key: cord-0005779-m31qvn8h authors: Hanique, G.; Dugernier, T.; Laterre, P. F.; Dougnac, A.; Roeseler, J.; Reynaert, M. S. title: Significance of pathologic oxygen supply dependency in critically ill patients: Comparison between measured and calculated methods date: 1994 journal: Intensive Care Med DOI: 10.1007/bf02425048 sha: 4885039e1f1a3756a17b04b9d61c5a9afaa31bf7 doc_id: 5779 cord_uid: m31qvn8h OBJECTIVE: Oxygen supply dependency at normal or high oxygen delivery rate has been increasingly proposed as a hallmark and a risk factor in critical illnesses. We hypothesized that as fas as an adequate oxygen delivery is provided, oxygen consumption, when determined by indirect calorimetry, is not dependent on oxygen delivery in critically ill patients whereas calculated oxygen consumption is associated with artefactual correlation of oxygen consumption and delivery. DESIGN: Oxygen delivery, oxygen consumption and their relationship were analyzed prospectively. Metabolic data gained from both measured and calculated methods were obtained simultaneously before and after volume loading. SETTING: The study was completed in the intensive care unit as part of the management protocol of the patients. PATIENTS: 32 consecutive patients entered the study and were divided into 3 groups according to a clinical condition known to favour oxygen supply dependency: sepsis syndrome, adult respiratory distress syndrome and acute primary liver failure. INTERVENTION: The rise in oxygen delivery was obtained by colloid infusion (oxygen flux test) performed in hemodynamically and metabolically stable patients. All were mechanically ventilated. No change in therapy was allowed during the test. MEASUREMENTS AND RESULTS: Oxygen consumption was simultaneously evaluated by calculation (Fick Principle) and direct measurement using indirect calorimetry. Oxygen delivery was derived from the cardiac output (thermodilution) and arterial content of oxygen. Oxygen supply dependency was considered while observing an increase in oxygen delivery greater than 45 ml/min·m(2). Irrespective of patient's clinical diagnosis and outcome, measured oxygen uptake remained unaltered by volume infusion whereas both oxygen delivery and calculated oxygen consumption increased significantly. Arterial lactate level>2 mmol/l and measured oxygen extraction ratio>25% failed to identify oxygen supply dependency when measured data were considered. CONCLUSION: Analysis of oxygen uptake, when measured by indirect calorimetry, failed to substantiate oxygen supply dependency in the vast majority of the critically ill patients irrespective of diagnosis and outcome. Mathematical coupling of shared variables accounted for the correlation between oxygen delivery and calculated oxygen consumption. mal or high oxygen delivery rate has been increasingly proposed as a haUmark and a risk factor in critical illnesses. We hypothesized that as fas as an adequate oxygen delivery is provided, oxygen consumption, when determined by indirect calorimetry, is not dependent on oxygen delivery in critically ill patients whereas calculated oxygen consumption is associated with artefactual correlation of oxygen consumption and delivery. Design: oxygen delivery, oxygen consumption and their relationship were analyzed prospectively. Metabolic data gained from both measured and calculated methods were obtained simultaneously before and after volume loading. Setting: the study was completed in the intensive care unit as part of the management protocol of the patients. Patients: 32 consecutive patients entered the study and were divided into 3 groups according to a clinical condition known to favour oxygen supply dependency: sepsis syndrome, adult respiratory distress syndrome and acute primary liver failure. Intervention: the rise in oxygen delivery was obtained by colloid infusion (oxygen flux test) performed in hemodynamically and metabolically stable patients. All were mechanically ventilated. No change in therapy was allowed during the test. Measurements and results: oxygen consumption was simultaneously evaluated by calculation (Fick Principle) and direct measurement using indirect calorimetry. Oxygen delivery was derived from the cardiac output (thermodilution) and arterial content of oxygen. Oxygen supply dependency was considered while observing an increase in oxygen delivery greater than 45 ml/min, m 2. Irrespective of patient's clinical diagnosis and outcome, measured oxygen uptake remained unaltered by volume infusion whereas both oxygen delivery and calculated oxygen consumption increased significantly. Arterial lactate level>2mmol/1 and measured oxygen extraction ra- failed to identify oxygen supply dependency when measured data were considered. Conclusion: analysis of oxygen uptake, when measured by indirect calorimetry, failed to substantiate oxygen supply dependency in the vast majority of the critically ill patients irrespective of diagnosis and outcome. Mathematical coupling of shared variables accounted for the correlation between oxygen delivery and calculated oxygen