendidos en altitudes mayor a mts, que no tienen hipoxemia severa (pafi < ), la respuesta debe evaluar dentro de los a minutos posteriores a su inicio y los pacientes que no mejoran amci ® significativamente y progresa la dificultad respiratoria no deben mantenerse con esta terapia. el monitoreo del paciente con caf para la toma de decisión de éxito o fracaso de esta estrategia y considerar la posibilidad de intubación incluye la evaluación gasométrica, la oximetría de pulso, así como considerar los criterios para intubación: frecuencia respiratoria > por minuto, deterioro de conciencia, inestabilidad hemodinámica, pao /fio < (a nivel del mar), sao /fio < , índice de rox< , , spo < % ( , - , - , , ) . se recomienda crear o ajustar protocolos institucionales de sedoanalgesia basado en objetivos con escalas validadas. se recomienda el uso de analgesia multimodal que incluya analgésicos opioides, no opioides y bloqueos regionales en el paciente crítico por sospecha o diagnóstico de covid- . se recomienda sedación profunda con agentes como midazolam o propofol para mantener rass entre - y - en pacientes covid- con sdra severo, necesidad de uso de relajantes neuromusculares o posición prona. se puede considerar en planos de sedación superficial agentes como propofol o dexmedetomidina (coadyuvante) para mantener rass entre y - en pacientes seleccionados con sospecha o diagnóstico de covid- con sdra no severo. en la actualidad no se encuentra evidencia de alta calidad proveniente de ensayos clínicos, sino editoriales, series, reportes de casos y artículos de revisión de expertos ( ) ( ) ( ) . la creación y aplicación de protocolos de sedoanalgesia adaptados a cada institución ha mostrado disminución del tiempo en la uci y menores complicaciones ( , ) . es importante definir objetivos guiados por escalas, recomendándose sedación profunda o completa en situaciones especiales como ventilación mecánica invasiva por sdra severo, disincronía ventilatoria persistente, posición prona y bloqueo neuromuscular (bnm), como puede observarse en pacientes covid- con compromiso pulmonar severo. mientras que se debe procurar sedación ligera, cooperativa o no sedación en pacientes en ventilación mecánica invasiva en pacientes con sdra no severo, ventilación no invasiva y en el retiro de la ventilación ( , ) . los opioides han sido el pilar de la analgesia en dolor moderado a severo. el fentanilo es actualmente el más usado; el remifentanilo reduce el tiempo en ventilación en pacientes amci ® renales, hepáticos, ancianos y neurológicos; la hidromorfona se prefiere en el retiro de la ventilación y en pacientes extubados; y la metadona ha mostrado disminuir la tolerancia a opioides ( ) . se propone el uso de estrategias de analgesia multimodal asociando medicamentos no opioides como el paracetamol, ketamina a dosis analgésicas (< , mg/kg) en dolor somático, lidocaína en dolor visceral, y pregabalina en dolor neuropático ( ) . la sedación ligera o cooperativa son mejores con propofol en cuanto a tiempo de despertar y con dexmedetomidina para preservar funciones cognitivas y el impulso respiratorio, con menor desacondicionamiento ( ) . en sedación profunda, el propofol ha mostrado más fácil titulación y menos acumulación que el midazolam; sin embargo, su uso se ve limitado hasta horas y a dosis < , mg/kg/h, ante el riesgo de pris (síndrome relacionado con la infusión de propofol). el midazolam, sin dosis techo ni tiempo límite y de bajo costo, ha sido el más utilizado de los sedantes, disminuyendo su uso por su asociación con delirium y de retraso en los tiempos en ventilación; sin embargo, la pandemia covid- ha vuelto a aumentar su uso. la dexmedetomidina ha sido utilizada como adyuvante en sedación profunda, disminuyendo el consumo de sedantes, con menos efectos secundarios ( , ) . se muestran los medicamentos para sedoanalgesia y relajación neuromuscular que se pueden utilizar en los pacientes con covid- en la tabla . se recomienda iniciar una estrategia individualizada de ventilación mecánica ajustadas a las condiciones específicas de severidad en el paciente crítico con covid- . amci ® se recomienda la ventilación protectora en modos controlados por volumen o por presión que garanticen un volumen corriente < cc/kg de peso predicho teniendo como metas una presión meseta < cm h o y una presión de conducción < cm h o. se recomienda emplear fracciones inspiradas de oxígeno para lograr metas de saturación de acuerdo con la pao /fio entre y % en el paciente con sospecha o diagnóstico de covid- . en la paciente embarazada entre y %. se recomienda en el paciente crítico por covid- iniciar con peep individualizado a la severidad del compromiso pulmonar y ajustar el nivel de peep de acuerdo con la tabla de fio /peep. el estudio arma ( ) demostró que la ventilación con bajos volúmenes corrientes (vt) se asocia con reducción de: mortalidad (p= . ), en días libres de ventilación mecánica (p= . ) y días libres de falla orgánica (p= . ). una revisión sistemática posterior confirmó que el uso de bajos volúmenes se asocia con menor progresión a sdra ( ) . un metaanálisis que revisó estudios y meta-análisis en uci confirmó que la ventilación protectora era una de las tres intervenciones que mejora la sobrevida en pacientes con sdra ( ) . esto fue confirmado por landoni en un análisis de estudios multicéntricos con impacto en mortalidad en uci ( ) . recientes publicaciones han sugerido que en covid- puede haber dos fenotipos que se diferencian en la distensibilidad ( , ) . sin embargo, el mismo estudio arma demostró que "el beneficio de ventilación con vt más bajo fue independiente de la distensibilidad de las vías respiratorias, lo que sugiere que el vt más bajo fue ventajoso independientemente de la distensibilidad pulmonar". más aún, el uso de bajos vt se asoció con una reducción en las concentraciones de interleuquina lo cual explicaría el mayor número de días sin falla orgánica múltiple y sugeriría una reducida respuesta inflamatoria asociada a la ventilación protectora ( ) . con el tiempo la evidencia ha demostrado que la ventilación protectora, además de vt y presión meseta bajos, debe incluir presiones de conducción menores de cm h o ( ) ( ) ( ) . existe suficiente evidencia que demuestra que fio y pao altas se asocian con aumento en la morbimortalidad ( ) ( ) ( ) . en sdra el estudio arma y una más reciente publicación demostraron que el tener metas conservadoras de pao se asocia con mayor sobrevida ( , ) . hasta el momento, la literatura en ventilación mecánica ha demostrado que la mejor estrategia para ajustar el nivel de peep en sdra es la tabla de fio /peep ( , ) . amci ® se recomienda la ventilación mecánica protectora en sdra por covid- independiente del fenotipo de presentación. se recomienda la clasificación de fenotipos en sdra para pacientes con covid- para ajustar la toma de decisiones de manera individualizada en ventilación mecánica. el manejo ventilatorio en covid- tiene los mismos principios generales de los pacientes con sdra ( ) . sin embargo, la identificación de fenotipos podría impactar en la evolución y pronóstico ( ) . gattinoni ha postulado el desarrollo de un sdra típico (fenotipo h: con alta elastancia, alto cortocircuito, alto peso pulmonar) o una presentación atípica (fenotipo l: caracterizado por baja elastancia, bajo shunt, bajo peso pulmonar). ( ) . pelosi et al sugiere clasificar los pacientes con tres fenotipos similares ( ) . con base en tales fenotipos se han propuesto estrategias ventilatorias diferenciales para minimizar el daño inducido por el ventilador (vili) ( ): . el primer paso, en el fenotipo l, es revertir la hipoxemia aumentando la fio . . en el tipo l, hay varias opciones no invasivas: cánula nasal de flujo alto, presión positiva continua en la vía aérea (cpap) o ventilación no invasiva (niv). se debe evaluar el esfuerzo inspiratorio y, de estar disponible, medir la presión esofágica. la peep alta puede disminuir los cambios de presión pleural y detener el ciclo vicioso que exacerba la lesión pulmonar. sin embargo, la peep alta, en pacientes con distensibilidad normal, puede tener efectos hemodinámicos perjudiciales. en cualquier caso, las opciones no invasivas son cuestionables, ya que pueden asociarse con altas tasas de fracaso y retraso de la intubación. . la magnitud de las presiones pleurales inspiratorias puede determinar la transición del tipo l al h. la presión esofágica > cmh o aumenta el riesgo de vili y, por lo tanto, la intubación debe realizarse lo antes posible. los tipo l, si son hipercápnicos, pueden ser ventilados con volúmenes > ml / kg (hasta ml / kg). la posición prona debe ser usada solo en último caso, ya que las condiciones pulmonares son buenas. la peep debe reducirse a - cm h o, dado que la capacidad de reclutamiento es baja y el riesgo de falla hemodinámica aumenta. la intubación puede evitar la transición al fenotipo tipo h. . los pacientes tipo h deben ser tratados como sdra grave, incluyendo mayor peep, si es compatible con la hemodinamia, posición en pronación y soporte extracorpóreo. en el fenotipo se deben aplicar las estrategias de ventilación protectora convencional ( , ) . amci ® se recomienda en paciente con covid- considerar hipoxemia refractaria cuando no se obtienen las metas de oxígeno propuestas, a pesar de las maniobras ventilatorias recomendadas y cumple con los siguientes parámetros: pafi < , fio > , y peep apropiado, considerando la altitud. se recomienda considerar la utilización de ecmo, en sitios donde esté disponible y con alta experiencia para obtener resultados aceptables, en pacientes con hipoxemia refractaria luego de haber implementado ventilación protectora, relajación neuromuscular y posición prona. se recomienda administrar tromboprofilaxis en todos los pacientes con covid- con hipoxemia refractaria que no presenten contraindicaciones. la hipoxemia refractaria no es un concepto estático y absoluto, según la definición de berlÍn del sdra, se clasifica el sdra en leve, moderado y severo de acuerdo con la relación pao y fracción inspirada de oxígeno, con peep mayor de cms de h o. la hipoxemia severa es aquella que cuenta con una pafi menor de ( ) ( ) ( ) . la hipoxemia refractaria hace referencia a un estado de hipoxemia severa que a pesar de las diferentes estrategias ventilatorias no aumenta la pafi y tiene consecuencias en el estado ácido básico y metabolismo celular permitiendo una anaerobiosis ( , ) . para definir la hipoxemia refractaria deben coincidir varios escenarios , una pafi menor de , una fracción inspirada de oxígeno mayor de . , a pesar de un peep apropiado no se tiene en cuenta en la definición el ph ni la paco ni el tiempo transcurrido ( ) . algunas de las medidas terapéuticas no ventilatorias que se han empleado en sdra y covid- con hipoxemia refractarias son la oxigenación con membrana extracorpórea (ecmo) y la tromboprofilaxis o anticoagulación de rutina. la oxigenación extracorpórea a través de una membrana ha sido una estrategia controvertida en pacientes con hipoxemia refractaria de diferentes orígenes, en la epidemia de la influenza por el virus h n fue usada en pacientes con hipoxemia refractaria teniendo resultados aceptables ( ) . en el estudio eolia los resultados no mostraron mejoría en la supervivencia, aunque hay diferentes posiciones y estudios post hoc de este ensayo clínico con beneficios, su uso se limita a casos muy restringidos y en sitios de alta experiencia para obtener resultados aceptables ( ) . en sdra por covid- el ecmo se ha usado en hipoxemia refractaria entre un a . % en diferentes series con resultados variables ( , , ) . un tipo de pacientes hipoxémicos y con ventilación mecánica han presentado cuadros tromboembólicos pulmonares en estos casos la trombólisis de rescate con activador de plasminógeno tisular rtpa (alteplase) se ha recomendado con resultados alentadores en serie de casos, pero su evidencia es muy débil para ser recomendada( - ). dada la alta frecuencia de enfermedad tromboembólica reportada en covid- se ha reportado la utilidad de la tromboprofilaxis, especialmente en casos de dímero d o índice de sic elevado ( ) . amci ® se recomienda monitorizar sistemáticamente la oxigenación con los índices: pao /fio y sao /fio , y en donde esté disponible el monitoreo continuo con capnografía. se recomienda monitorizar de forma rutinaria la presión meseta y la presión de conducción como estrategia al pie de la cama para verificar la ventilación protectora. el sdra y covid- , es una condición dinámica que apenas se está caracterizando, hay varias presentaciones que no cumplen con todos los criterios de berlÍn ( , ) . gattinoni ha caracterizado en dos presentaciones el sdra en los pacientes con neumonía por coronavirus sars-cov- , una con alta compliance, mínima reclutabilidad; la otra con baja compliance, pulmones pesados y reclutabilidad, tal vez esta presentación sea el verdadero sdra ( , , ) . los pacientes que requieren ventilación mecánica por falla ventilatoria en covid- , son los que mayor mortalidad tienen al parecer por la lesión pulmonar inducida por la intubación tardía y el gran esfuerzo respiratorio con presiones transpulmonares oscilantes y muy negativas ( , , ) . la monitoria de estos pacientes soportados con ventilación mecánica tiene dos objetivos: el primero detectar el deterioro clínico para sugerir estrategias más avanzadas como el ecmo, y el segundo es evitar el daño pulmonar inducido por la ventilación mecánica. se debe tener presente la mayor posibilidad de contagio con el número de manipulaciones en el paciente, por esto nunca olvidar el perfecto uso de los elementos de protección personal y disminuir el número de contacto con el paciente. las metas que se buscan con la ventilación mecánica en el paciente con sdra por covid- son mantener una oxigenación adecuada teniendo en cuenta la altura sobre el nivel del mar con pao entre y mmh y metas de saturaciones reportadas entre y % a y % , mantener una ventilación adecuada evitando el espacio muerto , disminuir el trabajo respiratorio y protegiendo el pulmón del daño ocasionado por la ventilación mecánica y las repercusiones hemodinámicas ( ) .  el confort de los pacientes en ventilación mecánica es la principal señal de un uso adecuado del modo ventilatorio y los parámetros ventilatorios apropiados para la patología y demanda del paciente ( ) .  las curvas y bucles son herramientas indispensables para valorar la mecánica respiratoria del paciente soportado con ventilación mecánica, se puede diagnosticar amci ® las asincronías del paciente y el ventilador, el origen, tipo y frecuencia además de la respuesta al manejo. también se evalúa la resistencia de la vía aérea ( ) . variables fisiológicas:  es importante valorar la oxigenación del paciente, la literatura actual sugiere el monitoreo de la pafi es el más representativo y sencillo test para valorar la oxigenación y representa el shunt pulmonar, se debe hacer mínimo diariamente, o cuando se haga una intervención en el ventilador o paciente; en sdra por covid- la hipoxemia se relaciona directamente con mortalidad, debe mejorar con la ventilación mecánica ( , ) .  la medición de la paco indica la de la ventilación, la hipercapnia tiene relación directa con el espacio muerto en el paciente con sdra, y varios estudios la relacionan con la mortalidad. puede evaluarse directamente en los gases arteriales o relacionarla con el pco expirado por medios de la capnografía, gattinoni propone una forma de evaluarla al lado de la cama del paciente relacionando el etco /paco , cuando es < de sugiere un shunt elevado y mayor espacio muerto; áreas de pulmón ventiladas y no aireadas. otras tecnologías incluidas en el ventilador moderno como la capnografía volumétrica se está validando para evaluar el espacio muerto, la reclutabilidad y la titulación de peep ( , ) .  la saturación venosa mixta svo , refleja de manera subrogada la función ventricular, no todos los pacientes tienen catéter de arteria pulmonar para su medición por lo que se está reemplazando con el ultrasonido en la cabecera del paciente; recordar que el % de los pacientes con sdra cursan con falla ventricular derecha ( ) . monitoria de mecánica ventilatoria y protección pulmonar:  para evitar el daño pulmonar debe propender por un volumen corriente bajo ( - ml/kg de peso predicho) y presión plateau menor de cms h , para garantizar la ventilación con protección pulmonar ( , ) .  driving pressure ( presión cambiante de la vía aérea, presión diferencial o presión de conducción) es la presión plateau (presión pico en ventilación controlada por presión) menos peep, debe ser menor de cm h , está relacionado con aumento en la mortalidad en pacientes ventilados por que representa una medición indirecta del strain pulmonar porque relaciona el volumen corriente con la compliance del sistema respiratorio y este a su vez se relaciona con el volumen espiratorio pulmonar final ( ) .  la medición de la compliance del sistema respiratorio es necesaria y nos clasifica el paciente de acuerdo con su fenotipo para trazar el plan de manejo ventilatorio, cuando la compliance es baja, esto se puede hacer al lado de la cama del paciente con los ventiladores modernos ( , ) .  la construcción de la curva presión/volumen aún es una herramienta útil para ubicar el área de ventilación segura del paciente, evitando el atelectrauma y la sobredistensión pulmonar(estrés) , el peep se calcula dos puntos por encima del punto de inflexión inferior y el punto de inflexión superior nos indica hasta dónde podemos aumentar el volumen corriente este punto debe estar por debajo de cms h para evitar la sobre distensión, con los ventiladores modernos se puede construir esta curva ( , ) . amci ®  las curvas presión tiempo en pacientes ventilados con modos volumétricos pueden monitorizar la resistencia de la vía aérea, la compliance pulmonar, el trabajo respiratorio, las curvas de flujo puede también indicar si se presenta autopeep, resistencia aumentada de la vía aérea entre otras ( ) .  presión transpulmonar, en casos más complicados donde es más difícil obtener la meta de oxigenación a pesar del peep en aumento una opción es el catéter esofágico, para medir la presión transpulmonar en la inspiración y espiración y calcular así el stress pulmonar y evitar las presiones oscilatorias y sobre todo negativas para evitar el daño pulmonar. esta herramienta también ayuda a evaluar el trabajo respiratorio, y el diagnóstico de las asincronías que se presenten en el paciente ventilado ( , ) . se recomienda no utilizar de forma rutinaria la relajación neuromuscular en el paciente crítico con covid- con sdra. se recomienda utilizar la relajación neuromuscular en pacientes en posición supino o prono, que están fuera de parámetros de protección pulmonar (presión de conducción mayor y presión plateau mayor a ) con pafi menor y cuando ya no es posible limitar el volumen corriente. se debe considerar la utilización de protocolos estandarizados con el fin de disminuir la variabilidad, y según disponibilidad seleccionar el cisatracurio como primera opción, en caso de escasez se pueden utilizar otras opciones teniendo en cuenta su farmacodinamia y farmacocinética. el de marzo de , la organización mundial de la salud emite una serie de orientaciones para el manejo de la infección respiratoria aguda grave (irag) en pacientes con sospecha o diagnóstico de covid- . en el paciente críticamente enfermo con sdra moderado o grave (pao /fio < ) por covid- no está indicado de forma sistemática el bloqueo neuromuscular mediante infusión continua debido a que no se cuenta con evidencia suficiente que sustente mejoría en la supervivencia con respecto a una estrategia de sedación ligera sin bloqueo neuromuscular, se debe considerar su uso cuando se evidencia asincronía paciente-ventilador a pesar de la sedación, hasta el punto de que no se pueda limitar el volumen corriente de forma fiable, hipoxemia o hipercapnia que no mejoran con el tratamiento ( ) . recomendaciÓn se recomienda no utilizar de forma rutinaria oni en pacientes adultos que presenten sdra e infección por sars-cov- . fuerte en contra fundamento a la fecha (mayo de ) no contamos con estudios sobre el uso de óxido nítrico inhalado (oni) como tratamiento de pacientes con infección covid- . existe evidencia indirecta sobre el uso de oni en el síndrome de dificultad respiratoria aguda (sars-cov), y la infección por coronavirus en el síndrome respiratorio de oriente medio (mers-cov) ( ) . en cochrane realizó una revisión sistemática que incluyó ensayos de calidad moderada con pacientes adultos con sdra tratados con óxido nítrico inhalado. los resultados no mostraron ningún efecto estadísticamente significativo sobre la mortalidad (rr . , % ci . - . ). se mostró mejora transitoria en el índice de oxigenación a las horas (md (diferencia media) - , , ic del % - , a - , ) y mejoría en pao /fio a las horas (md , , ic del % , a , ). no se identificó diferencia significativa en los días libres de ventilación y finalmente se presentó aumento estadísticamente significativo en la incidencia de insuficiencia renal en pacientes con óxido nítrico inhalado (rr , , ic del % , )( ). amci ® en se realizó un estudio observacional que incluyó pacientes tratados de dos hospitales de beijing con oni como tratamiento para sars ( ) . en comparación con ningún tratamiento, oni mejoró la saturación arterial de oxígeno (spo ) de % a % (p< . ); se asoció a menor necesidad de oxígeno suplementario (p< . ) y menor necesidad y retiro de cpap y bial (p < . ). los cambios en radiografía de tórax mejoraron en de los pacientes que recibieron oni. sin embargo, debido a problemas graves de validez por pequeño tamaño de la muestra (n= , oni= , control= ), no aleatorización y no enmascaramiento en la asignación, se considera que este estudio cuenta con baja calidad metodológica, lo cual limita la interpretación de los resultados. en un estudio retrospectivo multicéntrico que incluyó pacientes con mers-cov en condición crítica en arabia saudita, se mostró que el manejo con ventilación no invasiva (niv) tenía mayor probabilidad de requerir óxido nítrico en comparación con los pacientes con ventilación mecánica invasiva ( , % vs , %, p a , ) ( ) . en una serie de casos en la que participaron pacientes con infección por mers-cov confirmada o probable, pacientes recibieron oni debido a hipoxemia refractaria. en el seguimiento a días, cinco de los pacientes continuaron vivos ( ) . los estudios sobre mers-cov se limitaron a una serie de casos y una cohorte retrospectiva con baja calidad de evidencia. en ambos estudios, los pacientes recibieron otras terapias de rescate (relajación neuromuscular, ventilación oscilatoria de alta frecuencia, ecmo y posición en prono), por lo tanto, se desconoce el efecto terapéutico clínico del oni en el tratamiento de la infección por mers-cov. a la fecha ( de mayo de ) tres ensayos clínicos evalúan el papel del óxido nítrico inhalado en pacientes con covid- y sdra leve/moderado, y como profilaxis para los trabajadores de la salud covid- (tabla ). tabla . comparación de ensayos clínicos que evalúan el papel del óxido nítrico inhalado en pacientes con covid- y sdra leve/moderado, y como profilaxis para los trabajadores de la salud covid- . no se cuenta con evidencia por el momento que respalde el uso de óxido nítrico inhalado en pacientes con covid- . los resultados de los ensayos en curso, así como ensayos clínicos de alta calidad son necesarios para apoyar su uso. sólo evidencia indirecta metodológicamente limitada de óxido nítrico en pacientes con sras mostró una mejor oxigenación, una menor necesidad de oxígeno suplementario y mejoría en la radiografía de tórax. en pacientes con sdra y mers-cov, no mostró un beneficio claro e incluso mostró un mayor riesgo de insuficiencia renal ( ) . otros estudios han evaluado el efecto tóxico asociado a su uso documentando metahemoglobinemia( ), inhibición de la agregación plaquetaria y formación de dióxido de nitrógeno ( ) . razones por la cuales guías recientemente publicada no recomienda su uso de forma rutinaria( ). recomendaciÓn se recomienda el uso temprano de la ventilación en posición prona, por al menos horas continuas, en pacientes con sdra por covid- con pao /fio < mmhg. la ventilación en posición prono como estrategia ventilatoria propuesta desde los años ( ), cuenta con evidencia que demuestra resultados positivos en cuanto a mejoría de mortalidad, mejoría en el trastorno de oxigenación y el reclutamiento alveolar en pacientes con sdra. los mecanismos por los cuales la posición prona conduce a la mejoría en el trastorno de oxigenación y del reclutamiento alveolar en los pacientes con sdra, incluyen ( ) ( ) ( ) ( ) : amci ®  mejoría de la relación ventilación/perfusión y mayor homogeneidad en la distribución de aire en los pulmones.  aumento del volumen de fin de espiración.  disminución del efecto compresivo del corazón en los pulmones.  mejoría del drenaje de las secreciones.  optimización del reclutamiento alveolar, con mejoría de la distribución del volumen corriente, a su vez, limita el desarrollo del daño alveolar pulmonar. los estudios coinciden en el efecto benéfico que esta terapia tiene en la mejoría de la oxigenación, el objetivo se centrará en evaluar las recomendaciones con respecto a:  beneficio de la terapia con respecto a la mortalidad al día , al día y a los meses.  beneficio de la terapia según el grado de severidad de sdra con respecto la relación pao /fio .  tiempo de terapia en posición prono con mayor beneficio.  número de sesiones de la terapia en posición prono.  recomendaciones según balance riesgo/beneficio en lo que respecta a los efectos adversos: retiro o desplazamiento no planeado de catéteres, obstrucción de tubo endotraqueal, neumonía asociada a ventilador, lesiones de presión. se eligieron artículos que con las características metodológicas consistentes ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . de estos ocho artículos se excluyó uno por corresponder a pacientes pediátricos ( ) . al evaluar los escritos de forma cronológica, se puede apreciar en los primeros artículos ( , ) , la dificultad para lograr enrolar (reclutar) el suficiente número de pacientes, de tal manera que algunos estudios fueron detenidos de forma prematura ( , , , ) . era entonces esperable que los resultados no fueran concluyentes, y que no lograran ser robustos, al no alcanzar el tamaño de muestra deseado, comprometiéndose la confiabilidad, el poder y corriendo el riesgo de obtener resultados falsamente negativos. sin embargo, se podía percibir en los diferentes estudios, una notoria mejoría en la oxigenación, sin repercusión en la mortalidad ( ) ( ) ( ) ( ) ( ) ( ) . por otro lado, es necesario tener en cuenta que los estudios iniciales ( ) ( ) ( ) ( ) no se realizaron con el uso de ventilación protectora asociada a la pronación. esto es un elemento pertinente, pues la ventilación protectora puede per se, brindar un efecto adicional en la mejoría de la oxigenación. otro efecto importante que debe analizarse es el bloqueo neuromuscular, cuya evidencia hoy sugiere su uso en criterios ya mencionados ( ) . con el tiempo y según la experiencia de cada centro, se fue utilizando con menor dificultad ( ) . sin embargo, no se tenía aún claro qué tipo de pacientes obtenían el mayor beneficio de la terapia, además que el tiempo de la terapia en posición prona, seguía siendo una incógnita. la evidencia reflejaba hasta el momento que los pacientes con sdra más severos y la terapia aplicada por más tiempo se asociaban con una tendencia a la reducción en mortalidad. para dirimir qué tipo de pacientes se beneficiarían más de la terapia, se tomó como base, la severidad del sdra según la relación pao /fio ( ) . a pesar de que los estudios iniciales( - ) enfrentaban el reducido tamaño de muestra, algunos análisis identifican beneficio de la mortalidad ( ) en pacientes con sdra más severo, constituyendo un probable umbral de beneficio cercano y por debajo de - mmhg ( ) . amci ® antes del estudio proseva ( ) en totalidad estudios reportan mortalidad al día ( , ) , un estudio mortalidad al día ( ) , uno estudio mortalidad al día ( )y uno mortalidad al día ( ) . sin embargo, al tomar todos los estudios, aún no se alcanzaba suficiente significancia estadística para reducir la mortalidad a los días y meses. con el estudio proseva -guerin et als -en el año ( ) , se alcanza más poder estadístico, demostrando un beneficio importante en pacientes con pao /fio menor de mmhg, ventilados con bloqueo neuromuscular y ventilación protectora en su totalidad, y logrando una reducción de la mortalidad al día y mantenida hasta el día con respecto al grupo control ( . % ( de participantes) versus . % ( de ) (p< . ). de tal manera que, según la evidencia disponible, en lo que al trastorno de oxigenación se refiere (según la relación pao /fio ), sugiere que el mejor candidato para esta estrategia ventilatoria es el paciente con sdra severo con una pao /fio menor de mmhg. es de primordial importancia detenerse a considerar por otra parte, el número de horas que se implementaría la terapia. el estudio inicial realizado por gattinoni et al. ( ) , llevó a los pacientes a un período corto de horas, sin encontrar resultados positivos en mortalidad. (resultados que no se pueden solamente atribuir a la calidad del estudio, sino también, al reducido número de horas de la ventilación en posición prono). mancebo et als (la abreviación latina para "otros "es et al.), y fernández et al. ( , ) por su parte, optan por ventilar un mayor número de horas ( - horas) obteniendo resultados (que sugieren una reducción en mortalidad) con tendencia a disminuir mortalidad. si bien diferentes metaanálisis sugieren no (la ausencia de beneficio) beneficio de la ventilación en prono ( , ) , los resultados son diferentes cuando se aborda la terapia con períodos mayores a horas ( ) . teniendo en cuenta, que el estudio con más poder estadístico ( ) postula horas de terapia en posición prono, la recomendación es la pronación por un tiempo mayor a horas, contemplando hasta las horas por sesión. otra pregunta que surge con frecuencia es el número de veces que se puede implementar la terapia. existen diferentes estudios en los cuales se indica el número de veces en promedio en que se llevó el paciente a posición prono ( , ) , otro protocolo en donde se estipula un número límite de días en los que se llevó a cabo la terapia( ), y otro estudios en los cuales no se precisó el número de sesiones de la terapia ( , ) . se podría entonces recomendar con respecto a la mayor evidencia disponible ( ) , pronar a los pacientes en varias sesiones ( en promedio) (depende de los criterios para continuar o suspender el prono que deben ser individualizados para cada paciente, en cada zona geográfica y en cada unidad de cuidados intensivos, es difícil saber si es el promedio para todos), y considerarla más veces si es necesario. en lo que respecta a los efectos adversos, tres estudios reportaron barotrauma y neumonía asociada a ventilador ( , , ) ; dos estudios desplazamiento de catéter central ( , ) y siete estudios reportaron extubación ( ) ( ) ( ) ( ) ( ) ( ) ( ) . sin embargo, los efectos adversos no alcanzaron significancia estadística para proscribir la terapia ( ) . recientemente fue publicado el consenso colombiano de sdra( ) en el cual se hace referencia a las recomendaciones para realización de ventilación prono. se presenta la lista de chequeo, y medidas que deben ser realizadas en la maniobra para lo cual se cuenta con la participación de terapia respiratoria, enfermería y médico. se recomienda implementar un protocolo de retiro de ventilación mecánica basado en la prueba de respiración espontánea y articulado con un protocolo de sedación y analgesia en el paciente críticamente enfermo por sospecha o diagnóstico de covid- . desde diciembre de , un número de casos de neumonía por síndrome respiratorio agudo severo sars-cov /covid- en wuhan china se identificaron, como causa de insuficiencia respiratoria aguda( ). el síndrome de dificultad respiratoria aguda (sdra) ocurre en el % de los pacientes hospitalizados y en el % de los pacientes admitidos a la unidad de cuidados intensivos (uci) en wuhan ( ) . mientras la ventilación mecánica es una intervención que potencialmente salva la vida, esta puede llevar a múltiples complicaciones y contribuir a la lesión pulmonar ( ) . es por todo esto que el retraso en el retiro de la ventilación mecánica puede aumentar el riesgo de amci ® infecciones, aumenta la sedación innecesaria, el trauma de la vía aérea y aumento en el costo de la atención de estos pacientes ( ) . el retiro de la ventilación mecánica es un proceso de tres pasos, el primero es conocido como preparación la cual depende de variables fisiológicas, criterios clínicos y predictores de weaning (destete), el segundo paso es el propio weaning, el cual consiste en la disminución del soporte ventilatorio entregado al paciente, con el objetivo de llevar al último paso que es la extubación( ), ilustración . por todo lo anterior, se recomienda realizar un proceso de retiro de ventilación mecánica invasiva adoptando un protocolo, seleccionando adecuadamente a los pacientes, ya que evidencia sugiere que la adecuada selección de los pacientes disminuye los días de ventilación mecánica, disminuye la estancia hospitalaria y la estancia en uci ( ) . se recomienda realizar el retiro de la ventilación mecánica siguiendo los pasos antes mencionados, iniciando con la preparación, la cual consiste en: preparación . asegurarse que la lesión pulmonar que llevó a la falla respiratoria esté resuelta. . adecuado intercambio de gas, definido como adecuados índices de oxigenación con peep (presión positiva al final de la expiración) a cmh o, y fio (fracción inspirada de oxígeno) < . . al igual que el proceso de intubación, es un proceso que genera aerosoles por lo cual se recomienda la aplicación de lidocaína dosis de , a , mg por kilogramo de peso, a minutos antes la extubación con el objetivo de disminuir el reflejo de tos ( ) y la exposición del personal de salud. se recomienda en el paciente con sospecha o diagnóstico de covid- a quien se considera realizar vmni, utilizarla en salas de presión negativa, donde estén disponibles, que garanticen la seguridad del recurso humano, con todo el equipo de protección personal necesario. se recomienda considerar la vmni en pacientes con covid- con hipoxemia leve (pao /fio < y > o sao /fio < y> ) en salas de presión negativas, donde estén disponibles que garanticen la seguridad del recurso humano, con todo el equipo de protección personal necesario. fuerte a favor se recomienda considerar la vmni en pacientes con covid- con hipoxemia leve (pao /fio < y > o sao /fio < y> ) y con historia de epoc o cuadro de edema pulmonar agudo asociado en salas de presión negativas, donde estén disponibles que garanticen la seguridad del recurso humano, con todo el equipo de protección personal necesario. se recomienda colocar doble filtro en el circuito del ventilador para reducir el riesgo de generación de aerosoles en vmni del paciente crítico con sospecha o diagnóstico de covid- . se recomienda la intubación inmediata en pacientes críticamente enfermos por covid- si se evidencia respiración toraco-abdominal, uso de músculos accesorios, frecuencia respiratoria > , hipoxemia (pao /fio < o sao /fio < ), fracaso ventilatorio (ph< . con paco > mmhg), hacor> . existe suficiente evidencia que demuestra que la vmni es una estrategia que reduce la mortalidad en pacientes críticos ( , , ) . además, reduce la necesidad de intubación. los números de casos necesarios a tratar (nnt) son: ocho para salvar una vida y para evitar una intubación ( ) . estos desenlaces son fundamentalmente en pacientes con epoc y edema pulmonar agudo ( ) ( ) ( ) ; también hay evidencia a favor, aunque menos fuerte, en pacientes inmunosuprimidos ( , ) . se ha planteado mayores tasas de éxito con interfaces faciales totales o con helmet ( , ( ) ( ) ( ) ( ) ( ) . por el contrario, en falla respiratoria hipoxémica hay evidencia en contra del uso de vmni ( ) . la experiencia previa con h n , sars y mers no apoya el uso de la vmni en falla respiratoria hipoxémica de origen viral ( ) ( ) ( ) ( ) ( ) ( ) . además, se ha cuestionado el uso de vmni en covid- por el riesgo de contagio al generar aerosoles ( ) . recientemente se demostró que la distancia de dispersión de aerosoles era menor de un metro ( ) . por otro lado, el fracaso de la vmni se ha asociado con alta morbimortalidad ( ) ( ) ( ) . ello obliga a evaluar estrictamente la posibilidad de éxito o fracaso. así, en falla respiratoria amci ® hipoxémica la escala hacor ha sido validada para este fin y un puntaje> contraindicaría la vmni ( ) . adicionalmente si se emplea la vmni el prolongar la decisión de intubación puede aumentar la mortalidad y es por ello necesario monitorizar estrictamente al paciente y evaluarlo para establecer, ojalá antes de dos horas, si el paciente responde a la vmni ( , , ) . las indicaciones para intubación en este caso son respiración toracoabdominal, uso de músculos accesorios, frecuencia respiratoria mayor de , hipoxemia (pao /fio < o sao /fio < ), fracaso ventilatorio (ph< . con paco > mmhg), hacor> o índice de rox (spo /fio )/frecuencia respiratoria) < ( , , , , , ) . recomendaciÓn se sugiere el uso de posición prono en pacientes no ventilados críticamente enfermos por covid- que no responden a la oxigenoterapia convencional de acuerdo con los protocolos institucionales, las condiciones de cada servicio y la tolerancia individual de cada paciente. débil a favor fundamento los pacientes con enfermedad por coronavirus (covid- ) están en riesgo de desarrollar un síndrome de dificultad respiratoria aguda (sdra) ( ) . en pacientes intubados con síndrome de dificultad respiratoria aguda grave, la posición prona (pp) temprana y prolongada (al menos horas diarias) mejora la oxigenación y disminuye la mortalidad ( , ) .debido a que las unidades de cuidados intensivos (uci) están sobrecargadas con pacientes con covid- , la pp en paciente despierto con respiración espontánea puede ser útil para mejorar la oxigenación y prevenir las transferencias hacia uci. un estudio describió la viabilidad del uso de la ventilación no invasiva y la cánula de alto flujo asociado a la pp estableciendo su tolerancia y su seguridad en pacientes con sdra moderado y severo( ); la pronación puede reclutar todas las regiones pulmonares y favorecer el drenaje de secreciones de la vía respiratoria, mejorando el intercambio gaseoso y la supervivencia en el síndrome de dificultad respiratoria (sdra) ( ) . en una comunicación corta proveniente de italia en el cual se incluyeron pacientes que son sometidos al pp asociada con el uso de ventilación no invasiva, se concluye que proporcionar niv en la posición prona a los pacientes con covid- y sdra en salas generales en un hospital en italia era factible. la frecuencia respiratoria disminuyó durante su implementación y la oxigenación mejoró durante una pronación posterior a su línea de base. si la intubación se evitó o se retrasó, queda por determinar ( ) . en otro reporte de caso, publicado recientemente por un grupo francés( ) de pacientes con covid- e insuficiencia respiratoria hipoxémica manejados fuera de la uci, el % amci ® fue capaz de tolerar pp durante más de horas. sin embargo, la oxigenación aumentó durante el pp solo un % y no se mantuvo en la mitad de los pacientes después del regreso a la posición supina. estos resultados son consistentes con los hallazgos de pequeños estudios previos de pp en pacientes no intubados ( ) . un ensayo clínico controlado que evalúe el uso del pp en pacientes no intubados puede ser un mecanismo para seleccionar pacientes que bien puedan beneficiarse de esta estrategia terapéutica. dada la evidencia débil que soporta el uso del pp en pacientes no intubados en términos de la disminución de la necesidad de entubación o ingreso a cuidados intensivos y la duda razonable de aumentar desenlaces deletéreos en aquellos pacientes en los cuales se retarde el tiempo de intubación, no se emite recomendación, a favor o en contra, del empleo de esta estrategia de manera rutinaria. en situaciones en las cuales hay limitación de recursos y de disponibilidad de camas en cuidados intensivos el uso de la pp asociada a vni o cánula de alto flujo podría ser una estrategia útil para mejorar la oxigenación en pacientes infectados con covid- e hipoxemia. se recomienda considerar la elevación de biomarcadores como la troponina i o t y el nt-pro-bnp en el paciente con covid- como indicadores de injuria miocárdica aguda, sin embargo, no reemplazan la ecocardiografía en el enfoque del paciente con sospecha de disfunción miocárdica. fuerte a favor fundamento la injuria miocárdica aguda asociada a covid- se reporta con frecuencia teniendo en cuenta los cambios en biomarcadores como la troponina y cambios electrocardiográficos, pero su impacto en la función cardíaca se desconoce y mucho menos su correlación con los cambios ecocardiográficos. los pacientes con covid- pueden desarrollar una serie de complicaciones cardiacas desde injuria miocárdica, arritmias, infarto, hasta miocarditis fulminante con falla cardiaca aguda y shock cardiogénico ( ) . la troponina i, se ha encontrado más elevada en pacientes con curso fatal por covid- ( ) . los niveles de nt-pro-bnp han sido reportados con elevación severa en pacientes con miocarditis y disfunción sistólica, con una disminución progresiva en relación a la mejoría de los pacientes, pero no parece tener un correlación significativa con el cambio de la fracción de eyección (fevi) ( ) . la evidencia clínica sugiere que la elevación de los biomarcadores es más relacionada al compromiso sistémico que el daño miocárdico directo, q. deng y colaboradores en un análisis retrospectivo de pacientes, reportaron niveles iniciales de troponinas normales casi en la mayoría, en el , % de los casos los niveles incrementaron significativamente, principalmente en los que fallecieron y solo pacientes tenían fevi menor al % y ninguno inferior al %, lo cual no sugiere una asociación entre las dos amci ® pruebas ( ) . en una publicación donde se compara el fenotipo de pacientes con covid- con un histórico de pacientes con sdra por influenza ( ) , se encontró que los primeros tenían mayor elevación de troponinas % vs %, pero en los parámetros ecocardiográficos contrario a lo que se esperaría los índices de rendimiento ventricular fueron mayores para el grupo de covid- : Índice cardiaco . vs . l/m/m ; fevi vs %; tapse vs mm, nuevamente aunque no fue uno de los objetivos del estudio, parece no encontrarse correlación entre los biomarcadores que sugieren injuria miocárdica y los parámetros ecocardiográficos, el cual constituye uno de los pilares de la exploración cardiaca. se recomienda considerar como marcadores iniciales de mal pronóstico en el paciente crítico con covid- con sospecha de disfunción miocárdica aguda la elevación persistente de troponina i, mioglobina o creatin kinasa; independiente de la fracción de eyección del ventrículo izquierdo evaluada mediante ecocardiografía. fundamento los pacientes con covid- admitidos a la unidad de cuidados intensivos presentan con frecuencia disfunción cardiaca primaria, que puede corresponder a cardiomiopatía por estrés o miocarditis viral, pero también pueden ser consecuencia del compromiso sistémico ( , ) . aunque parece que en los fenotipos cardiovasculares estudiados, el compromiso hemodinámico severo de la función sistólica izquierda y derecha es menor ( ) . en el estudio de deng y colaboradores con pacientes con covid- , la fiebre, la disnea, hipoxemia, la obesidad y niveles elevados de cpk, troponina y nt-pro-bnp se relacionaron significativamente con mayor severidad ( ) . en el subgrupo de pacientes con miocarditis frente a controles, el perfil clínico se describe con mayor edad, niveles de temperatura más elevados ( . ± . vs . ± . ; p: . ), mayor proporción de disnea ( , vs %), y de dolor torácico ( , vs , %). en los pacientes fallecidos el % tuvieron picos de elevación de troponina i y de nt-pro-bnp dentro la semana que precedió la muerte, el % presentaron alteraciones electrocardiográficas y solo el % presentaron fracción de eyección menor o igual al % ( ) . shi y colaboradores, enrolaron pacientes para describir el significado clínico del compromiso miocardio de pacientes con covid- en wuhan, pacientes fallecieron, de los cuales el % presentaron injuria miocárdica aguda ( ) . el área bajo la curva (auc) de la troponina i inicial para predecir muerte intrahospitalaria fue de , (ic %, de , - , ) con una sensibilidad y especificidad del %, el auc para mioglobina fue de . y para cpk-mb fue de , ( ). un punto de corte para el pico más alto de troponina i de . , tuvo un hazard ratio para mortalidad de . (ic %, . - . ; p= . ). en un análisis multivariado la edad avanzada, la respuesta inflamatoria y las enfermedades cardiovasculares subyacentes se asociaron con mayor riesgo de lesión miocárdica en pacientes con covid- . con la información disponible parece que los biomarcadores de lesión miocárdica aguda elevados amci ® al ingreso y de forma persistente pueden predecir el riesgo de mortalidad intrahospitalaria en los pacientes con sospecha o diagnóstico de covid- con afectación cardiovascular. se recomienda no realizar de forma rutinaria ecocardiografía en pacientes críticos con covid- . se debe practicar ecocardiografía en pacientes con sospecha o diagnóstico de covid- si presenta alguna de las siguientes condiciones: . síntomas y signos de insuficiencia cardíaca aguda de novo. . shock o deterioro súbito hemodinámico refractario a líquidos y/o vasoactivos con sospecha de origen cardiogénico. . sospecha de infarto agudo de miocardio o embolismo pulmonar para determinar intervenciones terapéuticas con un beneficio clínico. . cambios en el electrocardiograma, arritmias ventriculares o paro cardiorrespiratorio no explicados por otra causa. para nuestro conocimiento, en el momento no existe estudios clínicos que evalúen los criterios para realización de ecocardiograma en el paciente con covid- . las sociedades de ecocardiografía han recomendado realizar el ecocardiograma en el contexto clínico en el cual, la información obtenida proporcione un cambio en la conducta o se espere un beneficio clínico al realizar este procedimiento ( ) ( ) ( ) ( ) . igualmente, se recomienda realizar el examen a la cabecera del paciente y el escaneo debe ser dirigido a contestar preguntas específicas según el contexto clínico del paciente ( ) ( ) ( ) ( ) ( ) . ward et al, en su publicación describe cómo el uso del ecocardiograma limitado (dirigido) en la university of chicago medicine (ucm), aumentó significativamente durante la pandemia ( % frente a %, p < . ), posterior a la implementación de recomendaciones sobre el uso apropiado de la ecocardiografía en tiempos de pandemia ( ) . los pacientes con infección por sars -cov- pueden presentarse con comorbilidades cardiovasculares que potencialmente estén descompensadas y/o compromiso cardiovascular por covid- . en este último, podemos encontrar alguno de los siguientes fenotipos: falla cardiaca aguda en el marco de compromiso directo viral o secundario al estrés metabólico y liberación de citoquinas, síndrome coronario agudo, cor-pulmonar secundario a tep o por compromiso secundario al sdra ( , , , ) . las manifestaciones cardiovascular puede sospecharse en el marco de choque que no esté explicado por causas extracardiacas evidentes que no responde a líquidos, dolor torácico con clínica de síndrome coronario agudo, cambios electrocardiográficos y elevación de biomarcadores de lesión miocárdica, signos de falla cardiaca descompensada, deterioro súbito de la oxigenación, arritmias o paro cardiorrespiratorio ( , , ) . ante estas manifestaciones, el ecocardiograma podría ser útil para entender el origen de la descompensación aguda, al estar enfocado a amci ® responder preguntas acerca de la función ventricular global y segmentaria (en el abordaje de síndrome coronario agudo), compromiso del ventrículo derecho, alteraciones valvulares, derrame pericárdico, si existe una contribución cardiovascular al compromiso pulmonar, si en el marco del choque existe evidencia de componente cardiogénico y cómo podría guiarse/optimizarse el soporte hemodinámico de estos pacientes( - ). se sugiere en pacientes críticamente enfermos con covid- que cursan con shock y sdom, ajustar la monitoria a las condiciones clínicas del paciente y recursos disponibles. se puede considerar el cap para el monitoreo del gasto cardiaco, la valoración de la perfusión y orientar los elementos hemodinámicos del tipo de shock, el cap de gasto cardiaco continuo puede disminuir la exposición del personal de salud frente al catéter de medición convencional. se sugiere la utilización de la tdtp dependiendo de la disponibilidad del recurso para orientar el diagnóstico diferencial del sdra versus edema pulmonar cardiogénico en los pacientes con covid- . fundamento los pacientes con infección severa por sars-cov- , cursan con alto riesgo de falla renal y cardiovascular, con necesidad de un manejo restrictivo de líquidos, lo que justifica la monitoria estricta en uci ( , ) . el catéter venoso central es útil para la monitoria inicial de estos pacientes, sin embargo, su predicción a respuesta a volumen está limitada ( ) ( ) ( ) . la monitoría no invasiva tiene limitaciones en casos severos de inestabilidad hemodinámica, ventilación espontánea y en presencia de peep alto, lo que limita su uso para el cálculo de gasto cardiaco y la predicción de respuesta a líquidos ( , ) . la monitoria con cap puede ser considerada en pacientes con covid- que cursan con choque y doms, con el objetivo de realizar un diagnóstico definitivo de los componentes del choque, valorar la hipoperfusión, la función cardiaca y el estado de volemia ( , ) . igualmente, los pacientes con sospecha tep o compromiso del ventrículo derecho pueden beneficiarse de esta monitoria( ). richard et al, en su estudio determinaron los desenlaces asociados al uso de cap vs cvc en pacientes con shock, sdra, o ambos, sin evidenciar diferencias en mortalidad ( . % vs . % p =. ) o estancia hospitalaria. el uso de cap no garantiza la mejoría de desenlaces en pacientes con covid- , sin embargo, la presencia de una monitoria continua ayudaría a optimizar los recursos y disminuiría la interacción con el paciente, con menor exposición del equipo médico ( ) . la monitoria por tdtp puede utilizarse en pacientes con covid- que cursan con choque, buscando optimizar el manejo hídrico, valorar el agua extravascular pulmonar (evlw) y el índice de permeabilidad vascular pulmonar (pvpi) con el fin de establecer el diagnóstico amci ® definitivo del edema pulmonar: sdra vs cardiogénico ( ) ( ) ( ) . hu et al, en su estudio evaluaron los desenlaces del uso de evlw y la presión de cuña de la arteria pulmonar (pawp) como estrategias para el manejo de líquidos en pacientes sdra, no encontraron diferencias significativas en las tasas de supervivencia (p = , ). no obstante, en el grupo de evlw la duración de la ventilación mecánica y la estancia en la uci fueron significativamente menor (p < , ), al igual que el balance hídrico (p < . ), con mejoría significativa en los índices de oxigenación (p = . )( ). no se puede emitir una recomendación a favor o en contra para la utilización de un protocolo de ultrasonido rutinario a la cabecera del paciente (pocus). sin embargo, se podría considerar el uso en pacientes seleccionados, con los adecuados epp y desinfección de los equipos; donde el pocus pueda tener ventajas sobre otras modalidades de monitoria o en pacientes con limitaciones para monitoria invasiva que requieren evaluación del estado hemodinámico o determinación de severidad del compromiso pulmonar. las recomendaciones sobre la utilidad de pocus en pacientes con covid- están enfocadas principalmente en la evaluación de la severidad/progresión de la lesión pulmonar, diagnóstico de manifestaciones cardiovasculares, monitoria hemodinámica y en la guía de fluidoterapia ( , ( ) ( ) ( ) . en la valoración del compromiso pulmonar por covid- , el pocus ofrece una ventaja sobre otras modalidades de monitoreo, debido a la capacidad de enmarcar el compromiso pulmonar en una línea de tiempo según sus hallazgos: desde la aparición de un patrón de "líneas b", consolidaciones subpleurales con evolución a consolidaciones multilobares, irregularidades en el artefacto de la línea pleural y finalmente aparición de patrón de "líneas a" una vez inicie la recuperación, con adecuada correlación tomográfica ( ) ( ) ( ) ( ) . en la diferenciación del origen del choque, el pocus ha demostrado superioridad versus el concepto clínico al evaluar: función ventricular (incluyendo ventrículo derecho), vena cava inferior, líquido libre abdominal, lesiones aórticas, compromiso pulmonar y búsqueda de trombosis venosa profunda identificando tep ( , ) . en cuanto a la monitoria hemodinámica de pacientes con covid- , adicional a la función y gasto cardíacos, se recomienda variables dinámicas de respuesta a líquidos y ultrasonido pulmonar en el diagnóstico de sobrecarga hídrica ( ) . la variabilidad de gasto cardiaco calculado por pocus durante la elevación pasiva de miembros inferiores, identifica los respondedores a líquidos con sensibilidad del % y un lr (-): . [ %ci, . - . ]) ( ) . la variabilidad de la vena cava inferior muestra limitaciones en pacientes con aumento de presiones de cavidades derechas y respiración espontánea ( ) . en cuanto a otras modalidades de monitoría no invasiva, es importante conocer las limitaciones en el marco de compromiso hemodinámico severo, ventilación espontánea, alteraciones valvulares aórticas, entre otras ( ) . marik ( ) . el ultrasonido tiene limitaciones específicas como la necesidad de un operador experimentado y la adecuada calidad de las imágenes. adicionalmente, en los pacientes con covid- , esta modalidad de monitoreo requiere una mayor interacción con el paciente, mayor uso de epp en comparación con otras modalidades el pac( ). se recomienda perseguir al inicio de la reanimación del paciente críticamente enfermo con covid- , metas clínicas de fácil medición, como la presión arterial media (entre y mmhg) o el gasto urinario (mayor a , cc/k/h) y metas de perfusión como el lactato en sangre arterial (menor a mmol), la saturación venosa central de oxígeno (entre y %) y la diferencia veno arterial de co (menor a mmhg). se han reportado casos de disfunción ventricular como causa de choque asociado a covid- , sin embargo, no se ha descrito un manejo específico o cambios en las metas de reanimación para estos pacientes, las manifestaciones de hipoperfusión tisular son: alteración de la conciencia, oliguria, piel fría y moteada y pulso débil. a nivel de gases sanguíneos las metas de reanimación pueden ser globales como el lactato (en sangre arterial vn< mmol) y la diferencia veno arterial de co (pv-aco vn < mmhg) o regionales como la saturación venosa central de oxígeno medida en la sangre venosa tomada de un catéter central (vn: - %). se puede optimizar la perfusión, interviniendo los principales determinantes: fluidos para aumentar el volumen intravascular, inotrópicos para aumentar la fuerza de contractilidad, vasopresores para recuperar la presión de perfusión y transfusión de glóbulos rojos para aumentar la hemoglobina como transportador de oxígeno ( ) , las recomendaciones dadas en el documento anterior siguen siendo válidas e incluyen entre otras que todo paciente con covid- en estado de shock debe ser ingresado de forma inmediata a la unidad de cuidados intensivos, garantizando el aislamiento indicado, procurando recuperar la presión arterial media a valores > mmhg, para ello la utilización de un catéter venoso central en los pacientes que no responden al manejo inicial y el procedimiento debe ser realizado por el médico con mayor entrenamiento, idealmente guiado por ecografía si hay disponibilidad y las competencias, así mismo las estrategia de control estricto de fluidos para no generar efectos deletéreos relacionados a la sobrecarga de volumen, es lo más indicado. se recomienda en la reanimación inicial de pacientes en estado de shock con sospecha o amci ® diagnóstico de covid- , guiar la fluidoterapia con el uso de índices clínicos como el tiempo de llenado capilar, temperatura de la piel y depuración de lactato; en fases avanzadas donde el monitoreo clínico es insuficiente utilizar medidas dinámicas como la variabilidad de presión de pulso (vpp), la variabilidad de volumen sistólico (vvs), la respuesta a la maniobra de elevación pasiva de piernas o la prueba de oclusión teleespiratoria de acuerdo a los recursos disponibles y la experiencia. fuerte a favor fundamento sobre los objetivos de intervención y el tipo de agente vasoactivo a utilizar en pacientes con covid- y shock no existe una evidencia directa y las recomendaciones se basarán en evidencia indirecta de pacientes críticos con diversos tipos de shock en especial el séptico y vasopléjico. la falla circulatoria aguda asociado a sdra en covid- se presenta con una frecuencia del - % y en la admisión a urgencias la hipotensión y un lactato ≥ es infrecuente( , ). la baja sensibilidad del qsofa y crb- para predecir la severidad del covid- y la necesidad de intervenciones de terapia intensiva refleja lo infrecuente del shock en esta condición. factores como la vasoplejia, fuga capilar asociada al estado hiperinflamatorio, altos requerimientos de peep y disfunción cardiaca pueden ser generadores o contribuyentes del shock y deben ser considerados en el abordaje diagnóstico, en su interpretación para lograr tomas de decisiones adecuadas. en pacientes con sdra, una reanimación óptima de líquidos debe tomar en cuenta aspectos como tiempo (oportunidad), tipo (cristaloides balanceados y/o no balanceados o coloides) y volumen (ni mucho, ni poco) con el objetivo de disminuir la mortalidad, el tiempo de vm y de cuidados intensivos, sin que ello afecte los índices de oxigenación, de perfusión tisular y la morbilidad asociada con su uso inadecuado. la administración agresiva de líquidos puede empeorar la oxigenación y la disfunción ventricular, lo que potencializa un mayor tiempo de ventilación mecánica e incluso la mortalidad. la evidencia ha demostrado que una estrategia conservadora de fluidos (balance - +/- amci ® en una revisión sistemática y un metaanálisis de rct (n = . ) una terapia dirigida al aclaramiento temprano de lactato frente a una terapia guiada por la saturación venosa central de oxígeno (svo ), se asoció con una reducción significativa de la mortalidad (rr , ), menor estadía en la uci (dm , días), y menor duración de la ventilación mecánica (dm - , horas). pero se debe resaltar que un nivel alto de lactato no siempre indica hipovolemia; también puede ser causada por uso de adrenalina, agonistas beta o por disfunción mitocondrial, insuficiencia hepática e isquemia mesentérica ( ) . por otra parte, el llenado capilar (crt), una prueba técnicamente fácil y accesible, realizada cada minutos se asoció con una reducción no significativa de la mortalidad (hr , ) en comparación con la medición de lactato sérico cada horas. dado el potencial beneficio sobre mortalidad, duración de estancia en uci y la duración de la ventilación mecánica, así como su accesibilidad, sugerimos utilizar parámetros dinámicos de temperatura de la piel, tiempo de llenado capilar y / o medición de lactato sobre parámetros estáticos para evaluar la capacidad de respuesta a la fluidoterapia en pacientes con covid- y shock( ). se recomienda en pacientes adultos con covid- y estado de shock, escoger la norepinefrina como el vasopresor de primera línea y a la vasopresina el de segunda. si no se cuenta con norepinefrina el uso de vasopresina o epinefrina serían la primera elección; la dopamina no se recomienda por el mayor riesgo de arritmias. se recomienda iniciar dobutamina frente al aumento de la dosis de norepinefrina en pacientes en estado de shock con evidencia de disfunción cardíaca e hipoperfusión persistente a pesar de la reanimación inicial. fuerte a favor fundamento sobre los objetivos de intervención y el tipo de agente vasoactivo a utilizar en pacientes con covid- y shock no existe una evidencia directa y las recomendaciones solo pueden basarse en evidencia indirecta de pacientes críticos con sepsis y sdra. en pacientes en shock séptico los agentes vasoactivos para alcanzar una pam de - es un objetivo razonable. una presión media más alta puede incrementar . veces el riesgo de arritmias cardiacas y no está exento de riesgo de isquemia en las extremidades ( ) . para aproximarnos a la escogencia de los vasoactivos en shock séptico, basados en su perfil de riesgo/beneficio, la guía scandinavian society of anaesthesiology and intensive care medicine (ssai ) task force for acute circulatory failure( ), la revisión sistemática de cochrane database con rct con un n: ( ) y el ensayo clínico controlado de honarmand k et al con un n: , ( ) amci ®  la noradrenalina es el agente vasoactivo más ampliamente estudiado con el menor riesgo a priori de efectos no deseados, razón por la cual se sugiere usar como el agente vasoactivo de primera línea en pacientes con covid- y shock.  si la noradrenalina no está disponible la vasopresina o epinefrina se muestran como la mejor alternativa. los factores que determinan la elección entre vasopresina y epinefrina pueden incluir disponibilidad y el perfil de seguridad de estos agentes. con la vasopresina, la isquemia digital puede ser una preocupación y con epinefrina, la taquicardia, la isquemia miocárdica y el exceso de producción de lactato.  el uso de dopamina se ha asociado un . veces mayor de riesgo de aparición de arritmias frente a la norepinefrina y un posible aumento del riesgo de mortalidad. por ello la dopamina no debe utilizarse en pacientes con covid- y shock donde haya disponible de norepinefrina o las alternativas señaladas  en shock distributivo la adición de vasopresina a las catecolaminas evidenció baja certeza de reducción de la mortalidad (rr , ; ic del %: , a , ), alta certeza de una reducción de la fibrilación auricular (rr , ; ic del %: , a , ) y certeza moderada de un mayor riesgo de isquemia digital (rr , ; ic del %: , a , ). en vista de estos hallazgos se plantea la vasopresina como un agente vasoactivo de segunda línea a ser utilizado si la pam objetivo no se ha alcanzado con norepinefrina en pacientes con covid- y shock. no existe evidencia directa en pacientes con covid- y shock, para establecer una recomendación sobre cuál es el agente inotrópico óptimo. en una guía de práctica clínica de que evalúa el agente inotrópico óptimo en pacientes con insuficiencia circulatoria aguda (shock), no se identificaron rct que comparen dobutamina versus placebo o ningún tratamiento. con base en una justificación fisiopatológica, sugerimos agregar dobutamina, más que no suministrar ningún tratamiento, en pacientes con covid- y shock con evidencia de disfunción cardíaca e hipoperfusión persistente a pesar de la reanimación con líquidos y altas dosis de norepinefrina. el uso de dobutamina en estado de shock, incluso en pacientes con covid- con shock, debe ser investigado. recomendaciÓn se recomienda no suspender la medicación estándar para falla cardiaca en pacientes con sospecha o diagnóstico de covid- , especialmente los iecas, ara-ii, y b-bloqueadores, si la condición clínica permite continuar el uso de esta medicación, ya que no se ha podido confirmar una asociación nociva. amci ® previos alrededor de la relación independiente de la edad avanzada, enfermedad cardiovascular subyacente (enfermedad coronaria, insuficiencia cardíaca y arritmias), tabaquismo activo y epoc con muerte por covid- ( ) ( ) ( ) ; esos mismos reportes sugieren que las mujeres son proporcionalmente más propensas a sobrevivir a la infección por covid- que los hombre; existen además consideraciones especiales desde el punto de vista cardiovascular, que se deben tener en cuenta al decidir cualquier terapia en paciente afectados por covid- y existe la hipótesis de un efecto nocivo de la terapia estándar para falla cardiaca en estos pacientes ( ) . en un estudio observacional que incluye paciente con infección por covid- , se evaluó la relación entre la enfermedad cardiovascular subyacente, y la asociación entre la terapia farmacológica cardiovascular y la mortalidad ( ); respecto a los factores de riesgo cardiovascular, el . % de los pacientes tenían hiperlipidemia, el . % tenía hipertensión, el . % tenía diabetes mellitus, y en relación a los medicamentos, los sobrevivientes usaron más comúnmente ieca y las estatinas que los no sobrevivientes, mientras que no se encontró asociación entre la supervivencia y el uso de ara ii; respecto a los otros medicamentos incluidos b-bloqueadores, antiplaquetarios e insulina no se encontraron diferencias significativas; sin embargo, y teniendo en cuenta el impacto sobre mortalidad del uso de betabloqueadores en la falla cardiaca, consideremos que la decisión de continuar su uso debe basarse en el análisis clínico de cada paciente y su estabilidad clínica. se recomienda establecer un protocolo de reanimación ajustado al contexto del paciente con covid- con una organización administrativa ajustada a la pandemia que incluya las siguientes estrategias:  desarrollar una estrategia de prevención del paro cardiorrespiratorio en el paciente con sospecha o diagnóstico de covid- basada en la detección oportuna.  formar un equipo multidisciplinar formado en rcp con líderes médicos, de en enfermería y en terapia respiratoria, los cuales deben educar a todo el equipo de trabajo en la identificación de signos de alerta temprana, cambios abruptos de variables clínicas, técnicas de monitoreo, interpretación de paraclínicos y de alarmas de monitoreo.  entrenamiento del personal sanitario a través del uso de la simulación clínica en manejo de crisis, epp, y procesos de atención fundamentales en la atención del paro cardiaco en el paciente con sospecha o diagnóstico de covid-  promover la comunicación asertiva, planeación y retroalimentación de las intervenciones realizadas antes y después de un evento de paro cardiaco (briefing y debriefing), con el fin de establecer modificaciones que conllevarán a mejoras en la atención de futuros eventos. amci ® el pronóstico y sobrevida de un paciente con sospecha o diagnóstico de covid- que presenta paro cardiaco depende de la prevención a través del reconocimiento oportuno de las causas reversibles de éste, la no presencialidad y un ritmo de paro no desfibrilable lo hacen de mal pronóstico. la prevención va a depender del nivel de entrenamiento del equipo previamente, y en época de pico de pandemia cuando el talento humano especializado disminuya, se hace necesario que en los equipos de trabajo estén liderados por especialistas en la disciplina para que puedan guiar al equipo. los nuevos procesos de atención del paciente, la alta contagiosidad del virus, y el uso de nuevos medicamentos hacen que se requiera un entrenamiento del personal para estandarizar los procesos y disminuir el error médico. la crisis de covid- está ejerciendo una presión sin precedentes sobre las personas, los equipos y los sistemas organizacionales, conllevando a errores médicos que van desde la infección cruzada por el personal sanitario con la posibilidad de cometer errores en la atención. cada día trae nuevos desafíos: picos en volumen y gravedad, escasez de equipos y estrés en los médicos sobrecargados, que se manifiesta según la experiencia de wuhan en insomnio y depresión. se propone implementar una estrategia antes, durante y después del trabajo clínico, denominada circle up covid- desarrollada por center of medical simulation dirigida a convertir equipos de trabajo muchas veces insustituibles , en eficientes , seguros, fuertes y que se apoyan mutuamente incluyendo en mejora de la salud psicológica . impactando en el rendimiento del equipo , y promoviendo el bienestar y la resiliencia( - ) se recomienda establecer un protocolo de reanimación ajustado al contexto clínico del paciente con covid- que incluya las siguientes modificaciones:  implementar criterios de selección e inicio de maniobras de rcp en la atención del paro cardíaco basados en la bioética y en el pronóstico de supervivencia a corto y largo plazo de los pacientes.  promover la prevención del paro cardiaco mediante la detección oportuna del riesgo y definir intubaciones programadas.  asegurar la correcta protección con los epp necesarios al abordar el paro cardiaco y la intubación que son procedimientos generadores de aerosoles.  priorizar el manejo de la vía aérea antes del inicio de las compresiones torácicas, haciendo énfasis en la reducción de la exposición de aerosoles (código azul protegido).  utilizar filtro de alta eficiencia contra virus para todas las estrategias de ventilación (bolsa mascarilla con cierre hermético y en el circuito del ventilador).  promover la realización de la intubación por el operador de mayor experticia con uso de videolaringoscopio si está disponible y considerar el acceso supraglótico solo si el intento de intubación es fallido. amci ®  en caso de parada cardiaca en ventilación mecánica iniciar el masaje cardiaco evitando las desconexiones del circuito del respirador.  en caso de paro en posición prono si el paciente se encuentra vigil retornar rápidamente a la posición supino y si está en ventilación mecánica es razonable realizar compresiones en la espalda. fuerte a favor fundamento se hace necesario el entrenamiento en el manejo de los procedimientos generadores de aerosoles y se sugiere que el que realiza la intubación orotraqueal debe ser el más experto. el riesgo de aerosolización es de . en el proceso de intubación orotraqueal, el de compresiones torácicas es de , , ventilación mecánica no invasiva de , , ventilación manual pre-intubación de , , succión después de intubación , . se ha descrito que si no se ha capacitado previamente en el retiro de los epp existe más riesgo de auto contaminación y aumenta ésta sin un líder supervisor al retirarlo. según revisión de cochrane sobre ropa y equipo de protección para los trabajadores sanitarios para evitar que se contagien con el coronavirus y otras enfermedades altamente infecciosas da a conocer que la capacitación presencial, la simulación por ordenador y la capacitación por vídeo dieron lugar a menos errores a la hora de quitarse el epp que la capacitación impartida solo como material escrito o una conferencia tradicional ( ) ( ) ( ) ( ) ( ) ( ) . se recomienda no considerar la existencia de manifestaciones neurológicas específicas o típicas atribuidas a la infección por sars-cov- . se recomienda realizar la valoración neurológica integral del paciente con diagnóstico o sospecha de sars-cov- teniendo en cuenta manifestaciones frecuentes relacionadas a covid- : disgeusia, anosmia, cefalea, vértigo, confusión, delirium, alteración de estado de consciencia, eventos cerebrovasculares, ataxia, polineuropatías inflamatorias y convulsiones. una revisión sistemática realizada por asadi-pooya et al. entre diciembre y marzo de mostró que el % de los pacientes con covid- presentaron sintomatología neurológica. analizaron cinco artículos (n= ) donde eran retrospectivos, y era prospectivo, encontrando cefalea entre el y el %, vértigo entre el y el %, confusión en el %, alteración del estado de consciencia en el %, eventos cerebrovasculares en un %, ataxia en un , % y convulsiones en un , % ( ) . amci ® menor a participantes donde recolectarán información sobre el compromiso neurológico en pacientes con covid- con un seguimiento hasta febrero de ( ) . la hiposmia y la disgeusia de aparición súbita son manifestaciones clínicas muy prevalentes en pacientes con covid- evidentes aun en ausencia de sintomatología respiratoria alta. lechien et al publicaron un estudio multicéntrico que incluyeron hospitales europeos reclutando pacientes infectados con covid- levemoderado donde , % presentaron alteraciones relacionadas con el olfato y , % presentaron alteraciones relacionadas con el gusto, donde la anosmia se presentaba antes que cualquier otro síntoma en el , % de los casos y el , % de los casos no presentaba rinorrea u obstrucción nasal, la recuperación del olfato fue presente en el % de los pacientes y las mujeres fue el grupo poblacional más afectado (p= , ) ( ) . otras manifestaciones clínicas son las alteraciones de la agudeza visual, y dolor tipo neuralgia ( ) . respecto a las patologías psiquiátricas; la serie de mao comenta que el , % de los pacientes tiene clínica de alteración del estado de consciencia, concepto que se aproxima a la defunción de delirium. severance et al. encontraron que pacientes con sintomatología psicótica aguda presentaron niveles elevados de inmunoglobulina g para coronavirus del tipo hku , nl y oc con diferencias estadísticamente significativas respecto a los individuos controles (n= ) (p< , ). donde la respuesta inmune para nl fue asociado con el espectro-esquizofrenia (or: . , ci . - . , p= . ) pero no se correlaciona con desórdenes afectivos ( ) . aún no se ha descrito una correlación directa de este trastorno psicótico con covid- . los síntomas musculares se han observado en pacientes infectados por covid- incluyendo la miopatía del paciente en estado crítico (miopatía difusa no necrotizante con degeneración grasa de fibras musculares), la miopatía necrotizante (ligada a falla orgánica múltiple) y la miopatía de filamentos gruesos( ). se recomienda considerar como predictores clínicos neurológicos de alerta para sospechar covid- : anosmia, disgeusia, delirium y alteraciones neuromusculares inespecíficas sin otra causa aparente de explicación. se recomienda no establecer de rutina predictores neurológicos específicos de mal pronóstico en el paciente críticamente enfermo con covid- . se deben tener en cuenta los factores de riesgos generales de mal pronóstico para la población general como la edad avanzada, las comorbilidades cardiovasculares y el tabaquismo. page la proteína spike (s) del covid- es reconocida por la enzima convertidora de antígenos (eca ) de la célula huésped cuyo papel es el punto de entrada molecular a tejidos pulmonares, gastrointestinales y neuronales ( ) . la forma como el covid- ingresa al sistema nervioso central es desconocido, pero se especula que inicialmente invade terminales nerviosas periféricas y después llega al sistema nervioso central a través de una ruta guiada por sinapsis nerviosas con un patrón ascendente (ruta dada por el coronavirus hev y el oc- ) ( , ) . en modelos de roedores el covid- ingresaría al cerebro a través del nervio olfatorio, atravesando la lámina cribiforme propagándose por el tálamo y el tallo cerebral; explicándose por la expresión de los receptores de la enzima convertidora de antígenos (eca ) en la superficie de las mucosas nasales, las neuronas y la glía ( , , ) . una segunda forma de ingreso es a través de la vía hematológica mediante arterias cerebrales atravesando la barrera hemato-encefálica utilizando las células inflamatorias como un modelo similar al del caballo de troya ( , , ) logrando una ubicación definitiva en células neuronales y endoteliales del lóbulo frontal como lo demostraron en estudios post-mortem descritos por paniz -mondolfi et al, lo que explicaría los cambios comportamentales de paciente ( ) . la tercera forma de acceso al sistema nervioso central es mediante el drenaje del sistema linfático cerebral invadiendo ganglios linfáticos hiliares y mesentéricos con sintomatología gastrointestinal asociada ( ) . una vez ha logrado ingresar tiene la capacidad de infectar macrófagos, microglía, y astroglía los cuales secretan factores proinflamatorios como interleuquina , interleuquina , y factor de necrosis tumoral alfa ( ) . esta condición se exacerba con el desencadenamiento de la tormenta de citoquinas liderada por la interleuquina , interleuquina , interleuquina e interferón gamma ( ) . de esta forma los coronavirus siendo neurotrópicos ocasionan múltiples manifestaciones clínicas ya mencionadas, así como encefalitis, parálisis flácida, incluyendo la asociación con guillain-barré ( ) . los síntomas que harían sospechar la presencia de neurocovid- son la náusea, el vómito y la anorexia, estos síntomas pueden ser el reflejo del compromiso del virus en el área postrema del piso del cuarto ventrículo que hace parte del complejo vagal dorsal de la médula oblonga. sin embargo, estos síntomas pueden enmascararse como una respuesta inespecífica relacionada con un compromiso gastrointestinal ( ) . como se mencionó previamente la anosmia y la disgeusia son síntomas significativos para sospechar en covid- ( ) ; esto es debido a una lesión directa sobre el nervio olfatorio (i par craneal), y la lesión de alguno de los tres nervios encargados de registrar el sentido del gusto como lo son el vii, ix y x pares craneales, así como el compromiso del núcleo solitario y del tálamo como zona de relevo; de hecho el núcleo del tracto solitario es muy cercano al centro respiratorio que podría ocasionar disnea de origen central ( ) , otros núcleos como el núcleo dorsal motor del vago y el núcleo ambiguo están relacionados con funciones cardiovasculares a tener en cuenta ( ) . respecto a los factores de riesgo destaca el tabaquismo el cual aumenta la posibilidad de neuroinfección debido a interacciones funcionales entre el receptor nicotínico de acetilcolina y el receptor eca el cual está sobreexpresado en pacientes fumadores ( ) . amci ® en pacientes con infecciones severas vs infecciones no severas ( . % vs . %, p = . ), incluyendo eventos cerebrovasculares ( , % vs , % p= , ), alteración del estado de consciencia ( . % vs . %; p< . ) y lesiones musculoesqueléticas ( , % vs , % p< ) ( ) . la encefalopatía que se manifiesta como una alteración aguda o subaguda del estado de consciencia presentándose en pacientes con comorbilidades, factores de riesgo cardiovasculares, edad avanzada y deterioro cognitivo previo ( , , ) . así como aquellos individuos con hipoxemia la cual induce metabolitos anaerobios en el sistema nervioso central, edema celular, intersticial e isquemia ( ) . los eventos cerebrovasculares pueden ser desencadenados por cuadros de hipoxia, inmovilización, un incremento de la respuesta proinflamatoria o por predisposición a la hipercoagulabilidad ( ) . respecto a este último rubro tanto la edad (hazard ratio , /por año % ic , - , ) y la coagulopatía definida como como un tiempo de protrombina mayor a segundos, o tiempo de tromboplastina mayor a segundos (hr , % ic , - , ) fueron considerados predictores independientes de complicaciones trombóticas ( ) ; otros trabajos reportan incremento del conteo plaquetario y niveles elevados de dímero d ( ) . de hecho, un scoping review realizado por wilson y jack muestra que la presencia de eventos cerebro vasculares es un factor de riesgo de mal pronóstico para pacientes infectados por covid- ( ) . mao et al. reportaron eventos cerebro vasculares en pacientes con covid- , los factores de riesgo más relevantes fueron los clásicos factores de riesgo cardiovasculares (diabetes, hipertensión y edad avanzada), así como una presentación sistémica severa, teniendo como un denominador común el compromiso estructural de grandes vasos ( ) . la presencia de convulsiones (clínicas o subclínicas) puede ser una manifestación de eventos cerebro vasculares, meningoencefalitis o hipoxia cerebral. siendo los factores de riesgo más importantes en su exacerbación las alteraciones electrolíticas como hipocalcemia, las reacciones adversas a medicamentos y la epilepsia como comorbilidad de base ( , ) . otros tipos de coronavirus como lo son el e, , y oc se han aislado de líquido cefalorraquídeo (lcr) de pacientes con esclerosis múltiple sugiriendo posiblemente sean agentes etiológicos en la exacerbación de brotes de esta patología sin embargo aún no se ha documentado la asociación entre covid- y ésta condición ( ) . otras patologías en las cuales se ha asociado la presencia de esta familia de microorganismos es la enfermedad de parkinson, la esclerosis lateral amiotrofia, la neuritis óptica y la encefalitis aguda diseminada ( , ) . múltiples trabajos han documentado la asociación entre polineuropatía y coronavirus. la mayoría de ellos consideran que existe una estrecha relación entre una polineuropatía autoinmune exacerbada por la infección por coronavirus o bien un compromiso nervioso periférico inducido por bloqueo neuromuscular, alteraciones hidroelectrolíticas o disvitaminosis( ). amci ® se recomienda que todo paciente con acv isquémico se considere sospechoso de infección por covid- si presenta: sintomatología asociada sospechosa de infección por covid- , contacto cercano con individuos con sintomatología infecciosa, allegados con viajes recientes, si la historia clínica es atípica, si la información suministrada no es clara, si presenta deterioro del estado de alerta inexplicable, y si al examen físico presenta hallazgos compatibles con una infección por covid- . se recomienda que todo paciente con acv isquémico de quien no se pueda recibir información se considere sospechoso de covid- ya que el evento cerebro vascular es una complicación que se ha reportado en pacientes con infección por covid- . hay una gran evidencia que correlaciona la presencia de infección por covid- con factores de riesgo cardiovasculares. esto se demostró en un metaanálisis que incluyó estudios de china (n= ) donde las comorbilidades más frecuentes fueron hipertensión ( , %, % ic: - , %), diabetes ( , %, % ic , - , %), enfermedad cardiovascular ( . %, % ic: . - . ) y patologías respiratorias ( . %, % ic: . - . %). al comparar severidad vs no severidad la presencia de hipertensión tuvo un or de . ( % ci: . - . ), y la enfermedad cardiovascular un or de . ( % ci: . - . ) respectivamente ( ) . existieron pocos casos de hipercoagulabilidad en pacientes sin factores de riesgo cardiovasculares ( ) . la cohorte de wuhan (n= ) publicada por wang et al. mostró otros factores de riesgo que podrían eventualmente estar asociados a estado de embolia y trombosis como shock en , %, arritmias , % y miocarditis en un , %. situaciones que conllevarían a hipercoagulabilidad, lesión endotelial y eventualmente la aparición de acv. ( ) . en este orden de ideas existe una estrecha correlación entre la presencia de factores de riesgo cardiovasculares que ocasionarían acv y que podrían eventualmente estar relacionados con la patogenia de covid- . ante esta inquietud khosravani et al. publicaron en stroke un informe especial donde realizan ciertas recomendaciones para el abordaje de los pacientes con acv en el contexto de la pandemia por covid- de una forma rápida, eficaz y segura para los diferentes profesionales de la salud. surge así el código stroke protegido el cual consiste en:  usar elementos de protección personal y una mascarilla al paciente  ejecutar protocolo de aislamiento de contacto y gotas  ejecutar protocolo de aerosoles si el paciente está sometido a ventilación mecánica no invasiva, manejo de aspiración de secreciones o maniobras de reanimación cardiopulmonar básica y avanzada  si el paciente presenta deterioro del estado de alerta con necesidad de soporte ventilatorio alto con fracción inspirada de o mayor a % se recomienda intubar temprano y proceder con el transporte. se debe proceder con el código stroke protegido si el paciente presenta alguna de las siguientes condiciones:  si el paciente presenta sintomatología sospechosa de covid- (fiebre, tos, dolor torácico, disnea, cefalea, mialgias, emesis)  si existe algún contacto cercano con sintomatología infecciosa  si el paciente o alguno de sus allegados ha presentado viajes recientes amci ®  si el paciente es covid- positivo  si refiere al interrogatorio una historia clínica atípica o poco clara  si el paciente o alguno de sus acudientes es incapaz de suministrar información  si el paciente presenta deterioro del estado de alerta  si al examen físico se encuentran signos compatibles con patologías diferentes a covid- por último, estas son las recomendaciones en el momento de realizar el traslado a saber:  no apresurarse dentro de la sala de reanimación o dentro de la unidad de cuidados intensivos y mantener la calma  designar un líder para el traslado del paciente y para supervisar el uso adecuado de los elementos de protección personal  limitar el número de personas encargadas del transporte  evitar la contaminación con otras áreas del hospital( ). se recomienda no realizar neuroimagen de rutina en pacientes críticos por covid- con cefalea y anosmia, dado que no existe una evidencia concluyente que demuestre una estrecha correlación entre estos síntomas y hallazgos imagenológicos. fuerte en contra fundamento en la mayoría de los casos la cefalea es un síntoma no específico que no es característico de irritación meníngea la ocurrencia de cefaleas aisladas en ausencia de otros síntomas sugiere un mecanismo benigno más que un compromiso de sistema nervioso central ( ) . sin embargo, el covid- al tener una capacidad neuroinvasiva, se han reportado casos de encefalitis virales con o sin necrosis hemorrágicas de compromiso temporal mesial y talámico que ameritarían estudio de imagen diagnóstica ( ) . un estudio retrospectivo publicado por kandenmirli et al. evaluó pacientes en hospitales infectados con covid- de los cuales requirieron manejo en uci donde el % de ellos (n= ) presentaron sintomatología neurológica. la resonancia magnética cerebral fue realizada en % (n= ) de estos pacientes. el % tuvieron hallazgos agudos, el % tuvieron alteraciones corticales de la captación de señal en el modo flair, pacientes tuvieron anormalidades en la señal flair en la sustancia blanca profunda y subcortical, pacientes con lesiones en el lóbulo frontal, en el lóbulo parietal, en el lóbulo occipital, en el lóbulo temporal, en la corteza de la ínsula, y en el giro cingular ( ) . amci ® un paciente presentó trombosis de seno venoso y otro presentó un infarto en el tercio medio del territorio de la arteria cerebral media. en % de los pacientes no se encontraron hallazgos que sugieran compromiso intracraneal de covid- . una correspondencia escrita por helms et al. reportaron pacientes con sdra y covid- en dos unidades de cuidados intensivos en francia entre marzo y abril del , el % presentaron signos neurológicos como delirium evaluados mediante cam-icu ( %), agitación ( %), signos del tracto cortico espinal ( %), síndrome disejecutivo ( %). de ellos se realiza resonancia magnética en pacientes encontrando alteraciones en la perfusión en un %, un realce de leptomeninges en un %, y un acv isquémico en un %; dos pacientes asintomáticos presentaron áreas isquémicas con hiperintensidad focal ( ) . ante estos hallazgos los principales diagnósticos diferenciales son las patologías autoinmunes, encefalitis, convulsiones e hipoglucemia. los pacientes con compromiso frontal bilateral poseen hipoxemia que ocasionan hipoperfusión fronto temporal. las microhemorragias corticales (y no) son consecuentes de la ruptura de la membrana hematoencefálica resultando en este patrón mencionado. el estado postictal muestra un compromiso simétrico de la sustancia blanca. de esta forma hay que considerar otras condiciones como las comorbilidades cardiovasculares, las reacciones adversas a los medicamentos, e hipoxia inducida por sdra que ocasionarían patrones imagenológicos de confusión, que ponen en duda la estrecha relación entre covid- y hallazgos de resonancia magnética ( ) . en este orden de ideas necesitamos más datos para determinar cuáles son los hallazgos imagenológicos relacionados con neurotropismo y qué patrones pueden encontrarse directamente relacionados con la presencia de convulsiones, hipoxia o el desencadenamiento de una tormenta de citoquinas( , , ). se recomienda la valoración neurológica completa en los pacientes con sospecha o infección por covid- . se recomienda la monitorización electroencefalográfica continua por al menos h o según la consideración del especialista en neurociencias en el paciente en estado crítico con sospecha o infección por covid- en quien se sospeche crisis epilépticas o estatus no convulsivo. las manifestaciones neurológicas en pacientes con infección por covid- pueden estar presentes en el % de los casos ( , , ) . en el paciente en estado crítico con infección por covid- se han observado complicaciones vasculares que puede causar ataque cerebrovascular agudo isquémico o hemorrágico con tazas de entre el al % por lo que el examen neurológico debe realizarse para documentar la presencia de déficit amci ® neurológico focal que haga sospechar esta patología ( , , ) . es conocido que los pacientes en unidades de cuidado crítico tienen patologías que aumenta el riesgo de crisis o estado epiléptico, entre las cuales se encuentran ( ) ( ) ( ) ( ) :  pacientes sin patologías neurológicas hospitalizados en unidad de cuidado intensivo  hemorragia subaracnoidea  hemorragia intracraneal  trauma cráneo encefálico moderado a severo  infección del sistema nervioso central  tumor cerebral  encefalopatía hipóxico-isquémica algunas de estas patologías se presentan más frecuentemente en pacientes por covid- por lo que la monitorización electroencefalográfica continuar es requerida en este grupo de pacientes. el virus puede producir descompensación de paciente con epilepsia conocida, crisis por fiebre, crisis producidas por el estado crítico del paciente o las patologías subsecuentes que se han observado en esta infección ( ) . el tiempo de monitorización requerido debe ser entre a horas para lograr una sensibilidad de a %( , ). se recomienda realizar tomografía cerebral simple ante las manifestaciones neurológicas focales que nos hagan sospechar ataque cerebrovascular isquémico o hemorrágico. la resonancia cerebral puede ser necesaria como estudio complementario para determinar otros diagnósticos diferenciales en los pacientes con sospecha o infección por covid- . las manifestaciones neurológicas en pacientes con infección por covid- pueden estar presentes en el % de los casos ( , , ) . en el paciente en estado crítico con infección por covid- se han observado complicaciones vasculares que puede causar ataque cerebrovascular agudo isquémico o hemorrágico con tazas de entre el al % por lo que el examen neurológico debe realizarse para documentar la presencia de déficit neurológico focal que haga sospechar esta patología ( , , ) . la tomografía cerebral hace parte de la valoración inicial del ataque cerebrovascular isquémico y del estudio para determinar la presencia de otros diagnósticos diferenciales como ataque cerebro vascular hemorrágico en paciente con dicha patología puede ser necesario realizar angiotac con extensión a tórax en caso de sospecha de oclusión proximal o estudios endovasculares en pacientes que sea indicado ( ) . la realización de resonancia cerebral usualmente documenta alteraciones en los pacientes con covid- en el - % de los casos evaluados no relacionada con el acv. se recomienda la realización de punción lumbar en el paciente con sospecha o diagnóstico de covid- con base en los reportes de casos disponibles:  paciente con crisis epilépticas de novo.  paciente con alteración del estado de conciencia persistente a pesar de encontrarse metabólicamente compensado, descartado ataque cerebrovascular u otra causa de encefalopatía.  paciente con manifestaciones como mielitis, neuropatía craneal múltiple o sospecha de polineuropatía desmielinizante aguda. las capacidades neurotrópicas de los coronavirus en general han sido expuestas desde la infección por sarscov. en cuanto al sars-cov- , asadi-pooya y colaboradores( ), han descrito, la posibilidad de ingreso al sistema nervioso central tras el ingreso por la mucosa nasal o por una gran viremia en el torrente sanguíneo. se han descrito procesos inflamatorios asociados (encefalitis) y en previamente con el sars y el mers hasta lesiones desmielinizantes (encefalomielitis aguda diseminada). estas primeras manifestaciones en con el sars fueron presencia de crisis epilépticas de novo, en quienes excluyendo otras causas tanto por neuroimagen además de pruebas microbiológicas en lcr, les fue descubierto el sars cov mediante pcr rt. en la presente pandemia, takeshi moriguchi y colaboradores ( ) describieron el primer caso de encefalitis asociado a sars-cov- , en un hombre joven en japón, que, tras días de clínica respiratoria, desarrollo crisis epilépticas y alteración del estado de conciencia, sin antecedente conocido de epilepsia. se realizo imagen por resonancia cerebral, demostrando hiperintensidades a nivel temporal y lcr que mostró pleocitosis linfocitaria, se descartaron otros virus ( herpes, herpes zoster) y se le realizó pcr rt para sars-cov- siendo positiva. inclusive en este paciente los primeros hisopados faríngeos fueron negativos, pero los hallazgos en tomografía de tórax hicieron sospechar la infección por sars-cov- . otro caso descrito de encefalitis hemorrágica aguda, fue también descrito en la revisión de ahmad y colaboradores ( ) . donde una mujer joven presentó cuadro respiratorio de fiebre de días de evolución y compromiso del estado de conciencia. en esta paciente se aisló el sars-cov- en hisopado faríngeo y ante el compromiso severo del estado de conciencia, se realizó resonancia que mostró compromiso hemorrágico bitalámico, en regiones temporales e ínsula, apoyando que se tratara de una diseminación tras neuronal probablemente con puerta de entrada mucosa olfatoria y siguiendo la diseminación por el los tractos del primer nervio hasta la corteza entorrinal, que es la vía propuesta de infección descrita inclusive por grupos como el de montalvan ( ) y natoli ( ) . amci ® precisamente, en la revisión sistemática de montalvan ( ) se describen caso de mielitis en contexto de paciente con infección por sars-cov- , en quien se documentó la infección en lcr. se recomienda la medición de ácidos nucleicos por rt-pcr para sars-cov- en líquido cefalorraquídeo en los pacientes con sospecha o confirmación de infección por sars-cov- que realice crisis epilépticas de novo, en quien se descarte otras causas de estructuralidad (acv, tumores) o causas metabólicas (alteraciones hidroelectrolíticas, hipoglicemia, uremia etc.). se recomienda la medición de ácidos nucleicos por rt-pcr para sars-cov- en líquido cefalorraquídeo en pacientes con sospecha o confirmación de infección por sars-cov- con alteración franca del estado de conciencia, en quien se haya descartado como causante hipoxia, ataque cerebrovascular, alteración hidroelectrolítica o estatus no convulsivo mediante imágenes y electroencefalograma. se recomienda la medición de ácidos nucleicos por rt-pcr para sars-cov- en líquido cefalorraquídeo en pacientes con sospecha de encefalitis, mielitis o síndrome de guillain barré. en pacientes críticos, se ha recomendado búsqueda activa de compromiso del snc por sars-cov- , sobre todo en pacientes con crisis epilépticas que no sean sintomáticas a trastornos metabólicos, además de hallazgos imagenológicos y curso clínico. las descripciones hechas por asadi y takeshi ( , ) , muestran pacientes con cursos tórpidos, en los que el común denominador es una alteración del estado de conciencia persistente a pesar que otras variables (metabólicas, vasculares e infecciosas diferentes al sars-cov- ). de igual forma pacientes que realicen en contexto de la enfermedad, un cuadro de debilidad generalizada aguda, con arreflexia e incluso compromiso de nervios craneales como los descritos por zahra sedaghat( ). page amci ® se recomienda en los pacientes críticos con compromiso pulmonar por covid- , un manejo orientado de fluidos frente a una estrategia liberal, ajustando el balance de fluidos de acuerdo con la evaluación clínica y/o a la capacidad de respuesta a volumen para garantizar la perfusión renal. se recomienda ajustar la intensidad de la monitoria en el paciente crítico con covid- al grado de severidad de la enfermedad para alcanzar tempranamente metas de reanimación que se reflejen en menor riesgo de lesión renal aguda. se recomienda evitar el uso de medicamentos nefrotóxicos teniendo en cuenta la farmacocinética y farmacodinamia individual, así como las interacciones farmacológicas en el paciente crítico con covid- . el manejo de la volemia en los pacientes críticos ha cambiado considerablemente en las últimas décadas orientándose a un manejo titulado, evitando la administración empírica de altos volúmenes de líquidos durante la fase de reanimación de los pacientes siendo el flujo sanguíneo el determinante primordial del aporte tisular de oxígeno; los principales componentes de este deben optimizarse y balancearse para evitar la disoxia tisular. en estados de bajo flujo, los mecanismos compensadores neurohumorales producen una redistribución del flujo a lechos no esplácnicos y a nivel renal una redistribución corticomedular convirtiendo el tejido medular renal en una zona vulnerable a la lesión. de igual forma, el flujo sanguíneo renal se ve reducido de forma refleja en presencia de hipoxemia y/o hipercapnia. diversas fuentes de información nos han indicado cómo orientar adecuadamente el manejo del estado de perfusión tisular en los pacientes críticos con o sin una condición de shock, siendo la estimación aproximada del estado de volumen del paciente el pilar fundamental sobre el cual se basará toda la estrategia de restablecimiento o mantenimiento de la volemia del paciente con el fin de mantener la perfusión adecuada. aunque históricamente se prioriza la normalización del volumen en la reanimación de un paciente inestable, hemos comprendido la importancia que tiene el tiempo para lograr las metas en el pronóstico general del paciente y evidencias como el trabajo de ospina y cols. soportan el uso temprano de vasopresores para lograr de forma temprana metas de perfusión mientras buscamos la normovolemia. los pacientes con enfermedad pulmonar asociada a covid- deben mantenerse normovolémicos para preservar el flujo sanguíneo renal siendo la evaluación del estado de volumen un verdadero reto clínico. la fiebre, el aumento de pérdidas insensibles, la baja ingesta o las pérdidas por el tracto digestivo, pueden hacer que un paciente con covid- tenga hipovolemia, situación que puede desencadenar daño renal de no ser revertida apropiadamente y a tiempo. del otro lado del espectro, la administración liberal de líquidos además del potencial de empeorar la lesión pulmonar en presencia de una membrana alveolo capilar seguramente alterada, puede producir por sí misma un incremento en el riesgo de desarrollar lesión renal como lo demostró el estudio de grissom. desde el punto de vista de las metas amci ® hemodinámicas que se deben tener con un paciente con covid- , se recomienda seguir los lineamientos de la campaña sobreviviendo a la sepsis, orientadas a mantener un óptimo estado de volumen, unas presiones de perfusión en un rango que permita la regulación de los flujos regionales en los distintos órganos y un gasto cardíaco dentro de unos rangos establecidos para una perfusión sistémica óptima. el examen clínico sigue teniendo vigencia absoluta para una adecuada aproximación al paciente, por ello debemos buscar los indicadores clínicos tradicionales de hidratación (piel, mucosas, enoftalmos, edema, etc.), el llenado capilar como lo describe hernández y cols en el estudio andrómeda-shock, el estado de alerta, las funciones cognitivas y la rata urinaria son entre otros unos marcadores aceptables para hacernos una idea del estado de adecuación de la perfusión periférica. la oliguria como marcador de perfusión renal está presente en / parte de los pacientes al ingreso a uci sin tener en sí sola una implicación pronóstica, sin embargo, la persistencia de esta en el tiempo es un indicador de alerta y obliga a una evaluación más detallada de las diversas variables que pudieran ocasionarla. debemos recordar que la administración de cargas de líquidos solamente está justificada cuando hay una respuesta cardiovascular a dicha administración, situación que se puede prever con una prueba de elevación pasiva de las piernas o con métodos más invasivos como la variabilidad de la onda de pulso, del volumen sistólico y/o del gasto cardíaco, entre otros. el esfuerzo respiratorio del paciente, los volúmenes utilizados en las estrategias de ventilación protectora y las arritmias frecuentemente presentes en los pacientes con compromiso pulmonar limitan el rendimiento diagnóstico de diversos dispositivos utilizados para la evaluación del estado de volumen y el gasto cardíaco, situación que debemos conocer y manejar( , - ). se recomienda no utilizar de forma rutinaria la administración de tratamientos específicos antivirales para el paciente crítico con covid- , con lesión renal aguda o crónica se recomienda no utilizar de rutina remdesivir en los pacientes con falla renal crónica y debe suspenderse en los pacientes que desarrollan lesión renal aguda con tfg < ml/min. las intervenciones farmacológicas en los ensayos clínicos deben ajustarse a la farmacocinética y farmacodinamia específicas de cada molécula. la incidencia de falla renal reportada por criterios de kdigo, en los estudios chinos fue de . % de los pacientes críticamente enfermos y de . % en los pacientes con covid- y amci ® sdra. sin embargo, otros estudios han demostrado que hasta un %de pacientes con covid- que ingresan a la uci pueden presentar falla renal aguda. la falla renal en los pacientes con covid- es multifactorial como se ha descrito en preguntas anteriores por lo que se recomienda la toma diaria de creatinina sérica y el seguimiento continuo del gasto urinario y otros parámetros de la función renal como hematuria, proteinuria, tasa de filtrado glomerular, nitrógeno ureico en sangre, dímero d. los medicamentos que se emplean en el manejo de la infección covid- que actualmente incluyen oseltamivir, lopinavir/ritonavir, ribavirina, y la cloroquina o hidroxicloroquina son metabolizados principalmente en el hígado, aunque en la orina se encuentran metabolitos derivados de oseltamivir, ribavirina y de la hidroxicloroquina. por esto en ninguno de los estudios realizados en torno a la infección por sars-cov- se ha realizado ninguna recomendación en cuanto a la modificación de su dosis. la hidroxicloroquina por su parte se metaboliza a cloroquina, que a su vez se metaboliza a monodesetilcloroquina y a bisdesetilcloroquina. este medicamento no es dializable en las diálisis intermitentes y la única recomendación en los pacientes con falla renal, es hacer seguimiento electrocardiográfico estrecho para vigilar la prolongación del qtc. el favipiravir es un inhibidor de la polimerasa dependiente de rna que se encuentra en fase experimental para el tratamiento de la infección por sars-cov- . la eliminación de este medicamento se realiza por vía renal y en los pacientes con falla renal en estadios leves a moderados se ha encontrado una concentración dos veces mayor en el riñón que sus niveles en sangre; sin embargo, esto no se ha asociado con ningún evento adverso por lo que la recomendación actual es no disminuir la dosis en pacientes con falla renal. el remdesivir se elimina por vía renal por lo cual no se recomienda administrar en pacientes con falla renal y los pacientes que desarrollan falla renal con el medicamento durante los estudios han sido retirados de los ensayos clínicos. no se cuenta con estudios que evalúen el remdesivir en una tfg < ml/min. en la tabla se describen algunas intervenciones farmacológicas propuestas en medio de la pandemia para el manejo del covid- y su relación con la tasa de filtración según tfg. recientemente , izzedine et al publicaron una carta editorial en el kidney international may , donde alertan sobre el posible efecto nocivo de la hidroxicloroquina en la aparición de falla renal aguda al inhibir la autofagia celular que es un proceso importante en la remodelación de los túbulos renales, siendo estas células de alto recambio, pudiendo todo esto contribuir a la aparición de falla renal aguda( , , - ) se recomienda aplicar las indicaciones tradicionales de terapia de soporte renal en pacientes críticamente enfermos con covid- . se recomienda el inicio de terapia de soporte renal en pacientes críticos con covid- con hipercalemia severa o acidosis metabólica severa, refractarias a pesar del manejo médico óptimo o cuando el balance positivo de fluidos es deletéreo, con mayor requerimiento de oxígeno suplementario y que no responde a diuréticos. se recomienda el inicio temprano de terapia de soporte renal dentro de las primeras horas de una indicación absoluta, asegurando previamente una adecuada reanimación de la perfusión tisular. en ausencia de trastornos hidro-electrolíticos y severa sobrecarga de volumen, el tiempo de inicio de diálisis es controversial. amci ® se recomienda en pacientes críticos con covid- que requieren soporte renal, las modalidades de terapia continua o extendida si cursa con inestabilidad cardiovascular, de acuerdo con la disponibilidad institucional. se debe considerar en pacientes críticos con covid- , que requieren inicio de soporte renal preferir la vía femoral para inicio de la terapia para disminuir el riesgo de contaminación por proximidad, la siguiente vía se establecerá de acuerdo con la evolución y condiciones del paciente. en pacientes diagnosticados con covid- se puede presentar la insuficiencia renal aguda como parte de su enfermedad. en estudios observacionales de usa y china la ira se reportó entre un y % de los pacientes. la enfermedad renal en pacientes con covid- se puede manifestar como ira, hematuria o proteinuria, y conllevan un mayor riesgo de mortalidad. la ira se asocia con cambios hemodinámicos y liberación de citocinas, pero no se descarta citotoxicidad directa por el virus. en un estudio realizado en nueva york con pacientes covid- positivos se diagnosticó lesión renal aguda en % de ellos, siendo leve con aumento de creatinina dos veces por encima del nivel basal en % de los pacientes, moderada en % de los pacientes, y severa con más del triple de la creatinina basal en %. hubo hematuria en el % de los pacientes y proteinuria en el %. se requirió terapia dialítica en el % de todos los pacientes con diagnóstico de ira, y el % de los pacientes que requirieron diálisis estaban en ventilación mecánica. la ira fue notada dentro de las primeras horas de admisión a uci en el % de los pacientes y se relaciona con la severidad de la enfermedad. existen además predictores independientes: edad, raza negra, diabetes, hipertensión, enfermedad cardiovascular, ventilación mecánica, y uso de vasopresores. la terapia dialítica debe instaurarse precozmente una vez realizado el diagnóstico, idealmente dentro de las primeras horas, después de asegurado que se ha completado el proceso de reanimación correspondiente. las indicaciones te trr en pacientes críticos con ira en covid- no difieren del paciente crítico general y se debe considerar ante: manifestaciones severas de uremia, sobrecarga de volumen, trastornos ácidos básico, refractarios, hipercalemia severa con manifestaciones cardiovasculares. pero no hay datos clínicos que respalden el inicio temprano vs tardío en esta población particular. pero un planteamiento válido es que la sobrecarga de volumen en pacientes que desarrollan sdra es perjudicial, dificultando el soporte ventilatorio óptimo, por lo cual se puede considerar un umbral más bajo para el inicio de trr con esta indicación específica: sdra + sobrecarga de volumen + infección covid- ( ) . amci ® el paciente debe ser dializado en el cubículo de cuidado intensivo o en la habitación de aislamiento en los casos en que esté disponible y siempre evitar traslado a unidades con otros pacientes. la crrt es la modalidad preferida para este tipo de pacientes, pero debe quedar claro que esto depende de las facilidades de la institución que albergue al paciente y de la experticia de los profesionales. el acceso vascular en el paciente crítico general debe ser en su orden: vena yugular interna derecha, venas femorales comunes, vena yugular interna izquierda, y debe ser colocado por el médico encargado del paciente si está capacitado para ello, para evitar exposiciones innecesarias del personal de la salud. sin embargo, por precaución por el riesgo de contaminación, recomendaciones de expertos basadas en seguridad sugieren la utilización el catéter femoral. el tipo de catéter recomendado es un catéter doble lumen transitorio. sería ideal el monitoreo a través de cámaras del procedimiento para evitar el contacto prolongado del personal de enfermería durante el procedimiento de diálisis. en algunos casos específicos y de acuerdo con la disponibilidad, la diálisis peritoneal puede ser una alternativa. en los casos de crrt el líquido efluente no es contaminante para el personal de la salud. para terminar, es importante hacer énfasis en que en algunos hospitales ha habido escasez de insumos y esto puede llegar a convertirse en un serio problema. se recomienda para casos de fuerza mayor:  un litro de solución salina al . % con cloruro de potasio a necesidad  un litro de dextrosa al % en agua con meq de bicarbonato de sodio  un litro de solución salina al . % con gr de cloruro de magnesio  un litro de solución salina al . % con gr de cloruro de calcio esto nos da una solución de cuatro litros que contienen: meq/l de sodio, . meq/l de bicarbonato, . mmol/l de magnesio y . mmol/l de calcio, más una cantidad variable de potasio. esta solución se puede usar como líquido dializante en pacientes en terapias de reemplazo renal continuo. especial cuidado se debe tener en el proceso de anticoagulación, pudiéndose usar heparina no fraccionada, hbpm, y citrato en los centros donde se tenga experiencia ( , , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . se sugiere no utilizar de rutina la trrc más hemoperfusión en el paciente crítico con covid- . débil en contra page amci ® se puede considerar en el paciente crítico con covid- con lesión renal aguda en quien se considere inicio de trrc, considerar la utilización de filtros de fibra hueca con propiedades adsortivas o asociado con cartuchos para hemoperfusión directa. el síndrome de liberación de citocinas (tormenta de citocinas) es un importante determinante en la transformación de infección por covid- de leve a moderado y progresión de la lesión de un órgano como el pulmón con neumonía y sdra a compromiso sistémico con inestabilidad hemodinámica, cid y fom. los pacientes afectados de tormenta de citocinas se encuentran con niveles altos de il- especialmente, además de il- , tnf, que se relacionan con pobres pronósticos y mayor mortalidad. la asociación entre la lesión alveolar y renal (eje pulmón-riñón) es evidenciada en estudio del por panitchote y cols con pacientes con sdra secundaria a neumonía y sin enfermedad renal preexistente que desarrollaron lesión renal aguda en el % con aki en el % de ellos. recientemente en estudio en china zhou, con pacientes afectados de covid- se encontraron como indicadores de mal pronóstico pacientes con altos niveles de dímero d, il- , troponina i, dhl, ferritina y choque séptico. las terapias de depuración extracorpórea han sido utilizadas como tratamiento en pacientes con lesión severa por covid- ; dentro de estas se cuentan la crrt, hemoperfusión aislada, intercambio plasmático (tpe), plasmafiltración y adsorción (cpfa) y crrt + hemoperfusión. dentro de los beneficios de la crrt se cuentan la estabilidad hemodinámica, estabilidad del medio interno, depuración de toxinas pequeñas y medianas, incluidos mediadores inflamatorios, cuando se utiliza terapia convectiva, además de permitir soporte nutricional. la asociación de este procedimiento con membranas especiales (an + metilsulfonato y polietilamina oxiris) permiten hacer adsorción de citocinas (il- ) y endotoxinas, por periodos de h por días consecutivos para manejo de tormenta de citocinas. la hemoperfusión aislada o asociada a crrt, también permite la remoción de il- , utilizando cartuchos ha , con procedimientos de a horas de duración por días consecutivos ( , ( ) ( ) ( ) ( ) ( ) ( ) . no se puede emitir una recomendación a favor o en contra sobre el uso rutinario de la plasmaféresis como opción terapéutica en la fase de inflamación del paciente con covid- . amci ® el coronavirus covid- puede inducir el síndrome respiratorio agudo severo (sars), que conduce a la disfunción inmune, la liberación excesiva de citoquinas inflamatorias, y a una serie de reacciones en cascada de activación de citoquinas, que resultan en lesiones alveolares difusas, formación de membrana hialina, exudación de fibrina y otras manifestaciones de lesión del pulmón. en casos severos, la tormenta de citoquinas sistémicas invade el sistema circulatorio, lo que lleva a una inestabilidad hemodinámica, shock y mods ( ) . los niveles de il- , il- , tnf-a y otras citoquinas inflamatorias en pacientes con covid- grave son significativamente más altos, lo que puede estar relacionado con un mal pronóstico ( ) . por lo tanto, la plasmaféresis se puede usar con seguridad y efectividad en pacientes con covid- grave, para eliminar mediadores inflamatorios de gran peso molecular. la seguridad depende como todas las terapias extracorpóreas de un personal de la uci entrenado, preparado y capacitado para aplicar las intervenciones en forma óptimas ( ) . las terapias extracorpóreas de soporte de órganos pueden representar una parte importante de la respuesta y los médicos y otros profesionales de la salud deben estar familiarizados con estas terapias sofisticadas. se debe hacer un llamado a la acción, para crear conciencia sobre las diferentes técnicas extracorpóreas, cada una con criterios específicos y modalidades de prescripción, entrega y monitoreo( , ). se recomienda no utilizar de forma rutinaria el uso de un tratamiento específico dirigido a pacientes con infección por sars-cov- /covid- comparado con el manejo estándar para mejorar desenlaces clínicos fuertes. actualmente no existe una terapia dirigida que se a efectiva para el manejo del virus; un número alto de estudios han surgido en los últimos dos meses, la mayoría sin el rigor metodológico suficiente para tomar decisiones adecuadas con respecto al manejo del amci ® paciente con infección por sars-cov- . el conocimiento en la estructura del virus y el mejor entendimiento en la fisiopatología de la enfermedad genera un sinnúmero de potenciales fármacos que han sido ensayados para el manejo de la enfermedad. en tiempos de pandemia, con una patología catastrófica en términos de vidas humanas y costos hospitalarios; es importante encontrar soluciones a desenlaces importantes como mortalidad, días de estancia en uci y en el hospital, aumento en los días libres del ventilador, disminución de complicaciones mayores debido a la enfermedad entre otros. hasta el momento no se ha documentado ninguna terapia específica que pueda impactar sobre estos desenlaces; pero la calidad de los trabajos, tampoco dejan claro sin él no usar ningún tratamiento específico mejora los desenlaces al menos al disminuir el número de complicaciones. este nuevo beta-coronavirus es similar al coronavirus del síndrome respiratorio agudo severa (sars-cov) y del síndrome respiratorio del medio este (mers-cov); por lo tanto, varias moléculas que habían sido evaluadas en este tipo de enfermedad rápidamente se abrieron paso a ensayos clínicos en paciente con covid- . estos ensayos principalmente observacionales, aleatorios pero abiertos con un número pequeño de pacientes no han permitido sacar adecuadas conclusiones y es frecuente como ver las diferentes guías de las principales sociedades del mundo cambiar de forma frecuente sus recomendaciones; no existes evidencia de estudios clínicos aleatorios y controlados que midan desenlaces fuertes, la premura de un tratamiento efectivo ha sacrificado el rigor metodológico que una investigación requiere. una estructura viral y replicación conocidas generan posibles dianas para que diferentes fármacos puedan ser investigados, antivirales tipo arbidol el cual inhibe la fusión de la membrana en la envoltura viral a algunos receptores; antimaláricos como la hidroxicloroquina y la cloroquina, las cuales inhiben la entrada viral y endocitosis por múltiples mecanismos, así como los efectos inmunomoduladores demostrados en el huésped; antivirales que impiden la replicación como el lopinavir o darunavir inhibiendo las proteasas o la ribavirina, el remdesivir o el favipiravir que actúan como análogos de nucleótidos o fármacos que actúan modulando la respuesta específica del huésped como el tocilizumab el cual se une al receptor de la il- inhibiendo el punto de acción de esta; los corticosteroides con múltiples efectos en la modulación del sistema inmunológico del paciente o los fármacos para evitar la respuesta secundaria a esta cascada inflamatoria como son los anticoagulantes. por último, se han buscado estrategias con el fin de mejorar la inmunización pasiva del huésped en el uso del plasma de pacientes convalecientes o el uso de inmunoglobulinas enriquecidas entre otros tratamientos propuestos para esta enfermedad. como vamos a ver más adelante, actualmente no existe un tratamiento específico con el nivel de evidencia suficiente para recomendar de manera generalizada; tampoco existe suficiente evidencia del manejo del soporte básico sin el uso de fármacos dirigidos, que demuestre que esta estrategia se deba implementar de manera sistemática en todos los pacientes; por lo tanto, a continuación trataremos de resolver las inquietudes con respecto a los diferentes medicamentos que han sido usados en la pandemia del sars-cov- /covid- . se recomienda no utilizar antimaláricos tipo hidroxicloroquina (hcq) o cloroquina (cq) para el manejo de pacientes con infección por sars-cov- /covid- . para la fecha no hay un adecuado sustento bibliográfico que soporte el uso de antimaláricos en la prevención o manejo de pacientes con infección por sars-cov- tanto leve, moderada como severa. los mayores estudios no muestran utilidad clínica y tendencia a mayores eventos cardiovasculares con el uso de antimaláricos en pacientes con infección por covid- comparado con no darlo. su utilidad se deriva principalmente de resultados en estudios preclínicos e in vitro; como los presentados por wang y cols donde evaluaron medicamentos de manera in vitro contra el covid- , siendo el remdesivir y la cq efectivos de manera in vitro contra el nuevo coronavirus( ); liu y cols, donde la hcq fue efectiva en inhibir la infección por sars-cov- in vitro que junto con su potencial antiinflamatorio tenía potencial para el uso clínico ( ) y yao y cols, donde la hcq fue más potente que la cq para inhibir el sars-cov- in vitro y fue recomendado para el uso en humanos en dosis de mg dos veces al día por el primer día, seguido de mg dos veces al día por días más mantendría la concentración efectiva del fármaco en el tejido pulmonar ( ) . los pocos estudios clínicos, son de baja calidad y no han mostrado mejoría ni eficacia en el uso de antimaláricos para el manejo de paciente adultos con covid- , algunos estudios iniciales con pocos pacientes con resultados favorables ( ) e incluso con recomendaciones para uso en las primeras versiones de guías internacionales para la amci ® hcq y cq, encontrando superioridad en estudios observacionales, de pocos pacientes, sin comparadores para inhibir la exacerbación de la neumonía, hallazgos de las imágenes pulmonares, promover una conversión negativa al virus y acortar el curso de la enfermedad; la cq tuvo un efecto notable tanto en términos de resultado clínico como de eliminación viral ( ) ; considerando la hcq y la cq como un tratamiento costo efectivo ( ) . estudios posteriores con un mayor número de pacientes no han logrado reproducir los estudios preclínicos iniciales; mahévas y cols, evaluaron la efectividad de la hcq en pacientes admitidos a cuatro hospitales en francia, con neumonía por covid- quienes requieren oxígeno, pero no se encontraban en uci, comparado con una población con manejo estándar; la hcq se usó a dosis de mg día en las primeras horas a la admisión, este estudio no soporte el uso de la hcq en pacientes admitidos al hospital con covid- que requieren oxígeno al no reducir de forma significativa la admisión a la uci, el sdra o muerte en el día después del ingreso ( ) ; por el contrario, se han reportado efectos secundarios frecuentes (prolongación del intervalo qt, hipoglucemia, cambios en el estado mental, alteraciones gastrointestinales y retinopatía); silvia borda y cols, evaluó la seguridad y eficacia de dos dosis de cq en pacientes con covid- severo en un estudio aleatorizado, doble ciego fase iib en pacientes adultos hospitalizados con infección por sars-cov- , los pacientes fueron expuestos a dosis altas de cq ( mg dos veces al día por días) o dosis bajas ( mg dos veces al día en el día y una vez al día por días), los hallazgos preliminares de este estudio sugieren que la dosis más alta de cq no debe recomendarse para pacientes críticos con covid- debido a sus posibles riesgos de seguridad, especialmente cuando se toman simultáneamente con azitromicina y oseltamivir; estos hallazgos no pueden extrapolarse a pacientes con covid- no severo ( ); tang y cols, evaluaron la eficacia y seguridad de la hcq con el manejo estándar en un estudio multicéntrico, abierto, aleatorio y controlado en china, pacientes con covid- positivo se incluyeron en el análisis de intención a tratar ( en el grupo de hcq y en el grupo estándar), la hcq fue administrada a dosis de mg día por tres días y mantenimiento con dosis de mg día (duración del tratamiento: dos a tres semanas en pacientes con enfermedad leve a moderada o enfermedad severa respectivamente); la administración de hcq no resultó en una significativa mayor probabilidad de conversión negativa comparado con el tratamiento estándar, los efectos adversos fueron mayores en el grupo de hcq ( ) . con todo esto la hcq y la cq, si se usan deberá ser bajo estudios experimentales aprobados con una estricta monitorización y vigilancia clínica de la frecuencia cardíaca y el intervalo qt, los niveles de glucosa, la función hepática y renal, y el cribado clínico de trastornos mentales y visuales en pacientes que reciben estos fármacos. debe evitarse hcq/cq en pacientes con enfermedades cardiovasculares subyacentes. nuevas evidencias con un mayor número de pacientes podrían sacar la hcq y la cq inclusive de estudios clínicos; barbosa y cols, evaluaron en un estudio cuasialeatorio comparativo el uso fuera de registro de la hcq en pacientes positivos por el sars-cov- , el pronóstico primario fue la necesidad de escalar el soporte ventilatorio, cambio en el conteo de linfocitos o cambio en el índice de neutrófilos/linfocitos, un total de pacientes fueron incluidos, en el brazo de hcq. la administración de hcq fue asociada con la necesidad de aumentar el nivel del soporte ventilatorio comparado con aquellos que no recibieron hcq al día del estudio, no hubo beneficios en la mortalidad, reconstitución inmunológica y riesgo de intubación ( ) . el estudio con un mayor número de pacientes proviene de la ciudad de new york; geleris y cols, examinaron la asociación entre el uso hcq y la intubación o muerte en un centro médico de ny, se analizaron . amci ® estaban más enfermos en términos de oxigenación, en este estudio observacional la administración de hcq no fue asociada con una disminución en el riesgo compuesto de intubación o muerte ( ) . se recomienda no utilizar antimaláricos tipo hidroxicloroquina (hcq) o cloroquina (cq) en combinación con azitromicina (az) para el manejo de pacientes con infección por sars -cov- /covid- . fundamento para la fecha la evidencia no favorece el uso combinado de los antimaláricos en combinación con la azitromicina; por el contrario, la combinación de estos dos medicamentos puede ser deletérea, inclusive con un aumento reportado en la mortalidad y la aparición de arritmias ventriculares de novo; estudios iniciales fueron promisorios, gautret y cols, evaluaron inicialmente el efecto de la hcq en la carga viral respiratoria en conjunto con el uso de azitromicina, la presencia del virus al día fue el pronóstico primario; pacientes con tratamiento mostraron una significativa reducción en la carga viral al día de la inclusión comparado con los controles; la azitromicina adicionada a la hcq fue significativamente más eficiente en la eliminación viral ( ) ; nuevamente gautret y cols, realizaron un estudio observacional, no controlado, no comparativo de pacientes tratados con la combinación de hcq más azitromicina, presentando una mejoría significativa en disminución de la carga nasofaríngea del virus y una menor tiempo de enfermedad ( ) ; luego million y cols, evaluaron la combinación de hcq y az en un estudio retrospectivo de . pacientes con sars-cov- tratados con hcq ( mg tres veces al día por días) + az ( mg en el día , seguido de mg al día por los próximos días), el pronóstico fue mortalidad, empeoramiento clínico (ingreso a uci) o persistencia viral; la administración de hcq+az en combinación antes de que aparecieran las complicaciones del covid- es segura y asociada a una baja mortalidad en los pacientes ( ) ; soportado además por estudios in vitro que demuestran que la combinación de hcq y az tienen efectos sinérgicos para el sars-cov- a concentraciones compatibles con las que se obtienen en pulmones humanos ( ) . otros estudios por el contrario no han encontrado resultados positivos, es así como, magagnoli y cols, en un análisis retrospectivo de pacientes confirmados con infección por sars-cov- en centros de veteranos de los eeuu, un total de pacientes fueron evaluados (hcq, n= ; hcq+az, n= ; no hcq, n= ), en este estudio no hubo evidencia que el uso de la hcq tanto sola o en combinación con la az, redujo el riesgo de ventilación mecánica en pacientes hospitalizados con covid- ; una asociación con un aumento en la mortalidad fue identificada en pacientes tratados con hcq sola ( ) . nuevamente los estudios con un mayor número de pacientes se encuentran en la ciudad de new york; rosenberg y col, describieron la asociación entre hcq, con o sin az en el pronóstico de pacientes hospitalizados con covid- ; un estudio de cohorte multicéntrico retrospectivo en pacientes hospitalizados con covid- en hospitales de ny, los pacientes recibieron ; en pacientes hospitalizados en el área metropolitana de ny con covid- , el tratamiento con hcq, az o ambos, comparado con ningún tratamiento, fue no significativamente asociado con diferencias en la mortalidad hospitalaria ( ) . recomendaciÓn se recomienda no utilizar de forma rutinaria el uso rutinario del lopinavir/ritonavir para el manejo de pacientes con infección por sars-cov- /covid- . en la actualidad no existe evidencia a favor o en contra en el uso del tratamiento con antirretrovirales con lopinavir/ritonavir en el manejo de pacientes adultos hospitalizados con covid- ; no se observó ningún beneficio con lopinavir/ritonavir más allá de la atención estándar. se está en espera de cierre de diferentes ensayos futuros que confirme o excluyan el uso de lopinavir/ritonavir en el paciente covid- . en diciembre de , un nuevo coronavirus, designado sars-cov- , ha causado una pandemia ( , , , ) ; cuando hablamos de enfermedad producida por covid- hablamos de enfermedades que van desde las enfermedades leves autolimitantes del tracto respiratorio hasta neumonía rápidamente progresiva, neumonía grave, falla multiorgánica y muerte. hasta este momento no existen agentes terapéuticos específicos para las infecciones por coronavirus. después de la aparición del síndrome respiratorio agudo grave (sars) en , entre los fármacos aprobados se identificó lopinavir, un inhibidor del aspartato proteasa tipo del virus de inmunodeficiencia humana (vih), que tiene actividad inhibitoria in vitro contra el sras-cov, el virus que causa el sars en los seres humanos y el ritonavir combinado con lopinavir para aumentar su vida media plasmática a través de la inhibición del citocromo p ( ) . se comenzaron estudios evaluando la respuesta antiviral in vitro de la combinación de lopinavir/ritonavir y ribavirina en pacientes con sars; comparados con pacientes tratados con ribavirina sola, que sirvieron como controles históricos; el pronóstico adverso (sdra o muerte) fue significativamente más bajo en el grupo de tratamiento comparado con los controles históricos ( . % vs . %, p = . ) al día del inicio de los síntomas; una reducción adicional en el uso de esteroides y de infecciones nosocomiales fue vista en el grupo de tratamiento con una disminución en la carga viral y aumento en el conteo de linfocitos ( ) ; del mismo modo, el lopinavir tiene actividad, tanto in vitro como en modelo animal, contra el coronavirus del síndrome respiratorio de oriente medio (mers-cov) ( ) . estos estudios previos son el soporte inicial para el uso del lopinavir/ritonavir en la epidemia del covid- ; cao y cols, en mayo de publicaron en china, un estudio controlado, aleatorizado en pacientes hospitalizados con prueba ; los efectos adversos gastrointestinales fueron más comunes con el lopinavir-ritonavir, pero los eventos adversos serios fueron más común con el grupo control; el tratamiento con lopinavir-ritonavir fue suspendido en pacientes ( . %) secundario a los eventos adversos ( ) . otro estudio hung y cols, en hong kong, evaluaron en un trabajo multicéntrico, prospectivo, aleatorizado, fase la eficacia y seguridad de la terapia combinada por días de lopinavir mg y ritonavir mg cada h, ribavirina mg cada h y tres dosis de millones de ui de interferón beta- b en días alternos en pacientes con covid- comparado con lopinavir/ritonavir cada h (grupo control); el resultado primario fue tiempo en la negativización de la pcr viral en el hisopado nasofaríngeo en paciente con covid- ; pacientes fueron ingresados, en el grupo de combinación y en el grupo control; en el grupo de intervención de forma significativa se negativizo la prueba de pcr de forma más rápida ( días [iqr - ]) que el grupo control ( días [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ; hr . [ic % . - . ], p = . ); los eventos adversos fueron similares entre los grupos; ningún paciente murió durante el estudio ( ) . por último, un pequeño estudio de zhu y cols en china, con pacientes con sars-cov- ; evaluaron de forma retrospectiva los efectos antivirales y seguridad del lopinavir/ritonavir y el arbidol (antiviral aprobado en china y rusia para el sasr y la influenza), pacientes en el grupo de lopinavir/ritonavir y en el grupo de arbidol; los pacientes lopinavir/ritonavir presentaron un mayor tiempo para la negativización de la prueba de pcr viral (p < . )( ). se recomienda no utilizar de forma rutinaria remdesivir como antiviral para el manejo de pacientes con infección por sars-cov- /covid- . se debe considerar su uso en escenarios de estudios de investigación clínica aprobados. actualmente no hay disponibilidad del medicamento en el país (colombia) por lo cual no se incluye en los protocolos de manejo de paciente con covid- . en estados unidos el primer paciente con covid- mostró una mejoría significativa de sus síntomas con horas de tratamiento con remdesivir ( ) , lo que abrió la puerta a un nuevo tratamiento para el sars-cov- ; el remdesivir (gs- ) es un análogo de los nucleótidos que inhibe la rna polimerasa; con un amplio espectro antiviral, puede inhibir la replicación de múltiples coronavirus en las células epiteliales del sistema respiratorio ( ) ; estudiado ( ) . por último, un estudio publicado por antinori y cols, en milán, italia; de manera prospectiva (compasional) incluyó pacientes con neumonía por sars-cov- mayores a años bajo ventilación mecánica o con una saturación de oxígeno ≤ % al aire ambiente o un puntaje del national early warning score ≥ ; el pronóstico primario en cambio en el estado clínico en una escala ordinal de categorías ( = no hospitalizado de regreso a sus actividades diarias normales; = muerte); de los paciente ingresados, se encontraban en uci y en un piso de hospitalización de enfermedades infecciosas; un curso de días de remdesivir fue completado por pacientes ( %) y suspendido en , de os cuales ( . %) se descontinuo por eventos adversos; a los días, ( . %) pacientes de piso fueron egresados, permanecían hospitalizados y uno murió ( . %), en la icu ( . %) fueron egresados, ( . %) pacientes murieron, ( . %) aún se encontraban en ventilación mecánica y ( . %) estaba con mejoría pero aún hospitalizado; la hipertransaminasemia y la injuria renal aguda fueron los eventos adversos más frecuentes reportados ( . % y . %, respectivamente); los datos sugieren que el remdesivir puede beneficiar a pacientes con neumonía por sars-cov- hospitalizados por fuera de la unidad de cuidado intensivo ( ). page se recomienda no utilizar de rutina la ivermectina para el manejo de pacientes con infección por sars-cov- /covid- . para la fecha no se cuenta con la suficiente evidencia para emitir una recomendación para el uso de la ivermectina en pacientes con covid- , en estudios iniciales in vitro, caly y cols, demostró como la ivermectina, una droga autorizada por la fda como antiparasitario tiene un efecto antiviral de amplio espectro de manera in vitro, con una reducción significativa de la replicación viral en modelos experimentales ( ) , un estudio aún sin publicar, observacional multicéntrico de casos y controles (n: casos y n: controles), realizado entre el de enero y de marzo de , incluyó pacientes diagnosticados con covid- confirmados por laboratorio, la dosis fue de mcg/kg de ivermectina más la terapia médica de soporte en comparación con terapia médica sin ivermectina, el resultado principal fue la medición de supervivencia; en pacientes que requirieron ventilación mecánica, la mortalidad fue menor en el grupo de ivermectina ( , % y , % respectivamente) y las tasas de mortalidad global fueron más bajas con ivermectina ( no se puede emitir una recomendación a favor o en contra sobre el uso compasivo o rutinario de tocilizumab en pacientes con infección por sars-cov- /covid- . en pacientes individualizados se ha reportado desenlaces clínicos favorables. se puede considerar su uso en pacientes que cumplan con todos los siguientes criterios: ver tabla . el tocilizumab (tcz) un anticuerpo monoclonal humanizado igg k, el cual se puede unir de manera específica a los receptores solubles de membrana para la il- (sil- r and mil- r) y ha sido ampliamente usado en el tratamiento de enfermedades autoinmunes, tales como la artritis reumatoide, la enfermedad de still del adulto o vasculitis de grandes vasos ( ) . un primer estudio de xiaoling xu y cols, describió en china, pacientes tratados con tocilizumab, se documentó una mejoría en los síntomas, en los requerimientos de oxígeno y en los hallazgos imagenológicos de la tomografía de tórax; los niveles promedio de il- antes de la terapia fueron de . pg./ml; todos los pacientes recibieron lopinavir y metilprednisolona antes de la terapia. se trata de una serie con una muestra pequeña de pacientes en donde solo ( %) pacientes estaban en condición crítica ( ) . posteriormente luo y cols, en china, reportan el uso de tocilizumab en pacientes, con mejoría en el aumento de la pcr en todos los pacientes, excepto uno, y una disminución de la il . el nivel sérico de il- tendió a aumentar inicialmente y luego disminuyó en pacientes. los niveles medios de il- antes de la terapia fueron de . pg./ml; % de los pacientes recibieron metilprednisolona; el % fallecieron. es otra serie pequeña, con pacientes ( , %) en condición crítica ( ) . roumier y cols, en francia, estudiaron pacientes que recibieron tcz, observando que se redujo la necesidad de ventilación mecánica en comparación con los controles ( amci ® . ); en este estudio, no hubo diferencias en la reducción de la mortalidad y pacientes ( %) se encontraban en uci ( ) . klopfenstein y cols, también en francia, en un estudio retrospectivo de casos y controles, encontraron que pacientes que recibieron tcz (n= ), a pesar de tener más requerimiento de oxígeno, con resultados biológicos más pobres (mayor linfopenia y un nivel de pcr superior) al inicio del estudio que los pacientes sin tcz (n = ), presentaron el objetivo combinado (ingreso a uci y mortalidad) menor que los pacientes sin la terapia ( % vs %, p = . ); es otra serie, que disminuye la necesidad de ventilación mecánica ( % vs %, p = . ) de manera significativa ( ) . luego rimland ca y cols informan los primeros datos de pacientes con covid- tratados con tcz en los estados unidos, de ellos en ventilación mecánica; la pcr y el fibrinógeno mejoraron rápidamente, pero no hubo mejoría en otros marcadores o resultados clínicos. sólo a seis pacientes les tomaron niveles previos de il y de ellos dos tenían niveles bajos ( ) . en otro estudio mikulska y cols, próximo a salir en jama, en pacientes con sdra moderado a severo, hay mayor disminución de la mortalidad con el tratamiento combinado de tocilizumab y esteroides, en relación con cada una de estas terapias. por último, no todos los estudios han mostrado resultados positivos; kimmig y cols, de chicago (eeuu), en de los pacientes críticos con covid- , que recibieron tcz, se asoció con una mayor incidencia de infecciones bacterianas secundarias, incluida la neumonía asociada al ventilador ( . % vs. . % p = . ) ( ) . posterior a la recomendación hay nueva evidencia publicada y estudios aún sin publicar que puede soportar el uso de los inhibidores de la il- en pacientes con sars-cov- /covid- ; morena y col, en un estudio de tocilizumab como uso "off-label" en el tratamiento de neumonía por sars-cov- en milán, italia, este estudio abierto, prospectivo, describe las características clínicas y el pronóstico de pacientes con covid- confirmado y severo tratados con tcz iv, todos los pacientes, presentan niveles plasmáticos elevados de il- (> pg/ml) y saturación de oxígeno < % al aire ambiente, pacientes ( %) se encontraban con sistema de alto flujo de oxígeno y en ventilación invasiva, a los días luego del tratamiento se observa una caída dramática en la temperatura corporal y la pcr, con un incremento significativo en el conteo de linfocitos (p < . ); a los días del tratamiento, pacientes ( %) mostraron una mejoría en la severidad del cuadro; fueron dados de alta; ( %) mostraron empeoramiento de su cuadro clínico y de estos, murieron ( %). la mortalidad fue significativamente asociada con el uso de ventilación mecánica al inicio ( . % vs % de los pacientes en soporte de oxígeno no invasivo, p = . ), el efecto adverso más frecuente reportado fue la elevación de las enzimas hepáticas ( %), trombocitopenia ( %) e infecciones bacterianas serias e infecciones fúngicas en un ( %); los autores concluyen que el tcz ejerce un rápido beneficio sobre los marcadores inflamatorios y la fiebre, aunque no se consiguió un impacto clínico sobre el pronóstico, el riesgo aumentado de infecciones severas no es despreciable ( ) . capra y col, describieron pacientes en un hospital de italia con neumonía por covid- y falla respiratoria sin soporte ventilatorio y al menos uno de los siguientes: frecuencia respiratoria ≥ respiraciones/min, saturación ≤ % o pao /fio <= mmhg, los pacientes recibieron la terapia estándar para el momento (hidroxicloroquina, lopinavir y ritonavir) y fueron considerados el control; pacientes recibieron tzc con días de la admisión más el manejo estándar, los pacientes en el grupo de tratamiento mostraron de manera significativa una mayor sobrevida comparado con los pacientes control (hr para muerte, . ; % ic], . a . ; p = . ), ajustado para las características clínicas de base; de pacientes en el grupo de tcz y de en el grupo control murieron; % y . % de los pacientes que se dieron de alta en el grupo de tcz y en el control se recuperaron; la función respiratoria mejoró en el . % de los amci ® pacientes con tcz que aún se mantenía hospitalizados, donde el % de los controles empeoro y requirieron ventilación mecánica, dando al tcz un espectro positivo en términos de curso clínico y sobrevida en pacientes con covid ( ). guaraldi y col; evaluaron el papel del tcz en reducir el riesgo de ventilación mecánica invasiva en pacientes con neumonía severa por covid- quienes recibían tratamiento estándar para el momento (hidroxicloroquina, azitromicina, antirretrovirales y heparinas de bajo peso molecular) en un estudio retrospectivo, observacional en bologna, reggio emilia y módena, italia; el tcz fue dado a dosis de mg/kg de peso corporal de forma iv (con un máximo de mg) en dos infusiones separadas h o mg sc administradas en dos dosis simultáneas, una en cada muslo ( mg en total), cuando la formulación iv no se encontraba disponible; el pronóstico primario fue la combinación de ventilación mecánica invasiva o muerte; de pacientes ingresados, ( %) tenían neumonía severa por covid- y fueron incluidos, ( %) de pacientes en el grupo estándar requirieron ventilación mecánica, comparados con ( %) de pacientes tratados con tcz (p = · ; [ %] de pacientes tratados iv y [ %] de pacientes tratados sc); ( %) pacientes en el grupo estándar murieron, comparado con ( %; p < . ) pacientes con tcz ( [ %] del grupo iv y [ %] sc); luego de ajustar para sexo, edad, centro de reclutamiento, duración de los síntomas y puntaje de sofa, el tratamiento con tcz fue asociado con una reducción en el riesgo de ventilación mecánica invasiva o muerte (hr . , % ic . - . ; p = . ); ( %) de pacientes tratados con tcz fueron diagnosticados con nuevas infecciones en comparación con ( %) de pacientes en el grupo estándar (p < . ) ( ) . campochiaro y col, en un solo centro evaluó la eficacia y seguridad del tcz en pacientes con covid- severo, se diseñó un estudio retrospectivo en pacientes con características de hiper-inflamación (definida como una elevación tanto en la pcr, ≥ mg/l, normal < mg/l o ferritina ≥ ng/ml, normal < ng/ml en presencia de un incremento en la dhl > u/l), acompañado de un compromiso respiratorio severo, definido como hallazgos típicos en la radiografía y/o tomografía, la presencia de una saturación de oxígeno ≤ % al aire ambiente o una pao :fio ≤ mmhg ingresados a la uci, comparando pacientes con tcz iv al manejo estándar, pacientes fueron incluidos de los cuales fueron tratados con tcz; los pacientes se encontraban con alto flujo o ventilación mecánica no invasiva, a días de seguimiento, % de los pacientes con tcz experimentaron mejoría clínica comparado con un %del tratamiento estándar (p = . ); la mortalidad fue % en el grupo de tcz y % en el grupo estándar (p = . ); la incidencia de infección y trombosis pulmonar fue similar en ambos grupos ( ); somers y col, evaluaron un estudio observacional en pacientes con neumonía por covid- severo que se encontraban en ventilación mecánica, evaluando como pronóstico la probabilidad de sobrevida posterior a la extubación; pacientes fueron incluidos, recibieron tcz y no; en los modelos ajustados, el tcz, fue asociado con una reducción del % en el riesgo de muerte [hr . % ic . a . ]; aunque el tcz, fue asociado con un incremento en la proporción de pacientes con superinfecciones ( % vs. %; p < . ), no hubo diferencias en la mortalidad a días entre los pacientes tratados con tcz con o sin superinfecciones [ % vs. %; p= . ] ( ). price y col, también publicaron un estudio observacional de pacientes hospitalizados con covid- , los pacientes recibieron tcz si cumplían criterios del síndrome de liberación de citoquinas, se evaluaron pacientes; de los cuales ( %) recibieron tcz, estos pacientes que recibieron ventilación mecánica la sobrevida fue del % ( % ic, - ), luego del tcz pocos eventos adversos fueron reportados y tanto la oxigenación como los biomarcadores de inflamación mejoraron ( ) y por último, en un estudio preliminar con datos aún sin publicar perrone y col, evaluaron la eficacia del tcz en pacientes con neumonía por covid- , en un estudio amci ® multicéntrico fase en italia; se utilizó tcz, a dosis de mg/kg iv, una o dos administraciones con horas de diferencia; y casos fueron disponibles para un análisis de intención a tratar, pacientes murieron; las tasas de letalidad fueron de . % ( . % ic, . - . , p = . ) y . % ( . % ic, . - . , p < . ) a y días; el tcz redujo la tasa de letalidad a días pero no a días comparado con las esperadas sin presentar una toxicidad significativa; la eficacia fue más evidente en los paciente que no requerían ventilación mecánica ( ). recomendaciÓn se recomienda no utilizar de rutina bloqueadores de interleuquina- (anakinra) en pacientes con infección por sars-cov- /covid- . aunque su ventaja está en el perfil de seguridad, su vida media corta ( horas) y porque las infecciones oportunistas son raras ,no hay suficiente evidencia para emitir una recomendación sobre el uso de este medicamento; cavalli y cols, de milán, italia, realizaron un estudio de cohorte retrospectivo en pacientes con sdra moderado a severo con hiperinflamación (pcr ≥ mg/dl, ferritina ≥ ng/ml o ambos), manejados con ventilación mecánica no invasiva fuera de la uci y que recibieron tratamiento con hidroxicloroquina y lopinavir, los pacientes que recibieron anakinra, mg/kg dos veces al día intravenosa (n= , dosis alta) o mg dos veces al día subcutánea (n= pacientes, dosis baja) fueron comparados con una cohorte retrospectiva que no recibió anakinra (tratamiento estándar); la duración del tratamiento se prolongó hasta el beneficio clínico sostenido (reducción del % en la pcr, y una pafi > , durante al menos días consecutivos) o hasta la muerte, bacteriemia, o efectos secundarios (alt > veces valores de referencia); el tratamiento con anakinra a bajas dosis se interrumpió después de días debido a la escasez de efectos sobre la pcr y el estado clínico. a los días, el tratamiento con dosis altas de anakinra se asoció con una reducción en la pcr y mejoría en la función respiratoria en de pacientes ( %); en el grupo estándar, ocho de pacientes ( %) mostraron mejoría respiratoria a los días. en días de seguimiento, la sobrevida fue del % en el grupo de dosis altas de anakinra y del % en el grupo estándar (p = . ). se trata del primer estudio que demuestra seguridad y mejoría en los pacientes covid- , pero en el contexto fuera de la uci ( ) . huet y cols, de parís, francia, realizaron el estudio llamado ana-covid- en el que compararon pacientes tratados con anakinra subcutánea mg dos veces al día durante h, luego mg diarios durante días, con pacientes históricos; su criterio de inclusión fue tener una saturación de oxígeno del % o menos con un soporte de mínimo de l / min de oxígeno. la admisión a la uci por ventilación mecánica invasiva o muerte se produjo en ( %) pacientes en el grupo de anakinra y ( %) pacientes en el grupo histórico (hr . amci ® pacientes en el grupo histórico tuvieron un aumento en las aminotransferasas hepáticas ( ). recomendaciÓn se sugiere que la terapia con interferón sólo sea considerada en pacientes con formas graves de infección por covid- en el marco de un estudio clínico. estudios preliminares muestran que el virus del covid- induce una expresión muy débil de interferones en las células infectadas, lo que obstaculiza la respuesta inmune innata temprana a la infección y sugiere que el uso de interferón (ifn) exógeno para estimular la inmunidad antiviral ( ) . zhou q y col, en china, en un estudio observacional de pacientes con covid- con gravedad mixta proporcionó evidencia de muy baja calidad que la adición de interferón-α a la terapia con umifenovir no afecta el tiempo de eliminación viral o la duración en la estancia hospitalaria cuando se comparó con el umifenovir solo ( ) . hung if y cols, de hong kong, realizaron un ensayo multicéntrico, en adultos con covid- , en los que pacientes recibieron una combinación de lopinavir/ritonavir y tres dosis de millones de unidades internacionales ( · mg) de interferón beta- b en días alternos (grupo de combinación) y pacientes recibieron lopinavir/ritonavir (grupo control); la terapia de combinación fue segura y superior al control, para aliviar los síntomas y acortar la duración de la eliminación del virus y la estancia hospitalaria; se trata de un estudio fase , en pacientes con covid- leve a moderado (ningún paciente con ventilación en el grupo de combinación), en el que el ifn se administró en los primeros días de inicio de los síntomas y con el uso de un análogo de nucleósido oral (ribavirina), que no está en nuestras guías ( ) . se necesitan estudios de ifn solo o combinado en pacientes críticos con covid- . los efectos adversos de los ifn tipo i pueden limitar su uso para una intervención generalizada, como se propone en el brazo ifn-β con lopinavir/ritonavir del ensayo solidaridad de la oms. la administración por inhalación de vapor que se realiza actualmente en china ofrece la ventaja de acceso rápido al tracto respiratorio; sin embargo, la farmacodinamia y la farmacocinética de este modo de administración nunca se han evaluado. se sugiere no utilizar de rutina corticoides en el tratamiento de pacientes con sospecha o diagnóstico de covid- . no se puede considerar su uso profiláctico ni en pacientes con enfermedad leve sin requerimiento de oxígeno. débil en contra page en diciembre de , una serie de casos de neumonía de causa desconocida surgió en wuhan, hubei, china, con presentaciones clínicas muy parecidas a una neumonía viral; los análisis de secuenciación profunda de muestras del tracto respiratorio inferior indicaron un nuevo coronavirus, que se denominó novel coronavirus (covid- - ) ( ) . en la actualidad, en ausencia de terapia preventiva para sars-cov- , la piedra angular de atención para pacientes con covid- sigue siendo el manejo de apoyo, que va desde el tratamiento ambulatorio sintomático hasta el tratamiento intensivo completo con medidas de soporte en cuidados intensivos ( ) . dentro del manejo farmacológico se ha planteado la opción del uso de corticoides, la justificación estaría basada en la disminución de la respuesta inflamatoria del huésped a nivel pulmonar; es decir, un efecto inmunomodulador, ya que esta infección puede conducir a un síndrome de distrés respiratorio agudo (sdra); sin embargo, el beneficio puede verse superado por los efectos adversos, incluido el retraso en el aclaramiento viral y mayor riesgo de infección secundaria. a pesar de que la evidencia directa de corticoides en covid- es limitada, revisiones de los resultados en otras neumonías virales nos podrían orientar en principio en esta actual situación ( ) . teniendo en cuenta lo anterior; stockman y cols, en el . , realizaron una revisión sistemática sobre ensayos en pacientes con sars; quince ensayos examinan el uso de corticoides con diez o más pacientes en tratamiento; ensayos también recibían ribavirina; trece de estos estudios no fueron concluyentes; dos estudios describen un daño potencial con el uso de esteroides; en la literatura china estos autores encontraron catorce estudios con uso de esteroides en sars; doce fueron suspendidos por posible daño, la mayoría de estos ensayos se realizaron con muestras pequeñas de pacientes y de manera retrospectiva ( ) . arabi y cols, en noviembre de . , realizaron un estudio multicéntrico de cohorte retrospectivo en hospitales de atención terciaria de arabia saudita, donde se incluyeron pacientes; el uso de corticoides en pacientes con mers no se asoció con un cambio significativo a los días en la mortalidad y se documentó un retraso en la eliminación del arn de mers-cov ( ) . en cuanto hace referencia a la situación actual de pandemia por sars-cov- y compromiso pulmonar; wu y cols, en marzo de . realizaron un estudio retrospectivo de pacientes con covid- en china; para aquellos pacientes que desarrollaron sdra, el tratamiento con metilprednisolona estuvo asociado con una disminución del riesgo de muerte ( / [ %] con esteroides vs / [ %] sin esteroides; hr, . [ic %, . - . ]), con las limitaciones de los estudios retrospectivo, de un solo centro, con un limitado número de pacientes ( ). zha y cols, en marzo de . , describen el uso de corticosteroides en el tratamiento de pacientes con covid- ; no hallaron asociación entre la terapia con esteroides y el pronóstico de los pacientes sin sdra, siendo un estudio con una serie muy pequeña de pacientes ( ) . yang y cols, en marzo de . , en una revisión sistemática y meta-análisis que incluyó . pacientes de estudios, describen como el tratamiento con corticoides estuvo asociado con una mayor mortalidad (rr = . , ic % = . - . , p = , ), mayor estancia (wmd = . , ic % . - . , p = < , ) y una mayor tasa de infección bacteriana (rr = . , ic % . - . , p = < . ); con algunas limitaciones en este metaanálisis, la mayoría de los estudios incluidos son estudios de cohorte retrospectivos, controles históricos, con un bajo nivel de evidencia y una falta de ensayos controlados aleatorizados con buen diseño, sin un estándar uniforme para el tiempo y la dosis de los corticoides utilizado en los estudios; los efectos de los corticosteroides pueden ser influenciado también por otras opciones terapéuticas, como los medicamentos antivirales ( ) . por último, li y cols, en mayo de . , en otra revisión sistemática y metaanálisis, con respecto al uso de corticosteroides en sujetos con amci ® infecciones por sars-cov- , sars cov y mers-cov, se determinó que hubo retraso en la eliminación del virus sin mejoría en la supervivencia, reducción en la duración de la hospitalización o tasa de admisión en la uci y/o uso de ventilación mecánica; presentándose varios efectos adversos. debido a la preponderancia de los estudios observacionales en el conjunto de datos y los sesgos de selección y publicación, se concluye especialmente con respecto al sars-cov- , que se necesita mayor investigación con ensayos clínicos aleatorizados. internamente en este meta-análisis sugiere precaución al usar esteroides en pacientes con covid- ( ). horby y col en una rama del ensayo de evaluación aleatorizada de la terapia covid- (recovery), estudio aleatorizado, controlado, abierto que compara una gama de posibles tratamientos con la atención habitual en pacientes hospitalizados con covid- , compararon el uso de la dexametasona a dosis de mg día (oral o intravenosa) una vez al día por días o el alta según lo que ocurriera primero contra el manejo habitual; en pacientes aleatorizados que recibieron dexametasona se compararon con pacientes en manejo estándar; ( . %) pacientes en el grupo de dexametasona y ( . %) pacientes en el grupo control murieron a los días, con un riesgo relativo ajustado para la edad (rr . ; % ic . a . ; p < . ). la mortalidad relativa y absoluta variaron significativamente en relación al soporte ventilatorio al momento de la aleatorización; la dexametasona redujo las muertes en una tercera parte de los pacientes que recibieron ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p < . ), y una quinta parte en los pacientes que reciben oxígeno sin ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p = . ), pero sin reducir la mortalidad en paciente que no recibieron soporte respiratorio al momento de la aleatorización ( . % vs. . %, rr . , % ic . a . ]; p = . ) ( ). se recomienda no utilizar plasma convaleciente como tratamiento de rutina en paciente con sars-cov -covid- . se debe considerar su uso en el marco de un ensayo clínico y con alguno de los dos escenarios siguientes: escenario a (enfermedad severa), definida como uno o más de los siguientes: disnea, frecuencia respiratoria > /min, spo < %, pao /fio < o empeoramiento radiológico con aumento > % de los infiltrados pulmonares en - horas. escenario b (enfermedad que amenaza la vida), definida como uno o más de los siguientes: falla respiratoria, choque séptico, o disfunción multiorgánica. se recomienda no utilizar plasma convaleciente para profilaxis clínica de rutina contra la infección por sars-cov- , solo se debe considerar en el marco de un ensayo clínico. ( ) . una revisión sistemática y meta-análisis exploratorio realizado en identificó estudios de infección por coronavirus sars e influenza severa, el estudio reveló una reducción de la mortalidad, especialmente si el plasma convaleciente se emplea en la fase temprana de la enfermedad cuando se comparó con placebo o no tratamiento (or . ; ic del % . - . ); sin embargo, hay que tener presente que los estudios son de baja calidad, carecen de grupos control y puede tener riesgo moderado a alto de sesgo ( ) . se ha sugerido que el plasma convaleciente de pacientes que se han recuperado de covid- puede ser una terapia potencial, proporcionando inmunidad pasiva de los anticuerpos específicos contra sars-cov- y podría servir para prevenir y tratar la enfermedad ( ) . las personas que se han recuperado de la infección por sars-cov- pueden generar anticuerpos neutralizantes ( , ) que podrían tener aplicación en la prevención de infección en ciertos escenarios, como las personas con comorbilidades subyacentes que predisponen a enfermedad grave y aquellas con exposición de alto riesgo como los trabajadores de la salud y los expuestos a casos confirmados de covid- . existen algunos riesgos asociados con el uso de plasma convaleciente, unos conocidos y otros teóricos; los riesgos conocidos son aquellos asociados con la transfusión de hemocomponentes, incluida la transmisión de virus (ej. vih, vhb, vhc, entre otros) ( ); riesgo muy bajo, con los estándares de calidad actuales de los bancos de sangre; también se pueden presentar complicaciones no infecciosas, como las reacciones alérgicas, anafilaxia, reacción febril a la transfusión, lesión pulmonar aguda relacionada con la transfusión (trali), sobrecarga cardiaca asociada a transfusión (taco) y hemólisis si se administra plasma abo incompatible ( ) . los riesgos teóricos incluyen el empeoramiento de la infección dependiente de anticuerpos (antibody-dependent enhancement of infection -ade); el ade puede ocurrir en varias enfermedades virales e implica una respuesta inflamatoria exagerada ante la presencia de ciertos anticuerpos ( ) . otro riesgo teórico es que la administración de anticuerpos a las personas expuestas al sars-cov- puede evitar la enfermedad, pero modifica la respuesta inmune de tal manera que esos individuos monten respuestas inmunes atenuadas, lo que los haría vulnerables a la reinfección posterior, si se comprueba que este riesgo es real estos individuos podrían ser vacunados contra covid- cuando exista una vacuna disponible ( ) . durante el brote actual en china, se utilizó plasma convaleciente en algunos pacientes con covid- ( ), desde esta publicación se identificaron publicaciones relacionadas con el tema, entre todos los estudios fueron tratados con plasma convaleciente un total de pacientes( - ) (tabla ). shen y cols en marzo describieron en china el primer reporte en el cual el plasma convaleciente puede ser una opción de tratamiento en pacientes con covid- ; reportaron una serie de casos de pacientes críticamente enfermos con covid- y síndrome de dificultad respiratoria aguda (sdra), todos en ventilación mecánica, a quienes se les administró plasma convaleciente con anticuerpos neutralizantes [ a días después del inicio de la enfermedad (ddie)], todos ellos posteriormente mostraron mejoría clínica, la carga viral de los pacientes disminuyó y fueron negativas en los días posteriores a la intervención ( ) . de forma similar, duan y cols en mazo en china reportaron mejoría clínica en una serie prospectiva de casos de paciente severamente enfermos con covid- , que recibieron plasma convaleciente con un tiempo medio de . ddie ( a días) después del inicio de los síntomas, e hicieron amci ® una comparación con un grupo control histórico comparables en edad, género y severidad de la enfermedad ( ) . zhang y cols en mazo , en china reportaron una serie de casos de pacientes con covid- críticamente enfermos, en falla respiratoria con ventilación mecánica y dos de ellos con ecmo (membrana de oxigenación extracorpórea), a quienes se les dio tratamiento con plasma convaleciente en un tiempo medio . ddie, posteriormente todos tuvieron mejoría clínica ( ) . posteriormente ahn y cols en abril en corea, describieron una serie de dos casos de paciente con covid- severamente enfermos, en falla respiratoria y con ventilación mecánica, quienes además de recibir hidroxicloroquina, lopinavir/ritonavir y metilprednisolona, fueron tratados con plasma convaleciente entre - ddie, ambos pacientes se recuperaron y fueron liberados de la ventilación mecánica, uno fue dado de alta al momento del reporte ( ) . ye y cols en abril en china, describieron una serie de pacientes con covid- con anormalidades imagenológicas y deterioro clínico a pesar del tratamiento estándar y con pcr para sars -cov- persistentemente positiva, aunque no estuvieron en falla respiratoria o con ventilación mecánica, de hecho, una de las pacientes era portadora asintomática; todos recibieron plasma convaleciente entre a ddie, en todos los pacientes, excepto , hubo resolución de los cambios de vidrio esmerilado y consolidación, todos mejoraron y fueron dados de alta ( ) . zeng y cols en abril en china, reportaron una serie de casos con covid- en falla respiratoria y se compararon con controles que no recibieron plasma convaleciente por limitación en la disponibilidad y compatibilidad abo; a este grupo de paciente, se les administró plasma convaleciente en promedio . ddie, en todos los casos se negativizó la pcr para sars-cov- a los días después del tratamiento; sin embargo, contrario a los reportes de los estudios previos, en este grupo se murieron pacientes ( % vs %, p = . ), pero tuvieron mayor porcentaje de aclaramiento del virus (pcr sars-cov- negativa % vs . %, p = . ) antes de la muerte e incluso el tiempo de sobrevida fue mayor en el grupo de tratamiento (p = . ) ( ) . salazar y cols en mayo , en houston, texas, reportaron una serie de pacientes con covid- severa o amenazante para la vida, el desenlace primario fue seguridad y el secundario fue el estado clínico de los pacientes al día luego de la transfusión; al día posttransfusión, pacientes ( %) mejoraron con relación a su estado clínico basal, ( %) no tuvieron cambios y pacientes tuvieron deterioro clínico. siete de los nueve pacientes que mejoraron ( %) habían sido dados de alta; para el día post-transfusión, ( %) de los pacientes presentaron mejoría y pacientes más, habían sido dados de alta; tres pacientes permanecían sin cambios, pacientes se deterioraron y uno murió por una condición no relacionada con el plasma; el promedio de estancia hospitalaria fue de . días y la estancia hospitalaria luego de la transfusión fue en promedio días; hubo una disminución de los valores promedio de pcr desde . mg/dl el día , a , mg/dl y . mg/dl los días y respectivamente; al momento de la publicación del artículo, solo permanecían intubados pacientes; todos los pacientes que requirieron ecmo ya se habían liberado y ( %) fueron dados de alta ( ) . también en texas, estados unidos, ramachandruni y col en mayo , reportaron una serie de casos con covid- severa, falla respiratoria y en ventilación mecánica o pao /fio < , todos con comorbilidades; a los cuales les administraron metilprednisolona y posteriormente plasma convaleciente; compararon los valores basales de pao /fio y posterior a la intervención; encontrando, mejoría de la pao /fio en % luego del tratamiento con esteroides y en % luego de la administración de plasma convaleciente ( ) . finalmente, en respuesta al brote de covid- en los eeuu y las tasas de mortalidad reportadas, la fda en colaboración con la mayo clinic y la comunidad nacional de bancos de sangre desarrollaron un programa nacional de acceso ampliado para recolectar y distribuir plasma convaleciente donado por amci ® individuos que se han recuperado de covid- ; entre abril y mayo , ; fueron incluidos . pacientes con covid- severa o potencialmente mortal o con riesgo alto de progresión a covid- severa o potencialmente mortal en el programa nacional de acceso ampliado; en ese tiempo, un total de . pacientes inscritos recibieron transfusión de plasma convaleciente covid- . en una publicación reciente, joyner y cols en mayo , en estados unidos, hicieron un análisis de seguridad después de la transfusión de plasma convaleciente covid- humano con compatibilidad abo en . adultos hospitalizados con covid- grave o potencialmente mortal, % de los cuales se encontraban en uci; la incidencia de eventos adversos serios (eas) durante las horas siguientes a la transfusión de plasma convaleciente fue < %, incluyendo mortalidad ( . %); de los eas reportados, hubo incidentes reportados como eas relacionados, incluyendo muertes, eventos de taco, trali y reacciones alérgicas graves asociadas a la transfusión; sin embargo, solo (de ) eas fueron considerados definitivamente relacionados con la transfusión de plasma convaleciente por el médico tratante; en este grupo de pacientes, la tasa de mortalidad a los siete días luego de la administración del plasma convaleciente, fue del , % ( ) . a pesar que la tasa general de letalidad para la covid- parece ser aproximadamente . % ( ), la tasa de mortalidad reportada parece no ser excesiva si la comparamos con los informes de wuhan que sugieren tasas de letalidad del % para los pacientes hospitalizados ( ) y % entre los pacientes en unidad de cuidados intensivos ( ) . los nueve estudios mostraron mejoría en muchos aspectos, incluyendo el aclaramiento del virus, la disminución del suplemento de oxígeno y la ventilación mecánica, la normalización de los valores de laboratorio, y la recuperación en los hallazgos pulmonares radiológicos. todos los estudios, reportaron que no se presentaron eventos de seguridad o reacciones adversas serias relacionadas con la administración de plasma convaleciente en pacientes con covid- , excepto en casos relacionados, según criterio de los médicos tratantes, en el estudio publicado por joyner y cols ( ) . esta serie de estudios son alentadores; sin embargo, la mayoría de los reportes de casos tienen limitaciones significativas: carecen de los ajustes para factores de confusión críticos, incluidos los co-tratamientos, las características basales, la gravedad de la enfermedad y el momento de administración del plasma y deben ser seguidas de investigaciones adicionales. para establecer mejor el papel del plasma convaleciente es necesario realizar estudios dirigidos a los siguientes escenarios: . el uso como profilaxis post-exposición . evaluar si el plasma convaleciente es útil en paciente con enfermedad leve . el efecto del plasma convaleciente en pacientes con enfermedad moderada . el tratamiento de rescate con plasma convaleciente en pacientes que requieren ventilación mecánica debido a covid- . finalmente, trabajos que evalúen la seguridad y farmacocinética del plasma convaleciente en los pacientes pediátricos con alto riesgo. actualmente están en curso varios estudios para evaluar el tratamiento de pacientes infectados con sars-cov- con plasma convaleciente. una búsqueda realizada el de mayo de en clinicaltrials.gov con los términos "plasma convaleciente y covid- " mostró ensayos en curso sobre el uso de plasma convaleciente en pacientes con amci ® covid- , que nos ayudarán a resolver las inquietudes relacionadas con esta intervención ( ) . page se recomienda no utilizar de rutina las las inmunoglobulinas hiperinmunes en pacientes con infección por sars-cov- /covid- . la inmunoglobulina hiperinmune (h-igiv) se deriva de individuos con altos títulos de anticuerpos contra patógenos específicos y se ha utilizado con éxito en el tratamiento de infecciones, como el citomegalovirus y la gripe h n ( ) . se propone que la inmunoglobulina hiperinmune combinada con medicamentos antivirales puede ser efectiva en el tratamiento de pacientes con covid- , estos anticuerpos (ac) recogidos de los pacientes recuperados serán específicos contra covid- al aumentar la respuesta inmune en pacientes recién infectados ( ) . existe evidencia más sólida para el uso de h-igiv en el tratamiento de enfermedades virales. cheng y cols en enero de , realizaron una revisión retrospectiva en hong kong, que reveló que el plasma convaleciente de los sobrevivientes de sars-cov administrados a pacientes con sars-cov que tenían enfermedad progresiva resultó en tasas de alta significativamente más altas en el día y tasas de mortalidad más bajas, en comparación con los controles históricos ( ) . hung y cols en febrero de , realizaron un estudio de cohorte prospectivo sobre la efectividad del plasma convaleciente de los sobrevivientes de h n con un título de ≥ : ofrecido a pacientes de la uci con infección grave por h n ; los pacientes que rechazaron las infusiones de plasma convalecientes fueron controles; veinte de los pacientes recibieron sueros convalecientes, el tratamiento con plasma convaleciente condujo a una reducción significativa de la carga viral respiratoria, los niveles séricos de citocinas (il- , il- , tnfα) y la mortalidad ( ) . posteriormente hung y cols en agosto de , publicaron un estudio multicéntrico prospectivo, doble ciego, aleatorizado y controlado en el que compararon la efectividad de la inmunoglobulina hiperinmune (h-igiv) del plasma convaleciente de los sobrevivientes de h n versus la inmunoglobulina iv (igiv) normal, en pacientes con h n en uci con soporte respiratorio y recibiendo oseltamivir; este estudio mostró, una reducción de la carga viral y una mayor supervivencia en el grupo que recibió h-igiv dentro de los días posteriores al inicio de los síntomas, demostrando la superioridad de la inmunoglobulina hiperinmune sobre la igiv en el tratamiento de la infección grave por h n ( ). el uso de inmunoglobulina hiperinmune ha demostrado una clara efectividad en el tratamiento de la gripe y el sars-cov; sin embargo, el plasma se debe recolectar y procesar de pacientes convalecientes y verificar que tenga títulos adecuados. según la experiencia con el sars-cov, lo ideal es recolectar plasma de pacientes con un curso de enfermedad más leve ( ) . poco se sabe sobre la seguridad de la inmunoglobulina hiperinmune cuando se usa para el tratamiento de infecciones por coronavirus, los riesgos incluyen la exacerbación de la infección dependiente de anticuerpos (antibody-dependent enhancement of infection -ade)( ); el ade puede ocurrir en varias enfermedades virales, e implica una respuesta inflamatoria exagerada ante la presencia de ciertos anticuerpos; sin embargo, los estudios en sars y mers no proveen información suficiente para extrapolarse a la infección por sars-cov- . no se encontraron estudios con inmunoglobulina hiperinmune en el tratamiento de pacientes con covid- . no se puede emitir una recomendación a favor o en contra para el uso de la inmunoglobulina intravenosa como tratamiento adyuvante en pacientes con covid- severo. se debe considerar la inmunoglobulina intravenosa como tratamiento adyuvante en pacientes con covid- severo, en el contexto de estudios clínicos en los siguientes escenarios. escenario a (enfermedad severa), definida como uno o más de los siguientes: disnea, frecuencia respiratoria > /min, spo < %, pao /fio < o empeoramiento radiológico con aumento > % de los infiltrados pulmonares en - horas. escenario b (enfermedad que amenaza la vida), definida como uno o más de los siguientes: falla respiratoria, choque séptico, o disfunción multiorgánica. en las enfermedades virales, los anticuerpos ejercen su efecto por neutralización viral (bloqueo de la entrada de células virales y, por lo tanto, replicación), activación del complemento, opsonización y mediación de citotoxicidad celular dependiente de anticuerpos. la neutralización viral es específica de antígeno; otras actividades antivirales son antígeno-inespecíficas y se realizan en parte a través de interacciones fc: fc receptor. en la infección por sars-cov- , el principal antígeno objetivo asociado con la neutralización es la proteína spike, que es responsable de la unión del sars-cov- a las células epiteliales, incluidos los neumocitos; los anticuerpos en las inmunoterapias pasivas covid- son de naturaleza policlonal, con múltiples epítopos contra los paratopes de sars-cov- , incluido el dominio de unión al receptor en la proteína spike ( ) . la inmunoglobulina intravenosa (igiv) es un producto derivado del plasma de miles de donantes utilizados para el tratamiento de inmunodeficiencias primarias y secundarias, afecciones autoinmunes/inflamatorias, trastornos neuroinmunológicos y secuelas relacionadas con infecciones; la igiv proporciona protección inmune pasiva contra una amplia gama de patógenos; actualmente, la experiencia con el uso de igiv en el tratamiento de la infección por sars-cov- es muy limitada; sin embargo, la justificación del uso de ivig en la infección por sars-cov- es la modulación de la inflamación ( ) . la igiv se ha usado en el tratamiento de otros coronavirus, incluido el sars cov. stockam y cols, en septiembre de , en respuesta a una petición de "the world health organization -who", realizaron una revisión sistemática de los efectos del tratamiento en los pacientes con síndrome respiratorio agudo, incluida la igiv o el plasma convaleciente; se evaluaron cinco estudios sobre el uso de igiv o plasma convaleciente administrado además de corticosteroides y ribavirina, se consideró que estos estudios no fueron concluyentes ya que los efectos de la igiv o el plasma convaleciente no podían distinguirse de otros factores que incluían comorbilidades, estadio de la enfermedad o el efecto de otros tratamientos ( ) . wnag y cols, en mayo , hicieron un estudio prospectivo, en un solo centro, de infección por sars en taiwán, se administró igiv si el paciente tenía leucopenia amci ® o trombocitopenia, o si había progresión rápida de la enfermedad en la radiografía; un total de pacientes recibieron igiv, de los cuales tenían citopenias graves, uno de ellos tenía evidencia de síndrome hemofagocítico y paciente tuvieron progresión radiológica de la enfermedad; el estudio sugiere que la igiv condujo a una mejora significativa en el recuento de leucocitos y plaquetas, pero reconoce que no había un grupo de control para evaluar objetivamente las respuestas ( ) . lew y cols, en julio , reportaron un estudio retrospectivo de un solo centro en singapur, se encontró que los pacientes adultos con sars tratados con un régimen de pulso de metilprednisolona ( mg) e igiv ( . mg/kg) diariamente durante tres días consecutivos tuvieron una hazard ratio ajustada de . para mortalidad en comparación con el grupo no tratado, con una tendencia hacia una recuperación más temprana; sin embargo, este hallazgo no fue estadísticamente significativo (ic del %: . a . ; p = . ); además, este resultado tuvo como factor de confusión el uso concurrente de esteroides ( ) . aunque algunas de las preparaciones de igiv comercializadas actualmente (gamunex-c y flebogamma) contienen anticuerpos que reaccionan de forma cruzada contra el sars-cov- y otros antígenos de virus, in vitro( ), hasta la fecha, ningún ensayo clínico de alta calidad ha demostrado eficacia y seguridad convincentes de igiv en epidemias de coronavirus. a pesar de que los datos para el uso de igiv en la infección por sars y mers son débiles, la dosis alta de ivig puede ser útil en la infección grave por sars-cov- a través de la modulación inmune, saturando fcγr y reduciendo ade ( ) . en general, la inmunoglobulina intravenosa es bien tolerada y el perfil de seguridad es bien conocido. las reacciones adversas comunes son leves y autolimitadas, pero se sabe que en pacientes de alto riesgo se producen efectos adversos graves, como trombosis, disfunción renal y muerte. en cuanto la evidencia (tabla ); xie y cols en abril, en wuhan, china, realizaron un estudio retrospectivo, revisando casos de covid- severa (disnea, fr > /min, spo < % en reposo, pao /fio < , progresión imagenológica > % en - horas) o críticamente enfermos (falla respiratoria con ventilación mecánica, choque, disfunción orgánica múltiple) en el cual evaluaron la mortalidad a días como desenlace primario y como desenlace secundario evaluaron la mortalidad a días, días de estancia hospitalaria, de uci y la necesidad de ventilación mecánica; reportaron que el tratamiento con igiv dentro de las horas posteriores al ingreso no sólo redujo el uso de la ventilación mecánica comparado con el tratamiento luego de horas del ingreso ( . % vs . %, p = . ), sino que también redujo la duración de la estancia en el hospital ( . ± . vs . ± . días, p = . ) y la uci ( . ± . vs . ± . días, p = . ); mejorando en última instancia la mortalidad a los días (p = . ); concluyen, que el estudio demostró que el tratamiento con igiv en pacientes con covid- con neumonía grave puede mejorar los indicadores en poco tiempo y mejorar la eficiencia del tratamiento de los pacientes con alta efectividad ( ) . el tratamiento con dosis altas de igiv ( g/día durante días) al inicio del distrés respiratorio, sumado al tratamiento de soporte y en un caso combinados con antivirales (lopinavir/ritonavir) y metilprednisolona en covid- grave publicado por cao y cols en marzo, en wuhan, china ( ), demostró la elevación de los recuentos de linfocitos, disminución de los marcadores inflamatorios, recuperación de la oxigenación, resolución parcial/completa de las alteraciones radiológicas pulmonares y las pruebas de hisopos nasales y orofaríngeos negativos dentro de unos pocos días después del inicio tratamiento (< días). lanza y cols en mayo , reportaron en nápoles, italia, el caso de una mujer de años que tenía covid- severa y que venía con deterioro clínico a la cual se le venía dando tratamiento con hidroxicloroquina más azitromicina, no se le administraron amci ® esteroides por el riesgo de disminuir la depuración de la viremia, a quién se le administró igiv el día después de iniciados los síntomas con mejoría clínica rápida, normalización de los gases arteriales y disminución marcada de los infiltrados pulmonares al día y respectivamente; como evento adverso, reportaron hipotensión durante el inicio de la infusión que se mejoró al disminuir la velocidad de infusión. la paciente finalmente se recuperó, negativizó rt-pcr sars-cov- y fue dada de alta ( ) . se recomienda la tromboprofilaxis farmacológica en todos los pacientes confirmados o sospechosos de covid- severo, a menos que está contraindicada, en cuyo caso es razonable la implementación de profilaxis no farmacológica. en términos generales se reconoce que los pacientes hospitalizados con enfermedad médica aguda, incluidas infecciones como la neumonía, tienen un mayor riesgo de eventos tromboembólicos ( ) . tang y cols, en china describieron múltiples trastornos de la coagulación en pacientes con covid- , aquellos pacientes que no sobrevivieron tenían significativamente mayores niveles de dímero-d y productos de degradación de la fibrina y con tiempos de coagulación convencionales más alargados al ingreso (p < . ); . % de los no sobrevivientes y . % de los sobrevivientes cumplían criterios para coagulación intravascular diseminada( ); este mismo grupo realizó un estudio con pacientes con covid- severo, pacientes con coagulopatía asociada a covid- (cac), definida por un sic score ≥ la utilización de tromboprofilaxis redujo de manera significativa la mortalidad a días ( . % vs . %, p = . ) así como también en aquellos con un se recomienda no utilizar de rutina antiagregación en pacientes con covid- severo con el fin de prevenir desenlaces neurológicos adversos. no se encuentran estudios en la literatura para el uso de antiagregantes para el manejo específico del covid- ; el manejo de los eventos cardiovasculares en pacientes covid- no difiere de la población general sin la enfermedad. no se establecen diferencias en los estudios descritos, ni en las publicaciones hasta la fecha de la revisión ( ) . no se puede emitir una recomendación a favor o en contra sobre el uso de la anticoagulación terapéutica de rutina con heparinas de bajo peso molecular o heparina no fraccionada en pacientes con bajo riesgo de sangrado y con un curso clínico grave o crítico, que además tengan elevación del dímero d mayor a mcg/ml ( ng/ml) y/o fibrinógeno mayor a mg/dl. diferentes publicaciones describen como una estrategia de tratamiento basada en profilaxis con heparina de bajo peso molecular (hbpm) para tratar la coagulopatía grave por covid- podría no ser suficiente. especialmente porque estos pacientes tienen dentro de su coagulopatía, una predisposición mayor a la presencia de trombosis que al sangrado. además, los bajos niveles de antitrombina que se han descrito en estos pacientes, los hace más resistentes a la heparina, lo que sugiere que las dosis profilácticas ya sea de heparina no fraccionada o hbpm pueden ser inadecuadas( - ). asociaciÓn colombiana de medicina crÍtica y cuidados intensivos. amci ® no se puede emitir una recomendación a favor o en contra sobre la anticoagulación terapéutica de rutina con heparinas de bajo peso molecular en pacientes con covid- en estado crítico, que presenten elevación del dímero d mayor a mcg/ml ( ng/ml). tang y cols, en china con un estudio retrospectivo donde se incluyeron pacientes con covid- severo, se evaluó la presencia de trombosis como desenlace asociado. este estudio describe como niveles de dímero d por encima de ng/ml estaban asociados a una mayor probabilidad de muerte y en estos pacientes el tratamiento anticoagulante reduce de manera significativa la mortalidad ( . , ic % . - . ) ( , ) . no se puede emitir una recomendación a favor o en contra para la medición rutinaria de niveles de anti xa en pacientes con covid- en los que se decide hacer anticoagulación terapéutica con hbpm. se puede considerar la medición de niveles anti xa si se cuenta con la disponibilidad del recurso. harr y cols, en un estudio en donde se incluyeron pacientes con hiperfibrinogenemia relacionada a trauma, se evidenció como los niveles de fibrinógeno se correlacionaron significativamente con la consistencia del coágulo y adicionalmente como se genera una relación inversa entre los niveles de fibrinógeno y la actividad de las hbpm, lo que sugeriría una potencial resistencia a la heparina. basados en que los pacientes covid- presentan niveles de fibrinógeno en muchas ocasiones con niveles > mg/dl e incluso > mg/dl lo que hace razonable considerar que aquellos pacientes covid- que requieren dosis terapéuticas de hbpm y es posible evaluar los niveles de anti xa, hacer ajustes y monitoreo del nivel de anticoagulación sería una opción razonable ( ) . se recomienda el uso de hbpm o hnf para la anticoagulación terapéutica en pacientes con una indicación específica con diagnóstico de covid- . amci ® como previamente se describió, una revisión sistemática comparó las dosis fijas de hbpm subcutánea con dosis ajustadas de hnf intravenosa o subcutánea en personas con clínica sugestiva de tep, esta revisión demostró que la incidencia de tep recurrente fue menor con hbpm que en los participantes con hnf (or . , ic % . a , ), también se asoció con una reducción en el tamaño del trombo (or . , ic % . a . ), evidencia de baja calidad. sin embargo, no hubo diferencias en la mortalidad general entre los participantes tratados con hbpm y los tratados con ufh (or . , ic % . a . ). por otra parte, los protocolos de manejo en escenarios de coagulación intravascular diseminada (cid), proponen el uso de hnf por encima de la hbpm en pacientes en los que se indica la anticoagulación. más aún, la presencia de falla renal aguda es común en los pacientes con covid- , por lo que la opción de tratamiento con hnf tiene también escenarios en donde podrían ser de elección ( , ) . capítulo . procedimientos y covid- recomendaciÓn se recomienda realizar la preoxigenación en pacientes con sospecha o diagnóstico de covid- , cuando estén disponibles, en áreas de presión negativa con mínimo recambios de aire por hora o en instalaciones con ventilación natural o que tengan un recambio de aire de mínimo l/seg si están disponibles. se recomienda como complemento opcional durante la preoxigenación en el paciente crítico con diagnóstico o sospecha de covid- la caja de acrílico para protección durante la intubación, la caja no protege contra la generación de aerosoles fuera de esta y requiere para su uso, entrenamiento previo. si es difícil su uso retírela inmediatamente. se recomienda utilizar en la mascarilla quirúrgica sobre la mascarilla de oxigenación en el paciente crítico con sospecha o diagnóstico de covid- . se recomienda utilizar filtros hpfa entre la máscara y el dispositivo disponible para la preoxigenación en el paciente crítico con sospecha o diagnóstico de covid- . se recomienda en el paciente con sospecha o diagnóstico de covid- preoxigenación por a min, si el paciente luego de minutos no tiene incremento en la mejoría inicie la administración de medicamentos. se recomienda en caso de compromiso hemodinámico considerar ventilación a dos manos con cierre hermético de la máscara sobre la cara del paciente con frecuencias altas (> por minuto y baja presión). amci ® fundamento el manejo de la vía aérea es un procedimiento considerado generador de aerosoles, la enfermedad covid- tiene una alta tasa de transmisión y el personal de salud requiere el uso estricto del epp ( , ) , revise el enunciado para epp recomendado en esta guía. la posibilidad de permanencia del virus en algunos ambientes puede durar hasta horas, por esto una estrategia para proteger al equipo de salud y otros pacientes podrías ser estar en áreas con presión negativa, lo cual no es fácil de encontrar en nuestro contexto o que tenga un adecuado recambio de aire( ). como medidas complementarias se pueden utilizar opciones como las cajas acrílicas para intubación, esta disminuye el riesgo de contaminación por gotas, pero no elimina los aerosoles, es necesario previo entrenamiento. en caso de que la caja sea una limitante retírela inmediatamente ( ) . los pacientes covid- , clásicamente se presentan con tos, esto es un factor de riesgo para quienes manipulan la vía aérea, la utilización de mascarilla por parte del paciente debajo del dispositivo bolsa mascarilla , la cual también deberá tener un filtro de alta eficiencia para disminuir el número de partículas que pueden estar en el ambiente durante la preoxigenación y posible ventilación, ésta última la cual será evitada al máximo ( , , ) . la preoxigenación es una técnica que pretende barrer el nitrógeno y aumentar la disponibilidad de oxígeno para que cuando el paciente presente apnea por los medicamentos para la intubación o por su condición clínica, se disponga de un tiempo mayor sin desaturación crítica y riesgo de colapso cardio-respiratorio. considere que los pacientes con formas moderadas y severas de covid- , pueden tener más comprometida esta reserva respiratoria y puede no ser efectiva la preoxigenación y cuando inicia la apnea, la desaturación será más precoz. si después de minutos de preoxigenación no hay mejoría de la saturación arterial, considere fallida esta maniobra y considere mayor riesgo de hipoxemia severa con probabilidad de bradicardia extrema y paro cardiorrespiratorio. en caso de requerir ventilación por disminución rápida de la saturación de oxígeno arterial y considere necesario ventilación manual bolsa mascarilla a dos manos no debe ser vigorosa y debe utilizar filtros hpfa, estos reducirán los aerosoles en el ambiente( , ). se recomienda la utilización de cajas de acrílico para intubación del paciente con sospecha o diagnóstico de covid- como complemento durante la intubación para disminuir el riesgo de contaminación por gotas, sin embargo, no protege % la generación de aerosoles y si ésta hace más difícil la intubación retírela inmediatamente. amci ® se recomienda minimizar los intentos de intubación orotraqueal en el paciente con sospecha o diagnóstico de covid- , el primer intento debe procurar ser realizado por el más experimentado en el manejo de la vía aérea. se recomienda la intubación con videolaringoscopio en pacientes con covid- teniendo en cuenta disponibilidad y entrenamiento); esta alternativa puede ofrecer ventajas frente a la laringoscopia tradicional. se recomienda administrar medicamentos para asegurar la vía aérea en secuencia de inducción rápida, para obtener en el menor tiempo posible condiciones para la intubación ( a s). se recomienda en caso de intubación fallida por personal experto, considerar dispositivos supraglóticos como las máscaras laríngeas como medida de rescate con el riesgo de generación de aerosoles. se recomienda contar con disponibilidad de vasopresor y atropina en el sitio donde se realizará la intubación. en caso de contar con lidocaína se recomienda utilizar a dosis de mg/kg sin epinefrina. administrada minutos antes de la intubación. como se describió en el aparte de preoxigenación, se deben garantizar todas las medidas basadas en bioseguridad y protección adecuada para el personal de la salud, ubicación en áreas que cuenten con presión negativa o salas con un óptimo recambio de aire pueden ayudar a disminuir el riesgo de contagio. las medidas complementarias como la caja de taiwán o caja de intubación puede complementar de forma opcional estas medidas durante el proceso de aseguramiento definitivo de la vía aérea pero no garantiza % la eliminación de aerosoles, pudiendo ser un obstáculo para quien realiza la intubación, de ser así, se deberá retirar inmediatamente, por eso sólo es un complemento al epp, que es la verdadera protección en estos escenarios (se debe incluir máscaras n o ffp fpp ) ( , ) . el paciente críticamente enfermo puede tener comprometida de forma significativa su reserva respiratoria y hemodinámica por su cuadro clínico y puede empeorar por los medicamentos utilizados durante la intubación orotraqueal. las complicaciones en el manejo de la vía aérea se presentan cuando se realiza más de un intento dentro de los cuales están el traumatismo, desaturación e hipoxemia ( ) . es por esto por lo que se debe procurar que el primer intento sea realizado por el más experimentado en el manejo de la vía aérea e idealmente se logre la intubación en el primer intento con la menor hipoxemia secundaria ( , , ( ) ( ) ( ) . basado en el planteamiento anterior y considerando la ventaja de intubar pacientes críticamente enfermos en el primer intento dadas sus condiciones clínicas, la revisión de amci ® demandas asociadas a manejo de vía aérea en los estados unidos sigue siendo preocupante al considerar posibles causas la falta de entrenamiento y falta de aplicación de las guías y recomendaciones de manejo así como en la utilización de equipos adecuados para pacientes específicos ( ) ; se ha planteado especialmente en los pacientes covid- los cuales tienen un importante compromiso pulmonar y alto riesgo de desaturación, la posibilidad de encontrar una vía aérea difícil no predicha y dificultades en su manejo( , ). es por esto que se requiere del mejor dispositivo para manejo de vía aérea invasiva disponible, siempre y cuando se cuente con el adecuado entrenamiento previo en su uso, la ventaja de los videolaringoscopio se debe a la superioridad al compararla con la laringoscopia convencional, siendo en algunos grupos la primera opción para intubaciones electivas ( , ) . como se ha mencionado, el riesgo de una rápida desaturación en pacientes con enfermedad pulmonar, así como en pacientes con covid- , se debe utilizar la inducción de secuencia rápida la cual se utiliza para pacientes con estómago lleno en los cuales se quiere lograr condiciones de inconciencia y de intubación óptimas en el menor tiempo posible para disminuir el riesgo de broncoaspiración. en estos casos de falla respiratoria con tan mala reserva se quiere aprovechar la ventaja que ofrece esa técnica para tener en poco tiempo al paciente intubado con menor riesgo de desaturación. es así como los medicamentos en una inducción de secuencia rápida incluyen el opioide, hipnótico y relajante, estos dos últimos administrados simultáneamente y lavados con un bolo de cc. la opción del opioide en nuestro contexto suele ser fentanilo a dosis de a mcg / kg iv, dando a minutos de latencia para su efecto, luego el hipnótico que puede ser propofol entre y , mg / kg si la estabilidad hemodinámica lo permite o considera usar vasopresor simultáneo. en caso de preferir evitar la hipotensión la ketamina a dosis de a , mg / kg es una opción más estable hemodinámicamente. con relación al relajante neuromuscular la succinilcolina es la clásicamente utilizada dosis de a , mg/kg pero debido a sus efectos secundarios como hiperpotasemia, fasciculaciones, mialgias y un importante riesgo de hipertermia maligna algunos grupos no lo consideran, el rocuronio a dosis de , mg/kg ha demostrado lograr tiempos y condiciones de intubación similar a la succinilcolina sin los efectos secundarios de esta ( , ) algunos grupos han considerado no utilizarlos si la condición clínica del paciente es crítica pues éste período de latencia puede ser acompañado de una hipoxemia severa y paro cardíaco, por lo tanto sólo usan hipnótico y relajante neuromuscular. ante una vía aérea difícil no predicha en la cual no se logre la intubación, considere los dispositivos supraglóticos como las máscaras laríngeas los cuales son más fáciles de insertar en comparación con la técnica de intubación orotraqueal, y deben estar dentro del planeamiento y organización de elementos para manejo de la vía aérea invasiva. al lograr ventilar con este dispositivo se logrará una recuperación del paciente, pero se pueden generar aerosoles pues este mecanismo de cierre puede permitir escape de aire y macropartículas durante el ciclo respiratorio ya sea manual o mecánico ( , ) . el cuadro clínico de pacientes críticos y particularmente covid- , puede asociarse a inestabilidad hemodinámica y requerimiento de soporte vasopresor. la adición de medicamentos como los opioides o hipnóticos pueden asociarse a hipotensión la cual puede no responder a volumen, es necesario evitar episodios de hipotensión en especial en pacientes ancianos, con enfermedades cardiovasculares de base las cuales pueden tolerar menos estos cuadros de hipotensión, así como también pueden favorecer amci ® desbalance en la relación ventilación/perfusión a nivel pulmonar empeorando los cuadros de hipoxemia. la hipoxemia puede acompañarse de bradicardia y si no se corrige la ventilación o la bradicardia es muy probable que el paciente presente paro cardiorrespiratorio, por lo cual se recomienda utilizar una dosis de atropina para corregir la bradicardia, no mejorará la oxigenación, pero tendrá un tiempo adicional para recuperar la oxigenación y ventilación del paciente. en estos casos debe tener disponibles vasopresores y atropina desde el planeamiento de los medicamentos necesarios para el manejo de la vía aérea ( ) . se recomienda la intubación orotraqueal oportuna y no retrasar el inicio de la ventilación mecánica invasiva en los pacientes con sdra severo por covid- debido a mayor riesgo de desenlaces adversos. fundamento definir el momento de la intubación en esta población es un reto. la mayoría de los autores recomiendan el inicio "temprano" de la ventilación mecánica, sin embargo, la definición de cuando es temprano no es clara. este punto es motivo de análisis dado que a la luz de la evidencia actual la utilización de métodos no invasivos como la ventilación no invasiva y la cánula de alto flujo, para manejo inicial de pacientes con algún grado de hipoxemia es controvertido entre otras por el riesgo que supone al personal sanitario al ser un procedimiento generador de aerosoles. en el un estudio mostró que la intubación retrasada después de la falla al utilizar cánula de alto flujo o la ventilación no invasiva para pacientes con insuficiencia respiratoria moderada y grave se asoció con una mayor mortalidad. publicaciones recientes muestran que solo la quinta parte de los pacientes que murieron por covid- recibieron ventilación mecánica invasiva y soporte respiratorio más agresivo antes de la muerte, lo que indica que en muchos pacientes se habría retrasado la intubación. de los pacientes fallecidos solo el % recibieron tratamiento de oxígeno nasal o con mascarilla facial antes de su muerte. esta baja proporción puede tener varias explicaciones. primero, algunos pacientes con hipoxemia severa no tenían otros síntomas, como dificultad para respirar o disnea, es decir, desarrollaron una especie de hipoxemia silenciosa. en segundo lugar, la falta de suficientes ventiladores mecánicos invasivos es una razón importante que evitaría que los pacientes reciban intubación. tercero, el manejo de estos pacientes por un equipo de médicos no intensivistas; por lo tanto, pueden no estar seguros del momento en que un paciente requiere intubación. la serie de casos de la epidemia de covid- en wuhan mostró que la intubación tardía era común en la etapa inicial de la epidemia, mostrando que una de esas posibles razones del retraso incluía falta de ventiladores mecánicos invasivos y falta de capacitación clínica específica para el soporte respiratorio. recomendaciÓn se recomienda tomar la decisión de intubación orotraqueal en el paciente crítico con sospecha o diagnóstico de covid- utilizando una combinación de variables clínicas, gasométricas y hemodinámicas. tabla la intubación orotraqueal (iot) efectiva y segura, programada debe prevenir el colapso respiratorio y hemodinámico. siempre es necesario asegurar la escena del procedimiento de intubación con las consideraciones técnicas y de protección personal adecuadas. conocer los pasos para la realización del procedimiento de intubación orotraqueal (iot) contextualizados al paciente covid- , reduce los riesgos innecesarios. la iot es un procedimiento generador de aerosoles por lo tanto lo ideal es realizarlo en una habitación con presión negativa, sin embargo, la baja disponibilidad en el país obliga a utilizar otras alternativas de seguridad. una habitación de presión negativa es un cuarto que tiene una presión más baja que las áreas adyacentes, lo que mantiene el flujo de aire fuera de la habitación y hacía habitaciones o áreas contiguas. las puertas de la sala deben mantenerse cerradas, excepto al entrar o salir de la sala, y la entrada y la salida deben minimizarse. la intubación en el paciente crítico con covid- es de los procedimientos que mayor riesgo de aerosolización tiene, por lo tanto, se debe adoptar una posición de intervención oportuna, pero también segura, para evitar desenlaces desfavorables en el paciente y disminuir el riesgo de contaminación en el personal de salud, se recomienda individualizar cada caso mediante la combinación y análisis de los criterios clínicos, gasométricos y hemodinámicos de cada paciente. ( , ( ) ( ) ( ) se recomienda no realizar de rutina broncoscopia en los pacientes con sospecha o diagnóstico de covid- , debido al riesgo de generación de aerosoles. se puede considerar en atelectasias masivas con compromiso significativo de la oxigenación adicional a la lesión pulmonar per sé y la hemorragia alveolar para control local directo. en general la realización de broncoscopia en pacientes con sospecha o confirmación de covid- debe ser evitada y realizarse sólo con indicación de emergencia como cuerpo extraño en la vía aérea, hemoptisis masiva, obstrucción grave de la vía aérea central o atelectasia lobar o pulmonar completa( ). esto debido a la alta carga viral en la mucosa nasal y faríngea de los pacientes con infección por sars-cov- ( ) y la alta producción de aerosoles infecciosos que se generan durante este procedimiento. en caso de ser necesaria su realización, deberá ser llevada a cabo por el operador con mayor experiencia amci ® minimizando el tiempo de exploración y el personal expuesto en la sala. es mandatorio utilizar epp completo que incluya respirador fpp o fpp , bajo protocolo supervisado de donning y doffing ( ) . son de elección los broncoscopios desechables de un solo uso, pero de no ser posible se prefiere el uso de un broncoscopio flexible por encima de uno rígido por la más fácil manipulación de este. idealmente el procedimiento se llevará a cabo en el mismo cubículo del paciente que deberá contar con presión negativa y recambio de aire de a veces por hora. recomendaciÓn se recomienda no realizar de rutina la broncoscopia para la recolección de muestras para el diagnóstico de covid- en el paciente críticamente enfermo. la broncoscopia es una prueba de segunda elección para la toma de muestras respiratorias en los pacientes con sospecha o confirmación de covid- ( ) . la toma de muestras del tracto respiratorio superior por hisopado nasofaríngeo u orofaríngeo es el método primario y de elección para determinar la infección por sars-cov- . solo si resultaran dos pruebas negativas y persistiera una alta sospecha diagnóstica estaría indicado tomar muestras del tracto respiratorio inferior por broncoscopia, ya sea aspirado endotraqueal (bas) o lavado bronco alveolar (bal) ( ), prefiriendo la realización de minibal para la recolección de muestras ( ). las muestras deberán ser recogidas en un recipiente estéril, e introducidas en una bolsa con autocierre. deben manejarse con cuidado extremo evitando manipulaciones innecesarias y bajo protocolos de protección para el personal que las maneja, y trasladarse al laboratorio para su análisis. pueden almacenarse a - ºc las primeras h de su recolección; si se demorara más el análisis, precisa almacenarse a temperatura de - ºc ( ) . en una serie china la sensibilidad del bal fue de % frente a % en muestra de esputo (no recomendada) y % en hisopado nasofaríngeo ( ) por lo que el especialista que realiza el procedimiento deberá sopesar el riesgo de este procedimiento en cada caso, valorando que se beneficiarán aquellos pacientes que tengan una indicación adicional para su realización. se recomienda la realización de la traqueostomía cuando está indicada, en los pacientes covid- sospechosos y confirmados con pronóstico razonable de vida, después del o día de ventilación , previa valoración y consenso por el equipo quirúrgico y de cuidado intensivo, asegurando que las condiciones clínicas, ventilatorias y hemodinámicas se encuentran controlada. en el contexto de pacientes hospitalizados en cuidado intensivo, la traqueostomía se realiza para facilitar el destete de la ventilación mecánica, mejorar la limpieza de la vía aérea y el manejo de las secreciones, aumentar la comodidad de los pacientes y la movilización y disminuir la probabilidad de complicaciones como la estenosis traqueal; sin embargo no hay una clara disminución en la mortalidad ( ) ( ) ( ) . la infección actual por sars-cov , tiene diferentes estadios de gravedad, uno de ellos es el compromiso pulmonar el cual se caracteriza por un síndrome de dificultad respiratorio agudo (sdra). de acuerdo con el comportamiento de la covid- , entre un % a un % de los pacientes requieren ventilación mecánica ( , ) , este grupo de pacientes con manifestación grave del compromiso pulmonar requiere estrategias de protección pulmonar en la ventilación mecánica, sedación profunda y posiblemente parálisis muscular y puede tener una mortalidad entre el % y el % ( , ) . una de las principales características en éste grupo de pacientes es la mortalidad temprana, definida ésta como aquella que se produce en menos de días; de acuerdo a la experiencia en wuhan, china; leung ( ), reporta que la mortalidad se presenta en los primeros cinco días luego de la admisión hospitalaria y de acuerdo a lo referido por graselli et al ( ) , en la región de lombardía, italia, la mediana de mortalidad se presenta al día siete después del ingreso. con estas consideraciones, al principio de la pandemia y en las aproximaciones iniciales no se recomendaba realizar la traqueostomía en los primeros días posteriores a la intubación orotraqueal. sin embargo, con el conocimiento de la fisiopatología y las experiencias en otras series, como medida para facilitar la liberación de la ventilación mecánica, se ha podido realizar el procedimiento después de la primera semana de inicio de la ventilación. de acuerdo con el curso natural de la enfermedad, el paciente en promedio se intuba al día a de iniciado los síntomas, una semana posterior a la intubación para la traqueostomía, estaríamos alrededor del día de la enfermedad, donde los pacientes ya tendrán una disminución de la carga viral. esto sin embargo no evita la utilización de los epp necesarios. esta medida en específico fue discutida y consensuada entre la sociedad de medicina critica amci y la asociación colombiana de cirugía. no existe evidencia que permita evaluar el riesgo real de infección del personal asistencial de los pacientes con sospecha o diagnóstico de covid- en la realización de traqueostomías. se debe considerar en la traqueostomía y la realización de ésta como un procedimiento generador de aerosoles (organización mundial de la salud). se recomienda que los epp requeridos para la realización del procedimiento, deben incluir máscaras ffp o n , protección ocular, vestido antifluido idealmente desechable y amci ® guantes; este nivel de protección representa el mayor nivel de seguridad para realizar el procedimiento en el paciente con sospecha o diagnóstico de covid- . no existe actualmente artículos que permitan evaluar cual es el riesgo real de infección del personal asistencial en la realización de traqueostomías en pacientes con covid- ; quizás el ejemplo más cercano, es una serie de casos, reportada durante la epidemia del síndrome respiratorio agudo grave en el ( ), en el cual se realizaron traqueostomías sin ninguna infección del personal, en este reporte se aseguró un adecuado uso del equipo de protección personal (epp), el cual incluía las medidas de barrera, máscaras ffp y cuando existía la disponibilidad, respiradores con suministro de aire purificado. la traqueostomía y la realización de ésta es considerada por la organización mundial de la salud (oms) un procedimiento generador de aerosoles, bajo esta perspectiva, el epp requerido para la realización del procedimiento, debe incluir máscaras ffp o n , protección ocular, vestido antifluido idealmente desechable y guantes; este nivel de protección representa el mayor nivel de seguridad para realizar el procedimiento mencionado. es obligatorio, que todo el personal reciba el entrenamiento para la postura, el uso y el retiro de los epp, si estos pasos no se realizan de la forma adecuada, representan una fuente de contaminación( ). se recomiendan no esperar la negativización de la pcr para sars-cov para realizar la traqueostomía en el paciente con diagnóstico de covid- . fuerte en contra fundamento los estudios de zou et al y lescure et al ( , ) , muestran que la carga viral de los hisopados nasales y faríngeos es elevada en la primera fase de la enfermedad, con una disminución entre el día nueve al quince, pero esta puede permanecer detectable hasta por tres semanas ( ) . existen recomendaciones acerca de la necesidad de realizar la traqueostomía una vez la pcr para sars-cov sea negativa ( , ) ;aunque este esquema suena lógico, es importante tener presentes las siguientes consideraciones. la sensibilidad de una sola muestra para ruta-pcr puede ser sólo del %( ) y es posible que sea necesario realizar una segunda prueba para minimizar el riesgo para quien realiza el procedimiento, aunque esta aproximación no siempre puede ser viable desde el punto de vista clínico, epidemiológico y administrativo. amci ® recomendamos que la mejor estrategia es diferir la realización de la traqueostomía hasta días luego de la intubación cuando esta indicada, con el conocimiento acerca de la evolución natural de la enfermedad, en ese momento en la mayoría de los pacientes, lo más probable es que la condición ya se encuentre en la tercera semana desde el inicio de los síntomas, en cuyo caso lo más probable es que ya exista una disminución de la carga viral; este hecho no evita que se deba utilizar de la forma correcta los epp. recomendaciÓn se recomienda escoger la técnica teniendo en cuenta la experticia que tenga en el grupo tratante y la anatomía del paciente para la decisión de la técnica. se recomienda la guía ecográfica para disminuir la probabilidad de complicaciones del procedimiento si la anatomía es desfavorable para la realización de traqueostomía percutánea. se recomienda la traqueostomía quirúrgica en pacientes de riesgo elevado de complicaciones donde se requiere un control más rápido y seguro de la vía aérea. se recomienda no utilizar de forma rutinaria la utilización de broncoscopia para la realización de traqueostomía por vía percutánea. no hay evidencia directa hasta la fecha de publicación del consenso si existe superioridad entre las dos técnicas en el paciente con sospecha o diagnóstico covid- . en pacientes críticos no existen diferencia en los desenlaces cuando se evalúa el rendimiento de la técnica percutánea y la técnica quirúrgica, la elección de uno u otro método está dado por la anatomía del paciente, el entrenamiento de los profesionales y la disponibilidad de los diferentes insumos y técnicas. tampoco se ha logrado hasta la fecha evaluar durante la pandemia de covid- si existe una diferencia entre las dos técnicas y por lo tanto no es posible acercarse a una recomendación basada en la literatura. sin embargo, es importante que para la decisión de la técnica a utilizar se considere la anatomía del paciente y los siguientes aspectos:  no se recomienda la utilización de broncoscopia para la realización de traqueostomía por vía percutánea, ésta aumenta la generación de aerosoles y el número de personas expuestas a estos ( , ) . amci ®  si la anatomía es desfavorable para la realización de traqueostomía percutánea, la guía ecográfica puede disminuir la probabilidad de complicaciones del procedimiento ( ) .  la traqueostomía quirúrgica es una alternativa para la realización del procedimiento en las unidades de cuidado intensivo en momentos de sobrecarga laboral y adicionalmente puede tener un mejor y más rápido control de la vía aérea, especialmente en pacientes con riesgo elevado de complicaciones ( ) . recomendaciÓn se recomienda el uso de la terapia ecmo en sdra severo refractario por covid- (pao /fio < , posición prona, requerimiento de relajantes neuromusculares en algunos casos vasodilatadores pulmonares y maniobras de reclutamientos) sin respuesta clínica manifestado por:  pao /fio < mmhg por mas de horas  pao /fio < mmhg por mas de horas  ph < . + paco > mmhg por mas de horas además del criterio anterior, se recomienda tener en cuenta la edad, las comorbilidades y la expectativa de sobrevida del paciente con buena calidad de vida y en circunstancias donde no exista limitación de recursos. no hay estudios clínicos aleatorizados sobre el uso del ecmo en pacientes con covid- ( , ) . existe el estudio eolia ( ) , el cual fue detenido durante su realización, y de acuerdo a un análisis bayesiano posterior puede interpretarse como una disminución de la mortalidad en los pacientes en ecmo con sdra severo ( , , ( ) ( ) ( ) ( ) . de igual manera debe considerarse la racionalización de los recursos y el estado de prevalencia de la pandemia en un lugar determinado. el inicio de la terapia puede evaluarse en función de la cantidad de pacientes en falla respiratoria y la disponibilidad de personal y otros recursos; si el hospital debe comprometer todos los recursos en proveer medidas básicas de cuidado intensivo no debe utilizar el ecmo ( , ) . los pacientes jóvenes sin comorbilidades son considerados de alta prioridad al igual que los trabajadores de la salud ( , ) . amci ® se recomienda no desarrollar nuevos centros de ecmo en época de pandemia, sobre todo en situaciones con limitación de recursos. fuerte en contra fundamento actualmente se recomienda el uso del ecmo con las mismas indicaciones para sdra basado en la capacidad de las instituciones de salud para iniciar éste tipo de terapias ( ) . en épocas de crisis la capacidad de los hospitales está saturada y obliga a la reubicación y optimización de los recursos ( , ) . los centros que ofrecen la terapia en ecmo deben ser centros con resultados favorables y tiempos de soporte de pacientes relativamente cortos ( ) . cuando estamos en tiempos de capacidad hospitalaria convencional y existe disponibilidad de camas de cuidado intensivo se pueden ofrecer los servicios de ecmo vv, va, e-cpr inclusive a pacientes no covid- , cuando estamos en contingencia y capacidad nivel se debe hacer un triage respecto a pacientes jóvenes y ofrecer ecmo vv, va, escoger muy bien los casos para pacientes no covid- y no ofrecer e-cpr, cuando estamos en contingencia y capacidad nivel es porque ya se están usando sitios de expansión y están casi saturados se restringe el ecmo a todas las indicaciones y se prioriza a pacientes con indicaciones no covid- con mayor riesgo de sobrevida, el ecmo vv queda para pacientes jóvenes, con disfunción de órgano y covid- positivo, no se ofrecerá ecmo va o e-cpr y cuando estamos en capacidad de crisis es porque la capacidad total hospitalaria está sobresaturada y no es posible realizar ecmo tanto en pacientes covid- como en los no covid- ( , ) . se recomienda practicar e implementar medidas de capacitación y vigilancia continua para mejorar la higiene de manos, evaluando la adherencia a protocolos establecidos en los trabajadores de la salud mediante listas de chequeo y supervisión para evitar infecciones cruzadas en el entorno del paciente con sospecha o diagnóstico de covid- . se recomienda establecer protocolos específicos para reducir el riesgo de infecciones que se deriven de la interacción y el cuidado del paciente crítico con sospecha o diagnóstico de covid- . amci ® se recomienda implementar prácticas de cuidado para la prevención de contagio de covid- . se debe utilizar el equipo de protección personal (epp) para la prevención de enfermedades de componente infeccioso asociado a exposición con fluidos corporales derivados del paciente crítico con sospecha o diagnóstico de covid- . las infecciones relacionadas con la atención sanitaria (iras) son definidas por la organización mundial de la salud como aquellas "infecciones que se presentan en un paciente durante el proceso de atención en un hospital u otro centro sanitario que no estaban presentes o no se estaban incubando en el momento del ingreso; se incluyen las infecciones contraídas en el hospital pero que se manifiestan tras el alta hospitalaria y también las infecciones profesionales entre el personal del centro sanitario". las iras representan una importante carga de enfermedad que se asocia a un impacto negativo en la economía del paciente y del sistema sanitario. la organización mundial de la salud plantea la higiene de manos como la principal medida necesaria para reducir y prevenir las iras; por esta razón establece directrices sobre la higiene de manos en la atención sanitaria y basada en esta propone la estrategia multimodal para la mejora de higiene de manos. las estrategias mencionadas anteriormente han demostrado el incremento en el cumplimiento de higiene de manos y disminución en las infecciones relacionadas con la atención en salud. la estrategia multimodal se articula a través de cinco componentes: cambio del sistema, formación, evaluación/ retroalimentación, recordatorios en el lugar de trabajo clima institucional. a través de estos componentes, se garantiza que el centro sanitario cuenta con la infraestructura necesaria para practicar adecuadamente el lavado de manos incluyendo dentro de este el acceso a un suministro seguro continuo de agua, jabón, preparado alcohólico y toallas; a su vez se proporciona educación, evaluación y retroalimentación con regularidad a todos los profesionales sanitarios ( se recomienda realizar un plan de cuidados organizado y específico en paciente crítico con sospecha o diagnóstico de covid- , ofreciendo el uso óptimo de recursos e intervenciones. se recomienda evitar el uso de excesivo de papelería relacionada con los registros usados para gestión de insumos y atención de los pacientes. se recomienda realizar intervenciones educativas enfocadas a mejorar la adherencia y adecuado uso de los epp. se debe procurar el cuidado de los elementos de protección personal bajo un protocolo que conserve las condiciones de integridad de estos. la actual reserva de elementos de protección personal (epp) es insuficiente debido al aumento de la demanda global, por el incremento de casos de covid- y por la información errónea que ha conllevado a compras de pánico y almacenamiento. por esta razón la organización mundial de la salud a través de su guía: uso racional del equipo de protección personal para la enfermedad por covid- ha implementado las siguientes estrategias para optimizar la disponibilidad de (epp): usar los (epp) adecuadamente, minimizar la necesidad de (epp) y coordinar el suministro adecuado de (epp). ( ) la duración máxima del uso continuo de la n es de a horas, siguiendo las recomendaciones del manual de medidas básicas para control de infecciones en ips de minsalud. pero en lo cotidiano, ningún trabajador tolera a horas continuas con un respirador. por esto, su uso continuo en el sitio de trabajo dependerá de la necesidad de pausar para comer, para ir al baño, etc. en este caso, se guardará en una bolsa de papel para su nueva colocación, si tiene menos de horas, se desechará si está visiblemente contaminada o se torna húmeda. el reusó de la n dependerá de la casa del fabricante, de si contiene o no celulosa en su estructura del respirador. por ejemplo, la recomendación del consenso colombiano acin sobre la desinfección para los respiradores sin celulosa es con peróxido de hidrógeno vaporizado al % por minutos. los respiradores n de uso industrial tienen mayor contenido de celulosa que los de uso médico por lo tanto para procesos de esterilización, solo los n de uso médico podrán ser esterilizados mediante de peróxido de hidrógeno vaporizado (sterrad®)( - ). amci ® se recomienda elaborar el protocolo de pronación del paciente críticamente enfermo por covid- , garantizando el entrenamiento al personal de salud, organizando el recurso humano, dispositivos de apoyo y tiempo establecido para cambios de posición para prevenir las lesiones por presión en el paciente. fuerte a favor fundamento la estrategia de pronación es una alternativa eficiente en el manejo del síndrome de dificultad respiratoria en pacientes críticos y es fundamental la gestión del profesional de enfermería en la prevención de complicaciones y eventos adversos, lo cual aportará significativamente a la calidad del cuidado ofrecido favoreciendo las mejoras en la oxigenación. es importante optimizar los cuidados de enfermería en torno de los cuidados de piel en los pacientes en ventilación mecánica en decúbito prono, los estudios han demostrado como principal complicación las lesiones de presión con una incidencia hasta de . %, siendo las más frecuentes las grado y ( ). una lesión se puede producir si se supera una presión en el tejido capilar arterial de mmhg denominándose interfaz de presión. basándose en lo anteriormente mencionado, el cambio de posición es un componente integral de la prevención y el tratamiento de las upp, con una justificación sólida y de amplia recomendación en la práctica de enfermería ( ) . el uso de superficies especiales para el manejo de la presión (semp) a partir del estudio de defloor ( ), se determinó un antes y un después en el uso de las semp en conjunción de los cambios posturales. este realizo un importante aporte para reducir la incidencia de lesiones por presión comparado con los colchones de estándar. se recomienda promover actividades para controlar el nivel de estrés en el personal durante las jornadas de trabajo: identificar y reconocer los propios límites, buscar o proponer ayuda psicológica profesional cuando sea requerido, promover estilos de vida saludables, y organizar los turnos de trabajo asegurando periodos de descanso. se recomienda compartir las emociones con pares y superiores, analizar objetivamente las situaciones adversas, manejar fuentes de información objetivas y científicas, realizar pausas activas durante el turno y brindar espacios grupales para expresar emociones, miedos e incentivar al equipo de trabajo reconociendo su labor. amci ® se recomienda utilizar recursos de salud mental ocupacional, apoyo por enfermedad y licencia familiar, además de garantizar una adecuada dotación de personal. los estilos de superación personal y el crecimiento psicológico desempeñan un papel importante en el mantenimiento de la salud mental de las enfermeras. es razonable suponer que los niveles de ansiedad y estrés entre los profesionales de la salud son proporcionalmente más altos que los de la población general debido al contacto directo con pacientes infectados. esto puede explicar por qué las enfermeras de primera línea son excepcionalmente vulnerables a la fatiga y al agotamiento (wang, okoli, et al. ) , agotamiento mental, falta de moral del personal, control / autonomía de decisión, menor calidad de vida y baja satisfacción laboral (cheung y yip, ). ( ) . una investigación reciente realizada en china continental menciona el impacto negativo de la pandemia de covid- en los trabajadores de atención médica de primera línea, incluidos los mayores niveles de ansiedad (shanafelt, ripp y trockel, ), depresión (xiang et al. ), estrés postraumático síntomas, soledad e impotencia (xiang et al. ) ( , ) . los aspectos traumáticos y estresantes de la participación en una pandemia también ponen en riesgo el daño psicológico a los médicos ( ) . la experiencia psicológica de las enfermeras que atienden a pacientes con covid- se puede resumir en temas: primero, las emociones negativas presentes en la etapa inicial consisten en fatiga, incomodidad e impotencia que fue causado por el trabajo de alta intensidad, el miedo y la ansiedad, y la preocupación por los pacientes y sus familiares. segundo, los estilos de auto afrontamiento incluyeron ajustes psicológicos y de vida, actos altruistas, apoyo de equipo y coordinación racional. tercero, encontramos crecimiento bajo presión, que incluía un mayor afecto y agradecimiento, desarrollo de posición de responsabilidad profesional y autorreflexión. finalmente, encontraron que las emociones positivas ocurrieron simultáneamente con emociones negativas( ). se recomienda ofrecer mecanismos de apoyo para amortiguar el estrés relacionado con la pandemia por covid- . esto incluye intervenciones para pacientes y familias ofreciendo recursos de salud mental y educación al egreso, previo a este reforzar visitas virtuales. se recomienda anticipar las necesidades de salud mental de los pacientes, el personal y las familias para ofrecer una respuesta integral de salud pública. se debe incluir atención psicológica en la hospitalización para pacientes, familiares y personal afectado por covid- . se recomienda proporcionar atención de salud mental en las comunidades, mientras que se requiere distanciamiento social y los recursos del sistema de salud son limitados. amci ® se recomienda mantener una estrategia de comunicación asertiva con la familia, teniendo en cuenta la formación del personal sobre las estrategias para comunicar malas noticias. ser solidarios con el duelo de las familias y acompañar el proceso de afrontamiento aún en la distancia, identificando factores de riesgo para patología mental o duelo complicado, utilizando los recursos institucionales de salud mental para mejorar las intervenciones. la pandemia tiene el potencial de crear una crisis secundaria de angustia psicológica y desbordamiento del sistema de salud mental. los miembros de la familia pueden experimentar angustia, miedo o ansiedad por la hospitalización de un ser querido, particularmente cuando las medidas de control de infecciones restringen las visitas. la telesalud (incluida la cobertura de seguro para la telesalud), el suministro extendido de medicamentos, el aumento de la capacitación en salud mental del proveedor, el apoyo virtual de pares y los grupos virtuales de apoyo al uso de sustancias pueden ayudar a garantizar que se satisfagan las necesidades de salud mental de la comunidad ( ). el sistema de salud y los líderes de enfermería deben asegurarse de que su personal de enfermería clínica esté protegido y respaldado para que puedan proporcionar esta dimensión crucial de la atención de covid- . se recomienda crear grupos centralizados y definidos para atención de pacientes con sospecha o diagnóstico de covid- que se encarguen de elaboración, socialización e implementación de protocolos. estos deben incluir los aspectos de infraestructura, áreas delimitadas, utilización de epp, listas de chequeo, observadores, insumos y recursos que permitan atención integral. se recomienda organizar el plan de atención del paciente con sospecha o diagnóstico de covid- de enfermería con la asignación de actividades, número de personas según escalas que midan escalas de carga laboral para definir el número adecuado de los miembros del equipo de trabajo, tiempo de atención, gestión de recursos, gestión de riesgo y un líder por turno que garantice el cumplimiento fuerte a favor fundamento la implementación de estrategias de gestión en contingencias genera un trabajo organizado, enfocado en la prevención y tratamiento centralizado, elaboración y socialización de protocolos claros, áreas específicas, delimitadas y asignadas, con un uso racional del recurso humano que se despliega en fases, desde el inicio de la emergencia considerado como detección temprana hasta la atención directa de pacientes con sospecha amci ® o confirmación de sars-cov- . dentro de las fases tempranas, se busca la gestión de los recursos necesarios para la atención de estos pacientes, con una asignación de zonas o servicios y unas condiciones particulares, tratamientos específicos y actividades de atención especiales para las cuales se discriminan medicamentos, dispositivos e insumos necesarios para el cuidado de enfermería. los grupos de atención deben contar con capacitación, gestión y supervisión, apoyo logístico, apoyo psicológico y retroalimentación ( , ) . el plan de atención de enfermería debe tener presente la minimización de exposición, la prevención de infecciones en el personal y cuidados especiales derivados de la condición clínica de los pacientes con esta infección, altamente contagiosa y con síntomas o necesidades que rompe el modo operacional convencional y que requiere implementación basada en la práctica clínica. por lo tanto, el plan debe ser centralizado oportuno, ordenado, seguro y eficiente e incluye: relación enfermería/paciente de acuerdo a criticidad, capacitaciones y entrenamiento al personal de enfermería de línea de frente en el área crítica de aislamiento mediante videos, infografías y procesos prácticos (el contenido de capacitación incluye el uso de elementos de protección personal, higiene de manos, desinfección de áreas, manejo de residuos y esterilización de dispositivos de atención al paciente y manejo de exposición ocupacional), asignación de actividades clínicas (atención directa) y administrativas (supervisión, observador, líderes, gestión de recurso humano y medicamentos), soporte y contratación de personal adicional ante la contingencia con preparación académica o inducción, asignación de turnos razonables con períodos de descanso (alimentación, eliminación), coordinación con otros departamentos y optimización de flujos de trabajo, estrategias de control de infecciones y trabajo en equipo ( , ) . se recomienda que las muestras clínicas tomadas para el diagnóstico de covid- deben conservarse a temperatura entre - a °c, y luego de las horas deben permanecer congeladas a una temperatura de - °c. se recomienda que se realice el envío al laboratorio de salud pública de referencia dentro de las horas posteriores a la toma de la muestra del paciente. se recomienda que el transporte de las muestras debe realizarse con geles o pilas congeladas. se recomienda considerar que las muestras del tracto respiratorio bajo presentan la mejor certeza diagnóstica en pacientes con neumonía para adultos intubados y ventilados mecánicamente con sospecha de covid- . se recomienda contar con elementos de protección personal de acuerdo con las precauciones establecidas para el paciente con sospecha o diagnóstico por covid- para evitar la transmisión a profesionales de la salud. se debe evitar perder el circuito cerrado en los pacientes ventilados mecánicamente y valorar el riesgo de las acciones en pacientes con peep alta. se recomienda realizar la toma de muestra post mortem no invasiva por hisopado nasofaríngeo dentro de las primeras seis ( ) horas posteriores al fallecimiento, para que esta sea útil para su análisis. las muestras clínicas tomadas para el diagnóstico de coronavirus deben conservarse a temperatura entre - a °c, y luego de las horas deben permanecer congeladas a una temperatura de - °c. sin embargo, la muestra puede conservarse en un tiempo máximo de refrigeración por horas. no obstante, se sugiere que se realice el envío al laboratorio de salud pública de referencia dentro de las horas posteriores a la toma. si no se conserva la cadena de frío adecuada, la muestra puede ser inviable. el transporte de las muestras debe realizarse con geles o pilas congeladas ( , , ) .se debe tener en cuenta que no conservar la cadena de frío durante el transporte de la muestra, degradan la partícula viral, obteniéndose falsos negativos ( ) . las muestras del tracto respiratorio bajo presentan la mejor certeza diagnóstica en pacientes con neumonía. para adultos intubados y ventilados mecánicamente con sospecha de covid- en comparación al tracto respiratorio superior (nasofaríngeo u orofaríngeo). en el caso de aspirado traqueal, es importante considerar que para la obtención de las muestras para el diagnóstico de covid- se deben contar con elementos de protección personal de acuerdo a las precauciones estándar para evitar la transmisión a profesionales de la salud, circuito cerrado y valorar su realización en aquellos pacientes con peep alta ( ) . la toma de muestra post mortem no invasiva por hisopado nasofaríngeo se debe hacer antes de seis ( ) horas post mortem, para que esta sea útil para su análisis( , - ). se recomienda en los pacientes con diagnóstico covid- , monitorizar continuamente la oxigenación mediante saturación arterial de oxígeno con pulso oxímetro y la aparición temprana de signos clínicos de dificultad respiratoria durante la monitorización (aleteo nasal, cianosis, tirajes intercostales). se recomienda no suministrar de forma rutinaria suministrar oxígeno si la saturación de oxígeno (spo ) está por encima de %, y no se evidencian signos clínicos de dificultad respiratoria durante la monitorización continua del patrón respiratorio. se recomienda como parámetro importante para evaluar la oxigenación y guiar el suministro de oxígeno mediante los diferentes dispositivos la transferencia de oxígeno, medida por la pao / fio o sao /fio . se propone iniciar la oxigenoterapia por cánulas de bajo flujo y ajustar el flujo (máximo l) hasta alcanzar la spo objetivo ≥ %; si el paciente se encuentra en estado crítico iniciar con mascarilla con bolsa de reserva (a - l / min). una vez que el paciente esté estable, el objetivo de oxigenación es mantener niveles de spo entre y % en pacientes no embarazadas y entre - % en pacientes embarazadas. se recomienda no utilizar de forma rutinaria el uso de dispositivos que generan aerosoles durante la administración de oxígeno (dispositivos venturi o nebulizador de alto flujo o jet) en pacientes con sospecha o diagnóstico covid- . en las diferentes guías publicadas para manejo de pacientes positivos para covid- las metas de oxigenación durante la terapia de oxígeno en adultos recomiendan iniciar la oxigenoterapia a l / min y ajustar el flujo hasta alcanzar la spo objetivo ≥ % durante la reanimación; o use mascarilla con bolsa de reserva (a - l / min) si el paciente está en estado crítico. una vez que el paciente esté estable, el objetivo de oxigenación es > % de spo en pacientes, no embarazadas y ≥ - % en pacientes embarazadas( ). los dispositivos para la oxigenoterapia se pueden dividir en dos grupos, dependiendo de si cubren la totalidad o una parte de los requerimientos respiratorios del paciente. unos son de bajo flujo o para esfuerzos mínimos del paciente, estos dispositivos completan su ventilación con aire ambiente y los sistemas de alto flujo cubren la totalidad de los requerimientos inspiratorios del paciente. escalones terapéuticos: oxigenoterapia convencional a diferentes concentraciones de bajo flujo (son las cánulas nasales, las mascarillas simples y las mascarillas con reservorio), es el primer escalón terapéutico ante cualquier paciente que presente una situación de hipoxemia (spo ) < % respirando aire ambiente. el objetivo debe ser ajustar la fio (hasta . ) para mantener un nivel de oxigenación adecuado, considerado este como una spo > %. la administración de oxígeno se considera un procedimiento generador de aerosoles de riesgo bajo y por lo tanto es adecuado para pacientes covid- positivos( ). b. en adultos con signos de emergencia (respiración obstruida o ausente, dificultad respiratoria severa, cianosis central, shock, coma y / o convulsiones) deben recibir vía aérea amci ® de emergencia manejo y oxigenoterapia durante la reanimación para apuntar a spo ≥ %. una vez el paciente está estable, objetivo> % de spo en adultos no embarazadas y ≥ - % en mujeres embarazadas. c. para el manejo del paciente con covid- la máscara de no re inhalación se considera como la opción de preferencia para escalar el paciente antes de la intubación y considerar la transferencia a uci; esto se debe a que puede proporcionar altas fracciones inspiradas de oxígeno ( ) . d. los dispositivos que generan aerosoles durante la administración de oxígeno (dispositivos venturi o nebulizador de alto flujo o jet), no están indicados para manejo de covid- ( ). se recomienda aplicar las estrategias de retiro de la ventilación mecánica habituales para pacientes adultos críticos en general, hasta el momento no se ha construido una evidencia contundente para el destete en covid- . se recomienda en el paciente críticamente enfermo por covid- un descenso de la presión de soporte (psv) según tolerancia clínica, de esta forma el paciente podrá ser sometido a la realización de prueba de respiración espontánea con una presión de soporte de entre - cm h o. se recomienda que el destete automatizado puede ser considerado como una herramienta útil según disponibilidad de equipos para realizarlo. se recomienda no utilizar las maniobras que incrementan la aerosolización como la prueba de respiración espontánea en pieza en t o el cuff-leak test en el momento de realizar la medición de los predictores de éxito en el destete. fuerte en contra fundamento la realización de las pruebas de respiración espontánea sigue siendo un factor predictor importante en el éxito en el retiro del soporte ventilatorio mecánico y la indicación de tiempo de duración sigue siendo de a minutos debido a que las intubaciones realizadas en el mismo periodo de tiempo no han tenido diferencias significativas en el éxito del destete ( , ) . en los pacientes que han sido ventilados por más de horas y que el motivo por el cual fueron llevados a ventilación mecánica ya ha sido superado se debe establecer un protocolo de destete que debe incluir una prueba diaria de respiración espontánea y la minimización o retiro de la sedación (si no existe alguna contraindicación)( , ). la movilización temprana como factor coadyuvante en el éxito de la liberación mecánica ya se ha documentado en otros escenarios similares, razón por la cual la implementación amci ® temprana de este tipo de estrategias será un punto de vital importancia para recuperar la funcionalidad de los pacientes con covid- ( ) . se recomienda que la extubación de los pacientes críticamente enfermos por covid- se debe realizar con los elementos de protección personal requeridos para el riesgo de aerosoles. se recomienda no estimular la tos y el esputo inducido en los pacientes con sospecha o diagnóstico de covid- posterior a la extubación inmediata. se recomienda no utilizar de forma rutinaria la vmni en la falla respiratoria post extubación en pacientes críticos que no tengan una enfermedad concomitante que sea respondedora a la vmni como el epoc o edema pulmonar de origen cardiogénico en pacientes con sospecha o diagnóstico de covid- . fuerte en contra se recomienda mantener un umbral bajo para decidir intubación en caso de sospecha de fallo en la extubación en el paciente con sospecha o diagnóstico de covid- . la estricta monitoria y manejo del paciente posterior a la extubación surgen como un reto insoslayable para el personal de cuidado intensivo, enfocando todos sus esfuerzos en evitar la re-intubación, lo que se traducirá en un descenso significativo de la morbilidad y la mortalidad que supone una re-intubación ( ), la cual se puede definir como el no requerimiento de re intubación en las primeras horas post extubación ( , ) . en los últimos años la cánula nasal de alto flujo (caf) se ha convertido en una herramienta útil en el soporte de oxigenoterapia en los pacientes extubados que presenten riesgo de reintubación ( , ), y a la vez no presenten hipercapnia ( ) . la utilización de ventilación mecánica no invasiva de manera profiláctica en la falla respiratoria post extubación no ha demostrado tener éxito evitando la re-intubación en las primeras horas ( , ) excepto en las situaciones donde el paciente presente una enfermedad pulmonar o alteración cardiaca concomitante que sea respondedora a el manejo con vmni como lo son la enfermedad pulmonar obstructiva crónica (epoc) y el edema pulmonar de origen cardiogénico ( , ) . los pacientes extubados en los que se halla documentado epoc, se sugiere posterior a la extubación la implementación de una estrategia de niv de manera protocolaria ( , ), con una intensidad de hora cada horas durante un período mínimo de horas ( ). se recomienda utilizar en los pacientes con extubación reciente que no expresen predictores de riesgo de fracaso, sistemas de oxigenoterapia convencionales de bajo flujo que generen menos riesgo de aerosolización, fuerte a favor se podría considerar cánulas de alto flujo de oxígeno y/o la ventilación mecánica no invasiva (con una máscara facial adecuadamente ajustada y ramas inspiratorias y espiratorias separadas) como terapia de puente después de la extubación, pero se deben brindar las condiciones estructurales necesarias (habitaciones de presión negativa o habitaciones aisladas de puertas cerradas) y con epp estrictos para el personal sanitario. fuerte a favor fundamento las pautas de anzics establecen que la caf y/o la ventilación no invasiva (con una máscara facial bien ajustada y ramas inspiratorias y espiratorias separadas) pueden considerarse como terapia de puente después de la extubación, pero deben proporcionarse epp estricto en el aire. la terapia cpap o bipap (con alta presión espiratoria final) podría ser útil para prevenir la eliminación del reclutamiento en estos pacientes. en el momento de la extubación, los pacientes a menudo han estado enfermos durante más de una semana. es probable que su carga viral disminuya en ese punto, por lo que el riesgo de transmisión del virus puede ser menor (en comparación con la intubación inicial) ( ) . de no contar con predictores de que nos indiquen que podría fracasar la extubación se deben utilizar entonces sistemas de oxigenoterapia convencionales de bajo flujo que generen menos riesgo de aerosolización( ). se recomienda limpiar y desinfectar con frecuencia el área de retiro de epp, incluso después de que se haya completado cada procedimiento de eliminación. se debe limpiar esta zona, pasando de las áreas más limpias a las más sucias, antes de ingresar a la habitación del paciente y realizar el manejo y disposición final de residuos. se recomienda realizar la limpieza de superficies con un desinfectante adecuado o con una solución de hipoclorito sódico que contenga ppm de cloro activo (por ejemplo, un producto con hipoclorito en una concentración de - gr/litro, se hará una dilución : en el momento de su utilización). amci ® se recomienda que los recipientes que contengan los residuos deberán quedar en el lugar designado a tal efecto, que permanecerá cerrado hasta que, según el procedimiento de gestión de residuos de la institución sean retirados. los circuitos, filtros, succión cerrada y tot deben ser dispuestos en bolsas de color rojo las cuales deben ser de polietileno de alta densidad de . milésimas de pulgada y deben contar con un rótulo donde se indiquen: el nombre del generador, las palabras residuos biolÓgicos (covid- ) . una vez dispuesto, apretar y asegurar con nudo la bolsa de residuos y remover la bolsa de residuos del recipiente de residuos. posteriormente, desinfectar el exterior de la bolsa con solución desinfectante. luego colocar la bolsa de residuos en otra bolsa adicional de residuos y apretar y asegurar con nudo la bolsa de residuo. finalmente desinfectar la exterior bolsa de residuos con solución desinfectante. una vez terminada la disposición de los residuos de extubación, desinfectar los guantes con que manipuló los residuos con solución desinfectante y ubicar la bolsa de residuos dentro del vehículo de recolección interna de residuos. finalmente desinfectar el exterior de la bolsa de residuos con solución desinfectante. una vez terminada la disposición de los residuos de extubación, desinfectar los guantes con que manipuló los residuos con solución desinfectante y ubicar la bolsa dentro del vehículo de recolección interna. acogerse a la ruta sanitaria que asegure el menor riesgo de contaminación en el traslado interno de los residuos en la habitación del paciente (zona limpia) y zona sucia, se debe garantizar la ubicación de recipiente plástico de color rojo, liviano, resistente a los golpes, en material rígido impermeable, de fácil limpieza, y resistentes a la corrosión. los recipientes deberán ser lavados y desinfectados de acuerdo con los procedimientos establecidos por el prestador de servicios de salud( - ). se recomienda utilizar un ajuste de peep del paciente crítico por covid- , basado adicional a la tabla de peep, en las condiciones clínicas del paciente, en los índices de oxigenación, en la mecánica respiratoria del paciente y en los métodos de monitoreo disponibles. se recomienda titular la peep más alta que mantenga o mejore la relación safi y permita una presión plateau ≤ cmh o. se recomienda utilizar otras estrategias de titulación de peep probadas y con las cuales el equipo de trabajo esté familiarizado, dependiendo de la disponibilidad del recurso: ensayo peep decremental precedido por una maniobra de reclutamiento; titulación mediante la amci ® estimación de la presión transpulmonar con catéter esofágico o tomografía de impedancia eléctrica. fuerte a favor fundamento la titulación de la peep debe hacerse en función de la distensibilidad, oxigenación, espacio muerto y estado hemodinámico. puede titularse la peep mediante la estimación de la presión transpulmonar con catéter esofágico o tomografía de impedancia eléctrica. podría también titularse a partir de la fórmula (dp=plateau-peep) teniendo en cuenta que sea lógico el acoplamiento matemático fisiológico (lo que resultaría en una peep de cmh o si la presión plateau es de cmh o). la titulación de la peep requiere consideración de los beneficios (reducción de atelectrauma y mejora del reclutamiento alveolar) frente a los riesgos (sobre distensión inspiratoria final que conduce a lesión pulmonar y mayor resistencia vascular pulmonar)( , , ). se recomienda aplicar los protocolos de rehabilitación física como estrategia beneficiosa en el tratamiento respiratorio y físico de pacientes críticamente enfermos por covid- . se recomienda realizar la movilización precoz del paciente críticamente enfermo por covid- durante el curso de la enfermedad siempre que sea posible hacerlo de forma segura, asegurando la protección personal del personal sanitario. derivado del tratamiento médico intensivo para algunos pacientes con covid- , incluida la ventilación pulmonar protectora prolongada, la sedación y el uso de agentes bloqueantes neuromusculares, los pacientes con covid- que ingresan en la uci pueden presentar un elevado riesgo de desarrollar debilidad adquirida en la uci empeorando su morbilidad y mortalidad. por lo tanto, es esencial la rehabilitación temprana después de la fase aguda del síndrome de distrés respiratorio agudo (sdra) para limitar la gravedad de la debilidad adquirida en uci y promover la recuperación funcional. según la guía de la oms y la ops, enfatizan extremar el uso de los elementos de protección personal (epp) durante las intervenciones de rehabilitación física. la rehabilitación física proporciona intervenciones a través de movilizaciones, ejercicio terapéutico y programas individualizados a las personas que superan la enfermedad crítica asociada con covid- durante la ventilación mecánica y luego de esta, con el fin de permitir un retorno al hogar con funcionalidad. la prescripción de la movilización y ejercicio terapéutico debe de ser considera cuidadosamente en función del estado del paciente teniendo en cuenta, la estabilidad hemodinámica y clínica de la función respiratoria. cuando las movilizaciones, ejercicio terapéutico o programas de rehabilitación están indicados, debe realizarse una correcta planeación teniendo en cuenta amci ® la identificación/uso del personal mínimo necesario para realizar la actividad de manera segura. y el aseguramiento de todo el material que requerido esté a la mano y funcione correctamente y esté perfectamente limpio y desinfectado. si el material/equipo tiene que ser compartido con otros pacientes, límpielo y desinféctelo después de cada uso, entre paciente y paciente. se requiere personal entrenado específicamente para la limpieza y desinfección de los equipos, en una habitación aislada. y siempre que sea posible, evitar el traslado del material entre las áreas infectadas y no infectadas del hospital, manteniendo el equipamiento en las zonas aisladas ( ) ( ) ( ) ( ) ( ) . ( basados en un estudio preliminar aún sin publicar, se podría sugerir el uso de dexametasona a dosis de mg (oral o venosos) por días o hasta el alta si ocurre primero en pacientes hospitalizados con sospecha o diagnóstico de covid- que requieren suplencia de oxígeno, incluyendo aquellos con ventilación mecánica, que sean menores de años y con más de días de síntomas. amci ® actualmente no existe una terapia dirigida que se a efectiva para el manejo del virus; un número alto de estudios han surgido en los últimos dos meses, la mayoría sin el rigor metodológico suficiente para tomar decisiones adecuadas con respecto al manejo del paciente con infección por sars-cov- . el conocimiento en la estructura del virus y el mejor entendimiento en la fisiopatología de la enfermedad genera un sinnúmero de potenciales fármacos que han sido ensayados para el manejo de la enfermedad. en tiempos de pandemia, con una patología catastrófica en términos de vidas humanas y costos hospitalarios; es importante encontrar soluciones a desenlaces importantes como mortalidad, días de estancia en uci y en el hospital, aumento en los días libres del ventilador, disminución de complicaciones mayores debido a la enfermedad entre otros. hasta el momento no se ha documentado ninguna terapia específica que pueda impactar sobre estos desenlaces; pero la calidad de los trabajos, tampoco dejan claro sin él no usar ningún tratamiento específico mejora los desenlaces al menos al disminuir el número de complicaciones. este nuevo beta-coronavirus es similar al coronavirus del síndrome respiratorio agudo severa (sars-cov) y del síndrome respiratorio del medio este (mers-cov); por lo tanto, varias moléculas que habían sido evaluadas en este tipo de enfermedad rápidamente se abrieron paso a ensayos clínicos en paciente con covid- . estos ensayos principalmente observacionales, aleatorios pero abiertos con un número pequeño de pacientes no han permitido sacar adecuadas conclusiones y es frecuente como ver las diferentes guías de las principales sociedades del mundo cambiar de forma frecuente sus recomendaciones; no existes evidencia de estudios clínicos aleatorios y controlados que midan desenlaces fuertes, la premura de un tratamiento efectivo ha sacrificado el rigor metodológico que una investigación requiere. una estructura viral y replicación conocidas generan posibles dianas para que diferentes fármacos puedan ser investigados, antivirales tipo arbidol el cual inhibe la fusión de la membrana en la envoltura viral a algunos receptores; antimaláricos como la hidroxicloroquina y la cloroquina, las cuales inhiben la entrada viral y endocitosis por múltiples mecanismos, así como los efectos inmunomoduladores demostrados en el huésped; antivirales que impiden la replicación como el lopinavir o darunavir inhibiendo las proteasas o la ribavirina, el remdesivir o el favipiravir que actúan como análogos de nucleótidos o fármacos que actúan modulando la respuesta específica del huésped como el tocilizumab el cual se une al receptor de la il- inhibiendo el punto de acción de esta; los corticosteroides con múltiples efectos en la modulación del sistema inmunológico del paciente o los fármacos para evitar la respuesta secundaria a esta cascada inflamatoria como son los anticoagulantes. por último, se han buscado estrategias con el fin de mejorar la inmunización pasiva del huésped en el uso del plasma de pacientes convalecientes o el uso de inmunoglobulinas enriquecidas entre otros tratamientos propuestos para esta enfermedad. amci ® a los diferentes medicamentos que han sido usados en la pandemia del sars-cov- /covid- . de manera reciente en datos preliminares aún sin publicar horby y col en una rama del ensayo de evaluación aleatorizada de la terapia covid- (recovery), estudio aleatorizado, controlado, abierto que compara una gama de posibles tratamientos con la atención habitual en pacientes hospitalizados con covid- , compararon el uso de la dexametasona a dosis de mg día (oral o intravenosa) una vez al día por días o el alta según lo que ocurriera primero contra el manejo habitual; en pacientes aleatorizados que recibieron dexametasona se compararon con pacientes en manejo estándar; ( . %) pacientes en el grupo de dexametasona y ( . %) pacientes en el grupo control murieron a los días, con un riesgo relativo ajustado para la edad (rr . ; % ic . a . ; p < . ). la mortalidad relativa y absoluta variaron significativamente en relación al soporte ventilatorio al momento de la aleatorización; la dexametasona redujo las muertes en una tercera parte de los pacientes que recibieron ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p < . ), y una quinta parte en los pacientes que reciben oxígeno sin ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p = . ), pero sin reducir la mortalidad en paciente que no recibieron soporte respiratorio al momento de la aleatorización ( . % vs. . %, rr . , % ic . a . ]; p = . ) ( ) . no se emite recomendación a favor ni en contra para el inhibidor de la janus quinasa (baricitinib) en los pacientes con sospecha clínica o diagnóstico de covid- severo. uno de los reguladores conocidos de la endocitosis es la proteína quinasa asociada a ap (aak ); la interrupción de aak podría, a su vez, interrumpir el paso del virus a las células y también el ensamblaje intracelular de partículas del virus. uno de los seis fármacos de unión a aak de alta afinidad es el inhibidor de la janus quinasa (jak y jak ), llamado baricitinib, que también se une a la quinasa asociada a la ciclina g, otro regulador de la endocitosis ( ) . el baricitinib alcanza concentraciones plasmáticas suficientes para inhibir aak con mg o mg una vez al día; por su baja unión a proteínas plasmáticas y a su mínima interacción con las enzimas cyp, permite combinarlo con los antivirales. sin embargo, algunos piensan que el bloqueo de la señal jak-stat por baricitinib puede producir un deterioro de la respuesta antiviral mediada por interferón, con un posible efecto facilitador sobre la evolución de la infección por sars-cov- ; otras limitantes son la linfopenia (no dar si < cel./ mm ) y el aumento de la cpk. ( , ) . cantini y cols, en abril , en italia, administraron baricitinib a mg/día vía oral por semanas a pacientes con covid- moderado y los compararon con un grupo control; la terapia mejoró significativamente los parámetros clínicos, respiratorios y de laboratorio (pcr); ninguno de los pacientes requirió uci vs % del grupo control, sin eventos adversos. se amci ® trata de un estudio piloto de seguridad e impacto clínico en pacientes que no estaban en uci ( ) . ¿en pacientes hospitalizados con sospecha o diagnóstico de covid- el uso de n-acetil cisteína modifica el curso clínico de la enfermedad o genera beneficios en desenlaces clínicos de interés? basados en evidencia indirecta para el manejo del sdra y resultados observaciones en covid- , se podría utilizar el uso de n-acetil cisteina a dosis de mg/kg/día durante los primeros cinco días del sdra, aunque no se ha demostrado impacto en la mortalidad, su utilización parece relacionarse con una disminución significativa en la estancia en la unidad de cuidados intensivos y con disminución de los marcadores inflamatorios en pacientes con covid- . la severidad de la infección en covid- , en gran parte depende de la respuesta inmunológica de cada persona, sin embargo, se encuentran mecanismos fisiopatológicos de relevancia. sobreproducción de moco en vía aérea superior e inferior, que en parte explica la dificultad en la mecánica ventilatoria y los retos de ventilación en estos pacientes, la descarga desmedida de citoquinas proinflamatorias que se asocian a la falla multiorgánica y la coagulopatía asociada a la disfunción endotelial. esto mecanismos fisiopatológicos son comunes en el sdra, incluido los casos asociados a covid- ( ). amci ® enfermo con falla respiratoria aguda, la cual engloba falla respiratoria hipóxica (tipo ), falla respiratoria hipercápnica aguda (tipo ), sdra y lesión pulmonar aguda, se revisaron ensayos clínicos, más de pacientes. el análisis del grupo de n acetilcisteína intravenoso mostró una reducción de estancia en uci, de . días, con una heterogeneidad muy baja del %, con valoración de la evidencia calificada como de alta calidad y baja probabilidad de sesgo ( ) . en covid- , fue utilizada con recuperación completa en un caso severo de un paciente con déficit de glucosa fosfato deshidrogenasa (g pd), con control de la hemolisis y resolución del compromiso pulmonar. en pacientes sin déficit de g pd, también ha sido asociada a mejoría clínica y disminución significativa de los niveles de pcr y ferritina ( ) . en una revisión de costo efectividad nacional, se identificaron referencias, de ellos era revisiones sistemáticas de la literatura, dos de las cuales incluían metaanálisis (lu y zhang ), y fueron incluidos en la evaluación. estos estudios incluyeron información de ensayos clínicos que comparaban la aplicación de nac intravenosa frente a placebo o cuidado usual en pacientes con sdra. los tres estudios reportan como resultado de mortalidad rr de . con ic al % de . a . (lu ), rr de . con ic al % de . a . (lewis ) y rr de . con ic al % de . a . (zhang ) . para el tiempo de estancia en uci solo las revisiones con metaanálisis reportaron resultados, encontrando una diferencia de promedio de días de estancia de - . días con ic al % de - . a - . (lu ) y de - . días con ic al % de - . a - . (zhang ). una de las revisiones reportó que en ninguno de los estudios analizados se presentaron eventos adversos. no se encontraron resultados para los desenlaces de infección, sobreinfección, ni uso y tipo de antibiótico utilizado. en el análisis se encontró una reducción estadísticamente significativa de los días de estancia en uci de los pacientes que recibieron tratamiento con n-acetilcisteína intravenosa con dosis entre y mg/kg/día durante los primeros cinco días del sdra, en comparación con los pacientes que recibieron placebo o manejo usual. no se reportó diferencia estadísticamente significativa en la reducción de la mortalidad de los pacientes que recibieron nac. ( ) calidad de vida . ¿cómo podemos medir la calidad de vida, en los pacientes con covid- que egresan de la uci? se recomienda utilizar los marcadores disponibles de severidad y del riesgo de mortalidad por covid- en los pacientes internados en la uci. amci ® las secuelas inmediatas en los pacientes víctimas del devastador ataque sistémico del covid- durante su estancia en la uci son valorables, pero no se dispone de herramientas que permita medir el grado de afectación de la calidad de vida de estos pacientes posterior al egreso de la uci o de alta hospitalaria, por lo tanto, se sugiere realizar estudios de creación, validación y utilización de instrumentos de valoración de la calidad de vida en pacientes con covid- posteriores al alta hospitalaria. parte importante de los pacientes con diagnóstico de covid- que ingresan a la uci, evolucionan tórpidamente presentando deterioro progresivo de los diferentes órganos llegando en pocos días a una falla multiorgánica ( ) , estos pacientes presentan características clínicas y de laboratorio que se relacionan de manera significativa con mayor severidad y riesgo de mortalidad ( , ) . a pesar de conocer con alguna precisión el riesgo de severidad y mortalidad de los pacientes que ingresan a la uci, no disponemos de un score que nos permita evaluar y predecir el grado de afectación en la calidad de vida de los pacientes que logran sobrevivir. aproximadamente un , % del total de pacientes con enfermedad por covid- ingresan a uci, y de estos , % sometidos a ventilación mecánica ( ); lamentablemente los pacientes con enfermedad severa que logran sobrevivir y recuperarse han sido sometidos a una larga estancia en la uci y a ventilación mecánica invasiva con una intubación prolongada, que puede producir disfunción en la deglución impidiendo a la persona alimentarse de forma correcta y segura. es importante diagnosticar esta disfagia en los pacientes que se están recuperando del covid- y tratarla correctamente desde el principio para evitar complicaciones importantes como la malnutrición y la deshidratación, así como el riesgo de neumonía aspirativa. además de la disfagia, la fibrosis pulmonar y el riesgo de trombos son los problemas más frecuentes, pero no los únicos. una de las características de la enfermedad severa por covid- es que el virus provoca una enfermedad multiorgánica, con un amplio y heterogéneo abanico de secuelas cuyo alcance todavía se desconoce y aunque el órgano más afectado es el pulmón, puede afectar también otros órganos o sistemas incluido el snc, que en los casos más graves puede presentar encefalitis, delirios, desorientación y confusión, síntomas que pueden persistir tras el alta de la uci. otra secuela frecuente son las polineuropatías, esta afectación suele comenzar con una sensación de hormigueo en las extremidades y en los pacientes con covid- se presenta además con un cuadro de miositis que provoca debilidad y cansancio al caminar, a veces incluso en reposo; en algunos pacientes se presenta tal debilidad que dificulta llevar el alimento a la boca e incluso deglutirlo. sin embargo, la primera y más frecuente de las manifestaciones neurológicas del covid- es la pérdida del olfato, que a veces perdura como secuela tiempo después del alta. un estudio en pacientes ingresados en el hospital clínico san carlos de madrid revela que el % había sufrido anosmia en mayor o menor grado. la importancia de este síntoma radica en que las fosas nasales pueden ser la vía de acceso del virus al sistema nervioso central. amci ® otras posibles secuelas neurológicas asociadas a la infección por covid- son la ageusia, la cefalea y amnesia a corto y mediano plazo. también son importantes las secuelas que afectan al sistema cardiovascular. un estudio publicado en la journal o the american medical association advierte que un % de los pacientes presenta una elevación de las enzimas que indican daño en el miocardio. la inflamación que provoca el virus puede provocar directamente ese daño y también puede agravar el estado de pacientes que ya tengan una patología cardiovascular de base, muchas miocarditis son reversibles, pero hay una parte importante que deja como secuela una pérdida de la función contráctil. todavía se desconoce el alcance y es difícil medir el impacto de la enfermedad sobre el corazón porque en algunos casos, los síntomas de insuficiencia cardíaca se confunden con los de la neumonía. otra de las complicaciones más frecuentes, y potencialmente más grave, afecta al mecanismo de coagulación de la sangre. durante el ingreso hospitalario se han visto numerosos casos de ictus. la secuela más importante es el riesgo de que se formen trombos, que pueden ir al pulmón o al cerebro, y si se producen en las arterias, pueden dar lugar a un infarto, aunque este efecto es mucho menos frecuente. eso explica que algunos pacientes de covid- dados de alta hayan tenido que volver a ingresar por trombosis. finalmente es importante tener presente que a las afectaciones que haya podido producir el virus, hay que sumar las secuelas neurológicas propias de una estancia prolongada en una unidad de cuidados intensivos que también pueden ser graves y a veces no se distinguen bien unas de otras. debilidad muscular, desorientación, depresión y problemas psicológicos son secuelas muy habituales entre los pacientes que salen de la uci por enfermedades diferentes. por la anterior razón es difícil, por ahora, saber qué es efecto directo del virus y que puede derivarse del proceso de hospitalización. aún es difícil decir si los daños a largo plazo dependen del propio virus o de los efectos adversos del proceso tratante. sin embargo, este análisis de las posibles secuelas del covid- en el cuerpo, se presenta con más dudas que certezas. como es habitual en medicina, las causas pueden ser múltiples y muchas veces reflejan la participación de varias complicaciones que se han podido dar durante el proceso infeccioso directo o por la hospitalización, la información sobre los mecanismos de invasión del sars-cov- en todos los órganos sigue siendo, por ahora, escasa. y también lo es nuestro conocimiento sobre los efectos adversos de los medicamentos, muchos de ellos experimentales, que se han utilizado durante esta crisis. gran parte de lo que conocemos actualmente sobre los efectos de este virus proviene de la experiencia clínica de otros colegas y de las historias de pacientes que han sufrido la enfermedad, quedando todavía mucho por descubrir. dado el actual panorama, diferentes hospitales e instituciones de salud se preparan en torno a la rehabilitación, habilitando ya unidades multidisciplinares poscovid- para el seguimiento de estos pacientes y algunos centros están contactando con los pacientes dados de alta para evaluar su estado y hacer un seguimiento a su salud. también están en marcha varios estudios multicéntricos para evaluar el alcance de las secuelas, prácticamente todos los centros sanitarios deberán tener pautas de seguimiento y control para los pacientes ya dados de alta, creándose necesario la utilización simultánea de amci ® instrumentos de medición de calidad de vida, que en nuestro país colombia, ya se han utilizado previamente con este fin ( , ) . con este instrumento de medición de la calidad de vida se realizaron algunos estudios piloto tanto en pacientes crónicos como en la población general con el fin de determinar la comprensión del instrumento y factibilidad de aplicación del mismo en cuanto a la consistencia interna, la revisión realizada por vilagut y cols demostró que la aplicación de la escala arrojó en diversos estudios un alfa de cronbach igual o superior a . en todas las escalas excepto en función social ( ) . y aunque un número cada vez mayor de estudios mide los resultados físicos, cognitivos, de salud mental y de calidad de vida relacionada con la salud (cvrs) en los sobrevivientes adultos de la uci, los datos sobre las propiedades de medición de tales instrumentos son escasos y, en general, de calidad deficiente a justa. se necesitan análisis empíricos que evalúen el rendimiento de los instrumentos en adultos sobrevivientes de la uci para avanzar en la investigación en este campo ( ) . finalmente, el conocimiento de las secuelas y complicaciones dejadas por la infección del covid- , permitirá identificar importantes variables clínicas que acompañan a esta enfermedad y que afectan de manera importante la calidad de vida de los pacientes que padecen la enfermedad severa en la unidad de cuidados intensivos. en la actualidad no existen estudios para evaluar el riesgo de malnutrición aguda en pacientes hospitalizados por sars-cov- . experiencias con otras infecciones virales por influenza, se han identificado como factores asociados con mortalidad, la presencia de malnutrición, la adquisición de infección intrahospitalarias, la falla respiratoria y la presencia de infiltrados en la radiografía de tórax ( ) . las guías espen recomiendan utilizar el must o el nrs- ( ), para la tamización del riesgo nutricional, estos puntajes de tamización previamente han sido validados en múltiples patologías y contextos clínicos; sin embargo, existen otros puntajes útiles desde la perspectiva clínica como la valoración global subjetiva, mini-nutritional asessment( ), puntaje nutric ( ) y la global leadership initiative on malnutrition (glim) ( ) . el proceso de diagnóstico nutricional debe involucrar, dos componentes: la identificación del riesgo con la utilización de alguno de los puntajes previamente validados en otros contextos y posteriormente el diagnóstico de los pacientes con malnutrición y la valoración de la gravedad de ésta; en este último paso es importante la valoración del índice de masa corporal, los hábitos de consumo calórico y proteico, la presencia de inflamación, los trastornos gastrointestinales, las enfermedades de base y siempre que sea factible el cálculo de la masa muscular. tabla . en vista del riesgo de infección al personal de salud, no siempre será necesario la visita nutricional al paciente, ésta podría ayudarse con entrevista al familiar, interrogatorio vía amci ® telefónica y sólo en caso necesario el examen del paciente para lo cual se requiere el uso de equipo de protección personal completo. esta estrategia de interrogatorio al familiar o al paciente por vía remota o telefónica puede ayudar a identificar los patrones de consumo y los hábitos nutricionales de riesgo y en caso de ser necesario la valoración nutricional disminuye el tiempo de exposición a un ambiente contaminado. para la atención presencial de pacientes en el ámbito de cuidado intensivo, es necesario definir cuál es el riesgo que existe de infección para el personal de salud, para aclarar esta pregunta se debe definir si hay un riesgo de generación de aerosoles( ). aunque no existen pautas específicas para la nutrición en pacientes con covid- , las diferentes sociedades científicas han desarrollado guías de pauta clínica para la nutrición de pacientes con esta enfermedad ( , ) . idealmente la nutrición debe ser iniciada de forma temprana, esto se refiere al inicio en las primeras a horas del ingreso a cuidado intensivo o en las primeras horas luego de la intubación y el inicio de la ventilación mecánica( ) y se prefiere la vía enteral. aunque no existen estudios para evaluar el momento del inicio de la nutrición en pacientes con infección por sars-cov , el inicio temprano de la nutrición ha mostrado beneficios en términos de mortalidad y reducción de infecciones con dicha estrategia ( , ) . adicionalmente es importante, evaluar el riesgo de morbilidad y mortalidad asociado a la malnutrición aguda en el ámbito del paciente crítico, en los pacientes que no se alcance la meta de aporte calórico y proteico por vía enteral o que exista contraindicación para ésta, se debe considerar el inicio de nutrición por vía parenteral, especialmente cuando su riesgo nutricional agudo sea elevado (puntaje nutric ≥ , nrs ≥ ) ( ) ( ) . el choque no es una contraindicación para la utilización de nutrición enteral ( ) y no es una indicación para el uso de nutrición parenteral, quizás la mejor estrategia, es vigilar la presencia de disfunción gastrointestinal, en combinación con la presencia de intolerancia a la nutrición enteral, especialmente en pacientes con acidosis láctica en progreso y cuando sea necesario escalar la dosis de vasopresores o exista incapacidad para la reducción de éstos. no es necesario medir el residuo gástrico de rutina, es preferible iniciar procinéticos de forma rutinaria. la sonda debe colocarse con cuidado de evitar riesgo de contaminación, preferiblemente al entubar al paciente. algunos pacientes pueden presentar diarrea, ya que se ha descubierto la presencia de la proteína ace (receptor del virus sars-cov- ) en células del esófago, estómago, duodeno y recto. no existe evidencia que indique que la nutrición enteral durante la posición prono aumente el riesgo de complicaciones. sugerimos no suspender nutrición enteral al durante la pronación, se debe iniciar con dosis trófica de ml/h. amci ® se recomienda una estrecha monitorización de la tolerancia a la nutrición enteral para pacientes en posición prono. se recomienda para aumentar la tolerancia de la ne a los pacientes en posición prona, una elevación del tórax entre - º (posición de trendelenburg inversa) no realizar endoscopias digestivas para ubicación de sondas avanzadas recomendaciones de nutrición parenteral los pacientes con covid- pueden requerir niveles significativos de sedación y bloqueo neuromuscular, lo que puede aumentar la incidencia de intolerancia gastrointestinal. la nutrición parenteral (np) debe utilizarse donde la alimentación enteral no está disponible o no logra completar el % de los requerimientos. si existen limitaciones para la ruta enteral, se podría recomendar nutrición parenteral periférica (npp) en la población que no alcanza el objetivo proteico energético por nutrición oral o enteral. la np temprana debe 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of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition espen guideline on clinical nutrition in the intensive care unit safety and outcomes of early enteral nutrition in circulatory shock gastrointestinal function in intensive care patients: terminology, definitions and management. recommendations of the esicm working group on abdominal problems key: cord- -ehxpdavo authors: lee, joyce s.; collard, harold r. title: acute exacerbation of idiopathic pulmonary fibrosis date: - - journal: idiopathic pulmonary fibrosis doi: . / - - - - _ sha: doc_id: cord_uid: ehxpdavo acute exacerbation of idiopathic pulmonary fibrosis (ipf) is a clinically important complication of ipf that carries a high morbidity and mortality. in the last decade, we have learned much about this event, but there are many remaining questions: what is it? why does it happen? how can we prevent it? how can we treat it? this chapter attempts to summarize our current understanding of the epidemiology, etiology, and management of acute exacerbation of ipf and point out areas where additional data are sorely needed. predicted and a diffusing capacity for carbon monoxide of % predicted. his highresolution computed tomography (hrct) scan demonstrated peripheral, subpleural predominant reticulation and traction bronchiectasis without honeycombing. he was referred for surgical lung biopsy and had a video-assisted thoracic surgery procedure with biopsies obtained from the right lung. his perioperative course was uncomplicated. his pathology was reviewed and was consistent with a usual interstitial pneumonia (uip) pattern, confi rming the diagnosis of ipf. his initial postoperative course was uncomplicated, but approximately days postoperatively, he developed increased dyspnea and cough with occasional production of clear sputum. he had new-onset hypoxemia ( % on room air) with diffuse crackles to auscultation that were more prominent in the left chest. a repeat hrct demonstrated new ground-glass opacities in the left lung ( fig. . ). all microbiologic data were negative, and there was no evidence of cardiac dysfunction or ischemia. this case was thought to be due to an acute exacerbation (aex) of ipf triggered by surgical lung biopsy possibly due to single lung ventilation of the left lung. unfortunately, the patient progressively worsened despite supportive care and subsequently died from his aex of ipf. our view of the natural history of ipf has changed over the last decade with the recognition that there are several distinct clinical courses that patients may follow [ ] . although most patients with ipf experience a steady decline in lung function over time, some will decline quickly, while others seem stable for many years. increasingly, we recognize that some patients may also have a more unpredictable course [ ] . these patients experience periods of relative stability followed by acute episodes of worsening in their respiratory status [ ] . episodes of acute respiratory decline in ipf can be secondary to complications such as infection, pulmonary [ , ] . such episodes of acute respiratory deterioration have been termed aex of ipf when the cause for the acute worsening cannot be identifi ed. acute exacerbations likely comprise almost % of these acute respiratory events, and the clinical characteristics and prognosis are indistinguishable from acute exacerbations of known cause. this chapter will discuss only aex of ipf. the phenomenon of aex has been recognized since the late s, when it was initially reported in the japanese literature [ - ] . a survey of providers in the usa suggests that most clinicians believe aex to be somewhat or very common [ ] . the true incidence of aex remains unknown, and the incidence may vary by country due to different genetic and environmental factors. largely due to differences in case defi nition, patient population, sample size, and duration of follow-up, the range of aex incidence in clinical studies ranges anywhere from % to % [ , ] . the largest and probably most robust study of patients with ipf that were followed longitudinally over years found a -and -year incidence of . % and . %, respectively [ ] . the clinical presentation of aex is generally quite dramatic and characterized by acute to subacute worsening of dyspnea over days to weeks [ ] . some patients experience symptoms of worsening cough, sputum production, and fever mimicking a respiratory tract infection [ , ] . most reported cases of aex have required unscheduled medical attention (emergency room or hospital care), but there may well be less severe cases that do not get noted by patients and providers and, therefore, are not documented. the occurrence of aex is unpredictable and can sometimes be the presenting manifestation of ipf [ - ] . a few risk factors have been identifi ed, including lower baseline forced vital capacity (fvc) % predicted and having been a nonsmoker [ ] . it seems likely that patients with more severe ipf are more likely to develop clinically signifi cant aex of disease, and this perception is supported by the increased incidence of aex that was observed in the only study of advanced disease reported in the literature to date, namely, step-ipf [ ] . precipitating factors such as surgical lung biopsy and bronchoalveolar lavage (bal) have also been reported [ , - ] . the occurrence of aex after videoscopic-assisted surgical lung biopsy is particularly intriguing, as the exacerbation appears to be more pronounced in the lung that was ventilated (i.e., the nonsurgical side receiving single lung ventilation) [ ] . however, the precise relationship between these precipitating factors and aex remains unclear. acute exacerbations have also been described in non-ipf ild, including nonspecifi c interstitial pneumonia (nsip) [ ] , connective tissue disease-associated ild [ - ] , and hypersensitivity pneumonitis [ , ] . compared to ipf aex, patients with an underlying nsip pattern appeared to have a better prognosis following their aex [ ] . a uip pattern may be a risk factor for aex in the context of connective tissue disease-associated ild and hypersensitivity pneumonitis, as the presence of a uip pattern appeared to be a risk factor in some case series [ , ] . whether aex of non-ipf forms of ild shares a similar pathobiology as aex of ipf is unknown. the etiology of aex of ipf remains unknown. several hypotheses have been proposed, including the following: ( ) aex of ipf represents an abrupt acceleration of the patients underlying disease; ( ) aex is a collection of occult, pathobiologically distinct conditions (e.g., infection, heart failure); or ( ) aex is a combination of both processes that can serve as an occult trigger that leads to acceleration of the underlying fi broproliferative process. occult aspiration of gastric contents has been suggested as a possible trigger or cause of aex of ipf. ger is nearly universal in patients with ipf [ , ] and is thought to be a risk factor for aspiration [ , ] . bal pepsin levels, a biomarker for aspiration of gastric secretions, were shown to be elevated in a subset of patients with aex of ipf [ ] . in addition, patients with asymmetric ipf on hrct scan had a higher rate of ger and aex compared to patients with non-asymmetric disease, suggesting a role for ger and occult aspiration in a subset of patients with ipf [ ] . infection has also been suggested as a cause of aex of ipf. data in support of this hypothesis include animal studies [ ] as well as some human studies [ , ] . in one case series, . % of aex cases occurred between december and may [ ] , lending further support to occult infection as a cause of aex. however, in a prospective study of aex of ipf ( n = ), acute viral infection, as determined by the most current genomics-based methodologies, was found in only % of this cohort [ ] . while some cases may well have been missed (i.e., the virus had come and gone by the time testing was obtained), these data suggest that there are many cases of aex that are not primarily due to occult infection. an alternative explanation is that aex of ipf is caused by an inherent acceleration of the pathobiology of ipf [ ] . there is indirect evidence for this in several studies that evaluated serum biomarkers and gene expression in aex. serum biomarkers of alveolar epithelial cell injury/proliferation have been shown to be increased in aex, in a pattern that is qualitatively distinct from what is seen in acute lung injury (table . ) . gene expression studies performed in patients with aex of ipf [ ] have shown that patients have increased expression of genes encoding proteins involved in epithelial injury and proliferation including ccna and alpha-defensins. interestingly, there was no evidence from the same study for upregulation of genes commonly expressed in viral infection. there are no specifi c laboratory tests that aid in the evaluation and diagnosis of aex of ipf. often, patients are found to have impaired gas exchange with a decrease in sp-d marker of alveolar type ii cell injury and/or proliferation plasma levels higher in aex compared to stable [ ] thrombomodulin membrane protein expressed on the surface of endothelial cells which serves as a receptor for thrombin plasma levels higher in aex compared to stable and log change in thrombomodulin was predictive of survival [ ] von willebrand factor marker of endothelial cell injury and is involved in hemostasis higher plasma % in aex compared to stable [ ] aex acute exacerbation, ipf idiopathic pulmonary fi brosis, kl- krebs von den lungen- , pai- plasminogen activator inhibitor- , rage receptor for advanced glycation end products, nf-kb nuclear factor-kb, st , sp-d surfactant protein d their arterial oxygen tension [ ] . in patients that can tolerate bronchoscopy with lavage, an increase in bal neutrophils has been reported [ , ] . nonspecifi c elevations in serum lactate dehydrogenase (ldh) and c-reactive protein (crp) have also been observed [ ] . serial levels of serum kl- and baseline thrombomodulin may help identify patients at increased risk for death from aex [ , ] . although many experimental biomarkers have been investigated, as shown in table . , none are routinely used in clinical practice. high-resolution ct scans are often obtained during aex of ipf. the fi ndings include new, generally bilateral, ground-glass opacities and/or consolidation superimposed on the underlying uip pattern [ ] . the pattern of ground-glass changes during an aex may have prognostic signifi cance, with more diffuse abnormality correlating with worse outcomes [ ] . surgical lung biopsy is not frequently obtained during aex of ipf. a small case series of seven patients who had a surgical lung biopsy during their aex demonstrated primarily diffuse alveolar damage (dad) associated with underlying changes typical for uip ( fig. . ) [ ] . one case had organizing pneumonia and uip and another case had dad without underlying uip. autopsy series and other case series have demonstrated similar fi ndings [ , , , - ] . several defi nitions have been used over the last decade to defi ne aex of ipf [ , , ] . in order to standardize these criteria, a consensus defi nition was proposed by the national institutes of health-funded us ipf network (ipfnet) in (table . ) [ ] . other defi nitions that have been described are generally similar; however, they often include a reduction in pao as one of their criteria as well as bilateral chest x-ray abnormalities (instead of a hrct scan) [ , ] . the ipfnet criteria have helped to standardize the defi nition of aex of ipf, but satisfaction of all criteria is quite diffi cult to achieve in many clinical settings. specifi cally, it is not infrequent that in patients who appear to have aex of ipf, microbiologic data and occasionally radiologic data are not collected due to the severity of illness or because the clinician does not feel the tests will change clinical management. by maximizing specifi city at the cost of sensitivity, these criteria (along with the selection of only mild to moderate patients for enrollment) have likely contributed to the low prevalence of aex observed in recent clinical trials [ - ] . the choice of defi nition has signifi cant implications for outcome analyses in clinical trials and should be a focus for further discussion among clinical trialists. there is no known effective treatment for preventing or improving outcomes in aex of ipf. previous or concurrent diagnosis of idiopathic pulmonary fi brosis unexplained development or worsening of dyspnea within days high-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage exclusion of alternative causes, including left heart failure, pulmonary embolism, and other identifi able causes of acute lung injury a patients who do not meet all fi ve criteria should be termed "suspected acute exacerbation" while there are no data to support effi cacy, vaccination and treatment of comorbidities like heart disease and ger seem prudent as measures that could prevent episodes of acute decline in respiratory function due to known causes such as infection, heart failure, and aspiration. some novel therapies have suggested a reduction in aex in clinical trials; these include warfarin [ ] , pirfenidone [ ] , and, most recently, bibf [ ] . unfortunately, both warfarin and pirfenidone have subsequently been shown to have no impact on the rate of aex, suggesting that the initial observations were inaccurate [ , ] . although commonly prescribed for the treatment of aex of ipf, there have been no controlled trials assessing the effi cacy of high-dose corticosteroids. recent international guidelines on ipf management suggested that the majority of ipf patients with aex could be treated with corticosteroids [ ] ; however, approaches to dosing, route, and duration of therapy were not provided. although most clinicians would treat patients who develop an aex of ipf with high-dose corticosteroids, the effi cacy of this treatment is unclear. perhaps we should be more critical of the use of corticosteroids to treat aex of ipf. there are two distinct viewpoints regarding the role of corticosteroids in aex of ipf. the fi rst viewpoint is that aex of ipf is histopathologically similar to acute respiratory distress syndrome (ards) characterized by dad and acute lung injury [ ] and should, therefore, be treated similarly to ards. in the ards literature, the mortality benefi t of corticosteroids is unclear [ - ] . in one study, increased mortality was observed in ards patients treated with delayed corticosteroids (after days) [ ] . if we were to follow the ards paradigm, most clinicians would not use corticosteroids in the treatment of aex of ipf. a second viewpoint for the role of corticosteroids in ipf is that some patients with aex of ipf have organizing pneumonia on biopsy [ ] . organizing pneumonia is generally thought to be steroid responsive, and it may be that the pathobiology is different enough between ards and aex of ipf to warrant continued use of corticosteroids. there remains equipoise on the effi cacy of corticosteroids in aex of ipf, and this treatment intervention should be studied more carefully [ ] . the use of another immunosuppressant, cyclosporine a, to treat aex of ipf has been reported. these studies suggest some benefi t to the use of cyclosporine a plus corticosteroids [ - ] . however, conclusions that can be made from these data are limited by problems with study design and small sample size, and benefi t has not yet been validated in a randomized controlled trial. other experimental therapies that have reported possible effi cacy to treat aex of ipf include tacrolimus [ ] , hemoperfusion with polymyxin b-immobilized fi ber column [ - ] , and sivelestat [ ] . these investigations were all limited by small numbers and suboptimal study design. supportive therapy is the standard of care in aex of ipf. supportive care for respiratory failure almost always requires higher oxygen supplementation and consideration of additional means of ventilatory support, including mechanical ventilation (see discussion below) and noninvasive positive-pressure ventilation (nippv). yokoyama et al. described the outcomes of patients with aex of ipf treated with nippv to avoid intubation in acute respiratory failure [ ] . in this retrospective case series of patients, patients failed a nippv trial and went subsequently succumbed to respiratory failure. the other fi ve patients survived more than months after the onset of their aex. however, the use of ventilatory support in aex (both mechanical ventilation and nippv) has never been studied in a randomized controlled trial. a few select centers have experience with emergent transplantation for aex of ipf [ - ] . these critically ill ipf patients have generally been bridged to lung transplant with extracorporeal membrane oxygenation (ecmo) and/or mechanical ventilation [ ] . outcomes of patients who have undergone emergent transplantation have been mixed [ , ] . emergent lung transplantation requires careful patient selection and is not done at all transplant centers. the prognosis of aex of ipf is poor, with most case series reporting very high short-term mortality rates [ , - ] . this is particularly true for those patients requiring mechanical ventilation. a systematic review of mechanical ventilation in ipf and respiratory failure ( n = ), including aex, reported a hospital mortality of % [ ] . short-term mortality (within months of hospital discharge) was %. the routine use of mechanical ventilation in patients with aex of ipf is not recommended in the international consensus guidelines because of its low likelihood of benefi t and high risk of complications and further suffering [ ] . careful consideration regarding intubation and goals of care must be made, given the poor prognosis associated with this condition. ideally, a discussion concerning end-of-life issues should be held between the patient and their provider in the outpatient setting with the inclusion of the patient's family, if