consumption. Key words: Adult respiratory distress syndrome -Acute hepatic failure -Indirect calorimetry -Lactate -Multiple organ failure -Oxygen delivery, Oxygen uptake -Sepsis syndrome Multiple organ failure (MOF) is a prominent cause of death in the critically-injured patient [1] [2] [3] . Sepsis [1, 3] and adult respiratory distress syndromes [2, 4] are the commonest conditions whose course is complicated by the emergence of MOF. Abnormalities of DO 2, VO2 and their relationship have been postulated as one of the major mechanisms leading to MOF during critical illnesses such as sepsis syndrome, septic shock and ARDS [5] [6] [7] . In these latter conditions, imbalance between oxygen demand and delivery has been observed either by an inappropriately low DQ as a result of a decrease in cardiac output, hemoglobin concentration and arterial oxygen saturation or by an abnormality of tissue oxyten extraction in the setting of increased oxygen demand and normal or high oxygen delivery [5, 8] . These mechanisms were believed to underly cellular hypoxia, dysfunction and eventually death [5] . However, studies on DO2/u 2 relationship remain controversial. A pathologic supply dependency of oxygen uptake in which VO2 varies directly with DO2 over a wide range of oxygen supply even at normal or high delivery rates has been reported in sepsis syndrome and ARDS [5, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . Its features included increased oxygen demand and defective peripheral oxygen extraction with increased critical DO2 and the accumulation of blood lactate as a marker or anaerobic metabolism and pathologic dependence [8] . Importantly this pathologic dependence as well as elevated blood lactate levels were believed to increase the mortality in sepsis syndrome and ARDS by reflecting occult cellular hypoxia [5] . Other investigators, who measured VO2 by indirect calorimetry either in ARDS or sepsis syndrome, failed to reproduce this pathologic dependence [16, [19] [20] [21] and/or disputed its prognostic significance [20, 21] . These discrepancies could be explained by differences either in interventions used to alter DO 2 (oxygen "flux test"), or in the patient population with regard to diagnosis, delay before study and metabolic status. Most importantly in the vast majority of these studies [5, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] , VO2 and DO2 were calculated, which may explain the dependence of VO2 on DO2 by mathematical coupling of the shared variables between DO2 and VOz, i.e. cardiac output and arterial oxygen content [22, 23] . Owing to the potential widespread pathophysiologic, prognostic and therapeutic implications of VO 2 dependence on DO 2 in the critically-ill patients both variables were simultaneously and prospectively evaluated by calculation and direct measurement in 3 groups of patients with ARDS, sepsis syndrome and fulminant hepatic failure before and after volume loading. The endpoints of this prospective study were to investigate the influence of the technique used for the VO2 evaluation (measurement or calculation) on the VO2/DO2 relationship and to evaIuate the presence of pathologic supply dependance in these patients with regard to their clinical diagnosis and metabolic status, and its prognostic implications with regard to outcome. Thirty-two consecutive critically-ill patients were included in the study (May 1989 to April 1991). These patients were divided for analysis into 3 groups according to their diagnosis at the time of the oxygen flux test. Multiple evaluations were undertaken in some patients during the acute phase of their clinical course, each result being considered as a separate datum. This strategy was justified by the important spontaneous and treatment-induced changes in hemodynamic and metabolic status in critical illness so that the difference between successive evaluations on a same patient may be as important as between different patients. Inclusion criteria were a clinical diagnosis of sepsis syndrome, adult respiratory distress syndrome (ARDS) or acute hepatic failure (AHF), hemodynamic/metabolic stability before the oxygen flux test and a minimal increase of DO 2 of 45 ml/min, m 2 after volume loading. The latter figure was arbitrary selected in order to rely on effective oxygen flux tests to define the presence of oxygen supply dependency. Group 1 included 14 patients (2602 flux tests) with sepsis syndrome according to the criteria as defined by Bone et al. [23] whereas Group2 included 13 patients (1602 flux tests) with ARDS and Group 3 included 5 patients (10 O 2 flux tests) with AHE Criteria for ARDS included: a) PaO2/FIO2 68.4 btmol/1; b) a prothrombin time_< 1.6 INR (<40~ and, c) the presence of severe encephalopathy (grade III-IV) within 2 weeks of appearance of first symptoms. All group 1 patients had either bacterial, fungal or viral infection that was confirmed by culture of blood, sputum, urine or a known site of infection. Primary diagnosis in the ARDS group included sepsis confirmed by culture (5 patients), hematological neoptasia (2 patients), acute necrotising pancreatitis (2 patients), graft versus host disease (1 patient), allogenic bone 13 marrow transplantation-(1 patient), fulminant hepatic failure (1 patient) and kidney/pancreas transplantation (1 patient). Causes of AHF were non-A non-B viral hepatitis (2 patients), infection with hepatitis-B virus (1 patient), paracetamol intoxication (1 patient) and acute alcoholic hepatitis (1 patient). As far as possible, care was taken to avoid any crossover between these 3 diagnostic patient groups: according to the criteria used to define sepsis syndrome and ARDS and with the standard evaluation techniques, no group 3 patient had ARDS or sepsis syndrome at the time of evaluation. Similarly, no patients with sepsis syndrome had ARDS or AHF at any time during the ICU stay. However, a septic focus and hepatic failure were documented respectively in 5 and 1 patients of the ARDS group. The severity of disease was assessed at the time of evaluation by the Apache II score [25] , the Goris score and the number of system organ failures [26] . The critical condition of these patients was reflected by the global and specific mortality rate. Table 1 summarized the details of the patient population. Dependence of VO 2 on DO 2 was evaluated by increasing DO 2 while observing a change in VO 2 following baseline determinations (oxygen flux test). A total of 52 02 flux tests were selected on the basis of a minimal increase of DO 2 of 45 ml/min .m 2. O 2 flux test was carried out by volume loading. Intravenous infusion of packed-red cells and colloids (fresh frozen plasma or albumin 5%) was used in order to keep the arterial oxygen content as stable as possible. The volume infused ranged from 200 ml to 1085 ml (mean_+ SEM: 607 ml_+ 18) according to the clinical status of the patients. The mean duration of the infusion was 1.28 h+0.06. Before starting the infusion care was taken that the patients were in stable hemodynamic and metabolic conditions. Temperature, heart rate, arterial and right filling pressures, arterial oxygen and carbon dioxide tensions, and continuously measured VO 2 and VCO 2 were checked for stability by arterial blood gas analysis, indirect calorimetry and pulmonary artery catheterization for at least the last 2 h before the 02 flux test. All patients were mechanical!y ventilated with a volume-cycled machine, a mean_+SEM FIO 2 of 0.4+0.01 (range: 0.21-0.75) and positive end-expiratory pressure as clinically indicated. They were all sedated with a continuous infusion of an opiate (fentanyl, 100-300 p.g/h) and benzodiazepine (midazolam: 2-3 rag/h). All patients required a continuous infusion of dopamine (median dose 6 ~tg/kg/min) to maintain hemodynamic stability. No change of therapy was allowed during the oxygen flux test and the preseding 2 h. On the day of the test all patients were administered no caloric substrates except for 50 to 100g glucose/day. All the data were obtained simultaneously at baseline and after volume infusion. 9 Cardiac output (CO; 1/min) was measured by the thermodilution technique (pulmonary artery catheter): each reported value was the mean of 3 successive measurements. The arterio-venous 02 content difference (AVD; ml/dl) was: AVD = CaO 2 -CvO 2 9 Oxygen delivery (DO2; ml/min) was calculated as follows: DO 2 = COxCaO2 x 10 9 Oxygen uptake (VO2; ml/min) was measured and calculated. VO 2 was calculated (VO2c) by the use of the Fick equation: VO2c = CO• 10 Measured VO 2 (VO2m), VCO 2 and respiratory quotient (RQ) were obtained simultaneously from continuously performed gas exchange measurements by an automatic metabolic monitor (Deltatrac/Datex | which has already been validated [27, 281 . Each reported value was the mean of 3 successive measurements obtained immediately after the 3 determinatious of CO, and during blood sampling. This metabolic monitor is based on the open gas circuit principle and consists of a paramagnetic oxygen-sensor, a CO 2 analyser using the infrared absorption technique and a flow meter. The use of the Haldane transformation gives the monitor the opportunity to measure only the expired gas flow, the inspired gas flow being deduced on the assumption that 0 2 and CO 2 are the only 2 gases to be exchanged into the lung. Consequently, there is an increase in the VOzm measurements errors at high FIO 2 levels [29] . This is minimized by the use of a differential paramagnetic oxygen sensor so that the results remain accurate until an FIO 2 level of 75% [28, 30] . The accuracy of VO2m was regularly assessed by burning a known quantity of ethanol. The increase of VO2m was considered significant if > 6o70 [27, 28] . 9 Oxygen extraction ratio was derived from both the indirect (EO2c) and direct (EO2m) methods of VO 2 evaluation: EO2c = VO2c/DO 2 = AVD/CaO2; EO2m = VO2m/DO 2. 9 Arterial lactate level (normal value<2 mmol/l) was measured in the arterial blood using an electrochemical method (Roche-Kontron; Basel, Switzeriand). 