applicable. acute exacerbation of ipf is responsible for substantial morbidity and mortality in patients with ipf. we suggest that aex of ipf represents an acute acceleration of the fi broproliferative process (i.e., the underlying pathobiology of ipf) that is triggered 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pulmonary fi brosis outcome of patients with idiopathic pulmonary fi brosis (ipf) ventilated in intensive care unit outcome of patients with idiopathic pulmonary fi brosis admitted to the icu for respiratory failure prognosis of patients with advanced idiopathic pulmonary fi brosis requiring mechanical ventilation for acute respiratory failure key: cord- - a pviol authors: kamilia, chtara; regaieg, kais; baccouch, najeh; chelly, hedi; bahloul, mabrouk; bouaziz, mounir; jendoubi, ali; abbes, ahmed; belhaouane, houda; nasri, oussama; jenzri, layla; ghedira, salma; houissa, mohamed; belkadi, kamal; harti, youness; nsiri, afak; khaleq, khalid; hamoudi, driss; harrar, rachid; thieffry, camille; wallet, frédéric; parmentier-decrucq, erika; favory, raphaël; mathieu, daniel; poissy, julien; lafon, thomas; vignon, philippe; begot, emmanuelle; appert, alexandra; hadj, mathilde; claverie, paul; matt, morgan; barraud, olivier; françois, bruno; jamoussi, amira; jazia, amira ben; marhbène, takoua; lakhdhar, dhouha; khelil, jalila ben; besbes, mohamed; goutay, julien; blazejewski, caroline; joly-durand, isabelle; pirlet, isabelle; weillaert, marie pierre; beague, sebastien; aziz, soufi; hafiane, reda; hattabi, khalid; bouhouri, mohamed aziz; hammoudi, driss; fadil, abdelaziz; harrar, rachid al; zerouali, khalid; medhioub, fatma kaaniche; allela, rania; algia, najla ben; cherif, samar; slaoui, mohamed taoufik; boubia, souhail; hafiani, y.; khaoudi, a.; cherkab, r.; elallam, w.; elkettani, c.; barrou, l.; ridaii, m.; mehdi, rihi el; schimpf, caroline; mizrahi, assaf; pilmis, benoît; le monnier, alban; tiercelet, kelly; cherin, mélanie; bruel, cédric; philippart, francois; bailly, sébastien; lucet, jc; lepape, alain; l’hériteau, françois; aupée, martine; bervas, caroline; boussat, sandrine; berger-carbonne, anne; machut, anaïs; savey, anne; timsit, jean-françois; razazi, keyvan; rosman, jérémy; de prost, nicolas; carteaux, guillaume; jansen, chloe; decousser, jean winoc; brun-buisson, christian; dessap, armand mekontso; m’rad, aymen; ouali, zouhour; barghouth, manel; kouatchet, achille; mahieu, rafael; weiss, emmanuel; schnell, david; zahar, jean-ralph; artiguenave, margaux; sophie, paktoris-papine; espinasse, florence; sayed, faten el; dinh, aurélien; charron, cyril; geri, guillaume; vieillard-baron, antoine; repessé, xavier; kallel, hatem; mayence, claire; houcke, stéphanie; guegueniat, pascal; hommel, didier; dhifaoui, kaouther; hajjej, zied; fatnassi, amira; sellami, walid; labbene, iheb; ferjani, mustapha; dachraoui, fahmi; nakkaa, sabrine; m’ghirbi, abdelwaheb; adhieb, ali; braiek, dhouha ben; hraiech, kmar; ousji, ali; ouanes, islem; zaineb, hammouda; abdallah, saousen ben; ouanes-besbes, lamia; abroug, fekri; klein, simon; miquet, mattéo; thouret, jean-marc; peigne, vincent; daban, jean-louis; boutonnet, mathieu; lenoir, bernard; merhbene, takoua; derreumaux, celine; seguin, thierry; conil, jean-marie; kelway, charlotte; blasco, valery; nafati, cyril; harti, karim; reydellet, laurent; albanese, jacques; aicha, narjess ben; meddeb, khaoula; khedher, ahmed; ayachi, jihene; fraj, nesrine; sma, nesrine; chouchene, imed; boussarsar, mohamed; yedder, soumaya ben; samoud, walid; radhouene, bousselmi; mariem, bousselmi; ammar, asma; cheikh, asma ben; lakhal, hend ben; khelfa, messaouda; hamdaoui, yamina; bouafia, nabiha; trampont, timothée; daix, thomas; legarçon, vincent; karam, henri hani; pichon, nicolas; essafi, fatma; foudhaili, nasreddine; thabet, hafedh; blel, youssef; brahmi, nozha; ezzouine, hanane; kerrous, mahmoud; haoui, saad el; ahdil, soufiane; benslama, abdellatif; abidi, khalid; dendane, tarek; oussama, ssouni; belayachi, jihane; madani, naoufal; abouqal, redouane; zeggwagh, amine ali; ghadhoune, hatem; chaari, anis; jihene, guissouma; allouche, hend; trabelsi, insaf; brahmi, habib; samet, mohamed; ghord, hatem el; habiba, ben sik ali; hajer, nouira; tilouch, najla; yaakoubi, sondes; jaoued, oussama; gharbi, rim; hassen, mohamed fekih; elatrous, souheil; arcizet, julien; leroy, bertrand; abdulmalack, caroline; renzullo, catherine; hamet, maël; doise, jean-marc; coutet, jérôme; cheikh, chaigar mohammed; quechar, zakaria; joris, magalie; beauport, dimitri titeca; kontar, loay; lebon, delphine; gruson, bérengère; slama, michel; marolleau, jean-pierre; maizel, julien; gorham, julie; ameye, lieveke; berghmans, thierry; paesmans, marianne; sculier, jean-paul; meert, anne-pascale; guillot, max; ledoux, marie-pierre; braun, thierry; maestraggi, quentin; michard, baptiste; castelain, vincent; herbrecht, raoul; schneider, francis; couffin, severine; lobo, david; mongardon, nicolas; dhonneur, gilles; mounier, roman; le borgne, pierrick; couraud, sophie; herbrecht, jean-etienne; boivin, alexandra; lefebvre, françois; bilbault, pascal; zelmat, setti-aouicha; batouche, djamila-djahida; mazour, fatima; chaffi, belkacem; benatta, nadia; sik, ali habiba; talik, i.; perrier, maxime; gouteix, eliane; koubi, claude; escavy, annabelle; guilbaut, victoria; fosse, jean-philippe; jazia, rahma ben; abdelghani, ahmed; cungi, pierre-julien; bordes, julien; nguyen, cédric; pierrou, candice; cruc, maximilien; benois, alain; duprez, frédéric; bonus, thierry; cuvelier, grégory; ollieuz, sandra; machayekhi, sharam; paciorkowski, frédéric; reychler, gregory; coudroy, remi; thille, arnaud w.; drouot, xavier; diaz, véronique; meurice, jean-claude; robert, rené; turki, olfa; ben, hmida chokri; assefi, mona; deransy, romain; brisson, hélène; monsel, antoine; conti, filomena; scatton, olivier; langeron, olivier; ghezala, hassen ben; snouda, salah; ben, chiekh imen; kaddour, moez; armel, anwar; youness, lafrikh; abdelhak, bensaid; youssef, miloudi; najib, al harrar; mustapha, amouzoun; noufel, mtioui; mohamed, zamd; salma, el khayat; ghizlane, medkouri; mohamed, benghanam; benyounes, ramdani; montini, florent; moschietto, sébastien; gregoire, emilien; claisse, guillaume; guiot, julien; morimont, philippe; krzesinski, jean-marie; mariat, christophe; lambermont, bernard; cavalier, etienne; delanaye, pierre; benbernou, soumia; ilies, sofiane; azza, abdelkader; bouyacoub, khalida; louail, meriem; mokhtari-djebli, houria; arrestier, romain; daviaud, fabrice; francois, xavier laborne; brocas, elsa; choukroun, gérald; peñuelas, oscar; lorente, josé-angel; cardinal-fernandez, pablo; rodriguez, josé-maria; aramburu, josé-antonio; esteban, andres; frutos-vivar, fernando; bitker, laurent; costes, nicolas; le bars, didier; lavenne, franck; devouassoux, mojgan; richard, jean-christophe; mechati, malika; gainnier, marc; papazian, laurent; guervilly, christophe; garnero, aude; arnal, jean michel; roze, hadrien; richard, jean christophe; repusseau, benjamin; dewitte, antoine; joannes-boyau, olivier; ouattara, alexandre; harbouze, nadia; amine, a. m.; olandzobo, a. g.; herbland, alexandre; richard, marie; girard, nicolas; lambron, lucile; lesieur, olivier; wainschtein, sarah; hubert, sidonie; hugues, albane; tran, marc; bouillard, philippe; loteanu, vlad; leloup, maxime; laurent, alexandra; lheureux, florent; prestifilippo, alessia; cruz, martin delgado maria; romain, rigal; antonelli, massimo; blanch, torra lluis; bonnetain, franck; grazzia-bocci, maria; mancebo, jordi; samain, emmanuel; paul, hebert; capellier, gilles; zavgorodniaia, taissa; soichot, marion; malissin, isabelle; voicu, sebastian; garçon, pierre; goury, antoine; kerdjana, lamia; deye, nicolas; bourgogne, emmanuel; megarbane, bruno; mejri, olfa; hmida, marwa ben; tannous, salma; chevillard, lucie; labat, laurence; risede, patricia; fredj, hana; léger, maxime; brunet, marion; le roux, gaël; boels, david; lerolle, nicolas; farah, souaad; amiel-niemann, hélène; kubis, nathalie; declèves, xavier; peyraux, nicoals; baud, frederic; serafini, micaela; alvarez, jean-claude; heinzelman, annette; jozwiak, mathieu; millasseau, sandrine; teboul, jean-louis; alphonsine, jean-emmanuel; depret, françois; richard, nathalie; attal, pierre; richard, christian; monnet, xavier; chemla, denis; jerbi, salma; khedhiri, wafa; necib, hatem; scarfo, paolo; chevalier, charles; piagnerelli, michael; lafont, alexandre; galy, antoine; mancia, claire; zerhouni, amel; tabeliouna, kheira; gaja, ali; hamrouni, bassem; malouch, abir; fourati, sami; messaoud, rihab; zarrouki, youssef; ziadi, amra; rhezali, manal; zouizra, zahira; boumzebra, drissi; samkaoui, mohamed abdennasser; brunet, jennifer; canoville, bertrand; verrier, pierre; ivascau, calin; seguin, amélie; valette, xavier; du cheyron, damien; daubin, cedric; bougouin, wulfran; aissaoui, nadia; lamhaut, lionel; jost, daniel; maupain, carole; beganton, frankie; bouglé, adrien; dumas, florence; marijon, eloi; jouven, xavier; cariou, alain; poirson, florent; chaput, ulriikka; beeken, thomas; maxime, leclerc; haikel, oueslati; vodovar, dominique; chelly, jonathan; marteau, philippe; chocron, richard; juvin, philippe; loeb, thomas; adnet, frederic; lecarpentier, eric; riviere, antoine; de cagny, bertand; soupison, thierry; privat, elodie; escutnaire, joséphine; dumont, cyrielle; baert, valentine; vilhelm, christian; hubert, hervé; leteurtre, stéphane; fresco, marion; bubenheim, michael; beduneau, gaetan; carpentier, dorothée; grange, steven; artaud-macari, elise; misset, benoit; tamion, fabienne; girault, christophe; dumas, guillaume; chevret, sylvie; lemiale, virginie; mokart, djamel; mayaux, julien; pène, frédéric; nyunga, martine; perez, pierre; moreau, anne-sophie; bruneel, fabrice; vincent, françois; klouche, kada; reignier, jean; rabbat, antoine; azoulay, elie; frat, jean-pierre; ragot, stéphanie; constantin, jean-michel; prat, gwenael; mercat, alain; boulain, thierry; demoule, alexandre; devaquet, jérôme; nseir, saad; charpentier, julien; argaud, laurent; beuret, pascal; ricard, jean-damien; teiten, christelle; marjanovic, nicolas; palamin, nicola; l’her, erwan; bailly, arthur; boisramé-helms, julie; champigneulle, benoit; kamel, toufik; mercier, emmanuelle; le thuaut, aurélie; lascarrou, jean-baptiste; rolle, amélie; de jong, audrey; chanques, gérald; jaber, samir; hariri, geoffroy; baudel, jean-luc; dubée, vincent; preda, gabriel; bourcier, simon; joffre, jeremie; bigé, naïke; ait-oufella, hafid; maury, eric; mater, houda; merdji, hamid; grimaldi, david; rousseau, christophe; mira, jean-paul; chiche, jean-daniel; sedghiani, ines; benabderrahim, a.; hamdi, dhekra; jendoubi, asma; cherif, mohamed ali; hechmi, youssef zied el; zouheir, jerbi; bagate, françois; bousselmi, radhwen; schortgen, frédérique; asfar, pierre; guérot, emmanuel; fabien, grelon; anguel, nadia; sigismond, lasocki; matthieu, henry-lagarrigue; gonzalez, frédéric; françois, legay; guitton, christophe; schenck, maleka; jean-marc, doise; dreyfuss, didier; radermacher, peter; frère, antoine; martin-lefèvre, laurent; colin, gwenhaël; fiancette, maud; henry-laguarrigue, matthieu; lacherade, jean-claude; lebert, christine; vinatier, isabelle; yehia, aihem; joret, aurélie; menunier-beillard, nicolas; benzekri-lefevre, dalila; desachy, arnaud; bellec, fréderic; plantefève, gaëtan; quenot, jean-pierre; meziani, ferhat; tavernier, elsa; ehrmann, stephan; chudeau, nicolas; raveau, tommy; moal, valérie; houillier, pascal; rouve, emmanuelle; lakhal, karim; gandonnière, charlotte salmon; jouan, youenn; bodet-contentin, laetitia; balmier, adrien; messika, jonathan; de montmollin, etienne; pouyet, victorine; sztrymf, benjamin; thiagarajah, abirami; roux, damien; de chambrun, marc pineton; luyt, charles-edouard; beloncle, françois; zapella, nathalie; ledochowsky, stanislas; terzi, nicolas; mazou, jean-marc; sonneville, romain; paulus, sylvie; fedun, yannick; landais, mickael; raphalen, jean-herlé; combes, alain; amoura, zahir; jacquemin, aemilia; guerrero, felipe; marcheix, bertrand; hernandez, nicolas; fourcade, olivier; georges, bernard; delmas, clément; makoudi, sarah; genton, audrey; bernard, rémy; lebreton, guillaume; amour, julien; mazet, charlotte; bounes, fanny; murat, gurbuz; cronier, laure; robin, guillaume; biendel, caroline; silva, stein; boubeche, samia; abriou, caroline; wurtz, véronique; scherrer, vincent; rey, nathalie; gastaldi, gioia; veber, benoit; doguet, fabien; gay, arnaud; dureuil, bertrand; besnier, emmanuel; rouget, antoine; gantois, guillaume; magalhaes, eric; wanono, ruben; smonig, roland; lermuzeaux, mathilde; lebut, jordane; olivier, andremont; dupuis, claire; radjou, aguila; mourvillier, bruno; neuville, mathilde; d’ortho, marie pia; bouadma, lila; rouvel-tallec, anny; rudler, marika; weiss, nicolas; perlbarg, vincent; galanaud, damien; thabut, dominique; rachdi, emna; mhamdi, ghada; trifi, ahlem; abdelmalek, rim; abdellatif, sami; daly, foued; nasri, rochdi; tiouiri, hanene; lakhal, salah ben; rousseau, geoffroy; asmolov, romain; grammatico-guillon, leslie; auvet, adrien; laribi, said; garot, denis; dequin, pierre françois; guillon, antoine; fergé, jean-louis; abgrall, gwénolé; hinault, ronan; vally, shazima; roze, benoit; chaplain, agathe; chabartier, cyrille; savidan, anne-charlotte; marie, sabia; cabie, andre; resiere, dabor; valentino, ruddy; mehdaoui, hossein; benarous, lucas; soda-diop, marième; bouzana, fouad; perrin, gilles; bourenne, jeremy; eon, béatrice; lambert, dominique; trebuchon, agnes; poncelet, géraldine; le bourgeois, fleur; michael, levy; camille, guillot; naudin, jérôme; deho, anna; dauger, stéphane; sauthier, michaël; bergeron-gallant, krystale; emeriaud, guillaume; jouvet, philippe; tiebergien, nicolas; jacquet-lagrèze, matthias; fellahi, jean-luc; baudin, florent; essouri, sandrine; javouhey, etienne; guérin, claude; lampin, marie; mamouri, ouardia; devos, patrick; karaca-altintas, yasemin; vinchon, matthieu; brossier, david; eltaani, redha; teyssedre, sonia; sabine, meyet; bouchut, jean-christophe; peguet, olivier; petitdemange, lucie; guilbert, anne sophie; aoul, nabil tabet; addou, zakaria; aouffen, nabil; anas, benqqa; kalouch, samira; yaqini, khalid; chlilek, aziz; abdou, rchi; gravellier, perrine; chantreuil, julie; travers, nadine; listrat, antoine; le reun, claire; favrais, geraldine; coppere, zoe; blanot, stéphane; montmayeur, juliette; bronchard, régis; rolando, stephane; orliaguet, gilles; leger, pierre-louis; rambaud, jérôme; thueux, emilie; de larrard, alexandra; berthelot, véronique; denot, julien; reymond, marie; amblard, alain; morin-zorman, sarah; lengliné, etienne; pichereau, claire; mariotte, eric; emmanuel, canet; poujade, julien; trumpff, guillaume; janssen-langenstein, ralf; harlay, marie-line; zaid, noorah; ait-ammar, nawel; bonnal, christine; merle, jean-claude; botterel, francoise; levesque, eric; riad, zakaria; mezidi, mehdi; yonis, hodane; aublanc, mylène; perinel-ragey, sophie; lissonde, floriane; louf-durier, aurore; tapponnier, romain; louis, bruno; forel, jean-marie; bisbal, magali; lehingue, samuel; rambaud, romain; adda, mélanie; hraiech, sami; marchi, elisa; roch, antoine; guerin, vincent; rozencwajg, sacha; schmidt, matthieu; hekimian, guillaume; bréchot, nicolas; trouillet, jean louis; besset, sébastien; franchineau, guillaume; nieszkowska, ania; pascal, leprince; loiselle, maud; sarah, chemam; laurence, dangers; guillemette, thomas; jacquens, alice; kerever, sebastien; guidet, bertrand; aegerter, philippe; das, vincent; fartoukh, muriel; hayon, jan; desmard, mathieu; fulgencio, jean-pierre; zuber, benjamin; soufi, a.; khaleq, k.; hamoudi, d.; garret, charlotte; peron, matthieu; coron, emmanuel; bretonnière, cédric; audureau, etienne; audrey, winters; christophe, duvoux; christian, jacquelinet; daniel, azoulay; cyrille, feray; aissaoui, wissal; rghioui, kawtar; haddad, wafae; barrou, houcine; carteaux-taeib, anna; lupinacci, renato; manceau, gilles; jeune, florence; tresallet, christophe; habacha, sahar; fathallah, ines; zoubli, aymen; aloui, rafaa; kouraichi, nadia; jouet, emilie; badin, julie; fermier, brice; feller, marc; serie, mathieu; pillot, jérôme; marie, william; gisbert-mora, chloé; vinclair, camille; lesbordes, pierre; mathieu, pascal; de brabant, fabienne; muller, emmanuel; robaux, marie-aline; giabicani, mikhael; marchalot, antoine; gelinotte, stéphanie; declercq, pierre louis; eraldi, jean-pierre; bougerol, françois; meunier-beillard, nicolas; devilliers, hervé; rigaud, jean-philippe; verrière, camille; ardisson, fanny; kentish-barnes, nancy; jacq, gwenaëlle; chermak, akli; lautrette, alexandre; legrand, matthieu; soummer, alexis; thiery, guillaume; cottereau, alice; canet, emmanuel; caujolle, marie; allyn, jérôme; valance, dorothée; brulliard, caroline; martinet, olivier; jabot, julien; gallas, thomas; vandroux, david; allou, nicolas; durand, arthur; nevière, rémi; delguste, florian; boulanger, eric; preau, sebastien; martin, ruste; cochet, hélène; ponthus, jean pierre; amilien, virginie; tchir, martial; barsam, elise; ayoub, mohsen; georger, jean francois; guillame, izaute; assaraf, julie; tripon, simona; mallet, maxime; barbara, guilaume; louis, guillaume; gaudry, stéphane; barbarot, nicolas; jamet, angéline; outin, hervé; gibot, sébastien; bollaert, pierre-edouard; holleville, mathilde; legriel, stéphane; chateauneuf, anne laure; cavelot, sébastien; moyer, jean-denis; bedos, jean pierre; merle, philippe; laine, aurelie; natalie, de sa; cornuault, mathieu; libot, jérome; asehnoune, karim; rozec, bertrand; dantal, jacques; videcoq, michel; degroote, thècle; jaillette, emmanuelle; zerimech, farid; malika, balduyck; llitjos, jean-françois; amara, marlène; lacave, guillaume; pangon, béatrice; mavinga, josé; makunza, joseph nsiala; mafuta, m. e.; yanga, yves; eric, amisi; ilunga, jp; kilembe, ma; alby-laurent, fanny; toubiana, julie; mokline, amel; laajili, achraf; amri, helmi; rahmani, imene; mensi, nidhal; gharsallah, lazheri; tlaili, sofiene; gasri, bahija; hammouda, rym; messadi, amen allah; allain, pierre-antoine; gault, nathallie; paugam-burtz, catherine; foucrier, arnaud; chatbri, bassem; bourbiaa, yousra; thabet, lamia; neuschwander, arthur; vincent, looten; beck, jennifer; vibol, chhor; amelie, yavchitz; resche-rigon, matthieu; pirracchio, jean mantzromain; bureau, côme; decavèle, maxens; campion, sébastien; ainsouya, roukia; niérat, marie-cécile; prodanovic, hélène; raux, mathieu; similowski, thomas; dubé, bruno-pierre; demiri, suela; dres, martin; may, faten; quintard, hervé; kounis, ilias; saliba, faouzi; andré, stephane; boudon, marc; ichai, philippe; younes, aline; nakad, lionel; coilly, audrey; antonini, teresa; sobesky, rodolphe; de martin, eleonora; samuel, didier; hubert, noemie; nay, mai-anh; auchabie, johann; giraudeau, bruno; jean, reignier; darmon, michaël; ruckly, stephane; garrouste-orgeas, maïté; gratia, elisabeth; goldgran-toledano, dany; jamali, samir; dumenil, anne sylvie; schwebel, carole; brisard, laurent; bizouarn, philippe; lepoivre, thierry; nicolet, johanna; rigal, jean christophe; roussel, jean christian; cheurfa, cherifa; abily, julien; lescot, thomas; page, isaline; warnier, stéphanie; nys, monique; rousseau, anne-françoise; damas, pierre; uhel, fabrice; lesouhaitier, mathieu; grégoire, murielle; gaudriot, baptiste; gacouin, arnaud; le tulzo, yves; flecher, erwan; tarte, karin; tadié, jean-marc; georges, quentin; soares, m.; jeon, kyeongman; oeyen, sandra; rhee, chin kook; gruber, pascale; ostermann, marlies; hill, quentin; depuydt, peter; ferra, christelle; muller, alice; aurelie, bourmaud; niles, christopher; herbert, fabien; pied, sylviane; loridant, séverine; françois, nadine; bignon, anne; sendid, boualem; lemaitre, caroline; dupre, celine; zayene, aymen; portier, lucie; de freitas caires, nathalie; lassalle, philippe; le neindre, aymeric; selot, pascal; ferreiro, daniel; bonarek, maria; henriot, stépahen; rodriguez, julie; taddei, mara; di bari, mauro; hickmann, cheryl; castanares-zapatero, diego; deldicque, louise; van den bergh, peter; caty, gilles; roeseler, jean; francaux, marc; laterre, pierre-françois; dupuis, bastien; machayeckhi, sharam; sarfati, celine; moore, alex; mendialdua, paula; rodet, emilie; pilorge, catherine; stephan, francois; rezaiguia-delclaux, saida; dugernier, jonathan; hesse, michel; jumetz, thibaud; bialais, emilie; depoortere, virginie; michotte, jean bernard; wittebole, xavier; jamar, françois title: proceedings of réanimation , the french intensive care society international congress date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: a pviol nan introduction the study of the bacterial cartography in thoracic surgery is extremely important for the treatment of post-operative infections due to the severity of the underlying pathology, the fragility of patients after surgery in addition to the choice of the empiric antibiotic therapy. we led a prospective study following all the patients who underwent a pulmonary resection surgery for a period of months from january to july , jointly with the microbiology department, chu ibn rochd, casablanca. the bronchial secretions were collected by a protected distal bronchial sample using a (combicath) after the intubation. results during the period of the study, patients underwent a pulmonary resection, % for a neoplastic pathology. the medium age was years ± and % of our sample were male. % of our patients had smoking habits and of them had pulmonary tuberculosis, had repeated respiratory infections. the antibiotics used in pre-operative: % of beta-lactams; % of fluoroquinolones; % of macrolides. moreover, % of our patients were classified asa . of the obtained samples, were positive ( . %). the most frequently observed germs were the acinetobacter baumannii ( . %), pseudomonas aeruginosa ( . %), klebsiella pneumoniae ( . %), staphylococcus aureus ( . %). the acinetobacter baumannii was the most resistant germ ( % sensibility to carbapenem). these patients were followed until their d after surgery, of them developed a post-operative pneumonitis with cases of multi-resistant acinetobacter baumanii, of which deceased. conclusion pneumonitis after pulmonary resection are common and severe that's why it is necessary to establish a global prevention strategy mainly based on general patricians and pneumologists' awareness concerning the choice of the prescribed antibiotics, in order to avoid the spread of multi-resistant germs. introduction carbapenemase-producing enterobacteriaceae (cpec) are increasingly reported worldwide and constitutes a real challenge antibiotic for clinicians to preserve the bacterial ecology. its incidence has remarkably increased in our intensive care unit during the last years. the esbl spread has a major consequence in term of antibiotic choices. carbapenem antibiotic are regarded as the most effective treatment. however numbers of authors suggest that alternatives antibiotics (i.e. noncarbapenems) could be used in esbl-pe infections. there are some conflicting data regarding the use of alternatives in case of esbl-pe infections. moreover as far as we know, there are no data in icu. objectives the aim of this study was to describe esbl-pe infections in icu and therapeutic options chosen in these specific situations. patients and methods prospective multicentric observational cohort study conducted in volunteers icu. all consecutive patients hospitalized in icu with esbl-pe infection according to cdc definitions were included. severity of illness was defines according to bone criteria, saps ii and sofa. demographic datas, empirical and definitive antibiotic therapy (et and dt), clinical evolution, and outcome were recorded. in vitro antimicrobial susceptibility testing was performed by the disk diffusion method or the vitek system according to the guidelines of the antibiogram committee of the french microbiologic society. results during the study period patients with esbl-pe infection met eligibility criteria with respectively a median age and saps ii score of ( - ) and ( - ). the median sofa score at first day of antibiotic therapy and icu admission were ( - ) and ( ) ( ) ( ) ( ) ( ) ( ) ( ) respectively. the most frequent site of infection were respiratory tract ( %), urinary tract ( %) and abdominal ( %). the most frequent isolated species were: escherichia coli ( %), klebsiella sp ( %) and enterobacter sp ( %). respectively , and % patients had septic shock, severe sepsis and sepsis according to bone criteria. among esbl-pe, . % were carbapenem and . were blbi sensitive. among the whole population, ( %) patients received a carbapenems as et. ( %) received a dt with carbapenems and ( %) patients received an alternative dt. the most frequent reasons for maintaining carbapenems as dt were: antibiotic susceptibility tests ( % of cases), severity level ( % of cases) immunosuppression ( % of cases). the median length of icu stay after infection was respectively ( - ) and ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) days for carbapenems and alternatives dt (p = . ). the d mortality was % for patients with carbapenems dt and % for patients with alternatives dt (p = . ). surprisingly, there were no differences between the groups (carbapenems vs alternatives) in term of severity. conclusion alternatives are frequently used for esbl-pe infections in icu. in our cohort ( %) patients received antibiotics other than carbapenems regardless of the severity. introduction bacterial resistance to antibiotics is a common problem worldwide. in south america, this prevalence is reported to be the highest in the world. however, in french guyana, there is no data on the epidemiology of colonization and infection caused by extended spectrum b-lactamase producing enterobacteriaceae (esbl-pe). we conducted this study to investigate the prevalence of colonization with esbl-pe and subsequent icu acquired infection in french guiana. introduction the implementation of hemofiltration (hf) as a renal replacement therapy in septic shock patients requires the supply of large quantities of replacement solutions. these solutions are either industrially prepared in autoclaved expensive plastic bags (conventional hemofiltration, chf) or continuously provided in unlimited amounts at the dialysis machine directly from the water treatment plant to form the replacing solutions (on-line hemofiltration, olhf).the aim of our study was to evaluate the safety and effectiveness of on-line hemofiltration compared to conventional hemofiltration in septic shock patients. the investigative protocol was approved by the institutional ethics authorities and all patients or their legally authorized representatives provided written informed consent. it was a prospective, randomized, clinical study, including septic shock patients with acute renal failure. patients were randomized to receive either on-line hemofiltration (n = ) or conventional hemofiltration (n = ) for renal replacement therapy during days. hemodynamic monitoring was conducted by conventional devises, including: electrocardiogram and a radial arterial catheter for invasive arterial pressure every h during period study. we collected serum samples also every h (urea, potassium and sodium levels, troponin, hemoglobin, platelets, c-reactive protein and lactates). results the evolution of heart rate (hr), mean arterial pressure (map), biological markers were comparable between the two groups over time except a significant decrease in map in the olhf group compared to chf group only at h (p = . ) and h (p = . ) and a significant decrease in c-reactive protein level in the olhf group at h (p = . ). conclusion on-line hemofiltration seems to be a safe and reliable method of renal replacement therapy in septic shock patients. it may be associated with attenuated pro-inflammatory cytokine profile (c-reactive protein). none. introduction therapeutic plasma exchange (tpe) is crucial for the management of auto-immune diseases like thrombotic thrombocytopenic purpura or myasthenia gravis. tpe is performed either by centrifugation, with specific machines which are not routinely available in icus, or by using specific plasma separation membranes with widely spread in icus hemofiltration machines. regional citrate anticoagulation for tpe is well established with centrifugation but has been seldom described for membrane tpe. we are reporting the experience of our icu in this field. patients and methods retrospective study including all patients who received tpe with citrate regional anticoagulation between and in an -bed icu. tpe is performed solely in the icu in our institution. results patients were included. tpe was required for thrombotic microangiopathy ( patients), vasculitis ( patients), hyperviscosity syndrome ( patients), guillain-barré syndrome ( cases) and others ( patients) . mean saps score was [standard deviation (sd) . ] . tpe were performed, with a mean number of . (sd . ; range - ) tpe per patients. coagulation of the circuit of tpe occurred in ( %) patients. coagulation of the circuit occurred in . % ( / ) of the tpe. minor adverse events have been reported in two patients: one had a rash during the first tpe (no recurrence during the next tpes) and the other had paresthesia during the first two tpes (the calcium infusion was increased and there had been no recurrence during the next tpes). no serious adverse events related to citrate were observed. conclusion regional anticoagulation with citrate allowed us to perform tpe in patients, without significant adverse events. the rate of circuit coagulation was . % per tpe. none. introduction a reduced incidence of membrane thrombosis after injection of anti-thrombin (at) has been reported in septic patients with acquired deficit in at undergoing continuous hemofiltration. as this strategy was routinely performed in our unit until , we investigated its cost-effectiveness. patients and methods data about the use of hemofiltration, the consumption of at and hemofiltration devices during (period with routine use of at) and (period with use of at only if a membrane thrombosis occurred) were extracted from the administrative database of the institution. a decisional tree was built to modelize the impact of at on the consumption of hemofiltration devices and blood products. the decisional tree took into account the probability of membrane thrombosis with and without at and the probability of transfusion after membrane thrombosis. costs were obtained from the pharmacy of the institution (at, hemofiltration devices) and from the literature (blood products). results during , days of hemofiltration were performed, with the use of doses of at ( , €) and hemofiltration devices ( , €) . during , (− %) days of hemofiltration were performed, with the use of (− %) doses of at ( €) and (+ %) hemofiltration devices ( , €) . the mean cost of day of hemofiltration decreased from € to € with the diminution of the use of at. according to the decisional tree, at was almost never cost-effective. the only circumstances associated with a benefit for the use of at was the association of a probability of thrombosis with at inferior to . , of a probability of thrombosis without at equal , of a probability of transfusion after thrombosis equal and a cost of transfusion of €. in these extremely favorable circumstances, at could decrease the daily cost of hemofiltration of . - . €. discussion the model has several limits: the losses of utility related to transfusion and to interruption of hemofiltration due to thrombosis were not taken into account; the cost of at measurement was not estimated; the work load of changing a membrane and of transfusion after membrane thrombosis was not analyzed. conclusion our results suggest that anti-thrombin is not costeffective to reduce the costs of hemofiltration related to membrane thrombosis. none. introduction in intensive care unit (icu), some patients suffering from acute kidney injury need renal replacement therapy (rrt). it requires the circuit anticoagulation, this could be done by a regional citrate method. today, this is a recommended approach for the everyday care, even if the technique isn't widespread yet [ ] . the ionized calcemia dosing through the filter ("post-filter" ionized-calcemia) is used to monitor the technique efficacy, with a target of . - . mmol/l showing a good filter anticoagulation. the objective of our study was the assessment of efficacy and safety of our regional citrate anticoagulation protocol, with a less restrictive post-filter ionized calcemia target ( . - . mmol/l). the main goal was the analysis of the circuit lifespan, considering a lifespan above h, as well as the search of some clinical and biological factors affecting the technique efficacy. moreover, we analyzed the side effects incidence of the protocol (hypernatremia, metabolic alcalosis), and their consequences. the study received the scientific ethical agreement of university hospital of toulouse, and is registered with number - . patients and methods patients, admitted to one of the two university hospital icus of toulouse, needing a continuous rrt method, without any need for systemic heparin anticoagulation, and without severe hepatocellular failure, were included in the study. filters included over a -year period were analyzed. results results show a mean filter lifespan of h, with a lifespan above h for . % of all filters. coagulation was the cessation reason for . % of filters, most of them before h of the filter use. a value of post-filter ionized calcemia at day below . mmol/l was the main factor influencing a filter lifespan above h. an age older than and a saps ii severity score below were other factors conditioning a filter lifespan of more than h. side effects of citrate were rare and didn't have any clinical impact among our patients. discussion these results suggest that citrate used for anticoagulation in rrt could have an additional anti inflammatory effect through the induced hypocalcemia, as well as an energetic gain which could lead to a renal protection against ischemia-reperfusion mechanism [ ] . moreover, these results call into question the need of post-filter ionized calcemia dosing for the monitoring of citrate anticoagulation efficacy, since the method safety is monitored by the total-to-ionized calcium ratio. conclusion during continuous rrt in icu, a regional citrate anticoagulation protocol with a non-restrictive post-filter ionized calcemia target seems to be efficient and could reduce side effects. these results need to be confirmed with a randomised control study. introduction continuous veno-venous haemofiltration (cvvh) is used to treat acute kidney injury in critically ill patients. to optimize its efficiency, cvvh requires effective anticoagulation. systemic anticoagulation with standard heparin, the most used, can lead to major bleeding complications. hemofilters that are able to adsorb heparin molecules on their surface such as an st and oxiris membranes represent an alternative. the objective of this study was to compare these two types of filters in terms of duration, efficiency, dysfunctions and cost. materials and methods from october to may , we conducted a retrospective, observational, and non-interventional study. all patients admitted in the intensive care unit needing cvvh were included. the primary endpoint was the filter lifespan: an st versus oxiris. the secondary endpoint was the filter efficiency (urea reduction ratio: urr). the main analysis did not consider the anticoagulation type. we conducted a subgroup analysis taking into account the use or not of an anticoagulation. results sessions in patients were carried out using filters representing , h of treatment. the mean an st filter lifespan was ± h and ± h for oxiris filters (p > . ). there is no significant difference in terms of duration between the two filters. the subgroup analysis taking into consideration the use or not of anticoagulation did not show any difference either. the mean urr was ± % in the an st group and ± % in the oxiris group (p > . ). concerning the dysfunctions, there were no significant difference between the two filters. one hundred and seventy-six an st filters were used for a total cost of , euros. two hundred and ten oxiris filters were used for a total cost of , euros. conclusion the an st and oxiris lifespans are not significantly different. they were as efficient in terms of blood epuration and had as many dysfunctions. the use of an oxiris filter rather than an an st to extend the circuit's lifespan in the same clinical conditions is not justified considering the extra cost generated. introduction because oliguria is a poor prognostic sign in patients with acute renal failure (arf), diuretics are often used to increase urine output in patients with or at risk of arf. from a pathophysiological point of view there are several reasons to expect that loop diuretics could have a beneficial effect on renal function. however, a review of literature shows that the use of loop diuretics in patients with arf has been associated with inconclusive results despite the theoretical benefits [ ] . to assess the adjunctive effect of diuretics, to alter the progression to kidney injury or failure, in patients at risk for acute renal failure. patients and methods this is a retrospective chart review of consecutive patients who developed arf with oliguria in the intensive care unit. chart abstractors were well trained residents. two chart reviewers (senior intensivists) studied all the charts. an explicit protocol was used to precise all needed definitions. uniform handling of data was ensured especially for conflicting, missing or unknown data. oliguria was defined as urine output lower than . ml/kg/h for at least h. rifle score was assessed before and after urinary output normalisation. therapeutic intervention to optimize pre-renal perfusion was described. mean arterial blood pressure (mbp) before and after therapeutic initiation, oliguria duration, delay from oliguria onset to diuretic administration, delay from diuretic administration to urinary output normalisation were measured. results patients were studied over a years period. ] h. the delay from diuretic administration to urinary output normalization was [ . , ] h. after resumption of diuresis, rifle score was assessed as (patients without risk, %; r, %; i, %; f, % l, zero; e, zero) (fig. ) . increased serum creatinine level, above . fold normal range, was observed only in ( %) patients. conclusion rapid optimization of pre-renal hemodynamic disturbances associated with short delay administration of diuretics could significantly alter the progression to kidney injury or failure in at risk acute renal failure icu patients. the ventilator associated pneumonia (vap) is a common and severe complication of assisted ventilation. it's the leading cause of nosocomial infections in intensive care unit and remain responsible for a high morbidity and mortality because of the emergence of multidrug resistant (mdr) bacterial agent such us acinetobacter baumannii (ab). the aim of this study was to determine the incidence, risk factors and prognosis of ab vap. patients and methods retrospective study extending over a year period (january -january ) that included all patients over patients were divided into two groups: one consisting of patients who developed vap to ab and the second developed vap to another bacterial pathogen. results one hundred and forty patients developed vap. the incidence rate of ab vap was . % with a density of incidence of . per ventilator days. age, male gender, the time between hospitalization and mechanical ventilation and the medical pathology were risk factors for developing ab vap. ab was resistant to ceftazidime in %, to imipenem in %, tobramycin in % and netilmycin in . %, rifampin in % with a sensitivity to colistin in % of cases. the resistance of this germ to imipenem increased from % in to . % in . the evolution of patients with ab vap developed frequently septic shock compared to other patients ( vs . %; p = . ). the ab vap mortality was higher ( vs %; p = . ). conclusion the increasing incidence of multi-drug resistant ab vap is responsible for a high morbidity and mortality. so we need to identify risk factors and to strengthen the means of prevention of hand contamination and cross transmission during invasive procedures. introduction central line associated bloodstream infections (clabsi) are among the serious hospital-acquired infections. the aim of this study is to determine the incidence of clabsi, the pathogens and the risk factors that play a role in the development of bsi among patients followed in a tunisian medical intensive care unit. patients and methods all patients admitted for more than h were included in the study over a -year period in an -bed medical icu. the enrollment was based on clinical and laboratory diagnosis of bsi. blood samples were collected from catheter hub of all patients for culture, followed by identification and antibiotic sensitivity testing of the isolates. was higher compared with the mean rate of clabsi in icu reported by the nnis system surveillance for , which is . / catheter.days [ ] . duration of catheterization, frequent manipulation of catheter, catheter location, catheter type, underlying diseases, suppression of immune system, and types of fluids administered through the catheter are significant risk factors in development of bsis [ ] . in our study both duration of catheterization and number of attempts are independent factors for clabsi. conclusion in a monocenter cohort, clabsi had a moderate density rate but are associated with poor outcome. identifying the risk factors is necessary to find solutions for this major health problem. introduction according to some studies, field-intubated patients have . - times greater risk of ventilator associated pneumonia (vap). endobronchial intubation (ei) can be unrecognized by the physicians and may result in complications such as atelectasis which in turn could increase the risk of vap. the aim of our study was to confirm this hypothesis. patients and methods this monocentric retrospective study included all consecutive patients > years who underwent an out-of-hospital tracheal intubation before their admission to the intensive care unit (icu) between january and december . exclusion criteria were suspected aspiration or pneumonia on admission, patients who died within the first days of icu stay, extubation in less than h and underlying disease making radiological interpretation difficult for vap diagnosis. vap were divided into early onset (< days) and late onset (≥ days) events and were independently diagnosed by two experienced intensivists who had no access to the initial chest x-ray performed to check the position of the tracheal tube, based on the clinical pulmonary infection score. onset of ventilator associated tracheobronchitis (vat) was also noted. inadvertent endobronchial intubation was determined by another independent physician based on the interpretation of admission chest x-ray. results patients were intubated out-of-hospital. of the patients excluded, had an extubation in less than h, were died within the first days, had a suspicion of pneumonia, a suspicion of aspiration and an underlying disease making radiological interpretation difficult. of the patients included, ( . %) had an ei upon admission. no significant difference was observed between the ei and non-ei group for gender, age, saps , comorbidities and diagnostic category (cardiorespiratory arrest, trauma, coma and cardiorespiratory failure). early-onset vap were diagnosed in % in the ei group and in % of non-ei patients (p = . ). adding early onset vat, the respiratory infection rate was % in the ei group and % in the non-ei group (p = . ) (fig. ). late-onset vap were observed in . % in the non-ei group and . % in the ei group, without difference between groups (p = . ). there was no inter-group difference in the duration of ventilation, duration of icu stay and icu mortality. staphyloccocus aureus was the most prevalent pathogen in patients with early-onset vap ( . %, only one strain was methicillin-resistant). conclusion this study found a high rate of inadvertent prehospital endobronchial intubation with a higher incidence of early-onset vap. these results support the implementation of specific procedures to decrease the incidence of ei. introduction ventilator-associated pneumonia (vap) is associated with increased hospital stay and high morbidity and mortality in critically ill patients. the classic dichotomy between early and late onset vap is no longer helpful available. the aims of this study were to determine the incidence of multidrug-resistant pathogens in the first episodes of vap and to assess potential differences in bacterial profiles of subjects with early-onset versus late-onset vap. patients and methods retrospective cohort study over a period of months including all patients who had a first episode of vap confirmed by positive culture. subjects were distributed into groups according to the number of intubation days: early-onset vap (< days) or late-onset vap (≥ days).the primary endpoint was the nature of causative pathogens and their resistance profiles. results sixty patients were included, men and women. the average age was ± years. the igs at admission was . [ ; ] apache [ ; ] . monomicrobial infections were diagnosed in of patients ( %).two different bacteria were isolated in cases ( %). a. baumannii was the most frequently isolated in % (n = ) of patients; followed by p. aeruginosa in % (n = ), enterobacteriaceae in % (n = ) and s. aureus in % (n = ). the isolated bacteria were multidrug-resistant in most cases ( / ). the vap group comprised episodes ( %) of early-onset vap and episodes ( %) of late-onset vap. a. baumannii was isolated in % of early vap (n = ) versus % of late vap (n = ) (p = ns), p. aeruginosa in % of early vap (n = ) versus % of late vap (n = ) (p = ns) and enterobacteriaceae in % of early vap (n = ) versus % of late vap (n = ) (p = ns). for the resistance profile of the different pathogens isolated, there was no difference between early and late onset vap. conclusion according to new data from the literature, there were no microbiological differences in the prevalence of potential multidrugresistant pathogens or in their resistance profiles associated with early-onset versus late-onset vap. the bacterial nosocomial infection is a major cause of morbidity and mortality in burned. the bacterial ecology in an icu has a major impact in terms of morbidity and mortality, particularly in the center of burned or length of stay of patients is increased compared to a general intensive care. we conducted an observational study spread over months in icu for severe burned burnt including any who have spent more than h with nosocomial infection (modified cdc criteria), and in which all biological and bacteriological samples were taken. the different types of infections studied were: skin, urinary, lung and bloodstream infections. they excluded all patients belatedly supported or having stayed in other healthcare facilities. results one hundred twenty ( ) patients showed nosocomial infection during this period. the sex ratio (m/f) was . and the mean age was ± years. bacteremia was present in . % of cases, followed by the urinary tract infection that was present in . % of cases, followed by the cutaneous infection in . % of cases, and last pulmonary infection in % of cases. infection was polymicrobial in . % of cases. the main bacteria identified were: acinetobacter baumanii ( . %) of which % is resistant to imipenem, enterobacteriaceae ( . %), pseudomonas aeruginosa ( %) of which . % is resistant to ceftazidime and . % is resistant to imipenem, enterococcus ( %) and staphylococcus aureus ( . %). conclusion the incidence of nosocomial infection is very high compared to literature. the rate of resistance to common antibiotics is very high. a drastic management of antibiotics in our context, the selection of patients and the frequent use in the operating room for skincare allow a better management of these patients. introduction acinetobacter baumannii (ab) ventilator-associated pneumonia (vap) is common in critically ill patients. the aims of this study were to describing the epidemiological characteristics of ab-vap, to identify risk factors for acquisition and factors predictive of a poor outcome. materials and methods a retrospective-prospective study was conducted at the medical intensive care unit of the university hospital ibn sina, rabat-morocco from january to december . they were included in the study that all patients developed vap with identified germ. for identification of risk factors of acquisition of ab vap, two groups of patients were compared: patients with ab vap versus patients with vap caused by other germs. to identify factors associated with mortality, two other groups were compared: survivors versus died. results patients presented vap among which were caused by acinetobacter baumannii. among isolates of ab, . % were drug susceptible, and . % were multidrug-resistant while % were extensively drug-resistant. they were independent risk factors for acquisition of ab vap in multivariate analysis: the presence of a central venous catheter before the occurrence of vap, duration of prior hospitalization ≥ days and icu duration of stay ≥ days. the mortality rate of ab vap was %. the independent risk factors for poor outcome in multivariate analysis were: duration of antibiotic treatment > days, the reintubation and the presence of a previous hospitalization. discussion our data were similar to those of the literature with a high incidence of vap due to the ab ( %) and a high rate of resistance to this bacterium particularly to carbapenems. however, and compared to the literature, the vap ab were responsible for a death rate much higher ( %). conclusion our data were similar to those of the literature with a high incidence of vap due to the ab ( %) and a high rate of resistance to this bacterium particularly to carbapenems. however, and compared to the literature, the vap ab were responsible for a death rate much higher ( %). introduction ventilator-associated pneumonia (vap) is common in critically-ill patients. in fact, - % of patients requiring invasive mechanical ventilation develop this complication. the onset of vap has been reported to be associated with increased mortality. however, data related to critically-ill elderly patients are scarce. the aim of this study is to assess the prognostic impact of vap in critically-ill elderly patients. patients and methods mono-center, retrospective study conducted from / to / / . all old patients (age ≥ years) requiring mechanical ventilation were included. two groups were compared: patients who developed vap (vap (+) group) and those who did not develop vap (vap (−) group). results during the study period, patients were included. the causes of admission in the intensive care unit (icu) were shock (n = ), acute respiratory failure (n = ) and disturbed level of consciousness (n = ). diabetes mellitus, hypertension and chronic obstructive pulmonary disease were the most common comorbidities ( . , . and . % respectively). mean age was . ± . years. sex-ratio (m/f) was . . mean apache(ii) score was ± . the mean duration of mechanical ventilation was ± days. thirty patients ( . %) developed vap. icu-mortality was significantly higher in the vap (+) group ( vs . %; p = . ). multivariate analysis identified two independent factors predicting icu mortality: shock on admission (or = . , ci % [ . - . ], p < . ) and vap (or = . , ci % [ . - . ], p = . ). conclusion vap is common in critically-ill elderly patients and is associated with worse outcome. therefore, preventing its onset is of paramount importance. increased health-care costs. among pathogens responsible of vap, acinetobacter baumannii which is characterized by its ability to spread in the hospital environment and to acquire resistance leading sometimes to therapeutic impasses is associated with a particularly high mortality reaching - %. objective to describe the epidemiological characteristics of a. baumannii vap, to determine their prognosis and identify factors associated with mortality. patients and methods it is a monocentric observational study conducted over a period of years in a tunisian intensive care unit (icu) including mechanical ventilated patients for more than h with confirmed a. baumannii vap. results one hundred and twenty-three patients were included in the study. a. baumannii was responsible for % of vap in our icu. the vap were late in % of cases. more than % of isolates pathogens were resistant to ticarcillin, piperacillin, piperacillintazobactam, ceftazidime and ciprofloxacin. sixty percent of germs were sensitive to imipenem. resistance to imipenem has increased consistently from % at the beginning of the study to % in . all pathogens were susceptible to colistin. a. baumannii vap was complicated by septic shock in % of cases. the median duration of mechanical ventilation and of icu stay were (iqr: [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and days (iqr: - ) respectively. the use of parenteral nutrition was the only factor associated with the occurrence of a. baumannii vap resistant to imipenem (odds ratio . , % ci [ . - . ], p = . ). icu mortality was %. it was higher in patients with a. baumannii vap resistant to imipenem ( vs %, p > . ). in the multivariate analysis, the age, the use of renal replacement therapy and the occurrence of vap relapse have been identified as factors associated with mortality. conclusion a. baumannii resistance to imipenem became threatening. the use of parenteral nutrition was the only factor associated with the occurrence of a. baumannii vap resistant to imipenem. the choice of empiric antimicrobial for vap caused by this pathogen must take in consideration the epidemiologic data of each country and each icu. a. baumannii vap was associated with high mortality. the age, the use of renal replacement therapy and the occurrence of vap relapse have been identified as predictive of poor outcome. none. admission in intensive care unit for severe adverse drug event: what finding? julien arcizet , bertrand leroy , caroline abdulmalack , catherine renzullo , maël hamet , jean-marc doise , jérôme coutet introduction adverse drug events (ade) remain a serious public health problem. they represent between . and . % of hospital admissions and between . and . % of intensive care unit (icu) admissions. they are defined as any injury related to a drug, and include both adverse drug reactions, expected or not, but also underuse, overuse and misuse, unintended or undesired, preventable or not. indeed, mortality from iatrogenic event would rise between . and . %, whereas these ade that resulted in icu hospitalization could be prevented in . - . % of cases. these unplanned admissions overload icu, limit access to health care for other patients and have serious economic consequences for the health system. it is therefore necessary to study these ade to know their main causes and attempt to find a solution to avoid them. the main objectives of our study were to clinically and pharmaceutically analyze and stratify the different ade leading to hospitalization in our icu. this is a monocentric prospective study, between june to january , in medico-surgery icu. from all admissions, we had included patients admitted in our hospital for involuntary ade (plausible, likely and very likely causal). we had collected clinical aspects (failure mode, igsii score, mortality in icu) and pharmaceutical aspect (number of drug, offending drugs) at daily medical staff meeting. conclusion hospitalizations in icu for ade are still too common despite their preventability for most cases. many patients with known cognitive disorder manage their treatment themselves and this is probably one of the reasons of iatrogenic events. anticoagulants and antiplatelet agents, by side effects, misuse, underuse or overuse are very often involved. the onset of kidney failure from dehydration and the continuation of nephrotoxic and antidiabetic treatment also remain one of the most common causes. consequently, it is necessary to continue and develop primary, secondary and tertiary prevention strategies to prevent their appearance, to limit their consequences and to reduce recidivism. introduction intensive care unit (icu) is usually identified as a place of acute care, concentrated over a short period. for many reasons, a prolonged stay in the icu has a pejorative connotation for the intensivist physician. the aim of our study is to describe the epidemiological, clinical, paraclinical profile of patients hospitalized for a long time in icu (over days) and to identify the main prognostic factors and those that can predict the duration of stay in icu. we conducted a retrospective study, over a period of years and months (january to june ), enrolling patients whose length of stay was greater than or equal to introduction despite an improvement in prognosis of patients with hematologic malignancies for the last decade, mortality of such patients admitted to the intensive care unit (icu) remains high. yet, it seems that a first icu stay does not modify prognosis of the malignancy. until now, there is no data on readmission in the icu of such patients and its effect on short and long term prognosis impact. patients and methods this retrospective, single-center study conducted on a years period in the medical icu from our university hospital included patients with hematological malignancies admitted for a first stay. objectives were to evaluate the icu, day and months mortality, to identify prognostic factors associated with mortality within uni-and multivariate analysis, to evaluate readmission rate within the days after discharge, to indentify the admission risk factors associated with icu readmission and the prognosis factors associated with mortality during the second icu stay. multivariate analysis poor performance status, igs ii, hlh, mv and anti-fungal administration were associated with increased icu mortality, infections with pseudomonas were associated with higher day mortality. catheter related infections were associated with better icu survival and cr was associated with lower day mortality. of ( . %) candidate patients for icu readmission after a first stay were readmitted within the days following discharge. median overall survival was lower in readmitted versus non readmitted patients. months mortality was . % for readmitted versus . % for no readmitted patients (p < . ). the second icu stay mortality was . % and month mortality was . %. by multivariate analysis, only mv was associated with prognosis. the months mortality rate of patients who survived to the second icu stay was significantly higher than the patients who survived to the first admission but were not readmitted ( . vs . %, p = . ). conclusion main features, short and long term mortality and prognostic factors associated with icu admission are in lines with previous studies. early readmission rate was high with a negative impact on survival. despite admission in the icu of patients with hematologic malignancies seems not to affect long term prognosis, early readmission seems to have a pejorative impact on the course of the malignancy. introduction lung cancer is among all types of cancer, the most common solid tumour admitted in intensive care [ ] . recent studies showed that the prognosis of patients with lung cancer during intensive care unit (icu) stay has improved [ ] . the aim of our study was to determine the causes of icu admission of lung cancer patients, their prognosis and to identify factors predicting hospital mortality and survival after hospital discharge. in fact, temporary full-code icu management in patients with relapsed aml seems to be appropriate. none of the life-sustaining interventions at admission and on day were able to predict survival. an icu trial of days might not be enough to appraise precisely the outcome. bone marrow transplant was associated with a high mortality in our study. in case of relapsed aml with bmt, icu management is still challenging. the growing population of chronically critically-ill patients has a poor prognosis despite all the resources mobilised [ ] . our primary objective was to analyse the prognostic value of different definitions used to describe them. our secondary objective was to look for early clinical and biological factors that could be associated with the in-hospital mortality. we conducted an epidemiological prospective study in intensive care units (neurosurgical, cardiosurgical and medical) of a large french teaching hospital (henri mondor, créteil). we included all the patients hospitalized for at least days. we tested definitions: the prolonged mechanical ventilation, the definition taken up by kahn et al. [ ] , the prolonged length of stay, the persistent critical illness and the persistent inflammation-immunosuppression and catabolism syndrome. two biological examinations were performed: upon entering the study and week later. the study endpoint was the in-hospital mortality. results thirty patients were included between april and july . among them, only % matched the definition of prolonged mechanical ventilation, which is still the most used in the literature. further, it was not associated with the mortality, but the prolonged length of stay was, with % of these patients, that did not survive to their hospital stay. other parameters that were significantly different between the patients who died and those who survived were an advanced age, an elevated igs ii score at hospital admission, an elevated sofa score at study entry, a late healthcare-associated infection and several biological variables: a high c reactive protein, low albumin and prealbumin and a poor percent of monocytes expressing hla-dr, all measured at day . conclusion the in-hospital mortality of chronically critically-ill is still high. a prolonged length of stay is the only definition who may be helpful to identify the patients with the poorest outcome. among the early factors associated with mortality, we found a late healthcareassociated infection and a low percent of monocytes expressing hla-dr, pointing to the value of studying the immune system of these patients. introduction as a result of demographic transition, the proportion of «very elderly» (≥ years) patients is increasing worldwide and more of these patients are nowadays admitted to intensive care units (icu). among physicians the discussion about appropriateness of these icu admissions still remains controversial mostly due to questionable outcome, limited resources and costs. the aim of the study was to determine and evaluate the clinical characteristics and outcome in a very old population admitted to a medical icu in an urban teaching hospital. we present here a monocentric, retrospective and observational study. we reviewed the charts of all patients (≥ years) admitted to a medical icu between and ( years). we collected epidemiological, clinical and biological parameters and all therapeutic measures during the icu stay. a longterm survival follow-up was also performed. two hundred eighty-four patients were included for statistical analysis. multivariate cox regression was also performed to identify risk factors for -day outcome. results a total of patients were included, which represented . % of admissions to the icu during the period of the study. the mean age was . ± . years, the sex ratio was . . most of patients ( %) were admitted from the emergency department. % of these admitted patients suffered of previous dementia. the mean charlson comorbidity score was . ± . and the mean mccabe score was . ± . . the admission diagnosis in the icu was mainly respiratory distress ( %), septic shock ( %), cardiac arrest ( %) and coma ( %). the mean saps-ii score within h of icu admission was . ± . . half of these patients required support by mechanical ventilation (mean duration . days) and vasoactive drugs and % of patients received renal replacement. icu and in-hospital mortality rates were and % respectively. overall survival at months after hospital discharge was %. multivariate regression revealed necessity of catecholamines and mechanical ventilation as independent risk factors and urinary sepsis as protective factor for -day outcome. in fine, for % of these patients, a limitation of active treatment was decided (on average after days of stay). for all others there was no justification for limiting care because of a well-established treatment plan (with family, gp, icu team). conclusion the proportion of elderly patients remains low, but they are increasingly being treated in intensive care units. nevertheless, the in-hospital mortality is high compared to the average mortality in our icu over the same period ( %). the prognosis is often not as poor as initially perceived by physicians. the indication for icu treatment in our study was mostly justified; in the setting of consistent patient care and good clinical practice. it remains therefore appropriate to discuss every single icu admission of elderly patients without any restriction related to age. thus, the ongoing cluster-randomized trial of icu admissions for the elderly patients (ice-cub study) is deeply awaited to confirm or not these results [ ] . keywords intensive care; prognosis; outcome; elderly patients; over -years old. introduction regardless of the route of delivery, the postpartum hemorrhage (pph) is defined as blood loss ≥ ml after childbirth, and severe pph as blood loss ≥ ml. pph is the leading cause of maternal mortality in africa. the aim of this prospective study was to assess the quality of the initial management of pph in algeria in oran ehu and to determine the factors of care with the severity of this complication. we conducted a prospective cohort study between april and september at the ehu oran. all women who delivered vaginally and showed hpp including the suspected cause was uterine atony were included. the severe pph was defined as bleeding that required invasive surgical treatment (hysterectomy, arterial ligation), a transfusion, a transfer to an intensive care unit or death of the patient. the quality of care was evaluated using objective criteria defined by a delay of diagnosis and care and mortality. results among the women who delivered vaginally during the study period, had a pph, link with uterine atony alleged at diagnosis, of which presented signs of severity. in % of cases, the delay in diagnosis of pph was less than min; % of women received oxytocin within min after diagnosis. the tranexanique acid was used in case. the examination of the cervix, uterine exploration and uterine massage was performed in , and %, respectively. the failure of first line treatment involved % of patients. among them, the time between the diagnosis of pph and administration of blood derivatives was greater than h in a third of cases. the administration of oxytocin delay exceeds min multiplied by . the risk of severe pph. however we had deaths in our series. discussion in our study the optimal period of care was not adequate, obtaining blood derivatives in our institution remains among the factors aggravating among the main risk factors for pph, uterine atony was the main source of complication. bleeding postpartum aggravated in our two patients has led to the deaths from late diagnosis and care that was not optimal. these hemorrhages pp is the leading cause of mortality: % of obstetric deaths ( % in the confidential survey - ) [ ] . a hysterectomy was indicated after failure to conservative treatment. the death rate is estimated at % following a disorder complicated hemostasis of disseminated intravascular coagulation (dic). in some series, the mortality rate is estimated between and % [ ] . conclusion the management of pph in obstetrics gynecology service the ehu oran was not optimal. the issue of timing of diagnosis and initial treatment is crucial. solutions must be sought locally to ensure the administration of essential medicines in time, especially the injection of oxytocin within min after diagnosis. introduction chronic obstructive pulmonary disease (copd) is a common pathology that would represent the third cause of death worldwide by . its evolution is interspersed with episodes of acute exacerbations (aecopd) that may indicate an admission in intensive care unit in the most. objective to study the evolution of management modalities of patients admitted in our intensive care unit for aecopd, to determine their prognosis and to identify factors associated with mortality. patients and methods it is a retrospective, monocentric study, performed in a tunisian intensive care unit (icu) over a period of years. we including all patients admitted in icu for aecopd. parameters collected were demographic features, comorbidities, regular treatment, dyspnea assessed by the mrc scale, initial clinical severity reflected by saps ii and apache ii scores, modalities and icu admission deadlines, initial arterial blood gas analysis, management of patients in the icu (ventilation modalities, prescription of antibiotics, use of vasoactive drugs) and their outcomes (incidence of nosocomial infections and their sites, length of stay and icu mortality). results a total of patients, which represents . % of all hospitalizations, with mean age of years (iqr: - ) were admitted for aecopd during the study period. the mean saps ii and apache ii were respectively (iqr: - ) and (iqr: - ). of these, % were ventilated with niv whose overall failure rate was % with a significant decrease between the beginning and the end of the study ( vs % p = . ). sixty-four percent of patients received antibiotics at admission. the prescription rate of antibiotics has decreased significantly over the years from to %. the incidence of nosocomial infections was %. it remained steady between and %. their sites were pulmonary in % of cases. icu mortality was %. in multivariate analysis, icu admission deadlines, niv failure and the use of vasoactive drugs were identified as factors associated with mortality. conclusion our study showed the importance of aecopd in the activity of our icu. the management of these patients has evolved over the years, which was reflected by the significant decrease in the prescription of antibiotics and the enhancement of niv success rate. this result could be attributed to the combination of several factors: precocious management of patients, experience of the healthcare team and the use of efficient ventilators. icu admission deadlines, niv failure and the use of vasoactive drugs were identified as factors associated with mortality. introduction aim. investigate the effect of music therapy on the tolerance of non-invasive ventilation (niv) during its introduction. currently, % of the trauma are intubated. thirty-three percent of the patient admitted in intensive care suffers from acute respiratory distress syndrome (ards). the fmhs chose oxygen concentrator as oxygen source in addition to oxygen pressurized bottles. their supply can be uncertain in conflict areas. insufficient data are available concerning the use of oxygen concentrator in intensive care unit. the primary endpoint was to determine over the total duration of oxygen therapy, the number of days on which the use of pressurized oxygen was needed for patients oxygenated by oxygen concentrator. the secondary endpoints were to identify when pressurized oxygen was needed, describe the characteristics of the population with oxygen therapy and estimate the oxygen quantity economised thanks to the use of oxygen concentrator. the study took place in the forward surgical unit of bouffard. it's a french role located in djibouti republic in africa. all patients over admitted in the intensive care and needing oxygen therapy were included. all the patients were oxygenated with an oxygen concentrator. the oxygen concentrators used were sequaltm integra om, that could deliver up to l/min of normobaric oxygen. the ventilator used were pulmonetictm ltv and . results thirty-six patients were included over the months' study period. sixty percent of the patients were men with an average age of two hundred and fifty-one days represents the total number of days of oxygen therapy divided into days of invasive ventilation, days of noninvasive ventilation and days of oxygen mask. the use of pressurized oxygen was necessary times over the days of oxygen therapy which represents . % of the total time. the causes of its use were in ten cases ( . %) criteria of severe ards, in six cases an emergency intubation and in three cases a transfer. one dysfunction of an oxygen concentrator happened during our study. the oxygen concentrator produced m of oxygen over the study period, which represents oxygen pressurized bottles of litres. this enabled an economy of , euros. conclusion it is safe to use oxygen concentrator to take care of critically ill patients in limited resources environment. the use of pressurized oxygen is still compulsory in two situations: in case of electricity failure and in case of high fio (above %). oxygen concentrators are sufficient in . % of the time. they enable to deliver oxygen any time which is essential when supply is uncertain in conflict areas. none. table ). for the same mv and level of ofr, fdo was in our experiment, with an ofr of l/min, when ifr = l/min (mv = l/min and ti/ttot = . ), the fdo is equal to % (± %) (see table ). to this value of ifr, the fdo is in accordance with the formula of ats, but when ifr increase beyond l/min, the fdo decrease and the formula is not in accordance with ats. this can be explain because during inspiratory phase, air room (fractional oxygen = . ) entry in airway mixes with ofr (fo = ), which modifies the fdo . in this case, when ifr increase then fdo decrease and vice versa. medical and paramedical staff must be aware that with patients who receive ofr by nasal cannula, any change of ofr and/or inspiratory flow changes the fdo . in this case, for maintain the same fdo , it is necessary that modify the value of ofr. the actual fio delivered under oxygen mask in patients with acute respiratory failure and the factors that may influence the fio are poorly known. in clinical practice, different methods including formula or conversion tables based on oxygen flow can be used to estimate delivered fio . we aimed to assess first the factors influencing measured values of fio , and second the best method to estimate fio in patients breathing under oxygen mask. we included icu patients admitted for acute hypoxemic respiratory failure from a previous prospective trial [ ] in whom fio was measured under oxygen mask using a portable oxygen analyzer. we collected demographic variables and respiratory parameters that may influence measured fio . low fio was defined according to the median measured fio . for each patient, measured fio was compared to "calc + %" formula (fio = oxygen flow in liters per minute × . + . ) to "calc + %" formula (fio = oxygen flow in liters per minute × . + . ), and to a conversion table [ ] . a ± % limit of agreement for each estimation method was arbitrarily considered acceptable. results among the patients included, median measured fio was % [ - ]. after adjustment on oxygen flow, the three variables independently associated with low measured fio using multivariate analysis were patient's height, a low paco , and a respiratory rate greater than breaths/min. using paired analysis, each estimation methods differed significantly from measured fio (p < . for each). values outside the limits introduction acute hyperglycemia is common in intensive care. it was associated with poor prognosis and increased mortality. the purpose of our study is to investigate the frequency of hyperglycemia in our icu, to determine the main causes of high blood sugar and to analyze the impact of this hyperglycemia. our study is prospective during months. it was conducted in the intensive care unit of the university hospital habib bourguiba sfax-tunisia. were included in our study all patients admitted to the service during the period of the study. for each patient included were collected from the icu admission, clinical and biological data. results during the study period, patients were hospitalized in our icu and the diagnosis of hyperglycemia (> mmol/l) was admitted in patients ( %). the comparison between patients who developed hyperglycemia and those free hyperglycemia group showed that, the patients of the first group were significantly older (p < . ). additionally, hyperglycemic patients had more medical history including history of diabetes (p < . ), a higher saps ii (p < . ), a more significant frequency of active infections (p < . ). moreover, the presence of hyperglycemia was associated with shock (p < . ) and respiratory distress (p < . ). their evolution was marked by the significantly higher frequency of infectious complications (p < . ), thromboembolic complications (p < . ) and acute renal failure (p < . ). the average duration of mechanical ventilation and the length of stay were also significantly prolonged in hyperglycemia group patients (p < . for both). finally, the presence of hyperglycemia was significantly associated with a higher mortality rate. conclusion we concluded that hyperglycemia is correlated with poor prognosis of morbidity and mortality. but strict glycemic control remain controversial. thus, further studies on this subject will be recommended to define the exact place of glycemic control in intensive care. none. the rrt was prophylactic in four cases started when phophatemia was more than mmol/l, and therapeutic for renal failure and established tls in three cases. the median duration stay in icu was [ ] [ ] [ ] [ ] j. thirteen patients left the icu without major metabolic dysfunction. two patients deceased due to infectious complications. discussion monitoring of electrolytes was done on average, three times a day which is hard to do in onco-hematology unit. the early use of rasburicase and the aggressive iv hydration helped to prevent tls for seven patients. the aggressive iv hydration was made according to echocardiography data and close monitoring of vital signs and urine output which has allowed to avoid volume overload and acute pulmonary edema. the early prophylactic rrt prevented renal failure and metabolic complications. conclusion early management of tls in icu can prevent tls and most of its serious complications and should be considered in tls prophylaxis recommendations. none. the both urinary (expressed as the ratio of ngal on urinary creatinine) and plasma ngal were predictive of aki stage . predictive value of plasmatic measurements was higher than the urinary one (auc of . and . , respectively, p = . between auc), but not higher than either baseline serum creatinine (auc = . ) or h diuresis (auc = . ). backward multivariate regression showed that plasma ngal concentration was associated with serum creatinine, crp and albumin, whereas urinary ngal was associated with leucocyturia and baseline creatinine. discussion previous positive studies with ngal did not compare the performance of this costly biomarker with simple usual clinical parameters to predict aki. moreover, several parameters were associated with ngal concentrations with a high risk of collinearity (crp) and/or false positive results (leucocyturia). our data do not support any added value of ngal concentration over baseline serum creatinine or urine output to predict aki. introduction acute renal failure (arf) is a common entity in intensive care, concern that the heavy morbidity and mortality it is associated [ ] . early diagnosis of this entity remains difficult, neither diuresis and creatinine are early parameters in the diagnosis of arf. the kidney is an organ that suffers long to become faulty, the priority is to recognize renal aggression and to achieve a therapeutic allowing reversibility of the infringement. a number of markers have been developed for the diagnosis of the ira but costs remain high not allowing their routine use. the measurement of resistance index with the renal doppler could be a solution for the diagnosis of aggression and also of the etiology. the elevation of creatinine was seen later within h after the ir > . discussion in our series the resistance index has a value of early diagnosis of renal prognosis aggression in the occurrence and development of renal failure. renal doppler associated with a strictly applied standardized protocol achieves the two goals of monitoring who aid in the diagnosis and guide treatment. although the recommendations of experts to this tool provides that it should probably not use the resistance index measured by renal doppler to diagnose or treat an ira (grade ) [ ] . identifying the cause of kidney aggression is a prerequisite before any therapeutic action. hypovolemia and soda hydro overload are the causes principales. excess filling hyper intra thoracic pressure and hypoxia are the main causes of kidney congestion. conclusion doppler is an early renal medium in the diagnosis of renal aggression. a larger series could assert this observation. none. ), had significantly more pre-eclampsia, / ( %) versus / ( %) p = . . pe were started at an average of . days after foetal extraction, and with an average of sessions. patients of the pe group had significantly lower nadir of hemoglobin but also lower hemoglobin level at day and day . nadir of platelets count was also lower and level remain lower at days , , and . acute kidney injury (using kdigo classification) was more frequent with a higher rate of dialysis in icu, in the pe group ( / ( %) vs / ( %) p = . ) with a more frequent need for dialysis at the exit of icu. proteinuria was significantly higher in the pe group ( . mg/mmol vs . mg/mmol, p = . ). adamts dosage was done only in patients with pe. we find a diminution of adamts activity (before pe) with an average of % [ - ] in this group. there was no death, and adverse effects were not significantly different. discussion this study shows that pe was used when diagnosis was uncertain in the most severe form of pp-tma. low hemoglobin, low platelets, acute kidney injury and high level of proteinuria are the main factors associated with the decision to begin pe. this technique was safe and not associated with major adverse events. several studies show that there are physiopathological crossovers between diseases associated with pp-tma, for example low adamts activity in hellp or mutation in alternative complement pathway which induced hellp. moreover, studies and case reports show a benefit of pe in hellp syndrome. our study did not find significant difference in adverse events (maybe due to a lack of power), but this is another argument to discuss pe in the management of pp-tma in severe patients. the main limits of our study are that none of the patients who had a plasmatic exchange had a diagnosis of ptt and that diagnosis tests were not performed in all patients with pp-tma (complements level, adamts …). conclusion pp-tma treated with pe has lower hemoglobin, lower platelets, higher rate of kidney injury and proteinuria than those treated without pe. no difference were found for adverse events. begining of pe should be discussed for management of a pp-tma without amelioration after foetal extraction. none. introduction diffuse alveolar damage (dad) is the typical histological feature of acute respiratory distress syndrome (ards). however, in a previous study including patients with criteria for ards, we found that only % of them had dad at autopsy exanimation [ ] . it has been shown that patients with ards and dad on open lung biopsy had higher mortality than those without dad [ ] . thus, we aimed to identify markers associated with dad in patients with ards. we included the patients who met criteria for ards at time of death in our large database of clinical autopsies [ ] . we assessed the proportion of dad according to the severity of ards including the degree of hypoxemia and the ancillary variables from the berlin definition: use of high levels of positive endexpiratory pressure (peep at least cmh o), radiographic severity ( or quadrants on chest radiograph), altered respiratory system compliance (≤ ml/cmh o), and large dead space defined as a corrected expired volume per minute (≥ l/min). results dad was associated with all the severity markers abovementioned using univariate analysis. after multivariable logistic regression, the three markers independently associated with presence of dad were the gender with an odds ratio ( conclusion dad was significantly more frequent in females. in addition to the severity of hypoxemia, diffuse infiltrates involving the quadrants was a significant marker of dad. introduction ventilation induced lung injury (vili) is responsible for an increased mortality in ards [ ] . mechanical ventilation may trigger an inflammatory response, comprising alveolar macrophage activation and recruitment, which may be specifically, repeatedly and spatially assessed by functional imaging techniques such as positron emission tomography combined with computerized tomography (pet/ct) [ ] . c-pk is a pet radiotracer with potential to quantify macrophage inflammation. we aim to assess its performance to detect lung macrophage recruitment in an experimental highvolume vili model. materials and methods vili was performed in anesthetized pigs under neuromuscular blockade by rapidly increasing the tidal volume (vt) to obtain a transpulmonary pressure (tpp) between and cmh o under zero end-expiratory pressure. pet/ct acquisitions were performed before (t ) and after h of high-volume ventilation (t ), and image-derived measurements were realized on the whole lungs, and regionally on distinct lung regions (divided along the anteroposterior and the cephalocaudal axes). c-pk lung uptake was estimated using the standardized uptake value (suv), normalized to the ct-derived tissue fraction in the region of interest (roi). mechanical lung aggression was estimated by ct-derived dynamic and static strains, and tidal alveolar hyperinflation (expressed as a fraction of the tidal variation in the roi volume). after euthanasia, alveolar damage and macrophage recruitment were assessed in the lung regions, using semi-quantitative scores. results between t and t , vt and tpp significantly increased from . ± . to . ± . ml/kg and . ± . to . ± . cmh o, respectively. suv on the whole lung significantly increased from . ± . to . ± . between t and t and dynamic strain from . ± to . ± . , whereas static strain did not significantly vary. tidal alveolar hyperinflation significantly increased from ± to ± % on the whole lung between t and t . regionally, dynamic strain, and tidal alveolar hyperinflation significantly differed between regions, as well as between t and t . regional suv differed between t and t but not between regions. regional static strain did not differ between regions, nor between t and t . in multivariate analysis, regional suv was independently and significantly associated with dynamic strain and tidal alveolar hyperinflation. histologic analysis showed significant regional differences in alveolar damage but not in macrophage recruitment. suv was positively associated with macrophage recruitment but not with alveolar damage. discussion in this experimental vili model, c-pk suv was significantly increased after h of injurious ventilation, and was significantly and positively associated with high-volume ct-derived mechanical parameters, such as dynamic strain and tidal alveolar hyperinflation. the radiotracer's specificity for macrophages is confirmed by the suv significant association with macrophage recruitment and the lack of association with alveolar inflammatory edema. conclusion c-pk is a macrophage-specific pet radiotracer, with potential to dynamically and specifically assess alveolar macrophage inflammation induced by high-volume ventilation. research founded by the french society of intensive care medicine (srlf) and la fondation pour la recherche médicale (dea ). the reverse triggering (rt) is the term used to name the contractions reflexes of the muscle diaphragmatic provoked ("triggered") by the periodic insufflations, delivered by the ventilator, at sedated patients under mechanical ventilation [ ] . the rt constitutes a new form of patient-ventilator interaction clinically difficult to detect and little known. the rt could have potential implications during the management of acute respiratory distress syndrome (ards). at present, the management of severe ards consists among others, on the use of an early and systematic perfusion of neuromuscular blockade agents (nmba) during a h' period, continuation to the acurasys essay which showed a reduction of the mortality in the group of the severe ards patient receiving nmba. the reason of the beneficial effect of curare is not perfectly known. it is possible that the phenomenon of rt is a mechanism implied in the deleterious role of the mechanical ventilation during ards. the abolition of this phenomenon by nmba could explain the beneficial effect of nmba in ards [ ] . the objective was to look for the phenomenon of rt in two groups of ards patients: a group receiving nmba and a group not receiving nmba. patients and methods physiological observational and comparative study in intensive care units. we record continuous signals of airflow, airway pressure, and esophageal pressure during h of consecutives patients with ards criteria and pao /fio ratio ≤ at a positive end-expiratory pressure (peep) of cmh o evolving for less than h under mechanical ventilation. recording of esophageal pressure of consecutives moderate to severe ards patients were blinded analyzed (group nmba n = ; group unless nmba n = ). any phenomenon of rt was observed in the group of mild ards patients receiving nmba (fig. a) . we confirmed the existence of rt on patients of in the group of mild ards who not receiving nmba (p = . ) (fig b) . discussion one of the main limits was the quality of the collection of the signal of esophageal pressure. the monitoring of esophageal pressure is technically difficult, and can d influence the quality of the signal and the reliability of the results. conclusion this study confirms the existence of the phenomenon of reverse triggering among deeply sedated patients not receiving nmba with a % incidence. more research is needed to determine if the reverse triggering is a risk factor independent from vili, associated with the bad prognosis of severe sdra patients and, if a strategy of early treatment based on nmba, could improve the prognosis of reached patients. after ecmo removal had a significant median reduction of days in the bipap-aprv group, p = . (fig. ). we reported the feasibility of a protocol based on bipap-aprv aiming at resuming sv as soon as possible in ards patients under ecmo. the occurrence of spontaneous inspiratory efforts in ards patients can major variability of transpulmonary pressure and as result jeopardise vt and driving pressure control. this might be an issue if protective ventilation is not guaranteed anymore. vt with bipap-aprv remains within safe range when the ratio fig. circles are pac group, rhombus are aprv group. mv mechanical ventilation, psv pressure support ventilation. data are presented as median (iqr), comparison between the groups at each time mann-whithney test, *p < . of spontaneous minute ventilation to total minute ventilation is between and % [ ] . bipap-aprv is more efficient than psv to increase lung aeration in patients with ards [ ] . recruitment of dependent region is more likely to achieve if sv is not supported by synchronized positive airway pressure as during bipap-aprv [ ] . our strategy targeting a percentage of sv between and % with high peep could be viewed as a compromise in order to promote sv and protective ventilation at the same time. conclusion protective ventilation combined with sv under ecmo by using a specific protocol based on bipap-aprv is feasible and safe. it may facilitate weaning and thus reduce the time under mv after ecmo. to what extend this beneficial effect is directly due to the presence of sv deserve further investigations. introduction since the first transplant from a patient in a state of brain death conducted in at the university teaching hospital ibn rushd of casablanca, the number of transplants has increased. however, it is still inadequate meet the growing needs of organs. the refusal of families remains the main obstacle to the developpement of organ transplantation in morocco. the aim of our study is to monitor and analyse the evolution of family refusal to organ donation in a brain dead patient. patients and methods this is a retrospective and comparative study from august until december .the data were collected from records of brain dead patients candidates for organ donation at the intensive care units on ibn rushed hospital. the coordination registers were also studied. a questionnaire was distributed to families who refused organ donation to investigate the causes of the refusal. results during this period, patients with brain death have been identified and families had been approached. families ( %) refused organ donation. the main causes of refusal were: fear of body mutilation ( %), lack of will ( %) and religious causes in % of cases. the refusal rate for families decreased from % in to % in . only patients experienced cardiac arrest before transplantation. during this period, cornea transplants from braindead patient were conducted with kidney transplants and two liver transplants. discussion the evolution of the refusal of families saw a decline through awareness and communication campaigns for organ donation. conclusion improvements to our health care system must be proposed including strengthening detection of potential donors and relationships with the donor's family and effective communication policy. in the icu, three major actors are involved in the caring relationship: patient, relatives and caregivers. acting as spontaneous testimonials of the lived experience, thank-you letters from relatives may be considered by icu teams as a source of original information which could help in improving care for critically ill patients and families. this study aimed to investigate the qualitative content of thank-you letters from relatives of patients who stayed in the icu. specifically, our research questions were, with regards to the letters' content, ( ) how is the caring relationship tackled and characterized by relatives? ( ) to what extent does this relationship impact their experience of icu? materials and methods the study took place in a -beds icu during a -month period. the research team consisted in a care assistant, a nurse (also clinical research associate), a psychologist (not working in the icu) and an intensivist. the corpus consisted in twenty thankyou letters received in the icu. we conducted a qualitative study according to the thematic inductive approach. the process of coding was intended to create established meaningful patterns. results two main themes emerged as specific determinants of the caring relationship: ( ) the temporality, comprising the time dedicated to the patients and their family, the time spent with the icu team, the striking time corresponding to significant events for relatives needed to be shared with the staff, the extension of the link with caregivers by evocating a new life after icu stay, the writing time as a countergift to the caregivers; ( ) the caregivers behaviour, including human skills detailed in many core values (kindness, availability, devotion, attention, goodwill, sensitivity) psychological support, emotional sharing, capabilities to give informations. relatives feel to be "at the center of all attention" in the same way as their loved ones. through the narration of icu experience, the caring relationship is characterized as follows: ( ) the caregiver becomes a close person with an equal relationship (feelings of friendship, emotional closeness); ( ) the icu team becomes a new family (contrasting with the poor living environment of icus); ( ) the relative becomes a caregiver (with appropriation of medical terms or speaking of his loved one as a patient); ( ) the caregiver is seen as a "super-hero" through an asymmetrical relationship with an overstatement of personal dedication and investment of the staff members (abnegation, vocation, involvement). the caring relationship impacts relatives' experience of intensive care in several ways: ( ) relatives are deeply touched by caregivers' human behavior, emotional support being a source of solace and resilience in particular for bereaved families; ( ) relatives express the idea that taking care of humans is not a valued and rewarded task and the emerging awareness of hospital realities and difficulties of work in the icu; ( ) the most striking transformational change in relatives is the perception of their own vulnerability and humanity, leading them to exhibit an outward-looking attitude (for example filling out their organ-donation card), and encouraging the icu caregivers to continue their missions for the others. conclusion thank-you letters provide both encouraging and informative messages for icu teams about relational care for patients and families notably the indivisibility of the families and their critically ill loved ones. the relatives' experience of the icu appears strongly influenced by the caring relationship in the way they express an authentic revelation of their own humanity and altruistic thoughts. the thematic content of thank-you letters questions determinants and fundamental values at stake in the patient-relatives-caregivers relationship. introduction far from medical paternalism, the doctor-patient relationship has now evolved to respect "the autonomy and patients' rights". changing behavior has been gradual, while the law offered the patient the freedom to consent to care and then of expressing their wishes regarding the therapeutic intensity they would benefit, in critical situations where consent would not be possible, through advance directives (ad) [ ] . their use is of paramount interest for intensivist in many critical situations. unfortunately, the use of ad remains marginal because of the unfamiliarity of patients with their use and an appropriation default by clinicians [ ] . the aim of our study was to investigate the perspective of the coming family physician generation on advances directives. patients and methods population of interest was general practitioner fellow (gpf) from class of to . we built an online questionnaire survey about knowledge and the place they want to give to ad in their forthcoming daily clinical activity. this questionnaire was sent to gpf emails obtained by universities, unions and via the official mailing lists of different regionals classes provided by the first contacted. descriptive analysis of quantitative data was expressed as mean and standard deviation, qualitative data in number and percentage. the comparison of continuous variables was performed by the student t-test and the comparison of categorical variables by a chi test. analyzes were conducted on biostatgv website and microsoft excel ® . results gpf answered the survey, mainly from ile de france (n = ), toulouse (n = ) and lille (n = ). for gpf the majority of patients do not know the ad ( . %) and % think that those who know do not know how to use it. . % of gpf think writing ad by patients requires better information. according to them, the information should concern the support offered in the icu ( . %), the use of mechanical ventilation ( . %), dialysis ( . %) and the evolution of patients after hospitalization in icu ( . %). nevertheless information on the prognosis of chronic diseases or organ failure seems interesting for only and . % of them respectively. . % of gpf wish to propose the drafting of ad to their patients. however, only . % of them are willing to suggest ad to patients with cancer or hematologic malignancies, . % to patients with neurological and/or degenerative disorders, . % to elderly patients. discussion despite the low proportion of the population we think these observations to be of interest because we probably selected the gpf the most interested in ad as the participation was not mandatory. conclusion a large majority of young of future general practitioner is willing to be involved in the implementation of ad with their patients, however the target population remains very limited, considering that half of them do not want to discuss ad with patients suffering from diseases potentially associated with icu admission or therapeutic intensity discussion. this study was conducted in adult intensive care units in public or private hospitals in four countries: canada, france, italy, spain. in each country, health care professionals were solicited for an exploratory interview about the sources of stress in the work environment: senior physicians, residents, experienced nurses (with more than years of experience in the service) and inexperienced nurses (with less than years of experience in the service). all the interview transcripts were analysed using an inductive coding approach. results one hundred and sixty professionals ( physicians and nurses) were included in the study. eight themes emerged from the analysis, and they concerned the stress linked to ( ) patient ( ) care, ( ) team, ( ) family, ( ) institutional context, ( ) environment, ( ) organizational context, ( ) individual dimensions. in each theme, sub-themes have been identified and determine more precisely the difficulties at work. discussion our findings emphasize the complexity of work in icus and show the specifics factors not taken into account in the generic stress scales such as stress in relation with family relationships, the end of life decisions and inequity of health care. conclusion the specific stress scale should allow to better identified stress in icu and to develop measures of prevention and support and training programs. introduction intensive care units (icu) is a place where caregivers face many constraints that can affect their physical and mental health due to the use of specific care and strong emotional charge related to patient death and pain of the families. the aim of the present study is to detect anxiety disorders and/or depression among staff working in icus. on september , a questionnaire was distributed to staff (medical and paramedical) operating in icus in the university hospital fattouma bourguiba monastir, tunisia ( medical icu, surgical icu, cardiologic ccus and nephrologic intermediate care unit). this questionnaire included demographic data of participants (age, sex, marital status, length of service, psychiatric history, consumption of anxiolytic and/or antidepressant) and the hospital anxiety and depression scale (had: scale composed by items to screen the anxiety (a) and/or depression (d) among hospital staff ). results during the study period, participants completed the questionnaire ( %), % of them were women, the median age was years ± . . forty-nine participants were doctors (the majority of them residents: / ). . % of participants (all paramedics) worked on night shift, seniority of more than a year in the icu was found in % of participants. . % of staff interviewed were married and only . % of them reported consumption of anxiolytics and/or antidepressants. . and . % of the participants had respectively symptoms suggesting anxiety and depression. the median had score was (iqr = ); the medical function seems to be significantly associated with the occurrence of symptoms of anxiety and depression compared to paramedics, however the type of icu (medical/surgical icus vs cordiologic/nephrologic icus) does not appear to be related to the occurrence of symptoms of anxiety or depression (table ) . conclusion anxiety and depression are common symptoms among caregivers in icus. improved conditions of work in these units should be a target to avoid burn out syndrome. none. anxiety, n (%) depression, n (%) introduction carbon monoxide (co) poisoning is one of the common causes of poisoning specially in the cold season, which leads to a significant morbidity and mortality. we retrospectively reviewed the medical data of patients who presented to the toxicology emergency department with co poisoning during january to march . we analyzed patients' characteristics, management, and outcomes. results a total of six hundred and sixty-six patients ( female and male), aged of ± years, were included; poisoning occurred between december and february in % of cases, secondary to an indoor heating system exposure in the majority of cases ( %). the estimated duration of exposure was . ± h [ . - h], with a mean carboxyhaemoglobin (cohb) level on arrival at . ± %. neurological changes were the most presenting symptoms including headache (n = , %), dizziness (n = , %), seizure (n = , . %) and loss of consciousness (n = , . %). digestive disorders involving vomiting and nausea were observed in . % (n = ). one woman without cardiovascular risk factors developed non stsegment elevation myocardial infarction complicated by lung edema. the majority of patients (n = , %) received normobaric oxygen during h (n = ) and h (n = ). hyperbaric oxygen therapy was administered at . ata during h to patients for neurological changes (n = ), pregnancy (n = ) and elevated cohb ≥ % (n = ). mechanical ventilation was required for patients, and admission into intensive care unit in patients ( %). death occurred in cases ( . %). conclusion the carbon monoxide poisoning is a common reason for emergency department visits in winter. the physician should be aware of the serious neurological and cardiovascular complications, if symptomatic treatment and oxygen therapy regimens were not respected. none. neuro-respiratory toxicity of baclofen in the rat: study of the concentrations/effects relationships and role of gabaergic introduction baclofen, a gaba-b receptor agonist is used as muscle relaxant agent and recently for the treatment of alcohol dependence. the number of poisonings has significantly increased since this new indication. clinical presentation of poisoning mainly includes sedation, hypotonia, respiratory depression and seizures. to characterize the neurorespiratory toxicity of this molecule at high doses, we aimed at investigating alterations in sprague-dawley rat ventilation and brain electrical activity after baclofen administration and studied their reversal by gaba-receptor antagonists. materials and methods rat ventilation was investigated using plethysmography and arterial blood gas analysis while brain electrical activity was studied using eeg with one implanted frontal electrode. three baclofen doses were used including . mg/kg ( % lethal dose- %), . mg/kg ( %) and mg/kg ( %). baclofen concentrations were obtained using hplc-msms assay. we modeled baclofen pharmacokinetics and analyzed the doses/effects and effects/concentrations relationships. results baclofen induced early-onset and prolonged dosedependent sedation (p = . ), hypothermia (p = . ), eeg and respiratory depression ( . ) characterized by significant increase in the inspiratory (p = . ) and expiratory times (p = . ). significant increase in paco and decrease in arterial ph and pao were observed at mg/kg (p = . ), peaking at min. eeg showed signal slowing, burst-suppression aspects and spikes peaking at - h post-injection without normalization at the end of the experiment at h. we did reverse baclofen-induced decrease in tidal volume with saclofen (a gaba-b receptor antagonist) and interestingly no alteration of baclofen-induced respiratory depression was observed with flumazenil (a gaba-a receptor antagonist). pharmacokinetic parameters of baclofen were obtained at the three doses and were dose-dependent. significant but non-linear relationships were observed between baclofen-induced effects and concentrations. conclusion baclofen causes dose-dependent neurorespiratory toxicity in rats. however, due to increased poisonings, its safety profile at high doses remains to be established in humans. none. poisoning was deliberate in % of cases. mean ingested dose was . ± mg. the majority of patients presented to the emergency room at . ± h after ingestion. digestive decontamination was performed in . % (n = ) of patients. clinical presentation was dominated by neurological symptoms; including coma (n = ), hypotonia (n = ), hyporeflexia (n = ), agitation (n = ), seizures (n = ) and delirium in case. hemodynamic manifestations included bradycardia in patients, three of them required atropine infusion. one patient presented with hypotension responding to vascular resuscitation. sixteen cases required mechanical ventilation. aspiration pneumonia was noted in cases. mean duration of ventilation was . h ± . mean hospital length of stay was h ± . complications included ventilation associated pneumonia in one case and moderate rhabdomyolysis in cases. all patients evolved favorably. there is no correlation between coma and assumed ingested dose. conclusion baclofen overdose causes mainly neurological effects and except for bradycardia cardiovascular effects were uncommon. prognosis is good if full supportive care is administered properly. none. introduction the lack of an effective treatment for the maintenance of abstinence from alcohol has led physicians to take an interest in baclofen. beyond efficacy, safety of baclofen, prescribed in high doses, is a concern, especially in case of drug overdose. indeed, patients with chronic alcohol abuse frequently develop psychiatric disorders, and are at risk of voluntary drug intoxications. thus, we set up a retrospective study to describe morbidity and mortality associated with baclofen overdose. conclusion baclofen, prescribed in high doses, may lead to severe intoxications: self-poisonings frequently require endotracheal intubation and are associated with an increased risk of death. dialysis decreases baclofen elimination half-time but clinical relevance of this difference could not be determined. none. introduction baclofen, a gaba-b receptor-agonist with muscle relaxant properties established since , has been recently used at elevated doses to treat dependence to ethanol. the number of prescriptions has exponentially increased without an exact evaluation of its toxicity. we aimed to describe acute baclofen poisoning requiring intensive care unit (icu) admission and study the relationships between the toxic encephalopathy and the plasma baclofen concentration. we conducted a single-centre retrospective study including all baclofen-poisoned patients admitted to the icu in - . when requested by the clinical situation, repeated electroencephalograms and measurements of the plasma baclofen concentrations were performed. toxic eeg encephalopathy on a scale of zero to five was graded according to the international rating system (markand, ). plasma baclofen concentration was determined using liquid chromatography coupled to mass spectrometry in tandem developed with a quantum ultra apparatus (thermo fisher scientific) and electrospray source ionization in positive mode (limit of quantification: ng/ml). linear regression and chi- or mann-whitney tests were used as requested for subgroup comparisons. baclofen pharmacokinetics and the relationships between the toxic encephalopathy and the plasma baclofen concentration were modeled using winnonlin software v. ) were closed to the observed values reported at therapeutic doses. the relationship between baclofeninduced encephalopathy as a function of the baclofen concentrations was described using a sigmoidal emax model. conclusion baclofen poisoning may be life-threatening. toxic encephalopathy is well-described with eeg and its grade correlated to the baclofen concentration. prescribers should be aware of the dangers of baclofen which benefits to treat dependence to alcohol are still lacking. none. results initial examination suggested that an illness other than bacterial meningitis was the cause of patients' complaints. first hypothesis was meningitis receiving uncomplete dosage regimen of antibiotics. thereafter owing to apparent loss of consciousness with abnormal eyes movements, non-tonico-clonic seizures were considered meanwhile. the ratio of individuals less y-o to those equal to and greater was / %. the male to female ratio was / %. the mean duration of hospitalisation was . ± . days (extremes - days). extrapyramidal syndrome predominant on the upper part of the body was noted by paediatrician neurologists who suggested considering a genetic disease. however, signs and symptoms were present in people from different families in different areas at the same time. the definitive diagnosis made on pictures and videos of children and adults and was facio-troncular dystonia resulting from drug-induced adverse effect. four urine samples were collected in children and sent to a toxicological laboratory in france. all urine samples were positive for haloperidol meanwhile the other causes of facio-troncular dystonia were excluded, including other neuroleptics, metoclopramide, antidepressants, amodiaquine, anti-histaminic drugs, anti-epileptics, and cocaine. from january to august , hospitalisations were recorded in patients. looking for the source of haloperidol showed that tablets sold as 'diazepam' and consumed by symptomatic patients contained haloperidol as the sole active pharmaceutical ingredient, suggesting that this large outbreak was due to haloperidol toxicity from falsified diazepam. initial treatment was diazepam to relieve severe facio-troncular dystonia which was efficient but resulted in long-lasting sedation more especially in children. a dosage regimen using bipéridène administered by intravenous and oral route was refined to prevent adverse effects related to this anticholinergic agent used in children. the complete reversal of the facio-troncular dystonia was the antidotal evidence supporting the toxicological diagnostic. the mortality rate was less than % meanwhile the direct causal relationship with adr is questionable. an epidemiological study, including toxicological analysis in controls in ongoing. indeed, facio-troncular dystonia induced by haloperidol does not result from a drug overdose but is an adr occurring in about % of patients treated with haloperidol. who is involved in the inquiry related to this counterfeature involving different countries. the cause of the error is presently under investigation. discussion this outbreak emphasizes the need to consider toxicity resulting from counterfeatured medicines when facing collective atypical signs and symptoms in countries with unrestricted access to medication with limited control of qualities of the medicinal drugs. conclusion counterfeatured medicinal drug may result not only in poor efficacy but also in onset of unexpected outbreak of unknown diseases that should suggest a toxic origin. in late -early , médecins sans frontières (msf) had to face an outbreak of severe facio-troncular dystonic syndrome (ftds) in north-east congo. this outbreak resulted from counterfeature of pills sold as diazepam. toxicological analysis revealed one pill contained about mg of haloperidol. ftds induced by haloperidol does not result from a drug overdose but is an adverse drug reaction (adr) occurring in about % of patients treated with haloperidol. nine-hundred and twenty-five individuals were admitted in msf structures for ftds. the ratio of individuals less than y-o and equal to or greater of age was / %, including ( . %) of children less than y-o. initial treatment was based on diazepam which relieved ftds but resulted in long-lasting sedation, preventing given any drug by the oral route. owing to the definitive diagnosis, a shift to the use of a more specific antidote was chosen. biperiden was selected as existing in the intravenous and oral form in the swiss pharmacopea. the study was approved by the ethical committee of the ministery of health of the republic democratic du congo. patients and methods as a whole, biperiden was used in cases ( % of the total). treated children presented with severe dystonia as evidenced by inability to cooperate and to swallow. verbal informed consent was obtained from relatives. the dosage regimen to treat drug-induced dystonic syndrome in the swiss pharmacopea is as follows: for parenteral use in children, intravenously or intramuscularly: . mg/kg or . mg/m bsa every , according to response and tolerance; a maximum of four doses per day should be used. the internal msf recommendations for biperiden use in children were . - . mg/kg of body weight that might be repeated four times a day. initially, biperiden administration was administered under medical supervision by the msf referent at the scene. results there was no pediatric preparation of biperiden. accordingly, the adult preparation was used in children. the preparation contained mg of biperiden in one milliter of solvent. the initial planned dose for children of y-o and less and those up to y-o were and mg, respectively. the mg ( ml) of biperiden was diluted in ml of saline resulting in a final dilution of mg/ml. six children were treated according this dosage regimen. however, the one mg dose was either of limited efficacy while being associated in others of signs suggestive of adr, including agitation, heart rate greater than b/ min, the upper limit for children aged of y-o and less. two children greater than y-o presented severe abnormal behavior resulting in an attempt at escape. owing to question about safety, the dosage regimen was changed, as follows: mg ( ml) of biperiden was diluted with ml of saline resulting in a final dilution of . mg/ml. an initial dose of . mg was administered intravenously as a bolus dose. the effects were looked for over min. in the absence of improvement in facial dystonia, a second bolus dose of . mg was administered, a third dose could be considered min later if the ftds did not resume. the cumulative initial dose should not be greater than mg. in addition to the reversal of facial dystonia, the therapeutic effect of biperiden included the return of swallowing to normal allowing to give further doses of biperiden by the oral route for three days. the first oral dose was administered no less than h after the last initial dose at a dose equal to the efficient initial cumulative dose. the following doses were halved every h. no adr related to biperiden were reported using this dosage regimen. the mean duration of hospitalisation was . ± . days. discussion the bioavailability of biperiden by the oral route is equal to %. accordingly, the corresponding intravenous dose should be divided by a factor three. dosage regimen of anticholinergic drugs in children are poorly documented. the dosage regimen recommended by the pharmacopea resulted in frequent and severe adr. titration of biperiden resulted in efficient and safe dosage. conclusion when biperiden administration is required by intravenous route in children of y-o and less, biperiden should be administered intravenously and titred using bolus dose of . mg till the therapeutic effect is obtained. introduction severe poisoning by rodenticides is frequent. it represents nearly % of patients admitted to the new intensive care unit (icu) of the region. that is why we decided to perform this study. the aim of this work was to describe the epidemiology, clinical features and management of all patients admitted to our unit for acute poisoning with rodenticides. patients and methods it was a retrospective study performed in the year from january to december. the study included all patients admitted in the icu for rodenticide poisoning. results patients were enrolled in the study. our patients were young with a mean age of ± years. poisoning was more common in females (n = ; %). the mean delay between rodenticide poisoning and first medical contact was about ± h in the cases where this information. most of our patients ( %) attended the emergency department of zaghouan with a non-medical transportation. it was a suicide attempt in most cases ( %) and an accidental poisoning in % of patients. the most frequent cause of poisoning in our study was organophosphorus pesticide (n = ; %). the second cause was alpha-chloralose poisoning with seven cases ( %). one patient ingested accidentally an anticoagulant rodenticide. most of patients had ingested (oral route) the rat poison (n = ; %). clinical examination found normal vital signs in ten cases ( %). nine patients ( %) had a shock, eight patients ( %) had an acute metabolic disorder and five patients ( %) had acute respiratory failure or were comatose. all patients enrolled in the study were admitted in the icu for a period of clinical observation of h. stomach pumping (gastric lavage) was performed in patients ( %). an antidote which was atropine was needed in twelve patients. three patients ( %) who ingested alpha-chloralose needed intubation and mechanical ventilation. all patients had a good outcome and were discharged from icu and from hospital. the mean icu length of stay was ± days. conclusion this is the first study of acute poisoning with rodenticides admitted in the new icu. the results of our study were similar to those published in recent literature. cases of acute poisoning with rodenticides reported in this work were not severe. none. introduction the systemic arterial load imposed to the left ventricle (lv) is a major determinant of normal/abnormal cardiovascular function. the lv mean ejection pressure (lvmep) is the best estimate of load faced by the lv throughout ejection. the contribution of the steady and pulsatile blood pressure (bp) component of arterial load to lvmep is debated. we studied the hemodynamic correlates of lvmep using carotid tonometry. intensive care unit patients equipped with an indwelling catheter were studied, thus allowing precise calibration of the tonometer. patients and methods carotid tonometry (complior analyse ® alam medical, france) was prospectively performed on hemodynamically stable, spontaneously breathing patients ( f, mean age ± sd = ± years). carotid waveforms were calibrated from diastolic bp and time-averaged mean bp invasively obtained at the radial (n = ) and femoral (n = ) artery. all patients were free of aortic stenosis. lvmep was the area under the systolic part of the carotid pressure waveform divided by ejection time. results lvmep ( ± mmhg) was strongly related to central systolic bp ( ± mmhg; r = . ) and was also related to mean bp (r = . ), peripheral systolic bp (r = . ), peripheral (r = . ) and central (r = . ) pulse pressure (each p < . ). the lvemp was not related to age, heart rate and stroke volume. systolic pulse wave amplification ratio from carotid to periphery was . ± . . conclusion lvmep was most strongly related to central systolic bp, which combines the influences of the steady and pulsatile components of central arterial load (r = . ). lvmep was less strongly related to peripheral systolic bp, which may be less informative given variable systolic pulse wave amplification across patients. introduction myocardial dysfunction is one of the main predictors of poor outcome in septic patients, with mortality rates next to %. many pathological findings were found in the sepsis induced cardiomyopathy including myocardial ischemia, alterations in microcirculation and proinflammatory cytokines. the aim of this study was to assess the prognostic value of a recently developed highly sensitive cardiac troponin i (hstni) assay in patients with septic shock. we performed a prospective observational study in septic shock icu patients within h of admission. exclusion criteria were age > years; pregnancy; post-cardiac arrest and braindead. hstni was measured soon after admission and , , and h after. patients were subjected to transthoracic echocardiography (tte) at study inclusion and regular biochemical and hemodynamic assessments were performed. pearson's chi square and fisher's exact tests were used. p < . was considered significant. conclusion circulating hs-ctni is present in patients with septic shock. a rise of hstni may be an indicator of poor outcome. also, right heart functional abnormalities exist in patients with septic shock. none. evolution of the right distribution width as a pronostic marker during the differents state of shock introduction right distribution width (rdw) has been recently proposed as a pronostic factor in different pathologic situations and especially to the septic patients who stay in icu. some works substantiate the relationship between an alteration of the red blood cell rheology during the septic shock and a severe state of the disease. no one has studied the rdw between the differents shocks yet. we are going to determinate the relationship between rdw and apache ii score, mortality rate in the intensive care unit (icu), at the hospital, at the day and . we investigated those parameters near patients who were admitted at the icu and needed norepinephrine between the first of march and the st of december. they were stratified in différent groups: septic shock n = , cardiogenic shock n = , hemorragic shock n = and obstructive shock n = . results we did not observe any correlation between the rdw and the icu mortality, hospital mortality and at the day and . only a poor significant correlation has been found between the cardiogenic shock and the mortality rate: at the hospital (p = . ), at day (p = . ) and at the day (p = . ) but not in the icu (p = . ). the receiver operating characteristics (roc) curves do not show significant differences between rdw, apache ii score and icu mortality rate or intra hospital. the sample of the hemorrhagic shock and obstructive shock was not usable for this calculation. compared to other studies which were focused on the septic shock where the mortality was approximately %, we determinated a mortality rate near %. conclusion the delta of the rdw d /d did not present any correlation with the mortality rate. in our study, the rdw in the different kind of shocks do not look like to be a good predictive marker of the mortality, except for the patients included in the cardiogenic shock where a poor significant correlation could be highlighted. conclusion cardiogenic shock was the most frequent complication of ami who led to icu admission, whereas mechanical complications are rare at the era of early coronary reperfusion strategies. in addition to severity score, serum creatinine and cardiogenic shock appeared as independent factors of hospital death. none. introduction pulmonary embolism (pe) in high-risk is a partial or total obliteration of the pulmonary arterial network by a fibrin-clot cruoric more than %, the management requires a rapid reduction of pulmonary arterial resistance and right ventricular post load through rapid revascularization by thrombolysis. our aim is to determine the value of thrombolysis in pulmonary embolism and describe the clinical, paraclinical and outcome pulmonary embolism at high risk. patients and methods this is a descriptive study of cases of pulmonary embolism at high risk admitted to the cardiology department to chu oran between and . signs of gravity of (pe) comprising: syncope, circulatory collapse, cardiogenic shock or acute pulmonary sonographic sign of heart. it was confirmed in chest ct. all patients received thrombolysis using the protocol accelerated by two types of molecules: streptokinase or actilyse. the sex ratio was . ; mean age years, ranging from to years; risk factors were dominated by contraception was % and the postoperative % the clinical picture was dominated by cardiogenic shock in % of cases. % cardiovascular collapse and syncope in %; doppler echo all patients had signs of dysfunction of the right ventricle represented by the dilatation of the right cavities and pulmonary hypertension. the cta found a (pe) bilateral in % right in %. thrombolysis using actilyse in patients and streptokinase in cases. the outcome was favorable in patients; with two cases that are complicated by chronic pulmonary heart and the death of patients with cancer. discussion the female predominance is explained by the increase of risk factors hormonal contraception, whose first generation combination hormonal. our patient had a high probability with clinical signs of severity based on the score wells [ ] . this diagnosis was confirmed by chest ct; which shows the vascular bed obstruction degree with a very good sensitivity and specificity. the suspect patients with severe pe and that presented signs of acute pulmonary heart ultrasound have effectively (pe). the indication of thrombolysis was chosen on hemodynamic criteria; success is found in % of patients with improved hemodynamics dice the early hours. this success is explained by the role of thrombolytic in lysis clot to obtain pulmonary arterial revascularization; and reduce pulmonary arterial resistance and the right ventricular afterload which accelerates the healing of right heart failure and improvement of pulmonary capillary volume. the cases who developed a chronic pulmonary heart; it was done immediately a right ventricular dysfunction with pulmonary arterial outset of very high pressures suggestive that the embolism occurred on an already pathological right heart. no cases of massive bleeding were noted in our series. conclusion severe pulmonary embolism is burdened with high mortality; diagnosis is based on the stratification of risk score, was facilitated by the non-invasive strategies that articlent around the doppler echocardiography and ct angiography; thrombolysis can reduce the high mortality related to severe pulmonary embolism. introduction hypertension is a frequent motif for admission to emergencies. the diabetic is increasingly exposed to this risk [ ] . the objective of this study is to evaluate the proportion of diabetic patients presenting to the emergency department with high blood pressure (bp) and to identify their epidemiological and clinical characteristics. introduction sepsis associated liver dysfunction (sld) is usually attributed to systemic and/or microcirculatory disturbance. hypoxic hepatitis, also known as shock liver or ischemic hepatitis, is a life threatening event associated with high morbidity and mortality. doppler ultrasonography is a non invasive method to measure doppler hepatic hemodynamic parameters. the primary objective of this study was to assess the accuracy of the hepatic hemodynamic parameters (portal venous blood flow pvbf and resistance index of the hepatic artery hari) in predicting sld in septic shock patients. the secondary aims were to identify factors associated with sld, investigate the effects of volume expansion (ve) on systemic and intrahepatic hemodynamics and to assess the intra-and interoperator reproducibility. we also analyzed -day mortality. in a prospective design, we included consecutive patients with septic shock ( males; median age: . years) admitted to the icu with septic shock in charles nicolle hospital of tunis from february to july . all patients were resuscitated following the surviving sepsis campaign guidelines. we measured systemic hemodynamic variables (mean arterial pressure (map), and cardiac index (ci)) and performed hepatic doppler before and after volume expansion. we measured pvbf and computed the hari. we recorded the liver function tests (alt, ast and bilirubin) for h. sld was defined as an increase in serum bilirubin ≥ µmol/l (hepatic sofa ≥ ). accuracy of the hepatic hemodynamic parameters to predict sld was measured by the area under the roc curve. p < . was taken to indicate statistical significance. the median sofa score at t was points and the median igs score was points. the sources of infection were as follows: the lungs (n = ), the abdomen (n = ) and the urinary tract (n = ). the incidence of sld in our cohort was . % (n = ). there was no significant difference between "sld group" and "no-sld group" in all hepatic hemodynamic parameters especially the pvbf and the hari. lactate levels were significantly higher in patients with sld (median . vs. . mmol/l). similarly, the platelet count was significantly lower in the "sld group" [mean (± sd) . ± . ( /l) vs. . ± . ( /l); p = . ]. there was no difference in duration of mechanical ventilation, icu length of stay and -day mortality between the groups. the pvbf was significantly lower in patients who died before d (median: vs. l/min in the survivors; p = . ). volume expansion caused a significant increase in ci, mean hepatic artery velocity and the pvbf. the intra-and interoperator reproducibility was good to excellent for the systolic and mean velocities of the hepatic artery, portal vein diameter and the pvbf. conclusion our results don't support the hypothesis that the hepatic sonography is predictive of sld in septic shock. our pilot study showed higher lactate levels and hematologic sofa in sld group. the pvbf was significantly lower in patients who died before d . more experience will be necessary to define the ultimate role of doppler ultrasonography in the evaluation of hepatic perfusion in patients with septic shock. introduction early surgery is the current trend for management of patients with valvular disease. that said many of them, particularly from developing countries, are still operated at a very advanced stage of disease. despite improvements in myocardial protection and surgical techniques, postoperative care after multiple valve surgery (mvs) for advanced rheumatic heart disease (rhd) remains to be a clinical challenge. we conducted a study to determine postoperative complications and morbidity-mortality risk factors in this subgroup of patients. results sixty-two patients were included: with out-of-hospital refractory cardiac arrest and with in-hospital refractory arrest. the initial rhythms was shockable rhythm in ( %) cases. at ecls initiation, the mean no flow was . ± . min and mean low flow (time between the time of refractory cardiac arrest and time at which an ecls flow was provided) was ± min. the mean ecls flow rate was . ± . l/min. initial blood test results were: arterial ph = . ± . and plasma lactate = . ± . mmol/l. eleven ( %) patients survived ( / ( %) acute coronary syndrome, / ( %) severe poisoning due to drug intoxication, / ( %) dilated cardiomyopathy, and / ( %) others). survival was lower for patients with out-of-hospital refractory cardiac arrest, of ( %), than for patients with in-hospital refractory cardiac arrest, of ( %), respectively, p = . . as expected, out-of-hospital refractory cardiac arrest was associated with a more prolonged low flow ( ± min vs ± min, p < . ) and a more profound acidosis (ph . ± . vs . ± . , p = . and arterial lactate . ± . vs ± , p = . ). in univariate analysis, survival was lower for patient with refractory cardiac arrest unrelated to drug intoxication, vs %, respectively, p = . . in addition, mortality was associated with arterial ph ( . ± . vs . ± . , p = . ) and low flow ( ± vs ± min, p = . conclusion in a highly selected group of critically ill patients with refractory cardiac arrest, the potential beneficial effect of ecls could be due only to its clinical impact on reversible causes of circulatory failure (i.e. severe drug intoxication in our cohort). further studies are needed to clarify whether the use of ecls could be considered as a disproportionate tool, specifically in patients with out-of-hospital refractory cardiac arrest due to acute coronary syndrome or associated with prolonged low flow or a profound acidosis. none. post-cardiac arrest shock treated with veno-arterial extracorporeal membrane oxygenation: an observational study and propensity-score analysis wulfran bougouin , nadia aissaoui , alain combes average time between introduction and removed of the ecd was h ( - ). among the esogastroduodenoscopy performed, ( %) were strictly normal. endoscopy showed minor gastric injuries in patients ( %). within these patients, ( %) also presented minor esophageal injuries. esogastric injuries characteristics were mostly similar to usual orogastric probe injuries. one patient ( %) experienced a serious ulcerous esophagitis mimicking a peptic esophagitis, not firmly related to the ecd. no patients necessitated hemostatic local procedure and no significant gastrointestinal bleeding was observed. eight patients ( %) were alive at d , including patients ( %) with a cerebral performance category score of . this compares favorably to outcomes from previous studies. conclusion ecd seems an interesting and safe semi-invasive method of cooling in ohca patients treated with °c-ttm. although it seems slower than more invasive devices to reach °c, ecd was able to strictly maintained the tt within the maintenance phase of ttm. further studies will be necessary to define the exact place of this new device within the cooling strategy in patients necessitating a precise ttm-strategy. none. fig. see text for description introduction since post-cardiac arrest care might influence the outcome, characteristics of receiving hospitals should be integrated in survival evaluation of patients transported in hospital. we aimed at assessing the influence of care level center on survival at discharge in a regional registry of out-of-hospital cardiac arrest (ohca). we prospectively collected utstein and in-hospital data for all non-traumatic ohca patients, in whom a successful return of spontaneous circulation (rosc) had been obtained, from a large metropolitan area (great paris). receiving hospitals were categorized in groups (a, b, c) depending on their respective characteristics (annual volumes, / catheterization availability and temperature management use). we compared patients' characteristics in the groups and performed a multivariable logistic regression using discharge survival at endpoint. results during the study period (may -dec ), patients were admitted in hospitals ( in group a, in group b and in group c). overall survival rate at discharge was / ( %). patients' baseline characteristics significantly differed, as hospitals from group a treated younger patients and more frequent shockable rhythms (p < . ). unadjusted survival rate differed significantly among the groups of hospitals (respectively , and . % for a, b, c, p < . ). however in multivariable analysis, the category of hospital was no longer associated with survival. conclusion in this population-based study, characteristics of receiving hospitals are not associated with survival rate at discharge. this could result from the strategy used for triage, which aims in matching patients' characteristics and resources. introduction acute kidney injury (aki) commonly occurs after cardiac arrest and is associated with an increased mortality and a delayed awaking. early recognition of aki remains challenging, given that serum creatinine increases belatedly after aggression. introduction out-of-hospital cardiac arrests (ohca) are an absolute urgency and have a very poor prognosis. pediatric guidelines differ from adult guidelines for cardiac arrest management. since , adult guidelines apply from the onset of puberty. the main objective was to describe the epidemiological characteristics and outcome of ohca victims while taking puberty into account. the secondary objective was to determine the prognostic factors for survival at d . materials and methods all patients less than years of age, victims of ohca between july , and september , care by a mobile emergency and resuscitation service (smur) participating in french national cardiac arrest registry (réac) were included. patients were split into groups: prepubescent patients (named "children": girls - years, boys - years), pubescent patients (named "adolescents": girls from to years and boys from to years) and "adults" (men and women - years). the "adolescents" group was consecutively compared to the "children" group and to the "adults" group. results children, adolescents and , adults under the age of have been included. ohca in adolescents occurred more often on public roads ( %) or in public places ( %) and were more often traumatic ( %) than those in children and adults. respiratory causes were more frequent in children ( %) than in adolescents ( %) and adults patients ( %). the proportion of shockable rhythm increased with age ( , and % for children, adolescents and adults respectively). survival at d was greater in adolescents ( %) than in children ( %) and adults ( %) (p = . and p = . respectively). in the studied groups, initial shockable rhythm was a survival factor at d (respectively or [ . - . ] for children, adolescents and adults). other risk factors are described in table . conclusion adolescents had better survival at d than the others groups. adolescents and adults had shockable rhythm more often than children. moreover, respiratory failure was less frequent in adolescent and adults patients compared to children. puberty seems to be a good limit to differentiate pediatric patients with ohca. none. introduction non-invasive ventilation (niv) is an effective alternative to endotracheal mechanical ventilation (mv) in the management of acute respiratory failure (arf) patients. nevertheless, it can be still difficult to assess its real feasibility, application and outcome in daily clinical practice. therefore, we report our clinical experience with routine use of niv since the last national recommendations ( ). our aims were to evaluate the clinical efficacy and outcome of niv, and to identify predictive factors for niv failure based on a daily use. patients and methods we conducted an observational retrospective single-center cohort study by reviewing all medical records from january to december in our -bed medical intensive care unit (icu). eligible patients were those having received niv during their icu stay. two groups were defined according to the indication of niv: niv for hypoxemic or hypercapnic arf (arf-niv), and niv used in the post-extubation period for weaning, prevention or treatment of post-extubation arf (post-extubation niv).the main evaluation criteria were the incidence of niv use, success/failure rate of niv and risk factors for niv failure in each group. niv failure was defined as the need for stopping niv whatever the reason (intubation, intolerance, death) within days after its initiation. ( ; ), and was longer in the post-extubation niv group ( days ( ; ) ) than in the arf-niv ( days ( ; ) for hypoxemic arf, ( ; ) for hypercapnic) (p < . ). the overall icu mortality was . % ( . % in hypoxemic group, . % in hypercapnic group, and . % in post-extubation niv group) (p = . ). in multivariate analysis, the main risk factors for arf-niv failure were: saps ii on admission (p < . ), absence of cardiologic history (p = . ) and the cause of arf (p = . ) with a higher failure rate for pulmonary infections than acute cardiogenic pulmonary edema (or . , p = . ). for post-extubation niv, the only independent risk factor for failure was normocapnia before niv initiation (p = . ). conclusion our large longitudinal study demonstrates the feasibility and efficacy of niv applied in daily clinical practice. provided it is performed in a suitable environment by an experienced team, niv should be considered as a first-line ventilatory treatment in various etiologies of arf and a very useful ventilatory support in the postextubation period. nevertheless, risk factors for niv failure should be known by icu clinicians, hypoxemic arf remaining the more difficult indication to manage with niv. réanimation médicale, hôpital saint-louis, paris, france; service de biostatistique et information médicale, hôpital saint-louis, paris, france; réanimation, institut paoli-calmettes, marseille, france; réanimation introduction acute respiratory failure (arf) is the leading cause for icu admission in immunocompromised patients. in these patients, oxygenation strategy is of major interest to avoid the need for mechanical ventilation (mv), which is associated with high mortality rates. in that setting, use of non-invasive ventilation (niv) and oxygen therapy with high flow nasal cannula (hfnc) could be interesting alone or in association, but data about initial ventilation strategy in immunocompromised patients are controversial. to assess how initial oxygenation strategy actually influences the risk of mv on the coming day within the three first days of icu stay. the study end-point was the need for mv on the coming day. we restricted analyses to these first three icu days given, based on our own experience, most of mv was expected to occur by then. we performed a post hoc analysis combining three prospective studies of critically ill immunocompromised patients (two randomized control trials, the ivnictus and the minimax studies and one prospective cohort, the trial-oh study). we only considered patients with arf and a delay between icu admission and study inclusion less than h. we excluded patients who required invasive mv within the first day, those with an icu stay less than day and those with acute pulmonary edema diagnosis at icu admission. in order to estimate and compare the causal effect of daily respiratory management strategy on the probability of intubation in the coming day, we computed inverse probability of treatment weights (iptw) using propensity-score, defined as the probability of actual treatment selection conditionally on observed covariates. to handle confounding in such dynamic regimens, we considered marginal structural models (msm), which have been proposed to estimate the causal effect of a time-dependent exposure when time-dependent covariates that can be affected by the previous treatment are present. two treatment exposure models were considered: niv versus oxygen therapy regardless the device (model ) and hfnc alone, niv alone versus niv + hfnc versus standard oxygen therapy alone (model ). results patients were included in the study. in model , there was no difference between niv and oxygen groups on mv whatever the landmark time. in model , while the unweighted or for intubation at day was significantly higher in the niv group (or . , %ci . - . ) and hfnc group (or . , %ci . - . ) than those in the standard oxygen alone group, these differences disappeared in the weighted samples. using msm, no effect of the oxygenation strategy on mv was found, regardless of the oxygenation devices but the landmark time was associated with a reduced occurrence of mv. conclusion we found no evidence of any significant difference from several oxygenation strategies on mechanical ventilation probability during the first days of icu in a large cohort of immunocompromised patients with arf. none. introduction the role of noninvasive ventilation (niv) is debated in the management of patients with acute hypoxemic respiratory failure. a recent study showed that patients treated with high-flow nasal cannulae oxygen therapy (hfnc) had lower intubation and mortality rates than those treated by the association of hfnc with niv ( ). high tidal volumes (vt) delivewred with niv may be associated with an increased risk of intubation ( ) . we aimed to identify risk factors associated to intubation, in hypoxemic patients with acute respiratory failure and especially the role of vt under niv. patients and methods this is an ancillary study from a multicenter, randomized, controlled trial including patients with acute hypoxemic respiratory failure (florali-study). we focused on only patients with moderate or severe hypoxemia (pao :fio ratio ≤ mmhg) and we excluded those with mild hypoxemia. the criteria for intubation were predetermined including worsened or persisted respiratory failure, impairment of neurologic status and hemodynamic instability. results after adjustment on the oxygenation strategy, the two factors independently associated with intubation were the presence of bilateral pulmonary infiltrates at admission (or . simulation conditions enables to reproduce its occurence, using different types of tools, from physiological parameters to heart rate variability and psychocognitive tests. future research is required to evaluate the impact of these parameters on teaching. none. with stratification by centre and operator experience. an only inclusion criterion was: "patients must be admitted to an icu and require mechanical ventilation through an endotracheal tube". patients were excluded if: contraindication to orotracheal intubation (e.g., unstable spinal lesion); insufficient time to include and randomize the patient (e.g., because of cardiac arrest); age < years; pregnant or breastfeeding woman; correctional facility inmate; patient under guardianship; patient without health insurance; refusal of the patient or next of kin to participate in the study; previous enrolment in a clinical randomized trial with intubation as the primary end point (including previous inclusion in the present trial). post-hoc analysis was performed to assess occurrence of spo < % during intubation procedure between groups of preoxygenation: bvm (at a minimum flow of l/min, niv ( % fio ), hfnc (at a minimum flow of l/min, with % fio ), and nrm (at a minimum flow of l/min). between-groups difference in desaturation occurrence was adjusted for baseline covariates significantly associated with the group membership (p < . ). multivariate analysis of the occurrence of a desaturation (< %) was performed using logistic regression. bag-valve mask was considered reference. results baseline characteristics were showed in table . groups were similar at baseline except for pao /fio ratio. in univariate analysis, age (p = . ), saps (p = . ), pao /fio ratio (p = . ),spo (p = . ) and method of preoxygenation (p = . ) were associated with occurrence of desaturation below %. in multivariate analysis, spo at randomization and method of preoxygenation were only predictors of desaturation below %. bvm and hrm were associated with similar risk of desaturation occurrence whereas niv (or . introduction intubation procedure is a challenging issue in intensive care unit (icu) [ ] . cardiac arrest related to intubation in critically ill adult patients has been poorly studied. the studies were not powered to conclude on this rare outcome [ ] . the main objective of our study was to establish the incidence of cardiac arrest and to assess the risk factors of cardiac arrest in a large prospective database of intubation procedures performed in icu. five prospective studies were included, with similar data collected before, during and after intubation procedures using the same methodology. the primary outcome was the incidence of cardiac arrest related to intubation. the secondary outcomes were the death (cardiac arrest without return of spontaneous circulation (rosc)), the cardiac arrests with rosc, the complications related to intubation, the length of icu stay and the -day mortality. the factors associated with cardiac arrest related to intubation procedures were assessed by univariate and multivariate analysis based on patient, provider and practice characteristics. results among the intubation procedures included, cardiac arrests ( . %) occurred, including with rosc ( . %) and without rosc ( . %). main patient, provider, procedure characteristics and outcomes according to cardiac arrest related to intubation are presented in table . in multivariate analysis, the independent predictors of cardiac arrest related to intubation were low systolic blood pressure prior to intubation, hypoxemia prior to intubation, no preoxygenation, overweight or obesity and age > years. mortality rate at day was significantly lower in patients intubated without cardiac arrest ( . %, of ) than with cardiac arrests overall ( . %, patients of , p < . ) and cardiac arrest with rosc ( %, patients of , p < . ). conclusion cardiac arrest related to intubation in adult icu is not a rare event occurring in . % of cases with high immediate mortality of . % and at day of . %. we identified five independent risk factors to cardiac arrest which of them could be modifiable. optimal preparation to intubation procedure could help to prevent those cardiac arrests. introduction naasotracheal intubation (nti) has been progressively given up in favour of the orotracheal intubation (oti) in intensive care unit (icu). this could be explained by more frequent infectious (sinusitis and ventilator associated pneumonia) and non-infectious (epistaxis, turbinates bones injury) complications the former being thought to be more frequent with nti. however, whereas infectious sinusitis is a risk factor for vap, no study has yet demonstrated that oti decreases the infectious sinusitis rate compared with nti. furthermore, nasal route could improve patient comfort and decrease auto-extubation. finally nti can be performed without laryngoscopy with less risk of lips and dental injury. in this prospective study, we aimed to compare the complication of nti and oti and to assess the comfort of the patient. we performed a prospective observational study in a -bed medical icu including patients requiring endotracheal intubation. the intubation route was let at the discretion of the physician in care of the patient, however oti was compulsory in case of cardiac arrest, severe hypoxemia (p/f < when available) and clotting perturbation. for each patient, age, sex, sapsii, mechanical ventilation duration. intubation route were recorded as well as complications during the placement of endotracheal tube. infectious and non infectious complications during invasive ventilation period were also recorded. in patients who were successfully extubated, pain, burning feeling, dryness and the wish of tube removal were assessed using visual analogic scales (vas conclusion despite its small size, and the absence of randomization, the present study suggests that nasotracheal intubation improves the comfort and the tolerance of tracheal intubation and is not associated to higher rates of vap. none. effect of mode of hydrocortisone administration in patients with septic shock: a prospective randomized trial oussama jaoued , rim gharbi , najla the baseline characteristics of patients were similar between the two groups. sepsis was secondary to community-acquired infection in % of cases. there was no difference in mortality between groups ( % in continuous groups and % in discontinuous group). sofa score was significantly higher at days , and in discontinuous group. length of stay, duration of mechanical ventilation, number of day without vasopressors, and the occurrence of adverse events were similar in the two groups. conclusion the mode of hydrocortisone administration in patients with septic shock has no influence on morbidity or mortality. the occurrence of adverse events was similar. introduction widespread activation of coagulation with platelet consumption is a pathophysiological feature of severe sepsis and septic shock. thrombocytopenia, either defined by platelet count below g/l or by a significant relative - -percent decrease in platelet count is a potent poor prognostic factor in sepsis. besides their role in hemostasis, platelets also carry various immune and inflammatory functions that are likely to impact on host defense against infections. we aimed to assess whether changes in the platelet count induced by sepsis is associated with the development of subsequent nosocomial infections. patients and methods patients were obtained from two prospective studies about immuno monitoring of dendritic cells and innate-like lymphocytes in critically ill septic patients ( , ) . adult patients with severe sepsis and septic shock were included. exclusion criteria were any immunosuppressive condition (hematological malignancy, hiv infection at any stage, bone marrow or solid organ transplantation, daily corticosteroid therapy > . mg/kg prednisone-equivalent, chemotherapy or any other immunosuppressive treatments), pregnancy, do-not-resuscitate orders on admission. in addition patients who died or who received platelet transfusion during the first week after icu admission were also excluded. platelet counts were collected on the day of sepsis diagnosis (d ) and then on d , d and d . the relative variation in platelet count at day n compared to day was calculated as follows: (count at day n − count at day ) × / (count at day between between d and d , between d and d and between d and d were also similar between patients with and without icuacquired infections (fig. ). discussion in this preliminary study from selected cohorts of nonimmunocompromised patients, sepsis resulted in mild alterations in platelet counts, making it unlikely to become associated with the development of nosocomial infections. it would be relevant to address this question in larger cohorts of non-selected patients, as well as the impact of platelet transfusions in this setting. conclusion changes in platelet counts were not associated with an increased susceptibility towards icu-acquired infections in non-immunocompromised patients with severe sepsis and septic shock. introduction sepsis is the leading cause of mortality in the intensive care unit (icu) patients despite the progress regarding their care. the immunodeficiency due to sepsis with the consequent profound lymphocyte alterations is now well proven. the objective of this work was to determine the prognostic impact of lymphocytopenia in septic patients in icu. retrospective study including all patients hospitalized for sepsis or septic shock between / / and / / . the sepsis and septic shock definitions were adjusted with the third international consensus definitions for sepsis and septic shock. were excluded from the study patients of onco-hematology. lymphocytopenia was defined as an absolute lymphocyte count less than level of /mm during the first h of hospitalization. the prognostic factors analyzed for the lymphopenic and non lymphopenic patients were in hospital mortality, the occurrence of nosocomial infections and hospital length of stay. results among the patients, aged ± years, patients were with septic shock and patients with sepsis. igsii score and sofa score were respectively ± and ± . four patients were immunocompromised due to hiv infection in one case and an immunosuppressive therapy in cases. lymphocytopenia was observed in patients ( %). twenty-eight patients ( %) died within an average of ± days. it was noted the occurrence of nosocomial infections. the median length of stay was days with extremes of one and days. the lymphopenic patients were comparable to non lymphopenic patients in terms of medical history and severity scores. mortality was comparable between the groups with a rate of % (n = ) in lymphopenic patients and % (n = ) in non-lymphopenic patients (p = . ). the earliness of death was correlated with the duration of lymphopenia (r = . , p = . ). the occurrence of nosocomial infections was not different between the two groups: % (n = ) for lymphopenic and % (n = ) for non lymphopenic patients. the hospital length of stay was not different between the two groups but was correlated with the duration of lymphocytopenia (r = . , p = . ). conclusion lymphocytopenia is frequently found in sepsis. lymphocytopenia was not associated with excess of mortality nor with the subsequent occurrence of infectious complications during the icu stay. his persistence was associated with an earlier death and a more prolonged hospitalization. none. introduction relative adrenal insufficiency (rai) is common in icu patients, particularly during septic shock ( ). it has been shown that the rai also occurs during cardiogenic shock ( ) . septic cardiomyopathy occurs in a significant proportion of septic shock patients. the aim of this study was to evaluate the role of rai on septic cardiomyopathy. patients and methods prospective observational study conducted in the intensive care in one university hospital in france. patients meeting the criteria for septic shock without prior corticosteroid therapy and without chronic heart disease were included. total blood cortisol levels were assessed immediately before (t ) a short corticotropin stimulation test ( . mg iv of tetracosactrin) and and min afterward. Δmax was defined as the difference between the maximal value after the test and t . rai was defined as an inappropriate adrenal response with Δmax < µg/dl and septic cardiomyopathy as the appearance of cardiac systolic dysfunction (left ventricle ejection fraction < %) within the first days of septic shock. we performed a multivariable analysis using backward stepwise logistic regression to identify independent predictors of septic cardiomyopathy. discussion although the definition of rai is not consensual, a threshold of Δmax at µg/dl has been widely used in septic shock, with or without the use of t ( ). the usefulness of substitutive doses of steroids in septic shock is controversial, but many authors assume this treatment has a potential in reversing overt vasoplegia. our data suggest an implication of rai in septic cardiomyopathy. conclusion we found rai to be an independent predictor of septic cardiomyopathy. these findings may suggest a new role for substitutive doses of steroids in the hemodynamic management of septic shock. introduction regional perfusion parameters, like lactate, pyruvate and glycerol, may predict outcome in septic shock patients. continuous venovenous haemofiltration (cvvh) has been considered beneficial in septic shock patients. the aim of our study was to investigate whether cvvh, in comparison to intermittent haemodialysis (ihd), is able to improve regional perfusion in septic shock patients studied by muscle microdialysis. patients and methods it was a prospective, randomized, clinical study, including septic shock patients with acute renal failure, aged over years. patients were randomized to receive either cvvh (n = ) or ihd (n = ) for renal replacement therapy. intermittent haemodialysis was carried out during the first h of the h study period. systemic haemodynamics and interstitial tissue concentrations of lactate, pyruvate, glucose and glycerol were obtained at baseline, , , and h after initiation of renal replacement by using muscle microdialysis. results regarding systemic haemodynamics parameters, cvvh caused a decrease in heart rate in contrast to ihd after h (− ± vs + ± /mn). there were no changes in vasopressor support throughout the -h study period and so systolic blood pressure remained stable in both groups. during the h of all renal replacement therapies there was no significant change in muscle pyruvate and glucose levels. during cvvh muscle lactate decreased constantly, as did muscle glycerol levels. this decrease reaches a significant levels at h for muscle lactate and at h for muscle glycerol (fig. ) . conclusion our results suggest that among septic shok patients, cvvh may improves regional perfusion in comparison with ihd. none. introduction acquired hypernatremia (h-na) is an independent risk of death among icu patients ( ). in the rct "hyper s" study, we compared normal to % hypertonic saline during the first h in patients with septic shock with normal serum na concentration (sna) at baseline. the study was prematurely stopped for potential harmful effect associated with more frequent h-na. we assessed the role of h-na on mortality. patients and methods data are a post hoc analysis of the "hyper s" study database including patients. sna was measured at h , every h for days and then daily until d . study fluids were stopped if sna > or > mmol/l increase over h. mild, moderate, and severe h-na were defined as sna > mmol/l, > mmol/l and > mmol/l, respectively. sna profiles were compared between d survivors and non-survivors. acute kidney injury (aki) was defined by doubling serum creatinine and/or need for dialysis. results patients with available data were analysed. ( %) developed h-na (mild: %, moderate: %, severe: %). no matter the absence or presence and its severity, h-na did not affect mortality ( , , , and %, respectively without, with mild, moderate, and severe h-na, p = . ). sna profiles were similar between survivors and non-survivors (table ) . a sensitivity analysis performed among survivors at d did not change the results. compared to patients without h-na, aki occurred in % of patients with h-n vs % (p = . ), atelectasis in versus % (p = . ) and icu acquired weakness in versus % (p = . ). conclusion hypernatremia occurrence is not associated with an increased risk of morbidity and mortality during hypertonic fluid resuscitation in septic shock. none. introduction guidelines about the moderate hypokalemia treatment (between . mmol/l and . mmol/l) are based on experts estimations, and non-specific ones for patients in the intensive care units (icu). the aim of this study was to evaluate the correction of the hypokalemia in an icu and the compliance of recommendations. materials and methods an observational epidemiological, retrospective and monocentric trial has been realized during a period of months (from january to february ). the study population included hospitalized patients in the icu who have shown a first moderate hypokalemia episode, all cause considered. patients who have presented an acute renal failure with a kdigo (kidney disease: improving global outcomes) score of three the day of their inclusion were excluded. the main primary study endpoint was percent correction of the serum potassium after h. the secondary study endpoints were the incidence rate of moderate hypokalemia and the efficacy about the hypokalemia correction in accordance with the achieved treatment consistent or not with recommendations. results patients had at least one episode of hypokalemia. the incidence rate of the hypokalemia first episode was . %. the study population included patients. igs score was . (± ). patients required mechanical ventilation at the inclusion. the serum potassium was greater than or equal to . mmol/l after h about patients ( . %) (corrected group). at h one patient had a serum potassium higher than mmol/l. the average total potassium was respectively . infusion of potassium and ( . %) patients have been a management compatible with the most common recommendations (input potassium chloride of mmol, use of the enteral administration and lack of continuous intravenous infusion). the percent correction of the hypokalemia after h was respectively of / ( . %) in the group in which recommendations had been respected and of / ( . %) in the other one (p = . ). discussion in our knowledge there are no previous studies that have specifically focused on the correction of the moderate hypokalemia in critically ill patients. in our study the incidence rate of the moderate hypokalemia was lower than data from the literature because we have only considered the first episode of the hypokalemia [ ] . among patients without contraindication to the enteral administration, this one was used in less than half of the cases. % of these patients received potassium with a continuous intravenous infusion and only patients received medical care conform to the guidelines. the medium potassium quantity provided was very lower to the guidelines. only % of the patients have been corrected after h without any difference in the medium potassium quantity which has been provided in relation to the uncorrected group. conclusion only . % of moderate hypokalemia in icu are corrected after h. the intravenous way is considerably used (in % of cases) with a poor return. a wide-ranging study is necessary to determine the best correction modes. none. results patients were included. mean ± sd age was ± years, % were male, mean ± sd saps ii was ± . icu length of stay was ± days and icu mortality rate was %. during the first days in the icu, % of patients received at least one nephrotoxic drug. % of patients received one, % received two, % received three and % received more than three nephrotoxic medications. diuretics, antibiotics and iodinated contrast media were the nephrotoxic drugs most frequently administered to, respectively, , and % of patients. aki (kdigo stage or higher) occurred in % of patients during the first days in icu. the proportion of patients with aki increased with the number of nephrotoxic drugs received: / ( %) of the patients not exposed to nephrotoxic drugs developed aki whereas, respectively, / ( %), / ( %), / ( %) and / ( %) of the patients receiving one, two, three, and more than three nephrotoxic drugs developed aki. the univariate association between the number of nephrotoxic medication and aki persisted in the multivariate analysis adjusted on baseline saps ii score (p < . ). conclusion the significant proportion of patients exposed to nephrotoxic drugs and the observed association with aki warrants further investigation. statistical adjustments for multiple potential confounders is needed in order to assess a potential causal relationship which would lay foundations for interventional studies. none. ( ) the minimal kidney aggression by current monomeric nonionic low-osmolar contrast media, late serum creatinine increase being explained by the occurrence of later (between the th and the nd hour) kidney injury due to critical illness or its therapy or ( ) insufficient sensitivity of early ( h) measurements of this biomarker to detect contrast-associated aki. competing interests partial financial support, no implication in data analysis and interpretation. introduction diabetic ketoacidosis, generally resulting from an absolute deficiency of insulin, is a frequent cause of hospitalization in intensive care unit. recommendations for diagnosis of diabetic ketoacidosis, care and site of admission have been published by the english society of diabetology. icu admission are recommended if one of the following criteria is present: gcs < , systolic arterial pressure (sap) < mmhg, spo < %, ketosis > mmol/l, hco < mmol/l, ph < . , potassium level < . mmol/l or anion gap > mmol/l. however, it is suspected that adhesion to recommendations remains low. in this study, we aimed at describing patients admitted for diabetic ketoacidosis in icu. we looked at adhesion to published recommendations regarding admission and care. we also described metabolic complications and looked for an association between complications and dose of initial insulin therapy. complications hypoglycemia (< . mmol/l) was observed in % of patients within the first h in which % were < . mmol/l. this was and % of patients between and h of icu stay. hypokalemia below . mmol/l happened in % of patients within the first h and in % between and h. neither hypoglycemia nor hypokalemia were correlated with initial insulin bolus or initial dosage of continuous intravenous insulin. hypophosphatemia < . mmol/l was observed in % of patients. discussion in this study, admission to icu was consistent with british recommendations since most patients presented at least one clinical or biological criterion indicating icu admission. arterial blood gas were sampled in the large majority of patients despite consistent data showing that venous blood gas might be sufficient in non-hypoxemic patients. also, initial insulin bolus and sodium bicarbonate perfusion were performed in a significant subset of patients despite absence of convincing data or recommendations supporting their use. finally, significant hypokalemia and hypoglycemia were frequent in these patients. these complications are in theory favored by insulin therapy but we did not observe a correlation between administration of an insulin bolus or the dose of continuous intravenous insulin perfusion. conclusion in this retrospective multicentre study, patients admitted in icu for diabetic ketoacidosis were correctly oriented regarding the british recommendations. metabolic complications (hypoglycemia and hypokalemia) were frequent but not correlated with initial dose of insulin. the appropriate rate for hypernatremia (h-na) correction is unknown. under-correction could be associated with worse outcome. experts recommend a rapid correction of acute (< days) and sever (> mmol/l) h-na with a rate of − mmol/l/h until na < mmol/l ( ). correction should be, therefore, obtained within h. in patients with septic shock resuscitated with iso-or hypertonic saline and who acquired acute severe h-na, we assessed if the correction rate was associated with mortality. patients and methods data are a post hoc analysis of the rct "hyper s" database comparing normal to % saline for h in septic shock. serum na (sna) was measured at h , every h for days and ) . h-na correction rate was more rapid in non-survivors, p = . (table ). over-correction occurred similarly in survivors ( %) and non-survivors ( %). the time to reach sna normalization was shorter in nonsurvivors (p = . ). after adjustment for sapsii and maccabe scores, more rapid correction rate remained significantly associated with mortality: or . ; % ci ( . - . ), p = . . conclusion in the context of acute severe h-na induced by fluid resuscitation, a rapid correction rate might be associated with even aggravated rather than improved mortality. introduction systemic capillary leak syndrome (slcs) is a rare disease characterized by recurrent life-threatening attacks of capillary hyper permeability in the presence of a monoclonal gammopathy (mg). during acute episodes, the leak of fluid and proteins from the intravascular compartment to the interstitium results in clinical signs of both acute hypovolemia and interstitial edema. biological profile is pathognomonic with marked hemoconcentration and paradoxal hypoproteinemia. hypovolemic shock is the classical feature of severe scls attacks. however, beside this typical hemodynamic profile, several case report described myocardial dysfunction during scls attacks. the objectives of this study were to assess frequency, characteristics and outcome of myocardial involvement during severe scls attacks. ( %) mechanical ventilation, ( %) renal replacement therapy, ( %) veno-arterial extracorporeal membrane oxygenation, ( %) intra-aortic balloon pump and ( %) an impella. compartment syndrome occurred in ( %) patients and ( %) died in icu. we then compared the patients with myocardial involvement to the without clinical and biological manifestations were similar in between groups. however, chest pain ( vs %, p = . ), dyspnea ( vs %, p = . ) and respiratory failure ( vs %, p = . ) were more frequent in patients with myocardial involvement than in others. there was no difference between groups regarding treatment received in icu, complication and outcome except for the use of va-ecmo ( . vs %, p = . ). conclusion myocardial involvement seems frequent in patients with severe scls attack, occurring in % of the cases. such patients exhibited classical features of scls attacks. myocardial involvement was responsible for altered lvef or transient ventricular hypertrophy. myocardial dysfunction could be severe, even requiring mechanical circulatory support. scls attacks should be known as a cause of severe reversible myocardial dysfunction and hypertrophy. none. introduction in refractory cardiorespiratory emergencies, ecmo appears a good alternative to conventional treatment. its extracorporeal circuit justifies curative anticoagulation explaining haemorrhagic and thrombotic complications. activated clotting time (act) is empirically and commonly used to assess anticoagulation but with large inter and intraindividual variabilities. in practice, antixa activity dosage is available to approach anticoagulant effect of heparin and is less expensive, but data during ecmo are missing. we sought to demonstrate the lack of correlation between antixa and act in patients under ecmo support. we prospectively include patients supported by ecmo in chu toulouse, france, between / and / for circulatory/respiratory support. anticoagulation was achieved by unfractionated heparin: initial bolus then continuous intravenous infusion ( - iu/h), for antixa target of . - . . concomitant dosing of antixa (laboratory) and act (hemocron ® ) was conducted two times a day on the same sample throughout the ecmo period. relationship between act and antixa was analyzed by spearman correlation (rho). after transformation into categorical variables (obtained target = ; outside the target = ), analyzes were completed by a concordance study (kappa). as recognized on literature act's targets were between and . results patients were included: men ( %), median age yo ( - ). indications were veno-arterial (n = ) and veno-venous ecmo (n = ). ecmo median duration was days (hours to days). spearman correlation test found low and inconsistent correlation between antixa and act (rho spearman < . ). this correlation lack present from the day one, worsens over time. analyzed kappa showed no discrepancy between the areas "targets" of act and antixa confirming the results (table ) . conclusion use of act for ecmo anticoagulation monitoring doesn't seem appropriate and high price probably justifies preferential use of antixa in clinical practice. analyzes of relationships between antixa and bleeding/thrombotic events are needed to confirm the antixa place and its target in these indications. introduction postcardiotomy cardiogenic shock (cs) has an incidence of % to % after routine adult cardiac surgery. in . - . % of cases, an venoarterial extracorporeal life support (va-ecls) is requested. the -month survival rate is . % ( ). survivors may suffer of physical and psychological impairments as well as an alteration of quality of life. this study was designed to assess the outcomes, long-term health- since icu discharge, % of patients reported physical sequelae., ecls-related limb pain occurs in % of patients while paresthesia occurs in % and chronic-tiredness in %. mean karnofsky score was % (table ) . conclusion after va-ecls for postcardiotomy cardiogenic shock longterm physical and psychological sequelae are frequent in survivor discussion interest for fluid management is growing in critical patients. nevertheless, no study has yet investigated its impact in selected patients with cardiogenic shock treated with va ecmo. our study suggested a possible association between fluid overload and mortality but lack the power to confirm these results with multivariate analysis. conclusion fluid management is a key therapy during va ecmo but fluid overload could be associated with worsen outcomes. further studies with larger population are warranted before considering fluid restriction trials. introduction extracorporeal life support (ecls) has taken an important place in the treatment of cardiogenic shock (cs) or refractory cardiac arrest (ca). however, ecls deplore a high mortality rate in the first days raising important ethic and economic consequences. in this context, continuation of support should be reassessed precociously. the aim of this study was the research of prognostic factors of -days mortality, h after ecls implantation for cs or ca. materials and methods all patients undergoing ecls in our tertiary center during a -year period were prospectively included. the ecls were managed with a multidisciplinary protocol based on consensus. clinico-biological data were collected just before and h after ecls implantation. these data were compared between survivors and deceased at month. , cpc score was respectively for patients, for , for . at months, cpc score changed only for the patients with a cpc score at (one died after another suicide attempt, one changed his cpc score to ). in the group without ca (n = ), had normal neurological status at months and at months (one patient died because of a cancer). among these patients, % returned at home and % returned to work. ( %) patients re-attempted suicide in the year. the major risk factor of mortality is the presence of a cardiac arrest on hanging site. all the other factors found to be related to mortality are well known risk factors in cardiac arrest of other origin. in univariate analysis, risk factors of neurological sequelae at months were a cardiac arrest on hanging site (p = . ) an elevated diastolic blood pressure ( vs mmhg; p = . ), a lower initial glasgow score ( vs ; p = . ), and an elevated blood glucose ( . vs . g/l p < . ) at admission in icu. discussion our cohort of self-hanging patients can be divided in two parts: a) patients with ca in the pre-hospital period with a high mortality and a good neurological recovery in / surviving patient, but with a small group; b) patients without ca with a very low mortality and a very good neurological recovery. these results seem to be better than in the most important cohort [ ] published until now in self-hanging patients without ca and not treated by hbot (mortality at . % and . % of poor neurological recovery). conclusion patients surviving a self-attempted hanging who have not presented ca and treated by hbot have mainly a good neurological outcome. randomized control study should be undertaken to confirm hbot effectiveness in that indication. introduction venoarterial extracorporeal membrane oxygenation (va-ecmo) is increasingly used to treat refractory cardiogenic shock or cardiac arrest. acute brain injury (i.e. ischemic stroke, haemorrhage and/or failure to awaken because of diffuse brain injury) may occur in up to % of patients on va-ecmo and is associated with increased mortality and poor functional outcome in survivors. however, early indicators of neurological outcome are lacking in this population. we aimed to assess the prognostic value of early electroencephalography (eeg) alterations during va-ecmo. we conducted a prospective single-center study in the medical icu of a university hospital on consecutive patients cannulated to va-ecmo. a standardized clinical neurological evaluation including the rass score, the gcs score, the full outline of unresponsiveness (four) score and brainstem reflexes was coupled to an intermittent eeg. eeg was recorded as soon as possible within the first h after va-ecmo cannulation. eeg characteristics were analyzed by a neurophysiologist who was blinded to the patient's condition. a severely altered eeg pattern was defined as a predominant delta frequency, discontinuous, unreactive and/or an isoelectric background. the primary endpoint was poor neurological outcome, defined as the composite of death or acute brain injury on neuroimaging within days. data are presented as median (interquartile range) or number (percentage). false-positive rates (fprs, corresponding to -specificity) of poor neurological outcome were calculated for each significant predictor, using an exact binomial % confidence interval (ci). results sixty-nine (age ( - ) years) patients with a sofa score of ( - ) were included. main indications for ecmo were: post cardiac surgery (n = , %), terminal dilated cardiomyopathy (n = , %), and acute myocardial infarction (n = , %). cardiac arrest before ecmo cannulation was noted in ( %) patients. eeg was recorded ( - ) days after va-ecmo cannulation and ( %) patients were sedated at time of eeg. at day , ( %) had a poor outcome (n = deaths and n = patients alive with acute brain injury). in univariate analysis, a lower rass score (p = . ), a lower four score (p = . ), a lower score on the motor component of the glasgow coma scale (p = . ), and a lack of cough reflex (p = . ) at the time of eeg were significantly associated with a poor outcome. a severely impaired eeg pattern or presence of a discontinuous background activity were also associated with a poor outcome (p = . and p = . , respectively). indicators of poor neurologic outcome are presented in the table . among all parameters, a discontinuous background activity was the only variable that constantly predicted poor outcome (false-positive poor outcome prediction rate of %, % ci - %). conclusion early intermittent eeg has a strong prognostic value for sedated patients on va-ecmo. presence of a discontinuous eeg background activity seems to be more accurate than clinical alterations to predict a bad neurologic outcome at days. none. table ). it was not found a significant association of ctp to mortality ( % in the case group and % in control group, p = . ). other factors that increased mortality were coma, seizures, shock, oedema, cellularity in csf > units/mm . otherwise, the ventilation length was prolonged with ctp group ( . vs . days, p = . ) and neurological sequels namely the epilepsy was more frequent with the group ctp: ( vs %, p = . ). conclusion the occurrence of ctp on bacterial meningitis was significantly associated with ct scan lesions which seems to be an association be in both directions. also, the positive culture predisposed more to the ctp. mortality was higher with the presence of ctp but without real significance. the ctp was a factor that extends the ventilation time and exposed to the post infectious epilepsy. introduction acute bacterial meningitis requires rapid triage and therapeutic decision-making. the aim of this study was to assess the overall ability of a point-of-care glucometer to determine bacterial infection in cerebrospinal fluid (csf). we performed a prospective, observational study. we included patients for whom an analysis of csf was indicated by the physician in charge with blood sampling performed for glucose concentration measurement within h. we simultaneously measured the glucose concentrations in csf and blood using a central laboratory and point-of-care glucometer. the diagnosis of bacterial meningitis was determined by two physicians after reviewing the complete medical chart. we compared csf and blood glucose concentrations and csf/blood glucose ratios obtained at the bed-side with a glucometer versus those obtained by the central laboratory. we determined the performance characteristics of the csf/blood glucose ratio provided by a glucometer to detect bacterial infection in the csf immediately after csf sampling. conclusion we demonstrated that the csf/blood glucose ratio measured by a glucometer can serve as a clinical decision support tool for the early detection of csf with a high probability of bacterial infection. this costless point-of-care method has the potential to expedite medical decision-making for the triage of adult patients with suspected meningitis in the emergency department immediately after lumbar puncture. none. introduction cardiac arrest remains a frequent cause of admission in intensive care unit. a majority of patients will die during their hospital stay mainly from consequences of hypoxic-ischemic brain injury after a decision of withdrawal of life sustaining therapy support by a prediction of poor outcome. the reliability of prognostication is crucial, but is still a difficult and uncertain exercise. eeg is the most widely used prognostic tool to support a clinical examination and is accessible in most hospitals. it is recommended for both prognostication and ruling out subclinical seizures. there is no high-level evidence for predicting poor prognosis using eeg because of the wide variety of classification systems used and the interrater variability. our objective is to assess the prognostic value of simple eeg features based on the recent american clinical neurophysiology society (acns) standardized classification and to study the interrater variability. we conducted a retrospective monocentric observational study in a bed medical intensive care unit of the university hospital la timone, marseille, france. all patients aged of more than year-old admitted for a resuscitated cardiac arrest between november and july who underwent therapeutic hypothermia and a full multimodal prognostic evaluation including a eeg were included in the study. outcome was classified according to the cerebral performance category score measured at day . unfavorable outcome was defined as death (cpc ), persistent vegetative state (cpc ), or severe neurological disability (cpc ). favorable outcome was defined as moderate neurological disability (cpc ), or no disability (cpc ). eeg was performed in all patients still comatose after rewarming between and h after admission and after discontinuation of sedation. eeg interpretation was made by independent senior neurophysiologists, blind to the outcome. eeg features are based on the latest acns classification. for each eeg feature, sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv) for predicting an unfavorable outcome were calculated. results during the study period, cardiac arrest were admitted of which patients went through a full neurologic evaluation and were finally included in the study. according to neurological outcome, % had a favorable evolution, and % had an unfavorable outcome. the presence of burst suppression, and epileptiform activity was constantly associated with an unfavorable prognostic with a % specificity and % false positive. a non-reactive eeg is strongly associated with an unfavorable evolution with a % specificity and % false positive. other features including periodic or rhythmic patterns and low voltage were inconstantly associated with unfavorable outcome. kappa score for all eeg feature was slight or fair and always under . . discussion this study allowed us to identify a homogenous cohort of comatose patient after cardiac arrest who underwent therapeutic hypothermia. we identified simple eeg features based on the new classification of the acns constantly associated with unfavorable outcome. these features must be known by intensivists to better integrate eeg in the multimodal evaluation of neurological prognostic. there is important interrater variability that must lead to caution and to always use multimodal approach to prognostic an unfavorable outcome. conclusion bedside eeg is an excellent tool for predicting outcome of post-anoxic coma through simple eeg features. burst suppression, epileptiform activity and non-reactive eeg are strongly associated to neurological outcome after cardiac arrest. however, the interrater variability emphasize the need of being well trained for the standardized methods of evaluating eeg parameters. introduction emergent reintubation is a well-known risk of laryngotracheal trauma and of ventilatory acquired pneumonia. to precisely define its risk before extubation for each patient is a part of quality of care in intensive care units. none of these consecutive children representative of picu activity has been reintubated. the coming prospective muticentric study which aims to validate alt in childhood must precisely define this criteria of evaluation. conclusion the different methods of alt are feasible in real clinical conditions in picu. because of the increasing use of cuffed etts in a wide variation of patients with different body weight, the best alt to use at the bedside must be definitively validated in this population. introduction prolonged mechanical ventilation (pmv) and chronic mechanical ventilation (cmv) in neonates is associated with a high morbidity and mortality. the objective of the study is to identify, among the patients with pmv, those that evolved to cmv, as well as the adverse respiratory, neurological and feeding sequelae. we conducted a retrospective study of the last years at the chu sainte-justine (montreal, canada). chart review included patients with pmv (≥ days) using the paediatric definition adapted from the namdrc consensus conference ( ) . demographic and clinical data, including follow-up at and months corrected age, was collected for each included patient. the evolution of pmv neonates with cmv (≥ days) and without ( - days) was compared. we identified neonates that met criteria for pmv. patients born between and (n = , % of the cohort) were analyzed. around half of the patients ( - patients a year) are transferred from the neonatal unit to the paediatric intensive care unit. in our center, they represent around % of total admissions, but their length of stay is among the longest. among these newborns, % were preterm (n = ) with % (n = ) born before weeks gestation. of all patients with a malformation ( %, n = ), had a thoracoabdominal anomaly and had congenital heart disease. thirty-six patients had cmv with mean ventilation time of days (range - days). survival at months corrected age was % ( / ) in the pmv group and % ( / ) in the cmv group. at months corrected age, % of patients were dependent on artificial enteral feeding (nasogastric tube or gastrostomy), with % in the pmv group and % in the cmv group. nine percent of patients had oxygen supplementation ( patients in the pmv group and in the cmv group), and % were mechanically ventilated. ten percent of patients had a tracheostomy ( patients in the pmv group and in the cmv group). discussion neonates with cmv have more sequelae. their rapid identification (at days of ventilation) is essential to implement multidisciplinary development care in order to minimize neurodevelopment impairment. conclusion most newborns in our pmv cohort have a congenital malformation. survival at months corrected age appears equivalent in both pmv and cmv group. artificial enteral feeding is more frequent in the cmv group and most patients have no respiratory support at months corrected age. none. the value of pressures and volumes in assessing the fluid responsiveness depend on the systolic cardiac function in adult ( ). we have studied the relative value of static filling volume and pressure to predict the fluid responsiveness, according to systolic cardiac function in children during acute circulatory failure. patients and methods patients under years old with an acute circulatory failure of two intensive care units during a year period of inclusion were analyzed. an exhaustive cardiac echography was performed initially (indexed end-diastolic volume (edvi) and e/e' from transmitral and tissue doppler were recorded), and the stroke volume index (svi) was measured before and after a fluid challenge (a ml/ kg of crystalloid over min results twenty-five children with acute circulatory failure were included. fluid responsiveness occurred in of the fluid loading events with low lvef, and in of the fluid loading events with normal lvef. pressure approach: for low and normal lvef, the auc-roc for fluid responsiveness was respectively . (ci . - )/ . ( . - ) for a e/e' .the best thresholds of e/e' in low lvef was . with a sensitivity of (ci - ) % and a specificity of (ci - ) %. for low and normal lvef auc roc was respectively . (ci . - . )/ . (ci . - . ) for the pvc. volume approach: for low and normal lvef, the auc-roc for fluid responsiveness was respectively . (ci - ) and . ( . - ). the best thresholds in normal lvef was an edvi below ml/m wit a specificity of (ci - ) and a sensitivity of (ci - ) %. discussion our study shows a variation of the diagnostic value of e/e' and edvi according to the left ventricular systolic function. therefore, the systolic function should be taken into account to analysed the e/e' and edvi value. few preload dependency markers are validated in children and none for children in spontaneous ventilation ( ) . our study suffers from a lack of power that calls into question the validity of our results. another limitation is that both approaches with volume and pressure are not very discriminant as it is known for static value in adults. our study illustrates that, on a pressure-volume curve, when the cardiac inotropism is reduced, the filling of the left ventricle is moved to the up and right of the curvilinear diastolic function curve. therefore, pressure variations are larger than volume variations. these values should be monitored on a larger scale to define their exact diagnostic value. conclusion static pvc value is a low preload-dependency surrogate. when lvef is low a pressure evaluation based approach seems more accurate. when lvef is normal a volume evaluation based approach seems informative as predicted by the slope of the end diastolic pressure volume curve. those both static approaches remain of poor diagnosis accuracy. introduction acute viral bronchiolitis is a primary cause of respiratory distress in paediatric intensive care unit (icu). prone position (pp) is commonly used in neonates to improve respiratory mechanics and has been found beneficial to adult patients with acute respiratory distress syndrome. we aimed to evaluate the effect of pp on work of breathing as compared to supine position (sp) in children with severe bronchiolitis requiring non-invasive ventilation. the protocol was approved by our irb ( -a - ). fourteen infants ( boys) with median age days [firstthird quartiles - ] with severe bronchiolitis requiring cpap were included after written informed consent. children were investigated in pp and sp each applied for h in a random order with a washout period of min between them. level of cpap was set at cmh o in both conditions. oesophageal pressure probe was inserted orally (cto- pressure transducer, gaeltec, scotland) to measure oesophageal pressure. flow and airway pressure (pmo in fig. ) were simultanuously recorded using a neurovent data acquisition system (neurovent inc, toronto, canada). one hundred breaths were analyzed in each condition, in which work of breathing was estimated from oesophageal pressure-time product (ptpes) and oesophageal swings (fig. ). data were expressed as median (first-third quartiles) and compared by using the wilcoxon two-sample paired sign test. a p-value below . was considered significant. . the edtb contains data from ventilated patients (invasively and non-invasively) and details concerning ionotropic and sedative treatment during picu courses. discussion as far as we know, this edtb is currently the only one as exhaustive available in picu worldwide. after almost years of multidisciplinary collaboration, we are able to collect many useful physiological, therapeutic and medical data in an ongoing edtb. although many concerns remain concerning data validation, organisation and exploitation, this edtb already contribute to the development of clinical decision support systems and virtual patient validation and we create international collaborations to further develop these tools. three research protocols using the database are ongoing including: validation of a neuromonitoring clinical decision support system, validation of a cardio-respiratory simulator, developement and validation of the automatic diagnosis of pediatric acute respiratory distress syndrome and development of spo forecast using artificial neuronal network. conclusion thanks to informatics and electronic devices improvement, data gathering in intensive care units has empowered. we hope that our work in picu will encourage other teams on the way of data gathering, in order to build an international picu edtb in a close future. none. introduction severe trauma is rare in the pediatric setting ( % of all trauma in france). however, its morbidity and mortality remain high, in relation to brain injury. pediatric traumatic brain injury (tbi) prehospital care is challenging for non-pediatric retrieval teams. though, we disseminated pediatric tbi pre-hospital care regional guidelines and thereafter intended to assess severe pediatric trauma pre-hospital care and secondary cerebral insults control. we conducted a retrospective study in a single pediatric trauma center. children admitted in emergency room with severe trauma and moderate to severe tbi (glasgow coma scale ≤ ) from june to march were included. pre-hospital and hospital data regarding primary care, equipment, medications and secondary cerebral insults control (i.e. blood pressure, oxygenation, co level, temperature, glycemia) were collected from medical files. two pediatric transport team experts assessed the quality of pre-hospital care, based on two major endpoints. results twenty-nine files were analyzed. median iss was . all the children had been referred directly from the trauma scene to the pediatric trauma center. they were all intubated in the prehospital setting, ( . %) presented with spo < % before or at emergency room admission, and ( . %) presented with a pco > mmhg at admission. at least one peripheral catheter was inserted in all the children. mean total fluid bolus was . ml/kg (± ). nor-epinephrine was administered in ( %) children. mean blood pressure was below age threshold in ( %) children during transport or at admission. an intracranial hypertension treatment (apart from sedation) was delivered in ( %) children before admission. body temperature was monitored in patients and were hypothermic at emergency room admission. experts concluded on sub-optimal care in children: major endpoint was "respiratory care", "hemodynamic care" and "neurologic care" in , and patients respectively. discussion on this small series, we showed pre-hospital sub-optimal care regarding secondary cerebral insults control, especially regarding co level, blood pressure and body temperature. our results will help to design new care improvement strategies (e.g. sedation, fluid bolus and ventilation optimization, early use of vasoactive drugs, systematic body temperature monitoring…). conclusion data on pre-hospital secondary cerebral insults care are rare in the pediatric setting. based on our results, we aim to improve quality of care of children presenting with traumatic brain injury, and to reduce its morbidity and mortality. introduction unsuccessful extubation from mechanical ventilation increases mortality and morbidity. to reduce the extubation failures in our intensive care unit we used a mechanical ventilator weaning protocol, based on published data. during the first part of the study, risk factors and incidence of extubation failure were first described. afterwards in the second part, our mechanical ventilator weaning protocol was tested to determined its efficiency regarding the extubation failure. patients and methods a monocentric and observational study, was first conducted. we included children aged from birth to old, during a period of months and collected for each patient their medical history, intubation and extubation parameters, and existing events of extubation failure or extubation complication. the second part of the study was prospective, we include patients extubated by applying our mechanical ventilator weaning protocol. results average duration of mechanical ventilation was . h in the first part of the study. using a univariate analysis, duration of mechanical ventilation was a risk factor of extubation failure with an average duration of . discussion our study confirms published data about extubation failure risk factor like duration of intubation, chronic respiratory affection, history of previous intubation, and the administration of benzodiazepine. it is the first pediatric study that shows a reduction of extubation failure by using a specific mechanical ventilator weaning protocol. the mean bias of our its retrospective and prospective character. conclusion our study shows the interest of a mechanical ventilator weaning protocol to reduce the incidence of extubation failure. we currently continue the apply our protocol to include more patients in order to confirm our results. stroke of the child is formidable though it is ten times rarer than in adults, but this scarcity can have adverse consequences on the speed and quality of the management and the consequences on later psychomotor development. our goal is to describe the clinical and therapeutic aspects of these pediatric stroke while bringing our experience. patients and methods retrospective study of cases of children hospitalized in general intensive care unit to the pediatric hospital canastel oran for stroke during the period from january to january . the clinical, etiological, para clinical, and scalable were studied and transcribed on a standard electronic form.all patients had a brain ct. magnetic resonance imaging(mri) was possible in patients for lack of availability of the technical facilities during the study. results ten cases were selected. the mean age was months ( month to years), % are male, patients had a history of chd like tetralogy of fallot and complicated bronchiolitis myocarditis, one patient had a history of petechial purpura, other was a factor deficiency, headache history was noted in patients, and patients with no particular antecedent was found. all patients arrived comatose / score on the scale of glasgow, isochores reactive pupils with a motor deficit of hémicorps, patients have degraded their neurological score with onset of clinical signs of hypertension intra cranial namely anisocoria and hypertension requiring osmotherapy, sedation and mechanical ventilation with an average duration of - day. o child arrived brain dead, patients had generalized tonic-clonic seizures which yielded after taking a benzodiazepine (diazepam) and phenobarbital (like gardenal). cerebral ct was performed in all cases and could we revealed the nature of the stroke hemorrhagic in cases and ischemic stroke in cases. two patients have benefited from an mri that found a thrombosis of the artery internal carotid right sylvian. besides symptomatic treatment, treatment was initiated based on the type of stroke, patients received low molecular weight heparin (lmwh) at . ml/kg in addition to symptomatic treatment, patients received vitamin k. four patients died in an array of autonomic disorders and evolved favorably and six patients were transferred to a pediatric unit. the average length of stay in icu was . days ( - days). discussion the mortality rate is important since no specialized center for children, and difficulty especially in the diagnostic imaging field while suspected stroke should be confirmed by imaging and the diagnostic delay. which is due to a poor assessment of the initial situation in half of the cases by the parents, the other half by the swiss magazine consulté.une doctor showed that in a study in % of children with stroke, this diagnosis was not primarily discussed and that in % of cases the cause of the stroke was poorly evaluated [ ] . heart disease certainly represent the second most important risk factor. a collaboration of a team must be multidisciplinary, death has affected mostly older children whose age is between and years, who have a hemorrhagic stroke against by infants who have an ischemic stroke have evolved and oriented they exceed the acute phase to pediatric services for further investigation and monitoring. conclusion the child may also be having a stroke, which usually reaches the elderly. this justifies a good knowledge of this disease, and multiply the initial management efforts to reduce mortality and improve prognosis. anwar armel , benqqa anas , samira kalouch , khalid yaqini , aziz chlilek introduction nosocomial infections are a main problem for public health for their cost as well as for the morbidity and mortality they generate. they are particularly common in intensive care units due to patient's lower defenses and of invasive procedures proliferation. work's purpose: • determine the epidemiology of bacterial noso-comiales infections (ibn) in the medico-surgical pediatric intensive care department of children's university hospital of casablanca. • to identify factors associated with these infections. we led a retrospective study of hospitalized patients, spending more than h in medical-surgical pediatric intensive care department, at the university hospital ibn rochd of casablanca, over a period of months from january to december . results during the studied period, patients were admitted at intensive care with a stay of more than h. thirty episodes of inb were recorded. the incidence rate was . % and the incidence density was . % per hospitalization's days. the admission average age was . ± -month starting from month to years with a male predominance ( %). most of admissions ( %) was related to medical background, . % received from other hospital department. furthermore, % of the patients received prior antibiotics, usually prescribed before icu admission. invasive procedures (intubation, central catheterization) were used in . % of patients, vvp only in . %, tracheotomy in . and . % had received surgery. gram-negative bacilli (bgn) were isolated for a lot of patients, dominated by acinetobacter baumannii. these bacteria were isolated throughout the study year. risk factors analysis underlined that the presence of invasive procedures enhances in risk, that is central venous catheter and the need for mechanical ventilation. conclusion nosocomial bacterial infections are dominated by pneumonia and central catheter infections, and are mainly due to bgn. the factors associated with these infections were identified. the guillain-barré syndrome (gbs) is the most common cause of acute flaccid paralysis in children since the acute anterior poliomyelitis eradication. few studies have been held on the topic and knowledge of gbs in children, although it is recognized that the etiologic mechanisms, and clinicobiological background, are the same as in adults, prognosis remains different. our work's aim is to study this disease's mortality factors of children hospitalized in pediatric intensive care. patients and methods it is a retrospective, descriptive, mono centric study to review patients with gbs between january and december and hospitalized at pediatric intensive care department of abderrahimharouchi hospital of casablanca. the used software is spss . to compare the bivariate variables, we used the khi test, and to compare quantitative variables, the anova to factor test was used. the level of significance was fixed at % with % confidence interval. the disease was predominant in male with a sex ratio of . men/women. after a prodromal event, usually infectious ( . %) and a free interval of days on average to start motor disorders. these are of two types: either a hypo or areflectic flaccid paralysis of the lower limbs ( . %) of ascending evolution in . % of the cases. either flaccid tetraplegia or hypo areflectic, ( . %). ventilation was required in . % of the cases, and specific treatments based on immunoglobulins were administered in . % of the cases. death's rate is still high ( . %) and mainly due to hospitalization complications. in our study respiratory disease was noted in . % of the cases, also other signs of serious illness such as swallowing disorders ( . %) and autonomic disorders ( . %) also noted what led to management in intensive care for all our patients. these patients study allowed to identify some mortality prognosis factors of the disease in intensive care units (such as male gender, ig administration duration, the occurrence of autonomic disorders like blood pressure instability), the most discriminating remains the occurrence of nosocomial infections. conclusion it must be underlined, that in view of our strict inclusion criteria, focusing only on patients admitted at intensive care and of the relatively small sample size ( cases), our results must be qualified and must be enhanced by additional and more varied studies to better understand this disease in children. introduction early surgical treatment is recommended for refractory intracranial hypertension (htic) in children to improve vital and functional prognoses, whether traumatic or vascular cause. the main objective of this study was to compare the mortality and morbidity of children with severe intracranial hypertension after severe head trauma (tc) or due to vascular cause after decompressive craniectomy (dc) or medical therapy alone. the secondary objective was to identify the initial severity factors associated with higher mortality. patients and methods a retrospective study was performed with data collected from patients aged under years-old admitted to our pediatric intensive care unit for severe intracranial hypertension of traumatic or vascular cause, between january and january . they were divided into groups: patients who received medical therapy alone and those treated with decompressive craniectomy after optimal medical management. results a total of children were included. among them, were treated with dc ( htic of vascular cause and htic of traumatic cause), and were supported by medical means only ( htic of vascular cause and htic of traumatic cause). in the population "traumatic intracranial hypertension", we note that children in the "dc" subgroup are more often in mydriasis upon arrival (p = . ) than in the subgroup treated medically. in this same population, children in the "dc" subgroup received higher doses of mida-zolam (p = . ), of mannitol (p = . ) and hypertonic saline (p = . ) than in the other subgroup. in the population "vascular intracranial hypertension" the two subgroups were comparable. in the case of traumatic intracranial hypertension, mortality rate in the "dc" subgroup was . % against . % for children treated medically (p = . ); "dc" children had more metabolic complications such as hypernatremia than "not dc" children, p = . . mortality rate in the «vascular intracranial hypertension» group was % for children treated with decompressive craniectomy, and . % for children treated medically alone (p = . ). patients treated surgically in the «vascular intracranial hypertension» group had longer overall stays (p = . ) and longer icu stays (p = . ). popc score (pediatric overall performance category) upon discharge for children with intracranial hypertension of traumatic cause treated with decompressive craniectomy was . ± . against . ± . among children treated medically, p = . . in "dc" children with intracranial hypertension of vascular cause, popc upon hospital discharge was . ± . against . ± . among non-operated children, p = . . the schooling rate was higher among children treated medically for intracranial hypertension of traumatic cause, p = . . the severity factors related with higher mortality identified in the population "traumatic intracranial hypertension" were mydriasis upon admission, a pim score higher and a lower temperature (< . °); the latter being the only factor identified for htic of vascular cause. in the case of traumatic intracranial hypertension, icp monitoring in survivors was . % against . % in children died, with no significant difference. in the population "vascular intracranial hypertension", all the patients who died had not been monitoring pic. discussion the severity factors related with higher mortality identified in the population "traumatic intracranial hypertension" were mydriasis upon admission, a pim score higher and a lower temperature (< . °); the latter being the only factor identified for htic of vascular cause. other studies have related other severity factors as initial glasgow scale, tardive decompressive craniectomy. conclusion decompressive craniectomy doesn't seem to improve the mortality rate or the outcome in patients with hypertension of traumatic cause in our study but the dc traumatic subgroup was more serious than the subgroup treated medically. in children with refractory intracranial hypertension of vascular cause dc significantly improves survival and outcome. further studies are needed to clarify the role of decompressive craniectomy and its timing in the therapeutic management of refractory intracranial hypertension. introduction shortage of heart grafts is a major problem, leading to a significant mortality rate in the national waiting list, essentially for young children with low weight. the potential paediatric brain-dead donors often have myocardial dysfunction (md), which seems to be reversible. the aim of this study is to assess prevalence, causes and consequences of md when the potential paediatric donors are taken over, up to multi-organ retrieval, and the evolution after cardiac transplantation. materials and methods this observational, monocentric, retrospective study included all brain-dead children aged - years old, who had their myocardial function assessed through a cardiac ultrasound performed by a cardiologist and identified from to . all adult patients and those who didn't undergo a cardiac ultrasound were excluded. md was defined as an lvef ≤ % with or without abnormal segmented cinetic parameters. the main evaluation criteria was the prevalence of md in potential identified donors. the secondary evaluation criteria were the causes and consequences of md on heart retrieval and the origin of this md. results out of included patients, had md. prevalence of md was of %. there was no significant difference between groups regarding aetiology of brain death nor administration of catecholamines. having a cardiopulmonary arrest during intensive care unit stay was associated with a significant risk of presenting a md (p = . ). having a md had no consequences on organ retrieval in general (p = . ), but was significantly associated with a decrease in heart retrieval opportunities (p = . ). the cause of heart grafts refusal was a poor ventricular function in % of cases ( cases out of ). the cause for non-retrieval was parental refusal in one-third of cases. evolution of the cardiac grafts was favorable in cases on , one transplanted patient died (from a non-cardiac cause) and patient was lost to follow up. conclusion md in paediatric brain-dead patients has direct consequences on heart retrieval and transplantation, and otherwise, organ shortage is a major ongoing problem. a better transplant management regarding hemodynamics (with the use of a protocol) could increase the number of heart transplants, especially in small children, and reduce mortality rate in national waiting list. the prone positioning (pp) is a strategy widely used in the treatment of severe forms of acute respiratory distress syndrome (ards) in adults. its early use significantly reduces mortality ( ). however, the studies do not strongly demonstrate its prognostic impact in pediatric ards. the aim of this study was to describe the prone positioning practices in the french-speaking pediatric intensive care units (picu). patients and methods this survey was conducted by email questionnaire to pediatric intensivists belonging to the french society of intensive care medicine and the french-speaking group of pediatric intensive care and emergency medicine. it was conducted from february to may . the survey was addressed to doctors, nurses, physiotherapists practicing in picu. it included questions about indications, contraindications, techniques and medical devices used, and complications. results one hundred and three persons answered ( doctors and nurses) which work in french hospitals and canadian hospital. sixty-eight percent of interviewed persons have more than years experience and % of them treat each year more than children ards. only % of the picu have a pp medical protocol. fifty percent of interviewed persons frequently use pp for the medical care of ards and % systematically use it. thirty-six percent begin pp at the early phase of ards during conventional ventilation, while % before the introduction of unconventional ventilatory strategies (ohf); only % use it after the respiratory failure unless unconventional ventilatory strategies. seventy-three percent report that pp is used with prolonged periods (> h/day), % with short periods (< h/day) and % with very long periods (> h/day). regarding the weaning criteria, most of interviewed persons seem to use multiple and combinated criteria: % use hypoxemia severity parameters (pao /fio , pao , sao ), % use the oxygen level (fio ) and % use the mechanical ventilation parameters (peep, p max, p plate). finally, despite a low level of scientific evidence in children, % of the persons gave a strong recommendation for pp as standard care in severe pediatric ards. see fig. . the survey confirmed the widely use of pp in pediatric ards. however, no specific protocol is avalaible in most of the picu. the timing of the pp beginning can be different according to children, early and prior to use of the conventional ventilation strategy in most cases. the duration of pp seems more consensual. most of the centers use extended periods longer than h/day. these results are close to guérin et al. advocating a duration > h/day. finally, the weaning is a great issue and depends on multiple criteria. in guerin et al. ( ) pp was interrupted if one of the following criteria were present: pao / fio ≥ mmhg, with peep of ≤ cm of water and a fio of ≤ . ; decreased pao /fio than %, compared to compared to the supine position, or the occurrence of complications. no study has validated pp weaning criteria during pediatric ards. conclusion the prone positioning is a strategy commonly used in pediatric intensive care units for the severe pediatric ards. the criterias of implementation and timing are variable, as well as the weaning criterias. more pediatric multicenter randomized studies will be necessary to confirm the benefits of pp in pediatric ards and to define clear weaning criteria. introduction allogeneic hematopoietic stem cell transplantation (hsct) recipients have profound defects in every immunity compartments that can lead to severe opportunistic infections (oi). % of hsct patients require admission to the icu because of diverse infectious or non-infectious complications with dismal outcomes. oi specific course in this population has not been described previously and the management of these infections may be a concern. the aim of this study was to investigate risk factors, management and outcomes of io in hsct recipients admitted to the icu. patients and methods this was a retrospective ( - ) single center study of patients admitted to icu after an allogeneic hsct. patients provided written informed consent according to helsinki declaration. data regarding the transplant, infections and life sustaining therapy use were analyzed. oi were considered if present at the time or during icu admission. results hundred and ninety-four patients (pt) were included. median age was [ ; ] years, . % were males. reason for transplantation was acute leukemia in ( %) pt and the hematological condition was still in complete remission at icu admission in % of patients. ( %) and ( %) had received a myeloablative conditioning regimen and anti-thymoglobulin serum respectively. % had acute graft versus host disease over grade at icu admission. oi was documented in patients ( %). an invasive fungal infection (ifi) was found in pt owing to mucormucosis, trichosporon septicemia and invasive aspergillosis ( possible, probable and proven according to eortc criteria). serum galactomannane antigen was positive in ( %). median time from transplantation and icu admission to ifi diagnosis was respectively [ ; ] and − [− ; ] days. lung was involved in % and patients with aspergillosis were admitted to the icu for acute respiratory failure in % (vs. % for others p = . ). they did not required invasive ventilation more frequently ( vs. % p = . ). and % required vasopressors and renal replacement therapy with no difference as compared to others. median icu length was [ ; ] days. demographic, stem cell source, and donor type were not associated with ifi occurrence in this population. however / had received a total body irradiation ( vs. % p = . ). ifi occurrence was not associated with icu or day mortality ( vs. % p = . and vs. % p = . respectively). a viral infection was found in pt owing to cmv, adenovirus, hsv and vrs infections. analyses were focused on cmv reactivation. median time from transplantation and icu admission to cmv reactivation was respectively [ ; ] and − [− ; − ] days. reactivation was mainly positive blood pcr but pt had cmv colitis. a preemptive treatment was started on the same day in median and lasts [ ; ] days. patients with cmv reactivation had more frequently multiple organ failure ( vs. % p = . ) and higher icu admission sofa score ( [ ; ] vs. [ ] [ ] [ ] [ ] [ ] [ ] p = . ). they trend to have higher admission creatinine serum level ( [ ; ] vs. [ ; ] umol/l, p = . ) and more frequently required emergency renal replacement therapy ( vs. % p = . ) mechanical ventilation ( vs. % p = . ) and vasopressors ( vs. % p = . ). median icu length was [ ; ] days and comparable to others. demographic, stem cell source, conditioning regimen and donor type were not associated with cmv occurrence. cmv reactivation was not significantly associated with icu or day mortality ( vs. % p = . and vs. % p = . respectively). conclusion oi was found in % of allogeneic hsct recipients admitted to the icu. ifi were mainly responsible for respiratory distress and cmv associated to multiple organ failure. non-invasive diagnostic tests were positives in a majority of these patients. in this cohort, io treatment was started quickly after the diagnostic and we did not find an association with mortality. intensivists should always consider oi in their diagnostic panel in this specific population. introduction over the last two decades, targeted therapies in patients with solid tumors have both increased their length of survival and significantly altered their immune functions. however, data on opportunistic infections in this setting remain scarce. in this systematic review, we sought to identify published cases of opportunistic infections in patients with solid tumors, with a special interest on clinical findings, trends over time and outcomes. materials and methods we performed a search of medical subject headings (mesh) on pubmed using the words pneumonia pneumocystis (pcp), invasive aspergillosis (ia), histoplasma, mucor, geotrichum, cryptococcus, coccidioidomycosis combined with the mesh term neoplasms (breast, lung, ovarian, urologic gastrointestinal, digestive system, abdominal, brain, carcinoid tumor, sarcoma, testicular, seminoma). we identify published cases of opportunistic infections in non hiv patients with solid tumors between / / and / / included. results regarding pneumocystis jirovecii pneumonia, cases could be identified. there were men and women, aged of . ( - ) years. underlying tumors were chiefly brain neoplasms (n = , %), lung neoplasms (n = , %) and breast neoplasms (n = , %). at the time of pneumocystis pneumonia onset, patients ( %) had a history of chemotherapy, ( %) had received long term or high dose steroids, and ( %) had an history of biotherapy targeting the malignancy. of note, patients ( %) had received only chemotherapy, ( %) had received steroids alone, ( %) everolimus therapy alone and ( %) received none of these treatments. regarding invasive aspergillosis cases could be identified. mean age was . ( - ) and ( %) were men. solid tumors associated with invasive aspergillosis were primarily lung neoplasms (n = , %) and brain neoplasms (n = , %). at aspergillosis onset, ( %) patients had a history of chemotherapy, ( %) were receiving long term or high dose steroids and ( %) had received targeted therapy. fourteen ( %) patients had received only chemotherapy, ( %) only steroids, and ( . %) had received targeted therapy alone. for both infection, there was a trend for a higher number of reported cases throughout the studied period. conclusion this systematic review provides objective data showing that an increased proportion of patients with solid tumors present with opportunistic infections. we are convinced that it is a clinically relevant but still neglected problem. selected oncologic population may be becoming eligible for antimicrobial prophylaxis against pneumocystis or aspergillus. care unit of strasbourg in france. patients were included only if they are non-immunocompromised according to the european organisation for research and treatment of cancer (eortc). invasive aspergillosis was defined as an association of microbiological evidence, a radiological imaging and a clinical context. results eighteen patients ( males) were identified during the study period. the median of igs ii was . (interquartile range (irq), . - . ). ninety-four percent was under mechanical ventilation. fourteen ( %) patients were suffering from liver failure. among liver failure, twelve ( %) were beforehand suffering from cirrhosis. the median meld score was (interquartile range (irq), - ). sixty-four percent of aspergillosis were due to aspergillosis fumigatus. hundred percent were pulmonary aspergillosis. fifty-six percent of aspergillosis were associated with bacterial pneumonia. the mortality rate at the date of the latest news (an average of years) was seventytwo percent. discussion invasive aspergillosis is not exceptional in the non-immunocompromised patient especially in patient developing liver failure. an active research of colonization/infection with aspergillus in these patients remain to be discussed. conclusion invasive aspergillosis in icu has a poor prognosis. the liver failure seems to be the most important risk factor in non-immunocompromised patients according eorct criteria. introduction chest wall elastance (ecw) has been found to increase in prone (pp) as compared to supine position (sp) in ards patients [ ] . this makes respiratory system elastance (ers) not reflecting lung elastance (el). little is known about the changes of ecw, el and lung resistance (rl) when moving the patient from the sp to the pp via the lateral position (lp). the goal of present study was to measure ecw, el and rl in ards patients in sp, lp and pp during the proning procedure. patients and methods it was a prospective, single-center, controlled study. ards patients intubated, sedated and paralyzed with pao /fio ratio < mmhg, peep ≥ cmh and an indication of pp were included. mechanical ventilation was delivered in volume controlled mode with constant flow inflation and end-inspiratory pause . s included into the inspiratory time. ventilator settings were unaltered during the procedure. an esophageal balloon catheter (nutrivent device) was used for esophageal pressure (pes) measurement. pressure at the airway opening (pao) and airflow were measured by fleish pneumotachograph proximal to endotracheal tube and upstream heat and moisture exchanger. pao, pes and airflow were continuously measured during min in sp, then during min in lp and min in pp. the side for the lateralization was that selected by routine practice (in the opposite side from central venous line). ers and resistance of the respiratory system (rrs) were obtained by fitting flow and pao signals breath by breath to the first order equation. ecw and resistance of the chest wall (rcw) were similarly obtained by fitting flow and pes signals breath by breath to the first order equation pertaining to the chest wall. el and lung resistance (rl) were obtained by subtracting ers and rrs from ecw and rcw, respectively. our ethical committee approved the protocol. data are shown as median (first and third quartiles). comparisons between positions were made by using paired-t-test. results twenty-nine patients, males, of ( - ) years, saps ( - ) and sofa score ( - ) were included ( - ) days after ards criteria were met. the ards severity was moderate in cases ( %) and severe in ( %). tidal volume averaged . ( . - ) ml/kg predicted body weight, peep ( - ) cmh o, fio ( - ) %, pao /fio ( - ) mmhg. the cause of ards was pulmonary in cases ( %), extra pulmonary in ( %) and undetermined in ( %). lateral positioning was on the right side in ( . %) and on the left side in patients ( . %). the results are shown in the table . conclusion during prone positioning in ards patients, as compared to sp we observed a higher rl in lp and an increased ecw in pp. introduction neuromuscular blocking agents (nmba) could exert beneficial effects in acute respiratory distress syndrome (ards) through properties on respiratory mechanics and particularly in modifying transpulmonary pressures (pl). patients and methods prospective randomized control study in moderate to severe ards patients within the first h of the onset of ards. all patients were monitored by an esophageal catheter and followed during h. moderate ards patients were randomized in two groups according to the systematic administration of a h continuous infusion of cisatracurium besylate or not (control group). the severe ards patients group received a h continuous infusion of cisatracurium besylate. the evolution during the h of the study of the oxygenation and the respiratory mechanics including inspiratory and expiratory transpulmonary pressures and driving pressure were assessed and compared. delta transpulmonary pressure (∆pl) was defined as inspiratory pl minus expiratory pl. results thirty patients were included, in the moderate ards group and in the severe ards group. nmba infusion was associated with an improvement in oxygenation both the moderate and the severe ards patients group accompanied by a decrease in both the plateau pressure and the total positive end expiratory pressure. the mean inspiratory and expiratory pl were higher in the moderate ards patients group receiving nmba as compared with the control group (fig. ) . in contrast, there was no modification of both the driving pressure and the ∆pl related to nmba administration. conclusion nmba could exert beneficial effects in moderate ards patients through higher observed inspiratory and expiratory transpulmonary pressures. none. introduction prone position (pp) is a major treatment in management of acute respiratory distress syndrome (ards). the use of pp in patients with severe ards associated with brain injury is at high risk of intracranial hypertension. the aim of this study is to analyze the effect of pp on intracranial pressure (icp) and cerebral perfusion pressure (cpp) in patients with ards and acute neurological condition requiring monitoring of icp. patients and methods it is a retrospective descriptive study including sixteen patients with acute brain injury (subarachnoid hemorrhage, severe head trauma, and hemorrhagic stroke) and continuous monitoring of icp who developed a severe ards during icu stay from january to december and for which pp was performed. pp sessions were analyzed. hemodynamic and respiratory parameters, blood oxygenation, pic and ppc were studied in supine, before pp and after pp. the study was approved by fics ethic comity. results a significant increase in pao /fio ratio was observed in pp, from ± to ± (p < . ). in pp, the icp was increased ± . - ± . mmhg (p < . ) while the cpp was stable ± versus ± mmhg (ns). median duration of pp session was h ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . increasing of icp during pp required medical treatment in sessions ( %). pp session was interrupted in sessions ( %). in subgroup of patients who respond to pp in terms of oxygenation, the increase of icp was lower than in non-responders ( vs %) (p < . ). cpp was not modified whatever the nature of the response to pp ( ± - ± in non-responders and from ± to ± in responders (ns)) (fig. ). discussion our study shows an improvement of oxygenation during pp in severe ards patient with acute brain injury. we observe a constant increment of pic during pp sessions. the increment of icp is less in responders to pp. significant increased icp requiring an enhancement in the medical treatment was observed in % of the cases, and lead in most cases to a discontinuation of the session. our data underlined the absolute necessity to monitor icp during pp session in patients with acute brain injury and ards, even if icp is controlled previously in supine. only prospective ( , ) and one retrospective studies evaluate the effects of pp on icp in patients with acute brain injury and acute respiratory failure (arf). they results are similar to ours. in all these studies, the severity of arf was often not well specified. roth and al. ( ) had included only % of ards in a population of patient with icp not controlled. in others studies, monitoring of icp during pp was not systematic. despite the retrospective nature of the study and the small number of patients, it is the only work studying the effects of pp on intracranial pressure in patients with acute brain injury at risk for intracranial hypertension and severe ards according to the berlin's definition. conclusion our work suggest that pp is a quite secure technique for use for the treatment of severe ards even patients at risk of intracranial hypertension with a benefit in terms of oxygenation without major increase of icp particularly in pp responders. introduction influenza-associated acute respiratory distress syndrome (ards) requiring extracorporeal membrane oxygenation (ecmo) support is known to have a good prognosis ( ). however, the incidence and impact of co-infection in this setting remain unknown. we conducted a retrospective, observational analysis of data prospectively collected from all patients admitted to our medical icu who received ecmo support for influenza-associated ards between and . co-infection was defined as isolation of a pathogen in the lower respiratory tract at a significant level or in the blood during the h following hospital admission. when no pathogen was identified in a patient receiving antibiotics prior to bacteriological sampling, an independent adjudication committee reviewed all charts to assess if the patient had a "high probability" or "low probability" for bacterial co-infection, based on clinical, radiological and biological results available. results are presented as median [iqr] . results among the patients hospitalized for an influenzaassociated infection in our icu, had an ards requiring support by either veno-venous-(vv, n = ), venoarterial (va, n = ) or venoarterio-venous-(vav; n = ) ecmo. - . ), pre-ecmo sofa score > (or . ; % ci . - . ) as independent predictors of hospital mortality, but not co-infection (or . , % ci . - . ). in a second analysis, patients with proven co-infection and high probability of co-infection were grouped and compared to patients with no co-infection and low probability of co-infection; and results were similar. as compared to others co-infected patients, those co-infected with a pvl-positive s. aureus had same characteristics and similar mortality rate, but all received a treatment active against pvl production. conclusion co-infection is frequent in patients with influenzaassociated ards supported by ecmo, occurring in roughly % of the cases. mortality of patients with co-infection is higher than those without, but seems mainly due to the severity of the disease. s. aureus was the most frequently identified pathogen, with a high prevalence of pvl-positive s. aureus, infection with a pvl-positive strain was not associated with a poorer outcome as compared to other co-infections. whether a treatment active against pvl production should be given in those patients remains to be determined. none. the pancreaticoduodenectomy (pd) is major surgery in visceral surgery. this technique performed for the first time in by whipple has seen much progress and development over the years that have enabled a significant reduction in mortality, while the morbidity remains high. the aim of this study was to analyze postoperative morbidity pancreaticoduodenectomies. we retrospectively studied cases of cephalic duodenopancreatectomy at the department of surgical emergencies resuscitation (wing ) spanning years, between january and december . the average age of patients was . years with % of females and % of males, the frequence of pancreatic resections was years. the indications of cephalic duodenopancreatectomy were: tumors of pancreatic head ( %), ampulla vater ( %), duodenum tumors ( %). the restoration of continuity after cephalic duodenopancreatectomy was realized with a rate of % for pancreaticogastrostomy and % for pancreaticojejunostomy. the average hospital stay was , days, with extreme lengths of - days. the postoperative course was marked by the occurrence of deaths ( %), the morbidity rate was , % after pj and % after pg; the most frequent complications were the pancreatic fistula ( %), the postoperative peritonitis ( %), the digestive bleeding ( %), the gastroparesis ( %). conclusion advances in the overall care of patients by surgical teams, anesthesiologists and intensivists, the dpc mortality is currently low in experienced centers. the multidisciplinary, involving surgeons, radiologists and especially intensive care, to manage more effectively the complications of this surgery remains burdened with high morbidity. introduction severe acute pancreatitis (sap) is a common but potentially lethal pathology due to the multiplicity and severity of complications that can occur at all stages of evolution. in the last decade, mini-invasive interventional treatments of infected pancreatic necrosis (ipn) have been developed. the aim of the present study was to assess the management and outcomes of sap patients, as well as to identify the role of ipn. this was a retrospective study of prospectively collected data from all consecutive patients admitted in intensive care unit (icu) in a single french center (hospital of nantes) from to . using logistic regression, we evaluated the association between ipn and patients characteristics at baseline and the outcomes. (fig. ) , highlighting the prognostic importance of respiratory failure and acute renal failure at the time of lt, as well as complex interactions between donor and recipient features. conclusion ventilator support and/or acute renal failure at the time of lt are major predictors of mortality but complex recipients/donors relationships may moderate these associations, as demonstrated by our cart analysis. none. subtotal gastrectomy ( / ). enlarged gastrectomy was performed in patients ( %). the mean operative time was . ± min. per-operative transfusion was required in patients ( . %). the average length of stay in icu was . ± days. postoperative mortality was . %. in our series, patients ( . %) had at least one postoperative complication: an anastomotic fistula diagnosed in patients ( . %), patients ( . %) had postoperative peritonitis and patients had ventilator associated pneumonia. reoperation was necessary for patients ( . %), it was performed after . days ( - days). in univariate analysis, risk factors for postoperative morbidity after gastrectomy was hypoalbuminemia (p = . ), anemia (p = . ), bmi (p = . ) and malnutrition (p = . ). age, sex, neoadjuvant chemotherapy, extended lymphadenectomy, splenectomy or pancreatosplenectomy, total gastrectomy and operative time were not significantly associated with higher postoperative morbidity. in multivariate analysis, malnutrition (p = . ) and bmi (p = . ) were significantly associated with the occurrence of postoperative complications. conclusion the results of our study are similar to those reported in medical literature. preoperative evaluation and nutritional rehabilitation are crucial to improve patient's outcome and reduce morbidity and mortality after gastrectomy for cancer. the mesenteric ischemia is a condition relatively rarely. it is marked by high mortality. mortality is primarily related to the land on which ischemia occurs and especially the time taken to diagnose. this delay is due to the low specificity of clinical signs and the absence of diagnostic laboratory test. the mesenteric ischemia remains a diagnostic and therapeutic challenge. patients and methods twenty cases of acute mesenteric ischemia have been collected at the surgical resuscitation (resuscitation ) at the hospital center ibn rochd of casablanca from january to december . results the mean age of our patients is year old. it is about a disease that the incidence increases these last years, particularly because of the waxing number of old patients and/or suffers from advanced cardiovascular diseases. the cardiovascular risk factor has been present in % of our patients. the abdominal pain has been present in all the patients. it is a sudden, intensive pain localized the most often at the level of the epigastria, becomes diffuse in few hours or even few days. other clinical signs have been described as the bilious vomiting that becomes fecaloid after few days. the digestive hemorrhages as the moelena and the hematemeses. a stop of the matter and the gazes was noticed in % of our patients. the absence of specificity of the clinical signs forced the realization of complementary examinations. the scanner becomes the reference imaging. it permits a differential diagnosis, the search of direct signs of vascular obstruction and the emphasis of intestinal pain. four etiologies are noticed: the arterial occlusion by emboli ( %), the arterial thrombosis ( %), the venous thrombosis ( %) and the "non occlusive" form ( %). the strategy of management of the acute mesenteric ischemia is multidisciplinary, based on the equips of radiology, vascular surgery and/ or visceral surgery and resuscitation. the treatment consists in measures of general resuscitation, the techniques of endoluminal vascular disobstruction and techniques of surgical revascularization. in spite of the improvements in the diagnosis and the therapeutic procedure of the ima, the disease still know a rate of mortality between and % according the studies. in our study, we noticed cases of death ( %), cases of good recovery ( %), cases are unknown evolution ( %). conclusion it is a vital emergency that the evolution still knows great mortality. it is very important to remind the acute mesenteric ischemia in the case of any acute abdominal symptom in order to anticipate about the natural evolution and to act in a reversible stage of the ischemia. none. introduction emergency departments staff are frequently exposed to many complex stressful situations and consequently burnout syndrome. our study aimed to describe epidemiological particularities and determine the risk factors of burnout syndrome in different categories of emergency. patients and methods we studied five academics and four regional hospitals. the level of burnout was assessed using the "maslach burn out inventory" score and the degree of depression with major depression inventory (mdi) test. results one hundred and forty-three correctly completed questionnaires were collected. the mean age of study population was ± years. sex-ratio was at . . fifty-one per cent of the care staff were married. physicians represented % and paramedical %. the general frequency of burnout syndrome was % (n = ). low level burnout was present in %, moderate level in % and high level in %. the depression frequency was %. a statistically significant correlation was found between burnout and depression firstly (p = . ) and between burnout and lack of equipment (p = . ). their relative risk was . [ . , ] and . [ . , . ] respectively). main risk factors associated with high level burnout are detailed in table . conclusion burnout syndrome frequency in our emergency departments is alarming. helping to resolve social and psychological problems and improving work conditions may help to decrease it. the healthcare activity is recognized as a major polluting activity. in france, it generates , tons of waste cremated each year, and represents % of the tertiary energy consumptions. in the united states, it generates tons of waste per day and % of total co emissions in were attributed to him. ultimately, such waste production is associated with adverse environmental and health effects. nevertheless, near half of the hospital waste would be recyclable, particularly in our intensive care units (icu) [ ] . furthermore, sustainable development solutions generate profits. the aim of this study is to make an overview of waste produced in a icu and offer solutions to conserve natural resources and reduce the carbon footprint bound to the healthcare activity. materials and methods experimental study, single-center, concerning a period of months in an icu-high surveillance unit compound of beds. we have identified all waste generated. our packaging were given to the recycling company in connection with the hospital. then we have studied the impact of the implementation of sustainable development solutions. results firstly, we have studied the non-recycled waste and the quantity produced over a period of month. approximately kg of waste is produced per patient per day with % of infectious waste and % of general waste. these results were linked with a bad distribution of garbage bags in the rooms ( l of infectious waste versus l of general waste). secondly, we have improved our way to sort and consume and we have created recycling dies without compromising patient safety. all these measures have not increased workload. changing bags in the rooms ( l of infectious waste and bags of l of general waste) allowed to reach the normal goals of sectors with a net benefit estimated at euros per year. the medical broken glass containing drugs was thrown into plastic containers of l for infectious waste to prevent the risk of cuts. by creating a specific die intended to the general waste, we could quantify the production of this glass to kg per week and to spare the use and the incineration of containers of l per year (global economy of euros). plastic packaging represented an important proportion of the cremated waste. we have created sectors of recycling including the polypropylene ( - kg per month), the polyethylene colorless and colored polyethylene. this plastic is sold to be recycled without additional cost for the hospital. the linerboards was cremated. we have created a recycling die ( kg per month). this sector was subsequently extended to the entire hospital structure, particularly the pharmacy that produces containers of l per month. they are now sold without additional cost. many unnecessary plastic waste is generated daily. we have removed using mild soap plastic bottles of ml by using the same mild soap in pump of ml (economy of euros). the use of l plastic bags for the transitional deposit of linen has been deleted (economy of euros). concerning the paper: % of the impressions were made in simplex. printers were parametrized on both sides by default allowing the economy of reams per year ( , sheets), several thousand liters of water and the reduction of co emissions. discussion recycling is only one component of the sustainable development in health. other avenues that could be considered to improve icu sustainability would include examining water use (for linen), electricity use (reducing non-essential use at night…). beyond these actions, we need to encourage our suppliers to turn to sustainable and recyclable packages to reduce the use of polluting and depletable fossil fuels such as oil. but also to develop with them circular economies where waste is returned to them to be reused. conclusion we must ask the question also resuscitate our tons of waste. our icu produce large quantities of waste (over tons per year per bed). however, a significant proportion, especially plastic, is recyclable with a significant environmental and financial benefit. waste management also requires an optimal and rational use of supplies because "the best waste is that which is not produced" and that excess is not a guarantee of quality. as already said st exupéry in : "we do not inherit the earth from our parents, we borrow it from our children. " so do not expect tomorrow to reduce major adverse ecological impact paradoxically generated by a great profession whose ultimate goal is to cure people. moreover, an external consultant is rarely applied and palliative cares are insufficiently developed after «non-readmission» decisions. for providing corrective measures, this study lead to propose a «nonreadmission» process by integrating the discussion for a real «patient's care project» at the end of the icu hospitalization. this process would lead to collect patient's opinion through advance directives, to ensure a collegial discussion including an external consultant and to allow reevaluation of global patient's clinical status and one or more organ failure(s). then, «non-readmission» decisions would be integrated in a therapeutic project which would promote the initiation of a palliative care program if necessary. the purpose of this process is well to respect patient's autonomy and dignity as required by french law and medical ethics. the proportion of elderly patients is steadily increasing. due to the growth of this part of the population who suffer from multiple pathologies, the need for hospitalization in intensive care increases. according to the simulations, the proportion of octogenarian patients in icu will increase reaching the third of icu patients. while chronological age is not a significant factor of poor prognosis in the icu ( ), many factors should be taken into account to evaluate the relevance of icu admission in the senior population and withholding such intensification should be consensually discussed between clinicians and obviously as often as possible with the patient himself ( ) . the aim of the study was to assess the role of stakeholders (ward physicians, intensivists, family doctor and patient himself ) in the decision of withholding icu admission for elderly patients in our internal medicine department. we made a prospective observational monocentric study, including all the elderly patients (defined as older than ) admitted in the internal medicine department from january to june . the only non-inclusion criterion was patient's refusal to participate to the survey. collected data involve physiological (cognitive, autonomy, nutritional status), morbidities (acute and chronic diseases) and social parameters (marital status, relatives). and evaluation of quality of life by the patient himself using an analog visual scale was also obtained. internal medicine physicians were asked to report any icu withholds decision for their patients. in absence of notification, every physician was questioned again the day of the concerned patient's discharge. results one hundred ninety-one patients were included between january and june . factors associated with a significant reduction of in hospital mortality were higher age (p = . ), higher lactate level (p = . ), chronic obstructive pulmonary disease (p = . ), diabetes mellitus (p = . ), immunodepression (p = . ) and respiratory failure (p = . ). conclusion in patients hospitalized for vs high body mass index, low left ventricular systolic function, high white blood cell count, low creatinine clearance, high lactate level and st-segment depression are the variables correlating significantly with high-sensitivity troponin-t concentrations. peak of hstnt was not significantly associated with in-hospital mortality in this setting. introduction mitochondria are evolutionary endosymbionts that are derived from ancestral aerobic bacteria and so might bear and release bacterial molecular motifs supporting the role of mitochondria in danger signal regulations. free circulating mitochondrial dna (mtdna) is elevated in a wild range of critical illness observed in intensive care units, and is associated with bad outcomes and mortality. the mtdna is a molecular pattern that belongs to mitochondrial damage associated molecular patterns (mtdamps), and can interact with pattern recognition receptors (prr) to induce self defense reaction. free mtdna activates inflammatory signaling pathways through toll-like endosomal receptor (tlr ) interactions. nevertheless, new evidence advocates a role of the receptor for advanced glycation end-products (rage) in mtdna signaling. experimental data suggest a role of mtdna-prr interaction in systemic inflammation and organ dysfunctions as septic acute kidney injury or pulmonary inflammation. impact of free circulating mtdna on endothelial cell is not known. the main purpose of this study was to test whether mtdamps and mtdna can induce endothelial dysfunction. we also evaluated the role of mtdna-rage axis in mtdamps induced endothelial dysfunction. mitochondria were isolated from livers of wild type c b mice. isolated mitochondria were sonicated on ice to obtain mtdamp preparations. semi quantitative evaluation of mtdamp content was tested by qpcr, with specific markers of mtdna (cytochrome b (cytb), nadph oxidase (nd )). intraperitoneal injection of mg of mtdamps was used as experimental model in wild type and rage ko mice, as previously described [ ] . the mtdamps were also administrated after ex vivo dnase preparation. endothelial function was assessed with a mulvany-halpern style myograph, h after mtdamp administrations on aorta (conductive vessel) and on d division of mesenteric artery (resistive vessel). endothelial-dependent relaxation was studied by cumulative expositions of the vessels to acetylcholine ( . - - . - m). endothelial-independent relaxation was studied by sodium nitroprussiate exposition. results the mtdamps preparation contains a high quantity of mtdna with a /cycle threshold (ct) ratio of . for cytb expression. intraperitoneal administrations of mtdamps induced a decrease of endothelial-dependent relaxation mainly on conductive vessel (p = . , n = per group) and to a lesser extent on resistive vessel (p = . , n = per group). rage-ko mice were protected from mtdamps-induced aorta dysfunction (p = . , n = per group). the ex vivo exposition of mtdamps to a dnase preparation decreased mtdna content in mtdamps solution with a /ct ratio of . for cytb expression. eventually, the pretreatment of mtdamps with a dnase preparation prevented the mtdamps-induced aorta dysfunction (p = . , n = ). discussion more than prognostic markers, mtdamps particularly mtdna seems implicated in endothelial dysfunction in critically ill patient. new evidence suggest rage interaction in endosomal tlr pro-inflammatory and pro-oxidant response to mtdna [ ] . also in sepsis, physiological clearance of circulating dna might be impaired, this results comfort the possibility of therapeutic regulation of free circulating mtdna to prevent septic organ dysfunction related to mtdamps accumulations. conclusion exogenous mtdamps can induce endothelial dysfunction in mice. the mtdna-rage axis is a key component of the signaling pathway involved in this dysfunction. the use of dynamic parameters to assess fluid responsiveness was supported by cyclic changes in stroke volume induced by mechanical ventilation. however, these parameters have several limits. venous to arterial carbon dioxide difference inversely related to cardiac index. consequently, fluid administration would be beneficial if carbon dioxide gap increases. objective to investigate whether carbon dioxide gap predicts fluid responsiveness in patients with acute circulatory failure. patients and methods we conducted a prospective study in the medical intensive care unit of hospital taher sfar at mahdia, between march and april . patients with circulatory failure and who required mechanical ventilation were included. we measured the variation of cardiac index between baseline and after volume expansion of ml of saline fluid. the picco was used to measure cardiac index. response to fluid challenge was defined as a % increase in cardiac index. before and after fluid administration, we recorded carbon dioxide difference and hemodynamic parameters. results among included patients, ( %) were responders. the causes of acute circulatory failure were septic shock (n = ), cardiogenic shock (n = ), and hypovolemia (n = ). carbone dioxide gap was significantly higher in responders group ( ± vs ± mmhg, p = . ). the area under the roc curve for carbon dioxide gap was . ( % ci . - . ). the best cutoff value was mmhg (sensibility = %, specificity = %, positive predictive value = % and negative predictive value = %). the area under the roc curve for delta carbon dioxide was . ( % ci . - . ). conclusion in this study, baseline carbon dioxide gap was not universal indicator to predict the fluid responsiveness in patient with circulatory failure. introduction supraventricular arrhythmia (sva) is commun in intensive care unit (icu). its incidence seems to be higher in patients with sepstic shock. sepsis-associated myocardial dysfunction promote the occurrence of sva by constituting an arrythmogenic substrate or under the effect of inotropic drugs. the aim of this study is to assess the incidence and prognostic impact of sva in patients with septic shock. patients and methods we retrospectively studied all patients with new onset sva suffering from septic shock in non cardiac surgical icu. myocardial dysfunction was evaluated by transthoracic echography (tte) after an adequate cardiac resuscitation using intravenous fluids expansion and adjunctive vasoactive agents. sva was detected by the electrocardiogram scope. during the study period clinical and biologic characteristics, hemodynamic tolerance (vasopressors doses, arterial pressure changes), current treatment (such as corticoid), duration of mechanical ventilation, duration of vasopressor requirement and hospital mortality were collected. results sixty patients were included in the study. the sva occurred in patients, with an incidence of %. the median time to onset was days. cardioversion was performed for patients with an effectiveness of %. clinical and biological characteristics were similar between the groups with and without sva: saps and sofa score at the beginning of septic shock, the existence of ards and cardiac biomarkers (nt-probnp, troponin). however, renal failure and the use of corticoid in septic shock were more frequent in the group with sva. the maximum doses of vasopressor agent were not significantly different between the groups with or without sva. myocardial dysfunction in sepsis defined by the left ventricle ejection fraction (lvef) less than % (or the need for inotropic drug for lvef > %) was not associated with the occurrence of sva (+sva group: n = ; −sva group: n = ; p: . ). sva was poorly-tolerated, observed by a significant decrease in mean arterial pressure and a significant increase in norepinephrine doses within h of the start of sva. the occurrence of sva was associated with longer duration of use of vasopressor agent and a longer duration stay in icu (+sva group: days, −sva group: days; p = . ). there was no difference in duration of mechanical ventilation and hospital mortality between the two groups. conclusion the occurrence of sva is common in septic shock, poorly tolerated hemodynamically and associated with longer duration stay in the icu and vasopressor need. sepsis myocardial dysfunction isn't necessarily associated to the occurrence of sva. introduction a short term beneficial effect of prone position on cardiac index has been shown in % of ards patients, and was related to an increase in cardiac preload in preload responsive patients ( ) . the aim of this study was to evaluate the long term hemodynamic response to prone position in a larger series of ards patients. patients and methods single center retrospective observational study performed on ards patients hospitalized in a medical icu between july and march . patients included were adults fulfilling the berlin definition for ards, undergoing at least one prone position session, under hemodynamic monitoring by the picco ® device, with availability of hemodynamic measurements performed before (t ), at the end (t ), and after the prone position session (t ). prone position sessions were excluded if they were performed > days after ards onset. the following variables were recorded: demographic, sapsii, ards severity and risk factor, sofa score and cumulative fluid balance at pp onset, delay between ards session and pp session, hemodynamic, arterial blood gas, ventilatory settings, plateau pressure, catecholamine dose and additional treatments. statistical analyses were performed using prone position session as statistical unit and mixed models taking into account both multiple prone position sessions by patient and multiple measurements during a prone position session. p < . was chosen for statistical significance. data are expressed as mean ± standard deviation. results patients fulfilled the inclusion criteria over the study period, totalizing prone position sessions ( ± sessions per patient). patients' age was ± y, % were male, % fulfilled the criteria for severe ards, and sapsii at icu admission was ± . ards risk factors were pneumonia in ( %), aspiration pneumonia in ( %), and sepsis in ( %) patients. duration of prone position sessions was ± h. hemodynamic measurements were performed in pp ± h after pp session onset. at session onset, sofa score was ± , and cumulated fluid balance was . ± . l. vasopressor were used in %, inhaled nitric oxide in %, and neuromuscular blocking agents in % of the sessions. hemodynamic and respiratory parameters before, during and after the prone position sessions are reported in table . cardiac index increased by at least %, decreased by at least % or remained stable in ( %), ( %), and ( %) of the sessions, respectively. as compared to both other groups, pp sessions with significant increase in cardiac index had the following significant differences at t by univariate analysis: lower cardiac index, lower global end-diastolic volume, lower cardiac function index, and lower vasopressor dose. multivariate analysis is under investigation. conclusion prone position is associated with an increase in global end-diastolic volume, reversible after return in supine position that may explain the positive effect of pp on cardiac index observed in ¼ of the pp sessions. introduction make sure that our patient have a good circulatory condition is a daily challenge for the intensivist. one of the therapeutics is fluid and one of his purpose is to increase venous return and then cardiac output. in order to examine that, there are several tools as the transthoracic echocardiogram wich allows the visualisation and the study of the respiratory variability from the inferior vena cava (ivc). unfortunately there are some situations where the ivc visualisation is difficult (obesity, gut surgery, emphysema). the ivc is easily seen by a transhepatic ultrasound in her retrohepatic section. we make the hypothesis that the shape of the ivc could be predictive of fluid responsiveness. we have performed fluid challenge in patients under mechanical ventilation. the need for fluid therapy is the intensivist in charge decision. we performed a echocardiogram and we take two measures of the icv: major axis and minor axis, the icv is measured avec the sus hepatic vena. a elastometry index (ei) is determined which is the ratio of minor axis to minor axis. the fluid challenge is ml of isotonic saline then we perform a new echocardiogram. a tag is written on the patient to take the same ultrasound slice. we retain one increase of % of the cardiac index (ic) as a success of the filling. we exclude the presenting patients a right cardiac insufficiency, an arrhythmia and/or a htap. the statistical analysis is realized with the software r. results between august, and january, we included patients. the average age is of years ( - ), igs of ( - ), ejectionnal fraction of % - ) and the s wave tricuspid is ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the causes of the filling were an oliguria ( %), a low blood pressure ( %), a low cardiac output ( %), a hyperlactatémia ( %) and an other cause in % of the cases. we find a positive correlation between the ei and the increase of the ic, also for the area of the vci and the respiratory variations of the vci (p . ) the other variables are not predictive (bp, e/e' , e/a). the data are summarized in the picture . roc curves has been established ( only % of the journals studied required authors to use stard. a high impact factor and the year of the study were the items associated with a better sqs the presence of a conflict of interest was associated with a lower sqs in univariate analysis. a higher impact factor (> ), was the only independent factors statistically significantly (p = . ) associated with higher sqs in a multivariate regression model. discussion our study showed that the sqs were very low. assessment of a study depends on quality of reporting. blindness and participant sampling are the cornerstone to evaluate such bias as spectrum, verification, review and selection bias of a study, and were unfortunately scarcely reported compared to existing data in diagnosis accuracy reporting. one of the limitation is the years sample of the study. we have planned to continue the analysis for a -year review starting just after the stard publication. conclusion our study showed that several items remain poorly reported. we recommend systematic use of stard criteria in the elaboration and reporting of future studies that evaluates the preload dependence. introduction neurological impairment, i.e. encephalopathy, is commonly observed in patients with decompensated cirrhosis and/or portosystemic shunts admitted in icu. often ascribed to high plasmatic levels of ammonia, encephalopathy could also be induced by drugs or infection, due to altered blood-brain barrier (bbb) permeability. this latter setting is often underdiagnosed and encephalopathy related to hyperammonemia (so called hepatic encephalopathy-he) being pointed out as the culpit of all neurological symptoms in cirrhotic patients. quinolones and betalactamins were recently found in the cerebrospinal fluid of he patients and it has been shown that the expression of efflux pumps, responsible for drugs passing through the bbb, was altered in animal models of he. the purpose of this study was to assess the incidence of neurological impairment, i.e. encephalopathy, in cirrhotic patients hospitalized in discussion overall, we reported a higher rate of lumbar puncture than those reporting in others studies concerning status epilepticus. furthermore the rate of % of pleocytosis directly linked to status epilepticus is slightly higher than in most studies. unfortunately we didn't realize a second lumbar puncture to assess the pleocytosis normalization during the days following the first lumbar puncture. the pathophysiological hypothesis of this phenomenon may be that prolonged/repeated seizures during status epilepticus would induce a blood-brain barrier dysfunction thereby favoring a cerebrospinal pleocytosis. conclusion in our study, % of status epilepticus without infectious or neoplastic origin had a cerebrospinal pleocytosis directly linked to status epilepticus. this pleocytosis was significantly associated with myoclonic seizures and blood leukocytosis. these data may help to interpretation of cerebrospinal fluid pleocytosis during status epilepticus. introduction neurological prognostication from cardiac arrest survivor is a current concern. eeg patterns and nse dosage are two important prognostic factors. nse threshold for prediction of poor outcome appear controversial, in part, because of variability in dosage timing and measurement techniques. synek score is routinely used in our center to classify comatose patients in post cardiac arrest. the aim of this study was to assess the prognostic value of nse and synek classification to predict poor neurological outcome. introduction traumatic brain injury (tbi) is a major public health problem. it is the leading cause of death and disability in young subjects. one of the principles of the tbi management is prevention of secondary cerebral insults including maintaining perfusion and cerebral oxygenation, control of intracranial pressure (icp). an increase in icp above mmhg is associated with poor outcome. cerebral hypoxia can occur with normal level of icp and cerebral perfusion pressure (cpp).monitoring of regional partial pressure of brain tissue oxygen (pbto ) is a safe and reliable method for measuring cerebral oxygenation. a retrospective single-center observational study was conducted between january and december , aimed to study the influence of pbto with severe tbi patients outcome at months through glasgow outcome scale (gos). the hourly values of icp, pbto and cpp were recovered on daily monitoring sheets. we compared two groups according to their gos. during the study period, patients underwent a monitoring icp and pbto . results the mean age was . ± . years. . % were men. the initial glasgow score was . ± . . the mean simplified acute physiology score (saps ii) was . ± . and injury severity score (iss) . ± . . at months, patients had died (gos ). forty patients had a good outcome: gos - (group ). sixteen patients had poor outcome: gos - (group ). in group , there are significantly more pbto hourly values below mmhg at day ( . ± . vs . ± , in group , p = . ); and more pbto hourly values greater than mmhg at day ( . ± . vs . ± . , p = . ). conclusion pbto less than mmhg or greater than mmhg at day is associated with poor outcome at months in the severe tbi. the pbto allows a more individual approach of monitored tbi. none. introduction organ donation in patients after a decision to withdraw life-supportive therapies (wlst) (maastricht condition: m ) have been performed in our hospital since may . we report here main characteristics of donors, data on m procedure and results on renal transplant recipients. patients and methods all potential donors were included in a survey from may to june , according to the french national m protocol defined by the french organ procurement agency (agence de la biomédecine:abm) [ ] .the demographical, clinical and biological characteristics of the donors, the different deadlines and times of the protocol and data of renal transplantation were collected and analyzed. results patients had inclusion criteria. patients were admitted in intensive care unit for cardiac arrest ( %), strokes ( %), traumatic brain injury ( %), ards ( %). of them, procedures ( %) were stopped ( refusals of organ donation, medical contra-indications discovered with additional exams, failure of vessel cannulation, deaths more than h after extubation). kidneys were harvested and transplantations performed ( renal cancer discovered during procurement surgery).the characteristics of the donors, deadlines of the protocol and transplant recipients are reported in the table . conclusion the french programm maastricht offered a new possibility of organ donation in our hospital. thanks to these donors, the number of renal grafts increases and the preliminary results on transplant recipients are encouraging in line with the preliminary report of the abm. nevertheless, it is necessary to follow the transplant recipients and extend the procedure to new centres. in this study, we found some relevant risk factors for microaspiration (age, low score at gcs) consistent with literature on the subject. patients with paralytic agents had less gam which may be due to higher peep, higher cuff pressure and less enteral nutrition because of the severity of the underlying diseases. conclusion this study did not show any increased risk of microaspiration in intubated copd patients, whatever stage of copd. introduction protected specimen brush (psb) is considered to be one of the standard methods for the diagnosis of ventilator-associated pneumonia (vap). to our knowledge, there is no study assessing effect of prior antibiotherapy on direct examination, bacteriological culture and concordance of direct microscopy and culture. patients and methods all consecutive episodes of suspected vap were retrospectively evaluated between january and december in a -bed intensive care unit. patient's characteristics and preexisting conditions were abstracted from the medical charts. after assessment of vap probability using the clinical pulmonary infection score (cpis), psb were performed in patients with a cpis of or more. based on antibiotic treatment in patients when bacteriological specimens were obtained, two groups were defined: no antibiotic group and antibiotic treatment started before psb group. two independent bacteriologists retrospectively reviewed direct examination and culture of psb to assess bacteriological concordance, defined as non-concordant when direct examination and culture were different, concordant when direct examination and culture were similar and partially concordant when either direct examination or culture were comparable but with other microorganisms lacking in one or the other method. results during this -months period, among mechanically ventilated patients, episodes of suspected vap with psb were evaluated. we found % of psb (n = ) performed without antibiotic treatment and % of psb (n = ) performed under antibiotherapy. we found no significant differences in patient's demographics, characteristics, and severity between both groups. patients received antibiotics for the following reasons: aspiration pneumonia (n = ), peritonitis (n = ), vap (n = ), community-acquired pneumonia (n = ), septic shock of unknown origin (n = ), pyelonephritis (n = ), meningitis (n = ), acute pancreatitis (n = ) and others (n = ). the median duration of mechanical ventilation in the antibiotic receiving group and in the group without antibiotics was . days (iqr; - days) and days (iqr: - ), respectively. when psb was performed under antibiotic treatment, direct examination was positive in % (n = ), culture was positive in % (n = ) and those methods were concordant, non concordant and partially concordant in % (n = ), % (n = ) and % (n = ), respectively. on the other hand, when psb was performed without antibiotics, direct examination was positive in % (n = ), culture was positive in % (n = ) and those methods were concordant, non concordant and partially concordant in % (n = ), % (n = ) and % (n = ), respectively. in univariate analysis, we found a significantly higher proportion of negative direct examination and negative culture in the antibiotic group (p > . ). moreover, these methods were significantly more frequently concordant (p = . ), with a higher rate of both negative microscopic exam and culture when compared to the no antibiotic group ( %, n = vs %, n = ). surprisingly, among the patients previously treated with antibiotics with positive culture, % (n = ) of the microorganisms showed antibiotics sensitivity. discussion whether prior antibiotic treatment may induce false negative of false positive treatment is a well-recognized phenomenon, the precise effect of antibiotics on direct examination and quantitative culture is not well assessed in vap. moreover, despite recent development of clinico-radiological score, diagnosis of vap remains difficult, with no gold-standard. therefore, bacteriological guided therapy is of particular importance. we found psb realization under antibiotic treatment is associated with a lower rate of positive direct examination and culture and suggest performing these bacteriological samples without antibiotherapy. some authors have suggested lowering the diagnostic threshold point of this bacteriological technique in order to preserve its accuracy. however, we can postulate that microorganisms responsible of superinfection in mechanically ventilated patients treated with antibiotics may be resistant and therefore the psb could be positive. conclusion in patients with a high pre-test probability of ventilatoracquired pneumonia, recent introduction of antibiotics significantly reduced the diagnostic accuracy of protected brush specimen by reducing rates of positive direct examination and culture. further studies should evaluate if antibiotic discontinuation may revert this effect. ann. intensive care , (suppl ): we have had non conflict of interest in this study. results we included patients in the phase and patients in the phase . baseline characteristics of patients were similar in both groups. compliance with all the measures has been improved between the two period from to . %. the incidence density decreased from . to . vap per ventilator days between observational and interventional period, but the all-cause mortality was almost equal in the groups ( . vs. %). discussion with the implementation of our bundle, observance of the team were improved in the second group, compared to the first and the incidence density decreased from . to . vap per ventilator days between both period. this result is consistent with the littérature. sure enough, many studies show the same effect of vap prevention with a decrease of nearly % of the incidence density of vap, after implementation of a «ventilator -bundle [ ] . conclusion the implementation of a "ventilator bundle, " has significantly reduced the incidence of vap in our service. in the contrary, our study failed to demonstrate a reduction in mortality. introduction with an increasing incidence and high mortality rates, sepsis is a public health issue. there is growing evidence that sepsis induces long lasting alterations of transcriptional programs through epigenetic mechanisms that may lead to protracted inflammation, organ failure, sepsis-induced immune suppression (siis), secondary infections and death. we hypothesized that epigenetic changes contribute to the pathophysiology of siis. to test this hypothesis, we studied the effects of histone deacetylases (hdac) inhibition with trichostatin a (tsa) in a double-hit murine model of siis and secondary pneumonia. materials and methods c bl/ mice were treated with tsa ( mg/ kg ip) or saline serum (ctl) min before induction of sepsis by cecal ligation and puncture (clp). surviving mice underwent intratracheal instillation of . × cfu of pseudomonas aeruginosa days after clp. we evaluated the effect of tsa on survival and cellular responses to the primary and secondary infections. cellular responses in the blood, spleen and bal were assessed by flow cytometry after clp (days , & ) and after pneumonia ( & h). we also studied lymphocyte apoptosis and dendritic cells (dc) expression of cd , cd , and mhcii. bacterial clearance was assessed in the bal and in the blood and h after pneumonia. continuous variables represented as mean ± sd were compared using student t test. kaplan-meier curves were compared by the log rank test. p < . indicated statistically significant differences. results whereas treatment with tsa did not change survival after clp, tsa improved survival after tracheal instillation of p. aeruginosa (p = . , fig. ). tsa-treated mice had significantly higher absolute dc, t and b-lymphocytes counts with reduced lymphocyte apoptosis after clp. four hours after secondary pneumonia, tsa-treated mice had significantly higher dc counts and improved bacterial clearance in the bal, with reduced systemic dissemination of p. aeruginosa. conclusion hdac inhibition with tsa improves survival in our murine model of secondary pneumonia, improves bacterial clearance and attenuate cellular features of siis. these results suggest that sepsisinduced epigenetic changes contribute to the advent of siis. comprehensive characterization of epigenetic changes associated with siis might allow us to identify new therapeutic targets to reprogram immune cells in sepsis and avoid siis. length of icu stay was ± days. patients acquired nis ( . % bsi, . % pneumonia, . % cri and . % uti. there was no bacteriological documentation of ni in . % of cases. nis occured days post burns. the most three isolated pathogens were: acinetobacter spp. ( %), p. aeruginosa ( . %) and extended spectrum betalactamase-producing enterobacteriaceae ( %). the most frequently administered antibiotics were polymyxin/carbapenem/teicoplanin combination ( %), polymyxin/carbapenem combination ( %) and carbapenem/tigecycline combination ( %). in our study, mortality rate was %. conclusion nosocomial infection occured in . % of cases in burn patients, caused by acinetobacter spp, p. aeruginosa and enterobacteriaceae blse. so, eradication of infection in burn patients require effective surveillance and infection control in order to reduce mortality rates, length of hospitalization and associated costs. introduction infection of the lower respiratory tract is the most common cause of infection in intensive care unit (icu) ( ) . although the attributable mortality of ventilator associated pneumonia remains debated, the recurrence of these infections is always associated with a significant morbidity ( ) . staphylococcus aureus methicillin-sensitive (sams) is one of the most frequently germs involved in icu pneumonia especially in trauma patients. the aim of the study was to establish the risk factors associated with microbiological treatment failure of pneumonia, caused by sams. materials and methods we retrospectively identified patients who developed a first episode of ventilator associated pneumonia caused by sams during a years-period ( - ). the primary end point was the microbiological treatment failure defined as a second episode of pneumonia caused by sams corresponding to either a persistent or a recurrence of the pneumonia (fig. ) . the primary aim of the study was to identify factors associated with a treatment failure, the secondary objective was to identify factors associated with the occurrence of second episode (i.e. persistent, recurrence, superinfection and/or relapse of pneumonia caused by any bacteria) during or after treatment of the first episode caused by sams. definition of outcomes was based after analysis of current concepts available in the literature. factors associated with primary and secondary objectives in univariate analysis (p-value < . ), or clinically relevant ones, were entered in a multivariate logistic regression. the final selection was performed using the stepwise selection based on the akaike criterion. results fifty-nine patients ( . %) developed a second episode of pneumonia and among them, ( . %) were considered as a microbiological failure. in a multivariate analysis, the association of oropharyngeal flora (fop) with the sams (or, . ; % ci, . - . ; p = . ) and the need of emergency surgery (or, . ; % ci, . - . ; p = . ) were predictive of a microbiological failure. empirical antibiotic therapy with amoxicillin-clavulanic acid (or, . ; % ci, . - . ; p = . ) and performing emergency surgery (or, . ; % ci, . - . ; p = . ) were predictors of a second episode of pneumonia caused by any bacteria. conclusion in this retrospective, monocentric study, the co presence of orophryngeal flora and the need of emergency surgery were associated with microbiological failure of pneumonia caused by sams in icu. introduction ventilator-associated pneumonia is a major iatrogenic problem since it is a cause of hospital morbidity, mortality and increase of health care costs. it has been studied many times, but data's revision is always necessary. our study aimed to describe epidemiology of ventilator-associated pneumonia and identify local causative pathogens. we carried out a prospective study in an intensive care unit. were included patients intubated for more than h, from april to may , and presenting signs of ventilator-associated pneumonia (fever, abundant and purulent secretion, increase of fio greater than . , signs on chest-x ray) with positive culture of endotracheal aspirate. were excluded patients with germ colonization. results a total of patients were ventilated for more than h. among them thirty-four patients aged of ± . years presented episodes of ventilator-associated pneumonia (that is . ± . episodes per patient). the mean sofa score was . ± . . the main reasons of mechanical ventilation were loss of consciousness secondary to poisoning ( %), respiratory distress ( %) and status epilepticus ( %). the mean duration of stay was . days with extremes at and days. the average time between hospitalization and suspicion of ventilator-associated pneumonia was . ± . days. the average value of the clinical pulmonary infection score at suspicion was ± . . the average time between recurrences was . days with extremes at and days. the culture of endotracheal aspirate identified two pathogens in %. it reveled acinetobacter baumanii in % in which % were imipenem resistant, pseudomonas aeroginosa in %, klebsielle pneumoniae in %, staphylococcus fig. see text for description aureus methicillin resistant in %. extended spectrum β-lactamases bacteria were found in % and carbapenemases producers in %. empirical antibiotherapy was always association of imipenem and colistin. it was necessary to adapt it to antibiograms in / . ventilator-associated pneumonia was complicated by septic shock in % and acute respiratory distress syndrome in %. patients evolved to healing in % of episodes (n = ), to superinfection in % (n = ) and to death in % (n = ). pseudomonas aeruginosa was the most frequent germ in superinfection ( / ) , acinétobacter baumanii was the most pathogen associated to death ( / ). conclusion ventilator-associated pneumonia is an iatrogenic disease that threatens lives. it's in part avoidable. preventive measures have to be implemented to reduce its frequency, consequences and costs. introduction during mechanical ventilation, mismatch between respiratory muscles activity and the assistance delivered by the ventilator results in dyspnea and asynchrony and is commonly observed in intensive care unit (icu) patients. proportional assisted ventilation (pav) is a ventilatory mode that adjusts the level of ventilator assistance to the activity of respiratory muscles estimated by an algorithm. to date, pav has been mostly studied in patients without severe dyspnea or asynchrony. we hypothesized that, compared to pressure support ventilation (psv), pav will prevent severe dyspnea or asynchrony. patients and methods were included icu mechanically ventilated patient exhibiting severe dyspnea or asynchrony with psv. three conditions were successively studied: ) psv on inclusion (baseline), ) psv after optimisation of ventilator settings in order to minimize dyspnoea and asynchrony (optimisation), and ) pav. ten-minutes recording were performed with each condition. the intensity of dyspnea was assessed by the visual analogic state (vas, only in patients able to communicate) and by the intensive care respiratory distress operating scale (ic-rdos) for all the patients. the electrical activity (emg) of extradiaphragmatic inspiratory muscles was measured. the fig. bayesian nma with random effect prevalence of asynchrony was quantified by the visual inspection of the airway flow and pressure traces. results patients were included, % male, aged [ - ] years, saps [ - ], mechanically ventilated for [ ] [ ] [ ] [ ] [ ] [ ] days. the tidal volume (tv) was higher in the optimisation and pav than in the basal condition (table ). the respiratory rate(rr) was lower with pav than in the other conditions. the dyspnea-vas was lower with optimisation and pav than with the basal conditions. the ic-rdos was lower with pav than with the two other conditions. the asynchrony index was lower with pav than with the two other conditions. parasternal emg activity was lower with pav and optimisation (fig. ) . conclusion in icu patients receiving mechanical ventilation with psv and exhibiting severe dyspnea or asynchrony, the optimisation of ventilator settings with psv and the pav mode decrease in the simiar way the severity of dyspnea and the prevalence of patient-ventilator asynchrony. introduction in spite of recent research and progress in weaning protocols, extubation failure still occurs in - % of patients and is associated with poor outcomes, with a mortality rate of - %. many risk factors for planned extubation failure have been suggested, including hypercapnia at end of spontaneous breathing trial (sbt). however, performing arterial blood gases at the end of sbt is not routinely recommended whereas etco may be routinely monitored during a low pressure support sbt. the aim of this prospective observational study was to determine the clinical usefulness of etco to predict extubation failure. patients and methods we recorded clinical data and etco during a successful h low level pressure support sbt (at the beginning, after min and at the end of the trial). patients ventilated through tracheostomy and unplanned extubations were excluded. extubation failure was defined as death or the need for reintubation within h ( ) after extubation; this delay was prolonged to days ( ) in case of noninvasive ventilation after extubation, which was systematic in older patients or those with cardiorespiratory disease, as per our weaning protocol. multivariable logistic regression analysis was performed to identify independent variables associated with extubation failure. results one hundred and fifteen ventilated patients were enrolled in our study from july to june . the median age of these patients was [ - ] years, their median simplified acute physiology score (saps) ii was [ - ] points and . % (n = ) were female. seventeen ( %) patients had chronic obstructive pulmonary disease. reintubation rate was % (n = ). etco at other time points as well as its changes during the sbt were also similar between groups. the three variables predicting extubation failure in the multivariable logistic regression model were a past medical history of cirrhosis, acute respiratory distress syndrome before weaning and lower minute ventilation at the end of sbt. conclusion etco during a successful sbt seems useless to predict outcome of extubation. introduction airway management in intensive care unit (icu) patients is challenging [ ] . "airway failure", defined as the inability to breathe without endotracheal tube, differs from "weaning failure", defined as the inability to breathe without an invasive mechanical ventilation. however, most of the studies assessing predictive factors of extubation failure did not separate airway from weaning failure. we aimed to describe incidence of extubation failure in critically ill patients, separating for the first time airway from weaning failure, in a prospective multicenter observational study. patients and methods a prospective, observational, multicenter study was conducted in french icus. all adult patients consecutively extubated in icu were included. an ethics committee approved the study design (code uf: , register: -a - ). the study was registered on clinicaltrials.gov (identifier no.nct ). clinical parameters were prospectively assessed before, during and after extubation procedure. extubation failure was defined as the need to reintubate less than h after extubation. extubation failure could be due to airway failure, weaning failure or mixed airway and weaning failure. results from december to may , intubation-procedures were studied in patients from centers. patients ( . %) were intubated twice. the median number of intubation-procedures included by center was . the flow chart of the study is shown in fig. . incidence of extubation failure was . % ( of intubation-procedures). incidence of airway failure, weaning failure and mixed failure were respectively . % ( of ), . % ( of ) and . % ( of ). conclusion extubation failure at h occurred in . % of the extubation procedures recorded, % due to airway failure, % to weaning failure and % to mixed airway and weaning failure. specific risk factors will be determined using this multicenter database. introduction acute on chronic liver failure (aclf) have been recently defined by an acute decompensation of a chronic liver disease associated to organ failure and a high mortality rate. few authors reported on the use of total plasma exchange (tpe) in patients with the current definition of aclf. the aim of this pilot study was to evaluate the efficiency and safety of tpe in critically ill cirrhotic patients admitted with aclf in the icu. patients and methods a prospective cohort of cirrhotic patients admitted to the icu between february and february . tpe was performed using a plasma filter (tpe , hospal ® ) on a cvvhdf machine (prismaflex ® , baxter ® ) connected to the patient with a femoral double lumen f catheter. the plasma volume exchanged per session was . - . of the total plasma volume. ratio and type of fluid replacement were % with % albumin solution followed by % with fresh frozen plasma. clinical and biological parameters, and the following scores meld, sofa, clif-sofa, clif-of and child pugh were evaluated prior, after tpe session and days distant of treatment. results seven male patients with a mean age of . ± . years comprised the study and had a total of tpe sessions. the etiology of cirrhosis was alcoholic (n = ) or post-hcv (n = ). the reasons of aclf were acute alcoholic hepatitis (n = ), variceal bleeding (n = ) and sepsis (n = ). prior to tpe, the mean scores of sofa, clif-sofa, clif-of, meld and child-pugh were respectively . , , . , . and c . . mean total bilirubin prior and after tpe sessions was reduced from . ± . µmol/l to . ± . µmol/l (reduction of . %; p = . e− ); at day , mean total bilirubin was still lower at ± µmol/l (p = . ). mean inr prior and after tpe improved from . ± . to . ± . (reduction of inr of . %, p = . e− ) and at day of treatment at ± . (reduction of %, p = . ). mean ggt levels reduced by . % (p = . ). mean platelet counts ( . ± . g/l) reduced by . % (p = ns). the probability of survival at , and days was . , . and . %. one patient was transplanted and still alive. tolerance during sessions was good similar to cvvhdf. two side effects related to the femoral catheter were observed (bacteremia and hemorrhagic shock post catheter ablation). conclusion this preliminary study of tpe in aclf showed a marked reduction of liver enzymes and improvement in coagulation parameters with a relative good safety. a specific caution should be undertaken regarding catheter related complications. tpe worth to be fig. flow chart of the free-rea study introduction extubation is a key moment for the patient on his way to recovery. extubation failure concerns - % of icu patients and is closely linked to nosocomial pneumonia. the practice concerning enteral feeding interruption at time of extubation has not been investigated. fasting before extubation may prevent aspiration and development of nosocomial pneumonia. thus, fasting and gastric content suctioning before extubation may be reasonably considered as a mean to reduce this burden. fasting before extubation may prevent aspiration and development of nosocomial pneumonia. thus, fasting and gastric content suctioning before extubation may be reasonably considered as a mean to reduce this burden. however, fasting, as recommended before elective general anesthesia is likely to be ineffective in the setting of extubation in the icu, due to patients' gastroparesis and prolonged gastric stasis. beyond the potentially unnecessary burden in terms of paramedical workload, fasting may have some side effects such as caloric deficit, hypoglycemia, or delayed extubation. given the current lack of objective data concerning the clinical practice of feeding/fasting and gastric tube suctioning before extubation in the icu, we undertook this descriptive study to assess current practice. materials and methods we conducted a retrospective, multicenter study in eleven intensive care units in the west of france over a month timespan. all patients extubated were included and data about enteral feeding during the peri-extubation period as well as extubation failure and nosocomial that pneumonia occured within days were recorded. data observed in the eleven participating centers were completed with a short email survey concerning declarative practice performed among intensive care units. results during the study period, patients were included. overall, patients ( %) failed extubation and needed reintubation within the days following planned extubation. pneumonia was significantly more frequent reintubated patients than the other ( vs. %, p < . ). hundred patients ( %) received enteral feeding at the time of extubation. compared to patients who did not receive enteral feeding, those patients had a higher disease severity (sapsii score , [ ; ] vs. [ ; ], p < . ; longer duration of mechanical ventilation [ ; ] vs. . [ ; ] days, p < . ). accordingly, those patients had a higher rate of extubation failure ( vs. %, p = . ) and pneumonia ( vs. %, p = . ). among the patients receiving enteral feeding, fasting was implemented before extubation for patients ( %). similarly, the incidence of pneumonia was not different between groups (n = ( %) vs. n = ( %), p = . ). after extubation, the fasting patients experienced a longer delay until feeding resumption as compared to non-fasting patients ( h [ ; ] vs. [ ; ] ), but this difference did not reach statistical significance. overall gastric content suctioning before extubation was not commonly performed; before extubation: % of the fasting patients and % of the non fasting patients. among the participating centers, while some centers imposed a fasting period before extubation to all their patients, some did it infrequently. however, no center never imposed fasting, illustrating between and within center heterogeneity. this heterogeneity was confirmed on the larger scale declarative email survey ( % response rate amont units) which showed that only % of the units had a written standardized operational procedure for extubation. survey respondents reported to practice fasting before extubation "always", "frequently" and "never or rarely" in respectively , and % of cases. conclusion both practices, fasting as well as pursued nutrition until extubation are commonly performed in icus, with little standardization of practice. safety seems equivalent, as no clinically significant difference in terms of reintubation rate and pneumonia were observed. thus, the equipoise condition appears met to undertake a trial evaluating feeding strategies in the peri-extubation period. introduction noninvasive ventilation (niv) has become a cornerstone for the supportive therapy of acute respiratory failure (arf). survival benefits in chronic obstructive pulmonary disease (copd) and cardiac patients have been demonstrated. although arf and copd patients are at risk of malnutrition that adversely affects patient outcomes, few data are available regarding the management of nutritional support in non-invasively ventilated patients. we sought to describe nutritional management in patients receiving niv as the first line therapy for arf. secondary objectives were to assess the impact of early nutrition use on the need for invasive mechanical ventilation, occurrence of icuacquired pneumonia, length of stay, and death. patients and methods we conducted an observational study from the multicenter french database fed by french icus. our institutional review board approved this study. adult medical patients admitted to the icu and receiving niv for more than days were included. exclusion criteria were patients admitted after surgery, readmitted in icu, patients with neuromuscular disease and treatment-limitation decisions on admission. four groups of patients were defined according to nutrition received during the first days of niv: ( ) no nutrition; ( ) enteral nutrition: patients who received enteral nutrition with or without parenteral nutrition; ( ) parenteral nutrition only ( ) oral nutrition only. the impact of nutrition on day- mortality was assessed through the use of a cox model adjusted on clinically relevant covariates. the impact of nutrition on other secondary end-point i.e. icu-acquired pneumonia occurrence, need for invasive mechanical ventilation were assessed using a fine & gray models. patients were censored after days of follow-up. choice among collinear variables was performed considering clinical relevance, rate of missing variables and reproducibility of definitions. results were given as hazard ratio (hr) for cox models and subdistribution hazard ratios (shr) and % confidence intervals (ci). the impact on duration of stay was estimated by a multivariate poisson regression. p values less than . were considered as significant. statistical analysis was performed using sas . (cary, nc). results during the study period, , patients were included in the database and met inclusion criteria. among them, received no nutrition; received enteral nutrition, received parenteral nutrition only, and received oral nutrition only. overall, patients developed icu-acquired pneumonia ( %), required invasive mechanical ventilation ( . %) and died before day- ( %). median length of stay was days [ ; ]. after adjustment for confounders, type of nutrition support was associated with an increase day- mortality (p = . ). compared to oral nutrition, enteral nutrition was associated with an increase day- mortality [shr . , % ci . - . ; p = . ] whereas parenteral nutrition and no nutrition did not influence this outcome. the type of nutrition was not associated with the occurrence of icu-acquired pneumonia (p = . ). however, patients who received enteral nutrition experienced more frequently icu-acquired pneumonia [shr = . , % ci . - . ; p = . ] as compared to oral nutrition patients. ventilator free days within the days were negatively associated with the type of nutrition (p < . ). compared to oral nutrition, parenteral and enteral nutrition were negatively associated with ventilator free days within the days [rr per day = . , % ci . - . ; p < . and rr per day = . , % ci . - . ; p < . ]. delta paco measured between the first days was not associated with any type of nutrition. conclusion more than half the patients receiving niv were fasting within the first two niv days. oral nutrition was prescribed for onethird of them and was well tolerated. lack of feeding or underfeeding had no impact on mortality and ventilator free days within the days. however, enteral nutrition was associated with an increased occurrence of icu-aquired pneumonia and a higher mortality rate. was high, caloric debt during temporary ecls was low in comparison with previous results [ ] . overnutrition was frequent in the nec group and would justify implementation of nutrition protocol. incidence of gi intolerance remains frequent and could justify systematic used of motility agents with introduction of en. conclusion enteral nutrition in patients treated with temporary extracorporeal life support is feasible and may be improve with systematic motility agents and implementation of nutritional protocol. introduction cardiac surgery with cardiopulmonary bypass (cpb) is associated with a generalized inflammatory response with concomitant immune paresis which predisposes to the development of postoperative infections and sepsis ( ) . lymphocytes are essential agents of innate and adaptive immune responses during infections or inflammation processes. lymphopenia has been associated with immune dysfunction during septic shock, and it has been shown that low absolute lymphocyte count was predictive of postoperative sepsis ( ) . furthermore, impaired lymphocyte function probably occurs after cpb. thus, we investigated mechanisms involved in postoperative lymphopenia and impaired lymphocyte function after cpb. the aims of this study were: ) to describe a potential relationship between lymphopenia and occurrence of postoperative infections. ) to demonstrate that cpb induces lymphocytes apoptosis. ) to demonstrate that cpb impaired lymphocyte function (ability to proliferate). ) to demonstrate that il- , pd-l (programmed cell death ligand ) and indoleamine , -dioxygenase (ido) could be interesting targets to restore lymphocyte ability to proliferate after cpb. patients and methods blood cell counts with differentials obtained within the first postoperative week were analyzed in patients undergoing cardiac surgery in . postoperative lymphopenia was defined as a lymphocyte count < . × cells l − . postoperative infections were defined following cdc criteria. study procedures: the following analysis were performed before (t ) and h after (t ) cardiac surgery with cpb: lymphocyte apoptosis; t-cell proliferation ability following polyclonal stimulation; hla-dr and pd-l expression on monocytes; plasma ido activity and il- levels; and the ability of lymphocytes to undergo a clonal proliferation when stimulated using specific inhibitors of il- and ido. the study was approved by our local ethics committee. patients were informed of the observational nature of the study and gave their consent. . early lymphopenia after cpb was associated with the occurrence of postoperative infection: postoperative infections occured with a median delay of days. patients who developed postoperative infections had a significantly lower lymphocyte count at day , day and day than patients without postoperative infections. . cpb induced lymphocyte apoptosis and decreased t-cell proliferation ability. . cpb during cardiac surgery decreased mhla-dr expression. . cpb increased ido activity, pd-l expression and il- plasma levels. . il- or pd-l inhibition of inhibition could restore ability of lymphocytes to proliferate, although ido inhibitors did not show any effect. we provided new evidences that cpb induces immunosuppression. we also demonstrated that il- and pd-l could be interesting targets to restore ability of lymphocytes to proliferate. as maintaining mv during cpb decreased plasmatic levels of il- , our study brings new evidences that ventilator strategies could be of interest to decrease postoperative infections. respectively . % (n = ), . % (n = ) and . % (n = ) of the included patients. mortality was of . % in the overall population (n = ) and was higher in neutropenic patients ( . vs. . % in non-neutropenic patients; p < . ). neutropenia was independently associated with poor outcome when adjusted for underlying malignancy, allogeneic stem cell transplantation and severity as assessed by organ support (or . ; % ci . - . ). mortality decreased progressively over time in both non-neutropenic (from to %; p < . ) and in neutropenic patients (from to %; p < . ). when adjusted for confounders, admission during a more recent period was independently associated with favourable outcome and did not change the final model. conclusion this preliminary analysis suggests a meaningful survival in neutropenic critically ill cancer patients despite an independent association between neutropenia and mortality. additional analyses are on-going in order to adjust for study weight, heterogeneity across studies, assess the influence of neutropenia duration or g-csf use, and confirm the influence of neutropenia in a predefined subgroup of patients. introduction candida bloodstream infections (cbi) are frequent and increasing in hospitalized patients, especially in intensive care units. considering the results of some experimental in vitro and animal studies, it seems that yeasts belonging to candida genus are able, so as to survive, to modulate the immune response of the host by guiding t cells polarization to th profile. th and th cytokines are known to be involved in host defense against cbi. however, these data are mainly experimental or collected after candidemia. the aim of this study is to precise kinetic of cytokines network during human cbi. this was an ancillary study of an institutional project dedicated to pathophysiology of candidiasis. we have included patients with candidemia and controls ( matched hospitalized controls and healthy subjects). the sera of cases were gathered before (almost days before), during and after the isolation of yeasts from blood culture, defined as day (d ). quantitative analysis of cytokines by luminex ® technology and of ( , )-β-d-glucans by fungitell ® test were performed on samples. the amplitude of th profile response was expressed by summing the amount of the most relevant cytokines for th , th and th profiles, in pg/ ml. for each patient, the highest level of response was considered as %. results are expressed for the population by means of the results. we then performed univariate analysis (fischer exact test for qualitative variables, mann-whitney and wilcoxon test for quantitative variables, spearman for correlation; graphpad prism v software) and a multidimensional analysis by principal component analysis (pca; igorpro software). results patients with candidemia exhibited an increase in proinflammatory cytokines (ifnγ, tnfα and il- ), in comparison with the anti-inflammatory cytokines (il- and il- ) before d (p = . ) in univariate analysis. the ratio between mean values reverses at d and d (p = . ) and the increase of th response level from d to d is correlated to the decrease of th response (r = − . ; p = . ) in univariate analysis and pca. a pro-inflammatory response (th ) is associated with a reduced mortality (rr = . [ . ; . ]) and with a lower β-d-glucans levels (p < . ). discussion we describe here a dynamic cytokine profiles in response to candidemia. pro-inflammatory response predominates before d and reverses after. this is contradictory to the postulate that an antiinflammatory background could predispose to invasive candidiasis in icu patients and exhibiting a "post-infectious immune suppression conditions". but the relative deficiency in th response compared to simultaneous anti-inflammatory cytokines secretion observed after cbi is in accordance with experimental data, suggesting the modulation of the immune response by candida. the link between cytokinic profile and mortality can also raise the hypothesis of an influence by genetic factors on the regulation and direction of the immune response and so, the existence of a high-risk population. conclusion these data suggest a relation between candida and the orientation of the immune response towards a pattern deleterious for the infected host. this could allow to determine the most relevant cytokines varying during cbi. they could be used as biomarkers to identify the patients who could benefit from an early treatment in a preemptive targeted therapeutic strategy. these data will be paralleled to genetic background and to circulating candida derived molecules to precise the relative part of the host and the pathogen in this complex interaction. introduction lung ultrasound is widely used in intensive care, ermergency and pneumology medicine, for assessing acute respiratory pathologies. it is noninvasive, radiation free and rapidly available at the patient's bedside and provides an excellent accuracy. so, lung ultrasound may be an interesting tool for the physiotherapist as it allows to assess with more accuracy the patient improving the chest physiotherapy indication and monitoring ( ) . as far as we are aware, no study has evaluated the impact of lung ultrasound on clinical-decision making by physiotherapists in the use of chest physiotherapy. this case report highlights the lung ultrasound interest in chest physiotherapy in patient with lung consolidation. patients and methods this was a case report written following the recommendations of the care guideline ( ). the case was a -years-old female patient, non intubated, hospitalized in a respiratory icu. she was hypoxemic (pao = mmhg and sao = %), with dyspnoea at rest and an increasing radiological opacity at the right lung base. hypoxemia was the indication for physiotherapist referral. at the clinical examination, the physiotherapist's findings were: decreased mobility, dullness and abolished vesicular sound at the base of right hemithorax. this clinical examination and chest x-rays analysis allowed the physiotherapist to propose several clinical hypotheses: pleural effusion, obstructive atelectasis or pneumonia. the chest physiotherapy treatment differs according to the type of lung deficiencies. for example, the physiotherapist must to refer the patient to the medical staff in case of pleural effusion or may implement hyperinflation technique in case of obstructive atelectasis. determining the nature of lung deficiencies is essential to provide the more suitable therapeutic strategy. so, the physiotherapist decided to perform a lung ultrasound examination to retain the more likely hypothesis. results ultrasound examination performed by the physiotherapist highlighted the presence of a lung consolidation at the infero-lateral and posterior parts of the right lung with a pneumonia pattern: presence of tissue-like sign, shred sign, dynamic air bronchogram and fluid bronchogram. the medical staff implemented antibiotic treatment. the ultrasound findings guided the physiotherapist to choose chest physiotherapy technique improving the alveolar recruitment: nearly prone position (left side down) and continuous positive airway pressure during min. the patient response to the treatment was monitored by ultrasound and showed a decrease of the lung consolidation size and apparition of b lines, meaning a gain of lung aeration. these findings were associated with spo improvement but without decrease of dyspnoea. discussion lung ultrasound allowed the physiotherapist to precise the nature of the radiological lung opacity. as it is more accurate than clinical examination or chest x-ray, this suggests a more suitable choice of chest physiotherapy techniques than conventional clinical decision-making process. ultrasound findings suggested a positive response to the chest physiotherapy treatment. the apparition of re-aeration signs (b lines, decreased consolidation size) showed a short-term efficacy of the chest physiotherapy treatment. this allowed the physiotherapist to continue the treatment during week and obtain a substantial clinical improvement. conclusion the use of lung ultrasound in the clinical decision-making process may help the physiotherapist to choose with more accuracy the therapeutic strategy. moreover, it allows to monitor the treatment in real-time and assess the patient's response. the use of this tool may allow the physiotherapist to determine the optimal indications for chest physiotherapy and thus avoid unnecessary or inappropriate treatments. introduction critical illness together with immobilization have deleterious effects on patients outcome, especially in the presence of sepsis. increased muscle catabolism and membrane inexcitability reduce muscular mass and impair function within the first days after sepsis onset ( ). early mobilization could potentially limit muscle wasting and functional impairment in this population. the purpose of this study was to test whether exercise during the early phase of sepsis is safe and beneficial and to which extent it can limit skeletal muscle protein catabolism and preserve function. patients and methods adult patients admitted with the diagnosis of severe sepsis were included and randomly allocated to two groups; ) control group (ctrl-g): manual passive/active manual mobilization twice a day or ) experimental group (exp-g): additional two times min of passive/active cycling exercise. both groups benefited from a reduced sedation, adjusted nutritional intake and bed to chair transfer as soon as possible. skeletal muscle biopsy and electrophysiological testing were realized at day- and day- . muscle histology, biochemical and molecular analyses of anabolic/catabolic and inflammatory signalling pathways were performed. a group of four healthy subjects was used to obtain non pathological values. hemodynamic parameters and patients perception were collected during each session. results twenty-one patients were included, however died before the second muscle biopsy. ten patients in ctrl-g and nine in exp-g were finally analysed. muscle fibre cross sectional area (µm ) was significantly preserved by exercise (relative changes were ctrl-g: − ± % vs exp-g: ± %, p = . ). markers of catabolic systems were highly increased during sepsis compared to healthy subjects and reduced in both groups days after admission. however the reduction in mrna (relative change) tended to be more important in exp-g: murf- (ctrl-g: − ± % vs exp-g: − ± %, p = . ), mafbx (ctrl-g: − ± % vs exp-g: − ± %, p = . ), lc b (ctrl-g: ± % vs exp-g: − ± %, p = . ) and bnip (ctrl-g: ± % vs exp-g: − ± %, p = . ). anabolic and inflammatory markers were not affected by exercise. electrophysiological testing, including direct muscular stimulation, was abnormal on day- in of evaluated patients. since only a limited number of patients could be reassessed a second time, comparison between groups was not possible. in general, all activities were well tolerated by patients with no adverse events. the pulmonary auscultation is used by respiratory therapist (rt) to evaluate the efficiency of a treatment. listen to the noises coming from the primary bronchi (pb) is important because it is the place where secretions can be accumulated. therefore, it is crucial to know exactly where to place the stethoscope's chestpiece on the chest. few studies have analyzed the chest area where the pb were located. our hypothesis is that pb are localized on a line that joins axillary fossa (bi-axillary line: bal). the aim of our study is to evaluate the probability to find the primary bronchi by analysis of chest radiography. patients and methods a retrospective study was performed by analysis of chest x-ray using the software: tm reception ® , which allows precise measures to the tenth of millimeter. all the x-rays were made on confined to bed patients hospitalized within intensive care unit, internal medicine and abdominal surgery rooms. the following measures (in mm) were made between: the exclusion criteria were: bmi < . kg/m and bmi > kg/m , scoliosis, minor patient, lack of visibility of one of the axillary fossa, lack of visibility of pb, clavicular asymmetry, kyphosis, lack of symmetry in the shot, atelectasis and pneumothorax. statistics: normality test: ks. mean values are expressed with their sd and % ci. discussion in this study, we performed analysis of chest x-rays of bedridden patients and we demonstrated that it is possible to localize easily, on either side of the bs, the right and left pb at ± mm distance (lp) above a line joining axillary fossa. this study constitutes a new tool for the rt who, by using stethoscope with a chestpiece of cm surface area, will be able to listen to noise coming from pb. conclusion the data presented herein (fig. ) show that right and left pb are located at a mean distance of (± ) mm and (± ) mm above the bal, on both sides of the bs. the bal represents thus an easy and precise mode to detect right and left pb by bedridden. finally, the distance between the hyoid bone and the sc is about cm. as the pb are located after the bifurcation, this information constitutes another useful way for the localization the right and left pb by bedridden patient. introduction critically ill patients frequently develop muscle weakness, which is associated with prolonged intensive care unit and hospital stay ( ). this randomized controlled trial (clinical trials nct ) was designed to investigate whether a daily training session using a tilt table, started early in stable critically ill patients with an expected prolonged icu stay, could improve strength at icu and hospital discharge compared to a standard physiotherapy program. the study protocol was approved by an ethics committee and informed consent was obtained from all patients. patients admitted in adult icu of marie lannelongue hospital, france, who were mechanically ventilated for at least days were included. exclusion criteria were cerebral or spinal injury, pelvic or lower limb fracture. patients were assessed each day for temporary contraindications for mobilization out of bed (rass score <− or > ; hemodynamic instability; a continuous intravenous dose of epinephrine/ . no significant difference was observed in terms of mrc score or in terms of pts with or without weakness (mrc > ) at icu or hospital discharge. however, the number of pts with weakness was significantly higher in the group before tilt mobilization, suggesting a more rapid improvement in the tilt group. the icu and hospital lengths of stay were not different between groups. discussion the prevalence of muscle weakness in our population is high before mobilization ( . %, % ci . - . ), is still . % at icu discharge but represents only ~ % at hospital discharge. this low hospital discharge prevalence is probably related to the early and intense physiotherapy in both groups, which may explain our inability to demonstrate superiority of the addition of tilt table positioning, although a faster recovery is suggested. conclusion training sessions using a tilt table, in addition to early and intense physiotherapy did not improve muscle strength evaluated using mrc score in surgical icu patients with muscle 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coordination prélèvements organes s reference . conditions à respecter pour réaliser des prélèvements d'organes sur les donneurs décédés après arrêt circulatoire de la catégorie iii de maastricht dans un établissement de santé. agence de la biomédecine. version n° mai crcl by cockroft-gault, mean (ml/mn delayed graft function, n (%) ( . %) réanimation médico-chirurgicale infectious diseases society of america. guidelines for the management of adults with hospital acquired, ventilator-associated, and healthcare-associated pneumonia reducing ventilator-associated pneumonia in intensive care: impact of implementing a care bundle chiche@aphp.fr annals of intensive care national nosocomial infections surveillance system. national nosocomial infections surveillance (nnis) system report, data summary from critères d'infection chez les brulés unité d'épidémiologie et recherche clinique international study of the prevalence and outcomes of infection in intensive care units risk and prognostic factors of ventilator-associated pneumonia in trauma patients ventilator-associated pneumonia: never enough, never give up! sahar habacha , bassem chatbri , aymen m'rad , youssef blel , nozha brahmi sahar habacha -sahar.habacha@gmail.com annals of intensive care weaning patients from the ventilator automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children: a cochrane systematic review and meta-analysis unité de réanimation et de surveillance continue, service de pneumologie et réanimation médicale noninvasive ventilation and weaning in patients with chronic hypercapnic respiratory failure: a randomized multicenter trial risk factors for extubation failure in patients following a successful spontaneous breathing trial s a multicenter prospective observational study of extubation procedures in intensive care units: the free-rea study audrey de jong -audreydejong@hotmail.fr annals of intensive care early identification of patients at risk for difficult intubation in the intensive care unit: development and validation of the macocha score in a multicenter cohort study faouzi saliba -faouzi.saliba@pbr.aphp.fr annals of intensive care réanimation médicale polyvalente, hôpital de la source mickael landais -mickaelandais@gmail.com annals of intensive care perioperative fasting in adults and children: guidelines from the european society of anaesthesiology the decision to extubate in the intensive care unit service de réanimation médicale s refeeding hypophosphoremia in a medical critical care unit: -month observational study gioia gastaldi -gioia.gastaldi@chu-rouen.fr annals of intensive care refeeding hypophosphatemia in critically ill patients in an intensive care unit. a prospective study refeeding syndrome: problems with definition and management biosit and inserm u , faculte de medecine, université rennes immune dysfunction after cardiac surgery with cardiopulmonary bypass: beneficial effects of maintaining mechanical ventilation s influence of neutropenia on mortality of critically ill cancer patients: results of a systematic review on individual data quentin georges brazil; department of critical care medicine and division of pulmonary and critical care medicine united kingdom; department of intensive care centre d'infection et d'immunité de lille equipe -basic and clinical immunity of parasitic di delta nlr") were calculated. statistical analysis used appropriate non parametric tests and cox regression for survival analysis. the ability of the variables to discriminate survivors from non-survivors was determined using roc curves results during the study period, cirrhotic patients were admitted in icu. the etiologies of liver cirrhosis were alcoholic in % of cases with severe score: median child-pugh score = %) deaths after icu discharge during the same hospitalization. nlr decreased for survivors between d and d univariate analysis, for predicting survival, higher values of nlrd , delta nlr, meld score at admission, sofa score at admission and at day and delta sofad -d were significant factors. predictors of death in multivariate analysis are shown in fig. . area under delta nlr roc conclusion the blood nlr is a novel inflammation index that has been shown to independently predict poor clinical outcomes. we have demonstrated that delta nlr is an independent predictor of mortality in critically ill cirrhotic patients the association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study gene-and exon-expression profiling reveals an extensive lps-induced response in immune cells in patients with cirrhosis celine dupre -duprecece@gmail.com annals of intensive care diagnostic accuracy of procalcitonin in critically ill immunocompromised patients the role of pattern-recognition receptors in innate immunity: update on toll-like receptors esm- is a novel human endothelial cell specific molecule expressed in lung and regulated by cytokines thoracic ultrasound: potential new tool for physiotherapists in respiratory management. a narrative review the care guidelines: consensus-based clinical case reporting guideline development department of physical medicine and rehabilitation icu-acquired weakness and recovery from critical illness o where should we place the stethoscope's chestpiece to hear the noise of the primary bronchi? frédéric duprez , bastien dupuis , grégory cuvelier , thierry bonus frédéric duprez -dtamedical@hotmail.com annals of intensive care o aerosol delivery using two nebulizers through high flow nasal cannula: a randomized cross-over spect-ct study correspondence: jonathan dugernier -jonathan.dugernier@uclouvain.be annals of intensive care introduction in , an international consensus conference took stock of the various measures to be implemented for the prevention of ventilator acquired pneumonia (vap) [ ]. these measures are often gathered in groups of or under the term of "ventilator-bundle. " the effectiveness of these "bundles" was poorly evaluated in african environment. objective to establish a vap prevention program and assess its impact on morbidity and mortality of patients under mechanical ventilation in our service. patients and methods prospective, mono centric, quasi-experimental before-after study. it took place in the intensive care unit of the university clinics of kinshasa in the democratic republic of congo (drc). this service is equipped with beds and a respirator for two beds. the observational period (phase ) was carried out from february st to december st, and the intervention period (phase ) from february st, to february st, . all consecutive patients intubated and mechanically ventilated for more than h were included. five preventive measures were held: hand hygiene, the elevation of the head of the bed at °- °, the daily lifting of sedation, oral decontamination with chlorhexidine and control cuff pressure of the endotracheal tube. compliance with this bundle was assessed by direct observation without the knowledge of caregivers. the diagnosis of "vap" was held before a clinically modified sore (m cpis) > . the main outcomes were the incidence of vap and mortality. the protocol for this study was approved by the ethics committee of the school of public health of the university of kinshasa, under the approval number: esp/ec/ / .introduction nosocomial infections (ni) are common in burn patients due to the loss of the first line of defense against microbial invasion, immunocompromising effects of burn injury, and invasive diagnostic and therapeutic procedures. the objective of this study was to identify the incidence of nosocomial infection (ni), the pathogens and their antibacterial patterns, and prognosis of these burn patients. patients and methods a retrospective study was conducted in a bed intensive burn care unit during months. patients were eligible for the study, if they met the following criteria: total burn surface area (tbsa) > %, length of icu stay ≥ h, and infected in accordance with the criteria of the national nosocomial infections surveillance (nnis) and the criteria of the sfetb [ ][ ]. in this study, nis were classified into four main groups: pneumonias, bloodstream infections (bsi), catheter related infections (cri), and urinary tract infections (uti). for included patients, skin levy, blood cultures, urine and sputum cultures were drawn during fever or clinical features of sepsis. results during the -month study period, patients were admitted to the icu, patients were included ( . %). were male and female. the mean age was ± yr. the mean tbsa was ± %. % were admitted from another hospital. burn injuries were due to domestic accidents in % and self immolation in %. the mean none. none. none. none. none. none. none. none. none. none. ann. intensive care , (suppl ): none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. consulting activities with fisher & paykel. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. none. failure extubation in intensive care unit: risk factors, incidence and evaluation of a mechanical ventilator weaning protocol lucie petitdemange , anne sophie guilbert none. none. none. none. none. none. opportunistic infections in patients with solid tumors: a systematic review julien poujade , elie azoulay none. invasive aspergillosis in non-immunocompromised patients hospitalized intensive care unit guillaume trumpff , max guillot , thierry braun , ralf janssen-langenstein , marie-line harlay , jean-etienne herbrecht introduction characteristics and outcomes of adult patients with invasive aspergillosis in intensive care unit have rarely been described. we performed a retrospective study on consecutive adult patients with invasive aspergillosis who were admitted form january through january to the intensive none. noorah zaid , nawel ait-ammar , christine bonnal , jean-claude merle , francoise botterel , eric levesque anesthesia and intensive care medicine, chu henri mondor, créteil, france; unité de parasitologie-mycologie, département de virologie, bactériologie-hygiène, parasitologie, hopital henri mondor, créteil, france correspondence: eric levesque -eric.levesque@aphp.fr annals of intensive care , (suppl ):s introduction liver transplant recipients have high rate of invasive fungal disease (ifd) with high morbidity and mortality, in part due to its delayed diagnosis. the fungal cell wall component ( , )-betad-glucan (bg) is a biomarker for fungal infection but its utility remains uncertain. this prospective study was designed to review our experience in ifd and to evaluate the impact of bg in the diagnosis of ifd. patients and methods from january to may , liver transplantation were performed in our institution. serum samples were tested for bg (fungitell; cape cod inc., usa) least weekly between liver transplantation and their discharge from hospital. ifd was defined as proposed by the european organization for research and treatment of cancer/mycoses study group. results nineteen patients ( %) were diagnosed with ifd including cases of candidiasis infection (ci) in eleven out of patients, invasive pulmonary aspergillosis (including one who had previously ci) and one case of septic arthritis of the hip caused by scedosporium spp. ifd was associated with significantly high mortality (log-rank p = . ). the area under the roc curves, for bg to predict ifd, was . ( % ci . - . ). using a cutoff of pg/ml, the most discriminative cut-off point from the roc curve, the sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) values of bg for overall ifd was % ( % ci, - ), % ( % ci, - ), % ( % ci, - ) and % ( % ci, - ). conclusion based on its high npv, bg value appears to be a good biomarker to rule out the diagnosis of ifd when the value is below pg/ml. a single point bg may guide the investigation and the decision to start antifungal therapy in patients at risk for ifd. none. monitoring of changes in lung and chest wall mechanics in the supine, lateral and prone positions during the prone positioning maneuver in ards patients zakaria riad , mehdi mezidi , hodane yonis , mylène aublanc, , sophie perinel-ragey, , floriane lissonde , aurore louf-durier, , romain tapponnier , jean-christophe richard , bruno louis, , claude guérin , plug working group réanimation médicale, hôpital de la croix-rousse, lyon, france; inserm, u , equipe , équipe biomécanique cellulaire et respiratoire, université paris-est créteil -faculté de médecine, créteil, france correspondence: zakaria riad -zakaria.riad@icloud.com annals of intensive care , (suppl ):s none. introduction systemic rheumatic diseases (srd) are autoimmune diseases that are rare but cause substantial morbidity and mortality. srds chiefly affect the lungs, however, data on critically ill patients with srd admitted for arf are scarce. patients and methods retrospective cohort conducted in french icus ( . the major comorbidities were cardiovascular ( %), tobacco exposure ( %), chronic kidney disease ( %) and neoplasia ( %). two-thirds of patients were on systemic corticosteroids at admission, the median dose of (iqr) mg per day. srd diagnosis was made in the icu in . % of patients. clinically or microbiologically documented bacterial pneumonia was the leading arf etiology ( . %). in % of cases, arf was related to an opportunistic infection (mainly aspergillus (n = ) and pneumocystis (n = )). others arf etiologies included specific lung involvement ( . %) and cardiac pulmonary edema ( . %). sofa on day one was [ ] [ ] [ ] [ ] [ ] [ ] [ ] . associated organ dysfunctions were mainly hemodynamic ( %) and renal ( %). mechanical ventilation was needed in % of patients (non invasive only in . % or invasive in . %), % needed vasopressors, and % renal replacement therapy. systemic corticosteroids were started in % of patients and % of patients received pulse steroids. cyclophosphamide and plasma exchange were required in and % of patients, respectively. length of icu stay was [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] days. icu-acquired infection occurs in % of cases. in total, patients ( . %) died throughout the icu stay. arf etiology was not associated with mortality. by multivariate analysis, shock on admission (or . [ . - . ], p < . ) and the use of invasive mechanical ventilation (or . [ . - . ], p = . ) were independently associated with mortality, whereas non-invasive ventilation was associated with decreased mortality (or . [ . - . ], p = . ). by considering among the connective tissue diseases, the groups of myositis and scleroderma (n = ), these diseases were associated with a trend for a higher mortality (or . [ . - . ], p = . ). conclusion in patients with srd, arf is associated with a high case fatality, primarily when mechanical ventilation is needed. particular attention must be given to specific srd-sub groups for which pulmonary flare may require intensive immunosuppression. none. none. none. severe acute pancreatitis in icu: management and outcomes of infected pancreatic necrosis charlotte garret , matthieu peron , emmanuel coron , cédric bretonnière , jean reignier , christophe guitton réanimation médicale, chu hôtel-dieu nantes, nantes, france; the acute pancreatitis appears as a pathology that we can define with difficulty because of its clinical presentation or prognosis. patients and methods in our study, we analysed cases of acute necrotic and hemorrhagic acute pancreatitis, hospitalized at the department of resuscitation of the surgical emergencies (p ) of the uhc ibn rochd casablanca during the period ( ) ( ) ( ) ( ) ( ) ( ) ( ) . the purpose of this study is to do a descriptive analysis of the epidemiologic, clinic, radiological, therapeutic and evolutive data of the acute necrotic pancreatitits, we included in our study patients with epidemiologic, clinic, radiologic, biologic criteria of acute necrotic pancreatitits diagnosis whatever is the biliary or alcoholic etiology. the valuation gravity of the pancreatitis has been based on:• ranson bioclinical score > /apache ii > ; • visceral failure.• spreading of the necrosis. the analysis of the results shows that: about the epidemiologic aspect: mean age ( year old), the biliary etiology predominates ( %). about the clinical aspect: pain ( %) vomiting ( %), stop of the transit ( %), the visceral distresses are: the shock ( %), respiratory distress ( %), and neurological distress ( %). about the radiological aspect: pleural effusion ( %), abdominal echography: vesicular lithiasis ( %), dilated principal biliary duct ( %), abdominal computerized tomography: stage e ( %). about the biological aspect: hyperglycemia ( %), hyper-amylasemia ( %). the indexes of gravity that have been appreciated in this study are: ranson score > ( %), imrie score > ( %), igs score ≥ ( %), osf score ≥ ( %). the treatment of the anhp has been symptomatic in particular and the evolution has been characterized by mortality about %, the cause was particularly infectious. the prognostic factors predetermined in this study are:• female type (p = . ).• hemodynamic distress (p = . ).• respiratory distress (p = . ).• scores of gravity:• ranson > (p = . ).• imrie > (p = . ).• osf ≥ (p = ).• infection (p = . ).• duration of the hospitalization (p = . ).• rate of c-reagent protein (p = . ). in conclusion, the mortality is still high in the anhp, considerable effort of search is necessary to prevent the infectious complications of mortality. none. predicting -day mortality following liver transplantation in patients with acute-on-chronic liver failure: a decision-tree model from the french national liver transplantation system, the optimatch study, - none. none. none. none. none. none. the french law and recent expert opinions have emphasized the need for a multidisciplinary approach in decisions to forgo life sustaining therapies for the critically ill. we sought to assess how icu nurses actually rank their involvement and perceive this process. materials and methods we conducted a cross sectional survey using a web-based questionnaire between june and september . results of the icus invited to participate, ( %) agreed. a total of icu participants completed the survey of whom % were nurses and % assistant nurses. median age was (inter quartile range - ) years and % were female. median work experience was ( - ) years and time in the icu was ( - ) years. eighty-five percent of the participants have been involved at least once in a multidisciplinary end-of-life discussion. less than half of the participants reported a good ( %) or partial ( %) knowledge of the current end-of-life legal framework. the decision to start a discussion about withdraw life-sustaining therapy (wlst) was initiated by a senior intensivist in % of the cases, by a nurse in % and an assistant nurse in . %. this decision was approved by % of the participants. the decision-making process was considered to be initiated at the right time for % of the participants, too late for %, and too early for %. the discussion occurred mostly in the afternoon ( %) or during the medical staff ( %), in a dedicated place in % of the cases. a median of ( - ) health-care professionals attended the wlst discussion. half the respondents reported being reluctant to talk during the discussions and % never expressed their own opinion. indeed, although the length of the discussion was ( - ) minutes, participants estimated to talk during only ( - ) minutes. the following reasons were mentioned by the participants to explain these facts: having cared for the patient for too short time ( %), lack of medical knowledge ( %), decision of wlst already taken by the medical staff ( %), their opinion not really taken into account ( %), reluctant to talk during meetings in general ( %), consider that the discussion is limited to a medical expertise ( %), limited professional experience ( %), and fear to express a different opinion ( %). nevertheless, % of the participants were partially ( %) or totally ( %) satisfied by the way the decision making process was conducted, % considered that collegiality was applied, and % agreed with the final decisions.conclusion icu nurses rank favorably multidisciplinary wlst discussions. nevertheless their involvement in the discussion remains limited. beyond factors related to work organization and professional experience, efforts should be made to recognize their role and value, and to encourage them to share their own opinions with the other members of the icu team. none. determinants and prognosis of elevation of high-sensitivity cardiac troponin t in patients hospitalized with vasodilatatory shock marie caujolle , jérôme allyn , dorothée valance , caroline brulliard , none. free plasmatic mitochondrial dna-receptor for advanced glycation end-products: a new signaling pathway of critical illness-induced endothelial dysfunction arthur durand , rémi nevière , florian delguste , eric boulanger, none. quality of reporting of fluid responsiveness evaluation studies: a five year systematic review izaute guillame , matthias jacquet-lagrèze , jean-luc fellahi none. none. none. none. none. introduction microaspiration of gastric and oropharyngeal contaminated secretions occurs frequently in intubated critically-ill patients, and plays a major role in the pathogenesis of ventilator-associated pneumonia (vap). at basic state, patients with chronic obstructive pulmonary disease (copd) have an increased risk of microaspiration (due to gastro-esophageal reflux disease, pharyngo-laryngeal dys-function…), this risk may even be more important under mechanical ventilation. the main purpose of this study is to determine if copd is a risk factor for global abundant microaspiration (gam) in intubated critically-ill patients. we gathered data about two prospective multicentric randomized trials focused on microaspiration in intubated patients. data about copd were retrospectively collected in order to complete previous data. microaspiration of gastric and oropharyngeal secretions was respectively determined by quantitative measurements of pepsin and salivary amylase in all tracheal aspirates during the first h after intubation. gam was defined as the presence at significant level of pepsin (> ng/ml) and/or salivary amylase (> ui/l) in at least % of the tracheal aspirates. in order to find gam independent risk factors, we realized an univariate and multivariate analysis of the variables collected. results out of patients included in the studies, were analyzed among which patients with copd. patients ( %) had gam. neither copd diagnosis, nor spirometric severity nor specific therapeutics were associated with gam. risk factors for gam in univariate analysis were the age, diabetes, low score in glasgow coma scale (gcs), and no recourse to paralytic agents or vasopressors. after none. none. implementation and impact assessment of a "ventilator-bundle" at the university clinics of kinshasa: before and after study josé mavinga , joseph nsiala makunza , m e mafuta , yves yanga , amisi eric , jp ilunga , ma kilembe none. none. amel mokline , achraf laajili , helmi amri , imene rahmani , nidhal mensi , lazheri gharsallah , sofiene tlaili , bahija gasri , rym hammouda , amen allah messadi burn care department, trauma and burn center, tunis, tunisia correspondence: amel mokline -dr.amelmokline@gmail.com annals of intensive care , (suppl ):s none. none. none. introduction mechanical ventilation (mv) weaning is a crucial step in critically ill patients. mv duration is associated with an increased risk of ventilator associated events, even though its specific impact on mortality has never been clearly demonstrated ( ). automated closed loop systems might help the weaning process. a recently published meta-analysis has reported a reduction in mv duration when using an automated weaning mode as compared to non-automated mode ( ) . however, the different automated modes have not been compared to each other. the objective of this network meta-analysis was to compare the performance of the three major automated weaning modes, i.e. the automode°, the smartcare° and the adaptative support ventilation (asv°) for mv weaning in critically ill and postoperative adult patients. we included all randomised control trials that compared automated closed loop weaning applications either to another automated application or standard care, including weaning according to a written weaning protocol or nurse driven protocols. the three modes of automated modes included in the study were asv°, smartcare° and automode°. the primary outcome was the duration of mv weaning, defined as the time between randomization and a successful extubation. we also planned subgroup analyses in the icu and the post-operative populations. the quality of the studies was assessed independently by two blinded investigators, using the evaluation recommended by the cochrane collaboration. a network bayesian meta-analysis using random effect models and based on aggregate data from the included studies was performed using the gemtc package (r project, vienna). this trial was declared in pros-pero in august (crd ). results search of databased identified articles; were screened for eligibility after removal of duplicates. abstract analysis led to the exclusion of articles with a final full text analysis of randomised control trials. ultimately, trials were included in the analysis, representing ventilated patients. nine studies included patients in the post-operative period while six were conducted in icu. the automated mode was asv° (a) in studies, smartcare° (c) in studies and auto-mode° (b) in studies. all studies reported the duration of mv weaning as defined in our protocol. in all studies, the control group was standard care with a weaning process driven either by nurses or physicians. in studies ( %) a written weaning protocol was used in the control group. all icu studies used sedation protocols based on sedation scores, none of them including systematic daily sedation interruption. each one of the automated application was associated with a significant reduction in the duration of mv as compared to the control. when comparing all different modes using the network meta-analysis framework, asv° appeared to be the best automated mode when it pertains to reducing the duration of mechanical ventilation weaning (fig. ) . subgroup analysis showed similar results in the post-operative and the icu populations. conclusion compared to standard weaning practice, the major automated weaning modes significantly reduced the duration of mv weaning in critically ill and post-operative adult patients. asv° was associated with the most significant effect when compared to the two other automated modes (smartcare°, automode°). further physiological respiratory studies would help to understand the underlying mechanisms accounting for the superiority of asv. none. none. introduction in intensive care unit (icu) patients, diaphragm dysfunction is associated with adverse clinical outcomes. ultrasound measurements of diaphragm thickness (tdi), excursion (exdi) and thickening fraction (tfdi) have been proposed as estimators of diaphragm function, but have never been compared to phrenic nerve stimulation. our aim was to describe the relationship between tdi, exdi, tfdi and diaphragm function evaluated using the change in endotracheal pressure after phrenic nerve stimulation (ptr,stim), and to compare their prognostic value. patients and methods ptr,stim and ultrasound variables were measured in mechanically ventilated (mv) patients < h after intubation ("initiation of mv", under assist-control ventilation, acv) and at the time of switch to pressure-support ventilation ("switch to psv"). diaphragm dysfunction was defined as ptr,stim < cmh o. results patients were included. at initiation of mv, ptr,stim was not correlated to tdi (rho = − · , p = · ), exdi (rho = · , p = · ) or tfdi (rho = − · , p = · ). at switch to psv, tfdi and exdi were correlated to ptr,stim, (rho = · , p < . and · , p = · , respectively), but tdi was not (rho = − · , p = · ). at switch to psv, a tfdi < % could reliably identify diaphragm dysfunction (sensitivity and specificity of and %, respectively), but tdi and exdi could not. this value was associated with increased duration of icu stay and mv, and mortality. conclusion under acv, neither tdi, exdi nor tfdi were related to ptr,stim. under psv, tfdi was strongly correlated to diaphragm strength and, when decreased, was associated with poorer outcome. alexandre demoule has signed research contracts with covidien, maquet and philips; he has also received personal fees from covidien and msd. none. none. none. management of enteral feeding during extubation in the intensive care unit: a multi-center retrospective study in french intensive care units mickael landais , noemie hubert , mai-anh nay , johann auchabie , bruno giraudeau , reignier jean , arnaud w thille , stephan ehrmann none. none. nutritional support in patients receiving temporary extracorporeal life support: a retrospective cohort study arthur bailly , laurent brisard , philippe bizouarn , thierry lepoivre , johanna nicolet , jean christophe rigal , jean christian roussel , bertrand rozec réanimation ctcv transplantation thoracique, chu de nantes -hôpital nord laennec, saint-herblain, france; chirurgie ctcv transplantation thoracique, chu de nantes -hôpital nord laennec, saint-herblain, france correspondence: laurent brisard -laurent.brisard@chu-nantes.fr annals of intensive care , (suppl ):s introduction the optimal nutritional intake in patients receiving temporary extracorporeal life support (ecls), including extracorporeal membrane oxygenation (ecmo) venovenous (vv) or venoarterial (va), remains controversial. enteral nutrition (en) is suspect to increase risk of gastrointestinal (gi) intolerance and intestinal ischemia. so, total parenteral nutrition (tpn) is often preferred. the purpose of this study is to describe the nutrition practices for critically ill patients receiving ecls and identify opportunities for improving nutrition therapy in this population. patients and methods retrospective analysis of patients requiring ecmo-va or ecmo-vv between and in the cardiac surgery intensive care unit of the university hospital of nantes. nutritional support was daily monitored with parenteral intake (glucose, lipid and propofol, protein and albumin, parenteral nutrition) and enteral nutrition until ecls weaning. two groups were compared during ecls period: no enteral nutrition delivered (none or tpn) (anec, n = ) and at least once enteral nutrition delivered (nec, n = ) including en alone and supplemental parenteral nutrition (spn). primary outcome was incidence of gi intolerance and risk factors. secondary outcomes were nutritional adequacy (calculated as overall of calories and protein delivered divided by the theoretical amount requirements: kcal/kg/d and . g/kg/d) and clinical outcome. data are reported as median ( th and th percentiles) or number (%), and analyzed with student's t test for continuous variables and χ test for categorical variables. p < . was considered as significant. none.introduction refeeding syndrome (rs) is a potentially lethal condition that remains underdiagnosed. it is characterized by severe electrolyte and fluid shifts associated with metabolic abnormalities in malnourished patients undergoing refeeding orally, enterally, or parenterally. clinical criteria have been proposed for determination of its risk and reported in the national institute for clinical excellence (nice) clinical guidelines. hypophosphoremia (hp) is a prominent feature of the rs and seems to be the earliest abnormality. phosphorus is a vital component of nucleic acids, enzyme systems, and various metabolic pathways. objective to determine the incidence of refeeding hypophosphoremia (rh) < . mmol/l, and severe rh < . mmol/l in a medical critical care unit. patients and methods monocentric, retrospective and observational study with patients from french-speaking icu nutritional survey study frans. critically ill adults (more than yo) were enrolled if they were hospitalized for more than days during a -month period and had an artificial nutritional support. refeeding hypophosphoremia is defined by the occurrence of hypophosphoremia after refeeding. we studied the incidence of hr, risk factors, and prognosis. results patients were enrolled between / / and / / . rh appears in . % and severe rh < . mmol/l in . % (fig. ) . there is no correlation between rs risk factors and rh in our study. logistic regression did not permit to identify neither risk factor nor prognostic modification. there is a lack in phosphoremia measuring ( . %), and overfeeding during the first days occurs in . %. discussion we define that an hypophosphoremia appearing after refeeding is a refeeding hypophosphoremia, and we do not consider others etiologies, such as mechanical ventilation, alkalosis, sepsis, alcoholism, malabsorptive states, poor intake, some medication. our cohort is too small to find some possible correlations with risk factors or prognosis. conclusion refeeding hypophosphoremia is common in our population. hypophosphoremia is not an independent predictor of icu or in-hospital mortality in critically ill patients. the knowledge of the sri requires the follow-up of the phosphoremia during nutrition after critical illness in particular in the undernourished patients. none. introduction to determine the possible relationship between days cumulated proteins ( days cpd) and energy deficits ( days ced) observed in ventilated patients and icu length of stay, duration of ventilator support, incidence of infections and days mortality. patients and methods mixed medical or surgical ventilated for at least days adult patients from icus from chu liège belgium were enrolled into the study. they were fed by enteral route with a target of kcal and . g of proteins by corrected kg of bodyweight and by day. if % of the target was not reached on day seven, parenteral nutrition was added with the same target. ced and cpd were calculated for days, taking into account all the sources of nutrition, and was defined as the difference between the amount of energy or protein intake and the target. results from / / till / / , patients were followed. data from patients could be cumulated on the first days. there were males, mean bmi was . ± . ; saps ii score on day was . ± . , sofa score at day was . ± . . they were ventilated for a median of days (iqr - ), median icu length of stay was days (iqr - ). mean sofa max calculated for the first days was . ± . and the day mortality was . %. on day , only % reached the target of kcal/kg and % the target of . g of protein/kg. mean days ced was − . ± . kcal and mean days cpd was − . ± . g. there was a significant negative relationship between both deficits and the sofa max (p = . for ced and p = . for cpd). however, there were no correlations between any of the deficits and icu length of stay, duration of mechanical ventilation, occurrence of infections and days mortality. discussion saps ii level, sofa max level, icu length of stay, all these parameters emphasize the high severity of this cohort of patients. it could indeed been thought that it is in this group of critically ill patients that the impact of nutrition could be easily demonstrated. clear relationships between sofamax on day and the days ced and cpd could be seen. however, both the deficit and the level of organ dysfunctions could be cause or consequence. unlike previous studies, usually performed in less severely ill patients, we did not find any relationship between ced or cpd and patient's outcome. conclusion contrary to some recent studies, we found no relationship between ced and cpe and outcome of patients. future studies are needed. none. cardiopulmonary bypass induces lymphopenia and decreases lymphocyte proliferation ability: il- and pd-l as potential therapeutic targets to reduce postoperative infection fabrice uhel , mathieu lesouhaitier , murielle grégoire , baptiste gaudriot , arnaud gacouin , yves le tulzo , erwan flecher , karin tarte , jean-marc tadié fig. incidence of hypophosphoremia at admission, the first day, and refeeding hypophosphoremia none. the prognostic impact of neutropenia in criticallyill cancer patients remains controversial. hence, several studies in critically ill cancer patients failed to demonstrate the impact of neutropenia on outcome [ ] . this lack of statistical association might however, reflect a lack of statistical power. a previous meta-analysis of aggregated data suggested % ( % ci - %) raw increase in mortality in neutropenic patients. the available data were, however insufficient to allow adjustment with confounders [ ] . the aim of this study was to assess the influence of neutropenia on mortality of critically ill cancer patients using individual data obtained from studies identified by our systematic review. secondary objectives were to assess the influence of neutropenia on mortality of critically ill patients while taking into account underlying malignancy, use of g-csf or changes related to period of admission. patients and methods this systematic review and meta-analysis was performed according to the prisma statements. public-domain databases including pubmed and the cochrane database were searched by using predefined keywords. the research was restricted to articles published in english and studies focusing on critically ill adult patients from may to may . the methods and objectives of this systematic review were reported in the prospero database (crd ). selected manuscripts' authors were then contacted to obtained part of their dataset. mortality was defined as either hospital or day- mortality. this preliminary analysis reports results from the whole dataset before and after adjustment using logistic regression. period of admission and use of g-csf were then assessed and were a pre-planned analysis. results our initial search yielded citations and studies were retained for further analysis. overall, studies were excluded for redundancy with other included studies, as containing only neutropenic patients, and two as containing only palliative patients. finally datasets ( %) containing sufficient data to allow comparison were obtained from authors. overall, patients were included in this study, including patients with neutropenia at icu admission. median age was of years (iqr - ). median sapsii score at icu admission was (iqr - ). respectively and patients had underlying haematological malignancy and solid tumours, and patients underwent allogeneic stem cell transplantation. mechanical ventilation, vasopressors, and renal replacement therapy were required in none. none. ( ) . in icus, cirrhotic patients are widely admitted and revalued after receiving optimal treatments for days. however, little is known about how manage these patients after day according to their prognosis. the blood neutrophil-to-lymphocyte ratio (nlr) as a novel inflammation index biomarker has been reported to be a predictor of clinical outcomes in various malignancies and in unselected critically ill patients ( ) . nlr has also been identified as a predictor of mortality in patients with stable liver cirrhosis. to our knowledge, the ability of nlr to predict outcome in critically ill cirrhotic patients has never been studied. the aim of this study was to evaluate the usefulness of inflammatory marker such as nlr for diagnosis of infection and predicting the outcome in hospitalized critically ill cirrhotic patients. we performed a retrospective monocentric study including consecutively cirrhotic patients hospitalized in a medical icu from to . for each patient, clinical and biological data at admission and day were collected. nlr at admission ("nlrd "), at day ("nlrd ") and the variation of nlr between admission and d none.introduction diagnosis of infection in immunocompromised patients can be difficult. however, diagnosing infection is very important, particularly in critically ill. this study aims to evaluate the benefit of procalcitonin (pct) blood level as a diagnostic marker for bacterial infection in patients with hematological malignancies admitted to the intensive care unit (icu). this retrospective single-center study included all consecutive patients with acute myeloid leukemia or high grade lymphoid malignancy admitted to the icu. patients were sorted into three subgroups, according to clinical and microbiological data: «infectious disease», «no infectious disease» and «unknown». initial serum pct and when available at day and day were recorded. receiver operating characteristic (roc) curve, sensitivity and specificity were calculated. serum pct was considered as decreasing when the decrease was ≥ % at day and/or ≥ % at day . mortality rates in the icu and at day- were also studied. results fifty-four patients were included in the study. at diagnosis, pct levels were significantly different between the "infection disease" group and the "no infection disease" group (p = . ). there was no difference between the "infection disease" group and the "unknown" group (p = . ). for the diagnosis of bacterial infection, best initial serum pct threshold was . ng per milliliter. for that threshold, sensitivity was . % and specificity was . %. pct area under the roc curve was . [ci % = . - ]. youden's j statistic was . . pct levels weren't different between groups according to the presence of neutropenia or in case of inaugural disease. there was a significant difference in pct values between groups according to the sofa score (p = . ), but not the saps score. mortality rate in the icu and at day- were significantly lower for the patients with decreasing pct (p < . and p < . , respectively). when comparing serum pct and crp predictive values, pct was significantly a better marker of bacterial infection (fig. ). discussion we found that serum pct, with a threshold of . ng/ ml, is a reliable marker of bacterial infection disease in patients with aggressive hematological malignancy admitted to the icu. our study confirms the results of a previous study in unselected immunocompromised patients admitted to the icu, showing a % sensitivity, a % specificity and an area under roc curve of . [ . - . ] for a threshold of . ng/ml ( ). the main limitations of our study are its retrospective design and the small number of included patients. conclusion pct is a reliable marker of bacterial infection in patients with hematological malignancies admitted to the icu. pct kinetic seems to be an interesting prognostic marker in this population. none. in this study, we have found that kinetics of secretion and expression of endocan is faster with huvecs stimlated by tlr agonist than tlr agonist. this results could suggest that endocan may be not only a marker of septic shock but could be also a specific marker to recognize the nature of pathogenic microorganisms in septic shock. furthermore, other studies with more tlr agonists could be useful to confirm these results. conclusion studying the effects of diverse tlrs agonists could make the plasmatic dosage of endocan more specific and helpful to recognize the nature of pathogenic microorganisms in septic shock. none. lung ultrasound: help to the diagnostic and the monitoring of response to physiotherapy. a case report of pneumonia aymeric le neindre introduction chronic critical illness (cci) syndrome is a new condition affecting an increasing number of patients, who survived an acute critical illness but have persistent severe organ dysfunction, requiring prolonged specialized care. cci is a iatrogenic process, reflecting the efficacy of modern life support technologies( ), and encompasses multiple organ failure, need for prolonged mechanical ventilation (mv), organ support, and palsy due to polineuromyopathy. the transition from acute to cci is gradual: definitions are based on duration of mv, with cut-offs of , or consecutive days of mv for ≥ h/day. cci patients may come from either medical or surgical icu; their health status fluctuates between improvements and deteriorations implying recurrent transitions between different levels of care ( ) .the risk of death is reported to be as high as %. despite a relatively young age ( years on average), functional status of cci patients discharged is seriously impaired, thus cci patients require long-term rehabilitation. aim: to estimate the frequency of cci syndrome in careggi, a large academic, tertiary care hospital; to describe the clinical course of cci patients through discharge, and their functional status at discharge. patients and methods administrative data on admission, transfer, death and discharge of all cci patients, consecutively admitted in one of the icu beds at careggi hospital from january to december , , were collected. cci was defined with the cut off of ≥ days of icu stay, representing the index event (ie) without contribution of previous or subsequent hospitalization in other hospitals. reasons for admission were grouped into the broad categories of medical causes, surgery, major trauma and cardio-respiratory arrest. patients discharged were evaluated in daily living, cognitive status, and mobility using barthel index. results we identified subjects who developed cci ( males; age . ± . years, mean ± sem); of them came from an external icu, began their cci course within careggi hospital ( from the emergency room, from a regular ward). average duration of the ie was . ± . days. these sample developed accumulative length of icu stay of days, corresponding to a % icu bed occupation over the theoretical total of , . when days of subintensive care and regular ward were separately added, days of highly specialized care and days of total acute hospital stay were reached. surgical patients had longer hospitalizations (p = . ).cci patients confirmed to be highly erratic: a total of transitions across different services were recorded in the patients, with a maximum of in of them. mean age was comparable between the patients who died ( %) and the remaining who were discharged alive ( . ± . vs. . ± . years; p = . ).fourteen subjects continued their icu stay out of hospital. only , whose age was lower ( . ± . years), were discharged home; half of the participants (n = , . %) were admitted to a residential rehabilitation facility. younger subjects scored better in the domains of self care (p = . ) and cognitive status (p = . ) but not in the domain of mobility, including walking ability: patients required maximal assistance in performing activities of daily living and transfers, other required medium/maximal assistance, with no statistical difference between dg group. conclusion cci is a relevant clinical condition that need to be assessed and possibly prevented, as it causes severe morbidity, long-term functional impairment and exceeding healthcare costs. none.conclusion early mobilization during the first week of the sepsis onset was safe and preserved muscle fibre cross sectional area. none. none. study of efficacy on icu acquired weakness of early standing with the assistance of a tilt table in critically ill patients none.introduction patients with high flow nasal cannula may benefit from combined aerosol therapy. clinical efficacy depends on pulmonary deposition which is related to the type of nebulizer. all new nebulizers or delivery methods require rigorous evaluation. the aim of this study was to compare lung deposition between two nebulizers (jet nebulizer vs vibrating-mesh nebulizer) through high flow nasal cannula in healthy subjects. patients and methods aerosol delivery of diethylenetriaminepentaacetic acid labelled with technetium- m ( mtc-dtpa, mci/ ml) to the lungs using a vibrating-mesh nebulizer (aerogen solo ® , aerogen ltd., galway, ireland) and a constant-output jet nebulizer (opti-mist plus nebulizer ® , convatec, bridgewater, nj) through high flow nasal cannula (optiflow ® , fisher & paykel, new zealand) was compared in healthy subjects. flow rate was set at l/min through the heated humidified circuit. pulmonary and extrapulmonary deposition were measured by single photon emission computed tomography combined with a low dose ct-scan (spect-ct) and by planar scintigraphy. results lung deposition was only . ± . and . ± . % of the nominal dose with the vibrating-mesh nebulizer and the jet nebulizer, respectively (p < . ). dose lost in the high flow circuit, humidification chamber and nasal cannula was higher with the vibrating-mesh nebulizer as compared to the jet nebulizer ( . ± . vs . ± . % of the nominal dose, p = . ). expressed as percentage of emitted dose, lung deposition was similar with both nebulizers. conclusion this study demonstrated that aerosol delivery through hfnc is poor in the specific conditions of the study despite the higher efficiency of the vibrating-mesh nebulizer as compared to the jet nebulizer. placing the nebulizer on the hfnc circuit at l/min induces high aerosol loss on the circuit and the oropharynx. key: cord- -tv cx authors: fromont, a.; moreau, t.; roullet, e. title: encefalomielite acuta disseminata date: - - journal: emc - neurologia doi: . /s - ( ) - sha: doc_id: cord_uid: tv cx l’encefalomielite acuta disseminata (emad) è una malattia infiammatoria autoimmune che coinvolge il cervello e il midollo spinale. descritta soprattutto nel bambino, generalmente fa seguito a un episodio infettivo o a una vaccinazione, ma può essere idiopatica. la sua presentazione clinica comprende un’encefalopatia acuta associata a segni e a sintomi neurologici multifocali. la sua diagnosi si basa sulla clinica e sulla risonanza magnetica, che rivela lesioni multifocali della sostanza bianca in ipersegnale t mal delimitate, della stessa età, che prendono il gadolinio e possono anche riguardare il talamo e i nuclei della base. il liquor può mostrare un’iperlinfocitosi con iperproteinorrachia e, a volte, la presenza di bande oligoclonali transitorie. la sua prognosi è piuttosto favorevole, passato l’episodio monofasico, con un trattamento specifico. È quindi fondamentale escludere fino dall’inizio le sue molte diagnosi differenziali. il trattamento dell’emad, di prima scelta, consiste in boli di corticosteroidi endovenosi a forti dosi. in caso di insuccesso bisogna ricorrere agli scambi plasmatici o alle immunoglobuline endovenose. anche se, di solito, è monofasica, possono verificarsi altri episodi che fanno allora pensare a un’emad multifasica. tuttavia, in alcuni casi queste nuove poussées sono una modalità di esordio di un’autentica sclerosi multipla. i criteri diagnostici dell'encefalomielite acuta disseminata (emad) non sono stati sempre ben definiti. in letteratura, per descrivere i pazienti con un'emad vengono usati diversi termini collegati a diverse caratteristiche di questa patologia. così, i termini di «encefalomielite postinfettiva» o «postvaccinale» sono utilizzati quando viene preso in considerazione il fattore scatenante. quando si tratta delle caratteristiche istopatologiche e della distribuzione delle lesioni, l'emad è chiamata acute perivascular myelinoclasia, encefalite perivenosa e vasculomielinopatia disseminata. infine, i termini di «encefalomielite acuta demielinizzante», hyperergic encephalomyelitis, «encefalite perivenosa postvaccinale» o «demielinizzazione postencefalite» sono utilizzati in riferimento ai meccanismi immunopatologici sottostanti. l'emad è una patologia rara, descritta soprattutto nel bambino. anche se, tipicamente, l'emad compare in seguito a un'infezione o una vaccinazione dopo un intervallo libero di alcuni giorni o settimane, rimane idiopatica in un quarto dei casi. i sintomi clinici sono multipli e non specifici. essi associano un quadro di encefalopatia ad alcuni deficit neurologici focali. la risonanza magnetica (rm) rappresenta un elemento significativo della diagnosi. una corretta diagnosi è importante per due ragioni: da una parte a scopo prognostico (una volta completato l'episodio monofasico l'emad ha una prognosi piuttosto favorevole), dall'altra la strategia terapeutica è specifica e presuppone che le diagnosi differenziali, tra cui la sclerosi multipla, siano state scartate. la distinzione tra emad e sclerosi multipla è spesso difficile: a volte sola la prova del tempo la consente. l'emad è più frequente nel bambino a causa della più alta frequenza delle vaccinazioni e dell'esposizione agli antigeni infettivi [ ] [ ] [ ] [ ] [ ] [ ] . nel bambino la sua incidenza è stimata pari a , / /anno [ ] . uno studio effettuato a san diego in alcuni pazienti di meno di venti anni rivela un'incidenza di , / /anno [ ] . tra questi pazienti, il % aveva subito una vaccinazione nel mese precedente la comparsa dei sintomi e il % aveva presentato un'infezione nei giorni precedenti. in uno studio pediatrico prospettico condotto per anni in germania, dal al , l'incidenza dell'emad era di , all'anno per bambini di meno di anni. l'incidenza era maggiore nel sottogruppo di bambini di meno di anni rispetto a quelli di - anni ( , vs , per rispettivamente) [ ] . contrariamente alla sclerosi multipla, non sembra esistere una preponderanza nelle donne [ , ] . due coorti pediatriche riferiscono, al contrario, una leggera predominanza dell'emad nei ragazzi con un sex-ratio maschio/femmina di , per [ ] e di , per [ ] . l'età media di comparsa nel bambino si situa tra i e gli anni [ , , , ] . una distribuzione stagionale in inverno e a primavera è stata messa in evidenza in alcuni studi realizzati negli stati uniti [ ] e in iran [ ] . nell'adulto l'incidenza esatta dell'emad non è nota. esistono poche coorti di emad nell'adulto. schwarz, nel , in uno studio retrospettivo, riporta casi di emad nell'adulto con un'età media di , anni e con una sex-ratio di , donne per uomo [ ] . queste emad sono state incluse tra il e il nel reparto di neurologia dell'ospedale di neurologia di heidelberg, in germania. in uno studio retrospettivo condotto presso centri francesi dal al , de sèze riporta emad adulti la cui età media è di , ± , anni e la cui sex-ratio è di , donne per uomo [ ] . la sola coorte prospettica di emad in alcuni adulti è quella di marchioni [ ] . sessanta pazienti, ricoverati in una delle tre cliniche neurologiche o di malattie infettive di pavia e di monza, in italia, rispettano i criteri di emad nel periodo tra il gennaio e il dicembre . la loro età media è di ± , anni, con una sex-ratio di , donne per uomo. tre quarti delle emad sono postinfettive o postvaccinali [ , , , ] (tabella ) . il tempo medio tra l'infezione e l'emad è di - giorni. le infezioni virali legate all'emad sono il morbillo, la parotite, la rosolia, la varicella, lo zoster, le infezioni legate al virus epstein-barr (ebv), al citomegalovirus (cmv), al virus herpes simplex (hsv), al virus dell'epatite a (hav) e al virus coxsackie [ ] [ ] [ ] [ ] . diversi studi hanno valutato il rischio legato ad alcune infezioni virali. così, l'emad insorge in un caso su casi di morbillo, in un caso su varicelle e in un caso su rosolie. in termini di mortalità e di danni neurologici, questi erano più bassi dopo una varicella o una rosolia che dopo un morbillo [ , ] . infezioni batteriche come quelle da borrelia burgdorferi, da leptospire e da streptococco ß-emolitico del gruppo a sono associate a un rischio di encefalomielite e di polinevriti [ ] [ ] [ ] [ ] [ ] . la causa principale di infezione batterica coinvolta nello sviluppo di emad è il micoplasma [ ] . grazie ai progressi nella gestione delle malattie infettive gravi, la cui diagnosi è più facile, l'emad nei paesi sviluppati sembra più frequente dopo infezioni non specifiche delle vie aeree superiori la cui eziologia è ancora sconosciuta [ ] [ ] [ ] . dati epidemiologici dell'encefalomielite acuta disseminata (emad) del bambino confrontati con quelli della sclerosi multipla pediatrica. sclerosi multipla [ ] età media di esordio , ± , anni , ± , anni sex-ratio (donna/uomo) / , / incidenza media , - , su [ ] ? dati epidemiologici dell'encefalomielite acuta disseminata (emad) dell'adulto confrontati con quelli della sclerosi multipla dell'adulto. emad [ ] sclerosi multipla [ ] età media di esordio , ± , anni ± anni sex-ratio (donna/uomo) , / / incidenza media ? / all'anno [ ] tabella . eziologie delle emad (secondo [ ] ). l'incidenza delle emad postvaccinali è stimata tra , e , / persone vaccinate [ ] (tabella ). la loro frequenza è diminuita da quando è stata abbandonata la produzione di vaccini mediante colture su tessuti cerebrali. così, per il vaccino antirabbico, quando era prodotto a partire da colture effettuate su cervello di coniglio, le complicanze di tipo emad erano di / vaccinazioni e di / contro / vaccinazioni per il vaccino tipo semple. anticorpi diretti contro gli antigeni della mielina sono riscontrabili nei pazienti che hanno sviluppato un'emad dopo la vaccinazione con il vaccino semple attenuato vivo, prodotto su colture di tessuti del sistema nervoso di conigli o capre [ ] . una suscettibilità genetica spiega probabilmente il motivo per cui le complicanze encefalomielitiche si sviluppano solo in una minoranza dei pazienti che ricevono il vaccino antirabbico preparato su cervelli di conigli. questa stessa differenza di suscettibilità genetica spiega perché alcuni individui sviluppano un'emad dopo un morbillo e altri no. la frequenza di queste complicanze è passata a / vaccinazioni con l'uso di vaccini antirabbici prodotti su embrioni di anatre. più recentemente, queste complicanze sono praticamente scomparse grazie al ricorso a vaccini prodotti a partire da cellule umane diploidi non neurali [ ] [ ] [ ] [ ] [ ] [ ] . attualmente, le emad postvaccinali sono riscontrate dopo la vaccinazione contro il virus del morbillo, contro la parotite e contro la rosolia. l'incidenza è di , - , su vaccini vivi antimorbillo [ ] , ossia molto inferiore al rischio di encefalomielite postinfettiva legato al morbillo stesso (superiore a per ) [ ] . contrariamente alle lesioni della sclerosi multipla, che sono eterogenee in termini di età e di composizioni cellulari e che hanno quattro pattern anatomopatologici descritti da lucchinetti [ ] , le lesioni di emad sono quasi sempre di età similare e sono di un unico tipo [ ] . macroscopicamente, le lesioni di emad producono un edema cerebrale diffuso con impegno delle amigdale e dell'uncus [ ] . le lesioni di emad sono caratterizzate da aree di demielinizzazione perivenose a «manicotti», infiltrazione di linfociti e di macrofagi. sono anche visibili, a livello dei piccoli vasi della sostanza bianca e della sostanza grigia, un'iperemia, un edema endoteliale, pareti vascolari invase da cellule infiammatorie, un edema perivascolare ed emorragie. quando le lesioni invecchiano, i macrofagi diventano più numerosi e i linfociti si rarefanno. negli stadi avanzati della malattia compaiono dei focolai di fibrosi fibrillare. in generale i danni assonali sono poco numerosi [ ] . la leucoencefalite emorragica acuta di weston hurst [ ] è una variante dell'emad con demielinizzazione rapidamente progressiva, spesso fulminante, con emorragia e infiammazione della sostanza bianca del sistema nervoso centrale. la leucoencefalite emorragica acuta è spesso scatenata da infezioni delle vie aeree superiori. la sua presentazione clinica è simile all'emad. le sue caratteristiche anatomopatologiche sono simili a quelle dell'emad; tuttavia, la demielinizzazione è più estesa e si associa a infiltrati di polimorfonucleati neutrofili. la leucoencefalite emorragica acuta è caratterizzata dalla distruzione di piccoli vasi sanguigni associata a un'emorragia acuta e a depositi di fibrina [ ] . È frequentemente letale e, talvolta, pone i pazienti in uno stato vegetativo per diverse settimane. alcuni pazienti sopravvivono, ma con un handicap grave [ ] . la suscettibilità genetica può essere responsabile nella determinazione della comparsa di un tipo particolare di variante dell'encefalomielite [ ] . la patogenesi dell'emad è poco chiara [ , ] . tenuto conto delle sue caratteristiche anatomopatologiche e della sua evoluzione monofasica classica, la sua fisiopatologia è simile al modello dell'encefalite allergica sperimentale (eas). l'induzione attiva dell'eas consiste nel somministrare per via sottocutanea a un animale uno dei componenti della mielina, come la myelin basic protein (mbp), la proteolipid protein (plp) e la myelin oligodendrocyte glycoprotein (mog), emulsionata in un potente adiuvante (l'adiuvante di freund). in funzione dei ceppi, dell'antigene o dell'adiuvante, gli animali sviluppano raramente una malattia acuta o cronica. il ratto lewis, per esempio, immunizzato con la mbp, sviluppa una malattia monofasica al termine del °giorno con tetraparesi, perdita di peso e incontinenza. la malattia dura - giorni. dal punto di vista istologico sono individuate lesioni infiammatorie demielinizzanti nel cervello e nel midollo spinale. al fine di studiare specificamente i meccanismi infettivi che potrebbero contribuire alla patogenesi dell'emad, è stato utilizzato il modello di encefalomielite murina di theiler. questa patologia è scatenata dall'inoculazione diretta, in un emisfero cerebrale di topi sensibili, del virus dell'encefalomielite murine di theiler. questi ratti sviluppano un'encefalite subacuta con demielinizzazione diffusa. la malattia, per essere prodotta, richiede il complesso maggiore di istocompatibilità (cmh) di classe con i linfociti t cd diretti contro gli epitopi virali, mentre la flogosi è perpetuata dal cmh di classe con i linfociti t cd reattivi ai determinanti della mielina. lo studio di questi due modelli ha portato a sviluppare due concetti, non necessariamente esclusivi [ ] : quello della cascata infiammatoria e quello del mimetismo molecolare. il primo concetto, di cascata infiammatoria, comporta un'infezione del sistema nervoso centrale da un agente neurotropo che induce danni nei tessuti del sistema nervoso centrale e una perdita di autoantigeni nella circolazione sistemica attraverso una breccia della barriera ematoencefalica. questi autoantigeni, giunti negli organi linfatici sistemici, portano a una rottura di tolleranza e a una risposta delle cellule t autoreattive capaci di penetrare nel sistema nervoso centrale e di far perdurare la flogosi del sistema nervoso centrale. il secondo concetto, quello di mimetismo molecolare, si basa sull'esistenza di un'analogia strutturale tra i peptidi delle proteine microbiche o virali e le proteine della mielina dell'ospite [ ] . durante l'inoculazione della sostanza patogena le cellule che presentano l'antigene, come i linfociti b o le cellule dendritiche, attivano i linfociti t. a loro volta, essi attivano dei linfociti b specifici dell'antigene. i linfociti t attivati e i linfociti b sono allora in grado di penetrare nel sistema nervoso centrale, dove possono incontrare l'epitopo mielinico omologo. ne deriva una reazione infiammatoria. il meccanismo attraverso il quale gli oligodendrociti muoiono nell'emad non è conosciuto. È stato supposto il ruolo di tabella . incidenza delle encefalomieliti acute disseminate (emad) in funzione dei vaccini (secondo [ ] ). citochine, chemiochine e molecole di adesione. così, il tnf-a sarebbe un fattore importante nella patogenesi dell'eas [ ] . l'up regulation del ligando fas sulle cellule t autoreattive e l'up regulation del fas sulle cellule presenti nell'organismo provocherebbero la distruzione delle cellule t per apoptosi [ ] . dell'ossido nitrico (no) è prodotto nell'eas e il no è implicato nella morte degli oligodendrociti [ ] . anche la produzione di radicali liberi è coinvolta nella morte degli oligodendrociti [ ] . la tossicità mediante le cellule immunocompetenti stesse può anche partecipare alla patogenesi della demielinizzazione [ ] . classicamente, l'emad è descritta come un evento monofasico che inizia da giorni a settimane dopo un'esposizione antigenica (infezione o vaccino). l'emad è una patologia polisintomatica che associa un quadro di encefalopatia ad alcuni deficit neurologici focali. l'esordio dei sintomi si verifica in - giorni. i disturbi iniziano spesso con segni generali: febbre, cefalea, nausea e vomito, poi si manifestano segni neurologici focali che associano in modo variabile, a seconda degli studi (tabelle e ): segni piramidali, disturbi sensitivi, segni midollari, atassia, paralisi dei nervi cranici, calo visivo, attacchi di epilessia e disturbi della parola (disartria o afasia), e della coscienza (dalla sonnolenza al coma). secondo i grandi studi pediatrici (tabella ) [ , , - , , ] , i segni clinici presentati dai bambini sono, il più delle volte, un quadro di encefalopatia, cefalee, manifestazioni cerebellari, un interessamento dei nervi cranici, una neurite ottica. nell'adulto (tabella ) i segni piramidali e l'interessamento del sistema nervoso periferico (poliradiculoneuropatia) sono più frequenti. tuttavia, i diversi segni e sintomi non sono sempre riferiti nella stessa maniera secondo gli studi. secondo tenembaum [ ] i disturbi della coscienza, l'atassia, i deficit motori, l'interessamento del tronco cerebrale si riscontrano sia nell'adulto sia nel bambino, mentre una febbre di lunga durata, gli attacchi epilettici e le cefalee si verificano più spesso nel bambino. i disturbi sensitivi sarebbero più frequenti nell'adulto. riguardo alla gravità dei sintomi, è molto variabile: va dalle forme fruste con irritabilità, cefalea e sonnolenza, fino al coma. gli interessamenti del tronco cerebrale possono essere all'origine di arresto respiratorio o di disturbi della coscienza [ , ] . alcuni pazienti possono essere ricoverati in rianimazione a causa di disturbi della vigilanza e di crisi di epilessia con stato di male. così, sonneville [ ] riporta una serie di pazienti affetti da emad e ricoverati in rianimazione per una delle ragioni precedenti. quattordici ( %) hanno avuto una ventilazione assistita. cinque ( %) sono morti e sette ( %) hanno riportato sequele funzionali. gli esami biologici eseguiti in caso di emad possono rivelare un'iperleucocitosi o una linfopenia. così, dale [ ] , nella sua casistica di emad, mostra in ( %) casi un'iperleucocitosi media pari a /mm ( - ), di cui il % con polimorfonucleati neutrofili; un paziente presentava un'iperlinfocitosi. il % dei pazienti aveva una linfopenia. la proteina c-reattiva (pcr) era elevata nel % dei casi e la velocità di eritrosedimentazione (ves) nel %, senza che vi sia il riscontro di un'infezione. negli studi, sono comunicati pochissimi dati sulle ricerche di agenti infettivi. marchioni [ ] , su una serie di emad, riporta tabella . confronto delle caratteristiche cliniche delle diverse coorti di encefalomielite acuta disseminata (emad) nel bambino. mikaeloff [ ] samile [ ] pohl [ ] leake [ ] anlar [ ] tenembaum [ ] dale [ ] anno il liquor nell'emad può essere normale. dale [ ] rileva un liquor infiammatorio (pleiocitosi o iperproteinorrachia) in delle emad valutate ( %) e marchioni [ ] in dei soggetti ( %). il liquor può mostrare un aumento della pressione e una pleiocitosi a predominanza linfocitaria (fino a /mm ) ma che, all'inizio, può essere a polimorfonucleati neutrofili con glicorrachia normale e colture sterili. nello studio di dale il liquor rivela un'iperlinfocitosi media di /mm in delle emad ( %). in quello di marchioni essa è di /mm in delle emad ( , %). il numero medio dei leucociti è di , ± , /mm nello studio di de sèze [ ] . il liquor può rivelare un'iperproteinorrachia. così, dale riscontra un'iperproteinorrachia media di , g/l in delle emad ( %) della sua coorte, rispetto a un tasso medio di , g/l in delle emad ( , %) di marchioni. nel suo studio de sèze rileva un'iperproteinorrachia superiore a g/l nel % ( su ) delle emad. l'indice di immunoglobulina g (igg) può essere aumentato, con la presenza di bande oligoclonali (ocb) sull'immunofissazione del liquor che testimoniano una sintesi intratecale. queste ocb sono presenti nello %- % delle emad [ , , , ] e possono essere transitorie [ , ] . così, in una casistica di nove pazienti portatori di emad con inizialmente ocb nella loro puntura lombare (pl), queste erano scomparse quando l'analisi è stata rifatta da giorni a mesi più tardi [ ] . l'interesse dell'analisi del liquor è essenzialmente a scopo di diagnosi differenziale con una patologia infettiva [ ] . così, l'elettroencefalogramma (eeg) [ ] non rivela alterazioni specifiche dell'emad, ma può mostrare un rallentamento generale o focalizzato del ritmo di fondo e delle scariche epilettiche. uno studio effettuato da hollinger, nel , trova anomalie sull'eeg in sette delle otto emad che hanno beneficiato di questo esame [ ] . queste alterazioni andavano da una sonnolenza aumentata a un rallentamento generalizzato moderato o grave con, a volte, un rallentamento focale, fino a scariche epilettiche. erano osservati disordini gravi in tre pazienti, che erano ben correlati con la gravità e con l'evoluzione della sindrome clinica. in uno studio di dale [ ] delle emad hanno beneficiato di un eeg. uno solo era normale. tutti gli altri mostravano onde lente (asimmetriche per e simmetriche per ). un solo tracciato rivelava una scarica epilettica. pochi studi riportano dati di potenziali evocati (pe) nel corso delle emad. dale ha valutato i pe visivi in emad [ ] . undici erano normali, dieci anomali (sette bilaterali e tre unilaterali), con un p di ampiezza o di latenza patologiche. gli otto casi di emad portatori di una neurite ottica bilaterale avevano dei pe visivi anormali. tra i casi di emad senza disturbi visivi clinici, solo due avevano dei pe visivi anomali. pohl nel [ ] ha valutato i pe in pazienti della sua casistica di emad. fra questi pazienti, otto avevano dei pe anormali ( %), di cui cinque avevano delle anomalie dei pe visivi ( %), quattro dei pe somestesici ( %) e uno dei pe uditivi ( %). confronto delle caratteristiche cliniche delle diverse coorti di encefalomielite acuta disseminata (emad) nell'adulto. de sèze [ ] lin [ ] marchioni [ ] schwarz [ ] anno la tc cerebrale è in genere normale all'inizio. ipodensità multiple possono comparire in - giorni nella sostanza bianca. con il tempo, è riportato un incremento dopo somministrazione di mezzo di contrasto [ ] . la rm è utile sia per la diagnosi di emad che per scartare altre patologie. le anomalie rm dell'emad sono visualizzate sulle sequenze t e fluid-attenuated inverse recovery (flair) sotto forma di ipersegnali di varie dimensioni, mal limitati, molteplici, asimmetrici e, generalmente, senza effetto massa [ ] . questi ipersegnali sono localizzati nella sostanza bianca sottocorticale e profonda, ma anche a livello della giunzione tra sostanza grigia-sostanza bianca dei due emisferi cerebrali, nel cervelletto, nel tronco cerebrale e nel midollo spinale [ ] (fig. ) . il midollo spinale è implicato nell' %- % dei casi [ , , , ] . le lesioni midollari sono spesso ampie, diffuse, possono estendersi in altezza su diversi corpi vertebrali e si potenziano spesso dopo somministrazione di gadolinio [ ] . le alterazioni in iposegnale t sono rare [ ] . nel bambino l'interessamento del cervelletto e del tronco cerebrale è più frequente che nell'adulto [ ] . contrariamente alle placche della sclerosi multipla, nelle emad la sostanza grigia dei nuclei della base e del talamo è spesso sede di lesioni. il quaranta per cento dei pazienti ha una lesione talamica. le lesioni del corpo calloso sono invece rare. per parlare di emad, le lesioni in ipersegnale devono avere la stessa età e non deve apparire nessuna nuova lesione. benché le lesioni di emad, tutte della stessa età e recenti, debbano teoricamente prendere il gadolinio, non è sempre così. il %- % degli ipersegnali t visualizzati nelle emad prendono il contrasto [ , , ] . questi aumenti si presentano sotto forma di anelli completi o meno, nodulari [ , ] . È rara la presa di contrasto delle meningi. la sede e la distribuzione delle lesioni di emad possono, sulle rm precoci, essere difficilmente distinguibili da quelle della sm. tuttavia, tre caratteristiche possono permettere di decidere a favore dell'emad: ipersegnali bilaterali e simmetrici, un risparmio relativo della sostanza bianca periventricolare o un interessamento della sostanza grigia profonda. il risparmio assoluto o relativo della zona periventricolare è tipico dell'emad ed è individuato nel % dei pazienti dello studio di dale [ ] . tuttavia, il % dei pazienti colpiti da emad ha lesioni periventricolari indistinguibili dalle lesioni della sm. l'esistenza o meno di un'atrofia cerebrale può orientare verso l'una o l'altra di queste due patologie. in effetti, se può essere messa in evidenza un'atrofia cerebrale precoce nella sclerosi multipla, questo non è il caso nell'emad. una classificazione delle lesioni dell'emad in quattro pattern diversi è stata proposta da tenembaum [ ] : • il primo pattern corrisponde a lesioni di piccole dimensioni, inferiori ai mm; • il secondo comprende le lesioni ampie, confluenti o tumefatte, con edema perilesionale ed effetto massa; • il terzo pattern riguarda le lesioni bitalamiche; • il quarto le lesioni di encefalomielite emorragica acuta. questi differenti pattern rm non sembrano correlati all'evoluzione né alla disabilità. negli ipersegnali t sono stati individuati bassi tassi di n-acetil-aspartato (naa), che riflettono una distruzione neuronale e livelli elevati di lattati, testimonianza di un metabolismo anaerobico [ , ] , senza aumento della colina nella fase acuta delle emad. l'assenza di aumento della colina indica l'assenza di proliferazione cellulare. la rm di diffusione-perfusione non è informativa, perché rivela anomalie di diffusione con un coefficiente apparente di diffusione (adc) aumentato, normale o diminuito nelle lesioni dell'emad [ , ] . la spect mostra un'ipoperfusione, spesso più estesa delle lesioni rm e mette in evidenza dei deficit circolatori cerebrali persistenti che potrebbero contribuire ai deficit cognitivi e di linguaggio conseguenti [ , ] . la pet rivela un ipometabolismo a livello delle lesioni dell'emad [ ] . prima dell'uso della rm venivano realizzate delle biopsie quando la tc cerebrale rilevava ampie lesioni con un possibile effetto massa. dall'avvento della rm, l'indicazione delle biopsie è riservata alle lesioni singole con effetto massa per escludere un tumore cerebrale o una metastasi. in assenza di classificazione istopatologica dettagliata che permetta di stabilire una diagnosi certa di emad, la biopsia stereotassica diagnostica di routine è sconsigliata, poiché ritarda il trattamento [ ] . [ ] per maggior chiarezza e al fine di uniformare i criteri di diagnosi, l'international pediatric ms study group (ipmssg), che raggruppa neurologi, genetisti, immunologi, epidemiologi, neuropsicologi e infermieri, ha proposto dei criteri diagnostici dell'emad (tabella ). questi criteri sono stati sviluppati per bambini di meno di anni. essi dovranno essere validati in modo prospettico e resta da determinare se questi criteri sono applicabili nell'adulto. anche se l'associazione di cefalee, disturbi della vigilanza, segni e sintomi neurologici focali deve far pensare a un'emad, devono essere escluse altre eziologie [ , ] . esse hanno una sintomatologia clinica febbrile simile all'emad. la pl permette di porne la diagnosi differenziale con una pleiocitosi più importante e con le colture. vanno considerate l'encefalite subacuta legata al virus dell'immunodeficienza umana (hiv) e la leucoencefalopatia multifocale progressiva (lemp), da cui la necessità di eseguire una sierologia hiv. la diagnosi di sclerosi multipla si basa sui criteri di mc donald [ ] revisionati nel [ ] e basati sulla disseminazione nel tempo e nello spazio. in caso di primo evento neurologico, la distinzione tra sclerosi multipla ed emad non è sempre semplice e spesso è la prova del tempo a permettere di dirimere. tuttavia, alcuni sintomi sono meno suggestivi di sclerosi multipla, come le cefalee, i disturbi della vigilanza, le crisi di epilessia, una neurite ottica bilaterale e un'afasia. inoltre, nella sclerosi multipla raramente si riscontra all'anamnesi il concetto di infezione o di vaccinazione che precedono la comparsa dei disturbi. tipicamente, le lesioni rm sono di età differenti e di sede piuttosto periventricolare, frequentemente con un interessamento del corpo calloso e con il risparmio dei gangli della base e del talamo. durante il follow-up rm non è raro che appaiano nuove lesioni t o che prendono il gadolinio, permettendo di confermare la disseminazione nel tempo. nella sclerosi multipla alcune bande oligoclonali permanenti sono spesso scoperte nel lcr. il quadro di sclerosi multipla pediatrica è più esplosivo che nell'adulto con la presenza, più frequente, di segni di ipertensione endocranica. la sclerosi multipla pediatrica (inizio prima dei anni) rappresenta dallo , % al % dei casi di sclerosi multipla [ , ] . mentre si riscontra una maggioranza di donne alla pubertà, con una sex-ratio di , , prima della pubertà la sex-ratio è vicina a . l'età media di esordio è di , ± , anni. le sclerosi multiple pediatriche esordiscono con un interessamento delle vie lunghe ( , %), una neurite ottica isolata ( , %) o un interessamento del tronco cerebrale ( , %) e, meno frequentemente ( %), con sintomi di encefalite (cefalee, vomito, sincope, disturbi della coscienza). l'evoluzione è, il più delle volte, remittente ( , %). in media, il tempo tra le prime due poussées è di anni. le sclerosi multiple pediatriche impiegano un tempo medio di , , e anni per raggiungere rispettivamente i limiti della disabilità: edss , (disturbo ambulatoriale), , (ricorso a un bastone) e , (ricorso a una sedia a rotelle). l'età media in questi limiti è, rispettivamente, di , , , e , anni. la sintomatologia può essere simile a quella dell'emad, ma l'evoluzione è spesso recidivante, con un interessamento tabella . criteri diagnostici dell'encefalomielite acuta disseminata (emad) secondo l'international pediatric ms study group (ipmssg, secondo [ ] ). primo evento clinico con una causa presunta infiammatoria o demielinizzante e a esordio acuto o subacuto che interessa diverse aree del sistema nervoso centrale; la presentazione clinica deve essere polisintomatica e deve comprendere un'encefalopatia definita da una o più fra le seguenti condizioni: poliviscerale del sistema nervoso centrale e periferico. il dosaggio dell'enzima di conversione dell'angiotensina, una radiologia del torace, una tc toracica e un lavaggio broncoalveolare permettono di porre la diagnosi. questa vasculite è frequente nel bacino del mediterraneo. l'esordio avviene generalmente tra i e i anni, con una predominanza maschile. il quadro clinico e la rm possono imitare un'emad. l'interessamento sottotentoriale è predominante nella malattia di behçet. tuttavia, evolve per poussées e comprende un interessamento oftalmico e cutaneomucoso. la nmo è una patologia che ha un tropismo sia a livello del nervo ottico sia a livello del midollo. può manifestarsi con una neurite ottica bilaterale, come nell'emad. la sua frequenza è stimata pari al % su una serie di soggetti etichettati «emad» da dale et al. d'altronde, la nmo, come alcune forme di emad, può manifestarsi attraverso forme midollari isolate [ ] . tuttavia, in questo caso, il carattere di disseminazione dell'encefalomielite è discutibile; si tratta più di encefalomielite postinfettiva. nelle coorti di emad alcuni casi di nmo sono stati rilevati con la prova del tempo. benché i criteri di wingerchuk della nmo suggeriscano che la rm cerebrale deve essere normale, nuove pubblicazioni ampliano lo spettro della nmo con la possibilità di lesioni rm simili a quelle della sclerosi multipla e dell'emad [ ] . la presenza di un marker biologico della nmo, l'anticorpo antiacquaporina , può aiutare nella diagnosi, anche se la sua specificità non è del % [ ] . sindrome da antifosfolipidi (apl) [ ] la presentazione iniziale e l'aspetto rm possono essere simili all'emad. precedenti di trombosi venose profonde, perdite fetali e la presenza di anticorpi anticardiolipidi e di anticoagulanti lupici sono patognomonici della sindrome da apl. la sintomatologia è spesso ingannevole, con cefalea, segni neurologici polimorfi acuti e disturbi della vigilanza. le neuroimmagini in rm rivelano infarti profondi che possono simulare lesioni della sostanza bianca. l'arteriografia o l'angiografia mediante risonanza magnetica (angiorm) sono allora utili per confermare la vasculite. a volte può rivelarsi necessario il ricorso alla biopsia leptomeningea. alcune vasculiti possono essere secondarie al lupus eritematoso disseminato, per esempio. la diagnosi è possibile per la presenza di anticorpi sierici specifici. l'angiografia può rivelare vasi patologici. si tratta di un'entità clinicoradiologica che associa cefalee, confusione, disturbi visivi e crisi di epilessia a alterazioni transitorie posteriori sulle neuroimmagini [ ] . la fisiopatologia è ancora incompletamente nota. la pres è stata riportata in diverse circostanze: assunzione di farmaci (inibitori del reuptake della serotonina, immunosoppressore, ecc.), eclampsia, ipertensione arteriosa grave ecc. cause tumorali: tumore cerebrale primitivo, metastasi l'inizio è generalmente a macchia d'olio, più insidioso di quello dell'emad; tuttavia, i disturbi della coscienza, le cefalee e i segni e sintomi neurologici focali sono i segni clinici riscontrati nell'emad. inoltre, la rm cerebrale può assomigliare a quella di un'emad con effetto massa, edema perilesionale. in questo caso una biopsia stereotassica può rivelarsi necessaria. può trattarsi, per esempio, di mitochondrial encephalopathy with lactate acidosis and stroke (melas). le encefalopatie mitocondriali si possono discutere nel bambino di fronte a un quadro di cefalee tipo emicranie, di deficit neurologici focali e di segni di encefalopatia. spesso il quadro si associa, contrariamente all'emad, a una sordità e a un ritardo dello sviluppo. l'aspetto rm può essere simile a quello di un'emad. la diagnosi si basa sul tasso elevato di lattati, sulla biopsia muscolare e sui test di genetica molecolare. l'adrenoleucodistrofia, malattia recessiva legata all'x, è secondaria a un'impossibilità di ossidare gli acidi grassi a catena molto lunga. essa si esprime tra i e i anni. in occasione di questa malattia esistono una demielinizzazione progressiva del sistema nervoso centrale e, spesso, un deficit surrenalico. la forma cerebrale si manifesta con un cambiamento dell'umore, con segni neurologici focali e con crisi di epilessia. la rm cerebrale rivela, sulle sequenze t , anomalie della sostanza bianca bilaterali confluenti. la diagnosi è posta con il dosaggio degli acidi grassi a catena molto lunga, il cui tasso si rivela elevato. la raccolta dell'anamnesi e la ricerca di una infezione recente, di un viaggio o di una vaccinazione sono fondamentali. la valutazione biologica comprende almeno un emocromo, la ricerca di una sindrome infiammatoria con una ves e una pcr, un'immunofissazione sanguigna, una valutazione autoimmune con anticorpi antinucleo, anticorpi anti-acido desossiribonucleico (dna) nativi, anticorpi anticardiolipidi e dosaggio del complemento. sono frequentemente eseguite diverse sierologie: sierologie hiv, hsv, ebv, vzv, cmv, virus dell'epatite b (hbv), virus dell'epatite c (hcv). viene eseguita una pl con citologia, biochimica, batteriologia e isofocalizzazione elettrica. infine, la rm cerebrale con sequenze t , t gadolinio, t e flair, permette di oggettivare le lesioni. può essere eseguita una rm midollare. ovviamente, un follow-up rm è indispensabile per controllare l'assenza di nuove lesioni. l'emad è considerata un evento monofasico. tuttavia, circa il % delle emad pediatriche evolverebbe verso una sclerosi multipla [ , , , , ] . il % e il % delle emad degli adulti evolverebbe verso una sclerosi multipla rispettivamente a e a mesi, secondo gli studi di de sèze [ ] e di schwarz [ ] . due terzi delle emad presenterebbero ulteriori poussées che corrispondono a emad multifasiche [ , , ] . il concetto di emad multifasica è tuttora dibattuto e la sua distinzione con una sclerosi multipla non è sempre facile. per tentare di chiarire le cose, il gruppo internazionale pediatrico di sclerosi multipla ha definito tre categorie [ ] : l'emad, l'emad ricorrente e l'emad multifasica. l'emad corrisponde a un primo episodio clinico con encefalopatia e segni e sintomi multifocali a inizio acuto o subacuto. la rm cerebrale deve manifestare degli ipersegnali focali o multifocali della sostanza bianca. non deve essere trovato alcun evento demielinizzante pregresso. se si verifica una poussée nelle settimane della diminuzione dei corticosteroidi o nei primi mesi dopo l'episodio iniziale, questa poussée precoce deve essere considerata come collegata alla precedente. si tratta, dunque, di un evento monofasico. l'emad ricorrente corrisponde a un nuovo evento demielinizzante, che risponde ai criteri dell'emad, che compaiono più di mesi dopo l'episodio iniziale e più di settimane dopo la fine della terapia con corticosteroidi. questo nuovo episodio deve avere le stesse caratteristiche cliniche e coinvolgere gli stessi territori in rm cerebrale che la malattia iniziale. l'emad multifasica corrisponde a diversi episodi di emad con encefalopatia e deficit multifocali che coinvolgono zone diverse del sistema nervoso centrale rivelato dall'esame neurologico e in rm cerebrale. queste poussées si verificano almeno mesi dopo la malattia iniziale e almeno settimane dopo la sospensione dei corticosteroidi. in caso di emad multifasica, un follow-up rm è fortemente consigliato a mesi per individuare eventuali nuove lesioni che potrebbero testimoniare una disseminazione nel tempo e, pertanto, una sclerosi multipla [ ] . il trattamento delle emad si basa sull'uso di terapie immunoattive non specifiche simili a quelle della sclerosi multipla quali gli steroidi, le immunoglobuline endovenose e gli scambi plasmatici. l'impiego degli steroidi è empirico. in effetti, il loro reale vantaggio è difficile da valutare, poiché sono disponibili solo osservazioni isolate e piccole serie di pazienti. non è stato realizzato alcun studio controllato. lo scopo del loro impiego è quello di ridurre l'infiammazione del sistema nervoso centrale e di accelerare il recupero clinico. diversi gruppi di pediatri riportano serie di pazienti portatori di emad trattati con alte dosi di steroidi o metilprednisone da a mg/kg/die fino a g/die in perfusione endovenosa o desametasone mg/kg per - gg [ , , , [ ] [ ] [ ] . questi trattamenti endovenosi sono seguiti da un trattamento per via orale a dosi decrescenti su - settimane. sotto steroidi, la percentuale di guarigione completa è del % all' % dei pazienti [ , ] . uno studio comparativo di emad trattate con metilprednisone con emad trattate con desametasone endovenoso mostra un'evoluzione più favorevole in termini di scala di handicap expanded disability status scale (edss) nei soggetti che hanno ricevuto metilprednisone [ ] . secondo alcuni studi l'evoluzione sarebbe influenzata dalla durata di diminuzione degli steroidi, con un rischio maggiore di poussée in caso di riduzione su meno di settimane [ , ] . le principali complicanze degli steroidi a forti dosi sono l'insorgenza di ulcere gastrointestinali, di emorragie digestive potenzialmente letali [ ] , di tromboflebiti cerebrali, il cui rischio aumenta in caso di realizzazione di una pl sotto steroidi, di scompenso di diabete, di ipokaliemia con il rischio di disturbi del ritmo cardiaco, di ipertensione arteriosa, di flush cutanei e di disturbi psichiatrici. tenuto conto di questi rischi, una prevenzione delle ulcere gastrointestinali e un monitoraggio della kaliemia, della glicemia, dell'elettrocardiogramma e della pressione arteriosa si rivelano indispensabili per il trattamento. le immunoglobuline endovenose (igev) alla dose di , g/kg/die per gg sono utilizzate anch'esse per il trattamento delle emad. nessuno studio randomizzato ha convalidato la loro efficacia in questa indicazione vs steroidi o scambi plasmatici. il loro impiego si basa su osservazioni che riportano un'efficacia puntuale, o utilizzate da sole [ , ] o in associazione con steroidi. alcune osservazioni riferiscono la loro efficacia nei casi di emad che non hanno risposto ai boli di steroidi [ , , ] o in caso di recidiva [ , ] . i principali effetti secondari delle igev sono il rischio di insufficienza renale, che richiede un'idratazione importante e il monitoraggio della funzione renale, il rischio di shock anafilattico, soprattutto se il paziente presenta un deficit di iga, una meningite asettica e reazioni tipo brivido-ipertermia. gli scambi plasmatici (sp) hanno un ruolo di immunomodulatore, eliminando gli autoanticorpi che si presume provochino la demielinizzazione e alterino l'interazione tra le cellule t e b. weinshenker, nel [ ] , in uno studio randomizzato vs placebo, testa l'efficacia degli sp in sclerosi multiple e in pazienti affetti da patologie infiammatorie con deficit neurologico grave (coma, afasia ecc.) dopo il fallimento dei corticosteroidi a dosi elevate. dopo sp il , % dei pazienti con sclerosi multipla rispondeva al trattamento vs il , % nel braccio placebo a mesi. un gruppo più ampio di malati è stato, in seguito, studiato dalla stessa equipe della mayo clinic. essi riportano l'utilizzo di sp in pazienti, di cui sclerosi multiple remittenti, neuromieliti ottiche e emad. dopo sp il % dei pazienti migliora. questo studio ha permesso di individuare tre fattori predittivi di buona risposta agli sp: il fatto di essere uomo, la conservazione dei riflessi osteotendinei e un trattamento precoce [ ] . gli sp non sono privi di effetti secondari: ipotensione, anemia grave, trombocitopenia da eparina e setticemia che ha come punto di partenza la sede della puntura. per questo motivo, e dal momento che richiedono attrezzature specializzate con un personale esperto, gli sp sono spesso utilizzati in ultima analisi dopo l'insuccesso degli steroidi e/o delle igev. alcune osservazioni puntuali riferiscono casi di emad resistente ai corticosteroidi che sono migliorate dopo l'uso di ciclofosfamide [ ] o di mitoxantrone [ , ] . il trattamento di prima scelta in presenza di un'emad consiste nell'utilizzo di corticosteroidi per via endovenosa a forti dosi, g/die per gg. in assenza di miglioramento dopo gg o di peggioramento malgrado la realizzazione dei boli di corticosteroidi, si ricorre agli sp [ ] . tipicamente, in queste due situazioni sono realizzati ep giorno su . il ruolo delle igev e degli immunosoppressori non è chiaramente stabilito. la prognosi dell'emad è di solito favorevole con, malgrado tutto, una percentuale di mortalità del % [ ] . secondo diverse casistiche di emad [ ] [ ] [ ] [ ] , il %- % dei casi recupera completamente dopo il trattamento. tuttavia, il %- % dei casi conserva deficit motori focali che vanno da una semplice atassia a emiparesi o a cecità. il %- % dei soggetti presenta sequele tipo crisi di epilessia. il %- % dei bambini presenta, nei postumi, dei disturbi del comportamento e cognitivi. alcuni studi mostrano che, anche in bambini che sembrano completamente guariti, esistono lievi deficit neurocognitivi che riguardano l'attenzione, le funzioni esecutive e il comportamento, rilevati dopo anni di follow-up [ ] . uno studio che paragona bambini portatori di emad con soggetti controllo appaiati per età e per sesso mostra che i bambini di meno di anni al momento dell'emad hanno un quoziente intellettivo significativamente più basso rispetto ai soggetti controllo durante la valutazione a , anni in media, mentre i bambini più grandi al momento dell'emad hanno un flusso verbale più lento in occasione della valutazione a , anni in media [ ] . altri studi saranno necessari per caratterizzare i disturbi neurocognitivi presentati nei postumi di emad. benché alcuni studi suggeriscano che i bambini con pregressa emad sarebbero a più alto rischio di sviluppare una sclerosi encefalomielite acuta disseminata ¶ i - - -a- multipla [ , ] , questo rischio è tuttora mal valutato e soggetto a controversie [ ] . nei bambini sarebbe stimato tra lo % per tenembaum [ ] e il % per mikaeloff [ ] . questi studi hanno diversi limiti, tra cui l'eterogeneità dei criteri di diagnosi delle sclerosi multiple pediatriche e durate del follow-up molto varie. nell'adulto, soltanto due studi hanno valutato questo rischio. il % per cento e il % delle emad negli adulti evolverebbero verso una sclerosi multipla, rispettivamente a e a mesi dopo gli studi di de sèze [ ] e di schwarz [ ] . il rischio di evoluzione dell'emad verso una sclerosi multipla sarebbe più basso di quello dei primi eventi infiammatori demielinizzanti (peid) del sistema nervoso centrale. inoltre, in uno studio su bambini con peid ed emad, il % sviluppa una sclerosi multipla definita da due eventi demielinizzanti [ ] . il % dei bambini con emad iniziale ( / ) sviluppa una sclerosi multipla, rispetto al % ( / ) dei bambini con peid iniziale. in questo studio, i fattori predittivi di evoluzione verso una sclerosi multipla sono: età di anni o più, una rm iniziale suggestiva di sclerosi multipla o un interessamento del nervo ottico. i fattori «protettivi» sono: una mielite al primo episodio e i disturbi della coscienza. se la clinica non è sufficiente per distinguere emad e inizio di sclerosi multipla, sarebbe logico pensare che la rmn sia contributiva. tuttavia, le caratteristiche rm non sono specifiche dell'una o dell'altra di queste patologie [ ] (tabella ). in effetti, se le malattie del corpo calloso e della sostanza bianca periventricolare sono più frequenti nei pazienti affetti da sclerosi multipla [ ] , queste si osservano anche nelle autentiche emad [ , ] . il % dei pazienti con emad ha una rmn suggestiva di sclerosi multipla. l'individuazione di boc nel liquor non è più uno strumento che permette di discriminare emad e sclerosi multipla. in effetti, se esse sono presenti nel %- % delle sclerosi multiple pediatriche e nello %- % delle emad, la differenza non è statisticamente significativa [ ] . se ciascuno degli elementi (clinica, neuroimmagini, ocb) preso separatamente non è di alcun aiuto per differenziare emad e sclerosi multipla, diversi studi hanno studiato dei fattori combinati. così, dopo diverse casistiche pediatriche i fattori prognostici a favore di un'emad monofasica sono: un'infezione o una vaccinazione pregressa, manifestazioni polisintomatiche, l'assenza di lesioni periventricolari e l'assenza di ocb [ , , ] . nell'adulto, de sèze [ ] mostra, in una coorte di emad seguita per anni, che un paziente con un primo episodio demielinizzante è a maggior rischio di emad se presenta due dei tre criteri seguenti: • sintomi atipici per una sclerosi multipla, comprendente alterazione della coscienza, ipersonnia, crisi di epilessia, deficit cognitivi, emiplegia, tetraplegia, afasia, neurite ottica bilaterale; • assenza di ocb nel liquor; • coinvolgimento della sostanza grigia (linfonodo della base o lesione corticale). con questi criteri, dei pazienti portatori di emad ( %) erano ben classificati. tra le sm, ( %) non avevano nessuno di questi criteri o ne avevano uno solo ed erano classificate correttamente. la sensibilità di questi criteri è dell' % e la specificità è del %. infatti, l'assenza di biomarker che differenziano formalmente emad e sm all'inizio conferma l'importanza di un follow-up preciso, poiché solo la prova del tempo permette di porre una diagnosi definitiva. questo articolo è dedicato al nostro amico, il prof. Étienne roullet †. 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intravenous immunoglobulin treatment in adult patients with steroid-resistant monophasic or recurrent acute disseminated encephalomyelitis intravenous gammaglobulin therapy in recurrent acute disseminated encephalomyelitis recurrent acute disseminated encephalomyelitis associated with acute cytomegalovirus and epstein-barr virus infection a randomized trial of plasma exchange in acute central nervous system inflammatory demyelinating disease a case of relapsing acute disseminated encephalomyelitis with high dose corticosteroid treatment multiple sclerosis, acute disseminated encephalomyelitis, and related conditions neuropsychological outcome after acute disseminated encephalomyelitis: impact of age at illness onset acute disseminated encephalomyelitis: current understanding and controversies service de neurologie, hôpital tenon, , rue de la chine ogni riferimento a questo articolo deve portare la menzione key: cord- -xn cf a authors: tanz, robert r.; shulman, stanford t. title: sore throat date: - - journal: practical strategies in pediatric diagnosis and therapy doi: . /b - - - - . - sha: doc_id: cord_uid: xn cf a nan sore throat is a common chief complaint. each year approximately million patients in the united states visit physicians because of throat complaints. the majority of these illnesses are nonbacterial and neither necessitate nor are alleviated by antibiotic therapy (tables - to - ). acute streptococcal pharyngitis, however, warrants accurate diagnosis and therapy to prevent serious suppurative and nonsuppurative complications. furthermore, life-threatening infectious complications of streptococcal and nonstreptococcal oropharyngeal infections may manifest with mouth pain, pharyngitis, parapharyngeal space infectious extension, and airway obstruction (tables - and - ). most episodes of pharyngitis are caused by viruses (see tables - and - ). it is difficult to clinically distinguish between viral and bacterial pharyngitis with a very high degree of precision, but certain clues may help the physician. accompanying symptoms of conjunctivitis, rhinitis, croup, or laryngitis are common with viral infection but rare in bacterial pharyngitis. many viral agents can produce pharyngitis (see tables - and - ). some cause distinct clinical syndromes that are readily diagnosed without laboratory testing (see tables - , - , and - ). in pharyngitis caused by parainfluenza and influenza viruses, rhinoviruses, coronaviruses, and respiratory syncytial virus (rsv), the symptoms of coryza and cough often overshadow sore throat, which is generally mild. influenza virus may cause high fever, cough, headache, malaise, myalgias, and cervical adenopathy in addition to pharyngitis. in young children, croup or bronchiolitis may develop. rsv is associated with bronchiolitis, pneumonia, and croup in young children. rsv infection in older children is usually indistinguishable from a simple upper respiratory tract infection. pharyngitis is not a prominent finding of rsv infection in either age group. parainfluenza viruses are associated with croup and bronchiolitis; minor sore throat and signs of pharyngitis are common at the outset but rapidly resolve. infections caused by parainfluenza, influenza, and rsv are often seen in seasonal (winter) epidemics. adenoviruses can cause upper and lower respiratory tract disease, ranging from ordinary colds to severe pneumonia. the incubation period of adenovirus infection is to days. upper respiratory tract infection typically produces fever, erythema of the pharynx, and follicular hyperplasia of the tonsils, together with exudate. enlargement of the cervical lymph nodes occurs frequently. when conjunctivitis occurs in association with adenoviral pharyngitis, the resulting syndrome is called pharyngoconjunctival fever. pharyngitis may last as long as days and does not respond to antibiotics. there are many adenovirus serotypes; adenovirus infections may therefore develop in children more than once. laboratory studies may reveal a leukocytosis and an elevated erythrocyte sedimentation rate. outbreaks have been associated with swimming pools and contamination in health care workers. the enteroviruses (coxsackievirus and echovirus) can cause sore throat, especially in the summer. high fever is common, and the throat is slightly red; tonsillar exudate and cervical adenopathy are unusual. symptoms resolve within a few days. enteroviruses can primary infection caused by herpes simplex virus (hsv) usually produces high fever with acute gingivostomatitis, involving vesicles (which become ulcers) throughout the anterior portion of the mouth, including the lips. there is sparing of the posterior pharynx in herpes gingivostomatitis; the infection usually occurs in young children. high fever is common, pain is intense, and intake of oral fluids is often impaired, which may lead to dehydration. in addition, hsv may manifest in adolescents with pharyngitis. approximately % of new-onset hsv-positive adolescent patients have herpetic lesions; most patients with hsv pharyngitis cannot be distinguished from patients with other causes of pharyngitis. the classic syndrome of herpetic gingivostomatitis in infants and toddlers lasts up to weeks; data on the course of more benign hsv pharyngitis are lacking. the differential diagnosis of vesicular-ulcerating oral lesions is noted in table - . a common cause of a local and large lesion of unknown etiology is aphthous stomatitis ( fig. - ) . some children have a combination of periodic fever (recurrent at predictable fixed times), aphthous stomatitis, pharyngitis, and cervical adenitis (pfapa); this syndrome is idiopathic and may respond to oral prednisone or cimetidine. pfapa usually begins before the age of years and is characterized by high fever lasting to days, occurring every to weeks, and resolving spontaneously. infants and toddlers with measles often have prominent oral findings early in the course of the disease. in addition to high fever, cough, coryza, and conjunctivitis, the pharynx may be intensely and diffusely erythematous, without tonsillar enlargement or exudate. the presence of koplik spots, the pathognomonic white or bluewhite enanthem of measles, on the buccal mucosa near the mandibular molars provides evidence of the correct diagnosis before the rash develops. acute exudative pharyngitis commonly occurs with infectious mononucleosis caused by primary infection with epstein-barr virus (ebv) ( table - ) . mononucleosis is a febrile, systemic, self-limited lymphoproliferative disorder that is usually associated with hepatosplenomegaly and generalized lymphadenopathy. the pharyngitis may be mild or severe, with significant tonsillar hypertrophy (possibly producing airway obstruction), erythema, and impressive tonsillar exudates. regional lymph nodes may be particularly enlarged and slightly tender. infectious mononucleosis usually occurs in adolescents and young adults; ebv infection is generally milder or subclinical in preadolescent children. in united states high school and college students, attack rates are to per , population per year. ebv is transmitted primarily by saliva. after a -to -week incubation period, patients with infectious mononucleosis usually experience an abrupt onset of malaise, fatigue, fever, and headache, followed closely by pharyngitis. the tonsils are enlarged with exudates and cervical adenopathy. more generalized adenopathy with hepatosplenomegaly often follows. fever and pharyngitis typically last to weeks, while lymphadenopathy and hepatosplenomegaly subside over to weeks. malaise and lethargy can persist for several months, possibly leading to impaired school or work performance. laboratory studies of diagnostic value include atypical lymphocytosis; these lymphocytes are primarily ebv-specific, cytotoxic t lymphocytes that represent a reactive response to ebv-infected b lymphocytes. a modest elevation of serum transaminase levels, reflecting ebv hepatitis, is common. tests useful for diagnosis include detection of heterophile antibodies that react with bovine erythrocytes (most often detected by the monospot test) and specific antibody against ebv viral capsid antigen (vca), early antigen (ea), and nuclear antigen (ebna). acute infectious mononucleosis is usually associated with a positive heterophile test result and antibody to vca and ea ( fig. - ) . the findings of acute exudative pharyngitis together with hepatomegaly, splenomegaly, and generalized lymphadenopathy suggest infectious mononucleosis. early in the disease and in cases without liver or spleen enlargement, differentiation from other causes of pharyngitis, including streptococcal pharyngitis, is difficult. indeed, a small number of patients with infectious mononucleosis have a throat culture positive for group a streptococci. serologic evidence of mononucleosis should be sought when splenomegaly or other features are present or if symptoms persist beyond days. patients with infectious mononucleosis require supportive treatment. corticosteroids may be indicated for acute life-threatening conditions, such as airway obstruction caused by enlarged tonsils. in the evaluation of a patient with sore throat, the primary concern is usually accurate diagnosis and treatment of pharyngitis caused by group a streptococci, which accounts for about % of all episodes of pharyngitis. the sequelae of group a streptococcal pharyngitis, especially acute rheumatic fever and acute glomerulonephritis, at one time resulted in considerable morbidity and mortality in the united states and continue to do so in other parts of the world. prevention of acute rheumatic fever in particular depends on timely diagnosis of streptococcal pharyngitis and prompt antibiotic treatment. group a streptococci are characterized by the presence of group a carbohydrate in the cell wall, and they are further distinguished by several kinds of cell wall protein antigens (m, r, t). these protein antigens are useful for studies of epidemiology and pathogenesis. group a streptococcal pharyngitis has been endemic in the united states; epidemics occur sporadically. episodes peak in the late winter and early spring; rates of group a streptococcal pharyngitis are highest among children aged to years old. spread of group a streptococci in classrooms and among family members, especially in crowded living conditions, is common. transmission occurs primarily by inhalation of organisms in large droplets or by direct contact with respiratory secretions. pets do not appear to be a frequent reservoir. untreated streptococcal pharyngitis is particularly contagious early in the acute illness and for the first weeks after the organism has been acquired. antibiotic therapy effectively prevents disease transmission. within hours of institution of therapy with penicillin, it is difficult to isolate group a streptococci from patients with acute streptococcal pharyngitis, and infected children can return to school. molecular epidemiology studies of streptococcal pharyngitis have shown that numerous distinct strains of group a streptococci circulate simultaneously in the community during the peak season. "dna-fingerprinting" techniques further demonstrate that children with streptococcal pharyngitis serve as a community reservoir for strains that cause invasive disease (e.g., sepsis, streptococcal toxic shock syndrome, cellulitis, necrotizing fasciitis) in the same geographic area and season. the classic patient with acute streptococcal pharyngitis has a sudden onset of fever and sore throat. headache, malaise, abdominal pain, nausea, and vomiting occur frequently. cough, rhinorrhea, conjunctivitis, stridor, diarrhea, and hoarseness are distinctly unusual and suggest a viral etiology. examination of the patient reveals marked pharyngeal erythema. petechiae may be noted on the palate, but they can also occur in viral pharyngitis (see table - ). tonsils are enlarged, symmetric, and red, with patchy exudates on their surfaces. the papillae of the tongue may be red and swollen; hence the designation "strawberry tongue." anterior cervical lymph nodes are often tender and enlarged. combinations of these signs can be used to assist in diagnosis; in particular, tonsillar exudates in association with fever, palatal petechiae, and tender anterior cervical adenitis strongly suggest infection with group a streptococci. however, other diseases can produce this constellation of findings. some or all of these classic characteristics may be absent in patients with streptococcal pharyngitis. younger children often have coryza with crusting below the nares, more generalized adenopathy, and a more chronic course, a syndrome called streptococcosis. when rash accompanies the illness, accurate clinical diagnosis is easier. scarlet fever, so-called because of the characteristic fine, diffuse red rash, is essentially pathognomonic for infection with group a streptococci. scarlet fever is rarely seen in children younger than years old or in adults. the rash of scarlet fever is caused by infection with a strain of group a streptococci that contains a bacteriophage encoding for production of an erythrogenic (redness-producing) toxin, usually erythrogenic (or pyrogenic) exotoxin a. scarlet fever is simply group a streptococcal pharyngitis with a rash and should be explained as such to patients and their families. although patients with the streptococcal section one respiratory disorders streptococcal toxic shock syndrome is usually associated with a primary cutaneous rather than a pharyngeal focus of infection. the rash of scarlet fever has a texture like sandpaper and blanches with pressure. it usually begins on the face, but after hours it becomes generalized. the face, especially the cheeks, is red, and the area around the mouth often appears pale in comparison (circumoral pallor). accentuation of erythema occurs in flexor skin creases, especially in the antecubital fossae (pastia's lines). the erythema begins to fade within a few days. desquamation begins within a week of onset on the face and progresses downward, often resembling that seen after a mild sunburn. on occasion, sheetlike desquamation occurs around the free margins of the fingernails and is usually more coarse than the desquamation seen with kawasaki disease. the differential diagnosis of scarlet fever includes kawasaki disease, measles, and staphylococcal toxic shock syndrome (table - ). although signs and symptoms may strongly suggest acute streptococcal pharyngitis, laboratory diagnosis is highly recommended, even for patients with scarlet fever (fig. - ) . scoring systems for diagnosing acute group a streptococcal pharyngitis on clinical grounds have not proved very useful. using clinical criteria alone, physicians overestimate the likelihood that patients have streptococcal infection. the throat culture has traditionally been used to diagnose streptococcal pharyngitis. plating a swab of the posterior pharynx and tonsils on sheep blood agar, identifying β−hemolytic colonies, and testing them for the presence of sensitivity to a bacitracinimpregnated disk is the "gold standard" diagnostic test, but it takes to hours to obtain results. there are a number of rapid diagnostic tests that take less than minutes. these "rapid strep" tests detect the presence of the cell wall group a carbohydrate antigen after acid extraction of organisms obtained by throat swab. rapid strep tests are highly specific (generally > %), with the throat culture used as the standard. unfortunately, the sensitivity of most of these rapid tests can be considerably lower. in comparison to hospital or reference laboratory throat culture results, the sensitivities of these tests are generally % to % and can be lower. however, when both throat cultures and rapid tests performed in physicians' offices are compared with cultures performed in reference laboratories, the sensitivities, specificities, and overall accuracy of the office culture and the office rapid test are quite similar; the latter often performs better than the culture. the low sensitivity of these tests, coupled with their excellent specificity, has led to the recommendation that two swabs be obtained from patients with suspected streptococcal pharyngitis. one swab is used for a rapid test. when the rapid antigen detection test result is positive, it is highly likely that the patient has group a streptococcal infection, and the extra swab can be discarded. when the rapid test result is negative, group a streptococci may nonetheless be present; thus, the extra swab should be processed for culture. physician offices that have demonstrated that their rapid test and throat culture results are comparable may be able to rely on the rapid test result even when it is negative, without performing a backup culture. in general, patients with a negative result of the rapid test do not require treatment before culture verification unless there is a particularly high suspicion group a streptococcal infection (e.g., scarlet fever, peritonsillar abscess, or tonsillar exudates in addition to tender cervical adenopathy, palatal petechiae, fever, and recent exposure to a person with group a streptococcal pharyngitis). testing patients for serologic evidence of an antibody response to extracellular products of group a streptococci is not useful for diagnosing acute pharyngitis. because it generally takes several weeks for antibody levels to rise, streptococcal antibody tests are valid only for determining past infection. specific antibodies include antistreptolysin o (aso), anti-dnase b, and antihyaluronidase (aht). when antibody testing is desired in order to evaluate a possible post-streptococcal illness, more than one of these tests should be performed to improve sensitivity. treatment begun within days of the onset of group a streptococcal pharyngitis is effective in preventing acute rheumatic fever. therapy does not appear to affect the risk of the other nonsuppurative sequela, acute post-streptococcal glomerulonephritis. antibiotic therapy also reduces the incidence of suppurative sequelae of group a streptococcal pharyngitis, such as peritonsillar abscess and cervical adenitis. in addition, treatment produces a more rapid resolution of signs and symptoms and terminates contagiousness within hours. for these reasons, antibiotics should be instituted as soon as the diagnosis is supported by laboratory studies. there are numerous antibiotics available for treating streptococcal pharyngitis (table - ). the drug of choice is penicillin. despite the widespread use of penicillin to treat streptococcal and other infections, penicillin resistance among group a streptococci has not developed. penicillin can be given by mouth for days or intramuscularly as a single injection of benzathine penicillin. intramuscular benzathine penicillin alleviates concern with patient compliance. a less painful alternative is benzathine penicillin in combination with procaine penicillin. intramuscular procaine penicillin alone is inadequate for prevention of acute rheumatic fever because adequate levels of penicillin are not present in blood and tissues for a sufficient time. other β-lactams, including semisynthetic derivatives of penicillin and the cephalosporins, are at least as effective as penicillin for treating group a streptococcal pharyngitis. their broader spectrum, their higher cost, and the lack of formal data concerning prevention of acute rheumatic fever relegate them to second-line status. the decreased frequency of dose administration of some of these agents may improve patient compliance and makes their use attractive in selected circumstances. patients who are allergic to penicillin should receive erythromycin or another non-β-lactam antibiotic, such as clarithromycin, azithromycin, or clindamycin. resistance of group a streptococci to erythromycin has increased dramatically in areas such as japan, france, spain, taiwan, and finland, where erythromycin has been widely used. this has not yet emerged as a major problem in the united states, where the rate of macrolide resistance is about %. sulfa drugs (including sulfamethoxazole combined with trimethoprim), tetracyclines, and chloramphenicol should not be used for treatment of acute streptococcal pharyngitis because they do not eradicate group a streptococci. antibiotic therapy has greatly reduced the likelihood of developing suppurative complications caused by spread of group a streptococci from the pharynx or middle ear to adjacent structures. peritonsillar abscess ("quinsy") manifests with fever, severe throat pain, dysphagia, "hot potato voice," pain referred to the ear, and bulging of the peritonsillar area with asymmetry of the tonsils and sometimes displacement of the uvula (fig. - ; see table - ). on occasion, there is peritonsillar cellulitis without a well-defined abscess cavity. trismus may be present. when an abscess is found clinically or by an imaging study such as a computed tomographic scan, surgical drainage is indicated. peritonsillar abscess occurs most commonly in older children and adolescents. sore throat necrotizing fasciitis diarrhea *case definition of streptococcal toxic shock syndrome requires (i) isolation of group a streptococci from (a) a normally sterile site (blood, synovial or peritoneal fluid) or (b) a nonsterile site (throat, wound). (ii) severity is defined by (a) hypotension and (b) two or more of renal impairment, coagulopathy, liver involvement, adult respiratory distress syndrome, a generalized erythematous macular rash (with or without later desquamation), and soft tissue necrosis (necrotizing fasciitis, myositis, gangrene). the definitive diagnosis requires criteria ia and iia plus b. criteria ib and iia plus b are considered probable if no other identifiable cause is present. alt, alanine aminotransferase; ast, aspartate aminotransferase; bun, blood urea nitrogen. retropharyngeal abscess represents extension of infection from the pharynx or peritonsillar region into the retropharyngeal (prevertebral) space, which is rich in lymphoid structures (figs. - and - ; see table - ). children younger than years old are most often affected. fever, dysphagia, drooling, stridor, extension of the neck, and a mass in the posterior pharyngeal wall may be noted. surgical drainage is often required if frank suppuration has occurred. spread of group a streptococci via pharyngeal lymphatic vessels to regional nodes can cause cervical lymphadenitis. the markedly swollen and tender anterior cervical nodes that result can suppurate. otitis media, mastoiditis, and sinusitis also may occur as complications of group a streptococcal pharyngitis. additional parapharyngeal suppurative infections that may mimic streptococcal disease are noted in table - . furthermore, any pharyngeal infectious process may produce torticollis if there is inflammation that extends to the paraspinal muscles and ligaments, producing pain, spasm, and, on occasion, rotary subluxation of the cervical spine. the differential diagnosis of torticollis is presented in table - . oropharyngeal torticollis lasts less than weeks and is not associated with abnormal neurologic signs or pain over the spinous process. nonsuppurative complications include acute rheumatic fever (see chapters and ), acute post-streptococcal glomerulonephritis (see chapter ), and possibly reactive arthritis/synovitis. in addition, an association between streptococcal infection and neuropsychiatric disorders such as obsessive-compulsive disorder and tourette syndrome has been postulated. this possible association has been called pandas (pediatric autoimmune neuropsychiatric disorders associated with streptococci). therapy with an appropriate antibiotic within days of onset of symptoms is highly effective in preventing rheumatic fever, but acute glomerulonephritis is not prevented by treatment of the antecedent streptococcal infection. pharyngitis caused by one of the nephritogenic strains of group a streptococci precedes the glomerulonephritis by about days. unlike acute rheumatic fever, which occurs only after group a streptococcal pharyngitis, acute glomerulonephritis also can follow group a streptococcal skin infection. treatment with penicillin cures group a streptococcal pharyngitis but is unable to eradicate group a streptococci from the pharynx in approximately % of patients ( fig. - ) . this causes considerable consternation among such patients and their families. penicillin resistance is not the cause of treatment failure. a small proportion of these patients are symptomatic and are thus characterized as having clinical treatment failure. reinfection with the same strain or a different strain is possible, as is intercurrent viral pharyngitis. some of these patients may be chronic pharyngeal carriers of group a streptococci who are suffering from a new superimposed viral infection; others may be noncompliant with regard to therapy. many patients who do not respond to antimicrobial treatment are asymptomatic and are identified when follow-up culture specimens are obtained, a practice that is usually unnecessary. patients who are compliant with regard to therapy are at minimal risk for acute rheumatic fever. one explanation for asymptomatic persistence of group a streptococci after treatment is that these patients were chronic carriers of group a streptococci who were initially symptomatic because of a concurrent viral pharyngitis and who did not truly have acute streptococcal pharyngitis. patients who are chronically colonized with group a streptococci are called chronic carriers. carriers do not appear to be at risk for acute section one respiratory disorders headache pyuria (sterile); gallbladder hydrops rheumatic fever or for development of suppurative complications, and they are rarely sources of spread of group a streptococci in the community. there is no reason to exclude these carriers from school. there is no easy way to identify chronic carriers prospectively among patients with symptoms of acute pharyngitis. the clinician should consider the possibility of chronic group a streptococcal carriage when a patient or a family member has multiple culturepositive episodes of pharyngitis, especially when symptoms are mild or atypical. a culture specimen is usually positive for group a streptococci when the suspected carrier is symptom-free or is receiving treatment with penicillin (intramuscular benzathine penicillin is recommended in order to eliminate concern about compliance). carriers often receive multiple unsuccessful courses of antibiotic therapy in attempts to eliminate group a streptococci. physician and patient anxiety is common and can develop into "streptophobia." unproven and ineffective therapies include tonsillectomy, prolonged administration of antibiotics, use of β-lactamase-resistant antibiotics, and culture or treatment of pets. available treatment options for the physician faced with a chronic streptococcal carrier include the following: . obtaining a rapid test, throat culture, or both each time the patient has pharyngitis with features that suggest streptococcal pharyngitis, and treating with penicillin each time a test is positive. . treating with one of the regimens effective for terminating chronic carriage. the first option is simple, as safe as penicillin, and appropriate for many patients. the second option should be reserved for particularly anxious patients; those with a history of acute rheumatic fever or living with someone who had it; or those living or working in nursing homes, chronic care facilities, hospitals, and perhaps schools. the two antibiotic treatment regimens that have been effective for eradication of the carrier state are: • intramuscular benzathine penicillin plus oral rifampin ( mg/kg/ dose up to mg, given twice daily for days beginning on the day of the penicillin injection) • oral clindamycin, given for days ( mg/kg/day up to mg, divided into three equal doses) clindamycin may be preferred because it is easier to use than intramuscular penicillin plus oral rifampin and may be somewhat more effective. in controlled, comparative trials, no other antibiotic regimens have been demonstrated to reliably terminate the chronic streptococcal carrier state. successful eradication of the carrier state makes evaluation of subsequent episodes of pharyngitis much easier, although chronic carriage can recur upon reexposure to group a streptococci. some patients seem remarkably susceptible to group a streptococci. the reasons for frequent bona fide acute group a streptococcal pharyngitis are obscure, but appropriate antibiotic treatment results in resolution of symptoms and eradication of group a streptococci. the role of tonsillectomy in the management of patients with multiple episodes of streptococcal pharyngitis is controversial. fewer episodes of sore throat have been reported among patients treated with tonsillectomy (in contrast to patients treated without surgery) during the first years after operation. the patients enrolled in that study had experienced numerous episodes of pharyngitis, but it appears that not all episodes were caused by group a streptococci. of particular concern is the reported tonsillectomy complication rate of % and the improvement over time noted among the nontonsillectomy patients. in addition, the presence of tonsils is not necessary for group a streptococci to infect the throat. tonsillectomy cannot be recommended except in unusual circumstances. it seems preferable to treat most patients with penicillin whenever symptomatic group a streptococcal pharyngitis occurs. obtaining follow-up throat specimens for culture helps distinguish recurrent pharyngitis from chronic carriage. certain β−hemolytic streptococci of serogroups other than group a cause acute pharyngitis. well-documented epidemics of food-borne group c and group g streptococcal pharyngitis have been reported in young adults. in these situations, a high percentage of individuals who have ingested the contaminated food promptly developed acute pharyngitis, and throat cultures yielded virtually pure growth of the epidemiologically linked organism. there have been outbreaks of group g streptococcal pharyngitis among children. however, the role of these non-group a streptococcal organisms as etiologic agents of acute pharyngitis in endemic circumstances has been difficult to establish. group c and group g β streptococci may be responsible for acute pharyngitis, particularly in adolescents. however, the exact role of these agents, most of which are carried asymptomatically in the pharynx of some children and young adults, remains to be fully characterized. when they are implicated as agents of acute pharyngitis, groups c and g organisms do not appear to necessitate treatment, inasmuch as they cause self-limited infections. acute rheumatic fever is not a sequela to these infections, although post-streptococcal acute glomerulonephritis has been documented in rare cases after epidemic group c and group g streptococcal pharyngitis. arcanobacterium (formerly corynebacterium) haemolyticum is a gram-positive rod that has been reported to cause a scarlet fever-like illness with acute pharyngitis and scarlatinal rash, particularly in teenagers and young adults. detecting this agent requires special methods for culture, and it has not routinely been sought in patients with scarlet fever or pharyngitis. the clinical features of a. haemolyticum pharyngitis are indistinguishable from group a streptococcal pharyngitis; pharyngeal erythema is present in almost all patients, patchy white to gray exudates in about %, cervical adenitis in about %, and moderate fever in %. palatal petechiae and strawberry tongue may also occur. the scarlatiniform rash usually spares the face, palms, or soles. it is erythematous and blanches; it may be pruritic and demonstrate minimal desquamation. erythromycin appears to be the treatment of choice. section one respiratory disorders ( to ) , and infection has been documented in several travelers from western europe. the pathogenesis of diphtheria involves nasopharyngeal mucosal colonization by c. diphtheriae and toxin elaboration after an incubation period of to days. toxin leads to local tissue inflammation and necrosis (producing an adherent grayish membrane made up of fibrin, blood, inflammatory cells, and epithelial cells) and it is absorbed into the blood stream. fragment b of the polypeptide toxin binds particularly well to cardiac, neural, and renal cells, and the smaller fragment a enters cells and interferes with protein synthesis. toxin fixation by tissues may lead to fatal myocarditis (with arrhythmias) within to days and to peripheral neuritis within to weeks. acute tonsillar and pharyngeal diphtheria is characterized by anorexia, malaise, low-grade fever, and sore throat. the grayish membrane forms within to days over the tonsils and pharyngeal walls and occasionally extends into the larynx and trachea. cervical adenopathy varies but may be associated with development of a "bull neck." in mild cases, the membrane sloughs after to days and the patient recovers. in severe cases, an increasingly toxic appearance can lead to prostration, stupor, coma, and death within to days. distinctive features include palatal paralysis, laryngeal paralysis, ocular palsies, diaphragmatic palsy, and myocarditis. airway obstruction (from membrane formation) may complicate the toxigenic manifestations. accurate diagnosis requires isolation of c. diphtheriae on culture of material from beneath the membrane, with confirmation of toxin production by the organism isolated. laboratories must be forewarned that diphtheria is suspected. other tests are of little value. treatment includes equine antitoxin to neutralize circulating toxin, as well as systemic penicillin or erythromycin. in a teenager, the retropharyngeal space normally does not exceed mm when measured from the anterior aspect of the c vertebral body to the posterior pharynx. in infants, the retropharyngeal space is usually less than one width of the adjacent vertebral body. however, during crying, this distance may be three widths of the vertebral body. also, under normal circumstances, the retrotracheal space does not exceed mm in teenagers when measured from the anterior aspect of c- to the trachea. dotted lines depict the "thumbprint" sign, noted on a lateral neck radiograph, made by a swollen epiglottis. (from reilly bm: sore throat. in practical strategies in outpatient medicine, nd ed. philadelphia: wb saunders, .) acute symptomatic pharyngitis caused by neisseria gonorrhoeae occurs occasionally in sexually active individuals as a consequence of oral-genital contact. in cases involving young children, sexual abuse must be suspected. the infection usually manifests as an ulcerative, exudative tonsillopharyngitis but may be asymptomatic and resolve spontaneously. gonococcal pharyngitis occurs in homosexual men and heterosexual women after fellatio and is less readily acquired after cunnilingus. gonorrhea rarely is transmitted from the pharynx to a sex partner, but pharyngitis can serve as a source for gonococcemia. diagnosis requires culture on appropriate selective media (e.g., thayer-martin medium). recommended therapeutic regimens include a single intramuscular dose of mg of ceftriaxone or a single oral -mg dose of ciprofloxacin. spectinomycin is ineffective performance of a predictive model for streptococcal pharyngitis in children group a streptococcal infections and acute rheumatic fever acute pharyngitis optical immunoassay test for group a ß-hemolytic streptococcal pharyngitis: an office-based, multicenter investigation potential mechanisms for failure to eradicate group a streptococci from the pharynx the changing epidemiology of invasive group a streptococcal infections and the emergence of streptococcal toxic shock-like syndrome: a retrospective populationbased study persistence of group a streptococci in eukaryotic cells-a safe place? what is a throat culture streptococcal pharyngitis: the carrier state, definition and management streptococcus associated toxic shock persistence of acute rheumatic fever in the intermountain area of the united states outbreak of group a streptococcus septicemia in children: clinical, epidemiologic, and microbiological correlates working group on severe streptococcal infections: defining the group a streptococcal toxic shock syndrome: rationale and consensus definition other pathogens community-wide outbreak of group g streptococcal pharyngitis periodic fever, aphthous stomatitis, pharyngitis, adenitis: a clinical review of a new syndrome arcanobacterium haemolyticum in children with presumed streptococcal pharyngotonsillitis or scarlet fever chlamydial pharyngitis mononucleosis caused by epstein-barr virus and cytomegalovirus in children: a comparative study of cases pharyngitis associated with herpes simplex virus in college students pharyngoconjunctival fever caused by adenovirus type epstein-barr virus infections: biology, pathogenesis, and management epstein-barr virus infectious mononucleosis in children: i. clinical and general laboratory findings epstein-barr virus infectious mononucleosis in children: ii. heterophil antibody and viral-specific responses arcanobacterium haemolyticum: biology of the organism and diseases in man life-threatening infections of the head and neck clinical infections and nonsurgical treatment of parapharyngeal space infections complicating throat infection pharyngitis followed by hypoxia and sepsis: lemierre syndrome peritonsillar abscess: clinical and microbiologic aspects and treatment regimens upper respiratory tract infections in young children: duration of and frequency of complications deep neck infections and respiratory distress in children new approaches to the treatment of group a streptococcal pharyngitis treatment of streptococcal pharyngotonsillitis: reports of penicillin's demise are premature penicillin and the marked decrease in morbidity and mortality from rheumatic fever in the united states efficacy of tonsillectomy for recurrent throat infection in severely affected children: results of parallel randomized and nonrandomized clinical trials effect of antibiotic therapy on the clinical course of streptococcal pharyngitis resistance to erythromycin in group a streptococci streptococcal pharyngitis: the case for penicillin therapy duration of positive throat cultures for group a streptococci after initiation of antibiotic therapy clindamycin treatment of chronic pharyngeal carriers of group a streptococci in gonococcal pharyngitis. examination and testing for other sexually transmitted diseases and pregnancy are recommended. chlamydia species and mycoplasma pneumoniae may cause pharyngitis, although the frequency of these infections is disputed. chlamydia trachomatis has been implicated serologically as a cause of pharyngitis in as many as % of adults with pharyngitis, but isolation of the organism from the pharynx has proved more difficult. chlamydia pneumoniae has also been identified as a cause of pharyngitis. because antibodies to this organism show some crossreaction with c. trachomatis, it is possible that infections formerly attributed to c. trachomatis were really caused by c. pneumoniae. diagnosis of chlamydial pharyngitis is difficult, whether by culture or serologically, and neither method is readily available to the clinician.m. pneumoniae most likely causes pharyngitis. serologic (positive mycoplasma immunoglobulin m [igm]) or, less often, culture methods can be used to identify this agent, which was found in % of college students with pharyngitis in one study. polymerase chain reaction (pcr) is diagnostic.there is no need to seek evidence of these organisms routinely in pharyngitis patients in the absence of ongoing research studies of nonstreptococcal pharyngitis. the efficacy of antibiotic treatment for m. pneumoniae and chlamydial pharyngitis is not known, but these illnesses appear to be self-limited. treatment of more complicated m. pneumoniae infections, such as pneumonia (table - ), is indicated with erythromycin, azithromycin, or clarithromycin; doxycycline may be used if the patient is older than years. key: cord- -e anaxck authors: mostov, perry d. title: treating the immunocompetent patient who presents with an upper respiratory infection: pharyngitis, sinusitis, and bronchitis date: - - journal: prim care doi: . /j.pop. . . sha: doc_id: cord_uid: e anaxck nan usually diffuse nature. as such, the term uri has come to encompass multiple clinical entities including pharyngitis, sinusitis, and bronchitis, as well as nonspecific respiratory infections, a designation that includes the common cold. the classification scheme based upon the predominate anatomic site of the presenting symptom complex tends to be poorly specific for directing therapy [ ] . these diagnoses and their treatment will be examined relative to the nonspecific uri. determining the evidence-based indications and relative value of antibiotic therapy for each may limit unnecessary use. although a thorough examination of the viral uri is beyond the scope of this article, brief review of the nonspecific or undifferentiated uri and its treatment may provide some context for a discussion of these more specific conditions. the inappropriate use of antibiotics, for respiratory infections in particular, has been implicated in the emergence of antibiotic resistance, especially in streptococcus pneumoniae [ ] . guidelines for diagnosis and treatment of the uri based upon a nonfocal presentation have been developed in an effort to limit the indiscriminate use of antibiotics for what are generally viral illnesses [ ] . the course of the viral uri, also termed acute rhinopharyngitis, is generally self-limited in nature and mild in severity. symptoms may persist for greater than week in duration in more than % of cases, and persist for weeks in % [ ] . the cause is most commonly rhinovirus and to a lesser extent coronavirus (typically in midwinter), and adenovirus (typically in spring to fall). although laboratory identification can be accomplished, the time required to identify the cause may exceed the duration of the illness and the yields may be highly variable [ ] . syndromes involving symptoms of greater severity and more commonly including the lower respiratory tract are caused by influenza, parainfluenza, and respiratory syncitial virus [ ] . there may be some benefit in the prompt identification of influenza to initiate timely neuraminidase inhibitor therapy [ , ] . it appears, however, that neither a rapid influenza test nor a clinical prediction rule is superior to clinical judgment in establishing the diagnosis [ ] . treatment of the uri is essentially symptom-directed, because antibiotic treatment does not appear to contribute to resolution of the illness. their benefit in preventing life-threatening complications, such as meningitis, sepsis, or abscess, in such patients has not been adequately assessed [ ] . bacterial sinusitis may develop as a complication in a minority of patients and is reviewed later. improvement is expected in the uri by the first week, notwithstanding reports that sinus changes may be demonstrated on ct studies in most patients in the first few days of illness [ ] . a recent systematic review of the literature has found insufficient evidence to warrant the use of antibiotics for uris in adults or children [ ] . adults experienced a greater rate of adverse effects with antibiotics than with placebo. patients who have respiratory infections may have certain expectations for antibiotic prescriptions, and physicians may prescribe antibiotics based on their perceptions of these expectations; however, patient satisfaction has been correlated with physician time spent with them and the patient's understanding of their diagnosis to a greater extent than the prescription of an antibiotic [ ] . when patients who had upper respiratory symptoms were randomized to receive immediate antibiotics, or to have antibiotic use delayed by hours, clinical outcomes were not significantly different for most symptoms, although some symptom scores worsened in the delayed use groups who had sore throat and otitis media [ ] . significant variability of symptom scores was noted between these trials. clinical decision support systems, guiding physicians in appropriate antibiotic use for respiratory infections may reduce inappropriate use [ ] . use of oral and topical nasal decongestants provides benefit for shortterm use in adults; there is no evidence supporting their use in children [ ] . studies of treatment with antihistamines alone for the common cold have shown no faster recovery, and only small benefit for sneezing and rhinorrhea at the expense of sedation. in combination with decongestants, no effect was seen in small children, but some benefit in general recovery and nasal symptoms was noted in older children and adults [ ] . intranasal ipratropium decreases rhinorrhea, and may decrease sneezing and promote nasal drying [ ] . evidence for the use of zinc in the treatment of uri is inconclusive [ ] , and echinacea extract showed no significant effects in either infection rates with rhinovirus or symptom severity [ ] . the role of vitamin c in prevention appears to be limited to perhaps those individuals exposed to severe physical or low-temperature stress, and therapeutic benefit was limited or equivocal [ ] . the pharynx is the common portal to the human respiratory and digestive tracts and is exposed to multiple potential pathogens. pharyngitis is predominantly viral in etiology, accounting for as much as % of all cases in adults [ ] . the cardinal feature, sore throat, is also a feature of the common cold. in adenovirus infections it is usually accompanied by adenitis and conjunctivitis, and is associated with erosive stomato-pharyngitis in herpes simplex [ ] . in coxsackie virus infections sore throat is associated with pharyngeal vesicles (herpangina) or with hand and foot vesicles [ ] . epstein-barr virus infection is characterized by the fatigue, functional impairment, and cervical lymphadenopathy of mononucleosis [ ] . bacterial causes of sore throat include group a b-hemolytic streptococcus (gabhs), the most common cause of bacterial pharyngitis, and non-group-a streptococcus. less common causes are mycoplasma pneumoniae, chlamydia pneumoniae, and neisseria gonorrhoeae. a rare cause is arcanobacterium haemolyticum, which is associated with an exanthema that may mimic the rash of scarlet fever [ ] . among these various causes, the only commonly occurring infection for which antibiotic therapy is beneficial is gabhs. the goals of treating gabhs include expediting clinical recovery, decreasing the likelihood of suppurative complications (such as abscess), preventing acute rheumatic fever, and limiting transmission of the disease [ ] . at the same time, by excluding from treatment those patients who have pharyngitis who are not infected by gabhs, the adverse effects of treatment and the emergence of antibiotic-resistant bacteria are avoided [ ] . gabhs may account for % to % of pharyngitis in adults and % to % in school age children, yet in a national survey % of adults [ ] and % of children [ ] who had pharyngitis were treated with antibiotics. the typical symptoms of streptococcal pharyngitis are sudden onset of sore throat accompanied by fever. in children, abdominal pain and vomiting are also reported. the presence of cough and rhinorrhea suggest a non-gabhs etiology. the physical findings may include pharyngeal erythema, tonsillar exudates, and enlarged cervical lymph nodes. fever, palatal petechiae and uvular swelling, none of which are specific for streptococcal infection, are also found. all of these historical and physical features are common to infections by other agents, including group c and group g streptococcus [ ] . because a physician may be unable to clinically distinguish gabhs from the causes of pharyngitis for which antibiotics should be withheld, a laboratory test will in some cases be necessary to confirm the diagnosis [ ] . a throat culture, consisting of a throat swab incubated on blood agar and confirming gabhs growth by the inhibitory effects of bacitracin, has been the standard for diagnosis; however, results of this culture are only available after to hours, with a delay in immediate and appropriate therapy. with this delay, the benefits of timely treatment, which include reducing risk of disease transmission, diminishing symptoms, and speeding recovery, are jeopardized [ ] . rapid antigen detection testing (radt) for gabhs was developed to provide more immediate, albeit more costly results, with a demonstrated specificity exceeding % relative to blood agar culture [ ] . a clinical score based on the cumulative presence or absence of specific clinical features may be used to exclude or entertain the diagnosis of gabhs, thereby reducing the need for both throat cultures and unnecessary antibiotics [ , ] . use of a sore throat score to determine treatment of children and adults in a university-based family practice demonstrated a % reduction in antibiotic prescription compared with usual care [ ] . in a community-based family practice, mcisaac and colleagues [ ] assessed a clinical score for validity that resulted in a reduction in antibiotic prescription of . %, and a reduction in throat cultures of . %. sensitivity and specificity of the score relative to culture was . % and . % respectively ( table ) . a systematic review of the clinical diagnosis of strep throat by ebell and coworkers [ ] showed that the presence of tonsillar or pharyngeal exudates or exposure to strep throat infection in the previous weeks were reliable in predicting the likelihood of gabhs pharyngitis (positive likelihood ratio [lr] of . , . , and . , respectively). the absence of tender anterior cervical nodes, tonsillar enlargement, or exudates were reliable predictors that gabhs was not present (negative lr of . , . , and . , respectively). no single element of the history or physical examination alone was sufficient for excluding or diagnosing strep throat. based on the prevalence of gabhs in a given population, clinical prediction rules can be used to calculate the individual's probability of gabhs pharyngitis ( table ) . the american college of physicians (acp) developed guidelines for the diagnosis of pharyngitis in adults based upon clinical prediction rules [ ] . throat culture is excluded from this diagnostic algorithm because the delay in its result precludes an immediate treatment decision and the potential benefit of symptom relief. an additional concern is the failure of culture to discriminate between infection and the carrier state. instead, recommendations are to assess by radt the patient who have two to three clinical criteria (intermediate risk) and treat only for a positive test. patients who have three or four criteria are treated empirically. all others are neither tested nor treated. this approach acknowledges the chance of undertreatment based on testing only those designated as intermediate to high risk by criteria (both sensitivity and specificity of approximately %), while emphasizing the relatively low likelihood of suppurative complications and acute rheumatic fever. a cost-effectiveness analysis compared five strategies in the diagnosis and management of pharyngitis in adults assuming a gabhs prevalence of % [ ] . a decision model was constructed to evaluate the strategies of observation only, empiric therapy, two-plate throat culture, radt (optical immunoassay) followed by culture to confirm negative results, or radt alone. the findings of this analysis generally supported the acp guidelines, except that a marginal superiority in costs and effectiveness is seen with culture. the other strategies differed little in cost-effectiveness; however, empirical therapy achieved reasonable cost-effectiveness only when very high gabhs prevalence is assumed. guidelines provided by the infectious disease society of america for the diagnosis and management of gabhs pharyngitis calls for laboratory testing based on epidemiological and clinical features and exclusion of those who appear at low risk [ ] . confirmatory culture of negative radt results in adults is not recommended. a confirmatory throat culture is advised for radt negative children and adolescents because there is a higher prevalence of gabhs and acute rheumatic fever. follow-up cultures are not recommended after appropriate therapy in asymptomatic individuals except under circumstances of an epidemic in a closed community or recurrent infection in a household when carriage is suspected. treatment of gabhs is aimed at eradication of the organism from the upper respiratory tract [ ] . a cochrane review [ ] assessed the benefits of antibiotic treatment of sore throat. studies demonstrating a reduction in rheumatic fever with antibiotic therapy found benefits were modest, with large numbers of individuals needed to treat to derive meaningful benefit [ ] . a reduction in symptoms (sore throat, headache, or fever) by about one half was seen with antibiotic therapy at . days of illness. five patients would need to be treated with antibiotics to eliminate one sore throat by day and seven patients would need to be treated to eliminate one sore throat by day . a subgroup analysis of patients evaluated with a throat swab for streptococcus revealed significantly greater symptom reduction with antibiotic treatment in those who had a positive swab than a negative swab. antibiotic therapy resulted in a reduction in the incidence of suppurative complications, including otitis media, sinusitis, and quinsy (peritonsillar abscess) compared with placebo. penicillin is recommended for the treatment of gabhs pharyngitis [ ] . in penicillin-allergic patients, erythromycin is recommended. gabhs resistance to penicillin has not been reported; however, some resistance to macrolides, including erythromycin, has been seen [ ] . first-generation cephalosporins are acceptable alternatives for patients who have a history of non-anaphylactic allergy to b-lactam antibiotics. although a -day course of penicillin is recommended for eradication of gabhs, shorter courses of therapy with other agents have been shown to be effective [ , ] . providing written instructions on the use of the antibiotics for sore throat has improved compliance [ ] . treatment of pharyngitis with corticosteroids has demonstrated inconsistent results. in one study [ ] , a single dose of oral dexamethasone ( . mg/kg) provided greater pain relief than placebo in children who had moderate to severe pharyngitis caused by gabhs and non-gabhs. in a somewhat smaller study with a similar design [ ] , the antigen-positive subset of children reported an improvement in time to onset of pain relief with dexamethasone treatment compared with placebo. no significant decrease in time to onset of pain relief or time to complete pain relief was seen in the antigennegative treatment group compared with placebo. inflammation of the mucosa of the paranasal sinuses, or sinusitis, is among the group of respiratory illnesses (excluding pharyngitis) which was ranked second in frequency of visits to outpatient clinics in [ ] . the term rhinosinusitis may more accurately describe the condition, because inflammation of the nasal mucosa is usually present as well [ ] . although it is usually caused by a viral infection, rhinosinusitis is often attributed by patients and physicians to bacterial cause. noninfectious causes of sinusitis include allergy, foreign body, deviated septum, tumor, polyps, and barotrauma [ ] . although bacterial sinusitis may complicate only . % to % of uris, it accounts for a disproportionate % of antibiotic prescriptions written [ ] . acute bacterial rhinosinusitis (abrs) shares symptoms with the viral uri, including rhinorrhea, nasal congestion, facial pressure, and fever, which may lead the patient to request antibiotics from their physician. though antibiotic therapy may be beneficial for bacterial sinusitis, the definitive diagnosis is made by sinus aspiration, an invasive procedure not typically performed in the office setting. instead the physician must rely on the presentation of a persistent symptom complex, including facial pressure, nasal obstruction, nasal discharge, hyposmia, and fever [ ] . the treatment guidelines for sinusitis have generally been directed at reducing the inappropriate use of antibiotics for viral respiratory infections [ ] . this article addresses the evaluation and therapy of abrs in immunocompetent adults and children aged years and older. the paranasal sinuses typically involved in abrs are the maxillary and ethmoid sinuses. these sinuses are present at birth, having formed in the third and fourth gestational month [ ] . the sphenoid sinus develops through early childhood and the frontal sinuses develop by adolescence. infections of the frontal sinuses typically present with greater intensity and severity and may require hospital admission. bacterial infection typically follows the impairment of mucus clearance and the obstruction of sinus ostia caused by viral respiratory infection. the paranasal sinuses are ordinarily sterile. with infection, the most common microorganisms isolated from maxillary sinuses are s pneumoniae, haemophilus influenzae, and moraxella catarrhalis. sinusitis has been defined as acute when symptom duration is of less than weeks, and chronic when symptoms persist for more than weeks [ ] . complications are potentially quite serious because of the anatomical relationship of the sinuses to the eyes and brain. these complications include orbital cellulitis, orbital abscess, and potentially life-threatening intracranial complications such as cavernous sinus thrombosis, meningitis, and brain abscess. chronic sinusitis is defined by the presence of two major, or one major and two minor criteria. criteria are listed in box [ ] . noninfectious factors such as allergy and irritants appear to initially cause inflammation, and then bacteria may have some role in its persistence. antibiotic therapy for chronic rhinosinusitis has not been shown to improve outcomes in children, whereas the benefits of antibiotic therapy for adult chronic sinusitis have not been studied [ ] . endoscopic surgery may be used in the treatment of chronic rhinosinusitis that has failed to resolve with conservative therapy [ ] . the diagnosis of abrs is complicated by the symptoms it shares with viral uri and by the lack of data correlating these symptoms with sinus aspirate findings [ ] . clinical impression alone may result in % to % accuracy in diagnosis by the primary care physician [ ] . current guidelines provide for a diagnosis of abrs in patients who have duration of illness with typical symptoms of more than to days [ , , ] . patients who have rhinovirus infection may have symptoms from one to days, but most are well by days, and % have resolution of symptoms by days [ ] . evaluation of patients' symptoms and physical features relative to radiological findings has been studied. features associated with significant ct findings (air-fluid levels or complete sinus opacification) included purulent rhinorrhea, erythrocyte sedimentation rate greater than , purulent nasal secretions, and ''double sickening,'' or symptom worsening after an initial resolution [ ] . ct findings are, however, not specific for abrs, and are seen in patients who have uri [ ] . williams and colleagues [ ] used sinus radiographic changes to identify five predictors of abrs, namely, maxillary toothache, poor response to decongestants, history of discolored nasal discharge, mucopurulent nasal discharge on examination, and abnormal transillumination. no single finding had sufficient specificity and sensitivity to be diagnostic [ ] . although transillumination of the sinuses was found to be an independent predictor of sinusitis, its utility is limited to the maxillary and frontal sinuses, it is difficult to perform and is likely unreliable in younger children; its practical use appears limited [ ] . hansen and coworkers [ ] found a relationship between positive bacterial culture of sinus aspirates and unilateral tenderness of the maxillary sinus, maxillary pain, maxillary toothache, and mucopurulent nasal discharge. a study of emergency room patients who had symptoms of sinusitis [ ] , some for more than days, found an increased likelihood of abrs (with purulent sinus aspirate, not cultured) in those who had unilateral predominate purulent nasal discharge and unilateral predominate facial pain by history, bilateral purulent nasal discharge, and pus in the nasal cavity. reviewing the studies to identify clinical signs and symptoms of abrs, it appears that purulent nasal discharge, unilateral maxillary tenderness, and worsening of symptoms after initial improvement predict a higher likelihood of the diagnosis [ ] . radiography has been employed in the evaluation of abrs, but there are significant limitations in its ability to reliably predict this diagnosis. in particular, mucosal thickening lacks specificity as a finding in abrs, and is no more predictive than clinical judgment. patients who had either complete sinus opacification or air fluid levels benefited from treatment for abrs with amoxicillin [ ] . these findings have relatively high specificity, approximately % and % respectively. the sensitivity of a radiographic negative for these three findings is about %, and the normal study can be powerful evidence for excluding abrs [ , ] . management guidelines exclude radiography from the routine evaluation of sinusitis in both children and adults [ ] [ ] [ ] . ct has the ability to visualize the paranasal sinuses and the osteomeatal complex, the anatomic entity central to the diagnosis of abrs. lindbaek and colleagues [ ] found no difference in outcomes for patients who had a clinical diagnosis of sinusitis, but only mucosal thickening on ct treated with either amoxicillin or placebo. in patients undergoing ct examination for reasons other than sinusitis but who had a history of recent uri, % were found to have sinus abnormalities [ ] . the changes seen in ct examination are not sufficiently specific for sinusitis, and ct should be used carefully and within the clinical context. when surgical management is being considered, as in cases of persistent infection or complicated infections, ct may be indicated in planning therapy [ , ] . the rational approach to treatment of abrs is somewhat limited by the diagnostic uncertainties that have been described. nevertheless, guidelines have been published that advocate antibiotic therapy dictated by the severity and duration of symptoms [ ] [ ] [ ] . antibiotic therapy has been shown to shorten the duration of symptoms in patients who have purulent rhinorrhea compared with placebo; however, no difference in overall recovery was seen, and the antibiotic group had a higher frequency of diarrhea [ ] . when study participants were limited to those who had pus in the nasal cavity, facial pressure, or nasal discharge lasting longer than days, the group treated with antibiotics experienced symptom improvement earlier ( versus days), but there was no significant difference in improvement at days [ ] . a cochrane review of antibiotic therapy for persistent (more than days) nasal discharge in children found a reduction in the probability of persistent symptom in the short to medium term, with eight children needed to be treated to achieve one additional cure [ ] . a systematic review of antibiotic therapy for acute maxillary sinusitis in adults included studies with significant variability among them that compared antibiotic to control or antibiotics from different classes [ ] . penicillin improved clinical cures and radiographic outcomes. no significant differences were seen between classes of antibiotics. recommendations of the american college of physicians-american society of internal medicine (acp-sim) are for symptomatic treatment or reassurance for those who have mild to moderate symptoms [ ] . antibiotics are reserved for those who have severe or persistent symptoms of more than days. it is surmised that the modest improvements seen in the studies using relatively nonspecific standards (clinical or radiographic) were caused by the inclusion of patients who have no bacterial infections. the agent with the narrowest spectrum active against the likely pathogens is recommended, and amoxicillin is preferred. the american academy of otolaryngology-head and neck surgery recommends initial therapy of adults who have mild disease and who have not received antibiotics in the previous to weeks with first-line agents such as amoxicillin. those who have mild disease but antibiotic use in the previous to weeks or moderate disease are treated with second-line agents, including fluoroquinolones. failure to respond after hours of therapy should prompt a re-evaluation of therapy [ ] . likewise, for the treatment of children, severity of disease and prior treatment with antibiotics determine therapy choice, excluding fluoroquinolones. efficacy is predicted according to a mathematical model based on the expected pathogens, spontaneous resolution rates, and in vitro activity. the american academy of pediatrics recommends antibiotic therapy for children who have sinusitis meeting the clinical definition and whose symptoms are severe or persistent [ ] . amoxicillin is recommended at usual doses ( mg/kg) in two divided doses for children who have mild to moderate disease and who do not attend day care and have not recently been treated with antibiotics. failure to improve (reduction in respiratory symptoms and in general well-being) within to hours should lead to reconsideration of the diagnosis or changes in therapy. high-dose amoxicillin ( mg/kg) is advised if patients fail to improve with usual doses of amoxicillin, have moderate to severe illness, have been recently treated with antibiotics, or attend day care. alternatives for b-lactam allergic patients include cefdinir, cefuroxime, or cefpodoxime. clarithromycin and azithromycin are recommended in anaphylaxis-type, b-lactam allergic patients. there are few data concerning the use of additional non-antimicrobial therapies for sinusitis. a -day course of prednisone ( . - . mg/kg) combined with cefpodoxime resulted in less pain and nasal obstruction in the first days compared with placebo in adults who have radiograph-or endoscope-documented maxillary rhinosinusitis [ ] . daily hypertonic saline use for months by patients who had a history of sinusitis resulted in improved symptom severity and sinusitis-related disability scores, and less antibiotic use [ ] . the addition of intranasal steroids to antibiotic therapy for acute rhinosinusitis in patients who had [ ] and did not have [ ] a history of chronic or recurrent sinus symptoms achieved a higher and more rapid rate of patient-reported clinical success than placebo. unlike the other diagnostic entities reviewed here, acute bronchitis refers to inflammation of a portion of the lower respiratory tract. like pharyngitis and sinusitis, however, it is a condition that shares a primary symptom, in this case cough, with the nonspecific uri, an illness of viral origin not requiring antibiotic therapy. and as with these other specific conditions, there is evidence for benefit from antibiotic therapy in only the minority of cases. because of its relationship to the viral uri, acute bronchitis, defined as an acute cough illness in an otherwise healthy adult, is included here for review [ ] . acute bronchitis generally refers to an infection of the respiratory tract in which cough is the predominate feature [ ] . when surveyed on the definition of acute bronchitis, there is disagreement among family physicians, some qualifying the cough as purulent, and others indicating that it must only be productive [ ] . although a systematic review found antibiotic therapy for acute bronchitis offers only modest benefit [ ] , it is reported that % to % of office visits for this diagnosis result in a prescription for antibiotics [ ] . treatment guidelines have been developed in an effort to limit unnecessary antibiotic therapy for this condition [ ] . the majority of cases of acute bronchitis are caused by infection by viruses, including influenza, parainfluenza, and respiratory syncytial virus, resulting in lower tract disease; and rhinovirus, coronavirus, and adenovirus, usually resulting in upper tract disease [ ] . an etiological study of adults who had lower respiratory tract infection and controls identified rhinovirus in %, and influenza in % of patients [ ] . noninfectious causes of acute cough include allergy, asthma, environmental exposures, heart failure, gastroesophageal reflux, and tumor [ ] . cough-variant asthma may be difficult to distinguish from uncomplicated acute bronchitis, which may also be associated with transient bronchial hyperresponsiveness but typically resolves after to weeks [ ] . the other causes are identified by unique epidemiological or clinical features (table ). bacterial infection causes fewer than % of the cases of infectious bronchitis; only bordetella pertussis, m pneumoniae, and c pneumoniae, have been identified as primary agents [ ] . pneumonia is a relatively frequent and important cause of cough that must be excluded as a diagnosis because it may be associated with significant mortality. the cough of acute bronchitis may be productive and may be accompanied by wheezing. this reflects hypersensitivity of the bronchial epithelium that can be measured by pulmonary function testing, with abnormalities most prominent or more weeks after infection [ ] . these abnormalities typically persist for to weeks, but may last longer. in a study of patients presenting to a general medical practice who have acute cough, purulent sputum, or abnormal auscultory findings, it was to weeks before most patients were well and able to resume usual activities [ ] . although the productivity of the cough, and in particular the purulence of the sputum, is associated with antibiotic use by physicians [ ] , this feature, a nonspecific sign of inflammation, is not predictive of a bacterial infection [ ] . established criteria for the diagnosis of pneumonia do not include purulent sputum, and only % of patients presenting with purulent sputum have pneumonia [ ] . a rule to exclude the diagnosis of pneumonia without the need for further evaluation is based on the absence of abnormal vital signs (tachycardia, tachypnea, and fever) and the absence of specific adventitious breath sounds (consolidation signs, such as rales, egophony, or fremitus) [ ] . although this may guide the physician in the decision to proceed with radiography, other factors that may influence this decision include the age and comorbidities of the patient, and the likelihood of a seasonal illness such as influenza. the use of c-reactive protein measurement to distinguish bacterial pneumonia from uncomplicated acute bronchitis has been studied but does not appear to offer an advantage in the evaluation of patients who have acute cough [ ] . infection with b pertussis should be considered if there is a history of exposure to an individual who has confirmed pertussis or when cough persists. nasopharyngeal swab for polymerase chain reaction testing is particularly useful for diagnosis in previously vaccinated individuals who less frequently meet clinical criteria for the disease [ ] . increasing reports of pertussis appear to be due to waning vaccine immunity in adolescents and young adults [ ] . use of serology for the diagnosis of pertussis and for diagnosis of infection with m pneumoniae or c pneumoniae is limited, in part because seroconversion may occur in asymptomatic individuals [ , ] . sputum culture is poorly sensitive for these species and is not recommended. m pneumoniae infection commonly produces an influenza-like tracheobronchitis with a self-limited course resolving in to weeks without treatment [ ] . it may also produce an atypical pneumonia. c pneumoniae infection of the respiratory tract is usually asymptomatic, but may be associated with bronchitis or pneumonia. there has been speculation that c pneumoniae may be implicated in adult new-onset asthma based on serological findings in these patients [ ] . therapy treatment guidelines derived from the available evidence recommend against routine antibiotic therapy for uncomplicated acute bronchitis [ ] . systematic reviews have failed to discover more than marginal benefit in treatment with antibiotics of acute bronchitis patients, including smokers [ , ] . although a shorter duration of cough (by . days), productive cough (by . days), and feeling ill (by . days) was noted in the treated group in one review [ ] , there was no difference at follow-up for night cough, productive cough, or activity limitations. in another systematic review [ ] , there were significantly more side effects in the antibiotic treatment group. no trials have specifically examined antibiotic treatment for smokers who have acute bronchitis, but a review of existing data found the same or less benefit for smokers compared with nonsmokers [ ] . in a trial of azithromycin or vitamin c therapy for adults who had acute bronchitis, there was no significant difference in health-related quality of life after days [ ] . antibiotic therapy is recommended for acute bronchitis caused by pertussis [ ] . a cochrane review of antibiotics for pertussis [ ] found that short-term therapy with azithromycin ( days), clarithromycin ( days), or erythromycin ( days) was as effective as long-term therapy with erythromycin in eradicating infection from the nasopharynx with fewer side effects in the short-term treatment. although the clinical course of the illness is not altered, treatment is recommended for individuals who have bronchitis and who have been exposed to documented pertussis in order to decrease spread of the disease [ ] . although there is scant evidence supporting the use of antibiotics for acute bronchitis, the evidence for use in chronic bronchitis and its exacerbation is mixed [ ] . the us food and drug administration (fda) no longer considers antibiotic trials for acute bronchitis warranted because of lack of evidence of benefit [ ] . nevertheless many of the antibiotics with indications for chronic bronchitis are used by physicians for the treatment of acute bronchitis. perhaps this is due in part to the failure to distinguish between the otherwise healthy patients with acute, self-limited cough and the patient who has worsening symptoms associated with irreversible lung disease [ ] . various agents used to provide symptom relief for the patient who has acute bronchitis have been studied. because bronchial hyperresponsiveness with bronchospasm is a feature of the disease in a significant percentage of patients [ ] , it is not surprising that the evidence supports the use of bronchodilators in individuals who demonstrate airflow obstruction [ ] . cough scores did not change after treatment in children who had no airway obstruction. in studies of adults, there was no difference in cough at days for treatment or control groups; however subgroups who had airflow limitation had lower cough scores, and those who had wheezing at baseline had quicker resolution of cough [ ] . there is little evidence to support the use of antitussives specifically for acute bronchitis. guidelines suggest that there may be modest responses to dextromethorphan and codeine preparations [ ] . few studies have evaluated the efficacy of guaifenesin as an expectorant, although its use is widespread. it has been found to inhibit capsaicin-induced cough in patients who have uri [ ] . an herbal agent, pelargonium sidoides (eps ) was studied against placebo in adults who had acute bronchitis and less than days of cough [ ] . a significant decrease in symptom severity scores and in work disability was found in the treatment group, with no difference in adverse effects. the approach to the patient who has acute cough should be to first identify, based on history and physical examination, individuals likely to have pneumonia who require further evaluation and specific therapy (strength of recommendation [sor]: a) in the remaining patients there is a subset for whom treatment with antiviral therapy for influenza may be indicated based upon clinical judgment, and seasonal prevalence. if there is known exposure to pertussis, macrolide therapy should be considered. antibiotic therapy is otherwise not indicated, and is unlikely to provide benefit to the patient. symptomatic therapy, including inhaled-bronchodilators for those who show evidence of airway obstruction, and antitussives for those who have chest discomfort or sleep disturbance from cough, may be added. table evidence-based recommendations for the treatment of uri antibiotics are not indicated in the treatment of a nonspecific uri in adults and children. a delayed antibiotic therapy may decrease use with no effect on outcome except symptom score for otitis media and pharyngitis. oral and topical decongestants are beneficial in adults with uri. a decongestant/antihistamine combinations improve recovery and nasal symptoms in older children and adults with uri. radt for gabhs is recommended if pretest likelihood is intermediate to high. a culture for gabhs is recommended to confirm negative radt in children and adolescents. c penicillin is recommended therapy for gabhs if no allergy history. a oral dexamethasone is recommended to speed pain relief in pharyngitis. b antibiotic therapy does not improve outcomes in children with chronic sinusitis. a radiographs are not recommended for routine evaluation of acute sinusitis in children and adults. antibiotics are recommended for persistent or severe symptoms in acute sinusitis. combination prednisone and antibiotics decrease symptoms in acute sinusitis. antibiotic therapy is not indicated for acute bronchitis unless symptoms persist after pertussis exposure. a bronchodilator therapy is recommended in bronchitis with evidence of airway obstruction. antitussive therapy may improve cough in bronchitis. c patient education on appropriate antibiotic use decreases use of antibiotics for uri. a patient education by the physician on the appropriate treatment of acute bronchitis can result in lower antibiotic usage without affecting clinical outcomes [ ] . these efforts may include providing an informational leaflet, or during the visit reviewing with the patient the following. there is a very high likelihood that the illness will resolve with or without antibiotics. inappropriate antibiotic use is associated with emergence of antibioticresistant bacteria. antibiotic use is associated with risk of adverse events, including serious allergic reactions. avoid terms such as bronchitis that engender fear but have no value in specifying treatment. the patient presenting to the primary care physician with infection of the upper respiratory tract is most likely experiencing a frequent and usually self-limited viral infection. the viral uri is characterized by nonspecific symptoms including sore throat, nasal congestion, and cough that may respond to symptom-targeted measures. in those who have pharyngitis and features typical of streptococcal infection, rapid in-office testing may guide antibiotic treatment and limit their unwarranted use. the appropriate treatment of acute sinusitis is dictated by an assessment of historical and physical features generally not requiring diagnostic imaging. when cough is the predominate symptom in the immunocompetent individual and pneumonia is excluded, then treatment with antibiotics is not indicated. physician responsibility in the judicious use of antibiotics may reduce the emergence of bacterial resistance and also decrease adverse reactions. patient education may mitigate demands for unnecessary therapy and preserve satisfaction with their care. table summarizes the evidence-based recommendations for the treatment of uri. national ambulatory medical care survey: summary bacterial infections of the upper respiratory tract antibiotic prescribing for children with cold, upper respiratory tract infections, and bronchitis antibiotic prescribing for adults with colds, upper respiratory infections, and bronchitis by ambulatory care physicians evaluation and treatment of the patient with acute undifferentiated respiratory tract infection antibiotic resistance and the need for the rational use of antibiotics principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults: background aetiological role of viral and bacterial infections in acute adult lower respiratory tract infection (lrti) in primary care neuraminidase inhibitors for preventing and treating influenza in children neuraminidase inhibitors for preventing and treating influenza in healthy adults performance characteristics of clinical diagnosis, a clinical decision rule, and a rapid influenza test in the detection of influenza infection in a community sample of adults computed tomographic study of the common cold antibiotics for the common cold and acute purulent rhinitis antibiotics and respiratory infections: are patients more satisfied when expectations are met? delayed antibiotics for symptoms and complications of respiratory infections clinical decision support and appropriateness of antimicrobial prescribing nasal decongestants for the common cold antihistamines for the common cold effectiveness and safety of intranasal ipratropium bromide in common colds zinc for the common cold an evaluation of echinacea angustifolia in experimental rhinovirus infections vitamin c for preventing and treating the common cold acute pharyngitis family medicine principles and practice prospective study of the natural history of infectious mononucleosis caused by epstein-barr virus arcanobacterium haemolyticum pharyngitis and exanthema. three case reports and literature review practice guidelines for the diagnosis and management of group a streptococcal pharyngitis principles of appropriate antibiotic use for acute pharyngitis in adults antibiotic treatment of adults with sore throat by community primary care physicians: a national survey antibiotic treatment of children with sore throat clinical symptoms and signs in sore throat patients with large colony variant beta-haemolytic streptococci groups c or g versus group a rapid diagnosis of pharyngitis caused by group a streptococci the diagnosis of strep throat in adults in the emergency room a clinical score to reduce unnecessary antibiotic use in patients with sore throat the validity of a sore throat score in family practice the rational clinical examination. does this patient have strep throat diagnosis and management of adults with pharyngitis antibiotics for sore throat two dosages of clarithromycin for five days, amoxicillin/clavulanate for five days or penicillin v for ten days in acute group a streptococcal tonsillopharyngitis the effect of written information on adherence to antibiotic treatment in acute sore throat effectiveness of oral dexamethasone in the treatment of moderate to severe pharyngitis in children oral dexamethasone for the treatment of pain in children with acute pharyngitis: a randomized, double-blind, placebo-controlled trial national hospital ambulatory medical care survey: outpatient department survey principles of appropriate use of acute rhinosinusitis in adults: background acute community-acquired bacterial sinusitis: the value of antimicrobial treatment and the natural history antimicrobial treatment guidelines for acute bacterial rhinosinusitis principles of appropriate use for acute sinusitis in adults subcommittee on management of sinusitis and committee on quality improvement diagnosis of chronic rhinosinusitis do antibiotics improve outcomes on chronic rhinosinusitis? current concepts in therapy of chronic rhinosinusitis and nasal polyps rhinovirus infections in an industrial population. ii. characteristics of illness and antibody response use of symptoms, signs, and blood tests to diagnose acute sinus infections in primary care: comparison with computed tomography clinical evaluation for sinusitis. making the diagnosis by history and physical examination predicting acute maxillary sinusitis in a general practice population analysis of symptoms and clinical signs in the maxillary sinus empyema randomised, double blind, placebo controlled trial of penicillin v and amoxicillin in treatment of acute sinus infections in adults antibiotic treatment of patients with mucosal thickening in the paranasal sinuses, and validation of cut-off points in sinus ct incidental paranasal sinus abnormalities on ct of children: clinical correlation the role of computed tomography and magnetic resonance imaging in patients with sinusitis with complications does amoxicillin improve outcomes in patients with purulent rhinorrhea? a pragmatic randomized double-blind controlled trial in family practice are antibiotics beneficial for patients with sinusitis complaints? a randomized double-blind clinical trial antibiotics for persistent nasal discharge (rhinosinusitis) in children antibiotics for acute maxillary sinusitis treatment of functional signs of acute maxillary rhinosinusitis in adults. efficacy and tolerance of administration of oral prednisone for days efficacy of daily hypertonic saline nasal irrigation among patients with sinusitis: a randomized controlled trial comparison of cefuroxime with or without intranasal fluticasone for the treatment of rhinosinusitis. the caffs trial: a randomized controlled trial nasonex sinusitis group. effective dose range of mometasone furoate nasal spray in the treatment of acute rhinosinusitis viral infection of the respiratory tract uncomplicated acute bronchitis diagnosis of acute bronchitis in adults: a national survey of family physicians antibiotics for acute bronchitis principles of appropriate antibiotic use for treatment of acute bronchitis in adults acute bronchitis principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background acute bronchitis: course of symptoms and restrictions in patients' daily activities the relation between purulent manifestations and antibiotic treatment of upper respiratory tract infections does this patient have community acquired pneumonia? diagnosing pneumonia by history and physical examination diagnosing pertussis: the role of polymerase chain reaction overview of pertussis: focus on epidemiology, sources of infection, and long term protection after infant vaccination harrison's principles of internal medicine chlamydia pneumoniae as a respiratory pathogen quantitiative systematic review of randomized controlled trials comparing antibiotic with placebo for acute cough in adults antibiotic treatment of acute bronchitis in smokers azithromycin for acute bronchitis: a randomized, double-blind, controlled trial antibiotics for whooping cough (pertussis) antibiotics in chronic obstructive pulmonary disease exacerbations. a meta-analysis beta -agonists for acute bronchitis do inhaled beta-agonists control cough in uri's or acute bronchitis? effect of guaifenesin on cough reflex sensitivity efficacy and safety of an extract of pelargonium sidoides (eps ) in adults with acute bronchitis. a randomized, double-blind, placebocontrolled trial reducing antibiotic use for acute bronchitis in primary care: blinded, randomized controlled trial of patient information leaflet key: cord- -a t u authors: nan title: alphabetic listing of diseases and conditions date: - - journal: handbook of autopsy practice doi: . / - - - - _ sha: doc_id: cord_uid: a t u part ii begins with a list of special histologic stains, their for use and their corresponding references. at the end of this list is a procedure for removal of formalin precipitate from tissue sections. diseases. there may also be a list of possible associated conditions. these entities are generally linked pathogenetically to the main disease entry. any asterisk after a related disease indicates that that disorder is also listed as a disease entry. many disease entries will be followed by a three-column table that provides the reader with a listing of the pathologic findings to be expected with the disease as well as the prosection and dissection procedures necessary to demonstrate those findings. it is expected that routine hematoxylin-eosin stains will be done on all sections submitted for histologic examination. special stains will be recommended in the procedures column of the tables, when indicated. any table immediately following the two columns of disease entries always refers to the disease in the right column. prepare smears of undiluted blood. obtain blood for molecular studies for preservation of small intestinal mucosa and for preparation for study under dissecting microscope, see part i, chapter . submit sample for histologic study. submit stool for chemical analysis. record weight and submit sample for histologic study. freeze liver for molecular studies record appearance of spine (see also chest roentgenogram). for removal and specimen preparation, see chapter . request luxol fast blue stain. for removal and specimen preparation, see chapter . below-normal weight in infants. kyphoscoliosis. very low concentrations of cholesterol and decreased triglycerides; serum~-lipoprotein or absent; a.-lipoproteins present. acanthocytosis (spiny red cells). gene mutations ( ) . abnormal shape of villi; vacuolation of epithelial cells. fatty stools fatty changes. gene mutations ( ) systemic manifestations of malabsorption syndrome* and of vitamin a deficiency. * kyphoscoliosis. axonal degeneration of the spinocerebellar tracts; demyelination of the fasciculus cuneatus and gracilis ( ) . possible involvement of posterior columns, pyramidal tracts, and peripheral nerves. atypical retinitis pigmentosa ( ) with involvement of macula. angioid streaks ( ) . synonym: cerebral abscess. note: for microbiologic study of tissues and abscesses, see part i, chapter . include samples for anaerobic culture. it is best to study the brain after fixation but if specimen is examined fresh, aspirate and prepare smears of abscess content. photograph surface and coronal slices of brain. request giemsa stain, gram stain, pas stain, and grocott's methenamine silver stain for fungi. external examination if there is evidence of trauma, see also under "injury, head." prepare roentgenograms of chest and skull. submit for microbiologic study. for removal and specimen preparation, see chapter . for microbiologic study, photography, and special stains, see under "note." for exposure of venous sinuses, see chapter . sample walls of sinuses for histologic study. for exposure of paranasal sinuses, mastoid cells, and middle ears, see chapter . for removal and specimen preparation, see chapter . procedures depend on suspected lesions as listed in right-hand column. skin infections in upper half of face. edema of forehead, eyelids, and base of nose, proptosis, and chemosis indicate cerebral venous sinus thrombosis. * trauma; craniotomy wounds. skull fracture and other traumatic lesions. for possible intrathoracic lesions, see below under "other organs." the national transportation safety board (ntsb)* has authority over aircraft wreckage and the legal authority to investigate and to determine the cause of air crashes. ( ) the dead are the responsibility of the medical examiner or coroner. local police will seal off the area of the crash. other than for the purpose of determining that death has occurred, no one should be allowed to approach the bodies or any objects until the identification teams and the medical examiner or coroner have taken charge. the sudden influx of bodies after a commercial air carrier accident and the request for speedy identification of the victims would overburden almost any institution. managing such a disaster is eased by writing a contingency plan beforehand. temporary morgue facilities may have to be established near the scene of the crash. refrigerated trucks may serve as storage space. a practical approach is to deal first with those bodies that seem to be the easiest to identify, in order to narrow the field for the more difficult cases. if bodies are scattered, their locations can be referenced to stakes in the ground or spray paint on pavement; only then should these bodies (or parts) and personal effects be collected. for large-scale crashes a locations can be referenced to a string-line grid benchmarked to gps coordinates. records and diagrams of the relative positions of victims are prepared during this phase. if bodies are still within the airplane, their positions are recorded, and photographed. the personnel of the medical examiner or coroner can augmented by d-mort team staffed by forensic pathologists, anthropologists, dentists, morgue technicians, and investigators supplied by the national disaster medical system. ** the airline will provide a list of the passengers and the federal bureau of investigation (fbi) disaster team will make itself available to take and identify fingerprints and aid in the acquisition of other identifying data such as age, race, weight, height, and hair color and style. if dental records can be obtained, this provides one of the most certain methods of identification. a medical history indicating amputations, internal prostheses, or other characteristic surgical interventions or the presence of nephrolithiasis, gallstones, and the like will be helpful. fingerprints (and footprints of babies) should be taken in all instances. wallets with identification cards,jewelry, name tags in clothing, or other personal belongings may provide the fastest tentative identification. the medical examiner may elect to autopsy only the flight crew but not the passengers of an aircraft crash. however, the grossly identifiable fatal injuries should be described, photographed, and x-rayed. this may reveal identifying body changes. if comparison of somatic radiographs, dental records, fingerprints, or photographs do not identify the victim, dna comparison must be considered. burned or fragmented bodies of passengers and the bodies ofcrew members, and particularly the pilots, must have a complete autopsy, including roentgenographic and toxicologic examinations, which must always include alcohol and carbon monoxide determinations. internal examination might reveal a coronary occlusion, or roentgenograms may disclose a bullet as evidence that violence preceded the crash. in some airplane crashes, particularly in light airplane accidents, suicide must be considered. in such cases police investigation is required to determine if the pilot exhibited suicidal ideation in the recent past.. when resources permit, autopsies should be performed on all deceased occupants of aircraft crashes, including passengers, in order to distinguish among blunt impact trauma, smoke inhalation, and flash fires as causes ofdeath, and to answer future questions concerning pain and suffering, intoxication, and sequence of survivorship. after a crash victim has been identified, the coroner or medical examiner will issue a death certificate. if remains of a decedent cannot be found, a judge can, upon petition, declare a passenger dead and sign a death certificate prepared by a medical examiner. *phone # ofntsb command center: - - **phone # of dmort: - - . entry should be followed. usually, the circumstances that led to drowning are not apparent from the autopsy findings but can be reconstructed from reports of witnesses and the police. because the reflex drive to seek air is triggered by hypercarbia, not hypoxia, loss of consciousness and drowning can ensue after hyperventilation and breath-holding by experienced swimmers who then drown without a struggle. there are no specific autopsy findings. a search for trauma, including a posterior neck dissection, should be made in all instances. head and cervical injuries may be responsible for loss of consciousness and drowning, usually in individuals diving into shallow water. toxicologic examination as described below for scuba diving accidents is always indicated. with scuba diving fatalities, investigation of the equipment and circumstances is usually more important than the autopsy. scuba fatalities should be studied by or with the aid of diving experts-for instance, members of a diving club or shop (not the one providing the gear used by the decedent) or the u.s. navy. ( ) careful investigation of the scene and study of reports of witnesses and the police are essential. the investigation should ascertain the site of diving (currents and other underwater hazards), the estimated depth, the water temperature (exposure to cold), and a description of water clarity. electrocution should be considered if the site has electric underwater cables (see "injury, electric"). cerebral concussion should be considered if explosives were used in the vicinity. knowledge of the method of recovery of the body and the type of resuscitation efforts can aid in the interpretation of apparent wounds. the medical history of the diving victim should be sought, as it may lead to a diagnosis for which the autopsy is typically silent, such as seizure disorder, or may reveal asthma, emphysema, or chronic bronchitis, all of which increase the risk of air trapping and arterial air embolism. although drowning may be the terminal event in some scuba deaths, the investigation should be focused on the adverse environmental and equipment factors that place a capable swimmer at risk of drowning (see "embolism, air" and "sickness, decompression"). because scuba divers risk arterial air embolism if they ascend with a closed glottis, on can attempt to document gas bubbles at autopsy, but their interpretation is problematic: bodies recovered immediately are subjected to resuscitation efforts, which can by themselves produce extra-alveolar air artifacts, and bodies not recovered immediately tend to be found in a putrefied condition, full of postmortem gas. in the remaining cases, the pathologist must consider the potential of introducing artifactual gas bubbles by the forcible retraction of the chest plate and by sawing the calvarium. the following procedures apply primarily to scuba diving accidents. interrogation of witnesses is important; the behavior and complaints of the decedent, if any, might help distinguish between a natural death by heart disease and an unnatural death by air embolism. external examination eyes and ears head (skull and brain) chest blood (from heart and peripheral vessels) heart tracheobronchial tree and lungs a procedures photograph victim as recovered and after removal of wet suit and other diving gear. record condition of clothing and gear. impound all diving equipment for study by experts, particularly scuba tank, breathing hoses, and regulators. residual air in tank should be analyzed. record color of skin (including face, back, soles, palms, and scalp). palpate skin and record presence or absence of crepitation. record extent and character of wounds. prepare histologic specimens. record appearance of face (including oral and nasal cavities) and of ears. prepare roentgenograms. if air embolism must be expected, as in the presence of pneumomediastinum, follow procedures described under "embolism, air." for evaluation of findings, see also above under "note." if decompression sickness (caisson disease) is suspected, also prepare roentgenograms of the elbows, hips, and knees. otoscopic examination. funduscopic examination. save vitreous for possible toxicologic and other studies. for removal of brain, see chapter . record contents of arteries of the circle of willis and its major branches and basilar artery. strip dura from base of skull and from calvarium. for removal and specimen preparation, see chapter . for demonstration of pneumothorax, see under "pneumothorax". if gas is visible in coronary arteries, photograph. photograph and aspirate gas in heart chambers. submit samples of heart blood and peripheral blood for toxicologic study and drug screen. examine lungs in situ. save bronchial washings for analysis of debris. fresh dissection is recommended. if decompression sickness is suspected, prepare sudan stains from fresh-frozen lung sections. complete toxicologic sampling should be carried out (see chapter ). record nature of gastric contents. remove neck organs toward end of autopsy. for posterior neck dissection, see chapter . incise tongue. for removal, see chapter . for removal, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . consult roentgenograms. in decompression sickness, fatty change of liver, and ischemic infarctions of many organs. interstitial emphysema. aspiration (see above). trauma to cervical spine. mottled pallor of tongue after air embolism. contusion of tongue after convulsive chewing. nitrogen bubbles in spinal cord arteries may occur after rapid ascent. air embolism;' cerebral edema in decompression sickness. aseptic necroses (infarcts, "dysbaric osteonecrosis"), most often in head of femur, distal femur, and proximal tibia. infarcts indicate repeated hyperbaric exposures. nitrogen bubbles in and about joints and in periosteal vessels ("bends") occur during rapid ascent. related terms: automobile accident; motorcycle accident. note: a visit to the scene can make the interpretation of the autopsy findings easier. the vehicle can also be inspected in a more leisurely fashion at the impound lot. this is particularly useful for correlating patterned injuries with objects in the vehicle. most vehicular crashes occur as intersection crashes or because a vehicle with excessive speed left a curved road. the medical examiner or coroner should gain a basic understanding of the crash mechanism so that informed descriptions can be rendered, e.g., "impact to the b pillar of the decedent's automobile by the front of a pickup truck which failed to stop for a stop sign at an intersection, resulting in a -feet intrusion into the cabin; restraint belts not employed; air bag deployed; extrication required which took minutes." police are responsible for determining mechanical and environmental risk factors for the crash and for determining some human risk factors such as suicidal or homicidal intent. the pathologist determines other risk factors for crashes such as heart disease, a history of epilepsy, and intoxication by carbon monoxide, drugs, and alcohol. suicide as a manner of death should be considered when a single-occupant vehicle strikes a bridge abutment or a large tree head-on, with no evidence of evasive action or braking. in such a situation, the standard police traffic investigation should be supplemented of interviews of the victim's family and friends. the ambulance run sheet is an invaluable source of observations that often are not available from the police. this document should be acquired in all instances, even if the paramedics determined that death occurred and did not transport. the basic autopsy procedures are listed below. most traffic victims who die at the scene or who are dead on arrival at the hospital died from neurogenic shock caused by wounds of the head or vertebral column, or from exsanguination from a tom vessel or heart. as such, they have little lividity, and little blood is found in the vehicles. presence ofintense lividity may indicate suffocation or heart disease as a cause of death. if postural asphyxia is suspected, the first responders to the scene should be interviewed to determine the position of the decedent in the vehicle, and the vital signs, ifany, ofthe decedent from the time of the crash to the time of extrication. posterior neck dissection is indicated in these instances. if manifestations of heart disease, intense lividity, and absence oflethal wounds suggest that a crash occurred because the driver was dead, other drivers on the road may have observed that the victim was slumped at the wheel before the crash. the determination of heart attack at the wheel is usually simple, because most such victims realize that something is wrong, and bring the vehicle to a stop at the side of the road, or coast gently into a fixed object. in such instances, damage to the vehicle is minor, and wounds to the decedent are usually trivial. while pattemed wounds can often be matched to objects (see below), patternless wounds usually cannot be visually matched to specific objects, although an opinion can sometimes be given as to what object was struck, based on the direction of motion and position ofthe body with respect to the vehicle. impacts with the a-pillar produce narrow vertical zones of facial laceration and fractures extending from forehead to jaw. tempered glass shatters into small cubes on impact, and leaves so-called "dicing" wounds, which are abraded cuts arranged in a somewhat rectilinear pattern. windshield glass leaves shallow, abraded, vertically oriented cuts on the face or scalp. with pedestrians, the lower extremities are of particular forensic interest, to determine the height and direction of impact from vehicles that left the scene. scalp hair and blood should be collected from such "hit and run" victims and from occupants of a suspect car if police have a question as to which occupant was the driver; these exemplars can be compared to fibers and tissue recovered from the vehicle in question. likewise, foreign material in wounds can sometimes be matched to suspect vehicles, and should be sought and retained as evidence. for pedestrians, the distance between the impact point on the lower extremities and the soles of the feet should be recorded. the legs should be opened to inspect tibial fractures; cortical fractures initiate propagation opposite to the side of impact, where they usually have a pulled-apart appearance, and then splinter the cortex at the side of impact. abrasions are better impact markers than contusions, because subcutaneous blood extravasation can be caused not only by impact to the skin, but also from blood extravasating from underlying fractures. if no cutaneous abrasions or fractures of the leg bones are found, the skin of the legs should be incised to expose contusions. fracture descriptions should include location in the bone (e.g., proximal metaphysis or shaft), whether the fracture is complete or incomplete, and whether the fracture is displaced or distracted. lacerations of intervertebral disks, facet joint capsules, and ligamenta flava should not be loosely termed "fractures." the presence or absence of blood extravasation in soft tissue adjacent to the fractures should be recorded, and its volume estimated if it appears severe enough. venous air embolism from tom dural sinuses cannot be diagnosed without a pre-autopsy chest radiograph or an in situ bubble test. if an x-ray machine is readily available, an anterior-posterior chest radiograph should be obtained in every traffic victim who dies at the scene or after a failed resuscitation attempt. if a hemothorax is suspected, the rib cuts should be placed further lateral and the chest plate reflected so that the internal mammary vessels can be inspected before the chest plate is removed. after measuring and removing the bloody effusion, the underlying serosal surfaces should be inspected for defects. lacerations of the heart and aorta will be obvious. tamponaded lacerations of the aorta, around which the adventitia still holds, must be noted as such. if no lacerations are found at the usual sites, lacerations of the azygous veins must be considered, especially in association with fracture dislocations of the thoracic vertebral column; other sites are the internal mammary arteries, especially with fractures of ribs i and or of the sternum, and intercostal arteries with displaced rib fractures. only after the serosal defect is identified should the organs be removed, because that procedure creates many more holes in the serosa. for that reason, as much information as possible should be gained by in situ observation. the only evidence of concussion of the heart may be a cardiac contusion or a sternal fracture. the usual clinical history suggests cardiovascular instability that is not associated with craniocerebral trauma and which does not respond to the infusion of intravenous volume agents. the autopsy assistant may saw but should not retract the skull cap and remove the brain. the pathologist should observe in situ whether shallow lacerations of the pontomedullary junction with stretching of the midbrain are present. these lesions cannot be distinguished from artifact by examining the brain later. thus, only after appropriate in situ inspection should the pathologist remove the brain. a posterior neck dissection is required if no lethal craniocerebral or cardiovascular trauma is found, or if suffocation is suspected; neck trauma must be ruled out to diagnose suffocation in a traffic fatality. sudden death in a patient with seemingly trivial wounds may be caused by undiagnosed trauma of the craniocervical articulation. a posterior neck dissection is required in these instances. the diagnosis of diffuse axonal injury of the brain in victims with no appreciable survival interval requires that suffocation be ruled out and that no resuscitation from a cardiac arrest has been attempted. clinicians are quick to apply the label "closed head injury" when a victim of a traffic crash has cerebral edema on a computerized axial tomogram of the head, even if no cerebral contusions, scalp contusions, or skull fractures are evident. this may be a misinterpretation, because cerebral edema can be caused by hypoxic encephalopathy made evident after resuscitation from a cardiac arrest, or from hypoxia caused by suffocation. procedures possible or expected findings record presence of lividity. photograph all external wounds; measure all lacerations and any abrasions or contusions with a pattern. collect scalp hair and blood (see below) from victims of hit and run accidents. collect foreign material in wounds. intense lividity and absence of lethal wounds may indicate that the crash occurred because the driver was dead from heart disease or suffocation. wound documentation. patterned injuries often sometimes be matched to objects in or about the vehicle (the most common patterned wound is that from tempered glass; see above under "note"). impact patterns in pedestrians may help to reconstruct the accident. hair and blood of the victim may be matched to transfer evidence on a vehicle suspected of having left the scene. part ii / diseases and conditions internal examination of body cavities heart and great vessels abdomen skull and brain; neck soft tissue compartments at any location prepare roentgenograms of chest is cases with head impact and skull fractures. collect samples for toxicologic study from all victims, including passengers. create pleural window to detect pneumothorax. if blood is seen, examine internal mammary vessels (see under "note"). measure volume of blood in cavity bleeds, and note whether chambers of heart and great vessels are collapsed or filled. record evidence of cardiac contusion, sprain of intracardiac inferior vena cava, laceration of pericardial sac, and fracture of sternum. laceration of heart or great vessels (measure volume of blood). follow routine procedures for dissection of heart and great vessels (see chapter ) . in situ bubble test to confirm venous air embolism. record evidence of trauma and volume of blood in peritoneal cavity; estimated volume of blood in retroperitoneal soft tissues. autopsy assistant may saw the skull but pathologist should inspect brain in situ and remove it personally. for removal and specimen preparation of brain, see chapter . record brain weight. posterior neck dissection is indicated if there is no craniocerebral or cardio-vascular trauma, or if suffocation is suspected. record evidence of trauma and estimate volume of blood. venous air embolism.' evidence of alcohol or drug intoxication. pneumothorax, hemothorax, e.g., after laceration of internal mammary vessels. evidence of significant hemorrhage. indirect evidence of cardiac concussion. evidence of exsanguinating wounds. evidence of cardiovascular disease that may have felled the driver before the crash. in european countries, the concentration is expressed in promille (grams per liter). in the united states, it has become customary to refer to concentration by percentage (grams per deciliter), and values in these units have been written into legislation and included in the uniform vehicle codes. unless qualified, the use of promille or percentage does not indicate whether the result of the analysis is weight/weight, weight/ volume, orvolume/volume. another common way ofexpressing concentration, milligrams per deciliter, has also been used to indicate alcohol concentrations. the method ofexpressing concentration must be clearly specified whenever the alcohol level is mentioned. the desired expression canbe derived from the toxicologic report by using the following equation: i, ~g/ml = mg/dl = . g/dl = . mmolll = . promille = . % what is the legal interpretation of alcohol (ethanol) intoxication? objective impairment of driving ability is observed at threshold blood alcohol concentrations of . -. g/dl. as of august all states and the district of columbia have adopted laws that make it criminal offense for a driver to operate a motor vehicle with a blood alcohol concentration of . g/ dl or greater. many states have an enhanced penalty for high concentrations such as . g/dl or above. several states have zero tolerance laws, under which drivers who are minors are legally operating only if their blood alcohol concentration is . g/dl or less, and in some states, not detectable at all. blood alcohol concentrations obtained at autopsy are valid until putrefaction begins. specimen tubes with sodium fluoride should be used, and the specimen should be stored in the refrigerator. if the air space above the blood samples in the container is large, alcohol can evaporate and a falsely low blood alcohol level can result. putrefactive changes before autopsy or during storage may cause a falsely high blood alcohol concentration. ethanol can be produced in the specimen container; this is more likely in the absence of a preservative. because fluoride inhibits bacteria far more than fungi, higher fluoride concentrations are required for the inhibition of fungal growth ( ) . although there is no major difference in the alcohol concentrations ofblood samples from the intact heart chambers and the femoral vessels ( ), autopsy samples from pooled blood in the pericardial sac or pleural cavity are unsatisfactory. we therefore recommend that blood be withdrawn from peripheral vessels. is there normal "endogenous" blood alcohol (ethanol) in a living person? blood alcohol concentrations are generally believed to be negligible in the absence of ingested alcohol. "endogenous" ethanol in human blood exists at a concentration of about . g/dl, which is below the limit of detection for most methods ( ) . first in such a list would be postural asphyxia, for example, in drunks who fall asleep face down. also, depressant drugs in the tricyclic, analgesic, barbiturate, and benzodiazepine classes all potentiate the effect of alcohol ( ) . also included in such a list would be infancy and childhood; ischemic heart disease;' chronic bronchitis and emphysema;' other chronic debilitating diseases; poisoning with carbon tetrachloride' or carbon monoxide;' and other causes of hypoxia.' how can one estimate blood alcohol (ethanol) concentrations from vitreous, urine, or tissue alcohol levels and from alcohol in stomach contents? the ratio of serum, plasma, urine, vitreous, and various tissues has been compiled by garriot ( ) . the values may vary considerably. for vitreous, the ratios varied from . - . . these variations may depend on whether blood alcohol concentrations were increasing or decreasing at the time of death. most other body fluids and tissues showed ranges closer to . most urine values were above the blood alcohol concentrations. in another study ( ) , the blood/vitreous (bn) ratio in the early absorption phase was . (range, . - . ; sd . ) and in the late absorption and elimination phase, the bn ratio was . (range, . - . ; sd . ). blood ethanol concentrations probably can be estimated using b = . v for early absorption and b = . v for later phases. a urinelblood ethanol ratio of . or less indicates that the deceased was in the early absorption phase. how can one use alcohol (ethanol) concentrations in postmortem specimens to estimate the blood alcohol concentration at various times before death? with certain limitations, one can base calculations of this kind on the assumption that the blood alcohol level decreases from its peak at a fairly constant rate of . -q. g/dl/h until death ( ) . if blood is not available, conversion factors (see above) must be used. alcoholics have been reported to metabolize at a rate of up to . g/dl/h ( ) . example: the driver of an automobile drinks at a party until midnight. he leaves his host at about : a.m. and is involved in a head-on collision at : a.m. he dies in the emergency room at : a.m. there are multiple injuries and the patient exsanguinates. the autopsy is done at : p.m. although this appears quite unlikely, let us assume that no satisfactory blood sample was obtained before death and that no blood or plasma expanders were given. if under such circumstances the alcohol concentration in the vitreous was found to be . g/dl, what was the alcohol concentration in the blood at the time of the accident? vitreous and blood alcohol concentrations may be assumed to have remained unchanged after death. therefore, the blood alcohol level at the time of death must have been approx . (vitreous humor alcohol) x . (conversion factor, see above) = . g/dl. the time interval between the accident ( : a.m.) and death ( : a.m.) is hand min or / h. if we assume that the decedent was not an alcoholic and that the blood alcohol concentration was decreasing from its peak at a constant rate of . g/dl/h, then the concentration at the time ofthe accident is estimated to have been . (concentration at time of death) + ( / x . ) = . + . = . g/dl or . %. the blood alcohol concentration at the time of the accident could have been lower if the victim stopped drinking later than h or / h before the accident. in the latter case, the peak alcohol level would have occurred after the accident, reflecting the time to absorb the latest drink. the blood alcohol concentration at the time of the accident could have been lower or higher if the time when the patient stopped drinking, the time of the accident, or the time of the death is uncertain. the blood alcohol concentration at the time of the accident could have been higher if the victim was a chronic alcoholic. the elimination rate in such persons may be as high as . mg/dl, which would change the figures in our example above to . + ( / x . ) = . + . = . g/d or . %. only rough estimates are possible. first, the peak blood alcohol level must be determined or calculated, as described in the previous paragraphs. tables (see below) are available that relate blood alcohol level to the minimal amounts of whiskey, wine, or beer that must have been consumed ( ) . however, tables of this type are often based on the minimum amount of alcohol circulating in the body after specific numbers of drinks; such tables do not yield reliable results if used conversely. furthermore, inasmuch as drinking and elimination of alcohol may take place concomitantly, over a longer period the total amount of alcohol consumed may have been much greater than the tables would indicate. it cannot be lower. according to these tables, pints of ordinary beer or fl oz of whiskey would be the minimal amounts needed to produce a blood alcohol level of about mg/dl in a person weighing - pounds. the total body alcohol can be calculated from the blood alcohol level by using widmark's formula: average concentration of alcohol in entire body = . concentration of alcohol in the blood in a person weighing kg, the blood alcohol concentration would be increased mg/dl ( . %) by the absorption of oz of ethanol ( z of -proof whiskey). strength of alcohol is measured in "proof'; absolute alcohol is proof. therefore, in the united states, alcohol content as volume percent is half the proof (for example, -proof whiskey contains % alcohol by volume). the alcohol content of various beverages is shown in the following table. approximate alcohol content in various beverages t toata from glaister, rentoul e. medical jurisprudence and toxicology, th ed. e & s livingstone, edinburgh, with permission. twithin h after consumption of diluted alcohol (approx %) on an empty stomach, assuming body weight of - pounds ( . - . kg) reproduced from ( ) with permission. *one ounce (about ml) of whiskey or z (about ml) of beer. what is the toxicity of alcohol other than ethanol? in general, the toxicity increases as the number of carbon atoms in the alcohol increases. thus, butyl alcohol is two times as toxic as ethyl alcohol: but isopropyl alcohol is only twothirds as toxic as isobutyl alcohol and one-half as toxic as amyl alcohol. primary alcohols are more toxic than the corresponding secondary isomers ( ) . anemia, hemolytic synonyms and related terms: acquired hemolytic anemia; extracorpuscular hemolytic anemia; hereditary hemolytic anemia (hereditary elliptocytosis, pyropoikilocytosis, stomatocytosis. spherocytosis); immunohemolytic anemia; intracor-puscular hemolytic anemia; microangiopathic hemolytic anemia; spur cell anemia. possible associated conditions: disseminated intravascular coagulation;* eclampsia;* glucose- -phosphatase deficiency (g pd); hemolytic uremic syndrome;* malignant hypertension; lymphoma* and other malignancies; paroxysmal nocturnal hemo-globinuria; sickle cell disease;*thalassemia;* thrombotic thrombocytopenic purpura.* (see also below under "note.") note: hemolysis also may be caused by conditions such as poisoning with chemicals or drugs, heat injury, snake bite,* or infections or may develop as a transfusion reaction* or be secondary to adenocarcinoma, heart valve prostheses (see below), liver disease (see below), renal disease, or congenital erythropoietic porphyria. * procedures prepare skeletal roentgenograms. jaundice; skin ulcers over malleoli. in young patients: thickening of frontal and parietal bones with loss of outer table ("hairon-end" appearance); paravertebral masses caused by extramedullary hematopoiesis; deformities of metacarpals, metatarsals, and phalanges. osteonecrosis* of femoral heads. remove and place in fixative as early as possible in order to minimize autolysis (alternatively, formalin can be injected in situ; see below). samples should include oxyntic corpus and fundus mucosa. record weights. submit tissue samples for histologic study. record weight of thyroid gland. for removal and specimen preparation, see chapter . request luxol fast blue stain. for removal and specimen preparation, see chapter . if there is a clinical diagnosis of anemia-related amblyopia, follow procedures described under "amblyopia, nutritional." jaundice. manifestations of malnutrition. * stomatitis with cheilosis and perianal ulcerations due to folic acid deficiency. chronic exfoliative skin disorders. vitiligo. macrocytosis; poikilocytosis; macroovalocytes; hypersegmentation of leukocytes; abnormal platelets. atrophic glossitis with ulcers. pharyngoesophagitis (folic acid deficiency). previous total or subtotal gastrectomy. carcinoma of stomach. autoimmune gastritis (diffuse corporal atrophic gastritis) with intestinal metaplasia. crohn's disease;* sprue;* other chronic inflammatory disorders; jejunal diverticula; intestinal malignancies; fish tapeworm infestation; previous intestinal resection or blind intestinal loop; enteric fistulas. hepatosplenomegaly. alcoholic liver disease. * giant epithelial cells. hyperthyroid goiter; thyroiditis. demyelination of cerebral white matter (in advanced cases). demyelination in posterior and lateral columns of spinal cord, most frequently in thoracic and cervical segments. demyelination of peripheral nerves. retinal hemorrhages; demyelination of optic nerves. hypercellular; megaloblastic. myeloproliferative disorder. brain other organs if mycotic aneurysms are expected and microbiologic studies are intended, follow procedures described below under "aneurysm, mycotic aortic." request verhoeff-van gieson, gram, and grocott's methenamine silver stains. for cerebral arteriography, see chapter . if arteriography cannot be carried out, rinse fresh blood gently from base of brain until aneurysm can be identified. record site of rupture and estimated amount of extravascular blood. for paraffin embedding of aneurysms, careful positioning is required. expected findings depend on type of aneurysm. mycotic aneurysms are often multiple and deep in brain substance. berry aneurysms are the most frequent types and often are multiple. most frequent sites are the bifurcations and trifurcations of the circle of willis. saccular atherosclerotic aneurysms are more common than dissecting aneurysms, which are very rare. with congenital cerebral artery aneurysm: coarctation of aorta;* manifestations of hypertension;* and polycystic renal disease. with mycotic aneurysm: infective endocarditis;* pulmonary suppurative processes; and pyemia. aneurysm, dissecting aortic (see "dissection, aortic.") aneurysm, membranous septum of heart note: for general dissection techniques, see chapter . most aneurysms ofthe membranous septum probably repre-sent spontaneous closure of a membranous ventricular septal defect by the septalleafiet of the tricuspid valve. aneurysm, mycotic aortic note: (i) collect all tissues that appear to be infected. ( ) request aerobic, anaerobic, and fungal cultures. ( ) request gram and grocott methenamine silver stains. ( ) no special precautions are indicated. ( ) no serologic studies are available. ( ) this is not a reportable disease. chest and abdominal organs aorta other organs submit blood samples for bacterial culture. en masse removal of adjacent organs is recommended. photograph all grossly identifiable lesions. aspirate material from aneurysm or para-aortic abscess and submit for culture. prepare sections and smears of wall of aneurysm and of aorta distant from aneurysm. request verhoeffvan gieson and gram stains. septicemia and infective endocarditis. * streptococcus, staphylococcus, spirochetes, and salmonella can be found in mycotic aneurysm. para-aortic abscess. septic emboli with infarction or abscess formation. aneurysm, syphilitic aortic part ii / diseases and conditions heart and aorta other organs en masse removal of organs is recommended. for coronary arteriography, see chapter . request verhoeff-van gieson stain from sections at different levels of aorta, adjacent great vessels, and coronary arteries. see also under "syphilis." aneurysm usually in ascending aorta. may erode adjacent bone (sternum). syphilitic aortitis may cause intimal wrinkling, narrowing of coronary ostia, and shortening of aortic cusps. disruption of medial elastic fibrils. aortic valvulitis and insufficiency;* syphilitic coronary arteritis; syphilitic myocarditis. external examination aorta prepare chest and abdominal roentgenograms. open aorta along line of blood flow, or bisect into anterior and posterior halves. photograph tear(s). measure bloody effusions in body cavities. measure or estimate amount of blood in mediastinum. request verhoeff-van gieson stain. cutaneous impact trauma. mediastinum widened by hemorrhage in case of tarnponaded dissection. a bleed into a body cavity of less-thanexsanguinating volume should point to an alternate mechanism of death such as neurogenic shock or lethal concussion; a posterior neck dissection may be required in such instances. microscopy may show transmural rupture, false aneurysm, or localized dissection. angiitis (see "arteritis, all types or type unspecified.") angina pectoris note: see under "disease, ischemic heart" and chapter . angiokeratoma corporis dittusum (see "disease, fabry's.") angiomatosis, encephalotrigeminal (see "disease, sturge-weber-dimitri.") angiopathy, congophilic cerebral synonyms and related terms: beta amyloid angiopathy due to~-amyloid peptide deposition (~a ) (associated with alzheimer's disease; hereditary cerebral hemorrhage with amyloid angiopathy of dutch type; or sporadic beta amyloid angiopathy); hereditary cerebral amyloid angiopathy, due to deposition of other amyloidogenic proteins such as cystatin c (icelandic type) and others (e.g., transthyretin, gelsolin) ( ). procedures possible or expected findings request stains for amyloid, particularly congo red, and thioflavine s (examine with polarized and ultraviolet light, respectively). request immunostain for~a . some tissue should be kept frozen for biochemical studies. multiple recent cerebral cortical infarctions or small cortical hemorrhages, or both, or massive hemispheric hemorrhages, both recent and old. amyloid deposition in leptomeninges and cortical blood vessels. senile plaques are usually present. in some cases, angiopathy is part of alzheimer's disease. * other organs a prepare material for electron microscopy. electron microscopic study permits definite confirmation of diagnosis. organs and tissues may be minimally affected by amyloidosis. anomaly, coronary artery possible associated conditions: with double outlet right ventricle; persistent truncal artery; tetralogy of fallot;* and transposition of the great arteries.* note: coronary artery between aorta and pulmonary artery, often with flap-valve angulated coronary ostium. coronary artery may communicate with cardiac chamber, coronary sinus, or other cardiac veins, or with mediastinal vessel through pericardial vessel. saccular aneurysm of coronary artery with abnor-mal flow, infective endarteritis of arteriovenous fistula, and myocardial infarction may be present. ifone or both coronary arteries originate from pulmonary trunk, myocardial infarction may be present. heart perform coronary angiography. if infective endarteritis is suspected, submit blood sample for microbiologic study. ectopic origin of coronary arteries or single coronary artery. sudden death. for a detailed description of possible additional findings, see above under "note." anomaly, ebstein's (see "malformation, ebstein's") anorexia nervosa note: sudden death from tachyarrhythmias may occur in advanced cases and thus, autopsy findings may not reveal the immediate cause of death. external examination all organs record height and weight, and prepare photographs to show cachectic features. record abnormalities as listed in righthand column. follow procedures described under "starvation." record weight of endocrine organs and submit samples for histologic study. cachexia, often with preserved breast tissue; hirsutism; dry, scaly, and yellow skin (carotenemia). mild edema may be present. parotid glands may be enlarged. manifestations of starvation.* ovaries tend to be atrophic; other endocrine organs should not show abnormalities. synonyms: cutaneous anthrax; gastrointestinal anthrax; pulmonary (inhalational) anthrax. note: ( ) collect all tissues that appear to be infected. this is a reportable disease. bioterrorism must be considered in current cases. external examination and skin blood photograph cutaneous papules, vesicles, and pustules. prepare smears and histologic sections. submit samples for bacteriologic study. submit sample for serologic study. disseminated anthrax infection may occur without skin lesions. edema of neck and anterior chest in nasopharyngeal anthrax. anthrax septicemia. see above under "note." part ii i diseases and conditions lungs gastrointestinal tracts and mesentery neck organs record character and volume of effusions. after sampling for bacteriologic study (see above under "note") perfuse one or both lungs with formalin. extensive sampling for histologic study is indicated. extensive sampling for histologic study is indicated. photograph meningeal hemorrhage in situ. pleural effusions;* hemorrhagic mediastinitis; anthrax pneumonia (inhalational anthrax; woolsorter's disease). histologic sections reveal hemorrhagic necrosis, often with minimal inflammation and gram-positive, spore-forming, encapsulated bacilli. gastrointestinal anthrax with mucosal edema and ulcerations. hemorrhagic mesenteric lymphadenitis. tongue, nasopharynx, and tonsils may be involved. hemorrhagic meningitis (hemorrhage tends to predominate). external examination distal colon and rectum photograph perineum. measure depth of anal pit, if any. dissect distal colon, rectum, and perirectal pelvic organs in situ (as much as possible). search for opening of fistulous tracts from lumen. use roentgenologic study or dissection, or both, to determine course of tract. absence of normally located anus; anal dimple. abnormal termination of the bowel into the trigone of the urinary bladder, the urethra distal to the verumontanum, the posterior wall of the vagina, the vulva, or the perineum. aortitis note: see also under "arteritis" and "aneurysm, ascending aortic." heart and aorta other organs and tissues remove heart with whole length of aorta and adjacent major arteries. record width and circumference of aorta at different levels. describe and photograph appearance of intima and of orifices of coronary arteries and other aortic branches. submit multiple samples for histologic study and request verhoeff-van gieson stain. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. secondary aortic atherosclerosis or intimal fibroplasia. widening of aorta; syphilitic aneurysm. * giant cell aortitis; rheumatoid aortitis; syphilitic aortitis; takayasu's arteritis.* manifestations of rheumatoid arthritis, * syphilis,* systemic sclerosis,* hodgkin's lymphoma, and many other diseases associated with vasculitis. external examination brain spine and spinal cord other organs prepare roentgenogram of spine. for removal and specimen preparation, see chapter . for removal of spinal cord and specimen preparation, see chapter . expose nerve roots. record appearance and photograph spinal cord in situ. submit samples of spinal cord and inflamed tissue for histologic study. request gram, gomori's iron, and grocott's methenamine silver stains. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. signs of previous spinal surgery or lumbar puncture (myelography). evidence of previous trauma or previous myelography. cerebral arachnoiditis. fibrous arachnoidal adhesions and loculated cysts. tuberculosis;* syphilis;* fungal or parasitic infection. systemic infection (see above). ascending urinary infection or other manifestations of paraplegia. arch, aortic, interrupted synonym: severe coarctation. note: the basic anomaly is a discrete imperforate region in the aortic arch, with a patent ductal artery joining the descending thoracic aorta. type a interruption is between the left subclavian and ductal arteries; type b between the left subclavian and left common carotid arteries; and type c (rare) between the left common carotid and brachiocephalic (innominate) arteries. for general dissection techniques, see part i, chapter . possible associated conditions: bicuspid aortic valve (with type a); di george syndrome* with thymic and parathyroid aplasia (with type b); hypoplasia of ascending aorta (with all types); persistent truncal artery (truncus arteriosus); ventricular septal defect. arrhythmia, cardiac note: see also under "death, sudden cardiac." toxicologic studies may be indicated, for instance, if digitalis toxicity (see "poisoning, digitalis") is suspected. if a cardiac pacemaker had been implanted, the instrument should be tested for malfunction. arteriosclerosis (see "atherosclerosis.") arteritis, all types or type unspecified synonyms and related terms: allergic angiitis and granulomatosis (churg-strauss);* allergic vasculitis; anaphylactoid purpura* and its synonyms; angiitis; buerger's disease;* cranial arteritis; giant cell arteritis;* granulomatous arteritis (angiitis); hypersensitivity angiitis; infectious angiitis; necrotizing arteritis; polyarteritis nodosa;* rheumatic arteritis; rheumatoid arteritis, syphilitic arteritis; takayasu's arteritis;* temporal arteritis; thromboangiitis obliterans; and others (see also below under "note"). note: autopsy procedures depend on ( ) the expected type of arteritis, such as giant cell arteritis,* polyarteritis nodosa,* or thromboangiitis obliterans (buerger's disease*); and ( ) the nature of suspected associated or underlying disease, such as aortic arch syndrome,* beh~et's syndrome,* cogan's syndrome, degos' disease,* dermatomyositis,* erythema nodosum and multiforme,* goodpasture's syndrome,* polymyositis, rheumatic fever, * rheumatoid arthritis,* syphilis,* and other nonspecific infectious diseases, systemic lupus erythematosus,* systemic sclerosis (scleroderma),* or takayasu's disease. for histologic study of blood vessels, verhoeff-van gieson stain or a similar stain is recommended. temporal and ophthalmic arteritis. arteritis of ciliary and retinal vessels. clinically, polymyalgia. anemia. arteritis, takayasu's synonyms: aortic arch syndrome; pulseless disease. external examination heart, aorta, and adjacent great vessels kidney eyes and optic nerve brain for in situ aortography, clamp distal descending thoracic aorta and neck vessels as distal as possible from takeoff at aortic arch. remove heart together with aorta and long sleeves of neck vessels. for coronary arteriography, see chapter (method designed to show coronary ostia). test competence of aortic valve. open aortic arch anteriorly and measure (with calipers) lumen at origin of great neck vessels. photograph aorta and neck vessels and submit samples for histologic study. request verhoeffvan gieson stain. submit tissue for histologic examination. for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . facial muscular atrophy and pigmentation. narrowing at origin of brachiocephalic arteries. dilated ascending aorta. narrowing of coronary arteries at origins. myocardial infarction. aortic insufficiency. * aortic atherosclerosis. thromboses of brachiocephalic arteries. giant cell arteritis. * diffuse mesangial proliferative glomeulonephritis ( ) . atrophy of optic nerve, retina, and iris; cataracts; retinal pigmentation. ischemic lesions. artery, patent ductal synonym: patent ductus arteriosus. note: the basic anomaly is persistent postnatal patency of the ductal artery, usually as an isolated finding (in % of cases in infants, and in % in adults). it is more common in premature than full-term infants and at high altitudes than at sea level. possible complications in unoperated cases include congestive heart failure, * plexogenic pulmonary hypertension,* ductal artery aneurysm or rupture, fatal pulmonary embolism,* or sudden death. in some conditions, such as aortic atresia* or transposition with an intact ventricular septum,* ductal patency may be necessary for survival. possible associated conditions: atrial or ventricular septal defect;* coarctation ofthe aorta;* conotruncal anomalies; necrotizing enterocolitis in premature infants; postrubella syndrome; and valvular or vascular obstructions. artery, persistent truncal synonym and related terms: type i, pulmonary arteries arise from single pulmonary trunk (in %); type , pulmonary arteries arise separately but close-by (in %); type , pulmonary arteries arise separately but distal from one another (in %). note: the basic anomaly is a common truncal artery, with truncal valve, giving rise to aorta, pulmonary arteries, and coronary arteries, usually with a ventricular septal defect. interventions include complete rastelli-type repair, with closure of ventricular septal defect, and insertion of valved extracardiac conduit between right ventricle and detached pulmonary arteries. possible associated conditions: absent pulmonary artery (in %); atrial septal defect (in %); absent ductal artery (in %); coronary ostial anomalies (in %); di george syndrome;* double aortic arch; extracardiac anomalies (in %); interrupted aortic arch* (in %); right aortic arch (in %); truncal valve insufficiency (uncommon) or stenosis (rare); trun-cal valve with three (in %), four (in %), or two (in %) cusps. heart and great vessels if infective endocarditis is suspected, follow culture procedures for endocardial vegetation described in chapter . request verhoeff-van gieson stain. infective endocarditis,* usually of truncal valve. late postoperative conduit obstruction. postoperative late progressive truncal artery dilation with truncal valve insufficiency. hypertensive pulmonary vascular disease. cerebral abscess,* if right-to-ieft-shunt was present. arthritis, all types or type unspecified note: for extra-articular changes, see under the name of the suspected underlying conditions. infectious diseases that may be associated with arthritis include bacillary dysentery, * brucellosis, * gonorrhea, rubella,* syphilis, * tuberculosis, * typhoid fever, * and varicella. * noninfectious diseases in this category include acromegaly,* beh<;et's syndrome,* felty's syndrome,* gout,* rheumatoid arthritis,* and many others, too numerous to mention. remove synovial fluid and prepare smears. submit synovial fluid for microbiologic and chemical study. for removal of joints, prosthetic repair, and specimen preparation, see chapter . for removal and specimen preparation, see chapter . in the polyarticular variant, facial asymmetry may be noted. rheumatoid factor positive in some cases. pericarditis.* interstitial pneumonitis; pleuritis. (see also under "arthritis, rheumatoid.") lymphadenopathy. splenomegaly. monarthritis or severe, erosive polyarthritis; see also under "arthritis, rheumatoid" and above under "externalexamination and skin." ankylosing spondylitis* may be present. chronic iridocyclitis. see "arthritis, rheumatoid." arthritis, rheumatoid synonyms and related terms: ankylosing spondylitis;* felty's syndrome;* juvenile rheumatoid arthritis* (still's disease); rheumatoid disease; and others. possible associated conditions: amyloidosis;* polymyositis (dermatomyositis*); psoriasis;* sjogren's syndrome;* systemic lupus erythematosus;* systemic vasculitis, and others. subcutaneous rheumatoid nodules on elbows, back, areas overlying ischial and femoral tuberosities, heads of phalangeal and metacarpal bones, and occiput. deformities and subluxation of peripheral joints (see also below under "joints"). subaxial dislocation of cervical spine may be cause of sudden death. pneumothorax;* pleural empyema.* t-cell abnormalities ( ) . bacteremia. positive rheumatoid factor. rheumatoid granulomas in myocardium (septum), pericardium, and at base of aortic and mitral valves; constrictive pericarditis;* aortic stenosis;* coronary arteritis. systemic vasculitis (arteritis*). rheumatoid granulomas in pleura and lung (with pneumoconiosis*); bronchopleural fistula; rheumatoid pneumonia with interstitial pulmonary fibrosis and honeycombing; bronchiectasis;* bronchiolitis with cystic changes; pulmonary arteritis. pneumoconiosis* in caplan arthrogryposis ( ) may be a primary muscle disease, or it may involve abnormalities of the brain, spinal cord, and/or peripheral nerves. etiologies are numerous, as are the modes of inheritance. critical to making the appropriate diagnosis is the collection of muscles from various sites for routine histology, muscle histochemistry, and electron microscopy. portions of peripheral motor nerves must also be prepared for histology and electron microscopy. abdominal cavity intra-abdominal lymphatic system puncture abdominal cavity and submit fluid for microbiologic study. record volume of exudate or transudate and submit sample for determination of fat and cholesterol content. prior to routine dissection, lymphangiography (see below) may be indicated. possible associated conditions: with pulmonary aspergillosis-bronchiectasis; * bronchocentric granulomatosis;* sarcoidosis;* tuberculosis. * with systemic aspergillosisleukemia;* lymphoma;* and other conditions complicated by immunosuppression (l, ) . other organs a carefully make multiple parasagittal sections through the unperfused lungs. culture areas of consolidation. if diagnosis was confirmed, perfuse lungs with formalin. prepare histologic sections from walls of cavities, cavity contents, and pneumonic infiltrates. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. assault note: all procedures described under "homicide" must be followed. asthma note: spray death* may occur in asthma sufferers from pressurized aerosol bronchodilators. record thickness and position. perfuse one lung with formalin. because mucous plugs may block bronchial tree, attach perfusion apparatus to pulmonary artery or to bronchus and pulmonary artery. monitor perfusion to ensure proper inflation. prepare photograph of fixed cut section. submit samples of pulmonary parenchyma and bronchi for histologic study. request azure-eosin and verhoeff-van gieson stains. record weight and thickness of walls. leave attached to stomach. photograph and submit samples for histologic study. eczema. conjunctival hemorrhages and subcutaneous emphysema may be present after fatal attack. pneumothorax;* mediastinal emphysema. low diaphragm (see below). increased igeconcentrations in fatal asthma; postmortem tryptase determination is of doubtful value in this regard ( ) . hypertrophy. low position of diaphragm. hyperinflated lungs. thick-walled bronchi with prominent viscid mucous plugs. typical microscopic inflammatory changes ( ) . asthmatic bronchitis with eosinophilic infiltrates. bronchocentric granulomatosis.* pulmonary atherosclerosis with breakup of elastic fibers. paucity of ecosinophils in mucous ( ) . cor pulmonale. refl ux esophagitis ( ) . peptic ulcer. * pneumatosis of small intestine; emphysema of colon. centrilobular congestion and necrosis. petechial hemorrhages in hypothalamus; necrosis of cerebellar folia; anoxic changes in cortex, globus pallidus, thalamus, sommer's sector of hippocampus, and purkinje cells of cerebellum. suspected changes in anterior hom cells of spinal cord in patients with asthma-associated poliomyelitis-like illness (hopkins syndrome) ( ). allergic polyps and other allergic inflammatory changes ( ) . increased erythropoiesis. atresia, aortic valvular synonym: aortic atresia; aortic atresia with intact ventricular septum; hypoplastic left heart syndrome. note: the basic anomaly is an imperforate aortic valve, with secondary hypoplasia ofleft-sided chambers and ascending aorta. for possible surgical interventions, see two-stage norwood and modified fontan procedures in chapter . possible associated conditions: atrial septal defect* (or patent foramen ovale, usually restrictive); dilatation of myocardial sinusoids thatcommunicate with coronary vessels; dilatation of right atrium, right ventricle, and pulmonary trunk; fibroelastosis ofleft atrial and left ventricular endocardium; hypertrophy of ventricular and atrial walls; hypoplastic left atrium, mitral valve, left ventricle, and ascending aorta; mitral atresia* with minute left ventricle; patent ductal artery (ductus arteriosus); small left ventricle with hypertrophic wall; tubular hypoplasia of aortic arch, with or without discrete coarctation. synonyms and related terms: congenital biliary atresia; extrahepatic biliary atresia; infantile obstructive cholangio-pathy; syndromic (alagille's syndrome) or nonsyndromic paucity of intrahepatic bile ducts ("intrahepatic" biliary atresia). possible associated conditions: alpha]-antitrypsin deficiency;* choledochal cyst;* congenital rubella syndrome;* polysplenia syndrome* ( ); small bowel atresia; trisomy - ; trisomy ; turner's syndrome;* viral infections (cytomegalovirus infection;* rubella*). dissect extrahepatic bile ducts in situ or leave hepatoduodenalligament intact for later fixation and sectioning (see below). record appearance and contents of gallbladder and course of cystic duct. in postoperative cases, submit sample of anastomosed hepatic hilar tissue for demonstration of microscopic bile ducts. remove liver with hepatoduodenalligament. prepare horizontal sections through ligament and submit for histologic identification of ducts or duct remnants. prepare frontal slices of liver and sample for histologic study. request pas stain with diastase digestion. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. jaundice. congenital rubella and other viral infections. alpha]-antitrypsin deficiency;* defects in bile acid synthesis. chromosomal abnormalities. in atresia of the hepatic duct, the gallbladder will be empty. in isolated atresia of the common bile duct, the gallbladder contains bile but it cannot be squeezed into the duodenum. atresia or hypoplasia of bile duct(s); choledochal cyst(s). biliary drainage created by kasai operation. obliterative cholangiopathy ( ) . intrahepatic cholelithiasis; postoperative ascending cholangitis; secondary biliary cirrhosis; giant cell transformation; paucity of intrahepatic bile ducts. pas-positive inclusions in alphal-antitrypsin deficiency.* polysplenia syndrome* ( ) with malrotation, situs inversus, preduodenal portal vein, absent inferior vena cava, anomalous hepatic artery supply, and cardiac defects. for other abnormalities outside the biliary tree, see under "possible associated conditions"). nephromegaly ( ) . atresia, cardiac valves (see "atresia, aortic valvular," "atresia, mitral valvular," "atresia pulmonary valvular, with intact ventricular septum," "atresia, pulmonary valvular, with ventricular septal defect," and "atresia, tricuspid valvular.") atresia, duodenal possible associated conditions: with membranous obstruction of the duodenum-annular pancreas; atresia of esophagus* with tracheoesophageal fistula; congenital heart disease; cystic fibrosis;* down's syndrome;* hirschsprung's disease; imperforate anus* or other congenital obstructions of the intestinal tract ( ); intestinal malrotation; lumbosacral, rib-, and digitllimb anomalies; single umbilical artery; spinal defects; undescended testis ( ). see also under "atresia, small intestinal." the basic anomaly is an imperforate pulmonary valve, with a hypoplastic right ventricle. in unoperated cases, ductal closure is the most common cause of death. for possible surgical interventions, see modified blalock-taussig shunt, mod-ified fontan procedure, and pulmonary valvulotomy in chapter . for general dissection techniques, see chapter . possible associated conditions: dilated myocardial sinusoids that may communicate with epicardial coronary arteries or veins; patent ductal artery (ductus arteriosus); patent oval foramen (foramen orale); tricuspid atresia with minute right ven-tricle; tricuspid stenosis with hypoplastic right ventricle (in %); tricuspid insufficiency with dilated right ventricle (in %). synonym: tetralogy of fallot with pulmonary atresia. note: the basic anomaly is atresia of the pulmonary valve and ofvariable length ofpulmonary artery, and ventricular septal defect (membranous or outlet type), with overriding aorta, and with pulmonary blood supply from ductal or systemic collateral arteries. for possible surgical interventions, see rastelli-type repair and unifocalization of multiple collateral arteries in chapter . possible associated conditions: right ventricular outflow tract a short blind-ended pouch ( %) or absent ( %); atresia of pulmonary artery bifurcation, with nonconfluent pulmonary arteries; right aortic arch ( %); atrial septal defect ( %); persistent left superior vena cava; anomalous pulmonary venous connection; tricuspid stenosis or atresia; complete atrioventricular septal defect; transposed great arteries; double inlet left ventricle; asplenia, polysplenia, or velocardiofacial syndromes; dilated ascending aorta, with aortic insufficiency. related term: jejuno-ileal atresia. possible associated findings: esophageal atresia* with tracheoesophageal fistula; lumbosacral, rib-, or digit/limb anom -alies; undescended testes (l) . note: see also under "atresia, duodena ." fascia lata, blood, or liver these specimens should be collected using aseptic technique for tissue culture for chromosome analysis (see chapter ) . intestinal tract for mesenteric angiography, see chapter . leave mesentery attached to small bowel, particularly to the atretic portion. trisomy . multiple atresias; proximal dilatation; volvulus; malrotation; meconium impaction; other evidence of cystic fibrosis. anorectal malformation (l) . annular pancreas ( ). atresia, tricuspid valvular note: the basic anomaly is an absent right atrioventricular connection ( %) or imperforate tricuspid valve ( %), with a hypoplastic right ventricle ( %), muscular ventricular septal defect ( %) that is restrictive ( %), and a patent oval atresia, urethral foramen ( %) or secundum atrial septal defect ( %). for possible surgical interventions, see modified fontan or glenn procedures in chapter . for general dissection techniques, see chapter . possible associated conditions: juxtaposed atrial appendages; large left ventricular valvular orifice; large left ventricular chamber; persistent left superior vena cava; pulmonary atresia; transposition of the great arteries ( %), with aortic co-arctation ( % of those); anomalies of musculoskeletal or digestive systems ( %); down's,* asplenia, or other syndromes. heart aorta and cervical arteries brain if infective endocarditis* is suspected, culture using the method described in chapter . for dissection of carotid and vertebral arteries, see chapter . for removal and specimen preparation, and cerebral anteriography, see chapter . if a foreign body is discovered during a medicolegal autopsy or if the discovery of a foreign body may have medicolegal impli-cations (e.g., presence of a surgical instrument in the abdominal cavity), the rules of the chain of custody apply. for the handling of bullets or bullet fragments, see "injury, firearm." if analysis offoreign material is required, commercial laboratories may be helpful. bolus (see "obstruction, acute airway!') burns note: fatal bums should be reported to the medical examiner's or coroner's office. the questions to be answered by the pathologist depend on whether the incident was accidental, sui-cidal, or homicidal, and whether the victim survivied to be treated in the hospital. a pending death certificate should be issued if the fire and police investigators are not sure of the circumstances at the time of the autopsy. for electrical bums, see under "injury, electrical." for victims who were treated at the hospital, autopsy procedures should be directed toward the discovery or confirmation of the mechanism of death, such as sepsis or pulmonary embolism.* death can be caused primarily by heart disease, with other-wise minor bums and smoke inhalation serving as the trigger that leads to lethal ventricular arrhythmia. because carbon monoxide concentrations are halved approx every min with % oxygen therapy, the pathologist must obtain the first clinical laboratory test results for co-hemoglobin. soot can be detected with the naked eye or d after inhalation of smoke. ambulance records should be examined to determine whether a persistent coma might have been caused by hypoxic encephalopathy following resuscitation from cardiac arrest at the scene. admission blood samples should be acquired to test for cohemoglobin and alcohol. this may not have been done in the emergency room. persons suffering from chronic alcoholism succumb to fire deaths more often than persons who do not drink. a very high initial serum alcohol concentration suggests a risk factor for the fire and presence of chronic alcoholism. patients with chronic alcoholism typically are deprived of alcohol when they are in the bum unit and this can cause sudden, presumably cardiac, death,just as it occurs under similarcircum-stances, not complicated by bums. under these circumstances, the heart fails to show major abnormalities. this mode of dying seems to have no relationship to the presence or absence of liver disease. if the body is found dead and charred at the scene, prepare whole body roentgenograms, before and after removal of remanants of clothing. see also under "identification of the body" and "external examination" in chapter ). one or two fingerpads may yield sufficient ridge detail for identification. if this is not possible, ante-and postmortem somatic and dental radiographs must be compared for identification, or dna comparison must be used. external examination, heart and lungs abdominal cavity and liver see below under "cardiomyopathy, dilated." record volume of ascites. record actual and expected weight of liver. request iron stain. see below under "cardiomyopathy, dilated." alcoholic cirrhosis and alcoholic cardiomyopathy rarely coexist. however, in genetic hemochromatosis,* cirrhosis and heart failure are common findings. cardiomyopathy, dilated (idiopathic, familial, and secondary types) note: for general dissection techniques, see chapter . external examination heart other organs and tissues record actual and expected weights. record ventricular thicknesses and valvular circumferences. evaluate relative atrial and ventricular chamber sizes. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. note: huntington's disease maps to the short arm of chromosome . the gene is widely expressed but of unknown function; it contains a cag repeat sequence, which is expanded (range, to ) in patients with huntington's disease. a sensitive diag-nostic test is based on the determination of this cag sequence, which can be done on fresh-frozen tissue or blood ( ) . in the absence of genetic confirmation, sampling of organs and tissues cannot be excessive because a complex differential diagnosis must be resolved. note: disseminated intravascular coagulation (dic) often is a complication of obstetrical mishaps such as abruptio placentae or amniotic fluid embolism,* or it complicates malignancies (such as adenocarcinomas or leukemia*) or bacterial, viral, and other infections. other conditions such as aortic aneurysm* or hemolytic uremic syndrome* are known causes also. ifthe nature of the underlying disease is known, follow the procedures under the appropriate heading also. note: this is a cause of diarrhea. microscopic colitis is associated with older age; collagenous colitis is associated with female sex ( ). the colon is grossly normal but microscopically, increased lymphocytes in the lamina propria and a subepithelial band of collagen is found. if only the lymphocytic infiltrate is found, the term "lymphocytic colitis" or "microscopic colitis" should be applied. a trichrome stain should be ordered in all instances, because the collagen band may be difficult to see without the special stain. i death, anaphylactic synonym: generalized anaphylaxis. note: autopsy should be done as soon as possible after death. neck organs should be removed before embalming. if death is believed to be caused by drug anaphylaxis, inquire about type of drug(s), drug dose, and route of administration (intravenous, intramuscular, and oral or other). this will determine proper sampling procedures-for instance, after penicillin anaphylaxis. allergy to bee stings, wasp stings, fire ants, and certain plants may also be responsible for anaphylaxis. however, envenomation also can be fatal in the absence of anaphylaxis. external examination search for injection sites or sting marks. if such lesions are present, photograph and excise with -cm margin. freeze excised tissue at - °c for possible analysis. prepare chest roentgenogram. foam in front of mouth and nostrils. swelling of involved tissue. antigen-antibody reaction in involved tissues. antibodies against suspected antigen. laryngeal edema may recede soon after death. foamy edema in trachea and bronchi; diffuse or focal pulmonary distention ("acute emphysema") alternating with collapse; pulmonary edema and congestion; accumulation of eosinophilic leukocytes. eosinophilic leukocytes in red pulp. death, anesthesia-associated. note: there are many possible causes of anesthesiaassociated death that are not drug-related, such as acute airway obstruction* by external compression, aspiration, arrhythmia of a heart not previously known to be diseased, tumor, or an inflammatory process. some ofthe complications are characteristically linked to a specific phase of the anesthesia, and many are not revealed by customary morphologic techniques. the task for the pathologist charged with investigating an anesthesia-associated death is to reconstruct the chain of physiologic events culminating in cessation of vital signs. autopsy morphology plays a supporting role; the main investigations center around the record left by the anesthesiologist, testing of anesthesia equipment, and toxicological testing. a consulting anesthesiologist can divine much more information from the anesthesia and recovery room records than can the pathologist, and can suggest avenues of further investigation. therefore, the most important step in these autopsies is to obtain the anesthesiaassociated records and to secure the consulting services of an independent anesthesiologist. the changes in the vital signs during and after anesthesia will help to focus the investigation toward a cardiac mechanism ofdeath or depression ofbrainstem function as a terminal mechanism. when information is gathered about drugs and chemical agents that have been administered or to which the victim may have had access, the pathologist must keep in mind that some non-medical chemicals and many drugs are known to affect anesthesia. drugs and their metabolic products, additives, stabilizers, impurities, and deterioration products (one of which can be carbon monoxide) may be present and can be identified in postmortem tissues. therefore, all appropriate body fluids and solid tissue should be submitted for toxicological examination. if the anesthetic agent was injected into or near the spinal canal, spinal fluid should be withdrawn from above the injected site into a standard toxicologist's collection tube with fluoride preservative. if the anesthetic agent was injected locally, tissue should be excised around the needle puncture marks at a radius of - em. serial postmortem analysis of specimens may permit extrapolation to tissue concentration at the time of death. the time interval between drug administration and death sometimes can be calculated from the distribution and ratio ofadministered drugs and their metabolic products. for a review of anesthetic death investigation, see ref. ( ) . halothane anesthesia and some other anesthetic agents may cause fulminant hepatitis and hepatic failure. the autopsy procedures suggested under "hepatitis, viral" should be followed. note: for special autopsy procedures in postoperative deaths, see chapter . in some instances, procedures described under "death, anesthesia-associated" may be indicated. for a review of investigational procedures and autopsy techniques in operating-room-associated deaths, see ref. ( ) . if the autopsy will involve anatomy or dissection techniques that are unfamiliar, the pathologist should not hesitate to invite the surgeon to the autopsy. in patients who develop a cerebral infarction after open heart surgery, arterial air embolism should be considered as a possible cause. the diagnosis often must be based on excluding other causes because the air has been absorbed prior to death. if a patient dies rapidly, the hospital records may be incomplete or scanty. for example, if a patient bleeds to death despite attempted repair of hepatic lacerations, hospital records may not suffice to reach the correct cause-of-death opinion; personal accounts from the surgeon and anesthesiologist may be needed. autopsy data on patients dying following thoracic surgery may be found in ref ( ) . d death, restaurant (see "obstruction, acute airway.") death, sniffing and spray related terms: glue sniffing; sudden sniffing death syndrome. note: no anatomic abnormalities will be noted at autopsy. sudden death may occur after cardiac dysrhythmia or respiratory arrest. procedures possible or expected findings lungs brain if poison had been inhaled at the time when death occurred, tie main bronchi. submit lungs in glass container for gas analysis. submit samples of small bronchi for histologic study. for removal and specimen preparation, see chapter . submit samples of fresh or frozen brain for toxicologic study. submit samples in glass containers (not plastic) for toxicologic study. trichloroethane, fluorinated refrigerants, and other volatile hydrocarbons are most often involved in the "sudden sniffing death syndrome." spray death may occur in asthma sufferers using pressurized aerosol bronchodilators. freons and related propellants may also be responsible for sudden death. toxic components of glue-such as toluene-accumulate in the brain of glue sniffers. also present in various glues are acetone, aliphatic acetates, cyclohexane, hexane, isopropanol, methylethyl ketone, and methylisobutyl ketone. aerosols may occlude the airway by freezing the larynx. carbon tetrachloride sniffing may cause hepatorenal syndrome (see also under "poisoning, carbon tetrachloride"). death, sudden unexpected, of adult note: medicolegal autopsies are usually indicated, and appropriate procedures should be followed. ifanaphylactic death is suspected, see also under that heading. for all unexpected deaths, the pathologist should learn the circumstances of the death, in order to determine whether the mechanism of death was rapid or slow, and to guide the selection of ancillary tests. whenever paramedics attended a person, the run sheet should be obtained to look for a history of recent drinking or ofchronic alcoholism may be an important clue. the combination of a history ofalcoholism, a negative test for ethanol, and absence ofcardiovascular disease, should suggest alcohol withdrawal as the cause ofa sudden death. the list of"possible or expected findings" below is not complete. for general toxicologic sampling, see chapter . possible associated conditions: atrial septal defect;*bicuspid aortic valve;* coarctation,* hypoplasia, or interruption (type a) of aortic arch; coronary artery from main pulmonary artery; right atrial arch; patent ductal artery;* right pulmonary artery from ascending aorta; subaortic stenosis;* tetralogy of fallot;* ventricular septal defect. * (in approx % of the cases, one or more of these associated conditions are found.) defect, atrial septal note: the basic anomaly is a defect of the atrial septum, usually at the oval fossa (in %). possible complications in unoperated cases include atrial arrhythmias, congestive heart failure; paradoxic embolism; plexogenic pulmonary hypertension « %), and pulmonary artery aneurysm. possible surgical interventions include surgical and transcatheter closure of defect. for deficiency, vitamin c synonyms: hypovitaminosis c; scurvy. external examination and skin other organs bones, joints, and soft tissues record extent and character of skin lesions; prepare sections of skin. describe appearance of gums, and prepare sections. record evidence of bleeding. for removal, prosthetic repair, and specimen preparation of bones and joints, see chapter . hyperkeratotic hair follicles with perifollicular hemorrhages (posterior thighs, anterior forearms, abdomen); petechiae and ecchymoses (inner and posterior thighs); subcutaneous hemorrhages. gingivitis. in rare instances, gastrointestinal or genitourinary hemorrhages. hemorrhages into muscles and joints. subperiosteal hemorrhages occur primarily in distal femora, proximal humeri, tibiae, and costochondral junctions (scorbutic rosary). deficiency, vitamin d synonyms: hypovitaminosis d; rickets. note: features or rickets may be found in familial hypophosphatemia (vitamin d-resistent rickets; fanconi syndrome). vitreous or blood (serum) other organs prepare skeletal roentgenograms. in infants with suspected rickets, record size of anterior fontanelle and shape of head; state of dentition; and shape of costochondral junctions, wrists, long bones, and spine. submit samples for calcium, magnesium, and phosphate determination. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. weigh parathyroid glands and submit samples for histologic study. submit samples of intestine for histologic study. for removal, prosthetic repair, and specimen preparation, see chapter . in infantile rickets, diagnostic sites for histologic sampling are costochondral junctions, distal ends of radius and ulna, and proximal ends of tibia and humerus. for adults, see under "osteomalacia." in infants, rachitic changes at costochondral junctions; in adults, osteoporosis* and osteomalacia*-with or without pseudofractures (milkman's syndrome ( ) . note: the term spinocerebellar degeneration encompasses a variety of lesions whose classification is controversial. a new approach has come from linkage analysis and molecular biology. for instance, friedreich's ataxia, the classic form of hereditary ataxia, is due to an intronic expansion of a gaa tri-nucleotide repeat. other forms are also identified by their specific gene loci. neuropathologic examination still is important and ample sampling is suggested, which should include cerebral cortex, basal ganglia (caudate nucleus, putamen, and globus pallidus), thalamus, subthalamic nucleus, midbrain (red nucleus and substantia nigra), pons (pontine nuclei), spinal cord (at cer-vical, thoracic, and lumbar levels), optic tract, optic nerves with lateral geniculate nucleus, and sensory and motor peripheral nerves. for removal and specimen preparation, see chapter . enlargement of head. poor demarcation between cortex and gelatinous white matter. extensive demyelination and vacuolation of white matter, particularly subcortically. optic atrophy. degeneration, striatonigral (see "atrophy, multiple system.") related term: thirst. note: possible underlying conditions not related to inaccessibility of water include bums, exposure to heat, gastrointestinal diseases, recent paracentesis, renal diseases, and use of diuretic drugs. see also under "disorder, electrolyte(s)." external examination vitreous urine prepare histologic sections of blisters, ulcers, or skin abrasions. submit sample for sodium, chloride, and urea nitrogen determination. skin turgor may be decreased and eyes may be sunken. microscopic changes help to decide whether skin lesions are antemortem or postmortem. sodium concentrations more than meqll, chloride concentrations more than meq/ and urea nitrogen concentrations between and meq/dl indicate dehydration. absence or minimal amount of urine. dementia (see "disease, alzheimer's.") drug abuse, amphetamine(s) note: methamphetamine abuse may be suggested by poor condition of the dentition. methylenedioxymethamphetamine ("ecstasy") abuse is often suggested by friends with whom the decedent was abusing drugs. follow procedures described under "dependence, drug(s)." drug abuse, cocaine note: cocaine is spontaneously hydrolyzed by blood esterases, even after death. however, one of its major metabolite, benzoylecgonine, is routinely identifiable by immunoassay screening tests. when cocaine is abused concurrently with heroin or other depressant drugs, it may be difficult to ascribe deth to a single agent, unless circumstances clearly point to a rapid cardiac mechanism or a slow brainstem depression mechanism. note: if narcotic paraphernalia and samples of the drug itself are found at the scene of the death, they should be submitted for analysis. helpful information about the nature of a drug may be obtained from witnesses. state crime laboratories may provide much assistance. if name of drug is known, see also under "poisoning,..." the slang name of a drug may be insufficient for identification because these names often are used for different compounds at different times of places. opoid narcotics can be injected intravenously, or subcutaneously, or snorted. death may occur with such speed that the bodies may be found with needles and syringes in the veins or clenched in the hands. drug abuse may be associated with a multitude of local (see below) or systemic complications, including malaria* and tetanus. * as stated in chapter , for a growing number of analytes, most notably tricyclic antidepressants, peripheral blood is preferred over central blood. peripheral blood is aspirated by percutaneous puncture before autopsy, from the femoral vein or the subclavian vein. the authors prefer the femoral approach in order to avoid any question of artifact in the diagnosis of venous air embolism. it may be pru-dent to add naf to some of the samples. related term: childhood dermatomyositis (or polymyositis) associated with vasculitis; dermatomyositis (or polymyositis) associated with neoplasia or collagen vascular disease; primary idiopathic dermatomyositis; primary idiopathic polymyositis. possible associated conditions: carcinoma (lung, stomach, intestine, and prostate in males; breast, ovary, and uterus in females; miscellaneous sites in both sexes); lymphoma* (rare) and other malignancies ( ); lupus erythematosus;* mixed connective tissue disease; progressive systemic sclerosis;* rheumatoid arthritis;* sjogren's syndrome;* and others. vasculitis of childhood polymyositis (dermatomyositis). external examination and skin heart lungs esophagus and gastrointestinal tract photograph grossly involved skin. prepare sections of involved (anterior chest, knuckles, knees) and grossly uninvolved skin and subcutaneous tissue. prepare roentgenograms. submit samples from myocardium for histologic study. perfuse one lung with formalin. submit samples from all segments for histologic study. arteritis* and phlebitis* with thrombosis, fibrosis, and infarctions. steatohepatitis and manifestations of diabetes mellitus* may be found ( ) . myositis with muscular atrophy and fibrosis; vasculitis in childhood cases. polyneuropathy (rare) ( ). arthritis. diabetes mellitus synonyms: type i (insulin-dependent or juvenile-onset) diabetes mellitus; type ii (insulin-independent or adult onset) diabetes mellitus; secondary diabetes mellitus (e.g., due to drugs or pancreatic disease). note: in infants of diabetic mothers, macrosomia and congenital malformations must be expected. record size and weight of placenta and total weight and length, crown to rump length, and crown to heel length of infant. compare with expected measurements (see part iii). expected histologic finding in-clude hyperpla-sia with relative increase ofb cells of the islands of langerhans with interstitial and peri-insular eosinophilic infiltrates, decid-ual changes of the endometrium, enhanced follicle growth in the ovaries, and leydig cell hyperplasia. possible associated conditions: acanthosis nigricans; acro-megaly;* amyotrophic lateral sclerosis; * ataxia telangiectasia;* fanconi's anemia;* friedreich's ataxia;* gout;* hemochro-matosis; *hyperlipoproteinemia; * hyperthroidism;* obesity;* turner's syndrome;* and many others, too numerous to mention. note: the term "caroli's syndrome" often is used for cases that also show histologic features of congenital he-patic fibrosis or other manifestations of fibropolycystic liver disease,* whereas the name "caroli's disease" refers to idiopathic dilatation of intrahepatic bile ducts, without associated abnormalities. possible associated conditions: choledochal cyst* and related extrahepatic biliary abnormalities ( ); congenital hepatic fibrosis; * cysts of kidneys (renal tubular ectasia or medullary sponge kidney; autosomal-recessive polycystic kidney disease, and rarely, autosomal-dominant polycystic kidney disease [ ] )* and of pancreas. record volume of effusions. prepare smears of fresh blood or of buffy coat, or make thick-drop preparation. submit sample for xenodiagnosis or animal inoculation and for serologic study. record weight. in chronic chagas' disease, perfuse intact heart with formalin (chapter ) and slice fixed heart in a frontal plane so as to create anterior and posterior halves. prepare photographs. histologic samples should include conduction system. include several sections of atrial (auricular) walls for histologic study of autonomous ganglia. perfuse at least one lung with formalin. leave affected hollow viscera intact and fill with formalin. cut fixed organs in half, photograph, and cut histologic sections on edge. record liver weight and submit samples for histologic study. record weight. prepare photographs of abnormalities. weigh and examine. prepare histologic sections. for removal and specimen preparation, see chapter . autopsy is desirable in suspected cases because the diagnosis can only be firmly established after neuropathologic examination. serologic studies are not available. unfortunately, all tissues (not just the brain and spinal cord) may remain infectious even after prolonged fixation and histologic processing. thus, the autopsy recommendations for most other infectious diseases do not apply here. this is a reportable disease in some states. special precautions are indicated and therefore, the procedures described here should be followed strictly ( ) ( ) ( ) ( ) : all persons in the autopsy room must wear disposable long-sleeved gowns, gloves, and masks. contamination of the autopsy table should be prevented by covering it with a disposable, non-permeable plastic sheet. autopsy generally should be restricted to the brain. if organs in the chest or abdomen need to be examined, this is best done in situ. to prevent aerosolization of potentially infectious bone dust, a hood or other protective device should be used while opening the skull with a stryker saw. after completing the autopsy, instruments and other potentially contaminated objects should be autoclaved in a steam autoclave ( h at °c). porous load is considered more effective than gravity displacement autoclaves. immerse autopsy instruments in distilled water before and during autoclaving, in order to protect them from corrosion. ifno autoclave is available, chemical disinfection (see below) is a satisfactory alternative. disposable items should be put in a container for infectious hospital waste and ultimately incinerated. contaminated objects not suitable for autoclaving (such as the stryker saw) should be soaked with a nnaoh solution for h (alternatively, nnaoh may be used for h). contaminated surfaces should be thoroughly washed with the same solution. aluminum should be treated for h with a fresh % naoci (sodium hypochlorite) solution with at least , ppm free chloride. wash waters should be collected; if no autoclave is available, n naoh or > volumes of % sodium hypochlorite bleach should be added to the water and left for a minimum of h before being discarded. before removing the body from the autopsy room, it should be sponged with % sodium hypochlorite. to deactivate cjd infectivity, tissue blocks, mm or less in thickness, should be fixed in formalin in a formalin-totissue ratio of at least : for at least h and then soaked in concentrated formic acid ( - %) for i h, followed by another h of formalin fixation. the fixation fluid should be collected and decontaminated, as described earlier for wash water. glassware and tissue carriers should also be decontaminated as previously described. after this deactivation, the tissue blocks can be processed in a routine fashion. at any stage of these procedures, special care must be taken to avoid cuts with potentially contaminated glassware, blades, or other objects. parenteral exposure to potentially contaminated material also should be avoided. remains of patients who have died of the disease should not be accepted for anatomy teaching for students. if specimens are prepared for pathology collections, they should be handled with great caution. morticians and mortuary workers should be warned of possible hazards posed by tissues of patients with transmissible spongiforme encephalopathies; they should be advised about proper use of disinfectants. clinical laboratories that receive autopsy tissues or fluids must be warned about the infectious nature of the material. if possible, decontamination should be done at the site where the autopsy was done. for the shipping of potentially infected material, see chapter . increased concentrations of nse ( ). spongiforme changes, astrocytosis, neuronal loss, amyloid plaque formation, prp deposition, and proliferation of activated microglia ( ). cerebrospinal fluid brain submit sample for neuron-specific enolase (nse). for removal and specimen preparation, see chapter and above under "note." submit fresh-frozen material for confirmation of diagnosis by histoblot technique on protease k-digested frozen tissue or western blot preparations on brain homogenates. immunohistochemical localization ofprp and hla-dr protein on paraffin-embedded tissue is possible. disease, demyelinating (see "degeneration, spongy, of white matter," "encephalomyelitis, all types or type unspecified," "leukodystrophy, globoid cell," "leukodystrophy, sudanophilic," "sclerosis, multiple;' and "sclerosis, schilder's cerebral.") disease, diffuse alveolar synonym: diffuse pulmonary disease. note: autopsy procedures are listed under the more specific diagnoses, such as "hemosiderosis, idiopathic pulmonary," "lipoproteinosis, pulmonary alveolar," "microlithiasis, pulmonary alveolar," "pneumonia, lipoid," and "syndrome, goodpasture's." glycosphingolipid storage in cornea; lens opacities; dilated vessels in conjunctiva and lens; thrombi in blood vessels ( ). disease, fibropolycystic, of the liver and biliary tract note: "fibropolycystic disease of the liver and biliary tract" comprises a group of well defined conditions, which may occur together and hence need a collective designation. the conditions include autosomal-recessive (infantile) and auto-somal dominant (adult) polycystic disease of the liver; caroli's disease or syndrome;* choledochal cyst,* congenital hepatic fibro-sis,* multiple biliary microhamartomas, and related disorders. for autopsy procedures, see also under more specific designations. disease, glycogen storage synonyms: andersen's disease or brancher deficiency (glycogenosis, type iv); cori's or forbes' disease (glycogenosis, type ill); cyclic amp dependent kinase (type x); glycogen synthetase deficiency (type ); hers' disease (glycogenosis, type vi); mcardle's disease (glycogenosis type v); phosphorylase b kinase deficiency (types ixa, b, and c); pompe's disease (glycogenosis, type it); tarui disease (glycogenosis type vii); von gierke's disease (glycogenosis, type ia); x-linked glycogenosis (type vill). note: if the diagnosis had not been confirmed prior to death, samples of liver, skeletal muscle, blood, and fascia (for fibroblast culture, see below) should be snap-frozen for enzyme assay, which will determine the specific deficiency. types ia and b, iii, vi, and hepatic phosphorylase b kinase deficiency (types ixa, b and c) are hepatic-hypoglycemic disorders, whereas types v and vii affect muscle energy processes. type ii also affects the musculature, whereas type iv may cause cirrhosis and death in infancy from extreme hypotonia. determination of type of glycogenosis usually can be based on (i) pattern of glycogen storage in liver, ( ) presence or absence of nuclear hyperglycogenation in liver, ( ) cytoplasmic lipid in liver, ( ) presence or absence of liver cirrhosis, and ( ) presence or absence of glycogen and basophilic deposits in skeletal muscles. possible associated conditions: fanconi syndrome* or gout* with type ia glycogenosis; neutropenia, recurrent infections, and crohn's disease with types ib or ie. glycogen primarily in retinal ganglion cells and ciliary muscle. glycogen in sympathetic nerve ganglia and neurons of cranial nerves in type vii. gouty arthritis. disease, graft-versus-host note: this disease occurs most commonly after bone marrow transplantation. the disease has also occurred after transfusion of viable lymphocytes, for example, to patients with cancer or leukemia. * in patients with graft-versus-host disease (gvhd), autopsy also may reveal recurrence of the underlying disease such as leukemia. possible associated conditions: alphal-antitrypsin deficiency;* amyloidosis;* ankylosing spondylitis;* primary sclerosing cholangitis;* sjogren's syndrome. * see also below under "possible or expected findings." note: in many instances, either chronic ulcerative colitis or crohn's disease* had been diagnosed clinically, but sometimes, the distinction is difficult to make, even at autopsy. many features described below occur in chronic ulcerative colitis but some manifestations of crohn's disease or conditions that may occur in all types of inflammatory bowel disease also are listed so that both positive and negative findings can be recorded properly. osteoporosis;* ankylosing spondylitis;* arthritis of peripheral joints; periarthritis; hypertrophic osteoarthropathy;* tendinitis (particularly of ankle and achilles tendons). disease, iron storage (see "hemochromatosis.") related terms: atherosclerotic heart disease. note: the most common anatomic finding at autopsy in subjects older than yr is coronary atherosclerosis. unusual under-lying or associated conditions include chronic aortic stenosis or regurgitation; coronary artery anomalies; coronary artery dissection; coronary embolism; coronary ostial stenosis (due to calcification of aortic sinotubular junction or, rarely, to syphilitic aortitis); coronary vasculitis (for instance, in polyarteritis nodosa* or acute hypersensitivity arteritis); hyperthyroidism,* gastrointestinal hemorrhage; * hypothyroidism, * idiopathic arterial calcification of infancy; intramural coronary amyloidosis; pheochromocytoma, polycythemia vera; * pseudoxanthoma elasticum,* radiationinduced coronary stenosis; severe pulmonary hypertension (with right ventricular ischemia); sickle cell disease;* and others. if bypass surgery had been performed, see "surgery, coronary bypass." macular rash ( ). multifocal fibrinopurulent pneumonia with sparing of the bronchi and bronchioles. exudate is rich in phagocytes, fibrin, and karyorrhectic debris. synonym: lyme arthritis note: this infection is caused by the spirochete, borrelia burgdoiferi, which is transmitted from rodents to human by the hard deer ticks, ixodes dammini, . ricinus, and others. brain and spinal cord for removal and specimen preparation, see chapter . request luxol fast blue stain for myelin. symmetric and zonal demyelination in corpus callosum, anterior commissure, optic chiasm, optic tracts, and white matter of frontal lobes. external examination and skin; oral cavity lungs aorta record distribution of skin lesions and submit tissue samples for histologic study. for preparation of angiograms of the pulmonary arterial and venous vasculature, see chapter . if aneurysm or dissection is present, follow procedures described under those headings. telangiectatic (often papular) lesions most commonly found in cheeks, scalp, nasal orifices, oral cavity, ears, neck, shoulders, fingers, toes, and nail beds. cyanosis and clubbing may be prominent. arteriovenous malformations/fistulas. aneurysm; * aortic dissection. * if cirrhosis is present, prepare angiograms of hepatic arteries and veins (chapter ). photograph and prepare sections of angiomatous lesions. note: parkinson's syndrome is caused by conditions that may simulate parkinson's disease; these include carbon monoxide* and manganese poisoning, corticobasal degeneration, druginduced parkinsonism, huntington's disease, multiple system atrophy,* progressive supranuclear palsy* (steele-richardson-olszewski syndrome), space-occupying lesions (rare), trauma (dementia pugilistica), and causes related to tumors and vascular diseases. brain for removal and specimen preparation, see chapter . histologic sections should include midbrain (substantia nigra), upper pons (locus ceruleus), medulla, nucleus basalis (substantia innominata), and basal ganglia. if parkinsonian syndrome was diagnosed, follow procedures described under the name of the suspected underlying condition (see above under "note"). depigmentation of substantia nigra and locus coeruleus; neuronal loss and reactive gliosis; eosinophilic intracytoplasmic inclusion bodies (lewy bodies) in some of the surviving neurons; no significant changes in basal ganglia. disease, pelizaeus-merzbacher synonyms: sudanophilic (orthochromatic) leukodystrophy. brain and spinal cord for removal and specimen preparation, see chapter . request luxol fast blueipas stain for myelin and bielschowsky's stain for axons. prepare frozen sections for sudan stain. brain generally atrophic. myelin loss in centrum ovale, cerebellum, and part of brain stem, with a tigroid pattern of residual myelin near vessels. axons are preserved. diffuse gliosis with relatively few lipoid-containing macrophages, compared to the myelin loss. lipoid material stains with sudan. brain and spinal cord for removal and specimen preparation, see chapter . request silver stains (bielchowsky or bodian stain). histochemical stains in pick's cells and bodies reveal phosphorylated neurofilaments, ubiquitin, and tubulin. some tissue should be kept frozen for biochemical studies. severe cerebral atrophy, involving primarily frontal and anterior temporal lobes (knifeblade atrophy; walnut brain). microscopically, severe neuronal loss accompanied by astrocytosis. characteristic argyrophilic, intracytoplasmic inclusions (pick's bodies), particularly in hippocampus and swollen, distended "ballooned" neurons (pick's cells). these changes are not always present. external examination, skin, and adipose tissue blood cerebrospinal fluid heart liver and kidneys brain, spinal cord, and peripheral nerves eyes submit sample for determinaion of phytanic acid concentration and for molecular studies. for obtaining a sample, see chapter . sample for histologic study. for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . ichthyosis. phytanic acid accumulation in adipose tissues. phytanic acidemia, mutation of phyh or pex ( ). increased protein concentrations. cardiomyopathy.* phytanic acid accumulation. axonal neuropathy. retinitis pigmentosa. hypoalphalipoproteinemia. lymphadenopathy with diffuse deposition of cholesterol esters. premature atherosclerotic cardiovascular disease ( ). hepatosplenomegaly with foam cells. enlarged tonsils with characteristic orange discoloration. polyneuropathy ( ) . in adults, corneal infiltrates. foam cells. request pas stain. in granulomas, bacilli are not always pas positive ( ) . section all grossly involved tissues for histologic examination. submit section for electron microscopy. emaciation. hyperpigmentation, particularly of exposed skin and in scars. hyperkeratosis. arthritis involving ankles, knees, shoulders, and wrists. ascites; fibrinous peritonitis. * nodules in peritoneum containing sickle-form particlecontaining cells (spc cells submit sample for determination of sodium, potassium, chloride, glucose, urea nitrogen, and creatinine concentrations. calcium and phosphate concentrations can also be tested. if sample is small, indicate priority for testing. if indicated, submit sample for chemical study. submit tissue samples for histologic study. considerably increased or decreased values for sodium (more than meqll or less than meqll) and chloride (more than meqll or less than meqll) indicate that changes were present before death. for further interpretation, see chapter . postmortem electrolyte concentrations are quite unreliable. may be useful for calcium determination. vacuolar nephropathy (vacuolar changes in proximal convoluted tubules) in potassium deficiency (may also occur after infusion of hypertonic solutions). disorder, hemorrhagic (see "coagulation, disseminated intravascular," ''disease, christmas:' ''disease, von willebrand's," "hemophilia," and "purpura,.••") disorder, inherited, of phagocyte function note: several conditions represent phagocyte function disorders. autopsy procedures for one of these disorders can be found under "disease, chronic granulomatous." consult this entry for other phagocyte function disorders. synonyms and related terms: fabry's disease* (angiokeratoma corporis diffusum); gangliosidosis;* gaucher's disease;* glycogenosis,* type ii; leukodystrophies (krabbe's or globoidcell,* metachromatic leukoencephalopathy*); mucopolysaccharidoses* (hunter, hurler, morquio, and sanfilippo disease); mucolipidosis; niemann pick disease* (type a, b, c, or sphingomyelinase deficiency); neuraminidase deficiency; neuronal ceroid lipofuscinosis (batten's disease or kufs' disease). hypopharyngeal pulsion diverticulum (zenker's diverticulum) at lower margin of inferior constrictor muscle of pharynx. traction diverticulum at midesophagus after an inflammatory process-for instance, tuberculous lymphadenitis. epiphrenic diverticulum may also occur. luxtacardiac or juxtapyloric diverticulum. heterotopic tissue in meckel's diverticulum, with or without peptic ulceration. colonic muscular hypertrophy and stenosis, usually in sigmoid colon. diverticulitis with perforation, fistulas, or peritonitis. * diving (see "accident, diving (skin or scuba).") related terms: dry drowning; fresh-water drowning; near-drowning; salt (sea)-water drowning (see the following table). primary drowning ("immediate drowning") deaths occurring within minutes after immersion, before or without resuscitative measures deaths from hypoxia and acidosis caused by glottal spasm on breath holding. there may be no evidence of water entering stomach or lungs and no appreciable morphologic changes at autopsy. note: the diagnosis is one of exclusion. the pathologist should help the police to determine: i) how did the person (or dead body) get in the water, and ) why could that person not get out of the water? it is not enough to ask if a person could swim but investigators should find out how well (what strokes did the victim know?) and how far he or she could swim. the inquiry must include the depth of the water and must address hazards such as undertow or underwater debris, and the behavior deaths occurring from within min to several weeks after resuscitation, because of metabolic acidosis, pulmonary edema, or infective or chemical pneumonitis deaths from hypoxia and acidosis caused by obstruction of airway by water related to: hypervolemia hemolysis hyponatremia hypochloremia hyperkalemia of the victim immediately before submerging. deaths of adults in bathtubs and swimming pools are usually from natural, cardiac causes, or they are suicides, unless the victim was drunk. diatom tests ( ) have not proven useful in the united states but there is enthusiasm for such tests among european pathologists. the distinction between hyponatremic deaths in fresh water and hypernatremic deaths in salt water derives from experimental studies; in practice, one cannot reliably predict the salinity of the immersion medium from autopsy studies. because many bodies of drowning victims are recovered only after the body floats to the surface, decomposition will often obscure even the nondiagnostic findings such as pleural effusions, which are often associated with drowning. external examination and skin (wounds) organ samples for diatom search serosal surfaces and cavities if identity of drowning victim is not known, record identifying features as described in chapter . prepare dental and whole-body roentgenograms. submit tissue samples for histologic study of wounds. inspect inside of hands. collect fingernail scrapings. record appearance and contents of body orifices. record features indicative of drowning. photograph face from front and in profile. take pictures of all injuries, with and without scale and autopsy number. remove vitreous for analysis. if diatom search is intended, clean body thoroughly before dissection to avoid contamination of organs and body fluids with algae and diatoms (see below). submit sample for toxicologic study. sample early during autopsy, before carrying out other dissections. use fresh instruments for removal of specimens to avoid contamination. submit subpleural portion of lung: subcapsular portions of liver, spleen, and kidneys; bone marrow; and brain. store samples in clean glass jars. for technique of diatom detection, see below. record volume of fluid in pleural spaces. photograph petechial hemorrhages. photograph layerwise neck dissection if strangulation* is suspected. open airways posteriorly, and photograph, remove and save mud, algae, and any other material in tracheobronchial tree. record size and weight of lungs. there may be wounds that were inflicted before drowning occurred-for instance, in shipwrecks or vehicular and diving accidents. other wounds may be inflicted after deathfor instance, from ship propellers or marine animals. sometimes, premortem and postmortem wounds can be distinguished histologically. object (hair?) held by hands in cadaveric spasm. cutis anserina and "washerwoman" changes of hands and feet are of no diagnostic help. foreign bodies; semen (see also under "rape"). foam cap over mouth and nose. in the autopsy room, water running from nose and mouth is usually pulmonary edema or water from the stomach. high concentrations of alcohol indicate intoxication (see under "alcoholism and alcohol intoxication"). evidence of alcohol intoxication may be found. diatoms may occur in the liver and in other organs of persons who have died from causes other than drowning. comparison with diatoms in water sample from area of drowning may be helpful. penny-sized or smaller hemorrhages may indicate violent respiratory efforts or merely intense lividity. presence of pleural fluid suggests drowning. for diatom detection (l) , boil - g oftissue for -- min in rnl of concentrated nitric acid and . rnl of concentrated sulfuric acid. then, add sodium nitrate in small quantities until the black color of the charred organic matter has been dispelled. it may be necessary to warm the acid-digested material with weak sodium hydroxide, but the material must soon be washed free from alkali to avoid dissolving the diatoms. the diatoms should be washed, concentrated, and stored in distilled water. for examination, allow a drop of the concentrate to evaporate on a slide, and then mount it in a resin of high refractive index. all equipment must be well-cleaned, and distilled water must be used for all solutions. there are several variations and adaptations of this method. drug abuse, amphetamine(s) note: methamphetamine abuse may be suggested by poor condition of the dentition. methylenedioxymethamphetamine ("ecstasy") abuse is often suggested by friends with whom the decedent was abusing drugs. follow procedures described under "dependence, drug(s)." ductus arteriosus, patent (see "artery, patent ductal.") synonyms and related terms. achondroplastic dwarf; asexual dwarf; ateliotic dwarf; micromelic dwarf; normal dwarf; pituitary dwarf; true dwarf; and many other terms, too numerous to mention. external examination bones and joints record height and weight. prepare skeletal roentgenograms. for removal, prosthetic repair, and specimen preparation, see chapter . growth retardation. abnormal growth of epiphyseal cartilage with enlargement of metaphysis. long bones and pelvis most commonly affected. cavernous hemangiomas (maffucci's syndrome). see above under "external examination." chondrosarcoma. dyscrasia, plasma cell note: these conditions are characterized by abnormally proliferated b-immunocytes that produce a monoclonal immunoglobulin. multiple myeloma, * plasma cell leukemia, plasma-cytoma, and waldenstrom's macroglobulinemia* as well as heavy-chain diseases and monoclonal gammopathies of unknown type belong to this disease family. amyloidosis* is closely related to these conditions. for autopsy procedures, see under "amyloidosis," "macroglobulinemia," or "multiple myeloma" and under name of condition that may have caused the plasma cell dyscrasia. such conditions include carcinoma (colon, breast, or biliary tract), gaucher's disease,* hyperlipoproteinemia, * infectious or noninfectious chronic inflammatory diseases, and previous cardiac surgery. synonym: shigella dysentery. note: (i) collect all tissues that appear to be infected. blood bowel eyes joints submit sample for culture and for serologic study. submit sample of feces or preferably bloodtinged mucus for culture. if bacteriologic diagnosis has already been confirmed, pin colon on corkboard, photograph, and fix in formalin for histologic study. submit sample of vitreous for study of sodium, potassium, chloride, and urea nitrogen concentrations. for removal and specimen preparation of eyes, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . escherichia coli septicemia. colitis with microabscesses; transverse shallow ulcers and hemorrhages, most often in terminal ileum and colon. dehydration* pattern of electrolytes and urea nitrogen. serous arthritis* of knee joints is a late complication. external examination record extent of pigmentation, facial features, and primary and secondary sex characteristics. prepare skeletal roentgenograms. for removal, prosthetic repair, and specimen preparation, see chapter . record size of apertures of cranial nerves in base of skull. unilateral skin pigmentation and precocious puberty in females (albright's syndrome), less commonly in males. synonyms and related terms: becker's muscular dystrophy; congenital muscular dystrophy; duchenne's progressive muscular dystrophy; dystrophinopathy; em-ery-dreifuss mucular dystrophy; facioscapulohumeral dystrophy; limb girdle dystrophy; myotonic muscular dystrophy. external examination record pattern of scalp hair. record status of skeletal musculature. obtain sections for histologic examination. dystrophin staining of the sarcolemma is absent in duchenne's muscular dystrophy and patchy in becker's dystrophy. frontal baldness (in myotonic muscular dystrophy). atrophy and wasting of muscles (generalized or local: predominantly distal in myotonic muscular dystrophy). pseudohypertrophy of calf muscles in duchenne's muscular dystrophy. dystrophic changes include variations in fiber size, fiber degeneration and regeneration, peri-and endomysial fibrosis, and fatty replacement of muscle. the liver, especially the right lobe, is the most common site of involvement. secondary infection or calcification may be present. the lung is the second most common site of involvement. fluid and air may be visible on the roentgenogram. cysts may be present in the abdominal cavity, muscles, kidneys, spleen, bones, heart, and brain. eosinophilia. edema, angioneurotic synonym: angioedema. note: possible causes and suggested autopsy procedures are described under "death, anaphylactic." related term: silo-filler's disease. n<yfe: this condition is causedby inhalationoftoxic gases, such as oxides of nitrogen (silo-filler's disease) and phosgene (coci ). see also "bronchitis, acute chemical" and "poisoning, gas." ( ) gunshot and shotgun wounds of the head involving dural sinuses; ( ) injury to large veins, particularly cranial sinuses (during neurosurgical procedures) and veins ofthe neck (knife wounds, surgery) or uterus (criminal abortion); ( ) insufflation offallopian tubes (particularly in pregnancy or during menstrual period); ( ) infusion of blood components or crystalloid; ( ) malfunctioning of dialysis machines; ( ) subclavian vein catheterization in the semi-fowler position; and ( ) fracture in the hub of a central venous catheter used for parenteral nutrition. possible causes of arterial air embolism include: ( ) open heart surgery involving the aorta, left atrium, or left ventricle; ( ) positive-pressure ventilation in newborn infants; and ( ) underwater ascent with closed glottis (see accident, diving) ifair embolism is suspected, the autopsy should be performed as soon after death as possible. decomposition gases may be produced within a few hours. roentgenography of the whole body may detect large quantities of air, and the roentgenograms may serve as a guide to the most advantageous way of dissection. the postmortem diagnosis of arterial air embolism is made largely on the basis of medical history and circumstances. the autopsy serves to rule out competing conditions. the diagnosis of venous air embolism is made by chest roentgenography before the autopsy ( ). the air in the right chambers of the heart can be confirmed at autopsy by aspiration into a syringe. the formerly recommended procedure of clamping the internal mammary vessels below the sternoclavicular joints, and then cutting across the sternum distal to these clamped vessels so that the sternoclavicular joint area remains intact, is designed to prevent the production of a vacuum that pulls air into the veins. the procedure is not necessary if the air is welldocumented by roentgenography before autopsy. at autopsy, a large fatal pulmonary air embolism is readily apparent. the right atrium and ventricle are distended with fine, frothy, brightred blood, which also may distend the pulmonary arteries and superior vena cava. microbiologic examination ofblood and pericardial sac contents may help to rule out the presence of gas-forming bacteria that may simulate air embolism (fig. ii-i). however, the presence of putrefactive emphysema in any part of the body points toward a bacterial origin of the gas. differentiation of air and decomposition gases at the autopsy table with the pyrogallol test is described below. a % pyrogallol solution is prepared (it should be waterclear). two lo-ml syringes (syringe a and syringe b) are loaded with ml of the pyrogallol solution in each, without permitting any air to enter the system. immediately before the solution is used, drops of . n naoh is aspirated through the needle of syringe a to adjust the ph to about ( drop per ml of solution); the mixture will turn faint yellow. six ml of gas is then aspirated from the heart or blood vessels. the needle is immediately sealed with a cork or replaced by a cap, and the syringe is vigorously shaken for about min. in the presence of air, the pyrogallol solution will turn brown. if the solution remains clear, decomposition gases were present. in the latter instance, drops of . n naoh and ml of room air should be aspirated into syringe b, which is then also sealed and shaken for min. the mixture should turn brown, thus serving as a fig. · . gas-forming bacteria simulating air embolism. the pericardial sac is opened and filled with water. the heart is kept submerged with a pair of scissors. the coronary arteries have been incised with a scalpel. note gas bubbles and foam on the water surface. no discoloration of % pyrogallol was noted. blood cultures were positive for enterococcus organisms. microscopically, gram-negative rods were found in most tissues. control that the pyrogallol solution had been properly prepared. syringe b may also serve as a reserve. if only one syringe is used, the decomposition gas can be expel ed and room air can be aspirated for the control test. if only small amounts of gas can be aspirated, the volume of the pyrogallol solution should be decreased so that the gas-fluid volume ratio is at least : . if no bacterial gas formation is present, the edges of the pericardial incision are elevated and the pericardial sac is fil ed with water. clamping of the ascending aorta and venae cavae prevents the escape of gas into these vessels. the heart is held under water while the coronary arteries are incised, and the escape of bubbles is recorded. when the right coronary artery is opened, care must be taken that the right atrium is not incised. air in the coronary arteries indicates systemic embolism. the heart chambers are then incised. when there is gas in any of the arteries or heart chambers, gas bubbles rise to the surface of the water in the pericardial sac ("bubble test"). sometimes the vessels have to be somewhat compressed in order to cause the gas to escape. because large amounts of air or other gases cause the heart to float, it must be kept submerged before the vessels and chambers are incised. basically the same procedure is used for demonstrating the presence of gas in the superior or inferior vena cava and the pelvic veins (for example, in cases of criminal abortion). in this situation, the abdominal cavity is filled with water and the inferior vena cava and its tributaries are incised. in support of the diagnosis of systemic arterial air embolism, the skull vault may be removed without puncturing the meninges, so that the cerebral arteries can be inspected for gas bubbles. the demonstration of gas bubbles in the meningeal vessels and in the circle of willis is meaningful only when the neck vessels are still intact and the internal carotid artery and basilar artery have been clamped before the brain is removed. in acute cases, gas bubbles will be visible within the cerebral vessels. they are released under water when the clamps are removed and the vessels are slightly compressed. for the collection of gas from blood vessels or cavities, a system oflittle quantitative reliability is an air-tight, water-filled glass syringe with a needle. the needle is inserted into the vessel or cavity in question and gas is carefully aspirated. a combined qualitative and quantitative method has been described by kulka ( , ) (see fig. - ). he devised an apparatus for gas collection and described it as shown in fig. - and caption. the entire system is filled with mineral oil so that, when the funnel is level with the upright bottle, the oil fills only about half of the funnel. in operation, the funnel is first raised to a position - cm above the level of the upright bottle. all the cocks are opened and the position is held until every trace of gas has been driven from the system through the needle, which is thereby coated on the inside by a film of oil. after all air has been expelled, the cocks are closed and the funnel is lowered to its original position. as a precautionary measure and control, the air-tightness of the whole system should be tested before operation. this is done by inserting the needle into musculature or skin and attempting aspiration in the manner described in the next paragraph. to make the test, the bottle is inverted and the needle is inserted into the cavity in question. when the needle is in position, all cocks are opened. the funnel is lowered about - cm, or until adequate suction is created. this aspirates the contents of the cavity, which may consist of air or other gases, either pure or mixed with blood or other liquid. any gas or liquid entering this system may be observed through the wall of the short bent glass tubing. in a positive test, gas bubbles will collect in the bottle above the level of the oil. if desired, this gas can be saved for further examination by closing all the cocks and returning the bottle to its upright position ( ). the volume ofintravenous air needed to cause death in adults depends of the cross sectional area of the cardiac cavity or great vessel that is the site of the gas lock, which in tum depends on the position of the decedent at the time of the embolism ( ). ml of gas can pass through an intravenous hub in just a few seconds. small amounts of air entering the systemic circulation may cause death within minutes. delayed air embolism with fatal outcome may also occur. other organs if purpura is present, prepare photographs and record extent. submit sample (from right atrium) for microbiologic study. collect blood from right atrium and right ventricle. after the heart has been removed, allow blood in pulmonary vessels to pool in the pericardial sac. centrifuge this blood and submit sample of flocculent layer above buffy coat for microscopic study ( ) . submit a section of lung for bacteriologic study. dissect pulmonary arteries; prepare histologic sections of all lobes; request mucicarmine stain and the aldan blue and phloxinetartrazine stain of lendrum. also request sudan stain on frozen sections. skin purpura. vernix, lanugo hairs, and meconium can be found in pericardial blood pool. meconium-type material in blood vessels. in histologic sections, squamous epithelium, meconium, and fat from vernix caseosa. complete or incomplete lower uterine tear; chorioamnionitis. manifestations ofdisseminated intravascular coagulation* and fibrinolysis. intrauterine pneumonia. large amounts of debris in the blood vessels of all sections of the lungs may be considered to be lethal if there is no other cause of death. small amounts in one or more blocks of pulmonary tissue are more likely incidental ( ). a small uterine tear is more likely followed by a fatal amniotic fluid embolization than is a large tear, which may result in fatal hemorrhage or fibrinogen depletion. chorioamnionitis, intrauterine pneumonia, and positive lung cultures of the mother indicate infection of the amniotic fluid. record weight and sample for histologic study. for removal and specimen preparation, see chapter . photograph horizontal sections through brain, brain stem, and spinal cord. prepare frozen sections and request sudan stain. prepare frozen sections of one-half of gland and paraffin sections of the other half. petechial hemorrhages of skin (chest, neck, and face). wounds; other traumatic lesions. bone fractures. petechiae of conjunctivas and retinas. fat may accumulate on surface ofblood pool. no useful technique is available for estimating the amount of fat globules in the blood. fat emboli in lumen of small vessels and in pulmonary air spaces. severe fatty changes may be the cause offat embolism. fractures are the most common cause of fat embolism. petechial hemorrhages, fat emboli ( ). abdominal cavity submit sample of subphrenic exudate for gram stain and cultures. record location and volume of subphrenic exudate. possible causes of subphrenic empyema include appendicitis, cholecystitis, * diverticulitis, intrahepatic abscess, pancreatitis,* ruptured viscus; penetrating abdominal wound(s), perforated ulcer of stomach or duodenum,* and other conditions. pleural cavities and lungs e procedures record volume of effusion or exudate in pleural space. basal pleuritis and pneumonia, adjacent to empyema. encephalitis, au types or type unspecified synonyms and related terms: acute disseminated encephalomyelitis;* acute hemorrhagic encephalitis; acute infective encephalitis or encephalomyelitis; acute poliovirus encephalitis or encephalomyelitis; amoebic encephalitis; arbovirus encephalitis (japanese encephalitis; eastern encephalitis, western encephalitis, venezuelan equine encephalitis, st. louis encep-halitis); bulbar encephalitis;* brain stem encephalitis;* herpes encephalitis (cytomegalovirus encephalits, epstein-barr virus encephalitis, varicella-zoster encephalitis); herpes simplex ence-phalitis; hiv encephalitis; measles encephalitis; measles inclusionbody encephalitis; postinfectiousencephalitis; postvac-cinal encephalitis; progressive multifocal leukoencephalitis or leukoencephalopathy; rabies* encephalitis; subacute encephalitis; subacute sclerosing panencephalitis; viral encephalitis, west nile encephalitis and other terms ( ), too numerous to mention. see also under "note" and under "possible or expected findings." note: if the condition that caused the encephalitis is known, see also under that heading. if the cause of the encephalitis is unknown, submit samples of tissue for microbiologic and toxicologic study, particularly if there is a suspicion of lead poisoning.* see also under "encephalitis, brain stem," "encephalomyelitis,...," "encephalopathy" and "myelopathy, myelitis." encephalitis, brain stem synonyms and related terms: brain stem abscess; infectious brain stem encephalitis; listeria monocytogenes brain stem encephalitis; viral brain stem encephalitis. note: see also under "encephalitis, limbic." brain for removal and specimen preparation, see chapter . necrotizing encephalitis, with or without abscess formation ( enterocolitis, other types or type undetermined note: a multitude of infectious and noninfectious agents may cause inflammation of the small bowel, large bowel, or both. if the condition is not listed under "colitis," "enteritis," or "enterocolitis" or under another specific heading such as "dysentery, bacillary," obtain sufficient material for microbio-logic and histologic study to identify organisms such as clos-tridium, chlamydia, shigella, salmonella, yersinia, helicobacter, verotoxic e. coli, and others. if lymphogranuloma venereum,* or tuberculosis* are suspected, see also under these headings. see also under "disease, inflammatory bowel" and "disease, crohn's." synonyms and related terms: c. difficile colitis; darmbrand; hemorrhagic necrosis (gangrene; infarction) of intestine; ischemic enteritis or enterocolitis;* neutropenic enterocolitis;* pseudomembranous colitis. note: the name "pseudomembranous enterocolitis" is descriptive; the condition may be infectious, ischemic, or both. if the intestinal changes are clearly ischemic, see above under "enterocolitis, ischemic." if the cause is in doubt and if pseudomembranes can be identified, follow the procedures described here. (l) collect all tissues that appear to be infected. for other infectious intestinal diseases, see under specific names, such as "enterocolitis, neutropenic" or "enterocolitis, staphylococcal." intestinal tract and mesentery other organs collect material from pseudomembranes for culture and for c. difficile toxin assay. sample intestinal wall with pseudomembranes for histologic study. if the condition is suspected to be caused by ischemia, follow procedures described above under "enterocolitis, ischemic." note: myoclonic seizures also have been described in a number of progressive encephalopathies with complex neurological symptoms, such as gmi and gm gangliosidosis,* and niemann-pick* and krabbe's disease but also acquired disorders, including alzheimer's disease,* creutzfeldt-jakob epilepsy, myoclonus (continued) disease,* posthypoxic encephalopathy, and subacute sclerosing panencephalitis. mitochondrial encephalomyopathy also can present with myoclonus epilepsy and a mitochondrial myopathy with ragged red fibers (merrf syndrome) in skeletal muscles. lafora-body-type material in the heart, liver, retinas, peripheral nerves, skeletal muscles, and sweat gland ducts (especially axillary). ragged red fibers in mitochondrial myopathies. epilepsy, symptomatic note: possible causes or underlying conditions include cerebrovascular diseases, congenital malformations ofthe brain, degenerative and demyelinating diseases of the brain, head injury,* intracranial and cerebral infections, toxic or metabolic disorders (alcoholism,* barbiturate,* carbon monoxide,* and lead poisoning,* hemodilution, hypocalcemia, or hypoglycemia),* and tumors of the brain. * f failure, congestive heart note: coronary atherosclerosis and manifestations of ischemic heart disease, * valvular heart disease, congenital cardio-vascular diseases, and manifestations of systemic or pulmonary hypertension are the most frequent findings in patients dying of or with congestive cardiac failure. other causes include cardiomyopathies* and secondary myocardial disease (such as amyloid or pericardial constriction). if the cause of the congestive cardiac failure is unknown or not immediately evident after dissection of the heart and of the great vessels, myocardium and other appropriate tissues may be submitted for microbiologic study-including viral cultures-and for electron microscopy. specimens can also be snap-frozen for possible immunofluorescent, biochemical, or histochemical studies, particularly of the myocardium. possible causes of congestive cardiac failure are too numerous to mention. dilatation of heart, with or without mural thrombosis. myocardium may be soft, normal, or firm. pulmonary congestion, with or without hemosiderosis; congestion of viscera with organomegaly. other organ manifestations include bowel edema or hemorrhagic enteropathy (without mechanical vascular occlusion) and zonal hepatic steatosis, fibrosis, or necrosis, with or withoutevidence of liver failure. acute renal tubular necrosis may be present also. synonyms and related terms: acute kidney failure; chronic kidney failure; renal failure; uremia. note: if acute kidney failure had been diagnosed, the autopsy procedures will depend on the expected causes, such as poisoning with ethylene glycol,* lead,* mercury,* or methyl alcohol;* disseminated intravascular coagulation* and its various underlying conditions; glomerulonephritis* and its various underlying conditions; diabetes mellitus;* or multiple myeloma. * the procedures described below deal primarily with chronic renal failure. if the patient had had dialysis, see also under "dialysis (for chronic renal failure )." if transplantation had been carried out, see also under "transplantation, kidney." lassa fever is a highly communicable disease and autopsy studies are not recommended in the usually available surround-ings. if lassa fever is suspected, contact the state health department and the centers for disease control and prevention, atlanta, ga, for disposition and further studies ( ).ifan autopsy is done, disinfection can be accomplished by washing instruments with . % phenol in detergent (i.e., lysol), . % hypochlorite solution, formalin, or paracetic acid. for shipping procedures, see chapter . this is not a reportable disease. synonyms: borreliosis; louseborne (epidemic) relapsing fever; tickborne (endemic) relapsing fever. note: (i) collect all tissues that appear to be infected. ( ) rat/mouse inoculation with infected blood is the most sensitive method for the detection of the organism. consult the state health department. ( ) before the autopsy, consultation with the microbiology laboratory is advised. ( ) request direct dark-field examination and giemsa or wright stain. ( ) no special precautions are indicated. ( ) serologic studies are of questionable value due to the antigenic variability of the organism. ( ) fever, scarlet note: usually, this disease is a nonfatal group a streptococcal tonsillitis and pharyngitis with skin rash. potentially fatal complications include suppurative otitis media,* mastoiditis, and pharyngeal abscess ( ), with or without septicemia. ( ) collect all tissues that appear to be infected. ( ) atresia, but may also be seen with viral myocarditis, type ii glycogen storage disease (pompe disease) and carnitine deficiency. thus, a metabolic disorder must be considered. it is ideal to perform the autopsy as soon after death as possible ( ) . urine plasma for removal, prosthetic repair, and specimen preparation, see chapter . malnutrition ( ) muscle necrosis (clostridial myonecrosis) and accumulation of gas; little leukocytic infiltration. other organs g procedures depend on expected findings or grossly identified abnonnalities as listed in right-hand column. see also above under "note" and under "skeletal muscles." synonyms and related terms: acute postinfectious glomerulonephritis (nonstreptococcal postinfectious glomerulonephritis;*minimalchangedisease;mesangialproliferativeglomerulonephritis;* focal and segmental glomerulosclerosis with hyalinosis (focal sclerosis); poststreptococcal glomerulonephritis; idiopathic nephrotic syndrome; iga nephropathy (berger's disease); membranous glomerulonephritis; membranoproliferative glomerulonephritis; mesangial proliferative glomerulonephritis; rapidly progressive glomerulonephritis (associated with systemic infectious or immunologic multisystem diseases; drug idiosyncrasy; or as primary crescentic glomerulonephritis or superimposed on another primary glomerular disease). possible associated conditions: acquired immunodeficiency syndrome (aids);* alport's syndrome;* amyloidosis; anaphylactoid purpura; bee stings; chronic allograft rejection; dennatomyositis;* dennatitis herpetiformis; diabetes mellitus;* drug dependence;*fabry's disease;* goodpasture's syndrome;* guillain-barre syndrome;* henoch-schonlein purpura;* hemolytic uremic syndrome;* infective endocarditis;* leprosy;* malig-nancies;mixedconnectivetissuedisease;myxedema;polyarteritis nodosa;* rheumatoid arthritis;* preeclamptic toxemia; renovascular hypertension; sarcoidosis;* serum sickness;* sjogren's syndrome;*syphilis;*systemiclupuserythematosus;*systemic sclerosis;* thrombotic thrombocytopenic purpura;* thyroiditis;* vasculitis; viral hepatitis;* wegener's granulomatosis;* and many other conditions. urate deposits in scleras and corneas. granulocytopenia note: midline granulomas may belong to the angiocentric immunoproliferative lesions, which are related to lymphomatoid granulomatosis* and malignant lymphoma. the name "idiopathic midline granuloma" should be reserved for the few cases without evidence of malignant lymphoma or wegener's granulomatosis* ( ). the diagnosis of idiopathic midline granuloma also can be ruled out if studies reveal fungal organisms or features of leishmaniasis;* leprosy,* rhinoscleroma, pseudotumor of the orbit or tuberculosis. * complications of nasal cocaine abuse also may mimic midline granuloma ( ). eosinophilic pneumonitis (degenerating eosinophils with charcot-leyden crystals) and granulomas. angiitis (mostly arteritis), typically with giant cells in tunica media ( ) . findings resemble those in polyarteritis nodosa. * heart ( ), grastrointestinal tract ( ), skin, muscles, and joints are commonly involved. however, renal disease is often (but not always) mild or absent. necrotizing vasculitis of small arteries and veins is present, with extravascular granulomas and eosinophilic infiltration of vessels and perivascular tissues. optic neuritis may be found ( ). may be affected by the vasculitis ( ). pcr studies on paraffin sections via rna in situ hybridization may confirm presence of epstein-barr virus-positive b-cell proliferations combined with dense t-cell accumulations ( ) ( ) ( ) . the condition closely resembles angiocentric t-/nk cell lymphoma ( ). infiltration of lymphocytoid cells, plasma cells, and macrophages with necroses and granulomatous features, which are found primarily in the vicinity of blood vessels. special stains may reveal evidence of infection. lymphoreticular and granulomatous infiltrates (see "lung"). lymphoreticular and granulomatous infiltrates (see "lung"). characteristic infiltrates may be present in all organs and tissues. involvement of spleen, lymph nodes, and bone marrow is uncommon. in rare instances, the disease is confined to the abdomen. in most instances, characteristic infiltrates are present ( ). septicemia; circulating immunoglobulin complexes, and antiendothelial antibodies ( ). angiocentric granulomatosis ( ) hemorrhage, intracranial (see under "hematoma, subdural" and under name of suspected underlying condition, such as "aneurysm, cerebral artery," "infarction, cerebral," "injury, head," and "tumor of the brain." hemorrhage, subarachnoid (see under name of suspected underlying condition, such as "aneurysm, cere-bral artery," "infarction, cerebral," "injury, head," and "tumor of the brain." hemosiderosis, idiopathic pulmonary note: this diagnosis is made by exclusion; involvement of organs other than the lungs (see below under "kidneys") suggests another disease. hepatitis, chronic synonyms and related terms: autoimmune hepatitis; chronic viral hepatitis b (with or without d) and c. note: the term "chronic hepatitis" is not a complete etiologic diagnosis and related names such as chronic active (aggressive) hepatitis, chronic active liver disease, and chronic per-sistent hepatitis are obsolete. most cases in these categories represent autoimmune hepatitis or chronic viral hepatitis b or c. many other liver diseases, including drug-induced hepatitis, inborn errors ofmetabolism (e.g., alphal-antitrypsin deficiency* or wilson's disease*), developmental disorders, and chronic biliary diseases such as primary biliary cirrhosis or primary sclerosing cholangitis also may present as chronic hepatitis. ifchronic hepatitis was the cause ofdeath, submassive hepatic necrosis or cirrhosis* is usually present, often with manifestations ofportal hypertension,*hepatic encephalopathy, hepatorenal syndrome,* and with ascites or spontaneous bacterial peritonitis. possible associated conditions: see also below under "possible or expected findings." conditions that may be associated with hepatitis c include ( ): autoimmune hepatitis; behcet's disease; diabetes mellitus (type );* glomerulonephritis;* guillain-barre syndrome;* idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; iga deficiency; lichen planus; mixed essential cryoglobulinemia; mooren's corneal ulcers; polyarthritis; porphyria cutanea tarda;* thyroiditis. * note: coinfection with other hepatitis viruses (e.g., c and g) and/or systemic viruses such as the immunodeficiency virus are common, particularly in drug addicts ( , ) . in many cases of fulminant hepatitis, tests for known hepatitis viruses are negative ( , ) . homicide note: not all of the following procedures can be carried out or will be required in all cases, nor will this checklist be sufficient in all instances. consult also the entries indicating the cause of death, such as "injury, firearm" or "injury, stabbing." if the victim is an infant, see all under "infanticide." before the body arrives or before autopsy is begun: . investigate the scene where the body was found and where the crime may have been committed (these may be two separate locations). if this is not possible, study the report and photographs submitted by the investigator or the police. study all available information. request previous medical records and roentgenograms of the victim. . emphasize to first responders and autopsy personnel that the body of the victim should not be undressed, washed, or otherwise disturbed until it has been inspected by the pathologist. embalming is not permitted before completion of the autopsy. advise first responders or transporters to put paper bags over the hands of the victim. this will protect possible evidence, such as hair from the assailant. . prepare record sheets to document the time of arrival and release of the body; chain of custody for the body and specimens; the name, age, sex, and other information about the victim; the names ofthe technician, pathologist and guests; and the specimens taken. . prepare roentgenographic and photographic equipment. after body arrives but before autopsy is begun: . if the body is left unguarded-for instance, overnight-a lock should be placed on the refrigerator or cool room where the deceased is kept, and the key should be retained by the technician. . if the pathologist is not accustomed to a busy autopsy room, he or she should feel free to ask all persons other than the pathologist(s), technicians, and law enforcement personnel who are not immediately involved in the actual performance of the autopsy to leave the morgue. . the body temperature of the victim can be recorded at the autopsy facility, but this is rarely useful, particularly if the victim seems to have been deadfor longer than a day ortwo or ifthe body had previously been stored in arefrigeratoror cool room. insert thermometer deep into the anus (about - cm). record temperature and manner and time of procedure. . aspirate vitreous from one or both eyes and store the specimen in a refrigerator. . prepare roentgenograms. in each case, a decision must be made whether roentgenograms should be made of the entire body or only of parts of it-or not at all-and whether they should be made before the victim is undressed, after the victim is undressed, or at both times. . take overall survey photographs that depict the anterior surfaces of the body as it is on arrival to the facility, before any undressing, manipulation for roentgenographs, or cleaning. . take close-up photographs of any trace evidence such as fibers or flakes of gunpowder before undressing or cleaning. . photograph the face of the victim for identification purposes after it has been cleaned of any blood and foreign matter. to avoid perspective distortion from wide angle lenses, the lens should be about ft from the face. . photograph all injuries and other forensically significant findings after blood and foreign matter have been cleaned off the body. a moist towel is useful; brushes are too abrasive. two photographs should be taken of each finding. one should include the autopsy number and a scale. a second photograph should be taken without any extraneous objects. collection and documentation of evidence: . fingerprinting can be done before or after the autopsy but should be done in all homicide cases. in cases involving close contact between assailant and victim, fingernail scrapings or clippings (use a new clipper) and hair with roots should be collected, and its source should be identified (hair pulled from scalp, axillae, and pubis is identified as that of the victim; hair in hands or under fingernails or on clothing of victim may be from the assailant). hair exemplars can be collected in cases of homicide by firearm but are rarely of use. if the body is decomposed or mutilated or for any other reason has not been identified, prepare roentgenograms ofthe head, neck, and torso before the autopsy (the radiographic appearance is altered by the autopsy). these can be used for comparison purposes if antemortem films are located. if films of the extremities are needed they can be prepared after the autopsy. dental roentgeno-.grams are taken, usually after the autopsy, when investigators have located antemortem dental records. detailed descriptions and sizes of clothing, with photographs of clothing, can be useful then there is no putative identity. . in cases in which sexual assault may have been involved, collect pieces of clothing that may contain seminal fluid stains. follow procedures described under "rape." . preserve clothing or part of clothing as evidence. wet clothing should be dried before it is stored in labeled and sealed bags. the autopsy: . the measured length and weight, extent of rigor, and color and distribution of livor should be recorded, along with the state of preservation, nutrition, and hydration. do not omit examination of the hands, particularly of the volar surfaces. . if air embolism is suspected, see procedure described under part ii "embolism, air". if pneumothorax is suspected, see procedure described under part ii "pneumothorax". if there is evidence of strangulation or other neck injury, perform a layerwise dissection of the neck that includes the hyoid bone and tongue. . prepare diagrams of wounds and identify their location by anatomic region. for wounds of the torso, state the distance from the soles of a foot and the distance laterally from to the right or left of the midline. . submit samples of wounds for histologic study when there is any question of the age of the wounds. . the records should show when body fluids and tissues were collected for laboratory analysis, the volume and appearance of such specimens, and what was done with them. if most of the toxicology specimens are collected immediately after the internal examination has commenced, the time of the internal examination serves as the collection time. in all instances, the following items should be collected: blood ofvictim for dna comparison and toxicologic study (determination of alcohol, carbon monoxide, and drug concentrations will be requested most frequently); vitreous; urine; gastric contents; at least one solid organ specimen for toxicologic study (liver and brain have the most comparison data if an extracerebral congenital malformation is suspected, follow procedures described under "malformation, arnold-chiari." if cerebrospinal fluid is aspirated with a syringe, record volume. record weight of brain; record size of brain in relation to inner dimensions of skull. describe size of ventricles. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. if a surgical shunt is present, its location should be recorded and both ends of the implanted specimen that was used for shunting may be submitted for microbiologic study. if the shunt is not patent, record site and nature of obstruction. related terms: antibody-mediated hydrops fetalis; erythroblastosis fetalis;* nonimmune hydrops fetalis. note: the classic example of antibody mediated (rh incompatibility) hydrops fetalis is hemolytic disease of the newborn (erythroblastosis fetalis*). however, nonimmune hydrops fetalis also may be caused by hematologic disorders, e.g., alpha-thalassemia* ( ) or it may have no known cause. infec-tions, e.g., with human parvovirus bl ( ), cytomegalovirus, or syphilis;* heart and vascular diseases ( ) (cardiac tumors, cardi-omyopathy,* myocarditis,* arterial calcification, and others); storage disease ( ); tumors (including neonatal leukemia*); and many other fetal (e.g., congenital chylothorax* or lymphatic dysplasia; pulmonary sequestration and cystic adenomatoid malformation) or maternal conditions, e.g., maternal thyrotoxicosis, also may cause nonimmune hydrops fetalis. if coronary insufficiency or myocardial infarction is suspected, follow procedures described under "disease, ischemic heart." for coronary arteriography, see chapter to. record distribution of atherosclerotic lesions in aorta. samples for histologic study should include aorta, coronary arteries, and peripheral arteries. see also above under "heart." submit samples of head, corpus, and tail for histologic study. if applicable, see also under "diabetes mellitus." for special procedures and stains, see above under "heart." other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for removal and specimen preparation, see chapter . obesity* is a common finding. eruptive xanthomas (palms, elbows, knees) in some but not all types of hyperlipoproteinemia. most prominent in apoprotein cii deficiency. xanthomas of tendons (knees, elbows, dorsum of hands), xanthelasmas, and arcus comeae in familial hypercholesterolemia. gangrene of lower extremities (see below under "arteries"). severe coronary atherosclerosis and myocardial infarcts in type hyperlipoproteinemia and multiple lipoprotein-type hyperlipidemia. atherosclerosis of abdominal aorta and its branches and of carotid arteries. coronary atherosclerosis (see above). pancreatitis* in familial apoprotein cii deficiency. foam cells with triglycerides in liver, spleen, and bone marrow in familial lipoprotein lipase deficiency. manifestations of diabetes mellitus* and hypothyroidism* in some cases of type hyperlipoproteinemia. cerebral infarct (stroke*) in type hyperlipoproteinemia. hypernatremia (see "disorder, electrolyte(s).") hyperoxaluria synonyms and related terms: oxalosis; primary hyperoxaluria type i (a anineglyoxylate aminotransferase deficiency); primary hyperoxaluria type ii (d-glyceric acid dehydrogenase deficiency); secondary hyperoxaluria (see under "note"). note: in ethylene glycol poisoning,*oxalatecrystals in media ofsmall arteries, with associated ischemic lesions. similardeposits may occur after long-term hemodialysis ( ). these conditions must be distinguished from the genetic disease. also, oxa-iate nephropathy may be a complication of short bowel syndrome. if patient with congenital hyperoxaluria underwent liver or combined liverlkidney transplantation ( ) , see also under these headings. remove vitreous for biochemical evalvation. submit tissue (i.e., fascia lata) for karyotype analysis. polycystic ovaries, testicular adrenal rests ( note: there are no diagnostic autopsy findings for hypoxia. possible causes of acute hypoxia include anesthesia-associated death,' compression of the torso by a vehicle, diving accident,' exposure to toxic gases-forinstance, carbon monoxide poisoning;' mechanical failure ofan oxygen supply system, as in an airplane; and sudden mechanical airway obstruction,' as in aspiration ofa foreign body orstrangulation. causes ofchronic asphyxia include prolonged exposure to high altitude and chronic pulmonary disease. profound medial hypertrophy of small pulmonary arteries and of pulmonary veins from chronic exposure to hypoxia. acute pulmonary edema may also occur in chronic hypoxia. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. malnutrition. empty and collapsed colon; small amounts of gray and dry meconium in terminal ileum; meconium masses in dilated and hypertrophied mid-ileum; liquid contents in proximal intestine ( ); appendicitis; bowel perforation. glandular inspissation and atrophy of intestinal mucosa. volvulus, infarction, necrosis, perforation, peritonitis, and acquired intestinal atresia may be present. absence of neural plexuses in congential megacolon* (hirschsprung's disease). manifestations of cystic fibrosis, with or without cirrhosis;* biliary atresia* ( ). immunodeficiency (see "syndrome, acquired immunodeficiency" and "syndrome, primary immunodeficiency.") impression, basilar note: basilar impression constitutes an upward bulging of the margins of the foramen magnum. when occipital condyles are displaced above the plane of the foramen magnum, basilar invagination is present. possible associated conditions: klippel-feil syndrome;* osteogenesis imperfecta;* osteomalacia;* paget's disease of bone;* rheumatoid arthritis; rickets; syringobulbia; syringomylia. * compression and secondary ischemic injury to lower brain stem and spinal cord. see also above under "skull and spine" and under "possible associated conditions." incompetence,••• (see "insufficiency,..•") related terms: battered-child syndrome; child-abuse or child-neglect death. note: vitreous should not be aspirated until the skull has been opened and trauma ruled out, because there is a risk of artifactual damage to the retina. in the presence of craniocerebral trauma the pathologist can opt to examine the eyes by removal, fixation, and histologic study; or retinal photography. follow general procedures described under "homicide" and, if necessary,. the procedures described under "rape." external examination see above under "note." prepare roentgenograms of entire body. see above under "note." in other situations, or after study of the fundus, submit sample of vitreous for chemical and possible toxicologic study. umbilical cord attachment prepare histologic sections of umbilicus. and end of umbilical cord blood submit sample for toxicologic study. consider retaining dried blood on filter paper for possible dna testing for paternity investigation. if there is a possibility that the cadaver represents a stillbirth, see part ii, "stillbirth". if infant is thought to have died shortly after birth, determine the location of air in the intestinal tract; roentgenograms may be helpful. save stomach contents and record amount. other organs see also under "homicide." in the abused child, bruises, hematomas, burn marks, or other patterned injuries. in any child, diaper rash, mongolian spots, self-inflicted fingernail scratches, skin infections, and emaciation. in the previously battered child, fractures in various states of healing. in hypertonic dehydration,' sodium concentrations more than meq/l. this may be caused by organic disease, improper medical treatment, or physical neglect. if infant was born alive, inflammatory changes may be found, depending on survival interval. for the hydrostatic lung test, see "stillbirth." the test is unreliable. extraneous material in air passages indicates that child was alive. air reaches the stomach after min, the small intestine after - h, the colon after - h, and the rectum after l h. there is no difference in the speed of gas propulsion between full-term and premature infants. bacterial gas production and previous resuscitation attempts are potential sources of errors. in questionable stillbirth, presence of milk proves that infant was alive and had been nursed. traumatic lesions and signs of neglect may be present. unilateral ulcers in visceral zoster. in rare instances, diffuse meningoencephalitis may occur. limited necrotic and inflammatory lesions in the cord or brain stem at the level of the affected ganglion are common. posterior hom myelitis ( ). ganglion cell necrosis; lymphocytic infiltration, hemorrhage, and, later, fibrosis. as a rule, only one ganglion is severely involved, but less severe lesions may occur in the ganglia that are immediately adjacent. diffuse lymphocytic infiltration; demyelination; axonal destruction; fibrosis. conjunctivitis; keratitis; iridocyclitis; retrobulbar neuritis; neuroretinitis; occlusion of retinal vessels. evidence of hematologic malignancies ( ) or other conditions, as listed above under "note." infection, middle ear (see "otitis media.") infection, pneumocystis carinii synonym: pneumocystosis. note: ( ) collect all tissues that appear to be infected. ( ) this organism cannot be cultured at present but is frequently associated with viral, bacterial, or fungal infections that can be diagnosed by culture. ( ) for rapid staining of aspirates, use gram-weigert stain, which will stain cysts of pneumocystis carinii and also fungi and bacteria. pneumocystis carinii is best demonstrated with grocott's methenamine silver stain. ( ) no special precautions are indicated. ( ) usually, no serologic studies are available. ( ) this is not a reportable disease. injury, fire (see "burns.") injury, firearm note: protect all drains of autopsy table, which will prevent accidental loss of bullets or bullet fragments. recovery of bullet fragments and pellets can also be improved by passing tissue fragments, blood, and other appropriate materials through a fine nonmetallic sieve. caution must be exercised because sharp edges andjagged projections ofbullets and bullet fragments may cause injury ( ). this applies particularly to the black talon bullet. bullets and bullet fragments should not be touched with forceps or other metal instruments that may produce artifactual markings; they must be placed in properly labeled evidence containers, and the chain of custody must be preserved. from a birdshot wound, at least pellets should be recovered. the firearms examiner will divide the total pellet weight by and derive median pellet weight. from a buckshot wound, all pellets should be recovered. in many of these cases, procedures described under "homicide" must also be followed. do not excise wounds before completion of autopsy (see below). as an academic exercise, excised firearm wounds may be used later for analysis of metal traces by neutron activation or for tests for carboxyhemoglobin. in practice, however, a high quality photograph is adequate to establish the presence or absence of gunpowder stippling or soot deposition toward the end of establishing the range of fire. the dimensions of the stippled areas and soot deposits should be recorded. after completion of external examination, dry the wet clothing and keep as evidence. clothing may also be used for possible test firing or for stain, powder, or particle analysis. external examination if identity of victim is unknown, follow procedures described in chapter . prepare initial roentgenograms of the body regions that have been shot, before disrobing of body, and then lateral films of body regions with bullets. follow up with films of other body regions as needed in the course of autopsy. if the body is decomposed to the extent that the external examination cannot be relied upon to determine cutaneous gunshot perforations, prepare roentgenograms of the entire body before autopsy. record location and number of bullet holes in all layers of garments, indicating whether the involved area is bloodstained or shows gunpowder or soot. if there are several cutaneous perforations, number or letter each consecutively and refer to these numbers in all records. location of bullet holes should be described by recording distance from soles of feet or top of head, and from midline of body. prepare diagrams and photograph holes, with and without labels. photographs should show surrounding garments and extent of blood stains. in hairy areas, shave around bullet wounds for better photographic documentation. for evaluation of distance from where a shot had been fired, see fig. additional roentgenograms during the autopsy may be needed to find bullets embolized to the femoral veins or down the spinal canal. systemic roentgenograms may reveal bullets from obscure entrance wounds, particularly in decomposed bodies, old bullets, bullets in the skin flaps reflected at autopsy, or bullets external to the body in clothing. bullet(s) may have been arrested in hollow viscus or blood vessel and may have been transported to distant sites by peristalsis or bloodstream ("bullet embolus"). bullets may be deflected in unexpected directions from bony surfaces. soot ("smudging") and gunpowder stippling may occur around entrance wound, depending on the muzzle-to-skin distance. there may also be an impression from a recoiling handgun or from a power piston. wounds may be stellate, round, jagged, or slit-like, with or without wide margins of abrasion. primer residues on hand of suicide victim after use of a handgun. fatal secondary injuries, particularly hemorrhages. alcohol intoxication is a frequent finding. fig. · . bullet wounds. differences in the appearance of cutaneous wounds of entrance and of exit and differences in wounds of entrance according to the distance between muzzle and skin at the moment of fire. entrance wounds often differ from exit wounds in that the former are usually surrounded by a narrow zone of abrasion. if the muzzle of a gun is in close contact with the skin at the moment of fire, the combustion products will be blown into the wound and will not be visible on the surface. for close-range wounds, the stippling of the skin around the wound, produced by particles of burned and unburned powder, becomes progressively more dispersed as the range of fire increases and is ordinarily not perceptible if the range has been greater than inches ( synonyms and related terms: acute radiation syndrome; chronic (delayed) radiation injury; radiation enterocolitis; radiation nephritis; radiation pneumonitis. note: procedures and expected findings depend on type of radiation damage, whether acute or chronic, localized or whole-body irradiation. if suspected radiation injury was associated with the administration of radionuclides such as p, , or au, follow procedures suggested in chapter . in fatal whole-body irradiation, findings are most likely related to bone marrow injury, and the suggested procedures and expected findings are those described under "pancytopenia." record extent of oropharyngeal and intestinal ulcerations and hemorrhages. late complications include malignant tumors (carcinoma, leukemia,* lymphoma*), manifestations of hypothyroidism,* and cataracts. organ changes in localized radiation injury depend on site of irradiation (lung, brain, kidney, intestine). the skin is involved in both acute (erythema) and chronic (atrophy, epilation) radiation injury. related terms: cutting injury; knife injury. note: in many of these cases, procedures described under "homicide" must also be followed. insuffiency, adrenal synonyms and related terms: adrenocortical insufficiency; polyglandular autoimmune syndrome (type i, usually in childhood, with parathyroid insufficiency and chronic mucocutaneous moniliasis; type ii, usually in adults, with two or more autoimmune endocrine disorders such as thyroiditis and diabetes mellitus*); primary adrenal insufficiency (addison's disease); secondary adrenal insufficiency (in hypothalamic-pituitary disease or steroid induced); x-linked adrenal hypoplasia. is caused by anatomic changes (see below under "adrenal glands"), drugs (enzyme inhibitors or cytotoxic drugs), or acth-blocking antibodies. possible associated conditions: aids with systemic infections ( ); antiphospholipidantibody syndrome ( ); autoimmune hepatitis; chronic lymphocytic thyroiditis; type i diabetes mellitus;* hypoparathyroidism;* hypothyroidism;* megaloblastic anemia;* surgical procedures, such as heart surgery or orthopedic procedures. large cell lymphoma ( ). should be removed as soon as possible (before embalming), either from cervical midline incision or from chest (neck of cadaver must be well-extended). photograph obstruction before larynx is opened, and inside of larynx and epiglottis after larynx is is opened in posterior midline. make gram-stained touch preparations. make histologic sections of larynx and epiglottis. hemophilus injluenzae (cannot always be isolated from larynx synonyms and related terms: acute or chronic lymphocytic leukemia, acute or chronic myelogenous leukemia, and hairy cell leukemia. multiple subtypes have been identified; they are characterized by cell surface markers, chromosomal abnormalities, staining reactions, and morphologic features. note: at the time of autopsy, most leukemias have been properly classified and often treated. in these cases, the goal of the autopsy is to document the extent of the disease and the presence of complications. if the leukemia had not been classified or if the features might have changed from the time of the last work-up (e.g., in suspected cases of superimposed diffuse large cell lymphoma [richter's syndrome]), material should be snap-frozen and studied in more detail. if the patient was treated by bone marrow transplantation,* see also under that heading. possible associated conditions: agnogenic myeloid metaplasia with myelofibrosis; bloom's syndrome;* cutaneous mastocytosis; down's syndrome;* immunodeficiency syndromes* (bruton's disease; louis-bar syndrome; wiskott-aldrich syndrome); infantile genetic agranulocytosis; klinefelter's syndrome;* lymphoma;* multiple myeloma;* polycythemia;* and many others. for sampling and specimen preparation, see chapter . increased protein concentration. material in sediment stains red with toluidine blue. metachromatic material. arylsulfatase-a deficiency. excessive loss of myelin with large amounts of metachromatic material (see above under "urine") in white matter and also in some neurons. demyelination with metachromatic material (see above under "urine"). leukoencephalopathy, progressive multifocal possible associated conditions: aids* and other immunosuppressed states; carcinoma; malignant myeloproliferative or lymphoproliferative disorder; sarcoidosis;* tuberculosis. * procedures submit portion of fresh brain for viral culture. fix remainder of brain and spinal cord in formalin and submit samples for histologic study. in situ hybridization for ic virus is available on paraffin-embedded tissue. small patches of demyelination with tendency to form confluent areas in the cerebral white matter. white matter necrosis may be present. eosinophilic intranuclear inclusions occur in affected oligodendroglia cells. subsequently, large, bizarre astrocytes develop. no inflammatory (lymphocyte) cell reaction is present. lightning (see "injury, lightning.") lipoproteinemia (see "hyperlipoproteinemia.") lipoproteinosis, pulmonary alveolar synonym: idiopathic alveolar lipoproteinosis. note: the condition has been described in allografts ( ); in such cases, see also under "transplantation, lung." elephantiasis of penis, scrotum, or vulva (in chronic cases); skin rash (l) and conjunctivitis (in acute cases); genital ulcers. suppurative or fibrosing inguinal, iliac, or pelvic lymphadenitis, with or without sinus tracts. rectal strictures and fistulas in chronic cases ( ) . systemic involvement in the acute stage with pericarditis,* and arthritis,* and meningitis,* proctitis ( ) lymphoma synonyms and related terms: aids-related lymphoma; adult t-cellieukemiallymphoma; angioimmunoblastic lymphadenopathy; b-celllymphoma; burkitt's lymphoma; cutaneous t-cell lymphoma (includes mycosis fungoides and sezary syndrome); hodgkin's disease; non-hodgkin's lymphoma (low grade, intermediate grade, high grade, all with multiple subtypes too numerous to list, which vary in natural history); natural killer cell neoplasms; post-transplant lymphoproliferative disorders (ptld); t-cell lymphoma. note: at the time of autopsy, most lymphomas have been properly classified and often treated. in these cases, the goal of the autopsy is to document the extent ofthe disease and the presence of complications. if the lymphoma had not been classified or if the features might have changed from the time of the last work-up, material should be snap-frozen and studied in more detail. if the patient was treated by bone marrow transplantation, * see also under that heading. for current terminologies of hodgkin's disease and non-hodgkin lymphomas as well as for staging criteria, appropriate hematologic textbooks should be consulted. possible associated conditions: acquired immunodeficiency diseases (e.g., after organ transplantation; human immunodeficiency virus-l infection); autoimmune disease (e.g., celiac sprue,*rheumatoid arthritis,* systemic lupus erythematosus,* or sjogren's syndrome*); chemotherapy with or without radiation treatment; epstein-barr virus infection; human t-cell leukemia virus infection; inherited diseases with immunodeficiency (e.g., klinefelter syndrome; * common variable immunodeficiency disease, wiskott-aldrich syndrome); radiation. the lesions are found most commonly in the urinary bladder and other parts of the urinary tract, but may also occur at many other sites, including skin ( ) and upper respiratory tract ( ). note: (i) collect all tissues that appear to be infected. ( ) usually, cultures are not indicated. ( ) request giernsa or wright stain. tissue blocks should be rinsed of blood and be as thin as possible before fixation in refrigerated buffered and neutral % formalin solution. this is to avoid precipitationofformalin pigment that may be confused with malaria pigment. the formalin solution should be used in a ratio of parts formalin to one part tissue and should be agitated every few hours. if one is dealing with tissues that contain formalin pigment, this pigment may be removed with a bleaching solution. ( ) usually, no special precautions are indicated. ( ) possible associated conditions: histoplasmosis* and other chronic fungal infections; immune connective tissue diseases such as rheumatoid arthritis* (l) ; malignancies (l); sarcoidosis;* silicosis;* tuberculosis* (l) . note record location and extent of skin changes or skin defects on back. prepare skeletal roentgenograms. if meningitis is suspected, submit sample of cerebrospinal fluid for culture. dse the posterior approach to remove the spinal cord. atrophic skin over meningocele, lacking rete pegs and skin appendages; skin defect in complete rachischisis. bony defects of spine. in meningocele and spina bifida occulta, arachnoid and dura herniate through the vertebral defect. spinal cord and roots are generally not involved. lumbosacral mass in meningomyelocele, with a highly vascular mass (area medullovasculosa) in spina bifida aperta. neural defects in complete rachischisis. diastematomyelia, hydrocephalus ( ) . pyelonephritis;* enlarged urinary bladder ("neurogenic bladder"). external examination heart lungs procedures prepare chest roentgenogram. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. record weights. prepare photographs and roentgenograms of fresh and fixed lung specimens. perfuse one lung with formalin. for preparation of paper-mounted sections, see chapter . submit one lobe for microbiologic and chemical study. decalcify tissue for histologic study. request van gieson's, hale's colloidal iron, pas, and sudan stains. miliary mottling in lower lung fields. mitral stenosis* may be a cause of microlithiasis (mostly intra-alveolar ossification). * cor pulmonale and heart failure ( ) (l) , see also under that heading. ( ) collect all tissues that appear to be infected. ( ) viral isolation, especially with ebv, is not diagnostically useful, due to long incubation periods. ( ) note: these diseases are characterized by a deficiency of a variety of hydrolases, resulting in accumulation of gly-cosaminoglycans (mucopolysaccharides) and glycolipids within lysosomes of fibroblasts, macrophages, white cells, and parenchymal cells of many organs ( , ) . mucopolysaccharides are also excreted in the urine. the general approach is similar in all types. formalin may dissolve all of the stored material and leave empty vacuoles in the involved cells. therefore, frozen sections should be utilized or tissues should be fixed in absolute alcohol. the accumulated material will show intense metachromasia if stained with toluidine blue. it will also stain with pas, alcian blue, and colloidal iron. oil red a will also stain the material from frozen sections. for specimen preparation for elec-tron microscopy, see chapter is. characteristic external features include dwarfism; thickened long bones; coarse facial features; coarse hair; macrocephaly; prognathism; hypertelorism; malformed teeth, and scaphocephalic skull with hyperostosis of sagittal suture; short neck; chest deformity; umbilical and inguinal hernias; lower thoracic and lumbar gibbus; genu valgum and coxa valga; pes planus and other joint deformities; wide hands (clawhands) and feet. coarse thickened skin, covered with lanugo-like hair. hyperlordosis; ovoid deformities of vertebrae; odontoid hypoplasia; large, shoe-shaped sella turcica; kyphosis; hypoplasia of femoral heads; osteoporosis.* if patient underwent bone marrow transplantation ( ), see also under that heading. chronic upper respiratory infections. large cytoplasmic granules in neutrophils. storage of mucopolysaccharides in osteocytes, chondrocytes, and fibroblasts of periosteum, tendons, fasciae, and other connective tissues; dysostosis multiplex. other tissues histologic sampling cannot be excessive. ( ) collect all tissues that appear to be infected. ( ), see also under that heading. blood; other organs and tissues record extent of skin lesions and prepare photographs; prepare sections of affected and unaffected skin. request gram stain of sections and smears. submit samples of blood and grossly affected organs or tissues for microbiologic study. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. extensive epidermal necrosis. shedding of granular and horny layers of epidermis. septicemia; staphylococcal infection of nose, throat, ears, eyes, heart valves, urogenital tract, and other sites. bronchial epithelial detachment and bacterial pneumonia ( ). synonyms and related terms: acute kidney failure; *acute tubular necrosis; lower nephron nephrosis. note: the morphologic diagnosis of this condition may be difficult to discern from autolysis. the features that suggest tubular necrosis are: tubular dilation with epithelial flattening, intertubular edema and necrotic epithelial cells in the collecting ducts. the autopsy should be performed as soon as possible. needle specimens of the kidneys obtained in the immediate postmortem period may yield acceptable material. ifnephrotoxic drugs or chemicals are thought to be responsible for tubular necrosis, submit samples for toxicologic study (see also under synonyms and related terms: multiple endocrine neoplasia (men), type (parathyroid hyperplasia or adenoma; pancreatic islet cell hyperplasia, adenoma, or carcinoma; pituitary hyperplasia or adenoma); or type a (medullary thyroid carcinoma, parathyroid hyperplasia or adenoma; and pheochromocytoma); or type b (medullary thyroid carcinoma, pheochromocytoma, mucosal and gastrointestinal neuromas, and marfanoid features). note: in men, type , foregut carcinoids and subcutaneous and visceral lipomas also may be found. in type a, cutaneous lichen amyloidosis may be observed. mixed syndromes include (i) familial pheochromocytoma and islet cell tumor, ( ) von hippel-lindau syndrome, pheochromocytoma and islet cell tumor, ( ) neurofibromatosis* with features of men or , and myxomas, spotty skin pigmentation, and generalized endocrine overactivity (carney complex). in all instances, the autopsy should be done as soon as possible so that tissues for biochemical study can be frozen without delay. nephritis note: see under specific designation, such as "glomerulonephritis" and "pyelonephritis," or under name of suspected underlying condition, such as "gout" or "lupus erythematosus, systemic." nephroblastoma (see "tumor of the kidney(s).") synonyms and related terms: renal stones; urolithiasis. possible associated conditions: carcinomatosis; cushing's syndrome;* cystinuria;* fanconi syndrome;* hyperoxaluria;* hypervitaminosis d;* gout;* multiple myeloma;* osteoporosis;* polycystic renal disease;* primary hyperparathyroidism;* rheumatoid arthritis* ( ); sarcoidosis* ( ). kidneys ureters, urinary bladder, and urethra other organs remove kidneys, ureters, and urinary bladder en bloc. excise and bivalve kidneys to reveal renal pelves. open ureters. record size, number, and appearance of stones, and save for chemical analysis ( ). record heart weight. dissect and record weights of all parathyroid glands. other procedures depend on suspected underlying conditions, as listed above under "possible associated conditions." nephropathy note: see under name of suspected underlying condition, such as "diabetes mellitus," "disorder, electrolyte(s)" (hypercalcemia, potassium depletion), "gout," "hypertension (arterial), all types or type unspecified," or "poisoning,.. ." (heavy metal). if kidney failure was present, procedures under that heading should also be followed. renal tissue may need decalcification or fixation in water-free solution. ( ) note: in this condition, lesions in the brain and cranial nerves, spinal cord, and spinal roots may be schwannomas (including bilateral vestibular schwannomas); multiple meningiomas; gliomas (generally of spinal cord), mostly ependymomas ( %) and pilocytic astrocytomas; or schwannosis of spinal dorsal root entry zones. intracortical meningioangiomatosis; glial hamartia (intracortical, basal ganglia, thalamus, cerebellum, and dorsal horns of spinal cord) and cerebral calcifications also may be found. cutaneous abscess (j). acute necrotizing nocardial pneumonia with abscesses or sinus formation into surrounding tissues; empyema. pulmonary and mediastinallymph nodes other organs submit samples for culture and histologic study. submit samples from all organs and tissues with suspicious gross lesions for culture and histologic study. poorly encapsulated abscesses of any organ; endocarditis ( ) . related term: total parenteral nutrition. note: air embolism* or blood loss may have occurred if line became detached from the catheter hub. metabolic complications such as fluid overload or disturbances of acid-base and electrolyte balance often cannot be diagnosed reliably at autopsy. the disease(s) that may have necessitated parenteral nutrition therapy are not considered here; they include the acquired immunodeficiency syndrome (aids);* cancer cachexia; inflammatory bowel disease; liver or kidney failure;* severe pancreatitis;* short bowel syndrome, and others. obstruction, acute airway synonyms and related terms: aspiration; bolus death; "cafe coronary"; croup; restaurant death. note: ifpermission has been obtained, remove neck organs through straight incision from chest to chin to avoid dislodging a foreign body. ifdissection has to be accomplished from chest, neck of unembalmed cadaver should remain well extended during procedure. inspect larynx and trachea from above and below, respectively, before opening them carefully along the posterior midline. for removal, prosthetic repair, and specimen preparation, see chapter . submit samples of osteocartilaginous and synovial tissues for histologic study; sagittal or frontal saw section through spine provides for best routine evaluation. heberden's nodes at interphalangeal joints of fingers. degenerative changes, primarily of spine, hip joints, and knee joints. histologic and macroscopic degeneration of cartilage; exposure of subchrondral bone; formation of marginal osteophytes; bone cysts; synovial fibrosis; hypertrophic synovitis. o procedures if artificial joints (e.g., hip or knee) had been implanted, record state of implant site. loose joint prostheses. synonyms: hypertrophic pulmonary osteoarthropathy; pac-hydermoperiostosis (idiopathic hypertrophic osteoarthropathy [ j). note: in all instances, an underlying disease must be identified; they include cardiac disease (cyanotic congenital heart dis-ease with right-to-left shunt; infective endocarditis*); gastroeso-phageal reflux ( ); neoplasms of lungs, esophagus, intestine, and liver; chronic liver disease; inflammatory bowel disease;* pulmonary disease (e.g., abscess;* bronchiectasis;* cystic fibrosis;* emp-yema;* emphysema;* lipoid pneumonia* ( ); pneumocystis pneumonia; sarcoidosis;* tuberculosis*); hyperthyroidism. * external examination elastic arteries other organs prepare roentgenograms of extremities. for removal, prosthetic repair, and specimen preparation, see chapter . record presence of aneurysms (thoracic aorta, subclavian) or arteriovenous fistula of brachial vessels. if abdominal aortic aneurysm had been surgically repaired, search for evidence of graft infection ( ) . procedures depend on expected findings or grossly identified abnormalities as listed above under "note." clubbing of fingers or toes (see below under "elastic arteries"); swelling of extremities. periosteal new bone formation in distal shafts of bones of forearms and legs. all bones of extremities may be involved. see above under "external examination." unilateral clubbing. clubbing of toes but not of fingers. swelling; fistulas. bone defect(s) and focal osteosclerosis. bacterial or fungal infections, most common in metaphyseal region of bones; paravertebral or psoas abscess in osteomyelitis of spine. bacterial or fungal osteomyelitis, with or without cavitation and fistulas. trauma, surgery, insertion of prosthesis, generalized ( ) or contiguous infection, inflammatory bowel disease ( ), diabetes mellitus,* and peripheral vascular diseases, deep vein thrombosis ( ). synonyms and related terms: aseptic necrosis of bone; avascular necrosis of bone; idiopathic osteonecrosis; perthes' dis-ease; postfracture osteonecrosis; renal transplant associated osteonecrosis. note: possible underlying conditions include chronic alcoholism,* decompression sickness,* diseases that have been treated with high doses of corticosteroids ( ), gaucher's disease,* human immunodeficiency virus infection* ( ), tuberculosis* ( ), sickle cell disease, * systemic lupus erythematosus,* tuberculosis* ( ), and bisphosphonate therapy ( ). other organs submit sample for biochemical study. for removal, prosthetic repair, and specimen preparation, see chapter . if osteonecrosis is suspected because one of the possible underlying conditions (see above) is present, prepare saw sections through femoral heads, medial femoral condyles, and heads of humeri. procedures depend on suspected underlying conditions, as listed above under "note." osteopetrosis synonymsand related terms: albers-schonberg disease; autosomal-dominantosteopetrosis; carbonic anhydrase-it deficiency; malignant infantile osteopetrosis ( ); marble bone disease. note: manifestations of renal tubular acidosis may have been a clinical complication. possible associated conditions: bone marrow transplantation* (for infantile osteopetrosis). anemia, recurrent infections, bleeding, and bruises may have resulted from myelophthisis associated with osteopetrosis. upper airway obstruction in malignant infantile osteopetrosis may have necessitated tracheostomy ( ). in heritable osteoporotic disorders of connective tissue (osteogenesis imperfecta,* marfan' s syndrome,* and others) are pre-sented separately. for"osteomalacia," see above. for "osteodystrophy," see under "failure, kidney." possible associated conditions: acromegaly;* chronic alco-holism;* chronic obstructive pulmonary disease; chronic kidney failure* ( ); cushing's syndrome;* debilitating disease (various kinds, often with immobilization); diabetes mellitus* ( ); epilepsy;* hyperthyroidism ( );* hypogonadism; malabsorption syndrome;* malnutrition;* primary biliary cirrhosis;*rheu-matoid arthritis;* scurvy;* steroid therapy or anticonvulsant medication. normal parathyroid glands in uncomplicated cases. hyperparathyroidism* ( ) (without osteitis fibrosa) may be present, however. features of osteitis fibrosa (osteoclastic osteoporosis; see "hyperparathyroidism") or osteomalacia* exclude the diagnosis of uncomplicated osteoporosis. osteoporosis, which may be localized, occurs in various neoplastic (e.g., mastocytosis) and inflammatory diseases. external examination brain and base of skull with middle ears examine external ear canal. for removal and specimen preparation, see chapter . culture any lesion appearing to be infectious. draining, foul-smelling greasy material associated with acquired cholesteatoma. bacterial or viral infection, with or without mastoid osteitis. neck abscess, sinus thrombosis ( ) and brain abscess* and meningitis* may complicate otitis media. otosclerosis ( , ) note: otosclerosis may be a measles-virus-associated disease ( ) and therefore, studies to rule out a past infection may be indicated. for removal and specimen preparation, see chapter . for current methods of temporal bone studies, see ref. ( ) . spongy bone in the capsule of the labyrinth. trabeculae of woven bone show pagetoid changes. if stapedectomy had been done, a prosthesis may be in place. brain is externally normal or mildly atrophic. characteristic is midbrain atrophy with aqueduct dilatation and depigmentation of the substantia nigra. neuronal loss with reactive gliosis, associated with neurofibrillary tangles (globose tangles). primarily affected are globus pallidus, subthalamic nucleus, red nucleus, substantia nigra, tectum, periaqueductal gray matter, and dentate nucleus (grumose degeneration). palsy, pseudobulbar (see "disease, motor neuron.") related terms: acute pancreatitis; alcoholic pancreatitis; chronic (or chronic fibrosing) pancreatitis; interstitial pancreatitis. note: some causes of pancreatitis such as adverse drug reactions (e.g., due to azathioprine, furosemide, or estrogens) cannot be diagnosed at autopsy. possible associated conditions: acute fatty liver of pregnancy; apolipoprotein cli deficiency; cystic fibrosis; *hyperparathyroidism;* kidney transplantation. * status post endoscopic retrograde cholangiopancreatography. synonyms and related terms: calcifying panniculitis; histiocytic cytophagic panniculitis; mesenteric panniculitis (mes-enteric lipodystrophy); "sclerema neonatorum." note: the term weber-christian disease described systemic panniculitis with fever, bleeding, pulmonary and pancreatic lesions, and other abnormalities also involving lungs and pancreas, among others. however, this condition is not a specific entity and thus, the name has become obsolete. the term histiocytic cytophagic panniculitis is more descriptive and preferred. leukemia* and subcutaneous t-celllymphoma* may closely simulate panniculitis. possible associated conditions: alphaj-antitrypsin deficiency;* dermatomyositis;* rheumatoid arthritis;* scleroderma and morphea; sjogren's syndrome;* systemic lupus erythematosus.* external examination, skin, subcutaneous tissue, and breasts chest heart lungs liver and spleen record extent and character of skin lesions. record size, location, and gross appearance of subcutaneous nodules. submit tissue samples for histologic study of grossly unaffected skin, skin lesions, and subcutaneous nodules. request verhoeff-van gieson, gram, and grocott's methenamine silver stains. request s-l protein stain. ascertain that cell infiltrates are not leukemic or lymphomatous ( ) . dimpling of skin; necroses; fistulas. panniculitis with subcutaneous nodules in trunk, breasts, and thighs ( ) . calcification may occur in breast tissue but also at other sites (e.g., in kidney failure*). pancreatic enzymeinduced fat necroses associated with severe pancreatitis. widespread hardening of fat tissue with rupture of fat cells and crystal formation in "sclerema neonatorum." focal traumatic panniculitis also may occur in newborns. s-ioo stain negative in panniculitis but positive in rosai-dorfman disease (sinus histiocytosis with massive lymphadenopathy). mediastinal panniculitis. pericarditis;* interstitial myocarditis. * pneumonia;* pleuritis. fat embolism. * features of alphal-antitrypsin deficiency* ( ) . fatty changes of liver; splenitis. intestinal mucosal erosions and ulcers, with or without perforation. massive gastrointestinal hemorrhage in histiocytic cytophagic panniculitis. blind intestinal loop ( ). for sampling and specimen preparation, see chapter . prepare samples for electron microscopy. vacuolar myopathy. ( ) . external examination, skin, and mouth record extent of skin lesions; photograph; submit multiple samples for histologic study, preferably of areas that are free of secondary infection. prepare sections for immunofluorescent staining. bullous and other lesions of scalp, eyelids, nose, axillae, umbilicus, inframammary areas, back, hands, groins, genitalia, anus, knees, and feet. similar lesions may occur in the mouth. acantholysis is suprabasal or near granular layer. igg deposits on the surfaces of keratinocytes. note: (i) collect all tissues that appear to be infected. collect inguinal, popliteal, axillary, and supraclavicular lymph nodes for aerobic culture. photograph enlarged lymph nodes, and prepare smears of fresh cut surfaces. submit consolidated areas for microbiologic study (see above under "note"). perfuse both lungs with formalin. submit samples of pulmonary tissue and bronchial lymph nodes for histologic study. submit samples of grossly abnormal organs, exudates, or drainage fluids for culture and gram stain. hemorrhagic necrosis; variable suppuration. severe hemorrhagic edema; pneumonia with lobular to lobar features. large areas of necrosis teeming with organisms and minimal to suppurative inflammation. plasmacytoma (see "myeloma, multiple.") platybasia note: possible causes or associated conditions include arnold-chiari malformation;* basilar impression* orinvagination; fusion ofatlas to the foramen magnum; klippel-feil syndrome;* malpositioning of odontoid process; osteitis deformans (paget's disease of bone*); osteogenesis imperfecta;* osteomalacia;* rickets; syringobulbia, syringomyelia. * skull and spine prepare roentgenograms of skull and cervical spine. flattening of the base of the skull (angle formed bythe planeoftheclivus andtheplane of the anterior fossa exceeds °). pleuritis (see "effusion(s) and exudate(s), pleural.") pleurodynia, epidemic synonyms: bornholm disease; devil's grip; epidemic myalgia; epidemic myositis. blood heart and pericardium submit samples for viral culture. sample for histologic study and for viral cultures (coxsackievirus a and b; echoviruses). if pericardia! fluid can be obtained, submit for viral culture also. cultures may be negative and search for viral rna by in situ hybridization may be indicated. chest organs other organs dissect thoracic duct and its tributaries (see chapter ). perfuse one or both lungs with formalin. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. submit samples of cystic lesions for histologic study. submit samples of cystic lesions for histologic study. gas in thoracic duct. emphysema* of lungs. necrotizing enterocolitis in premature infants. pyloric stenosis, colitis ( ), redundant sigmoid colon, ischemic bowel disease. mucosal pseudolipomatosis ( ) . usually, cysts are subserosal in adults and located between muscularis mucosae and muscularis propria in infants and children. mucosa may be inflamed. extraintestinal cysts, as listed above under "abdomen." cysts may also occur in vaginal mucosa. include bright-field and polarized light microscopy, transmission electron microscopy, scanning or transmission electron microscopy with energy dispersive x-ray analysis ( ), ion beam instrumentation, and secondary ion mass spectrometry. the last three methods are time-consuming, require much skill and expensive equipment, and do not lend themselves well to quantitation. ideally, bulk analysis and in situ microanalysis should be used in combination. analyses can be conducted in specialized laboratories at the following centers (for charges and other information, consult the appropriate laboratories): prepare chest roentgenogram. submit sample for microbiologic study. refrigerate sample for possible immunologic study. submit one lobe or samples of all lobes for bulk analysis and for in situ microanalysis (see above under "note"). microincineration may permit preliminary dust analysis. for demonstration of asbestos fibers, see chapter and ref. ( ) . submit one lobe or segment for microbiologic study. for pulmonary arteriography and bronchography, see chapter . prepare roentgenograms of entire lungs and slices. perfuse one lung (or both, if only routine studies are intended) with formalin. submit samples for histologic study of nodular dust lesions, diffuse fibrotic lesions, grossly uninvolved areas, bronchi, and bronchopulmonary lymph nodes. for preparation of paper-mounted sections, see chapter . prepare samples for transmission and scanning electron microscopic study. for removal, prosthetic repair, and specimen preparation, see chapter . alveolar rupture with dissection of air into the mediastinum in neonates with respiratory distress (see "syndrome, respiratory distress, of infant") and in adult patients ventilated on volume respirators. external examination prepare chest roentgenogram. photograph mediastinum. explore major veins and record compression in cases of tension pneumomediatinum. roentgenograms provide the best permanent record of a pneumomediastinum. air bubbles in mediastinal soft tissues. part ii / diseases and conditions abdomen and neck organs perfuse one lung with formalin. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. search for evidence of trauma of other lesions that may have allowed air to enter soft tissues. intubation injury (j); perforation or rupture of major bronchus, trachea, or esophagus. alveolar rupture, e.g., in asthma* ( ), may not be discernible. bronchiolitis obliterans ( ), interstitial pneumonia* ( ) and other lung conditions also may lead to pneumomediastinum. dissection of air from lesions in abdomen (e.g., retroperitoneal colonic perforation [ ] ) or in neck area. pneumonia, all types or type unspecified note: if the type of underlying infection is known, follow procedures suggested under the name of the infectious disease. if the etiologic agent of the pneumonia is unknown, proceed as follows: (l) collect all tissues that appear to be infected. and grocott's methenamine silver stains. ( ) special precautions may be required (see chapter ). ( ) serologic studies may be helpful once a specific etiologic agent is suspected. thus, collect serum at the time of autopsy or procure serum that was collected prior to death. ( ) this may be a reportable disease. related terms: acute interstitial pneumonia (hamman-rich syndrome); desquamative interstitial pneumonia (dip); idiopathic organizing pneumonia (or "bronchiolitis obliterans with patchy organizing pneumonia [boop]" or "cryptogenic organizing pneumonitis"); idiopathic pulmonary fibrosis; lymphoid interstitial pneumonitis (lip); nonspecific interstitial pneumonia (nsip) (or "cellular interstitial pneumonia" [eip]); usual interstitial pneumonia (uip); fibrosing alveolitis; pulmonary alveolitis; and many others. note: the conditions listed under "related terms" are histologic variants of idiopathic interstitial pneumonia. vip is synonymous with idiopathic pulmonary fibrosis (ipf) ( ). diffuse alveolar damage is the histologic finding in patients with the adult respiratory distress syndrome* (ards) causing interstitial and intra-alveolar fibrosis. this is an acute condition, referred to as acute interstitial pneumonia when it occurs as an idiopathic form of rapidly progressive interstitial pneumonia. possible associated conditions: acquired immunodeficiency syndrome* (aids) in patients with with lip or nonspecific interstitial pneumonia ( , ); trauma and shock in ards. secondary pulmonary fibrosis from inhalants (extrinsic allergic alveolitis or pneumonia; pneumoconiosis*), in drug-induced pneumonia, hypersensitivity pneumonitis (microgranulomatous hypersensitivity reaction of lung), rheumatoid arthritis,* sjogren's syndrome,* and other collagen-vascular diseases; primary biliary cirrhosis in patients with nonspecific interstitial pneumonia ( ). external examination postmortem chest roentgenograms provide the only reliable and permanent record of a pneumothorax and its main complication, mediastinal shift due to a tension pneumothorax (fig. - ) . if roentgenograms cannot be prepared, a reasonably reliable diagnosis still can be made if the prosector inserts a needle through the lateral chest wall. the needle should be connected to a water-filled flask. ifa pneumothorax is present, gas bubbles appear in the flask as shown in fig. - . one can also expose the intact parietal pleura and observe if the lung tissue is separated from the parietal pleura by gas. incising the thorax at the base of a water-filled skin pocket is the least reliable method. infants can be totally submerged under water before the chest cavity is incised. however, care must be taken not to make an accidental incision into the underlying lung tissue. poisoning, all types or type unspecified note: if a specific substance is suspected-for instance, arsenic or ethylene glycol-follow procedures described under the appropriate entry. similar entries can be found for poisons whose general character or source is known-for instance, gas or mushroom poisoning. for some substances, the appropriate entry can be found under "abuse,...," "death,...," or "dependence, ..." in all instances, routine sampling of toxicologic material should be done as described in chapter . if no specific substances can be incriminated, the toxicologist must be provided with all available clinical information, as shown in chapter . in most cases of fatal poisoning, the coroner or medical examiner must be notified. poisoning, alkaloid note: see under specific name of alkaloid-for instance, "dependence, cocaine," "poisoning, atropine," "poisoning, digitalis," or "poisoning, strychnine." only a fraction of this large group of plant poisons has been listed. whether the specific name of the alkaloid is known or unknown, complete toxicologic sampling is recommended. poisoning, antimony ote: toxicologic material should be submitted for anal ysis, as suggested under "poisoning, arsenic." iatrogenic antimony toxicity may occur after treatment with antimony compounds for conditions such as filariasis, fungal infections, and schistosomiasis.* external examination and eyes pharynx and gastrointestinal tract heart, liver, and kidneys record skin changes and eye abnormalities. for toxicologic sampling of contents, see chapter . submit tissue samples for histologic study. request frozen sections for sudan stain. if exposure was from du t in smelting work, dermatitis and conjunctivitis may be present. severe gastroenteritis in acute poisoning. if victim drank antimony trichloride, ulcerative pharyngitis and gastritis may be present. fatty changes of myocardium and hepatic and renal parenchyma. poisoning, arsenic note: toxicologic material will be contaminated by bringing it in contact with fluids. keratinized tissues take up arsenic from solutions. put plastic bags over hands of victim. if exhumed bodies are investigated for arsenic poisoning, include material from surrounding soil and coffin along with tissues submitted for chemical analysis. interpretation of toxicologic findings: after fatal poisoning, arsenic concentrations in the liver tend to exceed . - . mg/ioo g wet tissue. in acute poisoning, arsenic concentrations in hair may reach ! g/g ( ) and in nails ! g/g. organs collect all contents, particularly in accidental poisoning in children. body dry and warm after death. mydriasis. iatrogenic atrioventricular block ( ) . fruits of atropa belladonna or seeds of datura stramonium may be found. no characteristic findings. poisoning, barbiturate(s) note: this type of poisoning has become uncommon. barbiturates may cause sudden death. in all instances, concomitant alcohol intoxication* must be ruled out. standard toxicologic sampling is sufficient. blood bile urine esophagus and stomach liver and brain procedures submit samples of blood from portal vein and peripheral veins or heart for toxicologic study. refrigerate for possible toxicologic study. record total volume and ph value. request tests for protein, glucose, and ketones; request drug screen. submit all contents and record their character. analyze for barbiturates and alcohol. submit samples for toxicologic study. evidence of alcohol intoxication.* poisoning by other addictive drugs. gritty residues of unabsorbed tablets, powder, or capsules. mucosal corrosion, ulceration, and discoloration from capsules may occur. concentration of barbiturate in parenchyma important for interpretation. poisoning, bismuth note: accidental poisoning is common (industrial exposure or drugs with soluble bismuth compounds). search also for other heavy metals. acute kidney failure* may be the cause of death. external examination and oral cavity stomatitis with bluish black discoloration of gums; loose teeth; sticky white membranous patches in mouth and throat. jaundice. protein casts and tubular epithelial cells in sediment. gray or black mucosal membranes; swelling of mucosa; intestinal ulcers that may be perforated. hemosiderosis. fatty changes; hemosiderosis. fatty changes; renal tubular degeneration with amorphic basophilic deposits in epithelium of convoluted tubules. hemosiderosis. see above under "external examination." for removal and specimen preparation, see chapter . peripheral neuritis. synonyms: bromine poisoning; bromism. note: the lethal dose is about . g in children and i g in adults (ingested). after fatal methyl bromide poisoning, headspace gas chromatography revealed a subclavian blood concentration of . microgram/ml whereas inorganic bromide concentrations were micrograms/ml in the blood ( ). tissue concentrations were lower than those in the blood. toxicologic samples should include liver and kidneys. chemical bums on face and conjunctivitis indicate direct exposure; skin pustules over body and nodose bromoderma of the legs indicate bromism. blood is best suited for bromide determination. after ingestion of bromide, necrosis with brown discoloration of mucosa of upper gastrointestinal tract may be present. after inhalation of bromide, swelling and inflammation ofmucous membranes in upper and lower respiratory tracts may be present. there may be pulmonary edema. pneumonia occurs in bromism. organs to be analyzed for cd should have no contact with water or be contaminated with blood; they should be sealed in polyethylene bags. cd leaks into fixation fluid. postmortem blood concentrations are very high and no indicator of the antemortem values ( ). external examination and oral cavity blood urine gastrointestinal tract other organs procedures submit sample for toxicologic study. submit sample for determination of cadmium concentration. submit sample for toxicologic study and a portion of one lobe for microbiologic study. perfuse one lung with formalin. fix bowel as soon as possible. collect renal tissue for light microscopic and electron microscopic study. sample for toxicologic study. submit samples for histologic study also. poisoning, carbon monoxide note: if the victim had been in a fire, see also under "bums." carbon monoxide poisoning may rarely be responsible for automobile accidents. relatively low carboxyhemoglobin concentrations may contribute to death if there is concomitant poisoning-forinstance, with alcohol or drugs, particularly sedatives. anemia, atherosclerotic heart disease, and chronic pulmonary disease also increase sensitivity to carbon monoxide. ifblood had been withdrawn at time of hospital admissionfor instance, for crossmatching-submit this for carboxyhemoglobin determination. if no blood can be obtained, see under "heart, kidneys, and other organs." for quick-orienting qualitative tests, for quantitative methods of carbon monoxide determi-nation, and for interpretation of toxicologic findings, see below. request also determination of hemoglobin concentrations and of blood alcohol. request drug screen. for shipping of blood and tissues for carbon monoxide determination, see chapter . it should be noted that losses of up to % of the original saturation occurred when blood was kept in uncapped container at room temperature for yz wk or at °c for wk. external examination blood heart, kidneys, and other organs brain record color of fingernails, particularly in heavily pigmented persons in whom lividity is difficult to discern. record appearance of blood and submit sample of postmortem blood for toxicologic study. see also above under "note." if no blood can be obtained, prepare water extract of spleen, kidneys, or other organs. request determination of carbon monoxide content and of carbon monoxide-binding capacity of this mixture. submit tissue samples for histologic study. for removal and specimen preparation, see chapter . pink skin and fingernails; bullous edema of skin; decubital ulcers. blood tends to be cherry red. for interpretation of toxicologic findings, see below. necrosis of papillary muscles in the heart or myocardial infarction may occur. renal tubular degeneration may also be found. acute kidney failure* has been observed after rhabdomyolysis complicated by compartment syndrome ( ) . hemorrhagic necrosis of basal ganglia (lenticular nucleus in globus pallidus); diffuse petechial hemorrhages in white matter; cerebral edema. acute hydrocephalus in infants ( ) . many methods of carbon monoxide determination have been described. currently, carboxyhemoglobin is detected in most medical examiner toxicology laboratories by visible spectrophotometry or gas chromatography. in hospitals, carboxyhemoglobin is frequently detected and reported in the course of routine arterial blood gas analysis. pink discoloration of skin and organs usually indicates the presence of more than % carboxyhemoglobin (but rule out cyanide poisoning* and exposure to cold*). in a healthy, middle-aged person, a carboxyhemoglobin concentration greater than - % is usually fatal. if the victim was anemic or suffered from chronic lung disease, particularly emphysema* or atherosclerotic heart disease, the concentration may be lower. in association with alcohol, sedatives, and other drugs, carboxyhemoglobin levels may also be much lower and yet fatal. a heavy cigarette smoker may have a carboxyhemoglobin concentration of - %, and higher levels may occur in police officers and other persons exposed to automobile exhaust in dense traffic. if the victim survived the carbon monoxide poisoning for several hours, postmortem blood samples usually will fail to show the presence of carboxyhemoglobin. in these instances, blood taken at the time of admission to the hospital may still be available and of particular value. if the victim had spent h in fresh air before death, - % of the carbon monoxide will have been removed, and - % will have been removed during each subsequent hour. even though clearance may be complete, death may still occur-primarily from brain damage and infectious complications in prolonged coma. or delayed by only a few hours, particularly after inhalation of carbon tetrachloride. sudden death probably is caused by cardiac dysrrhythmia. alcohol concentrations should be determined in all cases or, if death was delayed, evidence of drinking at the time of exposure should be sought. alcohol considerably increases the hazards of carbon tetrachloride. note: see also under "bronchitis, acute chemical" and under "poisoning, gas." hydrochloric acid is sold by plumbing supply houses and pool supply companies as muriatic acid. it is a liquid. chlorine is a water-soluble gas. as supplied for pool sanitation, liquid chlorine is usually acidic. for convenience, chlorine and hydrochloric acid are discussed here together. prepare photographs of face. conjunctivitis and cyanosis in chlorine gas poisoning; burns of lips from hydrochloric acid. see also above under "larynx and trachea." photograph opened esophagus and stomach. sample for histologic study, particularly if there is doubt whether a perforation was antemortem or postmortem. for removal and specimen preparation, see chapter . severe pulmonary edema, bronchopneumonia, and swelling of mucous membranes in chlorine poisoning. arterial thrombosis may occur. pulmonary fibrosis may develop after prolonged survival. swelling and ulceration of mucous membranes in chlorine poisoning; acute laryngotracheitis. tracheoesophageal perforation. corrosion of mucosa with thickening, hemorrhage, and blackish discoloration after ingestion of hydrochloric acid. antemortem and postmortem perforation may occur. glomerular capillary thromboses. hemorrhages in white matter ( ). poisoning, cyanide synonym: hydrocyanic acid (hydrogen cyanide) poisoning. note: hydrocyanic acid (hydrogen cyanide, hcn) is a water-soluble gas. its salts, sodium cyanide and potassium cyanide are sold as "eggs" to the jewelry industry. hydrocyanic acid is formed when cyanide salts are dissolved in acidic solutions. containers from which the poison might have been ingested or inhaled should also be submitted for toxicologic examination. for cyanide screening tests in the autopsy room and for interpretation offindings, see below. caution: stomach may still contain cyanide gas, formed by acidic reaction of cyanide salt. it may be best to open the stomach under a hood ( ). the odor is quite characteristic for cyanide poisoning but most persons are unable to smell this odor. it is helpful to know in advance if any person in an office or laboratory can smell cyanide. forensic pathologists who can smell the compound state that it has its own specific odor, which differs from the often quoted smell of bitter almonds. autopsies also can be done in a negatively pressured isolation room ( ). for odor, see above under "note." bright red skin color is not always present. corrosion around mouth and in oral cavity may be found after ingestion of potassium or sodium cyanide. blood is fluid and sometimes bright red. if potassium or sodium cyanide was ingested, brown-red mucosal corrosion may be present in stomach or in upper digestive tract. pulmonary edema. for odor, see above under "note." if death was not instantaneous, there may be hyaline thrombi in small blood vessels, minute hemorrhages, and necroses of lenticular nuclei. this test can be used for blood and gastric contents ( ) . dip squares of filter paper in a small amount ofsaturated picric acid. let these squares dry until barely moist. place a drop ofthe material to be tested-e.g., blood or gastric contents--on a piece of paper. let material dry for a moment, and then place one drop of % sodium carbonate in the center of the material to be tested. ifcyanide is present, a reddish purple color will chromatograph out from the material. the higher the concentration of cyanide the more blue the color will be. it is possible to recognize whole blood because the blood turns a rather dark brown and the reddish to purple color is clearly visible. high concentrations of sulfide interfere by giving a false-positive test. another screening test is done as follows ( ) . dip filter paper into normal blood. then treat the paper with potassium chlorate, whereupon brown methemoglobin forms. place this preparation into the fluid suspected of containing cyanide (e.g., blood, gastric contents, pulmonary edema fluid). if bright red cyanmethemoglobin forms, the reaction is positive. if the concentration of cyanide in the stomach is high and the concentration in the lungs is low, cyanide was ingested. alternatively, if the pulmonary cyanide concentration is high and the concentrtaion in the gastric contents is low, hydrogen cyanide most likely was inhaled. occasionally, minimal cyanide levels will be present in decomposed bodies. related term: digoxin toxicity. note: certain drugs may interfere with correct digitalis determination. blood heart vitreous procedures submit sample of peripheral blood for digoxin radioimmunoassay. freeze fresh myocardium for digitalis extraction. submit sample for digoxin radioimmunoassay. poisoning, drug(s) (see "dependence, drug(s), all types or type unspecified" or under "poisoning,•••" followed by specific name of drug.) poisoning, ethanol (ethyl alcohol) (see "alcoholism and alcohol intoxication," "cardiomyopathy, alcoholic," "disease, alcoholic liver," "syndrome, fetal alcoholic," and syndrome, wernicke-korsakorr.") poisoning, ethylene glycol related term: antifreeze poisoning. note: pulmonary and cerebral manifestations are the main findings in acute poisoning, and renal tubular necrosis is the primary finding in chronic poisoning. for general toxicologic sampling, see chapter . calcium oxalate crystals can be demonstrated in routine histologic sections but also in scanning electron micrographs of thick deparaffinized sections. eyes blood urine for removal and specimen preparation, see chapter . in acute cases, submit sample for ethylene glycol determination; in chronic cases, request determination of calcium concentrations. prepare sediment. papilledema; optic nerve atrophy. ethylene glycol in serum (i) . protein casts; calcium oxalate crystals ( ) . crystals are light yellow and birefringent, arranged as sheaves, rhomboids, or prisms. poisoning, food related terms: bacillary dysentery* (shigella food poisoning); botulism;* clostridium perfringens food poisoning; favism; mushroom poisoning;* salmonella food poisoning; staphylococcal food poisoning. note: if cause of food poisoning is unknown, submit suspected food for aerobic and anaerobic cultures, gram stain of smears, and routine toxicologic study. this should include tests for heavy metals (antimony, cadmium, and lead) that may have leaked from old cooking utensils. test for the presence of staphylococcal enterotoxin are done only in specialized laboratories. if botulism is suspected, follow procedures described under that heading. mushroom poisoning also is listed as a separate entity. if salmonella food poisoning is suspected, see under "fever, typhoid." see also under "enteritis" or "enterocolitis" or under another specific heading such as "dysentery, bacillary." obtain sufficient material for microbiologic and histologic study to identify organisms such as chlamydia, clostridium (type f strains), salmonella, shigella, verotoxic e. coli, yersinia, and others. external examination gastrointestinal tract submit contents for aerobic and anaerobic cultures (see above under "note"); prepare smears of contents for gram stain. submit samples for histologic study. debilitated states; patients in extremes of life. enteritis or enterocolitis. poisoning, gas note: anesthesia-associated death, * carbon monoxide poisoning,* and sniffing and spray death* are presented under the appropriate headings. procedures discussed here deal with other volatile substances, including chemical irritants such as ammonia (nh ), chlorine or hydrochloric acid poisoning (see also under that heading); methylene chloride, phosgene (coci ), sulfurous acid (h s ), or sulfur dioxide (s ) ' gases from body cavities, heart chambers, or blood vessels can be removed as described under "embolism, air." gases can also be trapped with a rubber dam after cutting organs under water. samples from various organs should be shipped in hermetically sealed nonplastic containers or in analyzing solutions. external examination, and oral cavity blood larynx and trachea record extent of chemical bums. submit sample for gas analysis. in many instances, inhaled gases can be demonstrated chromatographically in gas from head space above sealed blood specimen. chemical bums in and around mouth or conjunctivas. chemical bums. other organs if gas was inhaled and is to be analyzed, submit intact lungs with bronchi ligated in airtight, nonplastic container to laboratory that can conduct gas analysis. if survival was short, formalin perfusion of lungs is not recommended; it may cause artifactual ballooning and internal ruptures of organ. submit samples of tissue for routine histologic study. see above under "note." chemical pneumonia; pulmonary edema. after longer survival, obliterating fibrous bronchiolitis, chronic bronchitis, and saccular bronchiectasis* may occur. poisoning, glycol (see "poisoning, ethylene glycol.") poisoning, halogen (see "fluorosis," "poisoning, bromide," "poisoning, chlorine or hydrochloric acid," "poisoning, gas?, and "poisoning, iodine!') poisoning, heavy metal (see "poisoning, antimony," "poisoning, arsenic," "poisoning, cadmium," "poisoning, lead," poisoning, mercury," "poisoning, thallium!') poisoning, insecticide (see "poisoning, organophosphate(s)*) poisoning, iodine related terms: lugol's solution; tincture of iodine. for toxicologic sampling, see chapter . external examination and eyes urine, blood, and parenchymal organs lungs and upper respiratory tract stomach record color of skin and extent of corrosive lesions. submit samples for toxicologic study. submit samples for histologic study. submit contents for toxicologic study; photograph mucosa; prepare histologic sections. see above under "stomach." perioral corrosive lesions; yellow discoloration of skin; conjunctivitis after exposure to vapors. acute inflammation of respiratory tract after inhalation of vapors. corrosive gastritis; if starch was used as antidote, gastric lining will be bluish. histologically, well-preserved mucosa is present because of in vivo fixation. mucosa may show same changes as stomach. swelling of tubular epithelium. synonyms: propanol; rubbing alcohol. procedures see under "alcoholism and alcohol intoxication." nonspecific autopsy findings: visceral congestion; pulmonary and cerebral edema. poisoning, lead note: lead-free syringes and lead-free polyethylene containers should be used. blood lead concentrations can be determined by inductively coupled plasma mass spectrometry ( ). for screening methods, see ref. ( ) . this is a reportable disease in some states. external examination, oral cavity, and hair bluish lead line at gingival margin in victims with poor oral hygiene. external examination, oral cavity, and hair for diagnosis of chronic plumbism, analysis of scalp hair may be useful. analysis is done by neutron activation (see also under "poisoning, arsenic"). remove samples with lead-free syringe (see above under "note") or -ml vacutainer tubes (becton, dickinson and company). do not add anti-coagulant or preservative. for coliection procedures, see above under "blood" and under "note." request also determination of coproporphyrin concentrations. submit sample for histologic study; submit remaining tissue for toxicologic analysis. submit with contents for toxicologic study, particularly in acute poisoning. submit sample from each kidney for histologic study; submit remaining tissue of both kidneys separately for toxicologic study. submit at least g of fresh bone for toxicologic study. for removal and specimen preparation, see chapter . poisoning, lsd (d-lysergic acid diethylamide) (see "abuse, hallucinogen(s).") poisoning, lye related terms: ammonium hydroxide poisoning; calcium oxide or quicklime poisoning; poisoning by alkaline corrosives; potassium hydroxide poisoning; sodium hydroxide poisoning. external examination and oral cavity blood neck organs, esophagus, trachea, and lungs record extent of oral, perioral, and other facial corrosive injuries. photograph lesions. prepare histologic sections of tissue from inside of lips or mouth. submit sample for toxicologic study. after removal of heart, remove neck organs with hypopharynx, esophagus, larynx, and trachea. leave stomach attached to esophagus. open pharynx and esophagus along posterior midline. in acute cases, formalin perfusion of lungs is not recommended; it may cause artifactual baliooning and internal ruptures of organ. lye bums on face and chest in acute cases; scars and manifestations of malnutrition* in chronic cases. sweliing, edema, and necrosis of mucous membranes in acute poisoning. fibrosis and strictures in chronic cases. bronchitis* and bronchopneumonia. submit specimen from pharynx for histologic study. for removal and specimen preparation, see chapter . submit sample of brain for toxicologic study. exfoliative dermatitis. blue line at gingival margin; hypertrophy of gum; acute and chronic gingivitis; exfoliation and loss of teeth ( ) . degeneration of myocardium. increased concentrations of mercury ( ) . congestion. erosive gastritis and colitis. increased concentrations of mercury ( ) . degeneration of proximal tubules; calcifications. chronic kidney failure* may be the cause of death. induration of mucosa. increased concentrations of mercury ( ) . cortical hemorrhages. cholinesterase activity will be low. pulmonary edema if poison was inhaled. airways may contain aspirated material. cholinesterase activity can be determined reliably even after decomposition and embalming. clinically, guillain-barre syndrome has been observed after poisoning with organophosphate. in acute poisoning, the cholinesterase levels may be % of the normal values (see below). the cholinesterase levels in the blood are not affected by the duration of the postmortem interval; measurement may be attempted even on decomposed or exhumed bodies. severe fatty changes; periportal necroses. fatty changes in myocardium, skeletal muscles, and other organs. for toxicologic sampling (gastric contents, urine, blood, brain, and other organs), see chapter . rigor mortis after fatal strychnine poisoning may occur very soon after death and may be very severe (opisthotonos); it may persist until decomposition sets in. congestion of viscera; no characteristic morphologic autopsy findings. acute pancreatitis has been observed ( ). high strychnine concentrations (also demonstrable in exhumed bodies [ ] ). poisoning, thallium note: for toxicologic sampling, see below and chapter . thallium is used as a rodenticide and pesticide, and has some industrial applications. retrobulbar neuritis. chapter and . submit brain for toxicologic study. submit sections of brain and optic nerves for histologic study. submit specimens for toxicologic study (take from lower extremity). for removal, prosthetic repair, and specimen osteomalacia;* osteomyelofibrosis. preparation of bones, see chapter . for preparation of sections and smears of bone marrow, see chapter . submit samples for toxicologic study. synonym: acute anterior poliomyelitis. note: the disease has been nearly eliminated in the usa but not in many other countries. ( ) collect all tissues that appear to be infected. ( for removal and specimen preparation, see chapter . in acute cases, submit portions of brain and spinal cord for viral culture. neurogenic atrophy of skeletal muscles in areas of paralysis. electrolyte disorder. * hypertensive heart disease; myocarditis.* aspiration or bronchopneumonia (or both); edema; atelectasis; embolism;* alveolar wall necrosis (acute or organizing diffuse alveolar damage) after oxygen toxicity. acute ulcers. acute gastric dilatation; acute gastroduodenal ulcers; gastrointestinal erosions and hemorrhages. dilatation of colon; perforation of cecum. urolithiasis and nephrolithiasis,* pyonephrosis and pyelonephritis. * phlebothrombosis of legs, most commonly on left side. necrosis of anterior hom cells of spinal cord, with neuronophagia and perivascular inflammatory reaction. old lesions show neuronal loss and gliosis. medulla ("bulbar polio") and other areas of brain stem, cerebellum, and cerebrum, particularly the motor cortex, may be affected in various degrees. part ii / diseases and conditions pregnancy note: in some instances, procedures described under "death, abortion-associated," "embolism, amniotic fluid," or "toxemia of pregnancy" may be indicated. synonym: werner syndrome. external examination and skin abdomen procedures record volume of intraperitoneal fluid; prepare smears; submit samples of peritoneum for histologic study. colloid carcinoma of stomach or colon. well-differentated adenocarcinoma of ovary or, rarely, of appendix; ruptured appendiceal mucinous adenoma is the most common cause of peritoneal adenomucinosis. pseudotumor cerebri synonym: benign intracranial hypertension; meningeal hydrops. note: this condition, which generally affects young, obese females, is characterized by symptoms and signs of increased intracranial pressure without a demonstrable cause. hence, intra-cranial mass lesions, infections, and related conditions should be excluded. such conditions include adrenal insufficiency;* guillain-barre syndrome* (increased colloid-osmotic pressure); hyperadrenalism; hypervitaminosis a* (e.g., after treatment of acne); hypoparathyroidism;* hypothroidism;* infectious mono-nucleosis;* lyme disease; pregnancy; sydenham's chorea; throm-bus ofthe lateral or superior sagittal sinus (otitic hydrocephalus); and wiskott-aldrich syndrome. submit samples of all accessible organs and tissues, with or without gross lesions. submit material for electron microscopy. for removal and specimen preparation, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . heart small bowel liver procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. fix the bowel as soon as possible. record weight. submit samples for histologic study. for removal, prosthetic repair, and specimen preparation, see chapter . aortitis involving ascending aorta and aortic valve with regurgitation; mitral valve and adjacent myocardium and conduction system also may be involved. sprue-like changes with loss of villi. fibrosis or cirrhosis and other abnormalities, particularly in patients who had been taking methotrexate. psoriatic arthritis and spondylitis. synonyms and related terms: allergic purpura; anaphylactoid purpura; hypersensitivity vasculitis. external examination and skin rabies note: (i) in most instances, an autopsy limited to the brain is sufficient to confirm the diagnosis. ( ) rabies virus is especially infectious and thus, universal precautions should be strictly followed (see chapter ) . avoid the use of scalpels whenever possible. the generation ofaerosols should be assidu- see above under "note." if a complete autopsy is done, sample heart, lungs, kidneys, pancreas, submaxillary salivary glands, and adrenal glands; freeze or refrigerate sampled tissues and submit for viral study (see below under "brain and spinal cord"). obtain serum for serologic studies. freeze or refrigerate cerebral tissue immediately after removal and submit frozen to special laboratory for fluorescent antibody staining. take these sections from hippocampus or brain stem. place the refrigerated tissues in % neutral glycerol saline solution for preservation. fix remaining brain and spinal cord tissue in % formalin and submit for histologic study. as an alternative to freezing of tissue, immunoperoxidase methods for detection of rabies viral antigens can now be applied to formalin-fixed tissue ( in almost all instances, the procedures described under "assault" and under "homicide" must also be followed. see also refs. ( ) and ( ) . for the evaluation of bite marks, photographs with and without scales and black and white film should be used. a forensic dentist is required to compare the victim's bite marks to the teeth of suspects. swabs of possible sperm or other fluids must be sent to the crime lab for proper evaluation. external examination other organs and tissues genital organs comb pubic hair over a towel and then pull sample; also, pull samples of hair from head. collect fingernail clippings and place in containers marked "right" and "left." collect blood, hair, fibers, and residues of urine or saliva and/or semen that may have stained the victim's clothing or that may be found on the skin of the victim. for study of stains and scrapings, see below. introduce sterile dry cotton swab into the posterior vault of the vagina or-preferablyinto the cervical canal. prepare smear on glass slide and send to crime laboratory for identification of sperm (see also above under "note" using a sterile cotton swab moistened with sterile saline, lift suspected dried spermatic fluid from hair or skin of external genitalia, perineum, buttocks, or other sites. stains on clothing will be extracted by forensic laboratory personnel. let specimens air dry in absence of sunlight and then place in paper bags or envelopes and seal. smears are made for the demonstration of spermatozoa, cytologic changes, bacteria, and other possible findings (some crime labs prefer to make their own smears from the swabs). other samples are used for the determination of acid phosphatase, as described below. usually, the survival time of morphologically recognizable spermatozoa in the vagina is less than h, but on occasion this may be much longer. thus, within the first h after coitus, % of cervical smears have been found to be positive for spermatozoa. at day , spermatozoa have been found in % of the smears. obviously, if the assailant had had a vasectomy, spermatozoa will not be found at any time. spermatozoa have been found in the vagina of some women several days or weeks after death. dried stains (see above) may give positive results after longer intervals. acid phosphatase activities greater than bodansky units (for method, see above) indicate that probably less than h have elapsed since the time of intercourse (i) . in another study, vaginal swab specimens showed acid phosphatase activities of more than , king if there is evidence of parotid involvement, other salivary glands should also be studied. parotid gland can be biopsied from scalp incision. submaxillary gland can be removed with floor of mouth. for sampling and specimen preparation, see chapter . for removal, prosthetic repair, and specimen preparation, see chapter . chronic meningitis; space-occupying lesions (submeningeal nodular granulomas). granulomatosis. iridocyclitis; chorioretinitis; papilledema; posterior uveitis; keratoconjunctivitis sicca; conjunctival follicles; cataracts. involvement of lacrimal glands and other orbital tissues ( ) . sarcoidosis of parotid gland is common. sarcoid neuropathy and sarcoid myopathy. cystic changes, primarily of small bones of hands and feet. sarcoidosis of joints ( ). synonyms and related terms: bilharziasis; schistosoma haematobium infection; schistosoma japonicum infection; schis-tosoma mansoni infection. note: unless specifically stated, the changes listed below refer to chronic schistosomiasis mansoni and japonica. ( ) collect all tissues that appear to be infected. ( ) request direct examination for schistosoma. the following procedures have been described and recommended ( ). for demonstration of schistosoma eggs, compress -mm tissue fragments-for instance, mucosa of the urinary bladder-between glass slides. if this gives negative results, digest a -g portion of tissue in potassium hydroxide. for the recovery of adult worms of schistosoma mansoni and schistosoma haematobium, remove the viscera en bloc and rinse with water. separate the intestines from the mesentery. subsequently, perfuse the portal vein system, the liver, and one lung with saline ( ) . then pass the perfusion fluid through a monofilament nylon cloth with an aperture size of m. submerge the cloth in water and examine with a dissecting microscope. fix worms in formalin solution. examine the intestinal mucosa directly. from the urinary bladder, ureters, and surrounding connective tissue, worms can be recovered as follows. inject water into the tissue until the tissue increases or times in thickness. then compress the tissue gently with a glass plate. cut slices . - . cm in thickness. compress these slices between the glass plate and the stage of a dissecting microscope and examine for the presence ofadult worms. many worms also will be present in the fluid expressed from the tissue as it is cut. for the counting of eggs in tissues, urine, and feces, see ref. ( ) . immunodiagnostic methods (elisa and imrnunoblot) also have been developed prepare skeletal roentgenograms. there are no diagnostic laboratory tests but it still is advisable to save a blood sample. record heart weight. test competence of valves (chapter ). open heart in line of blood flow. photograph and measure valvular lesions. prepare sections of valves, myocardium, conduction system (if there was a history of heart block), and ascending aorta. perfuse at least one lung with formalin. submit any consolidated area for microbiologic study. fix intestines as soon as possible. abnormalities as listed in right-hand column. sample for histologic study and request amyloid stains or renal parenchyma. prepare roentgenograms of spine, sacroiliac joints, symphysis ossium pubis, and manubriosternal, sternoclavicular, and humeroscapular joints. if spine cannot be removed in its entirety, it can be split in midline and one half can be removed, with costovertebral and costotransversal joints. hip joints should be exposed. histologic sections should include synovia and periarticular tissue. secondary and peripheral osteoarthritis* may be present. leukemia* developed in some patients who had had radiation treatment ( or earlier). acute anterior uveitis. ( ) request fungal culture. ( ) request grocott's methenamine silver stain. ( ) record weight of all organs (for expected weights, see part iii). submit samples of all major organs, including endocrine glands, lymphatic and fat tissue, bone, and bone marrow for histologic study. hunger edema; skin changes secondary to vitamin deficiencies. hypoproteinemia. atrophy; hemosiderosis of spleen. degree of atrophy varies from organ to organ; atrophy of fat tissue, lymphoid tissue, and gonads usually is most pronounced. severe infections, such as tuberculosis,* may be present without having been apparent clinically. steatohepatitis, nonalcoholic (nash) note: the morphologic findings in the liver are indistinguishable from those in alcoholic liver disease* ( ). follow autopsy procedures described under "disease, alcoholic liver." if the patient had received a liver transplant, procedures described under "transplantation, liver" should be followed also. possible associated conditions: celiac sprue (rare); diabetes mellitus* (type ); hyperlipidemia; malnutrition* from bulemia (rare); morbid obesity with liver failure particularly after episodes of rapid weight loss (e.g., after recent gastroplasty); lipodystrophy; mild obesity;* short bowel syndrome (rare); total parenteral nutrition. * stenosis, congenital valvular pulmonary related terms: isolated (pure, simple, or dome-shaped) pulmonary stenosis. note: the pulmonary valve is usually acommissural in isolated congenital pulmonary stenosis. with other coexistant congenital heart disease (such as tetralogy), the pulmonary valve is usually bicuspid and hypoplastic, but may be unicommissural or dys-plastic and tricuspid. heart and great vessels; peripheral pulmonary arteries brain procedures culture any grossly infected valve. for general dissection techniques, see chapter . record weight of heart, thickness of ventricles, and annular circumferences. for removal and specimen preparation, see chapter . infective endocarditis* of pulmonary valve and tricuspid valve; infective endarteritis at bifurcation of pulmonary trunk. it is preferable to have autopsies of fetuses and stillborns performed by pathologists experienced in perinatal pathology. if such personnel are not immediately available, the attending pathologist may nevertheless collect important information. if attempts to induce abortion appear to have caused the death of the mother, see "death, abortion-associated." the placenta should be immediately procured from the delivery room should it not arrive in the laboratory with the fetus. this will avoid the possibility of the placenta being discarded by the delivery room staff. no fetal autopsy is complete without a careful examination of the placenta (see part i, chapter ). pathologic changes of placenta that are causative of stillbirth are summarized in ref. . fascia lata or other aseptically obtained tissue should be collected for tissue culture for karyotype analysis. if the fetus is at all autolyzed, then the fascia lata cells may not grow in tissue culture. therefore, if the fetus shows any evidence of autolysis, tissue should be taken aseptically, from placenta immediately beneath the chorionic plate. a portion ofplacenta and liver should also be snap-frozen for possible molecular analysis. the initial stage of the autopsy should include photography and radiography, taking anterior-posterior and lateral views. the photographs will record the degree of maceration, which can be roughly correlated with the duration of fetal demise before delivery [ ] external measurements should include body weight, circumference ofhead, chest and abdomen, crown-rump length, crown-heel length, and foot length. these measurements are compared with tables of standards for normal fetuses (see part iii of this book). assessment of growth retardation may be based on these data. a careful external examination should search for abnormalities such as jaundice, bulging fontanel, cranial bone softening, hyper-or hypotelorism, choanal atresia, external ear anomalies, cleft lip, cleft palate, macroglossia, micrognathia, colobomata, cystic hygroma, shortened neck, contractures, omphalocele, gastroschisis, abnormal external genitalia, anal atresia, absent vagina, sacral pits, open neural tube defects, hemihypertrophy, syndactyly, clinodactyly, transverse palmar creases, or incomplete descent of testes. the organ bloc may be removed in the manner similar to the adult, using the technique of letulle (see chapter ) . if the thyroid gland is noted to be in its usual location and if it appears normal, then the tongue may be left in the body. in macerated fetuses, it is suggested that the organ bloc be fixed overnight in formalin solution prior to dissection. to aid adequate fixation, the following simple steps may be done: i) wash the organ bloc thoroughly prior to fixation; ) place multiple transverse cuts through the liver and lungs; ) dissect the posterior leaves of the diaphragm away from the adrenal glands and kidneys; ) bivalve the adrenal glands and kidneys in the coronal plane; ) instill formalin in the lumen of the intestine, using a syringe; and ) gently instill formalin into both ventricles of the heart, being careful to avoid the ventricular septum. the procedure for dissection of the organs is similar to that of the adult except: ) the venous and arterial connections of the heart, including the patency of the ductus arteriosus must be determined before the heart is removed; ) the esophagus must be opened posteriorly prior to its complete removal so that esophageal atresia or tracheo-esophageal fistula may be recognized and photographed prior to further dissection; ) the location of the appendix and of the testes should be recorded. until the intestine has been examined for stenosis or atresia, the mesentery should be left attached. the degree of autolysis as seen grossly and with histologic examination of both the fetus and the placenta can be used to estimate the duration of time between fetal death and delivery ( , , ) . trichrome stain is useful for better visualizing histologic features in severely autolyzed tissue. to remove the brain, benecke's technique of one of its modifications may be used. stillbirth vs livebirth. a decision has to be made whether the infant was born alive or was stillborn. the hydrostatic lung test, described in the previous edition, appears unreliable. the presence of gas in the lungs does not rule out stillbirth. after death, air can be introduced into the lungs, or putrefaction gases might be present. however, air artificially introduced after death will not distend the alveoli and can be squeezed out, whereas this does not seem to be the case after active ventilation. the distribution of fat in the fetal zone of the adrenal cortex may indicate whether intrauterine death was acute, more prolonged, or chronic ( ). this is particularly helpful if the stillborn baby is macerated. if the mother died also, see under "death, abortion-associated" strangulation note: in many instances, procedures described under "hom-icide" must also be followed. if a rope or some other material had been used (see also under "hanging"), leave ligature in place until autopsy can be done. see also under "hypoxia." toxicologic sampling, particularly for alcohol, should be done in all instances (chapter ). results than body fluids. ( ) universal precautions should be strictly followed. the generation of aerosols should be minimized. to sterilize tissue surfaces in preparation for culture, swab the surface with povidone iodine. avoid searing the tissue surface since this will produce an aerosol. keep no more than one scalpel in the dissecting area at anyone time. have an assistant available with clean, gloved hands to receive specimens in containers, so as to minimize the degree of contamination on the outside of the containers. for cleaning procedures and related information, see chapter . ( ) hiv-l in tissue may be demonstrated using polymerase chain reaction (pcr), immunohistochemistry, in situ hybridization, or immunofluorescence. ( ) for immunocytochemical and molecular studies, fix tissue in ethanol or carnoy's solution. the virus can be identified using pcr in most tissues, whether fresh, frozen, or fixed in ethanol. ( ) serologic tests as well as direct fluorescent antibody tests are avail-able for many of the expected infections. ( ) this is not a reportable disease. external examination and skin record body weight and evidence of lipodystrophy following aids medications. record and photograph any skin lesions. examine oral cavity. if the diagnosis is in doubt, samples can be submitted for enzyme immunoassay. cachexia. severe loss of subcutaneous fat in face and extremities, associated with large fat deposits on upper back and upper abdomen ("protease paunch"). cutaneous kaposi's sarcoma (l) . test may be positive for many weeks after death ( ) . syndrome, myelodysplastic synonyms and related terms: chronic myelomonocytic leukemia;* refractory anemia; refractory anemia with excess of blasts; refractory anemia with excess of blasts in transformation; refractory anemia with ringed sideroblasts; refractory dysmyelopoietic anemias. note: the myelodysplastic syndromes are represented by a heterogeneous group of normocytic anemias, often with neutropenia, thrombocytopenia, and monocytosis. for expected bone marrow changes, see above under "synonyms and related terms." autopsy procedures are similar to those recommended for most cases of leukemia, with particular attention paid to intercurrent infections and thrombocytopenic hemorrhages. in all instances, material should be collected using aseptic technique for tissue culture for chromosome analysis. common findings in these conditions are deletion of the long arm ofchromosome , deletion of chromosome or , or trisomy . syndrome, nephrotic note: see under name of suspected underlying condition, such as amyloidosis,* anaphylactoid purpura,*diabetes mellitus,* glomerulonephritis,* goodpasture's syndrome,* heavy metal poisoning, hemolytic uremic syndrome,* infective endo-carditis,* polyarteritis nodosa,* syphilis, * or systemic lupus erythematosus. * if accelerated hypertension or constrictive pericarditis is the suspected underlying condition, see under "hypertension (arterial), all types or type unspecified" or "pericarditis," respectively. in all instances, the renal veins and the inferior vena cava should be opened in situ. "en masse" removal of organs is recommended for this purpose. if thrombosis is found, record exact location and size of clot and submit sample of clot with wall of veins for histologic study. see also under "thrombosis, venous." coronary atherosclerosis and its complications seem to be increased in patients with the nephrotic syndrome. submit sample for bacteriologic, viral, and serologic study. record weight and submit samples for histologic study. if heart block was present, submit samples of conduction system for histologic study (chapter ). submit consolidated areas for microbiologic study. perfuse at least one lung with formalin. for removal of urethra, see chapter . procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for removal and specimen preparation, see chapter . consult roentgenograms (see above under "external examination, skin, and oral cavity"). keratoderma (keratosis blennorrhagica) with vasculitis ( ) of sole of feet, of palms, and of circumcised glans penis. arthritis* of knees, ankles, and metatarsal and midtarsal joints, with or without ankylosis. osteoporosis.* usually, sterile culture. pericarditis; * myocarditis.* aortic valve lesions. pleuritis and pneumonia.* pulmonary fibrosis involving upper lobes. erosions, papules, and plaques in urethral or bladder mucosa. enteritis. thrombophlebitis. conjunctivitis; multifocal choroiditis; acute anterior uveitis; iritis; keratitis. arthritis* (see above under "external examination, skin, and oral cavity") resembling rheumatoid arthritis. * nonspecific synovitis. for removal and specimen preparation, see chapter . syndrome, reye's note: hypoglycemia* may have been present, but that condition is difficult or impossible to confirm after death. an immediate autopsy is indicated (see below under "liver" and "pancreas"). vitreous blood urine heart lungs submit sample for sodium, chloride, and urea nitrogen determination. submit sample for microbiologic (viral) and serologic study, for ammonia and bilirubin determination, and for determination of salicylate levels if there is a history of treatment with this drug. obtain sample for biochemical and toxicologic analysis. record weight. request frozen sections for sudan stain. submit fresh tissue for bacterial and viral culture. request paraffin sections and frozen sections for fat stain (see above under "heart"). influenza;* varicella.* manifestations of liver failure. evidence of salicylate administration. assay for organic acids should rule out acylcoenzyme a dehydrogenase deficiency, and toxicity, e.g., of acetaminophen and valproic acid (l) . cardiomegaly; fatty changes of myocardium and patchy myocytolysis. viral pneumonia rarely present. acute interstitial pneumonia;* bronchitis;* hemorrhages. lipid-laden histiocytes in alveoli. record body weight and length, stature, and distribution of head, axillary, and pubic hair. record and prepare photographs of features of face and neck. prepare skeletal roentgenograms. submit samples of breast tissues for histologic study. these specimens should be collected using aseptic technique for tissue culture for chromosome analysis (see chapter ) . procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. submit for histologic study. submit samples of all portions for histologic study. if biliary atresia is suspected, follow procedures described under that heading. dissect kidneys and ureters in situ and record findings. submit samples of gonads or-if gonads cannot be identified-equivalent ridges on mesosalpinx for histologic study. also submit samples of endometrium, cervix, and vagina. record weight and submit sample for histologic study. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for removal and specimen preparation, see chapter . procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for sampling and specimen preparation, see chapter . peroxidase-labeled gastrin antibodies seem to react with cells in all gastrinomas. aberrant gastrinoma may occur at hilus of spleen. metastases are found in regional lymph nodes and liver. there may be manifestations of multiple endocrine neoplasia. * secondary syphilis. levaditi's stain or warthin-starry stain is recommended for paraffin sections, and labeled fluorescent antibody techniques are recommended for frozen sections. india ink preparations or the fontana-masson silver stain has been used for the study of fresh lesions, and electron microscopy has also been employed. ( ) in adult autopsies, no special precautions are indicated (see below under "liver"). ( ) serologic studies are available from local and state health department laboratories. ( ) this is a reportable disease. external examination record and prepare photographs of all abnormalities listed in right-hand column. prepare smears and sections of acute lesions; prepare sections of older skin lesions or anogenital mucosal lesions. hunterian chancre in primary syphilis; condylomata lata. noduloulcerative gummas and scarring in later stages. cerebrospinal fluid lymph nodes heart and aorta other organs and tissues prior to wk gestation, the destructive effects of syphilis may not be seen. gummata are rare in neonates. tabes dorsalis is also uncommon. serologic diagnosis is difficult in the neonate because of transplacental transfer of maternal igg antibodies. acquired syphilis (syphilis in adulthood) is presented above under a separate heading. ( ) collect all tissues that appear to be infected. ( ) culture methods are not available, but animal inoculation can be performed. consultation with a microbiology laboratory is recommended. ( ) special stains for treponema pallidum rarely are positive except with material from fresh lesions of primary or secondary syphilis and of syphilitic hepatitis of the newborn. levaditi's stain or warthin-starry stain is recommended for paraffin sections, and labeled fluorescent antibody tech-niques are recommended for frozen sections. india ink preparations or the fontana-masson silver stain has been used for the study of fresh lesions, and electron microscopy has also been employed. ( ) in neonates, special precautions are indicated (see below under "liver") ( ) serologic studies are available from local and state health department laboratories. ( ) this is a report· able disease. (i) collect all tissues that appear infected. ( ) request aerobic and anaerobic cultures. however, the presence of tetanus bacilli established in culture is not diagnostic, since spores of c. tetani frequently contaminate wounds. record body weight and length and appearance of wound(s); photograph and excise wound(s) for histologic study. record evidence of parenteral drug abuse, especially subcutaneous injection (i.e., "skin popping"). prepare chest roentgenogram. evidence of weight loss; subcutaneous abscesses. tetanus may occur in drug addicts. tension pneumothorax* after mechanical ventilation. submit sample for microbiologic study. submit any consolidated area for microbiologic study. bacterial meningitis must be ruled out. aspiration and bronchopneumonia; embolism;* atelectasis. tetany note: see under name ofsuspected underlying conditions, such as hyperparathyroidism,* malabsorption syndrome,* or vitamin deficiency. * respiratory or metabolic alkalosis* cannot be confirmed after death; determination of blood ph is not helpful because acidity increases rapidly after death. the concentration of serum phosphates also increases after death. synonym: large ventricular septal defect with pulmonary stenosis* or atresia.* note: the basic anomaly consists of subpulmonary stenosis, ventricular septal defect, overriding aorta, and secondary right ventricular hypertrophy. for general dissection techniques, see chapter . surgical interventions include modified blalock-taus-sig subclavian-to-pulmonary arterial shunt; complete repair with patch closure of ventricular septal defect, and reconstruction of right ventricular outflow tract (with a patch or with an extracardial conduit). possible associated conditions: origin of left pulmonary artery from aorta; minor abnormalities of the tricuspid valve; absent ductal artery ( %); atrial septal defect* (in %; pentalogy of fallot); bicuspid pulmonary valve;* dextroposition of aorta; double aortic arch; hypoplastic pulmonary arteries; patent ductal artery;* patent oval foramen; complete atrioven-tricular septal defect* (usually with down's syndrome*); persis-tent left superior vena cava; pulmonary valve atresia (see "atresia, pulmonary valve, with ventricular septal defect"); right aortic arch ( %); second ventricular septal defect; origin ofleft anterior descending (lad) or right coronary artery (rca) from contralateral aortic sinus or coronary artery ( %); syndrome with absent pulmonary valve and massively dilated pulmonary arteries (rare). chest cavity heart lungs other organs record course of superior vena cava and of its tributaries. record course of thoracic aorta and of its main branches. record origin of pulmonary arteries. if infective endocarditis is suspected, follow procedures described under that heading (chapter ). for coronary arteriography, see chapter . perfuse both lungs with formalin. request verhoeff-van gieson stain. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. persistent left superior vena cava. right aortic arch with or without right-sided ductal artery; double aortic arch; absent ductal artery. origin of the left pulmonary artery from descending aorta. for possible additional findings, see above under "note" and under "possible associated conditions." infective endocarditis* (usually of pulmonary or aortic valve). see also above under "possible associated conditions." marked right ventricular hypertrophy. right ventricular dilatation and fibrosis with late postoperative right-sided heart failure or sudden death due to arrhythmia. old in situ thrombosis of small pulmonary artery branches. paradoxic embolism; cerebral abscess. * thalassemia synonyms and related terms: congenital hemolytic anemia; alpha-thalassemia; beta-thalassemia major (cooley's anemia); beta thalassemia minor (beta-thalassemia trait). note: the changes described below are observed primarily in beta-thalassemia major. unless the cause of the renal vein thrombosis and the nature of the complicating or underlying renal disease are known, follow procedures described under "glomerulonephritis." procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. in infants, manifestations of dehydration. * pulmonary embolism. * tumor of the kidney* (renal cell carcinoma); aortic aneurysm; lymphadenopathy; other mass lesions. inferior vena cava thrombosis involving orifice or whole length of renal veins. tumor thrombus (e.g., from renal cell carcinoma). femoral vein thrombosis. rare venous malformations also may cause renal vein thrombosis (l) . hemorrhagic infartion. parenchymal renal disease with nephrotic syndrome,* including amyloidosis* and vasculitis* (these last conditions may be associated with renal vein thrombosis). acute gastroenteritis in infancy. hyperparathyroidism,* pregnancy,* trauma, and other conditions. thrombosis, venous note: for peripheral venous thrombosis, the autopsy procedures are essentially similar to those described under "phlebitis." see also under "hypertension, portal," "syndrome, budd-chiari," "thrombosis, cerebral venous sinus," "thrombosis, lateral sinus," and "thrombosis, renal vein." thymoma (see "'fumor of the thymus.") thyroiditis synonymsand related terms: chronic fibrosing thyroiditis (riedel's struma); chronic thyroiditis with transient thyrotoxicosis; hashimoto's thyroiditis; pyogenic thyroiditis; subacute (granulomatous, giant cell, de quervain's) thyroiditis. possibleassociatedconditions: withhashimoto's thyroiditisautoimmune (chronic) hepatitis,*megaloblastic anemia,*rheumatoid arthritis,*sjogren's syndrome,*and systemic lupus erythematosus.* with riedel's struma-retroperitoneal fibrosis,* sclerosing cholangitis,* sclerosing mediastinitis,*and other conditions with idiopathic fibrosis. with subacute thyroiditis-viral infection. submit sample for determination of protein concentration; record appearance of sediment. for removal and specimen preparation, see chapter . thromboses of small vessels. glomerulonephritis.* hemorrhagic necroses. proteinuria; abnormal sediment. abruptio placentae, small placenta with accelerated maturation of villi; infarcts; fibrinoid necrosis of decidual arterioles. thrombotic occlusion of small vessels with hemorrhagic necroses; anterior lobe of pituitary gland may contain necroses (see also "syndrome, sheehan's"). submit samples for histologic study. if infection is expected, submit material for microbiologic study. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. transposition, complete, of the great arteries note: the basic anomaly is the origin of the aorta from the right ventricle, and of the pulmonary artery from the left ventricle, with a shunt, and usually with a right anterior aorta. there are four major types: ( ) with an intact ventricular septum ( %), ( ) with a ventricular septal defect* ( %), ( ) with a ventricular septal defect and subvalvular pulmonary stenosis* ( %), and ( ) with an intact ventricular septum and subvalvular pulmonary stenosis* ( %). for general dissection techniques, see chapter . interventions include atrial septostomy or septectomy; mustard or senning atrial switch procedure; rastelli-type repair with a valved extracardiac conduit; and jatene arterial switch procedure with lecompte maneuver. possible associated conditions: abnormal origin ofcoronary arteries ( %); atrial septal defect* ( %); coarctation of the aorta;* interrution of the aortic arch;* juxtaposition of atrial appendages ( %); overriding aorta ( %); overriding pulmonary artery ( %); patent ductal artery;* patent oval foramen; subvalvular pulmonary stenosis* ( %); tubular hypoplasia ofthe aortic arch;* ventricular septal defect* ( %), often mal-alignment type ( %). synonyms: atrioventricular and ventriculoarterial discordance; l-transposition. note: the basic anomaly is a mirror-image ventricular inversion, with a left anterior aorta, and with blood flow from right atrium to left ventricle to pulmonary artery, and from left atrium to right ventricle to aorta. for general dissection techniques, see chapter . interventions include patch closure of the ventricular septal defect; relief of pulmonary stenosis; relief of tricuspid insufficiency; and insertion of pacemakers. possible associated conditions: anterior and posterior av nodes ( %), prone to develop complete heart block; dysplasia or epstein's malformation* ofleft-sided tricuspid valve ( %); mirror-image epicardial coronary artery distribution ( %); right-sided mitral valve anomalies; subvalvular pulmonary stenosis* ( %); ventricular septal defect* ( %). kinyoun's, or other acid-fast stains. polymerase chain reaction for mycobacterial dna may be helpful in the differential diagnosis ofgranulomas ( ). ( ) universal precautions should be strictly followed and aerolization should be avoided. ( ) reliable serologic studies are not available. a definite diagnosis requires isolation of the organism. ( ) this is a reportable disease. cavitary, fibrocalcific, miliary, bronchial, and other types of pulmonary tuberculosis; granulomas in hilar lymph nodes. most organs and tissues may be involved, including liver, pancreas, spleen, kidneys, adrenal glands and other endocrine glands, gonads, and lymph nodes. tuberculous meningitis; tuberculoma. iridocyclitis or panophthalmitis. tuberculous arthritis and synovitis (hips, spine, knee); tuberculous osteomyelitis (anterior aspect of vertebrae; metaphysis of long bones). part ii / diseases and conditions procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. chronic ulcerative colitis may be associated with carcinoma of bile ducts, typically arising in psc.* metastases common in regional lymph nodes and lungs. i for removal, prosthetic repair, and specimen preparation and decalcification procedures, see chapter . if osteoblastic metastases appear to be present, search for primary tumor in prostate and breast, carcinoid tumors and hodgkin's lymphoma. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. cachexia. evidence of hypercalcemia (particularly in presence of osteolytic metastases). metastases to bone (e.g., from carcinoma of prostate, breast, bronchi, thyroid gland, kidney, or urinary bladder) usually involve red bone marrow. therefore, distal extremities are rarely involved by metastatic tumors in adults. metastases, commonly in lungs. metastatic calcification in patients with hypercalcemia. eosinophilia. myopathy.* metastases in liver and regional lymph nodes. see also above under "possible associated conditions." malakoplakia (rare) ( ) . part ii / diseases and conditions other organs and peripheral arteries tumor(s). if tumor is within a heart chamber (usually a myxoma), record extent of mobility and capability of tumor to obstruct a valvular orifice. submit samples of tumor(s) for histologic study and, particularly if the tumor is of unknown type, for immunohistochemical study and electron microscopy (chapter ). procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. metastatic carcinoma or melanoma. secondary cardiac effects by tumors include carcinoid heart disease, amyloid heart disease in multiple myeloma, and lymphocytic myocarditis in pheochromocytoma. treatment effects such as adriamycin cardiotoxicity may be noted also. tumor (myxoma) emboli in pulmonary or peripheral vessels ( ) . multiple aneurysms* of cerebral and other arteries may rarely be associated with atrial myxomas. procedures depend on expected findings or grossly identified abnormalities as listed above and in right-hand column. part ii / diseases and conditions if there was evidence of endocrine activity (see above), snap-freeze portion of fresh tumor for hormone assay. perfuse lungs with formalin. sample neoplastic and non-neoplastic tissue for histologic study. procedures depend on expected findings or grossly identified abnormalities as listed above and in right-hand column. for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . for removal and specimen preparation, see chapter . see above under "possible associated conditions." note that hypoglycemia* generally cannot be confirmed at autopsy. nonbacterial thrombotic endocarditis.* carcinoma may be associated with asbestosis or other types of pneumoconiosis,* chronic bronchitis,* emphysema,* interstitial pneumonia,* and many other bronchopulmonary diseases. see above under "possible associated conditions." metastases (regional lymph nodes, liver, bones, brain, and many other sites) and metastatic calcification. migratory thrombophlebitis.* encephalomyelitis;* cerebellar corticoid degeneration;* subacute spinocerebellar degeneration. * crooke cell hyperplasia. myasthenic syndrome (eaton-lambert syndrome); myopathy;* dermatomyositis.* peripheral neuropathy. see above under "external examination and skin." bones (with red marrow) are common sites of metastases. record presence or absence of testes. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. thmor of the soft tissues the possible sites and characteristics of soft tissue tumors vary so much that no universally applicable autopsy techniques can be presented. in all instances, the size, weight, and location of the tumor(s) must be recorded and tissue must be sampled for histologic study. if the tumor had not been classified prior to death, samples should be snap-frozen for immunohistochemical study. other samples should be prepared for electron microscopic study. evidence of paraneoplastic syndromes (see below) may require additional procedures. possible associated conditions: only a few paraneoplastic syndromes or systemic complications can be presented here. for the type of soft tissue tumor that was associated with each condition, see title of reference. kasabach-merritt syndrome ( ) (thrombocytopenia, microangiopathic hemolytic anemia, and acute or chronic coagulopathy associated with a rapidly enlarging hemangioma); liver function abnormalities ( ); neurofibromatosis ( ); osteomalacia ( ). heart esophagus, stomach, and duodenum other organs and tissues t in most instances, detennination of vitreous sugar concentration and of blood group is not indicated. inspect valves and prepare photographs and sections of vegetations. leave esophagus and part of duodenum attached to stomach. submit samples of tumor and of grossly uninvolved stomach for histologic study. request pas stain and warthin-starry stain for identification of h. pylori. portions of endocrine gastric tumor should be snap-frozen for immunohistochemical study and possible hormone assay. record location of tumor metastases. other organs procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. for dissection of the thoracic duct (for search of tumor cell clusters), see chapter . tumor of the uterus (with cervix) possible associated conditions: acquired immunodeficiency syndrome* (aids) ( ) if peritonitis is present, submit exudate for bacteriologic study. record volume of exudate and location of perforation. see "disease, ischemic heart." other procedures depend on grossly identified abnormalities as listed in right-hand column. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. perfuse at least one lung with formalin. for celiac arteriography, see chapter . open stomach and duodenum in situ and record site of perforation or penetration. record measured or estimated volume of blood in gastrointestinal tract. rinse ulcer with saline to locate eroded vessel(s). pin stomach and duodenum on corckboard (serosa toward board) and fix specimen in formalin before sectioning. prepare histologic sections of ulcer(s) and of remainder of stomach. request warthin-starry stain for h. pylori. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. free air in abdomen suggests perforation of ulcer. peritonitis. * perforation of ulcer. coronary atherosclerosis and manifestations of coronary insufficiency are commonly associated with peptic ulcer disease. in rare instances, pericardial fistula may be present from ulcer in hiatus hernia. peptic ulcers may be associated with emphysema,* tuberculosis,* and other chronic pulmonary diseases. vasculitis (see "aortitis," "arteritis, .•.," "phlebitis," and "purpura,•••") ventricle, double inlet left ( ) synonyms: single functional ventricle; univentricular heart; univentricular atrioventricular connection; holmes heart. note: the basic anomaly is the connection of both atrioventricular valves to the left ventricle, often with transposed great arteries and a restrictive ventricular septal defect. there are four major types, based on the ventriculoarterial connection: ( ) with congenitally corrected transposition ( %); ( ) with complete transposition ( %); ( ) with normally related great arteries (holmes heart; %); and ( ) double outlet, persistent truncal artery, or pulmonary atresia ( %). for general dissection techniques, see chapter . possible associated conditions: bicuspid pulmonary valve; bilateral mirror-image mitral valves (without tricuspid morphology); subvalvular aortic stenosis,* often with hypoplasia, coarctation, or interruption of the aortic arch; subvalvular pulmonary stenosis;* dual av nodes and progressive heart block in patients with congenitally corrected transposition. ventricle, double outlet right synonym: origin of both great arteries from right ventricle; taussig-bing anomaly. note: the basic anomaly is the origin of the aorta and pulmonary artery primarily from the right ventricle, usually with a ventricular septal defect, and often with subpulmonary stenosis. for general dissection techniques, see chapter . possible associated conditions: complete atrioventricular septal defect (often with asplenia syndrome); muscular discontinuity between aortic and mitral valves; right ventricular infundibular stenosis; ventricular septal defect* that may be subaortic, subpulmonary, doubly committed, or remote. examine histologically with h&e and oil red a stains. hepatomegaly and splenomegaly, jaundice. deficiency of acid lipase ( ). foam cells in the lamina propria. hepatomegaly, severe steatosis with cholesterol clefts in hepatocytes and kupffer cells. fibrosis. splenomegaly with lipid-laden foam cells. symmetric enlargement with dystrophic calcifications, giving the adrenals a gritty texture. vacuolated cells of the inner zona fasciculata and entire zona reticularis with cholesterol clefts. foam cells may be found in the lungs, bone marrow, lymph nodes, vessel walls, as well as schwann and ganglion cells. new insights into lipoprotein assembly and vitamin e metabolism from a rare genetic disease angioid streaks associated with abetalipoproteinemia familial hypobetalipoproteinemia: genetics and metabolism aviation pathology scuba diving accidents: decompression sickness, air embolism aetiology and occurrence of diving injuries. a review of diving safety scuba decompression illness and diving fatalities in an overseas military community diving-related emergencies bodies found in water achalasia and squamous cell carcinoma of the esophagus: analysis of patients esophageal achalasia and adenocarcinoma in barrett's esophagus: a report of two cases and a review of the literature a technique for necropsy evaluation of stenosis of the foramen magnum and rostral spinal canal in osteochondrodysplasia mutation analysis of the men i gene in multiple endocrine neoplasia type i, familial acromegaly and familial isolated hyperparathyroidism. i increased incidence of neoplasia in females with acromegaly benign and malignant tumors in patients with acromegaly pathology of acromegaly ethanol in sequestered hematomas stages of acute alcoholic influence/intoxication electrolyte imbalance in alcoholic liver disease collection and storage of specimens for alcohol analysis analysis for alcohol in postmortem specimens disposition of alcohol in man medicolegal aspects of alcohol. garriott jc blood, urine and other tissue specimens for alcohol analysis relationship between postmortem blood and vitreous humor ethanol levels larson cpo alcohol: fact and fallacy gradwohl's legal medicine left ventricular hypertrophy is more prominent in patients with primary aldosteronism than in patients with other types of secondary hypertension intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism association of adrenal medullae and cortical nodular hyperplasia: a report of two cases with clinical and morpho-functional consideration amyloidosis: recognition, confirmation, prognosis, and therapy electron microscopy of primary and secondary cutaneous amyloidosis and systemic amyloidosis ocular amyloidosis current status review: cerebral amyloid spinal cord compression by amyloid deposits the burden of "sticky" amyloid: typing challenges quantification of cerebral amyloid angiopathy and parenchymal amyloid plaques with congo red histochemical stain kidney involvement in takayasu arteritis pathogenesis of rheumatoid arthritis splenic involvement in rheumatic diseases aspergillus sinusitis in patients with aids: report of three cases and review invasive aspergillosis in systemic lupus erythematosus aspiration (see "obstruction, acute airway aspergillus endocarditis, myocarditis and pericarditis complicating necrotizing fasciitis. case report and subject review aspergillus-related lung disease biliary atresia and the polysplenia syndrome: its impact on final outcome biliary atresia nephromegaly and elevated hepatocyte growth factor in children with biliary atresia coccidiomycosis pneumonia in a nonendemic area associated with inftiximab codeine (see "dependence, drug[s], all types or type unspecified all types or type unspecified (see "enterocolitis, other types or type undetermined chronic ulcerative (see "disease, inflammatory bowei cytologic diagnosis of cryp -tococcus neofonnans in hiv-positive patients cryptococcosis as an opportunistic infection in immunodeficiency secondary to paracoccidioidomycosis hypereosinophilia in disseminated cryptococcal disease cryptococcosis-a review of autopsy cases from a -year period in a large hospital cryptosporidiosis in persons with hiv infection broncho-pulmonary cryptosporidiosis in four hiv-infected patients cryptosporidiosis and inflammatory bowel disease sclerosing cholangitis associated with chronic cryptosporidiosis in a child with a congenital immunodeficiency disorder cyanide (see "poisoning, cyanide cyst(s), choledochal choledochal cyst-dinical features and classification cyst(s), liver (see "disease, fibropolycystic, of the liver and biliary tract pulmonary related terms: congenital cystic adenomatoid malformation; congenital pulmonary lymphangiectasis; intralobular bronchopulmonary sequestration. references infection or calcification of cysts; pyelonephritis;* perinephric abscess. obstructive uropathy in recessive polycycstic renal disease, congenital hepatic fibrosis is present and cystic bile ducts may be present in dominant cases ( ). see above under "possible associated conditions the pathology ofhuman renal cystic disease cystic kidney: genetics, pathologic anatomy, clinical picture, and prenatal diagnosis hepatic fibrosis associated with hereditary cystinosis: a novel form of noncirrhotic portal hypertension ophthalmic manifestations and histopathology of 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endoscopic management in a patient with caroli's syndrome bartonella henselae endocarditis in an immunocompetent adult cat-scratch disease and bacillary angiomatosis attack, transient cerebral ischemic" and "infarction, cerebral!') cholesteryl ester storage disease: hepatopathology and effects of therapy with lovestatin clinical, biochemical and histological analysis of seven patients with cholesterol ester storage disease cutaneous manifestations of chronic granulomatous disease. a report of four cases and review of the literature aspergillus endocarditis in chronic granulomatous disease colitis complicating chronic granulomatous disease. a clinicopathological case report hypertrophic cranial pachymeningitis with spinal epidural granulomatous lesion ocular pathologic findings of chronic granulomatous disease of childhood review: creutzfeldt-jakob disease survival of creutzfeldt-jakob disease virus in formol-fixed brain tissue guidelines for high risk autopsy cases: special precautions for creutzfeldt-jakob disease tissue handling in suspected creutzfeldt-jakob disease and other human spongiforme encephalopathies (prion diseases) cerebrospinal fluid concentration of neuron-specific enolase in diagnosis of creutzfeldt-jakob disease autopsy case of sporadic creutzfeldt-jakob disease presenting with signs suggestive of brainstem and spinal cord involvement metastatic crohn's disease: a rare cutaneous manifestation crohn's disease with pulmonary involvement in a year old boy mesenteric fibromatosis asso-ciated with crohn's disease cholangiocarcinoma and crohn's disease the pancreas as a site of granulomatous inflammation in crohn's disease dermatomyositis associated with crohn's disease cardiocyte storage and hypertrophy as a sole manifestation of fabry's disease. report on a case simulating hypertrophic non-obstructive cardiomyopathy an atypical variant of fabry's disease with manifestations confined to the myocardium pulmonary involvement in fabry disease cerebrovascular complications offabry's disease high incidence of thrombosis in fabry's disease oral involvement in chronic graft versus host disease after allogenic bone marrow transplantation massive pericardial effusion complicating the course of chronic graft-versus-host disease (cgvhd) in a child with acute lymphoblastic leukemia following allogeneic bone marrow transplantation the histological spectrum of pulmonary graft-versushost disease in bone marrow transplant recipients bronchiectasis in bone marow transplantation oncocytic metaplasia of bile duct epithelium in hepatic gvhd immune-mediated myelopathy after allogeneic marrow transplantation gunther's (see ''porphyria, congenital erythropoietic heavy-chain synonyms and related terms: gamma heavy-chain inflammatory bowel disease (first of two parts) takayasu's arteritis associated with idiopathic ulcerative colitis cerebrovascular complications ofinflammatory bowel disease pathology of inflammatory bowel disease legionnaires' disease source of infection for sporadic legionnaires' disease: a review legionnaire's disease associated with macular rash; two cases severe skin loss after meningococcal septicemia: complications in treatment osteonecrosis following meningococcemia and disseminated intravascular coagulation in an adult: case report and review rhabdomyolysis during the subacute stage of meningococcal sepsis primary meningococcal arthritis in a child: case report and literature review chondrosarcoma as a complicating factor in paget's disease of bone lymphoma arising in paget's disease osteoarthritis and paget's disease sickle cell disease sickle cell disease and sudden death: a retrospective/prospective study of autopsy cases and literature review vascular lesions of the liver in sickle cell disease. a clinicopathologic study in living patients whipple's disease and "tropheryma whippelii periodic acid-schiff-negative granulomatous lymphadenopathy in patient with whipple's disease. localization of the whipple bacillus to noncaseating granulomas by electron microscopy serial imaging studies of cerebral whipple's disease: from onset to end the wilson's disease gene is a putative copper transporting p-type atpase similar to menke's gene the liver biopsy diagnosis of wilson's disease. methods in pathology hepatolenticular degeneration (wilson's disease) venous air embolism in homicidal blunt impact head trauma: case reports a practical device for demonstrating air embolism amniotic fluid . kulka w. laboratory methods and technical notes: a practical device for demonstrating air embolism proof of fatal air embolism venous air embolism from head and neck wounds hantavirus pulmonary syndrome: a clinical description of patients with a newly recognized disease liver involvement in hemorrhagic fever with renal syndrome hantavirus infection induces a typical myocarditis that may be responsible for myocardial depression and shock in hanta virus pulmonary syndrome lassa fever in the united states. investigation ofa case and new guidelines for management lassa fever: review of virology, immunopathogenesis, and algorithms for control and therapy early diagnosis of lassa fever by reverse transcription-pcr rheumatic pneumonia: reappearance of a previously recognized complication of rheumatic fever acute rheumatic fever and poststreptococcal acute glomerulonephritis caused by t serotype streptococcus scleritis, uveitis, and glaucoma in a patient with rheumatic fever comparison of clinical features and pathologic findings in fatal cases of typhoid fever during the initial and later stages of the disease typhoid fever complicated by acute renal failure and hepatitis: case reports and review hemophagocytosis and granulomas in the bone marrow of a child with down syndrome diseases involving intrahepatic bile ducts idiopathic eosinophilic esophagitis with stricture formation in a patient with longstanding eosinophilic gastroenteritis eosinophilic gastroenteritis presenting with colitis and cholangitis eosinophilic gastroenteritis presenting with acute pancreatitis idiopathic midline destructive disease: does it . mendenhallwmetai.lethalmidlinegranoloma-nasalnaturalkillerff-celi exist? nasal cocain abuse mimicking midline granuloma pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with epstein-barr virus infection recurrent bilateral spontaneous pneumothoraces associated with pulmonary angiocentric immunoproliferative lesion lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications wegener's granulomatosis: histological documentation of common and uncommon manifestations in patients necrotizing granulomatosis of the breast wegener's granulomatosis with gangrene of toes pathology of pulmonary granulomatous vasculitis. sarcoidosis gunshot (see "injury, firearm splenic involvement in rheumatic diseases wegener's granulomatosis, acute laryngotracheal airway obstruction and death in a -year-old female: case report and review of the literature antiendothelial antibodies in patients with wegener's granulomatosis: prevalence and correlation with disease activity and manifestations. i rheumatoi transfusion-transmitted disease references flattening, broadening, and possible fusion of villi. phlegmonous inflammation and edema, mainly in ileocecal region encephalitis.* leukopenia; thrombocytopenia; aplastic anemia ( ) (pancytopenia*) synovitis (arthritis*) hepatitis g virus infection in hepatitis c virus-positive patients co-infected or not with hepatitis b virus and/or human immunodeficiency virus hepatitis g and c coinfection in children tumor of the liver diaphragmatic related terms: congenital diaphragmatic hernia fulminant hepatitis in patients undergoing liver transplantation: evidence for anon-a, non-b, non-c marrow transplantation for hepatitis-associated aplastic anemia: a follow up oflong-term survivors langerhans cell histiocytosis research. past, present, and future an update on c onality, cytokines, and viral etiology in langerhans cell histiocytosis langerhans cell histiocytosis in adults pulmonary langerhans cell granulomatosis central nervous system disease in langerhans cell histiocytosis immunohistochemical analysis oflangerin in langerhans cell histocytosis and pulmonary inflammatory and infectious diseases pathological approach to the diagnosis of hydrocephalus thoracic lipomeningocele associated with diastematomyelia, tethered spinal cord, and hydrocephalus. case report infectious causes ofhydrops fetalis human parvovirus b infection associated with hydrops fetalis cardiac abnormalities associated with hydrops fetal is gmi-gangliosidosis presenting as nonimmune hydrops fetalis: a case report a case of recurrent infantile polycystic kidney associated with hydrops fetalis the pathologist and the hydropic placenta, fetus, or infant chronic diarrhea associated with thymoma and hypogammaglobulinemia (good's syndrome) systemic amyloidosis in a patient with hypogammaglobulinemia. i hcv infection in patients with primary defects of immunoglobulin production encepahomyelitis in primary hypogammaglobulinemia retinitis pigmentosaand hypogammaglobulinemia intestinal obstruction in the newborn with congenital syphilis meconium ileus and its equivalent as a risk factor for the development of cirrhosis: an autopsy study in cystic fibrosis biliary atresia and meconium ileus associated with nieman-pick disease postmortem cranial mri and autopsy correlation in suspected child abuse cytomegalovirus-associated pseudotumor simulating gastric malignancy in acquired immuno-deficiency syndrome: a case report with review of literature bone marrow fibrin ring granulomas and cytomegalovirus infection cutaneous reactions following herpes zoster infections: report of three cases and a review of the literature herpes zoster and internal malignancy posteriorhorn varicella-zoster virus myelitis death or injury caused by electrocution myocardial hemorrhagic necrosis in delayed death from electrocution safety in bullet recovery procedures: a study of the black talon bullet lightning injuries: prognostic signs of death lightning injuries adrenal insufficiency, recurrent bacteremia, and disseminated abscesses caused by nocardia asteroides in a patient with acquired immunodficiency syndrome ards and adrenal insufficiencyassociated with the antiphospholipid antibody syndrome adrenal insufficiency from bilateral adrenal hemorrhage after total knee replacement surgery non-hodgkin's lymphoma presenting with adrenal insufficiency and hypothyroidism: an autopsy case report a case ofprimary unilateral adrenal burkitt-like large cell lymphoma presenting as adrenal insufficiency effect of growth hormone on fatty liver in panhypopituitarism increased fracture frequency in adult patients with hypopituitarism and gh deficiency pituitary abscess the liver: an atlas and text of ultrastructural pathology intubation (see "injury, intubation iodine (see "poisoning, iodine attack, transient cerebral ischemic" and "infarction, cerebral heart (see "disease, ischemic heart isomorism (see "syndrome, polysplenia and asplenia a study on performance of two serological assays for diagnosis of leprosy detection of mycobacterium leprae infection by pcr pathology of eye in leprosy references intervillous abscesses containing grampositive, non-acid-fast bacilli bacteria are predominantly intracellular. enterocolitis. listeria monocytogenes can be cultured from meconium. generalized lymphadenitis. disseminated abscesses and/or granulomas, particularly after transplacental infection listeria monocytogenes empyema in an hiv infected patient fatal listeria meningitis, endocarditis and pericarditis in a patient with haemochromatosis liver abscesses due to listeria monocytogenes yust . brainstem abscess and meningitis due to listeria monocytogenes in an adult with juvenile chronic arthritis pulmonary hypertension associated with systemic lupus erythematosus: predominantly thrombotic arteriopathy accompanied by plexiform lesions the liver in systemic lupus erythematosus: pathologic analysis of cases and review of japanese autopsy registry data chronic pancreatitis: a complication of systemic lupus erythematosus disseminated perivenous necrotizing encephalomyelitis in systemic lupus erythematosus: report of an autopsy case skeletal muscle lymphocytic vasculitis in systemic lupus erythematosus: relation to disease activity clinically occult avascular necrosis of the hip in systemic lupus erythematosus storage histiocytes and hemophagocytosis: a common finding in the bone marrow of patients with active systemic lupus erythematosus extensive medium vessel vasculitis with sle: an unsual association cutaneous manifestations of sexually transmitted ing cause of proctitis in men who have sex with men lymphogranuloma venereum as a cause cutaneous malakoplakia in a patient with acquired immunodeficiency syndrome (aids) extensive malakoplakia ofthe nasopharynx: management of a rare disease malakoplakia and colorectal adenocarcinoma coinfection is common in measles associated pneumonia giant cell pneumonia: light microscopy, immunohistochemical, and ultrastructural study of an autopsy case subacute sclerosing panencephalitis manifesting as viral retinitis: clinical and histopathologic findings intestinal neuronal dysplasia thoracic lipomeningocele associated with diastematomyelia, tethered spinal cord, and hydrocephalus. case report disease, meningococcal encephalitis, all types or type unspecified" and "meningitis mercury (see "poisoning, mercury with myelofibrosis synonym: idiopathic myelofibrosis acute cardiac tamponade associated with pericardial extramedullary hematopoiesis in agnogenic myeloid metaplasia methyl alcohol) (see "poisoning, methanol (methyl alcohol) thrombotic thrombocytopenic (see "purpura, thrombotic thrombocytopenic epstein-barr virus in inflammatory diseases of the liver and liver allografts: an in situ hybridization study fulminant hepatitis due to epstein-barr virus infection the mucopolysaccharidoses: a clinical review and guide to management biochemical diagnosis of mucopolysaccharidoses: experience of diagnoses in a -year period ( - ) mucormycosis synonym: phycomycosis; zygomycosis. note: diseases that may be complicated by mucormycosis include bums,* diabetes mellitus,* leukemia,* lymphoma,* and tuberculosis cardiac involvement in mucopolysaccharidosis: effects of allogeneic bone marrow transplantation mitral and aortic regurgitation in patients with mucopolysaccharidosis toxic epidermal necrolysis possibly linked to hyperacute graft-versus-host disease after allogeneic bone marrow transplantation pulmonary complications in toxic epidermal necro-iysis: a prospective clinical study references possible or expected findings pyelonephritis;* nephrocalcinosis; granulomas; tumor infiltrates; manifestations of the conditions listed below under "other organs renal stones in patients with rheumatoid arthritis nephrolithiasis as a presenting feature ofchronic sarcoidosis: a prospective study nephrolithiasis and risk of hypertension posterior lens opacities; retinal hamartomas. peripheral neuropathy with focal schwannomatous changes or onion-bulb-like schwann cell or perineural cell proliferation neurofibromatosis type i. in: pathology and genetics of tumours of the nervous system neurofibromatosis type . in: pathology and genetics oftumours ofthe nervous system neurological complications involving the central nervous system in neurofibromatosis type i primary cutaneous nocardia asteroides infection after heart transplantation native valve endocarditis due to nocardia-like organisms hepatobiliary complications of total parenteral nutrition total parenteral nutrition: a histopathologic analysis of the liver changes in children obesity and breast cancer risk nonalcoholic steatohepatitis obesity cardiomyopathy: pathogenesis and pathophysiology bennett cpo pachydennoperiostitis in childhood unilateral hypertrophic osteoarthropathy associated with aortofemoral graft infection gastroesophageal reflux and esophagitis-associated hypertrophic osteoarthropathy hypertrophicosteoarthropathy caused by lipoid pneumonia achondroplasia" and dyschondroplasia, oilier's osteogenesis imperfecta synonyms and related terms: lobstein's syndrome osteogenesis imperfecta congenita; type i, ii, and iii; osteogenesis imperfecta cystica hypercalcemia in osteogenesis imperfecta treated with pamidronate gastrointestinal problems in patients who have type-iii osteogenesis imperfecta osteomalacia related terms: osteoporosis;* renal osteodystrophy; rickets. note: many possible causes of osteomalacia may not be apparent at autopsy, e.g., sodium fluoride or diphosphonate toxicity or use of anticonvulsant drugs osteomalacia associated with adult fanconi syndrome: clinical and diagnostic features epstein-barr virus in b-celllymphomas associated with chronic suppurative inflammation osteomyelitis and osteonecrosis in inflammatory bowel disease references hyperlipidemia; hyperuricemia. fracture or traumatic dislocation of hip see above under "note osteomyelitis and osteonecrosis in inflammatory bowel disease osteonecrosis and human immunodeficiency virus infection report of fifteen cases. therapeutic recommendations malignant infantile osteopetrosis: otolaryngological complications and management renal tubular acidosis and osteopetrosis with carbonic anhydrase ii deficiency: pathogenesis of impaired acidification spondylolysis in children who have osteopetrosis osteopetrosis with arnold chiari malformation type and brain stem compression osteoporosis and atherosclerosis in chronic renal failure endocrine disorders and osteoporosis otosclerosis: a measles virus associated inflammatory disease correlations between pathologic changes in the stapes and conductive hearing loss in otosclerosis the aetiology of otosclerosis: a review of the literature etiologic links between chronic pancreatitis and pancreatic cancer hyperparathyroidism and pancreatitis during pregnancy pancytopenia related terms: agranulocytosis;* aplastic anemia; fanconi's anemia.* note: some causes of pancytopenia such as adverse drug reactions (e.g., due to antimetabolites, sulfa drugs thrombotic thrombocytopenic purpura/hemolytic uremic syndrome secondary to pancreatitis retinopathy as asys-temic complication of acute pancreatitis references mesenteric panniculitis necrotizing pancreatitis. * vasculitis with thrombi; adrenocortical infarctions. vasculitis with thrombi and infarctions. relapsing polychondritis ( ). see also above under "possible associated conditions subcutaneous panniculitic t-cell lymphoma is a tumor of cytotoxic t lymphocytes abecassism. alpha i-antitrypsindefi-ciencyassociated panniculitis: resolution with intravenous alpha l-anti-trypsin administration and liver transplantation blind loop syndrome: an unusual cause of panniculitis. j am acad paracoccidioidomycosis synonyms: paracoccidioides brasiliensis infection cutaneous panniculitis and relapsing polychondritis: two cases normal subcutaneous fat, necrosis of adipocytes and classification of the panniculitides paraneoplastic pemphigus a case of pemphigus vulgaris with esophageal involvement rheumatoid constrictive pericarditis (clinical conference) benign paroxysmal (see "fever, familial mediterranean pneumatosis intestinalis in pediatric acquired immunodeficiency syndrome pneumatosis cystoides intestinalis: an unusual complication of systemic amyloidosis pneumatosis intestinalis in children with primary combined immunodeficiency pneumatosis cystoides intestinalis with abdominal free air in a -year-old girl after allogeneic bone marrow transplantation pneumatosis intestinalis: a review pneumatosis coli: a proposed pathogenesis based on study of cases and review of the literature collagenous inorganic dust pneumoconiosis, diffuse type: aluminosis; asbestosis; chronic pulmonary berylliosis; talcosis; collagenous inorganic dust pneumoconiosis, nodular type: silicosis; noncollagenous inorganic dust pneumoconiosis (includes mixed-dust fibrosis): baritosis; china clay pneumoconiosis; chromite pneumoconiosis; coal worker's pneumoconiosis; fuller's earth pneumoconiosis; hematite or magnetite miner's lung; siderosis or welder's lung; stannosis; organic dust pneumoconiosis: byssinosis. note: in addition to the aforementioned classic forms of pneumoconiosis, many other airborne substances have been impli-cated in recent years, for example, cerium uncommon causes ofoccupational interstitial lung diseases rare earth (cerium oxide) pneumoconiosis: analytical scanning electron microscopy and literature review diagnostic criteria for chronic beryl ium disease (cbd) based on the uk registry - pneumocystis carinii (see "infection, pneumocystis carinii this condition is diagnosed by inspection, palpation, and roentgenography. tension pneumomediastinum may autopsy evaluation of asbestos exposure: retrospective study of cases with quantitation of ferruginous bodies in digested lung tissue atypical mycobacteriosis as a complication of talc pneumoconiosis silicosis, mixed dust pneumoconiosis, and lung cancer complications associated with the use ofthe esophageal-tracheal combitube pneumomediastinum: an unusual complication of asthma in a young man spontaneous pneumomediastinum in a patient with bronchiolitis obliterans after bone marrow references i. katzenstein a-l, myers j. idiopathic pulmonary fibrosis: clinical relevance of pathologic classification update on lymphoid interstitial pneumonitis lymphocytic interstitial pneumonitis and nonspecific interstitial pneumonitis histologic diagnosis of extrinsic allergic alveolitis role of electron microscopy in interstitial lung disease detennination of arsenic in hair using neutron activation arsenic intoxication associated with tubulointerstitial nephritis atrioventricular block after administration of atropine in patients follow-ing cardiac transplantation death following intentional methyl bromide poisoning: toxicological data and literature review pulmonary edema, alveolar wall damage, and interstitial pneumonia after acute inhalation. severe pulmonary fibrosis may develop in chronic cases. gastroenteritis after nonlethal food poisoning. degeneration of proximal tubules and proteinuria in acute poisoning degenerative changes of liver and myocardium problems in the analysis of cadmium in autopsied tissues elevated urinary cadmium concentrations in a patient with acute cadmium pneumonitis cadmium-associated renal disease the effects of storage conditions on the stability of carbon monoxide in postmortem blood acute renal failure, poisoning, carbon tetrachloride synonym: tetrachloromethane poisoning. note: toxicologic sampling of body fluids and organs should be done routinely in all cases. in many instances, however, death occurs i wk to d after exposure, and by this time no carbon tetrachloride is demonstrable. death may be sudden compartment syndrome, and systemic capillary leak syndrome complicating carbon monoxide poisoning southern je acute hydrocephalus following carbon monoxide poisoning prevention of occupational cyanide exposure in autopsy prosectors gradwohl's legal medicine references possible or expected findings digoxin values in digitalis toxicity are greater than ng/ml ( ) digoxin concentration may be higher or lower than concentration in serum, depending on how long before death drug was taken (i) digoxin concentrations in postmortem specimens after overdose and therapeutic use a fluorimetric determination ofmyocardial digoxin at autopsy, with identification of digitalis leaf, digitoxin and gitonin ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis ethylene glycol poisoning: case report of a record-high level and a review lead concentrations in human plasma, urine and whole blood trace metals (lead and cadmium screening) an emg case report oflead neuropathy years after a gunshot injury aminoaciduria and glycosuria following severe childhood lead poisoning risk of nervous system cancer among workers exposed to lead demonstration of mercury in the human brain and other organs years after metallic mercury exposure spontaneous exfoliation of teeth following severe elemental mercury poisoning: case report and histological investigation for mechanism. oral surg oral med oral pathoi acute chemical pancreatitis associated with nonfatal strychnine poisoning homicide by strychnine poisoning coronary arteritis, with or without aneurysms and infarctions, primarily in childhood. myocardial hypertrophy secondary to hypertension. * minimal or no involvement by polyarteritis nodosa; considerable involvement in other types ofnecrotizing vasculitis (see "arteritis, all types or type unspecified") with or without formation of aneurysms and infarctions, may occur in all organs. the liver may show bile duct injury and rarely, nodular regenerative hyperplasia ( ) more frequently involved in giant cell elastic arteritis.* polyarteritis of small muscular arteries, including vasa nervorum. arthritis* may rarely be present with swollen joints. infarctions;* subarachnoid hemorrhage; arteritis of cerebral arteries. papillitis; retinal hemorrhages polyarteritis nodosa-like vasculitis in human immunodeficiency virus infection the coexistence of familial mediterranian fever and polyarteritis nodosa: report of a case microscopic polyarteritis during polymyalgia rheumatica remission development of polyarteritis nodosa in the course of inactive systemic lupus erythematosus bone marrow pathology in relapsing polychonditis: high frequency of myelodysplastic syndrome relapsing polychondritis associated with subclinical sjo-gren's syndrome and phlegmon of the neck giant cell arteritis and polymyalgia rheumatica posterior scleritis and polymyalgia rheumatica polymyalgia rheumatica in patients with ankylosing spondylitis: a report of cases inflammatory changes of hip synovial structures in polymyalgia rheumatica polymyositis (see "dermatomyositis polyneuritis (see "syndrome, guillain-barre familial, and related syndromes related terms: cowden's disease (multiple hamartoma syndrome); familial colonic polyposis gardner's syndrome; non-polyposis syndrome (hereditary nonpolyposis colorectal cancer syndrome) sampling for histologic study depends on expected findings or grossly identified abnormalities as listed in right-hand column. (see also below under "soft tissues syndrome; mucocutaneous pigmentations (buccal, perioral, priorbital, distal extremities) in peutz-jeghers syndrome;* papules in face and oral mucosa in cowden's disease; tumors of skin and subcutis (see below under "soft tissues gardner's syndrome. osteomas or exostoses (mandible, calvara desmoid in familial adenomatous polyposis malignant potential in intestinal juvenile polyposis syndromes ampullary carcinoma in familial adenomatous polyposis adenoma of the common bile duct in gardner's syndrome may cause relapsing acute pancreatitis orbital osteoma in gardner's syndrome myelopathylmyelitis," and "syndrome, guillain-barre.") references possible or expected findings hypertrichosis; erythrodontia; scarring and mutilation of hands and face. hemolytic anemia. erythrocytes contain large amounts of uroporphyrin i; nonnoblasts and reticulocytes exhibit intense red fluorescence uroporphyrin i and coproporphyrin i in high concentrations. splenomegaly (may have been treated by splenectomy) correction of congenital erythropoietic porphyria by bone marrow transplantation successful cord blood stem cell transplantation for congenital erythropoietic porphyria (gunther's disease) congenital erythropoietic porphyria associated with nephrotic syndrome atypical red cell inclusions in congenital erythropoietic porphyria possible associated conditions: adverse drug reaction; chronic alcoholism;* chronic hepatitis c ( ); human immunodeficiency virus infection porphyria cutanea tarda and human immunodeficiency virus: two cases associated with hepatitis c porphyria cutanea tarda and antibodies to hepatitis c virus an unhappy triad: hemochromatosis, porphyria cutanea tarda and hepatocel ularcarcinoma-a case report variegate porphyria possible associated conditions: ebstein's malformation of tricuspid valve. references possible or expected findings chronic eczematous skin lesions or superficial scarring; nail changes. perivascular pas-positive hyaline ( ) brown protoporphyrin deposits with red to yellow birefringence with a maltese cross configuration in hepatocytes, kupffer cells, and bile canaliculi erythropoietic protoporphyria cytofluorometry as a diagnosis of protoporphyria recessive inheritance of erythropoietic protoporphyria with liver failure pseudogout synonym: calcium pyrophosphate dihydrate (cppd) deposition disease puncture grossly affected joints and submit sample of synovial fluid for crystal analysis under compensated polarized light ( ) references possible or expected findings punctate calcium deposits in kneejoints and, less commonly, in joints of hips, ankles, shoulders, or wrists or in symphysis ossium pubis and intervertebral disks. arthritis* with synovitis. crystals of calcium pyrophosphate dihydrate in periarticular tissue ( ) and synovial fluid. cartilage contains calcium salts of pyrophosphate, hydroxyapatite, and orthophosphate. alkaptonuria;* gout calcium pyrophosphatedihydratedeposition disease presenting as tumoral calcinosis (periarticularpseudogout) calcifications in dermis; calcifications of blood vessels. diaphragmatic hernia.* hypertensive cardiomegaly. characteristic plaques in pericardium and endocardium, with or without mitral valve involvement. coronary atherosclerosis may have been a causeofangina( ).coronarythrombosisand myocardial infarction may be present also. accelerated atherosclerosis; calcification of peripheral vessels. gastrointestinal hemorrhage;* peptic ulcer degeneration of bruch's membrane with retinal hemorrhages; sclerosis of choroid vessels calcification of elastic fibers in pseudoxanthoma elasticum new report of severe coronary artery disease in an eighteen-year-old girl with pseudoxanthoma e asticum. case report and review of the literature hivrelated thrombotic thrombocytopenic purpura: report of cases and a review of the literature beham-pyelonephritis synonyms and related terms: acute ascending pyelone angiotropic large cell lymphoma presenting as thrombotic micro-angiopathy (thrombotic thrombocytopenic purpura) splenic pathology in thrombotic thrombocytopenic purpura emphysematous pyelonephritis in diabetic patients nephrobronchialfistulaandlungabscessresulting from nephrolithiasis and pyelonephritis a case ofan enterorenal pyothorax (see "empyema, pleurai.") fistula and pyelonephritis with airin renal pelvis systemic amyloidosis secondary to pyonephrosis. resolution after nephrectomy medicolegal investigation of death the laboratory's role in detecting sexual assault toluidine blue in the detection at autopsy of perineal and anal lacerations in victimes of sexual abuse sarcoidosis presenting as heart disease sarcoidosis and its ocular manifestations rheumatic features of sarcoidosis cutaneous sarcoidosis: differential diagnosis schistosoma mansoni and s. haematobium infections in egypt. i. evaluation of techniques for recovery of worms and eggs at necropsy. am i a quantitative post-mortem study of schistosomiasis mansoni in man immunodiagnosis of schistosomiasis. screen with fast-elisa and confinn with imrnunoblot hepatic connective tissue changes in hepatosplenic schistosomiasis schistosomiasis in women: manifestations in the upper reproductive tract sclerosis, systemic amyotrophic lateral (see "disease, motor neuron diffuse (see "sclerosis, schilder's cerebrai multiple synonyms and related terms: acute and subacute variants: acute multiple sclerosis (marburg type), acute necrotizing myelopathy; concentric sclerosis (ba type); concentric lacunar leukoencephalopathy; encephalitis periaxialis diffusa (schilder's type; see also next entry silicone ganuloma in acral skin in a patient with silicone-gel implants and systemic sclerosis organizing diffuse alveolar damage associated with progressive systemic sclerosis bayle , fiessinger in. brain involvement in scleroderma: two autopsy cases skeletal muscle pathology in systemic sclerosis mechanisms of scleroderma-induced lung disease thberous sclerosis complex and subependymal giant cell astrocytoma bilateral temporal arachnoid cysts associated with tuberous sclerosis poisoning, alkaloid accident, diving [skin or scuba scurvy (see "deficiency, vitamin c shigellosis (see "dysentery, bacillary shock related terms: anaphylactic shock; bacteremic shock; many others. note: see also under name of suspected underlying condition, such as "bums intestinal histological and ultrastructura inflammatorychanges in spondyloarthropathy and rheumatoid arthritis the sacroiliac joint in the spondyloarthropathies granulomatous ileitis in a patient with ankylosing spondylitis sporotrichosis synonym: sporothrix (sporotrichum) schenckii infection. note: ( ) mckiernan . partial lipodystrophy in coeliac disease coeliac disease and lymphoma: current status review: nonalcoholic steatohepatitis alcoholic and non-alcoholic wernicke's encephalopathy. be alert to the preventable and treatable disease non-alcoholic fatty liver disease in the metabolic syndrome the placenta in stillbirth estimating the time of death in stillborn fetuses: i. histologic examination of fetal organs: an autopsy study of stillborns estimating the time of death in stillborn fetuses: ii. histologic evaluation ofthe placenta; a study of stillborns estimating the time ofdeath in stillborn fetuses: iii. external fetal examination; a study of stillborns fat distribution in the adrenal cortex as an indication of the mode of intrauterine death stimulant(s) (see "dependence, drug(s), all types or type undetermined cutaneous manifestations of the acquired immunodeficiency syndrome aids: cardiac findings from autopsies the liver in hiv infection neuropathology of the spinal cord in the acquired immunodeficiency syndrome postmortem enzyme immunoassay for human immunodeficiency virus bk virus-associated renal failure among hiv patients - or write to american registry ofpathology sales office pathology of acquired immunodeficiency syndrome (aids) in children thymus involution in the acquired immunodeficiency syndrome micrencephaly in children congenitally infected with human immunodeficiency virus-a gross-anatomical morphometric study a rapid method for detecting the predominant ashkenazi jewish mutation in the bloom's syndrome gene bloom syndrome: multiple retinopathies in a chromosome breakage disorder severe eczema in a patient with di-george's syndrome digeorge's syndrome orthe iii -iv pharyngeal pouch syndrome: pathology and a theory of pathogenesis basal ganglia calcification and psychosis in q . deletion syndrome down's synonyms and related terms: mongolism possible associated conditions: acute lymphocytic, my references epicanthal folds; cleft lip/palate; high arched palate; furrowed tongue; rhagades. depressed nasal bridge small, broad or fiat nose; slanted palpebral fissures; fiat occiput; brachycephaly; palmar "simian crease"; short fifth middle finger ventricular septal defect;* complete atrioventricular septal defect* ( ). duodenal stenosis and atresia; imperforate anus. microcephaly; poorly developed secondary gyri hypoplastic brain stem, medulla and cerebellum; polymicrogyria; neurofibrillary tangles; meningomyelocoele. acute lymphocytic leukemia; acute myelocytic leukemia; acute megakaryocytic leukemia cardiovascular disease in down syndrome possible or expected findings hyperelasticity of skin, bruises or scars, hemorrhages, and hyperpigmentation. lipomatous pseudotumors that may be calcified or ossified. normal or abnormal amounts and fragmentation of elastic tissue. abnormalities of collagen. dislocation of hip, shoulder, patella, radius, or clavicle. loose-end clavicles; spondylolisthesis mitral valve prolapse; aortic insufficiency.* aortic dissection, aneurysm, ectasia, occlusion ( ). various congenital anomalies. congenital anomalies of gastrointestinal and genitourinary tracts. bleeding from various organ sites vascular ehlers-danlos syndrome: imaging findings note: this syndrome belongs to a large family (with more photograph abnormal features as listed in right-hand column. record appearance of external genitalia. prepare skeletal roentgenograms. procure long bones and vertebral bodies short-limb dwarfism* with narrowing of the rib cage; polydactyly; dysplasia of fingernails; thin and sparse hair; premature eruption of teeth; defective dentition; eye abnormalities; upper lip bound down by multiple frenula. cryptorchidism; epispadias; hypospadias. chondrodysplasia with acromelic micromelia (shortening of the distal segment of the limb); fusion of capitate and hamate bones of wrist; defects of lateral aspect of proximal tibia see lesions listed above under "external examination empty sella synonyms and related terms: primary empty sella syndrome; secondary empty sella syndrome (e.g., after surgical removal or spontaneous infarction of pituitary adenoma) chorea, philic pneumonia: histopathologic features in nine cases. am rev resp hereditary ascariasis and hookworm chronic eosinophilic pneupophosphatemic vitamin d-resistant rickets; galactosemia;transport defect; tyrosinemia. * excludes fan- weight and external measurements; record and photograph abnormalities as listed in right-hand column. prepare skeletal roentgenograms. radiographs of long bones. submit for tissue culture for possible enzyme analysis. possible or expected findings redlblond hair, fair skin (diminished pigmentation); dehydration;* stigmata of hypothyroidism;* delay of sexual maturation. rickets; osteomalacia.* positive rheumatoid factor. various types of pneumonia after splenectomy, presence of accessory spleen may account for treatment failure. manifestations of portal hypertension.* lymphadenopathy of mediastinal and paraaortic lymph nodes. anemia;* neutropenia sinusoidal lymphocytosis of the liver in felty's syndrome with a review of the liver involvement in felty's syndrome splenic involvement in rheumatic diseases felty's and pseudo-felty's syndrome nodular regenerative hyperplasia of the liver in rheu-matic diseases: report of seven cases and review of the literature fetal alcohol syndrome: craniofacial and central nervous system manifestations goodpasture's syndrome anti-glomerular basement membrane glomerulonephritis: a morphologic study of cases gronblad-strandberg (see "pseudoxanthoma elasticum acute inflammatory polyradiculoneuropathy; guillain-barre-strohl syndrome hemolytic uremic syndrome/thrombotic thrombocytopenic purpura: pathophysiology and treatment cyclosporin-induced hemolytic uremic syndrome: factors that obscure its diagnosis enterohemorrhagic escherichia coli :h : an emerging pathogen hemolytic uremic syndrome as a presenting form of hiv infection hemolytic uremic syndrome in prostatic carcinoma diabetes secondary to genetic disorders. baillieres suprasellar tumors of maldevelopmental origin in klinefelter's syndrome. a report of two cases klippel-feu synonym: congenital fusion of cervical vertebrae primary yolk sac tumor of the prostate in a patient with klinefelter's syndrome extragonodal germ cell tumors are often associated with klinefelter syndrome organs and tissues procedures possible or expected findings external examination prepare roentgenograms of chest, neck, and head skull, spine, brain, and spinal cord myasthenia gravis disorders with dysraphia (see below), fusion of cervical vertebrae. congenital elevation of the scapula (sprengel's deformity) chiari malformation;* basilar impression;* meningomyelocele; platybasia;* spinal cord compression; weight and length; record and photograph abnormalities as listed in right-hand column. record weight and sample for histologic study. if renal transplantation ( ) had been carried out, see also under that heading. follow procedures described under "glomerulonephritis retinal dystrophy ( ) and other retinal changes the cardinal manifestations of bardet-biedl syndrome, a form of laurence-moon-biedl syndrome laurence-moon-biedl syndrome accompanied by congenital hepatic fibrosis pediatric renal transplantation in laurence-moon-biedl syn-drome possible or expected findings typical skeletal proportions. arachnodactyly; pectus excavatum genu recurvatum; dislocation of joints diaphragmatic hernia. * infective endocarditis. * atrial septal defect. * myxomatous transformation of mitral ring. mitral valve prolapse. aortic and pulmonary dilatation and valvular insufficiency.* aortic dissection* with dissection of adjacent vessels. ascending aortic aneurysm multiple cysts (see "cyst(s), pulmonary") aortopulmonary fistula: an uncommon complication in dystrophic aortic aneurysm peripartum acute myocardial infarction in marfan's syndrome aneurysm of the cervical internal carotid artery associated with marfan's syndrome--ease report noonan's syndrome in association with acute leukemia lymphatic dysplasia in a neonate with noonan's syndrome noonan syndrome: a clinical description emphasizing the cardiac findings cerebral arteriovenous malformation in noonan's syndrome clinical variability in a noonan syndrome family with a new ptpnii gene mutation peutz-jeghers syndrome bilateral large-cell calcifying sertoli cell tumor of the testes in peutz-jeghers syndrome: a case report ovarian tumors associated with the peutz-jeghers syndrome robin sequence and a deficiency of the left forearm in a girl with a deletion of chromosome g -gter congenital heart disease in the pierre robin syndrome glossoptosis-apnea syndrome chiari i malformation, caudal regression syndrome, and pierre robin syndrome: previously unreported combination risk factors for squamous cell carcinoma of the esophagus heterotaxy syndrome; ivemark's syndrome possible associated conditions: with asplenia: right isomerism (bilateral mirror-image right-sided symmetry) of heart, lungs, and abdominal viscera; common atrium; total anomalous pulmonary venous connection; absent coronary sinus; complete atrioventricular septal defect;* subpulmonary stenosis;* pulmonary valve atresia;* midline symmetric liver; malrotation of bowel; absent spleen. with polysplenia: left isomerism (bilateral mirror-image left-sided symmetry) ofheart and lungs, with variable sidedness ofabdominal viscera primary immunodeficiencies reiter's syndrome-like patternin aids-associated psoriasiformdermatitis reference pneumothorax;* pneumomediastinum;* pneumoperitoneum. septicemia. right ventricular hypertrophy and/or dilatation. intubation trauma and mural edema and hemorrhage in trachea; hyaline membrane disease intubation trauma. hemorrhages or other evidence of birth trauma; germinal matrix hemorrhages in premature infants; infarctions of subcortical white matter in term infants coalson . pathology of bronchopulmonary dysplasia pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia inborn errors of metabolism and reye's syndrome: differential diagnosis prevalence and non-specificity of microvesicular fatty changes liver histopathology in clinical reye syndrome ultrastructural study of intranuclear inclusions in the exo-crine pancreas in reye's syndrome neuropathologic findings in reye syndrome sanfilippo's (see "mucopolysaccharidosis scheie's (see "mucopolysaccharidosis segawa's (see "syndrome, dystonia severe acute respiratory (sars) note: this highly contagious illness, caused by a coronavirus (sars-cov)details, see biosafety level laboratory for autopsies of patients with severe acute respiratory syndrome: principles, practices, and prospects pathology and pathogenesis of severe acute respiratory syndrome pulmonary involvement in primary sjogren's syndrome polymyositis and sjogren's syndrome associated with bronchiolitis obliterans organizing pneumonia the gastrointestinal manifestations of sjogren's syndrome clinicopathological factors relating malignant lymphoma with sjogren's syndrome acute transverse myelopathy and cutaneous vasculopathy in primary sjogren's syndrome primary localized cutaneous amyloidosis with unusual clinical features in a patient with sjogren's syndrome disease, parkinson's erythema multiforme man related terms: armadillo disease; continuous muscle fiber activity; neuromyotonia autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options sudden infant death (sids) (see "death, sudden unexpected, of infant.") syndrome, superior vena cava related term: superior vena cava obstruction continue dissection of veins into neck and axillas. record and photograph site of thrombosis or of compression by surrounding pathologic conditions. submit samples for histologic study. benign or malignant tumors; fibrosing mediastinitis;* postradiation fibrosis; infectious disease (tuberculosis,* histoplasmosis*); thoracic aortic aneurysm;* chronic constrictive pericarditis;* chest trauma; arteriovenous fistula between ascending aorta and superior vena cava toxic shock synonyms and related terms: staphylococcal scarlet fever. note: ( ) collect all tissues this is a reportable disease. premature aging; increased number of pigmented nevi; infantile sex organs; webbed neck; broad chest with wide spacing of nipples. short fourth metacarpal; abnormal epiphyseal fusions; osteochondrosis-like changes of spine bicuspid aortic valve;* coarctation of aorta. * rarely other anomalies ( ) decreased/absent follicles. intestinal telangiectases. biliary atresia. * horseshoe kidney; double ureters. streak gonads without germ cells or follicles hashimoto's thyroiditis. * manifestations of diabetes mellitus,* hypertension,* or thyrotoxicosis. neuroblastoma and related tumors ( ). keratoconus acute aortic dissection, aortic insufficiency, and a single coronary artery in a patient with turner's syndrome neuroblastoma and related tumors in turner's syndrome turner's syndrome associated with bilateral retinal detachments weil's (see "leptospirosis related terms: alcoholic wernicke's encephalopathy; korsakoff's psychosis; nonalcoholic wernicke's encephalopathy ( , ); and specimen preparation, see chapter . for selection of histologic samples, see right-hand column melissas . wernicke's encephalopathy after vertical banded gastroplasty for morbid obesity syndrome, respiratory distress, of infant.") syndrome, wiskott-aldrich (see "syndrome, primary immunodeficiency malformation, ebstein's" and "preexcitation, ventricular alcoholic and non-alcoholic wernicke's encephalopathy. be alert to the preventable and treatable disease cerebro-hepato-renal syndrome; infantile refsum's disease. * note: this congenital familial cholestatic syndrome results from impaired assembly of peroxisomes and has its main manifestations in the brain, liver, and kidneys postmortem findings and prenatal diagnosis ofzellwegersyndrome. case report alcoholism and alcohol intoxication" and "disease, alcoholic liver possible associated condition: multiple endocrine neoplasia primary cardiac gastrinoma causing zollinger-ellison syndrome localization, syphilis, acquired synonym: treponema pallidum infection. note: congenital syphilis is presented below under a separate heading and surgical management of gastrinoma fundic argyrophil carcinoid tumor in a patient with sporadic-type zollinger-ellison syndrome nonimmune hydrops fetalis due to congenital syphilis associated with negative intrapartum mater-nal serology screening syringomyelia synonyms and related term: hydromyelia; idiopathic syringomyelia; secondary syringomyelia; syringobulbia. possible associated conditions: with idiopathic syringomyelia-arnold chiari malformation, type i;* basilar impression;* . oppenheimer eh, dahms bb. congenital syphilis in the fetus and neonate congenital syphilis: detection of treponema pallidum in stillborns with secondary syringomyelia-intramedullary gliomas (ependymoma, pilocytic astrocytoma) and vascular tumors; spinal arachnoiditis and pachymeningitislisted in right-hand column. prepare roentgenograms of spine and joints. for removal and specimen preparation, see chapter . for histologic sampling, see right-hand column. hypertrophy of body parts. muscle atrophy of upper extremities and hands cervical spinal cord is swollen and tense, with cavitation (syrinx) containing clear fluid. wall of cavity consists of degenerated glial and neural elements, with marked gliosis. spinal cord parenchyma is markedly compressed. see also above under hydrops fetalis caused by alpha-thalassemia: an emerging health care problem limb defects in homozygous alpha-thalassemia: report of three cases poisoning, thallium thirst (see "dehydration thromboangiitis obliterans (see "disease, buerger's purpura, thrombotic thrombocytopenic" and "syndrome, hemolytic uremic the pathological manifestations of pulmonary toxoplasmosis in the acquired immunodeficiency syndrome a spectrum in the pathology of toxoplasmosis in patients with acquired immu transfusion (see "reaction to transfusion bone marrow note: if the patient had symptoms of acute or chronic graft-versus-host disease (gvhd), see "disease, graftversus-host morphology and diagnostics of human toxoplasmosis fatal myocardial coinfection by toxoplasma gondii and parvovirus b in an hiv patient if there is evidence of infection, submit material for microbiologic studies. if there is evidence of recurrent leukemia or lymphoma, sample as described under those headings. if the patient had symptoms of thrombotic thrombocytopenic purpura (tip) or hemolytic uremic syndrome (hus), see these headings. record average size. fix specimens in b-plus®. make touch preparations. request giemsa or wright stain. for preparation of sections and smears (imprints), see chapter . manifestations of graft-versus-host disease (e.g., scleroderma-like changes).* septicemia. interstitial pneumonia* and cytomegalovirus infection* or human herpesvirus infection ( ). bacterial, fungal bacterial or fungal infections in gvhd.* other manifestations of gvhd. * recurrent leukemia,* lymphoma* (including posttransplant, epstein-barr virus associated lymphoproliferative disorder). recurrent solid tumor, e.g., carcinoma of breast, lung (small cell carcinoma), ovary lymphomatous or leukemic infiltrates myeloid cells may be absent in marrow graft rejection or nonimmunologic marrow graft failure. references hematomas; hemorrhagic necroses; infarcts; bacterial or fungal infections leukoencephal-opathy; vascular siderocalcinosis; neuro-axonal spheroids ( ) human herpesvirus infection and associated pathogenesis following bone marrow transplantation pulmonary veno-occlusive disease in an adult following bone marrow transplantation. case report and review of the literature acute renal failure following bone mar-row transplantation transplantation-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome thrombotic microangiopathies associated with drugs and bone marrow transplantation record status of all vascular anstomoses. if there are hemorrhages, record volume and site. record weight, ventricular thickness, and valve circumferences. take multiple sections from all areas of myocardium. cut coronary arteries in cross sections; request verhoeff-van gieson stain. procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. references cushingoid features (see "syndrome, cushing's") after steroid therapy. suture dehiscence. hemothorax or hemomediastinum in recent cases. left ventricular hypertrophy, from cyclosporine-related hypertension. acute transplant rejection (for grading, see ref. ). chronic transplant vasculopathy with coronary artery stenosis ( ) opportunistic infection ( ). pneumonia a working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart and lung rejection study group autopsy findings in cardiac transplant patients: a lo-year experience fulminant toxoplasmosis following heart transplantation banff schema for grading liver allograft rejection: an international consensus document record status of all vascular anstomoses. if there are hemorrhages, record volume and site. record lung weights separately. if lung infection is suspected, submit material for microbiologic possible or expected findings cushingoid features (see "syndrome, cushing's") after steroid therapy. suture dehiscence. hemothorax or hemomediastinum in recent cases. opportunistic infection (in patients with a single lung transplant, infections may involve references the nontransplant lung, as well). chronic bronchitis* and bronchiectasis.* acute rejection (rare); chronic airway rejection (obliterative bronchiolitis); chronic vascular rejection. (for grading of rejection, see ref .) post-transplant lymphoprolijerative disorder a working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart and lung rejection study group recurrent salmonella enteritidis and hepatic tuberculosis tularemia synonyms and related terms: francisella tularensis infection; pasteurella tularensis infection cerebral abscesses complicating tularemia meningitis endocrine (see "neoplasia, multiple endocrine any type note: ifthe tumor had been treated by surgery, irradiation, chemotherapy, or other means (the most common situation possible associated conditions: with adrenocortical adenoma-conn's syndrome with adrenocortical carci-noma-cushing's syndrome;* hypoglycemia;* virilization. with pheochromocytoma-cerebellarhemangioblastoma ery-throcytosis; hypercalcemia; hypertension,* multiple enarteries record body weight and abnormal features. photograph skin changes. record heart weight and thickness of ventricles. procure multiple sections of myocardium possible associated conditions.") focal myocarditis. * hypertensive cardiovascular disease (see "hypertension myocardial infarction without severe coronary artery disease (with pheochromocytoma) asystematicreviewoftheassociationbetween barrett's esophagus and colon neoplasm malakoplakia and colorectal adenocarcinoma an unusual case of colonic mixed adenoendocrine carcinoma: collision vs composite tumor. a case report and review of the literature submit lymph nodes for histologic study. remove neck organs with tongue together with esophagus. open pharynx and esophagus in posterior midline. if fistulas and abscesses are suspected, dissect esophagus but leave attached to mediastinum, stomach and diaphragm. record width of lumen of esophagus at various levels. photograph and record size and location of tumor; sample tumor and uninvolved esophagus for histologic study. request pas stain of uninvolved esophagus (sample from all levels). procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. references cachexia. eczematoid dermatitis with adult renal cell carcinoma. cushing's syndrome,* galactorrhea or feminization or masculinization in some cases of renal cell carcinoma. evidence of hyperalcemia. pulmonary tumor embolism after invasion of renal vein and inferior vena cava. acquired renal cystic disease prolactin, renin, and prostaglandins in some renal cell carcinomas. see above under "possible associated conditions wilms tumor associated with polycythemia: case report and review of the literature renal medullary carcinoma: a potential sickle cell nephropathy of children and adolescents acquired cystic kidney disease byler's disease, carcinoid syndrome,*cirrhosis* of any type (mostly nonbiliary), congenital hepatic fibrosis, * cushing's syndrome,* erythrocytosis, genetic hemochromatosis, * glycogen storage disease (type ),* hepatitis b or c virus infection, hereditary tyrosinemia (type i),* hypercalcemia, hypercholesterolemia, hypoglycemia,* neurofibromatosis,* osler-rendu-weber disease* (hereditary hemorrhagic telangiectasia), polycythemia,* porphyria (acute intermittent and porphyria cutanea tarda), * pseudohyperparathyroidism,* and thorium (thorotrast) deposition. with bile duct carcinoma (cholangiocarcinoma}-clonorchis sinensis or opisthorchis viverrini infection, fibropolycystic liver and biliary tract disease,* hepatolithiasis, hypercalcemia, pri-mary sclerosing cholangitis,* and thorium (thorotrast) deposition. with hepatoblastoma-alpha-fetoproteinemia, cardiac and renal malformations, cleft palate, diaphragmatic hernia,* down's syndrome,* familial colonic polyposis,* hemihypertrophy, nephroblastoma. with angiosarcoma-thorium (thorotrast) deposition. see also below under "possible or expected findings describe and photograph cut surfaces. sample tumor and nonneoplastic liver for histologic study. if thorium deposition is suspected, prepare roentgenograms of liver slices and submit samples for energy-dispersive x-ray microanalysis of paraffin sections. procedures depend on expected findings or grossly identified abnormalities as listed above and in right-hand column. cachexia. precocious puberty. feminization and gynecomastia in rare cases of hcc. spider angiomas; clubbing of fingers. see above under "possible associated conditions thorotrast storage may cause cirrhosis, hcc, bile duct carcinoma, or angiosarcoma. see above under "possible associated conditions tumor of the lung or bronchus possible associated conditions: abnormal concentrations of hormons or other metabolites in blood and tumor tissue (adrenocorticotropic, antidiuretic, growth hormone, parathyroid-like substances, or -hydroxyindolacetic acid); acanthosis nigricans s syndrome;*dermal hyperpigmentation; feminization; hyperglycemia; hypercalcemia; hypoglycemia;* hypokalemia; hyponatremia; precocious puberty. for syndromes affecting the brain, peripheral nerves or muscles, see below under "possible or expected findings organs and tissues procedures possible or expected findings external examination and skin record body weight. record abnormal features as listed in right-hand column; prepare photographs. prepare histologic sections of normal and grossly abnormal skin clubbing of fingers; spider angiomas. for other rare tumor-related changes, see above under "possible associated conditions thmor of the pancreas possible associated conditions: with carcinoma of the exocrine pancreas--cushing's syndrome;* diabetes mellitus* (rare); hypercalcemia; hyperglycemia with islet cell tumor-abnormal concentrations of hormons in blood and tumor tissue (see below under "pancreas"); features. dermal hyperpigmentation. for other rare tumor-related changes, see above under "possible associated conditions biliary obstruction caused by tumor in head of pancreas. islet cell tumor with adrenocorticotropic hormone, gastrin, glucagon, insulin, or other peptide hormones. see above under "possible associated conditions paraneoplastic pemphigus associated with pancreatic carcinoma pancreatic cystadenocarcinoma in peutz-jeghers syndrome testes may have been surgically removed to achieve androgen deprivation. urinary obstruction and hydronephrosis. * osteoblastic metastases hemolytic uremic syndrome in prostatic carcinoma thmor of the small intestine possible associated conditions: acquired immunode oncogenic osteomalacia associated with prostatic cancer gardner's syndrome) submit sample of non-neoplastic small bowel for histologic study. procedures depend on expected findings or grossly identified abnormalities as listed above. cachexia. mucocutaneous pigmentations associated with peutz-jeghers syndrome. * carcinoid tumor. lymphoma (see also above under "possible associated conditions"). familial polyposis or related syndrome. * celiac sprue. * crohn's disease. * see above under "possible associated conditions kasabach merritt syndrome in infants paraneoplastic hepatopathy associated with soft tissue sarcoma neurofibro-thmor of the spinal cord possible associated conditions: with angioma-cerebellar hemangioblastoma; segmental cutaneous vascular nevi; with matosis in children with soft tissue sarcoma tissues record abnormal features; photograph and submit nevi for histologic study. for removal and specimen preparation, see chapter . see also below under "vertebral column bone erosion and calcification of spinal canal. vertebral hemangiomas may be associated with arteriovenous malformation of spinal cord. manifestations of von hippel-lindau disease. * thmor of the stomach possible associated conditions: hypoglycemia;* megaloblastic anemia;* skin changes (as listed under "possible or expected findings)weight. record abnormal features; photograph and submit samples of normal and abnormal skin for histologic study. possible or expected findings cachexia; lower leg lymphoedema ( ) metastases common in liver, retroperitoneal and supraclavicular lymph nodes (virchow's node), ovaries (krukenberg tumor), and peritoneal cui de sac (blumer's shelf') carcinoma of the stomach with hyperkeratosis palmaris and plantaris and acanthosis of the esophagus gastric lymphoma ofmucosa-associated lymphoid tissue and helicobacter pylori gastric signet-ring cell carcinoma: unilateral lower extremity lymphoedema as the presenting feature thmor of the testis possible associated conditions: demyelinating neuropathy record location, size, and weight of both testes and of testicular tumor. submit samples of tumor and of ininvolved testis and epididymis for histologic study. snap-freeze tumor tissue for hormone assay. possible or expected findings cachexia. cryptorchism; hypospadia. gynecomastia. increased concentrations of alphafetoprotein and human chorionic gonadotropin testicular microlithiasis. secondary testicular tumors (metastases to the testes) are rare, except in association with leukemia* in children. references pulmonari embolism.* paraneoplastic diseases as listed above under "possible associated conditions chronic inflammatory demyelinating polyneuropathy (clop) associated with seminoma dermatomyositis associated with intratubular germ cell tumor and metastatic germ cell cancer testicular cancer in association with developmental renal anomalies and hypospadias submit samples of lymph nodes, spleen, peyer's plaques, and bone marrow for histologic study. other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. references cachexia. dermal hyperpigmentation. pemphigus foliaceus (rare). hypogammaglobulinemia and other immunoglobulin abnormalities. usually, thymoma presents as an infiltrating, anterior mediastinal mass that rarely metastasizes. carcinoid tumor, malignant lymphoma* (hodgkin's disease), and metastases from carcinomaofthe breast* and other tumors also may occur in this location herpes simplex*) and fungal infections (e.g., candidiasis*) due to thymoma-related immunodeficiency ( ). manifestations of paraneoplastic diseases and conditions as listed above under "possible associated conditions thrombotic thrombocytopenic purpura accompanied by transient pure red cell aplasia and thymoma glomerulonephritis associated with myasthenia gravis thymoma and cellular immune deficiency in an adolescent possible associated conditions: with papillary carcinoma-familial adenomatous polyposis thyroid carcinoma associated with familial adenomatous polyposis an association between acromegaly and thyroid carcinoma thyroid carcinoma causing fatal laryngeal obstruction prostate cancer metastasis to thyroid gland schistosomiasis and the risk of bladder cancer in human papilloma virus infection ( ) or herpesvirus infection ( ) with invasive cervical carcinoma. erythropoietin may be found in some tumors. thrombosis. * myopathy* may be associated with carcinoma of the cervix. cerebellar cortical degeneration* may be associated with carcinoma of the uterus. manifestations of uremia (see "failure, kidney") invasive cervical cancer in human immunodeficiency virus-infected and uninfected hospital patients association of risk factors for cervical cancer and human papilloma viruses in invasive cervical cancer association of herpesvirus infection with the development of genital cancer tyrosinemia type ii: a challenge for ophthalmologists and dermatologists hereditary tyrosinemia type i (chronic form): pathologic findings in the liver richner-hanhart syndrome (tyrosinemia ii): early diagnosis of an incomplete presentation with unusual findings acute pancreatitis-associated acute gastrointestinal mucosal lesions: incidence, characteristics, and clinical significance uncinariasis (see "ancylostomiasis uremia (see "failure, kidney from: handbook of autopsy practice urticaria pigmentosa of childhood (see ''mastocytosis, systemic acute aortic dissection;* aneurysma(s) of cerebral arteries; aortic insufficiency;* calcific aortic stenosis,* coarctation of the aorta;* infective endocarditis;* shone's syndrome; turner's syndrome. * organs and tissues procedures possible or expected findings heart if infective endocarditis is suspected, see chapter . open heart in cross-sections (see chapter ). photograph aortic valve and test valvular competence note: reye's syndrome* is a possible postviral complication of varicella that must be distinguished from varicella encephalitis. varicella may also cause exacerbation of tuberculosis.* (i) collect all tissues that appear infected bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions varicella-zoster virus infection in children with underlying immunodeficiency virus infection group a beta-hemolytic streptococcal epiglottitis as a complication of varicella infection optic neuritis: a rare complication of primary varicella infection hsv-l-induced acute retinal necrosis syndrome presenting with severe inflammatory orbitopathy, proptosis, and optic nerve involvement varicella with acute motor axonal neuropathy descending necrotizing mediastinitis in a child with chicken pox double outlet right ventricle with intact ventricular septum respiratory syncytial (see "pneumonia, all types or type unspecified vitamin a (see ''deficiency, vitamin a" and "hypervitaminosis a vitamin bt (thiamine) (see "syndrome, wernicke-korsakott vitamin bt (see "anemia, megaloblastic deficiency deficiency, vitamin d" and "hypervitaminosis d waldenstrom's macroglobulinemia (see ''macroglobulinemia, waldenstrom's.) waterhouse-friderichsen syndrome (see "disease, meningococcal wegener's granulomatosis (see "granulomatosis, wegener's werdnig-hottman disease (see "disease, motor neuron acid esterase activity in cultured skin fibroblasts and amniotic fluid cells using -methylumbelliferyl palmitate which may be secondarily infected by bacteria. dark field microscopy will identify the organism expected findings mucosal ulcers, resembling those of typhoid fever, primarily of distal ileum and colon. villous shortening, crypt hyperplasia with mucosal microabscesses. microabscesses in regional mesenteric lymph nodes zellweger's syndrome (see "syndrome mucormycosis" and procedures under "diabetes mellitus abscesses and granulomas may occur in all organs and tissues. granulomatous lesions in central nervous system ( ) and eyes ( ). fungal osteomyelitis* that may be multifocal, including sites such as metacarpals and metatarsals. external examination other procedures depend on expected findings or grossly identified abnormalities as listed in right-hand column. osteosclerosis of vertebrae, ribs, clavicles, pelvic bones, scapulae, skull, and metaphyseal ends of femur and humerus. osteomyelofibrosis or osteoreticulosis; rarely, panhyperplasia of bone marrow; increase of megakaryocytes.changes associated with chronic granulocytic leukemia* or with polycythemia vera* may imitate idiopathic myelofibrosis. widespread extramedullary hematopoiesis ( ) with splenomegaly. infectious diseases, including tuberculosis;* gouty arthritis; ascites and other manifestations of portal hypertension;* or hepatic vein thrombosis (budd-chiari syndrome*). cardiac tamponade ( ) . synonyms and related terms: hepatic porphyria; protoporphyrinogen oxidase deficiency ( ) .note: the manifestations of the disease closely resemble those in porphyria cutanea tarda and hereditary coproporphyria. measurements of porphyrins and porphyrin precursors are the only clearly distinguishing features. for autopsy procedures, see under "porphyria cutanea tarda." fibrin and platelet thrombi, with or without microaneurysms and purpura in kidneys, adrenal glands, pancreas, heart, and brain; lesions may also be present in liver; spleen ( ), lymph nodes, muscle, bone marrow, and synovium. fibrin thrombi can be demonstrated with labeled antihuman fibrin antibodies. lesions in precapillary arterioles. hypertrophic osteoarthropathy* (with pleural mesothelioma).pleural effusions. * asbestosis may be complicated by pleural mesothelioma. other organs and tissue sample bladder tumor and uninvolved urinary bladder for histologic study.cachexia. hydronephrosis* (obstructive uropathy) and hydroureter, usually caused by distal ureteral obstruction. recurrent nephrolithiasis* or pyelitis may have been present and is a risk factor for urinary bladder carcinoma.chronic urocystitis; infestation with schistosoma haematobium ( ) (uncommon in north america). manifestations of uremia (see "failure, kidney"). key: cord- -iuu yes authors: mainous, arch g.; hueston, william j. title: upper respiratory infections and acute bronchitis date: - - journal: management of antimicrobials in infectious diseases doi: . / - - - - _ sha: doc_id: cord_uid: iuu yes upper respiratory infections include the following: uncomplicated upper respiratory infections also known as the “common cold,” acute otitis media, pharyngitis/tonsillitis, and acute sinusitis. these conditions, along with acute bronchitis, are very common illnesses that are commonly seen in outpatient settings and are widely treated with antibiotics. in fact, these conditions are the primary indications for outpatient antibiotic prescriptions. these conditions tend to have overlapping clinical characteristics yet evidence regarding the utility of antimicrobial treatments varies across conditions. upper respiratory infections include the following: uncomplicated upper respiratory infections also known as the "common cold," acute otitis media, pharyngitis/tonsillitis, and acute sinusitis. these conditions, along with acute bronchitis, are very common illnesses that are commonly seen in outpatient settings and are widely treated with antibiotics. in fact, these conditions are the primary indications for outpatient antibiotic prescriptions. these conditions tend to have overlapping clinical characteristics yet evidence regarding the utility of antimicrobial treatments varies across conditions. uncomplicated upper respiratory infections (uris) are characterized by rhinorrhea, nasal congestion, sneezing, sore or "scratchy" throat, and cough [ ] . the incubation period varies between and h. while a low-grade fever in some cases is present, in adults, temperature elevation is rare. early symptoms may be minimal and limited to malaise and nasal symptoms. the nasal discharge is initially clear and watery. there is a subsequent transition period where the nasal discharge becomes viscous, opaque, and discolored (white, yellow, green) [ ] . the color of the secretions is not predictive of a bacterial infection. the clinical presentation is similar in both adults and children. the episode tends to be self-limited. the median duration of a cold is week, with most patients improving by the th day; however, lingering symptoms may last up to weeks. uris, or the "common cold," are exactly as the name implies -common. uris are consistently one of the five most common diagnoses in ambulatory physician office visits [ , ] . adults have two to four uris annually, and children in day care have as many as six or seven [ , ] . the significant costs of uris can be conceptualized as both direct and indirect costs. the direct costs of uris include the costs associated with the substantial number of office visits. uris account for more than million physician office visits a year [ ] . in addition, microbiologic and laboratory diagnostic tests are sometimes performed but are of dubious clinical value and, therefore, contribute unnecessarily to the cost of uris [ ] . the total economic impact of non-influenza-related uris has been estimated to approach $ billion annually (direct costs, $ billion per year; and indirect costs, $ . billion per year) in the united states [ ] . indirect costs for uris include productivity losses related to lost workdays for adults who are sick as well as adults who have to deal with sick children. other indirect costs that are many times overlooked are the impact of uris on missed opportunities to immunize young children. although the interpretation of guidelines by the american academy of pediatrics and the advisory committee on immunization practices, particularly for fever and moderate illness, rests with the clinician [ , ] , a large proportion of children are not immunized on schedule due to visits for uris [ ] . this finding also suggests additional visits for immunizations thereby requiring additional direct costs and indirect costs inherent in taking children to the physician's office. the mechanisms of transmission suggest that uris can be spread through contact with inanimate surfaces [ ] and hand-to-hand contact [ ] . uris have a seasonal variation with an increased prevalence in the united states between september and march. it is unclear why this variation exists, although it may be related to increased crowding of indoor populations in the colder months. temperature is not the key to seasonal variation without the presence of a pathogen. evidence from antarctica showed that spacious well-ventilated rooms reduced transmission of uris as compared to crowded poorly ventilated rooms regardless of temperature [ ] . viruses have been shown to be the major pathogens in uris [ ] . one study established viral etiology in % of uris [ ] . rhinoviruses were found in % of the patients by viral culture or pcr assay. coronaviruses were the second most common group of causative agents, followed by influenza a or b virus. identified bacterial pathogens were chlamydia pneumoniae, haemophilus influenzae, streptococcus pneumoniae, and mycoplasma pneumoniae. none of the patients had beta-hemolytic group a streptococcus. in terms of bacterial pathogens, infections without evidence of a viral infection occurred in only . % of the cases. a variety of studies in the s showed a high rate of prescribing antibiotics for uris [ , ] . more recent data have indicated a drop in the prescribing of antibiotics; however, the use of antibiotics is still far from optimal [ ] . controlled trials of antimicrobial treatment of uris have consistently demonstrated no benefit [ , ] . in eight trials of antimicrobial treatment of uris, six found no difference between the groups either in terms of improvement or in terms of complications. complications tend to be minimal and occur at a rate of - %. one trial found some slight benefit in decreasing the presence of purulent rhinitis [ ] . another found a decrease in rhinorrhea at day but no difference between the groups at day [ ] . similarly, an additional trial attempted to isolate "bacterial colds" for which antibiotics might be effective treatments [ ] . although there was some indication of patient improvement at day , the differences were gone by day . it is important to remember that the normal presentation of a uri is a week to days. few successful treatments have been identified. vitamin c, zinc gluconate, and echinacea have all shown mixed results [ , ] . antihistamines, with a few exceptions, have not been shown to be effective treatments [ ] . the most effective symptomatic treatments are over-the-counter decongestants [ ] . acute sinusitis has considerable overlap with uris in its constellation of signs and symptoms. one half to two thirds of patients with sinus symptoms seen in primary care are unlikely to have sinusitis [ ] . in patients who presented with a uri, % had radiographic evidence of maxillary sinusitis but had no symptoms of sinus infection [ ] . uris are often precursors of sinusitis, and, at some point, symptoms from each condition may overlap. sinus inflammation from a uri, without bacterial infection, is also common. in a series of children undergoing computerized tomography (ct) for non-sinus-related diagnoses, % had evidence sinus inflammation with no clinical signs of sinusitis and with complete resolution following their viral illness [ ] . acute sinusitis tends to start with a uri that leads to sinus ostial obstruction. the signs and symptoms that increase the likelihood that the patient has acute sinusitis are a "double sickening" phenomenon whereby the patient seems to improve following the uri and then deteriorates, exhibiting symptoms such as maxillary toothache, purulent nasal discharge, poor response to decongestants, and a history of discolored nasal discharge [ , ] . other authors have stressed that the symptoms need to persist longer than week to distinguish sinusitis from a uri [ ] . it should be pointed out that the commonly used sign of facial pain or swelling has low sensitivity for acute sinusitis [ ] . since sinusitis is most often a complication of upper respiratory viral infections, it follows the same seasonal pattern as colds. this pattern produces a winter peak with more cases seen than those exposed to upper respiratory tract infections. in children seen in a large health system, sinusitis is frequently found as a comorbidity with otitis media. nearly half of all children with sinusitis also had otitis media [ ] . children are also more likely to have posterior ethmoidal and sphenoid inflammation, while adults have mainly maxillary and anterior ethmoidal sinusitis [ ] . some medical conditions may increase the risk for sinusitis; these include cystic fibrosis, asthma, immunosuppression, and allergic rhinitis [ ] . cigarette smoking may also increase the risk of bacterial sinusitis during a cold because of reduced mucociliary clearance. sinus inflammation can be caused by viral, fungal, and bacterial infections as well as allergies. the majority of acute sinusitis is caused by viral infection. as indicated above, many cases of the common cold have concomitant sinus inflammation. the inflammation associated with viral infections clears without additional therapy. bacterial superinfection of uris is rare and occurs in only . - % of colds. studies examining the treatment of sinusitis confirm that response rates to antibiotics are either small [ ] . when sinusitis is confirmed by a ct scan, response rates to antibiotics are improved [ ] . cultures of material obtained from patients with sinusitis show that the most prevalent organisms are strep. pneumoniae and, especially in smokers, h. influenzae. these two organisms are present in % of cases of bacterial acute sinusitis [ ] . when antibiotics are used for the treatment of bacterial sinusitis, the selection of antibiotics should include sufficient coverage of these two organisms. fungal sinusitis are very rare and usually occur in immunosuppressed individuals or those with diabetes mellitus [ ] . antibiotics are commonly prescribed for adult patients who present with complaints that are consistent with acute sinusitis. the effectiveness of antibiotics is unclear. three recent placebo-controlled, double-blind, randomized trials in general practice settings have yielded mixed results [ , , ] . two of these trials showed no beneficial effect of antibiotics [ , ] ; the third trial, however, demonstrated a significant effect of penicillin and amoxicillin [ ] . the trial showing an effect used more stringent enrollment criteria than the other two; the criteria in the trial are more consistent with those used in daily practice by primary care physicians. these data suggest that patients with more severe signs and symptoms may benefit from an antibiotic. if an antibiotic is to be used, some evidence with trimethoprim/sulfamethoxazole suggests that short-duration treatment (e.g., days) is as effective as longer treatment [ ] . further, narrow-spectrum agents seem as effective as broad-spectrum agents [ ] . in patients with severe signs and symptoms, antibiotics have some utility in treating acute sinusitis. if antibiotics are to be used, then short-course therapy with narrow-spectrum agents is recommended. the key to the judicious use of antibiotics is to first make an accurate diagnosis of sinusitis rather than overtreating uris. the evaluation and management of otitis media has been subject to a wide variance in approaches. the variation in management of otitis media is typified in an examination of the management of otitis media in nine countries in the mid- s [ ] . in this study, antibiotics were used over a wide range ( - %) of episodes of otitis media with similar variation in the types of antibiotics used and duration of therapy. to help bring some consensus to the process, the american academy of pediatrics issued a guideline for the evaluation and treatment of otitis media in [ ] . while the guideline suffers from a lack of definitive evidence in several areas of care, the recommendations are an effective tool for bringing some clarity to an issue that has suffered from a wide variation in management strategies. the aap guideline recommends that the diagnosis of otitis media requires three essential components: an acute onset of illness, presence of a middle ear effusion, and signs and symptoms of middle ear inflammation. middle ear effusion is evident in children with bulging of the tympanic membrane, reduced or absent mobility of the membrane with pneumatic otoscopy, an air-fluid level behind the membrane, and pain in the effected side. inflammatory signs noted in the report include erythema of the tympanic membrane along with pain on that side. in considering all these factors, the combination of reduced mobility, erythema, and a bulging tympanic membrane is the best predictor of otitis media. the most essential step in managing otitis media is assuring that the diagnosis is correct. otitis media may be overdiagnosed, especially in younger children, which complicates the evaluation of treatment effectiveness. studies show that a physician's certainty about the diagnosis of otitis media is dependent on the patient's age. in a multinational study, it was found that physicians were certain of the diagnosis in only % of children under the age of [ ] . this increased to % in those between year and months of age and up to % in those over months of age. historically, acute otitis media has been one of the most common pediatric conditions seen in primary care. however, since the introduction of vaccines against common respiratory pathogens, there is evidence that the frequency of this problem has decreased considerably. in the netherlands, visits to general practitioners for otitis media with effusion in children under the age of fell by % between and [ ] . a similar decrease in visits for acute otitis in children has been reported in a large health system in the united states [ ] , with a smaller reduction in visits noted in the emergency department setting [ ] . the introduction of h. influenzae b vaccine in the s, followed by universal childhood immunization with conjugated strep. pneumoniae, may be responsible for the reduction in otitis media cases encountered. since otitis media is a complication of an upper respiratory infection, it has a peak incidence in the winter when colds are most likely to occur. unlike sinusitis, which is more likely to affect adults, otitis media is predominantly a disease of younger children with a peak incidence between and months of age [ ] . otitis media occurs with varying frequency in children. in a large population study, it was found that during the first years of life about a third of children never had otitis media and another third had one or two episodes, while the remaining third had three or more episodes. otitis media occurs more often in males, children in lower socioeconomic groups, and in certain ethnic groups such as native americans. because of differences in the mechanics of the posterior pharynx and eustachian tube, children born with craniofacial congenital abnormalities such as cleft lip/palate and those with trisomy also are more likely to have otitis media as a complication of a cold. otitis media arises from eustachian tube dysfunction that accompanies uris or allergic rhinitis. inflammation of the eustachian tube and middle ear results in tube occlusion and fluid accumulation in the middle ear space. eustachian tube obstruction is more common in younger children because of less cartilage support of the tube making collapse more likely. the eustachian tube obstruction not only causes entrapment of existing fluid but also produces a negative pressure in the middle ear that results in additional fluid accumulation that characterizes serous otitis media. contamination of this fluid with bacteria results in acute suppurative otitis media. suppurative otitis media is most often caused by the same organisms that result in sinusitis. studies of middle ear aspirates suggest that strep. pneumonia is the most common bacterial cause of otitis media and is found in about % of effusions. h. influenzae accounts for approximately another %. b. catarrhalis and staphylococcus aureus each make up fewer than % of cases. in neonates, gram-negative species also should be considered as potential etiologic agents. otitis media also may result from noninfectious obstruction of the eustachian tube. allergic rhinitis, as noted above, is one such mechanism. other causes include enlargement of the adenoids and posterior pharyngeal tumors. treatment recommendations from the aap/aafp guidelines for the management of acute otitis media suggest that observation rather the initial use of antibiotics is appropriate depending on the child's overall health, age, severity of illness, and likelihood that they can follow-up if necessary. for healthy children over the age of , antibiotics are recommended only if the child is severely ill; if the child is mildly ill or if the diagnosis is uncertain, then observation is acceptable. for children younger than this, antibiotics are recommended for a certain diagnosis of otitis media and for those under age months where the diagnosis is uncertain. antibiotics are not recommended for use in healthy children between months and years who have an uncertain diagnosis (aap subcommittee). if patients who are observed fail to improve in - h, then antibiotic therapy is recommended. based on the aap/aafp guidelines, routine observation or "wait and see protocol (wasp)" as an alternative to universal antibiotic use has been evaluated in emergency room setting. a randomized trial of the wasp approach compared with routine antibiotics showed that antibiotic use was reduced from to % with no differences in prolonged fever, ear pain, or unscheduled subsequent visit for the ear infection [ ] . despite evidence that the wasp or observation period is effective, primary care physicians have been slow to adopt this in practice [ ] . when antibiotics are selected for the management of acute suppurative otitis media, selection of an agent should provide coverage for the two most common organisms, the aap/aafp recommends initial treatment with amoxicillin at a dose of - mg/kg per day. second, the duration of antibiotic treatment is unclear. in a meta-analysis of trials that compared short-duration antibiotic therapy with the traditional day course, no benefit was found of using longer courses of treatment; however, methodologic problems may complicate the interpretation of these results [ ] . in their guidelines, the aap/aafp recommends that a - day course of antibiotics should be sufficient for treatment. in addition to short-course therapy, a single intramuscular dose therapy of ceftriaxone has been shown to be equally beneficial to longer courses of amoxicillin [ ] , cefaclor [ ] , or trimethoprim-sulfamethoxazole [ ] for the treatment of acute suppurative otitis media. where antibiotic resistance to s. pneumonia is high or where patient compliance is an issue, ceftriaxone may be a viable alternative. in addition, some studies have evaluated the use of a single dose of azithromycin ( mg/kg) for treatment of uncomplicated otitis media. in a review of these studies, the overall success rate was % [ ] . macrolide resistance to s. pneumoniae was the largest impediment to success. based on this, it was suggested that single-dose azithromycin may be an alternative in areas with resistance to s. pneumoniae is uncommon. the primary concern in the treatment of otitis media is a primary treatment failure (i.e., persistent illness or an early recurrence of disease following initial therapy of a new otitis episode) [ ] . a meta-analysis of randomized trials supports initial antibiotic use demonstrated no significant differences in failure rates when comparing "standard" or first-line (penicillin, amox/ampicillin, erythromycin, and sulfamethoxazole) and "extended-spectrum" or second-line antibiotics or with duration of therapy. the only factor that appears to be consistently linked to a higher likelihood of a primary treatment failure is a child's age [ , ] , with children younger than years of age having treatment failures in - . % of cases. for older children, treatment failures occur in - % of episodes [ , ] . also of concern is how to manage a new case of otitis media when a previous treatment failure has occurred. in a study that examined failure rates in new infections for children who had a previous treatment failure, there was no benefit of starting therapy with an extended-spectrum agent compared to "first-line" drugs. thus it appears that in a case of previous treatment failure, new cases should be managed with narrow-spectrum agents such as amoxicillin or tmp-smx [ ] . the use of second-line antibiotics when a first-line agent will suffice creates two problems. first, in most cases the use of broad-spectrum drugs adds significant expense to therapy. others have reported that use of second-line agents compared to amoxicillin or smx-tmp adds % to the overall cost of the episode [ ] . since the results of this study show comparable failure rates for first-and second-line antibiotics, there appears to be no justification for this additional cost. second, the injudicious use of broad-spectrum antibiotics may increase the potential for future development of antibiotic resistance. the overuse of antibiotics has been proposed as one reason for the observed growth in antibiotic resistance reported in common childhood organisms such as s. pneumoniae. otitis media is a condition in which antibiotics are frequently prescribed for children and where broad-spectrum antibiotics may be used unnecessarily. limiting the use of broadspectrum drugs to situations in which they are beneficial (i.e., managing the resistant case of otitis) may help reduce further development of drug resistance in children. sore throat is a common reason that patients consult with a physician. most of these are viral infections related to upper respiratory infections, but about - % are secondary to infection with group a beta-hemolytic streptococcus. the primary role of the physician is to differentiate streptococcal pharyngitis from viral illnesses. since most patients with sore throats probably do not visit their doctor, it is difficult to state with any certainty how often sore throats occur in healthy populations. however, pharyngitis is one of the most common diagnoses for physician office visits. estimates from suggest that more than million visits in the united states each year are for pharyngitis [ ] . frequently antibiotics are prescribed for these conditions without evidence of a bacterial etiology. both viral and group a streptococcal pharyngitis have peak occurrences in the winter and early spring. streptococcal infection, in particular, can be recognized in epidemic patterns frequently affecting groups that spend considerable time together in close quarters such as day cares, schools, and places of employment. strep throat also is related to patient age. while infection in the very young (< year old) is uncommon, the peak occurrence for strep throat is between and years of age with diminished risk over the age of . the most common causes of pharyngitis are respiratory viruses. adenovirus and the rhinoviruses account for about % of cases of sore throat in children that are seen by physician [ , ] . coxackievirus, herpesvirus, and epstein-barr virus can cause tonsillitis but are less common that adenovirus [ ] . adenovirus, coxackievirus, and epstein-barr virus can cause exudative pharyngitis that can mimic the appearance of streptococcal infection. while exudative tonsillitis is thought to be a hallmark of group a streptococcal infection, this sign is actually present more often from adenovirus than streptococcus. it is important to identify group a streptococcal infections because trials of antibiotics in undifferentiated sore throat populations show little benefit [ ] . group a beta-hemolytic streptococcus can cause an acute tonsillopharyngitis and may colonize the oropharynx without symptoms. the asymptomatic carrier rate of group a strep ranges from about to % of healthy children, a rate that nearly matches the true infection rate [ , ] . this means that in testing for group a streptococcus, positive tests are just as likely to occur from carriers of group a strep who have a concomitant virus as those actually infected with the organism. in contract to group a streptococcal tonsillopharyngitis, treatment of the carrier state is not necessary and does not reduce symptoms or reduce complications [ ] . the reasons for antibiotic treatment of beta-hemolytic group a streptococcal pharyngitis are to alleviate symptoms, reduce the spread of disease, and reduce the risk of suppurative and nonsuppurative complications. although some authors have suggested that antibiotics are not justified to reduce the risk of rheumatic fever, a complication of beta-hemolytic group a streptococcal pharyngitis, the american heart association in still recommends antibiotic treatment [ , ] . differentiating group a streptococcal pharyngitis from viral disease is the most vexing problem in the management of acute sore throat. the clinical impression of the treating physician has been shown to be fairly inaccurate at making this differentiation [ ] [ ] [ ] . a clinical prediction rule for presence of strep throat that has some utility uses the presence of tonsillar exudate, pharyngeal exudate, or exposure to strep throat infection and the absence of tender anterior cervical nodes, tonsillar enlargement, or exudate. no individual element of history-taking or physical examination is accurate enough by itself to rule in or rule out strep throat [ ] . another dilemma in identifying group a strep in patients with pharyngitis is the sensitivity of rapid group a antibody kits compared to a throat culture. many studies have shown that a rapid test is less sensitive than the culture for identifying the presence of group a strep. the rapid tests have a high degree of specificity, but their sensitivity in clinical practice can be unacceptably low. sensitivities for the rapid test compared to a standard blood agar culture vary considerably but are generally in the range of - %. studies also have demonstrated that in circumstances when the colony counts are low, rapid tests are more likely to miss the presence of group a streptococcus. however, when the seroconversion of aso titers is used as the gold standard for infection, rapid tests perform very well [ ] . it is likely that rapid tests miss patients who have a small number of organisms and who are likely to be colonized instead of infected. thus, rapid testing may be more specific in identifying patients with actual strep-related disease than cultures, which also identify those who are likely to be carriers. this comparison suggests that follow-up throat cultures are not necessary and may actually confuse treatment decisions. rapid strep testing without culture also has been shown to be the most cost-effective approach to managing acute pharyngitis [ ] . as indicated above, reports regarding the role of chlamydia and mycoplasma indicate that these two organisms also may be associated with acute pharyngitis. however, there have been few treatment trials that demonstrate any benefit of treating non-group a streptococcus with antibiotics that would treat either of these organisms. in a study using erythromycin to treat non-group a strep pharyngitis [ ] , patients who received placebo had the same speed of symptom resolution as those treated with active antibiotics. once group a streptococcus has been implicated in the infection, the choice of antibiotic is controversial. with only scant evidence that treatment reduces the symptomatic period and a low risk of complications from untreated group a streptococcal pharyngitis, some investigators suggest that antibiotic treatment carries more risks than not treating and encourages future health seeking and antibiotic expectations for future sore throats [ ] . however, formal decision analyses suggest that in cases of moderate probability of strep throat ( - %) with symptom duration of days or less, rapid strep testing and treatment is beneficial [ ] . selection of an appropriate antibiotic and duration of therapy are important considerations in treating strep pharyngitis. penicillin v resistance in group a strep as well as erythromycin resistance has led to investigations of other drugs for management of strep throat. since streptococcal pharyngitis is a self-limited problem even without antibiotic therapy, much of this resistance has been based on positive throat cultures following the termination of treatment. this may be misleading since colonized patients may continue to harbor streptococcus even after therapy. when drug failure rates are examined with penicillin, cultures remain positive in - % of treated patients [ , ] . however, single-dose therapy with amoxicillin at mg/kg/day for days appears to be very successful resulting in excellent clinical responses and low rates ( - %) of posttreatment carrier rates [ , ] . treatment with other agents such as azithromycin and clarithromycin produces no better results than amoxicillin or penicillin v [ ] [ ] [ ] ; however, these treatments amount to a much greater expense. attempts at "short-course" therapy have been studied with azithromycin [ ] . both short-course treatment with azithromycin and days of cefaclor have exactly the same clinical cure rates ( %) by day of therapy. however, patients treated with cefaclor were less likely to become recolonized with group a strep over the next days than those treated with the short course of azithromycin ( % vs. %). since the significance of rapid recolonization is still unclear, shortcourse therapy with azithromycin or other antibiotics still requires additional investigation. while the carrier rate does not require treatment [ ] , some clinicians attempt to eradicate those colonized by group a strep to prevent spread to other family members and close contacts. a regimen of intramuscular penicillin v plus oral rifampin has been shown to reverse the carrier status in % of patients treated [ ] . there have been no studies performed more recently that have explored whether this regimen remains effective with increased group a strep resistance to penicillin. despite evidence that chlamydia and mycoplasma may be associated with acute pharyngitis, there have been no studies that have shown a benefit from treatment of patients with non-group a streptococcal pharyngitis with antibiotics: studies with penicillin [ ] , which would not be expected to cover these agents, and macrolides [ ] , which would have not shown any significant improvement over placebo. until specific tests that can rapidly identify these organisms are developed which would allow for targeted treatment and studies can demonstrate that treatment reduces symptoms and complications, indiscriminate antibiotic therapy for non-group a strep pharyngitis should be avoided. acute bronchitis is an inflammatory condition of the tracheobronchial tree usually associated with a generalized respiratory infection. cough begins early in the course of the illness and is the most prominent feature of the condition. an initially dry cough may later result in sputum production which characteristically changes from clear to discolored in the later stages of the illness. the cough may last for a significant time. although the duration of the condition is variable, one study showed that % of patients had a cough for more than weeks and % had a cough for more than weeks [ ] . patients with acute bronchitis usually have a viral respiratory infection with transient inflammatory changes that produce sputum and symptoms of airway obstruction. acute bronchitis is essentially a diagnosis of exclusion. the history should include information on cigarette use, exposure to environmental toxins, as well as medication history (e.g., use of angiotensin-converting enzyme inhibitors). the chronicity of the cough should be established to distinguish acute bronchitis from chronic bronchitis since they have different treatments. both acute bronchitis and pneumonia can present with fever, constitutional symptoms, and a productive cough. while patients with pneumonia often have rales, this finding is neither sensitive nor specific for the illness. when pneumonia is suspected on the basis of a presence of a high fever, constitutional symptoms, severe dyspnea, and certain physical findings or risk factors, a chest radiograph should be obtained to confirm the diagnosis. asthma and allergic bronchospastic disorders can mimic the productive cough of acute bronchitis. when obstructive symptoms are not obvious, mild asthma may be diagnosed as acute bronchitis. further, since respiratory infections can trigger bronchospasm in asthma, patients with asthma that occurs only in the presence of respiratory infections resemble patients with acute bronchitis. asthma should be considered in patients with repetitive episodes of acute bronchitis. patients who repeatedly present with cough and wheezing can be given full spirometric testing with bronchodilation or provocative testing with a methacholine challenge test to help differentiate asthma from recurrent bronchitis. finally, nonpulmonary causes of cough should enter the differential diagnosis. in older patients, congestive heart failure may cause cough, shortness of breath, and wheezing. reflux esophagitis with chronic aspiration can cause bronchial inflammation with cough and wheezing. bronchogenic tumors may produce a cough and obstructive symptoms. acute bronchitis in the otherwise healthy adult is one of the most common medical problems encountered in primary care [ , ] . the prevalence of acute bronchitis peaks in the winter and is much less common in the summer. viral infection is considered the primary cause of most episodes of acute bronchitis. a wide variety of viruses have been shown as causes of acute bronchitis including influenza, rhinovirus, adenovirus, coronavirus, parainfluenza, and respiratory syncytial virus [ ] . nonviral pathogens including mycoplasma pneumoniae and c. pneumoniae (twar) have also been identified as causes [ , ] . the etiologic role of bacteria like h. influenzae and s. pneumoniae in acute bronchitis is unclear since these bacteria are common upper respiratory tract flora. sputum cultures for acute bronchitis are therefore difficult to evaluate since it is unclear whether the sputum has been contaminated by pathogens in the nasopharynx. usually, laboratory and imaging tests are not needed in the diagnosis of acute bronchitis. however, a new test under consideration might be helpful in differentiating viral acute bronchitis from more serious bacterial infections such as pneumonia. by measuring procalcitonin, a precursor to the hormone calcitonin, christ-crain and colleagues have been able to distinguish patients at high risk for bacterial infections (those with higher procalcitonin levels) from those with low risk for bacterial infection. evaluation of this method in the emergency department has led to reductions in antibiotic prescribing without any differences in clinical outcomes for patients presenting with acute cough syndromes [ ] . while a point-of-care version of the test for procalcitonin has been developed that can be done quickly in a physician's office, the test is still expensive and has not been evaluated outside the emergency department. antibiotic treatment for acute bronchitis is quite common with evidence indicating that - % of adults visiting a doctor for acute bronchitis receiving an antibiotic [ , ] . clinical trials of the effectiveness of antibiotics in treating acute bronchitis have had mixed results. one reason for the lack of consensus is that in each of the nine trials, different antibiotics were used as well as different outcomes. in an effort to quantitatively review the data, two different meta-analyses were recently conducted [ , ] . in the fahey et al., meta-analysis resolution of cough was not affected by antibiotic treatment and neither was clinical improvement at reexamination. importantly, the side-effects of antibiotics were more common in the antibiotic groups compared to placebo. the smucny et al., meta-analysis concluded that antibiotics may be modestly effective for a minority of patients with acute bronchitis, although it is unclear which subgroups might benefit. the conclusion of both meta-analyses was that the benefits or antibiotics are marginal and are not useful for the general group of patients with acute bronchitis. recent data from clinical trials suggest that bronchodilators may provide effective symptomatic relief to patients with acute bronchitis [ , ] . treatment with bronchodilators demonstrated significant relief of symptoms including faster resolution of cough, as well as return to work. one study evaluated the effect of albuterol in a population of patients with undifferentiated cough and found no beneficial effect [ ] . 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bronchitis in ambulatory care: the use of antibiotics and bronchodilators are antibiotics effective treatment for q acute bronchitis? a meta-analysis quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults symptomatic effect of inhaled fenoterol in acute bronchitis: a placebo-controlled double-blind study albuterol delivered by metered-dose inhaler to treat acute bronchitis a randomized controlled trial of oral albuterol in acute cough key: cord- -clctlm l authors: diamantaki, eleni; proklou, athanasia; pediaditis, emmanouil; amargianitakis, vasilis; kondili, eumorfia title: acute respiratory failure before icu admission: a practical approach date: - - journal: mechanical ventilation in critically ill cancer patients doi: . / - - - - _ sha: doc_id: cord_uid: clctlm l acute respiratory failure (arf) is a common and life-threatening event in cancer patients. it is the leading cause of admission to icu among the patients with hematologic and solid malignancies and is often associated with poor outcome. timely identification of the cause of arf and the initiation of the appropriate therapy may improve the survival. pulmonary infections represent the leading cause of arf in those patients, and unless proven otherwise, arf must be considered as an infectious emergency. noninfectious causes of arf include cardiogenic and noncardiogenic pulmonary edema, acute pulmonary embolism, and complications related both to the underlying malignancy and the toxic effects of chemotherapy. this chapter reviews the most common causes of arf in oncologic patients and discusses the diagnostic and therapeutic approach before icu admission. acute respiratory failure (arf) occurs in up to half patients with hematologic and solid malignancies and is the leading cause of icu admission in those patients. it is associated with poor outcome, with an overall mortality of - % depending on the cause, the need for mechanical ventilation, the concomitant organ dysfunctions, the presence of graft-versus-host disease, and the goals of care [ , ] . delay in identification of the cause of arf and the initiation of the appropriate therapy may further increase mortality. the most common cause of arf in cancer patients is pulmonary infections, as a result of the immunosuppression posed by the underlying disease or the cancer therapy. other frequent causes include cardiogenic and noncardiogenic pulmonary edema (acute respiratory distress syndrome [ards]), antineoplastic therapy (chemotherapy, radiation therapy)-induced lung injury, cancer-related medical disorders (such as venous thromboembolism, transfusionrelated acute lung injury), and direct involvement of the respiratory system by malignancy and progression of underlying disease. in cancer patients with arf, the diagnostic strategy is to guide the immediate empirical treatment, most notably antimicrobial therapy as well as life-supporting interventions [ ] . however, investigations must be obtained very rapidly to confirm or refute the initial diagnoses. differential diagnosis of arf in cancer patients is a challenging process for the clinical physician. the cornerstone in the etiological diagnosis of arf consists of a comprehensive clinical evaluation aimed at identifying the most likely causes and, therefore, at determining the appropriate diagnostic approach. a thorough physical examination provides key information on the respiratory manifestations (bronchial, interstitial, alveolar, vascular, or pleural symptoms), the severity of the arf, and the time elapsed since respiratory symptom onset. both invasive and noninvasive diagnostic strategies can be used to identify the cause of arf in cancer patients. the invasive strategy relies on fiberoptic bronchoscopy with bronchoalveolar lavage (fo-bal), and the noninvasive strategy on imaging studies, on microbiological examination of blood and sputum, and on serological test. it is already established that stable patients presenting with arf and pulmonary infiltrates should undergo fb-bal as microbiological and cytological examination of the bal can be diagnostic in up to % of cancer patients with arf [ ] . however, in severely hypoxemic patients, fo-bal has been described as inadvisable or contraindicated because of the risk of deterioration in respiratory status with a subsequent need for mechanical ventilation [ ] . imaging tests are of importance, in the identification of the cause of arf. chest x-ray should be performed in any patient presented with symptoms and signs of arf, though it is neither specific nor sensitive in providing a specific diagnosis in particular in patients with febrile neutropenia. high-resolution computed tomography (hrct) with sections at -mm intervals and, if needed, sections during expiration is more sensitive than chest radiography even in non-neutropenic patients. however, hrct provides diagnostic orientation rather than a definitive diagnosis in cancer patients with arf [ ] . hrct yields an overall sensitivity and negative predictive value of %, in identifying the cause of arf in cancer patients with lung infiltrates, but low specificity and positive predictive value [ ] . in some times hrct may help to select the nature and site of endoscopic sample collection. recently lung ultrasound (lus) has been introduced as diagnostic test in patients with arf. lus is a noninvasive and bedside-available imaging test, and many studies have shown that compared to chest x-ray, it has a higher diagnostic accuracy for pleural effusion, consolidation, pneumothorax, and interstitial syndrome and may be used as alternative to ct [ ] . this chapter reviews the most common causes of arf in oncologic patients and discusses the diagnostic and therapeutic approach before icu admission. must be considered as an infectious emergency. several factors increase the risk of infection in those patients, including chemotherapy, corticosteroid-induced immunosuppression, multiple hospital admissions, and exposure to broad-spectrum antibiotics [ ] . causative pathogen depends on the underlying immune state. in patients with impaired humoral immunity, such as those with acute and chronic lymphocytic leukemia and multiple myelomas, streptococcus pneumoniae and haemophilus influenzae are the predominantly isolated organisms. in patients with impaired cell-mediated (t-cell) immunity as those with hodgkin disease or those therapy with corticosteroids, the predominantly isolated organisms are pneumocystis jirovecii pneumonia (pjp), followed by mycobacteria, cryptococcus, legionella pneumophila, and viral infections (mainly herpes virus and cytomegalovirus). neutropenic patients are usually infected by gram-positive cocci (staphylococcus aureus and streptococcus pneumoniae), gram-negative enteric bacilli (pseudomonas aeruginosa and klebsiella pneumoniae), or opportunistic fungi (mainly aspergillus)-especially in the case of prolonged neutropenia [ , ] . when evaluating pneumonia in patients with cancer, determining the level and the duration of immunosuppression, the previous exposure to antimicrobials (over the last month), the length of the illness, the presenting symptoms, and the radiographic pattern will better predict the suspected pathogens. hereby we discuss the most common pulmonary infections in the immunocompromised patients. in patients with bacterial pneumonia, clinical manifestation is the typical one occurring in non-oncologic patients with pneumonia, including acute onset of shaking chills, tachypnea, tachycardia, fever (which occurs in virtually all patients with bacterial pneumonia), and productive cough. however, in the setting of neutropenia, clinical diagnosis is often jeopardized by nontypical clinical findings [ ] . sputum production is seen in less than % of neutropenic patients, while in severe neutropenia (neutrophils < cells/mm ), purulent sputum is present in less than % of patients. routine clinical examination often reveals rales and signs of consolidation. to determinate the cause of pneumonia, blood cultures should be performed routinely; however, the results may be of limited value. similarly, sputum analysis is often low yield, and the results are difficult to interpret. identifying the exact cause of pneumonia in patients with cancer often requires fiberoptic bronchoscopy with bal as sputum is seldom produced. the overall diagnostic yield of bal in neutropenic and non-neutropenic patients with suspected pneumonia is % and %, respectively [ ] . chest x-ray findings of bacterial pneumonia in cancer patients are nonspecific. the initial chest radiograph may be normal (mainly in neutropenic patients) or demonstrate lobar consolidation (usually missing in neutropenic patients) and diffuse interstitial infiltrates. aspergillus lung disease may present in four district clinical syndromes, i.e., allergic bronchopulmonary aspergillosis, aspergilloma, chronic-necrotizing pulmonary aspergillosis, and invasive aspergillosis. invasive aspergillosis is a rapidly progressive and potentially fatal infection, which typically occurs in the setting of prolonged neutropenia, treatment with corticosteroids and broad-spectrum antibiotics, and underlying leukemia or lymphoma [ ] . the clinical features include tachypnea, fever, dyspnea, nonproductive cough, pleuritic chest pain with or without a friction rub, progressive hypoxemia, and sometimes hemoptysis in patients with prolonged neutropenia or immunosuppression. often the only evidence of aspergillus pneumonia is fever with pulmonary infiltrates that do not respond to antibiotics. chest radiographic features are variable and may show patchy bronchopneumonia, multiple nodular densities, and peripheral, wedged-shaped infiltrates. ct scans may demonstrate the characteristic halo (an area of ground-glass infiltrate surrounding nodular densities) or the air-crescent sign [ ] . definitive diagnosis of invasive aspergillosis requires the demonstration of the organism in tissue. visualization of the specific fungi using gomori methenamine silver stain or calcofluor or a positive culture from sputum, needle biopsy, or bronchoalveolar lavage (bal) confirms the diagnosis of invasive aspergillosis. however, a negative result does not exclude pulmonary aspergillosis. the incidence of pneumocystis jirovecii pneumonia (pjp) (formerly known as pneumocystis carinii) is high among patients with lymphoproliferative malignancies and solid tumors and those receiving long-term corticosteroids or immunomodulation agents. pjp typically presents as an acute or subacute pulmonary process with fever, nonproductive cough, dyspnea, shortness of breath, and severe hypoxemia. physical examination is often unrevealing except for fever and tachypnea. chest examination is commonly normal; however, diffuse rales, and eventually signs of consolidation, may be present as the disease progresses. chest x-ray findings are nonspecific consisting of diffuse alveolar or interstitial infiltrates in % of the patients. high-resolution computed tomography (hrct) represents the gold standard imaging modality in detecting parenchymal abnormalities. the most common hrct finding is bilateral ground-glass opacities with apical predominance and peripheral sparing. the range of other hrct findings includes a combination of ground glass and consolidative opacities, linear-reticular opacities, cystic abnormalities, multiple nodules, and parenchymal cavities. the standard method for diagnosis of pjp relies on the microscopic visualization of p. jirovecii organisms in respiratory specimens. bronchoalveolar lavage (bal) combined with colorimetric and direct or indirect immunofluorescence stain of bal fluid is considered the method of choice with sensitivity and specificity more than %. an alternative is an examination of material obtained by induced sputum [ ] . however, the sensitivity of this method is more dependent on the experience of the personnel performing the procedure and evaluating the samples, with high variation in the diagnostic sensitivity reported (ranged between and %). most recently highly sensitive molecular techniques, using semi-or fully quantitative polymerase chain reaction (pcr) targeting p. jirovecii-specific genes, have been introduced. a meta-analysis of pcr studies has shown a pooled sensitivity of % and specificity of % [ , ] . cmv pneumonia has a high mortality rate of - %, especially in patients that require mechanical ventilation. cancer patients in risk are the bone-marrow transplant recipients [ ] . fever, nonproductive cough, and dyspnea are common presenting symptoms. radiographic patterns in cmv pneumonia include lobar consolidation, focal parenchymal haziness, and bilateral reticulonodular infiltrates. ct may reveal ground-glass opacities, bronchial wall thickening, reticular opacities, and nodules. the diagnosis of cmv pneumonia depends on isolation of the virus from patients with a positive finding on chest radiograph and appropriate clinical signs [ ] . cmv may be isolated from the lung with bronchoalveolar lavage (bal) or open-lung biopsy. in support of the diagnosis, cmv antigen or inclusions are found with histological examination. cmv isolated from clinical samples in the absence of clinical symptoms may represent viral colonization or subclinical replication disease. ards is a clinical syndrome characterized by the acute onset (within days) of severe hypoxemia (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen [pao /fio ] of less than despite the application of peep or cpap ≥ cm h o) and the presence of bilateral alveolar or interstitial infiltrates that cannot be fully attributed to cardiac failure or fluid overload [ ] . even though the incidence of ards in the general population is estimated to be - cases per , , the exact incidence of ards in patients with cancer remains unknown. in oncologic patients with or without neutropenia, ards may be related to infectious or noninfectious causes. causes of primary ards include bacterial or opportunistic infections such as invasive pulmonary aspergillosis, pneumocystis jirovecii pneumonia, and fungal and severe viral infections. secondary ards is related to a systemic process such as severe sepsis or septic shock from extrapulmonary bacterial or fungal infections. in a recent retrospective study in up to % of ards, the causative was an infection, including one-third due to invasive fungal disease [ ] . mortality in oncologic patients with ards remains high although a significant decrease has been recorded over the time. risk factors for higher mortality include the need for mechanical ventilation, allogeneic bonemarrow transplantation, niv failure, severe ards, and invasive fungal infection. ards treatment, although supportive, is considered significant, in both identifying and treating-if possible-the underlying cause [ , ] . pulmonary toxicity of antineoplastic agents, known as drug-induced toxicity (dit), is a common cause of respiratory failure in oncologic patients and should be included in the differential diagnosis of arf in patients who are on or have been treated with antineoplastic agents. table . shows the most common chemotherapeutic and immunosuppressive agents associated with pulmonary toxicity. up to % of patients treated with chemotherapy will develop dit. the extent of lung injury depends on both physical and biological factors including the pharmacokinetic properties of the drug and the drug dose and whether it is used as single therapy or as combination with other chemotherapeutics, the prior exposure to radiation and high oxygen concentration, and the presence of preexisting lung disease [ ] . dit may manifest in a broad variety of pulmonary syndromes, including acute interstitial pneumonitis, nonspecific interstitial pneumonia, ards, capillary leak syndrome, hypersensitivity pneumonitis (hp), cryptogenic organizing pneumonia (cop), eosinophilic pneumonia (ep), alveolar hemorrhage, and fibrosis [ ] . symptoms are usually nonspecific including low-grade fever, nonproductive cough, pleural pain, and shortness of breath and can manifest days or even years after the exposure. routine clinical examination usually reveals rales and/or a pleural friction rub. the diagnosis of dit remains an exclusionary process, in particular when considering common or atypical infections, as well as recurrence of the underlying neoplastic process. diffuse pulmonary infiltrates are the most common findings in chest x-ray, while high-resolution computed tomography (hrct) findings are mainly dependent on the type of the drug-induced pulmonary syndromes and usually consist of pleural effusions, ground-glass opacities, traction bronchiectasis, and fibrosis. pulmonary function tests in the majority of dit cases may reveal a pattern of restrictive abnormality, with decreased values of dlco. bronchoscopy can be helpful in determining the presence of pneumonitis and for the differential diagnosis of lymphangitic carcinomatosis, vasculitis, alveolar hemorrhage, or pneumonia from infectious agents. most drug-induced immunological reactions, such as hp, cop, and ep, may be excluded if bal cytology is normal. in regard to the management in many instances, dit may respond to withdrawal of the offending agent and the judicious application of corticosteroid therapy [ ] . venous thromboembolic disease (vtd) may be present both in the form of deep venous thrombosis (dvt) or pulmonary embolism (pe) and is one of the leading causes of morbidity and mortality in oncologic patients [ ] . it is now well established that the incidence of vtd is higher in patients with cancer than in the general population and that the malignancies that are most frequently associated with thrombotic complications are those of the pancreas, brain, stomach, lung, and pleura [ ] . the most common symptoms are shortness of breath, pleuritic or substernal chest pain, palpitations, cough, hemoptysis, and syncope. even though hypoxemia is considered a typical finding in acute pe, up to % of the patients present with normal arterial oxygen saturation. as the majority of preventable deaths associated with pe can be ascribed to a missed diagnosis and anticoagulation is associated with a risk of bleeding, it is crucial to exclude or confirm the diagnosis of pe to avoid unnecessary anticoagulation or promptly start such treatment if it is appropriate [ ] . in patients with suspected pe, both the diagnostic and therapeutic strategies rely on well-established and extensively validated algorithms, which utilize the clinical stratification of severity (assessment of the risk of death), the clinical probability (pretest probability), the plasma d-dimer measurement, and imaging tests [ ] . stratification of severity is based on patient's clinical status at presentation, with high-risk pe being suspected or confirmed in the presence of shock or persistent arterial hypotension. for patients with suspected pe, the pretest probability is determined by using validated clinical prediction rules, and two alternative classification schemes may be utilized, i.e., the three category schemes (low, moderate, or high clinical probability of pe) and the two category schemes (pe likely or unlikely) [ ] . regarding the specific for pe diagnostic tests, computed tomography pulmonary angiography (ctpa) remains the gold standard diagnostic method in patients with suspected pe, with and % sensitivity and specificity, respectively. plasma d-dimer testing has a high negative predictive value for excluding pe, though its positive predictive value remains low [ ] . hereby describe the diagnostic and therapeutic workup should be followed in patients with suspected pe, based on the proposed algorithms [ , ] . in patients with suspected pe and presented with shock or hypotension, bedside transthoracic echocardiography represents the most useful initial diagnostic approach. an echocardiography evidence of right ventricular dysfunction is sufficient to prompt immediate reperfusion without further testing. following patient's stabilization, a ctpa should be performed to confirm the diagnosis. in hemodynamically stable patients, the first step in the diagnostic and therapeutic algorithm is the determination of the pretest probability. in patients with a low/ intermediate clinical probability, the first-line test is the measurement of plasma d-dimers, and a negative d-dimer test rules out the diagnosis of pe. in the case of a positive d-dimer test, a ctpa should be performed. in patients with high clinical probability, ctpa represents the first-line test. patients with cancer, particularly those with hematologic malignancies and those undergoing a major surgical operation, are subjected to multiple transfusions of fresh frozen plasma, platelets, and packed red blood cells, and thus they are at a risk for developing transfusion-related acute lung injury (trali). the diagnosis is mainly based on clinical criteria, and several definitions of trali have been introduced in the last decades (table . ). accordingly, the syndrome is characterized by the presence of hypoxemia and bilateral infiltrates occurring during or within h of a transfusion, in the absence of cardiac failure or volume overload [ ] . although any blood component can cause trali, plasma-rich units are more likely to be the culprits. the precise mechanisms of the capillary leak syndrome in trali have not been fully elucidated, but currently, two main hypotheses have been proposed. the first hypothesis supports the activation of recipient's neutrophils by passively transporting leukoagglutinating antibodies. the activated neutrophils, in turn, are carried to the lungs and activate the complement leading to endothelial damage, capillary leak, and lung injury [ ] . the second hypothesis supports that neutrophils accumulate and are primed in the patient's pulmonary microvasculature as a result of preexisting systemic inflammation. activation of these neutrophils by lipids or other mediators contributes to endothelial damage in susceptible patients. signs and symptoms include tachypnea, frothy pulmonary secretions, hypotension (less commonly hypertension), fever, tachycardia, and cyanosis. routine clinical examination reveals diffuse rales. the differential diagnosis should include the transfusion-associated circulatory overload (taco) and respiratory distress due to anaphylactic transfusion reactions. the mainstay of treatment for trali remains supportive care with supplemental oxygen in all reported cases and mechanical ventilator support in up to twothirds of patients. if the suspected blood product is still being transfused, it should be discontinued immediately. in contrast to ards from other causes, the majority of the patients recover completely, with improvement of hypoxia and resolution of pulmonary infiltrates that occur within h of the transfusion. cardiogenic pulmonary edema (cpe) should always be included in the differential diagnosis of acute respiratory failure in oncologic patients, in particular when chemotherapy with cardiotoxic drugs has been preceded. the etiology of pulmonary edema is multifactorial and includes increased hydrostatic pressure from highvolume infusions and/or multiple transfusions, cardiotoxic effects of chemotherapy, and renal impairment. anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), taxanes (paclitaxel and docetaxel), and alkylating agents (cyclophosphamide, ifosfamide, melphalan) are chemotherapeutics drugs with well-established cardiotoxicity [ ] . even though a universally accepted definition does not exist, the american society of echocardiography and the european association of cardiovascular imaging define cancer therapeutic-related cardiac dysfunction as a decrease in the left ventricular ejection fraction (lvef) of > %, to a value < % confirmed by repeat imaging [ ] . the diagnostic and therapeutic approach in cpe in cancer patients is the same as in any other patients [ ] . in most cases, clinical manifestation consists of hypoxemia, tachycardia, tachypnea, shortness of breath, orthopnea, and profuse diaphoresis. hypotension may present and indicate severe lv systolic dysfunction and the possibility of cardiogenic shock. pink, frothy sputum may be present in patients with severe disease. in regard to routine clinical examination, auscultation of the lungs usually reveals fine, crepitant rales (most commonly heard at the lung bases), but rhonchi or wheezes may also be present, while cardiovascular findings are notable for s , accentuation of the pulmonic component of s , and jugular venous distention. apart from clinical examination, laboratory and imaging tests are of great importance for establishing the diagnosis of cpe. plasma levels of the b-type natriuretic peptide (bnp) and its amino-terminal fragment n-terminal probnp (nt-probnp) have been shown to be useful, in addition to clinical judgment, for the etiological diagnosis in patients with acute onset of dyspnea, and should be measured in all patients with arf and suspected cpe. bnp has a high negative predictive value, and being lower than the recommended cutoff value of pg/ml in patients with suspected cpe makes the diagnosis unlikely [ ] . a bedside echocardiogram in a patient with cpe remains the cornerstone in determining the etiology of pulmonary edema. echocardiography can be used to evaluate lv systolic and diastolic function, as well as valvular function, and to assess for pericardial disease. chest x-ray may be proved as a useful diagnostic test for cpe. pulmonary venous congestion, pleural effusion (particularly bilateral and symmetrical), interstitial or alveolar edema, and cardiomegaly are the most specific findings for cpe. however, it should mention that in up to % of patients, chest x-ray maybe nearly normal. more recently, lung ultrasound (lus) has been introduced as a simple, noninvasive diagnostic method in patients with suspected cpe. in cases in which there is a moderate to high pretest probability of acute cpe, lus can be useful in strengthening a working diagnosis. findings of b-lines on ultrasonography have been reported to have a sensitivity of . % and a specificity of . % for acute cpe [ ] . the prognosis of acute respiratory failure in critically ill cancer patients prognostic factors in critically ill cancer patients admitted to the intensive care unit diagnostic strategy in cancer patients with acute respiratory failure diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data ct signs and patterns of lung disease role of hrct in detection and 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diseases after hematopoietic stem cell transplantation: a mini-review diagnosis and treatment approaches to cmv infections in adult patients acute respiratory distress syndrome: the berlin definition acute respiratory distress syndrome in patients with malignancies the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a metaanalysis pulmonary toxicity in patients treated with gemcitabine plus vinorelbine or docetaxel for advanced non-small cell lung cancer: outcome data on a randomized phase ii study antineoplastic therapy induced pulmonary toxicity pulmonary toxicity induced by mitomycin c is highly responsive to glucocorticoids incidence of venous thromboembolism in patients hospitalized with cancer epidemiology of cancer-related venous thromboembolism treatment of venous thromboembolism in patients with cancer: a network metaanalysis comparing efficacy and safety of anticoagulants the task force for the diagnosis and management of acute pulmonary embolism of the european society of cardiology. esc guidelines on the diagnosis and management of acute pulmonary embolism clinical prediction rules for pulmonary embolism: a systematic review and meta-analysis diagnostic accuracy of d-dimer test for exclusion of venous thromboembolism: a systematic review risk-adapted management of acute pulmonary embolism: recent evidence, new guidelines transfusion-related acute lung injury: current concepts for the clinician transfusion reactions: newer concepts on the pathophysiology, incidence, treatment and prevention of transfusion related acute lung injury (trali) the prevention, detection and management of cancer treatment-induced cardiotoxicity: a meta-review expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the american society of echocardiography and the european association of cardiovascular imaging guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the european society of cardiology (esc) pro-b-type natriuretic peptide levels in acute decompensated heart failure point-of-care ultrasonography for the diagnosis of acute cardiogenic pulmonary edema in patients presenting with acute dyspnea: a systematic review and meta-analysis key: cord- -vetdsk authors: woodfork, karen title: bronchitis date: - - journal: xpharm: the comprehensive pharmacology reference doi: . /b - - . - sha: doc_id: cord_uid: vetdsk bronchitis is characterized by bronchial inflammation that results in … bronchitis is characterized by bronchial inflammation that results in cough and sputum production. this inflammation can be acute in nature, usually resulting from a viral infection, or it may be a long-standing manifestation of chronic obstructive pulmonary disease. acute infectious bronchitis differs from chronic bronchitis with respect to etiology, pathophysiology, and treatment. acute bronchitis is among the most frequent reasons for visits to the physician's office. it can be defined as an infectious, generally viral, respiratory illness that last for - weeks that occurs in an otherwise healthy adult with cough as the predominate feature gonzales and sande ( ) . in addition to cough and usually sputum production, acute bronchitis frequently involves upper respiratory symptoms and constitutional complaints, such as fatigue and body aches. an illness comprised of these symptoms may be classified as acute bronchitis once the diagnosis of pneumonia is excluded. as a form of chronic obstructive pulmonary disease (copd), chronic bronchitis is characterized by irreversible or incompletely reversible airway obstruction that produces a decrease in maximal expiratory airflow chitkara and sarinas ( ) . the definition of chronic bronchitis is symptomatic. that is, it is a condition that results in a mucusproducing cough that is present for at least months of the year for consecutive years and does not have some other underlying etiology such as tuberculosiswisniewski ( ) . depending on its severity, chronic bronchitis may produce minimal to significant functional impairment. acute bronchitis is a form of lower respiratory tract infection gonzales and sande ( ) . although an etiology is formally identified in only a small percentage of clinical cases, the identity of the disease-producing organism may be used to classify acute bronchitis. chronic bronchitis is the most common form of chronic obstructive pulmonary disease (copd), a group of conditions involving airway obstruction, decreased maximal expiratory airflow, and breathing-related symptoms. emphysema, or destruction of the alveoli, is the other major manifestation of copd chitkara and sarinas ( ) . nonremittant asthma, involving bronchoconstriction that is irreversible or only partially reversible, may also be classified as cop d. it is not unusual for individuals to experience combined forms of copd involving sputum production, alveolar destruction, and bronchospasm. copd can be classified on the basis of severity pauwels et al ( ) . stage (at risk) is characterized by normal spirometric readings and the presence of chronic cough and/or sputum production. stages i, ii, or iii copd is present if the forced expiratory volume in second divided by the forced vital capacity (fev /fvc) is less than %. chronic both acute and chronic bronchitis give rise to a persistent, sputum-producing cough. bronchial hyperresponsiveness, wheezing, and difficulty breathing (dyspnea) may occur, and difficulty breathing upon exercise (exertional dyspnea) is fairly common. in most cases of acute bronchitis, the symptoms of cough and sputum production last for to weeks gonzales and sande ( ) . infections such as otitis media, sinusitis, and, more rarely, pneumonia may result from either the primary viral infection or a secondary bacterial infection. acute bronchitis resulting from influenza may additionally produce more rare complications of muscular inflammation (myositis) and muscle cell lysis leading to potentially fatal renal damage (rhabdomyolyisis). additional consequences of acute bronchitis are seen in children. reye syndrome may occur in children with influenza, particularly if they are treated with aspirin. viral lower respiratory infection in early life has been associated with the later development of asthma gern ( ) . in contrast to acute bronchitis, which resolves following the termination of the causative infection, chronic bronchitis generally worsens with time, even with optimal treatment chitkara and sarinas ( ) . cessation of exposure to a triggering stimulus, such as tobacco smoke, is the only currently available therapeutic management that can slow the progression of chronic bronchitis. usually, by the time treatment is sought, there is irreversible damage to the lungs. progression of chronic bronchitis leads to shortness of breath, initially manifesting only during exercise but also occurring at rest as the disease worsens. increasing pulmonary dysfunction can result in pulmonary hypertension, right ventricular enlargement, and right-sided heart failure (cor pulmonale). signs of cor pulmonale include peripheral edema, enlargement of the liver and other internal organs, and increased breathing difficulty. weight loss may occur, and muscle wasting can contribute to the development of exercise intolerance. an individual affected with chronic bronchitis is susceptible to repeated episodes in which the symptoms of cough, sputum production, and dyspnea worsen mccrory et al ( ) . these episodes, termed acute exacerbations of chronic bronchitis, may result from viral or, more rarely, bacterial infection. environmental exposure to tobacco smoke, air pollutants, or allergens may also produce acute exacerbations of chronic bronchitis. the cause of approximately one-third of acute exacerbations is unknown. immunocompromised individuals, persons with comorbid conditions, such as diabetes, cardiovascular disease, pulmonary disease, and alcoholics gonzales and sande ( ) . these individuals are also at higher risk of developing complications of acute bronchitis, such as pneumonia. chronic bronchitis is the most common form of chronic obstructive lung disease (copd), with emphysema (alveolar destruction) being the next most frequently observed manifestation. nonremittant asthma may also be classified as cop d. it is common for individuals with copd to exhibit characteristics of chronic bronchitis, emphysema, and/ or bronchospastic disease. individuals with copd are more susceptible to lower respiratory infections such as acute bronchitis and pneumonia ward and casaburi ( ) , chitkara and sarinas ( ) . in more advanced disease, they may develop pulmonary hypertension, resulting in right ventricular enlargement and, as the disease progresses, right-sided heart failure (cor pulmonale). acute bronchitis is usually caused by viruses associated with lower respiratory tract infections, including influenza a and b, parainfluenza, respiratory syncytial virus, and human metapneumovirus and upper respiratory tract infections, such as rhinovirus, corona virus, and adenovirus bandi et al ( ) . the most common cause of acute bronchitis is influenza, with a much smaller percentage of acute bronchitis cases resulting from bacterial infection. chlamydia pneumoniae has been responsible for several recent outbreaks, particularly in young adults. bordetella pertussis may cause atypical symptoms resulting in prolonged cases of acute bronchitis in previously immunized adults. mycoplasma pneumoniae is an additional established etiologic agent of acute bronchitis. there is very little evidence that acute bronchitis may be caused by bacterial species that are characteristic of pneumonia infections (e.g., streptococcus pneumoniae). chronic bronchitis most frequently develops in tobacco smokers, approximately - % of whom eventually show symptoms of this disorder viegi ( ) . passive exposure to smoke can also contribute to the development of chronic bronchitis. other causative factors include exposure to indoor or outdoor air pollution, occupational dusts (e.g., grain, coal), or chemical irritants (e.g., sulfur dioxide). chronic bronchitis may also develop in people with a history of recurrent lung infections or airway hyperresponsiveness hogg ( ) . acute exacerbations of chronic bronchitis are commonly associated with influenza, parainfluenza, coronavirus, or rhinovirus infections mccrory et al ( ) . elevated levels of particulate air pollution and ozone are also associated with acute exacerbations. the role of bacterial infection in acute exacerbation of chronic bronchitis remains controversial. pathogenic bacterial such as haemophilus influenzae, streptococcus pneumoniae, and moraxella catarrhalis are present in the sputum of approximately half of all those experiencing acute exacerbations but are also frequently present during periods of stable disease hirschmann ( ) . clinical trials have shown that antibiotic therapy is helpful in % or less of those with acute exacerbations. however, in the subset of exacerbations in which purulent sputum is a predominant feature, the extent of bacterial eradication correlates with the degree of resolution of the exacerbation and its associated inflammation white et al ( ) . thus, an increase in bacterial load, acquisition of a new bacterial pathogen, or a change in the antigenic makeup of the resident bacterial population, may be responsible for certain acute exacerbations of chronic bronchitis. the role of bacterial infection in the progression of chronic bronchitis is unclear wilson ( ) . acute bronchitis is a widespread condition that usually occurs in outbreaks and epidemics, especially during the winter months. its incidence is approximately - cases per , persons per year file ( ) . an elevated risk for the development of acute bronchitis is seen among the very young and the elderly, smokers, immunocompromised individuals, persons with comorbid conditions, such as cardiovascular or pulmonary disease, and alcoholics. such individuals are also at increased risk for developing complications such as pneumonia. chronic bronchitis and emphysema are related manifestations of chronic obstructive pulmonary disease (copd) and often coexist in an individual. according to the national health interview survey, . million americans have been diagnosed with chronic bronchitis, million with emphysema, and . million with both barnes et al ( ) . in the us, copd is the primary cause of death for over , people a year. a large number of cases may be undiagnosed, as a recent survey involving the direct measurement of pulmonary function suggests that nearly million individuals in the us suffer from copd mannino et al ( ) . chronic bronchitis is most commonly seen in individuals over the age of . it is more common in women than men across all age groups and may be more severe in women barnes et al ( ) . in the - and + age groups, it is more common in whites than blacks, whereas the reverse is true in the - age group. the most significant risk factor for the development of chronic bronchitis is cigarette smoking, with morbidity and mortality increasing in proportion to the extent and duration of smoking viegi ( ) . occupational exposures to dusts (e.g., coal, grain, and cadmium and other heavy metals) and industrial chemicals (e.g., isocyanates, certain adhesives, and welding fumes) also pose significant risk for the development of chronic bronchitis. environmental tobacco smoke and air pollution are also associated with an increased risk of developing copd. a history of childhood respiratory infections correlates with an increased risk of copd hogg ( ) . latent infection with adenovirus may enhance the inflammatory response to environmental causes of chronic bronchitis, as may infection with the ulcerogenic bacterium helicobacter pyloriroussos et al ( ) . colonization of the lower airways with haemophilus influenzae, a pulmonary pathogen, may be associated with chronic bronchitis and its acute exacerbations wilson ( ), bandi et al ( . host factors are also involved in the development of cop d. low socio-economic status, high alcohol consumption, and a tendency toward atopic allergic reactions and hypersensitivity are associated with copd viegi ( ) . low dietary intake of fresh fruit and vegetables, antioxidants such as vitamin c and beta-carotene, fish, and omega- fatty acids has also been associated with impaired lung function romieu and trenga ( ) . an inherited deficiency in alpha- antitrypsin (alpha- proteinase inhibitor) results in earlyonset emphysema viegi ( ) . genetic factors may also be involved in the development of chronic bronchitis in general. the signs and symptoms of acute bronchitis result from the pathogen itself and from the immune response to the infection. the acute phase of this illness lasts from - days and involves constitutional symptoms such as fever, fatigue, and muscle aches gonzales and sande ( ) , balter ( ) . it is during this phase that viral colonization of the tracheobronchial epithelium occurs. in response to this infection airway epithelial cells and resident monocytes and macrophages release cytokines that recruit and activate immune cells. infection with influenza a virus provides an example of this process. influenza a infection stimulates the release of chemotactic chemokines including rantes, monocyte chemotactic protein- (mcp- ), and macrophage inflammatory protein- alpha (mip- alpha), pro-inflammatory cytokines such as tumor necrosis factor-alpha (tnf-alpha), interleukin- beta, (il- beta), il- , and il- , and antiviral cytokines such as interferon-alpha (ifn-alpha) and ifn-betajulkunen et al ( ) . neutrophils are among the first cells recruited to the tracheobronchial epithelium, and their increased number correlates with the development of airway hyperresponsiveness. t lymphocytes are recruited and activated by rantes and other cytokines released by monocytes. eosinophils are recruited and activated and may persist for weeks after the initial infection. the protracted phase of acute bronchitis involves coughing, wheezing, and sputum production and lasts from - weeks. it frequently involves a significant decline in pulmonary function that can be measured as a decrease in the forced expiratory volume inn second (fev ). the bronchial hyperresponsiveness, which was initiated during the acute phase, persists for several weeks and correlates with the extended presence and activation of inflammatory cells. the pathological hallmark of chronic bronchitis is airflow limitation secondary to inflammation and increased mucus production in the large (> mm) airways. the disease process begins when damage to the airways initiates inflammation and remodeling of the airway epithelium, leading to mucus hypersecretion, obstruction of the airways, and increased susceptibility to bacterial colonization macnee ( ), turato et al ( ) , cosio- piqueras and cosio ( ) . the presence of pathogenic bacteria in the lung is a common cause of acute exacerbations of chronic bronchitis and may also be related to disease progression. an ongoing cycle ensues in which inflammation and infection produce further epithelial damage, which perpetuates additional inflammation and airway remodeling. chronic bronchitis is initiated when repeated exposure to tobacco smoke, environmental lung irritants (e.g., coal or grain dust, air pollutants), and/or respiratory infections produce damage in the large airways. recruitment of inflammatory cells results from upregulation of adhesion molecules such as icam- and e-selectin on the subepithelial blood vessels. neutrophils are the predominant cell type recruited into the lumen of the airways. macrophages and cd + t lymphocytes are the predominant cells that infiltrate the subepithelial space. eosinophils are prevalent in the subepithelium during acute exacerbations of chronic bronchitis, while large numbers of neutrophils are seen here only in severe disease. while enlargement of the mucous glands was formerly believed to a defining feature of chronic bronchitis, it is now believed that inflammation of these glands is more characteristic. inflammatory cells in the airway lumen and epithelium release mediators that control the inflammation and airway remodeling that is characteristic of chronic bronchitis reid and sallenave ( ) . neutrophils release reactive oxygen species such as superoxide and peroxynitrite that produce tissue damage and further inflammation. elevated levels of pro-inflammatory molecules, such as il- , ltb , and tnf-alpha, and diminished levels of the anti-inflammatory cytokine il- are seen in the sputum of individuals with chronic bronchitis. elevated levels of the mucus-stimulating cytokines il- and il- are seen in patients with chronic bronchitis. neutrophils in the airways release neutrophil elastase, a serine protease that increases the production of mucus and stimulates the proliferation of mucus-producing goblet cells. squamous metaplasia occurs, resulting in the replacement of many ciliated columnar epithelial cells with squamous epithelial cells. overall, these processes of excessive bronchial mucus secretion and impaired clearance result in airway obstruction, irritation, and an increased likelihood of infection. many similarities exist between the processes occurring in the large and small (< mm) airways of those with chronic bronchitis. subepithelial infiltration of cd + t lymphocytes and goblet cell proliferation contribute to inflammation and mucus secretion, respectively. in addition, fibrosis of the airway walls decreases the elastic recoil of the lung, while hypertrophy of the bronchiolar smooth muscle produces airflow restriction. attachments of the alveoli to the bronchioles may be lost as well. in the pulmonary arteries, chronic bronchitis causes proliferation of smooth muscle cells and deposition of elastic and collagen fibers turato et al ( ) . this appears to be the result of endothelial dysfunction that results from hypoxemia or other, unknown factors. pulmonary hypertension occurs as a consequence of pulmonary artery narrowing, and the right ventricle may become enlarged as a result of prolonged pumping against elevated arterial pressure. right ventricular failure (cor pulmonale) is a common complication of chronic bronchitis. the initial, acute phase of acute bronchitis begins with - days of constitutional symptoms such as fever, malaise, and muscle aches gonzales and sande ( ) . these symptoms are variable in extent and duration, and depend upon the nature of the infectious agent. for example, rhinovirus infection produces minimal or no constitutional symptoms whereas influenza and parainfluenza produce the most severe and prolonged symptoms. the protracted phase of acute bronchitis lasts for - weeks and involves coughing, increased sputum production, and wheezing. acute bronchitis is distinguished from upper respiratory infections by the presence of cough, sputum, and wheezing with the former. the signs and symptoms of acute bronchitis differ from those of pneumonia in that pneumonia causes abnormal lung sounds that indicate the presence of fluid (e.g., rales) and elevations in vital signs (heart rate > beats/minute, respiratory rate > breaths/minute, and temperature > c). while pneumonia can be confirmed with radiography, this is unwarranted in low-risk individuals who have elevated vital signs without abnormal lung sounds, particularly during a known viral outbreak. x-ray testing in the absence of abnormal lung sounds may be necessary in the elderly and in those with co-morbidities that place them at high risk of pneumonia and other complications. chronic bronchitis is a manifestation of chronic obstructive pulmonary disease (copd) involving cough and sputum production, with or without wheezing, that lasts for at least months for consecutive years chitkara and sarinas ( ) . it most frequently appears in smokers over the age of and is associated with acute exacerbations in which coughing, wheezing, and sputum production are increased. persons with chronic bronchitis are at increased risk of developing pneumonia and other respiratory infections. significant difficulty breathing during exercise, and, as the disease progresses, also at rest usually manifest during the mid-sixties to early seventies. spirometric measurement of the forced expiratory volume in second (fev ) and the forced vital capacity (fvc) may be used to assess pulmonary function and to stage the severity of copd pauwels et al ( ) , lenfant and khaltaev ( ) . a complete blood count can be used to rule out infection and may reveal an elevation in red blood cells resulting from chronic hypoxemia (polycythemia). a sputum culture may be used to check for acute infection. a chest x-ray can be performed to exclude other causes of cough such as pneumonia and lung cancer. in severe cases of chronic bronchitis, radiography may reveal right ventricular hypertrophy as well as enlargement and rapid tapering of the pulmonary arteries. if emphysema is present as well, each region of severe disease will be visible as a radiolucent area surrounded by a hairline shadow. acute exacerbations of chronic bronchitis are associated with worsened dyspnea and increased sputum production and purulence. acute exacerbations can be classified as severe (type ) if all three symptoms are present and moderate (type ) if two of the three are present mccrory et al ( ) . a mild exacerbation is diagnosed if one of the above symptoms occurs along with at least one indicator of recent respiratory infection (e.g., fever, cough, and wheezing). because of its predominantly viral nature, acute bronchitis is best treated symptomatically, unless an influenza etiology is established and antiviral treatment is initiated early enough to ensure effectiveness. antibiotics are useful in cases where bacterial infection is confirmed. the medications available for the treatment of chronic bronchitis/chronic obstructive pulmonary disease (copd) do not decrease the progressive decline in respiratory function that is characteristic of this condition. rather, they only lessen its symptoms and their complications. the only intervention that slows the progression of copd is decreased exposure(s) to substances that worsen this condition such as tobacco smoke, occupational dusts and chemicals, and air pollutants. smoking cessation is the most significant intervention that has the potential to slow the progression of chronic obstructive pulmonary disease chitkara and sarinas ( ) . pharmacological therapy for tobacco dependence is added to counseling to increase the likelihood of success. nicotine replacement therapy is most commonly given as a transdermal patch, with nicotine gum, nasal spray, inhaler, or lozenge used to counteract breakthrough cravings. smoking cessation is more likely to succeed when nicotine replacement therapy is used in combination with the antidepressant bupropion. with this combination, nicotine is gradually withdrawn while bupropion is maintained for months or longer. those with acute bronchitis frequently exhibit wheezing and other signs of reversible bronchoconstriction. although chronic obstructive pulmonary disease is characterized by bronchoconstriction that is incompletely reversible following administration of a bronchodilator, long-term therapy with bronchodilators decreases the symptoms of airflow limitation in individuals with chronic bronchitis. thus, bronchodilator therapy is central to the management of chronic bronchitis and its acute exacerbations chitkara and sarinas ( ) . inhalation is the preferred route of administration because it maximizes the delivery of the agent to the lungs and minimizes systemic side effects. short-acting beta- adrenoceptor agonists such as albuterol produce rapid bronchodilation by action on the beta- adrenoceptors on the airway smooth muscle. anticholinergics are the preferred drugs for the treatment of acute bronchitis smuncy et al ( ) . in the treatment of chronic bronchitis, beta- adrenoceptor agonists may be used on a scheduled basis or as-needed to treat acute bronchospasm. beta- adrenoceptor agonists are also used in the treatment of acute exacerbations of chronic bronchitis mccrory et al ( ) . the efficacy of long-acting beta- adrenoceptor agonists such as salmeterol is under study. the bronchodilatory effect of anticholinergics is additive with that of beta- adrenoceptor agonists. combination products that deliver a metered dose of a beta- adrenoceptor agonist and ipratropium can simplify drug administration. those with acute bronchitis frequently exhibit wheezing and other signs of reversible bronchoconstriction. although chronic obstructive pulmonary disease is characterized by bronchoconstriction that is incompletely reversible following administration of a bronchodilator, long-term therapy with bronchodilators decreases the symptoms of airflow limitation in individuals with chronic bronchitis. thus, bronchodilator therapy is central to the management of chronic bronchitis and its acute exacerbations chitkara and sarinas ( ) . inhalation is the preferred route of administration because it maximizes delivery of the agent to the lungs and minimizes systemic side effects. anticholinergic bronchodilators such as ipratropium block the muscarinic receptormediated bronchoconstriction, mucus secretion, and bronchial vasodilation that result from vagal stimulation of the airways. the duration of action of ipratropium is longer than that of the short-acting beta- adrenoceptor agonist bronchodilators. it can decrease the volume of sputum produced without altering its viscosity. an ipratropium inhaler may be used in acute bronchitis where bronchospasm is problematic smuncy et al ( ) . in chronic bronchitis, ipratropium is a mainstay of therapy chitkara and sarinas ( ) . some individuals who are nonresponsive to beta- adrenoceptor agonists derive symptomatic relief with ipratropium. the bronchodilatory effect of ipratropium is additive with that of beta- adrenoceptor agonists. combination products that deliver a metered dose of a beta- adrenoceptor agonist and ipratropium can simplify drug administration. although chronic obstructive pulmonary disease is characterized by bronchoconstriction that is incompletely reversible following administration of a bronchodilator, long-term therapy with bronchodilators decreases the symptoms of airflow limitation in individuals with chronic bronchitis. thus, bronchodilator therapy is central to the management of chronic bronchitis and its acute exacerbations chitkara and sarinas ( ) . theophylline exerts a wide variety of physiological actions including central nervous system stimulation, cardiac stimulation, and smooth muscle relaxation. its major action on the lung results from the inhibition of the cyclic nucleotide phosphodiesterases that break down cyclic amp and cgmp, second messengers that mediate bronchodilation. theophylline also inhibits the release of inflammatory mediators by immune cells. its narrow therapeutic index, potentially life-threatening side effects, and numerous drug interactions have made theophylline a second-line therapy for chronic bronchitis. while its efficacy as compared to other bronchodilators is questionable, a subset of patients appears to benefit from theophylline. lower therapeutic doses used in combination with a beta- adrenoceptor agonist may be beneficial in some cases. oxygen oxygen therapy is indicated when the symptoms of chronic obstructive pulmonary disease (copd) become severe enough to limit activities of daily living chitkara and sarinas ( ) . it may also be used as-needed during exercise in those who don't qualify for continuous oxygen use. oxygen therapy reduces mortality and improves quality of life in persons with severe cop d. it is also useful in the management of acute exacerbations of chronic bronchitis mccrory et al ( ). antibiotics although antibiotics are frequently prescribed for acute bronchitis, most cases are viral in origin, rendering them useless. antibiotic therapy does not decrease the duration of illness, limitation of activities, or loss of work time in most cases of acute bronchitis fahey et al ( ), smuncy et al ( , bent et al ( ) . thus, the frequency of antibiotic use can safely be reduced without affecting patient outcomes gonzales et al ( ) . in the rare cases in which acute bronchitis is caused by mycoplasma pneumoniae or chlamydia pneumoniae, fluoroquinolones, tetracycline, and macrolides are effective gonzales and sande ( ) . acute bronchitis caused by bordetella pertussis may be treated with erythromycin, but it is only effective early in the course of illness. the role of bacterial infection in acute exacerbation of chronic bronchitis remains controversial. in those exacerbations in which purulent sputum is a predominant feature, the extent of bacterial eradication correlates with the degree of resolution of inflammation associated with the exacerbation white et al ( ) . the united states national heart, lung, and blood institute and the world health organization recommended that antibiotics be given for acute exacerbations in which there is evidence of infection, e.g. increased sputum production, change in sputum color, and/or fever pauwels et al ( ) . commonly used antibiotics include amoxicillin-clavulanate, azithromycin, and several cephalosporins and fluoroquinolones. although glucocorticoids are frequently employed in the therapy of chronic bronchitis, their use is controversial chitkara and sarinas ( ) . glucocorticoids block immune cell activation, cytokine release, and mucus secretion in vitro, yet only - % of individuals with chronic obstructive pulmonary disease actually respond to them. it is impossible to predict who will respond to glucocorticoids. indeed, those who benefit from oral glucocorticoids during acute exacerbations may not realize any value from chronic inhaled glucocorticoid use. systemic glucocorticoids (e.g., prednisolone) are used for the treatment of acute exacerbations of chronic bronchitis and can alleviate symptoms, decrease hospitalization time, and reduce relapse rate among steroid-responsive individuals mccrory et al ( ) . chronic treatment with inhaled glucocorticoids such as fluticasone produces a modest reduction in the incidence of acute exacerbations, with no impact on the rate of functional decline. the united states national heart, lung, and blood institute and the world health organization recommend long-term maintenance therapy with inhaled glucocorticoids in symptomatic patients who exhibit a documented spirometric response to glucocorticoids or who have an fev- of < % of predicted and suffer from repeated exacerbations requiring antibiotic or glucocorticoid therapy pauwels et al ( ) . systemic glucocorticoids should be used in the management of acute exacerbation, but chronic treatment should be avoided due to the potential for severe adverse effects. because influenza vaccines significantly decrease morbidity and mortality in persons with chronic bronchitis, annual influenza vaccination is recommended pauwels et al ( ) . the pneumococcal vaccine has been used in patients with chronic bronchitis, but there are insufficient data to support its general use for this purpose. non-steroidal antiinflammatory drugs non-steroidal antiinflammatory agents such as ibuprofen and antipyretic pain relievers, such as acetaminophen, may be used to lessen the symptoms of the acute phase of acute bronchitis (e.g., fever, muscle aches) gonzales and sande ( ) . in cases of acute bronchitis caused by influenza a, amantadine or rimantadine may be effective if given within hours of the onset of symptoms gonzales and sande ( ) . these drugs block the proton channel required for the dissolution of the viral ribonucleoprotein complex early in the process of replication. zanamivir and oseltamivir are effective against influenza a and b and, like amantadine and rimantadine, must be taken within the first hours of illness. these drugs inhibit neuraminidase, a viral surface glycoprotein involved in the release of progeny virus and in the spread of infection from cell to cell. a large number of experimental therapies are under development for the treatment of chronic obstructive pulmonary disease. with the exception of novel antiinfective agents and the anticholinergic bronchodilator tiotropium, there are few experimental therapies under development for the treatment of acute infectious bronchitis. mucolytic agents because mucus hypersecretion and impaired mucociliary clearance are characteristic of chronic bronchitis, attempts are being made to speed the transport of mucus up the bronchiotracheal tree wegner ( ) . oral expectorants such as guaifenesin are of little benefit in chronic obstructive pulmonary disease. n-acetylcysteine is an orally administered glutathione precursor that reduces the sulfhydryl bonds of mucus proteins. it has been shown to thin the sputum without producing significant improvement in pulmonary function. preliminary studies suggest that n-acetylcysteine may reduce the frequency of acute exacerbations, an action that may be related to its efficacy as an antioxidant. heliox heliox is a mixture of helium and oxygen that changes pulmonary airflow from turbulent to laminar. it has been shown to decrease the work of breathing in severe, stable, chronic obstructive pulmonary disease and may potentially be useful in the treatment of acute exacerbations of chronic bronchitis chitkara and sarinas ( ) , rodrigo et al ( ) . phosphodiesterase- (pde- ) is a cyclic amp-specific phosphodiesterase that predominates in pro-inflammatory and immune cells. cilomilast is a new, orally active, selective inhibitor of pde- . initial studies of cilomilast revealed significant functional improvement of chronic obstructive pulmonary disease (copd) with minimal side effects giembycz ( ) . there is a significant decrease in the number of cd + and cd + inflammatory cells characteristic of copd without alteration of sputum values or fev- gamble et al ( ) . tiotropium is an inhaled anticholinergic that is available in europe and is pending fda approval in the united states barnes ( ) . it exhibits very slow dissociation from m- muscarinic receptors and m- muscarinic receptors, allowing it to provide once-daily dosing and a greater degree of stability in lung function than ipratropium. tiotropium may be useful in acute or chronic bronchitis. leukotriene b- (ltb- ) is a mediator of neutrophilic inflammation that is elevated in the sputum of persons with chronic bronchitis. several antagonists of ltb- receptors are in clinical development and may be useful in the treatment of chronic bronchitis kilfeather ( ) . a number of agents that act through cytokine pathways that mediate the symptoms of chronic obstructive lung disease (copd) are under investigation barnes ( ) , reid and sallenave ( ) . interleukin- (il- ), an anti-inflammatory cytokine, decreases in those with cop d. clinical trials of il- in various inflammatory disorders are underway. il- may hold promise in chronic bronchitis as well. interleukin- (il- ) is a neutrophil-attracting cytokine that is elevated in the sputum of persons with cop d. inhibitors of il- and antagonists of its receptor, cxcr , are being developed and may be useful in the treatment of chronic bronchitis. tumor necrosis factor-alpha (tnf-alpha) is a pro-inflammatory cytokine that activates various immune cells and stimulates the production of inflammatory cytokines and other mediators. its levels are elevated in the sputum of individuals with cop d. monoclonal antibodies directed against tnf-alpha, such as infliximab and recombinant soluble tnfalpha receptor (etanercept) are effective in rheumatoid arthritis and other inflammatory disorders and may be useful in the management of chronic bronchitis. inhibitors of oxidative stress n-acetylcysteine is a cysteine donor, enhancing the production of the antioxidant glutathione and decreasing oxidative stress. it has been shown to reduce the frequency of acute exacerbations of chronic bronchitis wegner ( ) . additional antioxidants, such as stable glutathione compounds and superoxide dismutase analogs, are in clinical development. inducible nitric oxide synthetase (inos) is responsible for the production of peroxynitrite, a potent oxidative species released during inflammation. inhibitors of inos are under development and may be useful in the treatment of chronic bronchitis. inhibitors of proteases (e.g., elastase) that are released by neutrophils during the inflammatory processes of chronic obstructive pulmonary disease are under development barnes ( ) . these compounds may slow the progression of emphysema that accompanies certain cases of chronic bronchitis. the p mitogen-activated protein (map) kinase is involved in the expression of inflammatory cytokines and proteases involved in chronic bronchitis. inhibitors of map kinase have been developed and may be useful in treating chronic bronchitis barnes ( ) . inhibitors of phosphoinositide- kinase-gamma (pi- kgamma), an enzyme involved in neutrophil activation, may also be of value. inhibitors of the nf-kappab signaling pathway are in development and may be tested for the treatment of chronic bronchitis. models of acute infectious bronchitis involve animals infected with a causative viral agent. for example, mice, ferrets, and chickens infected with influenza viruses are commonly used in the search for new anti-influenza drugs sidwell and smee ( ) . a number of animal models are commonly employed in the study of chronic bronchitis nikula and green ( ) . hamsters, dogs, or rats exposed to sulfur dioxide (so ) for - weeks develop clinical and histological signs of chronic bronchitis. mice, rats, guinea pigs, dogs, sheep, and monkeys have been used to study the role of cigarette smoke in the development of chronic bronchitis and emphysema. rats, mice, hamsters, and guinea pigs exposed to organic dusts (e.g., cotton dust) and bacterial endotoxin have been used to model occupational exposures, which result in chronic bronchitis and other forms of lung inflammation. exposure to other substances such as nickel and nitric acid has also been examined. lazarus, s.j., experts strive to better define the pathophysiology of cop d. this article examines new directions in the study of copd pathology: http://www.medscape.com/ viewarticle/ croxton, t.l., weinmann, g.g., senior, r.m., wise, r.a., crapo, j. d. and buist, a.s., clinical research in chronic obstructive pulmonary disease: needs and opportunities: http://www.nhlbi.nih.gov/meetings/workshops/copd_clinical.htm united states department of health and human services, cdc, nch s. national health interview survey. this web site contains data on the prevalence of copd symptoms in the united states and their impact on activity and daily life. it also has epidemiological information on a number of other medical conditions: http://www.cdc. gov/nchs/nhis.htm bandi, v.a., apicella, m.a., mason, e., murphy, t.f., siddiqi, a., atmar, r.l., greenberg, s.g., . nontypeable haemophilus influenzae in the lower respiratory tract of patients with chronic bronchitis. am. j. respir. crit. care med., , - . chronic obstructive pulmonary disease : new treatments for copd population:national health interview survey antibiotics in acute bronchitis: a meta-analysis recent advances in diagnosis and management of chronic bronchitis and emphysema disease of the airways in chronic obstructive pulmonary disease quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults the epidemiology of respiratory tract infections antiinflammatory effects of the phosphodiesterase- inhibitor cilomilast (ariflo) in chronic obstructive pulmonary disease viral and bacterial infections in the development and progression of asthma cilomilast: a second generation phosphodiesterase inhibitor for asthma and chronic obstructive pulmonary disease principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background uncomplicated acute bronchitis do bacteria cause exacerbations of copd childhood viral infection and the pathogenesis of asthma and chronic obstructive lung disease molecular pathogenesis of influenza a virus infection and virus-induced regulation of cytokine gene expression -lipoxygenase for the treatment of copd chronic obstructive pulmonary disease surveillance-united states management of acute exacerbations of copd: a summary and appraisal of published evidence animal models of chronic bronchitis and their relevance to studies of particle-induced disease gold scientific committee global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease cytokines in the pathogenesis of chronic obstructive pulmonary disease heliox for treatment of exacerbations of chronic obstructive pulmonary disease diet and obstructive lung diseases helicobacter pylori infection and respiratory diseases: a review in vitro and in vivo assay systems for study of influenza virus inhibitors beta -agonists for acute bronchitis (cochrane review) treatment for acute bronchitis? a metaanalysis pathogenesis and pathology of copd epidemiology of chronic obstructive pulmonary disease (copd) st century perspective on chronic obstructive pulmonary disease novel mechanistic targets for the treatment of sub-acute and chronic bronchitis resolution of bronchial inflammation is related to bacterial eradication following treatment of exacerbations of chronic bronchitis the role of infection in copd global initiative for chronic obstructive lung disease: pocket guide to copd diagnosis, management, and prevention bronchitis and acute febrile tracheobronchitis, including exacerbations of chronic bronchitis chronic bronchitis and emphysema costs of chronic bronchitis and copd: a -year follow-up study few smokers develop cop d. why clinical management of chronic obstructive pulmonary disease pulmonary pathophysiology: the essentials acute bronchitis is a very common respiratory illness. an elevated risk for the development of acute bronchitis is seen among the very young and the elderly, smokers, key: cord- - zqgqx authors: sethi, sanjum s.; zilinyi, robert; green, philip; eisenberger, andrew; brodie, daniel; agerstrand, cara; takeda, koji; kirtane, ajay j.; parikh, sahil a.; rosenzweig, erika b. title: right ventricular clot in transit in covid- : implications for the pulmonary embolism response team date: - - journal: jacc case rep doi: . /j.jaccas. . . sha: doc_id: cord_uid: zqgqx abstract severe acute respiratory syndrome coronavirus is associated with a prothrombotic state in infected patients. after presenting a case of right ventricular thrombus in a covid- patient, we discuss the unique challenges in the workup and treatment of covid- patients highlighting our covid- modified pulmonary embolism response team (pert) algorithm. severe acute respiratory syndrome coronavirus (sars-cov- ) causes covid- related critical illness and multiorgan dysfunction in a subset of those infected. given this increased potential for hypercoagulable events, yet being mindful of exposure risks and practical considerations in caring for covid- patients, we present the first report of a covid- patient with clot in transit, along with an algorithm for diagnosing and treating venous thromboembolism in covid- patients. a -year-old man was admitted following days of shortness of breath and nonproductive cough. upon presentation, the patient had a temperature of . f, heart rate of beats per minute, blood pressure of / mmhg, and a respiratory rate of breaths per minute. he was hypoxic with a peripheral oxygenation saturation (spo ) of %, while breathing liters per minute of supplemental oxygen via nasal canula with an additional liters per minute applied by non-rebreather mask. his past medical history was notable only for obesity (body mass index ) and type diabetes mellitus. the primary differential diagnosis for the patient's presentation includes bacterial pneumonia, viral upper or lower respiratory infection, and pulmonary embolism. given the patient's age, few medical comorbidities and the significant community spread of sars-cov- virus, covid- illness was the most likely diagnosis. his chest radiograph revealed diffuse bilateral hazy opacities ( figure ). sars-cov- nasopharyngeal swab polymerase chain reaction test was positive. initial venous blood gas was significant for a ph of . , paco mmhg, pao mmhg with a lactate of mmol/l. following intubation, his arterial blood gas improved slightly to ph . , paco mmhg, pao mmhg with with a fraction of inspired oxygen (fio ) of %. the pao :fio (p:f) ratio of , along with his chest radiograph findings of diffuse bilateral hazy opacities, was consistent with moderate ards. ( ) the patient's initial laboratory studies (table ) were most notable for a white blood cell count of . x /µl and serum creatinine . mg/dl. his high sensitivity troponin-t was initially ng/l with a subsequent value of ng/l, n-terminal btype natriuretic peptide was , pg/ml, ferritin was , ng/l, and d-dimer was greater than µg/ml (upper limit of detection). tte was obtained given severity of hypoxemia, hemodynamic instability, and elevated d-dimer out of concern for acute pe. tte revealed a left ventricular ejection fraction of % with global hypokinesis, and moderate to severely dilated right ventricle with moderate to severely reduced right ventricular systolic function (video ). there was flattening of the interventricular septum throughout the cardiac cycle consistent with both pressure and volume overload of the right ventricle. additionally noted was a . cm x . cm well circumscribed mobile echodensity attached to the right ventricular free wall concerning for clot in transit ( figure ). he was intubated for hypoxemic respiratory failure and admitted to the intensive care unit (icu). during the patient's initial course in the icu, he became progressively hypotensive over the course of the first hours, requiring maximum doses of norepinephrine ( mcg/min) and vasopressin ( . u/hr). given his progressive shock in the setting of high inflammatory markers, he was started on mg/kg of intravenous methylprednisolone per day. tte was obtained with the resultant findings described above. given these findings, the pulmonary embolism response team (pert) was consulted and the patient was given mg (over hours) of tissue-type plasminogen activator (tpa) and systemic anticoagulation with unfractionated heparin once the tpa infusion was complete. the patient was started on a dobutamine infusion for inotropic support and considered for venoarterial extracorporeal membrane oxygenation (ecmo) in case his hemodynamic condition worsened. after administration of tpa, the patient was weaned off pressors within hours. he was subsequently weaned off inotropic support over the ensuing days. his repeat tte revealed normal left ventricular systolic function, mild dilation of the right ventricle with preserved right ventricular systolic function. the previously seen clot in transit was no longer visualized and the right ventricular function was improving (video ). bilateral lower extremity venous doppler ultrasounds were negative for deep vein thrombosis. the patient had no immediate bleeding complications following administration of tpa. the usual risk stratification schema for acute pulmonary embolism rely on a combination of hemodynamic clinical parameters, such as hypoxemia, tachycardia, and hypotension along with serum biomarkers, such as troponin or brain natriuretic peptide followed by confirmatory imaging tests. ( ) an extremity duplex ultrasound examination and tte may even be performed by the same clinical provider in the same clinical setting using a portable or handheld device as a bedside screen to limit exposure and ppe use. both troponin and n-terminal b-type natriuretic peptide may be elevated in the setting of severe covid- illness. d-dimer elevations are also common, but have also been associated with a high prevalence of underlying venous thromboembolism. ( ) another potential risk stratification tool would be the sepsis-induced coagulopathy (sic) score, which uses common clinical and laboratory values to identify higher risk patient subsets. a sic score > has an association with worse outcomes at days. ( ) diagnostic cta remains the gold standard for the diagnosis of acute pulmonary embolism. nonetheless, exceptional circumstances specific to the covid- pandemic, such as potential infection of clinical or ancillary staff by a patient with poorly controlled cough and refractory hypoxemia limiting patient transport may make empirical anticoagulation preferable to cta or v/q scanning. the clinical team should always carefully balance the risks and benefits of empiric anticoagulation without objective imaging. cta should be performed at the discretion of the treating team and if needed after discussion with the pert team so that considerations can be made based on feasibility and safety of performing the confirmatory test versus the risk of empiric treatment under these conditions. patients admitted to the hospital with covid- critical illness should be given vte prophylaxis as standard of care, unless contraindicated. retrospective, observational data suggests a possible benefit to more intensive anticoagulation, however, this association should be verified in prospective randomized controlled trials prior to changing treatment algorithms given the known risks associated with therapeutic anticoagulation. ( ) the preferred anticoagulation for hemodynamically stable covid- positive patients with proven vte is enoxaparin mg/kg sq twice daily (based on total body weight; max kg). using low molecular weight heparin (lmwh) will reduce the use of ppe as routine monitoring with activated partial thromboplastin time or heparin assay is not necessary. dose adjustment or the use of unfractionated heparin should be considered for those with reduced kidney function. the roles for systemic thrombolysis, catheter or surgical thrombectomy, and ecmo are as yet undefined. we propose an algorithm that outlines our approach for testing and treatment for vte in the setting of covid- (figure , disclaimer: this algorithm is not a societal guideline, but a product of consensus of pert members at our institution). systemic thrombolysis remains a class i recommendation for hemodynamically unstable pe. ( ) however, the hemodynamic effect of the underlying pe must be clinically distinguished from the systemic vasodilatory effects that may accompany covid- . in the setting of right heart strain, there have been limited anecdotal reports of success with catheter-based treatments. however, caution must be advised with regards to resource utilization, including ppe, icu beds, cardiac catheterization laboratories and operating rooms. similar considerations must be made for the use of ecmo in properly equipped centers. in our case, the patient had severe right ventricular dysfunction with a large clot in transit. while surgical or catheter-based options were considered, the hemodynamic profile and low bleeding risk suggested that systemic thrombolysis would be the optimal approach. this led to dramatic improvement in the patient's hemodynamic profile. we used the standard dose of mg due to the significant right ventricular strain suggesting concomitant pe, the patient's critical illness, and the low bleeding risk. because a confirmed vte was visualized on echocardiogram, tpa was a reasonable therapy. right ventricular dysfunction in the absence of confirmed vte is clinical conundrum which requires careful balancing of the risks and benefits of systemic thrombolysis prior to use but is generally discouraged. on post-tpa day , the patient was noted to have bleeding within the oropharynx, which ultimately required compression packing to allow for continued systemic anticoagulation, which has since been removed. he remains off of vasoactive medications, and is making progress towards extubation. the patient remains hospitalized as of this writing, but the plan is to continue oral anticoagulation for at least - months after discharge. in summary, we present the first reported case of a clot in transit during covid- critical illness. covid- appears to be associated with an increased propensity for thromboembolic disease. heightened suspicion is necessary to clinically detect vte in this disease and treat accordingly, while mindful of the inherent risks to healthcare workers and resources available, depending on the level of crisis, in the overall health system. case covid- illness in native and immunosuppressed states: a clinical-therapeutic staging proposal isth interim guidance on recognition and management of coagulopathy in covid- covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up clinical pathology of critical patient with novel coronavirus pneumonia (covid- ) pulmonary artery thrombosis in a patient with severe acute respiratory syndrome covid- complicated by acute pulmonary embolism. radiology: cardiothoracic imaging acute pulmonary embolism and covid- pneumonia: a random association? covid- complicated by acute pulmonary embolism and right-sided heart failure. jacc: case reports prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia incidence of thrombotic complications in critically ill icu patients with covid- acute respiratory distress syndrome: the berlin definition diagnosis, treatment and follow up of acute pulmonary embolism: consensus practice from the pert consortium american college of chest physicians evidence-based clinical practice guidelines abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia new criteria for sepsis-induced coagulopathy (sic) following the revised sepsis definition: a retrospective analysis of a nationwide survey anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy the task force for the diagnosis and management of acute pulmonary embolism of the european society of cardiology after treatment with the tissue plasminogen activator (tpa), the right ventricular thrombus is no longer visible. the right ventricle function has improved and the right ventricle size has decreased key: cord- -c bkhgaz authors: azadeh, natalya; limper, andrew h.; carmona, eva m.; ryu, jay h. title: the role of infection in interstitial lung diseases a review date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: c bkhgaz interstitial lung disease (ild) comprises an array of heterogeneous parenchymal lung diseases that are associated with a spectrum of pathologic, radiologic, and clinical manifestations. there are ilds with known causes and those that are idiopathic, making treatment strategies challenging. prognosis can vary according to the type of ild, but many exhibit gradual progression with an unpredictable clinical course in individual patients, as seen in idiopathic pulmonary fibrosis and the phenomenon of “acute exacerbation”(ae). given the often poor prognosis of these patients, the search for a reversible cause of respiratory worsening remains paramount. infections have been theorized to play a role in ilds, both in the pathogenesis of ild and as potential triggers of ae. research efforts thus far have shown the highest association with viral pathogens; however, fungal and bacterial organisms have also been implicated. this review aims to summarize the current knowledge on the role of infections in the setting of ild. interstitial lung disease (ild) comprises a broad and heterogeneous spectrum of pulmonary parenchymal disorders of known and unknown causes. idiopathic ilds include idiopathic interstitial pneumonias (iips) such as idiopathic pulmonary fibrosis (ipf), idiopathic nonspecific interstitial pneumonia (nsip), acute interstitial pneumonia, idiopathic lymphoid interstitial pneumonia (lip), and cryptogenic organizing pneumonia. ild can also present as a manifestation of an underlying systemic illness, such as in connective tissue disease (ctd) or sarcoidosis, and can also result from occupational, environmental, or drug exposures (pneumoconiosis, hypersensitivity pneumonitis, or drug-induced ild). parenchymal lung diseases of infectious nature are generally excluded from the classification of ilds. however, the potential role of infectious agents in the development of certain ilds of unknown cause, such as ipf, continues to be of concern and remains to be clarified. furthermore, it appears likely that the phenomenon of "acute exacerbation" (ae), which can worsen the clinical course of fibrotic ilds, is in part associated with infections. diagnostic evaluations of patients with suspected ild also need to consider infections, since they can cause various histopathologic patterns commonly associated with ilds including nsip, lip, organizing pneumonia, and eosinophilic pneumonia, among others (table ) . this is particularly important, since immunosuppressive agents are commonly used in the treatment of ilds. moreover, in recent years, there have been several studies examining the role of antimicrobial therapy in the treatment of ilds (especially ipf), including in the setting of ae. most research looking at the role of infections in the pathogenesis of ild and as triggers of ae focus on viruses; the role of bacteria is less well studied. recent microbiological molecular techniques using the s sequence of bacteria to identify strains have allowed evaluation of alterations in the lung microbiome and its association with disease processes, including pulmonary fibrosis. [ ] [ ] [ ] in this narrative review, we explore the relevance of infections in the development of ilds, as triggers of acute exacerbation phenomenon, and in the diagnosis of ilds. the pathogenesis of ipf, the most common form of ild, is largely unknown. ipf is characterized by the histopathologic pattern of usual interstitial pneumonia, which manifests as a temporally and geographically heterogeneous pattern of parenchymal fibrosis. many experts theorize that repeated episodes of alveolar injury in a predisposed host with dysfunctional healing mechanisms are central to the development and progression of ipf. , environmental factors that are thought to contribute include dust, particulate exposures, aspiration of gastric contents, and infection. [ ] [ ] [ ] no definitive evidence exists to support the causal role of infections in the pathogenesis of ipf. moreover, during aes, infectious triggers are identified in only a minority of patients (possibly due to limitations of testing methods). in the setting of ipf and ipf with ae, we present evidence that supports a possible association with infection that does not necessarily imply cause and effect. moreover, many of the studies presented further on were carried out in an era when immunosuppressive agents (such as systemic corticosteroids) were commonly used in the treatment of ilds, and thus the data with respect to infections must be interpreted accordingly. several studies have pointed toward an association between viruses and ipf, including epstein-barr virus (ebv), cytomegalovirus (cmv), adenovirus, and hepatitis c virus (hcv). it has been theorized that these viruses provide a persistent antigenic stimulus in predisposed hosts, leading to fibrosis. evidence from animal (murine) models shows that infection with gamma-herpesvirus can induce fibrosis and exacerbate established fibrosis, evidenced by increased total lung collagen, acute lung injury (ali), histopathologic diffuse alveolar damage (dad), and reduced lung function. , the most frequently identified virus appears to be ebv. , egan et al showed in vivo ebv replication (localized to pulmonary epithelial cells) in % of patients with ipf vs % of control subjects. importantly, the patients evaluated were classified as immunocompetent, and the majority had not received ipf-targeted therapy at the time of the biopsy procedure. tang et al attempted to show the association between chronic viral infection and ipf. using polymerase chain reaction (pcr) techniques, they found one or more herpesviruses more frequently in patients with ipf vs control subjects ( % of the patients with ipf vs % of control subjects (p < . )). these viruses included cmv, ebv, human herpesvirus- [hhv- ], and hhv- . they found that herpesviruses were found more frequently in patients with sporadic cases of ipf than in familial cases (p < . ), supporting the role of these viruses as triggers or in the pathogenesis of ipf. yonemaru et al studied patients with ild ( cases of ipf, seven cases of ctd-ild, cases of sarcoidosis) and emphysema ( cases) and compared cmv, ebv, herpes simplex virus (hsv), adenovirus, and parainfluenza serologies. they showed that cmv igg, complement fixation, and ebv igg titers were significantly higher in patients with ipf and ctd-ild compared with the other groups. in contrast, adenovirus and parainfluenza titers demonstrated no significant difference among the groups. interestingly, in these patients, increased cmv igg and complement fixation suggests that latent cmv infection may be more prominent in ild, giving further credence to the theory that such pathogens act as a chronic antigenic stimulus for lung injury. some speculate that the pathogen load required to trigger the cascade of inflammation and ultimately fibrosis may be too small for our tests to identify. to test this hypothesis, santos et al used immunohistochemical analysis in patients with iips who underwent open lung biopsy procedures. cmv and measles were detected in patients with both ipf and nsip and histopathologic dad. kuwano et al studied the presence of adenovirus dna in patients with ctd-ild and ipf. they used molecular techniques to identify the adenovirus genome in transbronchial biopsy specimens from patients with ipf, patients with ctd-ild, and patients with sarcoidosis. adenoviral dna was present in % of patients with ipf, % of patients with ctd-ild, and % of patients with sarcoidosis. patients who had received corticosteroids were more likely to be positive for the adenovirus dna, suggesting that the immune status of the host plays a significant role and that adenovirus is not truly associated with the pathogenesis of ild or as a trigger of ae. hcv causes liver fibrosis, and a number of case reports have suggested the possibility of its role in the development of ipf. ueda et al studied patients with ipf and showed that % had positive serum antibodies to hcv vs % of control subjects ( , healthy volunteers). arase et al studied a cohort of , patients with hcv and , patients with hepatitis b virus. in the hcv group, they noted a -and -year cumulative incidence of ipf of . % and . %, respectively, compared with zero cases of ipf in the hepatitis b virus group. the study concluded that age, smoking, and liver cirrhosis enhance the development of ipf in hcv-positive patients. however, a number of other studies have failed to replicate this association. the lack of a consistent signal among various cohorts suggests that hcv is unlikely to be an important trigger for the development of ipf. bacteria have been less well studied in the realm of ipf. richter et al it is currently difficult to determine whether patients with ipf are more susceptible to infection or colonization due to abnormal lung parenchyma, associated traction bronchiectasis, and immunosuppressive medications (which historically have been commonly used for treatment of ilds), or whether bacteria are involved as triggers of ae or in the pathogenesis of ipf. a study from israel found that the incidence of pulmonary tuberculosis in chronic ild (mostly iip) was / times higher than in the general population, and corticosteroid therapy was not found to be a confounding factor. this finding is thought to be related to an increased susceptibility to atypical infections as a result of abnormal lung parenchyma, rather than a trigger in the evolution of ild. the lung microbiome has also been an area of research in relation to various respiratory conditions. molyneaux and maher analyzed bal samples from patients with ipf using culture-independent metagenomic analysis. they found the phylum firmicutes (streptococcus and veillonella species), proteobacteria, and bacteroidetes were most commonly encountered. such data demonstrate that the lower airways (once thought to be sterile) are colonized with microbial communities that can possibly be involved in the pathogenesis or progression of lung injury and ultimately fibrosis. the same authors were able to show by longitudinal analysis of patients with ipf serum and bal samples that specific genes, some of which coded for antimicrobial peptides, were present in patients with ipf and such expression increased over time, supporting the theory that pathogens may provide chronic antigenic stimuli in patients with ipf. fungi even less information is available about the potential role of fungi in the pathogenesis of ipf or in ae of ipf. on occasion pneumocystis jirovecii is detected as a factor associated with acute deterioration. other studies have also suggested that a significant rate of colonization with p jirovecii occurs in patients with ipf and other ilds. for instance, vidal et al documented a % colonization rate with p jirovecii in patients with ipf. infectious causes need to be considered in the diagnostic evaluation of patients with suspected iip, since the histopathologic patterns of lung injury underlying some iips can also be seen in pulmonary infections (table ) . these patterns include nsip, organizing pneumonia, dad, lymphoid (lymphocytic) interstitial pneumonia (lip), and pleuroparenchymal fibroelastosis (ppfe). thus, it is imperative that infection be excluded in diagnosing these forms of iip. nsip is characterized histopathologically by varying degrees of interstitial chronic inflammation or fibrosis (or both) that appears temporally homogeneous with inconspicuous or absent fibroblastic foci. , this pattern of lung injury can be encountered in various clinical contexts. the diagnosis of idiopathic nsip requires exclusion of identifiable causes. for example, nsip is the most common form of ild found in patients with ctds, that is, as a form of ctd-associated ild. in their initial description of nsip, katzenstein and fiorelli postulated that this form of lung injury may represent a result of prior ali including infections. it has been known that nsip can be encountered in hiv-positive patients with or without p jiroveci pneumonia. , nsip has also been encountered as a pattern of lung involvement in viral infections such as human t-cell lymphotropic virus type . organizing pneumonia is a nonspecific response to a wide array of lung injury including infections. it is histopathologically characterized by the presence of organizing polypoid intraluminal plugs of granulation tissue within the alveolar spaces and ducts with varying degrees of bronchiolar involvement. , similar to idiopathic nsip, the diagnosis of cryptogenic organizing pneumonia entails exclusion of potential causes, including infections, aspiration and other inhalational injuries, drugs, ctds and other systemic inflammatory disorders. , [ ] [ ] [ ] [ ] in a retrospective study of cases of organizing pneumonia pattern confirmed on lung biopsy specimens, cases ( %) were related to pulmonary infections. an organizing pneumonia pattern of lung injury can be seen with many forms of pulmonary infections, including bacterial, viral, fungal, and parasitic. [ ] [ ] [ ] it seems likely that even some cases diagnosed as cryptogenic organizing pneumonia that have a self-limited clinical course represent resolving pulmonary infection. dad is the histopathologic pattern underlying an acute form of iip-acute interstitial pneumonia-and most cases of ards. , , it is characterized histopathologically by the presence of hyaline membranes, along with diffuse alveolar septal thickening, septal edema, and interstitial fibroblast proliferation. this pattern can be encountered in patients with various forms of ali. , , acute interstitial pneumonia (hamman-rich syndrome) refers to dad occurring in the absence of an identifiable cause. , , in one study looking at patients with dad, the majority of cases were thought to have potential triggers identified. in this study of consecutive cases of dad confirmed by surgical lung biopsy results, cases ( %) were thought to be infection related, most commonly viral pneumonias. idiopathic lip is currently classified as a rare form of iip along with idiopathic ppfe. histopathologically, lip manifests diffuse infiltration of the alveolar septa with mostly lymphocytes and varying numbers of plasma cells. the idiopathic form of lip is indeed rare and outnumbered by those cases associated with disorders of immunodeficiency, ctds, and other autoimmune disorders. , , [ ] [ ] [ ] similar to nsip, lip can be seen in hiv-positive patients and has also been associated with several viral infections, including ebv, hhv- , and human t-cell lymphotropic virus type . [ ] [ ] [ ] [ ] [ ] [ ] ppfe is a recently delineated entity and is characterized histopathologically by elastotic fibrosis involving the pleura and adjacent subpleural parenchyma. this process predominantly affects the upper lobes, in contrast to ipf. several underlying disease processes have been implicated in cases of ppfe, including infections (eg, mycobacterium and aspergillus). a history of recurrent infections has been described in some patients with ppfe, raising the possibility that it may result from infection-related lung injury. ppfe can also be seen as a rejection phenomenon in recipients of allogeneic lung or hematopoietic stem cell transplantation, drug or occupational exposures (asbestos, aluminum), chemotherapy, radiation, underlying autoimmune disease, and hypersensitivity pneumonitis. idiopathic ppfe is a very rare form of iip and may be associated with a genetic predisposition as a form of familial interstitial pneumonia. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] sarcoidosis sarcoidosis is a granulomatous inflammatory disorder of unknown cause and is diagnosed by a combination of chestjournal.org clinical, radiographic, and histopathologic findings. infection has been proposed as a trigger leading to an aberrant inflammatory cascade in a predisposed host. given the lack of histopathologic specificity in diagnosing sarcoidosis and the wide spectrum of its clinical manifestations, it is difficult to identify a common cause in such a diverse disorder. , mycobacterium is the most commonly implicated species. although mycobacterium has not been demonstrated in sarcoid granulomas by culture or acidfast stains, immunohistochemical studies have shown remnants of the mycobacterial cell wall within sarcoid specimens. [ ] [ ] [ ] in addition, pcr and nucleic acid testing have demonstrated mycobacterial nucleic acid in up to % of sarcoid specimens. a meta-analysis found that mycobacterial dna/rna was identified in % of sarcoid tissues, which was significantly higher than in nonsarcoid tissues of control subjects. , , propionibacterium has also been implicated in sarcoidosis and has been cultured in up to % of sarcoid specimens. , it is important to note that p acnes is a commensal bacterium and has been cultured in a large proportion of healthy control subjects. eishi et al found propionibacterium through real-time pcr in of patients with sarcoidosis but also found the species in up to % of control subjects. a systematic review of studies (> , patients) found a link between sarcoidosis and both p acnes, and mycobacteria. herpesvirus has also been implicated, although viruses have not been known to trigger granulomatous reactions. various other pathogens studied, including borrelia, rickettsia helvetica, chlamydia pneumoniae, ebv, and retroviruses, were not associated with sarcoidosis. these studies support, but do not confirm, the theory that various antigens can stimulate granulomatous inflammation in a predisposed host and that the microorganism acting as the trigger can vary. currently available antibiotics can target enzymes encoded by microbial genes found to be present in sites of granulomatous inflammation in sarcoid specimens. , a randomized placebo-controlled trial in patients with chronic cutaneous sarcoidosis who were randomized to receive concomitant levofloxacin, ethambutol, azithromycin, and rifampin vs placebo for weeks demonstrated reduced diameter of sarcoid skin lesions and overall clinical improvement in the treatment arm. the same regimen was used in patients with chronic pulmonary sarcoidosis with encouraging outcomes, including improved fvc, functional capacity, and quality of life. the same group is pursuing this regimen in a larger cohort of patients to confirm their findings (clinicaltrials.gov nct ). use of antimicrobial agents directed against target enzymes may be an innovative treatment alternative. there is also evidence that sarcoidosis may be transmissible; bone marrow transplants from donors with sarcoidosis have resulted in granuloma formation in recipients. , although this does not directly support infection, it supports the theory of an antigenic stimulus leading to granuloma formation. whether sarcoidosis is a result of active or latent infection or is an abnormal response to remnants of a cleared or partially cleared infection are theories that continue to be debated. infections may act simply as a stimulus for an aggressive inflammatory reaction in a predisposed host. in such predisposed hosts, there can be more than one type of antigenic stimulus leading to the clinical manifestations of sarcoidosis. there are other less common forms of ild in which the role of infection deserves mention. acute eosinophilic pneumonia is generally thought of as an acute respiratory illness of unknown cause. [ ] [ ] [ ] in recent years, cigarette smoking and medications have been identified as the inciting agents in a subset of patients with acute eosinophilic pneumonia. [ ] [ ] [ ] it should also be recognized that acute eosinophilic pneumonia can be of infectious origin, as seen in fungal pneumonias-for example, coccidioidomycosis, and parasitic infections. , since corticosteroids are frequently used in the treatment of idiopathic acute eosinophilic pneumonia, it is crucial for a possible infectious origin to be considered. interstitial pneumonia with autoimmune features is a recently described entity that comprises a cohort of patients with ild and features of autoimmunity (extrapulmonary and serologic) but do not meet criteria for established ctds. such patients pose a difficult question with respect to the role of immunosuppressive therapy. little is known about the pathogenesis of interstitial pneumonia with autoimmune features or indeed the role of infection in this patient population. pulmonary alveolar proteinosis (pap) is a diffuse lung disease characterized by an alveolar filling process with amorphous lipoproteinaceous surfactant-like material. most cases of pap represent an autoimmune disease mediated by the development of anti-granulocyte macrophage-colony stimulating factor neutralizing antibodies. , these antibodies induce a functional deficiency of granulocyte macrophage-colony stimulating factor, which is a critical mediator of surfactant protein and lipid homeostasis in the alveoli. a minority of pap cases are considered secondary forms, caused by exogenous agents or hematologic disorders. nocardiosis is a well-recognized infection that can complicate the course of patients with pap. in addition, p jiroveci, mycobacteria, and cmv have also been reported to induce pap. [ ] [ ] [ ] acute exacerbation in ilds the natural course of patients with ild is not fully understood and, in part, depends on the type of underlying ild. especially in the fibrotic ilds, ae accounts for significant morbidity and mortality. [ ] [ ] [ ] although no consensus definition for ae-ild exists, the generally accepted criteria are extrapolated from the ipf population given the similarities in presentation. ae is generally characterized by acutely (typically < month) worsening dyspnea and parenchymal infiltrates on imaging. it can occur in many forms of ild and is histologically characterized by dad in most cases. , such episodes are an important cause of ild-related mortality, with a -month survival of < % in patients with ipf. , , the various populations studied, evolving definitions of ae, and the retrospective design of the majority of studies make it difficult to assess the true frequency and sequelae of respiratory worsening in these patients. the theory that infection plays a role in the pathogenesis of the underlying disease, as well as in triggering aes, has not been fully evaluated, but there is some data to support this concept in the current literature. the true incidence of ae by any definition is unclear, and reports range from % to % per year. differences in definitions and in the cohorts studied largely explain this variation. most of the current data are derived from retrospective studies, and most clinical trials estimate a lower incidence of ae ( %- %), perhaps due to more strict definitions used for inclusion. , the definition of ae in ipf has been broadened in the most recent expert recommendations. , historically, ae excluded those with infection and other "reversible" conditions (ie, heart failure, venous thromboembolism). despite advancements in diagnostic methods, infection in patients with ild remains difficult to diagnose. bronchoscopy, although quite specific in diagnosing infection, is relatively insensitive, particularly in the context of recent antibiotic use. , given our inability to definitively rule infection in or out, it is not practical to define ae by the exclusion of infection. thus, the newly accepted definition includes ae with or without an identifiable trigger such as infection (table ). in the majority of patients with respiratory decline, no trigger can be identified, and the progression of the underlying ild remains the most likely cause. however, the host response to an external stimulus may be important. specifically, infections as antigens may play a role in triggering some fraction of exacerbations. additionally, the histopathologic finding of dad in patients with ae leads to the natural correlation with ali/ards. the causes of ali (histopathologic dad) are numerous and are also thought to include infection, aspiration, toxins, transfusion, and surgery. , many of these triggers may lead to events that are indistinguishable from idiopathic exacerbations of ild. the role of bronchoscopy should be a clinical decision made on a case by case basis. those with ae may have a tenuous respiratory status, and bronchoscopy may risk worsening this. in the setting of empirical antibiotic therapy and extensive laboratory investigations looking for identifiable triggers, bronchoscopy specifically looking for infection may not be necessary in all patients with ae. the risk of the procedure in this population, when weighed against the uncertain yield, makes it difficult to recommend for every patient, since its effect on outcomes remains unclear. the current evidence also does not support mandating other investigations when searching for possible triggers of ae (eg, specific blood work or serologic tests), clinical judgment must be used to determine appropriate and exhaustive testing looking for reversible triggers of ae, for example, testing for opportunistic pathogens in patients receiving immunosuppressive agents or testing for endemic pathogens. data from small retrospective studies report an infectious cause as a trigger for % to % of aes in patients with non-ipf fibrotic lung diseases. one larger study of patients with ild ( cases of ipf, cases of non-ipf) showed that % of patients were diagnosed with infection in the setting of acute respiratory worsening. there are also postmortem studies examining this issue: one such study of patients with ipf who underwent autopsy showed that % had an infection identified (including fungal, bacterial, and viral). another study found that . % of patients with ae had bronchopneumonia (fungal; . %; cmv, . %; and bacterial, . %) identified postmortem and not diagnosed clinically. such studies highlight difficulties in diagnosing infection in this clinical setting and further support the recent revisions to the definition of ae. although, infectious causes are found in % to % of patients with ae, identifying infection has not yet been demonstrated to affect outcomes. for example, blivet et al reported that in six of patients with confirmed treatable pathogens (including staphylococcus aureus, streptococcus pneumoniae, influenza a, and p jiroveci), outcomes were not affected and mortality remained high despite antibiotics targeting these organisms. of the two patients in whom p jiroveci was identified, only one patient's condition improved with antipneumocystis therapy. the patients who did the best in this cohort were those with noninfectious reversible causes of respiratory worsening, that is, pneumothorax and complications of anesthesia. in patients with ae: hsv (n ¼ ), ebv (n ¼ ), and torque teno virus (ttv) (n ¼ ). ttv was significantly more common in patients with ae and ali compared with stable control subjects. overall, the presence of a common respiratory virus was not detected in most patients with ae; however, the presence of ttv in a significant minority of the ae and ali cohort may be important and an area for future study. the results suggest that the presence of ttv is not specific for ae but may be associated with ali in general. konishi et al also failed to identify gene transcription profiles that would be expected in viral infections in both patients with ipf and patients with ipf with ae. , chlamydophila pneumoniae infection has been known to cause exacerbation of asthma and copd. a prospective study was conducted to investigate the possible role of c pneumoniae infection in triggering ae of ipf. sputum, blood cultures, and acute and convalescent serologic tests for c pneumoniae igg and iga (elisa) were performed prospectively in patients over a -year period. only two patients had an antibody response suggestive of acute or reactivated infection, suggesting that chlamydophila is an unlikely trigger for ae of ipf. although existing data do not support the role of infection/viruses in all cases of ae, or even in a majority, the possibility of viruses as a trigger remains to be explored. , unlike other respiratory conditions in which exacerbations are truly acute events, the onset of an ae in ild is generally more insidious. it is possible, therefore, that by the time of clinical presentation, any triggering viruses would no longer be detectable. moreover, a significant proportion of patients with ae may have occult infection despite a vigorous clinical workup. there is also some epidemiologic support for infectious causes of ae, which comes from studies that demonstrate ae occurring more frequently in winter and spring months and in patients taking immunosuppressive medications. song et al showed in their study of patients with ipf that there was an increased risk of opportunistic infections, possibly attributable to prior treatment with chronic corticosteroid therapy or other immunosuppressive agents. a polymorphism of the mucin (muc b) gene has been associated with both familial and sporadic ipf and is essential in mucosal immune defense. in healthy individuals, the mucociliary escalator constitutes an important innate pulmonary defense mechanism. in contrast to cystic fibrosis in which impaired mucociliary clearance predisposes to aes, mucociliary dysfunction of the peripheral airways has not been directly shown to cause ae-ild, even though recent studies implicate the mucin gene in the pathogenesis of several ilds. , attempts to implicate specific pathogens in the etiopathogenesis of ae have not often been successful; no association has been shown between ae and any specific organism. accumulating evidence suggests a multiple-hit hypothesis leading to progressive deterioration of lung function, with infections being possible contributors to such "hits." the prognostic implications of ae are profound; data suggest that up to % of deaths from ipf are preceded by an ae. the median survival of patients with ipf who experience an ae is approximately to months, so further research in this area is crucial, both to clarify the role of infection in respiratory worsening/ae and to evaluate the role of the lung microbiome and chronic infectious stimuli in the pathogenesis of ilds. although bacteria have been less commonly implicated in the pathogenesis of ilds, they have been studied in the setting of ae as well as in antimicrobial trials. most experts would agree with empirical antibiotic treatment in the setting of ae given the potential benefit and minimal risk to the patient, as occult infection remains a possibility. the efficacy of azithromycin in treating ipf was studied in a prospective open-label study: patients with ae received azithromycin in addition to high-dose pulse steroid therapy. outcomes were compared with a historical cohort treated with fluoroquinolone agents (n ¼ ). the primary end point of mortality at days was significantly lower in patients treated with azithromycin (mortality, % vs %; p < . ), and no serious adverse events were observed. whether these findings are attributable to azithromycin's antiinflammatory effects, antimicrobial effects, or a combination of both, cannot be ascertained from such studies and remains an area to be investigated. a placebo-controlled study evaluated the prophylactic use of co-trimoxazole for months compared with usual care for patients with fibrotic iip. although there were significant dropouts in the co-trimoxazole arm ( % vs % in placebo arm), post hoc analysis suggested that co-trimoxazole led to a reduction in infections and mortality. there are ongoing clinical trials looking at co-trimoxazole therapy in ipf (clinicaltrials. gov nct ). polymyxin-b-immobilized fiber column (pmx) helps remove endotoxins and is used for the treatment of endotoxemia. several studies from japan have reported an improvement of oxygenation in patients with ali/ ards treated with pmx. , given that dad is the most common pathologic finding in ali/ards and in ae, treatments targeting ali/ards may have relevance in the management of aes. a retrospective study aimed at clarifying this in patients with ipf with ae showed a significant improvement in the pao to fio ratio with pmx treatment. however, the improvements in oxygenation did not translate into a survival benefit, as -and -month survival rates ( % and %, respectively) of patients with ipf with ae remained low. a more recent retrospective japanese study suggests that survival in those patients who received pmx may have been improved. pmx is not a currently accepted treatment for ae-ild, but such research may support the role of infections as antigenic stimulus in the setting of ae. the role of infection in the pathogenesis of ild and ae-ild remains unclear and needs further exploration. the current literature suggests that infections may play a role in the complex interaction between a susceptible host and the environment, leading to the development or progression of ild. given the overlap in histopathologic manifestations of infections and ilds, infectious causes should always be considered in a patient with suspected ild prior to institution of immunosuppressive therapy. moreover, infections become a more significant concern when patients with ild receive chronic immunosuppressive medications as treatment for their ild. recent studies suggest a potential role for antimicrobial 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rahman, asma; niloofa, roshan; de zoysa, ishan m; cooray, akila d; kariyawasam, jayani; seneviratne, suranjith l title: neurological manifestations in covid- : a narrative review date: - - journal: sage open med doi: . / sha: doc_id: cord_uid: azzy t a covid- , a respiratory viral infection, has affected more than million individuals worldwide. common symptoms include fever, dry cough, fatigue and shortness of breath. some patients show neurological manifestations such as headache, dizziness, cerebrovascular disease, peripheral nerve and muscle symptoms and smell and taste impairment. in previous studies, sars-cov- and mers-cov were found to affect the nervous system. given the high similarity between sars-cov- and sars-cov- , effects on the nervous system by sars-cov- are a possibility. we have outlined the common neurological manifestations in covid- (information are up-to-date as of june ) and discussed the possible pathogenetic mechanisms and management options. two large cohort-based studies on neurological manifestations of covid- have been reported so far. in a study done in wuhan, china, mao et al. noted neurological manifestations in . % of covid- patients and these were significantly more common in patients with severe disease. central nervous system (cns) and peripheral nervous system manifestations were seen in . % and . %, respectively. in a study conducted in france, helms et al. found % of patients admitted to the intensive care unit because of acute respiratory distress syndrome due to covid- to have neurological signs. the differences in percentage between the two studies may be because the second study focused on more severely affected covid- patients. table summarizes the common neurological manifestations in covid- . the main cns manifestations observed are headache, dizziness, cerebrovascular disease (cvd), encephalopathy, delirium and other related manifestations as discussed below. headache and dizziness are the most common neurological manifestations recorded in several studies (table ) . , it is uncertain whether these two manifestations were caused by a direct effect of the infection on the nervous system or due to other factors such as stress, fear or anxiety. li et al., who analyzed the cohort of patients described by mao et al. and seven more, found % to have acute ischemic stroke. stroke was also reported in five patients younger than years from new york. based on brain magnetic resonance imaging (mri) findings from of their patients, helms et al. reported two to have acute cerebral ischemic stroke and one to have subacute cerebral ischemic stroke. in a retrospective cohort-based study from new york, . % had imaging-proven acute ischemic stroke and most ( %) strokes were cryptogenic, possibly related to an acquired hypercoagulability. a recent systematic review showed the incidence of acute ischemic stroke in covid- to be . % to . % with a mortality rate of %. in addition, several case reports of stroke in patients with covid- have been published ( table ). the cvd in covid- may be due to high levels of inflammation and/or a hypercoagulable state. raised serum interleukin and c-reactive protein concentration have been reported, and coagulation abnormalities are increasingly noted with raised d-dimer concentration pointing to a poorer prognosis. awareness by clinicians of the possibility of cvd in covid- patients may lead to more timely management decisions and thus a reduction in both morbidity and mortality. dixon et al. acute necrotizing encephalopathy a -year-old female patient with aplastic anemia reported seizures and reduced consciousness days after fever. ct and mri showed swelling of the brain. patient did not respond to steroid treatment and died on the th day after hospitalization. filatov et al. encephalopathy a -year-old female patient presented with encephalopathy and tested positive for covid- . csf tested negative for virus. pilotto et al. encephalopathy a -year-old female with covid- who progressively developed severe encephalopathy. improved with high doses of steroid treatment. poyiadji et al. acute necrotizing encephalopathy a female patient in her late s presented with acute necrotizing encephalopathy and later tested positive for covid- . the csf was not tested for sars-cov- virus. zayet et al. encephalopathy two cases having symptoms of encephalopathy followed by being positive for covid- . csf was tested negative for sars-cov- , and mri showed no signs of inflammation. avula et al. acute stroke a series of four patients presenting with radiographic evidence of acute stroke. beyrouti et al. acute ischemic stroke a series of six covid- patients with acute ischemic stroke. co et al. stroke a -year-old female patient with a past history of stroke presented typical symptoms of covid- initially. developed right upper and lower extremity weakness and severe dysarthria. fara et al. stroke a series of three patients presenting with stroke-like symptoms. the patients were found to have subocclusive severe stenosis of the common carotid artery. none had severe respiratory symptoms. gunasekaran et al. stroke a -year-old female patient presenting with typical symptoms initially, developed stroke during hospitalization immovilli et al. stroke a series of patients having stroke; two cases of hemorrhagic stroke and cases of ischemic stroke. reports an association between stroke and pneumonia severity in covid- patients. morassi et al. acute ischemic and hemorrhagic stroke a series of six patients who developed stroke. mainly presented severe pneumonia and multiorgan failure. oxley et al. large vessel stroke a series of five patients younger than years of age presented with large vessel stroke. al saleigh et al. one patient showing hunt and hess (h&h) grade aneurysmal subarachnoid hemorrhage, and the second patient having had an ischemic stroke with massive hemorrhagic conversion. csf tested negative for sars-cov- virus. valderrama et al. ischemic stroke a -year-old male patient with hypertension who tested positive for covid- . the patient presented to the hospital with symptoms of a stroke days later. zhai et al. acute ischemic stroke a -year-old male patient showing symptoms of a stroke and diagnosed with covid- . other cns manifestations bernard-valnet et al. acute meningoencephalitis both patients developed meningoencephalitis few days after diagnosis of covid- having mild respiratory and general symptoms. csf was tested negative for sars-cov- virus. chaumont et al. meningoencephalitis a -year-old patient developed meningoencephalitis week after infection. csf was tested negative for sars-cov- virus but the virus was detected in bronchoalveolar lavage. first munz et al. acute transverse myelitis the patient had typical respiratory symptoms of covid- and was discharged from the hospital. admitted back and diagnosed with multifocal myelitis. csf was negative for sars-cov- virus. al-olama et al. meningoencephalitis a -year-old male patient initially with typical covid- symptoms developed meningoencephalitis with intracerebral subdural hematomas. fluid from chronic subdural hematoma tested positive for sars-cov- rna. sharifi-razavi et al. intracerebral hemorrhage a -year-old with a history of fever and cough who tested positive for covid- . the patient presented with intracerebral hemorrhage after few days. reichard et al. acute disseminated encephalitis like pathology a patient was admitted due to coronary heart disease and underwent surgery. subsequently developed covid- . the patient died after weeks in hospital and autopsy revealed neuropathological lesions. sarma and bilello acute transverse myelitis a -year-old female patient with sars-cov- presenting lower back pain, bilateral symmetric upper, and lower extremity numbness. diagnosed with acute transverse myelitis. valiuddin et al. acute transverse myelitis the patient first presented with generalized weakness, following bilateral lower and upper extremity weakness. the csf tested negative for sars-cov- virus. vollono et al. focal status epilepticus a -year-old female patient whose primary presentation was focal status epilepticus. csf analysis was not carried out. wong et al. rhombencephalitis a -year-old male patient who initially had fever developed with acute brainstem dysfunction. mri showed changes in inflammation of the brainstem and upper cervical cord. csf was not tested for the virus due to low sample quantity. ye et al. encephalitis patient first presented with typical symptoms of covid- , followed by deteriorated consciousness. csf tested negative for virus. the condition gradually improved with the clearance of the virus and treatment. zanin et al. seizure/brain and spine demyelinating lesions a -year-old female patient who was found unconscious at home tested positive for covid- . the mri revealed demyelinating lesion in the brain and spine. csf tested negative for sars-cov- . zhang et al. adem first described case of adem with covid- . the mri showed patchy areas of abnormal signals in certain areas of the brain. zhao et al. there are reports of encephalopathy in covid- (table ) , and healthcare workers need to consider testing for sars-cov- in such patients. , delirium has been reported to occur in covid- , especially among older persons. beach et al. presented a case series, where three of the four covid- patients had delirium, without the presence of significant respiratory symptoms. at present, in most reported studies, csf had not been tested for sars-cov- . in the patient described by filatov et al., csf was tested and found to be negative. encephalopathy and delirium may be due to direct invasion of the cns by sars-cov- , inflammation secondary to a cytokine storm or as a result of septic encephalopathy. there are reports of encephalitis and meningitis in covid- . for instance, the sars-cov- virus has been detected in the csf of two patients with encephalitis, , raising the possibility of direct cerebral effects of the virus. mao et al. reported seizures and hemiplegia in one and two patients, respectively, prior to the onset of respiratory symptoms. however, in a retrospective study, lu et al. did not find an increased risk of symptomatic seizures in covid- patients. at present, it is uncertain whether the seizures are coincidental or due to sars-cov- viral effects or the drugs used in treatment. in the study by mao et al., . % of patients had peripheral nervous system manifestations. the common manifestations include guillain-barré syndrome (gbs) and other related variants and loss of the sense of taste and smell. currently, a total of reports on gbs and its variants in covid- have been reported. pathogen-associated antibodies that attack peripheral nerves due to molecular mimicry have been previously put forward as a disease mechanism in gbs. covid- -related gbs is mainly seen in the elderly while typical gbs can occur in all age groups. none of the patients with post-covid- gbs tested positive for sars-cov- in the csf, points to an immune mechanism such as inflammation secondary to a cytokine storm as a possible cause. some variants of gbs such as miller fisher syndrome and polyneuritis cranialis have been reported in two covid- patients from italy; both recovered fully within weeks. twenty cohort studies have reported on loss of smell (anosmia) and taste (ageusia) as early symptoms of covid- (table ) . these symptoms may appear early in the course of the disease or in otherwise asymptomatic individuals. a european study of covid- patients, conducted across four counties, found . % and % to have impairment of the sense of smell and taste, respectively. at present, there have been only a few studies on this aspect from the asia-pacific region. for instance, mao et al. found . % and . % of their cohort to have taste and smell impairment, respectively. compared with the european studies, the frequency of smell and taste impairment in the chinese study was low, which may be because the latter study was not specifically designed to assess this aspect. smell and taste impairment may also vary across different populations; individuals with a strong preference for spicy foods may have a reduced taste sensitivity than those with a lower preference. the variations may also be attributed to the method of testing, as most of the studies were questionnaire based. for instance, in a study by lechien et al., of the . % of patients self-reporting olfactory disorders, . % were subsequently found to be normal on objective testing. a standard quantifiable test needs to be developed to validate the variations of smell and taste impairment. increased awareness that olfactory and gustatory dysfunction is common and early symptoms in covid- would allow earlier diagnosis and thus effective self-isolation. currently, although complete recovery has been reported in the majority of patients, it may be too early to comment on the longer-term implications. it is still uncertain whether the taste and smell alterations are due to inflammation of the nasal tract or damage to the sensory neurons in the olfactory bulb. a large number of cells in the nasal epithelium express the angiotensin-converting enzyme (ace ) receptor which is the cell entry receptor for sars-cov- . however, brann et al. noted an absence of ace receptors in the olfactory sensory neurons and suggested inflammation may be the primary cause for small impairment. a previous mouse study found sars-cov- to be able to enter the brain through the olfactory bulb. ace receptors are found to be expressed in olfactory sustentacular cells and other non-neuronal cells in the olfactory epithelium. these cells maintain the integrity of the sensory neurons and damage to these may lead to alterations in smell and taste. skeletal muscle injury was recorded in . % of the covid- patients studied by mao et al. creatine kinase (ck), d-dimer, c-reactive protein and lactate dehydrogenase levels were found to be elevated in patients with skeletal muscle injury. in another report, myalgia was noted in . % of the studied covid- patients. clinicians should be aware of the range of neurological manifestations in covid- , as this would facilitate early recognition and appropriate management. further studies from different regions of the world, using appropriate brain imaging, electroencephalography (eeg) and csf analysis, could provide evidence for the neuro-invasive potential of sars-cov- . such studies would also shed further light on why many neurological manifestations are more common in the elderly with severe covid- . neurological involvement in covid- may be due to direct sars-cov- viral damage to the nervous system or through indirect means. ace receptors are highly concentrated in the substantia nigra and ventricles of the brain. it is also found in many neurons, astrocytes, oligodendrocytes, middle temporal gyrus and posterior cingulate cortex. a mouse cellculture study found ace receptor expression on astrocytes. ace receptors are also expressed on endothelial and arterial smooth muscle cells of blood vessels in the brain. these studies suggest that major cns manifestations are possible if the virus invades the brain. a recent autopsy study found sars-cov- viral particles, on electron microscopic examination, in the frontal lobe of the brain. virus-like particles were observed budding out of endothelial cells in the blood vessels of the frontal lobe, thus pointing to a hematogenous pathway of spread through the blood-brain barrier. in a study by ding et al., sars-cov- virus was detected exclusively in the neurons of the brain. the sars-cov- virus has also been found in the csf. a transgenic-mouse study found sars-cov- entry into the brain via the olfactory bulb, and a similar pathway has been postulated in humans. the entry of sars-cov- to the olfactory bulb through the cribriform plate might explain smell impairment in covid- . li et al. suggest the sars-cov- virus may spread to the medullary cardiorespiratory center in the brainstem via chemo and mechanoreceptors in the lung, as has been observed with some other respiratory viruses. this raises the possibility of a neurological mechanism for respiratory failure in some covid- patients. while ace- receptors are found in the alveolar epithelium of the lung, the mechanism of viral movement from the lungs to the nervous system remains unclear. the detection of the sars-cov- in csf or brain biopsies would further clarify this potential pathway. no previous studies have been published of such a mechanism in either sars-cov- or mers-cov infections. in addition to inflammatory effects in the brain, neurological manifestations may also be caused by hypoxia-related injuries, as alveolar and interstitial lung inflammation may lead to cns hypoxia. this in turn may cause cerebral vasodilation and cerebral edema. questionnaire boscolo-rizzo (italy) telephone surveys giacomelli (italy) questionnaire . hornuss (germany) the possibility that medications used to treat covid- may cause neurological manifestations should be remembered. for instance, other neurological infections that may occur due to the immunosuppressive effect of the medications or seizure thresholds may be reduced. headache is a common side effect of the monoclonal antibody tocilizumab and chloroquine. cases of tocilizumab-associated multifocal cerebral thrombotic microangiopathy and tocilizumabrelated demyelinating disorders have been reported. , chloroquine and hydroxychloroquine are also known to have certain neurological side effects such as seizure, balance disorder, peripheral neuropathy, parasthesia and hypaesthesia. considering the high transmission rate of the sars-cov- virus, carrying out autopsy studies are challenging. however, the findings from such studies would contribute to and shed light on the potential neurological mechanisms and prognosis in covid- and direct more evidence-based treatment plans. individuals with ms and neuromuscular disorders may be prescribed medications which suppress the immune system and thus are at a higher risk of developing severe covid- . however, guidelines specifically recommend having discussions with neurologists prior to modifying any courses of medication. patients who suffer with cvd have a . -fold higher risk of getting severe covid- . covid- seems to have a worsening effect on patients with parkinson's disease too. hainque and grabli report two patients with parkinson's disease where early diagnosis of covid- was challenging and thus associated with poorer outcomes. currently, there is no evidence that individuals with epilepsy are at a higher risk of developing covid- . limitations of this review include the small number of studies reporting on certain neurological manifestations, thus making it difficult to provide more definitive conclusions on these aspects. it is possible that subtle neurological findings were not documented (and thus underestimated) due to the high workload during the early part of the pandemic. further well-conducted studies from different regions of the world in the coming months would help expand this evidence base and thus provide better answers to the many questions at hand. ours is a broad overview on the main reported neurological manifestations in covid- and a more comprehensive clinical picture would emerge in the coming months. during the covid- pandemic, if a patient has neurological symptoms such as loss of the sense of smell and taste or delirium, testing for sars-cov- should be considered irrespective of them not having the other typical symptoms. at present, the long-term effects of neurological manifestations are still uncertain but should become better defined as more studies using brain imaging, eeg and csf findings become available. detailed and systematically conducted histopathology and autopsy studies should shed light on aspects of pathogenesis and pathology that are still undefined and uncertain. neurological manifestations have been reported in some covid- patients. the detection of sars-cov- in the csf of two patients and in endothelial cells of blood vessels of the frontal lobe of another provides evidence for a neurotropic potential of this virus. the nervous system may also be affected via indirect methods such as hypoxia, inflammation or an immune-mediated damage. future studies using brain imaging, eegs, csf analysis and histopathology would provide a clearer understanding of the effect of sars-cov- on the nervous system. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) received no financial support for the research, authorship, and/or publication of this article. suranjith l seneviratne https://orcid.org/ - - - neuroinvasion by human respiratory coronaviruses acute and 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on the case report entitled-ms arising during tocilizumab therapy for rheumatoid arthritis safety considerations for chloroquine and hydroxychloroquine in the treatment of covid- covid- and neuromuscular disorders covid- coronavirus and ms treatments cerebrovascular disease is associated with an increased disease severity in patients with coronavirus disease (covid- ): a pooled analysis of published literature rapid worsening in parkinson's disease may hide covid- infection key: cord- -wq cgqs authors: shanmugam, naresh; dhawan, anil title: acute liver failure in children date: - - journal: pediatric hepatology and liver transplantation doi: . / - - - - _ sha: doc_id: cord_uid: wq cgqs “acute liver failure” (alf) and “fulminant liver failure” are terms used interchangeably to describe severe and sudden onset of liver cell dysfunction leading on to synthetic and detoxification failure across all age groups. considerable variations exist between alf in children and adults, in terms of aetiology and prognosis. encephalopathy is not essential to make a diagnosis of alf in children but when present has a bad prognosis. early recognition of alf and initiation of supportive management improve the outcome. liver transplantation remains the only definitive treatment when supportive medical management fails. trey and davidson coined the term "fulminant liver failure" years ago to define onset of altered mental status within weeks of initial symptoms of liver dysfunction in an otherwise healthy individual with no previous history of liver disease [ ] . this definition was difficult to apply in children with alf as the disease process could start in utero and time quantification might not be possible and, also, encephalopa-thy might be difficult to diagnose. trying to address this issue, bhaduri and vergani defined alf in children as "a rare multisystem disorder in which severe impairment of liver function, with or without encephalopathy, occurs in association with hepatocellular necrosis in a patient with no recognized underlying chronic liver disease" [ ] . this newer definition for children failed to differentiate between acute hepatitis and alf as "severe impairment of liver function" is very subjective and can vary from person to person. paediatric acute liver failure (palf) study group has come up with practical definition to select cases for their multicentre study. they used the following criteria to define acute liver failure (alf) in children: ( ) hepatic-based coagulopathy defined as a prothrombin time (pt) ≥ s or international normalized ratio (inr) ≥ . not corrected by vitamin k in the presence of clinical hepatic encephalopathy (he) or a pt ≥ s or inr ≥ . regardless of the presence or absence of clinical hepatic encephalopathy (he), ( ) biochemical evidence of acute liver injury and ( ) no known evidence of chronic liver disease [ ] . due to its simplicity and objectivity, palf definition is widely used in children. palf has used inr as a surrogate marker to denote overall liver synthetic inadequacy and an impending multiorgan failure. coagulopathy is not only a key criterion in diagnosing paediatric alf but also helps as prognostic marker. due to short half of several liver-based clotting factors, pt/inr functions as a dynamic marker of synthetic inadequacy due to loss of functioning hepatocytes in alf. factors ii, vii, ix and x depend on vitamin k for carboxylation of terminal glutamic acid residues to convert them into active form ( fig. . ). correction of coagulopathy by intravenous vitamin k differentiates between vitamin k deficiency due to decreased absorption and synthetic liver failure. isolated prolonged aptr is not due to liver disease, as factor vii in extrinsic pathway (fig. . ) has the shortest half-life of the • encephalopathy is not essential in the diagnosis of alf in children. • coagulopathy is being used as a prognostic marker in paediatric alf. • role of liver assist devices and hepatocyte transplant is still limited. • auxiliary liver transplantation if feasible should be offered where indicated as it provides a chance for native liver regeneration. vitamin k-dependent factors; therefore, it is the first factor depleted in alf and invariably affects inr. due to defective synthesis and impaired clearance of procoagulant/anticoagulant factors, inflammatory mediators, infection, etc., there could be a degree of intravascular coagulation (ic) that invariably exists in alf which can progress to fulminant disseminated intravascular coagulation. haemostasis in liver disease is best assessed using thromboelastography (teg). teg is a point-of-care assay using a specialized machine that assesses clot formation in whole blood, including plasmatic and cellular components. teg provides a graphical representation ( fig. . ) of assembly of a clot in whole blood and provides an assessment of overall haemostasis. the causes of alf vary with the age and geographical location. infectious aetiology predominates as a cause of alf in children in the developing countries, while drug-induced alf predominates in adults and is indeterminate in children in europe and north america [ ] . [ ] . though exact frequency of alf in the paediat-ric age group is unknown, overall annual incidence of alf in the usa was around . million population among all ages [ ] . investigation of alf in children is outlined in table . . in developed countries drugs and toxins have become the most common identifiable cause of drug-induced acute liver failure in adults and children. drug-induced liver injury (dili) can be a dose-dependent response, an idiosyncratic reaction or a synergistic reaction when two medications are given together. it is essential to enquire about any indigenous/herbal medicine intake as some are potentially hepatotoxic [ ] . acetaminophen is the most common drug associated with alf and is normally a dose-dependent hepatotoxic agent. acetaminophen is detoxified mainly by glucuronidation ( %), sulphation ( - %) and n-hydroxylation ( %). a small fraction is metabolized via cytochrome p to yield n-acetyl-para-benzoquinoneimide (napqi), a toxic intermediate compound which irreversibly conjugates with the sulphhydryl group of glutathione and causes hepatocyte necrosis [ ] . napqi forms acetaminophen-protein adducts, which acts as a specific biomarker for chronic acetaminophen-related toxicity. in acute acetaminophen poisoning, serum levels after h of ingestion are useful in identifying high-risk patients. genetic polymorphism of cytochrome p isoenzymes could predispose affected people to acetaminophen toxicity. anti-tuberculosis drugs, particularly isoniazid, are associated with drug-induced alf. the mechanism of toxicity is similar to acetaminophen; oxidation via cytochrome p pathway results in toxic metabolites. the true incidence of idiosyncratic drug-induced liver injury (dili) is unknown; reports have suggested to up to new cases/ , /year [ ] . around % of idiosyncratic dili developed alf [ ] . dili is unpredictable, but genetic susceptibility of an individual to certain drugs and underlying mitochondrial cytopathies are proposed causes [ ] . the councils for international organizations of medical sciences/ roussel uclaf causality assessment method (cioms/ rucam) scale is helpful in establishing causal relationship between offending drug and liver damage. using the scoring system, suspected drug could be categorized into "definite or highly probable" (score > ), "probable" (score - ), "possible" (score - ), "unlikely" (score - ) and "excluded" (score ≤ ) [ ] . this scale is helpful in identifying druginduced hepatotoxicity even in newly marketed drugs and for a previously unreported older drug. chemotherapy drugs are known to produce veno-occlusive disease leading on to alf due to endothelial damage. few of the common drugs that cause alf are outlined in table . . water-borne viral hepatitis (hepatitis a and e) is the most common cause of alf in developing countries with poor sanitation facilities. following infection with hepatitis a virus, the risk of developing liver failure is . - . %, and this further increases with underlying chronic liver disease. usually the disease runs a benign course with spontaneous recovery, but some might require liver transplantation [ ] . with hepatitis e infection, the risk of developing alf in adults is . - . % [ ] . recent evidence suggests that case fatality due to hepatitis e-induced alf in pregnancy is similar to that of age-matched general population [ ] . the alf due to hepatitis b virus (hbv) can occur at the time of acute infection, reactivation of chronic hbv infection or seroconversion from a hepatitis b e antigen-positive to a hepatitis b e antibody (hbeab)-positive state. superinfection or coinfection of hbv-infected patients with hepatitis delta virus (hdv) can cause liver failure. hepatitis c virus (hcv) infection has not been reported as a cause of alf, and herpes simplex virus can cause alf, of which herpes simplex virus and (hsv) is the predominant cause of viral-induced alf during the first month of life. babies presenting with fever, rash, lethargy, poor feeding and raised transaminase (in thousands) are usually suggestive of hsv hepatitis. disseminated neonatal herpes with liver failure carries high mortality. in stable neonates with alf due to hsv, liver transplantation has been successful. treatment with high-dose acyclovir should be initiated in all neonates with alf, until serology results are known. other members of herpes virus family such as cytomegalovirus, epstein-barr virus and varicella-zoster virus can cause alf. dengue virus causing alf is common in tropical countries, which was thought to be multifactorial due to direct viral injury, dysregulated immune response, hypoxic/ischemic injury secondary to shock, etc. [ ] . neonatal haemochromatosis (nh) is the single most common cause of alf during the first month of life, due to massive iron deposition in the liver and extrahepatic tissues with sparing of the reticuloendothelial system. nh presents with jaundice, coagulopathy, moderately elevated alanine aminotransferase, high ferritin and raised iron saturation levels. the disease varies in severity; at one end of spectrum, it is associated with foetal death, while at the other end, spontaneous recovery is reported. the pattern of iron overloading is similar to hereditary haemochromatosis, but nh is entirely different condition affecting newborn, and so far no specific genetic mutation has been identified [ ] . current hypothesis suggests nh to be an alloimmune process where maternal antibody is directed towards foetal liver cells resulting in hepatocyte loss [ , ] . this hypothesis is supported by successful prevention of severe disease by antenatal and postnatal treatment with intravenous immunoglobulin. high serum ferritin is a non-specific marker and elevated in other causes of alf and so should not be used a marker for diagnosis. the diagnosis could be safely confirmed by labial salivary gland biopsy, showing extrahepatic iron deposits with reticuloendothelial system sparing [ ] . metabolic disorders are important cause of alf in paediatric population particularly during infancy. galactosaemia, tyrosinaemia type i and fructosaemia are few of the metabolic disorders that could present as alf. tyrosinaemia type i is an inborn error of amino acid metabolism, due to absence of enzyme fumarylacetoacetase, the last enzyme in a series of five enzymes needed to break down tyrosine. this results in formation of intermediate compounds, maleylacetoacetic acid and fumarylacetoacetic acid, which is converted to succinylacetone, a toxin that damages the liver and kidneys. oral ntbc (nitro- -trifluoromethylbenzoyl- , -cyclohexanedione) and phenylalanine-and tyrosine-free diet could help liver recovery, but some children might require lt. galactosaemia type is autosomal recessive disorder with mutation in galactose- -phosphate uridyl transferase (galt) gene located on chro-mosome p . lactose-free diet should be started in any infant presenting with alf or hepatitis until the quantitative galt activity is available. galactose-free diet and supportive treatment may allow recovery of alf. rarely inborn errors of bile acid synthesis can present as alf. mitochondrial disorders are group of spontaneous or inherited disorders of mitochondrial proteins resulting in defective oxidative phosphorylation, fatty acid oxidation, urea cycle and other mitochondrial pathways [ ] . deficiencies of complexes i, iii and iv, multiple complex deficiencies and mitochondrial dna (mtdna) depletion syndrome are associated with liver failure. diagnosis might be difficult due to particularly (mtdna) depletion syndrome where there is tissue-specific mitochondrial enzyme deficiency. these infants usually present with hypotonia, hypoglycaemia, feeding difficulties, seizures and deranged liver function. liver transplantation could be done in isolated liver-based mitochondrial disorders, and it is usually contradicted in multisystemic involvement [ ] . sasaki et al. have reported % survival in a cohort of nine children with mitochondrial respiratory chain disorder, which included children with extrahepatic manifestation such as developmental delay and failure to thrive [ ] . medium-chain acyl-coenzyme a dehydrogenases (mcad) are group of enzymes involved in β-oxidation of - carbon chain fatty acids in mitochondria. affected children could present with hypoketotic hypoglycaemia and recurrent liver failure, precipitated by otherwise minor illness. unless treated with dextrose supplementation, these episodes may quickly progress to coma and death. wilson's disease, an autosomal recessive disorder, could present as alf. the acute hepatic presentation is usually characterized by the presence of liver failure, coombs-negative haemolytic anaemia and low serum alkaline phosphatase. diagnosis might be difficult in acute presentation as blood test might show weakly positive autoantibodies, and tissue copper estimation might not be possible due to coagulopathy. new wilson index proposed by dhawan et al. used five parameters such as serum bilirubin, serum albumin, international normalized ratio, aspartate aminotransferase (ast) and white cell count (wcc) at presentation. based on serum levels, each parameter is graded from to , with a total maximum score of . they identified a cutoff score of more than for death without transplantation and proved to be % sensitive and % specific, with a positive predictive value of % [ ] . haemophagocytic lymphohistiocytosis (hlh) is a type of haematological malignancy that could present as alf in children. hlh is due to paradoxical overactivation of natural killer cells and of cd + t-cell lymphocytes resulting in destruction of own haemopoietic cells. it could be familial (inherited) or acquired. familial hlh usually presents during infancy, while secondary hlh usually occurs after systemic infection or immunodeficiency, which can affect people at any age. familial hlh is an autosomal recessive disease resulting in reduced or defective production of cytoplasmic granules such as perforin in cytotoxic cells resulting in paradoxical overactivation. hlh presents with fever, cutaneous rash, hepatosplenomegaly, pancytopenia and, in severe cases, alf [ ] . though rare, leukaemia or lymphoma could present with alf [ ] . other causes: autoimmune hepatitis (aih), particularly type (positive liver-kidney microsomal (lkm) antibody), can present with alf. alf due to aih with encephalopathy usually does not respond to any form of immunosuppression and needs urgent liver transplant [ ] . in spite of extensive investigation, the diagnosis could not be found in some of the children (indeterminate). there is centre-to-centre variation in incidence of indeterminate alf, probably due to incomplete investigations, which has been highlighted by narkewicz et al. [ ] . general investigation should include liver function tests, serum electrolytes, uric acid, lactate, cholesterol/triglyceride, amylase, serum amino acids, blood gas analysis, blood glucose levels, full blood count, blood grouping, coombs test coagulation studies (inr), urinary amino/organic acids and toxicology screen along with surveillance blood and urine cultures. in liver function tests, coagulation should be checked on regular basis that helps in monitoring the progression of disease. investigations to establish the underlying aetiology are listed in table . . detailed clinical history and physical examination give valuable clue of underlying diagnosis. this would provide guidance in choosing appropriate investigations. transplant-free survival is aetiology dependent. age of patient was not associated with outcome in adults [ ] , while in children, neonates have worst prognosis (fig. . ) , probably due to predominance of certain aetiology in different age groups. prognostic scoring helps in predicting mortality and helps in listing appropriate patients for transplantation. for non-acetaminophen alf, several prognostic scoring systems are available for adults, but in children there are no universally accepted criteria for listing. to date, inr and factor v concentration remain the best indicators of mortality without transplantation in paediatric alf. bhaduri and mieli-vergani showed that the maximum inr reached during the course of illness was the most sensitive predictor of the outcome, with % of children with an inr less than surviving compared with only of ( . %) with an inr greater than [ ] . in children, a factor v concentration of less than % of normal suggests a poor outcome. a prognostic score incorporating serum bilirubin, serum albumin, international normalized ratio, aspartate aminotransferase (ast) and white cell count (wcc) is available predicting the outcome of decompensated wilson's disease [ ] . in acetaminophen overdose adult criteria of inr > . , creatinine > μmol/l and hyperphosphatemia or metabolic acidosis arterial ph less than . , after the second day of overdose in adequately hydrated patients, is used to list children for liver transplantation [ ] . management of alf and its complications still remains a challenge. early diagnosis helps in initiation of investigation and safe transfer to a specialist centre. diagnostic algorithm for any child with abnormal liver function test is outlined in fig. . . all children with alf should be closely monitored in a quiet setting. vital parameters such as oxygen saturation, pulse, blood pressure and neurologic observations should be done on regular basis. prophylactic broad-spectrum antibiotics and antifungals should be started in all children, and acyclovir should be added in infants and neonates. hypoglycaemia should be avoided either by parenteral glucose or adequate enteral feeds. children with encephalopathy or an inr > (regardless of encephalopathy) should be admitted to an intensive care unit for continuous monitoring. prophylactic histamine blockers or proton-pump inhibitors should be started to all patients requiring mechanical ventilation [ ] . coagulopathy is corrected only if the patient is already listed for transplant or prior to an invasive procedure. to correct coagulopathy, fresh frozen plasma could be given at a dose of ml/kg and cryoprecipitate at ml/kg (if fibrinogen is < g/l). factor vii concentrates improve the coagulopathy for a short period. platelet count should be maintained above × /dl, as thrombocytopenia is an important risk factor for haemorrhage. n-acetylcysteine (nac) is being increasingly used as a part of general supportive measure in non-acetaminopheninduced alf, as it enhances circulation and improves oxygen delivery. in a prospective, double-blind trial in adults with non-acetaminophen alf, nac usage is associated with significant improvement in transplant-free survival in patients with early (stage i-ii) coma [ ] . a similar study in children failed to show any benefit, and paediatric acute liver failure study group does not recommend routine use of in non-acetaminophen-induced alf in children [ ] . bowel cleansing agents and benzodiazepine antagonists are of no proven benefit [ ] . elective intubation and mechanical ventilation should be considered for patients with grade / encephalopathy. apart from providing secure airway, sedation and controlled ventilation help in reducing sudden variation of intracranial pressure (icp). induction using suxamethonium and fentanyl and combination of morphine or fentanyl with a hypnotic such as midazolam for sedation is usually safe in children. normocapnia is to be maintained, as hypercapnia causes vasodilatation and increases cerebral congestion, while hypocapnia causes vasoconstriction and thus decreased blood flow to the brain. intravenous fluids should be restricted to two-thirds maintenance, with the idea of decreasing the possibility of development of cerebral oedema. ultrasonic cardiac output monitor (uscom), which is a non-invasive method to measure cardiac parameters, helps in decision-making regarding appropriate fluid regimens/inotropes even in small infants. in the presence of persistent hypotension, noradrenaline is the inotropic agent of choice. continuous filtration or dialysis systems should be considered when the urine output is less than ml/kg/h to prevent acidosis and volume overload. the most serious complications of alf are cerebral oedema with resultant encephalopathy and intracranial hypertension, progressively leading on to brain herniation and death. systemic hypertension, bradycardia, hypertonia, hyperreflexia and in extreme cases decerebrate or decorticate posturing are clinical features of raised icp. ammonia-lowering measures such as dietary protein restriction, bowel decontamination or lactulose are of limited or no value in rapidly advancing encephalopathy. mannitol is an osmotic diuretic commonly used to treat intracranial hypertension. a rapid bolus of . g/ kg as a % solution over a -min period is recommended, and the dose can be repeated if the serum osmolarity is less than mosm/l. hypertonic saline could be also used in emergency situation, where there is impending brainstem herniation. studies have shown mild cerebral hypothermia ( - °c) , sodium thiopental and hypernatremia (serum sodium > mmol/l) improves cerebral perfusion. disease-specific management is outlined in table . . intravenous immunoglobulin (ivig) at a dose of g/kg body weight given weekly from the th week until the end of gestation as antenatal prophylaxis to mothers whose previous pregnancy/child was affected with nh has been associated with milder phenotypic expression of the disease and % survival of babies [ ] . evidence is accumulating towards the usefulness of high-dose ivig ( g/kg), in combination with exchange transfusion resulting in significant decrease in the need for liver transplantation in nh. dietary intervention with restriction of phenylalanine and tyrosine together with oral medication, ( -nitro- -trifluoromethylbenzoyl)- , cyclohexenedione (ntbc), helps in normalization of liver function, but doesn't prevent long-term risk for development of hepatocellular carcinoma in children started beyond infancy. plasmapheresis is the removal or exchange of blood plasma. therapeutic plasmapheresis and therapeutic plasma exchange (tpe) are terms that are often used synonymously. tpe has been increasingly used over the past decade as a first-line and lifesaving treatment for various conditions classified by the american society for apheresis (asfa). in acute fulminant wilson's disease, it can rapidly remove significant amount of copper and, thereby, reduce haemolysis, prevent progression to renal failure and provide clinical stabilization. it has been reported to be used as a bridge to lt or can lead to elimination of the need for urgent lt. tpe is also helpful in stabilizing alf due to viral hepatitis, drug-induced hepatitis, etc. by removing albumin-bound toxins, large molecular weight toxins, aromatic amino acids, ammonia, endotoxin, indols, mercaptans, phenols, etc. simple liver assist devices detoxify blood by simple osmotic diffusion, while bioartificial liver support system which contains human or animal liver cells could perform complex synthetic function and detoxifying and detoxification. these devices have shown to decrease the toxins (ammonia, bilirubin, cytokines, etc.) but have no effect on mortality. successful use of these devices in children with alf as a bridge therapy, supporting liver function while the native liver regenerates, is not recommended outside research setting. liver transplant remains the only proven treatment that has improved the outcome of alf. appropriate patient selection and timing of transplantation are essential for graft and patient survival. several surgical techniques such split liver grafts, reduced grafts and auxiliary liver transplants are practiced, depending upon patient size, organ availability and surgical expertise available. auxiliary liver transplant is a surgical technique where the donor liver is placed alongside of native liver and the allograft supports the entire liver function, while the native liver regenerates. either left lateral segment or right lobe allograft could be used, based on recipient weight. once native liver regeneration is optimal [ ] , then immunosuppression could be weaned and eventually stopped. in a series from king's college hospital, of the children who received auxiliary liver transplantation for alf, immunosuppression was withdrawn successfully in patients at a median time of months after transplantation [ ] . this would be an ideal option in alf due to indeterminate aetiology, as spontaneous regeneration of native liver remains a possibility. liver transplantation is indicated in alf due to liverbased disorders while contraindicated in haematological malignancies, uncontrolled sepsis, systemic mitochondrial/ metabolic disorders and severe respiratory failure (ards) [ ] . relative contraindications are increasing inotropic requirements, infection under treatment, cerebral perfusion pressure of less than mmhg for more than h and a history of progressive or severe neurologic problems. hepatocyte transplantation, where hepatocytes are infused intraportally into the patient's liver, has been tried with variable success in certain liver-based metabolic disorders [ ] . research is underway to use alginate-encapsulated hepatocytes, which could be injected intraperitoneally. this could act as a bridge until native liver regenerates. hepatocyte transplantation is not recommended outside research setting. improved intensive care management has greatly increased the alf survival. when compared to adult alf, the spectrum of underlying aetiology, management and outcome varies in paediatric alf. acyclovir should be started in all neonates with 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acute liver failure in children high-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis clinical human hepatocyte transplantation: current status and challenges auxiliary liver transplantation for acute liver failure in children hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure cell therapy for liver disease: from liver transplantation to cell factory key: cord- -mivxm oh authors: groneberg, david a; poutanen, susan m; low, donald e; lode, hartmut; welte, tobias; zabel, peter title: treatment and vaccines for severe acute respiratory syndrome date: - - journal: lancet infect dis doi: . /s - ( ) - sha: doc_id: cord_uid: mivxm oh the causative agent of severe acute respiratory syndrome (sars), which affected over individuals worldwide and was responsible for over deaths in the – outbreak, is a coronavirus that was unknown before the outbreak. although many different treatments were used during the outbreak, none were implemented in a controlled fashion. thus, the optimal treatment for sars is unknown. since the outbreak, much work has been done testing new agents against sars using in-vitro methods and animal models. in addition, global research efforts have focused on the development of vaccines against sars. efforts should be made to evaluate the most promising treatments and vaccines in controlled clinical trials, should another sars outbreak occur. severe acute respiratory syndrome (sars) is an infectious disease characterised by substantial morbidity and mortality, first recognised after an outbreak in - . , the who issued a global alert on sars on march , after receiving reports from china's guangdong province, hong kong, and vietnam regarding clusters of respiratory illness of unknown aetiology. one of the first reports was made by who scientist carlo urbani, who was called to investigate cases of pneumonia of unclear aetiology in a hospital in hanoi; he later died of sars. following the who alert, probable sars cases were also reported from other regions in china, and other asian countries including singapore, taiwan, indonesia, thailand, and the philippines. other countries, including canada, the usa, and germany also identified cases. in retrospect, sars originated in guangdong at the end of . it first spread to other regions in asia and then international travel facilitated its spread to other continents. a cumulative total of probable cases of sars were recorded during the period from november , to july , , with deaths in countries. soon after sars was identified as a new disease, the who initiated a collaborative global network striving to work together to identify the aetiological agent of sars. in unprecedented time, a novel coronavirus-sars coronavirus-was identified as the probable causative agent of sars - (figure ) and koch's principles were demonstrated to be fulfilled by this agent. , this virus belongs to the coronavirus family-enveloped, positive-sense rna viruses associated with respiratory disease in human beings and animals. , evidence suggests that sars coronavirus originated from sars-like viruses in animals in the southern chinese province of guangdong; the most frequently implicated animal is the himalayan palm civet, an animal found in food markets and eaten as a delicacy. , sars coronavirus is organised into - open reading frames (orfs) containing approximately nucleotides. , , in total, sars-coronavirus sequences derived from different sars epidemic phases have been analysed and genotypes characteristic of each phase have been identified. , the different sars-coronavirus orfs represent typical viral genes such as protease and replicase, spike, envelope, membrane, and nucleocapsid, all of which may represent potential therapeutic targets (figure ). in common with all infections caused by coronaviruses, after infection sars coronavirus induces the synthesis of Ј coterminal sets of subgenomic mrnas in target the causative agent of severe acute respiratory syndrome (sars), which affected over individuals worldwide and was responsible for over deaths in the - outbreak, is a coronavirus that was unknown before the outbreak. although many different treatments were used during the outbreak, none were implemented in a controlled fashion. thus, the optimal treatment for sars is unknown. since the outbreak, much work has been done testing new agents against sars using in-vitro methods and animal models. in addition, global research efforts have focused on the development of vaccines against sars. efforts should be made to evaluate the most promising treatments and vaccines in controlled clinical trials, should another sars outbreak occur. cells. in laboratory settings, sars coronavirus is able to infect macaque monkeys, mice, ferrets, and domestic cats. clinically, sars is characterised by systemic symptoms such as fever and myalgia, followed by respiratory symptoms including a non-productive cough and dyspnea. laboratory findings include lymphopenia, and chest radiographs commonly exhibit unilateral or bilateral infiltrates. approximately % of cases deteriorate, requiring intubation and mechanical ventilation. the overall mortality rate has been reported to be about %. however, sars mortality rates in those over years old have been reported to be as high as %. affected children seemed to have milder symptoms with no reports of death. at the time of the - outbreak, physicians shared their personal experiences supporting or rejecting various treatments for sars. because of the rapid progression of the outbreak, multicentre, randomised, controlled interventional trials were not possible, and the success of various treatments remains largely anecdotal. thus, a consensus on therapeutic strategies has not yet been reached. since the outbreak, global research efforts have focused on testing new agents against sars with in-vitro methods and animal models. in addition, much effort has been placed on developing effective vaccines against sars. this review summarises the clinical experience of the use of various treatments during the outbreak and provides an overview of the data, both in vitro and in vivo, supporting, or otherwise, the effectiveness of these treatments and those that have been proposed since the outbreak. in addition, we summarise the progress made to date regarding sars vaccines. a summary of the pharmacological agents that have been used or proposed for the treatment of sars is shown in figure . during the - outbreak, suspected sars cases were usually treated initially with broad-spectrum antibacterial drugs effective against typical bacterial causes of acute community-acquired pneumonia. the administration of broad-spectrum antibiotics-eg, respiratory fluoroquinolones, second-generation cephalosporins, or third-generation cephalosporins-plus a macrolide is recommended at the first signs of the sars, because the initial features of the disease are nonspecific. however, after sars coronavirus is identified as the causative agent, antibiotics may be withdrawn, because there is no evidence that antibiotics are clinically beneficial in the treatment of sars. even before the causative agent of sars was discovered, treatment with ribavirin was used empirically to treat patients with sars. ribavirin is a synthetic nucleoside with broad-spectrum antiviral activity. clinical studies that have assessed the effectiveness of ribavirin in sars range from anecdotal case reports and retrospective case series to one randomised clinical trial with multiple treatment arms. however, none of these studies definitively determine whether or not ribavirin is effective against sars. case reports and case series suggest that combined treatments including ribavirin may be beneficial to some extent; however, in all of these studies, the effect of ribavirin is confounded by the concomitant use of other agents. for example, studies describe clinical and radiological improvements in patients treated with ribavirin and steroids, , but, without a control group, it is difficult to determine whether the improvements result from ribavirin, steroids, the combination of both, or the natural course of the illness. one study showed that the delayed initiation of combined therapy with ribavirin and steroids was among the risk factors associated with severe complicated disease, suggesting that ribavirin might be beneficial, but it is difficult to delineate the role of delaying the use of ribavirin from the delay in the use of steroids. the results of a randomised clinical study in guangdong, involving multiple different treatment arms, suggest that ribavirin given at a low dose ( - mg/day) was less effective compared with an early and aggressive use of steroids with interferon alfa. however, the lack of a control arm in this study does not allow for one to make definitive conclusions about whether or not ribavirin has any positive effect on sars compared with no treatment. invitro testing showed that ribavirin was not able to inhibit sars-coronavirus replication at clinically achievable concentrations. , this finding, combined with postmortem findings demonstrating high viral loads in most patients despite treatment with ribavirin, suggests that if ribavirin has any effect against sars coronavirus, it is likely to have only a small beneficial effect at best. this is important when the side-effects that have been associated with ribavirin use are considered. knowles and co-workers reported common adverse events in people with suspected or probable sars who were treated with ribavirin. % of these people had evidence of haemolytic anaemia; hypocalcaemia and hypomagnesaemia were reported in % and % of the people, respectively. the combination of the protease inhibitors lopinavir and ritonavir was used less frequently during the sars outbreak compared with ribavirin. the lopinavir/ ritonavir combination was first considered a potentially useful treatment after in-vitro studies showed it had antiviral activity against sars coronavirus. , chan and colleagues compared outcomes in people who received lopinavir/ritonavir as initial treatment, and as rescue therapy, with matched controls; all patients were given ribavirin and steroids according to a standardised protocol. the addition of lopinavir/ritonavir as initial treatment was associated with a statistically significant reduction in the overall death rate and intubation rate compared with matched controls (pϽ · ). however, the subgroup that received lopinavir/ritonavir as rescue therapy did not show a significant difference in these endpoints. chu and co-workers also assessed treatment with lopinavir/ritonavir compared with historic controls; all patients were also treated with ribavirin and steroids in a similar protocol to that of chan and collegues. adverse events (development of acute respiratory distress syndrome [ards] or death within days) were significantly lower in the lopinavir/ritonavir group than in the historic controls (pϽ · ). in addition, a significant reduction in the need for rescue pulsed steroids for severe respiratory deterioration (pϽ · ) and significantly lower nosocomial infections were also noted in those treated with lopinavir/ritonavir, compared with controls (pϽ · ). by multivariate analysis, it was demonstrated that the lack of treatment with lopinavir/ritonavir, age years old or greater, and positive hepatitis b carrier status were independent predictors of an adverse outcome including death or the development of ards requiring intensive care within days of onset of illness. based on these studies, lopinavir/ritonavir appears to be a promising anti-sarscoronavirus agent. other protease inhibitors have been studied in vitro for potential antiviral effects in sars. for example, yamamoto and colleagues screened a set of compounds that included antiviral drugs already widely used, and found that nelfinavir strongly inhibited sarscoronavirus replication. nelfinavir inhibited the cytopathic effect induced by sars-coronavirus infection, and the expression of viral antigens was much lower in infected cells treated with nelfinavir than in untreated, infected cells. in addition, barnard and colleagues found that two protease inhibitors-calpain inhibitor vi (val-leu-cho) and calpain inhibitor iii (z-val-phe-ala-cho)-inhibited sars coronavirus, suggesting that other protease inhibitors may also be useful in the treatment of sars. the membrane-associated carboxypeptidase angiotensinconverting enzyme (ace ), is a cellular receptor for sars coronavirus, interacting with the s domain of the spike protein. thus, peptides and small compounds that bind to ace , are possible agents for the treatment and prevention of sars. in addition, a soluble form of the receptor, antibodies to it, or the receptorbinding domain of the spike protein, may be candidate treatments. indeed, sui and co-workers searched a nonimmune human antibody library and successfully identified an anti-s human monoclonal antibody, r, that potently neutralises sars-coronavirus infection and efficiently inhibits syncytium formation by blocking binding to ace . r was shown to compete with soluble ace for association with the s domain of the spike protein and bound to it with high affinity. theoretical reasoning and in-vitro evidence suggest that fusion inhibitors are promising treatment candidates for sars. , peptides derived from the heptad repeat regions and of hiv- gp -a transmembrane protein involved in the fusion of hiv and target cellsare the basis for anti-hiv fusion inhibitors. based on similarities between the heptad repeat regions of gp in hiv- and the heptad regions in the spike protein of sars coronavirus, a common mechanism mediating fusion between each virus and target-cell membranes was postulated. , liu and colleagues tested two sets of peptides corresponding to the heptad regions in the spike protein for inhibitory activity against sars coronavirus, and found that one peptide-cp inhibited sars-coronavirus infection in vitro. it has been postulated that cp binds to heptad region of the spike protein and interferes with the conformational changes needed to allow fusion with target cells. rna interference (rnai) treatment is a process by which small interfering rnas (sirna) are administered, leading to degradation of mrna with identical sequence specificity. this technology has been used to silence genes in cultured cells and in animals, and to target hiv, hepatitis b, and hepatitis c viral infections. [ ] [ ] [ ] to explore the possibility of interrupting sars-coronavirus replication with sirnas, specific sirnas targeting the spike gene in sars coronavirus were synthesised. these sirnas effectively and specifically inhibited gene expression of the spike protein in sars-coronavirusinfected cells. another study assessed the in-vitro efficiacy of six sirna molecules targeting different sites of the replicase a region of the sars-coronavirus genome. judged by morphological changes, three of the molecules markedly inhibited the cytopathic effects caused by viral infection and replication. the three sirnas also inhibited the infection and replication of different strains of sars coronavirus, indicating that sirnas targeting the replicase a region may be an option for future clinical use. in-vitro studies have shown that glycyrrhizin, a component of liquorice roots, is able to inhibit sarscoronavirus replication. glycyrrhizin inhibits hiv replication in vitro and has been used clinically in the treatment of hepatitis c and hepatitis b with some success. the mechanism of glycyrrhizin-induced inhibition of viral replication-and specifically sarscoronavirus replication-is unclear, but possibly involves inhibition of replication through an antiviral effect of nitric oxide (no). glycyrrhizin upregulates expression of inducible no synthase and production of no in mouse macrophages. in addition, preliminary results by cinatl and colleagues show that glycyrrhizin induces no synthase in vero cells used to cultivate sars coronavirus. cinatl and colleagues showed that sars-coronavirus replication is inhibited when deta nonoate-a no donor compound-is added to the culture medium. this finding has been further corroborated by keyaerts and co-workers using a different no donor compound, s-nitroso-n-acetyl-penicillamine. keyaerts and colleagues also report their findings on the use of inhaled no gas to treat a number of people with sars. their results suggest an associated immediate improvement in oxygenation and a lasting effect after termination of inhalation of no, which is known to be a potent mediator of airway inflammation. , niclosamide wu and colleagues screened a set of marketed drugs that were not registered for antiviral use to determine if any had in-vitro activity against sars coronavirus. they found that niclosamide, an existing antihelmintic drug, was able to inhibit replication of sars coronavirus. the underlying mechanism by which the drug exerts this effect is unclear, but the study shows that niclosamide does not interfere with the virion's attachment to, or entry into, cells, nor does it appear to inhibit the protease activity. new compounds continue to be tested, with the goal of finding more potential candidate treatments for sars. for example, from over agents tested, wu and colleagues found compounds with potent anti-sars-coronavirus activity. more compounds are likely to be discovered in the future. during the - sars outbreak, systemic steroids became a mainstay of sars therapy in many centres. the rationale for their use was based on the paradoxical finding that, despite a fall in sars-coronavirus viral load and a rise in sars-specific igg typically seen during the rd week of illness, a clinical deterioration was observed in some people. in addition, pathological findings consistent with bronchiolitis obliterans organising pneumonia and ards led to the hypothesis that immune hyperactivity resulting from cytokine dysregulation may be a component of sars that could be reduced by steroid treatment. in most cases, steroids were administered as adjunctive therapy to ribavirin treatment. if the patient's review respiratory condition worsened clinically, pulsed, highdose steroids were added. however, most studies were confounded by the concomitant use of other agents, and none of the studies contained a control group. thus, whether or not steroids have a beneficial effect in the treatment of sars cannot be readily determined. in some studies, treatment regimens containing steroids seemed to be associated with chest radiographic improvements, fever defervescence, and improvement in oxygenation rates earlier than patients not treated with steroids. , , however, in a study by hsu and colleagues, adding steroids was not associated with clinical improvement, although the dose of steroids in this study was lower than in those where benefit was seen. ho and co-workers retrospectively compared the clinical and radiographic outcomes of people with probable sars who received ribavirin, of whom initially received pulsed, highdose steroids and of whom initially received lowdose steroids. pulsed, high-dose steroids were also given to any patient as rescue therapy in the presence of deteriorating respiratory status. the cumulative steroid dose, intensive care unit admission rate, need for mechanical ventilation, and mortality rates were similar in both groups after days. however, those people initially given pulsed steroids required less oxygen and had earlier radiographic improvement. in addition, they required substantially less rescue pulsed steroids. this study suggests that early initiation of pulsed steroids may have a role in the treatment of sars. however, definitive studies are needed and the potential benefits of steroids must be compared with the associated risks, such as the development of avascular necrosis, secondary sepsis, and fatal aspergillosis, some of which have been described in people with sars. , in beijing, hong and du evaluated people with sars who had received steroids and ribavirin, and who presented with largejoint pain, potentially caused by avascular necrosis, between march and may . both plain radiographs and magnetic resonance imaging examination were completed on the same day. people were identified with avascular necrosis. the mean time to diagnosis of avascular necrosis was days after the onset of sars, or days after steroid use. interferons type interferons have been shown to inhibit sarscoronavirus replication in in-vitro studies. , [ ] [ ] [ ] because of initial reports describing these in-vitro results, interferons were used clinically during the latter part of the outbreak. loutfy and colleagues described their clinical experience with interferon alfacon -a recombinant, non-naturally occurring type interferon containing common aminoacids from several natural interferon alfa subtypes-in people with probable sars treated in an open-label study in toronto. people with sars who received treatment with steroids alone were compared with nine people who received steroids plus interferon alfacon . the group treated with interferon alfacon had significantly improved oxygen saturation levels (p= · ) and a more rapid resolution of radiographic lesions. in addition, this group exhibited substantially less elevation in creatine kinase levels and a trend towards a more rapid normalisation of lactate dehydrogenase levels. however, this group also received higher doses of steroids, so it is difficult to determine whether or not the beneficial effects were due to the interferon alfacon . haagmans and co-workers investigated the prophylactic use of interferons in a macaque model. days before inoculation with sars coronavirus, macaques were given pegylated interferon alfa. substantially reduced viral replication, viral excretion, viral antigen expression by type pneumocytes, and pulmonary damage were noted in the treated macaques compared with untreated macaques. post-exposure treatment with pegylated interferon alfa yielded intermediate results. these results suggest that interferons have a role in the treatment of sars. because most patients develop antibodies against sars coronavirus and survive the disease, passive and active immunisation are viewed as possible effective means to prevent and/or treat sars. indeed, the development of various vaccines is one of the most important goals of ongoing sars research. one of the initial proposals to treat sars was to use sera from people convalescing from sars as passive immunotherapy. this passive immunisation was attempted with anecdotal success. since then, prior infection and passive transfer of murine neutralising antibodies have been shown to prevent replication of sars coronavirus in the respiratory tract in mice. technological advances enabling the development and purification of human monoclonal antibodies can be exploited to create specific monoclonal antibodies in large-scale production. indeed, monoclonal antibodies obtained from immortalised b lymphocytes isolated during convalescence from people with sars have been shown to neutralise virus infection in vitro and to prevent virus replication in a mouse model of sarscoronavirus infection. in addition, ter meulen and colleagues showed that prophylactic administration of a human igg monoclonal antibody reactive with whole inactivated sars coronavirus was able to reduce replication of sars coronavirus in the lungs of infected ferrets, completely prevent the development of sars-coronavirus-induced macroscopic lung pathology, and stop the shedding of virus in pharyngeal secretions. although passive immunisation strategies appear promising, the ideal approach to ensure rapid control of future outbreaks of sars is to generate an effective and safe vaccine. there are numerous teams worldwide working on the creation of vaccines using inactivated sars coronavirus, recombinant subunits, recombinant dna, and viral vectors. given the potential for antibody-directed viral enhancement and disease exacerbation, as reported for vaccines directed against another coronavirus (feline infectious peritonitis coronavirus), it is important that all vaccines created be carefully evaluated before being used clinically. of all of the vaccines in development, most work relates to viralvectored vaccines and dna vaccines. to date, three different viral-vectored vaccines have been described with successful results reported in animal models. [ ] [ ] [ ] gao and colleagues reported using three adenoviralbased vectors expressing codon-optimised sarscoronavirus spike, membrane, and nucleocapsid proteins. intramuscular vaccination with all three vaccines at day and day was shown to induce broad, virus-specific immunity in rhesus macaques. all six vaccinated macaques had antibody responses against the spike protein and t-cell responses against the nucleocapsid protein. in addition, all vaccinated animals showed strong neutralising-antibody responses to sars-coronavirus infection in vitro. challenge tests to determine whether or not this immune response was able to prevent, or reduce the severity of, infection with sars coronavirus were not completed. bisht and co-workers constructed recombinant forms of the highly attenuated modified vaccinia virus ankara (mva) containing the gene encoding the full-length sars-coronavirus spike protein and assessed whether expression of the spike protein alone in mva could raise neutralising antibodies and protectively immunise mice. both intranasal and intramuscular administration of the vaccine to balb/c mice at and weeks led to the production of serum antibodies against the spike protein that neutralised sars coronavirus in vitro. weeks after the second immunisation, vaccinated animals and control animals were challenged with sars coronavirus. those given the vaccine had reduced titres of sars coronavirus in the respiratory tract. likewise, the passive transfer of serum from mice immunised with the vaccine to naive mice led to a reduction in sars-coronavirus replication. these findings suggest that this mva-based vaccine is a promising sars-coronavirus vaccine candidate. bukreyev and colleagues reported their successful experience with the mucosal immunisation of african green monkeys with an attenuated parainfluenza virus expressing the sars-coronavirus spike protein. the complete sars-coronavirus spike protein gene was incorporated into a recombinant attenuated parainfluenza virus that is being developed as a live attenuated, intranasal paediatric vaccine against human parainfluenza virus type . four african green monkeys were vaccinated with a single dose of the vaccine, administered via the respiratory tract, and four other monkeys were vaccinated with a control. all monkeys were challenged with sars coronavirus days after immunisation. neutralising serum antibodies were noted in all of the vaccinated animals. after sarscoronavirus challenge, viral shedding was documented in all of the control animals but not in any of the vaccinated animals. the authors concluded that a vectored mucosal vaccine expressing the sarscoronavirus spike protein alone may be highly effective for the prevention of sars in a single-dose format. dna vaccines are also an attractive option for sars vaccines. thus far, three experimental studies have been published addressing dna vaccination in sars. [ ] [ ] [ ] yang and colleagues showed that giving mice a sars-coronavirus dna vaccine encoding the spike glycoprotein induced t-cell responses, neutralisingantibody responses, and protective immunity. alternative forms of the spike protein were assessed and all were found to induce substantial neutralisingantibody titres and strong immune responses mediated by cd and cd cells. in addition, a reduction in viral replication in the lungs by more than six orders of magnitude was noted after sars-coronavirus challenge; the protection was shown to be mediated by a humoral, but not a t-cell-dependent, immune mechanism. these findings show that dna vaccines based on the spike glycoprotein may lead to effective immune responses with protective immunity in animal models. kim and co-workers reported the generation and characterisation of dna vaccines targeting the nucleocapsid protein of sars coronavirus by antigen linkage to calreticulin, which has been shown to enhance mhc class i presentation to cd (+) t cells. with a murine model, it was shown that the vaccination with this dna vaccine leads to the generation of a more potent nucleocapsid-specific humoral and t-cellmediated immune responses, compared with nucleocapsid dna alone. in addition, mice vaccinated with the dna vaccine were capable of substantially reducing the titre of challenging vaccinia virus expressing sars-coronavirus nucleocapsid protein. in a similar study by zhu and colleagues, immunisation of mice with a nucleocapsid-based dna vaccine led to nucleocapsid-specific antibodies and specific cytotoxic t-cell activity. challenge tests were not completed. together, the data presented on potential vaccines reflect enormous international efforts. because a vaccine usually takes - years of clinical development after review entering phase i clinical trials before being licensed, it is not expected that any of these vaccines will be available for clinical use in the near future. however, given the pace and amount of progress to date, the period of time before clinical production of a sars vaccine may be substantially shortened compared with other vaccines. whether or not sars will re-emerge is a matter of debate. , however, in the event that sars does recur, the most promising-and immediately available-agents for the treatment of the syndrome seem to be type interferons, steroids, and lopinavir/ritonavir, based on the available data on agents already clinically approved. however, by the time another outbreak arrives, many of the other promising agents-eg, sars-coronavirusspecific receptor-binding inhibitors, fusion inhibitors, and sirnas-may have been approved for clinical use. the choice of agents will need to be determined based on the available data at that time. ideally, the most promising agents would be given in a controlled clinical trial. the difficulties in designing and implementing controlled clinical trials-which limited the ability of researchers to do such trials during the past sars outbreak, and which will continue to pose problems in the event of future outbreaks of sars or other novel pathogens-have been summarised. [ ] [ ] [ ] the best solution to facilitate the implementation of clinical trials in future outbreaks would be the establishment of an international collaborative clinical-trials group with access to appropriate contingency funds, and an internationally accepted ethics review board. until then, research based on in-vitro studies and in-vivo animal models should be continued to determine the best agent, or combination of agents, worthy of further clinical consideration. we declare that we have no conflicts of interest. data for this review were identified by searches of medline, current contents, and references from relevant articles; numerous articles were identified through searches of the extensive files of the authors. search terms were "severe acute respiratory syndrome", "sars", "treatment", "coronavirus", "infection", "sars coronavirus", "vaccination", and "antiviral". english language papers were reviewed. severe acute respiratory syndrome: global initiatives for disease diagnosis the aetiology, origins, and diagnosis of severe acute respiratory syndrome summary of probable sars cases with onset of illness from world health organization multicentre collaborative network for severe acute respiratory syndrome diagnosis. a multicentre collaboration to investigate the cause of severe acute respiratory syndrome coronavirus as a possible cause of severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome morphology and morphogenesis of severe acute respiratory syndrome (sars)-associated virus newly discovered coronavirus as the primary cause of severe acute respiratory syndrome koch's postulates fulfilled for sars virus nidovirales: a new order comprising coronaviridae and arteriviridae the structure and replication of coronaviruses the biology and pathogenesis of coronaviruses isolation and characterization of viruses related to the sars coronavirus from animals in southern china wild animals could be source of sars the genome sequence of the sars-associated coronavirus characterization of a novel coronavirus associated with severe acute respiratory syndrome molecular evolution of the sars coronavirus during the course of the sars epidemic in china epidemiological and genetic analysis of severe acute respiratory syndrome the molecular biology of coronaviruses mice susceptible to sars coronavirus virology: sars virus infection of cats and ferrets severe acute respiratory syndrome: clinical outcome and prognostic correlates epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong children hospitalized with severe acute respiratory syndrome-related illness in toronto antiviral treatment of sars: can we draw any conclusions? the broad-spectrum antiviral ribonucleoside ribavirin is an rna virus mutagen a cluster of cases of severe acute respiratory syndrome in hong 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severe acute respiratory syndrome-associated coronavirus (sarscov) by calpain inhibitors and beta-d-n -hydroxycytidine angiotensin-converting enzyme is a functional receptor for the sars coronavirus novel peptide inhibitors of angiotensin-converting enzyme substrate-based design of the first class of angiotensin-converting enzyme-related carboxypeptidase (ace ) inhibitors potent neutralization of severe acute respiratory syndrome (sars) coronavirus by a human mab to s protein that blocks receptor association interaction between heptad repeat and regions in spike protein of sars-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors cloaked similarity between hiv- and sars-cov suggests an anti-sars strategy inhibiting severe acute respiratory syndrome-associated coronavirus by small interfering rna modulation of hiv- replication by rna interference interference of hepatitis c virus rna replication by short interfering rnas short interfering rna-directed inhibition of hepatitis b virus replication silencing sars-cov spike protein expression in cultured cells by rna interference inhibition of sars-associated coronavirus infection and replication by rna interference effect of glycyrrhizin, an active component of licorice roots, on hiv replication in cultures of peripheral blood mononuclear cells from hiv-seropositive patients long-term treatment of chronic hepatitis c with glycyrrhizin [stronger neo-minophagen c (snmc)] for preventing liver cirrhosis and hepatocellular carcinoma lamivudine and glycyrrhizin for treatment of chemotherapy-induced hepatitis b virus (hbv) hepatitis in a chronic hbv carrier with non-hodgkin lymphoma induction of inducible nitric oxide synthase and proinflammatory cytokines expression by o,pЈ-ddt in macrophages inhibition of sars-cov infection in vitro by s-nitroso-nacetylpenicillamine, a nitric oxide donor compound role of nitric oxide in allergic inflammation and bronchial 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infection in vitro with clinically approved antiviral drugs interferon-beta a and sars coronavirus replication interferon alfacon- plus corticosteroids in severe acute respiratory syndrome: a preliminary study pegylated interferon-alpha protects type pneumocytes against sars coronavirus infection in macaques how the sars vaccine effort can learn from hivspeeding towards the future, learning from the past treatment of severe acute respiratory syndrome with convalescent plasma prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice an efficient method to make human monoclonal antibodies from memory b cells: potent neutralization of sars coronavirus human monoclonal antibody as prophylaxis for sars coronavirus infection in ferrets caution urged on sars vaccines a review of feline infectious peritonitis virus: molecular biology, immunopathogenesis, clinical aspects, and vaccination effects of a sars-associated coronavirus vaccine in monkeys mucosal immunisation of african green monkeys (cercopithecus aethiops) with an attenuated parainfluenza virus expressing the sars coronavirus spike protein for the prevention of sars severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice nucleic acid vaccines: an overview a dna vaccine induces sars coronavirus neutralization and protective immunity in mice generation and characterization of dna vaccines targeting the nucleocapsid protein of severe acute respiratory syndrome coronavirus induction of sars-nucleoproteinspecific immune response by use of dna vaccine sars-one year later seasonality of infectious diseases and severe acute respiratory syndrome-what we don't know can hurt us clinical trials and novel pathogens: lessons learned from sars preparing to prevent severe acute respiratory syndrome and other respiratory infections collateral damage: the unforeseen effects of emergency outbreak policies support from the deutsche atemwegsliga and the german research foundation (dfg gr / - ) to dag is gratefully acknowledged. key: cord- -rxudwp v authors: barbas, carmen sílvia valente; matos, gustavo faissol janot; amato, marcelo britto passos; carvalho, carlos roberto ribeiro title: goal-oriented respiratory management for critically ill patients with acute respiratory distress syndrome date: - - journal: crit care res pract doi: . / / sha: doc_id: cord_uid: rxudwp v this paper, based on relevant literature articles and the authors' clinical experience, presents a goal-oriented respiratory management for critically ill patients with acute respiratory distress syndrome (ards) that can help improve clinicians' ability to care for these patients. early recognition of ards modified risk factors and avoidance of aggravating factors during hospital stay such as nonprotective mechanical ventilation, multiple blood products transfusions, positive fluid balance, ventilator-associated pneumonia, and gastric aspiration can help decrease its incidence. an early extensive clinical, laboratory, and imaging evaluation of “at risk patients” allows a correct diagnosis of ards, assessment of comorbidities, and calculation of prognostic indices, so that a careful treatment can be planned. rapid administration of antibiotics and resuscitative measures in case of sepsis and septic shock associated with protective ventilatory strategies and early short-term paralysis associated with differential ventilatory techniques (recruitment maneuvers with adequate positive end-expiratory pressure titration, prone position, and new extracorporeal membrane oxygenation techniques) in severe ards can help improve its prognosis. revaluation of ards patients on the third day of evolution (sequential organ failure assessment (sofa), biomarkers and response to infection therapy) allows changes in the initial treatment plans and can help decrease ards mortality. acute respiratory distress syndrome (ards) is due to an increase in the pulmonary alveolar-capillary membrane permeability causing lung edema rich in protein and consequently acute hypoxemic respiratory failure in genetically susceptible patients exposed to determined risk factors [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . a recent study showed that the del/del genotype (patients homozygous for the base pair deletion in the promoter of nfkb ) is associated with an age-dependent increase in odds of developing ards (or . , % ci . - . ) and patients with the del/del genotype and ards also have increased hazard of -day mortality (hr . , % ci . - . ) and more organ failure (p < . ) [ ] . all age groups may be affected, although the syndrome has a higher incidence and mortality in older people [ ] . the most common precipitating causes of ards are pulmonary infections, nonpulmonary sepsis, shock, gastric aspiration, thoracic trauma, fat embolism, near drowning, inhalational injury, cardiopulmonary bypass, drug overdose, acute pancreatitis, and high-risk trauma (especially traumatic brain injury) [ ] . recent epidemiological studies suggested a variety of intrahospital risk factors for ards development such as multiple blood products transfusions, mechanical ventilation with high tidal volumes, excessive fluid resuscitation, and hospitalacquired pneumonia as well as high-risk surgeries (especially aortic vascular, cardiac, and acute abdomen); all risk factors are potentially preventable. chronic alcohol abuse, chronic liver disease, immunosuppression, hypoalbuminemia, and obesity are also all associated with the development of ards, whereas diabetes mellitus appears to be protective [ ] . after exposure to a risk factor, there is an important activation of neutrophils and release of harmful mediators including cytokines (such as interleukins , , and and soluble tumor necrosis factor-alpha receptors), proteases, reactive oxygen species, and matrix metalloproteinases leading to future damage. an overwhelming pulmonary inflammatory process is initiated leading to alveolar epithelial and vascular endothelial injury. alveolar epithelial injury of type i cells contributes to the pulmonary edema and the breakdown of this epithelial barrier exposes the underlying basement membrane, predisposing to bacteremia and sepsis. injury to type ii alveolar cells leads to an impairment of surfactant function with consequent collapse of the lungs. histopathologically there is diffuse alveolar damage with neutrophil infiltration, alveolar hemorrhage and hyaline membrane formation [ ] [ ] [ ] [ ] [ ] . there are localized destruction and occlusion of the vascular bed of the lungs by intravascular thrombosis and an increment of the anatomical dead space resulting in an increase of arterial carbon dioxide associated with a poor outcome. fibrosis can be evident histologically as early as one week after the onset of ards and procollagen iii peptide, a precursor of collagen synthesis, can be elevated in bronchoalveolar lavage fluid of ards patients at the time of tracheal intubation, its increment being associated with a poor ards prognosis. vascular injury and remodeling may lead to pulmonary arterial hypertension which may compromise right ventricular function associated with a poor clinical outcome [ ] . incorporation of modified risk factors such as acute increase of respiratory rate, presence of tachypnea, detection of pulse oximeter desaturation, increased necessity of oxygen supplementation, presence of low ph, acidosis, or hypoxemia in an arterial blood gas sample in clinical practice can improve the clinicians' ability to perform early diagnosis and prompt therapeutic intervention in ards [ ] . the presence of these modified risk factors may alert physicians to avoid secondary hospital exposures, such as blood products transfusions, excessive fluid administration, infusion of potentially toxic drugs, high tidal volume mechanical ventilation, and gastric aspiration. implementation of ventilator associated pneumonia prevention bundles decreases the incidence of vap and can lower the incidence of ards [ ] . implementation of automated ards electronic screening in usa hospitals such as "assist" (electronic alert from laboratory when the arterial blood gas analysis shows hypoxemia and the radiology department when chest x-ray shows bilateral pulmonary infiltrates) to identify intubated patients with ards in medical and surgical icus showed a sensitivity of . % ( % ci, . - . %) and specificity of . % ( % ci, . - . %) when compared to a manual screening algorithm that had a sensitivity of . % ( % ci, . - . %) and specificity of . % ( % ci, . - %) in icu patients over a -week period during enrollment in ardsnet trials [ ] . the results of this study indicated the advantages of having an in-hospital automated screening of ards over manual screening. the automated screening can increase the chances of ards diagnosis, alert the clinicians, and elicit the rapid response from the hospital team of intensivists to initiate clinical protocols and ards therapeutic interventions [ ] . most hospitals and intensive care units worldwide use the standard criteria for the diagnosis of acute lung injury (ali)/ards: presence of acute hypoxemia (pao /fio less than mmhg or . kpa for ali or less than mmhg or . kpa for ards), bilateral infiltrates seen on a frontal chest radiograph that are consistent with pulmonary edema, and no clinical evidence of left atrial hypertension, or (if it is measured) a pulmonary artery wedge pressure (pawp) of less than mmhg according to the - american-european consensus conference on ards (aecc) [ , ] . this definition aimed to simplify and standardize the diagnosis of ards worldwide. however, in clinical practice, in order to detect and diagnose ali/ards cases, physicians must focus on patients' complaints, physical examination alterations, patients at risk of developing the disease, or patients presenting finger pulse oximeter desaturation. following the ali/ards clinical suspicion, physicians should order an arterial blood gas analysis and a chest radiograph to be able to confirm the ali/ards diagnosis. recent updates of ards definition such as the delphi consensus [ ] or the berlin definition [ ] were published in order to improve ards diagnosis criteria. the berlin definition reclassified ards as mild (pao /fio < or . kpa), moderate (pao /fio < or . kpa), and severe (pao /fio < mmhg or . kpa) and removed the term ali and the necessity of a swan ganz catheter to access pawp. acute time frame was specified as the onset within week of a known clinical insult or new or worsening respiratory symptoms chest radiography criteria were clarified and bilateral opacities consistent with pulmonary edema were maintained as the main radiological criteria of ards, but it was recognized that these findings could be demonstrated on ct scan instead of chest radiograph. the recent berlin definition of ards is a decisive step forward in refining the diagnosis of the syndrome, but pao /fio is influenced by ventilator settings and this fact should be considered; bilateral pulmonary infiltrates can be the result of a wide variety of acute lung diseases that should be better investigated. left and right ventricular function, pulmonary artery pressures, and volemic status could be better evaluated by bedside echocardiography and extravascular lung water can be measured using picco catheter, in order to evaluate the degree of pulmonary edema. predictors of mortality should be calculated at icu admission. with the information, the icu team can program a more careful treatment plan according to disease severity. the berlin definition shows better predictive validity for mortality compared to the aecc definition, but the absolute value of the area under the receiver operating curve is still too small ( . ), suggesting that some factors are still missing. further discussion and research are needed before we reach a comprehensive definition of ards. critical care research and practice the typical findings of ards in a computer tomography reveal a heterogeneous bilateral pulmonary infiltrate predominantly in gravity-dependent regions of the lungs and more preserved lungs in nondependent lung regions. using quantitative analysis of the ct scan, the gravity-dependent pulmonary ards infiltrate is typically nonaerated lung tissue consistent with compressive atelectasis [ , ] . lung weight assessed by ct scan is increased in ards and is correlated with the severity of the syndrome [ ] . the finding of concomitant interstitial infiltrates suggests viral or mycoplasma, chlamydia or opportunistic pulmonary infections, or drug-induced lung disease. the differential diagnosis of bilateral pneumonia, alveolar hemorrhage, and acute interstitial lung disease such as acute interstitial pneumonia, hypersensitivity pneumonitis, acute eosinophilic pneumonia, and bronchiolitis obliterans with organizing pneumonia can be suggested by the characteristic ct scan findings of each specific disease [ ] . the results of stepwise lung recruitment maneuvers as well as positive end-expiratory (peep) titration to keep the lungs open with minimal collapse can be assessed by computer tomography analysis [ ] . this strategy is aimed at opening up the lungs and keeping the lungs open [ ] as quickly and early as possible as postulated by lachmann [ ] in order to have a huge improvement in lung function and avoid potential ventilator-induced lung injury. recently, our group reported the experience with maximal recruitment strategy (mrs) in patients with ards. mrs consisted of -minute steps of tidal ventilation with pressure-controlled ventilation, fixed driving pressure of cmh o, respiratory rate of breaths/minute, inspiratory/expiratory ratio of : , and stepwise increments in peep levels from to cmh o (recruitment phase). after that, peep was decreased to cmh o and, then, from to cmh o (peep titration phase) in steps of cmh o, each one lasting minutes. at each of the steps computer tomography image sequences from the carina to the diaphragm were acquired during an expiratory pause of - seconds. lung collapse was assessed online by visual inspection, for immediate clinical decision, and offline for quantitative measurements. mrs showed a statistically significant decrease in nonaerated areas of the ards lungs that was accompanied by a significant increment in oxygenation. the opening plateau pressure observed during the recruitment protocol was . (± . cmh o), and the mean peep titrated after mrs was . (± . cmh o). mean pao /fio ratio increased from (± ) to (± ; p < . ) after mrs and was sustained above throughout seven days. nonaerated parenchyma decreased significantly from . % (interquartile range (iqr): . to . ) to . % (iqr: . to . ) (p < . ) after mrs. the potentially recruitable lung was estimated at % (iqr: to ), (figure ). icu mortality was % and hospital mortality was %. the independent risk factors associated with mortality were older age and higher driving pressures (or higher delta pressure control). there were no significant clinical complications with mrs or barotrauma [ ] . a better evolution of these ards patients with less necessity of oxygen supplementation in the recovery phase of the disease and a better quality of life must be tested in prospective, controlled clinical trials. a recent metaanalysis showing beneficial effects on mortality using higher peep levels compared with lower peep in ards patients corroborates the results of our clinical case series of ards patients submitted to mrs [ ] . ards is a biphasic disease that progresses from an acute exudative phase, characterized by epithelial and endothelial injury, neutrophilic aggregation, formation of hyaline membranes, alveolar edema, and hemorrhage, to an organizing phase, characterized by regeneration and healing via resolution or repair with persistent intra-alveolar and interstitial fibrosis [ ] . it is crucial to make the diagnosis of ards in the acute phase (preferably less than hours) in order to make it possible to open up the lungs with recruitment maneuvers and keep the lungs open with sufficient peep levels to enable a more homogenous ventilation, minimizing the possible ventilator-induced lung injury (vili) triggers and allowing the recovery of the lungs [ ] [ ] [ ] . a recent study analyzing patients with ards graded into six findings according to the extent of fibroproliferation at the ct scan showed that higher ct scores were associated with statistically significant decreases in organ-failure free days as well as ventilator free days and were an independent risk factor for mortality (or = . , % ci . - . , p < . ) [ ] . positron emission tomography with ( f) fluorodeoxyglucose (fdg-pet) detects inflammatory cells and can assess lung inflammation in ards lungs helping in the understanding of ards physiopathology [ ] [ ] [ ] . lung ultrasonography is a new helpful tool that can be performed at bedside without radiation exposure. thoracic ultrasound is widely used for diagnostic and therapeutic intervention in patients with pleural effusion and pneumothoraces. the assessment of lung recruitment and peep titration in ards patients at bedside using lung ultrasonography is a new promising technique [ ] . currently, the two main limitations of this technique are its inability to detect lung overdistension and its operator-dependent characteristic. thoracic electrical impedance tomography (eit) is a highly promising imaging technique to apply at the bedside for peep titration in ards patients. new automated tools permit the calculation of the percentage of collapsed as well as overdistended lung tissue at decremental peep levels after lung recruitment maneuvers ( figure ). the regional distribution of collapse and overdistension may provide insights about the lung pathology. this technique permits daily peep adjustments at the bedside and verification of tidal volume distribution, avoiding excessive end-expiratory collapse or tidal overdistention [ ] [ ] [ ] [ ] . one of the main sofa score during first days after mrs * p < . advantages of this technique is the possibility of around the clock monitoring. further studies are needed to evaluate the clinical impact of these bedside techniques in ards patients' prognosis. randomized trials suggested that patients with acute hypoxemic respiratory failure are less likely to require endotracheal intubation when noninvasive ventilation (niv) is added to standard therapy [ ] . however, most of these studies analyzed mixed causes of acute hypoxemic respiratory failure and reported the highest intubation rates for patients with ards ( to %) and that the presence of ards was one factor independently associated with niv failure and higher mortalities rates ( to %). recently, zhan and colleagues [ ] analyzed patients with ards randomly allocated to receive either noninvasive ventilation or high-concentration oxygen therapy through a venturi mask. noninvasive positive pressure ventilation decreased the respiratory rate and improved pao /fio with time. the proportion of patients requiring intubation and invasive mechanical ventilation was significantly lower in the noninvasive ventilation group (one of versus of ; p = . ). therefore, noninvasive ventilation can be used as a first ventilatory support technique in selected patients with mild/moderate ards and a hemodynamic stable condition to avoid endotracheal intubation. a larger randomized trial, however, is required, with the need for intubation and mortality as the outcome of interest. a close-monitored initial trial of noninvasive ventilation should be considered in most mild/moderate ards patients, mainly the immunosuppressed ones with pulmonary infection in order to avoid intubation and invasive mechanical ventilation. however, early detection of collapse was more prominent in the right lung. after analyzing the sequence of eit images, the peep selected for this patient was cmh o, believed to represent the best compromise between collapse and overdistension. according to the ardsnet peep/fio table, this patient had been ventilated with a peep = cmh o in the previous hours. the patient was weaned from ventilator days later. niv failure must be recognized, and a prompt intubation and mechanical ventilation must be provided in order to avoid complications. protective ards mechanical ventilation strategies with tidal volumes equal to or less than ml/kg of predicted body weight have been traditionally associated with reduced mortality (when compared with ml/kg of predicted body weight) [ , ] . a recent meta-analysis, however, scrutinized the specific role of various ventilatory strategies used in randomized trials on lung protection (like plateau-pressure limitation and higher peep use) and showed that tidal volume per se is not exactly the most important parameter to prioritize. [ ] demonstrated decreased lung inflammation with this protective ventilatory strategy. although these results are encouraging, the physiologic background supporting the use of p-v curves to titrate peep lacks consistency nowadays. in many different situations, investigators have reported a large dissociation between closing pressures of the lung and the calculated value for the inflection point obtained from the inspiratory p-v curve. in general, patients with high values of inflection point tend to have a more severe disease, and this may explain the relative success of this strategy. nevertheless, we will probably use better tools to titrate peep in the next few years. a more consistent use of the p-v curve has been demonstrated for the analysis of lung recruitability [ , ] . airway pressure release ventilation is a modified form of continuous positive airway ventilation (cpap) described by stock and dows in that uses fairly high prolonged cpap levels with short and intermittent releases of the airway pressure to low cpap levels allowing ventilation and co clearance. this mode of ventilatory support enhances oxygenation by augmenting alveolar recruitment and requires less sedation when used in ards patients compared to conventional mechanical ventilation [ , ] . bipap ventilation combined with lung recruitment maneuvers can also be used in ards patients. wang and colleagues compared this modality of ventilatory support with assist/controlled volume ventilation in a prospective, randomized trial of ards patients showing a better pao /fio ratio, pulmonary compliance, and a shorter duration of mechanical ventilation [ ] . pressure support ventilation (psv) along with sufficient peep levels should be used as early as possible in ards patients to avoid respiratory muscle dystrophy and to decrease mechanical ventilation duration [ ] . the reason for the improvement in oxygenation obtained with psv in ards has been challenged in the recent years [ , ] . the apparent improvement in recruitment seems to have been overstated and there is evidence that it is related to an increased perfusion of better ventilated lung areas, but not to decreased lung collapse. growing concerns related to excessive tidal recruitment or excessive dyssynchrony during this mode of ventilation will have to be better addressed in the next years [ ] . the advantages of using assist modes are to keep the respiratory muscles' activity, but sometimes it is difficult to synchronize the patients to the ventilators. recently, neurally adjust ventilation (nava) was used in ards experimental models [ ] and ards patients [ ] demonstrating that the ventilation cycle and the magnitude of assist breath in nava matched the patients' breath pattern better than in psv, nava improving patient-ventilator synchrony compared to psv. high frequency oscillatory ventilation (hfov) is an alternative mode of ventilatory support that can improve oxygenation by means of a higher mean airway pressure coupled with small tidal volumes generated by a piston pump oscillating at a frequency of - hz and a higher respiratory rate. however, to date there are few studies involving a small number of patients comparing hfov to conventional ventilation. a recent meta-analysis suggested a trend towards mortality benefit and more ventilator free days. however, the results of this analysis should be interpreted cautiously as the main study contributing to its results used high tidal volume in the control group rather than protective lung ventilation strategy [ ] . the use of the position change (supine to prone) leads to consistent improvement in arterial oxygenation in ards patients. large randomized, controlled trials have consistently showed improvement in oxygenation without reduction in duration of mechanical ventilation or survival benefit. a recent meta-analyses suggest survival benefits in ards patients [ ] or, more specifically, in a subgroup of patients with severe ards (pao /fio < mmhg) [ ] . in our experience, the prone position can be an acceptable alternative to improve oxygenation in severe ards patients with arterial pulmonary hypertension and right ventricular dysfunction, which associated with the use of inhaled nitric oxide, can minimize intrathoracic pressures to facilitate right ventricular performance. the principles of a protective ventilation with proper peep titration and minimum driving pressures should also be pursued during prone positioning protocols. clinical studies suggested that elevated pulmonary artery systolic pressure in ards patients was associated with an adverse prognosis [ ] . these data have been further supported by a more recent analysis of hemodynamic data from the ardsnet fluids and catheter therapy trial (factt) [ ] . the investigators assessed the transpulmonary gradient (tpg) (mean pa pressure-pulmonary capillary occlusion pressure (pcop)) and the pulmonary vascular resistance index (pvri) in a group of patients randomized to receive a pulmonary artery catheter to guide their ards management. of note, all patients received a consistent protective ventilator strategy with target tidal volume ∼ ml/kg ideal body weight and plateau pressures maintained < cmh o. the highest recorded daily value of tpg and pvri was used for the analysis. in the population of patients randomized to receive a pulmonary artery catheter for ards management, none of the baseline measures of cardiopulmonary dysfunction, including central venous pressure, pa systolic, or diastolic pressure, pulmonary capillary occlusion pressure (paop), or cardiac index distinguished survivors from nonsurvivors. in the pulmonary artery catheter population, % demonstrated an elevated transpulmonary gradient (tpg > ). patients with a tpg > mmhg had a significantly greater mortality rate than patients with a tpg < mmhg ( % versus %; p = . ). patients with a persistently elevated tpg through day of therapy had a significantly greater mortality than patients with an elevated tpg at day - which subsequently normalized. in multivariate analysis, pulmonary vascular dysfunction as represented by an elevated tpg and pvri remained an independent predictor of an adverse outcome in the ards population. these data further support an important predictive role for pulmonary vascular disease in ards outcome [ ] . in the largest published echocardiographic series of ards, % of patients receiving a consistent lung protective ventilation strategy (mean peep of cmh o and mean plateau pressure (pplat) of cmh o) had evidence for acute cor pulmonale. in this population, % demonstrated evidence of a moderate-to-large patent foramen ovale [ ] . the incidence of right to left shunting increased to % in patients with echocardiographic evidence of acute cor pulmonale. increase of oxygenation and co removal by making the ards patients' blood pass throughout a membrane oxygenator outside the body is the principle of extracorporeal membrane oxygenation that can be applied venousvenous (good for oxygenation and co removal), arterialvenous (good for co removal), and venous-arterial (good for cardiovascular support). early clinical trials of ecmo employed primarily an arterial-venous strategy with larger bore catheters for patients with intractable hypoxemia [ ] . more modern investigations have used a safer venous-venous access approach [ , ] . a recent uk prospective, randomized, clinical trial (cesar) showed a survival advantage in the ecmo group ( % for ecmo versus % for controls). nevertheless, the study was criticized as there was no standardized protocol management for the control group and some patients in the ecmo arm did not receive the proposed treatment [ ] . the authors of cesar trial also recommended transferring adult patients with severe but potentially reversible respiratory failure and a ph less than . on optimal conventional management, to a center with an ecmo-based management protocol to significantly improve survival without severe disability. the authors demonstrated that this strategy is also likely to be cost effective in settings with similar services to those in the united kingdom [ ] . another recent approach for application of extracorporeal carbon dioxide removal new devices (ecmo-r) in ards patients is the demonstration that in severe ards even the low tidal volume ventilation with ml/kg of predicted body weight can cause tidal hyperdistension in the nondependent regions of the lungs accompanied by plateau airway pressures greater than cmh o and elevated plasma markers of inflammation. in this group application of ecmo-r could allow the authors to decrease the tidal volume to less than ml/kg with a consequent plateau pressure less than cmh o that was associated with a lower radiographic index of lung injury and lower levels of lung-derived inflammatory cytokines. however, prognostic implication of this new ecmo-r devices application in clinical practice is still under investigation [ ] . pumpless interventional lung assist (ila) is also used in patients with ards and is aimed at improving extracorporeal gas exchange with a membrane integrated in a passive arteriovenous shunt. ila serves as an extracorporeal assist to support mechanical ventilation by enabling low tidal volume and a reduced inspiratory plateau pressure in extremely severe ards patients. zimmermann and colleagues used ila in severe ards patients and observed a decrease in paco allowing the decrease in tidal volume and plateau pressure (ultraprotective ventilation) with a hospital mortality rate of % [ ] . some authors suggest the use of combined ventilatory strategies in patients with ards. bingold and colleagues [ ] successfully used superimposed high-frequency jet ventilation (shfjv) in combination with continuous positive airway pressure/assisted spontaneous breathing (cpap/asb) in five patients with h -n -associated ards to improve oxygenation. varpula and colleagues [ ] demonstrated a significant improvement in oxygenation in ards patients, when they compared apvr associated with prone ventilation to simv-pressure control/pressure support group. aprv after h appears to enhance improvement in oxygenation in response to prone positioning. rival and colleagues [ ] examined the effects of the prone position associated with a recruitment maneuver consisting of cmh o extended sigh in pressure control, in ards patients. the combination of both ventilatory techniques led to the highest increase in pao /fio ratio without significant clinical side effects. lubnow and colleagues [ ] examined the effects of days of the combination of high-frequency oscillatory ventilation (hfov) and extracorporeal carbon dioxide removal with the interventional lung assist (ila) in severe ards patients who failed conventional ventilation. they observed an increase in pao /fio ratio and ph and a decrease in paco . weaning from hfov/ila was successful in patients. the -day mortality rate was %, and hospital mortality rate was %. in conclusion, combined ventilatory strategies can be applied in severe ards patients, but the best match among all the available ventilatory techniques is still a matter of debate. pulmonary infection and sepsis are the most important triggering factors of ards. pulmonary infection has been associated with a higher risk of ards progression in comparison to nonpulmonary infection in at risk populations [ ] . a wide variety of organisms can invade the respiratory tract and trigger host innate and acquired immune system initiating the inflammatory cascade of ards, sepsis, and multiple organ failure [ ] . it is particularly pertinent to investigate the etiology of pulmonary infection on the first day assessing a nasal swab for a respiratory virus detection (influenza, adenovirus) lower respiratory tract secretion or a bronchoalveolar lavage fluid (balf) for bacteria (especially multiresistant species), other viruses as herpes and cytomegalovirus, coronavirus, or metapneumonic virus [ ] . opportunistic agents such as pneumocystis jiroveci must be investigated in immunosuppressed patients. urinary screening for legionella species is decisive, because if positive, specific therapy must be introduced [ ] . the assessment of balf on the first as well as on the third day of mechanical ventilation is of the utmost importance not only in terms of assessment of etiology of pulmonary infection but also of the assessment of proinflammatory mediators of ards (il- , il , il , il , soluble tumor necrosis factor-alpha receptors (stnfr), and soluble intercellular adhesion molecule- ) and mediators of ventilator-induced lung injury (that can also be obtained in the plasma) such as stnfr, il , il , and il- , indicators of epithelial cell injury (soluble advanced glycation end-product receptors-srage), and surfactant protein-d, components of the coagulation system (protein-c and plasminogen activator inhibitor ) [ , ] . elevated levels of procollagen peptide iii in lavage fluid from patients on day of ards were independent risk factors for mortality [ ] . procalcitonin (pct) and c-reactive protein (crp) are progressively being used in critical care setting in order to diagnose pulmonary infection and sepsis and to guide the antibiotic therapy. procalcitonin levels correlated with severe sepsis and bacteraemia [ ] . a pct-based algorithm guiding initiation and duration of antibiotic therapy in critical ill patients with suspected bacterial infections was associated with a % relative reduction in antibiotic exposure with no significant increase in mortality [ ] . the persistence of an elevated serum crp in critical ill patients with ards may alert the intensivist to a possible persistent infection or inflammatory process. at this moment, a new workup for infection and change in antibiotic therapy could help improve the patient's evolution. early and quick administration of antibiotics in sepsis and septic shock as well as early goal resuscitative measures for septic shock or early goaldirected therapy decrease mortality in this high mortality critically ill conditions [ , ] . we also suggest that preventive measures to avoid gastric aspiration (elevated decubitus, intermittent check for residual gastric content during diet infusion) and to avoid ventilation associated pneumonia (wash hands, elevated decubitus, special endotracheal tubes) should be implemented. the resolution of pulmonary edema is central to recover from ali as it entails regression of air space inflammation and restoration of a functioning alveolar-capillary membrane. accordingly, elevated extravascular lung water measured using this technique early in the course of ali/ards, particularly if indexed to predicted body weight, was associated with a poor prognosis [ ] . a study analyzing the evolution of ards patients showed that unknown-site infection (adjusted hazard ratio (hr) . , % ci . - . ) and multiple site infection (adjusted hr . , % ci . - . ) were associated with increased mortality [ ] . in ards patients it is of considerable significance to evaluate the source of infection as well all organs and systems affected by the sepsis syndrome in order to map the organism (number of nonpulmonary organ failures), to calculate the prognostic indices (acute physiology and chronic health evaluation (apache) and simplified acute physiology score (saps)) and to plan the multiorgan system approach to treat the disease. the higher the number of multiple organ failure associated with ards, the higher the hospital mortality. trauma patients with ards are associated with lower mortality and oliguricrenal failure, while septic shock patients are associated with the highest hospital mortality rates, suggesting that during the first day of hospitalization these ards patients should be stratified and treated according to the severity of the syndrome and associated comorbidities [ ] . in our case series of patients with early severe ards the mean apache ii score was . ± . (predicted mortality of %), median sofa score (day ) was ( to ), median nonpulmonary organ failure was ( to ), sepsis was present in % of our patients, and septic shock in %, vasopressors were used in . % of our patients, and continuous renal replacement therapy was used in . % of our patients. apache ii and day sofa score were not associated with hospital mortality, but day sofa score was [ ] (figure ) showing that a revaluation of the ards patients especially the ones with multiple organ failure and maintenance of sofa score higher than at day has to be considered in order to evaluate hidden sources of infection or to change the antibiotics according to day collected cultures. in moderate-severe ards patients (pao /fio < ), a phase iv randomized controlled trial comparing cisatracurium to placebo for hours showed an improved critical care research and practice adjusted -day survival rate and increased ventilator-free in the cisatracurium group without a significant increase in muscle weakness. short-term paralysis may facilitate patient-ventilator synchrony in the setting of lung protective ventilation. short-term paralysis would eliminate patient triggering and expiratory muscle activity. in combination, these effects may serve to limit regional overdistention and cyclic alveolar collapse. paralysis may also act to lower metabolism and overall ventilatory demand [ ] . inhaled nitric oxide is an endogenous vasodilator that reduces v/q mismatch and improves oxygenation by pulmonary vasodilation in alveolar units that are ventilated, reducing pulmonary vascular resistance in patients with ards. a cochrane review of clinical trials with patients showed only a transient improvement in oxygenation with no benefit regarding length of icu or hospital stay, ventilator-free days or survival. an increased renal impairment was observed in the inhaled nitric oxide-treated group [ ] . the effects of steroids in the late-stage fibrotic phase of ards (after days of onset) were tested in a phase iii study of the ards network. the study showed no mortality benefit in the treatment group, with a higher mortality in patients treated days after onset [ ] . recently, seam and colleagues tested the effects of methylprednisolone infusion in early ards patients compared to placebo. they observed that methylprednisolone therapy was associated with greater improvement in lung injury score (p = . ), shorter duration of mechanical ventilation (p = . ), and lower intensive care unit mortality (p = . ) than in the control subjects. on days and , methylprednisolone decreased interleukin- and increased protein-c levels (p < . ) compared with control subjects [ ] . from the available evidence, low-dose steroids ( - mg/kg/methylprednisolone) may be considered in patients with severe early ards. nevertheless, it is not recommended to initiate corticosteroids beyond days after the onset of ards. ketoconazole, lisofylline, sivelestat, n-acetylcysteine, and exogenous surfactant are not recommended as treatment for ards patients [ ] . cumulative positive fluid balance is associated with worse clinical outcomes in patients with ards. a phase iii study conducted by the ards network (the factt study) compared liberal versus conservative fluid strategy in patients with acute lung injury. they observed an improvement in oxygenation, lung injury score (lis), and shortened duration of mechanical ventilation without any increase in other organ failure in the conservative group, despite no difference in hospital mortality [ ] . beta-agonists were investigated in multicenter, prospective, randomized trials in their aerosolized presentation (the alta study) and their intravenous presentation (the balti- study). both studies showed no mortality benefit and betaagonists are not recommended as part of therapy for patients with ards [ ] . the omega study [ ] , a randomized, double-blind, placebo-controlled, multicenter trial analyzed patients with early acute lung injury allocated to receive either twicedaily enteral supplementation of n- fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. enteral nutrition, directed by a protocol, was delivered separately from the study supplement. the patients that received enteral supplementation had fewer ventilator-free days ( versus . , p = . ), more days with diarrhea ( versus %; p = . ), and no difference in the adjusted -day mortality ( . % versus . %; p = . ). more recently, a randomized, open-label, multicenter trial, the eden study [ ] , reported patients with acute lung injury, randomized to receive either trophic or full enteral feeding for the first days. initial trophic enteral feeding did not improve ventilator-free days, -day mortality, or infection complications but was associated with less gastrointestinal intolerance. finally, based on relevant literature articles and the authors' clinical experience, we suggest a goal-oriented management for critically ill patients with ards that can help improve clinicians' ability to care for these patients (as shown below). patients with ards. correct ards diagnosis. acute onset, increase respiratory rate, pulse oximeter desaturation and hypoxemia (pao /fio < ). (i) if possible, get a computer tomography (improved diagnosis accuracy, permits differential diagnoses, and helps to set recruitment maneuvers and adequate peep levels). (ii) lung ultrasound, fdg-pet ct, electrical impedance tomography, and pressure-volume p × v curves can help assess the correct diagnosis and set protective mechanical ventilation. (iii) get nasal swab and inferior respiratory tract secretion for infection diagnosis or a bal (infection diagnosis and proinflammatory mediators and procollagen iii measurements). (iv) get hemocultures and blood for infection detection. start resuscitative measurements for septic shock and start appropriate antibiotics. critical care research and practice (v) assessment of prognostic indices (apache, saps) and sequential organ failure assessment (sofa) score. standardize initial mechanical ventilation for blood gas measurements. tidal volume: ml/kg predicted body weight, peep of cmh o, rr = . classify ards severity. mild: pao /fio < , moderate: pao /fio < , and severe: pao /fio < . (i) if possible, get a doppler echocardiogram to assess left ventricular function, right ventricular function, systolic pulmonary artery pressure, and vena cava compressibility. (ii) measure extravascular lung water, if available. (a) in cases of severe ards consider recruitment maneuvers and adequate peep titration. (b) in cases of severe ards with right ventricular dysfunction and pulmonary artery hypertension consider prone position and inhaled nitric oxide. (c) in cases of excessive co retention: paco > mmhg and ph < . consider intratracheal gas insufflation and extracorporeal co removal. (i) early recognition of ards modified risk factors and avoidance of aggravating factors during hospital stay such as high tidal volume ventilation, multiple blood products transfusions, excessive fluid administration, ventilator associated pneumonia, and gastric aspiration prevention could help decrease its incidence. (ii) an early extensive clinical, laboratory, and imaging evaluation of "at risk patients" allows a correct diagnosis of ards, assessment of comorbidities, calculation of prognostic indices (apache, saps, sofa), stratification of the severity of ards, and planning a careful treatment. (iii) rapid administration of antibiotics and resuscitative measures in case of sepsis and septic shock associated with protective ventilatory strategies and early shortterm paralysis associated with differential ventilatory techniques (recruitment maneuvers with adequate peep titration, prone position, and new ecmo techniques) in severe ards can help improve its prognosis. (iv) revaluation of ards patients on the third day of evolution (sofa, biomarkers, and response to infection therapy) allows changes in the initial treatment plans and can help decrease ards mortality. 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computed tomography state-of-the-art mechanical ventilation understanding and avoiding ventilatorinduced lung injury: lessons from an insightful experimental study best strategy to recruit primary ards: what to look for fibroproliferative changes on high-resolution ct in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study imaging in acute lung injury and acute respiratory distress syndrome assessment of lung inflammation with f-fdg pet during acute lung injury lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: a [ f]-fluoro- -deoxy-dglucose pet/ct study bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment electrical impedance tomography bedside estimation of recruitable alveolar collapse and hyperdistension by electrical impedance tomography a unified approach for eit imaging of regional overdistension and 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pathophysiologic review and individual patient metaanalysis hemodynamic profile in severe ards: results of the european collaborative ards study comparison of two fluid-management strategies in acute lung injury pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome extracorporeal membrane oxygenation in severe acute respiratory failure. a randomized prospective study clinical review: extracorporeal membrane oxygenation extracorporeal membrane oxygenation for ards in adults efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (cesar): a multicentre randomised controlled trial tidal volume lower than ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study superimposed highfrequency jet ventilation combined with continuous positive airway pressure/assisted spontaneous breathing improves oxygenation in patients with h n -associated ards combined effects of prone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury prone position and recruitment manoeuvre: the combined effect improves oxygenation combination of high frequency oscillatory ventilation and interventional lung assist in severe acute respiratory distress syndrome clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ards virus-induced acute respiratory distress syndrome: epidemiology, management and outcome biomarkers of acute lung injury: worth their salt? type iii procollagen peptide in the adult respiratory distress syndrome. association of increased peptide levels in bronchoalveolar lavage fluid with increased risk for death predictive value of procalcitonin decrease in patients with severe sepsis: a prospective observational study use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial early goal-directed therapy in the treatment of severe sepsis and septic shock early interventions in severe sepsis and septic shock: a review of the evidence one decade later extravascular lung water indexed to predicted body weight is a novel predictor of intensive care unit mortality in patients with acute lung injury the influence of infection sites on development and mortality of ards predictors of hospital mortality in a population-based cohort of patients with acute lung injury neuromuscular blockers in early acute respiratory distress syndrome inhaled nitric oxide for acute respiratory distress syndrome (ards) and acute lung injury in children and adults efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in early acute respiratory distress syndrome randomized, placebo-controlled trial of an aerosolized beta- adrenergic agonist (albuterol) for the treatment of acute lung injury omega- (n- ) fatty acid, gamma-linoleic acid (gla) and anti-oxidant supplementation in acute lung injury (omega trial) initial trophic vs full enteral feeding in patients with acute lung injury: the eden randomized trial the authors would like to thank adriana pardini for revision of the language. key: cord- -j kioy e authors: lefkowitch, jay h. title: acute viral hepatitis date: - - journal: scheuer's liver biopsy interpretation doi: . /b - - - - . - sha: doc_id: cord_uid: j kioy e nan acute hepatitis is not usually an indication for liver biopsy. there are, however, at least three reasons why pathologists sometimes receive liver biopsy samples from patients with acute hepatitis. first, there may be doubt about the clinical diagnosis, or even a mistaken working diagnosis. second, a diagnosis of hepatitis may be well established but the clinician needs information on the stage of the disease or its severity. third, the patient may have received a liver transplant and the pathologist is being asked to help decide if symptoms or biochemical abnormalities are due to recurrent (or new) viral hepatitis or to some other cause such as rejection. for all these reasons, a knowledge of the pathology of acute hepatitis is essential. there is a further reason, no less important than the others: without a knowledge of acute hepatitis, the pathologist cannot hope to understand chronic hepatitis and cirrhosis, together the cause of most liver disease in the world. this chapter describes acute viral hepatitis and its immediate sequelae in the immunocompetent patient. the specific problems of diagnosing hepatitis in an immunosuppressed patient after transplantation are reviewed in chapter . the hepatitis viruses are listed in table . . while several other candidates have been extensively investigated in recent years, none has so far been established as a definite cause of viral hepatitis and most episodes of acute and chronic hepatitis can be attributed to one of the viruses listed, to autoimmune hepatitis (ch. ) or to a hepatotoxic agent (ch. ). an exception to this statement is fulminant hepatitis, the cause of which cannot currently be established in a substantial minority of patients, - including children. occasionally, a virus more often associated with infection of other organs, such as one of the herpes viruses [ ] [ ] [ ] or an adenovirus, , gives rise to a severe hepatitis. these agents are further discussed in chapter . mild acute hepatitis has been reported in patients infected with the sars virus (severe acute respiratory syndrome-associated coronavirus). , occasionally, mild serum liver test abnormalities and mild histological hepatitis ('bystander hepatitis') with apoptotic bodies, focal necrosis and lymphocytic inflammation are seen in systemic, non-hepatic viral infections such as pulmonary influenza and result from migration to the liver of and collateral damage by cd t-lymphocytes. changes seen under the light microscope range from minor degrees of cell swelling to cell death. they are accompanied by the inflammatory infiltration described below, reflecting the important role of cellular immunity in the pathogenesis of most forms of hepatitis. both hepatocellular damage and inflammation are usually most severe in perivenular areas, giving rise to a characteristic histological pattern ( fig. . ) . a periportal pattern of necrosis and inflammation, sometimes seen in hepatitis a, is less common. the mildest and probably reversible change is cell swelling. the cytoplasm of affected cells is rarified, granular and sometimes finely vacuolated. the more severe degrees of cell swelling are called ballooning degeneration ( fig. . ). this differs from the feathery degeneration of cholestasis, in which the cytoplasm has a reticular pattern (see fig. other hepatocytes undergo apoptosis, which is an important method of cell death in hepatitis. shrinkage and increased staining of the cytoplasm, sometimes called acidophilic change or degeneration, is probably a precursor of apoptosis, in which the hepatocytes shrink further, become very dense and undergo fragmentation. the apoptotic bodies seen lying free in the sinusoids represent the largest fragments or entire unfragmented apoptotic cells ( fig. . ). they are also called acidophil bodies or councilman bodies, councilman having first described them in yellow fever. apoptotic bodies sometimes contain pyknotic nuclear remnants and often appear to bulge beyond the plane of the section. another form of hepatocellular damage in acute hepatitis is focal (spotty) necrosis, in which liver-cell plates are disrupted or replaced by small groups of lymphocytes and macrophages. whether these mark a site of necrosis or of apoptosis is not clear; the damage to hepatocytes is deduced from their absence rather than seen. whatever its mechanism, loss of hepatocytes or liver-cell drop out, coupled with focal regeneration, leads to a characteristic irregularity of the liver-cell plates, which usually allows acute hepatitis to be distinguished from hepatocellular damage secondary to cholestasis. the loss of hepatocytes also leads to condensation of the extracellular matrix, best seen in reticulin preparations ( fig. . ). hepatocyte nuclei show prominent nucleoli and increased variation in size and may be multiple. when syncytial giant hepatocytes are very prominent, the term giant-cell hepatitis is appropriate. , this is only rarely of proven viral origin and is also more characteristic of acute hepatitis in neonates. in adults, autoimmune hepatitis and hepatitis c virus with or without human immunodeficiency virus co-infection are important associations. [ ] [ ] [ ] [ ] [ ] cholestasis in the form of bile thrombi in canaliculi is common in acute hepatitis but rare in chronic hepatitis, which is diagnostically helpful. it is a result of damage to the bile secretory apparatus of the hepatocytes, but may also result from interference with bile flow at the level of the portal tracts. the term cholestatic hepatitis is best kept as a clinical description of patients with a prolonged cholestatic course. mild hepatocellular siderosis or steatosis is occasionally seen. unlike classic acute inflammation, viral hepatitis is characterised by a mainly lymphocytic infiltrate within the parenchyma and portal tracts. in acute hepatitis, the most conspicuous inflammation is usually perivenular. the extent of portal inflammation is very variable and portal tracts may be either normal in size or expanded. the larger conducting tracts are often spared. the edges of small portal tracts may be well defined or blurred by outward extension of the infiltrate. this so-called spillover resembles the interface hepatitis of chronic hepatitis (ch. ) and may be difficult to distinguish from it. the parenchymal changes, clinical history and virological findings usually make the correct diagnosis clear. while most of the infiltrating cells in acute hepatitis are small t lymphocytes, plasma cells may also be prominent and there are often a few neutrophils and eosinophils. the plasma cells do not necessarily indicate autoimmune hepatitis, nor do a few eosinophils prove a diagnosis of drug injury. kupffer cells and other macrophages accumulate and enlarge, many of them forming discrete clumps together with lymphocytes. they may contain tan-brown ceroid pigment, staining with periodic acid-schiff (pas) agent after diastase digestion ( fig. . ) . they may also contain stainable iron ( fig. . ), but this is less common. sinusoidal and venular endothelial cells also take part in the hepatitic process. sinusoidal endothelial cells become swollen and may contain dense iron-positive granules ( fig. . ). terminal hepatic venules may show disruption of the endothelium and lymphocytic infiltration. in contrast to chronic hepatitis the parenchymal changes dominate the picture, but there is always some portal inflammation, affecting most or all of the small portal tracts ( fig. . ). the density of the infiltrate varies. interlobular bile ducts may show abnormalities including irregularity, crowding and stratification of the epithelium, cytoplasmic vacuolation and infiltration by lymphocytes ( fig. . ) . these changes, together with lymphoid follicle formation, are most often seen in hepatitis c. bile-duct loss (ductopenia) is very rare. the histological changes in acute hepatitis are infinitely variable, but a few patterns deserve special mention. these are confluent necrosis, bridging necrosis, necrosis of entire lobules and periportal necrosis. confluent necrosis signifies death of a substantial area of the parenchyma. focal as opposed to zonal areas of confluent necrosis haphazardly distributed in relation to lobular zones are more likely to be due to causes other than acute viral hepatitis; possibilities to be considered include opportunistic infections with herpes simplex or zoster viruses and lymphoma. bridging necrosis (figs . , . , and fig. . ) is the term given to confluent necrosis linking terminal venules to portal tracts. a possible explanation for this location is that it represents the entire zone of an acinus, a view supported by the curved shape of many bridges. bridging necrosis is a manifestation of severe acute hepatitis but its distribution even within a single biopsy may be irregular. necrosis and inflammation linking bridges of confluent necrosis with subsequent collapse may be mistaken for the septa of chronic liver disease. in making the important distinction between them, the pathologist is often helped by stains for elastic tissue. unlike stains for collagens, these normally give negative results in the parenchyma, but elastic tissue accumulates as septa age. figure . acute hepatitis: bridging necrosis. the field is the same as that shown in fig. . . a stain for elastic fibres is positive in two portal tracts (p) but not in the intervening area of collapse. a necrotic bridge (arrow) is also negative. inset: this contrasts with an elastic fibre-rich septum in chronic liver disease. (needle biopsy, orcein.) p p recent collapse is therefore negative (fig. . ) , whereas old septa are positive. substantial amounts of elastic tissue take months or years to accumulate, but small amounts can be detected by sensitive methods such as victoria blue as early as or months after onset of hepatitis. in a minority of patients with acute viral hepatitis confluent necrosis extends throughout entire lobules or acini (panlobular or panacinar necrosis) or several adjacent ones (multilobular or multiacinar necrosis). this is a common feature in patients with fulminant hepatitis. the term 'massive necrosis' is also sometimes used, but can be misleading in so far as a needle biopsy specimen may not be representative of the liver as a whole and can lead to over-or under-estimation of the true extent of liver damage. this throws doubt on the usefulness of liver biopsy as a means of assessing prognosis in severe acute hepatitis. sometimes multilobular necrosis involves only the subcapsular zone, and a small needle specimen may then give a falsely pessimistic picture (see fig. . ) . in multilobular necrosis the parenchyma is replaced by collapsed stroma, inflammatory cells and activated macrophages (fig. . ) . around the surviving portal tracts, there are prominent duct-like structures, some of which probably represent proliferation of pluripotential progenitor cells - (see fig. . d) . late-onset hepatic failure is a term used for patients developing encephalopathy between and weeks after onset of symptoms. study of liver biopsies and explanted livers from these patients has shown a consistent pattern of map-like necrosis together with areas of nodular regeneration. periportal necrosis rather than the more usual perivenular necrosis is a feature in some patients with hepatitis a (below). there are more similarities than differences between hepatitis types a, b, c, d and e, but certain patterns are more common in one type than another and are described here. they do not allow the pathologist to identify the cause of the hepatitis on histological portal tracts (p) can be identified but the parenchyma has been replaced by inflammatory cells, necrotic debris and duct-like structures. (needle biopsy, h&e.) p p appearance alone. the picture may be confused by the presence of more than one virus, or by additional damage resulting from alcohol abuse. two main patterns are described, occurring separately or together. [ ] [ ] [ ] one is a histological picture of perivenular cholestasis with little liver-cell damage or inflammation, easily mistaken for other causes of cholestasis ( fig. . ) . the second is a hepatitis with periportal necrosis and a dense portal infiltrate which includes abundant, often aggregated plasma cells (fig. . ). these two patterns may be related, the cholestasis resulting from interruption of bile flow by the periportal necrosis. other patterns of hepatitis as described above are also found, but fulminant hepatitis with multilobular necrosis is rare. extensive microvesicular change of hepatocytes, previously described in hepatitis d infection, has been seen also in severe acute hepatitis a (fig. . ) . fibrin-ring granulomas have been reported. , a chronic course is very rare. the histological appearances are broadly similar to those of other forms of viral hepatitis. some of the differences reported in the literature may well reflect patient selection rather than features specific for hepatitis b virus (hbv) infection. however, lymphocytes and macrophages sometimes lie in close contact with hepatocytes (peripolesis) or even invaginate them deeply (emperipolesis), which probably reflects the immunological nature of the cell damage. in a comparative study, periportal inflammation tended to be more severe in acute hepatitis b than in hepatitis c. liver cells and their nuclei may show a moderate degree of pleomorphism. in most cases of acute hepatitis, the hepatitis b core and surface antigens (hbcag and hbsag) are either not demonstrable or very sparse, but in one study of livers infected with a hbv mutant, hbsag could be demonstrated by immunostaining following clinical recovery of acute hepatitis b, occult infection and mild histological abnormalities including portal inflammation, focal necrosis, apoptosis and fibrosis may persist for at least a decade. reactivation of a previously occult or quiescent chronic hepatitis b infection may cause changes closely resembling acute hepatitis. in such instances the presence of ( ) portal tract lymphoid aggregates, ( ) significant lymphoplasmacytic interface hepatitis, ( ) any evidence of fibrosis on connective tissue stains, and ( ) substantial positivity of hbsag in hepatocytes on immunostaining all point to the underlying chronicity of the process. usually the histological features of hepatitis c are those of any acute hepatitis, but two distinguishing features have been noted. first, there may be prominent infiltration of sinusoids by lymphocytes in the absence of severe liver-cell damage, giving rise to a picture reminiscent of infectious mononucleosis (fig. . ) . second, lymphoid follicles and bile-duct damage, features also associated with chronic hepatitis, may be seen within a few weeks or months of onset. there may be cholestasis. the common finding of steatosis in hepatitis c is discussed in chapter . fulminant hepatitis c is very rare in the western world but may be commoner in parts of asia. co-infection or superinfection with the hepatitis d virus (hdv) alters the course of type b hepatitis. it encourages chronicity and enhances severity, - except after liver transplantation. the antigen, hdag, can easily be demonstrated immunohistochemically in paraffin sections and is mainly found in hepatocyte nuclei (fig. . ) . these may have finely granular eosinophilic centres (so-called 'sanded' nuclei ). cytoplasmic and membraneassociated staining is also sometimes seen. severe acute hepatitis in a patient with markers of hbv infection may be due to superinfection by hdv of a chronic hbv carrier. in an outbreak of hdv infection among venezuelan indians, notable features included early small-droplet fatty change, sparse lymphocytes and abundant macrophages in the parenchyma and substantial portal infiltration. later in the attack, there was extensive necrosis and collapse. microvesicular fatty change and acidophilic necrosis of hepatocytes have been reported from colombia and north america. in non-immunosuppressed patients with current hdv infection, liver biopsy is likely to show substantial necrosis and inflammation. however, there are hdvendemic regions where the virus produces little significant disease. following liver transplantation, on the other hand, hdv without hbv is sometimes demonstrable in the absence of hepatitic changes, indicating that hdv can survive in the absence of hbv. it does not then appear, however, to be capable of causing liver damage. hepatitis e is the result of enteric infection by an rna virus with four genotypes. , the disease has caused epidemics in asia and has also been found in africa, north and south america and europe. in the western world, it is most often seen in travellers (fig. . ) but sporadic disease is sometimes due to local ingestion of virus-contaminated meat. infection does not appear to lead to chronic disease, but may cause severe decompensation of pre-existing chronic liver disease due to other causes. , the possibility of posttransplantation chronic hepatitis and cirrhosis due to use of hepatitis e virus-infected donor organs (liver, kidney, pancreas) has been raised in several reports. [ ] [ ] [ ] there is little detailed information on the pathological changes of hepatitis e virus infection in man. in a small number of patients studied, the appearances were like those of hepatitis a, with prominent cholestasis and a predominantly portal and periportal inflammatory infiltrate. portal lymphoid aggregates and periportal ductular reaction with neutrophilia at the edges of portal tracts are also described. histological cholestasis has been described in an elderly patient with a prolonged cholestatic clinical course. the liver of a pregnant woman with fatal hepatitis e showed little portal inflammation, much cholestasis and prominent phlebitis, and virus particles were seen in bile ductules by electron microscopy. the distinction of acute hepatitis from bile-duct obstruction rests mainly on the finding of typical hepatitic changes in the parenchyma. the portal tract oedema of duct obstruction is absent. drug-related hepatitis may be indistinguishable from viral hepatitis and should always be suspected if the cause of the hepatitis is in doubt. features more common in drug-induced than in viral hepatitis include sharply defined perivenular necrosis, granulomas, bile-duct damage, abundant neutrophils or eosinophils and a poorly developed portal inflammatory reaction. cholestasis may overshadow the hepatitic features. autoimmune hepatitis may have a clinically acute onset, histologically indistinguishable from viral hepatitis or alternatively with histological features of chronic disease. this is discussed more fully in chapter . in steatohepatitis there is usually conspicuous fatty change. mallory bodies may be present in ballooned hepatocytes and the infiltrate typically includes neutrophils. the key to the diagnosis is the presence of pericellular fibrosis in affected areas. the differentiation of acute from chronic hepatitis is briefly discussed under bridging necrosis in chapter . while the parenchymal changes predominate in acute hepatitis, especially in perivenular areas, portal and periportal changes predominate in chronic disease. the distinction is sometimes difficult to make, especially when extensive lobular changes are found during an exacerbation of chronic hepatitis or in reactivated chronic hepatitis b as described earlier. as far as can be deduced from the available evidence, most examples of hepatitis a, b and e are followed by complete or near-complete resolution and a return of the liver to normal. a chronic course is probably more common when hepatitis b is complicated by delta infection than otherwise, and in hepatitis c the risk of chronicity is high. even in patients whose hepatitis resolves, some residual changes may persist for many months after clinical recovery (figs . , . ). localised collapse, scarring and regeneration following severe hepatitis with bridging or panlobular necrosis sometimes produce a histological picture indistinguishable from cirrhosis. necrosis is usually severe. regenerative hyperplasia of surviving hepatocytes or progenitor cells may be seen. most individuals with hepatitis c virus infection develop chronic hepatitis. this has substantial impact on daily liver biopsy practice. chronic hepatitis also develops in many patients with hepatitis b. cirrhosis resulting from infection with a hepatitis virus almost always follows a period of chronic hepatitis, with repeated or continuous hepatocellular necrosis and regeneration. occasionally it may follow directly after a single episode of severe acute hepatitis. this may develop on the basis of cirrhosis in patients infected with hbv or hcv. occasionally, however, hepatocellular carcinoma is found in the absence of cirrhosis, usually after a prolonged period of chronic liver disease. fulminant non-a-g viral hepatitis leading to liver transplantation activation of hepatic stellate cells in liver tissue of patients with fulminant liver failure after treatment with bioartificial liver viral hepatitisrelated acute 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and pathologic features in patients with acute hepatitis b and c pathology of livers infected with 'silent' hepatitis b virus mutant talc liver long-term histologic and virologic outcomes of acute self-limited hepatitis b short incubation non-a, non-b hepatitis transmitted by factor viii concentrates in patients with congenital coagulation disorders liver biopsy features of acute hepatitis c compared with hepatitis a, b and non-a, non-b, non-c the role of hepatitis c virus in fulminant viral hepatitis in an area with endemic hepatitis a and b natural course of delta superinfection in chronic hepatitis b virusinfected patients: histopathologic study with multiple liver biopsies a histological study of hepatitis delta virus liver disease natural course of patients with chronic type b hepatitis following acute hepatitis delta virus superinfection sanded nuclei in delta patients influence of delta infection on severity of hepatitis b histologic studies of severe delta agent infection in 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virus infection presenting as a prolonged cholestatic jaundice virus-like particles in the liver of a patient with fulminant hepatitis and antibody to hepatitis e virus hepatocellular carcinoma without cirrhosis in the west: epidemiological factors and histopathology of the non-tumorous liver. groupe d'etude et de traitement du carcinome hepatocellulaire hepatitis e. an overview and recent advances in clinical and laboratory research apoptosis and necrosis in liver disease hepatitis b virus epidemiology, disease burden, treatment and current and emerging prevention and control measures structural biology of hepatitis c virus hepatitis e: an emerging awareness of an old disease history of viral hepatitis: a tale of dogmas and misinterpretations acute and chronic viral hepatitis key: cord- - tp i vh authors: hackert, volker h.; dukers-muijrers, nicole h. t. m.; hoebe, christian j. p. a. title: signs and symptoms do not predict, but may help rule out acute q fever in favour of other respiratory tract infections, and reduce antibiotics overuse in primary care date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: tp i vh background: from early , the dutch region of south limburg experienced a massive outbreak of q fever, overlapping with the influenza a(h n )pdm pandemic during the second half of the year and affecting approximately . % of a , population. acute q fever shares clinical features with other respiratory conditions. most symptomatic acute infections are characterized by mild symptoms, or an isolated febrile syndrome. pneumonia was present in a majority of hospitalized patients during the dutch – q fever epidemic. early empiric doxycycline, guided by signs and symptoms and patient history, should not be delayed awaiting laboratory confirmation, as it may shorten disease and prevent progression to focalized persistent q fever. we assessed signs’ and symptoms’ association with acute q fever to guide early empiric treatment in primary care patients. methods: in response to the outbreak, regional primary care physicians and hospital-based medical specialists tested a total of subjects for q fever. testing activity was bimodal, a first “wave” lasting from march to december , followed by a second “wave” which lasted into and coincided with peak pandemic influenza activity. we approached all notified acute q fever cases and a random sample of q fever negative individuals for signs and symptoms of disease. using data from / ( . %) q fever positive and / ( . %) q fever negative respondents from wave , we built symptom-based models predictive of q-fever outcome, validated against subsets of data from wave and wave . results: our models had poor to moderate auc scores ( . to . %), with low positive ( . – . %), but high negative predictive values ( . – . %). male sex, fever, and pneumonia were strong positive predictors, while cough was a strong negative predictor of acute q fever in these models. conclusion: whereas signs and symptoms of disease do not appear to predict acute q fever, they may help rule it out in favour of other respiratory conditions, prompting a delayed or non-prescribing approach instead of early empiric doxycycline in primary care patients with non-severe presentations. signs and symptoms thus may help reduce the overuse of antibiotics in primary care during and following outbreaks of q fever. from march , south limburg, the southernmost region of the netherlands, experienced a massive outbreak of human q fever related to an abortion storm on a local dairy-goat farm. laboratory-confirmed symptomatic human q-fever cases were first reported in april, peaked in may, and then steadily declined over subsequent months. culling of infected goats took place around the turn of the year. by april , no more new cases were reported to the regional public health service (phs), and the number of notified human cases reported to the regional phs had totalled , whereas the number of infections was estimated to run into thousands [ ] . a majority of acute q fever infections are understood to be asymptomatic or only mildly symptomatic. symptomatic patients usually present with a febrile syndrome or flu-like illness frequently said to be associated with myalgia and headache. during the dutch q fever epidemic, which lasted from to , pneumonia was present in as many as % of hospitalized patients. although most cases of acute q fever are self-limiting, early antibiotic treatment with doxycycline within the first days of symptoms may shorten duration of disease, and may prevent progression to persistent focalized infection, commonly referred to as chronic q fever, in cases with underlying risk factors, including vascular and valvular anomalies [ , ] . in patients with known valvular heart disease, combining doxycycline with hydroxychloroquine has been shown to prevent progression to q fever endocarditis [ , ] . definitive diagnosis usually relies on laboratory testing. while polymerase chain reaction (pcr) may provide timely outcomes, serological assays still are the mainstay of laboratory testing, resulting in diagnostic delay and foregone or inappropriate treatment [ ] . during the dutch epidemic of q fever, general practitioners (gp's) with experience in treating q fever patients tended to start empiric antibiotic therapy ahead of laboratory confirmation, which had a median delay of days from onset of illness in [ , ] . while doxycycline was the most commonly prescribed initial antibiotic, a substantial proportion of subjects were treated with a penicillin, which is considered to be ineffective in q fever [ ] . a complicating factor in the diagnostic workup of cases was the influenza a(h n )pdm pandemic which overlapped with the regional outbreak for several months during the second half of the year. several studies have assessed the diagnostic potential of signs and symptoms in respiratory disease, including influenza and q fever [ ] [ ] [ ] [ ] . however, evidence regarding the predictive usefulness of signs and symptoms in patients with suspected q fever is scarce, and has been limited to hospital settings. a dutch study performed during the - q fever epidemic in the netherlands, for example, found that signs and symptoms did not differentiate between acute q fever and other respiratory infections in hospitalized patients [ ] . however, it is the primary care setting where signs and symptoms of disease are essential in the initial diagnostic workup and in guiding early clinical decision-making. our study, which used data from a cohort of subjects a majority of whom were tested by general practitioners, aimed to assess whether signs and symptoms could support decision-making in primary care. specifically, we assessed whether signs and symptoms could accurately identify acute q fever in suspect cases prior to laboratory confirmation, or help rule out the diagnosis in favour of other respiratory infections where, depending on national guidelines, treatment with amoxicillin as a first-line antibiotic or a delayed or non-prescribing approach would be considered more appropriate. the study area was the catchment area of one of the largest dutch general hospitals, located in south limburg, netherlands ( km , municipalities, , inhabitants). in march , the regional food and consumer product safety authority notified the south limburg phs of a large dairy-goat farm where out of pregnant goats had aborted due to laboratory-confirmed q fever. the study period was defined by the time of veterinary notification (march ) and the time when the outbreak source had been eliminated through culling of infected goats and vaccination of remaining goat populations, and new community cases were no longer reported (april ). we performed a retrospective case-control study assessing the association of acute q fever case status with signs and symptoms of disease in a sample of questionnaire respondents from the cohort of all individuals tested for acute q fever by gp's or hospital-based medical specialists in the period from march through april (n = ). medical specialists requesting tests were from a variety of fields, including internal medicine, infectious disease, or respiratory medicine. all notifiable community cases (n = ) were reported to the regional phs by the affiliated regional testing laboratory. disease onset in community cases was physicianreported. the testing laboratory also provided data on all non-notifiable q fever negative individuals tested in the study period, including date of birth, gender, zip code as a proxy for residential address, name and address of gp, testing dates, and testing results. promptly following notification, all notified community cases were approached with a questionnaire assessing the presence or absence of individual presenting signs and symptoms of disease preceding testing, underlying medical conditions, and risk exposure activities, among others. response in this group was . %( / ). among the subjects who had tested negative (non-notifiable controls), a random selection of individuals were approached with the same questionnaire via their gp's (response: . %( / )). the entire cohort of subjects was tested for igg-and igmtype antibodies to phase-i and phase-ii c. burnetii antigen by serion elisa classic, according to manufacturer's instructions (serion elisa classic, institut virion\serion gmbh, würzburg, germany). elisa-positive specimens were subjected to confirmation by indirect immunofluorescent antibody assay (ifa) (c. burnetii ifa igm/igg test kit, fuller laboratories, fullerton, california). pcr was routinely performed on all elisa-negative samples. the presence of phase-ii igm antibodies to c. burnetii (absorbance > % above extinction of the cut-off control) in a single serum sample, confirmed by ifa, or the presence of c. burnetii dna in pcr (cycle threshold ≤ ) was considered diagnostic of acute q fever [ ] [ ] [ ] . overall, . % ( / ) of all patients tested were confirmed with a diagnosis of acute q fever by serology or pcr. testing activity followed a bimodal distribution over time. a larger first testing wave from march to december (wave ) was followed by a second smaller one from december through april (wave ) (fig. ) . the larger first wave, including subjects tested from week (march ) until week (december ), contained % of all tested patients, with a q fever positive rate of %, thus yielding % of all notifiable patients with a laboratory-confirmed diagnosis of acute q fever in the study period. by contrast, the second wave, although it counted more than a quarter of all tested patients, had a positive rate of only % and identified just % of all notified patients. characteristics of tested subjects are summarized in table . statistical analyses were performed using spss statistics . (ibm corporation, new york, usa). for derivation and validation of our symptom-based prediction, we fig. weekly counts of all individuals tested for q-fever by south limburg gp's and hospital-based medical specialists (n = ), along with weekly counts of notified q-fever cases (by gp-reported week of disease onset, n = ) used questionnaire data from all adult questionnaire recipients with a complete questionnaire response tested during wave , i.e., all questionnaire recipients from the age of years who had been tested in the weeks before week and had answered all questions about presenting signs and symptoms of disease which preceded testing. of all patients tested during wave , ( . %) had received the questionnaire, with response from questionnaire recipients (response rate . %), and a complete response from recipients (complete response rate . %). children and adolescents under the age of were excluded since the association of signs and symptoms with q fever in this age group are known to be less clear-cut than in adults [ , ] . a holdout sample of all subjects tested during wave (i.e., the immediate post-outbreak phase) with a complete questionnaire response was used for additional validation of the models derived from our wave data. of all patients tested during wave , ( . %) had received the questionnaire, with response from questionnaire recipients (response rate . %), and complete response from recipients (complete response rate . %). characteristics of questionnaire respondents are summarized in table . we first assessed association of q fever status with sex, age, smoking habits, test ordered by gp versus (hospital-based) medical specialist, and presence or absence of individual presenting signs and symptoms of disease in all complete questionnaire respondents tested during wave , using univariable logistic regression. for a full list of signs and symptoms assessed by our questionnaire refer to table . as a next step, we assessed associations with q fever status, entering the full set of variables into stepwise backward multivariable logistic regression, a procedure that eliminates statistically non-significant variables along the way. variables that were statistically significantly (p < . ) associated with q fever outcome in univariable or multivariable regression were selected for inclusion in our prediction models (refer to next paragraph). sex, age, active smoking habits, and test ordered by gp versus medical specialist were selected as potential predictors regardless of their association with outcome in univariable or multivariable regression in the steps described above. distance of residential address from the outbreak farm was not included as a candidate predictor, since this information would usually be unavailable to physicians at the time when patients present to their office, or may be unknown altogether in situations where no outbreak source has (yet) been identified. the entire dataset of complete questionnaire respondents tested during wave was randomly split into four subsets, each including roughly % of respondents. one subset was set aside for validation (henceforth referred to as the validation subset), while data of the remaining three subsets combined (including roughly % of the respondents, henceforth referred to as the prediction subset) were used for derivation of our prediction model. to build the prediction model, we used the prediction subset, entering all variables selected according to the procedure described in the previous paragraph into backward stepwise logistic regression. coefficients obtained from the variables that were statistically significantly associated with q fever outcome (p < . ) were used to calculate a sum score. predictive performance of the model was then assessed by applying the score to the validation subset to determine area under the curve (auc) of the receiver operator curve (roc), sensitivity and specificity (based on cut-points specific to the model, calculated according to the youden index), and the model's positive (ppv) and negative predictive value (npv) (based on an estimated regional seroprevalence of . %, derived from comparison of two regional population samples, one pre-outbreak dating from , and the second one post-outbreak dating from ) [ , ] . for additional validation, the same score was applied to the immediate post-outbreak holdout sample from wave , again using auc to assess predictive performance of the model. the entire process was repeated for the remaining three subsets, resulting in four prediction models, each applied once to its specific validation subset from wave , and once to the holdout sample from wave . finally, we compared models in terms of their auc's of the roc, assessing statistical differences between auc's using a bivariate approach [ , ] . uni-and multivariable associations of acute q fever outcome with potential predictors univariable associations of q fever status with sex, age, smoking habits, test ordered by gp versus (hospital-based) medical specialist, and presence or absence of individual presenting signs and symptoms of disease in all complete questionnaire respondents (q fever positive n = , q fever negative n = ) tested during wave , based on univariable logistic regression, are summarized in table . statistically significant multivariable associations for the same set of complete questionnaire respondents are summarized in table , eliminating non-significant associations through backward stepwise logistic regression. prediction models derived from the four prediction subsets (model through ) table shows sets of statistically significant predictors, referred to as model through , derived from backward stepwise logistic regression for the four prediction subsets including roughly % of the respondents each. coefficient, p value, standard error (se), and odds ratio (or) are included for each predictor, in addition to relevant model statistics. predictive performance of model through figure summarizes performance characteristics of the four prediction models, based on each model's coefficient score applied to the corresponding validation subset from wave (left column), and to the holdout sample from wave (right column). auc's ranged from . to . from least to best performing model, generally considered to be poor to moderate in terms of predictive accuracy. sensitivity of the models ranged between . and . %, with specificities between . and . %, ppv's between . and . %, and npv's between . and . %. the difference between model performance in terms of auc was statistically significant between the leastand best-performing model applied to their corresponding validation subsets (model versus model , p = . ), but not between the least-and best-performing model applied to the holdout sample (model versus model , p = . ). comparing performance of each model on the validation subset versus the holdout sample (rows in fig. ) showed no statistically significant differences either. given the poor to moderate performance of our prediction models, our study suggests that signs and symptoms of disease do not accurately predict acute human q fever in gp patients, confirming findings from a dutch study in hospitalized patients [ ] . however, signs and symptoms may be useful in ruling out acute q fever in favour of other acute lower respiratory tract infections. this is especially relevant in cases where pneumonia is not suspected and a non-prescribing or delayed prescribing approach would seem more appropriate, helping reduce the overuse of antibiotics. in the cohort of patients tested in our region, this would have been particularly relevant in the immediate post-outbreak phase where the number of tests for acute human q fever remained high but the proportion of seropositive cases was very low ( %), and prevalence of pneumonia was also low ( %). even during the outbreak phase, only . % of tested individuals were q fever positive, and ruling out acute q fever by symptoms would likely have contributed to a reduction in antibiotic overuse. male sex, fever, and pneumonia were positive predictors of acute q fever across all four of our models, in accordance with other studies [ , ] . cough was a negative predictor in three models, suggesting that cough as a symptom may be useful in ruling out q fever in suspected cases. cough is considered a common symptom in upper respiratory tract infections. its presence, according to our findings, may point to respiratory conditions other than q fever [ ] . specifically, cough has been described as a symptom suggestive of influenza, rather than, for example, common cold [ ] . overall, in our sample cough was the most prevalent symptomsecond only to flu-like illnessin questionnaire respondents from the second wave, both in q fever positive and q fever negative subjects. this, combined with the low rate of q fever positive findings during the second wave, may suggest that the rise in q fever testing activity by gp's and medical specialists during the second half of and the early months of mayat least to some degreehave resulted from patients presenting with respiratory symptoms due to increasing pandemic influenza a(h n )pdm activity in that period. moreover, due to long persistence of anti-coxiella phase ii igm following infection, some of the subjects who tested positive during the second wave may have been misclassified as acute q fever. while abdominal pain was a negative predictor of acute q fever across all four models, gastrointestinal symptoms such as abdominal pain and diarrhoea were much less prevalent than cough in both q fever positive and q fever negative subjects from both waves, and the nature of the observed negative association of abdominal pain with q fever remains unclear. studies on the gastrointestinal symptoms in patients with influenza report prevalence rates ranging from . to . % for influenza a(h n ) infections, and . to . % for influenza a(h n )pdm infections, suggesting a possible association of gastrointestinal symptoms in our study with the swine flu [ ] . use of signs and symptoms of disease to rule out acute q fever would be most appropriate in patients with nonsevere lower respiratory tract infections, i.e., in cases where pneumonia is not suspected clinically. in such cases, use of antibiotics has been shown to provide little benefit in primary care, both overall and in patients aged years and above, but may cause slight harms [ , ] . nevertheless, inappropriate use of antibiotics remains common in this population, as a study performed in , outpatients was recently able to show [ ] . in a subgroup of patients with laboratory-confirmed influenza, in whom no pneumonia had been diagnosed, ( %) were prescribed an antibiotic. given the low yield of q fever positives in wave of our study, we assume that q fever testing during wave was in large part instigated by patients presenting with unspecific, but most likely influenza-related, symptoms. although we have no data on rates of antibiotic prescriptions in this group, the percentage of subjects receiving inappropriate empiric doxycycline or other antibiotics may have been even higher than in aforementioned study. therefore, under circumstances where outbreaks of q fever overlap with other respiratory conditions, symptom-based prediction may deliver the greatest gain in terms of reducing antibiotic overuse. in cases with clinical suspicion of pneumonia, however, the benefit of antibiotics would outweigh potential harms. for instance, several national guidelines recommend doxycycline as a second or first line drug for empiric treatment of community-acquired pneumonia (cap), where it is generally considered to be safe and effective [ ] [ ] [ ] [ ] [ ] . in cases of lower respiratory tract infections where acute q fever is included in the differential diagnosis and pneumonia is suspected, use of doxycycline would thus seem an appropriate choice in an outpatient setting. the combination of doxycycline and hydroxychloroquine should be considered in patients with known valvular heart disease to prevent evolution to q fever endocarditis (but is not recommended in patients with increased risk of acute q fever endocarditis as revealed by high igg anticardiolipin levels included in routine testing in some countries) [ , , ] . local antimicrobial resistance patterns are an important consideration in the choice of empirical treatment. while doxycycline is generally considered to be highly effective against atypical pathogens, including c. burnetii, doxycycline resistance is becoming more common in streptococcus pneumoniae, particularly in isolates with reduced penicillin susceptibility. although overall frequency of doxycycline resistance in s. pneumoniae in was %, rates vary widely geographically and over time, ranging from % to more than %, and more than % in penicillin-resistant strains, potentially limiting the use of doxycycline for more severe pneumococcal infections [ ] [ ] [ ] [ ] . in our study, the prevalence of pneumonia in subjects tested during wave was % overall, but % in q fever positive subjects, which is higher than the % rate found in q fever positive patients from a large -year cohort of patients with q fever from the french national reference center for q fever [ ] . nevertheless, a huge majority of patients in our study had no suspicion of pneumonia and would have had potential benefit from symptom-based exclusion of q fever. predictive values are greatly impacted by prevalence of the disease in the base population. positive predictive values (ppv) tend to be low in situations where prevalence in the base population is low, as was the case in our study, where post-outbreak seroprevalence of prior exposure to c. burnetii in the base population was estimated a mere . % [ ] . with ppv ranging between . and . %, mirrored by low areas under the receiver (see figure on previous page.) fig. predictive performance of the four prediction models tested on their corresponding validation subsets from wave (left column) and the holdout sample from wave (right column). (legend). at cut-point calculated according to youden index based on cut-point calculated according to youden index and an estimated regional prevalence of . % operator curves, our models had no use as a diagnostic tool for acute q fever. conversely, negative predictive values (npv) tend to be high under circumstances of low disease prevalence. with npv ranging between . to . %, our models were able to rule out the presence of acute q fever with a relatively high degree of confidence. nevertheless, decisions favouring a delayed or non-prescribing approach should ideally be corroborated by information from patient history, including self-reported exposures to farms, farm animals and farm animal products, and other clinical findings supporting such approach. in other contexts, for example in a well-circumscribed population of patients with high-risk exposure to a known source, prevalence may be (much) higher, with resulting decline in npv. to the best of our knowledge, ours is the first study to use post-outbreak data to validate prediction models for acute q fever derived from outbreak data, thus enhancing the generalisability and robustness of our findings. moreover, our study is first to assess the predictive potential of signs and symptoms for the diagnosis of acute q fever in a large population of subjects most of whom were primary care patients. other studies attempting to predict q fever by signs and symptoms, including a retrospective case-control study from the netherlands, were performed in hospital settings. the dutch study reported that clinical signs and symptoms were not helpful in differentiating adult hospital-referred patients with acute q fever from a hospital-referred control group [ ] . a second study aimed to predict q fever in patients presenting with community-acquired pneumonia to the hospital. the only symptom independently associated with q fever in this study was headache. the prognostic score derived from multivariable logistic regression included male sex, age - years, a low leukocyte count and a high c-reactive protein (crp) level, along with headache, as predictors of q fever pneumonia [ ] . a third study attempted to predict acute q fever in febrile patients from rural kenya, based on parameters including a range of clinical signs and symptoms. the study identified acute lower respiratory infection, abdominal pain, diarrhoea and a history of fever lasting > days as independent significant positive predictors of acute q fever. a prediction score derived from a modelling approach similar to ours was reported to reliably identify acute q fever in febrile patients with undifferentiated illness [ ] . our study had a number of limitations. selection of subjects for inclusion in our study was based on laboratory q fever testing outcomes rather than random sampling, with a potential for selection bias, e.g., due to variations in diagnostic strategies between individual physicians. laboratory confirmed cases of acute q fever and patients who were q fever negative were both selected based on signs and symptoms leading to addition of q fever in the differential diagnosis, possibly resulting in some weakening of the association under study. our laboratory data were strictly limited to outcomes of q fever testing, precluding us from assessing signs and symptoms in relation to possible alternative outcomes. as mentioned above, misclassification of positive laboratory results as acute q fever infection cannot be entirely ruled out, since phase-ii igm antibodies to c. burnetii, which at the time of the outbreak were considered to be reliable markers of acute q fever infection, have been shown to persist for longer periods in individual patients, thus complicating the differentiation between past q fever infections and acute respiratory infections with different aetiologies [ ] . validation and testing of our models were performed on samples from the same base population, potentially compromising generalisability of our findings. the lack of external validation of our models, however, may have partly been offset by the fact that we performed validation against a holdout sample, i.e., data from the second wave of q fever testing. testing during the second wave took place in what may be described as an immediate post-outbreak transition period where q fever was increasingly replaced by other aetiologies of clinical respiratory disease, thus distinguishing the population of individuals tested during the second wave from those included in the first wave. splitting our first-wave dataset for internal validation may have resulted in loss of power, and may have contributed to discrepancies between our four models in terms of predictors included in each model. nevertheless, all four models showed poor to moderate performance in terms of auc, but performed equally well in terms of their negative predictive value, suggesting that signs and symptoms of disease may be useful for symptom-based exclusion of acute q fever. whereas the youden index is a commonly used method for cut-point selection in roc analysis, there are several other approaches, whose application may have led to different results [ ] . our study suggests that signs and symptoms of disease, considered in combination with age, sex and active smoking habits, do not accurately predict q fever. however, presence of cough and gastrointestinal symptoms may point to different, possibly viral respiratory aetiologies, and help rule out acute fever in the absence suspected pneumonia and fever. in these cases, physicians in primary care may favour a delayed or non-prescribing approach if no known risk factors for progression to persistent focalized (or chronic) q fever (e.g., heart valve or vascular anomalies) are present. a history of exposure to farms, single-point source outbreak with high attack rates and massive numbers of undetected infections across an entire region from q fever to coxiella burnetii infection: a paradigm 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what do we know? amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis by bacterial and viral aetiology amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: a -country, randomised, placebo-controlled trial outpatient antibiotic prescribing for acute respiratory infections during influenza seasons bts guidelines for the management of community acquired pneumonia in adults: update diagnosis and treatment of adults with community-acquired pneumonia recommendations and guidelines for the treatment of pneumonia in taiwan british thoracic society community acquired pneumonia guideline and the nice pneumonia guideline: how they fit together nice guidelines to family doctors on diagnosis of pneumonia antiphospholipid antibody syndrome with valvular vegetations in acute q fever antimicrobial susceptibility/ resistance of streptococcus pneumoniae distribution of serotypes and patterns of antimicrobial resistance among commensal streptococcus pneumoniae in nine european countries in: mandell, douglas, and bennett's principles and practice of infectious diseases kucers the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs clinical features and complications of coxiella burnetii infections from the french national reference center for q fever evaluation of commonly used serological tests for detection of coxiella burnetii antibodies in well-defined acute and follow-up sera defining an optimal cut-point value in roc analysis: an alternative approach lyophilization to improve the sensitivity of qpcr for bacterial dna detection in serum: the q fever paradigm publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank sander van kuijk, clinical epidemiologist at the department of clinical epidemiology and medical technology assessment at maastricht university / mumc+, for statistical advice, review of our manuscript, and valuable suggestions for improvement. we also thank public health nurses rick boesten, elleke leclercq, and hans frantzen, and communicable disease consultant henriëtte ter waarbeek of phs south limburg for their contribution to data logistics. we wish to thank medical microbiologist frans stals, zuyderland medical centre, for providing laboratory data. farm animals or farm animal products may increase the likelihood of acute q fever. it should be noted that pcr testing, whose sensitivity may be enhanced by lyophilisation, may shorten diagnostic delay and support early decision-making [ ] . we recommend further validation of our findings in different larger independent cohorts. authors' contributions vh conceptualised and designed the study, collected, analysed and interpreted the patient data, and wrote the manuscript. nd and ch were major contributors in designing and conceptualising the study, and in writing the manuscript. all authors read and approved the final manuscript. this work was supported by the netherlands organization for health research and development (zonmw) (grant number - - - ). the funder had no role in no role in the design of the study and collection, analysis, or interpretation of data nor in writing the manuscript. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. this study was ethically approved by the medical ethics committee of the maastricht university medical centre (number ). no administrative permissions were required to access the raw data used in this study. all data were de-identified prior to analysis. not applicable. the authors declare that they have no competing interests.received: march accepted: september key: cord- -nmjwzk e authors: bent, stephen; saint, sanjay; vittinghoff, eric; grady, deborah title: antibiotics in acute bronchitis: a meta-analysis date: - - journal: am j med doi: . /s - ( ) - sha: doc_id: cord_uid: nmjwzk e purpose: most patients with acute bronchitis who seek medical care are treated with antibiotics, although the effectiveness of this intervention is uncertain. we performed a meta-analysis of randomized, controlled trials to estimate the effectiveness of antibiotics in the treatment of acute bronchitis. subjects and methods: english-language studies published january to april were retrieved using medline, bibliographies, and consultation with experts. only randomized trials that enrolled otherwise healthy patients with a diagnosis of acute bronchitis, used an antibiotic in the treatment group and a placebo in the control group, and provided sufficient data to calculate an effect size were included. results: we identified eight randomized controlled trials that satisfied all inclusion criteria. these studies used one of three antibiotics (erythromycin, doxycycline, trimethoprim/sulfamethoxazole). the use of antibiotics decreased the duration of cough and sputum production by approximately one-half day (summary effect size . ; % ci, . to . ). for specific symptoms, there were nonsignificant trends favoring the use of antibiotics: a decrease of . days of purulent sputum ( % ci, − . to . ), a decrease of . days of cough ( % ci, − . to . ), and a decrease of . days lost from work ( % ci, − . to . ). conclusion: this meta-analysis suggests a small benefit from the use of the antibiotics erythromycin, doxycycline, or trimethoprim/sulfamethoxazole in the treatment of acute bronchitis in otherwise healthy patients. as this small benefit must be weighed against the risk of side effects and the societal cost of increasing antibiotic resistance, we believe that the use of antibiotics is not justified in these patients. stephen bent, md, sanjay saint, md, mph, eric vittinghoff, phd, deborah grady, md, mph purpose: most patients with acute bronchitis who seek medical care are treated with antibiotics, although the effectiveness of this intervention is uncertain. we performed a meta-analysis of randomized, controlled trials to estimate the effectiveness of antibiotics in the treatment of acute bronchitis. subjects and methods: english-language studies published january to april were retrieved using medline, bibliographies, and consultation with experts. only randomized trials that enrolled otherwise healthy patients with a diagnosis of acute bronchitis, used an antibiotic in the treatment group and a placebo in the control group, and provided sufficient data to calculate an effect size were included. results: we identified eight randomized controlled trials that satisfied all inclusion criteria. these studies used one of three antibiotics (erythromycin, doxycycline, trimethoprim/ sulfamethoxazole). the use of antibiotics decreased the dura-tion of cough and sputum production by approximately onehalf day (summary effect size . ; % ci, . to . ). for specific symptoms, there were nonsignificant trends favoring the use of antibiotics: a decrease of . days of purulent sputum ( % ci, Ϫ . to . ), a decrease of . days of cough ( % ci, Ϫ . to . ), and a decrease of . days lost from work ( % ci, Ϫ . to . ). conclusion: this meta-analysis suggests a small benefit from the use of the antibiotics erythromycin, doxycycline, or trimethoprim/sulfamethoxazole in the treatment of acute bronchitis in otherwise healthy patients. as this small benefit must be weighed against the risk of side effects and the societal cost of increasing antibiotic resistance, we believe that the use of antibiotics is not justified in these patients. am j med. ; : - . ᭧ by excerpta medica, inc. a cute bronchitis is a common clinical disorder characterized by the acute onset of cough and sputum production in a patient with no history of chronic pulmonary disease and no evidence of pneumonia or sinusitis. this definition excludes patients with acute exacerbation of underlying pulmonary disorders, in whom a previous meta-analysis found that antibiotic use led to a small, statistically significant benefit ( ) . the effectiveness of antibiotics in patients with acute bronchitis remains uncertain, although the disorder is the tenth most common diagnosis seen by physicians in the united states, accounting for million office visits annually ( ) . the etiology of acute bronchitis is unclear. most studies have identified viruses (adenovirus, rhinovirus, coronavirus, influenza, parainfluenza, respiratory syncytial virus, and coxsackievirus) as the cause in the majority of patients ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . atypical bacteria, including mycoplasma pneumoniae, chlamydia pneumoniae, and legionella species, have been reported to cause % to % of cases of acute bronchitis ( ) ( ) ( ) , and typical bacteria (streptococcus pneumoniae, haemophilus influenzae, branhamella catarrhalis) have been recovered from the sputum in % to % of patients ( , , ) . however, the importance of positive bacterial cultures from sputum is not known, because many of these pathogens are part of the oropharyngeal flora ( , , - ) . recent evidence suggests that some bronchitis in adults may be caused by bordetella pertussis and parapertussis, which are better known for their role in causing whooping cough in children ( ) . the majority of patients diagnosed with acute bronchitis in the united states are treated with antibiotics ( - ) . in a nationwide survey of Ͼ , physicians, gonzales et al ( ) found that two-thirds of patients without underlying lung disease who were diagnosed with acute bronchitis were treated with antibiotics. in another survey, % of children with a diagnosis of acute bronchitis were given a prescription for antibiotics ( ) . although antibiotics are often used in the treatment of acute bronchitis, their efficacy is uncertain. clinical trials examining this issue have yielded conflicting results ( - ) , and qualitative reviews are similarly inconclusive ( , , , , ) . widespread antibiotic use carries a substantial cost, puts patients at risk for medication side effects, and promotes antibiotic resistance. to clarify the optimal treatment of this disorder, we performed a meta-analysis to determine whether antibiotics were beneficial in patients with acute bronchitis. using explicit inclusion and exclusion criteria and accepted quantitative methods ( - ) , a meta-analysis provides summary estimates of effectiveness that may clarify the disparate results of previous trials ( ) . the literature review began with a computerized medline search using the subheading "bronchitis, drug therapy" and the term "xs acute disease," and included english-language articles published between january and april . the reference lists of all retrieved articles were scanned, and experts were consulted to identify potential trials not identified in the medline search. inclusion criteria consisted of the following: randomized trials using an antibiotic in the treatment group and a placebo in the control group; subjects with acute bronchitis, no history of chronic lung disease, and pneumonia excluded by chest radiograph or clinical exam; therapy for at least days; and the presentation of sufficient data to calculate the difference in efficacy between the treatment and the placebo as a continuous variable. studies were excluded if they were nonexperimental in design or if they compared one antibiotic with another without a placebo arm. for each study, two authors independently abstracted the author, journal title, year of publication, sample size, average age of subjects, antibiotic regimen used, major outcome measure(s), and the inclusion and exclusion criteria. discrepancies in the abstracted data were resolved by consensus. the eight eligible studies did not use a common outcome measure. when several outcomes were available from one study, we chose "days of sputum production" as the main outcome, because this symptom is most characteristic of the disease ( ) . for studies that did not include the outcome "days of sputum production," we chose the outcome in the study that was the most clinically similar (sputum production score, cough amount score). we transformed each outcome into units of standard deviation, thus giving a comparable effect size for different outcomes. the study-specific effect size was the difference in the mean outcome for the antibiotic and placebo groups, divided by the pooled standard deviation of the outcome measure in that study. the summary effect size across studies was calculated as a weighted average of the study-specific effect sizes, with weights equal to the inverse of the estimated variance. the significance of the summary effect size, standardized by its estimated variance, was assessed by comparing it with the standard normal distribution. a test for heterogeneity was calculated by comparing the weighted average of the squared differences between summary and study-specific effect sizes with an appropriate x distribution, with the same weights being used. these calculations used standard formulas ( ) , which assume that the outcomes are normally distributed and the sample sizes are approximately equal in the antibiotic and placebo groups. we also calculated summary mean differences for all outcomes reported by four or more studies. the summary measure was the weighted average of the difference between the antibiotic and placebo groups in the mean outcome measure for each study. weights were given by the inverse of the variance of each mean difference, estimated using the pooled standard deviation for each study. tests of the significance of the observed summary mean differences and of heterogeneity were also performed ( ) . we examined the potential for publication bias using the correlation between the number of subjects and the effect size in each study. if small studies with negative results were less likely to be published, then the correlation between number of subjects and effect size would be large. if there was not any publication bias, then there should not be a significant correlation between the number of subjects and the effect size. our search identified reports, including randomized, placebo-controlled trials of antibiotics for the treatment of acute bronchitis ( - ) . two ( , ) of these studies had to be excluded because insufficient data were presented in the original articles, and attempts to retrieve the necessary data from the authors were unsuccessful. the remaining eight trials, all of which used one of three antibiotics (erythromycin, doxycycline, trimethoprim/ sulfamethoxazole), were included in the meta-analysis. reasons for exclusion are listed in table . the characteristics of the randomized controlled trials, including the two that were excluded because of insufficient data, are shown in table . the overall summary effect size was . ( % ci, . to . ) indicating a small (about one-fifth of a standard deviation), statistically significant benefit from the use of antibiotics (figure) , equivalent to approximately one half day less of cough and sputum production. three outcomes were reported by at least four studies (table ) . although each of these results favor antibiotics, none was statistically significant. for days of purulent days lost from work. the effect of antibiotic treatment on days lost from work was very small, and unlike days of cough and sputum production, did not approach statistical significance. a test for heterogeneity was not significant for the overall summary effect size (p ϭ . ) or for days of sputum production (p ϭ . ), suggesting that these results are homogenous and can be combined. a test for heterogeneity was significant for the summary mean difference for days lost from work (p ϭ . ) and days of cough * result is the mean in the antibiotic group minus the mean in the placebo group for the main outcome measure. a positive result indicates a benefit from antibiotics. a negative result indicates a benefit from placebo. † effect size is the difference between the mean outcome in the antibiotic and placebo groups divided by the pooled standard deviation. ‡ these studies did not provide data that allowed calculation of a confidence interval or a continuous outcome measure, and therefore could not be included in the overall summary effect size. § cough amount score was a patient-reported score on a severity scale of to . ¶ sputum production score was a patient-reported score on a severity scale of to . # sputum production score was a patient-reported score on a severity scale of to . ci ϭ confidence interval. effect sizes and summary overall estimate. effect size is the difference between the mean outcome in the antibiotic and placebo groups divided by the pooled standard deviation. horizontal lines denote % confidence intervals. dots represent point estimates. randomized controlled trials evaluating the efficacy of antibiotics in acute bronchitis have had inconsistent results. of the eight trials included in our meta-analysis, four showed no benefit from the use of antibiotics ( ) ( ) ( ) ) , whereas four reported a benefit ( , , , ) . part of the discrepancy may be because studies used different outcome measures, some of which are of uncertain clinical importance. for example, the outcome measures in one trial that reported a statistically significant benefit from antibiotics included a reduction in mean temperature from . Њc to . Њc and a reduction in the use of antihistamines ( ) . because the published trials used several outcome measures, we used the standardized effect size, expressed in units of standard deviation, to quantitate the overall effect of antibiotic therapy. we chose the outcome that is most characteristic of acute bronchitis (days of sputum production) in the six studies where it was available, and we used the most similar outcome in the two other studies (cough amount score, sputum production score). we found a small, statistically significant benefit to the use of antibiotics in patients with acute bronchitis approximately equal to one-fifth of a standard deviation unit. to relate the observed benefit in the summary effect size to clinical variables, we also calculated summary mean differences for all outcomes that were reported by at least four trials (duration of sputum production, duration of cough, and days lost from work), all of which showed small, nonsignificant trends favoring the use of antibiotics. our meta-analysis suggests that patients with acute bronchitis who are treated with antibiotics have a reduction in the duration of cough and sputum production of approximately one half day. our results should be interpreted with caution. as with all meta-analyses, we assumed that the individual trials are sufficiently similar to provide a meaningful summary. the studies did have several important differences. they took place in different geographic locations, used three different antibiotics (erythromycin, doxycycline, trimethoprim/sulfamethoxazole), and were conducted during a -year period. however, despite these differences, statistical tests for heterogeneity did not show differences between studies for the main outcome, or for the outcome of sputum production. although different antibiotics were used, all groups were treated for at least days, and the spectrum of organisms covered by the various antibiotics was similar. we identified randomized controlled trials in our literature review. results from two of these trials could not be included because insufficient data were reported ( , ) . both of these trials showed no benefit from the use of antibiotics. thus, their exclusion tended to bias our results in favor of antibiotics. in addition, the summary effect size may have been overestimated if publication bias made it more likely that studies showing benefit were published, whereas those showing no benefit were not. if there was publication bias, small studies with negative findings should have been unlikely to be published, whereas small studies with positive findings should have been more likely to be published, leading to a correlation between study size and effect size. we found no such correlation. we used similar methodology to an earlier meta-analysis that examined the effect of antibiotics in patients with acute exacerbations of chronic obstructive pulmonary disease ( ) . that study reported a summary effect size of . ( % ci, . to . ), also indicating a small, statistically significant benefit from the use of antibiotics. patients who were treated with antibiotics had a modest improvement in peak expiratory flow of approximately l/min compared with those treated with placebo. although the magnitude of benefit from antibiotic treatment in that meta-analysis is similar to that in the current meta-analysis, such a benefit may be more important for a patient with underlying lung disease who has less functional reserve. the costs of widespread antibiotic use are great for both patients and society. they include prescription costs, medication side effects, and an increase in antibiotic resistance. several studies have shown that widespread antibiotic use leads to the development of resistant organisms ( ) ( ) ( ) . antibiotic use for acute bronchitis constitutes a substantial portion of all antibiotic use in the united states, accounting for % of all prescriptions written for children ( ) . furthermore, side effects of antibiotics used for acute bronchitis are common, occurring in % to % of patients ( - , , , ) . the practice of routinely giving antibiotics for acute bronchitis encourages patients to expect antibiotics for subsequent episodes ( ) , which adds to the cycle of medication costs, side effects, and antibiotic resistance. we believe that there should be a clear, substantial benefit to antibiotics to justify these costs. some authors have suggested that certain subgroups of patients with acute bronchitis may benefit from antibiotics ( , , ) . in a study of patients randomly assigned to treatment with doxycycline or placebo, verheij et al ( ) reported that doxycycline resulted in clinical benefit among patients older than years and in those who felt ill at study entry. however, approximately % of the patients in that study had abnormalities on lung auscultation and therefore may have had conditions such as pneumonia that would show a large benefit from antibiotic treatment ( ) . others have suggested treating patients who test positive for mycoplasma pneumoniae or chlamydia pneumoniae ( ) , although there is no evidence from randomized trials to support this practice. in a randomized trial using erythromycin to treat acute bronchitis, king et al ( ) found no difference in outcomes between patients who tested positive and those who tested negative for mycoplasma pneumoniae. more research is needed to determine if there are subgroups of patients who are likely to have a substantial benefit from treatment with antibiotics. the studies included in this meta-analysis examined the effect of one of three different antibiotics (erythromycin, doxycycline, trimethoprim/sulfamethoxazole). none of the studies used one of the newer macrolide or floroquinolone antibiotics. we are not aware of any randomized, placebo-controlled trials of these agents in adults with acute bronchitis. future studies should determine the risks and benefits associated with use of these newer antibiotics. in summary, we found a statistically significant benefit from the use of antibiotics in acute bronchitis. treatment reduced the duration of cough and sputum production by approximately one half day. the decision to use antibiotics for the treatment of adults with acute bronchitis must be weighed against the costs associated with widespread use of these agents. in healthy patients with acute bronchitis who have no evidence of chronic pulmonary disease, we believe that the small benefit associated with antibiotic treatment does not outweigh the risk of side effects and the increase in antibiotic resistance. note added in proof: after this paper was submitted, a meta-analysis on a similar topic was published: smucny jj, becker la, glazier rh, mcisaac w. are antibiotics effective treatment for acute bronchitis? a meta-analysis. j fam pract. ; : - . antibiotics in chronic obstructive pulmonary disease exacerbations: a meta-analysis national ambulatory medical care survey: 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choosing the best treatment randomized placebo-controlled trials of antibiotics for acute bronchitis: a critical review of the literature implications of overviews of randomized trials summing up: the science of reviewing research obtaining medically meaningful answers from an overview of randomized clinical trials meta-analyses of randomized controlled trials meta-analysis, decision analysis, and cost-effectiveness analysis: methods for quantitative synthesis in medicine effect of antimicrobial use and other risk factors on antimicrobial resistance in pneumococci the effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group a streptococci in finland production of beta-lactamase in respiratory tract bacteria in children: relationship to antibiotic use patient knowledge of upper respiratory infections: implications for antibiotic expectations and unnecessary utilization what will it take to stop physicians from prescribing antibiotics in acute bronchitis? antibiotics in acute bronchitis/bent et al key: cord- -my g c authors: berger, a.; drosten, ch.; doerr, h. w.; stürmer, m.; preiser, w. title: severe acute respiratory syndrome (sars)—paradigm of an emerging viral infection date: - - journal: journal of clinical virology doi: . /j.jcv. . . sha: doc_id: cord_uid: my g c abstract an acute and often severe respiratory illness emerged in southern china in late and rapidly spread to different areas of the far east as well as several countries around the globe. when the outbreak of this apparently novel infectious disease termed severe acute respiratory syndrome (sars) came to an end in july , it had caused over probable cases worldwide and more than deaths. starting in march , the world health organization (who) organised an unprecedented international effort by leading laboratories working together to find the causative agent. little more than one week later, three research groups from this who-coordinated network simultaneously found evidence of a hitherto unknown coronavirus in sars patients, using different approaches. after koch’s postulates had been fulfilled, who officially declared on april that this virus never before seen in humans is the cause of sars. ever since, progress around sars-associated coronavirus (sars-cov) has been swift. within weeks of the first isolate being obtained, its complete genome was sequenced. diagnostic tests based on the detection of sars-cov rna were developed and made available freely and widely; nevertheless the sars case definition still remains based on clinical and epidemiological criteria. the agent’s environmental stability, methods suitable for inactivation and disinfection, and potential antiviral compounds have been studied, and development of vaccines and immunotherapeutics is ongoing. despite its grave consequences in humanitarian, political and economic terms, sars may serve as an example of how much can be achieved through a well-coordinated international approach, combining the latest technological advances of molecular virology with more “traditional” techniques carried out to an excellent standard. severe acute respiratory syndrome (sars) is the latest in a series of emerging infectious diseases, and certainly one of the most widely publicised. this acute and often severe respiratory illness seems to have emerged in southern china in late (world health organization, c) . it soon caused considerable international alarm, after several index cases had given rise to outbreaks of sometimes ଝ this review is dedicated to all those who were prepared to risk their lives to provide care to sars patients and control the first pandemic of the st century. * corresponding author. tel.: + - - - ; fax: + - - - . e-mail address: annemarie.berger@em.uni-frankfurt.de (a. berger). enormous scales, and when the disease's ability to spread to distant areas within a very short period of time became obvious (world health organization, d) . a definition was developed for suspected and probable sars cases, based on clinical and epidemiological criteria; it has since been modified on several occasions. while sars demonstrated very vividly that in the modern world with an enormous volume of intercontinental traffic, infectious agents may be spread rapidly across the globe, it also serves as an example of how modern technologyprovided there is the necessary will, determination, and coordination to make best use of it-may help in combating such threats with unprecedented speed and enormous success. sars is characterized clinically by fever followed by respiratory signs and symptoms which may lead to rapidly progressive respiratory failure. as of september , people have been notified to the world health organization (who) as fulfilling the criteria for "probable sars", and of these, have died from sars (http://www.who.int/csr/ sars/country/ /en/). what made sars-in contrast, e.g. to influenza-notorious is its propensity to cause hospital outbreaks; some of these have affected over people, including health care staff, other patients and visitors . in contrast to many other emerging viral infections such as ebola, hantavirus pulmonary syndrome, and nipah, sars also clearly demonstrated its ability for easy and rapid geographic spread. this is because the sars agent affected a generally rather mobile population, and because those infected normally remain well enough to travel for several days after onset of infectivity. on march , the who set up a worldwide network of virological laboratories investigating sars cases (world health organization, a) . the investigations conducted by the members of these networks were coordinated by who's department of communicable disease surveillance and response (csr) through normally daily telephone conferences and a password-protected internet website. thus results and planned further studies were communicated and views and comments exchanged almost in "real-time" which made possible the rapid progress in elucidating the aetiological agent. in its final form, this network comprised participating laboratories from ten countries (world health organization multicentre collaborative network for severe acute respiratory syndrome diagnosis, ). investigations had soon ruled out a novel influenza virus strain, possibly of avian origin, as the cause of sars, and then focussed on members of the paramyxoviridae family, including human metapneumovirus (hmpv), and chlamydia-like organisms, including chlamydia pneumoniae. however, further investigations did not confirm these findings; the said agents were indeed found in a number of sars patients but not in all (who multicentre collaborative networks for severe acute respiratory syndrome (sars) diagnosis, ). almost nobody knew at that stage that virologists in beijing had already discovered a new virus in samples from some of the earliest sars patients. however, the official line in china at the time was that the novel "atypical pneumonia" was caused by chlamydia (enserink, a) . nevertheless, before the end of march, laboratories in hong kong, germany, canada, and the united states of america found evidence of a novel coronavirus in patients with sars by cell culture, electron microscopy, and by polymerase chain reaction (pcr) using primers at low stringency designed for other agents followed by sequencing (peiris et al., b; drosten et al., a; ksiazek et al., ; poutanen et al., ; drosten et al., b) . these results could not rule out that very thorough and extensive testing had by chance led to the discovery of a novel agent that was not responsible for the new illness but rather an "innocent bystander". however, the sequences obtained in different parts of the world were shown to belong to the same, previously unrecognised, coronavirus (ruan et al., ) . it could also be shown that sars patients underwent seroconversion against this coronavirus, using cells infected with patient isolates as antigen for indirect immunofluorescent antibody tests (drosten et al., a; ksiazek et al., ; fig. ) . furthermore, no evidence of present or past infection with this agent could be detected in limited surveys of healthy control individuals not suffering from sars (ksiazek et al., ) . this strengthened the case for the novel coronavirus being the cause of sars, but only after it had been shown to cause a similar illness in artificially infected macaques could it be regarded as fulfilling all four of koch's postulates ; world health organisation multicentre collaborative networks for severe acute respiratory syndrome diagnosis, ) . on april , , less than a month after the laboratory network had been brought into existence, who officially announced that a new coronavirus, never before seen in humans or animals and now provisionally termed sars-associated coronavirus (abbreviated as sars-cov), was the cause of sars . coronaviruses are large, enveloped, positive-stranded rna viruses with a diameter of - nm. most but not all viral particles display the characteristic appearance of surface projections, giving rise to the virus family's name (corona, latin, = crown). they have the largest genomes of all rna viruses. based on their unique transcription strategy that involves the formation of "nested" mrna molecules (cavanagh, ) . within the coronaviridae, the genera torovirus and coronavirus (type species: infectious bronchitis virus, ibv) are distinguished. a unique feature of coronavirus genetics is a high frequency of rna recombination as a result of discontinuous transcription and polymerase "jumping" (lai and cavanagh, ) . one example is the porcine respiratory coronavirus (prcov), which evolved in the early s from the enteropathogenic porcine transmissible gastroenteritis coronavirus (tgev), known since the s (pensaert et al., ) . through a large deletion in the s gene, the virus acquired an altered tissue tropism, causing mild respiratory infections. based on homologies on the amino acid sequence level, the known coronaviruses can be divided into three groups. table gives an overview of coronavirus species, group assignment, host species, disease manifestation and availability of a vaccine. there are more than a dozen known coronaviruses affecting different animal species; whereas group i and ii coronaviruses affect various mammals, those in group iii infect birds. some of these cause major problems in the livestock industry or may affect companion animals; therefore, considerable efforts have been devoted to their control, including development of active immunisation. negative-stain transmission electron microscopy of respiratory samples from sars patients and of infected cell culture supernatants reveals pleomorphic, enveloped virus-like particles with diameters of between and nm (fig. ) . most but not all viral particles showed the characteristic coronavirus-like surface features (ksiazek et al., ) . in contrast to most coronaviruses, which infect only the cells of their natural host species and a few closely related species, the sars-cov is able to infect different cell cultures, such as african green monkey (cercopithecus aethiops) kidney cells (vero) and the human colorectal adenocarcinoma cell line (caco- ), causing a massive cytopathic effect (cpe) after as little as days or days (fig. ) . it should be mentioned that these cell lines were not commonly used for the isolation of human respiratory viruses. interestingly during cell culture passages of the frankfurt isolate a virus variant emerged with a nucleotide deletion of bases in the orf b . the biological significance of this finding remains to be elucidated. complete genome sequences of sars-cov were first published by a canadian laboratory and the centers for disease control (cdc), atlanta (marra et al., ; rota et al., ) . as of end-october , full genome sequences are available on http://www.ncbi.nlm.nih.gov/genomes/ sars/sars.html. the genomic data available so far from several sars-cov strains suggest that the novel agent does not belong to any of the known groups of coronaviruses, fig. . electron microscopy image of sars-cov particle from infected cell culture supernatant after ultracentrifugation, % formalin fixation and negative staining with uranyl acetate (photograph by h. r. gelderblom, robert koch institute, berlin, germany). including the two human coronaviruses (hcov) oc and e (drosten et al., a; marra et al., ; peiris et al., b; rota et al., ) , to which it is only moderately related (fig. ) . the sars-cov appears to be neither a mutant of a known coronavirus nor a recombinant between known coronaviruses (holmes, ) . it has been proposed that the new virus defines a fourth lineage of coronavirus (group iv) (marra et al., ) (fig. ) . however, more recently it was suggested that sars-cov may be an early split-off from the group lineage . the sequence analysis of sars-cov suggests that it is an animal virus with a still unknown natural host species that has recently developed the ability to productively infect humans. a genetically very close but not identical virus was found in wild animals (masked palm civets and a raccoon dog) from a wildlife market in guangdong . but uncertainties remain over the exact source of this virus; the animals sampled could have been infected from humans or another animal species (cyranoski and abbott, ; normile and enserink, ) . sequence analysis of different sars-cov isolates reveals two distinct genotypes. one genotype was linked with infections originating from hotel m in hong kong, the other one comprises isolates from hong kong, guangdong and beijing that had no association with hotel m (ruan et al., ; tsui et al., ) . to date, there is no information as to whether different sars-cov strains may have different degrees of virulence. there is little doubt that sars originated from guangdong province of southern china (breiman et al., ) . the first cases retrospectively identified as sars occurred there in november . interestingly, amongst these early cases there seems to have been a significantly higher percentage of food handlers, chefs, etc. than in the general population, lending further support to a zoonotic origin. the worldwide spread of sars-cov was triggered through a single infected individual from guangdong who spent some time in hong kong before succumbing to sars (chan-yeung and yu, ) . during that time he unwittingly infected several others that in turn gave rise to a series of outbreaks (centers for disease control and prevention, ) . through sometimes several generations of transmissions, this event carried the virus to different hong kong hospitals and communities as well as to vietnam, singapore, canada, the united states of america, and beyond to a total of countries and areas of the world (world health organization, d). the virus travelled in infected humans and was passed on over several generations, as reflected in the genetic relatedness of isolates from these countries. although china was late in admitting it, the sars-cov had unsurprisingly also been spread within mainland china; in the end, the worst affected area was the capital, beijing, with cases in total, which surpasses the count for guangdong with by far (world health organization western pacific region, country office china: http://www.wpro.who.int/wr/chn/chn sars.asp). the incubation period of sars is short, ranging from to days. large studies consistently noted a median incubation period of days (booth et al., ; lee et al., ; tsang et al., ) . however, the time from exposure to the onset of symptoms may vary considerably . the who continues to conclude that the current best estimate of the maximum incubation period is days (who update -sars case fatality ratio, incubation period, http://www.who.int/csr/sars/archive/ a/en/). based on the latest data, the case fatality ratio is estimated to be < % in persons aged years or younger, % in persons aged - years, % in persons aged - years, and greater than % in persons aged years and older ; who update -sars case fatality ratio, incubation period, http://www.who.int/csr/sars/ archive/ a/en/). pregnant women with sars appear to have a worse prognosis and a higher mortality. therefore, early delivery or termination of pregnancy should be considered in those who are seriously ill with sars. for women who are relatively well with sars, however, there seems to be no reason for elective preterm delivery, such as reducing the risk of materno-fetal transmission (wong et al., a) . compared with adults and teenagers, sars seems to take a less aggressive clinical course in younger children (hon et al., ) . multivariable analysis showed that the presence of diabetes, advanced age or other comorbid conditions were independently associated with a poor outcome (booth et al., ; donnelly et al., ; fowler et al., ) . at the present time, with no new cases-apart from the isolated laboratory-acquired one-having been reported since june , sars-cov has apparently been driven out of the human population (world health organization, d) . in the meantime, who has issued a consensus document on sars epidemiology (who department of communicable disease surveillance and response, ). the pattern of geographic spread of sars was similar across all affected areas: typically, a patient with sars arrived from a previously affected area, was not identified as such when hospitalised, and thus infected health care workers, other patients and hospital visitors; these then infected their close contacts, and then the disease moved into the larger community (hawkey et al., ) . the virus seems to be spread predominantly by respiratory droplets over a relatively close distance , however, at least under some circumstances direct and indirect contact with respiratory secretions, faeces or animal vectors may also lead to transmission (hong kong department of health, ; who environmental health team, ; tsang et al., ; ng, ) . shedding of sars-cov in faeces and urine also occurs but its significance is unknown. the duration of infectivity is still unclear. faecal shedding seems to last for several weeks; this however does not necessarily mean that there is sufficient excretion of infectious viral particles to infect other individuals (peiris et al., a) . practising stringent droplets and contact precaution significantly reduces the risk of infection after exposure to patients with sars. therefore, the protective role of the mask suggests that the main route of transmission is by droplets . sars-cov spreads more efficiently in sophisticated hospital settings. evidence suggests that certain procedures, such as intubation under difficult circumstances and use of nebulizers increase the risk of infection . the only case of laboratory-acquired sars-cov transmission so far occurred in singapore in september . it involved a postgraduate who worked in a virology laboratory. subsequent investigation showed inappropriate laboratory standards (who severe acute respiratory syndrome (sars) in singapore-update , http://www.who.int/csr/ don/ /en); no secondary transmission arose from this case. it demonstrates the need for optimal biosafety precautions in laboratories working with sars-cov; these constitute the only places on earth where sars-cov is currently known to still exist and might be at the source of a re-emergence. blood transfusions or administration of blood products have not been implicated in transmission anywhere. this is despite the demonstration of viraemia during the clinical phase of the illness, albeit at low to moderate titres (drosten et al., a) . nevertheless, the potential of blood-borne transmission led to the early implementation of measures such as exclusion of possibly exposed individuals from the donor pool. the sars-cov is only moderately transmissible. a single infectious case will infect about three secondary cases (lipsitch et al., ; riley et al., ) . nevertheless, the clusters of cases in hotel and apartment buildings in hong kong show that transmission of the sars-cov can be extremely efficient. attack rates in excess of % have been reported. one common observation in various areas was the occurrence of so-called "super-spreaders", i.e. individuals that transmit the infection to at least ten others (world health organization, b). these "super-spreaders" were mostly very ill and often died from sars, and invariably serious lapses in infection control precautions had occurred during their management. so far there is no evidence that differences in virus strains may be responsible for the "super-spreader" phenomenon. there is also no firm evidence suggesting that subsequent transmissions led to clinically less severe illness, possibly through attenuation of the virus. it is also unclear why children are relatively under-represented amongst sars cases, and why on average they seem to suffer less severe sars illness. studies on the stability of the new sars-cov demonstrate the virus is more stable at room temperature than the previously known human coronaviruses (sizun et al., ) . the virus has been shown to survive for up to hours on plastic surfaces and up to days in diarrhoea. nevertheless the virus loses infectivity after exposure to different commonly used disinfectants and fixatives. heat exposure at • c quickly reduces infectivity (world health organization (who): first data on stability and resistance of sars-cov compiled by members of who laboratory network available at http://www.who.int/csr/sars/ survival /en/index.html). as defined by the who, a person is suspected to have sars if she has documented high fever (> • c), plus cough or breathing difficulty, and has been in contact with a person believed to have had sars, or has a history of travel to or stay in a geographic area where documented transmission of the illness has occurred, during the days prior to onset of symptoms ("suspect case"). a suspect case with infiltrates consistent with pneumonia or respiratory distress syndrome (rds) by chest x-ray is reclassified as a probable case. the revised case definition as of may , (see: http://www.who.int/csr/sars/casedefinition/en/) for the first time includes virus-specific laboratory results: a suspect case that tests positive for sars-cov in one or more assays should also be reclassified as probable. while recommendations have been issued for the use of laboratory methods for sars-cov (see: http://www.who. int/csr/sars/labmethods/en/), there are, however, at present no defined criteria for negative sars-cov test results to reject a diagnosis of sars. given the rather low shedding of sars-cov from the upper respiratory tract (drosten et al., a) , and the insufficient sensitivity of presently available laboratory methods, premature exclusion on the basis of negative test results may lead to tragic consequences. positive laboratory test results for other agents able to cause atypical pneumonia may serve as exclusion criteria; according to the case definition, a case should be excluded if an alternative diagnosis can fully explain the illness. nevertheless, the possibility of dual infection must not be ruled out completely. the required epidemiological linkage has repeatedly proven to be problematic. until an area is recognised as being affected, only imported cases fulfil the criteria for sars but not those who became infected locally through contact with unrecognised cases. thus, precious time may be lost until cases are recognised and appropriate measures taken. a thorough analysis showed that the existing who criteria lack sensitivity in the pre-hospital setting (rainer et al., ) . this again may be problematic as it may delay appropriate management of sars cases. the human coronaviruses known prior to march are difficult to propagate in cell cultures. their disease associations-generally mild respiratory illness ("common cold"), enteric and rarely possibly neurological disease-led to their widespread neglect in medical virology; only few groups worked on various scientific aspects, and very few laboratories offered routine diagnostic tests, mainly by pcr. sars-cov, on the other hand, is readily propagated in vitro and may also be detected by pcr and indirectly through antibody testing. nevertheless, and despite considerable progress in this field, much remains to be done until laboratory tests become a useful tool for the management of sars cases (world health organization multicentre collaborative network for severe acute respiratory syndrome diagnosis, ) . the presence of the infectious virus can be detected by inoculating suitable cell cultures (e.g., vero cells) with patient specimens (such as respiratory secretions, blood or stool) and propagating the virus in vitro. once isolated, the virus must be identified as sars-cov using further tests. according to international consensus, such work has to be performed under biosafety level (bsl) three conditions. sars-cov-specific rna can be amplified from various clinical specimens, especially in respiratory secretions and in stool, by pcr. high concentrations of viral rna of up to million molecules per millilitre were found in sputum. viral rna was also detected, albeit at extremely low concentrations, in plasma during the acute phase and in faeces during the late convalescent phase, suggesting that virus may be shed in faeces for prolonged periods of time (drosten et al., a) . a commercial real-time rt-pcr test kit containing primers and positive and negative controls developed by the bernhard nocht institute (http://www.bnihamburg.de/) is available (http://www.artus-biotech.de). an inactivated standard preparation is also available for diagnostic purposes through the european network for imported viral infections (enivd; http://www.enivd.de). enivd is also preparing for an international external quality assessment scheme for sars-cov assays. the existing pcr tests cannot rule out, with certainty, the presence of sars-cov in patients . on the other hand, contamination of samples in laboratories performing pcr may lead to false-positive results, unless appropriate precautions are taken. various methods were developed for the detection of antibodies produced in response to infection with sars-cov by probably virtually all patients. the first type of antibody test to be employed was the immunofluorescence assay (ifa). using cells infected with the patient's own virus isolate and an antihuman igg:fitc conjugate, we were able to demonstrate specific seroconversion in the two frankfurt sars patients (drosten et al., a; fig. ). an enzyme-linked immunosorbent assay (elisa) was developed that detects antibodies in the serum of sars patients and reliably yields positive results at around day after the onset of illness (world health organization multicentre collaborative network for severe acute respiratory syndrome diagnosis, ). the neutralisation test (nt) assesses and quantifies, by means of titration, the ability of patient sera to neutralise the infectivity of sars-cov on cell culture; the nt titre may therefore be correlated to clinical immunity although this has yet to be demonstrated. however, nt is limited to institutions with bsl- facilities. the only antibody test commercially available so far is an ifa which yields a positive result from about day after the onset of illness (euroimmun, lübeck, germany). as the diagnosis of sars is based entirely on a set of clinical and epidemiological criteria so far, reported case numbers are likely to include a substantial number of non-sars patients. therefore, recovered patients should be tested systematically for specific sars-cov antibody reactivity to confirm their diagnoses in retrospect and thus allow a better understanding of epidemiological and other features . although electron microscopy has an important role in the rapid diagnosis of infectious agents in emergent situations (hazelton and gelderblom, ) , it has provided only circumstantial evidence in the case of sars. when a virus-like agent was first visualised in clinical material from sars cases by electron microscopy, its classification was ambiguous; it later turned out to be human metapneumovirus (poutanen et al., ) . even in cases in whom coronavirus-like particles were detected, these could not be distinguished from the 'classic' human coronaviruses. no specific treatment recommendations can be made at this time. primary measures include isolation and the implementation of stringent infection control measures to effectively prevent further transmissions. empiric therapy should include coverage for organisms associated with any community-acquired pneumonia of unclear aetiology, including agents with activity against both typical and atypical respiratory pathogens. treatment choices may be influenced by severity of the illness. oxygen supplementation is often necessary, and severe cases seem to do better if intensive care including artificial respiration is commenced early (so et al., ) . efforts are underway at various institutions to assess potential anti-sars-cov agents in vitro. ribavirin, a "broad spectrum" agent active against various rna viruses has also been used clinically in sars patients (koren et al., ) , but seems to lack an in vitro effect (cinatl et al., a) . corticosteroids were widely used in sars patients, particularly in china. the rationale for their administration is the observation that tissue changes suggest that part of the lung damage is due to cytokines induced by the virus (peiris et al., a) . some clinical reports also underline their usefulness (zhao et al., ) . other therapies are being explored, such as convalescent plasma (wong et al., b) or normal human immunoglobulin which may be beneficial through an immunomodulatory effect or through acting against agents causing secondary infections. preliminary clinical data suggest that protease inhibitors used for anti-hiv therapy, lopinavir and nelfinavir (yamamoto n, personal communication), might have some efficacy, both as initial therapy and in the rescue setting. hong kong researchers reported at the who global conference on sars in kuala lumpur in june that sars patients treated with kaletra (lopinavir with low-dose ritonavir) plus ribavirin experienced a % reduction in death rate. while efforts are underway to develop more targeted anti-sars-cov approaches, broad screening of available substances in vitro has led to some potentially important clues. recently glycyrrhizin, a compound found in liquorice roots (glycyrrhiza glabra l.), was reported to have good in vitro activity against sars-cov (cinatl et al., a) . the mechanism of glycyrrhizin's activity against sars-cov is unclear. glycyrrhizin has previously been used to treat patients with hiv- and chronic hepatitis c virus . interestingly, this compound may be contained in some of the herbal preparations widely used in sars patients in china as part of traditional chinese medicine (lin et al., ) . furthermore, interferons inhibit sars-cov in vitro. in a recent study (cinatl et al., b) , interferon ß was more potent than interferon ␣ or ␥. therefore, it could become a drug of choice in future, alone or in combination with other antiviral drugs. the rapid success in identifying the causative agent of sars results from a collaborative effort-rather than a competitive approach-by high-level laboratory investigators making use of all available techniques, from cell culture through electron microscopy (hazelton and gelderblom, ) to molecular techniques, in order to identify a novel agent. hopefully this approach, coordinated by who, will serve as a model for future instances of emerging infections that will undoubtedly take place (ludwig et al., ) . despite the exemplary efforts that led to the identification of the causative novel coronavirus and allowed enormous knowledge about it to be accumulated within only a few months, it is maybe surprising that this success in terminating the outbreak has to be attributed to "old-fashioned" measures such as rapid and strict isolation of suspect cases and thorough contact tracing (world health organization, c); one is left wondering whether the same might also have been achieved without knowledge of the aetiology. thanks to an internationally well-coordinated and in most cases timely and determined response no new cases of sars have been notified since june . several countries reported sars cases imported from areas reporting outbreaks but did not experience secondary transmission; likewise, vietnam was the first country to demonstrate that-through a combination of early detection and public alert followed by decisive public health action and often heroic efforts by individuals-further transmission could be curtailed (reilley et al., ) . the absence of new clinical cases worldwide suggests that sars-cov no longer circulates within the human population; however, the possibility of clinically "silent" infections or of long-term virus carriers cannot be ruled out completely. furthermore, the origin of the agent remains obscure; sars-cov or a closely related virus persisting in a hitherto unidentified animal reservoir may yet again cross the species barrier and lead to human outbreaks. numerous questions relating to the epidemiology of sars have yet to be answered (normile and enserink, ; breiman et al., ) . at the time of writing (october ) it is completely uncertain whether sars will ever reappear. it is unclear whether seasonal recurrences may occur. in southern china, unlike europe and north america, the annual influenza peak incidence is from march to july (huang et al., ); thus, it shows a similar epidemic curve as the sars outbreak in (enserink, b) . the advent of the next 'flu season will pose considerable problems, given the lack of reliable laboratory methods for the early diagnosis of sars. the case definitions, too, will need to be adjusted to a world without sars; in theory, new cases are "impossible" as the criterion of an epidemiological link cannot be fulfilled. precious time may therefore be lost before a reappearance is detected. vigilance for sars must clearly be maintained (see: alert, verification and public health management of sars in the post-outbreak period- august -rationale for continued vigilance for sars; http://www.who.int/csr/sars/postoutbreak/ en/). for this purpose, who has defined three geographical zones according to their presumed risk for a sars recurrence: a potential zone of re-emergence, comprising guangdong and other areas where animal-to-human of sars-cov might occur; nodal areas, comprising hong kong, vietnam, singapore, canada, and taiwan, with sustained local transmission in spring or entry of numerous persons from the potential zone of re-emergence; and low risk areas. sars-related vigilance should be staged according to the zone in which a particular area is situated; for low risk areas, surveillance should be for clusters of "alert" cases among health care workers, other hospital staff, patients and visitors in the same health care unit. a sars alert is defined as two or more health care workers or hospital-acquired illness in at least three individuals (health care workers and/or other hospital staff and/or patients and/or visitors) in the same unit fulfilling the clinical case definition of sars and with onset of illness in the same -day period. in the other zones, this should be supplemented by enhanced surveillance, plus special studies for sars-cov infections in animal and human populations in the potential zone of re-emergence. besides improving existing detection assays-for instance, pcr methods based on the amplification of the nucleoprotein gene may be intrinsically more sensitive, due to the coronaviral transcription strategy , and thus be valuable for early diagnosis-further laboratory research needs to include detailed physico-chemical analysis of sars-cov proteins to allow the development of novel compounds based on targeted drug design (anand et al., ) . although an effective vaccine cannot be expected to be available soon, the relative ease with which sars-cov can be propagated in vitro is clearly helpful. a suitable animal model for sars may be available in the form of cynomolgus macaques (macaca fascicularis) . while the availability of vaccines against animal coronaviruses, such as avian infectious bronchitis virus, transmissible gastroenteritis coronavirus of pigs, and feline infectious peritonitis virus, is encouraging, the obvious lack of protective immunity in humans after infection with hcov oc and e is not. there is also currently no commercial veterinary vaccine to prevent respiratory coronavirus infections, except for infectious bronchitis virus infections in chickens. further research is also urgently needed to determine whether immune pathogenesis plays a rôle in sars or whether immune enhancement may occur, the chances of developing an effective and safe vaccine therefore remain uncertain. it is to be hoped that after such an encouraging start in an atmosphere of open collaboration and mutual trust, progress in sars-cov research will not be impeded by patent matters (gold, ) . coronavirus main proteinase ( clpro) structure: basis for design of anti-sars drugs clinical features and short-term outcomes of patients with sars in the greater toronto area role of china in the quest to define and control severe acute respiratory syndrome update: outbreak of severe acute respiratory syndrome-worldwide outbreak of severe acute respiratory syndrome in hong kong special administrative region: case report severe acute respiratory syndrome: patients were epidemiologically linked glycyrrhizin, an active component of liquorice roots, and replication of sars-associated coronavirus treatment of sars with human interferons virus detectives seek source 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severe acute respiratory syndrome and pregnancy treatment of severe acute respiratory syndrome with convalescent plasma who multicentre collaborative networks for severe acute respiratory syndrome (sars) diagnosis severe acute respiratory syndrome-singapore severe acute respiratory syndrome (sars): over days into the outbreak chronology of travel recommendations, areas with local transmission world health organization multicentre collaborative network for severe acute respiratory syndrome diagnosis. a multicentre collaboration to investigate the cause of severe acute respiratory syndrome description and clinical treatment of an early outbreak of severe acute respiratory syndrome (sars) in guangzhou, pr china key: cord- -oulnk b authors: chau, tai-nin; lee, po-oi; choi, kin-wing; lee, chiu-man; ma, ka-fai; tsang, tak-yin; tso, yuk-keung; chiu, ming-chee; tong, wing-lok; yu, wai-cho; lai, sik-to title: value of initial chest radiographs for predicting clinical outcomes in patients with severe acute respiratory syndrome date: - - journal: the american journal of medicine doi: . /j.amjmed. . . sha: doc_id: cord_uid: oulnk b purpose to determine whether the initial chest radiograph is helpful in predicting the clinical outcome of patients with severe acute respiratory syndrome (sars). methods of patients who met the world health organization’s case definition of probable sars and who had been admitted to a regional hospital in hong kong, patients had laboratory evidence of sars coronavirus infection. the initial frontal chest radiographs of these patients were assessed in a blinded fashion by radiologists; individual findings were accepted if at least of the radiologists concurred. independent predictors of an adverse outcome, defined as the need for assisted ventilation, death, or both, were identified by multivariate analysis. results bilateral disease and involvement of more than two zones on the initial chest radiograph were associated with a higher risk of liver impairment and poor clinical outcome. forty-two patients ( %) developed an adverse outcome. multivariate analysis showed that lung involvement of more than two zones (odds ratio [or] = . ; % confidence interval [ci]: . to . ), older age (or for each decade of life = . ; % ci: . to . ), and shortness of breath on admission (or = . ; % ci: . to . ) were independent predictors of an adverse outcome. conclusion frontal chest radiographs on presentation may have prognostic value in patients with sars. s evere acute respiratory syndrome (sars) has become a global health hazard, and a novel virus, the sars-associated coronavirus, has been identified as the causal agent ( ) ( ) ( ) . more than persons worldwide have been affected by this disease, and patients have died since june . the case fatality rate is estimated to be % for patients younger than years and % for those older than years ( ) . the outbreak in asia demonstrated how sars can exert tremendous stress on local health care systems and intensive care services, emphasizing the need to identify patient characteristics on presentation that can lead to stratification into different management groups. together with the clinical characteristics of sars, such as fever and chest symptoms, and a recent history of contact with a suspected or confirmed sars patient, radiographic evidence of infiltrates consistent with pneumonia or acute respiratory distress syndrome is important in establishing the diagnosis ( ) . however, chest radiographs, which may be normal during the febrile pro-drome, may be abnormal in % to % of sars patients at the onset of fever ( - ) . studies involving patients with community-acquired pneumonia ( ) , acute interstitial pneumonia ( ) , or idiopathic pulmonary fibrosis ( ) have shown that quantitative and qualitative changes on chest radiographs might predict clinical outcome. we conducted a retrospective study to determine whether the initial chest radiograph has prognostic value in patients with sars. between february , , and april , , patients who met the world health organization's case definition of suspected or probable sars were admitted to isolation wards at princess margaret hospital in hong kong ( ) . two hundred and one patients had laboratory evidence of sars coronavirus infection and were included in this study. ten of these patients had an underlying illness prior to admission: were chronic hepatitis b virus carriers, had hepatitis b compensated cirrhosis, had mental retardation, had chronic rheumatic heart disease, and had ischemic heart disease requiring percutaneous coronary angioplasty. the study was approved by the hospital's ethics committee. standard entry forms were used to collect data on clinical history, physical examination, laboratory findings, and subsequent clinical course. adverse clinical outcome was assessed using the endpoint of the need for assisted ventilation, death, or both. the admission frontal chest radiographs of the patients were retrospectively and separately reviewed by radiologists (pol, cml, and kfm) who were blinded to the clinical outcomes. the laterality, zones and site of involvement, type of opacification, and dominant pattern of disease were recorded. each lung field was divided into three zones by drawing imaginary lines at the level of the inferior anterior angle of the second and fourth ribs ( ) . a peripheral location was defined as involvement confined to the outer one third of the lung; a central location was defined as involvement confined to the inner two thirds. consolidation was defined as air space opacity obscuring the underlying vasculature, whereas groundglass opacity was defined as clouding or hazes over the lungs without obscuration of lung vasculature. the dominant patterns were classified as lobar, lobular, interstitial, or diffuse ( ) . a diffuse pattern has been associated with acute respiratory distress syndrome. individual findings were accepted if at least of the radiologists concurred. all patients received antimicrobial treatment for community-acquired pneumonia after admission. combination therapy using intravenous ribavirin ( mg/kg/d) and hydrocortisone ( mg/kg/d) was started if patients did not respond to treatment within hours. methylprednisolone, administered intravenously for two to three pulses each time at a dose of mg to mg daily, was offered to patients who had persistent fever, radiological progression of lung infiltration, or signs of respiratory distress despite the initial antiviral treatment. the statistic and complete concordance were used to assess the level of agreement among the three radiologists in chest radiograph interpretation. complete concordance was defined as the percentage of identical findings among the radiologists for the various radiographic parameters. clinical features and laboratory findings of patients were analyzed using various radiographic features as independent variables. bivariate analysis was performed with the chi-squared test for categorical variables and an unpaired student t test for continuous variables. data with positive skewed distribution were log-transformed for comparison. a receiver operating characteristic (roc) curve was plotted to determine the appropriate cutoff value with maximum sensitivity and specificity, if necessary. multivariate analysis using backward stepwise regression was employed to identify variables that were associated with an adverse outcome (need for mechanical ventilation or death). a p value of less than . (two-tailed) was considered statistically significant. all analyses were performed using spss, version . (spss inc, chicago, illinois). initial frontal chest radiographs were obtained for the patients ( male and female). fifteen patients were health care workers and were residents of amoy gardens, a residential area where a community sars outbreak had occurred. fifty-two patients had a history of recent travel to sars-infected areas in mainland china. nasopharyngeal aspirate or stool specimens from patients ( %) yielded positive results by reverse-transcriptase polymerase chain reaction (rt-pcr). of patients who underwent serology testing for the sars coronavirus, ( %) had a fourfold or greater increase in antibody titers between acute-phase and convalescentphase sera tested in parallel. overall, patients ( %) required intensive care. forty-two patients ( %) needed assisted ventilation, of whom ( %) died. normal chest radiographs were seen in patients ( %) on admission. the middle and lower zones were more often affected than were the upper zones (table ). almost half of the patients ( %) had single zone involvement. the majority ( %) had a predominant lobular pattern of disease. most patients ( %) showed air space consolidation. one patient had right pleural effusion on the initial chest radiograph. an interstitial pattern and other associated findings such as cavitation or lymphadenopathy were not seen in any of the patients. the level of agreement and the percentage of complete concordance among the radiologists regarding assessment of the various radiographic features varied (table ) . interobserver agreement was generally good for normality, laterality, and number of zones involved, but fair to poor for location and type of opacification. patients with more than two zones of lung involvement presented significantly later than patients with fewer zones of involvement ( Ϯ days vs. Ϯ days after onset of symptoms, p ϭ . ) ( table ) . although patients with more zones of involvement had significantly higher levels of total white blood cell and neutrophil counts, the absolute value of these variables for the two groups of patients were within normal range. patients with greater lung involvement more often had elevated alanine aminotransferase levels ( % vs. %, p ϭ . ). they also had significantly worse outcomes in terms of admission to the intensive care unit and mortality. forty-two patients ( %) reached the endpoint of the need for assisted ventilation, death, or both. one patient with hepatitis b compensated cirrhosis died of liver failure. three patients with underlying heart disease ( with chronic rheumatic heart disease, with ischemic heart disease requiring percutaneous coronary angioplasty) died of respiratory failure. the risk of an adverse outcome increased significantly from % ( / ) to % ( / ) for patients with more than two zones involved. in the roc curve analysis, involvement of more than two zones was selected as a cutoff with a sensitivity of . and a specificity of . . the area under the roc curve was . ( % confidence interval: . to . ). in the bivariate analysis, variables associated with an adverse outcome were bilateral disease, involvement of more than two zones, diffuse infiltrate and infiltrates in both peripheral and central locations, older age, male sex, shortness of breath, and elevated alanine aminotransferase level (table ). days between the onset of symptoms and admission were not significantly associated with clinical outcome. as there was a strong collinearity among involvement of more than two zones, bilateral disease, and diffuse pattern and distribution (both peripheral and central) of disease, zonal involvement was chosen for analysis as it represented the extent of disease involvement and was easily assessed objectively. other factors associated significantly with an adverse outcome by bivariate analysis were included in the multivariate analysis. multivariate analysis showed that older age (odds ratio [or] per years ϭ . ; % ci: . to . ; p ϭ . ), shortness of breath (or ϭ . ; % ci: . to . ; p ϭ . ), and involvement of more than two zones (or ϭ . ; % ci: . to . ; p ϭ . ) were independently associated with an adverse outcome. chest radiography has been shown to be important in the diagnosis and management of patients with pneumonia. bilateral disease, multilobar shadows, and the presence of pleural effusion on initial chest radiographs are predictive of adverse outcomes in patients with communityacquired pneumonia ( - ) . the initial radiographic features of patients with sars have been described ( , , ) . our present study of the predictive value of initial chest radiography adds to these earlier studies. we observed that patients with more extensive lung involvement in terms of bilateral disease and more than two zones of involvement had more systemic disease and worse outcomes. patients with involvement of more than two zones had a higher risk of liver impairment and more severe lymphopenia, which may reflect systemic viral infection. a recent study reported that patients requiring . this new assay, however, is not widely available, and its correlation with radiographic abnormalities is not known. we also found higher lactate dehydrogenase levels and neutrophil counts in patients with greater lung involvement, which suggests that greater lung damage may occur in patients with extensive lung infiltrate on chest radiographs ( ). we found that older age, shortness of breath, and lung involvement of more than two zones were independently associated with the need for assisted ventilation or death. lee et al reported an odds ratio of . per decade of life ( ) , which is similar to our finding. booth et al ( ) found that comorbid conditions, particularly, diabetes mellitus, were independently associated with poor outcomes. in our study, patients with underlying heart disease had a greater risk of poor outcomes. positive hepatitis b surface antigen status has been shown to be an independent risk factor for progression to acute respiratory distress syndrome in sars ( ) . however, none of our patients with positive hepatitis b surface antigen status developed respiratory failure. one patient with hepatitis b compensated cirrhosis died of liver failure despite lamivudine therapy. a high absolute neutrophil count on presentation has been associated with an adverse outcome; this was thought to be related to severe lung injury ( ). we could not establish this association in our study. in the bivariate analysis, laterality and the number of zones involved were associated with clinical outcome. peiris et al observed that % of patients with acute respiratory distress syndrome had multilobar involvement on presentation compared with only % of patients without the syndrome ( ). however, multilobar change was not identified as an independent prognostic factor in their study, perhaps because their sample size was too small and their use of a single frontal chest radiograph was not adequate in defining the number of lobes involved. other reports did not consider initial radiographic abnormalities as a confounding factor for clinical outcome ( , ) . as there were correlations between chest radiographic findings and other confounding factors, we used multivariate analysis with logistic regression to determine the independent prognostic value of chest radiograph on presentation and found that involvement of more than two zones was independently associated with an adverse outcome. interobserver variability in the interpretation of chest radiographs has been a concern in the diagnosis of acute respiratory distress syndrome ( ) . in our study, the interobserver agreement on the normality, laterality, and number of zones was generally good. complete concordance among the radiologists was greater than %, which is considered acceptable. it may be argued that quantitative assessment of the total area of infiltrate rather than the number of zones in-volved may be a more accurate indicator of disease severity. area estimation, however, is highly subjective and may result in substantial interobserver variability. on the other hand, the level of agreement on assessment of type and distribution of opacification appeared unsatisfactory by the statistic. sars is a highly contagious infectious disease that is associated with substantial morbidity and mortality. patients' conditions may deteriorate rapidly with acute respiratory failure. indeed, % to % of patients require intensive care and mechanical ventilation ( , , ) , and short-term mortality rates range from % to % ( , ) . our study suggests that radiographic evidence, specifically, frontal chest radiograph on presentation, may have prognostic value in patients with sars. patients with more extensive lung involvement on the initial chest radiograph had a higher risk of mechanical ventilation or death. involvement of more than two zones on initial chest film, older age, and shortness of breath on presentation were independent predictors of an 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serum of patients with severe acute respiratory syndrome interobserver variability in applying a radiographic definition for ards severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts prognostic features of chest radiographs in sars/chau et al key: cord- - d c a authors: nan title: acute and chronic liver insufficiency date: journal: hepatology textbook and atlas doi: . / - - - - _ sha: doc_id: cord_uid: d c a the term “liver insufficiency” denotes a break down in the functions of the liver. the syndrome of functional liver failure covers a wide spectrum of clinical, biochemical and neurophysiological changes. in principle, liver insufficiency can occur without previous liver damage as well as with already existing liver disease. it is characterized by a deterioration in the synthesizing, regulatory and detoxifying function of the liver. this final stage of liver disease terminates in hepatic coma. the term "liver insufficiency" denotes a breakdown in the functions of the liver. the syndrome of functional liver failure covers a wide spectrum of clinical, biochemical and neurophysiological changes. in principle, liver insufficiency can occur without previous liver damage as well as with already existing liver disease. it is characterized by a deterioration in the synthesizing, regulatory and detoxifying function of the liver. this final stage of liver disease terminates in hepatic coma. serious liver disease can affect the main metabolic functions of the liver, with their Ϫ even more important partial functions, to widely differing degrees. (s. tab. . ) the result is either global insufficiency or partial insufficiency, each with very varied clinical and biochemy y ical symptoms. the failure of certain metabolic functions is responsible to a greater or lesser extent for the development and intensity of liver insufficiency. impairments in the functions of detoxification and protein metabolism are particularly significant in this respect. the compensated stage does not usually display any signs of liver insufficiency (except possibly jaundice), nor are there any typical ailments. functional parameters that can be quantified in routine laboratory tests (such as cholinesterase, albumin, quick's value, bile acids) may still be normal or only minimally impaired in the individual instance. in contrast, liver function tests (galactose, indocyanine green, megx, etc.) demonstrate a reduction of liver function which is already quite considerable. the decompensated stage, i. e. manifest liver insufficiency, can present as cellular decompensation (e. g. in the case of acute liver failure due to toxic or inflammatory mass necrosis) or be expressed only in the form of portal decompensation (e. g. in cases of postsinusoidal intrahepatic portal hypertension). • as a rule, chronic liver insufficiency is accompanied by a combined decompensation with a loss in function of the liver cells and, at the same time, the sequelae of portal decompensation (collateral varicosis, encephalopathy, ascites, hepatorenal syndrome, hepatopulmonary syndrome, variceal bleeding). (see chapters Ϫ and ) depending on the time period involved in the course of the disease, acute liver failure without pre-existing liver disease can initially be differentiated by massive liver cell disintegration due to a variety of causes. • in contrast, chronic liver insufficiency with pre-existing liver disease is mostly found in advanced liver cirrhosis with a progressive loss of function. • a sudden necrotising episode can also precipitate the change from chronic and still compensated liver insufficiency into acute liver failure (i.e. "acute-on-chronic" insufficiency) in the same way that acute liver failure which has been overcome may develop into chronic liver insufficiency. ( ) hepatic coma can be subdivided according to its aetiology as follows: ( .) hepatocyte disintegration coma (ϭ endogenous coma due to the loss of parenchyma), ( ( ( .) liver cell failure coma (ϭ exogenous coma due to metabolic disorders, almost always in the presence of cirrhosis), ( .) electrolyte coma (ϭ so-called "false" coma due to dyselectrolytaemia, almost always iatrogenic), and ( .) mixed forms of coma. (s. pp , , ) (s. tab. . ) acute liver insufficiency ᭤ j. w. morgagni ( ) was probably the first to describe acute yellow atrophy of the liver, i. e. hepatic coma. acute liver failure can be seen as identical to the "acute yellow atrophy" described by k. rokitansky in . this acute and severe clinical picture was subsequently termed "bilious dyscrasia" (p. j. horaczek, ), "icterus gravis" (c. ozanam, ), "acholia" (f. th. frerichs, ), "hepatolysis" (r. ehrmann, ), "hepatodystrophy" (g. herxheimer, ) r r or "liver dystrophy" (r. böhmig, ). the terms "hepatargia" (h. i. quincke, ) and "hepatic coma" were used to denote the final stage, which usually sets in at the end of acute or chronic liver failure. • acute liver failure in the course of acute viral hepatitis was termed "fulminant hepatitis" by w. lucké et al. ( ) , who also defined a subacute form with a less severe course. ( ) acute liver failure (alf) is defined as an acute clinical picture with jaundice due to a most severe disorder in the liver function and/or massive liver cell necrosis which, without any pre-existing liver disease, culminates in hepatic coma (ϭ endogenous coma) within weeks. potentially, the condition is fully reversible (c. trey et al., ) . • in addition, coagulopathy must also be present (d. f. schafer et al., ). clinically, there are three different courses of disease following the onset of jaundice: ( .) fulminant or hyperacute liver failure (ϭ occurrence of hepatic encephalopathy in the st week), ( ( ( .) acute liver failure (ϭ occurrence of hepatic encephalopathy between the nd and th week), and ( .) subacute liver failure (ϭ occurrence of hepatic encephalopathy between the th and th week). • surprisingly, however, it could be shown that Ϫ % of the hyperacute forms survived in spite of the development of hepatic coma and cerebral oedema. as opposed to this, the subacute forms displayed a survival rate of only Ϫ % despite a lower frequency of cerebral oedema and better liver function. (s. tab. in the pathological-anatomical context, hepatomegaly due to hyperaemia is often found at the outset. during the further course of disease, this can develop into liver atrophy as a result of parenchymal loss. histologically, acute liver failure shows a wide range of uncharacteristic changes. ( .) depending on the underlying cause, the morphological picture of acute necrotizing hepatitis may develop, with extensive confluent cellular destruction. the extent of necrosis, measured by the morphologically evidenced hepatic volume fraction of the still functioning liver parenchyma, yields reliable information on the chance of survival (j. scotto et al., ) . given a normal value of % hepatic volume fraction (hvf) of intact liver cells for each volume unit of the total liver, a decrease to < % (threshold Ϫ %) would possibly mean that the patient is unlikely to survive. ( ( ( .) in acute liver failure caused by toxins or hypoxia, massive fatty degeneration of the hepatocytes can vary substantially. in diffuse fatty degeneration featuring minute vacuoles and damage to the organelles, liver cell necrosis cannot, as a rule, be detected (e. g. acute fatty liver during pregnancy, reye's syndrome, in association with tetracycline or valproic acid). ( .) between these two "classical" morphological manifestations, there are also compound forms, i. e. courses of disease with a variety of histological changes of different intensities and combinations. on occasions, it is also possible to identify histological findings which point to a certain cause of the disease. ( , ) from a morphological point of view, acute liver failure is potentially reversible, so that even complete regeneration can be attained. precursory cellular necrosis is hence less of a determinant than the capacity to regenerate. there have been reports on the transition from virusinduced acute liver failure to chronic hepatitis. as the final stage of fulminant viral hepatitis (also known as acute liver dystrophy or submassive hepatitic necrosis), a postdystrophic scarred liver ("potato liver") can develop. (s. fig. . ) cicatricial distortions with a continuing effect, regenerative processes, intrahepatic vascular disorders and hypoxia-related damage lead to the conclusion that a posthepatitic, postdystrophic scarred liver may well be a special form of cirrhosis. ᭤ neither the functional state of liver insufficiency nor hepatic coma can be recognized histologically. the common target structures for the various causes of acute liver failure are usually the cellular and subcellular biomembranes of the hepatocytes. among other things, any damage to these biomembranes causes a massive inflow of calcium into the liver cells, which results in a severe disorder of the cell milieu and ultimately in cell death. in oxygen deficiency, the oxidative stress is mainly localized in the extracellular spaces. this is where the kupffer cells and neutrophils are involved in complex self-stimulating mechanisms, which can lead to the formation of inflammatory mediators and cytotoxic substances. • an important pathogenetic aspect is the "priming effect", which generally results in the increased production of oxygen radicals. the complex process of lipid peroxidation likewise effects massive liver cell damage in the form of self-perpetuation. • excessive immunological reactions, which occur in acute liver failure due to viral hepatitis, halothane hepatitis, etc., are significant. there are also isolated cases in which biotoxometabolites are produced and may act as neo-antigens. (s. fig. . ) consequently, severe damage to liver cells and widespread necrosis are usually the result of a network of altered cellular and humoral reactions, which for their part are often the initial cause of acute liver failure due to their synergistic and interactive effects (h. popper et al., ) . systemic reactions are responsible for the fact that other organs and functional sequences are equally affected, thus creating a wide spectrum of clinical findings and complications. acute liver failure is a rare occurrence. about five cases are found out of , hospital admissions (in the usa a total of ca. patients per year, in germany ca. ). however, there can be wide variations in frequency due to the effect of regional differences on individual aetiology. the causes of acute liver failure are numerous and varied. diabetes mellitus and overweight ( ) are extremely high risk factors. • primary or secondary hepatitis viruses are deemed a frequent cause, although there are regional and individual variations (e. g. drug dependence, pregnancy) regarding the predominant virus type. • a further common cause (ca. %) are drugs (particularly paracetamol, often taken with suicidal intent, and halothane), followed by mycotoxins, alcohol and carbon tetrachloride (such as can be found in cleaning agents or solvents, and also with "glue sniffers"), heat-stroke (up to % of cases), ecstasy, and vascular diseases. ( , ) (s. tab. . ) paracetamol: the first report on acute liver failure due to paracetamol poisoning was published in (d. g. d. davidson et al.). due to induced cyp ii e , paracetamol is metabolized to the extremely reactive molecule n-acetyl-p-benzoquinone-imine (napqi). this binds covalently to cellular proteins. a small amount of napqi is neutralized by glutathione; however, with a larger quantity of napqi (following an intake of > g paracetamol), the hepatic glutathione supplies are used up, so that the napqi becomes highly toxic. the overall picture of acute liver failure is first and foremost determined by the clinical findings. the symptoms are dramatic and subject to swift change. the course of disease can advance within a matter of days or, in a subacute form, take several weeks. ( , , , ) general symptoms: the acute clinical picture develops swiftly with conspicuous symptoms, such as fatigability, loss of appetite, nausea, weakness, lassitude, meteorism, apathy and disruption of the circadian rhythm. encephalopathy: rapidly, often within one or two days, there is evidence of dysarthria, muscle tremor, finger tremor, lack of concentration and asterixis. restlessness, hyperkinesis and hallucinatory experiences occur. even screaming attacks have been observed. these symptoms, which can still be classified under stages i and ii, are fully reversible. nevertheless, lethality of Ϫ % must be anticipated in stage ii. in contrast, stage iii is clearly less reversible. somnolence, stupor with confusion, deviant behaviour, hyperreflexia, babinski's reflex, clonus and spasticity as well as nystagmus are now observed. there is usually still a response to acoustic stimuli. the eeg shows a slowing down of basic activity ( . Ϫ . / sec.) together with mainly biphasic and triphasic potentials. lethality rises to over %. in stage iv, the patient is in a deep coma. there is evidence of areflexia, an absence of any corneal reflex and loss of tonicity; the brain waves flatten out to an isoelectric line. irrespective of therapy, lethality is Ϫ %. (s. tab. . ) cerebral oedema: as from coma stage iii, cerebral pressure can increase ( Ϫ % of cases) owing to water retention and/or vasodilation with hyperaemia, yet with a subsequent reduction in cerebral perfusion and hypoxia. intracranial cerebral compression is > mm hg. cerebral oedema is vasogenetic and/or cytotoxic, the latter feature appearing to predominate. clinical symptoms include disorders in the respiratory rhythm (in particular tachypnoea), hypertension, bradycardia and increased muscular tonus. singultus implies damage to and impending constriction of the brain stem. the pupils are dilated due to the pressure on the oculomotor nerve. chemosis can develop, which is a fatal prognostic sign. ( ) intracranial blood circulation sinks rapidly. in Ϫ % of cases, cerebral oedema is fatal. ( , , , , , , ) jaundice: with the foudroyant disintegration of liver cells, a comatose condition can set in within a few hours, even before jaundice is identified. in most cases, however, jaundice is already present. the intensity and time of onset vary. severe jaundice (> mg/dl) is considered to be a poor prognostic sign. the sweet aromatic smell of the exhaled breath (mercaptan derivatives) is seen as a reliable sign of acute liver failure, but it is not always present. the administration of poorly absorbable antibiotics (e. g. paromomycin) improves the condition of hepatic foetor, and can even eliminate it temporarily. (s. pp , ) fever: fever often occurs; it mostly remains at °c, but septic temperatures are possible. • in some cases, this may be a question of aetiocholanolone fever, whereby r r aetiocholanolone can also be quantified in the serum. • bacterial infections likewise cause fever and require appropriate treatment. toxins may also be responsible for the febrile condition (tissue toxins, endotoxins). (s. p. ) liver size: the liver may have normal size or it can be enlarged due to hyperaemia or massive fatty infiltration. a rapid shrinking of the liver to less than ml in volume ("dystrophy", "acute atrophy") Ϫ requiring sonographic or ct monitoring at the bedside Ϫ is deemed to be a poor prognostic sign. at present, there is no specific laboratory investigation which facilitates the diagnosis of acute liver failure. in view of the severity of this clinical picture, there are, however, a number of laboratory parameters which show marked pathological changes and thus require full diagnostic clarification. activin a serum levels were elevated, especially in patients with acute liver failure, due to a paracetamol overdose. this did not affect the final outcome, but was possibly a factor in the inhibition of liver regeneration. serum follistatin was also increased in patients with fulminant liver disease. ( , ) furthermore, the laboratory values allow an assessment of the complications involved and an evaluation of the prognosis. ( , , , , , ) various laboratory values are indicative of severe complications and thus considered to be criteria pointing to a poor prognosis. (s. tab. . group-specific component protein: this substance (ϭ α -globulin) is synthesized in the liver and binds actin. gcp is released upon hepatocyte decay; its pronounced reduction in the serum results from the decrease in synthesis in acute liver failure. ( ) the course taken by acute liver failure varies in each case as a result of the respective complications, which also decidedly worsen the prognosis. close-meshed and targeted laboratory investigations can usually identify complications early enough, so that successful therapy might still be possible. coagulation disorders: some Ϫ % of patients with acute liver failure are in danger of suffering from serious gastrointestinal bleeding. extensive cutaneous haemorrhages also occur frequently. in addition, disseminated intravascular coagulation (dic) sometimes develops. as a result, bleeding and coagulation disorders number among the most frequent causes of death ( Ϫ %). pathophysiology is based on the diminished synthesis of coagulation and fibrinolysis factors and inhibitors as well as a decrease in the breakdown of activated factors, a functional disorder of thrombocytes or thrombopenia, and latent consumptive coagulopathy. it is of great help to determine ptt and factor v. a high level of the thrombin-antithrombin iii complex (tat) points to a poor prognosis. the simultaneous development of portal hypertension in individual cases promotes a tendency towards nasopharyngeal and gastrointestinal bleeding. ( acid-base disorders: initial metabolic alkalosis (resulting from decreased urea synthesis with reduced bicarbonate consumption) may be superimposed by respiratory alkalosis as an outcome of disorders in lung function. during the further course, metabolic acidosis (with renal insufficiency) and respiratory acidosis (with pulmonary insufficiency) can be expected. in advanced or severe stages of the disease, lactate acidosis may develop in some % of all comatose patients owing to restricted gluconeogenesis. circulatory disorders: in general, acute liver failure is initially accompanied by hyperdynamic circulation. during the further course, approximately % of patients develop hypotension, which above all results in a considerable reduction in hepatic, cerebral and renal perfusion. at the same time, peripheral vasodilation is usually evident. bradycardia, generally resulting from cerebral oedema, worsens the cardiovascular conditions and is considered to be a poor prognostic sign. ultimately, the patient does not respond to volume expansion and catecholamines. hypoglycaemia: in Ϫ % of cases, hypoglycaemia develops and can all too easily be overlooked. the cause is seen to be a reduction in liver glycogen content, diminished glycogen synthesis and gluconeogenesis as well as hyperinsulinaemia due to reduced degradation of insulin in the liver. ( ) it is often difficult to eliminate such hypoglycaemia, even with i.v. glucose infusions. • furthermore, there is a danger of hypokalaemia and even hypophosphataemia, necessitating phosphate substitution with continuous monitoring of the serum values of phosphate and calcium (reactive hypocalcaemia is dangerous). the frequency of hyperamylasaemia is reported to be % of patients with acute liver failure; in Ϫ % of cases, pancreatitis could be identified clinically and sonographically. the cause is multifactorial. infections: because of their greater susceptibility, about % of patients with acute liver failure are subject to the threat of bacterial infection, which in % of cases is also the reason for their death. the typical signs of an infection, such as fever or leucocytosis, are often absent. increased levels of procalcitonin (> . ng/ml) are deemed to be a valid marker of bacterial infection. the respiratory tract and the urinary passages are most frequently affected. regular bacteriological examinations (sputum or urine as well as catheter after removal) should therefore be carried out. haemocultures have to be checked for both aerobians and anaerobians. multiple serological tests may be necessary for aetiological clarification. there is also a certain risk of fungal infections. ( ) the survival rate in acute liver failure is Ϫ %. this rate varies widely owing to a number of reasons. there is a better prognosis for poisoning from paracetamol or amanita phalloides, since successful therapy procedures are already established for these forms of intoxication. younger patients ( to years) have a better prognosis. this also applies to hav infection. a poor outcome can be expected in obesity, wilson's disease or the budd-chiari syndrome as well as in coma stages iii and iv (lethality over %) due to various complications (e. g. bleeding, renal or respiratory insufficiency, infection) Ϫ especially with younger (< years) or older patients (> years). acute liver failure which is due to halothane, the application of various medicaments or viral hepatitis (delta superinfection, hev in pregnancy) likewise has a less favourable prognosis. • laboratory parameters such as serum bilirubin, higher afp values (especially during the first three hospital days), coagulation factors, galactose test and cholinesterase have proved helpful in assessing the course of disease, liver function and prognosis. ( , , , , , , , ) the regenerative ability of the liver is of utmost importance for overcoming such a severe disease. ( ) after a regeneration period, an intact cell mass (hepatic volume fraction) of > % is required for survival. ( ) various factors are indicative of good regeneration: rising values of α -foetoprotein (and also γgt), hgf, egf, thfα, tnfα and interleukin- as well as a decline in serum phosphorous levels. ( ) it was possible to improve regeneration by means of hepatotropic substances, such as insulin and glucagon, so that these substances are also referred to as "goodies" for the liver (s. sherlock, ). subsequent investigations proved to be contradictory. ( , ) an increase in the regeneration rate of the liver cells can possibly be achieved either by hepatic arterial infusion of pge ( ) or by silymarin through stimulation of rna synthesis. (s. pp , ) (s. fig. . ) chronic liver insufficiency is due to the progression of an already existing chronic liver disease. this generally tends to be advanced cirrhosis of varied aetiology. basically, however, any liver disease can be a potential cause of chronic liver insufficiency. alcohol, infections and certain medicaments are also deemed to be common causes. thus a great number of substances and events can trigger liver insufficiency. the clinical picture of chronic liver insufficiency comprises both a compensated and decompensated form. these two stages of manifest chronic liver insufficiency affect the hepatocellular area or the portal system either exclusively or predominantly (ϭ cellular or portal compensation or decompensation); mostly they occur as a combined form of disease. the resulting spectrum of clinical and laboratory findings will reflect either a global or partial insufficiency of the liver. (s. p. ) general manifestations of the disease: the clinical picture of chronic liver insufficiency is characterized by a number of symptoms such as fatigue, apathy, lack of appetite, lack of concentration, infirmity, sensation of repletion and meteorism. clinical findings: organ-related so-called "minor signs" of liver insufficiency can be observed over a certain period of time. (s. tab. . ) Ϫ itching Ϫ skin stigmata of liver disease Ϫ tendency to "bruise" Ϫ nasal haemorrhage and ulorrhagia Ϫ tongue changes Ϫ intermittent acholic stool Ϫ intermittent dark urine Ϫ anaemia Ϫ thrombopenia Ϫ leucopenia Ϫ macrocytosis . fever . splenomegaly tab. . : so-called "minor signs" of chronic liver insufficiency constant meteorism ("first the wind and then the rain " ") and intermittent changes in the colour of stools and urine are distinct signs of impending insufficiency. the "blossoming" of spider naevi, an intensification of palmar erythema and tongue changes (e. g. transition of the moist "scarlet tongue" into a dry "raspberry tongue") are common. obvious features of the blood count are: anaemia (due to bleeding of the skin or mucosa, folic acid deficiency, reduced erythrocyte survival time) and thrombopenia (due to consumptive coagulopathy, dilutional thrombopenia with plasma dilution, immunothrombopenia, sequestration in splenomegaly and toxic inhibition of the bone marrow). decompensation in chronic liver insufficiency is characterized by the development of severe, life-threatening complications: . ascites and oedema . coagulopathy and bleeding . hepatic encephalopathy . hepatorenal syndrome . hepatopulmonary syndrome . impairment of liver functions of particular significance is the serious impairment of essential tasks performed by the liver such as the detoxification function (ammonia detoxification, biotransformation, radical scavenger function, clearance abilities of the res, etc.), the synthesis of vital proteins and the regulation of biochemical systems and substances Ϫ these are considered to be precursors of complicative developments. any insufficiency of bilirubin metabolism is reflected in increasing jaundice, likewise deemed to be an unfavourable sign with respect to prognosis. the term hepatic encephalopathy (he) describes the entire field of neuropsychiatric symptoms which can be found in patients suffering from acute or chronic liver disease. the term portosystemic encephalopathy (pse) stresses the presence of portosystemic shunts, which are as a rule associated with liver cirrhosis. • hepatic coma (in stages iii and iv) is the ultimate and total loss of consciousness (coma ϭ deep, sound sleep). in clinical terms, four or five stages can be defined, but the latent or subclinical stage as well as stages i and ii may progress so rapidly that only the comatose final stage is actually determined. generally, chronic liver insufficiency is seen as a liver failure coma, i. e. exogenous coma. recurrent hepatic encephalopathy points to the existence of a chronic liver disease, particularly liver cirrhosis. the serum levels of tnf correlate positively with the severity of he. (see chapter ) ascites and oedema are also found in severe hepatic diseases, pointing to serious disorders in the water and electrolyte metabolism. these complications are signs of decompensation in liver cirrhosis or chronic liver insufficiency. pleural effusion may also be evident. cirrhosisrelated pleural effusion without concomitant ascites has been described as a rarity. (see chapter ) all liver diseases resulting in liver insufficiency can also give rise to the hepatorenal syndrome. this syndrome is most frequently found in decompensated liver cirrhosis ("renal insufficiency in the terminal stage of cirrhosis"). it involves massive vasoconstriction of the renal cortical vessels with a critical drop in the glomerular filtration rate (urine production < ml/day, possibly developing into anuresis). at the same time, systemic vasodilation and hyperdynamic cardiac function are generally in evidence. the survival time is very short. lethality is approx. %. (see chapter ) in Ϫ % of patients with liver cirrhosis, coagulopathy leads to clinically relevant haemorrhagic diathesis. dangerous and considerable bleeding may occur (nasal, gingival), and there may well be pronounced cutaneous haemorrhages; the latter occasionally occur as sugillations, ecchymoses and petechial haemorrhages (s. this condition describes acute liver failure in cases of hitherto well-compensated liver disease. the result is a sudden deterioration in clinical status accompanied by jaundice as well as hepatic encephalopathy and/or the hepatorenal syndrome. there are a number of causes including ( .) well-known hepatotoxic factors (e. g. superimposed viral infection, alcohol consumption, hepatotoxic drugs, intoxication) and ( ( ( .) endogenous factors (e. g. sepsis, variceal bleeding, gastrointestinal haemorrhage, diarrhoea, hypoxia). acute liver failure is frequently the result of a chain of damaging events, like a vicious circle. the clinical and laboratory findings of this sudden deterioration largely correspond to those of acute liver failure (see above). this also applies to potential complications such as coagulopathy, he, ascites and/or hrs. except for the treatment of, for example, paracetamol intoxication and amanita phalloides poisoning, there is no causal therapy for liver insufficiency. all conservative treatment measures are based on four principles: . prevention and treatment of complications . substitution of substances which cannot be adequately produced in the liver as a result of hepatic synthesis disorders . bridging the period of time until toxins have been eliminated, liver functions and regenerative processes have improved or liver transplantation can be carried out . promotion of liver regeneration ᭤ intensive care: patients with alf or decompensated chronic liver insufficiency (e. g. coma stages iiϪiv, refractory ascites, hepatorenal syndrome, disseminated intravascular coagulation, gastrointestinal bleeding) require monitoring and treatment in an intensive care unit, preferably in a transplantation centre. ( , , , ) intensive care involves monitoring the cardiovascular system (blood pressure, pulse, ecg) and respiratory frequency. the patient's y y temperature and urine excretion have to be recorded every hour. the body weight is documented every day using a weighing bed. the water equilibrium should be carefully monitored. consistent preventive measures against infection must be guaranteed for those patients who are particularly at risk. regular physical measures for the prevention of pneumonia are a necessity. a moderate head-up position ( Ϫ °) is recommended. • a central venous catheter (monitoring central venous pressure, parenteral feeding), a nasogastral tube and a suprapubic bladder catheter are positioned for supply and monitoring purposes. nasal oxygen supply is advisable. the insertion of an epidural intracranial pressure probe is essential for early identification of cerebral oedema. feeding: provided the patient does not have a paralytic ileus, enteral feeding via a nasogastral tube is advisable to prevent villous atrophy and thus reduce the risk of bacterial translocation. (s. p. ) • parenteral feeding ( , Ϫ , kcal/day) consists of a continuous intravenous supply of glucose and fat emulsions (mct). hypertriglyceridaemia may, in the case of lipid infusions, point to a lipid metabolism disorder, but it can also be due to increased glucose intake, which results in fatty degeneration of the hepatocytes and a corresponding reduction in liver function. fructose, sorbitol and xylitol must be avoided! the supply of either liveradapted amino acids or branched-chain amino acids is recommended for chronic liver insufficiency Ϫ but not advisable in cases of acute liver insufficiency, because almost all amino acids are elevated in the serum in endogenous hepatic coma. a high daily dosage of watersoluble vitamins (possibly divided into two doses) is important. administration of zinc is recommended. electrolytes (na, k, ca, mg) and blood sugar must be carefully monitored, and any deviation from the norm should be corrected immediately. the risk of hypophosphataemia must be eliminated by early parenteral substitution. during refractory episodes, such as those involving the acid-base equilibrium and hyperhydration, haemodialysis is usually indicated. in hypoalbuminaemia, substitution with salt-free albumin is necessary. • with about % of patients, artificial respiration is called for, the aim being controlled hyperventilation. n-acetylcysteine is believed to promote the supply of oxygen to the tissues. ( ) as a result, this substance, which is free from side effects, was also recommended for cases of ccl intoxication ( ) and is even considered helpful in acute liver failure with a different aetiology. h antagonists and omeprazole are recommended. • the timely and repeated administration of fresh plasma (ffb) as well as of antithrombin iii has proved to be the most effective measure for balancing plasmatic coagulation disorders. bacterial infections are extremely common as a result of serious impairment of the cellular and humoral resistance (ca. %). close-meshed bacteriological investigations are required in the frequent absence of clinical signs of infection. this leads to early antibiotic therapy based on an antibiotic sensitivity test. although an antibiotic prophylaxis is not actually recommended, it should nevertheless be considered in the individual case, since the spreading of an infection has a decidedly nega-tive impact on prognosis. • administration of selenite (i.v.) may be advisable. around % of patients develop a fungus infection, with a mortality rate of %. (s. p. ) the administration of amphotericin b or fluconazol is an effective prophylactic measure. • bacterial or fungal infection can also be effectively suppressed by intestinal restimulating of the bacterial flora or intestinal sterilisation by means of neomycin (or paromomycin), a combination of nystatin and gentamicin, or lactulose. ( , ) (s. pp , , ) essential phospholipids (epl): in a pilot study, it was possible to achieve recompensation and lasting stabilization in nine out of ten patients suffering from severe liver insufficiency by i.v. administration of a new galenic form of polyenylphosphatidylcholine. ( ) • this clinical result accords with other clinical studies and might be supported by the finding that a considerable deterioration in liver function was associated with a deficit of epl. ( ) (s. p. ) paracetamol intoxication: liver damage due to paracetamol (> g) becomes manifest within ca. hours after intake. (s. p. ) for this reason, it is essential first of all to remove the non-absorbed fractions by gastric lavage and intestinal cleansing. as medicinal treatment, i.v. administration of the glutathione precursor nacetylcysteine is the therapy of choice (l. f. prescott et al., ) . dosage is mg/kg bw with glucose as a rapid i.v. infusion ( Ϫ minutes), followed by mg/ kg bw over hours and finally mg/kg bw during the next hours (ϭ about mg/kg bw within hours). this therapy has to be commenced as soon as possible (no later than Ϫ hours after intoxication), even though a hepatoprotective effect can still be achieved up to hours later. a serum concentration of < μg/ml within hours or < μg/ml within hours after intake can be considered prognostically favourable. (s. fig. . ) there is no specific antidote for amanita toxins. given timely and appropriate therapy, morbidity and mortality are surprisingly low. • in cases of therapy failure or a critical course of disease, liver transplantation may be indicated. cerebral oedema: mannitol ( . g/kg bw or ml, each as % solution) is used to treat the dreaded cerebral oedema. if renal function is sufficient, this course of therapy can be repeated every one to four hours, as required. serum osmolality should not exceed mosm/l, and intracranial pressure should not go above mmhg. when renal function is restricted, dehydration must be effected by haemofiltration. artificial respiration is required (often as peep ventilation). continuous monitoring of the intracranial pressure using an epidural intracerebral pressure probe is extremely helpful. frequently, there is increased susceptibility to cerebral convulsibility; therefore, phenytoin should be administered at an early stage. therapeutic application of thiopental (a. forbes et al., ) as i.v. solution (up to mg/hour) calls for intracranial pressure probe monitoring. ( ) other means of lowering the intracerebral pressure include the use of aminophylline, ranitidine, luxus oxygenation and semirecumbent positioning. ( , , , ) a prophylactic reduction in pco down to Ϫ mm hg through hyperventilation can be advantageous in the initial stage of a brain oedema. ( , ) moderate hypothermia (core temperature down to Ϫ °c, for Ϫ hours) may be useful in reducing the intracerebral pressure and cerebral blood flow as well as the cerebral uptake of ammonia. ( ) ornithine aspartate ( g/ hours as intravenous infusion) ( ) and flumazenil are advisable for the treatment of hepatic precoma and coma. dopamine ( to μg/kg bw/hr) should be administered early on to stabilize the circulation and renal blood flow. • n-acetylcysteine can be applied during oxygenation due to its positive effect on stabilizing the blood circulation and improving the serum coagulation factors. • indomethacine reduces cerebral ammonia uptake. the positive results achieved by the application of pge were reported in (m. abacassis et al.). according to a subsequent prospective study, % of patients with fulminant and subfulminant hepatitis survived. ( , ) the effect is attributed to improved arterial flow and regeneration of the liver ( . to . μg/ kg bw/hr by means of perfusor for up to hours, with the dosage gradually being phased out). lamivudine ( mg/day) proved to be effective: it was possible to achieve a lasting improvement in liver function and to avoid liver transplantation. no side effects were observed. in view of the loss of complex biochemical liver functions, drug intervention in the metabolic processes of the liver should be as varied as possible Ϫ even the use of therapeutic agents which are not clinically controlled may be biochemically or pharmacologically justified. the most important survival factor in acute liver failure is the patient's age. in the to -year age group, Ϫ % of patients survive, whereas those older than years have hardly any chance of survival. it would appear that the good regenerative ability of the liver in young people is the best guarantee for survival. • an attempt must be made at bridging the decompensatory phase by means of optimum intensive care and monitoring of the cerebral pressure as well as by applying clinically proven or indeed new therapeutic procedures or medication until the liver has adequately regenerated or until liver transplantation can be carried out. • basically, there are three techniques available for bridging the compensatory phase: ( .) extracorporeal systems ( ( ( .) biosynthetic artificial livers or hybrid organs, and ( .) transplantation of hepatocytes. ( , , , , ) • it has proved to be much more successful when the serum (ca. l fresh frozen plasma/day) is infused into the femoral artery rather than into the vein. in patient plasma separated by plasmapheresis was for the first time passed through activated charcoal and artificial resin in order to absorb toxins. in this way, the patient's own purified plasma is reinfused together with the solid components of the blood. this procedure produces fewer side effects and is easy to carry out. . total body wash-out: this technique is a modification of exchange transfusion. the circulatory system is washed out with electrolyte solutions and then refilled with donor blood whilst the patient is in a state of hypothermia (g. klebanoff et al., ). . haemodialysis: in temporary improvement could be achieved for the first time by means of haemodialysis in a patient presenting with fulminant hepatic failure (w. m. keynes). the procedure, however, is not generally recommended. it may be indicated in renal failure, acid-base disorders or with hyperhydration. following haemodialysis, substitution of reduced amino acids is necessary. this procedure turned out to be of more value than haemodialysis. no dialysate fluid is required. instead, a solution containing buffered bicarbonate is used to replace the ultrafiltrate. in fulminant hepatic failure, continuous venovenous haemofiltration is recommended because of its advantages for the circulation and metabolism. heparin or prostacyclin can be used as anticoagulants. . haemodiabsorption: the biologicdt system is a combination of haemodialysis and haemoadsorption (s.r. ash et al. ). ( ) plasma separation was subsequently added to this system (s.r. ash et al., ) . ( ) this newly developed biologicdtpf facilitates direct plasma contact with the haemodiadsorber. the system, which makes use of both a charcoal and a cation exchanger, dialyzes blood across a parallel plate dialyzer with a cellulose mem-brane. so far, results have been disappointing Ϫ only lactate, creatinine and bilirubin were reduced. the aim of albumin dialysis is to remove both soluble metabolites and albumin-bound substances (abs) from the blood of patients with acute liver failure. (s. tab. . ) benzodiazepines fatty acids bile acids phenylalanin bilirubin several peptides carbon hybrids tryptophan copper etc. tab. . : albumin-bound substances (abs) relevant in acute liver failure spad: single-pass albumin dialysis was the first method to be developed. the blood of the patient is extracorporeally dialyzed through an albumin-impermeable membrane against albumin in the secondary circuit. the loaded albumin is discarded. the spad method was further developed into a combination of dialysis, filtration and adsorption (ϭ molecular adsorbent recycling system). ( ) . the patient's blood is fed through a hollow-fibre filter and dialyzed against an albumin dialysate. the abs (s. tab. . ) pass through the pores in the filter and become bonded. plasma proteins, hormones and vitamins are not lost. the albumin dialysate is recirculated in a closed circuit where it is fed through a second dialyzer and two adsorber columns which bind the abs. the albumin dialysate is returned to the hollow-fibre filter. it is dialyzed against a bicarbonate solution in order to remove the excess water and water-soluble substances (ammonia, creatinine, urea, iron, copper) as well as to stabilize the electrolyte and glucose levels and the ph value. the results obtained to date are promising. ( , , ) fpsa: fractioned plasma separation and adsorption is a very efficient and multifactorial method, employing membranes and adsorbants. ( ) it is additionally characterized by the use of microparticles ( . Ϫ . μm), which are recirculated in suspension using high-speed flow ( Ϫ l/min) to optimize the in-line filtration process. in a further development, a special sulfone filter is applied. in the meantime, the prometheus method has been introduced. ( ) here, the plasma is separated out by an albumin-permeable filter and cleaned in a secondary circuit via an adsorber together with conventional high-flux haemodialysis. direct contact between the albumin plasma and the adsorber helps to increase the efficiency of this method. these liver support methods serve to detoxify the organism for a limited period of time. they are regarded as supportive measures in intensive care. survival time has often been prolonged, yet only in isolated cases has the overall life-span of the patient been extended. these methods of treatment, which are costly and involve considerable resources, can only be carried out in medical units that are equipped with all the facilities of intensive care and thus in a position to effect epidural brain pressure measurement, blood purifying processes and liver perfusion methods. • only young patients between the ages of and have a real chance of survival ( to %), provided they receive optimum intensive care. with patients over years, supportive techniques should only be applied to bridge the time period until a liver transplantation can be carried out. however, conservative treatment may be attempted for four or five days under the following conditions irrespective of age: ( .) there is a chance of regeneration during this period that can be made use of; ( ( ( .) this period of time does not preclude the patient's chances of liver transplantation (which calls for two to four days' preparation time); ( .) should there be no signs of recovery or regeneration, not even in younger patients (< years), transplantation is nevertheless indicated. • after four or five days, however, severe complications develop, also in younger patients, which render transplantation difficult or even impossible. especially older patients (> years) should undergo liver transplantation without delay. temporary substitution of the liver function using hepatocytes (e. g. in haemofiltration systems or bioreactors) is conceivable in acute liver failure, possibly in conjunction with activated charcoal filtration or with plasma separation. the importance lies in bridging the phase of acute liver failure until compensation of the liver function or liver regeneration is achieved. the bioreactor is filled with capillaries in which the patient's blood circulates; some of this blood has already been oxygenated extracorporeally. the efficacy of the system depends on an efficient exchange of the corresponding substances in both directions as well as stable hepatocyte functions. it is possible to use human (allogeneic) or animal (xenogeneic) hepatocytes as well as cell cultures (immortalized cells or tumour cell lines). if human cells are taken, hepatocytes per patient are required Ϫ as would be needed for a conventional liver transplant. regarding the use of animal hepatocytes, there is a possible risk in that no solution has yet been found to the question of zoonosis transmission and there may be an immune reaction to foreign antigens. bile flow also remains a problem. ( , , , , ) . the binding of microsomal liver enzymes to synthetic carriers is a promising method of temporarily compensating important liver functions (g. brunner, ) r r . freshly isolated hepatocytes of pigs, immobilized on collagen-coated microcarriers, remained vital in-vivo and in-vitro over a longer period in a perfusion system; they were able to conjugate bilirubin and synthesize proteins. these results provided the basis for developing an extracorporeal bioartificial liver (a. a. demetriou et al., ) . in more advanced systems, plasma was perfused through an activated charcoal column and a fibre system with cultured pig liver cells. ( , , , ) • using a bal, the plasma is separated by centrifugation and directed into a reservoir in order to increase both the plasma and metabolite flow. by integrating an activated charcoal column, it is possible to effect a greater elimination of toxins. the separated plasma reaches the hollow-fibre bioreactor, where it is perfused through the previously inserted hepatocytes ( ± hours). • such a system yielded increased production of coagulation factors in a patient with alcohol cirrhosis (d. f. neuzil et al., ). (s. fig. . ) attention has recently focused on temporarily replacing the liver function with hepatocytes which have been cultured in the extracapillary space of a cellulose-acetate hollow-fibre unit. each unit contains ca. g c a cells, an amount which is necessary for successful perfusion. elad has proved efficacious in clinical use. ( ) . blss: the bioartificial liver support system is made up of a blood pump, a heat exchanger to control the blood temperature, as well as an oxygenator and a bioreactor. the hollow-fibre bioreactor generally contains Ϫ g of porcine liver cells. initial experience with blss is encouraging. ( ) . bels: the berlin extracorporeal liver support system consists of a three-dimensional accumulation of approx. g pig liver cells. these cells are linked by means of capillaries and provided with oxygen independently of the patient's blood, so that they function and stay vital for several weeks. ( ) the modular extracorporeal liver support system was developed from bels. in contrast to bels, however, it consists of three modules: ( .) a cell module with human hepatocytes, ( ( ( .) single-pass albumin dialysis, and ( .) a dialysis module for constant venovenous haemofiltration. ( ) the clinical significance of bioartificial systems largely depends upon whether it is possible ( .) to keep functional hepatocytes alive in extracorporeal systems for an adequate period of time and ( ( ( .) to make such systems available at short notice for use in emergencies. the idea of extracorporeal liver perfusion (eclp) for removing toxins by way of perfusion using an animal liver goes back to andrews ( ) ( , ) although the procedure is relatively safe, the results obtained with perfused livers from humans or baboons would appear to be better than is the case with livers taken from pigs. ( ) ( ) . the transplanted split should be around % of the body weight of the recipient. slt has a higher complication rate than olt. ldlt: with regard to living donor liver transplantation, slt has become particularly important in cases where no cadaver organ is readily available. living donor liver transplantation was first carried out on children. the left lateral segment, usually segments ii and iii, of the donor's liver is used. around % of olt candidates are also suitable for ldlt. more than , living donor liver transplantations have been carried out worldwide. the donor mortality rate is . Ϫ . %. ( , , ) in auxiliary partial orthotopic liver transplantation (apolt) was successfully carried out for the first time in acute liver failure, with the subsequent possibility of dispensing with the transplant after regeneration of the patient's own liver. ( ) the corresponding part of a donor liver is transplanted orthotopically as left lateral segments ii and iii into the acutely diseased liver. the requisite partial resection of the liver is considered difficult. ( ) a european multicentre study ( centres) achieved equally good results in patients compared to orthotopic liver transplantation with the removal of the native liver (m.-p. chenard-neu et al., ) . apolt is intended as a temporary measure in acute liver failure with the aim of discontinuing immunosuppressive therapy after the patient's own liver has regenerated. so far, results imply that more complications are experienced in apolt than in olt. the concept of heterotopic transplantation of a complete or even partial ("spliced") donor liver should also be pursued further. heterotopic transplantation involves placing an auxilliary (additional) organ in the right upper abdomen (o. t. terpstra et al., ). in surgical terms, this technique is considered to be demanding due to the application of the piggy-back method (ϭ anastomosis of the donor liver with the appropriately prepared ostium of the hepatic veins to the infrahepatic caval vein, generally cranial to the opening of the renal vein). • these two methods (apolt and auxiliary heterotopic liver transplantation) are particularly suitable for juveniles with acute liver failure because they bridge the critical time span preceding the regeneration of the diseased liver. immunosuppression is thus only required for a restricted period of time. the transplant shrinks or is surgically removed. acute liver failure induced by ecstasy was successfully overcome using this technique. ( ) it allows the liver function to be compensated and gives the diseased liver time to regenerate. ( ) pigs with human immune system genes are expected to facilitate the production of transgenic donor organs (d. white, ) . this is the basis of all endeavours to use transgenic pig liver for the purpose of xenotransplantation (j. platt, ). in the future, genetic engineering should make it possible to eliminate the immunobiological risk of complement-activated, hyperacute rejection. however, the problem regarding the transmission of zoonoses has not yet been resolved. to date, a survival period of days has been achieved with three xenotransplants in alf and chronic liver insufficiency (j. fung et al., ). among the experimentally tested transplantation sites are the spleen, kidneys, lungs, pancreas, peritoneum, greater omentum and fatty tissue. up to now, the spleen has proved to be the most suitable site. the transplantation of foetal liver cells into the spleen may even culminate in a liver lobule-like formation with bile ducts and veins Ϫ however, the functional results have (so far) been no better than with normal hepatocytes. the question of the required number of hepatocytes has still not been resolved: the collapse of a certain liver function (e. g. normalization of factor viii values in serum) can be compensated by a far lower number of hepatocytes than is the case with total liver failure (e. g. acute liver failure). calculations made up to now have claimed that there are at least Ϫ liver cells in partially resected liver parenchyma. indications for the transplantation of hepatocytes predominantly involve those liver diseases in which functional failures occur in the liver cells (not in the bile ducts). • permanent transplantation would be indicated, for example, in order to eliminate congenital metabolic disorders of the liver cells. in this case, it is possible to use hepatocytes from the patient, with subsequent elimination of the defect by gene technology, as well as hepatocytes from healthy donors. a therapeutic effect lasting for over one year was achieved for the first time in a girl suffering from the crigler-najjar syndrome (i. j. fox et al., ). • human hepatocytes are most definitely more suitable than animal liver cells. the latter may well meet the requirements for a provisional substitute, but not for permanent transplantation. ᭤ looking into the future, it can be expected that the next few years will witness advances in gene technology (e. g. transgenic animal liver) and molecular biology (e. g. targeted blockade of the immune system against the liver transplant) or even produce new concepts of liver and hepatocyte transplantation. ᭤ it is no longer too bold to pin legitimate hopes on the development of an artificial liver. the preliminary objective hereby must be to replace the most important liver functions for a longer period of time, thus affording the diseased liver of the patient a greater chance to regenerate. are there histopathologic characteristics particular to fulminant hepatic failure caused by human herpesvirus- infection? 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failure heterotopic liver transplantation for fulminant hepatic failure: a bridge to recovery split liver/auxiliary liver transplantation for fulminant hepatic failure emergency liver transplantation for acute liver failure. evaluation of london and clichy criteria transplantation orthotopique du foie pour intoxication grave par amanite phalloide long-term followup of auxiliary orthotopic liver transplantation for the treatment of fulminant hepatic failure living donor liver transplantation for fulminant hepatic failure auxiliary versus orthotopic liver transplantation for acute liver failure liver transplantation for fulminant hepatic failure hepatocyte transplantation hepatocyte transplantation in acute liver failure human fetal hepatocyte transplantation in patients with fulminant hepatic failure hepatocyte transplantation in man transplantation of isolated hepatocytes. principles, mechanisms, animal models, clinical results alternatives to liver transplantation: from hepatocyte transplantation to tissue-engineered organs hepatocyte transplantation: a potential treatment for acute liver failure key: cord- -ifei ly authors: dixon, luke; varley, james; gontsarova, anastassia; mallon, dermot; tona, francesca; muir, david; luqmani, asad; jenkins, ieuan harri; nicholas, richard; jones, brynmor; everitt, alex title: covid- -related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia date: - - journal: neurol neuroimmunol neuroinflamm doi: . /nxi. sha: doc_id: cord_uid: ifei ly objective: to describe a novel case of coronavirus disease (covid- )-associated acute necrotizing encephalopathy (ane) in a patient with aplastic anemia where there was early brain stem-predominant involvement. methods: evaluation of cause, clinical symptoms, and treatment response. results: a -year-old woman with a background of transfusion-dependent aplastic anemia presented with seizures and reduced level of consciousness days after the onset of subjective fever, cough, and headache. nasopharyngeal swab testing for severe acute respiratory syndrome coronavirus (sars-cov- ) was positive, and ct during admission demonstrated diffuse swelling of the brain stem. she required intubation and mechanical ventilation for airway protection, given her reduced level of consciousness. the patient's condition deteriorated, and mri on day demonstrated worsening brain stem swelling with symmetrical hemorrhagic lesions in the brain stem, amygdalae, putamina, and thalamic nuclei. appearances were consistent with hemorrhagic ane with early brain stem involvement. the patient showed no response to steroid therapy and died on the eighth day of admission. conclusions: covid- may be associated with an acute severe encephalopathy and, in this case, was considered most likely to represent an immune-mediated phenomenon. as the pandemic continues, we anticipate that the spectrum of neurologic presentation will broaden. it will be important to delineate the full clinical range of emergent covid- -related neurologic disease. coronavirus disease (covid- ) is caused by severe acute respiratory syndrome coronavirus (sars-cov- ) and, was first detected in the human population in late december . as of april , , over million cases have been reported worldwide and over , people have died from the infection. the typical presentation of sars-cov- with fever and respiratory symptoms is well recognized, although there is comparatively little reported on the neurologic sequelae. despite the paucity of reported cases, there is increasing evidence that patients with severe covid- often develop neurologic manifestations such as impaired consciousness. there have been reported cases of covid- -associated encephalopathy and a single case of presumptive covid- -related acute necrotizing hemorrhagic encephalopathy associated with symmetrical hemorrhagic, necrotic lesions in both the thalamic nuclei and amygdalae. here, we report a further case of possible covid- -related necrotizing hemorrhagic encephalopathy associated with early brain stem involvement. a -year-old woman presented to the emergency department with recurrent fleeting episodes of vacant staring and speech arrest associated with flexion of both shoulders and a brief witnessed generalized tonic-clonic seizure (gtcs), followed by postictal reduced consciousness. shortly after arrival in the emergency department, the patient vomited and had a further gtcs. she had a history of aplastic anemia treated with intermittent red blood cell and platelet transfusions. the patient had no significant paroxysmal nocturnal hemoglobinuria clone. she had received immunosuppressive therapy in the past, but not recently. she had returned from a trip to afghanistan weeks before presentation and developed transient abdominal pain and diarrhea. ten days before her neurologic presentation, she developed a persistent cough, sore throat, shivering, and headache, with subsequent shortness of breath and myalgia. three days before presentation, she had a routine telephone hematology clinic consultation and the following day underwent a blood test (table, day- ) which showed a stable platelet count ( × /l), anemia (hemoglobin g/l), and leukopenia (total white cell count . × /l, lymphocyte count . × /l, neutrophil count . × /l). physical examination revealed reduced consciousness with a glasgow coma score (gcs) of of , body temperature of . °c, blood pressure of / mm hg, pulse of beats per minute, respiratory rate of breaths per minute, and oxygen saturation of % on ambient air. neurologic assessment found no focal deficits. chest radiography showed right basal consolidation, and a ct scan of the head showed early swelling of the brain stem (figure ). on admission, her blood cell count showed unchanged anemia and thrombocytopenia (platelet count × /l) which was consistent with the patient's history of aplastic anemia (table). unlike previous blood counts, there was new lymphopenia (lymphocytes . from . days earlier). nasopharyngeal swab rt-pcr testing for sars-cov- returned positive, thus confirming a diagnosis of covid- . the patient was started on levetiracetam and iv ceftriaxone, aciclovir, amoxicillin, and clarithromycin. in light of the severe thrombocytopenia and risk of hemorrhage, human leukocyte antigen-matched platelets (because of known platelet hla antibodies) were transfused intermittently to maintain the platelet count > × /l. twelve hours after admission, the patient's gcs fell to (e , v , and m ), with associated development of an extensor left plantar response and an unreactive left pupil. although the patient's respiratory symptoms remained relatively mild, she underwent endotracheal intubation for airway protection and was transferred to the intensive care unit for mechanical ventilation. repeat head ct showed increased hypodensity and swelling of the brain stem, and a new area of cortical and subcortical hypodensity in the left occipital lobe initially suggested an acute posterior circulation infarct. a subsequent computed tomography angiogram excluded an acute vascular occlusion but showed worsening brain stem swelling with subtle intrinsic pontine hemorrhage and new symmetrical hypodensities in the deep gray matter and amygdalae (figure ). appearances were suggestive of a rapidly evolving encephalopathy with severe involvement of the brain stem. on the fifth day of admission, lumbar puncture was performed immediately after platelet transfusion. csf opening pressure was cm water, and csf analysis showed increased protein concentration ( . g/l) and a normal white cell count of /mm . subsequent standard csf virology pcr (herpes simplex virus and , varicella zoster virus, adenovirus, cytomegalovirus, epstein-barr virus, enterovirus, parechovrius, and human herpesvirus ), csf pcr for sars-cov- , and csf culture were negative. on the sixth day of admission, an mri of the head demonstrated extensive, relatively symmetrical changes throughout the supratentorial and infratentorial compartments. there was diffuse swelling and hemorrhage in the brain stem and both amygdalae. extensive abnormal signal and microhemorrhage were found in a symmetrical distribution within the dorsolateral putamina, ventrolateral thalamic nuclei, subinsular regions, splenium of the corpus callosum, cingulate gyri, and subcortical glossary ane = acute necrotizing encephalopathy; covid- = coronavirus disease ; gcs = glasgow coma score; gtcs = generalized tonic-clonic seizure; sars-cov- = severe acute respiratory syndrome coronavirus . perirolandic regions ( figure ). these regions demonstrated severe swelling and restricted diffusion with peripheral enhancement (figure ). there was partial effacement of the ventricles, temporal uncal herniation, effacement of the basal cisterns, and moderate cerebellar tonsillar herniation secondary to the severe cerebral and pontine swelling. overall imaging features supported a diffuse hemorrhagic acute necrotizing encephalopathy (ane) with involvement of the brain stem. neurologic examination after withdrawal of sedation revealed intact corneal reflexes and normal pupillary total bilirubin (umol/l, - ) responses to light. doll's eye response was reduced. she coughed on suction and initiated breathing but required pressure support mechanical ventilation. she displayed no response to verbal command or painful stimuli. however, based on the severity of the mri findings, the patient was deemed to have a very poor neurologic prognosis. she showed no sign of neurologic improvement after high dose dexamethasone and on the th day of admission died after the withdrawal of ventilatory support. her family declined a postmortem study. to our knowledge, we report the second case of presumptive covid- -related hemorrhagic ane. similar to the previously reported case, our patient had relatively symmetrical hemorrhagic lesions in the amygdalae and thalamic nuclei although, by contrast, there was also extensive involvement of the pons and medulla and, to a lesser extent, the striatum and subcortical perirolandic regions. in our case, the patient's aplastic anemia with severe thrombocytopenia likely contributed to the hemorrhagic component of the encephalopathy. however, outside of bone marrow transplantation and active immunosuppressant therapy, there is no reported predisposition to encephalopathy in patients with aplastic anemia. , our patient was not lymphopenic before covid- , and therefore, it is unlikely that the aplastic anemia caused an impaired immune response. ane is a rare encephalopathy most frequently encountered in children and characterized by multiple, symmetrical lesions in the thalami, striatum, cerebral white matter, and brain stem. , ane has previously been linked to several infective agents including influenza-a, herpes simplex virus, influenza-b, mycoplasma, and human herpes virus- . , as in this case, ane is often rapidly progressive with seizures, reduced consciousness, and vomiting, usually occurring - hours after symptom onset of the viral infection. , as in our case, csf analysis frequently shows an elevated protein concentration but a normal white blood cell count. , the precise etiology and pathophysiology of ane remains unclear. in reported cases, the suspected causative pathogen is rarely detected in the csf by pcr assay. , in an autopsy of a patient with ane secondary to h n influenza, a notable absence of perivascular or meningeal inflammation was found. therefore, ane is not believed to be a product of direct infection but the result of an immune-mediated process involving proinflammatory cytokines. , a possible hyperinflammatory response in covid- is supported by the recent observation that covid- -related acute respiratory distress syndrome may be driven by a macrophage activation syndrome or cytokine storm. unfortunately, in our case, testing for interleukins in the serum or csf was not possible. despite this, an immunemediated phenomenon, as opposed to a neurotropic effect, is suggested because csf rt-pcr testing for sars-cov- was negative and no other potential causative agent was identified. further exploration of potential covid- -related cns pathology is needed and requires national and international collaboration to collect large, organized data sets. the possibility of an immune-mediated process and its therapeutic implications also warrants greater study. neurologic manifestations of hospitalized patients with coronavirus disease covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features epstein-barr virus-associated lymphoproliferative disorder with encephalitis following anti-thymocyte globulin for aplastic anemia resolved with rituximab therapy: a case report and literature review intact survival of refractory cmv limbic encephalitis in a patient with severe aplastic anemia after unrelated bone marrow transplantation acute necrotizing encephalopathy of childhood: correlation of mr findings and clinical outcome acute necrotizing encephalopathy associated with novel influenza h n (pdm ) infection: mri and correlation with brain necropsy acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in japan and taiwan influenza-associated encephalopathy in japan: pathogenesis and treatment detection of influenza virus rna by reverse transcription-pcr and proinflammatory cytokines in influenza-virus-associated encephalopathy the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease no targeted funding reported. key: cord- - pmro bu authors: tung-chen, yale title: acute pericarditis due to covid- infection: an underdiagnosed disease? date: - - journal: med clin (engl ed) doi: . /j.medcle. . . sha: doc_id: cord_uid: pmro bu nan despite various therapeutic schemes used since the onset of the sars-cov pandemic of covid- , mortality remains around - % in the different countries that have reported cases. after the knowledge that the virus enters the cell through the union of its protein s with the receptor for ace (angiotensin converting enzyme type ) has been speculated with the suspension of certain pharmacological groups that due to their mechanism of action increase the presence of these receptors and therefore could increase the passage of virus into the alveolar cells, this point remaining in controversy. on the other hand, in a recently published retrospective series of cases, a frequent elevation of d-dimer has been observed, which has been related to acute pulmonary thrombosis, which has dramatically worsened the prognosis in this subgroup of patients. it is striking that those patients with a higher d-dimer also show more marked desaturations even without observing pneumonia on ctpa (computarized tomography pulmonary angiography). unlike hemorrhagic viruses (ebola, marburg...), sars-cov- could be a highly prothrombotic virus that causes alterations in the coagulation cascade not well characterized at present that would lead to a progressive elevation of d-dimer in function of the severity and extent of microthrombosis. in turn, this hypothesis could explain that these patients have a clearly worse prognosis since in them, orotracheal intubation would provide oxygen to a lung with no microvascular perfusion due to disseminated microthrombotic disease, which would also only be seen in ctpa in very advanced stages and in which little can be done to reverse this situation. gradually a therapeutic scheme is being established that would include hydroxychloroquine and azithromycin (or in other cases lopinavir/ritonavir) in the early stages of moderate disease that does not require treatment in icu (intensive care unit) but given the analytical indication (elevation of ddimer) and imaging (thrombosis in ctpa) in many cases, should be evaluated the early inclusion of low molecular weight heparin (lmwh) at doses of at least high-risk prophylaxis in all these patients without thrombopenia < , platelets or acute bleeding and manifesting high d-dimer. given the paucity of prospective studies, the need for urgent effective management, and the relative safety of these lmwh doses, the hah (hydroxychloroquine-azithromycin-heparin) regimen could be tested in randomized clinical trials to improve the evolution of the disease in cases of torpid evolution. dear editor, the th of march of , the world health organization declared a pandemic caused by a novel coronavirus, named severe acute respiratory syndrome coronavirus (sars-cov- ). the infection mainly causes respiratory tract symptoms. acute pericarditis is the inflammatory condition that affects the sac surrounding the heart, which is most often due to viral infections. currently, to establish the diagnosis, it is essential the use of ultrasound. we herein report a case of a healthy -year-old woman who presented to the emergency department (ed) with dry cough, anosmia, malaise and low-grade fever. a nasopharyngeal swab for sars-cov- test was done, being positive. lung point-of-care ultrasonography (pocus) was performed, showing a thickened pleural line with prominent b-lines and subpleural consolidations in posterior lower lobes. no pleural effusion was detected. since she had no comorbidities but had lung abnormalities, she was discharged with hydroxichloroquine mg bid during days (offlabel use). on the th day of home isolation, she reported a prolonged pleuritic centrothoracic chest pain that improved sitting forward and worsened with supine position. the physicial exam was unremark-able. the pain was attributed to the lung involvement of the disease, and she was advised to monitor her oxygen saturation and step-up pain medication. as the pain worsened after two days, a pocus was performed at home showing the presence of a small pericardial effusion. there was a good biventricular function, an absence of valve disease, cavity growth, or ventricular hypertrophy. she was advised to return to the ed to complete the exam. the electrocardiography (ecg) revealed a sinus rhythm at bpm with t wave inversion in the inferior leads (ii, iii and avf). with these findings, she was diagnosis of acute pericarditis, meeting of the criteria : typical pain and pericardial effusion. at that moment, she started with colchicine . mg od for two weeks. the following day she reported the resolution of the pain. the etiology of acute pericarditis is highly variable, when no cause is identified, it is usually assumed to be viral or immunomediated, with a good long-term prognosis. in these patients, colchicine has demonstrated to reduce symptoms, decreasing the leukocyte motility and phagocytosis observed in inflammatory responses, and is generally well tolerated. poor prognostic factors include the presence of a large pericardial effusion, tamponade, myopericarditis, high crp or lack of response colchicine. therefore, when acute pericarditis is suspected, it is mandatory to obtain an ecg, a blood test with inflammatory and myocardial injury parameters and a transthoracic echocardiography. there is growing literature regarding the affection of the cardiovascular system in covid- infection. cardiac injury (troponin i elevation, ecg and echocardiography abnormalities) across different studies, which is around . % of the patients, arrhythmia was found in . %. in another study, patients with severe and critical covid- infection underwent a ct scan, chest pain was reported in % of the patients and pericardial effusion was found in . %, which suggests that acute pericarditis could be an under diagnosed pathology, and therefore, not correctly managed and treated. continued observations of the cardiovascular complications of the disease are needed. pocus is a fast, cost-effective and safe tool performed by the physician in charge of the patient, which allows diagnosing and monitoring nonspecific symptoms in order to rule out urgent conditions. as resources become scarce, the findings in this report raise the question as to whether home pocus, could be effectively established a means of extending hospital capacity in borderline patients as a novel care path, and in these patients diagnosed with acute pericarditis, colchicine could be a potential therapy worth to be initiated. to our knowledge, this is the first report to describe acute pericarditis due to sars-cov- , which might be an under diagnosed condition in this pandemic. we want to share our findings, given the urgent need for different diagnostic and therapeutic strategies in order to better manage covid- patients, and diminish the sars-cov- complications. this is the first case report to describe an acute pericarditis episode due to sars-cov- , which might be an under diagnosed condition in this pandemic, and therefore not correctly managed. this work has not been supported by public grants or financial support. no sources of funding were used to assist in the preparation of this case report. the author certifies that he has no commercial associations that might pose a conflict of interest in connection with the submitted article. i certify that the reporting of this case was conducted in conformity with ethical principles of our institution. we have obtained written informed consent from the patient clinical features of patients infected with novel coronavirus in wuhan china the novel coronavirus ( -ncov) uses the sars-coronavirus receptor ace and the cellular protease tmprss for entry into target cells epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study findings of acute pulmonary embolism in covid- patients hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label nonrandomized clinical trial esc guidelines for the diagnosis and management of pericardial diseases: the task force for the diagnosis and management of pericardial diseases of the european society of cardiology (esc) endorsed by: the european association for cardio-thoracic surgery (eacts) province and health commission of guangdong province for chloroquine in the treatment of novel coronavirus pneumonia recurrent pericarditis: autoimmune or autoinflammatory? complicated pericarditis: understanding risk factors and pathophysiology to inform imaging and treatment clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china the clinical and chest ct features associated with severe and critical covid- pneumonia yale tung chen is the guarantor of the content of the present report.the author certifies that he has no commercial associations that might pose a conflict of interest in connection with this case report. key: cord- -tq g authors: kim, beom joon; kim, eu suk; shin, myoung jin; kim, hong bin; lee, hee young; hong, keun-sik; park, hong-kyun; lee, jun; sohn, sung-il; hwang, yang-ha; ko, sang-bae; park, jong-moo; rha, joung-ho; kwon, sun u.; kim, jong s.; heo, ji hoe; lee, byung chul; yoon, byung-woo; bae, hee-joon title: management of acute stroke patients amid the coronavirus disease pandemic: scientific statement of the korean stroke society date: - - journal: j stroke doi: . /jos. . sha: doc_id: cord_uid: tq g nan cardioembolism due to viral myocarditis or cardiac failure. international stroke societies and organizations are currently working to devise an action plan to provide optimal stroke care amid the covid- pandemic. their plans can be summarized as follows: ( ) centralization of regional stroke systems of care and ( ) development and implementation of protected intramural code stroke protocols to ensure the quality of stroke care and protect hospital personnel from the sars-cov- infection. , , a recent chinese guideline for neurologists recommended performing brain and chest computed tomography simultaneously in cases of neurological symptoms or stroke with a high suspicion of covid- . as of mid-april , the covid- epidemic in korea seems to have stabilized, and the number of newly diagnosed cases per day remains below . the korean government is still warning about a possible second wave of new infections, emphasizing the importance of social distancing and personal hygiene. during this covid- pandemic, patients with acute stroke may be categorized into the following four groups: ( ) acute stroke patients with a laboratory-confirmed covid- ; ( ) acute stroke patients not yet diagnosed with covid- , but in quarantine because of an epidemiological suspicion of exposure to covid- -close contact with confirmed cases or a recent trip, within the last weeks, to covid- affected regions or abroad; ( ) acute stroke patients not yet diagnosed with covid- , but are febrile or have respiratory symptoms; ( ) acute stroke patients not diagnosed with covid- and who neither are febrile nor have respiratory symptoms. if hospitals and emergency rooms establish pre-arrival screening measures for covid- , including assessment of travel history and respiratory symptoms, it would save time for acute stroke care. otherwise, screening for covid- should be performed for every patient before the protected code stroke is activated. additional protective measures to mitigate the spread of sars-cov- transmission should be implemented in the following cases: ( ) acute stroke patients with a laboratory-confirmed covid- ; ( ) acute stroke patients not yet diagnosed with covid- but in quarantine because of an epidemiological suspicion of exposure to covid- . measures to contain sars-cov- transmission during acute stroke care in the emergency room in case of outof-hospital occurrence or at the place of onset in case of in-hospital stroke ( ) all medical staff should use personal protective equipment (ppe), including full-sleeved gown, n respirator, eye protection (goggles or face shields), and gloves. ( ) all non-intubated patients should wear a surgical mask. ( ) minimize close contact with patients-a brief neurological examination suffices to assess the national institute of health stroke scale score. ( ) limit neuroimaging studies to those that can detect large vessel occlusions and proceed to decide recanalization treatment; avoid advanced neuroimaging until covid- is excluded. ( ) secure a negatively pressurized or properly isolated room to monitor the stroke patient after intravenous thrombolysis or endovascular treatment. ( ) minimize in-hospital patient transportation-use an isolation stretcher or wheelchair with negative pressure and clear out the hallway during in-hospital patient transportation. ( ) use a negatively pressurized angiography suite, if available. otherwise, designate an angiography suite for treating a stroke patient with covid- and prepare isolation measures beforehand. after treatment, complete disinfection and decontamination must be performed. ( ) designate interventionists, technicians, and nurses for treating possible covid- cases and make sure they are accustomed to proper donning and doffing of ppe. ( ) turn off automatic doors to the suite. shut down doors and restrict access to the suite during any procedure. ( ) minimize the number of medical staff in the angiography suite during the procedure. one medical doctor may assume the role of crisis resource management. ( ) the patient should wear a surgical mask during the procedure unless an oxygen mask or intubation is needed. ( ) properly discard disposable items according to the institutional or national/regional guidelines. ( ) after the procedure, the patient should be admitted to a negatively pressurized or properly isolated intensive care unit or stroke unit. the covid- outbreak is ongoing, and the current situation is highly volatile. the statement and guidelines in this paper are based on scientific evidence and expert opinion available as of april . it is recommended that each stroke center develops and updates an institutional protocol for providing safe and efficient stroke care amid the covid- pandemic, based on its medical resources, local epidemics, and emerging prevention and treatment options against covid- . the management of a patient with acute stroke who is neither diagnosed as covid- nor in quarantine but has a fever or respiratory symptoms may depend on the local epidemiologic status of covid- . in an area with suspicion of widespread community transmission, applying the protected code stroke protocol to such a patient may be justified. it has been reported that asymptomatic covid- patients may be contagious. patients with acute stroke often require endotracheal suction or intubation, both of which can produce a large amount of virus-rich aerosols. in the long run, it should be discussed when and how to implement ppe and other containment measures against potentially contagious sources during acute stroke care in the emergency room. establishing regional or national stroke care networks is warranted. shortage of medical resources can occur when hospitals are designated as covid- dedicated centers or when hospitals shut down because of an in-hospital outbreak. these shortages may derange pre-existing regional stroke care systems. therefore, centralized triage systems, including flexible rerouting and sharing of resource information, maybe the best option in these cases. conventional stroke pre-notification by emergent medical services should include information on the diagnosis of cov-id- , exposure to covid- , fever, and respiratory symptoms. the covid- pandemic is rapidly spreading, and containing the virus and mitigating disease burden is currently the most important goal. however, physicians should endeavor to provide the best care to stroke patients even in these trying times. the korean version of this statement is provided as a supplementary material. supplementary materials related to this article can be found online at https://doi.org/ . /jos. . . the authors have no financial conflicts of interest. challenges and potential solutions of stroke care during the coronavirus disease (covid- ) outbreak infection prevention and control during health care when covid- is suspected olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (covid- ): a multicenter european study clinical course and outcomes of patients with severe acute respiratory syndrome coronavirus infection: a preliminary report of the first patients from the korean cohort study on covid- acute cerebrovascular disease following covid- : a single center, retrospective, observational study neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study temporary emergency guidance to us stroke centers during the covid- pandemic menon bk. protected code stroke: hyperacute stroke management during the coronavirus disease (covid- ) pandemic consensus for prevention and management of coronavirus disease (covid- ) for neurologists republic of korea: transmission of -ncov infection from an asymptomatic contact in germany challenges and potential solutions of stroke care during the coronavirus disease (covid- ) outbreak infection prevention and control during health care when covid- is suspected clinical course and outcomes of patients with severe acute respiratory syndrome coronavirus infection: a preliminary report of the first patients from the korean cohort study on covid- olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (covid- ): a multicenter european study acute cerebrovascular disease following covid- : a single center, retrospective, observational study neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study temporary emergency guidance to us stroke centers during the covid- pandemic menon bk. protected code stroke: hyperacute stroke management during the coronavirus disease (covid- ) pandemic cardiovascular implications of fatal outcomes of patients with coronavirus disease (covid- ) consensus for prevention and management of coronavirus disease (covid- ) for neurologists central disaster management headquaters of coronavirus disease . 코로나바이러스감염증- 중앙재난안전대책 본부 정례브리핑( 월 일). ministry of health and welfare brdid=&brdgubun =&datagubun=&ncvcontseq= &contseq= &b oard_id=&gubun=all. . accessed ?mid=a &bid= &act=view&list_ no= &tag=&npage= . . accessed transmission of -ncov infection from an asymptomatic contact in germany key: cord- - zuw pp authors: khodamoradi, zohre; boogar, shahrokh sadeghi; shirazi, farnaz kamali haghighi; kouhi, pariya title: covid- and acute pulmonary embolism in postpartum patient date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: zuw pp we report a -year-old woman in iran who sought care for left shoulder pain and cough days after a scheduled cesarean section. acute pulmonary embolism and coronavirus disease were diagnosed. physicians should be aware of the potential for these concurrent conditions in postpartum women. a n outbreak of viral pneumonia that emerged in late and spread rapidly worldwide was named coronavirus disease (covid- ) ( ) . cov-id- is caused by severe acute respiratory syndrome coronavirus (sars-cov- ). two other viruses of this family, severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus, also have caused outbreaks globally ( ) . venous embolism has been associated with severe infection. acute pulmonary embolism has been associated with severe acute respiratory syndrome coronavirus infections, but no cases have been reported with middle east respiratory syndrome ( , ) . a study reported a -year-old hospitalized woman with covid- and pulmonary embolism ( ). in addition, in covid- -positive patients, and years of age, from wuhan, china, computed tomography angiography (cta) confirmed pulmonary embolism ( ) . three cases of deep vein thrombosis with covid- also have been reported ( ) . pregnancy increases the risk for venous embolism ( ) . although approximately half of venous embolism occurs during pregnancy and half occurs during the postpartum period, the risk per day is greatest in the weeks immediately after delivery ( ) . we report a patient in iran who sought care for cough and shoulder pain days after an uncomplicated cesarean delivery in whom an acute pulmonary embolism and covid- infection were subsequently diagnosed. the ethics committee of shiraz university of medical sciences (shiraz, iran) approved the study. a healthy -year-old nonsmoking woman (gravid , term infant delivered, abortion/miscarriage) underwent an elective scheduled caesarean section at weeks days of gestation after an uncomplicated pregnancy. the uncomplicated surgery resulted in the birth of a healthy infant. mechanical prophylaxis to prevent deep vein thrombosis was used at delivery until ambulation. the woman was discharged on postpartum day in a good condition. on postpartum day , she sought care for sudden onset left-side shoulder pain and dry cough. she stated that she did not have fever, myalgia, or diarrhea. on postpartum day , she experienced mild shortness of breath. during her pregnancy, she had no known history of contact with persons who had confirmed or suspected covid- . at admission, physical examination revealed a blood pressure of / mm hg, body temperature of . °c, pulse rate of beats/min, respiratory rate of breaths/min, and oxygen saturation of % on ambient air. her body mass index was . kg/cm . her physical examination was otherwise unremarkable. laboratory test results showed a complete blood count and leukocyte differentials within reference ranges but elevated liver function tests, c-reactive protein level, and erythrocyte sedimentation rate. d-dimer was μg/ml (reference < μg/ml). results of her baseline electrocardiogram were unremarkable. she had a normal echocardiography with ejection fraction of ≈ %. because of the covid- pandemic and the patient's report of cough, she underwent screening for sars-cov- . throat swab samples were positive for sars-cov- by real-time reverse transcription pcr. moreover, because of her clinical features, history, risk for venous embolism, and high level of d-dimer, cta was performed. thoracic cta on the first day of hospitalization showed emboli in the right side interlobar artery, posterior basal segment, and the lingular branch ( figure, panels a, b) . hampton hump in the right side posterior basal segment was consistent with lung infarction. cta further revealed left-sided pleural effusion associated with new mixed consolidation and ground glass opacifications ( figure, panels c, d) . cta findings were consistent with pneumonia, pulmonary embolism, and lung infarction. the patient was treated with enoxaparin ( mg/kg subcutaneously ×/d). she was discharged in good condition with enoxaparin for months. multiple conditions made this patient susceptible to pulmonary embolism. because inflammation and coagulation are related, infected patients have hypercoagulable state ( ). virchow's triad, which contributes to thrombosis, has factors: venous stasis, hypercoagulability, and endothelial injury. septic patients have criteria of virchow's triad; cesarean section as a surgery contributed to virchow's triad in this patienet because endothelial injury made the patient prone to embolic events ( ) ( ) ( ) . the patient we report was young, was not critically ill or septic, and had no evidence of disseminated intravascular coagulation. alteration in coagulation pathways during pregnancy increases the risk for embolic events. the risk in the immediate postpartum period is particularly high. venous embolism is an important cause of maternal illness and death ( ). cta or ultrasonography for deep vein thrombosis may be important for covid- -positive pregnant or postpartum patients who have signs or symptoms of possible venous embolism, given their potentially heightened risk. in this patient population, with an already elevated risk for venous embolism, physicians should be aware of the potential for concurrent mild covid- and acute pulmonary embolism. co-infection of coronavirus disease and influenza a: a report from iran anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy pulmonary artery thrombosis in a patient with severe acute respiratory syndrome acute pulmonary embolism and covid- pneumonia: a random association? covid- complicated by acute pulmonary embolism coagulopathy and antiphospholipid antibodies in patients with covid- prevention of postpartum venous thromboembolism american college of obstetricians and gynecologists. acog practice bulletin no. : thromboembolism in pregnancy coagulation and sepsis we thank shiraz university of medical sciences and the center for development of clinical research of nemazee hospital and nasrin shokrpour for editorial assistance. dr. khodamoradi is an internal medicine resident in shiraz university of medical sciences, shiraz, iran. her primary research interests focus on internal medicine, gastroenterology, rheumatology, and cardiology. p anton-valentine leukocidin (pvl) is a cytotoxin produced by some strains of staphylococcus aureus. these strains are responsible for primary skin infections and necrotizing pneumonia. this rare entity is mainly described in young immunocompetent patients with an influenza-like prodrome and has a high case-fatality rate ( , ). we report a case of necrotizing pneumonia induced by pvl-secreting methicillin-susceptible s. aureus in a patient infected with severe acute respiratory syndrome coronavirus (sars-cov- ) and who had coronavirus disease (covid- ).in march , during the sars-cov- outbreak in france, a man in his 's who had no underlying conditions came to an emergency department because of fever, cough, and blood-streaked sputum that developed for days. a diagnosis of pleuropneumonia was made, and antimicrobial therapy was initiated with cefotaxime plus metronidazole. test results for streptococcus pneumoniae and legionella pneumophila serotype urinary antigens were negative. a reverse transcription pcr specific for respiratory viruses also showed negative results.the next day, further respiratory deterioration required transfer of the patient to an intensive care unit (icu) for intubation, mechanical ventilation, and inotropic support. spiramycin was added to the previous drug regimen. chest computed tomography showed a parenchymal consolidation of the left necrotizing pneumonia induced by panton-valentine leukocidin-secreting staphylococcus aureus is a rare but lifethreatening infection that has been described in patients after they had influenza. we report a fatal case of this superinfection in a young adult who had coronavirus disease. key: cord- -j u ga authors: sapey, elizabeth; bafadhel, mona; bolton, charlotte emma; wilkinson, thomas; hurst, john r; quint, jennifer k title: building toolkits for copd exacerbations: lessons from the past and present date: - - journal: thorax doi: . /thoraxjnl- - sha: doc_id: cord_uid: j u ga in the nineteenth century, it was recognised that acute attacks of chronic bronchitis were harmful. years later, it is clearer than ever that exacerbations of chronic obstructive pulmonary disease (ecopd) are important events. they are associated with significant mortality, morbidity, a reduced quality of life and an increasing reliance on social care. ecopd are common and are increasing in prevalence. exacerbations beget exacerbations, with up to a quarter of in-patient episodes ending with readmission to hospital within days. the healthcare costs are immense. yet despite this, the tools available to diagnose and treat ecopd are essentially unchanged, with the last new intervention (non-invasive ventilation) introduced over years ago. an ecopd is ‘an acute worsening of respiratory symptoms that results in additional therapy’. this symptom and healthcare utility-based definition does not describe pathology and is unable to differentiate from other causes of an acute deterioration in breathlessness with or without a cough and sputum. there is limited understanding of the host immune response during an acute event and no reliable and readily available means to identify aetiology or direct treatment at the point of care (poc). corticosteroids, short acting bronchodilators with or without antibiotics have been the mainstay of treatment for over years. this is in stark contrast to many other acute presentations of chronic illness, where specific biomarkers and mechanistic understanding has revolutionised care pathways. so why has progress been so slow in ecopd? this review examines the history of diagnosing and treating ecopd. it suggests that to move forward, there needs to be an acceptance that not all exacerbations are alike (just as not all copd is alike) and that clinical presentation alone cannot identify aetiology or stratify treatment. in the nineteenth century, it was recognised that acute attacks of chronic bronchitis were harmful. years later, it is clearer than ever that exacerbations of chronic obstructive pulmonary disease (ecopd) are important events. they are associated with significant mortality, morbidity, a reduced quality of life and an increasing reliance on social care. ecopd are common and are increasing in prevalence. exacerbations beget exacerbations, with up to a quarter of in-patient episodes ending with readmission to hospital within days. the healthcare costs are immense. yet despite this, the tools available to diagnose and treat ecopd are essentially unchanged, with the last new intervention (non-invasive ventilation) introduced over years ago. an ecopd is 'an acute worsening of respiratory symptoms that results in additional therapy'. this symptom and healthcare utility-based definition does not describe pathology and is unable to differentiate from other causes of an acute deterioration in breathlessness with or without a cough and sputum. there is limited understanding of the host immune response during an acute event and no reliable and readily available means to identify aetiology or direct treatment at the point of care (poc). corticosteroids, short acting bronchodilators with or without antibiotics have been the mainstay of treatment for over years. this is in stark contrast to many other acute presentations of chronic illness, where specific biomarkers and mechanistic understanding has revolutionised care pathways. so why has progress been so slow in ecopd? this review examines the history of diagnosing and treating ecopd. it suggests that to move forward, there needs to be an acceptance that not all exacerbations are alike (just as not all copd is alike) and that clinical presentation alone cannot identify aetiology or stratify treatment. 'next to avoiding a fatal issue, our efforts must be directed to prevent the case going on to chronic bronchitis, especially in those who have had previous attacks'. r douglas powell, london ( ) an exacerbation of chronic obstructive pulmonary disease (copd) is defined as 'an acute worsening of respiratory symptoms that results in additional therapy'. the word exacerbation has a latin root; stemming from the verb exacerbare meaning 'to provoke to anger' and the oxford english dictionary defines an exacerbation as 'the process of making a problem, bad situation, or negative feeling worse'. this accurately reflects the negative impact copd exacerbations (ecopd) have on patient quality of life, lung function decline and mortality. in the uk, national audit data highlight the high mortality and readmission rates (and thus healthcare costs) associated with ecopd. exacerbations impact on patients' quality of life and even a single exacerbation is associated with an increase in mean annual forced expiratory volume (fev ) decline. the early identification, provision of appropriate treatment and subsequent prevention (or ideally, primary prevention) of exacerbations has to be a central strategy for copd care. we use clinical symptoms to diagnose an exacerbation of copd, based on the triad of increased breathlessness, increased sputum volume and/ or increased sputum purulence. these criteria are essentially unchanged over the last years, finessed with clinical investigations such as a chest radiograph, arterial blood gas, ecg, a full blood count and sputum culture (all available since - ). [ ] [ ] [ ] [ ] [ ] in stark terms, our diagnostic approach to copd exacerbations has not fundamentally changed for almost years. we have no copd-specific biomarkers and the diagnosis is often one of exclusion. this is in contrast to many other acute presentations of chronic diseases, such as a myocardial infarction (mi) in ischaemic heart disease, where specific and sensitive diagnostic toolkits including biomarkers, imaging and interventions have revolutionised care pathways and patient outcomes. such disparity in advancement raises the question of why copd is so far behind other common, debilitating and progressive chronic diseases which are associated with acute flares of symptoms. why do we not have a better diagnostic and treatment toolkit for ecopd? perhaps to move forward, we need to examine the past. in , douglas powell identified cold weather, upper respiratory tract infections and pollution as an important causes of (acute) bronchitis, observing that 'dusty employments…dusty winds (and) irritating fogs' bring on typical attacks. today, the most important listed triggers of exacerbations of copd include viral and/ or bacterial tracheobronchial infection and inhalation of environmental irritants. in a study of hospitalised (and thus severe) exacerbations of copd, bacteria or viruses were identified in % using quantitative culture and pcr. bacteria were present in % of patients, most commonly haemophilus influenzae, streptococcus pneumoniae, moraxella the variability of inflammation in sputum in one patient with copd. a spontaneous sputum sample was collected over hours post waking and following mouth rinsing procedures daily for days (visits - ), and then twice weekly for further weeks (visits , ; , ; , ) in a patient with moderate severity copd in the stable state who had been an ex-smoker for years. a differential cell count was performed and cytokines were measured in sputum sol phase. each marker is the concentration of that mediator on the visit day. neutrophil (pmn) / ml (red circles), myeloperoxidase (mpo) mg/ml (green square); tnfα pm (cerise triangle): il nm (cyan triangle); ltb nm (black diamond). adapted from sapey et al. copd,chronic obstructive pulmonary disease; tnf, tumour necrosis factor. catarrhalis; staphylococcus aureus and pseudomonas aeruginosa, in descending order of prevalence. viruses were found in %, with rhinoviruses, influenza viruses, respiratory syncytial viruses, parainfluenza viruses and coronaviruses most commonly identified, again in descending order of prevalence. viral infections are important in copd, associated with frequent exacerbations, a higher total symptom burden at presentation and a longer period before symptom recovery, perhaps reflecting the lack of specific therapies available. coinfection (bacterial and viral) is common (seen in % of severe exacerbations), associated with increased lung and systemic inflammation, longer hospitalisation and more severe lung disease. the role of air quality is of increasing interest. short-term exposure to major air pollutants (trioxygen (o ), carbon monoxide, nitrogen dioxide, sulphur dioxide, particulate matter (pm) and pm . ) is associated with respiratory risk but a recent systematic review concluded that these pollutants were also associated with risk of exacerbation. other identified triggers and/or risk factors for exacerbation include discontinuation and poor adherence with medications, poor nutritional and lower socioeconomic status and dynamic hyperinflation. these causative triggers and predisposing factors have been consistently identified across the literature, but studies also highlight alternative pathologies which might account for symptoms, including thromboembolic disease and mi (identified in % and % of suspected copd exacerbations, respectively), suggesting comorbidity is important. the treatment of exacerbations has remained short-acting bronchodilators and corticosteroids with or without antibiotics for years, almost irrespective of the underlying cause. however, with global concerns about antibiotic use and an increasing number of clinical trials of new or repurposed therapeutics given at the time of exacerbation, identifying the exacerbation trigger has never felt more relevant. can clinical evaluation alone help identify the cause? from the late s onwards, a body of evidence supported the concept that the presence of purulent sputum at exacerbation presentation was indicative of a bacterial exacerbation (eg stockley et al, ) and this has been used ever since as a potential biomarker for bacterial infections. however, there are concerns about the ability of patients to self-report sputum colour without training or a colour chart to refer to daniels et al and in some studies, sputum colour could not differentiate between a viral or bacterial aetiology. a landmark study in suggested that exacerbations could be stratified using inflammatory profile. here, % of exacerbations were associated with bacteria, % with a virus, most commonly rhinovirus, % with a significant sputum eosinophilia and % with no significant inflammation (termed pauci-inflammatory). of note, these groupings did not reflect differences in symptom burden, clinical presentation or sputum colour, which could not differentiate between causes, meaning clinicians could not predict what the cause or inflammatory profile of the exacerbation was using standard clinical evaluation alone. this has important but perhaps predictable implications for clinical practice. moving forward, as with other acute presentations of chronic disease, we should not rely on clinical symptoms, signs or non-specific investigations to direct a stratified approach to exacerbation treatment. given copd is an inflammatory disease, the immune response may provide aetiological insight. in engel hypothesised that the structural lung damage described in chronic bronchitis and emphysema might be caused by repeated infections, with multiple acute insults leading to long-term lung damage. in , morgan suggested that there were differences in the acute and chronic inflammation seen in the bronchial tree and surmised that these differences may influence patient outcome and require different treatments. fifty years on from this observation, how far has our understanding of the inflammatory basis of acute exacerbations of copd progressed? there is a substantial and convincing body of evidence that airway inflammation is prevalent in stable copd and is fundamental to its pathogenesis with studies suggesting relationships with disease severity and inflammatory burden. however, pulmonary inflammation varies greatly between individuals and within individuals with copd even when clinically stable and this heterogeneity has proven challenging in biomarker evaluation or inflammation-targeted therapeutic intervention. figure provides an example of the variability of the inflammatory profile of spontaneous sputum inflammation day to day in one patient with copd. as shown, although some mediators share a common pattern of change (if one mediator is up, others are up and vice versa), not all do (eg, on visit , tumour necrosis factor (tnf)α has increased, but leukotriene b (ltb ) and interleukin- (il ) have decreased) and this suggests that the variability in mediators does not only reflect dilution of the sample, but true variability in inflammatory pattern. there appears to be a further amplification of inflammation during exacerbation in many (but not all) patients. once an insult (bacterial, viral or environmental) sufficiently activates the resident immune cells of the airways, it appears to trigger a cascade of inflammatory mediators. this in turn recruits a wave of activated immune cells to the airways, which are predominantly neutrophils but also include eosinophils, monocytes and cd +t cells and these cells have the potential to cause significant disruption and damage when they enter tissue en masse. for example, activated neutrophils release proteinases during migration through complex tissues, degranulation, frustrated where local host defences are overwhelmed, non-resident immune cells, predominantly neutrophils, but also t cells, b-cells and eosinophils are recruited into the lung tissue, following chemokines secreted by epithelial and endothelial cells and resident immune cells. fibroblasts may be activated by growth factor releases from macrophages and epithelial cells. . recruited and resident immune cells are able to release cytotoxic granular contents, reactive oxygen species and proteinases into the tissue and these have been causally associated with the development of mucus secretion, but also emphysema and small airways remodelling, leading to progression of the underlying copd. phagocytosis and neutrophil extracellular traps (net) formation. the concentration of proteinases initially far exceed and thus overwhelm their inhibitors leading to degradation of structural lung proteins including elastin and collagen causing bystander tissue damage and cleavage of enzymes, cytokines, receptors and opsonins including components of the complement cascade and immunoglobulins. while tissue damage is heightened in exacerbations of copd, tissue repair is blunted, effecting the structural integrity of the airways. this inflammatory cascade also results in systemic inflammation, with increases in acute phase proteins such as fibrinogen and c reactive protein (crp). relationships have been described between the degree of pulmonary and systemic inflammation in some studies, a potential link between the multimorbid diseases associated with copd and copd exacerbations (see later). these processes are illustrated in figure . copd severity (definable by a number of measures, but commonly by fev in one second (fev ) at one timepoint) is not synonymous with copd activity (the trajectory of lung function decline or exacerbation frequency). some patients have mild copd by fev which is rapidly progressing or with frequent exacerbations and vice versa. while hypothetically attractive, studies have not consistently linked disease activity (such as exacerbation frequency) to the presence of increased airways inflammation in the stable state. however, the presence of potentially pathogenic bacteria on sputum culture is associated with exacerbation frequency and there is a clear relationship with bacteria and inflammation which supports the concept of inflammatory burden increasing the susceptibility to exacerbations. it is likely that some studies have been underpowered to assess differences in inflammation or have failed to include patients with high exacerbation frequencies, which is understandable given the challenges of recruiting these unstable patients to research studies. there is an association between inflammation and exacerbation outcome. symptom resolution corresponds to abating inflammation and continuation of symptoms or recurrence of exacerbation corresponds to sustained inflammation, suggesting a causal relationship between inflammatory load and host experience. while it is attractive to assume that all exacerbations of a certain aetiology might share the same inflammatory profile and burden, the complexity of host, environment and exacerbation trigger interactions within copd are likely to produce patterns with greater subtlety than that. however, just as with stable copd, within copd exacerbations there might be phenotypes or 'treatable traits' which could help focus therapeutic choices. immune cell function might provide mechanistic insight. it has been proposed that some frequently exacerbating copd patients might experience a 'triple innate immune system hit' which could increase their susceptibility to bacterial exacerbations. first, the frequent exacerbator phenotype has been associated with a reduced ability of airway macrophages to phagocytose bacteria. theoretically, this would lead to increased neutrophil recruitment and in this group neutrophilic inflammation is commonly described. second, studies suggest the accuracy of neutrophil targeting is impaired in copd and associated with heightened bystander tissue damage. third, airway macrophages and monocytes from the frequent exacerbator phenotype are less able to clear dead and dying neutrophils (and eosinophils via efferocytosis, resulting in cell necrosis and localised inflammation and tissue damage). neutrophilic inflammation is corticosteroid resistant in copd but promisingly, studies have identified potential therapeutic targets to improve impaired cellular functions. nrf activators increase macrophage phagocytosis and pi k inhibitors have been shown to increase neutrophil migratory accuracy in vitro as well as reducing inflammation with pi k inhibitors under assessment in early phase studies as a potential therapy during copd exacerbations. due to advancements initially in asthma care, trials of therapies in those copd patients with an eosinophil signal are well underway (with studies currently listed on the clinicaltrials. gov website). results to date suggest that this trait is associated with a good treatment response to oral steroids at exacerbation and inhaled steroids in the stable state, with studies of specific antieosinophil therapies (including mepolizumab) showing promise in selected patient groups. furthermore, studies of community-treated exacerbation suggest that there is no advantage in treating adults without an eosinophil signal with oral prednisolone, as this provides no symptomatic benefit and an increase risk of harm. in hospitalised ecopd, studies suggest that oral corticosteroids and shorter courses appear adequate, with no benefit using high-dose intravenous therapy. excessive use of oral corticosteroids is associated with harm, which is especially clear in studies of patients on long-term maintenance but also potentially raises concerns about uncontrolled and/or unsupported use of 'rescue packs'. of note, a recent cochrane review concluded that there was no evidence of benefit from self-management interventions (including rescue packs) to reduce all-cause hospital admission, all-cause hospitalisation days, emergency department visits, general practitioner visits, dyspnoea scores, the number of copd exacerbations or all-cause mortality although more research was needed. however, the provision of a rescue pack for patients with exacerbations remains a recommendation from the national institute for health and care excellence in the revised guideline published in december (based on expert opinion). these studies begin to highlight that there are different types of copd exacerbations, with different responses to treatment and that a 'one size fits all' approach for both treatment and prevention is overly simplistic. to further advance inflammation-based treatments, a toolkit is needed to match exacerbation aetiology with host response and therefore treatment. in other words, we need to phenotype exacerbations. the value of phenotyping exacerbations of copd is to derive patterns for treatment response or to enhance our understanding of underlying mechanisms. a frequently used, yet rudimentary classification of an exacerbation phenotype is the categorisation as 'infective' or 'non-infective' exacerbations of copd. this is commonly used to direct treatment with antibiotics and systemic corticosteroids, respectively but does not inform underlying mechanisms, likely treatment response or if the exacerbation severity and outcomes are the same. recent advances which exploit developments in biomarker identification, mediator discovery and molecular diagnostics, for example in microbial detection, have furthered our understanding of the exacerbation event. there has been great interest in studying systemic plasma samples in copd to provide insight into the pathogenesis of exacerbations. one such study included exacerbating patients (unselected, of any aetiology), assessing preselected inflammatory mediators. of these, crp, interleukin- , myeloid-progenitor inhibitory factor , pulmonary and activation-regulated chemokine, adiponectin and soluble intracellular adhesion molecule- were significantly elevated at the exacerbation event. however, no plasma mediator alone provided a robust predictive tool for diagnosing an exacerbation event. crp combined with a major symptom (dyspnoea, sputum purulence or sputum volume) improved diagnostic accuracy but no mediator/symptom combination predicted clinical severity or recovery. this result may reflect that the study included 'all comers' with an exacerbation (all aetiologies) and therefore might have been underpowered to find predictive biomarkers if the biomarkers varied by aetiology or host response. to address this, further studies utilised differing approaches to identify phenotypes of exacerbations. the first attempts to investigate biomarkers in virus-associated exacerbations as a specific phenotype were made from the east london cohort. in this study, human rhinovirus (hrv) infection was examined in healthy controls and copd patients at stable state and during exacerbation. baseline cxcl (interferon gamma inducible protein ) was higher in copd than controls, but at exacerbation, there was an increase in serum cxcl in hrv positive exacerbations, correlating with sputum hrv virus load, and no increase in hrv negative exacerbations. a combination of 'cold' symptoms and serum cxcl at exacerbation was associated with a roc of . in predicting an hrv-associated exacerbation of copd. the studies described so far tested preformed hypotheses to identify associations between inflammatory profiles and exacerbation. in the first study of its kind, the beat-copd study employed cluster analysis using mediators sampled from the airways to determine biologically distinct exacerbation groups. four biological exacerbation phenotypes were described, mapping on to inflammation, independent of each other but clinically indistinguishable. sputum interleukin β (il β) was found to be most sensitive for bacteria-associated exacerbations (proinflammatory cluster, receiver operating characteristic curve (roc) . ), serum cxcl was (again) most sensitive for virus-associated exacerbations (th cluster, roc . ) and peripheral blood eosinophils (th cluster, roc . ) was the most sensitive for sputum eosinophilic-associated exacerbations. an independent validation cohort of subjects confirmed that sputum il β, serum cxcl and peripheral blood eosinophils these studies highlight four potential exacerbation phenotypes which might provide robust treatment pathways in time. . bacterial in origin, il- β as a biomarker, neutrophilic inflammation. . viral in origin, with cxcl as a biomarker. . eosinophillic in origin and as a biomarker. pauci-inflammatory. these appear to be biologically different even when clinically indistinguishable. however, while our understanding of each of these phenotypes needs to be improved, we understand very little at all about the so-called pauci-inflammatory exacerbation. indeed, it is unclear whether this represents copd at all or the acute presentation of a related comorbidity which may also cause or exacerbate breathlessness and a cough. the recognition and gravitas of comorbidities in copd has built over the last decade or more. whether the presence of comorbidities is based on self-report or systematically sought, they are common and affect mortality. exacerbations represent a period with multiple insults to both the lung and systemically. such insults include the aetiological factor itself (pathogen or environmental), lung physiological changes and additional work of breathing, hypoxia, periods of inactivity (which can effectively be prolonged periods of 'bed rest' during an in-patient admission), with a study suggesting that an acute medical admission is associated with a median step count of per day (iqr - ), dehydration, malnutrition, the therapies prescribed and their side effects (eg, oral corticosteroids and hyperglycaemia and antibiotics and gastrointestinal disturbance) and then the sequelae of these factors including systemic inflammation, hypo and hypernatraemia/kalaemia and altered sympathetic drive. figure summarises the complex relationships between comorbidity and exacerbations in copd. there is a significant and complex interplay between the exacerbation and the comorbid condition including the impact of comorbidities on the exacerbation itself; how an exacerbation contributes to comorbid disease; the prognostic role of comorbid disease and the subclinical presentation of a comorbid condition at the time of an exacerbation. cardiovascular disease highlights the interplay and is the most studied comorbidity in this context. patients presenting to hospital with a copd exacerbation have a host of comorbid conditions and the presence of a comorbid condition and the systemic manifestation of that figure comorbidity and copd exacerbations. there are many stressors during copd exacerbations which can predispose to or exacerbate comorbidities and the multimorbidity patients experience. this figure is a schematic of some of these factors, but is not exhaustive and each stressor can influence the other, irrespective of placement in the figure. stressor include the direct effects of infection and inflammation, dyshomeostasis including hypo and hypernatraemia, kalaemia and glycaemia, hypoxia and hypercapania. organ dysfunction is common, especially of cardiac and renal origin. patients are placed on short courses of oral corticosteroids and physical activity is reduced (and can equate to bed rest in some patients), both contributing to sarcopenia and osteopenia. copd, chronic obstructive pulmonary disease. comorbidity increases the duration of an exacerbation. coexistent ischaemic heart disease leads to far greater number of symptomdays per year, while an increased blood glucose in hospitalised patients leads to a longer stay and is associated with a higher risk of death. mi is more likely in the period following presentation with an exacerbation [ ] [ ] [ ] and there is evidence of increase platelet aggregation, increased arterial stiffness as well as myocardial injury as evidenced by cardiac biomarkers at the time of a copd exacerbation. the fact that comorbid disease may present subclinically at the time of the exacerbation is also important to consider, be it as a differential or as a further contributing factor to the symptoms and challenges of managing the condition. in a prospective case series, one in patients presenting to hospital with an exacerbation of copd had criteria that would meet diagnosis of a mi. impaired cognitive function is evident, if assessed, in a large proportion of patients at the time of discharge from a hospitalised exacerbation, with no evidence of recovery months later. prognostically, comorbidities present a greater risk of hospitalisation, particularly in the presence of lower lung function, as well as increased all-cause readmissions related to multimorbidity and older age. in the eclipse study (evaluation of copd longitudinally to identify predictive surrogate end-points), the best predictor of exacerbations was a former history of them. in addition, however, a history of reflux and heartburn was a further independent factor. the presence of acute kidney injury and lower limb muscle cross-sectional area at the time of exacerbation requiring hospitalisation are both prognostic of death. the prognostic copd exacerbation score such as the validated decaf score ("dyspnoea, eosinopenia, consilidation, acidaemia and atrial fibrillation" score predicting in-patient mortality) and the pearl score ("previous admissions, emrcd score, age, right-sided heart failure and left sided heart failure" score predicting -day readmission and mortality) include cardiac comorbidity in their calculations. patients deemed as frequent exacerbators are more likely to be depressed or have coexistent cardiovascular disease or osteoporosis. it is unclear if some events labelled exacerbations are actually a presentation of a comorbid condition (and studies suggest that clinicians are less likely to diagnose mi or pulmonary embolus (pe) if there is a concomitant diagnosis of copd, ) perhaps the so-called pauci-inflammatory exacerbations, or whether the comorbidity is exacerbating the copd. there remains a role for more timely identification of comorbid disease and addressing the contributing factors. the role of systematic identification of certain comorbidities and of preventative strategies, both pharmacologically and lifestyle-based are topics for ongoing discussion and research. in the meantime, opportunity exists to ensure optimal treatment for those with identified comorbid disease, such as ensuring beta-blockers are prescribed in those who meet the criteria or that hyperglycaemia or hyperlipidaemia are adequately addressed. despite a greater understanding of the biology and complexity of copd exacerbations, this has not (yet) translated into novel therapies to treat exacerbations. there has been no new intervention to treat copd exacerbations since the widespread adoption of non-invasive ventilation to treat exacerbations with hypercapnoeic respiratory failure in the early s. from the first introduction of guidelines such as gold in , the therapy for an exacerbation is unchanged. as described below, despite being commonly used, there remain significant research knowledge gaps in determining which exacerbations do and do not require treatments with antibiotics and corticosteroids. systemic corticosteroids were first used in rheumatological disease during the late s. despite evidence in the late s that many hospitalised patients were being treated with systemic corticosteroids, it was only at the turn of the millennium that small randomised clinical trails (rcts) first documented clinical efficacy, suggesting benefit on lung function and outcomes such as length of hospital stay. around the same time, the first small outpatient trials of steroids at exacerbation reported, with modest benefits confirmed in a larger rct. later it was defined that short course ( days) treatment was as effective as longer day courses, and without the need to taper dose. with a greater emphasis on exacerbation phenotyping, more recent studies have documented the ability to safely withhold steroids in exacerbations without an eosinophil signal. however, the practicality of achieving this at point-ofcare, and the optimal blood eosinophil cut-off to guide steroid therapy remain to be determined, and there are ongoing trials in the area. given the toxicity associated with repeated courses of corticosteroids, the need for effective novel anti-inflammatory agents is also great. disappointingly, there is no evidence of benefit with the anti-tnf agent entanercept or roflumilast, for example. anthonisen's rct demonstrated the superiority of antibiotics over placebo in exacerbations presenting with at least two of the three cardinal symptoms of increased breathlessness, sputum volume and sputum purulence. importantly, this had been conducted in patients with copd, rather than just those with chronic bronchitis. however, the placebo response rate was high, likely reflecting viral pathogens as a common cause of exacerbation, and more recent studies have not shown a benefit of antibiotics in other outcomes such as prolonging the time to next exacerbation. biomarkers such as sputum colour and procalcitonin have been suggested as strategies to better guide antibiotic therapy, but there remains unmet need to better define which exacerbations do and do not benefit from antibiotic therapy. it is also notable that there are no effective interventions to treat (or prevent) rhinovirus infections, thought to be the single the most common cause of a copd exacerbation. salbutamol has been available since the late s, with ipratropium following in the s. these replaced the non-selective β adrenoreceptor agonist isoprenaline. there are no good data on long-acting bronchodilator drugs at the time of exacerbation. the s audit referred to above highlighted the widespread use of theophyllines (in % of patients), and use of respiratory stimulants such as doxapram in the management of hospitalised exacerbations. use of theophylline has reduced, while respiratory stimulants have been replaced by non-invasive ventilation for the management of hypercapnoeic respiratory failure in the respiratory ward environment, following initial studies in the early s . models of care have changed, with the recognition that earlier access to treatment for exacerbations can be associated with faster recovery and reduced risk of hospital admission. however, the risks and benefits of patient-held rescue packs remain to be definitely established. research to develop new interventions at exacerbation of copd is hampered by robust outcome measures to assess exacerbation recovery. changes in lung function are not patient centred, and changes in symptoms scores not validated. 'clinical recovery' and 'treatment failure' are subjective constructs, while studies have also examined effects of exacerbation treatment on the time to the next event given that exacerbations cluster in time, with a high-risk period for a second event in the period following recovery from a first. we have at least made progress in prevention of exacerbations, though even when used optimally there seems to be a ceiling of reduction at around %. effective interventions (outlined in table ), alone and in combination, include non-pharmacological approaches such as pulmonary rehabilitation, and pharmacological approaches the mainstay of which remains long-acting bronchodilators with or without inhaled corticosteroids and, in selected cases, prophylactic antibiotics. for patients remaining hypercapnic following a hospitalised exacerbation, domiciliary non-invasive ventilation significantly reduces the risk of rehospitalisation (with an absolute risk reduction of % in a recent landmark study). similar to strategies to better target exacerbation treatment, there is also now emerging evidence on how better to target exacerbation prevention interventions, including the optimal use of inhaled corticosteroids. thus, while exacerbation prevention strategies are incompletely effective, the challenge here is rather selecting the right combination of interventions for the right patient at the right time, rather than the absence of effective prevention strategies. in , r douglas powell advised that our management aims should be to save life and prevent further episodes of then acute and chronic bronchitis, now copd. we still have a long way to go to achieve this. exacerbations of copd are still associated with significant mortality, morbidity, readmission and poor life quality. there have been no real advancements in routine care since the s. there is considerable unmet need for novel strategies to identify, treat and prevent exacerbations, and a pressing need to better use existing therapies. this remains a major challenge. how do we move forward? copd as a disease concept has always raised the question of 'lumping or splitting'; is this one disease or many? innovation in asthma care has provided a path which perhaps copd should follow. asthma phenotypes and now endotypes provide clinically blurred but biologically distinct clusters with an emerging arsenal of treatments for those with the most difficult to manage symptoms. the concept of 'treatable traits' has gained considerable momentum in stable copd, and perhaps now the same concept should be tested further in exacerbations. we are beginning to see some differences in biological signals across exacerbation aetiologies and host responses. to build on this, we need to continue with more stratified studies of ecopd, learning from the fruitful experience of focusing on those with an eosinophilic signal, but this time using poc testing to characterise and test treatments in (eg) viral or pauci-inflammatory exacerbations. this will provide more information about aetiology, but to personalise treatment, this must be incorporated into a holistic understanding of the impact of the hosts comorbidity and immune responses. from these data, we could build our ecopd toolkit, which we hypothesise might include poc identification of bacterial or viral pathogen (ensuring that the correct antibacterial or viral therapy is used and thus reducing redundant therapy), blood biomarkers to identify or exclude an eosinophil (corticosteroid use or avoidance) or cardiac (acute coronary syndrome, heart failure) or neutrophilic treatment pathway and a measure of acuity and respiratory compromise. by exploring these ideas, we may be able to introduce a stratified approach to treatment and prevention, which might, finally, really impact on these debilitating and costly events, to the benefit of our patients. contributors all authors wrote the manuscript and all contributed to the manuscript equally. funding e sapey was funded by the medical research council, grant number mr/ r / . other authors received no specific grant for this work from any funding agency in the public, commercial or not-for-profit sectors. no, there are no competing interests for any author. global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a year follow up study acute exacerbations and lung function loss in smokers with and without copd the impact of exacerbation frequency on mortality following acute exacerbations of copd: a registry-based cohort study copd: who cares when it matters most? national chronic obstructive pulmonary disease (copd) audit programme: outcomes from the clinical audit of copd exacerbations admitted to acute units in effect of a single exacerbation on decline in lung function in copd a treatise on the disease of the chest and on mediate auscultation. (translated by j forbes) de la numeration des globules rouges du sang ueber die form des menschlichen electrocardiogramms the determination of gases in blood and other solutions by vacuum extraction and manometric measurement. i notes on xrays ueber die isolierte farbung der schizomyceten in schmitt-und trockenpraparaten on consumption, on certain diseases of the lungs and pleura infection in the pathogenesis and course of chronic obstructive pulmonary disease infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease major air pollutants and risk of copd exacerbations: a systematic review and meta-analysis adherence to inhaled therapy, mortality and hospital admission in copd socioeconomic status, race and copd health outcomes physiological changes during symptom recovery from moderate exacerbations of copd venous 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derived mesenchymal stem cells in acute liver failure date: - - journal: cell biosci doi: . /s - - -z sha: doc_id: cord_uid: be zube acute liver failure (alf) is a life-threatening disease and is determined by coagulopathy (with inr ≥ . ) and hepatic encephalopathy as a result of severe liver injury in patients without preexisting liver disease. since there are problems with liver transplantation including lack of donors, use of immunosuppressive drugs, and high costs of this process, new therapeutic approaches alongside current treatments are needed. the placenta is a tissue that is normally discarded after childbirth. on the other hand, human placenta is a rich source of mesenchymal stem cells (mscs), which is easily available, without moral problems, and its derived cells are less affected by age and environmental factors. therefore, placenta-derived mesenchymal stem cells (pd-mscs) can be considered as an allogeneic source for liver disease. considering the studies on mscs and their effects on various diseases, it can be stated that mscs are among the most important agents to be used for novel future therapies of liver diseases. in this paper, we will investigate the effects of mesenchymal stem cells through migration and immigration to the site of injury, cell-to-cell contact, immunomodulatory effects, and secretory factors in alf. liver is one of the largest vital organs in human body that controls various biological processes, including the production of multiple hormones, storage of glycogen, neutralization of toxins and drugs, control of metabolism, metabolism of urea, and synthesis of plasma protein. typically, most physiological features of liver function are controlled by liver cells or hepatocytes; therefore, the loss of hepatocytes is the main cause of liver failure. several diseases related to malfunction of the liver are caused by damage to or loss of hepatocytes, including viral hepatitis, fatty liver disease, drug and toxin-induced liver injury, hepatocellular carcinoma, and hepatic abnormalities associated with autoimmunity and cirrhosis [ ] . (aspartate aminotransferase), alt(alanine transaminase), tbil (total bilirubin indirect level), alb (albumin)). liver failure is divided into three forms as follows. alf within h to several days with jaundice, coagulopathy and encephalopathy; acute-on-chronic liver failure (aclf) with a background of chronic liver disease leading to rapid progression of liver injury and associated with jaundice and ascites; and clf occurring within months to years [ ] . alf is an unpredictable and potentially catastrophic condition often encountered in intensive care units, with more than cases reported each year in the united states. the progression potential of acute hepatic dysfunction toward multi-organ failure demands rapid diagnosis and management of the disease. due to a set of hepatic and non-hepatic complications, alf indirectly leads to immediate follow-up for liver transplantation [ ] . alf, formerly known as fulminant hepatic failure, means the development of hepatocellular disorders such as coagulopathy and encephalopathy with inr ≥ . in patients without a history of liver disease within weeks. more than half of the cases of alf progression require liver transplantation and significant improvements have been reported in the last decade after liver transplantation. alf mortality is usually due to intracranial hypertension (ich) and infection [ ] [ ] [ ] ). however, patients with varying degrees of hemodynamic disorders and renal failure have also been reported [ , ] . clinically, the patients show coagulopathy, jaundice and hepatic encephalopathy. the period between the onset of the first clinical symptoms and hepatic encephalopathy is crucial in determining the prognosis of these patients [ , ] . there are obvious differences in the development mechanisms of early alf. the three main factors determining the prognosis of this disease include metabolic problems leading to the loss of liver cells, secretion of toxins and mediators from the liver tissue, and capacity of the remaining hepatocytes to repair the liver [ , ] . common treatments are therapies that are often meant to improve the complications of acute liver failure (alf). multiple organ failure (mof) and severe infection are the most prevalent factors of mortality in these patients. therefore, management of treatment for alf patients should focus on the handling and prevention of infection [ ] . alf patients with severe hepatic encephalopathy, those with renal failure and patients who have any of sirs criteria use broad-spectrum antibiotics [ ] . application of vasoconstrictors and dialysis reduce the incidence of cerebral edema [ ] . in case of hepatic encephalopathy, the patient is transferred to icu and ventilator devices are used to regulate the level of blood gases patients with alf have qualitative and quantitative coagulation abnormalities. in control of bleeding and during invasive procedures, there is indication for ffp and platelet administration [ ] . to prevent gastrointestinal bleeding in alf, patients admitted to icu are treated with h blockers or proton pump inhibitors (ppi) [ ] . patients with alf are at risk of hypovolemia for a number of reasons, including poor oral fluid intake, vomiting, and vasodilation, in which case bolus fluids are used and level of fluids is frequently maintained if necessary to keep serum sodium levels and prevent fluid overload [ ] . in addition to the mentioned treatments, - % glucose is administered when glycemic target is mg/dl and na level is - mmol/l, as well as n-acetylcysteine and stress ulcer prophylaxis agents [ ] . a wide variety of factors cause alf (table ) [ ] [ ] [ ] . the most common causes of this disease are viral infections and drug-induced liver inflammation. in asia and parts of europe, mainly viral hepatitis agents are involved and acetaminophen is the predominant factor in countries such as usa and australia [ ] . impaired function of both humoral and innate immunity is implicated in the pathophysiology of alf [ ] . the mechanism of alf begins with necrosis of hepatocytes [ ] . oxidative stress is triggered when liver injury is caused by factors such as viral infections, alcohol consumption, drug intoxication, autoimmune diseases, herbal remedies and many other factors [ ] [ ] [ ] . oxidative stress results in the production of reactive oxygen species, which in turn activates the janus kinase (jnk) signaling pathway [ ] and generates damageassociated molecular patterns (damps), followed by liver inflammation. liver inflammation is a major factor in immunopathology of several hepatic diseases [ , ] . damps activate hepatic macrophages (kupffer cells (kcs)) and induce the formation of inflammasome [ , ] that eventually leads to the secretion of il- , il- , and caspase [ ] . damps are detected by kupffer cells [ , ] that express a large number of damp receptors, including tlr , tlr , and rage [ ] . kcs are activated in this process and release inflammatory cytokines such as tnfα, oxygen radicals, and chemokines such as ccl under the effect of inflammatory signals. the presence of inflammatory factors mobilizes inflammatory cells such as neutrophils and monocytes and thereby increases inflammation [ , ] . hepatic encephalopathy (he) is a function of neurotoxins that reach the brain through the bloodstream [ ] . various factors such as blood ammonia levels, infection, necrotic liver, toxins, and systemic inflammatory response syndrome (sirs) can lead to he [ ] . in normal conditions, the ammonia produced in the body is efficiently excreted by the liver through the urea cycle and glutamine synthesis and thus a small amount of ammonia remains in hepatic vessels. in alf, ammonia levels rise in the hepatic vein, and the liver loses the ability to release ammonia from the hepatic veins. the muscles and brain begin ammonia detoxification through glutamine synthesis. therefore, both of these tissues are considered as an ammonia scavenging and glutamine releasing organs [ ] . tissue damage is the first factor triggering sirs reaction. as explained above, the injury leads to the release of inflammatory mediators such as damps, tnfα, il- , and il- . inflammatory cells such as lymphocytes and monocytes reach the damage site and enhance the inflammatory response. coagulation factors as well as primary and secondary homeostasis also become involved and result in sirs reaction [ ] . these reactions are associated with the development of he [ , ] , bacteremia [ ] and, in some cases, infection [ , ] . compensatory anti-inflammatory response syndrome (cars) occurs in reaction to sirs, leading to the secretion of anti-inflammatory factors (including il- and spli) from hepatic macrophages during the early stages. this reaction is meant to alleviate the inflammatory status [ , ] . both of these reactions eventually lead to dysregulation of the immune system and defective immune responses to microbial agents [ , ] . mscs are fusiform non-hematopoietic cells capable of adhering to plastic surfaces, which can be isolated from various tissues, including placenta, umbilical cord, bone marrow, adipose, and other tissues [ ] . despite their morphological and phenotypical similarities, mscs have different regeneration potentials [ ] , which is due to the microenvironment and cellular niches affecting their fate [ ] . the number of stem cells in many adult tissues is small and isolation of them is associated with several risks; for example, the cells exhibit a limited capacity for differentiation and proliferation after removal from the body, making it difficult to produce large numbers of stem cells [ ] . in comparison to adipose tissue and bm, in which mscs are affected by donor's age, placenta is a rich source of stem cells [ ] and high differentiation capacity and pluripotentiality of placental cells are related to their origin [ ] . pd-mscs have a higher proliferative potential than bm-mscs [ ] which reduces the number of passages to reach a large number of cells as well as the risk of cell aging [ , ] . among mcss, pd-mscs have a higher potential for in vitro proliferation and differentiation of hepatocytes [ ] . human bm-msc cells are involved in neovasculogenesis and synergize with endothelial colony forming cells (ecfcs) to create microvessels in vivo [ , ] . bm-msc cells serve as the gold standard for bone and cartilage repair [ ] . adipose tissue-derived mesenchymal stem cells (ad-mscs) are isolated from adipose tissue by liposuction, are capable of differentiation to hepatocytelike cells in the presence of hgf, fgf- , and fgf- factors and participate in the regeneration of hepatocytes and vasculogenesis [ ] . wharton's jelly mesenchymal stem cells (wj-mscs) exhibit stemness and pluripotential properties and have been shown to generate various types of neurons and connective tissue cells [ , ] . umbilical cord-derived mesenchymal stem cells (uc-mscs) have been recognized as low-immunogenicity cells because of their immunomodulatory properties. uc-mscs are involved in neovascularization and differentiation into hepatocyte-like cells [ , ] . umbilical cord blood has always been considered as a source of hematopoietic stem cells (hscs) [ ] . the phenotypic characteristics of uc-mscs are consistent with bm-msc cells [ ] . dental tissue-derived mesenchymal stem cells (dp-msc) have limited differentiation capacity relative to bm-mscs [ ] . dental pulp stem cells (dpscs) are dental stem and progenitor cells that are capable of selfrenewal and differentiation, which differentiate into neurons and adipocytes in addition to odontogenic cells [ , ] . the definition of mscs according to international society for cell therapy (isct) is as follows: mscs are ( ) able to bind plastic surfaces, ( ) able to differentiate into all three classes of chondrocytes, adipocytes and osteocytes in vitro, and ( ) capable of expressing cd , cd , and cd markers but not hematopoietic markers like cd , cd , cd , cd , and hla-dr [ ] . mscs release numerous factors such as vascular endothelial growth factor (vegf), insulin-like growth factor (igf- ), basic fibroblast growth factor (bfgf), nerve growth factor (ngf), transforming growth factor beta- (tgf-b ), placental growth factor (pgf), stromal cell-derived factor (sdf- /cxcl ), monocyte chemoattractant protein- (mcp /ccl ), hepatocyte growth factor (hgf), interleukin- (il- ), il- , il- , il- , g-csf and gm-csf [ ] [ ] [ ] [ ] . there are various tissue-specific factors in mscs depending on the tissues from which mscs are isolated. for example, factors such as hgf, bfgf, and il- are mainly secreted by mscs isolated from placental tissue or interferon-γ (ifn-γ), tumor necrosis factor α (tnfα), interleukin- alpha (il- α), and interleukin- beta (il- β) secreted by mscs from menstrual blood-derived stem cells (menscs) [ , ] . hence, it can be said that the selection of mesenchymal stem cells extracted from tissues is an important consideration in the treatment of diseases with respect to the secretory factors they produce. embryonic stem cells are isolated from embryonic tissues, especially multiple extraembryonic tissues. tissues such as amniotic fluid, wharton's jelly, amnion, chorion, embryonic membrane and placenta have mscs. the placenta is one of the largest organs with an essential role in the development of the fetus, which plays a role in the secretion of nutrients for the fetus and immune protection (tolerance) of it. it has recently been observed that pd-msc are a new alternative source of mscs for regenerative therapies [ ] . studies have shown that pd-mscs possess self-renewal capacity, have multilineage differentiation, lack ethical problems, are accessible, abundant, and show strong immunosuppressive effects [ ] [ ] [ ] ). in addition, placental tissue derived from the fetus is voluminous and can be easily manipulated to increase the number of mscs, which exceeds the number of mscs present in bone marrow and adipose tissue [ , ] . another advantage of these placental stem cells is that we do not require an invasive method to isolate them, whereas invasive methods are needed to isolate adult mscs [ ] . typically, pd-mscs can maintain a high proliferative capacity in culture medium for at least passages [ ] . some studies have recently suggested the differentiation of pd-mscs into hepatocyte-like endodermal cells [ , ] . investigations have shown that many perinatal resources of mscs such as amniotic membrane (am), chorionic plate (cp), parietal decidua [ ] , and umbilical cord (uc) have advantages relative to adult sources, including bone marrow (bm) [ ] [ ] [ ] . the mscs isolated from these tissues have their own characteristics as follows. vcam is a biomarker of chorionic plate with unique immunosuppressive activity that plays an important role in immune responses [ ] . cp-derived mesenchymal cells copiously secrete hgf and vcam . parietal decidua derived mesenchymal stem cells (dmscs) [ ] show a high secretion of ang and vegf but the lowest secretion of tgfβ . umbilical cord (uc) derived mscs have a high secretion level of igf and amniotic membrane (am) derived mscs highly release peg and tgfβ [ ] . considering the above statements, we show in this research that amniotic membrane-derived mesenchymal stem cells may be effective in treatment of premature ovarian aging due to overexpression of peg and tgfβ , cp-derived mscs could be used for angiogenic therapy because of pro-angiogenic activity, and parietal decidua derived mscs [ ] might be useful for the treatment of vital organ ischemia, and uc-mscs may be used for other therapies because of secreting a large number of factors [ ] . most animal and human studies on mscs have indicated therapeutic effects of these cells. however, there is evidence for low engraftment of mscs due to shortterm viability after injection [ , ] . mscs are trapped in the lung after injection and a lower number of these cells may reach their destination [ ] . therefore, the reduction of cell loss during migration is an advantage of topical over intravenous injection [ ] . several studies have indicated that a single injection of mscs is safe for the patient and does not stimulate the immune system, but re-injection of mscs may lead to the generation of alloantibodies [ ] . in addition, the fbs that is used to grow mscs could induce an immune response in the patient [ ] . in general, mscs show a dual behavior when faced with tumors and pd-mscs are no exception in this regard. for example, some in vitro studies have indicated that uc-mscs increase the expression of proliferating cell nuclear antigen (pcna) [ ] , induce the proliferation promoting genes like epgn/mzt a, downregulate transcription factors associated with the suppression of tumor development such as tal /fos/egr /klf , which stimulates different tumor populations [ ] . pursuant to this dual role of pd-mscs, one study introduces the antitumor role of these cells in a particular type of tumor but suggests a promoter role in another type. wj-mscs have an antitumor role in the face of squamous cell carcinoma in vitro, but stimulate the growth of cancer in vivo [ ] . clinicians have observed that a number of patients with alf may recover spontaneously and that the clinical outcome of these patients largely depends on the balance between loss and repair of hepatocytes [ ] . the damaged hepatocytes are rapidly replaced by normal hepatocytes in moderate disease, but in case of severe injury and widespread death of hepatocytes, the repair capacity of remaining hepatocytes may not be complete and lead to the deployment of liver progenitor cells (lpc) that act as hepatocytes [ ] . in most alf patients, these progenitor cells are insufficient to repair and replace hepatocytes, eventually leading to the adoption of limited therapeutic approaches by physicians [ ] . today, liver transplantation is the only way to treat liver failure patients. however, liver transplantation has failed for a number of reasons such as lack of proper organs, high costs, and the administration of immunosuppressive agents for long periods of time. other treatment strategies include bioartificial liver with less hepatocytes and drug therapy [ ] . hepatic failure is a disastrous consequence of liver loss, in which the repair of residual hepatocytes is not performed in a timely and appropriate manner, resulting in increased mortality [ ] . massive hepatic necrosis in acute liver failure [ ] is caused by sudden loss of hepatocytes due to a variety of acute injuries induced by hepatotoxic drugs, immune system attack, and viral infections [ ] [ ] [ ] . while most hepatocytes are completely destroyed in alf, the circulating bone marrow-derived cells and endogenous hepatocyte progenitor cells can rapidly regenerate the liver [ ] . cell-based therapies have been promising in regenerative medicine. mscs can be important sources of alternative therapy because of various properties such as self-renewal, proliferation and differentiation [ ] . the precise mechanism of mscs in alf is not completely understood [ ] . according to several studies, it can be stated that placenta-derived mesenchymal stem cells (pd-msc) are able to affect the liver damages in several ways: . pd-mscs are recruited to the damaged area by vcam- and vla- adhesion molecules [ , , ] affecting the remaining hepatocytes through cell-cell contact and secretion of tgf-α, egf, hgf, and vegf tropic factors [ , ] . increase treg cells, modulating the immune system as well as suppressing activated t-cells, nk cells, b-cells and il- production [ , ] . . pd-mscs decrease the inflammation of hepatocytes and prevent their apoptosis by suppressing tnfα and ifnγ, which leads to the regeneration of hepatocytes by releasing hgf, il- , paf and vegf [ , ] . . mscs are capable of secreting various angiogenic factors, including vegf, sdf- α, and mmp , which promote angiogenesis [ ] [ ] [ ] . . in addition to their immunomodulatory properties, mcss differentiate into vascular cells and pericytes in vivo [ ] . they also have the potential to differentiate into hepatocyte-like cells both in vivo and in vitro, leading to improvement of liver damage ( fig. ) [ , ] . a majority of studies have used the intravenous route to inject mscs, after which most mscs are trapped in lungs in the early stages [ , ] . after h, mscs move toward other organs (especially the liver and spleen) and settle in them [ ] . they also migrate to damaged tissues [ ] . for instance, in a study on patients with cirrhosis, mscs labeled with in-oxine were detected in the liver after h (through radioactivity assay) where they remained for days [ ] . elimination of mscs may be related to the immune system, which does not rule out the functional effect of these cells. one study has reported that phagocytosis of dead mscs induces the production of regulatory macrophages modulating the immune response by producing il- factors [ , ] . moreover, a small fraction of these cells that have been spared elimination could be responsible for the therapeutic effects [ ] . mscs play a critical role in liver regeneration because of their ability to produce and regulate platelet-activating factor (paf), hepatocyte growth factor (hgf) and vascular endothelial growth factor (vegf) [ ] . several studies have demonstrated the significance of mscs in liver diseases. mscs have been used in various investigations on alf in both animal models [ , ] and clinical trials [ , ] . nevertheless, the precise mechanism of the function of these cells remains unclear. since mscs are able to move to the site of injury and inflammation [ ] as well as being capable of proliferating and differentiating into hepatocytes [ , ] , they play an essential role in regenerative therapies. mscs show immunomodulatory feature because they do not express stimulatory molecules or hla ii [ ] and are therefore a good source for allogeneic and autologous transplantation. several studies have shown that mscs secrete tropic factors and can be effective in reducing inflammation, fibrosis and apoptosis of liver cells as well as repairing damaged tissue by stimulating angiogenesis [ ] . high migration ability is a major advantage of pd-mscs. migration involves the movement of mscs toward damaged and inflamed sites through interactions between mscs with cytokines and adhesion molecules secreted from the injured tissue environment [ ] . migration of mscs has been investigated in both animal [ ] and in human studies [ ] . for example, various researches have revealed that mscs express adhesion molecules and integrins such as vcam- and vla- , which are composed of cd and cd d components. compared with bm-derived mesenchymal stem cells (bm-mscs), placental mscs express a higher level of vla- and animal studies have indicated mscs binding to endothelial cell surface markers such as p-selectin and vcam- , which is indicative of the high implantation capacity of pd-mscs into damaged tissue [ , ] . a clinical trial of cirrhotic patients showed that in-oxinelabeled mscs were trapped in the lungs in the early hours after injection through peripheral blood and that they left there after h and migrated to the liver and spleen, remaining in these tissues for days [ ] . there are various mechanisms in the creation of an immunologically safe environment by placenta for the fetus [ ] . this feature is a strong advantage for pd-msc cell therapy in allogeneic transplantation, which prevents graft rejection, stabilizes the transplant and drives mscs, including bm-mscs and amniotic fluidderived mscs (af-mscs), toward the site of injury [ ] . embryonic-derived mscs are also capable of migrating to the placenta and blood brain barrier (bbb) [ ] . it can be argued that the beneficial effects of mscs in liver diseases (including alf) are not limited to hepatocyte repair, but rather the tropical factors released by fig. mesenchymal stem cells and its effects on acute liver failure them modulate the deleterious effects of the immune response [ ] . the immunosuppressive effects of mscs on the secretion of tnfα and ifn γ prevent from apoptosis of hepatocyte cells and reduce hepatic inflammation, and the suppression of these cytokines appears to be systemic [ ] . mscs in mice with alf suppress activated t-cells, decreasing the inflammatory cytokines tnfα, γ ifn and il- and exerting their immunosuppressive effects by increasing il- levels [ , ] . cells such as natural killer t (nkt) are of high importance in the pathogenesis of alf and are immunomodulatory targets mediated by mscs along with dendritic cells (dcs), macrophages and t-cells [ , ] . hgf is one of the most important factors in the repair of hepatic tissue, which is secreted by mscs. hepatocyte growth factor is an effective mitogen for hepatic tissue repair that is dependent on c-met receptor during tissue damage [ ] . the hgf/c-met signaling pathway is essential for liver repair and implantation of mscs in the affected area [ ] . many studies have reported the protective effects of hgf/c-met signaling pathway on liver injury [ , ] . hgf as well as other factors like tnfα and egf is considered a mitogenic factor associated with hepatocyte proliferation [ , ] . on the other hand, hgf together with ngf factor secreted by mscs induces apoptosis of hepatocyte stellate cells (hsc), indicating the antifibrotic property of these cells [ ] [ ] [ ] . many studies have shown that angiogenesis plays a crucial role in hepatic repair so that the injection of antiangiogenic factors such as anti-vegf inhibits hepatic repair [ , ] but factors such as bfgf enhance it [ ] . vegf boosts angiogenesis and contributes to the healing process [ ] . angiogenesis is essential for wound healing, regeneration and organogenesis [ ] . il- binds to gp and gp receptors, which activate the jak pathway and in turn phosphorylate tyrosines in the intracellular domain of gp , subsequently activating the mapk pathway and stat and transcription factors that lead to hepatocyte proliferation [ ] [ ] [ ] . recent experiments on animal models have shown that il- and tnf- are involved in regeneration of liver mass [ ] . limited information is available on the repair mechanism of mscs in various diseases; therefore, further in vivo studies provide a broad perspective for mscs use in clinical practice. choosing the right cell, determining the proper dose, selecting the appropriate injection site and timely injection can help improve the function and implantation of mscs in the target tissue, and they can be highly important and applicable for further research in the future. in this review paper, we concluded that pd-mscs can be considered as a good allogeneic source for alf in future because of their safety, easy accessibility, lack of immune system stimulation, secretion of appropriate factors for liver tissue and healing properties. mscs: mesenchymal stem cells; pd-mscs: placenta-derived mesenchymal stem cells; alf: acute liver failure; aclf: acute-on-chronic liver failure; clf: choronic liver failure; ich: intracranial hypertension; damps: damage-associated molecular patterns; sirs: systemic inflammatory response syndrome; cars: compensatory anti-inflammatory response syndrome; isct: international society for cell therapy; vegf: vascular endothelial growth factor; igf- : insulin-like growth factor ; bfgf: basic fibroblast growth factor; ngf: nerve growth factor; tgf-b : transforming growth beta- ; ifn-γ: interferon-γ; tnf-α: tumor necrosis factor α; il- α: interleukin- alpha; il- β: interleukin- beta; pgf: placental growth factor; sdf- /cxcl : stromal cell-derived factor ; mcp /ccl : monocyte chemoattractant protein- ; hgf: hepatocyte growth factor; g-csf: granulocyte-colony stimulating factor; gm-csf: granulocytemacrophage colony stimulating factor; am: amniotic membrane; cp: chorionic plate; uc: umbilical cord; lpc: liver progenitor 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recovery in intestinal ischemia reperfusion model hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair cholesterol enhances the toxic effect of ethanol and acetaldehyde in primary mouse hepatocytes expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat immunomodulation of activated hepatic stellate cells by mesenchymal stem cells inhibition of hepatic stellate cells proliferation by mesenchymal stem cells and the possible mechanisms nerve growth factormediated paracrine regulation of hepatic stellate cells by multipotent mesenchymal stromal cells expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats liver regeneration is an angiogenesis-associated phenomenon endothelial-directed hepatic regeneration after partial hepatectomy isolation and characterization of bipotent liver progenitor cells from adult mouse angiogenesis is crucial for liver regeneration after partial hepatectomy liver failure and defective hepatocyte regeneration in interleukin- -deficient mice the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade activation is a key signalling pathway involved in the regulation of g( ) phase progression in proliferating hepatocytes interleukin- -type cytokine signalling through the gp /jak/stat pathway acutephase response factor, increased binding, and target gene transcription during liver regeneration publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. key: cord- - wb m ux authors: boujaoude, ziad c.; pratter, melvin r. title: clinical approach to acute cough date: - - journal: lung doi: . /s - - - sha: doc_id: cord_uid: wb m ux acute cough is among the most common symptoms for which patients seek medical attention. it accounts for millions of days lost from school and work and billions of dollars spent on medical care. acute cough is defined as cough present for weeks or less. it most often is caused by a viral infection of the upper respiratory tract (“common cold”) or lower respiratory tract (i.e., “acute bronchitis”). the most effective treatment for cough due to the common cold is a combination first-generation antihistamine plus decongestant. antibiotics are not indicated for most cases of acute cough. occasionally, acute cough can be a symptom of a life-threatening condition. the act of coughing is relatively unique. from a health point of view, cough is a vital defense mechanism that helps protect the lungs from potentially noxious and dangerous exogenous substances and simultaneously facilitates the clearance of excessive lower respiratory tract secretions. excessive or pathologic coughing that serves no useful purpose, on the other hand, is among the most common symptoms for which patients seek medical attention. abnormal cough can be caused by a variety of respiratory and nonrespiratory disorders. the diagnostic evaluation and treatment of cough in the united states accounts for a substantial expenditure of health-care dollars [ ] . for epidemiologic purposes, cough is typically categorized based on duration: acute, defined as lasting less than weeks; subacute, lasting - weeks; and chronic, lasting more than weeks [ ] . the primary value of this division based on duration is that it is useful in predicting the most likely etiologies of cough compared with most other characteristics [ ] [ ] [ ] . among the three categories, acute cough is the most common and has the greatest impact on the general public. it results in millions of lost days from school and work and billions of dollars of health care expenditures. in the united states in the year , expenditures for over the counter cough (otc) and cold remedies just for adults were estimated at . billion dollars (ac nielson's database). paradoxically, despite its prevalence and health and economic effects, acute cough has received relatively little attention in the medical literature compared with chronic cough. although using time duration to categorize cough seems easy and attractive, the presumed precision of duration to define a cough as acute, subacute, or chronic (and the differential diagnostic implied) is less precise and the issue more complex then it appears. obviously, all cough at its beginning is acute. it is not currently possible to predict at the onset of cough in whom it will be of short duration (i.e., resolve within weeks) or in whom it will become subacute or chronic. the issue is further complicated by the fact that effective therapy can abort or abbreviate the duration of cough, whereas failure to institute effective therapy can convert what might have been an acute cough into a subacute or chronic one. furthermore, recurrent acute episodes of cough can be a manifestation of an undiagnosed chronic disease (e.g., asthma). nevertheless, keeping these caveats in mind, a relatively ''standard'' diagnostic and therapeutic approach based on duration of cough has proved useful [ ] . cough involves a complex reflex arc. it is usually initiated by the stimulation of afferent cough receptors. these receptors are present in the epithelium of the upper and lower respiratory tracts as well as in the pericardium, esophagus, diaphragm, and stomach. cough receptors can be divided into chemical receptors sensitive to acid, heat, and capsaicin-like compounds and mechanical receptors stimulated by triggers, such as touch or displacement [ ] . impulses from cough receptors travel predominantly via afferent pathways involving the vagus nerve to a ''cough center'' believed to be located in the medulla. this center is under some degree of voluntary control by higher cortical centers. the cough center, when stimulated, generates efferent impulses that travel down the vagus, phrenic, and spinal motor nerves to the expiratory respiratory musculature to produce the cough. three mechanisms have been proposed to trigger the cough reflex and are discussed below [ ] . a number of descriptive studies have been published that describe the spectrum and frequency of etiologies for chronic cough [ , , , ] . this is not the case for acute cough. despite its importance, there are no large, prospective studies that describe the spectrum and frequency of the causes of acute cough. it is presumed that acute cough is most commonly caused by viral respiratory tract infections. the infections that involve primarily the upper respiratory tract (urt) are designated collectively as the ''common cold.'' alternatively, infections that appear to involve primarily the airways of the lower respiratory tract (lrt) are termed ''acute bronchitis'' [ , ] . acute bacterial sinusitis, bordetella pertussis, mycoplasma, and chlamydia infections, allergic rhinitis, environmental irritant rhinitis, and foreign body aspiration are other causes of acute cough [ ] . importantly, on occasion acute cough can be the presenting or predominant symptom of a serious or even life-threatening condition (e.g., pulmonary embolism, congestive heart failure, pneumonia) [ , ] . the common cold is one of the most ubiquitous infectious diseases of humankind. adults in the united states, on average, experience two to four colds per year [ ] . at least viruses have been associated with the typical findings of the ''common cold.'' they include rhinoviruses, coronaviruses, parainfluenza viruses, respiratory syncytial virus, adenoviruses, and enteroviruses [ ] . the histological effects of these viral infections vary from extensive epithelial destruction of upper airway structures to the virtual absence of histological changes. in most cases these infections will cause clinical evidence of vasodilatation and hypersecretion of upper airway structures (particularly the nose, i.e., rhinitis). the resultant clinical syndrome includes nasal congestion, nasal discharge, postnasal drip (pnd), throat clearing, sneezing, and cough [ ] . the exact mechanisms by which viral infections associated with the ''common cold'' cause cough are unclear. one proposed mechanism is that the production of inflammatory mediators, such as bradykinin, prostaglandins, and tachykinins, produce excessive secretions that result in pnd that mechanically stimulates the cough receptors. this is supported by a randomized, double-blind, placebo-controlled study on the common cold that demonstrated statistically significant associations among cough, throat clearing, and pnd [ ] . cough improved in parallel with decreases in throat clearing and pnd. alternatively, it has been proposed that viral-induced inflammation of upper airway structures can directly irritate and activate the afferent sensory nerves in the upper airway [ ] . madison and irwin have proposed that this increase in cough sensitivity of the upper airway during urti may be due to an increased sensitivity of the rapidly adapting sensory receptors in the airway [ ] . in recognition of the possibility that both pnd and direct irritation of airway cough receptors can be factors in how upper airway cough is triggered, the term upper airway cough syndrome (uacs) was proposed in the american college of chest physicians (accp) cough guidelines to replace the term pnd [ ] . a third postulated, although unproven, mechanism for cough associated with the common cold is that inflammatory mediators produced at the site of upper airway infection are absorbed into the blood stream and reach the lower airways where they result in inflammation and hyperreactivity of sensory receptors [ ] . acute bronchitis is a common diagnosis made by primary care and emergency department physicians. it is used to describe an acute infection of the lrt that is manifested predominantly by cough with or without phlegm production that lasts for up to weeks [ ] . it often is accompanied by constitutional symptoms. several other disorders can have similar presentations. the common cold is the most difficult to distinguish from acute bronchitis because of the strong symptom overlap. furthermore, there is no diagnostic test that can differentiate between these two disorders. according to accp evidence based guidelines, the diagnosis of acute bronchitis should be made only when there is no clinical or radiographic evidence of pneumonia, and the common cold, acute asthma, or an exacerbation of copd have been ruled out as the cause of cough [ ] . various respiratory viruses appear to be the most common cause of acute bronchitis. fewer than % of patients will have a bacterial infection diagnosed as the cause [ ] . viruses associated with acute bronchitis include influenza b, influenza a, parainfluenza, and respiratory syncytial virus (rsv). in addition, viruses that are predominantly associated with urt infection, including coronavirus, rhinovirus, and adenovirus have been implicated in acute bronchitis. the bacteria that have been linked to acute bronchitis include mycoplasma pneumoniae, chlamydophila pneumoniae, bordetella pertussis, and bordetella parapertussis [ ] . the mechanism of cough in uncomplicated acute bronchitis is likely multifactorial. it presumably begins with mucosal injury, epithelial cell damage, and the release of proinflammatory mediators. transient bronchial hyperresponsiveness and even airflow obstruction can occur [ ] . an approach that may be useful to determine the cause and guide treatment of acute cough is shown in fig. . the initial step is to differentiate between life-threatening and non-life-threatening causes. initially, this is based on the history and physical examination. if clinical findings warrant it, diagnostic tests, typically starting with a chest roentgenogram, are obtained. in the case of suspected serious and potentially life-threatening cause (e.g., pneumonia, pulmonary embolism, and pulmonary edema), immediate diagnostic evaluation and treatment should be instituted. in the much more common circumstances of presumed non-life-threatening causes, the main conditions are respiratory tract viral infections, exacerbations of a preexisting condition, and environmental/occupational causes [ ] . for acute cough related to the common cold, the combination of a first-generation antihistamine (brompheniramine) plus a decongestant (pseudoephedrine) has been shown in a double-blind, placebo-controlled study to hasten resolution of both cough and postnasal drip [ ] . in contrast, the newer, so-called second-generation ''nonsedating'' antihistamines have been shown to be ineffective in treating the symptoms of the common cold [ ] . the efficacy of a combined first-generation antihistamine plus decongestant preparation is postulated to be related to the anticholinergic properties of the antihistamine and vasoconstricting property of the decongestant [ ] . another double-blind, placebo-controlled study showed that the fig. a practical approach to this common problem. it is important not to miss a serious condition. outlined is guidance for how to approach the vast majority of patients with common and mundane causes of acute cough, such as viral urti lung ( ) (suppl ):s -s s nonsteroidal anti-inflammatory drug, naproxen, favorably affects the cough of the common cold [ ] . a number of other treatments are commonly used to treat the common cold. topical a-adrenergic therapy can be used in the short term (e.g., - days), although no prospective data showing its efficacy are available. prolonged use is not advised because of the risk of rhinitis medicamentosa. zinc-containing lozenges abbreviated the symptoms of the common cold, including cough in one prospective study [ ] . two other studies and a metaanalysis, however, did not support the purported benefit of zinc in treating the common cold [ ] . because zinccontaining therapy is associated with a significant incidence of side effects, its use cannot be recommended [ ] . topical anticholinergic therapy has been shown in one prospective study to decrease rhinorrhea and sneezing in the common cold, but its efficacy on decreasing cough was not evaluated [ ] . interferon may decrease symptoms of the common cold, but only if used prophylactically. further limiting interferon's value is the significant potential for side effects. [ ] . specific antiviral therapies for the common cold have shown some promise, but their efficacy is limited by the myriad of potential viral causes of the common cold and also by side effects [ ] . although there is limited clinical evidence to support their use for cough associated with the common cold, the expectorant guaiphenesin, is found in a wide range of common cold medications, often in combination with an antitussive. guaiphenesin can reduce the viscosity of respiratory tract mucus, which could increase the efficacy of the cough reflex and mucociliary clearance to clear secretions [ ] . it is unclear, however, how this would decrease the cough of the common cold, which is predominantly an upper airway process. if the cough is due primarily to acute bronchitis then perhaps the effect on mucus and mucociliary function might be useful. opioids (e.g., codeine) are believed to inhibit cough primarily by their effect on the cough center. because of the potential for abuse and addiction with opioids, nonopioid antitussives (e.g., dextromethorphan) may be preferred for the treatment of acute cough. they are widely available without prescription. a meta-analysis of six studies concluded that mg of dextromethorphan, on average, reduced cough by % compared with placebo, but other studies have demonstrated that efficacy is at best marginally superior to placebo [ ] . benzonatate has an anesthetic action similar to that of benzocaine. this action is the rationale for its purported antitussive effect on peripheral cough receptors. little evidence is available to support its use. in one study the effect of benzonatate did appear to be potentiated when combined with guaiphenesin [ ] . acute bronchitis should be considered when the acute cough is productive or associated with lrt symptoms, including wheezing, shortness of breath, or chest tightness. the possibility that the symptoms are actually a result of viral-induced exacerbation of asthma must be considered. because acute bronchitis is primarily a viral illness, routine treatment with antibiotics is not justified. even when bacterial infection is suspected, antibiotics are still not recommended routinely because clinical trials suggest that antibiotics at best only modestly reduce the duration of symptoms. specifically, a meta-analysis of eight trials of acute bronchitis suggested that the duration of symptoms was reduced by only a fraction of a day by the use of erythromycin, doxycycline, or trimethoprim-sulfamethoxazole [ ] . although the results were statistically significant, they appear clinically trivial. the accp guidelines on cough do not recommend the routine use of antibiotics to treat acute bronchitis [ ] . a difficult issue is whether physicians can reliably recognize the occasional patient with acute cough due to a cause (e.g., bordetella pertussis, mycoplasma, or chlamydia) that will respond to early antibiotic therapy. certainly if one suspects bordetella pertussis the prompt institution of an antibiotic seems to be appropriate. both the accp guidelines [ ] and those of the centers for disease control and prevention (cdc) recommend macrolides as first-line therapy for pertussis [ ] . according to the accp guideline, antitussive agents are only occasionally useful and the routine use of inhaled bronchodilators or mucolytic agents is not indicated [ ] . when a patient has evidence of airflow obstruction or wheezing, b agonists can be helpful. the routine use of inhaled anticholinergics is not recommended [ ] . in its january publication, the cdc did recommend that for suspected influenza a infection that antiviral therapy with oseltamivir or zanamivir is appropriate. the current concern about h n ''swine flu'' serves to heighten the importance of this recommendation in cases of suspected influenza a infection especially if associated with significant respiratory symptoms. in contrast, based on evidence that many strains of influenza a virus are resistant to both amantadine and rimantadine these drugs are not recommended [ ] . if the cause of acute cough is related to irritant or allergic exposures, then eliminating or avoiding the causative agents would make logical sense. despite a lack of published data, the use of second-generation antihistamines, nasal steroid preparations, or leukotriene inhibitors would appear to make sense in this setting. acute cough is most commonly caused by a viral urti (i.e., the common cold). pnd was postulated to be the main mechanism involved, but based on the accp guidelines, direct irritation and inflammation of upper airway structures is a plausible alternative causative factor. therefore, upper airway cough syndrome (uacs) is now the recommended term to describe most upper airway causes of cough [ ] . although acute cough is by definition transient and self-limited, it is one of the most common reasons that patients seek medical attention. despite the fact that most of the time it will be due to a viral etiology, patients often request and physicians often inappropriately prescribe antibiotics. there are a number of otc medicines purported to be useful for treatment of the symptoms of the common cold despite the lack of convincing evidence for efficacy. the best evidence for treatment of cough associated with the common cold is the use of a combination first-generation antihistamine and an effective decongestant (i.e., pseudoephedrine). this is not to imply that every patient with an acute cough related to the common cold requires treatment. typically, the common cold is a self-limited illness and the potential for side effects from first-generation antihistamines and oral decongestants must be weighed against the moderate efficacy of the treatment. managing cough as a defense mechanism and as a symptom: a consensus panel report of the the diagnosis and treatment of cough chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy an algorithmic approach to chronic cough chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy the type vanilloid receptor: a sensory receptor for cough acute cough: epidemiology, mechanisms and treatment overview of common causes of chronic cough: accp evidence-based clinical practice guidelines chronic upper airway cough syndrome secondary to rhinosinus diseases (previously referred to as postnasal drip syndrome). accp evidence-based clinical practice guidelines cough and the common cold cough and the common cold clinical significance of cough as a defense mechanism or a symptom in elderly patients with aspiration and diffuse aspiration bronchiolitis effectiveness of antihistamines in common cold epidemiology of viral respiratory infections gender differences in health-related quality of life in patients complaining of chronic cough pharmacotherapy of chronic cough in adults uncomplicated acute bronchitis chronic cough due to acute bronchitis an empiric integrative approach to the management of cough evaluation of oral terfenadine for treatment of the common cold introduction to the diagnosis and management of cough effects of naproxen on experimental rhinovirus colds. a randomized, double-blind, controlled trial zinc gluconate lozenges for treating the common cold: a randomized, double-blind, placebo-controlled study a meta-analysis of zinc salts lozenges and the common cold zinc gluconate lozenges for treating the common cold in children: a randomized controlled trial effectiveness and safety of intranasal ipratropium bromide in common colds: a randomized, double-blind, placebo-controlled trial antivirals for the common cold antitussive effect of guaifenesin in young adults in natural colds antitussive efficacy of dextromethorphan in cough associated with acute upper respiratory tract infection inhibition of cough-reflex sensitivity by benzonatate and guaifenesin in acute viral cough antibiotics in acute bronchitis: a meta-analysis recommended antimicrobial agents for the treatment and postexposure prophylaxis of pertussis: cdc guidelines symptomatic effect of inhaled fenoterol in acute bronchitis: a placebo-controlled double-blind study high levels of adamantine resistance among influenza a (h n ) viruses and interim guidelines for use of antiviral agents consultancies, stock ownership, equity interests, patent-licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article, except as disclosed below. all funding sources supporting the work and all pratter is a paid consultant on cough related issues to: jaymac parmaceutical company, coco pharmaceutical, and wyeth. he is a speaker with astrazeneca key: cord- - okbdw a authors: sin, david; mclennan, gordon; rengier, fabian; haddadin, ihab; heresi, gustavo a.; bartholomew, john r.; fink, matthias a.; thompson, dustin; partovi, sasan title: acute pulmonary embolism multimodality imaging prior to endovascular therapy date: - - journal: int j cardiovasc imaging doi: . /s - - - sha: doc_id: cord_uid: okbdw a the manuscript discusses the application of ct pulmonary angiography, ventilation–perfusion scan, and magnetic resonance angiography to detect acute pulmonary embolism and to plan endovascular therapy. ct pulmonary angiography offers high accuracy, speed of acquisition, and widespread availability when applied to acute pulmonary embolism detection. this imaging modality also aids the planning of endovascular therapy by visualizing the number and distribution of emboli, determining ideal intra-procedural catheter position for treatment, and signs of right heart strain. ventilation–perfusion scan and magnetic resonance angiography with and without contrast enhancement can also aid in the detection and pre-procedural planning of endovascular therapy in patients who are not candidates for ct pulmonary angiography. acute pulmonary embolism (pe) is a frequently encountered disease associated with high morbidity and mortality [ ] . most cases of acute pe originate from lower extremity deep vein thrombosis [ ] . the thirty-day mortality rate is estimated to be %, and the one-year mortality rate is estimated to be % [ ] . the incidence of acute pe is higher in males ( per , people) compared to females ( per , people) [ ] [ ] [ ] . advanced age is correlated with increased incidence of acute pe [ , ] . acute pe presents with variable severity [ ] [ ] [ ] [ ] . this can be explained by the varying degrees of pulmonary vasculature obstruction secondary to venous thromboembolism. gradual increases in pulmonary artery pressure can be seen when greater than - % of an arterial bed's cross-sectional area is occluded as a result of stressed endothelial cells releasing thromboxane and other vasoactive mediators [ ] . increased pulmonary artery pressure resulting from acute pe obstruction increases right heart strain secondary to elevated right ventricular afterload [ ] . right ventricular dysfunction can be observed acutely as a result of the increased afterload as well as myocardial ischemia [ ] . continued stress on the ventricles can cause protracted contractions, ischemia, and desynchronization of the left and right ventricles [ ] . prolonged elevation of pulmonary vascular pressures can also cause pulmonary hypertension that lasts beyond the original event [ ] . dyspnea, pleuritic chest pain, and cough are the most common presenting symptoms of acute pe, while other signs of acute pe include unilateral leg edema, sinus tachycardia, and tachypnea [ , ] . initial testing for patients with suspected acute pe should include brain natriuretic peptide, troponin, and ecg (table ) . these investigations can be helpful in narrowing down the differential diagnosis. these tests also provide prognostic data when acute pe is present [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the wells score is used to determine the pre-test probability of acute pe in hemodynamically stable patients. a patient's wells score categorizes them as having a low, intermediate, or high pre-test probability of acute pe [ , , , ] . the low, intermediate, and high risk categories correspond to . %, . %, and . % pre-test probability of acute pe, respectively based on a meta-analysis [ ] . a wells score of zero essentially excludes the possibility of acute pe with a low false-negative rate and a high sensitivity. the modified geneva score may also be used to determine the pre-test probability of acute pe. this scoring system utilizes clinical variables to categorize a patient into low, intermediate, or high risk groups that corresponded to %, %, and % prevalence of acute pe in one study [ ] . a simplified version of the modified geneva score has been found to maintain diagnostic accuracy and has been externally validated [ , ] . patients who are categorized as having a low or intermediate pre-test probability of acute pe can be assessed with a laboratory d-dimer test. a negative d-dimer test result in these patients essentially excludes the possibility of acute pe. a meta-analysis found that patients with a negative d-dimer and without a high pre-test probability of acute pe had a . % -month incidence of venous thromboembolism [ ] . it is important to consider that the d-dimer can also be nonspecifically elevated in certain conditions, such as pregnancy, recent hospitalization, active neoplastic disease, and other chronic inflammatory states. a prospective longitudinal study of patients with systemic lupus erythematosus with recurrent activity found that unexplained, persistent elevation of d-dimer levels, especially above . µg/ ml, were associated with elevated risk of thrombosis [ ] . another study found that d-dimer levels in patients with estimated glomerular filtration rate of - ml/min were % sensitive in ruling out acute pe although they were not specific enough to diagnose acute pe in this population [ ] . increased age has been associated with elevations in d-dimer concentrations, and a greater age-adjusted d-dimer threshold was found to be more specific ( % versus %) although less sensitive ( % versus %) in detecting acute pe in patients greater than years old [ ] . patients with a high pre-test probability and occasionally those with intermediate pre-test probability require imaging to assess for acute pe. computed tomography pulmonary angiography (ctpa) is usually the non-invasive imaging modality of choice. ctpa offers % sensitivity, % specificity, and % positive predictive value when diagnosing acute pe in patients considered to have a high pre-test probability [ ] . a positive d-dimer test result also requires ctpa imaging to confirm or exclude acute pe [ , , ] . the simplified pulmonary embolism severity index (spesi) is a sensitive clinical prediction score used to risk stratify diagnosed acute pe patients [ , , ] . this tool considers the variables of age > years old, history of cancer, chronic cardiopulmonary disease, heart rate ≥ beats per minute, systolic blood pressure < mmhg, and arterial oxyhemoglobin saturation < %. a patient is scored by receiving one point per variable present [ ] . a score of is considered low-risk with an associated . - . % -day mortality rate while a score of ≥ is considered high-risk with a . - . % -day mortality rate [ , ] . stratifying diagnosed acute pe patients by prognostic risk can be helpful in identifying low-risk patients who may benefit from outpatient therapy and revealing higher risk patients who should receive inpatient treatment [ ] . the european society of cardiology pe guidelines utilize the spesi in addition to right ventricular strain on echocardiogram or ct, elevated troponin levels, and hemodynamic instability to classify patients with pe as low-, intermediate-low, intermediate-high, and high-risk pe [ ] . other prognostic scoring systems including the bova and fast scores utilize clinical, imaging, and laboratory data to estimate risk of early pe-associated mortality although their implications for clinical decision-making have not yet been elucidated [ ] [ ] [ ] [ ] [ ] [ ] . the performance of endovascular therapy for acute pe treatment is evolving and gaining increasing interest. endovascular treatment enables the removal of thromboembolic material from the pulmonary arterial system through catheter-directed lysis or aspiration thrombectomy. endovascular treatment can be especially beneficial in patients with persistent hypotension or shock secondary to acute pe [ ] . this treatment has the potential to improve right ventricular function by relieving elevated pulmonary vascular pressures and stabilizing hemodynamics [ ] . a pulmonary embolism response team can help decide on the best therapy for a patient with acute pe [ ] [ ] [ ] . endovascular therapy can be considered in patients with contraindications to systemic thrombolysis who have submassive acute pe, evidenced by elevated troponin and brain natriuretic peptide, and right heart strain [ , , ] . endovascular therapy of acute pe usually involves placing a side hole infusion catheter through the thromboembolism and infusing tissue plasminogen activator (tpa). one mg of recombinant tpa per hour per catheter for a maximum total of mg is a typical dosage per the seattle protocol [ ] . the ultima trial found that - mg of recombinant tpa over h in addition to unfractionated heparin reversed right ventricular dilatation at h greater than unfractionated heparin alone [ ] . these doses are lower than that used in systemic thrombolysis and are therefore thought to be associated with a lower risk of intracranial or other hemorrhage [ ] . aspiration thrombectomy with immediate removal of the offending thromboembolic material from the pulmonary arterial system is another endovascular treatment approach [ ] . aspiration thrombectomy is specifically beneficial for patients with contraindication to systemic or catheter directed thrombolysis secondary to elevated bleeding risk [ , ] . the perfect registry prospectively enrolled patients receiving catheter-directed therapy for acute pe in a multicenter registry. the study showed that catheterdirected therapy for acute pe decreased right-sided heart strain and pulmonary artery pressures without causing major bleeding events [ ] . the optalyse pe trial was a prospective, multicenter, parallel-group trial that included patients with acute pe treated with ultrasound-assisted catheter-directed thrombolysis. the patients were randomized to groups that varied by tpa dose (range of to mg) and infusion duration (range of to h). the endpoints of rv/ lv diameter ratio and thromboembolic burden were significantly decreased in the treatment groups. major bleeding occurred in only % of patients, and one intracranial hemorrhage event was attributed to ultrasound-assisted catheter-directed thrombolysis [ ] . studies have confirmed that endovascular treatment of acute pe is safe and effective with regard to short term hemodynamic stabilization. additional studies should be done to assess the effect of catheter-directed therapy on long-term sequela of pe namely cted and cteph with right ventricular failure. computed tomography pulmonary angiography (ctpa) is the current non-invasive imaging modality of choice to assess acute pe. its strengths include its accuracy, speed of acquiring images, and widespread availability. ctpa may reveal alternative diagnoses contributing to a patient's presentation if acute pe is not visualized [ ] . a prospective randomized trial assessing acute pe detection with ctpa compared to pulmonary angiography as gold standard found ctpa to have % accuracy [ ] . ctpa also offers superior spatial resolution and multi-planar reconstruction [ ] . wide-array ct scanners can cover substantial length per rotation and are associated with reduced motion artifacts. dual-energy ct can help to rule out acute segmental and sub-segmental pe by color-coding perfusion based on the iodine concentration (iodine or z-effective mapping) [ ] . dual-energy ctpa involves using two distinct energy levels to capture the image [ ] . this technique enables differentiation between tissues with similar attenuation values using various processing techniques such as iodine maps, virtual non-contrast (vnc) and virtual monochromatic images (vmi). iodine maps accentuate iodine-containing tissue and improve the sensitivity of perfusion defects. vnc images imitate non-contrast images by virtually removing iodine and can be used for calcium scoring or as a substitute for true non-contrast images. vmi imitate an x-ray beam with one energy level and are created by a linear combination of basis pair images in different proportions. vmi can decrease artifacts and thereby improve specificity [ , ] . lung perfusion maps can be derived from iodine maps (figs. and ) [ ] . a pulmonary perfused blood volume (pbv) map color codes parenchymal tissue by iodine concentration [ , ] . perfusion defects are normalized to the vascular iodine concentration, and areas that do not fall within this attenuation range are excluded. hence, lung abnormalities appear dark on pbv maps. pbv maps can also be merged with conventional ct images to better analyze the lungs' form and function [ , ] . dual-energy ct can salvage suboptimal studies and reduce the contrast exposure to patients. this is accomplished by using low-energy vmi less than kev, which exhibits greater photoelectron attenuation and thus greater contrast [ ] . as many as % of regularly acquired ctpa studies are non-diagnostic, and % of those are caused by poor contrast enhancement [ ] . while poorly enhanced studies often require repeat contrast doses and repeat scanning with associated radiation exposure, low energy vmi avoids this by virtually increasing vessel attenuation and contrast-to-noise ratio (cnr). the subjective image quality was found to be best at kev vmi when compared to polyenergetic images in one study [ ] . another study found that kev produced the greatest cnr and sound-to-noise ratio (snr) while maintaining image quality and using % of the typical iodine concentration [ ] . dual-energy ct has also been found to produce high snr, and cnr while requiring only % of the typical iodine based contrast agent dose [ ] . high-energy vmi has the ability to reduce artifacts, with kev producing the least artifacts [ ] . beam hardening artifacts originating from dense contrast in the superior vena cava is especially reduced with high-energy vmi [ ] . the high-pitch helical mode of dual-source scanners also results in diagnostic image quality by requiring decreased breath hold duration and thus leading to reduced motion artifacts. this mode is also associated with decreased radiation and contrast exposure to the patient [ ] . a retrospective study of ultra-high-pitch dual-source ctpa in patients with suspected pe found that a reduced voltage ( kv) compared to a standard voltage ( kv) resulted in significantly reduced radiation dose, greater subjective image quality, and improved snr and cnr. diagnostic agreement between readers for the reduced voltage was very high (κ = . ) [ ] . iterative reconstructive algorithms can further reduce patients' radiation exposure [ ] . a retrospective study of patients divided into three groups differentiated by ct optimization technique found that iterative reconstruction resulted in a significant radiation dose reduction of - % when combined with automated tube current modulation. the same study found that iterative reconstruction improved levels of objective noise [ ] . another study found that iterative model reconstruction could reduce radiation doses up to % while preserving image quality [ ] . ctpa can be helpful in the planning stages of endovascular therapy for acute pe. in the coronal orientation, it can reveal both the number and distribution of emboli. during fig. -year-old female with known anca-negative, mediumsize-vessel vasculitis presenting with progressive dyspnea over a period of weeks. a dual-energy ctpa demonstrates filling defects of several subsegmental arteries, one of them illustrated in this axial plane (arrow). b z-effective map of the dual-energy ctpa demonstrating iodine distribution with blue colors representing high iodine concentration and yellow and red colors representing low iodine concentration. this axial plane at the same level shows a wedge-shaped area of low iodine concentration (arrows) corresponding to an area of reduced perfusion caused by the embolus seen in a. further perfusion defects can be appreciated on the same plane (arrowheads) corresponding to more emboli not detected with regular ctpa imaging the procedure coronal reconstruction can be correlated to ctpa images to ensure proper catheter position within the acute thromboembolic material. right heart strain is a common pathology associated with acute pe, and ctpa reveals signs of right heart strain including increased rv/ lv diameter ratio of . or greater, interventricular septal bowing towards the left ventricle, contrast reflux into the hepatic vein as well as inferior vena cava (ivc), and increased ivc diameter compared to baseline [ ] . capturing the pulmonary artery size allows its comparison to prior cts and may show an acute enlargement secondary to pe. ctpa also enables characterization of the venous anatomy including proximal ivc and the patency of the central veins. this information is important for access planning purposes (figs. and ) . dual-energy ct perfusion images simulate true perfusion by allowing the comparison of a tissue's innate physical density with its enhancement during acquisition [ ] . these perfusion images do not require changing the cta protocol, which confers the benefits of not requiring additional radiation or contrast and thereby minimizing motion misregistration from repeated acquisitions [ ] . the resulting images correlate well with those of scintigraphic perfusion images. pbv images have shown modest correlation with lung scintigraphy in cteph patients [ ] . one study of dual-energy ct perfusion images compared to scintigraphy showed % sensitivity and % specificity [ ] . another c-e signs of right heart strain and acute pe on axial ctpa imaging including reflux of contrast into hepatic veins and ivc (c), acute dilatation of main pulmonary artery (d) as well as rv to la ratio of more than with straightening of the interventricular septum. f and g are representative coronal and axial ctpa slices showing patent svc and patent bilateral internal jugular veins. this information can be gained from the ctpa and is helpful for procedure planning purposes, particularly if the endovascular treatment approach will be pursued via internal jugular vein access study comparing dual-energy ct perfusion images to scintigraphy at the segmental level showed % sensitivity and % specificity [ ] . acute and chronic pe present differently on ctpa. acute pes are typically located at vessel bifurcations and may completely or partially obstruct pulmonary vasculature [ , ] . a complete obstruction is characterized on ctpa as a hypoattenuating contrast defect occupying a vessel's entire lumen and can be seen in acute pe. the vessel diameter at the obstruction level is usually maintained or increased slightly. partial obstructions may be located centrally (indicative of acute pe) or eccentrically (indicative of chronic pe). complete obstruction in the setting of acute pe can cause distal infarcts that appear on ctpa as a triangular subpleural consolidation or ground-glass opacity with fine reticular changes. chronic pe appearance varies based on the extent of obstruction and degree of chronicity. complete obstruction presents as a lack of contrast distal to the obstruction and an immediate narrowing of the vessel diameter. partial obstruction is characterized by a narrow diameter and partially attenuated vessel or dilation distal to the obstruction. chronic nonobstructive pe manifests as a narrow vessel, irregular intima, and intraluminal bands and webs [ ] . the abrupt narrowing of vessels is caused by recanalization of the thrombus. thrombi along a vessel wall can become endothelialized or "laminated" and will appear as an irregular intimal surface contour that forms obtuse angles with the contrast column. laminated thrombi often present with calcifications. bands are linear structures that run along the long axis of a vessel and may appear in the setting of chronic pe. webs are networks of bands that are often found at vessel bifurcations in chronic pe and are associated with distal neovasculature [ , , ] . chronic pe raises vascular resistance and is characterized by dilation of the central pulmonary arteries secondary to pulmonary hypertension. the main pulmonary artery (mpa) diameter at the level of its bifurcation lateral to the ascending aorta is used to assess for the presence of pulmonary hypertension. mpa diameters greater than mm in men and mm in women are typical predictive cut-offs for pulmonary hypertension [ ] . a greater cut-off of . mm has also been suggested [ ] . a mpa-to-ascending aorta diameter ratio greater than is also a reliable method of assessing for pulmonary hypertension. this measurement offers % sensitivity, % specificity, % positive predictive value, and % negative predictive value [ ] . in cteph pulmonary arteries can appear tortuous with calcified walls [ ] . chronic pe can present with right ventricular hypertrophy evidenced by ventricular wall thickness greater than mm [ ] . development of right ventricular dysfunction causes right ventricular enlargement [ ] . right ventricular enlargement can dilate the tricuspid valve annulus leading to tricuspid regurgitation. the lung parenchyma distal to the occlusion or stenosis of chronic pe presents with a mosaic perfusion pattern that appears as well-demarcated hypoattenuated tissue with narrow vasculature contrasted with the hyperattenuated tissue being in possession of larger vasculature of well-perfused lung parenchyma. areas of infarction can resolve in the long-term to form peripheral nodules, cavities, subpleural scars, or irregular peripheral lines [ ] . right heart strain is important to recognize on ctpa and has characteristic signs on imaging as previously described (fig. ) . a rv/lv diameter ratio ≥ . is predictive for poor clinical outcomes after acute pe [ , , ] . a study of fig. -year-old female presenting with severe shortness of breath and chest pain. the patient has a history of metastatic breast cancer. a-c coronal ctpa slices showing pulmonary embolus in right and left pulmonary arteries extending into multiple segmental branches. d rv to lv of . suggestive of right heart strain. e in this case there is no significant contrast reflux into suprahepatic inferior vena cava and / or hepatic veins patients found that rv/lv diameter ratio ≥ . was an accurate predictor of in-hospital death or clinical deterioration [ ] . a meta-analysis found that right ventricular dilation is associated with elevated -day mortality, increased risk of death from pe, and increased -month mortality rate (or . ) [ ] . ten to fifteen percent of acute pes cause infarction of the lung. this appears as a wedge-shaped peripheral lung opacity, often referred to as a "hampton hump," on ctpa. these opacities can have a central ground glass appearance [ ] . ctpa has its inherent limitations secondary to artifacts. patient breathing causes motion artifacts that particularly affects the lower lung zones. cardiac motion may also disrupt the pericardial zone image quality. attenuation along a vessel may be disturbed by beam hardening artifacts from contrast originating from abutting vasculature, wires, or medical devices [ ] . studies have found . % to . % of ctpa studies to be non-diagnostic [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ventilation/perfusion (v/q) scanning was the mainstay diagnostic method for acute pe before the development of newer ct techniques [ ] . this imaging modality can be valuable when estimating the probability of an acute pe [ , ] . patients who are pregnant, have renal failure or contrast allergies, or cannot fit into a ct scanner also particularly benefit from v/q scans. v/q scans expose patients' breasts to times less radiation compared to ct, which helps to reduce breast cancer risk in young women [ ] [ ] [ ] . the fetal radiation dose associated with v/q scans has been estimated to be . - times higher than the fetal radiation dose associated with low-dose ctpa. while v/q scans are associated with a greater fetal risk for childhood cancer compared to ctpa, their aggregated radiation risk for a pregnant patient and her fetus is lower compared to ctpa. this difference in aggregated radiation risk increases with greater maternal body mass index and increased gestational age and suggests that v/q scans are more dose-efficient than ctpa for pregnant patients [ , ] . v/q scan is the indicated diagnostic test for acute pe in pregnant patients with a normal chest radiograph. a retrospective study of pregnant or postpartum women suspected to have an acute pe found that the patients with a normal chest radiograph were more likely to have a diagnostic image from v/q scanning compared to ctpa. various retrospective studies have found that - % of v/q scans of pregnant patients suspected to have acute pe resulted in diagnostic studies [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ctpa has also been associated with a significantly higher incidence of sub-optimal studies for assessing acute pe in pregnant patients compared to age-matched non-pregnant controls [ ] . this further contributes to the evidence supporting v/q scan as the diagnostic test of choice in pregnant patients with a normal chest radiograph who are suspected to have acute pe. v/q scans make use of ventilation agents labeled with technetium- m (tc- m) or radioactive noble gases such as xenon- or krypton- m. technetium- m-labeled diethylenetriaminepentaacetic acid (dtpa) is the most commonly used agent [ ] . tc- m-labeled macro-aggregated albumin (maa) is injected intravenously to image perfusion for v/q scans. the patient is positioned upright for the scan, which acquires multiple planar images. single-photon emission computed tomography (spect)/ct using a low-dose ct technique may also be performed to better localize abnormalities [ ] . the perfusion scan may be acquired before or after the ventilation scan. imaging perfusion first guides the projection used for ventilation scans using xenon- . a normal perfusion scan can preclude the need for a ventilation scan, which is particularly valuable for patients requiring minimization of radiation exposure such as the pregnant patient population. some authors have proposed primarily using perfusion-only scintigraphy in the diagnostic assessment of acute pulmonary embolism to reduce potential viral transmission by aerosolization in the setting of the current global covid- pandemic [ ] . -year-old male patient with acute dyspnea. a ctpa shows emboli in the left pulmonary artery bifurcation and the lower lobe segmental artery on the right side (arrows) b significant enlargement of the right ventricle with a nearly inversed configuration of the inter-ventricular septum, consistent with right heart strain. c a less specific, but also typical sign of right heart strain is the reflux of contrast material into the inferior vena cava and hepatic veins v/q scans are interpreted with a corresponding chest radiograph taken within - h of the scan. acute pe is often visualized as peripheral wedge-shaped perfusion defects in a lobar, segmental, or sub-segmental distribution in the absence of an associated ventilation abnormality. this mismatched defect can also be found with other conditions including malignancy, vascular abnormalities, vasculitis, veno-occlusive disease, and mediastinal lymphadenopathy and therefore a chest radiograph is valuable for comparison purposes [ ] . the most commonly used criteria for interpretation of v/q scans for acute pe are the modified prospective investigation of pulmonary embolism diagnosis (pioped) ii and prospective investigative study of acute pulmonary embolism diagnosis (pisaped) criteria [ , ] . patients can be categorized as high probability, intermediate probability, very low probability, normal, and non-diagnostic using the modified pioped ii criteria. a normal scan is characterized by diffusely homogenous radiotracer activity in the lungs on ventilation and perfusion scans while a high probability scan is characterized by two or more large segmental mismatch defects or segmental defect equivalents. a very low probability scan will appear as a non-segmental defect [ ] . the pioped ii criteria have found v/q scans to have % sensitivity and % specificity for acute pe, and the pisaped criteria found to have % sensitivity and % specificity for diagnosing pe [ , ] . utilizing spect can improve v/q scan sensitivity and specificity by enabling three-dimensional visualization of the lung. the addition of spect has been found to offer a % sensitivity and % specificity for diagnosing acute pe [ ] . magnetic resonance angiography (mra) is an evolving imaging modality that can be used for evaluating the possibility of acute pe in certain patient populations. pregnant or young patients may benefit from mra instead of ctpa if acute pe is suspected due to the lack of ionizing radiation exposure. patients with history of anaphylactoid reactions to iodine contrast media and those with chronic kidney disease may benefit from mra as well [ ] . mra assessment for acute pe includes axial and coronal static steady-state free precession (ssfp) sequences, contrast-enhanced d mra using t -weighted gre sequences, and an optional time-resolved contrast-enhanced d mra for dynamic perfusion imaging [ ] . the static ssfp sequences are acquired during free breathing or inspiratory breath-hold. these sequences can detect acute pe without the use of iv contrast due to the bright blood signal (fig. ) . a non-contrast mra is especially valuable for pregnant patients who ideally should not receive gadolinium contrast [ , ] . the d-balanced ssfp sequence is commonly used. it creates t /t weighting with radiofrequency pulse phase alteration and gradient echo refocusing that results in a steady state. a long t with high signal contrast causes blood to appear bright which facilitates thrombus detection [ ] . this sequence offers high sensitivity for field heterogeneity and requires only a short repetition time to minimize artifacts [ ] . balanced ssfp has also been shown to provide fast, accurate measurement of pulmonary artery diameters [ ] . arterial spin labelling makes use of slice selective acquisition with repeat imaging after an initial inversion pulse. it can be particularly valuable when combined with faster sequences. this technique acquires an image with upstream blood tagged by an inversion radiofrequency pulse and another image without such tagging [ ] . a subtraction between these images depict signal solely from the tagged blood and helps with visualizing vessels and tissue perfusion [ ] . the fresh blood imaging technique makes use of the ekg-gated d partial fourier fast spin echo technique. this sequence makes arterial blood in systole appear dark because of flow void and in diastole appear bright because of slows flow. veins produce some intensity in systole and diastole due to slow flow [ ] . an image with high signal intensity in the arteries and low signal intensity in the veins can be created by subtracting the systolic and diastolic images [ ] . however this sequence is not commonly used to diagnose pe due to its susceptibility to misregistration [ ] . contrast-enhanced d mra offers high spatial resolution of the pulmonary vasculature (fig. ) . this technique utilizes intravenous gadolinium contrast that causes t shortening in adjacent tissues leading to a high signal intensity in mra images [ ] . coronal images are typically acquired during inspiratory breath-holds. usually pre-contrast images for subtraction purposes are obtained, followed by arterial phase images, and late arterial phase images [ ] . timing the acquisition accurately achieves high snr and allows separation of the arterial and venous phase [ ] . the time at which the pulmonary arteries show maximum contrast enhancement is assessed utilizing a bolus-tracking technique (fig. ) [ ] . bolus-tracking techniques include utilization of dynamic low resolution magnetic resonance fluoroscopy and starting the acquisition just before contrast enters the pulmonary arterial tree. one could also utilize a test bolus injection of to ml of contrast to assess the time required for the contrast to reach the target vasculature [ ] . d t -weighted spoiled gradient echo sequence acquisition uses values of tr = . - ms, te = . - . ms, flip angle = - °, matrix = × × , fov = mm, and parallel imaging factor (r) = [ ] . acquiring data in an oval area of k-space and zero-filling corners enables isotropic spatial resolution. fractional echo read-out can reduce te and tr. this sequence can achieve mm spatial resolution in phase encoded direction and . mm spatial resolution in frequency encoded direction [ ] . timeresolved contrast-enhanced d mra is performed with repeated rapid volumetric sequences that sample the center of the k-space more frequently than the periphery [ , ] . data that are missing at each time point are shared between k-spaces by applying a variety of techniques [ ] [ ] [ ] [ ] . the images are captured during shallow breathing after the first contrast-enhanced d mra acquired in coronal orientation demonstrates filling defects, among others a long filling defect in the left lower lobe artery with a "railway sign" (a, white arrows) and the filling defect is shown as a "polo mint sign" on the axial reconstruction of the same data set (b, white arrow). c time-resolved, contrast-enhanced d mra reveals extensive wedge-shaped perfusion defects in the left upper and lower lobes (black arrows) pass of a gadolinium contrast bolus. there is some evidence that time-resolved contrast-enhanced mra during patient free-breathing may achieve accurate diagnoses and vessel measurements, which could make this sequence especially beneficial in the pediatric population and in patients with severe dyspnea [ ] . when using power injectors this technique is particularly helpful for visualizing perfusion defects when pursuing subtraction images (fig. d and c) [ , ] . imaging plays a crucial role in the assessment of acute pulmonary embolism (pe) prior to endovascular intervention. ctpa is the modality of choice for the diagnosis of acute pe given its availability as well as excellent sensitivity and specificity. this imaging modality facilitates detection and characterization of the extent of the pulmonary embolus (particularly helpful in coronal view to correlate with angiography in the case of endovascular treatment) and enables assessment of right heart strain. further, ctpa allows evaluation of the access route for endovascular interventions to ensure patency of the central venous system. mri offers a limited role in the diagnosis of acute pe in certain patient populations, specifically in pregnant patients. in current clinical practice d mra largely relies on gadolinium based contrast administration for diagnosis of acute pe. however, non-contrast mra sequences such as ssfp are evolving for the assessment of the pulmonary arterial vasculature. funding not applicable. for the clinical guidelines committee of the american college of physicians ( ) evaluation of patients with suspected acute pulmonary embolism: best practice advice from the clinical guidelines committee of the american college of 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publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -cu nx authors: luo, lingfei; gu, yiqin; wang, xiaoguang; zhang, yinghua; zhan, longwen; liu, jiqian; yan, hongjing; liu, yun; zhen, shanshan; chen, xiuhua; tong, rui; song, chiping; he, yingying title: epidemiological and clinical differences between sexes and pathogens in a three-year surveillance of acute infectious gastroenteritis in shanghai date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: cu nx acute infectious gastroenteritis cases in shanghai, reported over three years, were analyzed. pathogens were identified in patients; of these, and were bacterial and viral cases, respectively. vibrio parahemolyticus and salmonella were the dominant bacteria, and caliciviridae and reoviridae were the dominant viral families in the local area. the acute gastroenteritis epidemic peaks appeared in august and january, which represented the active peak periods of bacteria and viruses, respectively. logistic regression analyses with sex stratification showed that abdominal pain, fever and ingestion of unsafe food at restaurants were independent factors more frequently associated with bacterial gastroenteritis irrespective of sex; red cell-positive fecal matter was associated with bacterial gastroenteritis with an odds ratio (or) of . only in males; and white blood cell count was associated with bacterial gastroenteritis with an or of . only in females. pathogen stratification showed that age, vomiting and red cell-positive fecal matter were associated with males with ors of . , . and . , respectively, in bacterial gastroenteritis; and the migrant ratio was higher in males with an or of . only in viral gastroenteritis. in conclusion, although bacterial and viral gastroenteritis shared many features, epidemiological and clinical factors differed between sexes and pathogens. isolation and identification of bacterial pathogens. bacterial detection is a vital part of the acute gastroenteritis control and prevention strategy established by the local health administration department. bacterial identification is the systematic work of a multisectoral collaboration in china's centers for disease control and prevention, and it is difficult to detail all processes in this report. briefly, detection was carried out via classic bacterial isolation, culture, and identification in combination with molecular diagnostic strategies . in addition, bacterial samples were subjected to vitek ® compact (biomérieux, france) for simultaneous microbial identification. the above technologies covered the most common diarrhea-related bacteria, including vibrio cholerae, salmonella, shigella, vibrio parahemolyticus, yersinia enterocolitica, campylobacter jejuni, enterotoxigenic escherichia coli (etec), enteropathogenic e. coli (epec) and others . to learn the pathotypes of diarrheagenic e. coli, suspected e. coli colonies on smac or macconkey plates were further analyzed by pcr using primers targeting the genes eae, bfp, stx , stx , ipah, pcdv, elta and esta. a first pcr detection was performed with stx / stx and eae primers focusing on the identification of stec or epec. positive eae and negative stx /stx samples were then examined by pcr with bfp primers to differentiate tepec from aepec. negative eae and stx /stx samples were further screened by pcr using pcvd primers for plasmidic eaec sequences, ipah primers for detecting invasion plasmid antigen genes of eiec, and detection of the elta and esta genes of etec labile and stable enterotoxins , . the diagnosis of epidemic dysentery and cholera was performed according to the laboratory methods for the diagnosis of epidemic dysentery and cholera recommended by the u.s. centers for disease control and prevention and the world health organization . laboratory standard operating procedures for detection were performed according to the practical guidance for clinical microbiology-laboratory diagnosis of bacterial gastroenteritis and the final report and executive summaries from the aoac international presidential task force on best practices in microbiological methodology . detection of viral pathogens. viral detection is another vital part of the acute gastroenteritis control and prevention strategy established by the local health administration department. gastroenteritis virus detection was performed according to methods reported by other peers , , , , . briefly, fecal specimens were prepared as % (w/v) suspensions in distilled water and then centrifuged for min at g in a . ml collection tube www.nature.com/scientificreports www.nature.com/scientificreports/ (biovisualab, shanghai, china) to remove debris. viral dna and viral rna were extracted from the suspensions using a qiaamp dna mini kit and a qiaamp viral rna mini kit (qiagen, the netherlands), according to the manufacturer's instructions. the virus panel was established with routine diarrhea surveillance data that were accumulated by local centers for disease control and prevention and by reference to information from peers [ ] [ ] [ ] [ ] . rotavirus, norovirus, enteric adenovirus, astrovirus, sapovirus, mimiviruses, aichivirus, bocavirus, parechovirus, cytomegalovirus, hepatitis a, coronaviruses, picornaviruses, toroviruses, and other enteroviruses were detected by polymerase chain reaction (pcr) or reverse transcription pcr using primer sets, as reported previously , , , - . statistical analysis. continuous variables are presented as the means ± standard deviations (sds); differences between groups were evaluated using the mann-whitney u-test for independent samples. categorical variables are presented as frequencies (percentage); differences in frequencies were evaluated using the chi-square test or fisher's exact probability test. to identify independent factors and to distinguish factors associated with pathogen or sex, logistic regression analyses were applied in subjects with known pathogens. to identify factors that tended to be associated with pathogens, the dependent variables were defined as viral case = and bacterial case = , and the multivariable logistic regression analyses were performed by sex. to identify factors that tended to be associated with sex, the dependent variables were defined as female = and male = , and the multivariable logistic regression analyses were performed by viral and bacterial gastroenteritis. potential independent variables were selected by univariate analyses; factors with p < . were introduced into the starting model of the multivariable logistic regression analyses and then eliminated manually using the backward step-by-step approach, depending on the largest p-value. all analyses were performed using spss software for windows (ver. . ; spss inc., chicago, il, usa), and the significance level (alpha) was set at . . general information from three-year-round surveillance. this report included annual cases from three full years of acute infectious gastroenteritis that occurred in two sentinel hospitals of shanghai from to . in total, subjects, males and females, were involved. as shown in table , the average age of patients was older among females, and the ratio of local residents was significantly higher in the female group. regarding the symptoms associated with acute gastroenteritis, the percentages of subjects with nausea, vomiting, watery stools and abdominal pain were significantly higher in the female group than in the male group. the rate of patients with fever was significantly higher in males ( . %) than in females ( . %). no significant difference in vomiting frequency, duration of vomiting, diarrhea frequency, duration of diarrhea, average body temperature or rate of dehydration existed between the sexes. since the number of patients with dehydration was low in both sexes, differences in blood pressure may be an inherent sex difference rather than a pathological feature associated with acute gastroenteritis. the epidemiological questionnaire showed that . % and . % of male and female patients, respectively, had a history of the possible ingestion of unsafe foods. the foodborne source of males more frequently tended to be from restaurants and delivery foods, while the foodborne source of females more frequently tended to be from home ( table ). the rates of drinking unsafe water, exposure to patients with diarrhea within days and travel within one week were very low in both sexes (table ) . clinical laboratory tests showed that the fecal red cell-positive rate was significantly lower in females ( . %) than in males ( . %) ( table ). in conclusion, age, symptoms, epidemiological factors and clinical laboratory tests differed between sexes in patients with acute gastroenteritis. annual dynamic characteristics of the acute gastroenteritis epidemic. to understand the seasonal epidemic characteristics of acute infectious gastroenteritis, all cases were aligned by month. as shown in fig. a , all annual acute gastroenteritis epidemics, including , , and merged data, displayed two peaks in the summer and winter. to learn if the epidemic peaks were associated with pathogen differences, all identified viral and bacterial cases were aligned again by month. as shown in fig. b , cases infected by bacteria peaked in august, and cases infected by viruses peaked in january. pathogenic spectrum. pathogens were successfully identified in patients, and and subjects were infected by bacteria and viruses, respectively. of the identified cases of bacterial acute gastroenteritis, . %, . %, . % and . % were infected by vibrio parahemolyticus, salmonella, epec and etec alone, respectively; . %, . % and . % were coinfected by vibrio parahemolyticus and salmonella, epec and vibrio parahemolyticus and epec and salmonella, respectively (fig. ) . of differences between viral and bacterial gastroenteritis by sex. the difference between the sexes shown in table does not taken into account the possible role of pathogens. therefore, the clinical and epidemiological characteristics of bacterial and viral cases were further compared by sex. of males, as shown in table , and subjects were identified as having bacterial and viral gastroenteritis, respectively. the rates of nausea, watery stools, abdominal pain, fever, ingesting possible unsafe foods, ingesting unsafe foods at restaurants, leukocyte-and red-cell-positive fecal matter and the average vomiting frequency, body temperature and white blood cell count variables were significantly higher in the bacterial group than in the www.nature.com/scientificreports www.nature.com/scientificreports/ viral group; conversely, the average vomiting duration, heart rate and diastolic pressure and the rate of ingesting unsafe foods at home variables were significantly higher in the virus group than in the bacterial group. no significant difference in the age, percentage of local residents, vomiting rate, diarrhea frequency, duration of diarrhea, dehydration rate, systolic blood pressure, or rate of ingesting delivery food variables was observed between the viral and bacterial gastroenteritis groups ( table , left panel) . of females, and subjects were identified as having bacterial and viral gastroenteritis, respectively. the rates of nausea, vomiting, abdominal pain, fever, ingesting unsafe foods at restaurants, leukocyte-and red-cell-positive fecal matter and the white blood cell count variables were significantly higher in the bacterial group than in the viral group; conversely, the average vomiting duration was significantly longer and the rate of ingesting unsafe foods at home was significantly higher in the viral group than in the bacterial group. no significant differences in the age, percentage of local residents, frequency of vomiting, frequency of watery stools, frequency of diarrhea, duration of diarrhea, rate dehydration, heart rate, blood pressure, or rate of ingesting possible unsafe food variables was observed between the viral and bacterial gastroenteritis groups ( independent factors differentially associated with pathogen by sex. bacterial gastroenteritis shares many clinical manifestations and epidemiological features with viral gastroenteritis [ ] [ ] [ ] . although the above stratified analyses showed differences between sexes and pathogens, such analyses could neither identify www.nature.com/scientificreports www.nature.com/scientificreports/ www.nature.com/scientificreports www.nature.com/scientificreports/ independent factors nor quantify the associations. thus, logistic regression analyses were adopted to distinguish the associations. among males, univariate analyses showed that nausea, vomiting frequency, watery stools, abdominal pain, fever, ingesting unsafe food at restaurants, fecal leukocyte-positive, fecal red cell-positive and white blood cell count were potential independent factors that were differentially associated with viral and bacterial gastroenteritis. multivariable logistic regression analyses revealed that only abdominal pain, fever, fecal red cell-positive and ingesting unsafe food at restaurants were independent factors that more frequently occurred in bacterial gastroenteritis than viral gastroenteritis with ors of . , . , . and . , respectively (table ) . among females, nausea, vomiting, duration of vomiting, abdominal pain, fever, ingesting unsafe food at restaurants, fecal leukocyte-positive, fecal red cell-positive and white blood cell count were potential independent variables that were differentially associated with viral and bacterial gastroenteritis. further multivariable logistic regression analyses revealed that abdominal pain, fever, and ingesting unsafe food at restaurants were independent factors that more frequently occurred in bacterial gastroenteritis with ors of . , . and . , respectively (table ) . white blood cell count was also an independent factor and higher in bacterial gastroenteritis than in viral cases (table ) . table . clinical and epidemiological differences between viral and bacterial gastroenteritis by sex. continuous variables are presented as the means ± standard deviations (sds); difference between groups were evaluated using the mann-whitney u-test for independent samples. categorical variables are presented as frequencies (percentages); differences in frequencies were evaluated using the chi-square test or fisher's exact probability test. www.nature.com/scientificreports www.nature.com/scientificreports/ independent factors differentially associated with sex by pathogen. to identify the independent factors of acute infectious gastroenteritis that were differentially associated with sex by pathogen, logistic regression analyses were applied to bacterial and viral cases. initial univariate analyses showed that age, domiciliary register and vomiting frequency and age, domiciliary register, nausea, abdominal pain, vomiting and fecal red cell-positive were potential independent variables in associated with sex in the viral and bacterial groups, respectively. further multivariable logistic regression analyses using the above candidate variables revealed that, in bacterial gastroenteritis, an increase of year old resulted in a decreased male/female (ratio) with an or of . (table ) , vomiting occurred less frequently in males than in females with an or of . , and red cell-positive fecal matter occurred more frequently in males than in females with an or of . (table ). in the viral group, only domiciliary register remained an independent factor associated with males with an or of . (migrant vs. local resident) (table ). in this report, we collected data across a -year period from two sentinel hospitals located in the minhang district of shanghai. our analysis strategy consisted of three steps: first a pooled analysis with male and female patients irrespective of pathogens to understand sex differences; second, sex and pathogen stratification analyses with patients whose pathogens were identified to determine epidemiological and clinical differences between sexes and pathogens; and third, logistic regression analyses to distinguish the factors associated with sex and pathogens. in the pooled analysis, the percentage of local residents and the rate of ingesting possible unsafe food at home variables were lower in males, and the rate of ingesting possible unsafe food at restaurants was higher in males, which is consistent with the characteristics of male social behavior. the rates of nausea, vomiting, watery stools and abdominal pain were higher, and the rates of fever and red cell-positive fecal matter were lower in females, suggesting a sex difference in symptoms associated with acute gastroenteritis. although the pooled analysis did not implement pathogen classification, it reflected the features of acute gastroenteritis that clinicians face every day. next, stratification analyses by sex and pathogen showed that the distributions of clinical and epidemiological factors differed not only between viral and bacterial groups but also between sexes. the results obtained by foregoing two steps guided us to implement sex and pathogen stratification in subsequent logistic regression analyses. independent factors differentially associated with pathogens were evaluated by sex stratification; logistic regression analyses revealed that abdominal pain and fever were two common independent symptom factors that more frequently occurred in bacterial gastroenteritis than in viral gastroenteritis, regardless of sex. clinically, acute infectious gastroenteritis is classified into two pathophysiologic types: noninflammatory and inflammatory. the noninflammatory gastroenteritis is mostly caused by viral infection with milder disease; while, inflammatory gastroenteritis is more severe and always resulted from infection of invasive or with toxin-producing bacteria , - . in addition, fever and abdominal pain are two common symptoms in acute gastroenteritis caused by salmonella infection ; our data showed that . % identified bacterial cases were salmonella infection (fig. ) . thus, higher prevalence of fever and abdominal pain in acute bacterial gastroenteritis were observed. ingesting unsafe food at restaurants was a common transmission route for both sexes and was more frequently associated with bacterial gastroenteritis; which is consistent with that bacterial infections are more often associated with foodborne transmission [ ] [ ] [ ] and acquired easily at places with high population mobility , . white blood cell count was higher in bacterial cases only in females with low or of . , suggesting the relative pathology of www.nature.com/scientificreports www.nature.com/scientificreports/ infectious acute gastroenteritis differed between sexes. however, testing stool for leukocytes to screen for inflammatory diarrhea has fallen out of favor due to a wide variability in sensitivity and specificity , . independent factors differentially associated with sex were further evaluated in logistic regression analyses with pathogen stratification. in bacterial gastroenteritis, age and vomiting were associated with males with ors of . and . , respectively; for ease of understanding, these associations were translated to females, and age and vomiting were associated with females with ors of . and . , respectively, meaning that with a -year old increase, the female/male ratio will increase . times, and vomiting is more frequently associated with female patients. the age quartiles of female and male bacterial cases are . , . and . ; and . , . and . years old respectively; the nd and particularly the rd quartiles of female age were older; which is why female/male ratio will increase . times with a -year old increase. red cell-positive fecal matter remained an independent factor that was more frequently observed in males with or of . (table ); in addition, the above sex stratification analysis showed that red cell-positive fecal matter was an independent factor that was more frequently observed in bacterial cases only in males with or of . (table ) . these two analysis methods mutually confirmed that red cell-positive fecal matter is common in males with bacterial infections. bacteria, such as vibrio parahemolyticus and salmonella, predisposing to cause inflammatory infections with bloody stool [ ] [ ] [ ] , which could be used to explain why bloody stool is more frequently observed in bacterial infections, but could not interpret gender difference. since the proportions of vibrio parahemolyticus and salmonella infections were similar between males ( . % and . %) and females ( . % and . %), higher bloody stool rate in male cases should not be caused by differences in rates of bacterial infection. although we could not give a reasonable explanation to partial gender differences; these evidences have clinical significance and will guide translational study to interpret a pathological mechanism. in fact, gender differences exist widely in clinical medicine and have been paid more and more attention in recent years . in viral cases, only domiciliary register remained an independent factor associated with males; the migrant/local resident ratio was . times higher in males than in females, suggesting the prevalence of viral gastroenteritis is relatively higher in migrant workers. some parameters, such as body temperature, heart rate and blood pressure, were not potential independent variables in univariate analyses; this finding is because body temperature was only recorded in subjects with fever, and heart rate and blood pressure were only recorded in patients with dehydration. as to why some variables did not remain independent factors in the final equation, this is partially explained by the high colinearity between variables, for example, the pearson correlation coefficient between fecal leukocyte-positive and fecal red cell-positive was . (p < . ), and the narrow differences between two groups, for example, the percentage of nausea between bacterial and viral cases ( . % vs. . %) in males and the vomiting frequency between bacterial and viral cases ( . ± . vs. . ± . days) in males. however, most of the above differences involved complex pathophysiological principles, and we cannot offer a perfect explanation. regardless, logistic regression analysis can effectively assess confounders and select independent variables associated with sex and pathogen. acute gastroenteritis caused by viral infections was dominated by rotavirus and norovirus , . rotavirus always causes severe gastroenteritis in young children , , while norovirus causes most outbreaks of nonbacterial acute gastroenteritis in all age groups . recently, some scholars reported that the rotavirus predominance of acute gastroenteritis has been replaced by norovirus due to the wide implementation of rotavirus vaccination . our data showed that caliciviridae (norovirus gii and gi) and reoviridae (rotavirus a) constituted more than % of viral infections. since a norovirus vaccine is still under development , rotavirus vaccination needs to be implemented in local areas. bacteria are the second leading cause of acute gastroenteritis; shigella, salmonella, campylobacter, diarrhoeagenic escherichia coli, pathogenic vibrio, yersinia, and clostridium difficile are the most commonly reported bacteria correlated with acute gastroenteritis , . our data showed that vibrio parahemolyticus and salmonella were the dominant bacteria identified in the local area, and these findings are consistent with those of a previous study with a small sample size . this report included the following limitations: first, this report only focused on the outpatients of two sentinel hospitals, and all subjects were sporadic adult cases; thus, this study does not represent the infectious gastroenteritis epidemic in schools, although it is known that acute gastroenteritis is highly prevalent in schools and always causes outbreaks , . second, based on our sampling rates, pathogens were only identified in . % ( / ) of patients, and more effort should be made to improve the representative accuracy of our results. third, in the stratified and logistic regression analyses, we only considered mixed viral cases and mixed bacterial cases and did not subgroup the subjects by bacterial classification, virus classification or by multiple infections due to the restrictions of sample size. since all of the above factors might influence the symptoms and clinical examinations of acute gastroenteritis, our analyses may be influenced by related bias. acute gastroenteritis aetiological characteristics of adult acute diarrhoea in a general hospital of shanghai acute gastroenteritis outbreak caused by a gii. norovirus laboratory methods for the diagnosis of epidemic dysentery and cholera acg clinical guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults viral gastroenteritis laboratory diagnosis of bacterial gastroenteritis burden of acute gastroenteritis caused by norovirus in china: a systematic review molecular epidemiology of genogroup ii norovirus infections in acute gastroenteritis patients during - in pudong new area incidence of norovirus-associated diarrhea age, primary symptoms, and genotype characteristics of norovirus outbreaks in shanghai schools in codex alimentarius commission, procedural manual, twenty-fourth edition world health organization, strengthening surveillance of and response to foodborne diseases, introductory module world health organization, strengthening surveillance of and response to foodborne diseases, investigating foodborne disease outbreaks world health organization, five keys to safer food manual risk of waterborne illness via drinking water in the united states diarrheagenic escherichia coli associated with acute gastroenteritis in children from soriano escherichia coli and community-acquired gastroenteritis novel approach for detection of enteric viruses to enable syndrome surveillance of acute viral gastroenteritis simultaneous detection of seven enteric viruses associated with acute gastroenteritis by a multiplexed luminex-based assay molecular diagnosis of diarrhea: current status and future potential development and assessment of molecular diagnostic tests for enteropathogens causing childhood diarrhoea: a multicentre study acute diarrhea vibrio parahaemolyticus: a review on the pathogenesis, prevalence, and advance molecular identification techniques outbreak of salmonella infantis gastroenteritis among people who had eaten at a hash house in southern italy acute gastroenteritis due to vibrio parahaemolyticus in spain. presentation of cases diagnostic accuracy of stool assays for inflammatory bacterial gastroenteritis in developed and resource-poor countries sex and gender in medical literature in sex and gender aspects in clinical medicine global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis cost-effectiveness analysis of a rotavirus immunization program for the united states clinical update: rotavirus gastroenteritis and its prevention global mortality associated with rotavirus disease among children in vomiting, diarrhea, constipation, and gastroenteritis status of vaccine research and development for norovirus infectious diarrheal disease caused by contaminated well water in chinese schools: a systematic review and metaanalysis an investigation of an acute gastroenteritis outbreak: cronobacter sakazakii, a potential cause of food-borne illness. front microbiol this work was supported by a grant of the shanghai municipal commission of health and family planning (serial number: ). l.l., y.g. and x.w. conceptualized the study, drafted the initial manuscript, and reviewed and revised the manuscript. y.z., l.z., j.l., h.y., y.l., s.z., x.c., r.t., c.s. and y.h. collected data, carried out the initial analyses, and reviewed and revised the manuscript. all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. competing interests: the authors declare no competing interests.publisher's note: springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this license, visit http://creativecommons.org/licenses/by/ . /. key: cord- - fosk c authors: sharma, sat; anthonisen, nicholas title: role of antimicrobial agents in the management of exacerbations of copd date: - - journal: treat respir med doi: . / - - sha: doc_id: cord_uid: fosk c acute exacerbations of chronic obstructive pulmonary disease (aecopd) are a common occurrence and characterize the natural history of the disease. over the past decade, new knowledge has substantially enhanced our understanding of the pathogenesis, outcome and natural history of aecopd. the exacerbations not only greatly reduce the quality of life of these patients, but also result in hospitalization, respiratory failure, and death. the exacerbations are the major cost drivers in consumption of healthcare resources by copd patients. although bacterial infections are the most common etiologic agents, the role of viruses in copd exacerbations is being increasingly recognized. the efficacy of antimicrobial therapy in acute exacerbations has established a causative role for bacterial infections. recent molecular typing of sputum isolates further supports the role of bacteria in aecopd. isolation of a new strain of haemophilus influenzae, moraxella catarrhalis, or streptococcus pneumoniae was associated with a considerable risk of an exacerbation. lower airway bacterial colonization in stable patients with copd instigates airway inflammation, which leads to a protracted self-perpetuating vicious circle of progressive lung damage and disease progression. a significant proportion of patients treated for copd exacerbation demonstrate incomplete recovery, and frequent exacerbations contribute to decline in lung function. the predictors of poor outcome include advanced age, significant impairment of lung function, poor performance status, comorbid conditions and history of previous frequent exacerbations requiring antibacterials or systemic corticosteroids. these high-risk patients, who are likely to harbor organisms resistant to commonly used antimicrobials, should be identified and treated with antimicrobials with a low potential for failure. an aggressive management approach in complicated exacerbations may reduce costs by reducing healthcare utilization and hospitalization. first described by badham in and then by laennec in tial part of the natural history, is a common cause of medical visits, hospital admissions and death in copd. [ ] we reviewed published , copd is a devastating respiratory illness that affects a literature on the etiology, pathophysiology, treatment and outcome sizeable world population and is the fourth leading cause of death of acute exacerbations of copd (aecopd) by searching medin us after heart disease, cancer and stroke. [ , ] primarily a conse-line, embase, and cinahl ® databases. the following search quence of tobacco consumption in the developed world, copd terms were used: acute exacerbation of copd, copd exacerbaaffects patient's quality of life, utilization of healthcare resources, tion, aecopd, acute exacerbation of chronic bronchitis and and also has adverse economic impacts on the patient and society. aecb. the search encompassed all publications from until at present, more than million adults have copd in the us and december . additionally, consensus statements, review million worldwide, and the disease accounts for approximately articles, and articles written by selected authorities were reviewed. deaths in the us and . million globally annually. [ , ] the prevalence of copd has continued to increase internationally . definition of acute exacerbation of chronic because of rapidly increasing smoking rates in developing nations. obstructive pulmonary disease (aecopd) by the year , copd is predicted to become the fifth leading cause of death and disability worldwide. [ ] acute deterioration of aecopd lacks a uniform and widely accepted definition in the chronic symptoms frequently occurs and besides being an essen-published literature. worsening of one or more chronic symptoms including dyspnea, cough, sputum production, or sputum purulence appears to be the most commonly accepted definition. [ ] currently, the clinical practice guidelines have incorporated winnipeg criteria (increased dyspnea, increased sputum volumes and increased sputum purulence) to define and grade the severity of aecopd (table i) . anthonisen et al. [ ] showed that the presence of two or more of these clinical features predicted benefit of antimicrobial therapy in aecopd. an american-european working ii two of the above three symptoms present iii one of the above symptoms present plus at least one of the following: upper respiratory tract infection in the last days, fever, increased wheezing, and increased cough group proposed a widely accepted definition of aecopd as follows: "a sustained worsening of the patients' condition, from were considered to be a consequence of infection with respiratory the stable state and beyond normal day-to-day variations, necessiviruses. [ ] tating a change in regular medication in a patient with underlying copd." [ ] atypical bacteria are difficult to isolate but the investigators have performed serologic testing to evaluate the role of chlamydia and mycoplasma in aecopd. although mycoplasma infection as . role of bacteria in aecopd a cause of exacerbation is uncommon, chlamydia pneumoniae infection is reported to account for - % of exacerbations, although a concomitant bacterial pathogen may also be present. [ ] . pathogens in aecopd the predominant pathogens and their relative frequency in aecopd are listed in table ii. approximately half of the exacer-at least % of aecopd are caused by infections, although bations yield positive sputum cultures for aerobic bacteria. fagon other causes including environmental factors (air pollution, cold et al. [ ] performed bronchoscopy with protected specimen brush air, allergens) may be responsible. [ ] the common etiologic orgabefore empiric antimicrobial therapy in patients requiring nisms are bacteria ( - %), viruses ( - %) and atypical bacmechanical ventilation for respiratory failure due to aecopd. teria ( - %). interestingly, more than one infectious agent is the the findings were similar to that of sputum culture and showed culprit in - % of all exacerbations. [ ] [ ] [ ] that haemophilus parainfluenzae was the most common pathogen the role of viruses in aecopd was previously examined with ( of organisms), followed by streptococcus pneumoniae ( of serial serology and viral cultures but more recent studies have ), non-typeable h. influenzae ( of ), and moraxella catarutilized polymerase chain reaction (pcr) techniques. the specific rhalis ( of ). a variety of other gram-negative ( of ) and viruses and proportion of exacerbations caused by each of these gram-positive ( of ) bacteria were also isolated. are detailed in table ii. soler et al. [ ] analyzed serologic samples for viruses in of patients with exacerbations of copd that monso et al. [ ] performed bronchoscopies and protected specirequired intensive care admission. viruses were isolated in six men brush cultures in a group of patients with moderately ( . %) of the cases, influenza virus in five and respiratory severe stable copd and in patients who were experiencing an syncytial virus in one exacerbation. in three of the five influenza acute exacerbation. in the stable group, % of protected speciinfections, a concomitant bacterial pathogen was also present. men brush cultures isolated bacterial pathogens (> cfu/ml) more recent data have demonstrated the increasing role of respira-compared with . % of culture-positive samples in the exacerbatory viruses in aecopd. seemungal et al. [ ] observed that % tion group. non-typeable h. influenzae was the most common of all exacerbations were preceded by a cold. in an east london bacterial pathogen in both groups. soler et al. [ ] also demonstrated copd study, patients developed exacerbations. [ ] viruses positive cultures in bronchoscopic samples during an acute exacerwere detected by reverse transcriptase pcr, viral culture of nasal bation. interestingly, a remarkably high incidence of pseuaspirates and serology in ( . %) exacerbations. the role of domonas aeruginosa and other gram-negative bacilli ( of viruses in copd exacerbations is becoming clearer: viruses cause patients) was evident in this study. colonization and infection with more severe exacerbations, increase airway obstruction, slow gram-negative organisms including p. aeruginosa occurred in symptom resolution and induce systemic and airway inflamma-patients who had repeated courses of antimicrobial therapy, as is tion. [ , ] rhinoviruses were detected in . % of exacerba-often the case in bronchiectasis. [ ] the consistent results of these tions; viral infections caused higher symptom scores and increased studies prove that the bacteria are recovered in the distal airways levels of inflammatory markers (plasma fibrinogen and in-of copd patients during exacerbations and may be responsible for terleukin- ). in addition, more severe and frequent exacerbations the observed clinical symptoms. in the literature there exists criticism of data incriminating ber of bacteria and neutrophils in the sputum during exacerbabacteria as causative agents of aecopd. in support, hirschtions. [ , , ] bacteria were thought not only to be the primary mann [ , ] eloquently debated that current evidence does not subcause of the exacerbations but were also considered to be the stantiate the role of bacteria because: (i) bacterial colonization is secondary invaders following acute viral or mycoplasma infection. not prevalent during exacerbations, and available pathologic and patel et al. [ ] recently demonstrated that lower airway colonizaserologic data fail to demonstrate activation of host defense retion in the stable state was associated with increased exacerbation sponse; and (ii) antimicrobial trials in aecopd do not validate frequency and colonization. furthermore, non-typeable h. inadvantage, and symptomatic improvement does not coincide with fluenzae colonization led to higher total symptom score and sputhe eradication of bacteria. while more data are definitely needed tum purulence. however, evaluating the role of bacterial infection to further elucidate the pathogenesis of aecopd, and the role of in aecopd has been a difficult task for a variety of reasons. bacteria and antimicrobials, the evidence reviewed in this paper because the airways of many stable patients with copd are definitely establishes the importance of bacteria and the use of colonized by h. influenzae, s. pneumoniae and m. catarrhalis, antimicrobials in patients presenting with two or more symptoms evaluation of the expectorated sputum during exacerbations may of aecopd. be inconclusive. serologic studies attempted to establish a causal relationship between bacterial infection and acute exacerbation by finding an acute antibody response in serum to these bacteria. [ ] these studies had conflicting results and, in general, failed to establish a correlation between the antibody titers and exacerba-the role of infection in aecopd has been controversial for a tions. [ ] most studies used the whole organism preparations of long time, although the antimicrobials are prescribed frequently to unrelated strains as the antigen for serologic studies, and therefore treat these patients. early investigators identified increased nummeasured a mixture of antibodies to a combination of antigens. [ ] [ ] [ ] future studies may utilize antibody response to more specific surface antigens of bacteria to establish the importance of bacterial infection in copd. positive sputum culture does not predict benefit of antimicrobial therapy in aecopd. [ ] increased sputum purulence was previously thought to be associated with bacterial exacerbations. [ ] airway infection rather than colonization activate secondary host defenses and recruit neutrophils to the airways. [ ] therefore, an acute exacerbation will be associated with change of sputum color from mucoid to purulent (myeloperoxidase from neutrophil azurophil granules is green colored), which will reverse on resolution. [ ] stockley et al. [ ] studied sputum characteristics in copd patients presenting with an acute exacerbation. a positive bacterial culture was obtained from % of patients who expectorated green, purulent sputum. white or clear sputum yielded a positive bacterial culture in only % of exacerbations. in contrast, on repeat sputum culture in stable state, the incidence of positive bacterial culture was similar ( % and %, respectively) with purulent and mucoid sputum. furthermore, all exacerbations associated with mucoid sputum improved without antimicrobials. this study provides additional evidence that bacteria play an important role in causing acute exacerbations and that antimicrobial success can be predicted simply by recognizing sputum color. table ii . pathogens associated with acute exacerbations of copd [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] frequency of specific organism proportion of pathogens exacerbations (%) (%) influenza table iii . relative risk of an exacerbation according to whether a new bacterial pathogen or a strain of bacterial pathogen was isolated (reproduced from sethi et al., [ ] with permission) frequency of exacerbation data published by sethi [ ] lend credence to their previously sethi et al. [ ] recently published data strongly supporting the advanced model of recurrent bacterial infections, where virulence bacterial etiology of some exacerbations (table iii) . they cultured of the infecting organism and the strain-specific immune response sputum samples for pathogenic bacteria on a monthly basis in appear to be important determinants of acute exacerbation. acqui-copd patients during stable state as well as during exacerbations sition of a new strain of organism by a patient who possesses preand typed the strains of bacteria using molecular methods. about existing protective antibodies will lead to no increase in symptoms % of exacerbations were associated with positive sputum culand hence colonization. the absence of defending antibodies to tures. about % of exacerbations were associated with positive the newly acquired bacterial strain will cause an exacerbation. sputum cultures. a bacterial pathogen was isolated in . % of development of antibodies to the infecting bacteria will help clear exacerbations compared with % with no pathogen (p < . ). the organism. recurrent infections from antigenically different virulent strains in repetitive fashion are an attractive model of interestingly, a new bacterial strain was isolated in % of exacerpathogenesis of aecopd (figure ). [ ] bations compared with . % of exacerbations in which no new strains were identified (p < . ). in particular, acquiring a new . trials of antimicrobial therapy in aecopd strain of h. influenzae, s. pneumoniae, and m. catarrhalis correlated with a significantly higher rate of acute exacerbations, there- the role of bacterial infection in aecopd can also be assessed fore providing credibility to the concept that bacteria play a by systematically evaluating the efficacy of antimicrobial therapy. causative role in aecopd. anthonisen et al. [ ] helped settle the controversy over the roles of bacterial infection and antimicrobials in aecopd. over a -year period, patients with copd developed exacerbations; exacerbations were treated with placebo and with antimicrobial therapy. the exacerbations were classified according to the winnipeg criteria based on symptoms of increased dyspnea, increased sputum volume, and increased sputum purulence. a type i exacerbation was defined when all three symptoms were present, type ii when two symptoms were present and type iii when there was only one symptom (table i) . therapeutic success was defined as 'resolution' if all symptoms returned to baseline within days, 'no resolution' if all symptoms did not resolve and 'failure with deterioration' when symptoms worsened. considering all exacerbations, treatment with antimicrobials led to higher resolution ( . %) compared with placebo ( %, p < . ) [ figure ]. deterioration occurred in . % of those treated with antimicrobials, compared with . % with placebo (figure ). the rate of peak flow recovery was faster with antimicrobial treatment compared with placebo. analysis according to the a priori subgroups showed that the exacerbations classified as type i achieved the greatest success with antimicrobial therapy ( . % vs % with placebo, p < . ). in type ii exacerbations, the antimicrobials were still associated with better outcome than placebo, whereas the success with antimicrobial therapy was not significantly better than placebo in type iii exacerbations. correspondingly, deterioration occurred less frequently on antimicrobial therapy in patients categorized as type i or type ii exacerbations. overall, the length of illness was days shorter for the antimicrobial-treated group compared with the placebo-treated group. a meta-analysis by saint et al. [ ] reviewed nine randomized controlled trials published from through to . the outcome data were retrieved from each of the studies and transformed complex organisms such as enterobacteriaceae and pseudomonas into units of standard deviation, and the effect size was calculated. spp. similarly miravitlles et al. [ ] found that h. influenzae and p. the overall effect size was . ( % ci . , . ), thus, estabaeruginosa were more common in patients with fev values of lishing a benefit with antimicrobial therapy compared with place-< % of predicted. these studies further corroborate that patients bo. the mean change in pefr favored the antimicrobial-treated with poor lung function tended to have more frequent exacerbagroup by a difference of . l/min ( % ci . , . , tions, and received repeated antimicrobial therapy that likely led to p < . ). the meta-analysis also demonstrated that the studies alteration of the airway microbial flora. that included a large number of patients and also inpatients displayed a greater benefit from antimicrobial therapy, possibly be- . aecopd and natural history of copd cause these exacerbations were more severe. discrepancies in outcome in these studies were possibly secondary to design flaws, small numbers of patients, unclear selection criteria, non-standard . vicious circle hypothesis evaluation criteria and lack of patient stratification. [ ] [ ] [ ] patients it has been suggested that the progressive deterioration of lung with different severities of copd have exacerbations with diverse function in patients with copd is produced by bacterial colonizaorganisms; therefore, further studies should be conducted to assess tion of the lower respiratory tract and recurrent infective exacerbadifferent classes of antimicrobials in specific clinical situations. in tions. airway colonization in low numbers may not engender an patients with more severe air flow obstruction, the bacteriology inflammatory response. [ ] as bacterial counts increase, neutroshifted from pneumococcus spp. and haemophilus spp. to more philic host response leads to release of pro-inflammatory cytokines, and activated proteinases. wilkinson et al. [ ] have recently shown that increase in airway bacterial load and change in the colonizing bacterial type contributed to greater airway inflammation and accelerated decline in fev . in stable copd patients, the relationship between absolute fev and change in bacterial load was statistically significant (r = . , p < . ). stockley et al. [ ] recently confirmed that purulent sputum correlated directly with the myeloperoxidase content of sputum and with various other indicators of airway inflammation. visual measurements of sputum color correlated strongly with myeloperoxidase, interleukin- , leukocyte elastase (both activity and total quantity), sputum volume, protein leak, and secretory leukocyte proteinase inhibitor. this study provides a useful scientific tool for improving the monitoring of chronic airways diseases and response to treatment. inflammatory cytokines along with bacterial products im- pair mucociliary function, mucus gland hyperplasia, mucus hyper-tained different results. lung health study data were analyzed to secretion, and tissue damage, particularly of the small airways and assess the influence of respiratory illnesses on the rate of decline the alveoli, leading to airflow obstruction. bacterial colonization is of fev , over the -year study duration. [ ] acute respiratory relatively common in stable copd patients. acquisition of a new illnesses were associated with an excessive decline in lung funcbacterial pathogen or a newer strain of the colonizing bacteria tion proportional to the exacerbation frequency among individuals allows proliferation of organisms and an increase in the bacterial who continued to smoke, as opposed to no deterioration in individload. the higher bacterial load facilitates neutrophilic influx and uals who ceased smoking. kanner et al., [ ] who demonstrated that inflammatory response ensues. [ , [ ] [ ] [ ] frequent respiratory tract infections in patients with copd led to a therefore, a self-perpetuating vicious circle of host-and bactemore rapid decline in lung function, supported this hypothesis. ria-mediated respiratory tract damage sets in. sustained by prod-recently, seemungal et al. [ ] prospectively measured pef in ucts of inflammation, this cycle impairs host defense response and copd patients before, during, and after acute outpatient exacerbapredisposes to further bacterial colonization and infections. this tions. incomplete recovery of lung function was noted in % of process has been termed the 'vicious circle hypothesis' and is patients at days, and % of patients had not returned to baseline likely responsible for progressive deterioration of lung function lung function at months. these studies support the hypothesis (figure ). [ ] that repeated acute exacerbations are a factor in progressive airways obstruction and likely affect the natural history of copd. [ ] [ ] [ ] [ ] whether the acute exacerbations lead to decline in lung func- tion or contribute to the progression of copd has been more clearly elucidated in recent studies. the early studies of fletch-acute exacerbations are a common cause of hospitalization and er, [ ] howard, [ ] and bates [ ] demonstrated that acute respiratory death in patients with copd. the previously reported mortality illnesses did not contribute to the progression of airway obstrucrates of - % [ ] have now decreased to %, as recently tion over the long-term. however, more recent studies have obreported by connors et al. [ ] however, these patients continue to have poor long-term prognosis, as a mortality rate of % at year and % at years was reported. the predictors of high long-term mortality have been identified as follows: severity of physiologic abnormalities during exacerbation, poor overall health status, comorbidities, poor nutrition as indicated by low body mass index, and low serum albumin. in , ball et al. [ ] found that the presence of cardiovascular comorbidity and more than four exacerbations in the previous year were associated with treatment failure. in a retrospective study of exacerbations in patients with copd, dewan et al. [ ] identified patient host factors and not the antimicrobial choice as influencing treatment outcome. the use of home oxygen and frequency of exacerbation correctly classified treatment failure in % of the patients. the presence of cardiovascular comorbidity combined with greater than four exacerbations in the previous year has a sensitivity of % and specificity of % in predicting treatment failure. [ , ] in other studies, advanced age, significant impairment of lung function, poor performance status, comorbid conditions and a history of previous frequent exacerbations requiring systemic corticosteroids characterized the high-risk group. [ , ] additionally, the risk factors for relapse are increasing number of previous exacerbations, severity of airflow obstruction, and increasing baseline dyspnea. [ treatment failures in aecopd lead to return physician or aecopd are associated with a significant increase in healthclinic visits, require repeated courses of antimicrobial therapy, risk care utilization and are a frequent cause of hospital admishospitalization, and increase overall costs. [ ] furthermore, pasion. [ ] [ ] [ ] [ ] therefore, exacerbations are the major cost drivers in tients with severe copd have limited ventilatory reserve, and overall cost of copd, which consumes significant healthcare acute exacerbations are a common cause of acute respiratory resources. [ , ] several investigators estimated the cost of acute failure requiring intubation and mechanical ventilation. [ ] stratifiexacerbation in patients above the age of years to be $us . cation of patients into risk categories may allow physicians to billion, and $us million for patients below this age. [ ] the select appropriate antimicrobial therapy, so as to avoid treatment annual costs of aecopd in england and wales were estimated to failure and improve outcome in an era of increasing antimicrobial be £ million by mcguire et al.; [ ] this represents . % and . % resistance. [ ] [ ] [ ] [ ] [ ] of the national health services budget, respectively. data from france demonstrated that direct healthcare costs per acute exacer- bation were about ff , of which % were hospital related. [ ] several risk stratification schemes have been proposed to im-in a recent swedish study, the average healthcare costs per exacerprove initial microbial selection. lode [ ] in proposed that bation were sek , sek , sek and sek for mild, patients be divided into three groups based on severity of lung mild/moderate, moderate and severe exacerbations, respectivefunction, number of exacerbations each year, and presence of a ly. [ ] these translated to sek . billion per year nationally where comorbidity. treatment with oral amoxicillin, doxycycline, hospitalization was the key cost driver, accounting for % of the trimethoprim/sulfamethoxazole (co-trimoxazole) or a macrolide total cost. aecopd is costly; the costs are variable but higher for was recommended for low-risk patients (first degree). patients severe exacerbations and in patients requiring hospitalization. a with a longer history of copd, several exacerbations each year, retrospective study by destache et al. [ ] reported reduced overall other comorbidity, impaired lung function and inpatients were healthcare costs with the use of newer agents compared with firstconsidered high-risk patients (second and third degree). line antimicrobials. another such study by torrance et al. [ ] in , balter et al. [ ] initially suggested a five-group classifidemonstrated benefit and lower total costs with fluoroquinolones cation of patients with aecopd, and in a recent publication these in patients who had a history of moderate-to-severe bronchitis and patient are classified into four groups. [ ] the patients with acute at least four exacerbations in the previous year. simple bronchitis and no previous respiratory problems were several recent studies have supported the use of different classified as group , the group i patients had simple chronic antimicrobials based on patient stratification. [ ] [ ] [ ] [ ] these studies bronchitis with minimal or no impairment of pulmonary function utilized either computerized modeling or a prospective study and without any risk factors. group ii patients were similar to design. the use of newer broad-spectrum antimicrobials was group i but had one or more significant comorbid illnesses such as associated with better clinical outcomes and lower healthcare costs congestive heart failure, diabetes mellitus, chronic renal failure or in patients with aecopd who had moderate-to-severe exacerbachronic liver disease. group iii patients were classified as having tions and comorbid conditions. outpatient drug costs, an important chronic bronchial sepsis. this scheme is problematic and impracticomponent of total aecopd expenditure, vary inversely with cal for various reasons, as group patients do not have copd and severity of exacerbation. van barlingen et al. [ ] reported lower group iii patients are those who have bronchiectasis or are fredrug utilization costs in severe ( %) compared with mild ( %) quently colonized by gram-negative bacterial pathogens, which exacerbations. may not be the causative pathogen. in the older classification, the current antimicrobial trials in aecopd are focusing on sympdivision between group and group was arbitrary and the tomatic improvement as the outcome measure. [ , , , , [ ] [ ] [ ] ] treatment recommendations were identical. [ ] since exacerbations frequently recur, a disease-free interval (dfi) may be more meaningful. dfi is defined as "the length of time in . a practical approach days between the end of therapy and the beginning of next episode". [ ] an antimicrobial agent successful in eradicating bacteri-modified from the publications of wilson, [ ] grossman [ ] and al colonization from the lower airways will delay the recur-balter et al. [ , ] we proposed a simpler risk scheme to stratify rence. [ ] dfi is an outcome measure that should be evaluated aecopd (table iv) . [ ] it may be more practical to categorize all additionally in future clinical trials, to demonstrate clinical success patients with anthonisen's type i and type ii exacerbations into of antimicrobial therapy. either simple or complicated aecopd. [ ] since antimicrobial first-line antimicrobials demonstrated equivalent efficacy in the study by anthonisen et al. [ ] since then an array of newer antimicrobial agents have become available. these agents have generally been as successful in treating aecopd as previously approved antimicrobials. whether one antimicrobial agent is superior to another is not known, because the trials have not been designed with this goal in mind. a retrospective study by adams et al. [ ] looked at the risk factors for treatment failure at days after onset of aecopd. a return visit within days with persistent or worsening symptoms was defined as treatment failure. the failure table iv . risk stratification of patients with acute exacerbations of chronic obstructive pulmonary disease [ ] classification characteristics patients with chronic bronchitis and two or more of the chronic following symptoms (anthonisen's type i and ii): bronchitis increased cough; increased sputum volume; increased dyspnea patients with chronic bronchitis and anthonisen's type i chronic and ii exacerbations and at least one of the following bronchitis risk factors: fev < % predicted; experience more than four exacerbations/year; comorbid medical illness (congestive heart failure, diabetes mellitus, chronic renal failure, or chronic liver disease) rates were reported to be % with amoxicillin, % with amoxiciltherapy has not been shown to benefit type iii exacerbation, lin/clavulanic acid, % with trimethoprim/sulfamethoxazole, and % with macrolides. another retrospective study by destache et therefore, symptomatic therapy suffices for these patients. patients al. [ ] analyzed episodes of aecopd requiring antimicrobials with simple aecopd will have only mild-to-moderate impairin outpatients. the antimicrobials were divided into three ment of lung function (fev > % predicted), have fewer than groups: first-line (amoxicillin, trimethoprim/sulfamethoxazole, four exacerbations per year and are likely to be colonized with tetracycline, erythromycin), second-line (cefuroxime, cefaclor, usual strains of h. influenzae, s. pneumoniae, and m. catarrhalis, cefprozil), and third-line (amoxicillin/clavulanic acid, azithroalthough viral infections often precede bacterial superinfection. mycin, ciprofloxacin). deterioration of symptoms requiring addi-recommendations are to use any first-line antimicrobial agent, as tional antimicrobials within weeks of initial therapy was defined the consequences of treatment failure are not likely to be grave. as treatment failure. the patients who received first-line agents the patients with complicated aecopd have poorer underlying had significantly higher failure rates; the patients treated with lung function (fev < % predicted), significant medical third-line agents were hospitalized less frequently, and had a comorbidity (e.g. diabetes, congestive heart failure, chronic renal longer exacerbation-free interval. disease, chronic liver disease) and/or experience four or more in , < % of isolates of h. influenzae were β-lactamase exacerbations per year. the predominant organisms may not be positive in the us. [ ] since then, resistance to the commonly used more likely to be resistant strains of h. influenzae, s. pneumoniae, antimicrobials among non-typeable h. influenzae, s. pneumoniae and m. catarrhalis, but since treatment failure may have major and m. catarrhalis has dramatically risen over the past decades. implications, empiric antimicrobial therapy directed toward resis-in , the prevalence of β-lactamase producing h. influenzae exceeded %, [ ] and presently % of all h. influenzae strains tant organisms should be initiated. second-line antimicrobial are estimated to be β-lactamase positive. [ , , ] furthermore, % agents such as quinolones, amoxicillin/clavulanic acid, second-or of h. influenzae strains are known to possess multiple mechanisms third-generation cephalosporins or second-generation macrolides of antimicrobial resistance, including production of β-lactamase are recommended in these patients. occasional patients with repetand alterations in penicillin binding. additionally, % or more h. itive exacerbations are likely to become colonized with p. aerugiinfluenzae are cefaclor-and cefprozil-resistant, and % are nosa; some of these individuals have underlying bronchiectasis azithromycin-resistant. [ ] the prevalence of penicillin-resistant s. when studied by high-resolution imaging studies. since many of pneumoniae isolates increased from - % before to . % these patients have received multiple courses of antimicrobials, the in . [ ] the current data on resistance are similar: [ ] [ ] [ ] [ ] a presence of p. aeruginosa represents colonization. in unusual survey of medical centers from november to april circumstances when infection is documented, use of a quinolone showed that approximately % of s. pneumoniae are resistant to with antipseudomonal activity empirically and further tailoring the penicillin, with % of isolates exhibiting a high level of resistherapy based on sputum culture is appropriate. although none of tance (minimum inhibitory concentration ≥ μg/ml). [ ] these proposed classification schemes have been prospectively bronchopulmonary infections comprised . % and . % of tested for their utility and efficacy, they emphasize that potentially resistant infections with s. pneumoniae were from patients ≥ resistant organisms should be targeted in patients at high risk of years of age. the current overall pneumococcal resistance prevaantimicrobial treatment failure. lence in the us is: macrolides . %, clindamycin . %, tetracy-cline . %, chloramphenicol . %, and trimethoprim/ the initial cure rates ( % vs %, p = . ) and -month exacersulfamethoxazole . %. [ , ] in another study, a total of bation-free period ( % vs %, p = . ) were similar in patients isolates of s. pneumoniae and h. influenzae strains revealed receiving older versus newer antimicrobials. [ ] therefore, large ampicillin resistance of approximately % among h. influenzae clinical trials are needed to establish the adequacy of current isolates and did not significantly differ between strains from empiric guidelines and to address the role of newer broad-speccommunity-acquired infections or hospitalized patients. [ ] further-trum antimicrobials. more, β-lactamase-negative ampicillin-resistant strains and fluoroquinolone-refractory strains were rare ( . % and ≤ . %, . prescribing the appropriate antimicrobial respectively). macrolide-resistance to h. influenzae was . % (clarithromycin) in hospitalized patients with pneumonia. another there are several theoretical characteristics that would be desirrecent study from north america demonstrated nonsusceptibility able in selecting an antimicrobial for aecopd: (i) activity against rates to penicillin at . %, cefotaxime . %, imipenem . %, the most common and most likely etiologic organisms, including ciprofloxacin . %, erythromycin . %, and tetracycline h. influenzae, s. pneumoniae and m. catarrhalis; (ii) resistance to . %. [ ] destruction by β-lactamase; (iii) narrow spectrum of activity during - , jones et al. [ ] prospectively collected against the likely pathogen; (iv) good penetration into the sputum, isolates of h. influenzae, isolates of s. pneumoniae and bronchial mucosa and epithelial lining fluid; (v) easy to take, with isolates of m. catarrhalis from hospital laboratories in france, few adverse effects; (vi) prolonged dfi or delay of the next germany, greece, italy, spain, and the uk. s. pneumoniae isoexacerbation; (vii) cost effectiveness, including the drug and hoslates were . % susceptible to moxifloxacin, gatifloxacin and pital costs and the costs of treatment failure (table v) . [ ] levofloxacin, and h. influenzae and m. catarrhalis were % susceptible. the incidence of penicillin non-susceptibility to s. pneumoniae remained similar to or higher than previously reported: france, of ( . %); germany, of ( . %); greece, of ( . %); italy, of ( . %); spain, of ( . %); and the uk, of ( . %). the β-lactamase production among h. influenzae isolates ranged from . % to . % per country. a higher resistance against pneumococcus has been reported from spain ( . %) than in italy ( . %), whereas erythromycin resistance was higher in italy ( . %) than in spain ( . %). [ ] selective pressure from antimicrobial prescription appears to be the most important factor associated with drug-resistant s. pneumoniae. resistance is encountered more commonly in patients who have identifiable risk factors, including age > years, prescription of β-lactam antimicrobials during the past months, previous hospitalizations, and nursing home residence. [ , ] however, the majority of studies have not classified the exacerbations in detail and have not demonstrated a difference in clinical outcomes with newer or the older antimicrobial agents. [ ] [ ] [ ] grossman et al. [ ] assessed safety and efficacy of ciprofloxacin versus standard antimicrobial care in patients with moderate-tosevere bronchitis and at least four exacerbations in the previous year. a trend towards accelerated resolution with ciprofloxacin existed but the difference was not statistically significant in this open-label, uncontrolled study. a retrospective analysis performed by madaras-kelly et al. [ ] concluded that the use of older versus newer antimicrobials did not independently predict either the outcome or the subsequent development of an exacerbation. trimethoprim/sulfamethoxazole, combined in a ratio of : , is a bactericidal combination which works synergistically against bacterial organisms. both antimicrobials inhibit enzyme systems in , chlortetracycline was the first tetracycline discovered. involved in the bacterial synthesis of tetrahydrofolic acid by since then, tetracycline, demeclocycline, doxycycline, and minodifferent mechanisms. resistance occurs with development of a cycline have been synthesized for clinical use, although doxytarget enzyme with decreased bacterial affinity for the drugs and cycline and minocycline are the most frequently prescribed. the via dihydrofolic reductase gene mutations. although very popular tetracyclines are broad-spectrum bacteriostatic antimicrobials. in the s and s, the potential for resistance and increasing they either passively diffuse or are actively transported into the availability of safer agents has resulted in declining use of this bacterial cell. they inhibit ribosomal bacterial protein synthesis. antimicrobial. in older studies, comparisons with oral the mechanism of resistance to tetracycline is to prevent accumucephalosporins have generally shown equivalent efficacy. [ ] the lation of the drug inside the cell by decreasing influx or increasing sentry antimicrobial surveillance program reported - % efflux. many of the original trials of antimicrobial therapy demontrimethoprim/sulfamethoxazole resistance to common respiratory strated that tetracycline therapy was more effective than placebo in pathogens in europe and the us, and higher in latin america and milder infections. tetracyclines can be used in aecopd because asia-pacific regions. [ ] penicillin-resistant pneumococci have they are active against h. influenzae and atypical pathogens, but - % likelihood of cross-resistance to trimethoprim/ there have been reports of increasing resistance against sulfamethoxazole. [ ] consequently, local resistance patterns and pneumococci. [ ] [ ] [ ] ] severity of disease should be taken into account for appropriate use β-lactam antimicrobials are generally bactericidal by virtue of of trimethoprim/sulfamethoxazole in aecopd. inhibition of bacterial cell wall synthesis. bacterial resistance to β-lactams may occur by any of three general mechanisms: (i) . second-line antimicrobials decreased penetration of antimicrobial to the target binding protein in the bacterial plasma membrane; (ii) alterations in penicillin- the mechanism of antimicrobial action of newer macrolides is binding proteins; and (iii) production of β-lactamase, which may similar to that of erythromycin. these agents bind to the s cleave the penicillins or cephalosporins. production of βsubunit of bacterial ribosome and inhibit bacterial protein synthelactamase is the most important mechanism. the bacteria may sis. compared with erythromycin, these agents are more acid either synthesize β-lactamase constitutively or initiate synthesis in stable, have improved oral absorption and tolerance, and have a the presence of antimicrobials; the β-lactamase positivity varies broader spectrum of antimicrobial activity. macrolides and fluorobetween centers and countries. amoxicillin has been widely used quinolones are active against c. pneumoniae. there has been for the management of aecopd. [ ] in countries and centers increasing resistance to macrolides among gram-positive orgawhere resistance among h. influenzae and pneumococci remain at nisms. up to % of s. pneumoniae may have resistance to low levels, β-lactam antimicrobials are drugs of choice in patients erythromycin and cross-resistance to other macrolides. azithrowith purulent or type i and ii exacerbations. despite their relativemycin and clarithromycin have improved pharmacokinetics and ly poor activity and suboptimal respiratory pharmacokinetics, antimicrobial activity against h. influenzae compared with erythcephalexin and cefaclor have been extensively used for the manromycin. [ ] the significant advantages of azithromycin are enagement of aecopd. the newer cephalosporins, cefprozil and hanced potency against h. influenzae, once-daily administration, cefixime, may have some advantages such as activity against reduced rates of adverse effects (specifically gastrointestinal efresistant pneumococci, but have not been proven to be superior to fects), an abbreviated -to -day treatment course, and perhaps a amoxicillin [ , ] when organisms are fully sensitive to both reduced frequency of relapse during extended follow-up. [ ] [ ] [ ] [ ] agents. the efficacy and safety of a -day regimen of azithromycin and of the combination of amoxicillin/clavulanic acid is an improve-a -day regimen of amoxicillin/clavulanic acid were compared in ment over amoxicillin alone when prescribed for β-lactamasepatients with aecopd. major improvement or cure on day producing organisms. addition of clavulanic acid makes the com-occurred in % of patients in the azithromycin group compared bination therapy resistant to most but not all bacterial βwith % on amoxicillin/clavulanic acid. at days, the success lactamases. most studies of patients with lower respiratory tract was % and % in azithromycin-and amoxicillin/clavulanic infection have shown this agent to be equivalent to standard acid-treated patients, respectively. [ ] another recent randomized, comparators. [ ] comparison with cefixime and ciprofloxacin double-blind, multicenter trial compared the safety and efficacy of showed better clinical success in aecopd but no significant oral azithromycin and levofloxacin in outpatients with difference in bacterial eradication rates. [ ] aecopd. [ ] both treatments were well tolerated, and favorable clinical outcomes were demonstrated in % of patients receiving than primary care physicians compared the efficacy of azithromycin and % of patients receiving levofloxacin by day ciprofloxacin and clarithromycin. equivalent clinical success of therapy. at day , favorable responses were approximately ( % vs %) and bacteriologic eradication ( % vs %) were % and % and bacterial eradication rates were % and %, reported with ciprofloxacin compared with clarithromycin. derespectively, for patients in the two treatment groups. another spite a relatively high inhibitory concentration against s. study compared the clinical efficacy and tolerability of -day pneumoniae, ciprofloxacin has demonstrated clinical efficacy simcourses of dirithromycin and azithromycin given once daily for the ilar to amoxicillin, clarithromycin and cefuroxime. [ ] oral treatment of aecopd. comparable clinical efficacy was revealed levofloxacin or mg daily was compared with oral cefuroxbetween -day courses of once-daily dirithromycin and azithroime axetil ( mg twice daily) in a randomized, double-blind, mycin in aecopd. [ ] multicenter study. [ ] the cure rates in the intention-to-treat population were % for levofloxacin mg, % for levofloxacin clarithromycin per se has only intermediate activity against mg and % for cefuroxime axetil. another randomized, h. influenzae but synergy with one of its metabolites increases its double-blind study demonstrated equivalent clinical and bacterioactivity to satisfactory levels. [ , ] clinical studies of clarithrologic success with levofloxacin mg once daily for a -or -day mycin involving -to -day regimens in patients with mild-tocourse. [ ] a shorter course of gatifloxacin for days was commoderate infections have shown equivalence to ampicillin. [ ] a phase iii randomized, double-blind study in aecopd patients pared with -day gatifloxacin therapy and -day clarithromycin demonstrated that extended release clarithromycin at mg once therapy for acute exacerbation of chronic bronchitis. [ ] similar daily compared favorably with immediate release clarithromycin clinical success rates of > % were reported compared with mg twice daily: the clinical cure rates were % and %, comparator antimicrobials. another open-label noncomparative respectively. [ ] a recent study compared clarithromycin with post-marketing trial of gatifloxacin in the treatment of aecopd amoxicillin/clavulanic acid in the treatment of aecopd. clinical in community-based practice settings was reported recently. [ ] success was documented in % of patients receiving erythromy-overall cure rates were . % for h. influenzae, . % for s. cin and was equivalent to amoxicillin/clavulanic acid, and the pneumoniae and . % for m. catarrhalis; the most serious adinidence of adverse events was similar in the two treatment verse effects were nausea ( . %), dizziness ( . %), diarrhea groups. [ ] ( . %), and vomiting ( . %). [ ] another respiratory fluoroquinolone, moxifloxacin, has been reported to be efficacious in pa-fluoroquinolones, synthetic analogs of the original molecule tients with aecopd. [ ] [ ] [ ] these multicenter trials compared (nalidixic acid), exert their antimicrobial effect by direct inhibition oral moxifloxacin mg/day for days with oral clarithromycin of bacterial dna synthesis. [ ] [ ] [ ] two bacterial enzymes -dna mg/day for days or intramuscular ceftriaxone g once daily gyrase and topoisomerase iv -have essential roles in dna for days or oral amoxicillin/clavulanic acid (three mg tablets replication. fluoroquinolones bind to each of these enzymes, thus interfering with dna replication, leading to bacterial cell death. daily for days). similar clinical success rates, classified as resistance to fluoroquinolones occurs via mutations in the genes resolution or improvement of symptoms, occurred with moxifloxby encoding the subunits of dna gyrase and topoisomerase iv. acin. a multinational, double-blind study, mosaic (moxiflox-altered permeation mechanisms may contribute to resistance by acin oral tablets to standard oral antibiotic regimen given as firstenhancing cytoplasmic membrane efflux pumps. these agents line therapy in out-patients with acute infective exacerbations of penetrate well into the respiratory secretions and bronchial muco-chronic bronchitis), compared effectiveness of moxifloxacin sa, but the clinical relevance of this is uncertain. the respiratory ( mg once daily for days) and standard therapy (amoxicillin fluoroquinolones are active against both typical and atypical bac-[ mg three times daily for days], clarithromycin [ mg twice terial pathogens. the fluoroquinolones are highly active against βdaily for days], or cefuroxime-axetil [ mg twice daily for lactamase producing h. influenzae and m. catarrhalis. these days]). patients were stratified according to oral and inhaled antimicrobial agents have - % bioavailability after oral adcorticosteroid usage. the primary endpoint was clinical success ministration, a prolonged half-life (> - hours), low protein (sufficient improvement, no alternative antimicrobial therapy rebinding and renal clearance. fluoroquinolones are well tolerated, quired) - days after therapy. secondary predefined endpoints and adverse effects are mild and transient, including rash, dizziwere clinical cure (return to pre-exacerbation status), further antiness, headache, gastrointestinal disturbance (nausea, vomiting, microbial use, time to next exacerbation and bacteriologic success. diarrhea, abdominal pain) and minor hematologic abnormalities. in this parallel study, patients received moxifloxacin and the efficacy of fluoroquinolones has been established in sever-patients received standard therapy. in an intention-to-treat (itt) al randomized trials. a community-based study involving more population, clinical success rates were similar ( . % for mox-ifloxacin, % for standard therapy, p = . ) at - days after creased sputum volume, and increased sputum purulence), should therapy. moxifloxacin showed superior clinical cure rates over be treated. the traditional antimicrobials termed as first-line therstandard therapy in both itt patients ( % ci . , . ) and per apy are appropriate; these include amoxicillin, tetracycline, doxyprotocol patients ( % ci . , . ), and higher bacteriologic cycline and trimethoprim/sulfamethoxazole. cure rates with these success in microbiologically valid patients ( % ci . , . ). antimicrobials approach - % in mild-to-moderate exacerba-time to next exacerbation was longer with moxifloxacin; median tions. in patients who have more severe underlying lung disease, time to new aecopd was . days in moxifloxacin, and . frequent exacerbations, and comorbid conditions, failure of initial days in standard therapy, respectively (p = . ). the occurrence antimicrobial therapy may result in repeat visits, hospitalization, of failure, new exacerbation, or any further antibiotic use was less and increased morbidity and mortality. in these patients (complifrequent in moxifloxacin-treated patients for up to months of cated aecopd), second-line antimicrobials including macrolides follow-up (p = . ). [ ] a recent randomized, double-blind trial and fluoroquinolones, and second-or third-generation macrolides of gemifloxacin mg once daily antibiotic therapy was used to should be considered. investigate its efficacy and the magnitude and time course of effect clinical trials utilizing newer antimicrobials showed equivaof an aecopd on health status. clarithromycin mg twice lence but not superiority compared with the regimens already in daily for days was used as comparator drug, patients were use. future studies should attempt to identify patients with followed up for weeks. clinical success rates at the - week aecopd most likely to benefit from antimicrobial therapy. well follow-up visit were . % for gemifloxacin and . % for defined prospective analyses of cost, dfi, quality-of-life improveclarithromycin. bacteriologic success rates were . % for ment and recovery of lung function should be addressed in these gemifloxacin and . % for clarithromycin. significantly more studies to ascertain the utility of antimicrobial therapy in patients receiving gemifloxacin than clarithromycin remained free aecopd. of aecb recurrences ( . % vs . %, respectively; p = . ). [ ] the greatest improvement in st george's respiratory a study of infective and other factors in flora in sputum and functional impairment in patients with acute exacerbations of copd airway bacterial load and fev decline tions of chronic obstructive pulmonary disease (copd) requiring mechanical in patients with chronic obstructive pulmonary disease. am j respir crit care ventilation colour: correlation with airways inflammation bacterial infection in chronic obstructive pulmonary disease . wedzicha ja. airway infection accelerates decline of lung function in chronic in : a state-of-the-art review viral infections in obstructive airway diseases host-microbial interrelationships in respiratory infection pneumoniae infections with acute respiratory illness in patients with chronic . wilson r. outcome predictors in bronchitis chronic bronchitis characterization of distal bronchial . howard p. a long-term follow-up of respiratory symptoms and ventilatory funcmicroflora during acute exacerbation of chronic bronchitis. am rev respir dis tion in a group of working men the fate of the chronic bronchitis: a report of the -year follow-up in bacterial infection in chronic obstructive the canadian department of veterans affairs coordinated study of chronic pulmonary disease: a study of stable and exacerbated outpatients using the bronchitis effects of smoking intervention and the infective exacerbations of chronic bronchitis: use of an inhaled anticholinergic bronchodilator on the rate of decline of fev . relation between bacteriologic etiology and lung function lower respiratory illnesses promote fev decline in current smokers but not in ex-smokers with mild chronic and inflammatory markers in acute exacerbations and stable chronic obstructive respiratory viruses in exacerbations of chronic status following an ineffective exacerbation of chronic bronchitis do bacteria cause exacerbations of copd? survival of acute respiratory failure: a study of role of infection in chronic bronchitis outcomes following acute exacerba state of the art; bacterial infection in chronic obstructive lung tion of severe chronic obstructive lung disease. am j respir crit care med disease acute infective exacerbations of chronic tion and the frequency, character, and severity of copd exacerbations. thorax bronchitis acute exacerbation of copd: factors clinical audit indicators of outcome - following admission to hospital with acute exacerbation of chronic obstructive strain-specific and immunodominant pulmonary disease survival of patients with chronic obstructive pulmonary disease receiving fluenzae acute respiratory failure of chronic obstructive rev respir dis costs of copd in sweden according to markers of airway inflammation in patients with stable chronic bronchitis pharmacoeconomic evaluation of role of bacteria in the pathogenesis and progression of acute and copd severe exacerbations of chronic relationship of sputum color to nature and obstructive airways disease: health resource use in general practice and hospioutpatient management of acute exacerbations of copd pharmacoeconomic evaluation of acute new strains of bacteria and exacerbations of exacerbation of chronic bronchitis the economic burden of copd infectious etiology of acute exacerbations of chronic bronchitis antibiotics in chronic obstructive pulmonary medical costs of asthma and chronic obstructive pulmonary disease in the disease exacerbations: a meta-analysis the excess of acute exacerbations of chronic chronic bronchitis infections respiratories récidivantes du sujet - atteint de bronchite chronique obstructive: prise en charge médicale et coüts (recurrent respiratory infections in patients with chronic obstructive bronchitis: streptococcus pneumoniae in the united states, - the costs of exacerbations in chronic prevalence of antimicrobial resistance obstructive pulmonary disease (copd) clinical and economic considera-america: results from sentry antimicrobial surveillance program. clin tions in acute exacerbations of chronic bronchitis antimicrobial resistance among economic evaluation of ciprofloxacin clinical isolates of streptococcus pneumoniae in the united states during compared with usual antibacterial care for the treatment of acute exacerbations - , including a comparison of resistance rates since - . anof chronic bronchitis in patients followed for year comparison of streptococcus pneumoniae pharmacoeconomic analysis of selected and haemophilus influenzae susceptibilities from community-acquired respiraantibiotics in lower respiratory tract infection economic evaluation of alternative antibi-dis otic regimens in the management of acute exacerbations of chronic bronchitis streptococcus pneumoniae, haemophilus influenzae and moraxella catarrhal acute exacerbation of chronic bronchitis: is: a european multicenter study during antibacterial resistance in streptococcus model to evaluate the costpneumoniae and haemophilus influenzae from italy and spain: data from the effectiveness of different antibiotics in the management of acute bacterial protekt surveillance study antimicrobial resistance in isolates from evaluating antimicrobial treatment of acute exacerbations of chronic bronchitis. inpatients and outpatients in the united states: increasing importance of the s- s intensive care unit five day moxifloxacin therapy compared with antibiotics in the treatment of acute exacerbations of chronic obstructive day clarithromycin therapy for the treatment of acute exacerbations of chronic pulmonary disease comparison of -day, short-course outcome of adult lower respiratory tract infections in the community. lancet gatifloxacin therapy with -day gatifloxacin therapy and -day clarithromycin respiratory tract infections: when is antibiotic therapy indicated? clin - the safety and efficacy predictive factors of hospitalization for of short course moxifloxacin vs azithromycin in the treatment of patients with acute exacerbation in a series of patients with chronic obstructive pulmonary acute exacerbations of chronic bronchitis a one year community-based health factors associated with increased economic study of ciprofloxacin vs usual antibiotic treatment in acute exacerbarisk of exacerbation and hospital admission in a cohort of ambulatory copd tions of chronic bronchitis. the canadian ciprofloxacin health economic patients: a multiple logistic regression analysis. the eolo study group. study group clinical outcomes of ambula factors associated with relapse after tory acute exacerbations of chronic bronchitis with older versus newer anambulatory treatment of acute exacerbations of chronic bronchitis treatment of acute exacerbations of chronic bronchitis: antibiotic therapy recommendations on the management of chronic bronchitis surveillance of antimicrobial resistance in s pneumonia, h influenzae and m catarrhalis in the united states canadian guideline for the management of acute exacerbation of chronic bronchitis: executive summary cefaclor in the treatment of chronic bronchitis guidelines for the treatment of acute exacerbation of chronic bronchitis efficacy of cefixime in respiratory tract infections augmentin (amoxicillin/clavulanate) in the editors. asthma and copd: basic mechanisms and clinical management. treatment of community-acquired respiratory tract infection: a review of the london amoxicillin/clavulanic: an update of its antibacterial activi-inc., editor a comparison of cefuroxime and co-trimoxazole relapse rate in outpatients with acute exacerbations iof copd resistance to trimethoprim-sulfamethoxazole multivariate analyresults of a national multicenter surveillance study. antimicrob agents sis of risk factors for infection due to penicillin resistant and multidrug resistant chemother the treatment of acute exacerbation of chronic bronchitis: results of a randomized, double-blind study randomized, double-blind study comparing -and -treatment of adults with lower respiratory tract infections and effects on long day regimens of oral levofloxacin in patients with acute exacerbations of term outcome comparison of -day, short cause azithromycin levofloxacin in the outpatient treatment of acute bacterial exacerbations of - chronic bronchitis efficacy and tolerability of gatifloxacin a comparison of -day courses of in community treatment of acute exacerbations of chronic bronchitis. clin ther dirithromycin and azithromycin in the treatment of acute exacerbations of chronic obstructive pulmonary disease clarithromycin immediate-release tablets for the treatment of patients with . schaberg t, ballin i, huchon g, et al. a multinational, multicentre, non-blinded, acute bacterial exacerbation of chronic bronchitis a comparative study of clarithromycin and ampicillin in the treatoral tablets in the treatment of acute exacerbation of chronic bronchitis. j int ment of patients with acute bacterial exacerbation of chronic bronchitis studio multicentrico con moxifloxacina nel release clarithromycin tablets and amoxicillin/clavulanate tablets in the treat-trattamento delle riacutizzazioni de bronchite cronica short-term and long-term outcomes of comparative study of clarithromycin modified release and amoxicillin/clavumoxifloxacin compared to standard antibiotic treatment in acute exacerbations lanic acid in the treatment of acute exacerbation of chronic bronchitis a review of the comparative in vitro activities of antimicrobial agents, with a focus on five new "respiratory quinolones". j antimicrob mycin in acute exacerbations of chronic bronchitis and long-term clinical time course of recovery of health status following an infections current issues on resistance, treatment guidelines, and the appropriate use of fluoroquinolones for respiratory tract infections etiology, susceptibility, and treatment bg , st boniface general hospital, tache avenue of acute bacterial exacerbations of complicated chronic bronchitis in the prima- a , canada. ry care setting: ciprofloxacin mg b.i.d. versus clarithromycin mg b.i.d. e-mail: ssharma@sbgh questionnaire score occurred within the first weeks (mean . units, % ci . , . ; p < . ). [ ] subsequently, scores this study demonstrated sustained effect on health status even after a single episode of aecopd; recurrences unfavorably affect quality of life. treatments that reduce exacerbation frequency references could have a significant impact on health status. despite consider- key: cord- -feiy xed authors: tan, xiaodong; li, shiyue; wang, chunhong; chen, xiaoqing; wu, xiaomin title: severe acute respiratory syndrome epidemic and change of people's health behavior in china date: - - journal: health educ res doi: . /her/cyg sha: doc_id: cord_uid: feiy xed severe acute respiratory syndrome (sars) has become a new worldwide epidemic whose origin was until recently unknown. it is the unpredictable nature of this epidemic that makes people want answers to some important questions about what they can do to protect themselves. this study presents an inquiry into people's knowledge and self-reported changes in behavior in response to the epidemic. respondents were drawn from seven major occupational groups in the large central city of wuhan. although most respondents knew of sars, there was still . % who did not know about it. knowledge was lowest among farmers who had come to the city for temporary work. most respondents took action to avoid being infected by sars, including, most commonly, efforts to improve indoor ventilation, to disinfect the indoor environment and to increase hand-washing frequency. self-reported increases in hand-washing frequency were significant; however, among the seven occupational groups, reports of increased hand-washing were consistently greater among commercial service workers, students and farmers. while it seems that possible fears induced by the epidemic led to these changes, there are still about one-third of respondents who do not wash their hands as frequently as desired. there is also the challenge of devising strategies for maintaining the desired frequency of hand-washing among those who did change. severe acute respiratory syndrome (sars) is a new flu-like disease that made its appearance in late and spread to over countries by mid- . the cause, a coronavirus, was unknown for the first several months, making public health measures difficult and raising concern among the public. only recently has sars been identified as a new disease (anand et al., ; anonymous, a,b; lipsitch et al., ; zhao et al., ; donnelly et al., ) . due to the absence of effective vaccines or drugs, and especially due to its rapidly spread via the respiratory route, sars has frightened the public (anonymous, c-e; mei et al., ; sun et al., ) . on april , the ministry of health of china announced that the government would require daily notification of sars infections on the public media and began health promotion activities for the chinese society, such as disinfection in public places, health education on public media and control of public transmission (anonymous, f-h; ashraf, ) . the adoption of these measures, due to the initially unclear nature of sars transmission, actually increased panic among the chinese people who began wearing masks, reducing the chances of outdoor activities, disinfecting the environment and washing their hands. this survey attempted in a post hoc manner to document the changes in people's behavior that may have resulted from weeks of health promotion activities. as the epidemic took shape quickly, the authors realized that it was necessary to understand how the public viewed the condition in order to recommend appropriate preventive and control measures. therefore, a -item questionnaire was designed that sought information on the public's knowledge, attitudes, beliefs and practices about sars. the questionnaire was especially concerned about the changes in health behavior people may have undertaken around late april and early may . the study took place in the city of wuhan (population of . million) located in central china. respondents were drawn from seven occupations including clerks, students, workers, public transportation workers, commercial service workers, retired people and city working farmers (i.e. people who come from rural areas and work in cities temporarily). postgraduate students of the school of public health, wuhan university interviewed the respondents. three multiple-choice questions about sars knowledge addressed the nature of transmission (whether it was infectious and the route of transmission) and the clinical symptoms. seven questions about health behavior change in the previous weeks addressed recent preventive measures generally and hand-washing specifically. responses were categorized as 'increased', 'no change' and 'decreased'. data were coded, entered into an access database and analyzed with spss software. the interviewers attempted to reach respondents and obtained valid responses, a response rate of . %. the age distribution of the subjects ranged from to years with a mean of . ( . ). males comprised . % of the respondents. occupations of respondents are presented in table i , with the largest groups comprising students and commercial service workers. less than half ( . %) of respondents could answer all three knowledge questions about sars, . % could answer some of the questions, while . % knew the answer to none. comparisons of knowledge and occupation are shown in table ii . clerks had the best knowledge, with . % answering all three questions correctly. farmers who had come to the city to work had the lowest, with only % being able to answer all questions and . % being able to answer none. reported behavior change was recorded in two ways. respondents first reported on the changes they themselves took. second, respondents were asked about changes in their hand-washing behavior. self-reported behavior changes are displayed in table iii , and include improving indoor ventilation, disinfection of the indoor environment and hands, and increasing hand-washing frequency. the comparative results of self-reported handwashing behavior at two points during the sars epidemic are presented in table iv . people reported significant increases in the frequency with which they washed their hands before meals, washed their hands after returning home from outdoors and washed their hands after coming into contact with public materials, e.g. on public transportation. table v compares reported changes by occupation. three occupational categories in particular, i.e. farmers working in the city, commercial service workers and students, reported significantly greater increases in hand-washing than other groups. responses were compared by gender, but were not significantly different. sars, an atypical pneumonia of unknown etiology, was recognized at the end of february (bloom, ; bonn, ; cai, ; cameron et al., ; gillissen and ruf, ; li and zhang, ) . numerous scientists have been working in the affected countries to provide epidemiological, clinical and logistical support as required. in almost all documented cases, sars is spread through close face-to-face contact with infected droplets when a patient sneezes or coughs. some of the epidemic's origins remain unclear. for sars, three activities-case detection, patient isolation and contact tracing-can reduce the number of people exposed to each infectious case and eventually break the chain of transmission. in the absence of a vaccine, the most effective way to control a new disease such as sars is to break the chain of transmission from infected to healthy persons (buckley, ; donnelly et al., ; eaton, ; kontoyiannis et al., ; mackay, ; mandavilli, ) . unfortunately, these activities brought panic to ordinary citizens and did not show there is any gender difference, especially during the early days when the chinese government decided that sars was a real public health problem. the panic, in part, arose because people did not know how to protect themselves. a full weeks into major informational and control measures, many people still did not have complete knowledge about the epidemic. this study documented that even without thorough knowledge following health promotion and information efforts, most persons changed their health behaviors to avoid sars infection. the example of farmers, who had low knowledge and yet still reported behavior change, is illustrative of people's desire to protect themselves. the results show that when people perceive a health problem as serious they will take some kind of action. it is therefore incumbent on public health officials to learn quickly what people believe and provide information that will allay their fears in a timely manner. sars is unlikely to be the last emerging epidemic of our times and so the lessons learned here will be of value in anticipation of future disease outbreaks. the results also imply that the provision of health information on sars should be adapted to the various sociodemographic groups, such as those based on occupation/work settings, in order to increase access and understanding. in conclusion, sars has had a great influence on ordinary people in the city and has influenced motivation to practice more healthy behaviors, such as hand-washing. these changes are probably based on the immediate fear of sars and more time is needed to observe whether they will be sustained. the results presented here can be applied to planning communication about future emerging infectious diseases. follow-up is needed to determine how best to reinforce the maintenance of these new behaviors. we sincerely thank all the interviewers; it is they who helped the authors to get at the reality of the chinese people. we would also like to acknowledge the assistance of dr bill brieger in producing the final version of this paper. coronavirus main proteinase ( cl pro ) structure: basis for design of anti-sars drugs anonymous ( b) will sars hurt the world's poor? the war against an unknown pathogen: rising to the sars challenge anonymous ( e) update: outbreak of severe acute respiratory syndrome-worldwide an appropriate response to sars solid response to sars-almost global surveillance for severe acute respiratory syndrome (sars) china finally throws full weight behind efforts to contain sars. although sars claims more lives everyday worldwide, all eyes are on china as it tries to contain the largest outbreak clinical brief: severe acute respiratory syndrome (sars) closing in on the cause of sars differential diagnosis of severe acute respiratory syndrome (sars) in 'post-sars' stage. di yi jun yi da xue xue bao the sars epidemic: lessons for australia epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in hong kong sars could still affect the united kingdom, health secretary warns severe acute respiratory syndrome (sars) aminopeptidase n inhibitors and sars clinical features of patients with severe acute respiratory syndrome transmission dynamics and control of severe acute respiratory syndrome sars: 'a domino effect through entire system sars epidemic unmasks age-old quarantine conundrum study on the epidemiological characteristics of severe acute respiratory syndrome in shanxi province severe acute respiratory syndrome epidemiology in sichuan province description and clinical treatment of an early outbreak of severe acute respiratory syndrome (sars) in guangzhou key: cord- -s ecvk authors: thota, sai manohar; balan, venkatesh; sivaramakrishnan, venketesh title: natural products as home‐based prophylactic and symptom management agents in the setting of covid‐ date: - - journal: phytother res doi: . /ptr. sha: doc_id: cord_uid: s ecvk coronavirus disease (covid‐ ) caused by the novel coronavirus (sars‐cov‐ ) has rapidly spread across the globe affecting countries or territories with greater than six million confirmed cases and about . million deaths, with world health organization categorizing it as a pandemic. infected patients present with fever, cough, shortness of breath, and critical cases show acute respiratory infection and multiple organ failure. likelihood of these severe indications is further enhanced by age as well as underlying comorbidities such as diabetes, cardiovascular, or thoracic problems, as well as due to an immunocompromised state. currently, curative drugs or vaccines are lacking, and the standard of care is limited to symptom management. natural products like ginger, turmeric, garlic, onion, cinnamon, lemon, neem, basil, and black pepper have been scientifically proven to have therapeutic benefits against acute respiratory tract infections including pulmonary fibrosis, diffuse alveolar damage, pneumonia, and acute respiratory distress syndrome, as well as associated septic shock, lung and kidney injury, all of which are symptoms associated with covid‐ infection. this review highlights the potential of these natural products to serve as home‐based, inexpensive, easily accessible, prophylactic agents against covid‐ . . mers emerged in saudi arabia in and spread mostly to the middle east with a few cases in europe, asia and north america (hemida, ) . it accounted for around , cases with a higher mortality rate of . % (who, ). since , there have been a few active sporadic outbreaks of mers (ramadan & shaib, ) . the symptoms of sars and mers are similar and include fever, cough, shortness of breath, myalgia or fatigue (muscle pain), and diarrhea. in severe cases, both these infections result in pneumonia, severe respiratory infection, acute respiratory distress syndrome (ards), sepsis, and multiple organ failure (al hajjar, memish, & mcintosh, ; peiris, yuen, osterhaus, & stöhr, ) . there is an increased risk of progression associated with age and comorbid conditions such as diabetes, hypertension, cardio, pulmonary, and renal diseases. pathological analysis of sars and mers reveals diffused alveolar damage (dad), edema, elevated levels of collagen, fibrin and inflammatory cells in alveoli leading to decline in lung function and acute lung injury (alsaad et al., ; franks et al., ) . bats were reported to be the natural hosts for sars and mers coronaviruses which were transmitted to intermediate hosts, and finally to humans (omrani, al-tawfiq, & memish, ; salata et al., ) . the transmission of sars and mers was by direct contact or through droplets of coughs and sneezes from the infected patients (killerby, biggs, midgley, gerber, & watson, ; peiris et al., ) . treatment for sars and mers involved administration of antiviral drugs in combination with corticosteroids and interferon-α (ifn-α), however, the treatment had minimal benefits to patients and severe adverse effects (al ghamdi et al., ; tai, ) . covid- first emerged in december in china causing acute respiratory tract infections (guo et al., ) . this new virus is highly contagious and has spread rapidly across the globe. who declared the outbreak as "public health emergency of international concern" (who, b) . by the end of may , the virus had spread to countries or territories with greater than six million confirmed cases and about . million deaths. furthermore, during this period, there was a steep rise in the number of reported cases and associated mortality (who, d) . although the overall fatality rate for covid- -infected patients is lower ( . %) compared with sarsand mers-infected subjects, the spread of the disease has been exceptionally rapid, causing a global pandemic. figure shows the covid- global pandemic curve with the total number of confirmed cases and deaths. the current statistics on the extent of infections globally could be a significant underestimate given the lack of enough testing kits and a large number of asymptomatic carriers. covid- has very close similarities to the sars virus and hence is named sars-cov- . bats are believed to be the primary source of the virus and although the exact mechanism of transmission to humans is unclear, it is considered to have resulted f i g u r e structure of sars-cov- virus showing the single-stranded rna and nucleocapsid (n) along with spike (s), envelope (e), and membrane (m) proteins. schematic representation shows viral entry through the respiratory tract causing lung infection by damaging bronchioles and alveoli. this is associated with edema or swelling and elevated levels of fibrin, collagen, and inflammatory cells leading to pulmonary fibrosis. the spike (s) protein of sars-cov- binds to ace on the human bronchial and alveolar epithelial cells and activates fibrosis, oxidative stress, and inflammatory responses leading to acute lung infection. ace , angiotensin-converting enzyme ; sars-cov- , severe acute respiratory syndrome coronavirus [colour figure can be viewed at wileyonlinelibrary.com] either from direct contact, consumption of meat or through intermediate hosts (guo et al., ) . patients with mild infection show fever, fatigue, dry cough, slight nasal congestion, and muscle pain. in severe cases, shortness of breath (dyspnea) associated with dry cough or sputum/ phlegm production (expectoration), along with signs of pneumonia are observed (guan et al., ) . in critical cases, patients show ards associated with complete respiratory failure, sepsis, septic shock, and multiple organ dysfunction including heart, liver, and kidney. these patients need ventilators in the intensive care unit (cascella, rajnik, cuomo, dulebohn, & di napoli, ) . elderly patients with chronic comorbidities like diabetes, hypertension, cardiovascular, and cerebrovascular diseases are at greater risk of contracting covid- (lai et al., ) . laboratory studies show low blood levels of lymphocytes and white blood cells, and high levels of c-reactive protein and lactate dehydrogenase in covid- -infected patients (tian et al., ; wang, hu, et al., , p. ). post-mortem lung sections from covid- -infected patients revealed dad with thickening of alveolar walls, edema, fibrin, and proteinaceous exudates in alveolar spaces, vascular congestion, and pneumocyte hyperplasia with viral inclusions and multinucleate giant cells (tian et al., ; . the chest computed tomography (ct) of covid- patients shows bilateral multifocal ground-glass opacity indicative of alveolar exudate and transudate, as well as pleural thickening (guan et al., ; wang, hu, et al., ) . the transmission of covid- virus occurs with close, prolonged, and unprotected contact with symptomatic or patients who test positive for the virus (person-to-person), (ghinai et al., ) , as well as via respiratory droplets (cascella et al., ) . figure shows the schematic representation of sars-cov- viral entry through the respiratory tract of a healthy individual leading to acute lung infection. it is thought that short distance aerosol transmission could also be a possible mode of transmission, although the evidence in support of this is not strong. furthermore, the transmission of the infection from asymptomatic individuals has been reported leading to the fear of community transmission (mizumoto, kagaya, zarebski, & chowell, ; rothe et al., ) . a retrospective study conducted in china examined a total of patients including individuals who recovered from covid- infection and patients who succumbed to the infection. in this study, individuals who recovered had a median age of years, whereas those who died were older with a median age of years. furthermore, the prevalence of comorbidities was significantly higher among the patients who failed to recover versus those who recovered. this included hypertension ( . vs. . %), prior history of lung disease ( . vs. . %), diabetes ( . vs. . %), and heart disease ( . vs. . %). interestingly, the common symptoms associated with the infection like fever, muscle pain, fatigue, and cough were found to f i g u r e covid- pandemic curve showing the total number of confirmed cases (orange bars) and the total number of deaths globally (blue bars). in-set highlights the increasing number of deaths (who, d) [colour figure can be viewed at wileyonlinelibrary.com] the same extent in both the patient groups with the exceptions of shortness of breath ( . vs. %) and expectoration ( . vs. . %). furthermore, patients who died had a higher incidence of ards ( . vs. . %), acute cardiac injury ( . vs. . %), acute kidney injury ( . vs. %), septic shock ( . vs. %) compared with individuals who showed complete recovery (deng et al., ) . another study described % of infected individuals to exhibit generic symptoms, with only about % showing dyspnea with rapid and shallow breathing, pneumonia, and disturbed pulmonary gas exchange. included within this group of individuals showing progressive symptoms was a smaller subset ( %) who developed acute symptoms of lung infection, sepsis, and organ failure requiring icu admission. importantly, the course of progression of this viral infection is relatively slow spanning an incubation period of - days from the time of exposure to onset of symptoms. in individuals who progress to a more severe state, this usually happens by around day after appearance of the initial symptoms (thomas-rüddel et al., ). preventive measures to control the spread of covid- pandemic are crucial and should be followed strictly. coronaviruses are inactivated by ethanol, chlorine-containing disinfectants, and lipid solvents. washing hands regularly with soap and sanitizers containing % ethanol/isopropanol to prevent the spread of viral infection is the recommended standard (kampf & kramer, ) . environmental surfaces have to be cleaned regularly with detergent or bleach such as sodium hypochlorite (naocl) solution. close contact with symptomatic individuals has to be avoided, while also avoiding touching eyes, nose, and mouth. individuals with a prior history of respiratory distress should wear masks and cover their coughs or sneezes. health care workers (hcws) should follow appropriate safety measures during the diagnosis, hospitalization, and isolation of covid- positive patients (who, c). during sample collection, precautions should be taken to prevent direct contact or exposure to airborne droplets. it is very essential to quarantine symptomatic individuals prior to diagnostic testing with appropriate safety guidelines (adhikari et al., ) . hcws caring for covid- patients should self-monitor body temperature and respiratory symptoms. strict hygiene protocols should be implemented in hospitals. immunocompromised individuals should avoid public/private gatherings (cascella et al., ) . social distancing or physical space between two individuals should be maintained to prevent the spread of the covid- pandemic. when symptomatic or asymptomatic covid- -infected person coughs or sneezes, the respiratory droplets (> - μm size) (atkinson et al., ) containing the sars-cov- virus are released into the air, which can infect a healthy individual within m radius. the virus can enter into the subject through the mouth (oral), nose (mucosal), or eyes (conjunctiva). given this, social distancing requires maintaining at least m or ft distance between individuals to avoid respiratory droplet transmission (yu & yang, ) . it requires avoiding crowded places and public gatherings and implements staying at home and limiting the number of visitors. respiratory hygiene should be followed by covering mouth and nose with a tissue or bent elbow while coughing and sneezing. in addition to the above, indirect transmission of the virus by contacting contaminated environmental surfaces has been described. hence, touching eyes, nose or mouth should be avoided. quarantining refers to keeping an asymptomatic individual who has been exposed to covid- , in isolation (sharma et al., ) . quarantine can be implemented at home (self-quarantine) or the individual can be secluded in a specially designed facility. importantly, quarantined individuals should be monitored for sign of fever, cough, and any other respiratory symptoms for up to days. isolation refers to segregating confirmed covid- patients away from healthy individuals to avoid the spread of the infection. this can be implemented either at home or in a hospital/isolation facility (wilder-smith & freedman, ; tang et al., ) . infected patients are monitored and administered care to manage their symptoms. to date, treatment is symptomatic and supportive, with oxygen therapy and mechanical ventilation for ards and hypoxemia; fluid bolus therapy, vasopressors, and antibiotics for septic shock, as well as treatment to mitigate co-infections (who, a). there are no potentially effective drugs or vaccines available for the treatment of covid- and this has resulted in an explosion in research aimed at developing specific drugs. in parallel, existing drugs are being repurposed to test their efficacy against the sars-cov- virus. for example, broad-spectrum antiviral drugs (remdesivir, ribavirin, and ifn-α) (dong, hu, & gao, ) , antimalarial drugs (chloroquine and hydroxychloroquine) (gautret et al., ) , and combination of retroviral drugs (ritonavir/lopinavir) are being evaluated in covid- patients. early results suggest that patients treated with these repurposed drugs show no improvement in the mortality rate, while the viral rna load seems to show a slight decrease. however, in most patients, increased adverse events have been observed , which in more pronounced in individuals with underlying comorbidities (srinivasa, tosounidou, & gordon, ) . given the lack of targeted drugs to treat covid- , different approaches to mitigate covid- -associated complications are being evaluated. in this context, this review highlights the potential beneficial effects of natural products that are actively used in alternative/ traditional medicines to treat many of the acute pulmonary infections, routinely seen in covid- patients. these natural products can also boost immunity which is key to resist covid- infection. medicinal plants are the biggest age-old source of therapeutically beneficial phytochemicals used for maintaining good health, and to prevent and treat many diseases. these include plants and herbs that are both used in ayurveda, a traditional and alternative medicinal therapy based on holistic body healing, which originated in the indian subcontinent. a huge body of research is currently focused on understanding the therapeutic efficacy and mechanism of action of these phytochemical agents. the following sections describe dietary supplements and home-based remedies that have shown value as preventive agents for acute respiratory infections, pulmonary fibrosis, pneumonia, sepsis, and multiple organ failure; all of which are characteristic manifestations of severe covid- infection. in addition, many of these agents boost the immune system and imbues protection against infective agents. figure summarizes the beneficial properties of natural products against viral or chemically induced fibrosis, oxidative stress, inflammatory response, and associated acute lung injury in the setting of covid- . mechanistically, the available knowledge base shows that oxidative stress and dysfunctional immune system, in addition to existing comorbidities, contribute to many of the complications associated with covid- infection. for example, oxidative stress is an important factor resulting in pathogen-induced pulmonary fibrosis (cheresh, kim, tulasiram, & kamp, ) . along the same lines, an effective immune system is essential for surveying pathogens and neutralizing them in an efficient and timely manner to protect the individual from the infection. the medicinal plants described here contain diverse phytochemicals that have antiviral, antifibrotic, antioxidant, antiinflammatory, and immunomodulatory properties. these, when used in combination, could have a synergistic effect as prophylactic or supportive agents to minimize certain clinical symptoms observed in covid- -infected patients. in addition, certain species of bacteria, algae, and fungi also exert therapeutic effects against pulmonary fibrosis and acute lung injury. table summarizes the evidence in the literature supporting the therapeutic value of specific species of bacteria, algae, and fungi, as well as plants. the detailed summary of the therapeutic properties for each of the key natural products discussed in this review is provided in table s . among these, we have identified ginger, turmeric, garlic, onion, cinnamon, lemon, neem, basil, and pepper as well as mushrooms as readily available home-based remedies that have shown efficacy against pulmonary symptoms associated with covid- infections in various pre-clinical and clinical trials. ginger (zingiber officinale) has therapeutic properties against pulmonary fibrosis, pneumonia, ards, sepsis, and acute kidney injury. in addition, ginger along with its phytochemicals has antiviral, antifibrotic, antioxidant, antiinflammatory, and hepatoprotective properties (chang, wang, yeh, shieh, & chiang, ; mao et al., ; rahmani, shabrmi, & aly, ) . f i g u r e schematic illustration summarizing the beneficial properties of natural products and their impact on oxidative stress, inflammatory response, pulmonary fibrosis, and acute lung injury [colour figure can be viewed at wileyonlinelibrary.com] t a b l e literature-based evidence supporting the therapeutic value of various species of bacteria, algae, fungi, and plants ginger has significantly reduced pulmonary fibrosis and mitigated oxidative stress and inflammatory response in chemically induced pulmonary fibrosis in animal models. for example, bleomycin, a cytotoxic antibiotic used in cancer treatment, has idiopathic pulmonary fibrosis (ipf) as a side effect. in bleomycin-treated rats, zingerone, a bioactive compound in ginger has significantly reduced fibrosis score in histopathological sections of lungs, reduced levels of fibrosis marker, hydroxyproline and oxidative stress marker, and malondialdehyde (mda). in addition, it increased levels of antioxidant markers like reduced glutathione (gsh), superoxide dismutase (sod), and glutathione peroxidase (gsh-px) in the lungs . similarly, in ethanol-treated rats that exhibit symptoms of diffuse alveolar damage and acute lung injury leading to ards, extracts of ginger mitigated abnormalities in alveolar air space, wall thickening, infiltration of multinucleated cells and pneumocytes, lung cell proliferation, and fibrosis in the ethanol-treated rats. in addition, ginger significantly reduced the oxidative stress markers namely -hydroxy- -deoxyguanosine ( -ohdg), oxidized low-density lipoprotein (ox-ldl), and nadh oxidase levels. (shirpoor, gharalari, rasmi, & heshmati, ) . in a separate clinical study on ards patients, mg of ginger extract was shown to increase the tolerance of enteral feeding, significantly reduced nosocomial pneumonia and increased the icufree and ventilator-free days compared with the placebo group (shariatpanahi, taleban, mokhtari, & shahbazi, ) . ginger with its bioactive compounds has also ameliorated sepsis and acute kidney injury (aki) induced by cecal ligation and puncture (clp) in rats. specifically, in this study, the authors demonstrated that -gingerol and -gingerol significantly reduced pathological levels of aki markers, oliguria, blood urea nitrogen, urinary protein, serum creatinine levels, urinary sodium, and osmolarity in these rats. both compounds have also reduced the levels of oxidative stress markers, mda and nitrite, as well as increased the levels of antioxidants, gsh and sod. in addition, they also reduced levels of inflammatory markers such as tumor necrosis factor-α (tnf-α), interleukin (il)- β, and kidney injury marker, turmeric (curcuma longa) has potential therapeutic effects on pulmonary fibrosis, severe respiratory disorders, lung infections, liver abnormalities. curcumin, the bioactive compound in turmeric has been shown to have antifibrotic, antioxidant, antiinflammatory, and immunomodulatory activities (jurenka, ; menon & sudheer, ; srivastava, singh, dubey, misra, & khar, ) . in bleomycin-induced pulmonary fibrosis rats, curcumin increased the expression of cathepsins (catk, catl) which degrade collagen, and inhibited lung fibroblast proliferation by blocking transforming growth factor (tgf)-β (smith et al., ; zhang et al., ) . in these rats, curcumin also suppressed the inflammatory cytokine tnf-α released by alveolar macrophages ameliorating pulmonary fibrosis (punithavathi, venkatesan, & babu, ) . paraquat is a toxic herbicide that leads to pulmonary fibrosis, edema, acute lung injury, and respiratory failure. in the paraquatinduced pulmonary fibrosis rat model, curcumin reduced the deposition of collagen fiber and inhibited fibrosis. in parallel, it also improved the tidal volume (volume of air taken during normal breath) and arterial partial pressure of oxygen (pao ) in the lungs (chen, yang, et al., ) . in these rats, at the molecular level, curcumin decreased the levels of fibrosis marker hydroxyproline, as well as oxidative stress markers, and inhibited lung fibrosis (hosseini et al., ) . in addition, it is well documented that impaired immune system with imbalances in inflammatory cells and cytokines can aggravate lung fibrosis (hügle, ) . in this context, it is important to note that curcumin is a potent immunomodulator and can regulate the function of dendritic cells, natural killer (nk) cells, neutrophils, macrophages, t cells, and b cells, as well as inflammatory cytokines (gautam, gao, & dulchavsky, ) . all the above pre-clinical findings strongly implicate turmeric as an agent that can improve lung function, and protect against acute lung injury and associated dad, pulmonary fibrosis, and ards, all of which are observed in covid- patients. garlic (allium sativum) has potential therapeutic effects against respira- garlic is also a potent immunomodulator (ishikawa et al., ) . in a clinical study on humans, dietary consumption of g of garlic every - days, boosted the basal plasma ifn-α levels which are known to be protective against viral infections and prevent viral replication (bhattacharyya, girish, karmohapatra, samad, & sinha, ) . importantly, these pre-clinical studies highlight the efficacy of garlic in mitigating pulmonary fibrosis, lung injury, and sepsis-associated organ failure, all of which are symptoms observed in patients with advanced covid- infection. onion (allium cepa) has potential therapeutic benefits against acute respiratory tract infection and lung injury caused by collagen deposition, inflammatory cell infiltration, and pulmonary fibrosis. onion along with its bioactive compounds, quercetin, apigenin, and selenium is known to exert antiviral, antifibrotic antioxidant, antiinflammatory, antiasthmatic and hepatoprotective properties (kumar & pandey, ; marefati et al., ; suleria, butt, anjum, saeed, & khalid, ) . onion has been shown to significantly alleviate pulmonary fibrosis tnf-α, ifn-γ, and il- a (farazuddin et al., ) . in a separate clinical study, lower selenium levels were observed in patients with respiratory disorders admitted to the icus that correlated with decreased lymphocytes and increased c-reactive protein levels (lee et al., ) . in other studies, conducted on hospitalized patients with pneumonia and bronchiolitis, mg of sodium selenite was found to reduce signs of respiratory infection and improve the recovery time. at the molecular levels, it increased the levels of antioxidant glutathione peroxidase as well as the leukocyte count (hu, liu, yin, & xu, ; liu, yin, & li, ) . together, these pre-clinical and clinical studies highlight the potency of onion in ameliorating pulmonary fibrosis, acute respiratory tract infections, and lung injury which are the critical symptoms of covid- patients. cinnamon (cinnamomum verum or c. zeylanicum) along with its major bioactive compounds, cinnamaldehyde, eugenol, and linalool, has potent antiviral, antioxidant, antiinflammatory, and hepatoprotective properties (jayaprakasha & rao, ; kawatra & rajagopalan, ; rao & gan, ) . in ccl and lps-stimulated rat and mice, cinnamon extracts reduced mda and increased levels of antioxidant markers catalase and sod. it also reduced antiinflammatory markers tnf-α/il- , reduced phosphorylation of mapks (jnk, p and erk / ), and interfered with nf-κb activation by inhibiting the degradation of iκbα. it has also reduced necrosis and infiltration of lymphocytes in the liver of rats with hepatic injury (hong et al., ; moselhy & ali, ) . overall, these studies implicate promising therapeutic roles of cinnamon against the sars-cov- infection in covid- . lemon (citrus limon) has potential therapeutic benefits against pulmonary fibrosis, pneumonia, ards, sepsis, acute lung, kidney, and liver injury. lemons contain vitamin-c (vit-c) or ascorbic acid (aa), which is an antifibrotic, antioxidant, antidiabetic, as well as an immunomodula tor. it is also documented to be protective against respiratory infections (ashbel' & arziaeva, ; chambial, dwivedi, shukla, john, & sharma, ; hong, lee, lee, & kim, ) . consistent with this, individuals with lower ascorbic acid levels are prone to severe infections and other acute diseases (bakaev & duntau, ) . in a case study involving a patient with dyspnoea, hypoxemia, and ards, placed on ventilator support, vitamin-c ( mg/kg body weight every hr) administered intravenously improved bilateral lung opacities as seen by chest x-ray, attenuated sepsis-associated ards, and was extubated (bharara et al., ) . in an independent clinical study containing critically ill surgical patients from icus, patients receiving antioxidant therapy (aa and α-tocopherol) had a relatively lower risk of pulmonary morbidity (a measure of ards and pneumonia), multiple organ failure and mortality compared with the standard of care patients. importantly, patients on antioxidant therapy required mechanical ventilation and icu admission for a shorter period of time (nathens et al., ) . in a separate clinical study, elderly patients hospitalized for bronchitis and pneumonia were administered oral vitamin-c ( mg/day) and compared with the placebo arm. vitamin-c levels in the treated group were higher in the plasma and leukocytes, and these patients were showed pulmonary complications (hunt, chakravorty, annan, habibzadeh, & schorah, ) . in a pre-clinical study comparing the effect of sepsis in mice lacking the capacity to synthesize vitamin-c (l-gulono-γ-lactone oxidase deficient, −gulo) versus wild-type controls (+gulo), lack of vitamin-c resulted in multiple organ failure, pulmonary edema, and proinflammatory response, all of which were attenuated by intraperitoneal infusion of vitamin-c (fisher et al., ) . similar results were obtained in independent studies using sepsis and acute lung injury models treated with or without vitamin-c ( mg/kg) (fisher et al., (fisher et al., , . along the same lines, in paraquat-induced pulmonary fibrosis mice model, vitamin-c has blocked infiltration of lymphocytes, neutrophils, macrophages, and attenuates pulmonary fibrosis. it also significantly decreased collagen deposition and reduced levels of pro-inflammatory markers, tgf-β, il- , il- , and enhanced antioxidant markers namely catalase and sod . vitamin-c also has significant immunomodulatory properties. it gets accumulated in neutrophils and enhances phagocytosis, nk cell activity, and lymphocyte proliferation (carr & maggini, ; wintergerst, maggini, & hornig, ) . taken together, preclinical and clinical studies suggest that vitamin-c could have promising therapeutic benefits in individuals with pulmonary fibrosis, pneumonia, ards, sepsis, acute lung injury, and multiple organ dysfunction all of which are observed in advanced covid- patients. neem (azadirachta indica) has potential therapeutic benefits against pulmonary fibrosis pulmonary inflammation, acute lung injury, and alveolar damage. the bioactive compounds in neem are azadirachtin, nimbolinin, nimbolide, quercetin, and β-sitosterol. these are known to exhibit antiviral, antioxidant, and antiinflammatory (alzohairy, ; subapriya & nagini, ; tiwari, darmani, yue, & shukla, ) properties. in a bleomycin-induced pulmonary fibrosis mice model, nimbolide has been shown to significantly reduce pulmonary fibrosis by decreas- basil a.k.a. tulsi (ocimum sanctum) along with its bioactive compounds, quercetin, eugenol, and apigenin has been shown to exhibit antiviral, antioxidant, antiinflammatory, antiasthmatic, and immunomodulatory properties (mahajan et al., ; mediratta, sharma, & singh, ; pattanayak et al., ; saini, sharma, & chhibber, ). in healthy humans, weeks oral administration of ethanol extracts of tulsi significantly increased the levels of ifn-γ, il- , t-helper cells, and nk-cells (mondal et al., ). black pepper (piper nigrum), known as "king of spices", has antiviral, antioxidant, and antiinflammatory properties (butt et al., ; vijayakumar et al., ) . the bioactive compound piperine is known to enhance the bioavailability of many drugs and phytochemicals by increasing their absorption from the gastrointestinal tract (pattanaik, hota, prabhakar, & pandhi, ) . for example, mg black pepper when taken along with g turmeric was shown to increase the bioavailability of the latter by -fold (shoba et al., ) . in light of this, one would envision that the bioavailability of the supplements discussed above could be enhanced by combining them with black pepper. medicinal mushrooms are an untapped resource which show potential antiviral, antiinflammatory, and immunomodulatory properties against various viruses like hsv, ebv hepatitis c virus, (hcv), human immunodeficiency virus (hiv), h n strain of flu, and influenza (ellan et al., ; linnakoski et al., ; muszy nska, grzywacz-kisielewska, kała, & gdula-argasi nska, ) . the secondary metabolites from these mushrooms such as alkaloids, non-ribosomal peptides, polyketides, and terpenoids have shown protease inhibitory activities against hiv- and hepatitis c virus (el-fakharany, haroun, ng, & redwan, ; sato et al., ; sillapachaiyaporn et al., ) . papaya (carica papaya) along with its bioactive compounds show antiviral, antioxidant, and antiinflammatory properties (joseph, sankarganesh, ichiyama, & yamamoto, ; panzarini, dwikat, mariano, vergallo, & dini, ) . thrombocytopenia or low blood platelet count could be another risk factor correlating with both, severity and higher mortality in covid- patients (lippi, plebani, & henry, ) . similarly, low platelet count is also associated with ipf, multiple organ failure and acute kidney injury (nguyen, cruz, & carcillo, ; steiropoulos et al., ) . thrombocytopenia is a common clinical manifestation in dengue patients and studies suggest that activation of platelets leads to prothrombotic state in these patients (jayashree, manasa, pallavi, & manjunath, ; ojha et al., but was inactivated at temperatures greater than c (rabenau et al., ) . similarly, uv radiation for -min was also shown to inactivate the virus (duan et al., ) . in turn, these findings highlight the importance of boiling water before drinking. in addition, inhaling steam generated from water containing turmeric and tulsi is effective against respiratory tract infections (saleem, rani, & daniel, ; shuman, raju, & jogdeo, ; singh, singhi, & walia, ). furthermore, fumigating living rooms with medicated smoke from burnt neem leaves has also been shown to be effective in combating the virus (khedekar, goel, & ojha, ) . taken together, the prophylactic measures to protect against coronaviruses could include avoiding cold beverages, boiling/or uv-based sterilization of drinking water. the spike protein (s-protein) of sars-cov- virus recognizes and binds to the angiotensin-converting enzyme (ace , figure ) on bronchial and alveolar epithelial cells and vascular endothelial cells (zhang, penninger, li, zhong, & slutsky, ) . the viral membrane fuses with the host membrane, and the viral rna along with nucleocapsid proteins is released and replicated further in the host cells. the viral infection triggers apoptosis of epithelial and endothelial cells leading to secretion of inflammatory cytokines, il- β, il- , il- , tnf-α, and ifn-γ, that destroy the host cells (fu, cheng, & wu, ) . sars cov papain-like protease (plpro) upregulates the expression of tgf-β , a profibrotic cytokine (li et al., ) . the activation of tgf-β by proteolytic cleavage of its latent complex form is carried out by mmp- and mmp- (kobayashi et al., ; wang et al., ) . interestingly, as shown in figure , the bioactive compounds inhibit tgf-β activation by suppressing these mmps kumar, kumar, saravanan, & singh, ) . tgf-β induces proliferation of fibroblasts and their differentiation into myofibroblasts that secrete extracellular matrix (ecm) leading to fibrosis michalik et al., ) . in the canonical pathway, tgf-β phosphorylates the downstream effector proteins smad and smad that further activate the expression of pro-fibrotic proteins namely fibronectin, collagen type i/iii, α-sma, and vimentin (malmström et al., ) . the bioactive compounds inhibit the phosphorylated smad and smad , and enhance the expression of smad (a tgf-beta antagonist), leading to downstream suppression of fibroblast proliferation and their differentiation into myofibroblasts, as well as inhibition of pro-fibrotic gene expression (nie et al., ; smith et al., ) . in the non-canonical pathway, tgf-β activates p mitogenactivated protein kinase (mapk) that induces epithelial to mesenchymal transition (emt) zhang, (huang, ; park, kim, & lee, ). the non-structural proteins (nsp , nsp a, and nsp a) and spike proteins of sars-cov activates nf-κb, resulting in the inflammatory response and ros, which further drives the pathogenesis (liao et al., ) . s protein also degrades iκb-α, resulting in activation of nf-κb, that further upregulates tnf-α and il- (dediego et al., ; wang et al., ) . bioactive compounds inhibit expression of tnf-α and enhance iκb-α expression, together leading to suppression of nf-κb-mediated expression of inflammatory cytokines and chemokines. these compounds also have direct inhibitory effect on ros and inflammatory cytokines and enhance the expression of antioxidants. it has also been shown that the sars-cov virus downregulates the ace expression, and this could further trigger acute lung injury (glowacka et al., ; kuba et al., ) . covid- causes acute respiratory tract infections, pulmonary fibrosis, sepsis, and multiple organ failure, all of which could result in mortality. study on the severity and progression of covid- suggests that, among the patients who died, % had shortness of breath and % had expectoration. this implies that underlying pathogenesis like the initiation of fibrosis and alveolar damage might begin early during the - days of incubation period after exposure to the virus. natural products taken during these initial stages of viral infection could prevent further progression of the infection and stabilize the initial symptoms. furthermore, among the patients who died, around % had ards, suggesting that the major cause of mortality was the acute lung infection, pulmonary fibrosis and pneumonia. natural products that are effective against these pulmonary conditions could be beneficial supplements to promote the recovery of patients showing these advanced covid- -related symptoms. considering the widespread global outbreak of covid- , controlled clinical trials might not be feasible. in some clinical settings, antimalarial, retroviral drugs, and corticosteroids are being repurposed and are showing adverse side effects. in this context, given the therapeutic efficacy of many of the natural products, these could be administered in combination with the clinical standard of care to mitigate treatment-related side effects. importantly, unlike chemotherapeutic supplements, natural products have no adverse effects. in summary, natural products have shown therapeutic efficacy against multiple symptoms observed in advanced covid- patients. they are highly tolerated with no side effects and can be used in combination with existing clinical standard of care. in this setting, natural products have the potential to serve as prophylactic agents in populations that are at risk to develop covid- infection. these include elderly individuals as well as those who have underlying comorbid conditions. in addition, in symptomatic patients, natural product supplementation can halt the progression of the infection. in the case of patients who have progressed to an advanced stage, natural products can mitigate many of the complications and reduce mortality. importantly, natural product supplementation constitutes homebased remedies that are inexpensive and can be easily implemented on a community-wide scale. the authors declare no conflicts of interest. sai manohar thota conceptualized, designed, searched databases/ articles, and wrote the manuscript. venkatesh balan and venketesh sivaramakrishnan contributed to manuscript writing and provided scientific guidance. dedicated to india and her traditional medicine system-ayurveda. sai manohar thota https://orcid.org/ - - - venkatesh balan https://orcid.org/ - - - venketesh sivaramakrishnan https://orcid.org/ - - - epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (covid- ) during the early outbreak period: a scoping review treatment outcomes for patients with middle eastern respiratory syndrome coronavirus (mers cov) infection 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against bleomycin-induced pulmonary fibrosis by inhibiting tgf-β /smad pathways and overexpression of nox antifibrotic effects of curcumin are associated with overexpression of cathepsins k and l in bleomycin treated mice and human fibroblasts angiotensin-converting enzyme (ace ) as a sars-cov- receptor: molecular mechanisms and potential therapeutic target histopathologic changes and sars-cov- immunostaining in the lung of a patient with covid- preventive effects of rhodiola rosea l. on bleomycin-induced pulmonary fibrosis in rats quercetin ameliorates pulmonary fibrosis by inhibiting sphk /s p signaling non-smad pathways in tgf-β signaling gastrodin protects against lps-induced acute lung injury by activating nrf signaling pathway neferine, a bisbenzylisoquinline alkaloid attenuates bleomycininduced pulmonary fibrosis effects of andrographolide on the concentration of cytokines in balf and the expressions of type i and iii collagen mrna in lung tissue in bleomycin-induced rat pulmonary fibrosis protective role of andrographolide in bleomycin-induced pulmonary fibrosis in mice procyanidins and butanol extract of cinnamomi cortex inhibit sars-cov infection natural products as home-based prophylactic and symptom management agents in the setting of covid- the authors thank prof. arun sreekumar, baylor college of medicine, houston, texas, usa, for careful and insightful review of the manuscript. mr. thota and dr. sivaramakrishnan thank central research key: cord- -xenq xj authors: chen, hsing i title: acute lung injury and acute respiratory distress syndrome: experimental and clinical investigations date: - - journal: j geriatr cardiol doi: . /sp.j. . . sha: doc_id: cord_uid: xenq xj acute lung injury (ali) or acute respiratory distress syndrome (ards) can be associated with various disorders. recent investigation has involved clinical studies in collaboration with clinical investigators and pathologists on the pathogenetic mechanisms of ali or ards caused by various disorders. this literature review includes a brief historical retrospective of ali/ards, the neurogenic pulmonary edema due to head injury, the long-term experimental studies and clinical investigations from our laboratory, the detrimental role of no, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ali/ards. acute lung injury (ali) or acute respiratory distress syndrome (ards) is a serious clinical problem with high mortality. [ ] in animals and humans, ali can be induced by various causes such as brain injury, [ ] [ ] [ ] [ ] enterovirus, [ , ] japanese b encephalitis, [ ] and coronavirus. [ , ] the risk factors for ards included septicemia, acid aspiration, infection, traumatic injury, fat embolism, ischemia/ reperfusion, and other caused. [ , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] our cardiopulmonary laboratory has carried out experimental studies and clinical investigations on ali and ards since . [ ] [ ] [ ] , , ] the purposes of this review article are: ( ) to describe in brief the historical perspective of ards and ali; ( ) to draw attention of an important clinical issue of neurogenic ali; ( ) to present the experimental studies and clinical investigations from our laboratory from to ; ( ) to elucidate the functional role of nitric oxide (no) and other mediators involved in the pathogenesis of ards/ali; ( ) to define the risk factors for ards and ali; and ( ) to discuss the pathogenetic mechanisms and therapeutic regimen for ards/ali. ali or pulmonary embolism (pe) has been reported in humans and animals with intracranial disorders such as head trauma, brain tumor, intracranial hypertension or cerebral compression. early studies in our laboratory demonstrated that acute pe of hemorrhagic and fulminant type occurred accompanying severe hypertension and bradycardia (cushing responses) in rats following cerebral compression (cc) or intracranial hypertension (ich). the lung pathology was characterized by intravascular congestion and disruption of pulmonary large and small vessels leading to severe alveolar hemorrhage (alveolar flooding). these changes was prevented by spinal transection, sympathectomy and sympathoadrenergic blocking agents, but was not affected by decerebration, adrenalectomy, vagotomy and atropine. these results suggest that sympathetic nervous system is pivotal in the neurogenic pe. brain areas above the medulla oblongata and parasympathetic nervous system play little role. [ ] a series of studies was carried out to elucidate the hemodynamic events involved in the neurogenic pe. in anesthetized rats, we measured the aortic and pulmonary blood flow and used techniques of right and left heart bypass. the imbalance in the right and left ventricular output was characterized by a rapid and dramatic decline in aortic flow accompanying a gradual decrease in pulmonary arterial flow. in rats with a right heart bypass, ich produced severe pulmonary hypertension and pe. in the left heart-bypassed rats, ich induced systemic hypertension, http://www.jgc .com; jgc@mail.sciencep.com | journal of geriatric cardiology whereas no significant changes occurred in the lungs. [ ] in anesthetized dogs with a total heart bypass preparation, ich produced constriction of the systemic and pulmonary resistance and capacitance vessels. [ ] [ ] [ ] [ ] the implications of these findings are: ( ) central sympathetic activation elicits increase in the systemic and pulmonary vascular resistance associated with decreases in vascular capacity in both circulations; ( ) the major cause of volume and pressure loading in the pulmonary circulation is acute left ventricular failure resulting in a marked decrease in aortic flow; and ( ) systemic venous constriction causes a shift of blood from the systemic to the pulmonary circulation ( figure ) . a schematic representation summarizes the neural and hemodynamic consequence caused by cerebral compression (figure ). spectral analysis of the aortic flow and pressure wave was employed to evaluate the hemodynamics of steady and pulsatile components. in anesthetized dogs, ich caused significant increases in characteristic impedance, pulse wave reflection and total peripheral resistance with decrease in arterial compliance and cardiac output. the ventricular work was elevated. [ ] clinical study in patients with head injury of various severities, analysis of the heart rate variability with frequency analysis revealed increased low frequency percentage, and low to high frequency ratio with decrease in high frequency. the findings indicate augmented sympathetic and attenuated parasympathetic drive. these autonomic functional changes were related to the severity of brain-stem damage. [ ] these two studies further support the contention that central sympathetic activation is involved in the cushing pressor response and consequent hemodynamic and autonomic alterations. in s, my associates and i were interested in the study of chest disorders. we developed an isolated perfused rat's lung in situ preparation ( figure ). previous method involved removing the isolated lungs from the body and placing the organ on a force-displacement transducer to record the changes in lung weight and these procedures were rather complicated and unstable. our in situ preparation does not require removing the lungs. instead, the isolated lungs were left in situ. the whole rat was placed in a scale platform to measure the change in body weight (bw). since the lungs are completely isolated from the body, the changes in bw reflect the lung weight (lw) changes. the preparation can be accomplished in min. we used a digital-analogue converter to transfer the weight change from the scale platform to a recorder. the lw thus could be continuously monitored during the experiment. in this model, we can obtain the lung weight gain, lw/bw ratio, the changes in pulmonary arterial, capillary and venous pressures, the microvascular permeability (capillary filtration coefficient, k fc ), protein concentration in bronchoalveolar lavage (pcbal), dye leakage, and exhaled nitric oxide (no). the concentration of nitrate/nitrite, methyl guanidine (an index for hydroxyl radical), proinflammatory cytokines [tumor necrosis factor α (tnf α ) and interleukin- β (il- β )] and other factors in the lung perfusate can also be detected. early animal experimentations investigated the pathogenesis, modulators and mediators involved in the ali induced by phorphol, air embolism, platelets, hypoxia, ischemia/reperfusion, endotoxin [lipopolysaccharide (lps)]. the major finding is that cyclooxygenase products of arachidonic acid, thromboxane a in particular is involved in the ali and pulmonary hypertension caused by phorbol, platelets and air embolism. [ , ] furthermore, we found that l-arginine and inhaled no enhanced the lung injury caused by air embolism, while blockade of no synthase (nos) with n ω -nitro-l-arginine methyl ester (l-name) attenuated the ali. [ ] the result suggests that no is also involved. during the summers from  , we encountered a total of children suffering from hand, foot, and mouth figure . isolated and perfused lung in situ preparation. the system consists of a perfusion pump with heat exchanger and a venous reservoir. the rat is artificially ventilated. pulmonary arterial pressure (pap) and venous pressure (pvp) are monitored with transducers. the whole rat is placed on a balance platform to record the body weight change. since the lung is isolated from the whole body, the change in body weight reflects the lung weight change. disease. [ ] chest radiography on admission revealed clear lung. however, out of cases developed severe dyspnea, hyperglycemia, leukocytosis, and decreased blood oxygen tension. arterial pressure (ap) and heart rate (hr) fluctuation ensued. spectral analysis of the ap and hr variabilities showed elevation in sympathetic activity at the onset of respiratory stress. thereafter, parasympathetic drive increased with declines in ap and hr. these children died within h after the onset of ards. before death, chest radiography revealed severe lung infiltration. similar to japanese b encephalitis, destruction of the medullary depressor area caused initial sympathetic activation. reversetranscriptase polymerase chain reaction (rt-pcr) found marked inos mrna expression in the lung parenchyma, suggesting inos may also be involved in the pathogenesis of ards in patients with enterovirus infection. furthermore, we have reported ards in patients with leptospirosis. [ ] in leptospirosis-induced ards, histochemical stain demonstrated spirochetes bacteria in the alveolar space. the pathology included alveolar hemorrhage, myocarditis, portal inflammation and interstitial nephritis. antigen retrieval immunohistochemical stain disclosed inos expression in the alveolar type cells, myocardium, hepatocytes and renal tubules. spectral analysis of ap and hr variabilities indicated decreased sympathetic drive with increased parasympathetic activity. the changes in autonomic functions led to severe hypotension and bradycardia. biochemical determinations suggested multiple organ damage. the pathogenesis of lung and other organ injury might also involve inos and no production. [ , ] in subjects with scrub typhus, orientia tsutsugamushi infection caused alveolar injury. marked inos expression was found in the alveolar macrophages with increase in plasma nitrate/nitrite, suggesting that no production from the alveolar macrophages accounts for the ali. [ ] the victim from rabies was a woman bitten by a wild dog. in addition to sign of hydrophobia, hypoxia, hypercapnia, hyperglycemia and increased plasma nitrate/nitrite were observed. the woman died of alveolar hemorrhage shortly after admission. [ ] recently, we encountered five cases with long-term malignancy. these subjects displayed signs of respiratory distress following an episode of hypercalcemia. two cases died of ards after the plasma calcium was increased above mmol/l. search of literatures revealed that holmes et al. [ ] reported a patient who died of ards following a hypercalcemia crisis caused by a parathyroid adenoma. we conducted animal experiments in whole rodent and isolated perfused rat's lungs. our results indicated that hypercalcemia (calcium concentration > mmol/l) caused severe ali in conscious rats and isolated lungs. immunohistochemical staining showed inos activity in the alveolar macrophages and epithelial cells. reversetranscriptase polymerase chain reaction (rt-pcr) found marked increase in inos mrna expression in lung parenchyma. hypercalcemia also increased nitrate/nitrite, methyl guanidine, proinflammatory cytokines and procalcitonin. pretreatment with calcitonin or l-n ( iminoethyl)-lysine (l-nil, an inos inhibitor) attenuated the hypercalcemia-induced changes. we proposed that hypercalcemia produced a sepsis-like syndrome. the ali caused by hypercalcemia may involve no and inos. [ , ] in addition to the aforementioned animal experimentations and clinical observations that no production through the inos may be involved in the lung injury due to various causes, our research team demonstrated that endotoxemia produced in anesthetized rats by intravenous administration of lipopolysaccharide (lps, endotoxin) provoked systemic hypotension, endothelial damage and ali accompanied by increased plasma nitrate/nitrite and expression of inos mrna, tnf α and il- β . the lps-induced changes were abolished by nonspecific and specific inos inhibitors such as n ω -monomethyl-l-arginine (l-nmma), l-name, aminoguanine and dexamethosone. [ ] this study suggested that no/inos, tnf α and il- β were involved in the endotoxemia-induced ali. generation of no from the activated neutrophil caused alveolar injury from smoke inhalation. [ ] experiments in many laboratories using specific inos inhibitors and/or inos-knockout animals have supported the contention that no/inos is responsible for the oxidative stress and endothelial damage in the ards/ali caused by endotoxin, ozone exposure, carrageenan treatment, hypoxia, acute hyperoxia, bleomaycin administration, acid aspiration and other causes. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] our laboratory further provided evidence to suggest that the no/inos system is involved in the pathogenesis of ali caused by air embolism, [ ] fat embolism, [ ] [ ] [ ] ischemia/ reperfusion, [ ] [ ] [ ] oleic acid [ ] and phorbol myristate acetate. [ ] in these recent studies, various insults caused increase in nitrate/nitrite in plasma or lung perfusate, upregulation of inos mrna in lung parenchyma accompanied with elevation of proinflammatory cytokines such as tnf α , il- β and il- . lin et al. [ ] have suggested that an increase in inos mrna triggers the release of proinflammatory cytokines in septic and conscious rats. the inflammatory responses results in multiple organ damage including ali. inhibition of inos with s-methylisothiourea (smt) or l-nil attenuated the inflammatory changes, release of no and cytokines and prevented the organ dysfunction and ali. [ ] in animal experiments and clinical investigations, the risk factors causing ali/ards include head injury, intracranial hypertension, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] sepsis, [ , , , , , , , [ ] [ ] [ ] [ ] and infections. [ ] [ ] [ ] [ ] [ ] [ ] , , [ ] [ ] [ ] ] pulmonary embolic disorders journal of geriatric cardiology | jgc@mail.sciencep.com; http://www.jgc .com such as fat and air embolism are less common causes. [ , , , , [ ] [ ] [ ] ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as pulmonary artery thromboendarterectomy, thrombolysis after pulmonary embolism and lung transplantation. [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] gastric aspiration occurs frequently in surgical patients under anesthesia and other causes such as blunt thoracic trauma, impaired glottis competency, and pregnancy. [ , , ] it is one of the major causes of acute respiratory syndrome (ards). [ , ] intratracheal instillation of hydrochloric acid (hci) or gastric particles has been employed as experimental model of acute lung injury (ali). [ , [ ] [ ] [ ] in addition, amphetamine, phorbal myristate acetate, oleic acid have been employed for the induction of ali. [ ] [ ] [ ] [ ] [ ] phorbol myristate acetate (pma, -o-tetradecanoyl-phorbol- -acetate), an ester derivative from croton oil has been used to induce ali. [ , , , ] experiments in vivo and in vitro have demonstrated that pma is a strong neutrophil activator. [ ] [ ] [ ] [ ] activation and recruitment of neutrophil that lead to release of neutrophil elastase and other mediators may play an initial role in the pathogenesis of ali. [ , ] the oleic acid-induced ali has several clinical implications. first, the blood level of oleic acid was significantly elevated in patients with ards. [ , ] second, the proportion of oleic acid incorporated into surfactant phospholipids was also increased in patients with ards and sepsis. [ , ] these observations have provided evidence to suggest that serum level of oleic acid as a prediction or prognostic factor for ards. [ , ] early studies focused on the potential toxic effects of high oxygen fractions on inspired air. [ ] ventilator-induced ali was attributed to the deleterious effects on capillary stress due to alveolar overdistension. cyclic opening and closing of atelectatic alveoli during mechanical ventilation might cause lung injury and enhance the injured alveoli. recent evidence indicated that over distension coupled with repeated collapse and reopening of alveoli initiated an inflammatory cascade of proinflammatory cytokines release. [ , [ ] [ ] [ ] in spite of the risk factors and causes, the pathophysiology of ards/ali has generally considered to be initiated by formation of alveolar edema (even hemorrhage) that is enriched with protein, inflammatory cells or red blood cells. after damage of alveolar-capillary barrier, impairment of gas exchange occurs, with decrease in lung compliance and increases in dispersion of ventilation and perfusion and intrapulmonary shunt. hypoxia, reduction in arterial oxygen partial pressure to fraction of oxygen in inspired air pao /fio , hypercapnia ensued despite ventilation with high oxygen. [ , , , , , ] in addition to the potential toxic effects of no and free radicals, certain chemokines, cytokines, neutrophil elastase, myeloperoxidase and malondialdehyde have been shown to be associated with several types of ards/ali. [ , , , , [ ] [ ] [ ] the balance between proinflammatory and anti-inflammatory mediators is regulated by transcriptional factors mainly nuclear factor-Κ b (nf-Κ b). [ ] pulmonary fluid clearance and ion transport are important factors to determine the extent of lung edema. regulator factors include cystic fibrosis transmembrane conductance regulators, sodium-and potassium-activated adenosine triphophatase (na + -k + -atpase), protein kinases, aclenylate cyclase, and cyclic adenosine monophosphate (camp). [ , , , ] the treatment of ards/ali is difficult and complex. several review articles and monographs have addressed the issue of possible therapeutic regimen. the modalities include extracorporeal membrane oxygenation, prone position, mechanical ventilation with appropriate tidal volume and respiratory pressure, fluid and hemodynamic management and permissive hypercapnic acidosis. [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] other pharmacological treatments are anti-inflammatory and/or antimicrobial agents to control infection and to abrogate sepsis, adequate nutrition, surfactant therapy, inhalation of no and other vasodilators, glucocorticoids and other nonsteroid anti-inflammatory drugs, agents that accelerate lung water resolution and ion transports. [ , , [ ] [ ] [ ] [ ] [ ] although most animal experimentations on these pharmacological options showed favorable results, the effectiveness and outcomes in clinical studies or trials were conflicting. beta agonists to facilitate water removal and ion transport have been shown to be promising. these agents may also stimulate secretion of surfactant and have no serious side effects. there were several reports on the pharmacological and molecular actions of beta agonists, surfactant and vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme (ace). [ , , ] in addition to the experimental studies and clinical investigations on the pathogenesis of ali/ards, our laboratory has carried out several experimentations on the therapeutic regimen for this serious disorder. in conscious rats, regular exercise training attenuates septic responses such as systemic hypotension, increases in plasma nitrate/nitrite, methyl guanidine, blood urea nitrogen, creatinine, amylase, lipase, asparate aminotransferase, alanine aminotransferase, creatine phosphokinase, lactic dehydrogenase, tnf α, and il β . exercise training also abrogates the cardiac, hepatic and pulmonary injuries caused by endotoxemia. [ ] insulin exerts anti-inflammatory effects on the ali and associated biochemical changes following intravenous administration of lipopolysaccharide (lps). [ ] propofol ( , -diisopropylphenol) has been commonly used for sedation in critically ill patients. [ ] this anesthetic has rapid onset, short duration and rapid elimination. [ ] propofol protects the anesthetized rats from ali caused by endotoxin. [ ] in conscious rats, oleic acid results in sepsis-like responses including ali, inflammatory reactions and increased in neutrophil-derived factors (neutrophil elastase, myeloperoxidase and malondialdehyde), nitrate/nitrite, methyl guanidine, inflammatory cytokines. it depresses the sodium-and potassium-activated atpase, but upregulates the inos mrna expression. pretreatment and posttreatment with propofol alleviates or reverses the oleic acid-induced lung pathology and associated biochemical changes. [ ] pentobarbital, an anesthetic agent commonly used in experimental studies and a hypnotic for patients improves the pulmonary and other organ functions following lps administration. it also increases the survival rate. [ ] a later study by yang et al. [ ] further revealed that pentobarbital suppressed the expression of tumor necrosis factor α , which might result from decrease in the activities of nuclear factor-κβ and activator protein and reduction in expression of p mitogen-activated protein kinase. in vivo examination of cytotoxic effects of lps disclosed that lps caused multiple organ dysfunctions. these changes were attenuated by pentobarbital. pentobarbital also reduced the cell aptosis caused by deforoxamine-induced hypoxia. nicotinamide or niacinamide (compound of soluble b complex) abrogates the ali caused by ischemic/reperfusion or endotoxin by mechanism through inhibition on poly (adp-ribose) synthase or permerase cytoxic enzyme and subsequent suppression of inos, no, free radicals and proinflammatory cytokines with restoration of adenosine triphosphate atp. [ , ] n-acetylcysteine, an antioxidant and cytoprotective agent with scavenging action on reactive oxygen species and inhibitory effects on proinflammatory cytokines ameliorated organ dysfunctions due to sepsis in conscious rats. [ , ] in a similar endotoxin-induced ali model, we found that n-acetylcysteine improved the lps-induced systemic hypotension and leukocytopenia. it also reduced the extent of ali, as evidenced by reductions in lung weight changes, exhaled no and lung pathology. in addition, n-acetylcysteine diminished the lps-induced increases in nitrate/nitrite, tnf α , and il β [ ] in isolated lungs, n-acetylcysteine attenuated the ali caused by phorbol myristate acetate. [ ] in a recent study, we reported that posttreatment with n-acetylcysteine prevented the ali caused by fat embolism. [ ] our series of experimental studies provided results in favor of n-acetylcysteine. the conflicting results and practice guidelines from clinical studies in the recommendation of n-acetylcysteine in critically ill patients [ , ] were commented and analyzed by molnár. [ ] the clinical application of results from animal studies requires further investigations. ards or ali is a serious clinical problem with high mortality. the risk factors leading to ali/ards include head injury, intracranial disorders, sepsis and infections. pulmonary embolic disorders such as fat and air embolism are less common causes. ischemia/reperfusion lung injury may develop as a consequence of several pulmonary disorders such as lung transplantation. gastric aspiration occurs frequently in several conditions such as anesthesia, trauma and pregnancy. the ventilator-induced ali has been attributed to the deleterious effects on capillary stress due to alveolar overdistension. in experimental studies, phorbol myristate acetate and oleic acid have been employed to induce ali. the pathogenesis of ards/ali is complex. experimental studies and clinical investigations from our and other laboratories have indicated the detrimental role of nitric no through inducible no synthase (inos). activation and recruitment of neutrophils that lead to release of neutrophil elastase, myeloperoxidase, malondialdehyde and proinflammatory cytokines may play an initial role in the pathogenesis of ali/ards. the possible therapeutic regimen for ali/ards include extracorporeal membrane oxygenation, prone position, fluid and hemodynamic management and permissive hypercapnic acidosis etc. other pharmacological treatments are antiinflammatory and/or antimicrobial agents, inhalation of no, glucocorticoids, surfactant therapy and agents that facilitate lung water resolution and ion transports. adrenergic beta agonists are able to accelerate lung fluid and ion removal and to stimulate surfactant secretion. there are reports on the actions of vascular endothelial growth factor and related molecules as well as angiotensin-converting enzyme. our laboratory has reported experimental studies on the effectiveness of several regimen for ali/ards. in conscious rats, regular exercise training 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distress syndrome inhaled nitric oxide therapy in adults exercise training attenuates septic responses in conscious rats vascular endothelial growth factor and related molecules in acute lung injury angiotensin-converting enzyme protects from severe acute lung failure insulin attenuates endotoxin-induced acute lung injury in conscious rats comparison of propofol and midazolam for sedation in critically ill patients an update of its use in anaesthesia and conscious sedation the reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model n-acetylcysteine ameliorates lipopolysaccharide-induced organ damage in conscious rats post-treatment with n-acetylcysteine ameliorates endotoxin shock-induced organ damage in conscious rats n-acetylcysteine treatment to prevent the progression of multisystem organ failure: a prospective, randomized, placebo-controlled study antioxidant supplementation in sepsis and systemic inflammatory response syndrome n-acetylcysteine as the magic bullet: too good to be true experimental studies and clinical investigations were supported in part by grants from the "national science council". the grant no. this fiscal year is nsc - -b- - -my . the author is grateful to ms. s. y. huang for the assistance in typing an editing. i appreciate the long-term coworkers involved this and other studies in my laboratory. key: cord- -vsxe xs authors: alves, amanda mandarino; yvamoto, erika yuki; marzinotto, maira andrade nacimbem; teixeira, ana cristina de sá; carrilho, flair josé title: sars-cov- leading to acute pancreatitis: an unusual presentation date: - - journal: braz j infect dis doi: . /j.bjid. . . sha: doc_id: cord_uid: vsxe xs during sars-cov- (severe acute respiratory syndrome coronavirus- ) pandemic, the etiologic agent of covid- , several studies described the involvement of other tissues besides the respiratory tract, such as the gastrointestinal tract. angiotensin-converting enzyme- , the functional virus host cell receptor expressed by organs and tissues, seems to have an important role in the pathophysiology and presentation of this disease. in pancreas, this receptor is expressed in both exocrine glands and islets, being a potential target for the virus and subsequent pancreatic injury. there are few articles reporting pancreatic injury in covid- patients but most of them do not report acute pancreatitis. diagnosing acute pancreatitis secondary to sars-cov- infection is challenging due to the need to rule out other etiologies as well the notable heterogeneous presentations. herein we report the case of a patient with covid- who developed severe acute pancreatitis. sars-cov- (severe acute respiratory syndrome coronavirus- ), the etiologic agent of covid- pandemic, has spread rapidly worldwide since december . despite the infection primarily affecting the respiratory tract, gastrointestinal involvement has been reported in an increasing number of patients, with symptoms such as nausea, vomiting, diarrhea, abdominal pain and gastrointestinal bleeding [ ] . laboratory abnormalities such as hepatic and pancreatic j o u r n a l p r e -p r o o f injury have been evident in a subset of patients, although it remains unclear if these abnormalities have any impact on prognosis [ , ] . the more common causes of acute pancreatitis are gallstones and alcohol abuse, however viral-induced acute pancreatitis has also been described [ ] . angiotensin-converting enzyme- (ace ), the functional virus host cell receptor, expressed in both exocrine and endocrine pancreatic cells, plays a role in this disease process. the mechanisms of pancreatic injury in sars-cov- infection include direct cytopathic effects or indirect systemic inflammatory and immune-mediated cellular responses, resulting in organ damage or secondary enzyme abnormalities [ ] . this case report describes a patient with covid- that developed severe acute pancreatitis. a -year old female presented at the emergency department with dry cough, dyspnea, general malaise and epigastric pain which had persisted for a couple of days. comorbidities included only hypertension treated with losartan and hydrochlorothiazide. the patient reported minimal alcohol intake and did not smoke. on initial examination, the patient was hemodynamically stable and presented only with tachypnea ( breaths/min). chest radiography showed diffuse interstitial opacities. she was admitted to an inpatient unit, but her condition worsened over the first seven days showing signs of acute respiratory distress, being transferred to the intensive care unit and required mechanical ventilation for six days. she received intravenous antibiotics; however inotropic drugs were not plasma level of triglycerides was mg/dl and calcium level was normal ( . mg/dl). an endoscopic ultrasound was performed, after complete recovery from respiratory symptoms and after two negative results for rt-pcr, showing no microlithiasis. other causes of acute pancreatitis such as drugs, trauma and hypotension were excluded, and the patient was discharged after days of hospitalization without any long-term sequelae. initially reported as a respiratory tract pathogen, sars-cov- has been identified in many other tissues, such as the cardiovascular, renal and gastrointestinal tract, similar to sars-cov in [ , ] . both viruses have ace as the functional host cell receptor, enabling virus entry and replication [ , , ] . however, different from sars-cov, sarscov- does not use other receptors such as aminopeptidase n and dipeptidyl peptidase [ ] , being more selective. furthermore, sars-cov- has higher affinity to ace when compared to sars-cov, being more pathogenic [ ] and increasing the ability of community transmission [ ] . ace is abundantly expressed in many different tissues, justifying the involvement of different organs and extrapulmonary symptoms of those diseases [ , , ] . the expression of ace in the gastrointestinal tract during sars-cov- infection leads to digestive system dysregulation [ ] . symptoms like nausea, vomiting and diarrhea have commonly been described in % to % of cases [ , , ] . gastrointestinal findings are significant due to their association with adverse outcomes such a delayed hospital admission and evidence of more laboratory changes, including prolonged coagulation time [ ] . in addition to gastrointestinal symptoms, some blood abnormalities were found in severe patients, such as increased pancreatic enzymes [ , , , ] , suggesting pancreatic injury. in spite of gallstones and alcohol abuse being reported as the more common causes of acute pancreatitis, infectious agents, especially virus, are responsible for approximately % of cases [ ] , such as mumps, cytomegalovirus and influenza [ , ] . therefore, it is likely to consider sars-cov- as a potential cause of pancreatitis. curiously, in a recent study published by schepis et al., sars-cov- rna was detected in a pancreatic pseudocyst sample endorsing pancreatic involvement in covid- [ ] . furthermore, the mrna level of ace in pancreas was shown to be higher than in lung and expressed in both the exocrine glands and islets, being potential targets of sars-cov- , resulting in pancreatic injury [ ] . although the density of ace in pancreatic tissue is still controversial [ , , ] and has individual variation [ ] , higher mrna ace density, during those virus infections, may signal greater predisposition to trigger acute pancreatitis [ ] . ace receptor is highly expressed in pancreatic islet cells [ ] , therefore sars-cov- infection can theoretically cause islet damage resulting in acute diabetes [ ] . the patient in this case presented increased blood glucose levels, as found in six of nine patients with pancreatic injury in another study [ ] . dysglycemias were already observed with sars-cov [ ] and may alter disease prognosis, since diabetes and ambient hyperglycemia were independent predictors for death and morbidity in sars patients [ , ] . fortunately, a minority of these patients progressed to diabetes three years after hospital discharge [ ] . findings, as well as to report the presence of pancreatitis symptoms, making it difficult to establish an acute pancreatitis diagnosis. according to the current guidelines [ ] , diagnosis of acute pancreatitis requires at least two of the three following signs: ) abdominal pain, ) amylase or lipase > times the upper normal limit, and ) characteristic findings on diagnostic imaging. in the first study, conducted by wang, et al., nine out of patients ( %) had pancreatic enzyme abnormalities, with any change above the upper limit of normality being considered, and six of them ( %) also had hyperglycemia. no imaging tests were described, nor whether any of the patients had criteria for acute pancreatitis. patients with pancreatic injury had a higher incidence of gastrointestinal symptoms, such as diarrhea and anorexia, in addition to severe disease on admission. when compared with patients without pancreatic injury, there was no difference regarding mechanical ventilation or viral clearance [ ] . regarding tomographic changes, . % had some pancreatic finding. however, this article also did not describe whether any of these patients had criteria for acute pancreatitis, nor did report if serum values of amylase and lipase from those patients were associated with imaging changes [ ] . those articles demonstrated how asymptomatic or mildly gastrointestinal symptomatic patients with covid- and pancreatic enzymes abnormalities could be overlooked and acute pancreatitis underdiagnosed. herein we presented a patient with acute pancreatitis suspected due to altered pancreatic enzymes, with little or no gastrointestinal symptoms, and with subsequent diagnosis confirmed by ct scans. similar to this case, anand et al. diagnosed acute pancreatitis in a covid- patient by examining the ct scan, which was ordered due to suspected bowel obstruction [ ] . the notable heterogeneous presentation and the need to rule out other main etiologies, due to this rare association, are some of the challenges in the diagnosis. sars-cov- seems to have some tropism for pancreatic (exocrine and endocrine) cells, causing acute pancreatitis. physicians should be aware that asymptomatic or mildly gastrointestinal symptomatic patients with covid- require pancreatic enzymes and even abdomen imaging to diagnose pancreatitis. this diagnosis is important for adequate treatment and better management of systemic repercussions, such as sirs, decreasing sars-cov- mortality. this study was a case report study, patient identity remained anonymous, and the informed consent was obtained. be published, and agree to be accountable for all aspects of the work. no funding. the authors declare no conflicts of interest. gastrointestinal, hepatobiliary, and pancreatic manifestations of covid- review article: covid- and liver disease-what we know on st pancreatic injury patterns in patients with coronavirus disease pneumonia acute pancreatitis sars-cov- and the pathophysiology of coronavirus disease (covid- ) physiological and pathological regulation of ace , the sars-cov- receptor ace expression in pancreas may cause pancreatic damage after sars-cov- infection a pneumonia outbreak associated with a new coronavirus of probable bat origin receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus clinical characteristics of covid- patients with digestive symptoms in hubei, china: a descriptive, cross-sectional, multicenter study epidemiological, clinical and virological characteristics of cases of coronavirus-infected disease (covid- ) with gastrointestinal symptoms clinical characteristics of patients infected with sars-cov- in wuhan infectious causes of acute pancreatitis influenza a viruses grow in human pancreatic cells and cause pancreatitis and diabetes in an animal model sars-cov rna detection in a pancreatic pseudocyst sample binding of sars coronavirus to its receptor damages islets and causes acute diabetes plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with sars acute pancreatitis classification working group. classification of acute pancreatitis- : revision of the atlanta classification and definitions by international consensus we thank dr. sergio matuguma for performing the ecoendoscopy exam. we thank dr.joao marcos wolf maciel for providing the radiographic images. we thank mr. timothy finian coyne for reviewing the english version. key: cord- -jck zq authors: cheung, oi-yee; graziano, paolo; smith, maxwell l. title: acute lung injury date: - - journal: practical pulmonary pathology: a diagnostic approach doi: . /b - - - - . - sha: doc_id: cord_uid: jck zq a wide variety of insults can produce acute lung damage, inclusive of those that injure the lungs directly. the clinical syndrome of acute onset respiratory distress, dyspnea, and bilateral infiltrates is referred to as acute respiratory distress syndrome. the histologic counterpart of acute respiratory distress syndrome is diffuse alveolar damage, classically characterized by hyaline membranes. other histologic features of acute lung injury include intraalveolar fibrin, organization, interstitial edema, and reactive pneumocytes. diffuse alveolar damage and other histologic features of acute lung injury are nonspecific as to etiology, and once identified require the pathologist to search the biopsy for further features that may help identify a specific etiology. this chapter reviews the temporal sequence of acute lung injury and explores the large variety of specific etiologic causes with emphasis on helpful histologic features to identify. resultant endothelial and alveolar epithelial cell injury is attended by fluid and cellular exudation. subsequent reparative fibroblastic proliferation is accompanied by type ii pneumocyte hyperplasia. , the microscopic appearance depends on the time interval between insult and biopsy and on the severity and extent of the injury. dad is the usual pathologic manifestation of ards and is the best-characterized prototype of acute lung injury. from studies of ards, the pathologic changes appear to proceed consistently through discrete but overlapping phases ( fig. . )-an early exudative (acute) phase ( fig. . a and b) , a subacute proliferative (organizing) phase ( fig. . c) , and a late fibrotic phase ( fig. . ). , , , , the exudative phase is most prominent in the first week of injury. the earliest changes include interstitial and intraalveolar edema with variable amounts of hemorrhage and fibrin deposition ( fig. . ). hyaline membranes (fig. . ), the histologic hallmark of the exudative phase of ards, are most prominent at to days after injury (eslide . ). minimal interstitial mononuclear inflammatory infiltrates ( fig. . ) and fibrin thrombi in small pulmonary arteries (fig. . ) also are seen. type ii pneumocyte hyperplasia ( fig. . ) begins by the end of this phase and persists through the proliferative phase. the reactive type ii pneumocytes may demonstrate marked nuclear atypia, with numerous mitotic figures (fig. . ). the proliferative phase begins at week after the injury and is characterized by fibroblastic proliferation, seen mainly within the interstitium but also focally in the alveolar spaces ( fig. . ). the fibrosis consists of loose aggregates of fibroblasts admixed with scattered inflammatory cells, reminiscent of organizing pneumonia acute interstitial pneumonia (hamman- in experimental ards, the exact time of injury is known, and the entire lung proceeds through the phases at the same time. in a patient who develops diffuse alveolar damage from any cause, the acute lung injury may begin in different areas at different times, so a biopsy specimen may demonstrate injury at various phases in this sequence. ( in ards the inciting event is frequently extrathoracic, and lung injury is therefore superimposed on normal preexisting structure. a b figure . acute respiratory distress syndrome: fibrin thrombi in arteries. acute lung injury results in local conditions that lead to arterial thrombosis. thrombi in various stages of organization may be seen (larger pulmonary artery in part a, smaller pulmonary artery in part b). ( fig. . ); collagen deposition is minimal. reactive type ii pneumocytes persist. immature squamous metaplasia may occur ( fig. . ) in and around terminal bronchioles. the degree of cytologic atypia in this squamous epithelium can be so severe as to mimic malignancy ( fig. . ). the hyaline membranes are mostly resorbed by the late proliferative stage, but a few remnants may be observed along alveolar septa. some cases of dad resolve completely, with few residual morphologic effects, but in other cases, fibrosis may progress to extensive structural remodeling and honeycomb lung. as might be expected, a review of outcomes for survivors of ards revealed persistent functional disability at year after discharge from intensive care. by definition, ards has a known inciting event. the foregoing description is based on a model of ards due to oxygen toxicity, wherein the evolution of histopathologic abnormalities can be studied over a defined time period. , in practice, lung biopsy most often is performed in patients without a known cause or specific time of onset of injury. moreover, with some causes of acute lung injury, the damage evolves over a protracted period of time, or the lung may be injured in repetitive fashion (e.g., with drug toxicity). in such circumstances, the pathologic changes do not necessarily progress sequentially through defined stages as in ards, so both acute and organizing phases may be encountered in the same biopsy specimen. the basic histopathologic elements of acute lung injury are presented in box . . acute fibrinous and organizing pneumonia (afop) is a histologic pattern of acute lung injury with a clinical presentation similar to that of classic dad, in terms of both potential etiologic disorders and outcome. it differs from dad in that hyaline membranes are absent. the dominant feature is intraalveolar fibrin balls or aggregates, typically in a patchy distribution. organizing pneumonia in the form of luminal loose fibroblastic tissue is present surrounding the fibrin (eslide . ). the alveolar septa adjacent to areas of fibrin deposition show a variety of changes similar to those of dad, such as septal edema, type ii pneumocyte hyperplasia, and acute and chronic inflammatory infiltrates. the intervening lung shows minimal histologic changes. afop may represent a fibrinous variant of dad. in some patients, both dad and afop disease patterns may be present simultaneously. , specific causes of acute lung injury infection infection is one of the most common causes of acute lung injury. if the lung injury pattern is accompanied by a significant increase in neutrophils, areas of necrosis, viral cytopathic effect, and/or granulomas, infection should lead the differential diagnosis. among infectious organisms, viruses most consistently produce dad. , occasionally, fungi (e.g., pneumocystis) and bacteria (e.g., legionella) also can cause infections manifesting as dad. some of the organisms that are well known to cause acute lung injury with characteristic histopathologic changes are discussed next. considerable structural remodeling may take place after ards as these atelectatic spaces fuse to form consolidated areas of lung parenchyma at the microscopic level. influenza is a common cause of viral pneumonia. the histopathology ranges from mild organizing acute lung injury (resembling organizing pneumonia) in nonfatal cases to severe dad with necrotizing tracheobronchitis ( fig. . ) in fatal cases. , specific viral cytopathic effects are not identifiable by light microscopy. on ultrastructural examination, intranuclear fibrillary inclusions may be seen in epithelial and endothelial cells. the coronavirus responsible for severe acute respiratory syndrome produces the acute lung injury associated with this disorder. , [ ] [ ] [ ] both dad and afop patterns have been identified in affected patients. on ultrastructural examination, involved lung tissue revealed numerous to moderate numbers of cytoplasmic viral particles in pneumocytes, many within membrane-bound vesicles. [ ] [ ] [ ] the virus particles were spherical and enveloped, with spikelike projections on the surface and coarse clumps of electron-dense material in the center. most had sizes ranging from to nm in diameter, but some were as large as nm. measles virus produces a mild pneumonia in the normal host but can cause serious pneumonia in immunocompromised children. adenovirus is an important cause of lower respiratory tract disease in children, , although adults (particularly those who are immunocompromised) and military recruits also are occasionally affected. the lung shows necrotizing bronchitis, or bronchiolitis, accompanied by dad. the pathologic changes are more severe in bronchi, bronchioles, and peribronchiolar regions ( fig. . a ). two types of inclusions can be observed in lung epithelial cells: an eosinophilic intranuclear inclusion with a halo usually is less conspicuous than the more readily identifiable "smudge cells" (see fig. . b). these latter cells are larger than normal and entirely basophilic, with no defined inclusion or halo evident by light microscopy. on ultrastructural examination, smudge cell inclusions are represented by arrays of hexagonal particles. herpes simplex virus is mainly a cause of respiratory infection in the immunocompromised host. two patterns of infection are recognized: airway spread resulting in necrotizing tracheobronchitis ( fig. . ) and bronchitis and bronchiolitis, and dad. the characteristic histologic feature is the presence of multinucleated giant cells (fig. . a) with characteristic eosinophilic intranuclear and intracytoplasmic inclusions. [ ] [ ] [ ] [ ] [ ] these cells are found in the alveolar spaces and within alveolar septa (fig. . b ). viral inclusions are seen on ultrastructural examination as tightly packed tubules. interstitial (alveolar septal) edema fibroblastic proliferation in alveolar septa alveolar edema alveolar fibrin and cellular debris, with or without hyaline membranes reactive type ii pneumocytes blood-borne dissemination producing miliary necrotic parenchymal nodules. dad and hemorrhage can occur in both forms. , characteristic inclusions may be seen in bronchial and alveolar epithelial cells ( fig. . ). the more obvious type is an intranuclear eosinophilic inclusion surrounded by clear halo (cowdry a inclusion), and the other is represented by a basophilic to amphophilic ground-glass nucleus (cowdry b inclusion). rounded viral particles with double membranes are seen under the electron microscope. , varicella-zoster virus causes disease predominantly in children and is the agent of chickenpox. pulmonary complications of chickenpox are rare in children with normal immunity (accounting for less than % of the cases). by contrast, pneumonia develops in % of adults with chickenpox; immunocompetent and immunocompromised persons are equally affected. , the histopathologic picture in varicella pneumonia ( fig. . ) is similar to that in herpes simplex. although identical intranuclear inclusions are reported to occur, , these can be considerably more difficult to identify in chickenpox pneumonia. cytomegalovirus is an important cause of symptomatic pneumonia in immunocompromised persons, especially those who have received bone marrow or solid organ transplants, and in patients with human immunodeficiency virus infection. [ ] [ ] [ ] the histopathologic findings range from little or no inflammatory response to hemorrhagic nodules with necrosis ( fig. . a) and dad. the diagnostic histopathologic b a with many organisms (see fig. . b). , however, in the mildly immunocompromised patient this feature is not observed or the pathologic changes may be subtle. in such cases, several "atypical" manifestations have been described. , , dad is the most dramatic of these atypical presentations ( fig. . a), with the organisms present within hyaline membranes ( fig. . b) and in isolated intraalveolar fibrin deposits. the grocott methenamine silver (gms) method is routinely used to stain the organisms, which typically are seen in small groups and clusters (figs. . b and . b). , , bacterial infection common bacterial pneumonias rarely cause dad; however, this lung injury pattern has been described in legionnaires' disease, mycoplasma pneumonia, and rickettsial infection. [ ] [ ] [ ] [ ] [ ] pattern, seen in endothelial cells, macrophages, and epithelial cells, consists of cellular enlargement, a prominent intranuclear inclusion, and an intracytoplasmic basophilic inclusion ( fig. . b). hantavirus is a rare cause of acute lung injury. [ ] [ ] [ ] the infection produces alveolar edema, hyaline membranes, and atypical interstitial mononuclear inflammatory infiltrates (fig. . ). [ ] [ ] [ ] spherical membrane-bound viral particles have been found in the cytoplasm of endothelial cells by electron microscopy. pneumocystis jiroveci (previously known as pneumocystis carinii) is the most common fungus to cause dad. [ ] [ ] [ ] the histopathology of pneumocystis infection in the setting of profound immunodeficiency is one of frothy intraalveolar exudates ( [afb] stains or gms or warthin-starry silver stain, etc.) on every lung biopsy specimen exhibiting dad. systemic connective tissue disorders are a well-known cause of diffuse lung disease. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in some cases, lung involvement may be the first manifestation of the systemic disease, even without identifiable serologic evidence. histologic clues that suggest the acute lung injury is secondary to connective tissue disease include associated bronchiolitis (especially if it is follicular bronchiolitis), pleuritis, capillaritis, hemorrhage, and legionella is a fastidious gram-negative bacillus that causes acute respiratory infection in older adults and immunodeficient individuals. , , the histopathologic pattern is that of a pyogenic necrotizing bronchopneumonia ( fig. . a) affecting the respiratory bronchioles, alveolar ducts, and adjacent alveolar spaces. dad is common. , , the rod-shaped organisms (fig. . b) can be identified by dieterle silver stain. of note, in immunocompromised patients, any type of infection can cause dad, with pneumocystis pneumonia being the most common. for this reason, it is essential to use special stains (acid-fast bacilli and small vessel vasculitis ( fig. . b), and pulmonary edema also may be observed. , , immunofluorescence studies demonstrate immune complexes in lung parenchyma, and both immune complexes and tubuloreticular inclusions may be seen on ultrastructural examination. , , rheumatoid arthritis a significant percentage of patients with rheumatoid arthritis have lung disease. , , [ ] [ ] [ ] [ ] many different morphologic patterns of lung disease in rheumatoid arthritis have been described, , , with the rheumatoid nodule being the most specific. acute lung injury has been reported ( fig. . ), referred to as acute interstitial pneumonia in some publications and as dad in others. a cellular lymphoplasmacytic infiltrate. acute lung injury has been reported to occur in the following connective tissue diseases. pulmonary involvement in systemic lupus erythematosus (sle) may manifest as pleural disease, acute or chronic diffuse inflammatory lung disease, airway disease, or vascular disease (vasculitis and thromboembolic lesions). acute lupus pneumonitis (alp) is a form of fulminant interstitial disease (fig. . a) with a high mortality rate. patients present with severe dyspnea, tachypnea, fever, and arterial hypoxemia. alp represents the first manifestation of sle in approximately % of affected persons. , the most common histopathologic feature of this acute disease is dad (eslide . ). alveolar hemorrhage, with capillaritis b a polymyositis/dermatomyositis, a systemic connective tissue disorder, is well known to be associated with interstitial lung disease. , three main clinical presentations are recognized: ( ) acute fulminant respiratory distress resembling the so-called hamman-rich syndrome, ( ) slowly progressive dyspnea, and ( ) an asymptomatic form with abnormalities on radiologic and pulmonary function studies. three major histopathologic patterns have been observed: dad (fig. . a), organizing pneumonia ( fig. . b) , and chronic fibrosis (fig. . c )-the so-called usual interstitial pneumonia (uip) pattern. the rapidly progressive clinical presentation is associated with a dad histopathologic pattern on lung biopsy studies and carries the worst prognosis. dad associated with scleroderma and mixed connective disease also has been described. , many patients with connective tissue disease receive drug therapy during the course of their illness. a large number of drugs, including cytotoxic agents used for immunosuppression, are known to cause dad. in addition, as a desired result of therapy, patients may be immunosuppressed, making the exclusion of infection a high priority in the case of acute clinical lung disease. drugs can produce a wide range of pathologic lung manifestations, and the causative agents are numerous. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the spectrum of drug-induced lung disease runs the entire gamut from dad to fibrosis. between these two extremes, subacute clinical manifestations may include organizing pneumonia, chronic interstitial pneumonia, eosinophilic pneumonia, obliterative bronchiolitis, pulmonary hemorrhage, pulmonary edema, pulmonary hypertension, venoocclusive disease, and granulomatous interstitial pneumonia. , , dad is a common and dramatic manifestation of pulmonary drug toxicity. many drugs are known to cause dad. a few of the more common ones are discussed next. (drug-related lung disease is also discussed in chapter .) as a generalization, marked cytologic atypia and numerous foamy macrophages in the airspaces are histologic harbingers of possible drug reaction. dad frequently is caused by cytotoxic drugs, and the commonly implicated ones include bleomycin (fig. . ), busulfan ( fig. . ) , and carmustine. , , patients usually present with dyspnea, cough, and diffuse pulmonary infiltrates. [ ] [ ] [ ] [ ] [ ] the histologic pattern most commonly is one of nonspecific acute lung injury with hyaline membranes, but some changes may be present to at least suggest a causative agent. for example, the presence of acute lung injury with associated atypical type ii pneumocytes with markedly enlarged pleomorphic nuclei and prominent nucleoli (see fig. . ) is characteristic for busulfan-induced pulmonary toxicity, and, on ultrastructural examination, intranuclear tubular structures have been found in type ii pneumocytes in association with administration of busulfan and bleomycin. [ ] [ ] [ ] [ ] in most cases, the possibility that a drug is the cause of dad can only be inferred from the clinical history. considerations in the differential diagnosis typically include other treatment-related injury or complication of therapy (e.g., concomitant irradiation or infection). for example, oxygen therapy is a well-recognized cause of dad (fig. . ) and also may exacerbate bleomycin-induced lung injury. methotrexate (fig. . ) is another commonly used cytotoxic drug that can cause acute and organizing dad. methotrexate also produces other distinctive patterns, such as granulomatous interstitial pneumonia (see chapter ) that is seldom seen in association with other commonly used chemotherapeutic agents. to complicate matters further, methotrexate also is used in the treatment of rheumatoid arthritis, a disease known to produce dad independently as one of its pulmonary manifestations. , epidermal growth factor receptor tyrosine kinase inhibitors have been reported to be associated with dad. , the increasing use of targeted therapy drugs in cancer patients warrants a notice of this category as a potential cause. amiodarone is a highly effective antiarrhythmic drug that is increasingly recognized as a cause of pulmonary toxicity. , - because patients taking amiodarone have known cardiac disease, the clinical presentation often is complicated, with several superimposed processes potentially affecting the lungs in various ways. clinical and radiologic considerations typically include congestive heart failure, pulmonary emboli, and acute lung injury from other causes. , distinctive features may be present on chest computed tomography scans. the lung biopsy commonly shows acute and organizing lung injury (fig. . a and eslide . ). other patterns include chronic interstitial pneumonitis with fibrosis and organizing pneumonia. characteristically, type ii pneumocytes and alveolar macrophages show finely vacuolated cytoplasm in response to amiodarone therapy (see fig. . b), but these changes alone are not evidence of toxicity because they also may be seen in patients taking amiodarone who do not have evidence of lung toxicity. methotrexate and gold, common agents for treatment of rheumatoid arthritis, are frequently implicated in lung toxicity. methotrexate is discussed earlier in this chapter. organizing dad (fig. . ) and chronic interstitial pneumonia are commonly described pulmonary manifestations of so-called gold toxicity. , , acute eosinophilic pneumonia acute eosinophilic pneumonia was first described in and is characterized by acute respiratory failure, fever of days' to weeks' duration, diffuse pulmonary infiltrates on radiologic studies, and eosinophilia in bronchoalveolar lavage fluid or lung biopsy specimens in the absence of infection, atopy, and asthma. peripheral eosinophilia frequently is described but is not a consistent finding at initial presentation. , acute eosinophilic pneumonia is easily confused with acute interstitial pneumonia because both manifest as acute respiratory distress without an obvious underlying cause. histologically, the disease is characterized by acute and organizing lung injury showing classic features (fig. . ) of ( ) alveolar septal edema, ( ) eosinophilic airspace macrophages, ( ) tissue and airspace eosinophils in variable numbers, and ( ) marked reactive atypia of alveolar type ii cells (eslide . ). intraalveolar fibroblastic proliferation (patchy organizing pneumonia) and inflammatory cells are present to a variable degree. hyaline membranes and organizing intraalveolar fibrin also may be present (fig. . ) . the most significant feature is the presence of interstitial and alveolar eosinophils. infiltration of small blood vessels by eosinophils also may be seen. it is important of special stains applied to tissue sections or cytologic preparations (e.g., afb, gms, or warthin-starry silver stain) also is essential to rule out infectious organisms in this setting. so-called pulmonary hemorrhage syndromes may feature the histopathologic changes of acute lung injury, in addition to the characteristic alveolar hemorrhage and hemosiderin-laden macrophages. in some patients, dad may be the dominant histopathologic pattern. in a study by lombard et al. in patients with goodpasture syndrome, all showed acute lung injury ranging in distribution from focal to diffuse lung involvement. histopathologic examination demonstrated typical acute and organizing dad, with widened and edematous alveolar septa, fibroblastic proliferation, reactive type ii pneumocytes, and, rarely, even hyaline membranes (figs. . and . ). alveolar hemorrhage, either focal or diffuse, was present in all cases. capillaritis, an important finding indicating true alveolar hemorrhage, also was seen, as evidenced by marked septal neutrophilic infiltration. capillaritis was absent in one case for which dad was the dominant histopathologic pattern. microscopic polyangiitis can manifest as an acute interstitial pneumonia both clinically and histopathologically. affected patients have vasculitis as the known cause of acute lung injury. alveolar hemorrhage with arteritis, capillaritis ( fig. . ) , and venulitis may be seen in some cases. polyarteritis nodosa and vasculitis associated with systemic connective tissue disease (notably sle and rheumatoid arthritis) can also show acute lung injury with alveolar hemorrhage as the dominant histopathologic finding. , cryoglobulinemia is a rare cause of acute lung injury and alveolar hemorrhage. [ ] [ ] [ ] radiation can produce both acute and chronic damage to the lung, manifesting as acute radiation pneumonitis and chronic progressive fibrosis, respectively. the effect is dependent on radiation dosage, total time of irradiation, and tissue volume irradiated. concomitant chemotherapy and infections, which in themselves are causes of dad, may potentiate the effect of radiation injury. , , , acute radiation pneumonitis manifests to months after radiation therapy. , with traditional external beam radiation the pneumonitis is typically confined to the radiation field. however, more diffuse radiation pneumonitis can be seen following yttrium -impregnated microsphere chemoembolization for nonoperable hepatic tumors. clinical findings include dyspnea, cough, pleuritic pain, fever, and chest infiltrates. the lung biopsy specimen shows acute and organizing dad. , markedly atypical type ii pneumocytes with enlarged hyperchromatic nuclei and vacuolated cytoplasm constitute a hallmark of the disease (fig. . a) , and increased numbers of alveolar macrophages are seen. foamy cells are present in the intima and media of pulmonary blood vessels in some cases, and thrombosis ( fig. . b) , with or without transmural fibrinoid necrosis, is common. , [ ] [ ] [ ] disease presenting as classic acute respiratory distress syndrome by definition, ards must be associated with an identifiable inciting event. the histopathologic pattern is that of classic dad. the histopathologic changes should be consistent with those expected for the time interval from the onset of clinical disease (see later). in many cases the ards may be caused by a combination of factors, each potentiating the other. for the purposes of illustration, a few thoroughly studied causes are discussed next. to distinguish acute eosinophilic pneumonia from other causes of dad because patients typically benefit from systemic corticosteroid treatment, with prompt recovery. however, before initiation of immunosuppressive therapy, infection should be rigorously excluded by culture and special stains because parasitic and fungal infections also can manifest as tissue eosinophilia. treatment with steroids prior to the biopsy can make the number of eosinophils less impressive. acute interstitial pneumonia, also commonly referred to as hamman-rich syndrome, is a fulminant lung disease of unknown etiology occurring in previously healthy patients. [ ] [ ] [ ] acute interstitial pneumonia is one of the major idiopathic interstitial pneumonias included in the most recent classification scheme for diffuse interstitial pneumonia. patients usually report a prodromal illness simulating viral infection of the upper respiratory tract, followed by rapidly progressive respiratory failure. the mortality rate is high, with death occurring weeks or months after the acute onset. , the classic histopathologic pattern is that of acute and organizing dad, , with septal edema and hyaline membranes in the early phase and septal fibroblastic proliferation with reactive type ii pneumocytes prominent in the organizing phase. in practice, a combination of acute and organizing changes ( fig. . ) often is seen in the lung at the time of biopsy. a variable degree of airspace organization, mononuclear inflammatory infiltrates, thrombi in small pulmonary arteries, and reparative peribronchiolar squamous metaplasia also are seen in most cases. because acute interstitial pneumonia is idiopathic, other specific causes of acute lung injury must be excluded before making this diagnosis. considerations in the differential diagnosis include infection, connective tissue disease, acute exacerbation of idiopathic pulmonary fibrosis (ipf), drug effect, and other causes of dad. most cases of dad are not acute interstitial pneumonia, and detailed clinical information, radiologic findings (localized vs. diffuse disease), serologic data, and microbiologic results will often point to or rule out a specific etiologic condition. use figure . acute interstitial pneumonia (aip). idiopathic aip may take the form of every possible morphologic manifestation of acute respiratory distress syndrome, depending on the timing of biopsy relative to the onset of symptoms. here, a classic pattern of diffuse alveolar damage (dad) with hyaline membranes of variable cellularity is seen (midproliferative phase). interstitial fibroblastic proliferation may be more or less prominent from case to case and should not serve as a qualifying morphologic finding for the diagnosis. aip is nothing more than dad of unknown causation. oxygen is a well-known cause of ards and a useful model for all types of dad. , , oxygen toxicity also is important in that it is widely used in the care of patients, often in the setting of other injuries that can potentially cause ards, such as sepsis, shock, and trauma. exposure to high concentrations of oxygen for prolonged periods can lead to characteristic pulmonary damage. in pratt first noted pulmonary changes due to high concentrations of inspired oxygen. in nash et al. described the sequential histopathologic changes of this injury, later reemphasized by pratt. in neonates receiving oxygen for hyaline membrane disease, bronchopulmonary dysplasia was reported to occur. as might be expected, the features of hyaline membrane disease in neonates and oxygen-induced dad in adults are indistinguishable (see fig. . ). other inhalants such as chlorine gas, mercury vapor, carbon dioxide in high concentrations, and nitrogen mustard all have been reported to cause ards. , , massive extrapulmonary trauma and shock first became recognized as causes of unexplained respiratory failure during the wars of the second half of the th century. a variety of names were assigned to this wartime condition, including shock lung, congestive atelectasis, traumatic wet lung, da nang lung, respiratory insufficiency syndrome, posttraumatic pulmonary insufficiency, and progressive pulmonary consolidation. it which can be performed even on autopsy specimens. other ingested toxins (e.g., kerosene, rapeseed oil) also have been reported to cause ards. pathologist approach to the differential diagnosis of acute lung injury the histologic spectrum encountered in acute lung injury is broad. very early cases may look nearly normal with only mild interstitial and alveolar edema. other more advanced cases are clearly abnormal with fibrin, inflammation, and organization. the basic elements of the acute injury pattern include interstitial edema, alveolar edema, fibrin, hyaline membranes, reactive pneumocytes, and organization (see box . ). acute lung injury is a pathologic pattern and by itself is a nonspecific finding. from a practical perspective, after an acute lung injury pattern is became clear that shock of any cause (e.g., hypovolemia due to hemorrhage, cardiogenic shock, sepsis) could cause ards, and that in most cases, a number of factors come into play. in the typical presentation, dyspnea of rapid onset is accompanied by development of diffuse chest infiltrates several hours to days after an episode of shock. after ards begins, the mortality rate is high. , , paraquat is a potent herbicide that causes the release of hydrogen peroxide and superoxide free radicals, resulting in damage to cell membranes. [ ] [ ] [ ] oropharyngitis is the initial sign of poisoning, followed by impaired renal and liver function. approximately days later, ards develops. the histopathologic pattern in most cases is one of organizing dad (fig. . ). the diagnosis is confirmed by tissue analysis for paraquat, b a raise consideration of immunologically mediated pulmonary hemorrhage. care must be taken not to interpret the pigmented macrophages seen in the lungs of cigarette smokers as evidence of hemorrhage. the hemosiderin in macrophages related to true hemorrhage in the lung (from any cause) is globular, often slightly refractile, and golden-brown in color. , [ ] [ ] [ ] presence of atypical cells. viral infections often produce cytopathic effects, including intracellular inclusions (see chapter ) . examples of intracellular inclusions are the cowdry a and b inclusions seen in herpesvirus infection, cytomegaly with intranuclear and intracytoplasmic inclusions of cytomegalovirus, the multinucleated giant cells of measles virus and respiratory syncytial virus, and the smudged cells of adenovirus infection. , , , , chemotherapeutic drugs such as busulfan and bleomycin often are associated with markedly atypical type ii pneumocytes, which may have enlarged pleomorphic nuclei and prominent nucleoli. , markedly atypical type ii pneumocytes that may be suggestive of a viropathic effect also are seen in radiation pneumonitis. , , presence of foamy cells. alveolar lining cells with vacuolated cytoplasm accompanied by intraalveolar foamy macrophages are characteristic features seen in patients taking amiodarone, and amiodarone toxicity may lead to acute lung injury changes. [ ] [ ] [ ] in some cases of radiation pneumonitis, foam cells are seen in the intima and media of blood vessels. , presence of foreign material. foreign material in the spaces in the form of vegetable matter or other food elements is indicative of aspiration. massive aspiration events may cause dad. other foreign material, such as radiation impregnated beads may also be encountered. presence of advanced interstitial fibrosis. clinical ipf is associated with the changes of uip on pathologic examination (see chapter ), with advanced lung remodeling. of interest, ipf undergoes episodic exacerbation, and on occasion such exacerbation may be overwhelming, with resultant dad. it is prudent to examine lung biopsy sections for the presence of dense fibrosis with structural remodeling (microscopic honeycombing) in cases of dad, to identify the rare case of ipf that manifests for the first time as an acute episode of exacerbation. because the morphologic manifestations of acute diffuse lung disease may be relatively stereotypical, clinicopathologic correlation is often helpful in arriving at a specific diagnosis. a summary of the more important history and laboratory data pertinent to this correlation is presented in box . . identified, careful search for the following additional features often help to narrow the list of possible causes (summarized in immune status acuity of onset radiologic distribution and character of abnormalities history of inciting event (e.g., shock) history of lung disease (e.g., usual interstitial pneumonia with current acute exacerbation) history of systemic disease (e.g., connective tissue disease, heart disease) history of medication use or drug abuse history of other recent treatment (e.g., radiotherapy for malignancy) results of serologic studies: erythrocyte sedimentation rate determination, assays for autoimmune antibodies (e.g., ana, rf, anca, scl- , jo- ) results of microbiology studies one of the first questions to be addressed is whether or not a known inciting event was identified clinically (i.e., is this ards?). next, the results of any sampling procedures to identify infection should be checked, along with application of special stains to the tissue sections, to exclude infection. finally, data regarding related disease, such as infection, autoimmune disease, underlying lung disease, are needed. for example, if the patient is immunosuppressed, infection should always be the leading consideration in the differential diagnosis. another point to keep in mind is that patients with certain diseases may be taking medications with the potential to cause dad (e.g., amiodarone for cardiac arrhythmia). moreover, laboratory studies may reveal antibodies related to connective tissue disease (e.g., antineutrophil antibody, rheumatoid factor, jo- , scl- , antifibrillarin, anti-mpp , ss-a, ss-b). regarding the pathologist's role and responsibility in biopsy cases of acute lung injury, use of special stains for organisms (at a minimum, methenamine silver and acid-fast stains) is indicated. additional stains (auramine-rhodamine, dieterle or warthin-starry silver stain, immunohistochemical stains for specific organisms, or molecular probes) may be used, especially in patients known to be immunocompromised from any cause. the pathology in immunocompromised patients may not show necrosis, neutrophils, or granulomas, all features favoring an infectious etiology. self-assessment questions and cases related to this chapter can be found online at expertconsult.com. acute and fibrinous organizing pneumonia (eslide . ) a. history-a -year-old female presented with acute onset dyspnea. her past medical history was significant for rheumatoid arthritis for which she had recently begun methotrexate. imaging studies show bilateral ground-glass infiltrates in upper and lower lobes. a surgical lung biopsy was performed. b. pathologic findings-from scanning magnification, the lung architecture appears preserved without significant fibrosis. at higher power there is an extensive airspace filling process. many airspaces are filled with fibrin and scattered inflammatory cells. in other areas there is light pink material suggestive of edema. finally, some early fibroblastic polyps of organization are present. the interstitium shows diffuse alveolar damage with hyaline membranes (eslide . ) a. history-a -year-old male without significant past medical history presented to the emergency room with acute shortness of breath and cough. a week prior he participated in a half marathon without difficulty. he was taking no medications and had no exposures. his oxygen saturation was % on room air. he progressed to respiratory failure after being admitted to the intensive care unit. a surgical lung biopsy was performed. b. pathologic findings-from scanning magnification the biopsy shows preserved lung parenchyma without significant scarring. however, there is a diffuse process that gives the biopsy a "pink" appearance from low power. at higher power, the histologic features of diffuse alveolar damage (dad) are recognized including alveolar wall edema, reactive type-ii pneumocytes, and hyaline membranes. a few foci of organization are also present. a significant inflammatory cell infiltrate is not recognized. there is no pleuritis, hemosiderosis, granulomas, or necrosis. c. diagnosis-diffuse alveolar damage. d. discussion-features of acute lung injury are readily apparent, and the numerous hyaline membranes support a diagnosis of diffuse alveolar hemorrhage. the biopsy is negative for numerous eosinophils, foamy macrophages, alveolar hemorrhage, foreign material, neutrophils, necrosis, and granulomas. therefore the histology does not suggest a particular etiology on this case. acid-fast and fungal stains were negative. extensive serologic screening studies were negative, and cultures are negative to date. because the additional work-up is negative, this case is best categorized as acute 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tissue have been associated with: a. cri du chat syndrome b. holoprosencephaly c. beckwith-wiedemann syndrome d. down syndrome e. cornelia de lange syndrome answer: d acinar pulmonary dysplasia: a. features cystic change and enlargement of all lobes b. accounts for one of the most common surgical specimens in pediatric lung pathology hyperplasia: a. refers to an increased number of alveoli relative to the corresponding conducting airways which of the following is not in the macroscopic differential diagnosis of cystic lung lesions in children? a. adenomatoid malformation b. intralobar sequestration c. congenital lobar overinflation d. lymphangioleiomyomatosis e. pneumatocele answer: d . pulmonary sequestration is characterized by: a. communication with second-order bronchial lumina b. solely systemic vascular supply c. exclusive extralobar localization d. densely apposed, atelectatic airspaces e. multifocal aggregates of eosinophils answer: b . extralobar pulmonary sequestrations may occasionally contain which one of the following heterotopic tissues? a. bone b. glial nodules c. hepatoid anlage d. striated muscle e. enteric-type epithelium answer: d . congenital malformations of the pulmonary airways: a. are most often seen in stillborns or newborns b. represent malformations of each bronchopulmonary segment c. may be difficult to subclassify in fetal lungs d. must be distinguished from pleuropulmonary blastoma e. all of the above answer: e . which one of the following tissues may have implications for future lung pathology, if it is present in a congenital malformation of the pulmonary airways? a. striated muscle b. cartilage c. mucinous epithelium d. embryonic-type mesenchymal tissue e. lymphoid aggregates answer: c .e . which one of the following storage disorders does not usually involve the lung parenchyma? a. niemann-pick disease b. gaucher disease c obliterative bronchiolitis in children can be associated with all of the following except: a. adenovirus b. influenza c. stevens-johnson syndrome d. paragonimiasis e. graft-versus-host disease answer: d acute eosinophilic pneumonia (eslide . ) a. history-a previously healthy -year-old female presented to the emergency room with acute-onset shortness of breath and cough. she was initially evaluated and admitted to the medicine floor for presumed pneumonia. however, she quickly deteriorated and was transferred to the medical intensive care unit and required intubation. imaging studies showed bilateral ground-glass opacities without lobar distribution. additional history obtained from the patient's roommate revealed the patient was recently treated with sulfamethoxazole and trimethoprim for a urinary tract infection. b. pathologic findings-the overall architecture of the lung appears intact, but there is a diffuse acute lung injury pattern including alveolar wall edema, airspace fibrin, organization, and scattered hyaline membranes. pneumocytes show marked reactive atypia. there are numerous eosinophils in the airspaces, embedded within the fibrin, and within the interstitium. numerous airspace macrophages are also present. no necrosis or granulomas are identified. c. diagnosis-acute eosinophilic pneumonia. d. there are four key histologic features in acute eosinophilic pneumonia, all of which are satisfied in this case. i. alveolar septal edema ii. eosinophilic airspace macrophages iii. tissue and airspace eosinophils iv. reactive atypia of type-ii pneumocytes there is a differential diagnosis for the acute eosinophilic pneumonia pattern of injury including drug reaction, infection, connective tissue disease, smoking related, and idiopathic. rigorous exclusion of infection is imperative and requires both infectious stains on the tissue blocks and culture studies. recognition of this injury pattern is of particular importance as these patients typically respond dramatically to high-dose steroids and have a better prognosis than that of diffuse alveolar damage. in this patient the exposure to a sulfa drug in the days prior to presentation was the likely etiology. she was treated with steroids, dramatically improved, and was discharged in days. amiodarone-induced diffuse alveolar damage (eslide . ) a. history-a -year-old male presented to the emergency room with acute shortness of breath first noted the evening prior. his past history was significant for a deceased donor renal transplant days prior to presentation for end-stage renal disease secondary to diabetes. he also had a history of hypertension and atrial fibrillation. imaging studies showed bilateral ground-glass opacities in the upper and lower lobes. b. pathologic findings-from scanning magnification there is preserved architecture without significant fibrosis. there is diffuse alveolar wall thickening, mostly by edema. overlying pneumocytes show reactive epithelial changes. numerous hyaline membranes and focal fibrin in airspaces are present. some airspaces are filled with numerous macrophages showing finely vacuolated cytoplasm. some acute lupus pneumonitis (eslide . )a. history-a -year-old african-american female presented with the emergency room with cough and shortness of breath. upon further questioning, she reported some blood-tinged sputum. the patient was febrile, and chest imaging studies showed bilateral ground-glass infiltrates without lobar distribution. serologic studies revealed an elevated erythrocyte sedimentation rate and c-reactive protein and positive antinuclear antibodies and anti-double-stranded dna antibodies. a surgical lung biopsy was performed. b. pathologic findings-the biopsy shows preserved lung architecture with a diffuse abnormality from scanning magnification. there is extensive alveolar wall edema with numerous foci of hyaline membranes. patchy organization is present, along with a relatively diffuse lymphoplasmacytic interstitial infiltrate. c. diagnosis-acute lupus pneumonitis. d. discussion-based on the histologic features alone, this biopsy is diagnostic of diffuse alveolar damage. however, the clinical history is required to arrive are a more specific diagnosis of acute lupus pneumonitis. the biopsy does show a mild increase in lymphoplasmacytic interstitial inflammation that would be unusual for most cases of idiopathic acute respiratory distress syndrome.edema and a mixed lymphoplasmacytic infiltrate. no hemorrhage, necrosis, or hyaline membranes are present. c. diagnosis-acute fibrinous and organizing pneumonia (afop). d. discussion-afop presents in the same fashion as diffuse alveolar damage (dad) and the differential diagnosis for afop and dad is the same, including drug reaction, toxin exposure, connective tissue disease, infection, and as an idiopathic reaction. they both represent forms of acute lung injury. in this case the degree of lymphoplasmacytic inflammation in the interstitium raises the possibility of a background connective tissue disease. additional history revealed she had recently cut her methotrexate dose in half to save money. she had also recently experienced inflammatory flares in her joints. all of these factors support a diagnosis of afop related to rheumatoid arthritis. a definitive etiology for afop is identified in a minority of patients.pneumocytes show similar cytoplasmic vacuolization. there is no necrosis, neutrophils, or hemorrhage. c. diagnosis-diffuse alveolar damage (dad) with foamy macrophages.a drug reaction leads the differential diagnosis. d. discussion-based on the presence of the patchy but marked cytoplasmic vacuolization in the macrophages and pneumocytes, a drug reaction is the most likely etiology for the dad pattern. in particular, amiodarone is a commonly used drug that causes this cytoplasmic vacuolization, even in the absence of associated lung injury. this was communicated to the clinical services who identified the patient was indeed taking amiodarone, even on the day of transplant. amiodarone-induced lung injury is associated with prolonged use of the drug and with an inciting event (such as a major operation). this patient had been on amiodarone for several years. following clinicopathologic correlation, this case is best diagnosed as amiodarone-induced dad. the patient was treated with pulse high-dose steroids and eventually had a full recovery. key: cord- - trr d u authors: ventura, francesco; bonsignore, alessandro; gentile, raffaella; de stefano, francesco title: two fatal cases of hidden pneumonia in young people date: - - journal: j forensic sci doi: . /j. - . . .x sha: doc_id: cord_uid: trr d u abstract: acute respiratory distress syndrome (ards) is a severe lung disease characterized by inflammation of the lung parenchyma leading to impaired gas exchange. this condition is often lethal, usually requiring mechanical ventilation and admission to an intensive care unit. we present two fatal cases of hidden pneumonia in young people and discuss the pathophysiological mechanism of ards with reference to the histological pattern. a complete forensic approach by means of autopsy and histological, immunohistochemical, and microbiological, examination was carried out. in both cases the cause of death was cardio‐respiratory failure following an acute bilateral pneumonia with diffuse alveolar damage and ards associated with sepsis and disseminated intravascular coagulation. our cases suggest on one side the importance of an early diagnosis to avoid unexpected death while on the other that the diagnosis of ards has to be confirmed on the basis of a careful postmortem examination and a complete microscopy and microbiological study. acute respiratory distress syndrome (ards) is a severe lung disease characterized by inflammation of the lung parenchyma leading to impaired gas exchange with concomitant systemic release of inflammatory mediators by local epithelial and endothelial cells, causing inflammation, hypoxemia resulting often in multiple organ failure (mof), and disseminate intravascular coagulation (dic) ( ) . this condition is often lethal, usually requiring mechanical ventilation and admission to an intensive care unit ( ) . physiopathologically when the endothelium of lung capillaries and the alveolar epithelium are damaged, plasma and blood flood the interstitial and intra-alveolar spaces. such a change implies decreased lung compliance, pulmonary hypertension, reduced functional capacity, compromised ventilation ⁄ perfusion ratio, and hypoxemia ( ) . acute respiratory distress syndrome can occur within - h of an injury or attack of acute illness. in such a case the patient usually presents with shortness of breath and tachypnea, usually associated with hypoxemia, petechiae in the axillae, and neurologic abnormalities such as mental confusion ( ) . typical histological presentation involves diffuse alveolar damage (dad) and hyaline membrane formation in alveolar walls ( ) . hyaline membranes, especially, as a result of the acute inflammatory processes in the alveolar compartment ( ) is the histological hallmark of ards. if the underlying disease or injurious factor is not removed, the amount of inflammatory mediators released by the lungs in ards may result in a systemic inflammatory response syndrome (or sepsis if there is lung infection) ( ) . the evolution toward shock and ⁄ or mof follows the same pathophysiological path of sepsis ( ) . it is estimated that ards is caused by septic shock-characterized by leukocytosis or leukopenia, fever, hypotension, and the identification of a potential source of systemic infection with positive blood cultures for pathogenous agents-in more than % of cases ( ) . pneumonia is thought to be the most common lung disease leading to ards as it determines a direct lung injury in the immunocompetent host ( ) . in cases of severe ards the survival rate is % with appropriate and early treatment, but if the ards-induced severe hypoxemia is not recognized and treated or if the disease reaches medical attention only in the terminal phase then cardio-respiratory arrest occurs in more than % of patients ( ) . we present two fatal cases of hidden pneumonia in young people who died within a few hours. the clinical presentation, the radiological and laboratory findings in one case, and the postmortem examination with histological, immunohistochemical, and microbiological exams in both cases, led us to conclude for an acute cardio-respiratory failure secondary to bilateral pneumonia with dad and consequently ards associated with sepsis and dic. the features of the disease are discussed with reference to the histological and immunohistochemical evaluation. a -year-old man was found dead at home by his girlfriend who was sleeping with him. the night before he went out with his friends and came back home late. his friends reported that nothing ''strange'' happened during the evening he spent with them. the day after, in the afternoon, when he should wake up his girlfriend saw the presence of foam around his mouth and nose and when she tried to wake him up he did not respond. so she called the emergency services who could do nothing but declare him dead. he took psychodrugs and was known to be a drug addict and a heavy drinker. family history was reported negative for sudden death. death scene investigation was unremarkable. a complete postmortem examination was performed days after death. external examination did not show any visible sign of injury. the internal examination revealed polyvisceral stasis, diffuse microthrombosis, cerebral and pulmonary edema. free citrine liquid was found on both sides of the pleural cavities. a marked lung congestion and the release of foamy material were bilaterally observed. ''hydrostatic docimasia'' for large and small fragments was bilaterally positive in all fields. also known as ''the flotation test,'' or ''the lung test,'' this old test is still in use to check if there are areas of increased density within the adult lung parenchyma. in these cases lung specimens, being not inflated with air, do not float. such is the case of pneumonia ( ) . the microscopic histological study, performed using formalinfixed paraffin-embedded tissue sectioned at lm and stained with hematoxylin-eosin (h&e), revealed the typical findings of dad: alveolar septa mildly thickened by edema and capillary congestion, alveolar edema, hyaline membranes lining the denuded alveolar walls, hyperplastic type ii pneumocytes, alveolar infiltrates of polymorphonuclear neutrophilic leukocytes, pigmented macrophages, monocytes and plasma cells (fig. a) , fibrin thrombi in small arteries. in some fields, numerous endoalveolar erythrocytes were also observed. bronchial walls presented epithelial denudation, inside the lumen there were infiltrates of leukocytes, mostly neutrophils, and a moderate quote of eosinophilic amorphous material. all these findings were suggestive for a typical dad in the early exudative phase, confirmed by the positive results to immunohistochemical dye for surfactant apoprotein (pe- ) that outlines hyperplastic type ii pneumocytes ( ) . fungal infections were not found on slides by grocott staining. gram staining did not give evidence for bacterial colonies. the examination of other histological samples was unremarkable. the lung samples were also examined under a confocal laser scanning microscope ( ) , and a three-dimensional reconstruction was performed (fig. ) . additional microbiological tests ( ) to identify possible pathogenous agents were carried out through isolation of nucleic acids from formalin-fixed paraffin-embedded tissue sections. to control the course of extraction and check for pcr inhibitors, a fragment of the homo sapiens beta-globin gene was amplified. the purified dna sample was negative for all bacterial cultures. the positive result for beta-globin demonstrated that the dna extraction procedure was efficient in extracting amplifiable dna from the sample. toxicology was negative for drugs and alcohol. thus, viral infection was a diagnosis of exclusion, according with recent literature which reports a prevalence of viral etiologies in communityacquired pneumonia up to % ( ) and an extremely high incidence of lung injury and ards arising from coronavirus and avian influenza virus infection ( , ) . a -year-old previously healthy man presented to the hospital with a -h history of sore throat, fever, and cough. the clinical prodromes were followed by the acute onset of increasing shortness of breath quickly progressing in acute respiratory failure with hemoptysis. chest x-ray demonstrated bilateral diffuse airspace opacification; the high-resolution ct (hrct) confirmed the presence of bilateral, symmetric diffuse ground-glass attenuation associated with liquid in pleural cavities. the patient was admitted to the intensive care unit with severe leukopenia, but he got worse and after few hours died. two postmortem blood cultures were positive for group a beta-hemolytic streptococcus which is well known for causing invasive disease leading to death even though diagnosis is not always made in life, as in this case ( ) . no other pathogenous agents were present. an autopsy was performed within h after death. external examination was irrelevant. internal examination revealed an increased consistency and weight of the lungs ( g the left and g the right respectively) with positive hydrostatic docimasia in all fields and intense congestion which was ascribed to a bilateral pneumonia. the examination of other organs was unremarkable except for intense polyvisceral stasis. the histological examination of lung specimens (one sample per lobe and more samples in increased thickening pulmonary areas as common practice), performed by using the same method described earlier for the previous case, showed alveolar septa that mildly thickened by edema and capillary congestion, alveolar edema, hyaline membranes coating alveolar septal surfaces, flattened pneumocytes, alveolar infiltrates of polymorphonuclear neutrophilic leukocytes, pigmented macrophages, monocytes and plasma cells, fibrin thrombi in small arteries (fig. b) . all these findings suggested a typical dad, confirmed by positive results to immunohistochemical dye for surfactant apoprotein (pe- ) (data not shown) ( ) . in the kidneys was found a thrombotic microangiopathy compatible with dic. the lung samples were examined under a confocal laser scanning microscope, and a three-dimensional reconstruction was performed ( ) . the silent (case ) and the paucisymptomatic (case ) presentations, and the histological and immunohistochemical findings led us to the diagnosis of ards supporting the conclusion that both were affected by a quite rare type of pulmonitis definable as hidden pneumonia. acute respiratory distress syndrome is a pathological entity arising from multiple pulmonary or extrapulmonary causes ( ) . generally, patients with ards report a short prodromal illness characterized by few symptoms like fever and cough, followed by the acute onset of progressive shortness of breath which rapidly evolves to respiratory failure ( ) . chest radiographs typically show bilateral diffuse airspaces opacifications ( ) . chest hrtc scans are significative for bilateral ground-glass attenuation ( ) . the histological features of ards, investigated from open lung biopsies or autopsies, are those of dad, a nonspecific pattern of acute lung injury ( ) . acute respiratory distress syndrome has a poor prognosis, with reported mortality rates still appearing to be higher than % ( ) . the first case concerns a -year-old man found lifeless at home by his girlfriend. at autopsy polyvisceral stasis, diffuse microthrombosis, free citrine liquid on both sides of the pleural cavities, a marked lung congestion, and the release of foamy material were found. hydrostatic docimasia for large and small fragments was bilaterally positive in all fields. the histological evaluation of lungs samples stained with h&e, also examined under a confocal laser scanning microscope, gave evidence of a pattern of dad. the presence of hyperplastic type ii pneumocytes and hyaline membranes was confirmed by the positive reaction of the immunohistochemical dye for surfactant apoprotein (pe- ). additional tests were carried out to identify possible pathogenous agents through microbiological studies but all the cultures showed no bacterial growth. toxicology was negative for drugs and alcohol. the second case involves a -year-old previously healthy man who presented, after a -h history of sore throat, fever, and cough, an acute onset of increasing shortness of breath rapidly progressing in acute respiratory failure with hemoptysis. chest x-ray and hrct showed the typical pattern of ards, with bilateral, symmetric, diffuse ground-glass attenuation. despite admittance to the intensive care unit, the patient died after few hours. two blood cultures were positive for group a beta-hemolytic streptococcus. the macroscopical and histological patterns were similar to that of case . in both cases the cause of death was attributed to an acute cardio-respiratory failure secondary to acute bilateral pneumonia and consequently ards, sepsis, and dic. these cases demonstrate how ards can rapidly lead to death in young patients that can generally be successfully treated in case of pneumonia. in the first case the postmortem diagnosis of ards and sepsis with dic ( ) was made exclusively on the basis of a careful postmortem examination and a complete histological study. therefore, the authors underline that forensic pathological procedures should be applied in all cases of sudden death using systematic practical investigations to find the cause of death, more so in fatal cases involving young people. just in this way it is possible to perform an adequate differential diagnosis when sudden cardiac death is more likely to be expected because of the young age of the patient. the second case, which has attracted the medicolegal interest because of medical liability profiles that were assumed as fault for doctors, suggests that clinicians should be suspicious of all community-acquired pneumonia ( ) , especially in young people, because rigorous diagnosis as well as early and appropriate therapy is mandatory to avoid unexpected death ( ) . particularly, from a forensic point of view, in such cases the authors suggest the importance of taking postmortem bacterial and viral cultures. last, the forensic community should not forget the role played by ards as a potential cause of sudden and unexpected death in previously healthy young people. a shock toxin that produces disseminated intravascular coagulation and multiple organ failure low-tidal-volume ventilation in the acute respiratory distress syndrome the american-european consensus conference on ards. definitions, mechanisms, relevant outcomes, and clinical trial coordination irwin and rippe's intensive care medicine, th edn abbas ak robbins and cotran pathologic basis of disease nonhomogeneous immunostaining of hyaline membranes in different manifestations of diffuse alveolar damage the acute respiratory distress syndrome mechanisms of sepsis-induced organ dysfunction sepsis definitions conference a multicenter registry of patients with acute respiratory distress syndrome. physiology and outcome effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome in: chapman hc, editor. a manual of medical jurisprudence, insanity and toxicology an immunohistochemical study in a fatal case of acute interstitial pneumonitis (hamman-rich syndrome) in a -year-old boy presenting as sudden death using new technology to answer old questions in forensic investigations the microbiology of the autopsy viral community-acquired pneumonia in nonimmunocompromised adults writing committee of the world health organization (who) consultation on human influenza a ⁄ h . avian influenza a (h n ) infection in humans acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data acute deaths in nonpregnant adults due to invasive streptococcal infections pulmonary and extrapulmonary forms of acute respiratory distress syndrome comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings diagnostic imaging of idiopathic adult respiratory distress syndrome (ards) ⁄ diffuse alveolar damage (dad) adult respiratory distress syndrome due to pulmonary and extrapulmonary causes: ct, clinical, and functional correlations pulmonary pathology of acute respiratory distress syndrome epidemiology and outcome of acute lung injury in european intensive care units. results from the alive study post-mortem diagnosis of sepsis update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults incidence, clinical course, and outcome in patients with acute respiratory distress syndrome the authors thank prof. vittorio fineschi for his help in histological and immunohistochemical studies. they also thank margherita neri, m.d. and irene riezzo, m.d. for their excellent technical assistance in confocal microscopy. finally the authors thank claudio giacomazzi, m.d. for his help in microbiological studies. key: cord- -jjd fyh authors: singhavi, ravi; sharma, kamal; desai, hardik d; patel, rahul; jadeja, dhigishaba title: a case of hemolytic anemia with acute myocarditis and cardiogenic shock: a rare presentation of covid- date: - - journal: cureus doi: . /cureus. sha: doc_id: cord_uid: jjd fyh coronavirus disease (covid- ) cases are on the rise globally, and mortality- and survival-related data are emerging every day. in addition, upcoming reports are suggestive of increased risk of cardiac ailments in high-risk patients. in the context of cardiac involvement, acute myocarditis has become one of the unexplored areas in covid- patients, which could influence the long-term outcomes. in this report, we present a rare case that warrants further study on the subject due to the paucity of data in the literature. to date, no case of severe hemolytic anemias with stress cardiomyopathy/acute myocarditis in a patient of covid- has been formally reported in the literature. the bedside echocardiogram had shown a possibility of acute myocarditis. the patient’s marked left ventricular (lv) functional recovery without coronary intervention further corroborates the same. clinicians should be aware of the diversity of cardiovascular/hematological complications, as well as focused cardiac ultrasound study and the importance of echocardiography as a good screening modality for cardiovascular and hematological complications of covid- infection. as of july , , the novel causative virus -the severe acute respiratory syndrome coronavirus (sars-cov- ) -has affected , , people and caused , deaths, with a case fatality rate (cfr) of . globally [ ] . recent studies have shown that mortality in the takotsubo syndrome (tts) variant of myocardial involvement in coronavirus disease (covid- ) has been higher than mortality in tts without covid- and it affects both genders almost equally [ ] . in this report, we present a case of acute hemolytic anemia with acute myocarditis and cardiogenic shock in a male patient with covid- infection. a -year-old male presented to the emergency department with a one-day history of low-grade fever that had peaked to °f just the night prior to the hospitalization with minimal flu-like symptoms. physical examination on presentation showed blood pressure of / mmhg, heart rate of /minute, respiratory rate of breaths/minute, and % oxygen saturation on room air. the patient had no significant past or family medical history. laboratory tests on day one showed an elevated c-reactive protein (crp) of mg/l, erythrocyte sedimentation rate (esr) of mm for one hour, and elevated serum glutamic-pyruvic transaminase (sgpt) of iu. on day two of admission in the covid- intensive care unit (icu), laboratory findings returned with a hemoglobin of . gm%, total white cell count of , /cmm with a reduced platelet count of , /cu mm. peripheral smear showed normocytic hypochromic anemia with few fragmented rbcs and schistocytes with reticulocytosis with the possibility of hemolytic anemia due to smear features of fragmented rbcs. lactate dehydrogenase (ldh), which is often a surrogate marker of both hemolytic anemia and inflammation, was elevated at mg%. elevated cardiac biomarkers, viz. troponin i of , . ng/l and brain natriuretic peptide of , pg/ml, were also recorded. lactate was . mmol/l and serum creatinine was . mg/dl. electrocardiogram was mimicking of acute coronary syndrome, showing mild st depression and t wave inversion ( figure ). echocardiography revealed global hypokinesia, with a preserved wall thickness ( figure ) , and left ventricular ejection fraction (lvef) of %. high-resolution ct thorax (video ) and ct of abdomen-pelvis were unremarkable. the patient was managed in the icu on inotropes. covid- was strongly suspected despite normal high-resolution ct. differential diagnoses included acute coronary syndrome, sepsis, acute fulminant myocarditis, and vasospasm in the setting of covid- infection. a nasopharyngeal swab was positive for high viral load (by cycle time) for sars-cov- by reverse transcription-polymerase chain reaction (rt-pcr). given his positive covid- test and hemoglobin of a mere . gm%, the decision was made to defer coronary angiography. the patient was transfused pack cell volume to correct anemia along with iv noradrenaline infusion, low molecular weight heparin, iv vitamin k, and a low dose of diuretics and steroids in the form of injection methylprednisolone pulse therapy. clinically, the patient developed cardiogenic shock during the course of hospitalization and required uptitration of norepinephrine. he stabilized over the next two to three days and was finally discharged on day with a hemoglobin level of . gm%. discussion covid- has been primarily a respiratory disease, but many studies have reported that it affects multiple systems. cardiogenic shock due to myocarditis has been extensively reported as among the most common cardiovascular complications of covid- [ ] . previous studies have reported that angiotensin-converting enzyme (ace ) receptors mediated effects on lungs, kidneys, heart, vascular endothelium by downregulating their expression and enhanced vasoconstriction with deleterious effects of the unopposed reticuloendothelial system [ ] . it is also likely that virus-mediated immune response can cause consumption coagulopathies, acute hemolytic anemias, and other blood cell dyscrasias [ , [ ] [ ] . cardiac findings of previously published autopsy series of patients with covid- have reported cell necrosis without lymphocytic-myocarditis with no evidence of direct viral cytotoxicity [ ] . both acute myocarditis and acute hemolytic anemias and consequent severe anemia can together or alone produce acute heart failure and dilated lv/poor lv function. in this report, we presented a case of a covid- patient who developed acute myocarditis and severe acute hemolytic anemia, as evident from peripheral blood smear showing schistocytes (fragmented rbcs) in peripheral smear with acute severe anemia along with elevated ldh, which is also a surrogate marker for hemolysis. acute heart failure with cardiogenic shock with possible stress cardiomyopathy is often characterized by transient severe global lv dysfunction in the absence of significant coronary artery disease. the cardiogenic shock was diagnosed based on the intraaortic balloon pump in cardiogenic shock ii (iabp-shock ii) definition: systolic blood pressure of mmhg that requires more than minutes of inotropic support. exclusion of sepsis was supported by the normal value of serum procalcitonin apart from the corroborative echo finding of severe lv dysfunction [ ] . in this patient, despite low oxygen saturation, the ct scan was clear, and the low saturation could be explained by central oxygenation impairment apart from peripheral vasoconstriction due to low cardiac output and inotropes that were being administered to the patient. pao and sao correlation varies more widely below % saturation and hence may be misleading. severe acute myocarditis may sometimes manifest with low forward output and minimal pulmonary congestive manifestations [ ] . it is hypothesized that high catecholamines, exaggerated inflammatory/immune-mediated response, and direct viral cytotoxicity and consequent effects of acute anemia (high co state) may be the mechanism behind the development of such reversible transient stress cardiomyopathy secondary to acute heart failure due to acute myocardial damage and/or rapid rbc breakdown [ ] . to date, no case of severe hemolytic anemias with stress cardiomyopathy/acute myocarditis in a patient of covid- have been formally reported in the literature. in our patient, the bedside echocardiogram had shown a possibility of acute myocarditis. the patient's marked lv functional recovery without coronary intervention further corroborates the same. it is anticipated that as the number of covid- cases rises worldwide, there will be an increase in the number of associated cardiovascular manifestations and myriad complications. clinicians should be aware of the diversity of cardiovascular/hematological complications and focused cardiac ultrasound study and critical care echocardiography as good screening modalities for cardiovascular complications of covid- infection. human subjects: consent was obtained by all participants in this study. conflicts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. takotsubo syndrome a rare entity in patients with covid- : an updated review of case-reports and case-series cardiovascular complication in covid- sars-cov- receptor and regulator of the renin-angiotensin system: celebrating the th anniversary of the discovery of ace covid- update: covid- -associated coagulopathy autoimmune haemolytic anaemia associated with covid- infection rs: pulmonary and cardiac pathology in african american patients with covid- : an autopsy series from new orleans cardiogenic shock correlation between the levels of spo and pao . lung india international expert consensus document on takotsubo syndrome (part i): clinical characteristics, diagnostic criteria, and pathophysiology key: cord- -w qkjz authors: chen, wei; chen, yih-yuan; tsai, ching-fang; chen, solomon chih-cheng; lin, ming-shian; ware, lorraine b.; chen, chuan-mu title: incidence and outcomes of acute respiratory distress syndrome: a nationwide registry-based study in taiwan, to date: - - journal: medicine (baltimore) doi: . /md. sha: doc_id: cord_uid: w qkjz most epidemiological studies of acute respiratory distress syndrome (ards) have been conducted in western countries, and studies in asia are limited. the aim of our study was to evaluate the incidence, in-hospital mortality, and -year mortality of ards in taiwan. we conducted a nationwide inpatient cohort study based on the taiwan national health insurance research database between and . a total of , ards patients ( % male; mean age years) were identified by international classification of diseases, th edition coding and further analyzed for clinical characteristics, medical costs, and mortality. the overall crude incidence of ards was . per , person-years, and increased from . to . per , person-years during the study period. the age-adjusted incidence of ards was . per , person-years. the overall in-hospital mortality was . %. in-hospital mortality decreased from . % in to . % in (p < . ). the in-hospital mortality rate was lowest ( . %) in the youngest patients (age – years) and highest ( . %) in the oldest patients (> years, p < . ). the overall -year mortality rate was . %, and decreased from . % to . % during the study period. patients who died during hospitalization were older ( ± versus ± , p < . ) and predominantly male ( . % versus . %, p < . ). in addition, patients who died during hospitalization had significantly higher medical costs ( versus us dollars, p < . ) and shorter lengths of stay ( versus days, p < . ) than patients who survived. we provide the first large-scale epidemiological analysis of ards incidence and outcomes in asia. although the overall incidence was lower than has been reported in a prospective us study, this may reflect underdiagnosis by international classification of diseases, th edition code and identification of only patients with more severe ards in this analysis. overall, there has been a decreasing trend in in-hospital and -year mortality rates in recent years, likely because of the implementation of lung-protective ventilation. a cute respiratory distress syndrome (ards) is a syndrome of acute respiratory failure that is characterized by alveolar-capillary barrier leakage, lung edema formation, pulmonary epithelial cell death, and an acute inflammatory response that manifests with poor lung compliance, hypoxemia, and bilateral infiltrates on chest radiograph. , a variety of clinical disorders are associated with the development of ards, including pneumonia, aspiration of gastric contents, sepsis, trauma, and the transfusion of blood products. acute respiratory distress syndrome is a major clinical problem that contributes to the death of more than , people annually in the united states. , in addition, patients who survive ards have reduced exercise capacity and health-related quality of life and have increased costs and use of health care services during the years after discharge from the intensive care unit. [ ] [ ] [ ] [ ] [ ] although this syndrome has a considerable impact on public health, relevant large-scale epidemiologic investigations have been rare in recent years. before , when a uniform definition of ards was not in place, several studies showed that the incidence of ards was approximately . to . per , person-years. [ ] [ ] [ ] [ ] after the american-european consensus conference published a uniform definition for ards in , several studies conducted in the united states, australia, and europe showed that the incidence of ards was as high as . to per , person-years. [ ] [ ] [ ] [ ] [ ] subsequently, rubenfeld et al conducted a prospective population-based cohort study in hospitals in and around king county, washington, and found that the incidence of ards was . per , person-years in the united states and that the incidence was age dependent and increased from per , person-years for those to years of age to per , person-years for those to years of age. epidemiological studies conducted in asia, however, are limited. because race may be a risk factor for development of ards and there has been no large-scale study of ards conducted in a predominantly asian population, we conducted a retrospective cohort study using nationwide population-based data from the national health insurance research database (nhird) of taiwan. the aim of our study was to investigate the incidence, medical costs, in-hospital mortality, and -year mortality of ards during a -year period. we conducted a population-based study using data obtained from all admission records of the nhird. in taiwan, the national health insurance program, implemented in , provides compulsory health insurance that covers more than % of the population. national health insurance research database includes almost all outpatient and inpatient medical records, including information on patient characteristics, such as age, sex, dates of clinical visits, date of admission, and diagnostic codes. the cases of ards were obtained from whole-population inpatient data in nhird between and and were defined using international classification of diseases, th revision, clinical modification (icd- -cm) codes. this study has been reviewed and approved by the institutional review board of the ditmanson medical foundation chia-yi christian hospital, taiwan. patients who were hospitalized with a diagnosis of ards (icd- -cm codes . , . ) for the first time between and were enrolled in the study. patients whose sex was not identified or who were less than years old were excluded from this study because ards in children has different epidemiology and outcomes. , demographic characteristics, resource utilization, clinical features, in-hospital mortality, and -year mortality were studied. because participation in the national health insurance system in taiwan is mandatory, patients who withdrew from the system for at least months were regarded as dead. the date of withdrawing is regarded as the date of death. age at the time of the first diagnosis was categorized into groups: to , to , to , to , to , to , and over years old. comorbidities that were recorded included pneumonia (icd- -cm codes - ), sepsis (icd- -cm codes . , . , . , . , . , and . ), trauma (icd- -cm code . ), and acute pancreatitis (icd- -cm code . ). the incidence rates (per , person-years) of ards were calculated from to and were plotted for each age group and calendar year for both sexes. the number of ards patients was used as the numerator of the incidence rate, and the total population of taiwan was used as the denominator. the total population for each year was obtained from the department of statistics in the ministry of the interior of executive yuan in taiwan. the age-adjusted incidence rate per , person-years was age-adjusted to the world population in . we tested for temporal trends in ards incidence by poisson regression analysis. differences in demographic characteristics, clinical features, and resource utilization of patients by survival status were tested with student t test or the wilcoxon rank sum test for continuous variables and the x test for categorical variables. we also reported in-hospital mortality and -year mortality across each calendar year, and the temporal trend was tested by the cochran-armitage trend test. data analysis was performed with spss software, version of the spss system for windows (version . : ibm corporation, somers, ny). a -tailed p value less than . was considered statistically significant. a total of , newly diagnosed ards patients ( . % male; mean age years) were enrolled in the study. among them, . % (n ¼ , ) died during hospitalization. patients who died during hospitalization were older ( ae versus ae years, p < . ) and more likely to be male ( . % versus . %, p < . ). in addition, patients who died during hospitalization had significantly higher medical costs ( versus us dollars, p < . ) and shorter lengths of stay ( versus days, p < . ) than patients who survived. the most common etiologic comorbidities for ards were pneumonia ( . %), followed by sepsis ( . %), and trauma ( . %). some patients had more than one etiologic comorbidity. there were significant differences in etiology by hospital mortality status ( table ). the estimated incidence of ards from to is shown in figure a . the incidence of ards during the study period for total male and female populations was . , . , and . per , person-years, respectively. the ageadjusted incidence of ards was . per , personyears. the incidence increased from . to . per , person-years in the total population (p < . by trend test). it also increased from . to . per , person-years in the male population and from . to . per , personyears in the female population (fig. a) . figure b shows the age-and sex-specific incidence rates for ards in taiwan. overall, the incidence rate increased from . per , person-years in the group of to years of age to an estimated . per , person-years in the group of years of age and above. the age-specific incidence rates increased with advancing age, with a sharp increase occurring in patients over the age of that was evident in both men and women. as shown in figure , men had higher incidence of ards than women in all age groups. the overall in-hospital mortality rate of ards patients during the study period was . %. figure a shows a significant trend of a decreasing in-hospital mortality rate, from . % in to . % in (trend test, p < . ) in the overall population, and similar trends in both sexes. an abrupt decrease in the in-hospital mortality rate in was coincident with an outbreak of severe acute respiratory syndrome that year. figure b shows a significant increase in in-hospital mortality rate from . % in the group of to years of age to . % in the group of years of age and above (trend test, p < . ). the pattern of -year mortality of ards was very similar to that of in-hospital mortality in this study (fig. ) . the overall -year mortality rate of ards was . %. we observed a trend of decreasing -year mortality rates from . % in to . % in in patients with ards (trend test, p < . ). there were no sex differences in -year mortality. to our knowledge, this is the first large epidemiological study of ards in a predominantly asian patient population. the average incidence of ards was . per , person-years, and increased from . to . per , person-years during the study period. the average in-hospital mortality rate was . % and decreased significantly from . % to . % during the study period. the in-hospital mortality rate was lowest ( . %) in the youngest patients (age - years) and highest ( . %) in the oldest patients (age > years, p < . ). the overall -year mortality rate was . %, and decreased from . % to . % during the study period. this study used international classification of diseases, th edition (icd- ) coding to identify patients admitted with a new diagnosis of ards. several previous studies have used the icd- coding system to investigate the incidence and outcomes of ards. reynolds et al reported that the estimated incidence of ards in maryland was in the range of to cases per , people and the mortality rate was % to %, using icd- codes . and . . other studies have also used the icd- coding system to determine the incidence or prevalence of ards in particular populations, such as those with traumatic brain injury, spinal cord injury, and subarachnoid hemorrhage. because the icd- coding system is linked to the taiwanese healthcare reimbursement system, the accuracy of icd- coding is quite precise. indeed, more than studies using the taiwan nhird have been published, including a number of important epidemiologic observations. [ ] [ ] [ ] [ ] [ ] in the case of ards, the specificity of icd- coding is likely improved by the fact that the diagnosis is typically made only by intensivists or pulmonologists. we, however, acknowledge that reliance on icd- coding to identify patients with ards likely underestimates the true incidence of ards, especially with regard to mild or moderate ards. this may explain why the observed incidence of ards in this study is lower than that reported by rubenfeld et al in a study that used prospective ards phenotyping by trained investigators. overall, the in-hospital mortality in this cohort was considerably higher than mortality reported in other large cohorts. , there are several potential explanations. one possibility is that use of icd- coding identifies a more severely ill group of patients than other methods of ards phenotyping. the in-hospital mortality rate in ( %) in the current study is very close to the mortality reported for patients with severe ards in the report of the berlin definition of ards, ( %), which accounted for approximately one-third of the total study participants in the berlin study. , one possible interpretation is that the taiwanese study population is representative of severe ards and that icd- coding missed many of the less severe mild and moderate cases. if this were the case, then the calculated incidence of all ards in taiwan might be closer to per , person-years, which is close to the recent report in the united states. in support of this estimate, moss et al used multiple-cause mortality data to analyze the incidence of ards in a population that was more likely to be in the severe stage of the disease. that study showed that the incidence of ards was to per , person-years, which is very close to our finding. another potential explanation for the high mortality in the taiwanese cohort is that factors related to health care delivery or patient race lead to the differences in observed outcomes. as shown in figure , men had higher incidence of ards than women in all age group. one potential explanation is that the rate of alveolar fluid clearance is faster in women with acute lung injury compared with men, which might lead to more rapid resolution of pulmonary edema. in addition, cigarette smoking has recently been shown to be a risk factor for ards , and men are -fold more likely to smoke than women in taiwan. unfortunately, the nhird does not contain information about patient smoking. although a number of experimental studies have shown promising benefits in treating ards, no clinical studies have demonstrated an effective pharmacologic treatment. the reported mortality of ards ranges from % to % depending on the patient population. several studies have shown a decrease in ards mortality over time, [ ] [ ] [ ] mainly because of the implementation of new ventilator strategies. a protective lung strategy could reduce the risk of further lung injury, systemic inflammation, and subsequent multisystem organ failure in ards patients. , [ ] [ ] [ ] interestingly, in the current study, there was an abrupt decrease in mortality in , which coincided with the outbreak of severe acute respiratory syndrome in asia and an increase in incidence of ards (fig. a) . a possible explanation may be that physicians in taiwan that year were more aware of ards and provided better care and were more adherent to low tidal volume ventilation in ards patients. this study has both strengths and limitations. the major strengths include the large number of ards patients in the nhird as well as the long period of follow-up. to our knowledge, this is the first nationwide epidemiological study of ards, and the follow-up period is the longest available, so we can clearly see the trend of the disease. the limitations of the study are inherent to icd- database without any specified definition of ards and retrospective in nature. we did not have detailed data for definition of ards, such as the chest radiograph reports, ratio of arterial oxygen partial pressure to fractional inspired oxygen, and utility of positive end-expiratory pressure. in addition, major indexes as acute physiology and chronic health evaluation score, sequential organ failure assessment score, or lung injury score were lacking. second, because we were limited to the icd- coding data for each admission, we could not identify the actual etiologies of ards in this study. finally, no clinical data such as arterial blood gas analyses were available to grade the severity of ards. in conclusion, we provide the first study of large-scale epidemiological data for ards in asia. the incidence of ards may be underestimated because of the use of icd- coding in the nhird and severe ards may be overrepresented. nevertheless, the study provides valuable new information on the incidence and outcomes of ards in an asian patient population. consistent with findings in other countries, there has been a decrease in in-hospital and -year mortality 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patients with acute lung injury/ards have decreased over time eight-year trend of acute respiratory distress syndrome: a population-based study in olmsted county, minnesota improved survival of patients with acute respiratory distress syndrome (ards): - acute respiratory distress syndrome: epidemiology and management approaches the acute respiratory distress syndrome network. ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome effects of a clinical trial on mechanical ventilation practices in patients with acute lung injury key: cord- -xt zxajf authors: shanmugam, chandrakumar; mohammed, abdul rafi; ravuri, swarupa; luthra, vishwas; rajagopal, narasimhamurthy; karre, saritha title: covid- – a comprehensive pathology insight date: - - journal: pathol res pract doi: . /j.prp. . sha: doc_id: cord_uid: xt zxajf corona virus disease- (covid- ) caused by severe acute respiratory syndrome corona virus- (sars cov- ), a highly contagious single stranded rna virus genetically related to sars cov. the lungs are the main organs affected leading to pneumonia and respiratory failure in severe cases that may need mechanical ventilation. occasionally patient may present with gastro-intestinal, cardiac and neurologic symptoms with or without lung involvement. pathologically, the lungs show either mild congestion and alveolar exudation or acute respiratory distress syndrome (ards) with hyaline membrane or histopathology of acute fibrinous organizing pneumonia (afop) that parallels disease severity. other organs like liver and kidneys may be involved secondarily. currently the treatment is principally symptomatic and prevention by proper use of personal protective equipment and other measures is crucial to limit the spread. in the midst of pandemic there is paucity of literature on pathological features including pathogenesis, hence in this review we provide the current pathology centered understanding of covid- . furthermore, the pathogenetic pathway is pivotal in the development of therapeutic targets. the current pandemic of corona virus disease- (covid- ) caused by severe acute respiratory syndrome corona virus- (sars cov- ) led to complete lockdown in many countries contributing to major socio-economic crisis and irreparable recession, globally. sars cov- , a novel β cov was first identified in adults presenting with acute lower respiratory tract infection of unexplained etiology in china. [ ] though no age group is spared, severe forms occur in patients older than years specifically with co-morbidities. the majority of the infected individuals are asymptomatic or with mild form of disease and are potential transmitters. this disease is highly contagious and mainly spread through respiratory droplets, close contact with infected cases or materials (fomites) and nosocomially to other patients and health care workers in the hospitals. [ , ] covid- has a much lower case fatality ratio and significantly greater transmission rate than sars pandemic. [ , ] currently rt-pcr of upper and lower respiratory swabs or samples is the gold standard diagnostic test. serological tests based on antibody detection, though not helpful during the early phases of disease, can be used to confirm infection in later phase. a thorough literature search (pubmed, preprint servers and google scholar) using terms covid- and pathology/pathogenesis, sars cov- and pathology/pathogenesis and -ncov and pathology/pathogenesis was done to maximize the yield of literature, which ended on may . in this review, we have comprehensively discussed all aspects of covid- with special emphasis on the pathology including pathogenesis and therapeutic targets. it forms a ready resource for clinicians, pathologists, and researchers including epidemiologists aiding them in the diagnosis and treatment of these patients, and may also pave way to further research. the earliest case of sars cov- infection currently known was reported on st december in wuhan, hubei province of china. [ ] after this it spread rapidly to other parts of china as well as internationally affecting over countries as of april , leading to the current global pandemic. [ ] the world health organization declared covid- to be a public health emergency of international concern on january , and recognized it as a pandemic on march .[ , ] as of may , globally . million cases of covid- have been reported, resulting in , deaths and , , people have recovered. [ ] j o u r n a l p r e -p r o o f the basic reproduction number (r ) of the sars cov- is estimated to be between . and . , indicating its highly contagious nature. [ , ] the r may be even higher in places of public gatherings like in cruise ships, religious/political/academic/business congregations as well as in hospitals non-compliant with personal protective measures. [ , , ] the incubation period and serial interval is estimated at - days and days, respectively, which is similar to that for sars cov and mers cov. [ , , , ] early in the pandemic, the case-fatality rate (cfr) was estimated to be between . % and %, [ , ] lower than other hcovs (sars cov ( %- %) and mers cov ( %- %)). [ , , ] however, by the th of may many countries exhibited exponential rise in cfr. [ ] (table:i) unlike sars cov, the high percentage of sars cov- infected individuals manifest as asymptomatic or pauci-symptomatic infection who escape detection and become potential transmitters. [ , ] it is important to note that, not all close contacts are infected suggesting a role for individual genetic susceptibility. [ , , ] in humans, the virus usually gains entry through upper aero-digestive tract. more recently sars cov- was isolated from the feces of patients, indicating the possibility of fecal-oral spread. [ , ] furthermore, sars cov- infection in pregnant women raised a possibility of vertical transmission. [ ] however, the vertical transmission was ruled out based on negative testing for the virus on the swabs collected from the amniotic fluid, cord blood, neonatal throat and breast milk of the six infected pregnant women. [ ] the long range airborne transmission is also speculated which depends on flow dynamics of the virus from the infected person and also on ventilation status of the area. [ ] moreover, the expansion and spread of covid- can be visualized by mapping techniques like cartograms. [ ] the understanding of modes of transmission of sars cov- will enable application of appropriate containment measures. though there is generalized susceptibility to sars cov- infection for all age groups, body defense against infection as well as their underlying age related organ system compromise. [ , , , ] similar to sars cov, a recent study reported non-o blood group specifically group a had higher infection and death rates due to covid- owing to absence of protective anti-a igm antibodies. [ , ] many uncertainities still persist in the sars cov- epidemiology especially virus-host interaction including host susceptibility and the evolution of epidemic. the corona viruses (covs) are classified into α and β (seen in mammals including humans); γ and δ (seen in avian species). [ to pangolin cov with a difference of only one amino acid. [ ] recently another study suggested pangolin involvement in sars cov- origin due to evidence of re-assortment in covs. [ ] sars cov- differs from other β covs by the presence of unique polybasic cleavage site that contributes to increased pathogenicity and transmissibility. [ ] each virion is a enveloped, non-segmented, positive sense single stranded rna virus the sars cov- because of its similarity with sars cov is presumed to infect human cells through its densely glycosylated spike (s) proteins s fraction with receptor binding domain (rbd) which binds to the angiotensin-converting enzyme receptor (ace- r) with to fold higher affinity than sars cov. [ [ , ] after the virus gets attached to this receptor, the sars cov- with its unique polybasic s /s protease cleavage site with sprr insertion on the spike protein which is recognized and cleaved by transmembrane protease serine (tmprsss) expressed on host cells to expose the fusion protein (s fraction) that enables the fusion of both viral and the host cell j o u r n a l p r e -p r o o f membrane. [ ] it has been demonstrated that ace- r and tmprsss are highly co-expressed in alveolar type pneumocytes, epithelium of upper esophagus and absorptive enterocytes, forming the basis of speculation that the sars cov- can gain access into host through esophageal and intestinal epithelium apart from alveolar epithelium. hence, the potential target tissues for sars cov- should co-express ace- r and tmprsss. the current understanding of pathology stems from few case reports and autopsy case studies. the gross features include heavy and boggy lungs, patchy consolidation along with pleural fibrinous exudate and /or fibrosis, sometimes with purulent inflammation due to secondary bacterial infection with/without evidence of pericarditis. [ ] the microscopic features depend on stage and severity of the disease. early stages (asymptomatic/mildly symptomatic patients) show non-specific changes including pulmonary j o u r n a l p r e -p r o o f edema, focal pneumocyte hyperplasia, focal chronic inflammatory infiltrate and multinucleated giant cells with absence of prominent hyaline membrane formation. [ ] as, the disease progress there is diffuse alveolar damage with transparent hyaline membrane formation and severe pulmonary edema. however, in sars cov- , there is firbomyxoid exudates with visible fibrinous cords along with mucous plugging of bronchioles which has a bearing with respect to oxygen therapy. there is also widespread interstitial inflammatory infiltrates with severe epithelial damage,diffuse type ii pneumocyte hyperplasia consistent with ards. [ , , , , ] one study reported massive pulmonary interstitial fibrosis with variable degree of hemorrhagic necrosis, chronic inflammation with multinucleate giant cells and intracytoplasmic viral inclusion bodies in severe cases. [ ] interestingly, another study showed features of lymphocytic viral pneumonia in a patient who died early in the disease ( th day after development of symptoms), whereas five other patients who succumbed later ( th day after development of symptoms) exhibited acute fibrinous and organizing pneumonia (afop) showing extensive fibrinous deposits forming balls/mounds but not hyaline membrane in their alveoli. these patients also showed prominent vascular injury evidenced by endothelial cell detachment and prominent intracytoplasmic vacuolization in small and medium-sized pulmonary blood vessels. [ ] also, severe covid- infection has been associated with a novel pulmonary-specific vasculopathy known as pulmonary intravascular coagulopathy (pic), that parallels disease severity. [ ] these findings may be considered as important indicators of disease severity and prognosis. the liver shows mild lobular lymphocytic infiltration and moderate micro-vesicular steatosis along with mild lobular activity, possibly related to the viral infection itself and ischemia. there were no obvious histological changes in heart tissue except for mild interstitial chronic mononuclear infiltrate. [ , , ] hence the changes in the liver and heart are more likely secondary or related to the underlying diseases. [ ] the pathology in other organs have not been elucidated. it is too early to determine the specificity and consistency of these histopathological findings with respect to the stage and severity of the covid- owing to the paucity of information obtained from few biopsy/autopsy case reports. in addition, the histopathological features may be modified or altered by patients' immunity, presence of co-morbidities, secondary infections and therapy given to these patients especially steroids. only few patients present with gastrointestinal symptoms like diarrhea ( . %) and nausea/vomiting ( . %). [ ] in . % of covid- patients there was at least one underlying co-morbidity(hypertension, diabetes, chronic cardiovascular/ pulmonary/ renal disease and cancer). [ ] the severe form is characterized by ards that necessitates mechanical ventilatory support in an intensive care unit (icu), and also leads to multiorgan involvement resulting in shock, septicemia, and mods with high mortality. [ , ] a substantial proportion of patients developed diarrhea during hospitalization, potentially aggravated by various drugs including antibiotics. [ ] these patients may also present with cardiac sounding chest pain due to myocarditis and myocardial infarction. children are either asymptomatic or pauci-symptomatic (fever ( %), cough ( %), fatigue, rhinorrhoea or nasal congestion) and are less likely to have severe infections. [ , ] gastrointestinal symptoms like diarrhoea, abdominal cramps and vomiting, common in children, covid- positive patients frequently exhibit hematologic abnormalities in the form of lymphopenia, leukopenia, and thrombocytopenia, along with elevated levels of liver enzymes, lactate dehydrogenase, prothrombin time and d-dimers. [ ] lymphopenia is associated with disease severity and mortality. [ ] acute phase reactants such as crp, ferritin and procalcitonin and pro-inflammatory cytokine levels were higher in covid- than healthy adults. [ ] covid- patients needing icu management when compared to non-icu patients had higher plasma levels of pro-inflammatory cytokines (il , il , il , gscf, ip , mcp , mip a, and tnfα), increased total wbc and neutrophil counts, higher levels of d-dimer, creatine kinase, and creatinine. [ , ] similar laboratory findings were seen in children with covid- . [ ] findings on chest imaging in sars cov- pneumonia seems to be similar to ordinary viral pneumonia, with some peculiarities. chest x-ray and ct changes may be seen even before the detection of the virus from swab. in contrast, the chest x-ray may be normal in % of laboratory confirmed covid- cases. [ ] the commonest feature on chest x-ray is presence of bilaterally symmetrical ground glass opacities with or without associated consolidation in the posterior and peripheral lung fields. [ ] however, the ct findings vary with the duration of symptoms. [ ] in the initial phase (days - ) basal multifocal peripheral ground-glass opacities are noted. with disease progression (mid phase (days - ) there is linear opacities developing on a background of ground-glass opacities (crazy pavement pattern). in the late phase (days - ) the central ground-glass opacities become surrounded by denser crescentic shaped consolidation (forming more than three-fourths of a circle) or form complete ring of at least mm in thicknesscalled as 'reversed halo sign' or 'atoll sign' [ ] children also exhibit similar radiologic features. [ ] chest ct suggesting covid- had % sensitivity in concordance with positive these tests are complex, time consuming, expensive and need expertise to perform as well as to interpret. [ , , ] the molecular test based on point of care testing using cartridges are rapid and needs less expertise. high throughput technologies including ngs can be used for simultaneous screening of large number of samples but its application is limited to research only due to high expenditure. [ ] the serological tests detects either the viral antigens (spike protein and nucleo-capsid being target antigens), or the antibody response to the virus by immunochromatography and elisa methods. specifically, the antibody testing is not helpful in the early phases of infection. though simple, cost effective, easy to perform and interpret, there are chances of false positives especially due to cross reactive antibodies against other hcovs. additionally, a negative antibody test does not exclude sars cov- infection. [ , ] the role of virus isolation and culture as well as detection of the virus by its cytopathic effects on cell lines is highly limited due to requirements of bio-safety level- facility. [ , ] hence it is not j o u r n a l p r e -p r o o f recommended by who for diagnostic purpose [ ] currently the diagnostic tests for detecting sars cov- infection is variable and non-uniform owing to the use of different probes, kits and reagents. though there are numerous reports claiming efficacy of various drugs and vaccine against covid- , none are effective and safe to receive approval by regulatory authorities. the management of covid- mainly relies on effective implementation of infection preventive and control measures and delivery of timely supportive care including oxygen therapy and mechanical ventilation as and when indicated. as the r value is > (range . to . ), [ , ] efficiency of intervention strategies such as screening of incoming people, wearing masks, quarantine for travellers has already been proved. [ ] specifically, reducing travel volume to and from china has had a positive impact on transmission dynamics of covid- . [ ] . though preventive vaccines against sars cov- can be developed targeting the spike (s) glycoprotein or its receptor-binding domain (rbd), these are made ineffective due to generation of altered immunogens in the target proteins owing to rapid mutations and recombinations. [ , ] in sars cov, live attenuated vaccine with the deleted structural e gene mutant was effective in producing neutralizing antibodies which lowered viral loads and reduced disease severity. [ ] the development of inactivated vaccines against sars cov was hindered due to occurrence of harmful immune and/or inflammatory responses post challenge. j o u r n a l p r e -p r o o f [ , , ] sub-unit vaccines (purified proteins combined with adjuvants) and viral vector (adeno virus) vaccines against s glycoprotein or its rbd and n protein of sars cov and mers cov elicited higher humoral response as well as enhanced mucosal immunity with intranasal administration. [ , , ] furthermore, dna based vaccine against s glycoprotein of mers cov also showed robust neutralizing antibody response and is currently under clinical trial. [ ] based on these reports vaccines for sars cov- is likely possible. however, its efficacy and safety has to be proved before approval. in the absence of specific anti-viral therapy, treatment is mainly symptomatic and supportive that includes oxygen therapy, conservative fluid management, hemodynamic support and / or mechanical ventilation. mechanical ventilatory support with low tidal volume and low inspiratory pressure is indicated when the respiratory distress is refractory to conventional oxygen therapy or niv. [ ] extracorporeal membrane oxygenation (ecmo) is indicated in patients with refractory hypoxemia despite prone position mechanical ventilation. [ ] a recent retrospective study identified older age, high sequential organ failure assessment score (sofa) score, and d-dimer greater than µg/ml as poor prognostic factors which aid the clinician early in instituting aggressive treatment and monitoring for such patients. [ ] steroids, and injudicious antibiotic use should be discouraged. some studies report effective use of rna polymerase inhibitors remdesivir and immucillin-a as prophylactic and therapeutic agents against hcovs including sars cov- . [ , ] anti-malarial drug chloroquine and its analogue may show protective effect against virus by decreasing intracellular ph but may cause cardiac arrythmias owing to prolonged qtc interval in some patients. [ ] monoclonal antibodies against interleukin- (il- ) like sarilumab, siltuximab, tocilizumab and interleukin- (il- ) inhibitor like anakinra may be useful in severe cases and may control the effects of sirs which is the main culprit in the pathogenesis of severe cases. [ ] currently, there are , studies registered in clinical trials involving various investigational drugs and vaccine apart from those mentioned above and are still at phase-i level. [ ] theoretically, molecules involved at each step of sars cov- pathogenesis may become potential therapeutic targets. (figure: to conclude, sars cov- is highly infective and its control depends on strict implementation of preventive measures. though rt-pcr is the gold standard for sars cov- diagnosis, the results are variable and there is scope of false negatives owing to either sampling errors or due to usage of different primers and reagents by different vendors. serologic estimations of antibody titres though not helpful for diagnosis, may be useful for prognostication and follow-up. though currently available pathologic data is limited, it is of prime importance to unveil the pathogenesis which will enable the development of therapeutic options. however, studies on larger cohorts are needed to validate the findings obtained for generalized application. importantly, due to limited availability of time and resources for research during the current emergency situation there is a huge lag and gap in understanding covid- ; hence the current review removes the lag and bridges the gap and provides 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use of chloroquine as an antiviral treatment we thank dr. vaseemuddin mohammad (consultant nephrologist, tables: table i key: cord- - g tosjx authors: tumlinson, anne; altman, william; glaudemans, jon; gleckman, howard; grabowski, david c. title: post‐acute care preparedness in a covid‐ world date: - - journal: j am geriatr soc doi: . /jgs. sha: doc_id: cord_uid: g tosjx coronavirus disease (covid‐ ) has led to a surge of patients requiring post‐acute care. in order to support federal, state and corporate planning, we offer a four‐stage regionally oriented approach to achieving optimal systemwide resource allocation across a region's post‐acute service settings and providers over time. in the first stage, the post‐acute care system must, to the extent possible, help relieve acute hospitals of non‐covid‐ patients to create as much inpatient capacity as possible over the surge period. in the second stage after the initial surge as subsided, post‐acute providers must protect vulnerable populations from covid‐ , prepare treat‐in‐place protocols for non‐covid‐ admissions, and create and formalize covid‐ specific settings. in the third stage after a vaccine has been developed or an effective prophylactic option is available, post‐acute care providers must assist with distribution and administration of vaccinations and prophylaxis, develop strategies to deliver non‐covid‐ related medical care, and begin to transition to the post‐covid‐ landscape. in the final stage, we must create health advisory bodies to review post‐acute sector's response, identify opportunities to improve performance going forward, and develop a pandemic response plan for post‐acute care providers. c oronavirus disease (covid- ) is overwhelming the nation's acute care hospitals, creating an immediate and dire need to increase availability of inpatient beds, ventilators, and personal protective equipment (ppe). the supply of care provided after a hospital stay, commonly referred to as "post-acute care," has also been disrupted by the pandemic. post-acute care includes long-term acute care hospitals (ltachs) that provide hospital-level care for medically complex patients; inpatient rehabilitation facilities (irfs) that provide hospital-level intense medical rehabilitation focused on restoring functional independence for individuals with disabilities resulting from an injury, illness, or medical condition; skilled nursing facilities (snfs) that provide skilled nursing, medical management, and therapy services to individuals who do not require services provided in a hospital; and home health agencies (hhas) that provide skilled care delivered by healthcare professionals in the patient's home for the treatment of a medical condition, illness, or disability. under normal conditions, post-acute care providers relieve capacity in inpatient hospital settings and serve a little less than one-half of all medicare patients discharged by hospitals. their normal roles are defined and somewhat constrained by regulatory requirements, clinical capabilities, and other legacy issues. for example, snfs take a high portion of post-acute discharges for rehabilitative care, and they also serve as the nursing home residence for a very frail population that lives in these facilities for long periods of time. the role these providers will play now, at a time when hospital capacity is most constrained, is in tremendous flux. congress and the centers for medicare & medicaid services (cms) recently invoked emergency authority through legislation and waivers to offer significant new flexibilities to reduce constraints on the types of patients these providers may serve and when they can provide care. despite these flexibilities, the potential for covid- infection of buildings and post-acute care workers (whose access to ppe is much lower than in hospital settings) continues to pose significant and growing public health threats that hamper the ability of post-acute providers to help address hospital capacity constraints. states and local healthcare delivery systems are responding to capacity constraints in widely varying ways, ranging from prohibiting transfer of any patients to post-acute settings, regardless of a patient's tested or suspected covid- status, to mandating that post-acute providers accept any or all such patients to relieve hospital capacity issues. these inconsistencies suggest the need to approach nonhospital resources systemically, locally, and from a public health perspective. given the ongoing risk of inundation at hospitals, with the concomitant demand to identify alternative settings of care for noninfectious patients displaced by covid- patients, public health professionals should be considering how to ensure optimal use of post-acute care resources. most immediately, they need to ensure that hospitals have access to multiple postdischarge care options for non-covid- patients. this can alleviate capacity constraints on their ability to care for critically ill patients infected with the novel coronavirus while protecting the frail residential populations that snfs serve. with proper planning and coordination, post-acute care providers can help achieve several important goals in both the short and long term: . serve as a hospital relief valve for non-covid- patients, freeing up desperately needed capacity to manage the surge in covid- -positive patients; . help to prevent hospitalization of non-covid- patients; . protect current post-acute patients and workers from contracting the virus; and . in targeted cases, operate exclusively as designated postacute covid- centers. to achieve these goals, we suggest a four-stage regionally oriented approach to achieving optimal systemwide resource allocation across a region's post-acute service settings and providers over time. this framework is available to support federal, state, and corporate planning. but we caution that any plan's effectiveness will depend on strong local and regional leadership and timely implementation of strategies and tactics as outlined. nationally, congress and cms have a continued obligation to continuously monitor the effectiveness of current and forthcoming regulatory waivers and to adjust postacute care payment systems to account appropriately for costs associated with treating covid- patients. our framework borrows heavily from a report by gottlieb and colleagues that focused on the broader economic recovery ( figure ). we have adapted their framework to reflect the realm of post-acute care: • demand for hospital beds is expected to peak nationally in april, with variation across regions, and likely regional and local resurgences throughout the balance of the year. the postacute care system must, to the extent practical, relieve acute hospitals of non-covid- patients to create as much inpatient capacity as possible over the surge period. during this period, we should assume that covid- testing will often be unavailable, slow, or unreliable. further, we assume that local public health authorities will have limited opportunity to trace individual outbreaks. we recommend three strategies to optimize market-level post-acute care assets in this phase. top three strategies . use waiver authority to quickly outplace non-covid- patients in non-acute hospitals, as available. identify immediately any irfs or ltachs operating in the market. under normal circumstances, federal regulation constrains the patients they can admit. the recent legislation and cms waivers will allow these facilities to take any patient without disruption to their reimbursement. evaluate all non-covid- patients for potential outplacement to these hospital-level facilities, if available. . undertake rapid regional assessments of the immediate and usable capacity of snfs, hhas, and other sources of care to enable hospital discharges for non-covid- patients. not all markets have irfs or ltachs, and even in those that do, beds are limited. however, until accurate testing equipment is widely available, with priority given to first responder, hospital, and post-acute staff, we believe it is inadvisable to require nonhospital postacute providers (snfs in particular) to accept any or all discharges from acute care hospitals. without timely and reliable testing, we cannot assure the safety of current nursing home residents and post-acute patients. further, many snfs lack the building design and staffing resources to isolate infected or quarantined admissions. in some markets, and assuming effective testing regimes, some post-acute providers may have new available capacity, as well as the capabilities and willingness to accept non-covid- or even covid- -positive patients (see capability assessment recommendations). further, some patients may be able to be safely discharged to home, with a combination of home health and physician care (eg, through telehealth), assuming appropriate testing regimes for in-person caregivers. . direct regional post-acute care providers to identify separate, specialized capacity for covid- -positive discharges. local public health leaders must also identify post-acute care options for covid- -positive patients. many of these patients will be extremely debilitated following mechanical ventilation and risk remaining in the acute care setting for to weeks. post-acute care leaders should work to identify empty buildings/units or available capacity in the post-acute system that public health leaders can repurpose to permit the safe discharge or transfer of recovering covid- patients to create hospital capacity. it may even be necessary, depending on the market or region, to consider the relocation of nursing home residents to create space for covid- -positive patients. leaders will need to evaluate the risks and benefits of every option for post-acute covid- -positive care. local public health officials working in collaboration with health and post-acute care system leaders should take these steps: • perform rapid structural capacity assessment: how many irfs, ltachs, and specialized snfs and where they are. • contact irf and ltach assets in the market and develop plans for rapid discharge. recognize that most medicare advantage plans have also waived authorization and other requirements. move quickly to outplace as many patients as possible to these settings. per the recommendations in "national coronavirus response: a roadmap to reopening," post-acute care optimization strategy may shift to stage , "regroup and prepare" when hospitals in the state are able to treat everyone without resorting to crisis standards of care, the state has the ability to test everyone who presents with symptoms, cases decline for days, and the state performs active monitoring and contact tracing. as covid- cases and deaths begin to decline following the surge, public health officials must continue to contain virus transmission, particularly as movement restrictions are eased. further, they must prepare for possible subsequent surges by updating capacity management and patient transfer protocols, recognizing the continued need to manage post-acute care resources for all discharges, especially frail, vulnerable populations. top three strategies . protect vulnerable populations from covid- and other infections. prioritize infection control and early treatment protocols in nursing homes and other hot spots of vulnerable populations. public health officials and other healthcare system leaders collaborate to support nursing facility staff and leadership to ensure adequate training for and monitoring of infection control efforts. prioritize testing and contact monitoring for nursing facility residents, assisted living residents, families, and workers. in preparation for infection, hospitals and nursing facilities should work collaboratively to ensure strong advance care planning protocols among nursing facility and assisted living residents as well as sufficient supply of palliative care medications. . prepare treat-in-place protocols for non-covid- admissions. under normal circumstances, frail older adults visit an inpatient setting frequently. cms and legislative waivers will now permit a range of strategies for delivering high levels of medical and palliative care at home, virtually through telehealth, and in facility settings. public health officials and hospitals must explore and implement hospital-at-home programs, palliative care programming, and virtual home health. in these efforts, they should include residential care settings such as nursing home and assisted living facilities, where hospitalization rates were particularly high before covid- . . create and formalize post-acute care covid- designations and create transfer protocols for various designations. now is the time to fully develop optimal non-covid- and covid- post-acute placement options that requires fully assessing market providers and creating a -month strategy for relieving hospital capacity at various intervals. local public health officials working in collaboration with health and post-acute care system leaders should: • create community-level medical/public health task force for supporting "hospital-in-place" and covid- specific palliative care programs for vulnerable populations, particularly residential care and nursing home long-stay populations. • perform a more thorough assessment of provider capacity for optimal deployment of systemwide postacute care provider assets. • identify and request any missing waivers of current regulations and statute for payment to flow to nonmedical resources. • acquire and distribute necessary ppe, equipment, and supplies. • test and monitor staff and residents aggressively. per the recommendations in "national coronavirus response: a roadmap to reopening," post-acute care optimization strategy may shift to stage , "restructure to recovery," when a vaccine has been developed or an effective prophylactic option is available. as the country emerges from the initial surge in illness, deaths, and demands on our healthcare system, we will enter a period of aggressive testing, virus transmission controls, contact tracing, and, ultimately, widespread immunity through a vaccine. these disease control measures, regular testing, surveillance, and follow-up, should focus first on protecting first responders, doctors, and nurses, and then on the caregivers, residents, and staff of the post-acute care community including home health workers. by prioritizing these groups, we will assure an adequate supply of healthcare professionals to treat and manage the ongoing threat of virus infection and spread. top three strategies . tap post-acute providers to participate in the front lines of distribution and administration of prophylaxis and vaccinations. these providers are most likely to be interacting with high-risk individuals including nursing home residents. their staff also need maximal protection in working with populations most at risk for transmission and infection. . continue and deepen strategies to deliver non-covid- related medical care at home and in residential care communities. begin to adopt long-term strategies that will prevent non-covid- hospitalizations among populations at high risk for infection. . prepare strategic plan for transition of post-acute care resources to the post-covid- landscape. identify community needs and demands relative to resources; redeploy as necessary. local public health officials working in collaboration with health and post-acute care system leaders should follow these steps: • create communitywide healthcare task force for rationalizing and organizing distribution and administration of medications and vaccines according to centers for disease control and prevention priorities. • identify a frontline organizational "champion" within each provider to participate in communitywide effort, lead internal processes, and coordinate with other healthcare organizations. • prioritize improving and developing systems of handoff between settings of care to prevent vaccination or medication gaps. leaders in the post-acute sector are already recognizing the opportunity to improve the sector's approach to caring for patients discharged from hospitals and/or who are frail and in need of medical and social supports. in addressing the burdens on our emergent-care systems, the post-acute sector is discovering new ways to care for patients, whether through more on-site skilled nursing or by more effective use of telehealth. we must evaluate these lessons and enhance our post-acute care provider capabilities, clarify their roles going forward, and evaluate the effectiveness of regulatory and legal payment waivers. top three strategies . create local hospital/post-acute/public health advisory bodies. these groups will review what worked and what did not including the effectiveness of medicare and medicaid waivers. . identify opportunities to optimize post-acute care at the market level for system performance moving forward. document improvements in care delivery that can be made permanent. . create, revise, and revisit pandemic response plan to include optimal use of all delivery system resources, supplies/equipment, and staff necessary to meet demand. document what worked and what did not, and plan for the future. states are beginning to move covid- patients from hospitals to nursing facilities national coronavirus response: a road map to reopening postacute care preparedness for covid- : thinking ahead a pragmatist's advice for nursing homes hospital-level care at home for acutely ill adults: a randomized controlled trial a working draft of this article appeared on the anne tumlinson innovations (ati) website, https://atiadvisory. com/work/post-acute-care-preparedness-in-a-covid- -world/. we are grateful for the assistance of elizabeth walsh in the preparation of this manuscript.financial disclosure: there were no direct funding sources for the writing or production of the article. howard gleckman is a senior fellow at the urban institute. the views expressed in this article are the author's own and do not reflect the view of the urban institute. david grabowski reported that he receives research support from grants from the national institute on aging; the agency for healthcare research & quality; the arnold foundation; and the warren alpert foundation; serving as a paid consultant to vivacitas; serving on the scientific advisory committee for navihealth; and receiving fees from the medicare payment advisory commission, compass lexecon, analysis group, the research triangle institute, and abt associates.conflict of interest: anne tumlinson and jon glaudemans provide advisory and analytic services to a variety of clients in the post-acute sector. william altman currently serves as a consultant at kindred healthcare and was formerly employed there. the views expressed in this article are the author's own and do not reflect the view of kindred healthcare.author contributions: all authors made substantial contributions to conception and design, and/or acquisition of data, and/or analysis and interpretation of data; participated in drafting the article or revising it critically for important intellectual content; and gave final approval of the version to be submitted.sponsor's role: no sponsor. key: cord- - ci re a authors: alomari, safwan o.; abou-mrad, zaki; bydon, ali title: covid- and the central nervous system date: - - journal: clin neurol neurosurg doi: . /j.clineuro. . sha: doc_id: cord_uid: ci re a • as the number of patients with covid- is increasing worldwide, it is necessary to stress on the importance of the atypical clinical presentations (including those related to the nervous system) of covid- infection, since they might be the initial manifestations. • literature on this regard should be sent by the international and local health committees to all health-care providers during this covid - pandemic, to make sure that all providers are well informed and aware of these cases. • more studies are deeply needed to enable the concerned committees to make evidence-based guidelines for prevention, early detection and appropriate management of these cases. at the beginning of december , wuhan, the capital of hubei province and a large city of approximately million persons located in the central region of the people's republic of china, witnessed an outbreak of a cluster of persons with viral pneumonia of unknown agent. on january , a group of chinese scientists succeeded to identify the etiological agent of the epidemic as a previously unknown coronavirus, and they named it by -ncov (for novel coronavirus) [ , ] . at the beginning of january , the covid- virus has spread to other countries including japan, korea, thailand, iran, and the united states [ ] . the novel coronavirus disease received an official name by the world health organization (who) as coronavirus , on february , [ ] . later, the international committee on taxonomy of viruses has suggested sars-cov- as the name of the virus that causes covid- [ ] . the world health organization declared the virus outbreak a pandemic on march , [ ] . the primary symptoms of covid- include fever, dry cough, and fatigue [ ] . however, some patients diagnosed with covid- have not shown these typical symptoms, at the time of diagnosis; instead, they have exhibited only neurological symptoms as the initial symptoms, such as the following: non-specific manifestations including headache, malaise and unstable walking, cerebral hemorrhage, cerebral infarction; as well as other neurological diseases [ ] . until now, we have scarce literature on covid- aspects related to the nervous system. in this article, the authors discuss the neurological aspects of covid- and provide a concise review of the reported literature on this field. for a given virus, the ability to infect certain cells, tissues, or even species while not affecting others is referred to as viral tropism [ ] . this viral tropism, allowing a virus to replicate in and affect certain body tissues, would then lead to the symptomatic presentation of that virus. a j o u r n a l p r e -p r o o f major factor that dictates this tissue selectivity, is the virus's ability to bind and take over specific host cell surface receptors [ ] . recent research on sars-cov- has shown that similarly to sars-cov, this virus can invade tissues by binding to the angiotensin-converting enzyme (ace ) receptor on certain host cells ( figure a ) [ ] . this binding is mediated by the spike protein found on the surface of sars-cov- and was found to have up to times the binding affinity of sars-cov [ ] . while its mrna can be found in virtually all body tissues, the ace receptor is mostly expressed in lung alveolar epithelial cells, small intestine enterocytes, vascular endothelial cells, in addition to airway epithelial cells, and kidney cells [ ] . more recently, it was reported that brain also expresses ace receptors on glial cells and neurons and this is most prominent in the brainstem, the paraventricular nucleus (pvn), nucleus tractus solitarius (nts), and the rostral ventrolateral medulla which all play a role in cardiovascular regulation [ ] . on the other hand, viral tissue invasion does not solely rely on the presence of certain receptors and the ability to hijack them. recent studies on the novel coronavirus have shown that, like its predecessors, a substantial part of its symptomatology can be explained by the cytokine storm it triggers, leading to a systemic inflammatory response syndrome (sirs) or sirs-like phenomenon ( figure b) [ , ] . this inflammation is mediated by interleukins (il- and il- ) released by monocytes and macrophages to stimulate other monocytes and both b and t lymphocytes, in addition to monocyte chemoattractant protein- (mcp- ), a chemokine responsible for the transmigration of the monocytes across the blood-brain barrier (bbb) [ , ] . thus, this can then lead to the inflammation of the bbb and increase its permeability which facilitates the passage of more inflammatory cytokines and chemokines into the brain and can exacerbate the neuroinflammation and neurological symptoms experienced by the patient [ ] . additionally, during previous coronavirus epidemics (sars-cov and mers-cov), animal studies on transgenic mice showed that both of these viruses were able to reach the brain when neuroinvasion [ ] . finally, it is important to mention that the virus can also cause cns damage and neurological symptoms without invading the brain itself. as respiratory viruses invade the lungs and cause inflammation, this leads to alveolar and lung tissue damage. inflammation and edema affect the oxygen exchange that happens at the alveolar-capillary interface leading to hypoxemia and subsequently brain hypoxia with vasodilation, hyperemia and brain edema ( figure ) [ ] . this would then manifest itself starting with headaches and, if kept unchecked, could cause a change in the level of consciousness and even coma [ ] . being a respiratory virus itself, sars-cov- has been shown to cause significant hypoxemia in many of the patients [ ] and hence, this possible pathway of brain injury remains a factor in its symptomatic profile. there is still a debate regarding the exact role of brainstem invasion by the virus in causing respiratory failure in covid- patients. li and colleagues ( ) have suggested that sars-cov- can enter the brain, and it might be the cause of the respiratory failure in patients with covid- [ ] . on the other hand, turtle ( ) has reported that respiratory failure alone does not suggest central nervous system invasion by sars-cov- . turtle relied on certain points to support his conclusion; patients with pneumonia typically develop hypoxic, or type respiratory failure, with low co levels and a raised respiratory rate, while brain failure typically leads to type respiratory failure and involves low oxygen, high co and reduced respiratory rate. he mentioned that these manifestations of type respiratory failure were not reported to any great degree in any of the case series of patients from china . he also stated that if the neuroinvasion of the virus would be the cause of respiratory failure, the virus should be detected in the cerebrospinal fluid of these patients [ , ] . recently, olds & kabbani ( ) raised the question of nicotine associated neurological comorbidity in covid patients depending on published evidence that the viral target receptor j o u r n a l p r e -p r o o f ace is expressed in the brain and functionally interacts with nachrs [ , ] . they considered neural cells and astrocytes (especially in the hypothalamus and brain stem) more prone to infection in smokers because nicotine stimulation of the nachr was found to increase ace expression within them ( figure ) [ ] [ ] [ ] . ace signaling pathway is believed to counteract oxidative stress and neuroinflammation, thus, disruption in ace balance can lead to neurodegeneration of dopaminergic neurons [ ] or impairment in cholinergic pathways which might participate in the progression of alzheimer's disease [ ] . we believe that this association between smoking and covid- neurological manifestations, if proven, might be of great impact, since all the people worldwide are currently at high risk of being exposed to smoking and covid- infection. hence, more studies are strongly encouraged in this regard. data on covid- is not yet complete or comprehensive as we are still in the midst of the active pandemic [ ] [ ] [ ] [ ] . however, early research from wuhan, china reported that the most common symptoms that appeared among patients with covid- included fever ( . %), fatigue ( . %), and a dry cough ( . %) [ ] . while these symptoms are typical of respiratory viruses, other sources additionally reported neurological symptoms and manifestation in up to . % of retrospectively studied covid patients (table ) [ ] . acute transverse myelitis, also referred to just as transverse myelitis (tm), is a rare neurological disturbance consisting of an inflammation of the spinal cord. patients with tm may present with sensory changes, weakness and autonomic dysfunctions [ ] . while no preceding infection was found in some of the reported cases, transverse myelitis is usually associated with common viral infections such as varicella zoster (vzv), herpes viruses (hsv- and cytomegalovirus) and enteroviruses [ ] . in february of , in wuhan, china, an elderly patient presented to the hospital with fever and fatigue with no previous contact with covid- patients [ ] . he was found to have covid- based on pcr tests of his nasopharyngeal secretions. after a week of j o u r n a l p r e -p r o o f hospitalization, he developed lower extremity weakness and paresthesia progressing to paralysis, along with urinary and bowel incontinence. he was diagnosed with post-infectious acute transverse myelitis. igm antibodies of the most common infectious organisms associated with tm (mycoplasma pneumoniae, ebstein-barr virus, and cytomegalovirus) were negative, and it was concluded that the cause of his post-infectious tm was sars-cov- virus. although this case report provides a strong basis for covid- associated transverse myelitis, it is worth noting that csf serological tests and a spinal cord mri were not performed [ ] . symptoms. t -weighted mri of the spine showed evidence of transverse myelitis [ , ] . all work-up tests for the typical viral causes of transverse myelitis came back negative. the patient was able to improve on multiple empiric treatments, such as intravenous immunoglobulins, steroids, and antivirals [ ] . encephalitis and meningitis can be caused by viruses like herpes simplex virus, rabies and others [ ] . they can present with an acute onset fever, nausea and vomiting along with neurological manifestations; including headache, altered level of consciousness, behavioral disturbances, seizures, photophobia, or hemiparesis [ , ] . while treatable in most cases, early detection and appropriate treatment are important to avoid the development of long-term and more severe complications. if left untreated, mortality rates can reach up to % as reported in certain cases of herpes related encephalitis and meningitis [ ] . recently, during the covid- pandemic, a -year-old man was transferred to the university of yamanashi hospital in japan after being found unconscious in his home [ ] . he reported typical signs of meningitis and encephalitis. csf was found to be positive for sars-cov- , while his nasopharyngeal secretions were negative. this case provides evidence of the neuroinvasive potential of sars-cov- and its role in the development of meningitis/encephalitis. besides, it also raises the concern of having patients with covid- that have negative nasopharyngeal swabs for the virus. another case of covid- -associated encephalitis was reported by efe et al. ( ) in turkey [ ] . a -year-old female patient was found to be positive for sars-cov- after j o u r n a l p r e -p r o o f undergoing a left anterior temporal lobectomy for refractory seizures [ ] . this patient's preoperative magnetic resonance imaging (mri) and magnetic resonance spectroscopy (mrs) result were suggestive of high-grade glioma, however, a biopsy taken during her surgery was nondiagnostic. knowing that encephalitis may often be indistinguishable from other cns pathology on mrs [ ] , efe et al. thus reported that their patient could have a case of covid- -associated encephalitis mimicking a glioma [ ] . moreover, mild encephalitis/encephalopathy with a reversible splenial lesion (mers) was reported in a covid- patient [ ] . mers is an encephalitis/encephalopathy syndrome that is associated with viral infections [ , ] . this was the first reported case of mers associated with coronavirus infection, which adds to the expanding list of differential diagnoses to be considered in a covid- patient with neurological signs, most notably; cerebellar ataxia and disturbance in consciousness [ , , ] . infectious toxic encephalopathy, also known as acute toxic encephalitis, is a rare type of reversible brain dysfunction syndrome associated with cerebral edema, with no evidence of inflammation on cerebrospinal fluid analysis. metabolic disorders, systemic toxemia, and hypoxia are considered contributing factors during the process of acute infection [ ] [ ] [ ] . it has a wide clinical presentation. patients with a mild form of the disease may develop headache, dysphoria, or delirium. while more severe forms may lead to disorientation, paralysis, loss of consciousness and even coma. acute viral infection is a known cause of this disease. covid- infection has been suggested as a cause of this disease depending on many findings. first, patients with covid- may suffer from severe hypoxia and viremia [ ] , which might eventually lead to toxic encephalopathy. moreover, around % of patients with covid- develop neurological symptoms and other brain dysfunction symptoms [ ] . added to that, brain edema has been detected in autopsy studies of brain tissue of covid- patients [ ] . collectively, these proposals provide evidence that covid- could cause infectious toxic encephalopathy, although more detailed researches are still required. acute hemorrhagic necrotizing encephalopathy (ane) occurs most commonly in the pediatric age group but reported to be in adults as well. characteristic radiological features include multiple symmetric lesions with thalamic involvement. cerebral white matter, brain stem, and cerebellum are other reported areas to be involved [ ] . acute necrotizing encephalopathy (ane) is a rare complication of viral infections (including influenza viruses). intracranial cytokine storms, with subsequent blood-brain barrier breakdown, is the most accepted theory behind ane after viral infections [ ] . recent evidence showed that patients with severe covid- might have a cytokine storm syndrome [ ]. poyiadji et al. ( ) were the first to report a case of ane in a covid- patient. a female in her fifties presented with a -day history of fever, cough, and altered mental status. laboratory work-up was negative for influenza, with the diagnosis of covid- made by detection of severe acute respiratory syndrome coronavirus (sars-cov ) pcr. csf bacterial culture showed no growth after days, and tests for herpes simplex virus and , varicellazoster virus, and west nile virus were negative. testing for the presence of sars-cov- in the csf was unable to be performed. ct scan demonstrated symmetric hypoattenuation within the bilateral medial thalami, and ct angiogram and ct venogram were negative. brain mri showed hemorrhagic rim enhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. these imaging findings were consistent with ane and they concluded that ane was caused by sars-cov . the authors reported that the patient was treated by intravenous immunoglobulin but high-dose steroids were not initiated due to concern for respiratory compromise [ ] . more recently, dixon et al. ( ) reported another case of ane in a -year-old covid- patient with aplastic anemia [ ] . the patient present days after onset of symptoms and was shown to have swelling in the brainstem on ct scan. brain mri showed multiple symmetric hemorrhagic lesions in the brainstem and different nuclei. the patient died days after hospital admission [ ] . leukoencephalopathy is the name given to the group of diseases that affect the white matter of the central nervous system [ ] . since the beginning of the covid- pandemic, many reports [ ] . although it is mandatory to rule out other etiologies in these critical patients, such as hemorrhagic encephalopathy, sepsis-associated encephalopathy, posterior reversible encephalopathy syndrome in addition to other toxic and metabolic causes [ ] , leukoencephalopathy should be considered in covid- patients. acute disseminated encephalomyelitis (adem) is an autoimmune demyelinating disease of the cns characterized by a sudden and widespread inflammation. it affects mainly children and younger adults, and it is usually triggered by viral infections, but unlike viral encephalitis, it is not due to viral neuroinvasion [ ] . no cases of adem in patients with covid- have been reported in the literature yet. however, there is a case of a -year old boy that presented to the children's hospital of buffalo with signs and symptoms of adem while also reporting a history of an upper respiratory tract infection a week before [ ] . this patient was given a presumed diagnosed of adem (ms could not be ruled out) and was found to have human coronavirus oc (hcov-oc ) in his csf and nasopharyngeal secretions by rt-pcr. this was the first reported case of coronavirus-associated demyelinating disease in a pediatric patient. while sars-cov- is not yet associated with such cases, hcov-oc is a member of the betacoronavirus family to which sasr-cov- also belongs. in addition, the two viruses were shown j o u r n a l p r e -p r o o f to be closely related phylogenetically and are two of the only seven known human coronaviruses [ ] . although we have evidence that respiratory-related infections are an independent risk factor for acute cerebrovascular events [ , ] , evidence specific to sars-cov- infection is still far from conclusive. strokes were reported to have an incidence close to % in hospitalized patients with covid- [ ] . one of the early studies in this field was done by muhammad et al. ( ) on experimental mouse models and suggested that influenza virus can aggravate ischemic brain injury via triggering a cytokine cascade and can increase the risk of cerebral hemorrhage after treatment with tissue-type plasminogen activator [ ] . the infection of cov, especially sars-cov- , has been widely reported to cause cytokine storm syndromes, which may be one of the factors that cov causes acute cerebrovascular disease [ , ] . in addition, critically ill patients with severe sars-cov- infections often show elevated levels of d-dimer and severe platelet reduction, which may render these patients prone to acute cerebrovascular events [ ] . interestingly, several recent reports showed that covid- patients have a propensity to develop a hypercoagulable state [ ] [ ] [ ] [ ] . a brief report of three covid- patients, who were young (mean age of years) and previously healthy, with only one of the three having a risk factor for hypercoagulability (oral contraceptives) eventually developed cerebral venous thrombosis following their infection [ ] . in addition, a retrospective cohort study in new york city, showed that covid- patients had higher national institutes of health stroke scale scores at admission, in addition to higher peak d-dimer values and a significantly higher mortality rate when compared with non-infected patients with strokes [ , ] . although there are no other reports on electroencephalography findings in covid- patients, it is worth mentioning that helms et al. reported in their paper that in the patients who underwent electroencephalography, only nonspecific changes were detected; and only one patient had diffuse bifrontal slowing consistent with encephalopathy [ ] . similarly, filatov et al. ( ) reported eeg findings of bilateral slowing and focal slowing in the left temporal region with sharply countered waves in patients with covid- associated encephalopathy [ ] . j o u r n a l p r e -p r o o f helms et al. reported that csf samples obtained from patients were all negative for sars-cov- and none showed cells. however, examination of csf samples revealed oligoclonal bands were present in patients, with an identical electrophoretic pattern in serum. protein and igg levels were elevated in patient [ ] . these findings might support the theory that the sars-cov- can cause neurologic manifestations indirectly, probably by triggering a reaction, rather than by direct invasion of the nervous system, although csf was found to be positive for sars-cov- in another report [ ] . as the number of patients with covid- is increasing worldwide, it is necessary to stress on the importance of the atypical clinical presentations (including those related to the nervous system) of covid- infection, since they might be the initial manifestations. patients with covid- infection should be evaluated early for neurological symptoms. timely analysis of cerebrospinal fluid and early appropriate management of infection-related neurological complications might be the key to improve the prognosis of critically ill patients. since health-care providers might under-recognize these cases with atypical presentations, and these patients may represent a hidden source of the spread of the virus, we believe that literature on this regard should be sent by the international and local health committees to all health-care providers during this covid - pandemic, to make sure that all providers are well informed and aware of these cases. moreover, awareness campaigns addressing this issue should be directed to the population. since we have a scarce literature on this regard, more studies are deeply needed to enable the concerned committees to make evidence-based guidelines for prevention, early detection and appropriate management of these cases. potential maternal and infant outcomes from coronavirus -ncov (sars-cov- ) infecting pregnant women: lessons from sars, mers, and other human coronavirus infections. viruses zhonghua gan zang bing za zhi = zhonghua ganzangbing zazhi = chinese journal of hepatology coronavirus disease (covid- ) outbreak severe acute respiratory syndrome-related coronavirus</em>: the species and its viruses -a statement of the coronavirus study group clinical features of patients infected with novel coronavirus in wuhan, china. the lancet neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study cytokine determinants of viral tropism sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor cryo-em structure of the -ncov spike in the prefusion conformation tissue distribution of ace protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis angiotensin-converting enzyme : central regulator for cardiovascular function dysregulation of immune response in patients with covid- in wuhan, china advances in the research of cytokine storm mechanism induced by corona virus disease overriding the brain's intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines il- and il- production from cultured human endothelial cells stimulated by infection with rickettsia conorii via a cell-associated il- alpha-dependent pathway systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. frontiers in cellular neuroscience severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ace middle east respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase human respiratory coronavirus oc : genetic stability and neuroinvasion effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain. the journal of experimental medicine management of corona virus disease- (covid- ): the zhejiang experience the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients respiratory failure alone does not suggest central nervous system invasion by sars-cov- clinical characteristics of coronavirus disease in china is nicotine exposure linked to cardiopulmonary vulnerability to covid- in the general population? nicotine modulates the renin-angiotensin system of cultured neurons and glial cells from cardiovascular brain areas of wistar kyoto and spontaneously hypertensive rats nicotine and the renin-angiotensin system brain renin-angiotensin system and dopaminergic cell vulnerability angiotensins in alzheimer's disease &#x ; 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stolfi, ilaria; caramia, giuseppe title: management strategies in the treatment of neonatal and pediatric gastroenteritis date: - - journal: infect drug resist doi: . /idr.s sha: doc_id: cord_uid: otfnrarh acute gastroenteritis, characterized by the onset of diarrhea with or without vomiting, continues to be a major cause of morbidity and mortality in children in mostly resource-constrained nations. although generally a mild and self-limiting disease, gastroenteritis is one of the most common causes of hospitalization and is associated with a substantial disease burden. worldwide, up to % of children aged less than years with diarrhea are hospitalized with rotavirus. also, some microorganisms have been found predominantly in resource-constrained nations, including shigella spp, vibrio cholerae, and the protozoan infections. prevention remains essential, and the rotavirus vaccines have demonstrated good safety and efficacy profiles in large clinical trials. because dehydration is the major complication associated with gastroenteritis, appropriate fluid management (oral or intravenous) is an effective and safe strategy for rehydration. continuation of breastfeeding is strongly recommended. new treatments such as antiemetics (ondansetron), some antidiarrheal agents (racecadotril), and chemotherapeutic agents are often proposed, but not yet universally recommended. probiotics, also known as “food supplement,” seem to improve intestinal microbial balance, reducing the duration and the severity of acute infectious diarrhea. the european society for paediatric gastroenterology, hepatology and nutrition and the european society of paediatric infectious diseases guidelines make a stronger recommendation for the use of probiotics for the management of acute gastroenteritis, particularly those with documented efficacy such as lactobacillus rhamnosus gg, lactobacillus reuteri, and saccharomyces boulardii. to date, the management of acute gastroenteritis has been based on the option of “doing the least”: oral rehydration-solution administration, early refeeding, no testing, no unnecessary drugs. acute gastroenteritis (age), characterized by the onset of diarrhea with or without vomiting, continues to be a major cause of morbidity and mortality in children mostly in resource-constrained nations. although generally it is a mild and self-limiting disease, gastroenteritis is one of the most common causes of hospitalization and is associated with a substantial disease burden. , according to the world health organization (who), diarrhea is defined as the passage of three or more loose or liquid stools per day, or more frequently than is normal for the individual. when young children suddenly experience an episode of acute diarrhea, with or without vomiting, infectious gastroenteritis is by far the most common explanation. viewed from a global perspective, gastroenteritis in children is of enormous public health importance. worldwide, about . million children still die every year before reaching their fifth birthday. gastroenteritis alone is responsible for almost % of the deaths. in spite of the intense promotion of oral rehydration solution (ors) at the community level and the training of health care workers, diarrhea mortality remains unacceptably high: more than million children aged less than years die each year from gastroenteritis, almost all living in resource-constrained nations, where acute diarrhea represents a leading cause of child mortality, second only to pneumonia. age causes . million visits to primary care providers each year and , hospital admissions for children under the age of years; that is % of all the hospital admissions of children in the us. in general, resource-constrained nations have a higher rate of hospital admissions compared to rich nations. in the us, the admission rate is nine per , per year, for children younger than years old. in england each year, . million cases of gastroenteritis occur in the community and . million present to their primary care doctor. in europe, rotavirus infection accounts for more than % of hospitalizations for gastroenteritis and about one-third of emergency department visits. , , not surprisingly, the economic burden of acute diarrhea is substantial, not only in management costs but also in indirect costs, such as absence from work by parents or caregivers of sick children. the severity of acute diarrhea is related to etiology, with rotavirus infection disproportionately implicated in severe cases that frequently require hospitalization. , worldwide, up to % of children aged less than years with diarrhea are hospitalized with rotavirus: while most of the episodes are mild, about % of cases lead to dehydration requiring a doctor visit, and in resource-constrained nations, one in children will die from this dehydration. [ ] [ ] [ ] [ ] [ ] in europe, rotavirus infection accounts for more than % of hospitalizations for gastroenteritis and about one-third of emergency department visits. , otherwise, some agents have been found predominantly in resource-constrained nations, including shigella spp, vibrio cholerae, and the protozoan infections. mode of transmission is mainly horizontal, through physical contact with an infected person or with their excretions. the pathogens, most frequently transmitted during the passage through the birth canal, are enteropathogenic escherichia coli, salmonella, and enterovirus. although rare, the passage of the germ can also occur transplacentally during bacteremia. several maternal infections are asymptomatic. horizontal transmission can occur through direct contact with siblings, parents, or health care workers. some cases of transmission through the ingestion of contaminated water or infant formula are also reported. some viral infectious agents, such as adenovirus and rotavirus, can be transmitted by air. the relatively low incidence of the disease in newborns is the result of several factors: breastfeeding and the universal practice of giving birth at home in rural villages, and improvements in social and educational standards and medical care in advanced countries. , otherwise, newborns are particularly susceptible to enteric infections in early life, due to reduced local and systemic immune response, absence of an adequate intestinal flora, and reduced gastric acidity. in the newborn, the protective role of gastric motility and of the intestinal mucus is still uncertain. other external factors contribute to the balance of the intestinal ecosystem: nutrition, type of delivery, hygiene habits, use of antibiotics in the mother and infant and the supplementation with probiotics and/or prebiotic oligosaccharides in the newborn. [ ] [ ] [ ] the mortality risk for very low-birth-weight infants (less than g) due to acute diarrhea is times higher than for infants of low or appropriate birth weight (more than g). acute diarrhea has several risks and complications; it may lead to lifethreatening dehydration and electrolyte disturbances. when diarrhea is not halted, there is a risk of disturbed digestion and absorption of nutrients with nutritional deterioration. prevention is essential, and all health professionals should ensure caregiver education in the following main principles of prevention: • full and exclusive breastfeeding that protects against intestinal infections and prevents exposure to environmental contamination. , thriving breastfed babies under months of age do not require water supplements, even in hot weather. , • provision of safe water for drinking and food preparation. • proper hand-washing hygiene after toilet use and before food preparation and feeding. • safe disposal of human and other waste. table a-c shows the main characteristics of the principal bacterial, viral, fungal, and parasitic enteropathogens, respectively: typical age of presentation, type of diarrhea, duration of symptoms, clinical features, transmission, and seasonality. not always well defined, because some agents use both these pathogenetic strategies to induce disease. in europe, the most common bacterial agent is either salmonella or campylobacter, depending on country. aeromonas hydrophila and plesiomonas shigelloides (previously also known as aeromonas shigelloides) belonging to the family of vibronacee, can cause watery diarrhea. the pathogenic role of a. hydrophila as an enteric pathogen causing gastroenteritis is difficult to confirm, because of the frequency of other pathogens isolated with a. hydrophila in symptomatic and asymptomatic subjects. but a. hydrophila is recognized increasingly as a clinically significant enteric pathogen associated with diarrhea also in children younger than years of age living in a rural community, and is linked to local drinking water sources. campylobacter is the most common enteropathogen after years of age, particularly in northern european countries. c. jejuni and c. coli infections are endemic worldwide and hyperendemic in resource-constrained nations. infants and young adults are most often infected. c. jejuni, followed by c. coli and c. lari, are the most common bacterial causes of acute diarrheal illnesses in rich nations. c. jejuni has invasive properties, leading to epithelial ulceration and inflammatory infiltrates in the lamina propria, mainly in the colon, ileum, and jejunum. some c. jejuni isolates elaborate very low levels of cytotoxins, similar to shiga toxin. some isolates have been reported to elaborate an enterotoxin similar to cholera toxin. enterotoxin production has been more frequently observed in isolates from resource-constrained nations, where infection by c. jejuni has been associated with watery diarrhea. however, the clinical significance of the toxigenicity of these organisms is still unclear. symptoms and signs of c. enteritis are not distinctive enough to differentiate it from illness caused by many other enteric pathogens. diarrhea is often associated with blood, but it can be difficult to distinguish from other invasive forms. a cholera-like illness with massive watery diarrhea may also occur. bacteremia is uncommon (less than %) in immunocompetent patients with c. jejuni infection. newborn infection by campylobacter spp is rare; most cases were born to mothers with campylobacter diarrhea at the time of delivery. the transplacental passage of campylobacter fetus is responsible for abortion, premature birth, bacteremia, and meningitis. c. jejuni/coli infections can cause a series of complications as reactive arthritis, irritable bowel syndrome, and guillain-barré syndrome (gbs), an acute neurologic disease driven by autoimmunity and molecular mimicry in which the body stages a cell-mediated and humoral immunological response against peripheral nerve myelin. a recent systematic review of gbs estimated that %- % of all cases are preceded by an acute infectious illness, of which %- % are upper respiratory infections and %- % are gastrointestinal infections, one of the most common being enteritis due to campylobacter. , several studies have shown that patients with gbs (most of cases associated with the variant acute motor axonal neuropathy) have a recent history of infection due to c. jejuni. clostridium difficile is a major nosocomial pathogen that causes a spectrum of intestinal disease from uncomplicated antibiotic-associated diarrhea to severe, possibly fatal, antibiotic-associated colitis. in the last - years, a change in the epidemiologic pattern of c. difficile infection characterized by an increasing incidence and severity of infection has been observed. a few epidemiological studies recently conducted in the pediatric population demonstrated a twofold increase in the incidence of c. difficile infection in the last years, but with no increase in the incidence of severe complications, such as the need for colectomy or mortality. , the clinical presentation of c. difficile-associated disease can range from asymptomatic carriage in the gastrointestinal tract and mild diarrhea to potentially fatal pseudomembranous colitis. diarrhea is watery and usually nonbloody, but approximately %- % of patients have bloody diarrhea. fecal material typically contains excess mucus, and pus or blood may also be noted. the disease may progress to a pseudomembranous colitis, possibly including intestinal perforation and toxic megacolon. neonatal infections by c. difficile can be asymptomatic, but usually display fever, diarrhea, and irritability within hours after production of the toxins. escherichia coli are the predominant nonpathogenic facultative anaerobe of human colonic flora and usually remain harmlessly confined to the intestinal lumen. some e. coli have evolved the ability to cause a broad spectrum of human diseases, and different types associated with enteric infections are classified into five groups according to their virulence properties and are briefly described here. enteroaggregative e. coli (eaec) serotypes exhibit a characteristic aggregative pattern of adherence and produce persistent gastroenteritis and diarrhea in infants and children in resource-constrained nations. enteroinvasive e. coli serotypes have properties similar to invasive salmonella, but the presence of blood in the stool is less frequent. these can also produce an enterotoxin that cause watery diarrhea, resembling the effects of shigella in children and adults. enteropathogenic e. coli (epec) serotypes in the past were serotypes number about , and in rich countries are primarily responsible for gastroenteritis with bloody diarrhea, severe abdominal pain, and cramps that resolve in a few days with an adequate oral rehydration. since , gastroenteritis from shiga toxin-producing e. coli (stec), an e. coli strain with the capacity to produce a cytotoxin similar to that produced by shigella spp, has been identified as a significant health problem in the developed world. , infections with stec, of which ehec o is the most well-known serotype, have been recorded in many regions, including north america, western europe, central and south america, the middle and far east, africa and australia; also, eaec serotype o :h can produce shiga toxins (stec). [ ] [ ] [ ] infections by stec are characterized by abdominal cramps and acute bloody diarrhea; however, more serious sequelae may also result, including hemolytic uremic syndrome (hus), thrombocytopenia, and associated complications, which can lead to kidney failure and death in some individuals. , most outbreaks and sporadic cases of bloody diarrhea and hus have been attributed to strains of stec serotype o :h . however, in europe and recently in the us, the role of non-o stec strains (eg, o :h /h-, o :h /h-, o :h , o :h , o :h-, o :nm, o :h , o :h , o :h /h-, and o :h /h-) as causes of hus, bloody diarrhea, and other gastrointestinal illnesses is being increasingly recognized. , in many studies, a significant association between illness and the consumption of pink or undercooked hamburgers, pinkish ground beef, undercooked meat, or barbecued food has been demonstrated. , , the natural reservoirs of stec are ruminant animals, especially cattle, and transmission to humans usually occurs via contaminated food or water. helicobacter pylori (previously named campylobacter pyloridis)-infected children may have no symptoms or a wide variety of symptoms, and rarely potentially life-threatening complications, such as gastroduodenal ulcers and bleeding. symptoms of ulcers may include pain or discomfort (usually in the upper abdomen), bloating, an early sense of fullness with eating, lack of appetite, nausea, vomiting, blood in the stools, and diarrhea. in the last years, various studies have been performed investigating its role to modify the susceptibility to gastroenteritis in children. a study reported an increased risk of chronic diarrhea, compared with healthy control subjects, among infected age-matched gambian children with malnutrition. in a nested case-control design, the authors found an increased risk of severe cholera among h. pylori-infected subjects without vibriocidal antibodies. similarly, in an urban slum, h. pylori infection was twice as common among subjects with typhoid fever (salmonella typhi) than in neighborhood control subjects. another study reported increased diarrhea episodes among peruvian infants with recent h. pylori seroconversion. conversely, in a thai orphanage, no association was found between seroconversion and diarrheal disease. some investigators have even speculated that local inflammatory factors induced by infection may be protective. in a cross-sectional study of elementary school-age children in germany, the infection seemed associated with a reduced frequency of diarrheal illnesses. these epidemiological discrepancies could be explained, because h. pylori could be argued to increase or decrease susceptibility to enteric pathogens. depending on the age at acquisition and the anatomical site of colonization, for example, h. pylori decreases gastric acid secretion in some people, thereby potentially reducing the effectiveness of the gastric acid barrier to intestinal pathogens, but increases gastric acid secretion in others. in this prospective study, h. pylori did not seem to increase the risk of gastroenteritis in people more than years old. these data have recently been confirmed. klebsiella, enterobacter, citrobacter, and streptococcus group d have been isolated from feces of sick newborns and associated with intestinal disease, but there is insufficient evidence to define the pathogenic role of these agents. proteus and providencia, although rarely, may be responsible for intestinal infections in newborns. providencia species occur in normal feces and have been isolated from epidemic and sporadic causes of diarrhea, though their importance in the causation of diarrheal disease is not easy to assess. pseudomonas aeruginosa can colonize ( %- %) the intestine of the newborn during the first days of life. clinically, the infection may be asymptomatic at first, later developing into grayish-blue stool color or watery diarrhea, profuse vomiting, and systemic symptoms. salmonella pass through the intestinal mucosa and multiply within the lamina propria, may invade mesenteric lymphonodes, and systemic spread of the organisms can occur, giving rise to enteric fever. in fact, %- % of infants may have extraintestinal symptoms. the colonization and initial invasion probably occur at the distal ileum, while the mucosal edema and cryptic abscesses are frequently in the colon. the diarrhea is due to secretion of fluid and electrolytes by the small and large intestines. the incubation period is usually - hours, rarely for a few days. salmonella spp is normally acquired through the birth canal, and the mother can be an asymptomatic carrier. shigella spp are the leading bacterial causes of diarrhea worldwide and are relatively common in children. they cause invasive gastroenteritis, and symptoms can take as long as a week to show up, but most often begin - days after ingestion. mild symptoms are self-limiting, but s. dysenteriae serotype resistance to multiple antibiotics has the ability to elaborate the potent shiga toxin, which may lead to extraintestinal complications, including hus and death. cases of neonatal infections from staphylococcus aureus are reported in the literature. the pathogen produces two enterotoxins, g and i, that cause atrophy of intestinal villi, diarrhea, and poor growth during the first weeks of life. vibrio cholerae causes watery diarrhea through the production of cholera toxin without invading the intestinal mucosa. yersinia enterocolitica is a common enteropathogen usually causing relatively mild disease. y. enterocolitica crosses the intestinal mucosa, replicates in peyer's patches, and children infected present acute diarrhea associated with fever and pharyngitis, chronic or recurrent diarrhea, or abdominal pain associated with mesenteric adenitis. this infection looks like salmonella infections, with feces containing mucus with or without blood. the pathogen, within phagocytes, can reach other sites through the bloodstream. some of the y. enterocolitica pathogenic biotypes express the yst gene encoding for an heat-stable enterotoxin that may contribute to the pathogenesis of diarrhea. , viral enteritis (table b) viruses are responsible for approximately % of the episodes of acute gastroenteritis in children. viral gastroenteritis is of shorter duration than bacterial gastroenteritis and associated with an increased risk of vomiting and dehydration compared with those without viral infection. the severity of dehydration is significantly higher in children infected with either astrovirus or rotavirus group a. prolonged hospitalization is also more likely to occur with rotavirus infection. , , , , enteric adenoviruses are a common cause of viral gastroenteritis in infants and young children. although there are many serotypes of adenovirus that can be found in the stool especially during and after typical infections of the upper respiratory tract, only serotypes and cause gastroenteritis and are very difficult to grow in tissue culture. adenovirus directly infects intestinal enterocytes, causing villous hypoplasia and crypt hypertrophy. the virus causes a massive infiltration of the lamina propria of the villi by mononuclear cells. enteric adenovirus is associated with longer lasting diarrhoea, compared to other viral gents. , , maternal antibodies are certainly protective; however, among premature and/or low-birth-weight infants the infection spreads rapidly and can be associated with a poor prognosis and high morbidity. cytomegalovirus and herpes virus (cmv or hh and hhv - ; family herpesviridae, subfamily betaherpesviridae) can cause gastrointestinal symptoms such as diarrhea or colitis with profuse hematochezia and bowel perforation. most people who are infected with a non-polio enterovirus (ev; family picornaviridae, genus enterovirus) have no disease, but all ev may cause diarrhea. human ev (ev-d ) is a historically rarely reported virus linked with respiratory disease. in the last years, a large increase in respiratory disease associated with ev-d has been reported, with documented outbreaks in north america, europe, and asia. ev infections can be asymptomatic or can cause diarrhea, rashes, and hand, foot, and mouth disease. however, ev may be responsible for severe complications, including meningitis, encephalitis, cardiovascular and respiratory problems as pulmonary edema, or heart failure. cases of fatal ev encephalitis have occurred during outbreaks. most ev infections occur under years of age. coxsackie (family picornaviridae, genus enterovirus)-a and ev are two of the major pathogens responsible for hand, foot, and mouth disease, but the most severe cases are associated with ev . , pleconaril, a viral agent active against enteroviruses, has demonstrated efficacy against neonatal infection with systemic symptoms. however, further confirmatory studies are needed. results of phase i clinical trials suggest an ev vaccine has a clinically acceptable safety profile and immunogenicity. outbreaks of ev are a serious socioeconomic burden not only in the western pacific region. for this reason, an ev vaccine is now being tested and seems to submit your manuscript | www.dovepress.com have an acceptable safety profile and clinically acceptable immunogenicity. human astrovirus (family astroviridae, genus mamastrovirus) may also be responsible for sporadic infections or epidemics, occasionally in newborns and children. , human bocavirus (family parvoviridae, genus bocavirus), recently discovered, has been suggested to be involved in a large spectrum of clinical manifestations, including gastroenteritis. , human coronaviruses (hcovs; family coronaviridae, genus coronavirus) are common causes of upper respiratory tract infections. a new coronavirus was found to be a causative agent of severe acute respiratory syndrome (sars). sars-hcov caused a serious lower respiratory tract infection with high mortality. diarrhea is common in this condition, and in one study was registered in . % of patients. in the same study, sars-hcov was also isolated from intestinal tissue, and viral rna was detected in stool samples. moreover, non-sars hcovs can be found in stool samples of children with age. however, most of the hcov findings were coinfections with well-known enteric pathogens -norovirus and rotavirus. it is also difficult to determine whether hcovs in the respiratory tract in cases of age were primarily causing the respiratory or gastrointestinal symptoms. hcovs may also be found in occasional stool samples of children without gastroenteritis. these findings suggest that known hcovs may at most have a minor etiologic role in age of children. human rotavirus (family reoviridae, genus rotavirus) in the past was considered to be responsible for the most severe episodes of diarrhea in children. , there have been reports of epidemics in neonatal intensive care units caused by rotavirus or enterovirus that can determine cases of necrotizing enterocolitis or necrotizing enterocolitis-like symptoms: abdominal distention, bloody diarrhea, and septicemia secondary to enteric bacteria. improved diagnostic tools for norovirus (family caliciviridae, genus norovirus): have shown that it has a major role in both epidemic and sporadic cases of gastroenteritis. , sapoviruses (family caliciviridae, genus sapovirus): mainly infect children younger than years of age. the illness is milder than that caused by noroviruses. antibody prevalence studies show that virtually all children are infected with sapoviruses by the time they are years of age, indicating that sapovirus infection is widespread, although the illness most likely is sporadic with a high rate of asymptomatic infection. , , torque teno midi virus/small anellovirus (ttmdv/sav) is a member of the family anelloviridae. although human ttv infection is ubiquitous and several infecting genogroups of the virus have been identified, to date there is no consistent evidence of a link between ttv infection of humans and specific disease. [ ] [ ] [ ] [ ] in a recent hungarian study, viral shedding, molecular epidemiology, and genetic diversity of ttmdv/ sav were studied in human body fluids (nasopharyngeal aspirates of children with acute respiratory diseases and serum, stool and urine samples collected from eight healthy children with previous ttmdv/sav infection). in this study, shedding of ttmdv/sav and related viruses was detected in two other human body fluids, feces and urine, suggesting the existence of fecal-oral/urinary-oral transmission routes beyond the originally presumed blood-borne and later-suggested respiratory route. this finding extends the number of possible successful transmission routes. fungal enteritis (table c) the pathogenic role of candida in neonatal diarrhea is still difficult to prove. symptoms ascribed to candida-associated diarrhea in the literature include prolonged secretory diarrhea with abdominal pain and cramping but without blood, mucus, fever, nausea, or vomiting. disseminated candida infection can cause intestinal symptoms similar to necrotizing enterocolitis, especially in premature infants and in infants treated with antibiotics (especially third-generation cephalosporins) and with central venous catheters or in surgical patients. , candida infections frequently develop into systemic forms, and are a major cause of morbidity and mortality in neonatal intensive care units. the incidence of candidemia in the neonatal intensive care unit is steadily increasing, with an estimated incidence of %- % in very low-birth-weight infants and of %- % in extremely low-birth-weight infants. infection-associated mortality following candida bloodstream infections is as high as % (very low birth weight %- %, extremely low birth weight %- %), and neurodevelopmental impairment is common among survivors (extremely low birth weight %). [ ] [ ] [ ] [ ] [ ] because invasive fungal infections are common and extremely difficult to diagnose, prevention (decrease of risk factors that contribute to increased colonization and concentration of fungal organisms like maternal vertical transmission or nosocomial acquisition) and antifungal prophylaxis should be considered. parasitic enteritis -protozoan (table c) some waterborne protozoan parasites induce enteritis through their membrane-associated functional structures and virulence factors that alter host cellular molecules and submit your manuscript | www.dovepress.com dovepress dovepress signaling pathways, leading to structural and functional lesions in the intestinal barrier. cryptosporidium parvum has a high infectivity with significant enteric disease: rarely is asymptomatic. there have been reported cases of infection in the first month of life; the passage of the maternal antibodies and breastfeeding are a protective factor against infection. giardiasis is one of the intestinal protozoa that cause public health problems in most resource-constrained nations, as well as some resource-rich countries. many infected persons can be asymptomatic, leading to difficulties in the eradication and control of this parasite due to the number of potential carriers, such as school children. giardia lamblia is observed almost three times more in asymptomatic children than in symptomatic children. the first signs of acute giardiasis include nausea, loss of appetite and an upper gastro-intestinal uneasiness, followed or accompanied by a sudden onset of explosive, watery, foul-smelling diarrhea. stools associated with giardia infection are generally described as loose, bulky, frothy and/or greasy with the absence of blood or mucus, which may help distinguish giardiasis from other acute diarrheas. other gastro-intestinal disturbances may include: flatulence, bloating, anorexia, cramps. the acute stage usually resolves spontaneously in a few days. occasionally an acute infection will persist and lead to malabsorption, steatorrhea, loss of strength and weight loss. it has been estimated that about million people are infected each year in africa, asia and latin america. in the resource-rich countries the prevalence rate of giardiasis is - %. however, in resorce-constrained countries, giardia lamblia infects children early in life thus a prevalence rate of - % in children younger than years is common. children who are malnourished are more frequently infected. cryptosporidium and giardia most often cause diarrhea in immunocompromised children or in children from resource-constrained nations, and diarrhea tends to be chronic in both settings. , , although e histolytica generally causes bloody diarrhea, some studies have demonstrated that e histolytica could also be responsible for watery diarrhea, particularly in infants. that nondysenteric diarrhea is a common presentation of amebiasis in children less than years of age but it was also reported among children aged - years of age. , isospora belli is an opportunistic protozoan more frequent in developing countries of tropical and subtropical regions and should be monitored in both immunocompromised and immunocompetent patients with gastrointestinal complaints such as abdominal pain, nausea, and diarrhea. several helminths can also cause diarrhea, and their importance depends on geographic location, climatic conditions, poor sanitation, unsafe drinking water, and the immune status of the child. , strongyloidiasis is an infection caused by the intestinal nematode strongyloides stercoralis. infected healthy individuals are usually asymptomatic; however, it can cause watery or chronic diarrhea, abdominal cramping, failure to thrive, and cachexia. it is potentially fatal in immunocompromised hosts, due to its capacity to cause an overwhelming hyperinfection. a screening assay for strongyloides infection in suspected patients is needed for early detection and successful cure. trichuris trichiura infections are widespread globally, with prevalence and intensity-of-infection peaks in school age. nevertheless, as soon as infants start to explore their environment, thus coming into contact with contaminated soil, they are at risk of infection according to the levels of transmission in the area. the pathogen can cause inflammatory damage to mucosa, bloody diarrhea, iron deficiency, and anemia. most children with gastroenteritis do not require any laboratory investigations. many infants and children experience brief episodes of diarrhea, and are managed by their parents without seeking professional advice. even if advice is sought, health care professionals often consider that a clinical assessment is all that is required, and laboratory investigations are not undertaken. however, there may be particular circumstances when investigations may be helpful in diagnosis. frequently the signs and symptoms are not sufficient to make an etiological diagnosis as they often are nonspecific. the localization of the pathogen in the small intestine or in the colon, the characteristics of the feces (table ) , the clinical history of the disease, and environmental risk factors can support the diagnostic evaluation. it would be also important to be aware of any history of recent contact with someone with acute diarrhoea and/or vomiting and exposure to a known source of enteric infection (possibly contaminated water or food) or a recent travel abroad. severe watery diarrhea in the absence of mucus, pus, or blood suggests secretory diarrhea or malabsorption (such as by noninvasive vibrio cholera, etec, or by rotavirus, adenovirus, or astrovirus), while the presence of blood and mucus are more indicative of an invasive germ, such as salmonella, shigella, campylobacter jejuni, or yersinia enterocolitica. the presence of vomiting and fever with diarrhea is nonspecific and cannot help in the diagnosis. it would be also important to be aware of any history of recent contact with submit your manuscript | www.dovepress.com year and a few percent of adults. although these data support the potential for endogenous sources of human infection, there was early cir cumstantial evidence to suggest that this pathogen could be transmissible and acquired from external sources. therefore the possibility of other disorders would require careful consideration in such cases of diarrhea and/or vomiting as shown in table . regarding collection and transport of stool specimens, for stool culture for bacterial pathogens: one stool specimen is sufficient in most cases: • c. difficile toxin testing: one stool specimen is sufficient in most cases. • ova and parasite testing: specimen must be submitted in an appropriate preservative (sodium acetate-acetic acidformalin fixative). • viral pathogens: stool for viral pathogens are not routinely tested; for a suspected outbreak of viral gastroenteritis, one stool specimen submitted in a sterile container is sufficient in most cases. for the investigation of bacterial pathogens, stool specimens should be delivered to the laboratory as soon as possible, as a delay may compromise bacterial pathogen recovery. a single stool specimen, properly collected and promptly submitted, will identify most patients with a bacterial pathogen. additional stool specimens need to be submitted if the culture results are negative, symptoms persist, and other causes cannot be found. if there are concerns regarding timing or transport of the specimen, consult the laboratory. submit your manuscript | www.dovepress.com for physical and chemical study of feces, fecal ph less than or equal to . or the presence of reducing substances is a sign of intolerance to carbohydrates, mostly secondary to viral infection. for microscopic examination of stool, the presence of leukocytes is suggestive of an enteroinvasive infection, although the absence of leukocytes cannot exclude it. however, infections mediated by enterotoxins (etec, vibrio cholerae, and viruses) have no white blood cells in stool. for fecal culture, various culture media are used to isolate the bacteria. the clinical history, physicochemical characteristics of the stool, and laboratory tests thus allow the choice of an appropriate culture medium. in the presence of clinical signs and leukocytes in the stool, it is always necessary to perform culture for salmonella, shigella, and campylobacter. if stool cultures are not performed within hours of sample collection, it is necessary to keep the stool at °c. blood cultures are examined for evidence of bacteremia. research of bacterial toxins is conducted through enzyme-linked immunosorbent assay (elisa). the fecal rotavirus antigen is examined through elisa and latex agglutination test; search of adenovirus fecal antigen is performed using elisa. polymerase chain reaction (pcr) or other molecular investigations are performed for viral research, especially on stools for norovirus, adenovirus, sapovirus, and human bocavirus, and pcr of stool and blood is used for the detection of enteroviruses. a providencia genus-specific pcr method has been developed, and its specificity and sensitivity was evaluated to be % with various bacterial strains. recently, pcr methods have been applied to investigate the prevalence of the virulence genes specific for five major pathogroups of diarrheagenic escherichia coli in primary cultures from feces of animals slaughtered for human consumption in burkina faso that revealed the common occurrence of the diarrheal virulence genes in feces of food animals. another study investigated using pcr for the incidence, antimicrobial resistance, and genetic relationships of epec in children with diarrhea. regarding parasitic infection and study of trophozoites or oocysts, antigen detection of stool through elisa is used; the serological study can be helpful in rare systemic infections. , , for intestinal infection by enteroinvasive agents, it is possible to find low blood levels of albumin and high levels of alpha-l-antitrypsin in the stool, and an index of extended intestinal inflammation with dispersion of proteins. parents, caregivers, and children should be informed that it is possible to prevent the spread of gastroenteritis using some simple rules: • wash hands with soap and water, especially after using toilet or changing diapers and before preparing, serving, or eating food • do not share towels used by infected children • children should not attend any school or other child-care facility while they have gastroenteritis; they can go back to school from at least hours after the last episode of diarrhea or vomiting • children should not use swimming pools for weeks after the last episode of diarrhea , • implementing rotavirus vaccination: the new rotavirus vaccines are safe and reduce the severity of infection and prevent deaths, but they do not prevent all cases of rotavirus diarrhea. two live, oral, attenuated rotavirus vaccines were licensed in : a pentavalent bovine-human recombinant vaccine and a monovalent human rotavirus vaccine. both vaccines have demonstrated good safety and efficacy profiles in large clinical trials in resource-rich countries and in latin america. , immunization against rotavirus is recommended in europe and the us. , the protective effects of breastfeeding against gastroenteritis infections have been demonstrated in several studies. , antibacterial substances, such as lactoferrin, lysozyme, phagocytes, and specific secretory immunoglobulins plays a protective role. the ligand-specific action of κ-casein inhibits helicobacter pylori adherence to the gastric mucosa. human milk also has antiviral action through the lactoferrin and products of digestion of lactoferrin and milk fatty acids. all of these elements suggest that exclusive breastfeeding contributes to protection against common infections during infancy and lessens the frequency and severity of infectious episodes. breastfeeding promotes the colonization of the intestinal ecosystem with a predominance of bifidobacteria and lactobacilli (probiotics) rather than coliforms, enterococci, and bacteroides that characterize the intestinal microflora of infants fed with formula. some authors have demonstrated that the use of formulas supplemented with probiotics (bifidobacterium lactis and lactobacillus gg) have decreased the incidence (up to %) and severity of diarrhea. the probiotics, also submit your manuscript | www.dovepress.com dovepress dovepress defined as food supplements, improve intestinal balance, have beneficial effects on health, and are able to balance the intestinal ecosystem and reduce the duration and severity of diarrheal infections, especially in the course of rotavirus infections. the probiotics in the intestine determine resistance to colonization by other potentially pathogenic microbes through mechanisms of competition or inhibition, and the effects are expressed both on nonspecific innate and acquired immunity. lactobacillus rhamnosus gg (lgg) is considered particularly effective in the management of age; this is confirmed by a recent cochrane review documenting that lgg reduced the duration of diarrhea, mean stool frequency on day , and the risk of diarrhea lasting $ days. , according to a recent cochrane review, saccharomyces boulardii reduces the risk of diarrhea lasting $ days, and a more recent review confirmed that s. boulardii significantly reduced the duration of diarrhea and hospitalization. a recent randomized controlled trial evaluated the efficacy of treatment with lactobacillus reuteri dsm compared with placebo: the administration of l. reuteri reduced the duration of watery diarrhea, the risk of diarrhea on days and , and the relapse rate of diarrhea. it has been suggested that probiotics may decrease infant mortality and nosocomial infections because of their ability to suppress colonization and translocation of bacterial pathogens in the gastrointestinal tract. several meta-analyses evaluating probiotics in preterm infants suggest a beneficial effect for the prevention of necrotizing enterocolitis and death, but less for nosocomial infection. l. reuteri may reduce these outcomes because of its immunomodulation and bactericidal properties. a large, double-blinded, randomized controlled trial (rct) using l. reuteri was performed to test this hypothesis in preterm infants. this study suggested that although l. reuteri did not appear to decrease the rate of death or nosocomial infection, the trends suggest a protective role consistent with what has been observed in the literature: a protective role for mortality, nosocomial infection, and necrotizing enterocolitis. feeding intolerance and duration of hospitalization were significantly decreased in premature infants less than g. the use of formulas supplemented with probiotics (particularly bifidobacterium lactis and lactobacillus gg) seems to decrease the incidence (up to %) and severity of infectious acute diarrhea. symbiotics, a combination of prebiotics and probiotics that beneficially affect the host by improving survival and implantation of live microbial dietary supplements in the gastrointestinal tract, has recently been evaluated by two european rcts for the management of age. these studies are promising, but presently it would not be appropriate to recommend the use of symbiotics until confirmatory data are available. dehydration is probably the main complication of gastroenteritis in childhood. who classification of patients' hydration status is based on the presence of symptoms and signs. the presence of one of these signs or symptoms immediately classifies the patient as a more severe case. table summarizes the who management of rehydration. , all moderate and severe patients require close monitoring, but patients at the extreme ages of life, especially children under months, require meticulous observation and immediate measures if their condition worsens. according to current who recommendations, oral rehydration therapy (ort) is considered the treatment of choice to replace fluid and electrolyte losses caused by diarrhea in children with mild to moderate dehydration. intravenous rehydration is the treatment of choice in cases of failure of ort, and it has to be reserved for patients with severe dehydration or who eliminate more than - ml/ kg/hour. in the s, efforts by young scientists and researchers led to the development of ort for the treatment of dehydration that often accompanies acute attacks of diarrhea. many members of the research team responsible for this discovery were associated with noteworthy universities and medical research centers in the us. the goal of their research was to devise effective therapies for cholera-induced diarrhea; as a result of their hard work, they developed a new framework for treatment that would soon be adopted throughout the developing world as a key element in the overall strategy to combat acute diarrhea and the potentially fatal dehydration that accompanies the disease. in an article published in in the lancet, it was confirmed that cholera patients could be rehydrated orally with a simple solution of water, salt, and sugar, and equally importantly that field staff could easily be trained to administer the therapy. as stated in the article, ort also offers a practical treatment for large numbers of patients in the developing world who do not have access to traditional intravenous drip therapy. at first, studies on the efficacy of ort, when compared with intravenous therapy (ivt), were conducted only in patients with cholera. [ ] [ ] [ ] following that, other studies established the effectiveness of ort in children with acute diarrhea from other causes. some trials also compared the effectiveness of oral rehydration submit your manuscript | www.dovepress.com with ivt in children with different degrees and types of dehydration (mild, moderate, severe, and hypernatremic dehydration), and they concluded that the use of ors to rehydrate children is safe and that there are no significant differences in incidences of hyponatremia, hypernatremia, mean duration of diarrhea, weight gain, or total fluid intake if compared with ivt. in terms of outcomes, ort was associated with a higher risk of rehydration failure, while babies treated with ivt had a significantly longer stay in hospital and a higher risk of phlebitis, but no statistically significant differences were seen. the main reason for this failure is that ors neither reduces the frequency of bowel movements and fluid loss nor shortens the duration of illness; moreover, the unpalatability of regular ors (strong salty taste) also decreases this acceptance. however, the most important aspect of treatment of gastroenteritis is the water and electrolyte balance. it must be adjusted according to serum electrolytes, body water content (greater the younger the child), and the water demand must be calculated on the weight of the newborn infant (table a and b). different ors are now commercially available (table ). recently, some companies have added probiotics to the saline solution to obtain a quick balance of intestinal bacterial flora. the infant should be monitored closely to check the status of nutrition and hydration. infants with moderate dehydration, suspected infected by ehec, with bloody diarrhea, or systemic symptoms should be hospitalized. these newborns are at high risk of secondary complications. during ort, milk-feeding is often temporarily suspended. among all the oral solutions, the ideal one has a low osmolarity ( - mosm/l) and a sodium content of - mmol/l to avoid high levels of serum sodium. the solution should be administered frequently and in small amounts to prevent vomiting. initial oral rehydration is - ml/kg in the first hours. also consider giving the ors via a nasogastric tube if patients are unable to drink it or if they vomit persistently and to monitor them by regular clinical assessment. in cases of failure of oral rehydration, it is necessary to establish an appropriate parenteral rehydration fluid and electrolyte solutions (table ) . pediatric presentations of racecadotril were first authorized in france in , and today it is approved and widely used in seven european countries (france, spain, italy, portugal, greece, bulgaria, and romania) and outside europe. this antisecretory drug is a peripherally acting enkephalinase inhibitor that reduces intestinal water and electrolyte hypersecretion acting on the enkephalins (neurotransmitters of the gastrointestinal tract) through the selective stimulation of delta receptors inhibit adenylate cyclase activity by reducing the intracellular concentration of camp, thus reducing the secretion of water and electrolyte in the intestinal lumen. the result is a reduction of water and electrolyte secretion without changes in intestinal motility. moreover, the action of racecadotril takes place only when there is a hypersecretion and has no effect on the activity secretory baseline. new data have reconfirmed that racecadotril is an effective adjunctive therapy to oral rehydration in watery diarrhea. a recent individual patient data meta-analysis assessed the efficacy of the use of racecadotril as an adjunct to ors compared with ors alone or with placebo. raw data from nine rcts involving children aged month to years with age were available for the analysis. two trials compared the effect of racecadotril with placebo , with no treatment (two rcts), or with kaolin-pectin (two rcts). compared with placebo, racecadotril significantly reduced the duration of diarrhea after inclusion. almost two times more patients recovered at any time in the racecadotril group vs the placebo group (p , . ). there were no interactions between treatment and dehydration, rotavirus infection, type of study (outpatient/inpatient), or country. in the studies evaluating inpatients, the ratio of mean stool output racecadotril/placebo was reduced (p , . ). in outpatient studies, the number of diarrheal stools was lower in the racecadotril group (p , . ). in the responder analysis (defined as a duration of diarrhea of less than days), the proportion of responders was significantly higher in the racecadotril group compared with the placebo group. by adjusting for dehydration and rotavirus, the absolute risk difference was . % ( % confidence interval . - . ), and the associated number needed to treat was four. the secondary need for care in outpatients was significantly in favor of racecadotril in two studies. also, the need for ivt was lower in the racecadotril group compared with the placebo group. there was no difference in the incidence of adverse events between the groups. the results of this recent meta-analysis support the use of racecadotril as an adjunct to ors for the management of age in children. in addition, the safety of racecadotril in children has been demonstrated in clinical studies, including a large pre-and postaccess study showing that racecadotril has a favorable adverse-event profile in children. [ ] [ ] [ ] despite racecadotril's proven safety and efficacy in treating acute watery diarrhea, its cost-effectiveness for infants and children has not yet been determined in europe. the uk model highlights the potential savings arising from reduction in diarrhea duration and avoidance of reconsultation and referral rates in children with diarrhea. children presenting with age often have high levels of vomiting that can interfere with the oral rehydration process, which could limit the success of the oral therapy. ondansetron is widely used in the pediatric emergency department for vomiting and age; it can help with the successful delivery of ort, thereby reducing the need to treat with ivt. a recent study evaluated the spectrum of diagnoses for which ondansetron is used in the pediatric emergency room. medical records of patients months to years of age given ondansetron for years were retrospectively reviewed. patients without a primary discharge diagnosis of vomiting or gastroenteritis were defined as non-gastroenteritis, and they were compared to the gastroenteritis group. the non-gastroenteritis group includes % of the subjects, and they were older ( . vs . years) than the gastroenteritis patients. the most common primary diagnoses for non-gastroenteritis discharged patients were fever ( %), abdominal pain/ tenderness ( %), head injury/concussion ( %), pharyngitis ( %), viral infection ( %), migraine variants ( %), and otitis media ( %). although ondansetron is a widely accepted treatment for gastroenteritis submit your manuscript | www.dovepress.com in children - % of total use -this study identifies a broader spectrum of primary diagnoses for which ondansetron is being used. another study used rcts comparing antiemetics with placebo or no treatment in children and adolescents under the age of years, for vomiting due to gastroenteritis. the proportion of patients with cessation of vomiting in hours was % with intravenous ondansetron, % placebo, and % in the metoclopramide group (p = . ). in this case, the authors' conclusions were that oral ondansetron increased the proportion of patients who had ceased vomiting and reduced the number needing intravenous rehydration and so immediate hospital admissions. , today, it is still unclear if in spite of an improvement in the vomiting, ondansetron worsens diarrhea. some trials report a statistically significant increase in its frequency as an adverse event. in cochrane reviews, diarrhea was reported as a side effect in four of the five ondansetron studies. [ ] [ ] [ ] according to who, of the antiemetics available, those with the greatest evidence of efficacy in the prevention of nausea and vomiting (particularly in the treatment of postsurgery nausea and vomiting) were ondansetron and dexamethasone, ondansetron as first-line treatment with the addition of dexamethasone as required. zinc is an important trace element, as over enzymes require zinc for their activation and nearly transcription factors require zinc for gene expression. zinc is essential for epithelial barrier integrity, tissue repair, cell-mediated immunity, and immune function. zinc as an antioxidant and antiinflammatory agent is effective in gastrointestinal structure and function. diarrhea is associated with significant zinc loss, and the use of zinc supplements can reduce the duration and severity of diarrhea in children. in areas where the prevalence of zinc deficiency or the prevalence of moderate malnutrition is high, zinc may be of benefit in children aged months or more. the current evidence does not support the use of zinc supplementation in children below months of age. the who has recommended zinc supplementation in children with gastroenteritis. supplements should be started at the beginning of the symptoms. recommended doses and duration: • for children less than months of age, mg daily for days • for children from months to years of age, mg daily for days. this therapy decreases the severity and reduces the number of episodes of diarrhea occurring within - months following the intake of zinc. the physiological composition of intestinal microflora is essential to maintain an appropriate balance of microbiota and the intestinal barrier. probiotics, also defined as food supplements, improve the intestinal microbial balance of the host, have beneficial effects on health, prevent outbreaks of community-acquired diarrhea, reduce colonization of infants with pathogenic microorganisms, and reduce the duration and severity of diarrheal infections, balancing the intestinal ecosystem. in large clinical trials, lactobacillus reuteri, lgg, and saccharomyces boulardii have shown the best therapeutic effects (reducing mean duration and frequency of watery diarrhea and number of watery stools per day, and improving stool's consistency). [ ] [ ] [ ] particularly, a recent randomized double blind study carried out in three italian pediatric centers showed that l. reuteri dsm , taken together with a standard ors, significantly reduced the duration of watery diarrhea compared with placebo ( . ± . days vs . ± . days, p , . ). on days two and three of treatment, watery diarrhea persisted in % and % of the placebo and % and % of the l. reuteri recipients, respectively (p , . , p , . ). moreover, children receiving l. reuteri dsm had a significantly lower relapse rate of diarrhea ( % vs %, p , . ). the european society of gastroenterology, hepatology, and nutrition and the national institute for health and clinical excellence have suggested the use of probiotic strains with proven efficacy and in appropriate doses for the management of children with acute gastroenteritis as an adjunct to rehydration therapy. , probiotics and symbiotics are of interest as they elicit healthpromoting properties to the host, release various soluble low-molecular-weight molecules of different nature (surface and exogenous proteins, peptides, amines, lectins, sirtuines, nucleases, other enzymes, bacteriocines, fatty and amino acids, lactones, nitric oxide, etc), are able to interact with corresponding cell receptors, to reply quickly by induction of special sets of genes, to support stability of host genome and microbiome, to modulate epigenomic regulation of gene phenotypic expression, and to ensure information exchange in numerous bacterial and bacteria-host systems. all this plays an important role in the control for many physiological, biochemical, and genetic functions in supporting host health. recently, probiotic l. reuteri strain atcc pta demonstrated the ability to potently suppress human tumor necrosis-factor production by lipopolysaccharide-activated monocytes and primary monocyte-derived macrophages from children with crohn's disease: the primary mechanism of probiotic-mediated immunomodulation is transcriptional regulation. other researchers have confirmed these results, and it has been shown that l. reuteri produce biologically active small compounds, previously unknown, that can modulate host mucosal immunity. the identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immunomediated diseases. antibiotic therapy bacteria most cases of age in children are viral, self-limited, and need only supportive treatment. antibacterial therapy serves as an adjunct, to shorten the clinical course, eradicate causative organisms, reduce transmission, and prevent invasive comsubmit your manuscript | www.dovepress.com dovepress dovepress plications. selection of antibacterials to use in acute bacterial gastroenteritis is based on clinical diagnosis of the likely pathogen prior to definitive laboratory results. antibacterial therapy should be restricted to specific bacterial pathogens and disease presentations. in general, infections with shigella spp and vibrio cholera should usually be treated with antibacterials, while antibacterials are only used in severe unresponsive infections with salmonella, yersinia, aeromonas, campylobacter, plesiomonas spp, and clostridium difficile. antibacterials should be avoided in ehec infection. there is no evidence of benefit for antibiotics in nontyphoidal salmonella diarrhea in otherwise healthy people. the effects in very young people, very old people, and in people with severe and extraintestinal disease are not always so clear, and a slightly higher number of adverse events are noted in people who receive antibiotic treatment for nontyphoidal salmonella diarrhea. however, empiric therapy may be appropriate in the presence of a severe illness with bloody diarrhea and stool leucocytes, and particularly in patients with risk factors (ill-fed or debilitated patients), the use of systemic antibiotics has been recommended (table ) . , the benefits and risks of adverse drug reactions should be weighed before prescribing antibacterials. moreover, a major concern is the emergence of antibacterial-resistant strains due to the widespread use of antibacterial agents. aeromonas spp produce a β-lactamase that induces resistance to penicillin and first-generation cephalosporins. in fact, several studies have demonstrated a relatively high resistance rates for cephalothin and for trimethoprimsulfamethoxazole; low rates of resistance has been found to third generation cephalosporin (cefotaxime), to ciprofloxacin and to chloramphenicol. with high levels of resistance to many antibiotics, resistance of a. hydrophila to ciprofloxacin is still very low, which may suggest that ciprofloxacin and other quinolone class antimicrobials may be considered as potential drugs for the treatment of bacterial diarrhea caused by a. hydrophila. , , for campylobacter jejuni, antibiotics are initiated in cases of febrile diarrheas, especially those believed to have moderate to severe disease. considering the increased incidence of c. jejuni and the resistance of the great majority of isolated strains to quinolones, the administration of azithromycin empirically for acute diarrhea, when indicated, could be appropriate. , moreover, erythromycin treatment of acute c. jejuni diarrhea demonstrated antibacterial efficacy by reducing the mean number of days until first negative stool culture. according to recent studies, the management of clostridium difficile infections involves three basic principles: supportive care, discontinuing the precipitating antibiotic(s), and the initiation of effective anti-c. difficile therapy. discontinuation of the offending antibiotic may be sufficient for the resolution of mild symptoms and facilitates the reconstitution of the normal enteric flora. for mild-moderate c. difficile infection in children, metronidazole is the drug of choice, with efficacy similar to vancomycin. for severe infection, oral vancomycin with intravenous metronidazole is recommended. linezolid also has a potential impact, and in adults, recurrence is less frequent with fidaxomicin than with vancomycin. [ ] [ ] [ ] [ ] a vaccine against c. difficile is desirable and being developed for prevention. regarding enterobacteriaceae, an antibiotic-susceptibility profile indicated that enteropathogens are generally susceptible to meropenem and ceftriaxone, followed by amikacin and ciprofloxacin. almost all enteropathogens were resistant to ampicillin and amoxicillin. epec infection is primarily a disease of infants younger than years of age, often contracted during travel in hot countries. in moderate-severe forms of gastroenteritis caused by epec in nurseries, the use of antibiotics such as imipenem, amikacin, gentamicin, and fluoroquinolone seem to be useful in reducing morbidity, mortality, and time of excretion, but few studies have evaluated in a systematic manner the value of antimicrobials for the management of epec infection in children. , etec has been reported to be the most important pathogen responsible in traveler's diarrhea. eaec also plays an important role in traveler's diarrhea. pathogen-and geographic-based approaches to traveler's diarrhea treatment should be encouraged. fluoroquinolones and nonabsorbable rifaximin are the drugs of choice for travelers to high-risk areas in which e. coli is the predominant etiologic agent (latin america, the caribbean [haiti and the dominican republic], and africa), leaving azithromycin for travelers to south and southeast asia as well as patients with febrile dysenteric illnesses acquired in any region. antibiotic therapy for stec is complicated. the growth of o :h in the intestinal tract leads to diarrhea, and patients would presumably benefit if antibiotic treatment eliminated the bacteria. however, systemic dissemination of shiga toxin type produced by the bacteria in the intestinal tract can lead to life-threatening complications, including neurological damage and hus. antibiotic treatments that induce the phage lytic cycle, resulting in increased shiga toxin production, could lead to more serious disease. recent studies suggest that normal flora can have a profound impact on shiga toxin production. subinhibitory levels of antibiotics that target dna synthesis, including ciprofloxacin and sulfamethoxazole-trimethoprim, increased shiga toxin production, while antibiotics that target the cell wall, transcription, or translation did not. so ciprofloxacin and sulfamethoxazole-trimethoprim are not appropriate for treatment of o :h . in contrast, azithromycin significantly reduced shiga toxin levels, even when relatively high levels of o :h were recovered. moreover, the eradication rate reported in stec o :h infections is %. azithromycin might be considered a potentially effective and safe antibiotic, and may be used safely for decolonization of stec o :h long-term carriage. numerous outbreaks, as well as sporadic cases of stec infections and hus, have been documented worldwide. there are numerous reports on stec o :h as the most common serotype associated with hus, especially in children. several reports on non-o stec underline their potential to cause sporadic disease as well as epidemics. during , there was a large outbreak in northern germany, with a satellite outbreak in western france caused by an eaec of serotype o :h expressing a phage-encoded shiga toxin : clinicians were confronted with a large number of mainly adult patients with hus associated with severe hemolysis and neurological complications. medical centers used varying therapeutic regimens, including plasmapheresis, glucocorticoids, and the submit your manuscript | www.dovepress.com dovepress dovepress anti-c monoclonal antibody eculizumab, but currently there is no effective prophylaxis or treatment available for stec infections and hus. the probiotic escherichia coli strain nissle (ecn) seemed to have very efficient antagonistic activity on the ehec strains of serotype o :h and o :h , with reduced growth of pathogens. the outbreak strains perfectly showed the genome plasticity and evolution of e. coli as a result of horizontal gene transfer. these strains combine the virulence mechanisms of two pathotypes (eaec and ehec), leading to an improved ability to adhere to and infect host cells. furthermore, the acquisition of mechanisms mediating increased antibiotic resistance hampered patient treatment and recovery. these strains have conserved most of the virulence factors of an eaec strain, but several mobile genetic elements were responsible for the acquisition of new functions involved in high-frequency recombination, mobilization, and transfer of genes. despite the alternative mechanisms that have evolved to colonize and adapt to new niches, e. coli strains have maintained a core genome sequence, and therefore share several components that could be useful targets for a universal vaccine against e. coli. considering the increasing antibiotic resistance present among e. coli strains, which is derived from an uncontrolled use of antibiotics, vaccination is the most promising approach to control disease. helicobacter pylori is a leading cause of chronic gastritis, peptic ulcers, nonulcer dyspepsia, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. eradication of the pathogen has a failure rate of more than % in pediatric patients, particularly because of poor compliance, antibiotic resistance, and occurrence of side effects. treatment regimens generally include a proton-pump inhibitor (lansoprazole, omeprazole, pantoprazole, rabeprazole, dexlansoprazole, or esomeprazole), which allows the tissues damaged by the infection to heal, and two antibiotics to reduce the risk of treatment failure and antibiotic resistance. treatment requires several medications for - days. in pediatric patients, gastric mucosal lesion-caused h. pylori infection is a reversible process, and the eradication of this infection not only stops the activity of the inflammatory process but also restores the mucous membranes, reduces the incidence of recurrence of gastritis and peptic ulcer disease, and can lead to prevention of malignant disease in %- % of cases. adjuvant therapy with probiotics has been studied in recent years. in a recent randomized, placebo-controlled, double-blind study, children on h. pylori eradication therapy receiving seven strains of probiotic in addition to the standard triple regimen (omeprazole + amoxicillin + claritromicin or omeprazole + amoxycillin + furazolidon) were compared with patients on the same triple regimen receiving placebo. the findings reported a significant reduction in treatment complications and an improved therapeutic outcome: the rate of eradication was significantly higher, and children had a lower rate of nausea/vomiting and diarrhea during treatment. the long-term success of h. pylori eradication interventions for preventing gastric cancer, depends on the recurrence determinants (nonadherence and demographics) that are as important as a specific antibiotic regimen. despite plesiomonas shigelloides seeming to be a minor cause of bacterial enteritis, the pathogen has been implicated in gastroenteritis outbreaks in tropical regions and in cases of traveler's diarrhea. antibacterials are used only in cases of severe and unresponsive infections: the most effective are ciprofloxacin and azythromycin, and partially trimethoprimsulfamethoxazole. with salmonella spp, antibiotics are initiated in cases of febrile diarrhea, especially in case of moderate to severe disease. the administration of azithromycin empirically for acute diarrhea, when indicated, could be appropriate. , consistent evidence from several clinical trials suggests that antibiotic treatment (ampicillin, amoxicillin, cefixime, azithromycin, cotrimoxazole) did not shorten the duration of diarrhea or lead to an earlier resolution of clinical symptoms. intramuscular ampicillin protects children against relapse and reduces the carriage of salmonella infection significantly better than placebo, oral ampicillin, or amoxicillin. antibiotics are usually avoided in mild shigella illness, because mild forms of shigella dysentery are said to be self limiting, some shigella strains are resistant to antibiotics, and their use may lead to increased resistance. if necessary, in severe cases, the choice of antibiotic to use as first line against shigella dysentery should be governed by periodically updated local antibiotic sensitivity patterns of shigella isolates. other supportive and preventive measures recommended by the who should also be instituted along with antibiotics (eg, health education and hand-washing). ciprofloxacin has been recommended by the who as the drug of choice for all patients with bloody diarrhea, irrespective of their ages. according to a recent cochrane review, the authors did not find robust evidence to suggest that antibiotics of a particular class are better than those belonging to a different class. trials report that at various periods of time, different antibiotics have been effective against isolates of shigella dysentery in different parts of the world. these are ampicillin, cotrimoxazole, nalidixic acid, fluoroquinolones submit your manuscript | www.dovepress.com dovepress dovepress like ciprofloxacin, pivmecillinam, ceftriaxone, and azithromycin. however, limited data from a subgroup of studies suggest that a fluoroquinolone (ciprofloxacin) would be more effective than a beta-lactam (ampicillin) in reducing diarrhea among adults, and that beta-lactams would be more effective than fluoroquinolones in reducing diarrhea among children with proven shigella dysentery. emerging drug resistance to ciprofloxacin and second-line drugs such as pivmecillinam, ceftriaxone, and azithromycin is increasingly being reported in many parts of the world, as is multiple-drug resistance. , in india, for example, several shigella strains (s. flexneri, s. dysenteriae, s. boydii, and s. sonnei) isolated from children # years of age are resistant to ampicillin, cotrimoxazole, ciprofloxacin, and nalidixic acid. alternatives include ceftriaxone and azithromycin, but ceftriaxone is an injectable drug and azithromycin has limited therapeutic benefit, as organisms easily develop resistance to it. it has been noted that all shigella spp utilize a type iii secretion system to translocate bacterial proteins -invasins ipaa-d and ipgd -into host eukaryotic cells to initiate infection. because they are common to all virulent shigella spp, they seem to be ideal candidate antigens for a subunit-based broad-spectrum protective vaccine for prevention of shigellosis. vibrio cholerae strains from endemic outbreaks within the last decade revealed patterns of antibiotic resistance to ampicillin, tetracycline, and trimethoprim correlated with widespread therapeutic and prophylactic administration of antibiotics. treating severe cases of cholera with antibiotics is important, but the continuing spread of resistance to the most important therapeutic agents is a matter of concern, as some strains have either intermediate resistance or are resistant to ceftriaxone, ciprofloxacin, and tetracycline. the most common clinical manifestation of a yersinia enterocolitica infection is a self-limited gastroenteritis that resolved spontaneously within weeks. y. enterocolitica usually shows in vitro susceptibility to aminoglycosides, chloramphenicol, doxycycline, cotrimoxazole, third-generation cephalosporins, carabapenems, and fluoroquinolones. recently, in a case-control study conducted among children aged less than years, it was found that y. enterocolitica is generally susceptible to meropenem ( %), ceftriaxone ( %), and ciprofloxacin ( %), followed by ceftazidime ( %) and amikacin ( %). almost all y. enterocolitica was resistant to ampicillin. fungal fungal infections of the gastrointestinal tract are not common in children, especially in immunocompetent ones. in the neonatal period, candida infections frequently develop into systemic forms. fluconazole prophylaxis in infants , g ( mg/kg twice a week), while intravenous access is required, appears to be safe and effective in preventing invasive candida infections with or without diarrhea, while attenuating the emergence of fungal resistance. , new echinocandines -anidulafungin, caspofungin, and micafungin, recently introduced -seem to have some advantages over fluconazole and amphotericin b, as they better meet the needs of pediatric patients, neonates, and in particular preterm infants with invasive candidiasis and/or diarrhea from candida spp infection. micafungin, a dose-dependent candidacidal agent with excellent in vitro efficacy against most candida spp, including species resistant to amphotericin b, is approved for the treatment of invasive candidiasis in children, including preterm infants aged less than months. efficacy and safety were demonstrated in comparison with liposomal amphotericin b and fluconazole. the most appropriate dose in children weighing less than kg is mg/kg/day in the treatment of invasive candidiasis and or gastroenteritis and mg/kg/day as prophylaxis. in premature infants, the most appropriate doses to achieve appropriate levels in the brain parenchyma are mg/kg/day in infants weighing more than , g and mg/kg/day in those weighing less than , g, respectively. micafungin has few drug-drug interactions and an acceptable safety profile thus providing a promising drug in the prophylactic and therapeutic management of invasive candidiasis. micafungin has few drug-drug interactions, and an acceptable safety profile. [ ] [ ] [ ] data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both caspofungin and micafungin are effective and well tolerated also in neonates. , parasitic -protozoan the major causes of diarrhea worldwide in children are cryptosporidium parvum, giardia lamblia, and entamoeba histolytica: "the neglected parasitic disease." cryptosporidium is a diarrheagenic protozoan pathogen for children, and immunosuppressed individuals are disproportionately affected. until a few years ago, the most commonly used treatments, only partially effective, were paromomycin and azithromycin. recent investigations have focused on nitazoxanide, as it significantly shortens the duration of diarrhea and decreases mortality in malnourished children. nitazoxanide is not effective without an appropriate immune response, as in aids patients. , giardia lamblia is a diarrheagenic protozoan pathogen most commonly treated with metronidazole (mtz) or tinidazole submit your manuscript | www.dovepress.com dovepress dovepress but failures occur in %- % of cases. albendazole may be of similar effectiveness to metronidazole, may have fewer side effects, and has the advantage of a simplified regimen. nitazoxanide is a viable therapeutic option as an effective alternative to mtz in reducing the duration of diarrhea. , , auranofin, a gold complex classified by the who as an antirheumatic agent, has been revealed to be active against multiple mtz-resistant strains blocking a critical enzyme involved in maintaining normal protein function. these results indicate that auranofin could be developed as an antigiardial drug, particularly against mtz-resistant strains. entamoeba histolytica amebiasis is the fourth-leading cause of death and the third-leading cause of morbidity due to protozoan infections worldwide. in children, effective drugs for diarrhea are mtz and other nitroimidazoles. however, eradication of e. histolytica infection after completion of mtz requires additional therapy with luminal amebicides, such as paramomycin. nitazoxanide is a recent therapeutic advance, due to its action against luminal and invasive parasite forms. nitazoxanide-treated patients had statistically shorter durations of diarrheal illness. auranofin could represent a promising therapy for amebiasis. parasitic -helminths nematodes strongyloides stercoralis and trichuris trichiura are causes of diarrhea. strongyloides stercoralis can penetrate host skin and parasitize human intestines, leading to burning pain, tissue damage, ulcers, edema and obstruction of the intestinal tract, and diarrhea, as well as loss of peristaltic contractions. ivermectin is the first-choice therapy because of its higher tolerance, and albendazole is the second-choice therapy. , trichuris trichiura is chiefly a tropical infection, and children are especially vulnerable to infection due to their high exposure risk. light infestations (, worms) are frequently asymptomatic, but heavy infestations may cause mechanical or inflammatory damage to the mucosa, abdominal pain, profuse or chronic diarrhea, and bloody diarrhea. mebendazole seems to be the first-choice therapy and albendazole the second-choice therapy, while nitazoxanide shows no effect. an albendazole and nitazoxanide-albendazole combination showed only a minimal effect. there is a need to develop new anthelmintics against trichuriasis. age remains a major problem in children and still represents one of the leading causes of illness costs and of deaths, as an estimated . million gastroenteritis deaths occur each year in children less than years of age throughout the world, especially in resource-constrained countries. in rich countries, transmission occurs much more frequently from contaminated food compared to direct person-to-person contact, except for enteric viruses, which can also be transmitted by aerosol formation after vomiting. most cases of age in children are viral, self-limited, and need only supportive treatment. rehydration (oral or intravenous) with an appropriate fluid-and-electrolyte balance, with close attention to nutrition, remains central to therapy: this may turn into an additional benefit in limiting hospitalizations. intestinal infections often require drugs such as antiemetics, antidiarrheal agents, and probiotics that may deeply change the impact, severity, and duration of acute diarrhea. in cases of severe infectious diarrhea with a prolonged course, signs of inflammation, bloody stool, immunosuppression, and comorbidity, and in suspected outbreaks, fecal microbial analysis, should always be performed, and a specific therapy should be considered if indicated to shorten the clinical course, eradicate causative organisms, reduce transmission, and prevent invasive complications. selection of antibacterials to use in acute bacterial gastroenteritis is based on clinical diagnosis of the likely pathogen and on definitive laboratory results. based on epidemiological data and after collecting organic materials for etiological diagnosis (often a single fecal sample studied for etiologic agents is the customary way to make an etiologic diagnosis), an initial empiric therapy may be appropriate in case of a severe illness, particularly in infancy and the immunocompromised. in case of suspected ehec serotype o and eaec serotype o :h (but also of shigella dysenteriae serotype ), as it is estimated that %- % of infected individuals will develop hus following stec infection with e. coli o :h the most commonly involved serotype, antibiotics should be prescribed according to more recent guidelines. moreover, a major concern is the emergence of antibacterialresistant strains due to the widespread use of antibacterial agents: a continuous monitoring of antibiotic resistance in diarrhea-related bacterial pathogens is recommended. the benefits and risks of adverse drug reactions should be weighed before prescribing any kind of 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nitazoxanide-albendazole against trichuris trichiura infection: a randomized controlled trial submit your manuscript here: http://www.dovepress.com/infection-and-drug-resistance-journal infection and drug resistance is an international, peer-reviewed openaccess journal that focuses on the optimal treatment of infection (bacterial, fungal and viral) and the development and institution of preventive strategies to minimize the development and spread of resistance. the journal is specifically concerned with the epidemiology of antibiotic resistance and the mechanisms of resistance development and diffusion in both hospitals and the community. the manuscript management system is completely online and includes a very quick and fair peerreview system, which is all easy to use. visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors. key: cord- -j dydo authors: ahmed, khalid; mohamed, mouhand f.h. title: acute abdomen is not always surgical amid the covid‐ pandemic date: - - journal: br j surg doi: . /bjs. sha: doc_id: cord_uid: j dydo nan lima et al.'s recently published paper discussed the role of imaging in the diagnosis of acute abdomen cases amid the covid- era . saeed et al. reported that sars-cov- infection could lead to an acute abdomen-like presentation in the absence of identifiable surgical causes . both authors discussed the role of angiotensin-converting-enzyme- (ace ) receptor in the pathogenesis of this entity. our experience with similar cases makes us concur with both authors . herein we will summarize the likely non-surgical causes of acute abdomen in the covid- era and discuss important management points when dealing with such patients. the causes can be divided into respiratory and non-respiratory ( fig. ) . a respiratory cause for such presentation is pain referring from lower lungs involved by the sars-cov- . the sars-cov infection seems to increase the risk of colonic distension colitis pancreatitis thrombosis ; thus, the non-respiratory causes can be further classified as thrombotic and non-thrombotic. nonthrombotic causes include pancreatitis, peritonitis, colonic distension, and colitis, while thrombotic etiologies are mesenteric vessel ischemia (occlusive or non-occlusive), renal vessels infarcts, appendagitis, and omental infarcts (fig. ) . with the causes mentioned above in mind, it is wise to keep a broad differential of non-surgical causes of acute abdomen in the setting of sars-cov- infection, to avoid unnecessary surgical interventions . any patients presenting with an acute abdomen should be tested and retested for sras-cov- , even in the absence of respiratory symptoms. elevated serum ferritin may support covid- diagnosis . computed tomography (ct) scan of the abdomen and lower chest will be valuable in ruling some of the causes and identifying pulmonary involvement. if unrevealing, we suggest performing a ct angiogram of the abdomen, focusing on mesenteric and renal vessels. we believe in the role of multidisciplinary meetings (mdt), including radiologists, surgeons, internists, and infectious experts, to tailor an individualized, case-by-case management approach. mfhm and ka contributed equally to this letter. ka and mfhm wrote the initial and the final version and approved it for submission. role of chest ct in patients with acute abdomen during the covid- era covid- may present with acute abdominal pain case report: covid- masquerading as an acute surgical abdomen covid- and its implications for thrombosis and anticoagulation decrease in surgical activity in the covid- pandemic: an economic crisis we acknowledge the editor and the editorial team members for their prompt review of the letter. key: cord- -dep v pt authors: whyte, claire s; morrow, gael b; mitchell, joanne l; chowdary, pratima; mutch, nicola j title: fibrinolytic abnormalities in acute respiratory distress syndrome (ards) and versatility of thrombolytic drugs to treat covid‐ date: - - journal: j thromb haemost doi: . /jth. sha: doc_id: cord_uid: dep v pt the global pandemic of coronavirus disease (covid‐ ) is associated with the development of acute respiratory distress syndrome (ards), which requires ventilation in critically ill patients. the pathophysiology of ards results from acute inflammation within the alveolar space and prevention of normal gas exchange. the increase in proinflammatory cytokines within the lung leads to recruitment of leukocytes, further propagating the local inflammatory response. a consistent finding in ards is the deposition of fibrin in the air spaces and lung parenchyma. covid‐ patients show elevated d‐dimers and fibrinogen. fibrin deposits are found in the lungs of patients due to the dysregulation of the coagulation and fibrinolytic systems. tissue factor (tf) is exposed on damaged alveolar endothelial cells and on the surface of leukocytes promoting fibrin deposition, while significantly elevated levels of plasminogen activator inhibitor (pai‐ ) from lung epithelium and endothelial cells create a hypofibrinolytic state. prophylaxis treatment of covid‐ patients with low molecular weight heparin (lmwh) is important to limit coagulopathy. however, to degrade pre‐existing fibrin in the lung it is essential to promote local fibrinolysis. in this review, we discuss the repurposing of fibrinolytic drugs, namely tissue‐type plasminogen activator (tpa), to treat covid‐ associated ards. tpa is an approved intravenous thrombolytic treatment, and the nebulizer form has been shown to be effective in plastic bronchitis and is currently in phase ii clinical trial. nebulizer plasminogen activators may provide a targeted approach in covid‐ patients to degrade fibrin and improving oxygenation in critically ill patients. in early december multiple cases of pneumonia of unknown aetiology were reported in wuhan, hubei province, china [ ] [ ] [ ] . in january the world health organisation declared that this was caused by a new type of coronavirus, (sars-cov- ). the spread of sars-cov- has been exponential resulting in a global pandemic with more than two million confirmed cases. while most people with covid- develop only mild illness, characterised by a fever and continuous cough [ ] , approximately % develop severe disease that requires hospitalisation and oxygen support and % require admission to intensive care. covid- patients with respiratory distress present primarily with severe hypoxemia, yet respiratory system compliance can vary from near normal to exceptionally low [ ] . in severe cases, patients with covid- develop a type of acute respiratory distress syndrome (ards), sepsis and multiorgan failure. older age and co-morbidities are associated with higher mortality [ ] . a hallmark of ards is increased alveolar-capillary permeability triggered by exudation of fluid rich in cells and plasma proteins, including albumin, fibrinogen, proinflammatory cytokines and coagulation factors [ , ] (figure ). this leads to recruitment of inflammatory leukocytes, including neutrophils [ ] alveolar macrophages [ ] , monocytes and platelets, which propagate the local inflammatory response [ ] . fibrin deposition in the air spaces and lung parenchyma, are consistently observed with ards and contributes to hyaline-membrane formation and subsequent alveolar fibrosis [ ] [ ] [ ] [ ] . this promotes the development and progression of respiratory dysfunction and right heart failure [ ] . fibrin deposition is the net result of an alteration in the balance of the coagulation and fibrinolytic pathways, and several therapeutic strategies have been explored to target the dysfunction of these systems in ards [ ] [ ] [ ] [ ] . recent case studies describe fibrin deposits in biopsies of lung tissue from patients with covid- [ , ] , with ards commonly reported [ , ] . consistent with this large numbers of infiltrating immune cells have been found in covid- positive lung tissues, particularly monocytes and macrophages, [ , [ ] [ ] [ ] alongside the formation of fibrin, [ , , ] proteinaceous hyaline membranes and pulmonary fibrosis [ , ] . ct scans of covid- patient's lungs reveal characteristic ground glass opacities (gco), indicating partial filling of the bronchoalveolar airspace with exudate [ , ] . the timing of the accidental sampling in the covid- patients with lung cancer suggests these early fibrin lung depositions present prior to clinical symptoms of pneumonia [ ] . therefore, biomarkers to allow early identification of these changes would be highly beneficial in early diagnosis and timely treatment of covid- patients. this review will focus on the molecular mechanisms and role of inflammatory cells in underpinning fibrin deposition and persistence in the lungs of critically ill covid- patients and discuss potential therapeutic strategies to help support these patients. this article is protected by copyright. all rights reserved sequestration of leukocytes, particularly neutrophils, within the microvasculature of the lung is central to the development of ards, leading to a massive insult to the alveolar-capillary membrane, unrestricted inflammation and microthrombus formation (reviewed by [ ] ). neutrophils, resident alveolar macrophages and monocyte-derived macrophages, as well as recruited monocytes, infiltrate the lungs, enhance lung injury, and play a key role in the pathogenesis of ards [ ] [ ] [ ] [ ] . release of proinflammatory cytokines, including macrophage inflammatory protein (mip- ), interleukin (il- ), interleukin- (il- ), interleukin- (il- ) and tumour necrosis factor  (tnf-), encourage ongoing infiltration of immune cells from the intravascular compartment to the alveolar airspaces [ ] [ ] [ ] . indeed, these proinflammatory cytokines are used as biomarkers of ards and have been suggested to be important in progression of covid- associated ards [ ] . accumulation of coagulation factors in the lungs can also drive ards through the activation of proteaseactivated receptors (pars) which are expressed on cells in the lungs including alveolar epithelial cells, fibroblasts, monocytes and macrophages [ , ] . par signalling induced by tissue factor, coagulation factor xa, factor viia or thrombin can augment fibrosis in addition to driving fibrin generation. fibrosis is characterised by fibroblast migration, proliferation and deposition of collagen in the intra-alveolar spaces. par- can be acted upon in fibroblasts by both thrombin and factor xa to promote their proliferation, induce production of pro-collagen and amplify expression of various growth factors including connective tissue growth factor (ctgf) [ , ] . par signalling can enhance inflammation in acute lung injury (ali) by increasing the expression of pro-inflammatory cytokines, including il- [ ], il- , [ ] [ ] [ ] and platelet derived growth factor [ ] . accumulation of neutrophils in the lungs further contributes to the pathophysiology of ards [ ] . neutrophils release their dna alongside their nuclear and cytoplasmic contents into the extracellular environment during the cell death process, netosis. these web like cellular extrusions, termed neutrophil extracellular traps (nets) form a scaffold of chromatin decorated with cytoplasmic and granule proteins and histones. nets play a role in the fight against invading pathogens. however, if not tightly regulated, nets can contribute to the pathogenesis of non-infectious diseases where they can exacerbate coagulation and inflammation [ ] and have recently been reported as a contributing player in the pathogenesis of ards and ali where they cause further damage to the lungs [ , ] . net production has accepted article been identified in the lungs during ards, where levels of nets are greatly increased in the bronchoalveolar lavage (bal) of both ards patients and mouse models of induced ali and ards [ , [ ] [ ] [ ] . increased nets correlate with the severity of ards [ , ] and disease severity is reduced in mouse models when nets are degraded using dnase [ ] . a hypercoagulable state exists in the lungs of ards patients, leading to the deposition of fibrin in the intra-alveolar space [ ] (figure ). inflammation modulates coagulation by activating c-reactive protein (crp), thereby augmenting tissue factor exposure on monocytes and alveolar macrophages [ , ] which in turn promote thrombin generation and deposition of fibrin. hepatic synthesis of fibrinogen, an acute phase protein, is increased - -fold in plasma during infection [ ] and local synthesis in the lung epithelium is evident during pneumonia [ ] thereby further exacerbating fibrin deposition. fibrin deposition augments inflammation and fibrosis as well as damaging lung surfactant [ , , ] . this is coupled with a hypofibrinolytic state in the alveolar space, where fibrinolytic inhibitors have been shown to be elevated. levels of thrombin activatable fibrinolysis inhibitor (tafi) and protein c inhibitor were found to be significantly elevated in the bronchoalveolar fluid of patients with interstitial lung disease when compared to healthy controls [ ] . furthermore, it has been reported that α -macrogloblin levels are increased in obstructive lung disease, which may correlate with the increase in plasminogen observed in the bal of ards patients [ , ] . however, the principal fibrinolytic inhibitor described in the pathogenesis of ards is plasminogen activator inhibitor (pai- ), which is known to be elevated in severe acute respiratory syndrome coronavirus (sars-cov) and ali [ , ] . in ards, crp promotes local release of pai- from endothelial cells [ , ] . additionally, infiltration of platelets, the major circulating pool of pai- , may result in local release. we have recently shown that a significant amount of this active pai- remains associated with the stimulated platelet membrane [ , ] . attenuation of the plasminogen activation system leads to abnormal turnover of fibrin in the alveolar space. plasma pai- levels have been reported as an independent risk factor for poor prognosis and mortality in ali [ , , , [ ] [ ] [ ] [ ] . prabhakaran et al [ ] reported a significant increase in pai- antigen and activity in plasma and the edema fluid in ali, with evidence of significant pulmonary production [ ] . a clear role for pai- as a prognostic marker in ards was confirmed by a prospective observational study this article is protected by copyright. all rights reserved which demonstrated -fold higher levels in patients who progressed to ards than those with uncomplicated aspiration pneumonitis ( vs. ng/ml, respectively) [ ] . importantly, a hypofibrinolytic state and increased pai- was observed in the sars-cov epidemic in and [ ] . gralinski et al used a non-biased systems biology approach to study the dysfunctional fibrinolytic pathway in an infection model of sars-cov [ ] . fibrin persistence was mediated by overexpression of pai- which overcomes local upa and tissue-type plasminogen activator (tpa) [ ] . sars-cov infected cells contain high levels of tgf-β , which in turn stimulates expression of extracellular matrix protease inhibitors, including pai- [ ] which has been specifically linked to ards induced by sars-cov [ ] . these studies illustrate a clear role for pai- in the aetiology of ards and suggest it is a key protein contributing to abnormal turnover of fibrin in the alveolar space. plasma pai- has been reported as a potential biomarker for predicting disease progression in ali to ards, with one study concluding that pai- antigen > ng/ml was a % positive predictor for mortality [ ] . similar pathology of fibrin depositions in the lungs has been identified in covid- [ , ] , suggesting pai- may be a useful prognostic marker for patients at risk of developing ards and thus requiring critical care and ventilation. a common finding with covid- patients requiring hospitalisation is increased levels of d-dimers and and fibrin degradation products (fdp) which are associated with a higher risk of mortality [ ] . prothrombin time and activated partial thromboplastin time show a mild elongation [ ] . coupled with the fact critically ill covid- patients will be immobilised, there is an increased risk of hospital-associated venous thromboembolism (vte) [ ] . these findings have led to a recent recommendation for prophylactic anticoagulant therapy with low molecular weight heparin (lmwh) for patients hospitalised with covid- , without contraindications, to limit the extent of the coagulopathy [ , ] . heparin treatment (both unfractionated and lmwh) reduces inflammatory biomarkers [ ] , and therefore may be beneficial in reducing the inflammatory state in covid- this article is protected by copyright. all rights reserved anticoagulant therapy is essential to limit ongoing fibrin deposition and microthrombi formation in ards and treat the systemic prothrombotic complications in these patients. however, lmwh will be ineffective in clearing fibrin clusters deposited in the alveolar space. there is therefore a requirement to readdress the balance of fibrinolysis in the lung, either by enhancing plasminogen activation or downregulating fibrinolytic inhibitors. the significant increase in pai- in ards and ali curtails local upa, but also tpa, activity [ , , , ] . in a pig model of trauma, administration of tpa or upa prevented development of ards, with animals displaying normal pao [ ] . a phase clinical trial revealed a significant improvement in pao at hours in out of patients with severe ards secondary to trauma or sepsis following administration of upa or streptokinase [ , ] . these patients had a pao of less than mmhg, usually considered fatal, which increased to . mmhg following thrombolytic therapy with an overall % survival rate and no incidence of bleeding [ ] . the use of tpa to treat ards in covid- patients has recently been proposed by moore et al [ ] . an initial case report from patients from the current sars-cov- pandemic, demonstrates a transient improvement in p/f ratio in cases and sustained % improvement in case following administration of a mg bolus of intravenous tpa followed by a further mg infusion [ ] . the authors suggest that there is a precedent for increasing the dose of the bolus of tpa whilst maintaining heparin infusion, as the anticoagulant is effective against submassive pulmonary embolism [ , ] . in addition to readdressing the fibrinolytic balance, administration of tpa to ards patients may confer anti-inflammatory effects, as it has been shown to suppress neutrophil activation in a rat model of ali induced by il- α [ ] . a major consideration in anticoagulant or thrombolytic therapy is the undesirable complication of bleeding. in respiratory medicine, treatments are often delivered as aerosolised protein therapeutics as diffusion of proteins from the blood to the lungs can be limited [ ] . interestingly, nebulised anticoagulant therapy with antithrombin or heparin has been shown to reduce lung injury without an increase in systemic bleeding in animal models [ ] [ ] [ ] and ali patients [ ] . however, as discussed, heparin will prevent further fibrin deposition but will be ineffective in the removal of pre-existing fibrin. a recent publication compared the efficacy of the nebulised form of the plasminogen activator, streptokinase and nebulised heparin in the treatment of ards [ ] . the primary outcome in this trial was the change in pao /fio ratio, which was significantly higher in the streptokinase group from day to day , compared to the heparin and standard-of-care groups. importantly, icu mortality was significantly lower in streptokinase patients compared to other groups [ ] . a case report [ ] describes a young woman with ards who was resistant to conventional therapeutics and was treated with nebulised and intravenous tpa, followed by continuous treatment with nebulized unfractionated heparin. the patient this article is protected by copyright. all rights reserved stabilized following fibrinolytic treatment and demonstrated a significant enhancement in pulmonary gas exchange. plastic bronchitis is a condition that can develop from several respiratory disorders, resulting in casts of compacted mucous that have been shown to contain fibrin [ ] . plastic bronchitis is primarily observed in children and has been described in cases of influenza a (h n ) [ , ] and human bocavirus [ ] . nebulised tpa has been shown to be effective in preventing recurrent cast formation in plastic bronchitis [ ] . reports thus far are from single case studies, however, there is an ongoing phase ii clinical trial of nebulised tpa (platypus; alteplase, nct ) for treatment of plastic bronchitis. these data clearly indicate that use of nebulised fibrinolytics could allow a more targeted approach to correct the haemostatic imbalance that results in fibrin deposition, while limiting the risk of systemic activation of fibrinolysis that may trigger unwanted bleeding ( figure ). inhaled tpa is absorbed into the vasculature thus increasing fibrinolytic capacity in the plasma [ ] and the potential to lyse the microthrombi observed in covid- patients. however, it is conceivable that intravenous infusions of tpa may be necessary to disperse larger thrombi in the circulation. a potential caveat of a nebulizer formulation is that aerosolised proteins are susceptible to degradation so the formulation and excipient used must be considered [ ] . however, in the case of tpa, an extreme advantage is that a formulation of nebulised alteplase has been developed and is currently being tested in a phase ii clinical trial [ ] . the covid- global pandemic has necessitated a demand for novel therapeutics to limit the complications of ards and/or reduce the burden on ventilatory support in intensive care units. the indication that fibrin deposits occur prior to symptoms [ ] of the disease, suggests that targeting the fibrinolytic system to promote fibrin resolution could limit severity and improve pulmonary function. given the urgent time scale of the clinical requirement, repurposing of existing therapies, such as nebulised tpa, to promote fibrin dissolution in the lung and improve oxygenation is a pragmatic approach in addressing the ards complications associated with covid- . this article is protected by copyright. all rights reserved outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle bin cao. clinical features of patients infected with novel coronavirus in wuhan alimuddin zumla, eskild petersen. the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in wuhan, china covid- does not lead to a "typical" acute respiratory distress syndrome clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study activation and regulation of systemic 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cord- -cjq szcn authors: mottola, filiberto fausto; verde, nicoletta; ricciolino, riccardo; di mauro, marco; migliaccio, marco giuseppe; carfora, vincenzo; spiniello, giorgio; coppola, nicola title: cardiovascular system in covid- : simply a viewer or a leading actor? date: - - journal: life (basel) doi: . /life sha: doc_id: cord_uid: cjq szcn as of january , a new pandemic has spread from wuhan and caused thousands of deaths worldwide. several studies have observed a relationship between coronavirus disease (covid- ) infection and the cardiovascular system with the appearance of myocardial damage, myocarditis, pericarditis, heart failure and various arrhythmic manifestations, as well as an increase in thromboembolic risk. cardiovascular manifestations have been highlighted especially in older and more fragile patients and in those with multiple cardiovascular risk factors such as cancer, diabetes, obesity and hypertension. in this review, we will examine the cardiac involvement associated with sars-cov- infection, focusing on the pathophysiological mechanism underlying manifestations and their clinical implication, taking into account the main scientific papers published to date. since december , a new zoonotic betacoronavirus (sars-cov- ) has spread all over the world from wuhan in china [ ] , known as coronavirus disease . by august , about . million cases were recorded with about , deaths worldwide. it is an rna virus, identified as belonging to the betacoronavirus family, which also includes mers-cov, identified in as the cause of the middle east respiratory syndrome, and sars-cov, identified in and responsible for severe acute respiratory syndrome (sars) [ ] . the incubation period varies from to days, although cases with longer incubation periods of up to days have been identified. sars-cov- infection may cause a wide range of clinical presentations, from an asymptomatic to a severe forms. the main clinical symptoms develop within table . studies evaluating cardiovascular involvement during the coronavirus disease (covid- ) pandemic. poissy j, [ ] france pulmonary embolism had a high frequency ( . %), higher than that observed in influenza patients admitted to the icu (intensive care unit) for respiratory failure in . f a klof, [ ] the netherlands venous thromboembolism confirmed in %, arterial thrombotic events in . %. lodigiani c, [ ] italy thromboembolic events occurred in ( . %) patients. ischemic stroke and acs (acute coronary syndrome)/mi (myocardial infarction) in . % and . %, respectively. overt dic (disseminated intravascular coagulation) present in ( . %) patients. songping cui, [ ] china vte associated with a poor prognosis was present in %. the increase in d-dimer identified high-risk groups of vte. respectively. overt dic (disseminated intravascular coagulation) present in ( . %) patients. songping cui, [ ] china vte associated with a poor prognosis was present in %. the increase in d-dimer identified high-risk groups of vte. an increase in myocardial necrosis indices, such as troponin (tnt), the creatine kinasemyocardial band test (ck-mb) and myoglobin, has been reported in several patients with covid- . wang et al. in a single-center study showed that . % of hospitalized patients developed acute heart damage and that the patients who received care in the intensive care unit (icu) were more likely to have heart damage ( . %) compared to non-icu patients [ ] . shi et al. observed at presentation a high value of tnt in approximately % of hospitalized patients with covid- . compared to those without an increase in tnt, these patients were more likely to require invasive or non-invasive ventilation ( % versus %, and % versus %, respectively) and to develop acute respiratory distress syndrome ( % versus %) or acute kidney injury ( % versus %; p < . for all); in addition, the mortality rate was higher ( . % vs. . %; p < . ) and it increased with the entity of the reference value of high-sensitivity troponin i (hs-tni) [ ] . a recent meta-analysis showed that cardiac troponin i (ctni) values were significantly higher in patients with severe sars-cov- infection compared to those observed with mild forms [ ] . guo found that compared with patients with normal tnt levels those with higher levels had significantly higher levels of other heart damage biomarkers, specifically ck-mb and myoglobin, and also had higher levels of n-terminal pro-brain natriuretic peptide (nt-probnp). finally, they had a significantly higher level of high-sensitivity c-reactive protein, d-dimer and procalcitonin. during hospitalization, the patients with elevated tnt levels developed more frequent complications, including acute respiratory distress syndrome, malignant arrhythmias, acute coagulopathy and acute kidney damage [ ] . an increase in myocardial necrosis indices, such as troponin (tnt), the creatine kinase-myocardial band test (ck-mb) and myoglobin, has been reported in several patients with covid- . wang et al. in a single-center study showed that . % of hospitalized patients developed acute heart damage and that the patients who received care in the intensive care unit (icu) were more likely to have heart damage ( . %) compared to non-icu patients [ ] . shi et al. observed at presentation a high value of tnt in approximately % of hospitalized patients with covid- . compared to those without an increase in tnt, these patients were more likely to require invasive or non-invasive ventilation ( % vs. %, and % vs. %, respectively) and to develop acute respiratory distress syndrome ( % vs. %) or acute kidney injury ( % vs. %; p < . for all); in addition, the mortality rate was higher ( . % vs. . %; p < . ) and it increased with the entity of the reference value of high-sensitivity troponin i (hs-tni) [ ] . a recent meta-analysis showed that cardiac troponin i (ctni) values were significantly higher in patients with severe sars-cov- infection compared to those observed with mild forms [ ] . guo found that compared with patients with normal tnt levels those with higher levels had significantly higher levels of other heart damage biomarkers, specifically ck-mb and myoglobin, and also had higher levels of n-terminal pro-brain natriuretic peptide (nt-probnp). finally, they had a significantly higher level of high-sensitivity c-reactive protein, d-dimer and procalcitonin. during hospitalization, the patients with elevated tnt levels developed more frequent complications, including acute respiratory distress syndrome, malignant arrhythmias, acute coagulopathy and acute kidney damage [ ] . the pathophysiological mechanisms underlying myocardial injury caused by covid- are not well defined. an increase in the cardiac necrosis index may be caused by an increased oxygen demand by the myocardium, similar to what happens during a type myocardial infarction, or due to an inflammatory process caused by an exaggerated cytokine response by type and helper t cells, which could cause instability of the atherosclerotic plaque. huang et al. found that the patients with covid- admitted to an icu had higher serum cytokine levels, including interleukin il- , il- , il- , granulocyte colony stimulating factor, and tumor necrosis factor α. the activation or advanced release of these inflammatory cytokines leads to apoptosis or necrosis of myocardial cells, life , , of also leading to an increase in the indices of myocardial necrosis [ ] . another explanation may be direct damage of cardiomyocytes by the virus [ , ] . different studies speculate that the interaction between sars-cov- and angiotensin-converting enzyme (ace- ) in the heart could contribute to sars-mediated myocardial inflammation and damage [ , , ] . concluding on this point, it should be stressed that myocardial necrosis index measurements were likely to have been performed in those who were most ill or where there was reasonable suspicion of myocardial ischemia or myocardial dysfunction. a case of myocarditis in a patient with mers-cov infection was found to have acute heart failure, documented also by cardiac magnetic resonance imaging (mri) [ ] . similarly, in some patients with or without pre-existing cvd, covid- was associated with myocarditis. incardi et al. and fried et al. published clinical cases of patients with chest pain and diffuse st increase with elevated troponin and negative coronary angiography, but who subsequently resulted positive for covid- ; myocarditis was later confirmed with cardiac mri in both cases [ , ] . pericardial involvement has not been well described, although in our experience, we have shown cases with covid- and concomitant pericardial effusion (personal data not shown), one of which about a week after discharge in the absence of another triggering cause. indeed, several patients have been shown to have a feeling of chest tightness similar to that of an acute coronary syndrome in the absence of coronary obstruction and in the absence of an increase in myocardial necrosis indices and therefore attributable to the symptoms of covid- [ ] . further studies are needed to better clarify this possible association. in other infections (influenza, other coronaviruses, and others), patients with cvd have been shown to have an increased risk of heart failure during acute infections [ , ] . furthermore, in covid- patients a worsening in underlying heart failure has been observed [ ] . in a retrospective cohort study on patients, zhou et al. showed that with cardiac complications, such as a worsening of a previous heart failure or a new onset, myocardial infarction was common in patients with pneumonia, with cardiac arrest present in approximately % of patients; predisposing risk factors were the severity of pneumonia, advanced age and a pre-existing heart disease [ ] . moreover, an increase in n-terminal pro b-type natriuretic peptide (nt-probnp) has been linked to the severity of inflammation and worsening left ventricular function, and serious increases in nt-probnp and tnt have been shown in patients with worse outcomes than those who showed favorable outcomes [ , , ] . in a case series, chen et al. observed increased levels of nt-probnp and ctni in . % and % of patients, respectively. interestingly, levels of il- and other inflammatory cytokines, such as the expression of cytokine storm, were elevated especially in patients who experienced a more severe disease course requiring icu admission. [ ] . a recent latif study found that the mortality rate on heart transplant (ht) patients with concomitant covid- infection was %. the majority ( %) had evidence of myocardial damage and high inflammatory biomarkers. ht patients may be at increased risk of infection and adverse outcomes due to a number of common co-morbidities after heart transplantation, including hypertension, diabetes and cardiac allograft vasculopathy. furthermore, all require maintenance immunosuppression, which predisposes, on the one hand, to a greater infection risk and, on the other, it can have a protective action against the cytokine storm [ ] . however, whether the heart failure is due to a worsening in the left ventricular function in a patient with previous decompensation or is due to a new cardiomyopathy is still to be demonstrated, as well as the repercussions on the right ventricle, especially in patients with severe pulmonary micro-thromboembolism in acute respiratory distress syndrome (ards). few data are available in the literature on the incidence and management of cardiac arrhythmias related to covid- . wang et al. in patients with covid- pulmonary infection in wuhan observed cardiac arrhythmias in ( . %) patients and acute cardiac injury in ( . %). they reported heart palpitations as one of the most common initial symptoms of the disease ( . %) [ ] ; moreover, exacerbation and the new onset of paroxysmal supraventricular tachycardia (psvt), atrial fibrillation (af) and flutter were possible in patients with covid- . in patients with severe pneumonia, ards and sepsis, the incidence of af during hospitalization was very high (about - % of critically ill patients) [ ] . in italian covid- patients who died, a retrospective chart review identified a history of af in . % [ ] . during hospitalization, malignant ventricular arrhythmias, defined as sustained ventricular tachycardia (vt) or ventricular fibrillation (vf), occurred in ( . %) patients [ ] . arrhythmias may be due to myocardial damage; in fact, in patients with elevated tnt, a higher incidence of ventricular arrhythmia was reported. therefore, myocardial injury might result in atrial or ventricular fibrosis, thus, the substrate for subsequent cardiac arrhythmias even after hospital discharge and mri can help us stratify these patients. direct viral infection, hypoxia-induced apoptosis and association with the cytokine storm may be the mechanisms causing arrhythmias. systemic inflammatory response syndrome can be an important risk factor for arrhythmia onset: il- directly inhibits the human ether-à-go-go-related gene (herg) k + channel and prolongs action potential duration in ventricular myocytes [ ] ; indirectly, the systemic inflammatory response hyper-activates the cardiac sympathetic system via central hypothalamus-mediated (inflammatory reflex) and peripheral (left stellate ganglia activation) pathways [ ] . however, myocardial damage alone is not enough and there are other factors involved in enhancing the arrhythmic risk in covid- : in fact, in these patients, only half showed acute cardiac injury despite the high frequency of arrhythmias [ ] . an important role in the development of arrhythmias may be played by pharmacological treatment used for covid- patients that increases the susceptibility to qt-related life-threatening ventricular arrhythmias, particularly torsades de pointes. in fact, many drugs used to treat these patients have the ability to block cardiac potassium currents, with subsequent prolongation of the qt-interval and an increased risk for arrhythmias [ ] . in particular, chloroquine (cq) and hydroxychloroquine (hcq) are drugs used for these patients with known qt-prolonging effects [ ] . these drugs may increase the depolarization length duration and purkinje fiber refractory period, leading to atrioventricular nodal and/or his system dysfunction [ ] [ ] [ ] . in , capel et al. demonstrated an inhibitory effect of hcq on the hyperpolarization-activated current ion channels (also known as "funny current" channels) [ ] . these findings seems to correlate with a proposed mechanism by which refractory action potentials in cardiac myocytes may lead to a prolongation of the qt interval due to delayed depolarization and repolarization from abnormal ion currents. in an observational study in new york in hospitalized patients with covid- , treatment with hcq, azithromycin, or both, compared with neither treatment, was not significantly associated with in-hospital mortality, but cardiac arrest was significantly more likely in patients receiving hcq + azithromycin [ ] . in another study, about % of covid- patients treated with these drugs developed qt prolongation, with ventricular arrhythmia in covid- patients out of a group of treated with high-dose chloroquine [ ] . a chinese meta-analysis including patients in randomized controlled trials observed that hcq had an increased risk of mild adverse events compared to placebo cq. in addition, protease inhibitors (lopinavir/ritonavir; darunavir/ritonavir, darunavir/cobicistat) administrated in patients with covid- inhibited cyp a , which may further increase plasma levels of qt-prolonging drugs (in particular macrolides like azithromycin or fluoroquinolones, frequently administered to these patients) [ ] . therefore, some simple guidance could be useful for the management of these patients. while ecg monitoring is always available for covid- patients admitted to icu, in patients hospitalized in non-intensive rooms, clinicians should monitor qt-intervals according to the risk factors. in patients with congenital or acquired long qt syndrome (lqts), in those treated with other qt-prolonging drugs and/or with structural heart disease or bradycardia, ecg may be evaluated at baseline, h after administration of cq or hcq and/or anti-viral therapy and then every - days. in all other patients, qt-interval monitoring should be performed h after the start of therapy; if there is a worsening kidney/liver function and electrolyte disorders (in particular k + , ca + and mg + ), qtc-interval monitoring is indicated. it is important to pay attention to the particular clinical situation, like diarrhea, which may lead to hypokalemia, which may influence the qtc interval. moreover, all unnecessary qt prolonging drugs should be stopped. if qtc is higher than ms or if qtc increases by ≥ ms from baseline, then the safety of qt prolonging antiviral drugs should be reviewed, and serum potassium levels should be kept at > . meq/l; fever should be aggressively treated with paracetamol. the treatment of arrhythmia is the same for covid- and non-covid- patients. the treatment goals in all patients with af must consider ventricular rate control, rhythm control and thromboembolic prophylaxis. we should remember that the combination of amiodarone, the choice of antiarrhythmic medication for rhythm control, with hcq and/or azithromycin should preferably be avoided. drug interactions should always be considered before the administration of any drugs. asynchronous defibrillation should be performed in patients with vf, while synchronized electrical cardioversion should be performed in hemodynamically unstable vt. lastly, if there is no important drug interaction, we can attempt a pharmacological conversion. in patients with severe acute respiratory insufficiency, the correction of underlying reversible triggers should be considered and could interrupt the arrhythmia [ ] . for the prevention of torsade de pointes in the setting of covid infection, we can withdraw all qt prolonging drugs and normalize the potassium level (target > . meq/l), give intravenous magnesium supplementation and finally increase the heart rate by withdrawing bradycardiac agents, and if needed by i.v. isoproterenol or temporary pacemaker. vascular involvement in covid- is demonstrated by the high risk of thromboembolism observed in these patients. different case reports, case series and retrospective studies suggested that the incidence of pulmonary embolism (pe) in patients with covid- infection might be high [ , ] . in lille university, in a case series on covid- patients admitted to the icu for pneumonia, the authors observed an unexpected high prevalence ( . %) of pe; despite a similar severity score at the entrance to the icu, the frequency of pe in their covid- series was twice as high as the frequency they found in the same time interval in [ ] . an interesting observational study based on patients with covid- pneumonia showed a high prevalence of venous thromboembolism confirmed by ct pulmonary angiogram and/or ultrasonography ( %, % ci - %), and of arterial thrombotic events ( . %, % ci - . %) [ ] . in an italian study enrolling consecutive patients, thromboembolic events occurred in ( . %): with venous thromboembolism ( with pulmonary embolism with or without deep vein thrombosis and with isolated deep venous thromboembolism) and the remaining patients with ischemic stroke and/or myocardial infarction [ ] . similar results ( % of pe) were obtained in a retrospective study conducted by french researchers in patients with covid- [ ] . the pathogenic mechanism of a high prevalence of thromboembolic events may be linked to the hypercoagulative state observed in covid- patients. covid- has been described as causing a proinflammatory state due to cytokine-mediated diffuse microvascular damage [ ] [ ] [ ] [ ] . some authors observed a close interaction between high d-dimer values and adverse events in covid- [ , , ] . indirect suggestions of the hypercoagulative state were the observations of an advantage in the use of life , , of thromboprophylaxis in covid- patients. for example, one study observed a mortality benefit from thromboprophylaxis with subcutaneous unfractionated heparin or low molecular weight heparin in covid- patients with highly elevated d-dimer [ ] . a higher incidence of acute pe in patients with covid- infection should be suspected when a respiratory worsening, unexplained tachycardia, a fall in hypovolemia or sepsis, ecg changes suggestive of pe, and signs of deep vein thrombosis are observed. moreover, in these patients, there is an urgent need to improve specific venous thromboembolism (vte) diagnostic strategies, taking into account some limits: computed tomography pulmonary angiogram (ctpe) is often delayed or not performed due to co-morbid renal failure and cardiopulmonary instability, leading to an unacceptable risk for transfer; similarly, duplex ultrasonography (dus) is difficult to perform due to the large number of patients and difficulty in completely disinfecting the machines. thus, it is very important to use diagnostic scoring systems such as the wells' criteria, pulmonary embolism rule-out criteria (perc), or the geneva scoring system [ ] [ ] [ ] . concluding on this point, trials evaluating the correct management of thrombotic complications in these patients are needed, considering that novel oral anticoagulants (noacs) such as lopinavir/ritonavir may interact with drugs for covid- and, thus, they should be avoided. since covid- infects patients through the link to the ace receptor, it has been speculated that the use of angiotensin-converting enzyme inhibitor (acei) and an angiotensin receptor blocker (arb) may contribute to an increase in the level of ace , which makes the virus more likely to invade cells. in fact, based on previously conducted studies on sars-cov- , the sars-cov- virus has been shown to express numerous spikes of protein s on the surface of the viral envelope that were critical for the transmission of infection. the s glycoprotein includes two subunits with different action: s influences the virus tropism and attachment to the external membrane, while s is responsible for virus cell fusion and effective cell entry. this protein binds to the ace through the s subunit; due to the presence of transmine membranes serine proteases (tmprss ), also expressed by the host cell, which was able to perform the protein priming, it was essential to allow the virus to enter the cell. after these processes, the virus can enter the sarcoplasmic reticulum and begin its rna replication [ , ] . ace- is expressed on the surface of a variety of host cells, including type i and type ii pneumocytes, pericytes, cardiomyocytes, along with other cells of the digestive system such as enterocytes in the small intestine and finally in arterial and venous endothelial cells [ ] . interestingly, circulating ace levels in patients were gender dependent, and in a study published recently, researchers found that the distribution of ace is more widespread in males than in females. moreover, different ace polymorphisms were observed in different races, and this may suggest a possible link with the covid- diffusion and with the different outcome observed throughout the world [ , ] . on the other hand ace also serves a role in lung protection, and different studies show that ace inhibitors/arbs may potentiate the lung protective function of ace by reducing angiotensin ii levels, which is pro-inflammatory, pro-thrombotic and pro-oxidant [ , , ] . finally, in a recent study, metha et al. showed no association between acei or arb and a higher probability of positivity to the covid- test [ ] . thus, it should be underlined that these drugs are often used in the treatment of patients with underlying chronic diseases and therefore in more fragile patients who are already at a greater risk of mortality and complications. because of the important role played by inhibitors of the renin-angiotensin system (ras inhibitors) in patients with heart disease, particularly in those with heart failure, and since there is no clinical evidence to support the adverse or beneficial effects of ras inhibitors in covid- patients with cardiovascular disease, major cardiovascular societies recognize that patients with acei or arb should not stop the treatment. the management of patients with covid- and cardiovascular complications is not yet well defined. as evidenced by several studies, it seems that the main cause of myocardial damage is myocardial damage in the absence of epicardial coronary artery thrombosis, although it is possible that patients with covid- may still have concomitant acute coronary syndrome. a correct differential diagnosis between the various causes of myocardial injury is therefore essential in patients with myocardial damage, limiting fibrinolysis or coronary angiography to certain cases of st-elevation myocardial infarction (stemi) [ ] [ ] [ ] [ ] (figures - ) . because of the important role played by inhibitors of the renin-angiotensin system (ras inhibitors) in patients with heart disease, particularly in those with heart failure, and since there is no clinical evidence to support the adverse or beneficial effects of ras inhibitors in covid- patients with cardiovascular disease, major cardiovascular societies recognize that patients with acei or arb should not stop the treatment. the management of patients with covid- and cardiovascular complications is not yet well defined. as evidenced by several studies, it seems that the main cause of myocardial damage is myocardial damage in the absence of epicardial coronary artery thrombosis, although it is possible that patients with covid- may still have concomitant acute coronary syndrome. a correct differential diagnosis between the various causes of myocardial injury is therefore essential in patients with myocardial damage, limiting fibrinolysis or coronary angiography to certain cases of st-elevation myocardial infarction (stemi). [ ] [ ] [ ] [ ] (figures - ) . because of the important role played by inhibitors of the renin-angiotensin system (ras inhibitors) in patients with heart disease, particularly in those with heart failure, and since there is no clinical evidence to support the adverse or beneficial effects of ras inhibitors in covid- patients with cardiovascular disease, major cardiovascular societies recognize that patients with acei or arb should not stop the treatment. the management of patients with covid- and cardiovascular complications is not yet well defined. as evidenced by several studies, it seems that the main cause of myocardial damage is myocardial damage in the absence of epicardial coronary artery thrombosis, although it is possible that patients with covid- may still have concomitant acute coronary syndrome. a correct differential diagnosis between the various causes of myocardial injury is therefore essential in patients with myocardial damage, limiting fibrinolysis or coronary angiography to certain cases of st-elevation myocardial infarction (stemi). [ ] [ ] [ ] [ ] (figures - ) . however, one aspect to consider is the high contagiousness of the virus; thus, one of the priorities is to limit the exposure of healthcare personnel to the virus, carrying out only the fundamental tests for diagnosis and management of cardiovascular complications. in fact, in italy and spain, % and %, respectively, of infection are observed in health workers, and although personal protective equipment reduces the risk of contagion, they are unable to cancel it [ ] . another consideration to be made is the cleanliness and hygiene of the operating room and/or the devices used to make a diagnosis that could delay the same tests for other patients who need them. on the other hand, as a recent italian study shows, it should also be considered that the high fear of contagiousness and mortality from the virus has led to a drastic decrease in hospitalizations for acute coronary syndrome with a consequent increase in mortality [ ] . finally, another particular group of patients are covid- patients with cancer; they are at high risk of cardiovascular complications due to the association between antineoplastic (for example anthracyclines) or anti-covid- (tocilizumab and ritonavir) drugs and cardiotoxic effects [ , ] . several studies have highlighted a clear relationship between covid- infection and the involvement of the cardiovascular system, especially in patients who develop ards and those hospitalized in icus. however, further studies are needed to clarify the correct management of cardiovascular involvement and any long-term repercussions in the patients involved. however, one aspect to consider is the high contagiousness of the virus; thus, one of the priorities is to limit the exposure of healthcare personnel to the virus, carrying out only the fundamental tests for diagnosis and management of cardiovascular complications. in fact, in italy and spain, % and %, respectively, of infection are observed in health workers, and although personal protective equipment reduces the risk of contagion, they are unable to cancel it [ ] . another consideration to be made is the cleanliness and hygiene of the operating room and/or the devices used to make a diagnosis that could delay the same tests for other patients who need them. on the other hand, as a recent italian study shows, it should also be considered that the high fear of contagiousness and mortality from the virus has led to a drastic decrease in hospitalizations for acute coronary syndrome with a consequent increase in mortality [ ] . finally, another particular group of patients are covid- patients with cancer; they are at high risk of cardiovascular complications due to the association between antineoplastic (for example anthracyclines) or anti-covid- (tocilizumab and ritonavir) drugs and cardiotoxic effects [ , ] . several studies have highlighted a clear relationship between covid- infection and the involvement of the cardiovascular system, especially in 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disease reperfusion of st-segment-elevation myocardial infarction in the covid- era st-elevation myocardial infarction in patients with covid- csc expert consensus on principles of clinical management of patients with severe emergent cardiovascular diseases during the covid- epidemic management of cardiovascular disease during coronavirus disease (covid- ) pandemic european centre for disease prevention and control. infection prevention and control for covid- in healthcare settings-third update reduced rate of hospital admissions for acs during covid- outbreak in northern italy the novel coronavirus disease (covid- ) threat for patients with cardiovascular disease and cancer. jacc cardio vanvitelli covid- group. a focus on the nowadays potential antiviral strategies in early phase of coronavirus disease (covid- ): a narrative review this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the manuscript has been read and approved by all authors and has not been submitted for publication to other journals. we also declare that we have no conflict of interest in connection with this paper.life , , key: cord- -oybnk j authors: suassuna, josé hermógenes rocco; de lima, emerson quintino; rocha, eduardo; castro, alan; burdmann, emmanuel de almeida; do carmo, lilian pires de freitas; yu, luis; ibrahim, mauricio younes; betônico, gustavo navarro; cuvello, américo lourenço; Ávila, maria olinda nogueira; gonçalvez, anderson r. roman; costa, ciro bruno silveira; bresolin, nilzete liberato; de abreu, andrea pio; lobo, suzana margareth ajeje; do nascimento, marcelo mazza title: technical note and clinical instructions for acute kidney injury (aki) in patients with covid- : brazilian society of nephrology and brazilian association of intensive care medicine date: - - journal: j bras nefrol doi: . / - -jbn- -s sha: doc_id: cord_uid: oybnk j we produced this document to bring pertinent information to the practice of nephrology, as regards to the renal involvement with covid- , the management of acute kidney injury cases, and practical guidance on the provision of dialysis support.as information on covid- evolves at a pace never before seen in medical science, these recommendations, although based on recent scientific evidence, refer to the present moment. the guidelines may be updated when published data and other relevant information become available. este documento foi desenvolvido para trazer informações pertinentes à prática nefrológica em relação ao conhecimento sobre o acometimento renal da covid- , conduta frente aos casos de injúria renal aguda e orientações práticas sobre a provisão do suporte dialítico. como as informações sobre a covid- evoluem a uma velocidade jamais vista na ciência médica, as orientações apresentadas, embora baseadas em evidências científicas recentes, referem-se ao momento presente. essas orientaços poderão ser atualizadas à medida que dados publicados e outras informações relevantes venham a ser disponibilizadas. palavras-chave: lesão renal aguda; infecções por coronavirus; covid- ; cuidados críticos. we produced this document to bring pertinent information to the practice of nephrology, as regards to the renal involvement with covid- , the management of acute kidney injury cases, and practical guidance on the provision of dialysis support. as information on covid- evolves at a pace never before seen in medical science, these recommendations, although based on recent scientific evidence, refer to the present moment. the guidelines may be updated when published data and other relevant information become available. acute kidney injury; coronavirus infections; covid- ; critical care. the covid- pandemic is a global threat with the potential to deplete national healthcare systems. the colossal volume of reports and discussions produced in such a short term is an unprecedented fact in medicine, not only in traditional vehicles of scientific dissemination, but also in blogs, websites, social networks and conversations between peers. evidence is published at a rapid pace and no recommendation can be considered definitive. like the first version, made available online, this second edition is based on information available until the moment of its publication. the objective is to inform, recommend practices and assist in decision-making, recognizing that the situation does not allow for establishing strict guidelines. the brazilian society of nephrology (sbn) and the brazilian association of intensive care medicine (amib) understand that there are different scenarios of assistance to patients with acute kidney injury (aki) in our country. it is inevitable that there will be variations in practice, resulting from individualities in the clinical picture, the availability of human and material resources and other aspects, associated with the resources of each healthcare institution, including the type of organization and the type of contracting of nephrological care. every professional involved in nephrological care must provide the best possible assistance to the patients under their responsibility, adopt practices that minimize their personal risk of contamination, that of their patients and the whole range of other professionals who participate in hospital kidney support, including nurses and technicians, dialysis staff, healthcare professionals from all areas (for example, doctors and nurses in intensive care medicine), laboratory and radiology technicians, cleaning and transport staff, etc. each institution must define its bed allocation policy for patients with covid- , as well as that of the professionals responsible for the treatment, either by isolation of a cohort in a specific physical area, in a general inpatient unit or in a general hospital intensive care unit. protocols for the entry and circulation of nephrology team members in the environment of patients with covid- must be defined in advance, in order to minimize the use of personal protective equipment (ppe) and to limit nonessential traffic in isolation environments. since a larger contingent of patients with aki will be under intensive or semi-intensive care, interaction and collaboration between nephrologists and intensivists is essential. it is advisable to adapt visiting routines to digital format and all documentation/prescription to electronic format, avoiding the movement of papers and documents between the inpatient unit and other institutional sectors. it is imperative, during interactions with patients, that nephrologists and other members of the dialysis team follow the guidelines for safety and use of ppe. as covid- spreads, awareness of its manifestations also increase. it is now evident that covid- has different clinical phenotypes , not necessarily sequential, which may have direct implications in the risk of aki. the vast majority of symptomatic cases are benign, with flu-like syndrome and mild pulmonary involvement. phenotypes that are more serious include acute respiratory distress syndrome (ards) with alveolar damage due to viral cytopathic effect, systemic hyperinflammation syndrome (or cytokine storm) and hypercoagulability syndrome with micro and macrovascular manifestations . there is ample literature on the association of acute respiratory distress syndrome (ards) with aki, within the pathophysiological model of the crosstalk between the organs. it is not surprising to see the development of aki in patients with the extensive pulmonary damage that characterizes the severe forms of covid- and the adverse renal effects of the highly complex ventilatory support that these patients need. in a large series in new york, the main cause attributed to the development of aki was the systemic collapse that follows orotracheal intubation and the beginning of mechanical ventilation . in some cases, disease progression is much more severe, with hyperinflammation, often associated with acute cardiac injury. the striking feature of these cases is the significant increased circulating levels of inflammatory cytokines, notably il- , il- and ifn-ɣ, and other markers, such as troponin, ferritin and d-dimer , . these patients have a poor prognosis and evidently difficult-to-manage aki. autopsy studies have produced variable findings. one of the first series reported severe tubular necrosis, associated with lymphocytic tubulointerstitial nephritis, with macrophages and tubular deposition of the complement membrane attack complex . immunohistochemistry demonstrated direct renal infection by sars-cov- , which is not surprising, given the high expression of ace receptor in the renal tubular epithelium. the possibility of cytopathic action by direct viral invasion of the renal epithelium has been reinforced with ultrastructural and molecular studies [ ] [ ] [ ] . as these samples are skewed for the patients that died, it is not possible to assess the relevance of the findings in relation to the aki cases reported in clinical studies. in conclusion, the term aki is used for a wide variety of diseases that result in acute and subacute decrease in renal function, including, among others, processes of mechanical, ischemic, toxic, infectious origin and the branches of innate, adaptive humoral and cellular immunity. it is interesting to note that aki cases with covid- seem to reproduce this diversity. the etiologic factors involved are multiple and include direct viral cytopathic effect, decreased blood oxygen content and renal plasma flow, angiotensin ii activation, glomerulopathies, crosstalk injury, inflammatory deregulation, hyperviscosity, thrombotic microangiopathy, secondary sepsis and drug toxicity , - , - . in the first published series, almost all from china, the average incidence of aki associated with covid- was relatively low. on average, only . % ( . to %) affecting severe cases and only . % of patients ( . to . %) needing renal replacement therapy (rrt) , . - . these data did not suggest a higher incidence of aki in patients with covid- when compared to other patients with the same severity profile . in publications, the existence of two aki patterns was also highlighted; one early and one late. the latter was assigned a worse prognosis , . in late cases, the average time from admission to aki was seven days , . the experience in the west seems to be diverse and still in the process of being published. however, in a large series from new york, aki in the three kdigo stages was seen in % of patients . of these, % required artificial renal support. of the patients who died, % were in the kdigo stage ; %, in stage ; and % in kdigo stage . in particular, there was a strong association with ventilatory support, with % of patients on mechanical ventilation developing aki, versus % of those not ventilated. again in opposition to the initial publications, the majority of cases seen in the new york large serie occurred in the first two days of hospitalization, % in the first hours . anecdotal reports from european and brazilian centers also point to a high incidence of aki in patients on mechanical ventilation, between % to % of cases. this information is especially important to plan the allocation of dialysis machines and supplies as well as human resources to face the epidemic in places where the pandemic is still in the initial phase of dissemination through the population. as with other causes for ards, the development of aki in patients with covid- correlates with a worse overall prognosis and impacts mortality. , in a series with aki staging by the kdigo system (table ) , there was a progressive increase in the odds ratio for lethality, reaching . in patients staged as kdigo . in the american series mentioned above, the mortality initially reported was %, although % of the patients were still hospitalized . even though it is always necessary, in the current situation it is essential to reinforce the need for close collaboration between intensivists and nephrologists, sharing opinions at the bedside, and reviewing hemodynamic parameters and volume status. in the discussion of each case, priorities and the best treatment strategies are expected to be established in a shared way. within this perspective, the nephrologist shall be contacted in any situation of need, even with discrete degrees of renal dysfunction, since the nephrological involvement in intensive care is not limited to aki. the nephrologist's contribution includes additional situations, such as electrolyte disturbances, adjustment of medication doses, etiological diagnosis and management of kidney diseases of various etiologies. kdigo qualifies the severity of aki in stages (table ). in this sense, we recommend that patients with covid- in stage be already the subject of communication and discussion between the intensive care team and the nephrologist. patients classified as stage have a high probability of requiring artificial renal replacement therapy (rrt), justifying the immediate call of the nephrology team. practical details on the possible prescription/performance of rrt will be discussed below. protection of the workforce in nephrology and rrt healthcare professionals are at increased risk of exposure to sars-cov- , which is reflected in multiple morbidity and mortality reports. even when the infection evolves favorably, the mandatory temporary medical leave can overwhelm the remaining staff. for this reason, there was an initial recommendation to restrict the entry of nephrologists and dialysis nurses in the cohorts allocated covid- patients. the rrt prescription (and subsequent adjustments) was to be done remotely, as long as close contact with the medical team within the isolated cohort was assured. in the same way, the management of rrt procedures by icu nurses were encouraged, as long as they were properly trained. the experience with this strategy proved to be adequate while the number of cases remained relatively low. however, the excess of patients with covid- complicated by aki has caught many centers by surprise. in many places, the strategy of restricting the access of nephrology personnel proved to be inadequate by overburdening intensive care teams, which were already overwhelmed with other priorities. there was also occasional compromise in the exchange of information between doctors inside and outside the isolation units, and the impact on logistics that involved the insertion of vascular access and the flow of orders for the beginning, postponement, conduction and/or discontinuation of procedures. thus, in settings with a high prevalence of aki, we recommend that the direct participation of the nephrologist and nephrology nursing in the care within isolated areas is convenient, giving preference to professionals who have already developed antibodies against sars-cov- . for better operational capacity, we also recommend that patients be installed in contiguous, frontal or close beds, to enable simultaneous procedures to be carried out, supervised by the same dialysis technician or nurse. whenever possible, portable reverse osmosis equipment and systems should be exclusive and remain in the areas allocated to covid- patients, avoiding their displacement to other areas of the hospital. throughout the procedure, we recommend keeping the equipment outside or close to the bed access entrance. by the same perspective, we recommend that dialysis nurses remain in proximity and not inside the box/room. the use of standard procedures for disinfecting rrt equipment is suitable for the elimination of sars-cov- , including systems with a glass tank, which uses peracetic acid. there is no evidence of significant passage of sars-cov- across rrt filters. in bedside hemodialysis procedures, the dialysate waste should be drained in the hospital wastewater system. peritoneal dialysate can be discarded in the same way, keeping the ppe on throughout the process. although infrequent, there was a first report of detection, and persistence for more than days, of sars-cov- in the peritoneal effluent of a patient with covid- . bags of wasted peritoneal dialysate can also be depleted in the sanitary network, with particular care to prevent spilling and the dispersion of its contents. in compliance with the policy of restricting nonessential entry of personnel in covid- isolated areas, and to prevent wasting by having the nephrologist donning ppe solely for the purpose of catheter insertion, we advise that rrt access insertion ought to be performed the intensivist. however, with the work overload represented by the almost total occupation of icus by patients with covid- , experience has shown that the nephrologist must enter the isolated environment to insert dialysis catheters and perform other activities. the selection of catheters with adequate length and diameter is of paramount importance to ensure optimal blood flow. dialysis accesses with inconsistent or unsatisfactory flow promote clotting of the system, which results in blood loss and interruption of rrt. one should not insist on repeated flushing or other maneuvers. the most cost-effective solution is usually to replace the catheter. table shows dialysis catheter lengths recommended for different sites of central venipuncture. the different ranges stem from the diversity of biotypes in the population. catheters and dialysis lines are not a contraindication the placement of the patient in the prone position, but requires specific attention to avoid traction during pronation and supination maneuvers. whenever possible, particularly in the case of intermittent hemodialysis, it is recommended to temporarily disconnect the circuit. immediately after these maneuvers, the access must be inspected for traction, twisting and patency. the preferred site for vascular access implantation for rrt is the right internal jugular vein. it is common, however, that this route is no longer available due to the need of multiple simultaneous vascular lines in patients with severe covid- . the left internal jugular vein is the second option. the femoral access, which is easier to cannulate, may be inappropriate for patients under pronation protocols or ecmo. depending on the room layout, femoral access can reduce the risk of professional contamination at the time of insertion and facilitate the positioning of the equipment in an area that minimizes the risk of contamination by professionals. dialysis access through subclavian veins is often discouraged, because of the risk of accidents and of residual stenosis. however, they carry a lower risk of infection and may be the only remaining option for patients with inaccessible femoral internal jugular veins, under ecmo, or following a pronation protocol. due to the risks and difficulties associated with performing bedside chest x-rays, its routine use should be reconsidered. in services with availability and proper training, chest ultrasonography can be used to confirm the central positioning of the line and the absence of complications . chlorhexidine antisepsis is associated with a lower incidence of local and bloodstream infections. when available, the use of transparent dressings with chlorhexidine gluconate gel (chg) can reduce the number of exchanges and the need for handling. the routine of access care must also include the daily inspection of the insertion site and the integrity of the fixation points. in the absence of contraindications, all patients with covid- and a central vascular line should receive prophylaxis with low molecular weight heparin , in order to reduce the thrombotic risk . rrt modalities include continuous renal replacement therapy (crrt), prolonged intermittent hemodialysis (pirrt), conventional intermittent hemodialysis (ihd) and peritoneal dialysis (pd). the modality choice must be individualized, considering logistical aspects and the experience of each institution. it is not advisable to implement a new protocol or treatment modality in the midst of the covid- emergency. unfamiliarity increases the risk of adverse effects, increases the likelihood of errors, is detrimental to patient safety, and poses a higher risk of contamination to the team. crrt represent an efficient and safe treatment strategy, have an excellent stability profile, is performed in a closed system, and reduce physical contact with the patient. its preferential use, when available, can decrease the number of nurses and technicians exposed to sars-cov- . as there is concern about the low worldwide availability of kits and supplies for crrt, and to minimize the team's contact with infected patients, it is possible to skip scheduled exchange of filters, kits and systems, as long as these remain with optimal operational parameters. in some settings, intensive care nurses have adequate training and routinely conduct continuous therapies. this type of organization can reduce the need for dialysis nurses to enter the isolated areas and help conserve ppe stocks. in other scenarios, the dialysis nurse prepares the equipment, connects lines and solutions and performs the procedure. in this situation, machine setup and preparation must be done outside the patient's room or outside the isolation icu. only afterwards, and properly protected with ppe, should the nurse or technician enter the box/ room to start the procedure. once rrt starts, the assigned healthcare professional must constantly wear ppe, without leaving the treatment unit until the end of the work shift. should such professional need to enter the box, he/she must wear personal protective clothing, as established by the institutional's infection control committee. units with different arrangements must follow official guidelines and develop strategies along the same safety lines. the underlying logic should always be to minimize the inflow and outflow of professionals and equipment. most patients admitted to the icu will not have access to crrt, since the number of these machines in brazil is relatively limited. in this sense, the main options for extracorporeal treatment will be pirrt and ihd, evidently without reprocessing lines and capillaries. pirrt combines operational simplicity, reasonable cost, a good hemodynamic stability profile and excellent solute clearance, being widely used in the country. adaptations to the procedure make it possible to couple a convection component or use high cutoff filters. ihd is the procedure most commonly performed in the hospital environment, especially after hemodynamic improvement of critically ill patients. however, both are not routinely performed by intensive care doctors and nurses. intermittent methods are usually prescribed by the nephrologist and conducted by dialysis nurses and/or technicians. in some institutions, these professionals are part of the hospital staff, while in others rrt is outsourced. whichever the case, we recommend avoiding unwanted internal or interinstitutional circulation of machines and service providers. when facing covid- , it is essential to develop strategies that minimize occupational exposure and spread of sars-cov- . we strongly recommend the local stationing of equipment and advise against the relocation of the nursing staff from the covid- cohort area for the treatment of uninfected patients during the same work shift. during the procedure, we advise the nursing staff to avoid remaining inside the patient's box/room, rather controlling the procedure from the corridor or from a nearby area. if he/she needs to enter the box, we recommend proper paramentation, according to the routine established by the unit. as previously mentioned, we recommend that nurses or dialysis technician perform simultaneous procedures, in order to save ppe in situations of high demand, to reduce the risk of widespread staff contamination and, particularly, to assure that rrt will not be denied to all patients who needs it. it is advisable that the professional responsible for performing rrt eat meals in the icu, avoiding going out and returning for food. at the end of the procedure, the professional must dispose of all supplies safely, by placing them in bags for infectious substances. still inside the box/room and donning the ppe, he/she must perform the surface disinfection of the equipment and program a chemical disinfection cycle with peracetic acid. we recommend a second surface cleaning cycle, in a common area, before using the equipment on another patient. at the end of the daily use of the equipment, a final thermal disinfection cycle must be carried out, using citric acid or sodium hypochlorite, according to the manufacturer's recommendations. when using tank systems with central dialysate preparations, it must be brought to the icu door by the professional responsible for the preparation, and delivered to the dialysis nurse. before being transported to the patient's bed, the equipment must undergo surface disinfection. at the end of the procedure, there must be a new surface cleaning in the box/ room, and the equipment must be brought to the icu entrance to be collected by the professional responsible for its transport. we recommend a second surface cleaning cycle at the preparation center. in services with due experience, automated peritoneal dialysis with a flexible catheter, is a good treatment option, with the potential to reduce the length of stay of professionals at the bedside. to meet the needs of ultrafiltration, it may be necessary to work with hypertonic solutions (with a high glucose concentration), which can hinder glycemic control and require the addition of regular insulin to the dialysate bag. when available, the installation of a flexible catheter using the seldinger technique can reduce the risk of team contamination, enabling the procedure to start more quickly and allowing the adoption of the prone position, if necessary. in theory, the increase in abdominal pressure determined by the infusion of dialysate may interfere with the dynamics of mechanical ventilation in patients with ards that are difficult to manage. in such cases, we recommend reserving the pd for a later period, after the improvement of the ventilatory parameters. there is the potential to treat covid- 's severe hyperinflammatory phenotype with more sophisticated extracorporeal modalities, which have been shown to decrease the circulating levels of proinflammatory mediators and other harmful substances, at least in experimental studies. these therapies include devices capable of adsorbing cytokines and high-volume hemofiltration techniques. at present, it is not possible to endorse the use of these approaches, which are in the process of clinical experimentation. the ideal timing for rrt initiation in patients with critical illness, whether early or according to conventional indications at a later moment, is under intense investigation. the theoretical rationale for the early start of rrt consists in preventing homeostatic imbalances caused by renal dysfunction, which could help prevent or mitigate aki complications. in contrast, the "early" start may be unnecessary and harmful for some patients. in the two largest published multicenter studies, akiki and ideal-icu, the result was indifferent in relation to survival. however, among patients allocated to the late strategy, % of akiki and % of ideal-icu patients never came to need rrt . during the covid- epidemic, the decision about the initiation of rrt must necessarily be shared between the nephrologist and intensivist, and individualized for the patient's particularities. however, we recommend considering whether it is opportune to expose workers and deplete supplies in the absence of a strong indication for rrt, seeking the unproven benefit of early intervention. until further information, it is our recommendation that the conventional indicators for rrt implementation prevail in treating patients with covid- . these include volume control, prolonged anuria/oliguria, metabolic acidosis, uremia and electrolyte disturbances, notably hyperkalemia. in view of the risk that rrt intensification could result in greater contact and contamination of healthcare workers, cause depletion of consumables and compromise the availability of equipment, it is advisable to pay attention to the lack of evidence concerning improvements in aki prognosis when using high doses of rrt , . regarding the aki of covid- patients, our recommendation is that each institution maintains its policy on rrt dose, without seeking further increments. evidently, sub-dialysis, whether due to a reduction in treatment time or spacing in the interval between sessions, should not be practiced. the clinical picture of severe covid- is fundamentally dominated by severe acute respiratory syndrome (sars) and associated complications , . in addressing these cases, there is no consistent information to guide optimal fluid management. the tendency is to be based on strategies recommended for classic ards, where only a fraction of the lung parenchyma is aerated and the inflammatory lung injury is characterized by increased vascular permeability and diffuse alveolar damage, with an increase in physiological dead space and decreased pulmonary compliance. , since volume overload and hydrostatic pulmonary edema are frequent reasons for indicating rrt, it should be considered that excessive fluid resuscitation might precipitate its need, increase the risk of exposure of the workforce and consume resources in a situation of scarcity. in this context, it makes sense to approach volume management in a conservative way, which is associated with improved lung function and less time on mechanical ventilation and intensive care, while not increasing the risk of aki . this strategy has been recommended in pandemicrelated consensuses , . nonetheless, there is concern about the possibility that volume restriction strategies may not be suitable for all patients. in fact, there seems to be heterogeneity of clinical presentation on arrival at healthcare services, which implies in some patients presenting with classic ards, while others, even with extensive pulmonary opacities, due to low intake, vomiting or diarrhea, are hypovolemic . in these patients, adopting a "zero" water balance policy can worsen renal perfusion, accelerate functional loss and increase the need for rrt. in view of this new knowledge, we recommend that the volume management be individualized, with assessment on a case-by-case basis. hypervolemia should not be tolerated, to avoid or minimize the expansion of extravascular pulmonary water. care should be taken with routine maneuvers in intensive care, such as hydration maintenance, nutritional support with high volume and repeated use of volume responsiveness tests . in contrast, hypovolemia can decrease pulmonary perfusion, increase dead space, worsen hypoxemia and increase the adverse effects of positive pressure ventilation on renal blood flow. in selected patients, if possible based on consolidated strategies for guiding volume management, it may be necessary to resort to volume expansion maneuvers , . the purpose of anticoagulation during rrt is to maintain patency of the extracorporeal circuit. anticoagulation seeks to balance the risk of bleeding against the activation of coagulation by the underlying disease and by the contact of the blood with the artificial surfaces of the circuit. severe covid- cases can present with hypercoagulation, which has been correlated with more unfavorable progress . this coagulopathy can also interfere with rrt provision. decreased filter and extracorporeal circuit lifespan has been reported frequently with covid- . in patients with covid- , we recommend that, initially, each service follow its usual anticoagulation routine. when there is concern about a possible hypercoagulable condition and in order not to waste consumables, we do not recommend to perform repeated saline flushing maneuvers to maintain circuit patency without the use of anticoagulants. like any patient with aki treated with rrt, the first measure in cases of recurrent filter loss is to check the adequacy of vascular access. if this is not the case, it may be necessary to intensify anticoagulation, increasing the dose of conventional or low molecular weight heparin. during citrate anticoagulation, the post-filter ionised calcium target level can be decreased. many patients with severe covid- are treated with complex empirical or experimental protocols, which combine drugs in poorly studied associations. there is a clear risk of toxicity to the kidneys and to other organs and systems. we recommend daily monitoring of renal function biomarkers, including biochemical parameters, acid-base, fluid and electrolytic balance, and urine volume and composition. nephrotoxicity is not a frequent effect of chloroquine or hydroxychloroquine, but there is a risk of serious pharmacological interactions . there is no evidence from a solid source to guide the eventual need to adjust the doses of these drugs in patients with kidney disease. after analyzing the available evidence, the brazilian society of nephrology recommended a % reduction in the dose of chloroquine or hydroxychloroquine for patients with advanced kidney dysfunction . every patient with aki requires a daily prescription review, discontinuing drugs that are no longer needed, identifying undesirable drug interactions and adjusting medication doses. the patient flow after recovery from covid- in patients that remains dialysis-dependent is still unclear, notably the transfer from covid- isolation areas to conventional hospital sectors and/or hospital discharge for outpatient dialysis treatment. the provisional guideline issued by the cdc is not always applicable to brazilian hospitals . in many units, transfer to covid- free areas have occurred after hours of absence of fever and respiratory symptoms, in association with negative oral/nasopharyngeal rt-pcr for sars-cov- . apparently, most patients who manage to overcome the critical phase of covid- appear to regain independent kidney function, but little information is available on renal outcomes in patients with covid- complicated by aki. in aki associated with ischemia/sepsis, patients remain for approximately two weeks on rrt [ ] [ ] [ ] . in , in patients with sars, the period of dialysis dependence was longer, three weeks on average . perhaps patients with aki associated with covid- also need a longer time to wean from rrt. in a french series, a third of the patients were still on dialysis, even three weeks after treatment onset. more time is needed to confirm these preliminary impressions. weaning strategies for ars for patients with good urine output and adequate biochemistry should follow the usual practice of each service. many patients are discharged with improving kidney function but still without complete recovery. however, the longterm risk of chronic residual kidney disease is still unknown. only over the months will it be possible to establish whether there will be a persistent effect of covid- on residual renal function. bento fortunato cardoso dos santos, daniela ponce, joão luiz ferreira da costa, thiago reis. covid- illness in native and immunosuppressed states: a clinical-therapeutic staging proposal acute kidney injury in hospitalized patients with covid- . medrxiv acute kidney injury in patients hospitalized with covid- clinical features of patients infected with novel coronavirus in wuhan clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study human kidney is a target for novel severe acute respiratory syndrome coronavirus (sars-cov- ) infection ultrastructural evidence for direct renal infection with sars-cov- identification of a potential mechanism of acute kidney injury during the covid- outbreak: a study based on single-cell transcriptome analysis endothelial cell infection and endotheliitis in covid- acute kidney injury in covid- : emerging evidence of a distinct pathophysiology acute kidney injury in sars-cov- infected patients case - : a -year-old man with covid- and acute kidney injury collapsing glomerulopathy in a patient with coronavirus disease (covid- ) management of acute kidney injury in patients with covid- . the lancet respiratory clinical characteristics of coronavirus disease in china clinical, laboratory and imaging features of covid- : a systematic review and meta-analysis kidney disease is associated with in-hospital death of patients with covid- epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of critically ill patients with covid- infection in china clinical characteristics of non-surviving hospitalized patients with covid- : a single center, retrospective study. medrxiv clinical characteristics of sars--cov- infections involving hospitalized patients outside wuhan clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china characteristics and outcomes of critically ill patients with covid- in washington state clinical characteristics of deceased patients with coronavirus disease : retrospective study clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study sars-cov- in the peritoneal waste in a patient treated with peritoneal dialysis recommendations for the use of vascular access in the covid- patients: an italian perspective initiation strategies for renal-replacement therapy in the intensive care unit intensity of renal support in critically ill patients with acute kidney injury intensity of continuous renal--replacement therapy in critically ill patients the "baby lung" became an adult acute respiratory distress syndrome: the berlin definition comparison of two fluid-management strategies in acute lung injury clinical management of covid- : interim guidance, surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) intensive care management of coronavirus disease (covid- ): challenges and recommendations planning for a pandemic: an operational guide for intensive care units in australia and new zealand evaluation of fluid responsiveness during covid- pandemic: what are the remaining choices? abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia clinical pharmacokinetics and metabolism of chloroquine nota da sociedade brasileira de nefrologia em relação ao ajuste das drogas cloroquina e hidroxicloroquina pela função renal division of viral diseases. discontinuation of transmission-based precautions and disposition of patients with covid- in healthcare settings (interim guidance) the spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. the madrid acute renal failure study group intensity of renal support in critically ill patients with acute kidney injury intensity of continuous renal-replacement therapy in critically ill patients acute renal impairment in coronavirus-associated severe acute respiratory syndrome characterisation of acute kidney injury in critically ill patients with severe coronavirus disease- (covid- ) key: cord- - ey gzw authors: lo, anthony wi; tang, nelson ls; to, ka‐fai title: how the sars coronavirus causes disease: host or organism? date: - - journal: j pathol doi: . /path. sha: doc_id: cord_uid: ey gzw the previous epidemic of severe acute respiratory syndrome (sars) has ended. however, many questions concerning how the aetiological agent, the novel sars coronavirus (cov), causes illness in humans remain unanswered. the pathology of fatal cases of sars is dominated by diffuse alveolar damage. specific histological changes are not detected in other organs. these contrast remarkably with the clinical picture, in which there are apparent manifestations in multiple organs. both pathogen and host factors are important in the pathogenesis of sars. the choice of specific receptors and the unique genome of the sars‐cov are important elements in understanding the biology of the pathogen. for the host cells, the outcome of sars‐cov infection, whether there are cytopathic effects or not, depends on the cell types that are infected. at the whole‐body level, immune‐mediated damage, due to activation of cytokines and/or chemokines and, perhaps, autoimmunity, may play key roles in the clinical and pathological features of sars. continued research is still required to determine the pathogenetic mechanisms involved and to combat this new emerging human infectious disease. copyright © pathological society of great britain and ireland. published by john wiley & sons, ltd. severe acute respiratory syndrome (sars) is a new viral disease caused by a novel coronavirus, sars-cov ( figure ) [ , ] . the saga of sars has officially come to an end, as no more new cases have been reported since . many questions, particularly those related to how sars-cov causes disease, however, remain unanswered. the disease caused by sars-cov differs from the diseases caused by the previously known human coronaviruses, e and oc . sars-cov infection results in severe and potentially fatal lung disease [ , ] . although the majority of patients recovered after - weeks of debilitating febrile illness, a substantial proportion (up to one-third) developed severe inflammation of the lung, requiring ventilator support and intensive care. many patients in this group deteriorated into acute respiratory distress syndrome (ards). the mortality of this group of patients is high [ ] . manifestations in other organ systems are characteristic. lymphopenia [ ] , gastrointestinal symptoms [ ] , impaired liver function [ , ] , and impaired renal function [ ] are common. the possibility of viral infection in multiple organs has been raised and viral replication in the lung, kidney, and gastrointestinal tract was reported [ , ] . in addition, prolonged shedding of virus was found in some convalescent patients [ ] . however, chronic infection by sars-cov has not, to date, been documented in humans. moreover, asymptomatic carriage of sars-cov is rare [ ] . there are significant age differences in the prognosis of sars. children have a good prognosis [ ] , while elderly patients with chronic illnesses fare badly. sars is predominantly a lower respiratory tract disease, yet the most consistent and powerful prognostic indicator reported so far is blood lactate dehydrogenase (ldh) concentration [ ] , which is most likely a surrogate indicator and may reflect the extent of ongoing tissue damage. both pathogen and host factors are important for the progression of an infection. here, we review the pathology of sars infection. specific features of the pathogen sars-cov itself are then addressed. finally, host factors, particularly an emerging understanding of immunological and inflammatory responses to sars-cov infection, are discussed. virus particles can also be seen budding through the cytoplasmic membrane (b). each virion particle is - nm in size by transmission electron microscopy and is characterized by the numerous club-shaped projections on the outside, a ring beneath the envelope, and an electron-lucent centre. scale bars = nm (a) and nm (b) diffuse alveolar damage is the most characteristic pathology in sars most data on the human pathology of sars come from autopsy studies of fatal cases [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . these reports thus reflect the terminal stages and are likely to represent only the more severe end of the spectrum of sars. treatment and co-morbid conditions might also modify the pathological changes. diffuse alveolar damage at different stages of organization is the most consistent finding in the lungs of sars patients in the terminal stage (figures a- f ). multinucleated syncytial cells ( figures g and h ) are characteristic, although these cells are rare. apart from when secondary infection occurs, the lack of a prominent inflammatory response is also distinctive. sars-cov is explicitly detected in the alveolar lining cells ( figures i and j ) [ , [ ] [ ] [ ] [ ] [ ] [ ] . no specific pathology is identified in the gastrointestinal tract ( figure ) [ ], urinary system [ ] , or other organ systems [ ] , apart from that related to end-stage multi-organ failure or those changes secondary to treatment. it is important to note that in some organs such as the liver, while definitive and distinct morphological and functional changes are observed, sars-cov may not be unequivocally demonstrable [ ] . it is clear that our understanding of the pathology of sars is incomplete. an obvious large gap is the lack of information on the early pathological changes of sars. during the epidemic, very few biopsies were obtained from patients with clinically active sars. the study of animal models is important in a number of ways. it has allowed the establishment of sars-cov as the aetiological agent [ ] . it also provides controlled conditions for the study of early changes in the disease. initial studies of macaque models were promising. the histology of infected lung tissue is similar to that in humans [ ] [ ] [ ] . both acute and organized stages of diffuse alveolar damage were seen when the macaques were sacrificed on the sixth day after a heavy dose of the virus. sars-cov was detected in the alveolar epithelial cells and in the intra-alveolar syncytial cells. however, detailed morphological studies and viral distribution in other organs in these animal studies are lacking. in studies involving longer observation times, the disease in macaque models appears self-limiting and different from the genuine human disease. the usefulness of the macaque as a model of the disease remains to be established [ , ] . civet cats, domestic cats, and ferrets are thought to have been potential reservoirs of the virus during the epidemics and subsequent smaller outbreaks in mainland china [ ] . the animal coronavirus identified in civet cats shows high sequence identity with, but is distinct from, sars-cov [ , ] . recent evidence also suggests that wide chinese horseshoe bats harbour a closely related bat-sars-cov which might also act as the animal reservoir [ ] . again, details concerning the distribution of virus in different organs in these animals and the information on the pathology in the diseased or carrier animals are, surprisingly, sparse [ , ] . other common small laboratory animal models, such as the mouse, are not particularly useful. sars-cov has a low virulence in ordinary laboratory mice and very high levels of inoculation are required to produce self-limiting diseases. these features may be although the latter finding may be related to pre-morbid lung pathology, a correlation with interstitial fibrosis and disease duration has been demonstrated [ ] . diffuse alveolar damage at different stages of organization, from fibrin deposition (c, h&e, original magnification × ), to interstitial fibrosis (d, h&e, original magnification × ) and cellular organization (e and f, h&e, original magnification × ), can be detected. atypical pneumocytes with enlarged nuclei and prominent nucleoli are often seen and some pneumocytes coalesce into syncytial multi-nucleated cells (g, h&e, original magnification × ). multi-nucleated histiocytes may also be found (h, h&e, original magnification × ). sars-cov can be detected in pneumocytes by in situ hybridization (i, using a dna probe against the m gene, original magnification × [ ] ). a large array of antibodies against the viral proteins including nucleocapsid n, spike s, membrane m, and sars- a [ ] , has been developed for the detection of sars-cov in formalin-fixed, paraffin-embedded tissue sections (j, showing immunohistochemical staining with an anti-peptide antibody against n, original magnification × ) related to differences in the affinities of sars-cov for human receptors and their murine homologues [ ] . sars-cov uses a protector of lung damage, angiotensin-converting enzyme , as a receptor characterization of the functional cellular receptor of sars-cov provides important clues to the pathogenesis of sars. angiotensin-converting enzyme (ace ) interacts directly with the spike (s) proteins of the sars-cov [ ] [ ] [ ] [ ] [ ] . the level of expression of ace correlates with the efficiency of sars-cov infection in cell culture models [ ] [ ] [ ] . ace proteins are expressed by alveolar epithelial cells and by surface enterocytes of the small intestine [ ] , which are the primary target cells of sars-cov. studies in the intestine cell culture model, however, suggested that, in addition to ace , unknown co-factors or coreceptors are required to convey infectivity [ ] . in addition to being a cellular receptor, ace may contribute to the pathogenesis of dad in sars through its role in the tissue renin-angiotensin system. in a mouse model of alveolar damage induced by acid aspiration, the balance of the renin-angiotensin system appears to affect the development of dad. ace , which acts as a negative regulator of the local renin-angiotensin system, protects the mouse lung against experimental damage [ , ] . sars-cov co-infection in these damaged animals downregulates ace in the lungs of infected mice and the severity of lung damage can be alleviated by blocking the system [ ] . exciting as these findings appear, the case of a new coronavirus, nl , immediately provides an example that other factors are acting in the overall mechanism of lung damage. nl utilizes the same ace protein as its receptor in the lung. however, infection with nl results in only minor cold symptoms and alveolar damage is rare [ ] . the insert/deletion genotype of the ace gene was associated with dad after sars-cov infection in a small cohort of patients [ ] . this association was, however, not replicated subsequently in a larger series [ ] . we also could not detect any association between the ace genotype and disease severity in sars-cov infection [ ] . sars-cov may also use the c-type lectins as receptors for infecting immune cells c-type lectins, including cd and cd l, are also sars-cov receptors: these were identified through the study of proteins that interact with the s (spike) protein. cd , also known as dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (dc-sign), was shown to mediate viral entry in a lentiviral pseudo-type experimental model [ ] . in chinese hamster ovary (cho) cells expressing a human lung cdna library, s protein and its fragments interacted directly with a second related cell surface glycoprotein, cd l, also known as l-sign or dc-signr [ ] . cd l acts in conjunction with lsectin (liver and lymph node sinusoidal endothelial cell c-type lectin) and enhances viral infection [ ] . tissue cultures expressing cd or cd l were also susceptible to sars-cov infection [ , , ] . the possible involvement of dendritic cells is particularly interesting. although sars-cov does not replicate in dendritic cells, these cells may act as a reservoir and distribute the virus to other cell types [ , ] . this is an attractive concept and similar biological behaviours have been proposed for human immunodeficiency virus i (hiv i) [ ] . no sars-cov has been detected in dendritic cells in autopsy and biopsy studies reported so far. the genome of sars-cov consists of a single . kb positive-strand rna. the genomic sequences derived from different phases of the sars epidemic revealed no association with sequence variation and virulence [ , ] . there are two large open reading frames (orfs) and potential orfs in the sars-cov genome. the two large orfs encode non-structural proteins involved in replication. these proteins have relatively higher homologies to known coronaviruses. the remaining orfs are squeezed into the end of the genome. these orfs include four genes encoding known structural proteins (envelope, membrane, nucleocapsid, and spike proteins, respectively). the remaining potential orfs encode hypothetical sars-cov-specific proteins which lack obvious sequence similarity to known proteins [ , ] . the functions of these hypothetical proteins and their roles in sars pathogenesis remain obscure [ , ] . antibodies against some of these putative proteins, notably sars a and sars , can be detected in the serum of sars patients [ ] . there is also evidence suggesting that a number of these proteins, including sars a, b, a, and b, were expressed in pneumocytes and enterocytes in deceased patients [ ] . however, differential expression patterns of these proteins in cell types showing different responses to sars-cov infection have not been confirmed. by expressing the hypothetical proteins individually in tissue culture, we are beginning to see data on the cellular functions of these proteins. sars a appears to be important in mediating apoptosis in some cell types [ ] . the sars a protein is incorporated into the viron particle and may also act as one of the structural proteins [ ] [ ] [ ] . through an unknown mechanism, host cells overexpressing sars a have increased expression of fibrinogen mrna [ ] . sars a has been implied in mediating apoptosis through the caspase-dependent pathways [ ] . the effect of sars-cov infection varies in different cell types. apoptosis and syncytial formation are seen in infected monkey renal epithelial cells (vero e ) [ ] . persistent infection with no change in cellular morphology or doubling time was detected in the colon cancer cell line lovo [ ] . in clinical specimens, sars-cov was detected in the lungs and small intestine. severe cellular damage is characteristically detected in the lungs of sars patients, while no morphological changes are observed in the small intestine. the basis of these differences in cellular responses is not clear. the tissue/cellular tropism may be partly related to differential expression of membrane receptors for the sars-cov [ ] . these observations highlight the importance of host cell responses in sars-cov infection. it is also clear from these observations that cytopathic damage alone cannot explain the pathogenesis of sars. the marked heterogeneity of the disease course and outcome after sars infection suggests that host responses may play an important role in pathogenesis. dad or ards appears to be a common pathway of lung parenchyma damage initiated by a variety of aetiologies, including sars-cov infection itself, systemic sepsis, shock, and direct lung contusion. once an inflammatory process reaches a certain intensity, it may self-perpetuate. the cellular inflammatory infiltrate releases toxic metabolites and proteolytic enzymes, which may cause further damage to the lung parenchyma. the surrounding inflamed capillaries launch the coagulation cascade and recruit more immune cells [ , ] . our previous investigation in the h n influenza outbreak showed that patients who died of the disease had lymphoid depletion associated with marked elevation of circulating concentrations of cytokines, including interleukin- (il- ), il- receptor, and interferongamma [ ] . with the observation of characteristic lymphopenia in sars, it has been postulated that the sars-cov may similarly trigger an exaggerated hyper-cytokinemic response in patients with dad after viral infection [ ] . current understanding indicates that patients with a more intense immune response are those at risk of a poor outcome, as the immune system also mounts a profound reaction to the bystander, the lung parenchyma, and causes dad [ ] . sars patients have variable humoral responses to individual epitopes [ ] . however, early sero-conversion and high peak total sars-cov igg levels were associated with more severe disease in a cohort of patients [ ] . hence, particularly strong humoral responses to sars-cov infection might not be protective but, perhaps, might be harmful to the host. the specific epitopes upon which these 'damaging' antibodies act await further characterization. there is evidence that disarray of the immune system towards the host's own antigens may play a role in the pathology of sars. in the early phase, within week of sars-cov infection, igm and igg autoantibodies against antigens located in the cytoplasm of lung epithelial cells (figure ) were detected in the sera of chinese sars patients (lo, unpublished observations). in another cohort of sars patients, immune activity against antigens from lung epithelial cell lines and endothelial cell lines was found in some patients' sera obtained approximately month after infection [ ] . moreover, high levels of these autoimmune activities in the sera were shown to be cytotoxic to lung epithelial cells and endothelial cells in culture. autoimmune antibodies may be important in mediating tissue damage at certain stages of the disease. the cause of the autoimmunity is not fully understood. these autoantibodies may be the result of humoral responses to innate antigens exposed accidentally during direct damage of the lung and, perhaps, the endothelium by sars-cov. alternatively, autoimmunity may be due to crossreactivity of antibodies against some specific epitopes of the sars-cov proteins. the chemokines are a family of small proteins that play important roles in intercellular signalling and chemotaxis. based on their protein sequences, they are broadly divided into α-chemokines with a common c-x-c (cysteine-other-cysteine) structure of amino acid residues near the amino-terminus which interacts predominantly with neutrophils, and β-chemokines with a c-c (cysteine-cysteine) structure interacting with mononuclear cells. recently, chemokines have been recognized for their roles in integrating the innate and adaptive immune responses to viral infection through a cytokine-to-chemokine-to-cytokine signalling cascade [ ] [ ] [ ] . a global view of the spectrum of expression of the immune mediators was studied in sars by measuring the circulating concentrations of these mediators at different stages of the disease. most cytokines showed only transient and short-lived activation in patients after sars-cov infection [ ] . even in patients who developed dad, most cytokine concentrations were not significantly increased [ ] . in contrast, circulating concentrations of several chemokines, including cxcl (chemokine c-x-c motif ligand or monokine induced by γ -interferon), cxcl (chemokine c-x-c motif ligand or interferoninducible protein- ), and ccl (c-c motif ligand or monocyte chemoattractant protein- ), were markedly increased in sars patients [ , , ] . remarkably, the circulating concentration of cxcl measured early after infection is an independent prognostic indicator of disease outcome [ ] . these chemokines therefore appear to be important elements of the pathogenesis of sars. in the lung tissues obtained from seven sars patients who died [ ] , chemokines cxcl ( figure ) and il- were markedly activated ( and -fold compared with controls, respectively). the important roles of chemokines are underscored by the findings in an experimental mouse model of sars-cov infection in which cxcl and a neutrophil chemokine, cxcl (chemokine c-x-c motif ligand ), were also markedly activated [ ] . these findings in sars compare favourably with the specific situation in hiv patients with lung allograft rejection and interstitial alveolitis, in which similar activation of the chemokine cxcl and its receptor cxcr (chemokine c-x-c motif receptor ) was also found [ , ] . other than pneumocytes, chemokines are also expressed and secreted by various different cell types. global gene expression profiles, generated by cdna microarray analysis of peripheral blood mononuclear cells (pbmcs) after in vitro exposure to sars-cov, also reveal the importance of chemokine activation. within day after exposure to the virus, a number of chemokines (including cxcl , cxcl , and ccl ) were activated [ ] . pbmcs and macrophages do not support productive infection as viral replication is abortive and no infectious virus is produced. the roles of these cell types in the pathogenesis of sars remain to be clarified. nonetheless, these easily obtainable cell types provide convenient experimental models and allow some insight into the patterns of host responses to the infection to be studied. similar findings were also reported in other cell types, such as dendritic cells, where the cytokine expression profiles are predominantly of inflammatory chemokines ccl (chemokine c-c motif ligand ), ccl (chemokine c-c motif ligand ), cxcl , and ccl . unlike the usual response of dendritic cells to viral infection, anti-viral cytokines, including ifn-α (interferonalpha), ifn-β, ifn-γ , and il- b, were not activated [ ] . immunogenetics of the host may affect the severity of sars other than using serum inflammatory mediators to reflect the different degree of host inflammatory reaction during an infection, the intensity of the immune response is also genetically determined. the difference in genetic makeup between individuals is mostly accounted for by single base differences (single nucleotide polymorphisms, snps). many studies have shown an association between snps and predisposition to ards, and survival after sepsis or other insults [ , ] . in the context of predisposition to ards after trauma, among parameters such as circulating concentrations of il- , tumour necrosis factor and plasminogen activator inhibitor- (pai- ), and the genotype of pai- , insertion alleles at the promoter of pai- were associated with high concentrations of pai- in the plasma and a poor survival rate [ ] . in addition to pai- , other genetic polymorphisms, such as angiotensin-converting enzyme (ace) [ ] , cd [ ] , surfactant protein [ ] , and hla genotypes [ ] , are also associated with predisposition to, severity, and outcome of ards. although sasr-cov utilizes ace as its receptor and ace is known to be an important protector of lung damage in experimental ards, we and other groups found no solid association between alleles of the two ace genes (ace and ace ) and the severity of ards after sars infection [ , , ] . several immunogenetic studies have been reported in association with sars infection. among taiwanese sars patients, hla-b * was associated with both predisposition to infection and severity of infection [ ] . however, the association of this allele was replicated in another chinese community of hong kong involving sars patients [ ] . hla-b * was found to be a predisposition allele in the latter study. it should be noted that this latter allele is rare and is found in ∼ % of the general population. hence, this allele cannot be considered a major predisposition factor for sars infection [ ] . immunogenotype may play a role in determining the severity of host responses. there is considerable variability in the prevalence of immunogenotypes among different populations and the significance of detecting so-called 'predisposing' alleles in clinical practice is questionable. more studies are needed to uncover fully the real genetic determinants for both predisposition to infection and the host-pathogen interaction after infection with the virus. a considerable amount of knowledge of sars infection has accumulated as a result of almost years of research since the emergence of sars. some key issues about the pathogen, sars-cov, have been addressed. these include the rapid discovery of sars-cov receptors and the actions of some of the specific viral proteins in different host cells. understanding the molecular basis of differences in host 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