9 Values of VOzm, VO2c, VCO 2 and DO 2 were adjusted for the total 2 2 body area (ml/min.m). Cardiac index (CI; 1/min-m ) was equal to CO/total body area. Data were analyzed in the total population and in the 3 definite patient groups according to the following endpoints: a. Comparison between calculated and measured VO 2 before and after volume loading and analysis of the subsequent DO2/VO 2 relationship; b. Evaluation of a pathologic relationship between DO 2 and VO 2 with respect to clinical diagnosis using measured VO 2 as a reference standard and considering as random error changes in VO 2_< 60/o from baseline [28, 291; c. Study of the potential prognostic significance of DO2/VO 2 relationship with regard to patient's outcome by comparing metabolic data obtained before and after volume loading in patients who died and survived; d. Assessment of the value of arterial lactate level (>2 mmol/1) and oxygen extraction ratio (EO2m > 25%) in identifying an oxygen debt by analyzing DO2/VO 2 relationship with respect of these parameters. Results were expressed as means_+ SEM. Owing to uneven distribution of characteristics in some subgroups the Wilcoxon paired rank test was used to compare variables obtained before and after the oxygen flux test as well as to compare the individual changes in calculated VO 2 with that in measured VO 2. Comparison of metabolic data obtained before and after volume loading between patients who died or survived were carried out using a two-way analysis of variance with adjustment for repeated measurements. Equality of the variance-covariance matrices for the two levels At the time of evaluation, baseline DO 2 exceeded 330 ml/min-m 2 in all the patients studied. At the end of the volume infusion period, DO2 increased from 645+22ml/min-m 2 to 788+_23 ml/min-m 2 (p<0.001) on account of a significant increase in cardiac output and to a lesser extent in arterial oxygen content. Similarly calculated increased (145 + 4 ml/min, m 2 VO2 2 significantly to 163+-5ml/min-m, p<0.001) whereas measured VO2 did not change in the patient population (154+4 ml/min'm 2 to 156+4 ml/min-m 2, NS) (Fig. 1) . Changes in EO2m parallelled the ones in VO2m and DO2 whereas EO2c decreased while VO2c increased. The mean Table 2 . In 8 patients/9 tests (17~ VO2m increased by more than 6~ after volume infusion. When compared to the whole population, this subgroup did not behave differ- Table 3 . Clinical and metabolic data of the patients with 0 2 supply dependency a ently in terms of clinical diagnosis, outcome and arterial lactate level (Table 3) . (Table 4) Classification of the patients according to their clinical diagnosis at the time of the test did not modify the previous analysis. After volume loading and irrespective to patient's condition (sepsis syndrome, ARDS or liver failure) DO 2 and VOz c increased significantly whereas VOzm remained unaltered (Fig. 2) . Patients Oxygen supply dependency: impact on patient's outcome Patients were further divided for analysis according to outcome (Table 5 ). DO2, VO2m and VO2c were significantly greater and lactates conversely lower in survivors than in non-survivors, either before or after volume loada 02 supply dependency defined by an increase in VO2>6% Results are expressed as mean _+ SEM * denotes a p value of less than 0.01 Abbreviations as in Tables l and 2 Results are expressed as mean ___ SEM * p<0.05; ** p<0.01; *** p<0.001 Abbreviations as in Table 2 240" Table 1 and 2 16 ing. Changes in DO2, VO2c , VO2m and arterial lactate levels failed to identify those who ultimately died ( Table 5) . Irrespective of patient's outcome VO2m remained unaffected by volume loading (144_+6 to 147_+6mt/min.m 2 in non-survivors vs 165_+6 to 167_+5 ml/min.m 2 in survivors) whereas both DO2 and VO2c increased significantly (Fig. 3) . In order to assess the predictive value of arterial lactate level>2 mmol/1 and EO2m > 25~ in identifying an oxygen debt and oxygen supply dependency, DO2/VO 2 relationship was analyzed with respect of these parameters at the time of evaluation. Of 32 patients 9 (2807o) had blood lactates > 2 mmol/l. AHF was present in 6 of these patients and MOF in all of them. For both elevated and low arterial lactate levels dependence of VO2 on DO2 could only be demonstrated when VOzc was considered (Table 6). The same held true for EO2m (Table 6) . On the contrary, whatever the value of EO2m and arterial lactate, VO2m failed to substantiate any supply dependency. With the advance in the intensive care management during the initial resuscitative period, MOF has become in recent years the major cause of prolonged intensive care unit stay, morbidity and mortality for the critically-ill Table 2 patient [1] [2] [3] . Critical insults such as sepsis syndrome, ARDS and acute liver failure are known risk factors for the development of MOF [1 -3] . Although the pathogenesis of MOF is still a matter of speculation one hypothesis is that during the resuscitative phase alterations in microcirculatory physiology and local activation of cellular elements secondary to the initial injury mediates inadequate microcirculatory flow, defective peripheral oxygen extraction and occult tissue hypoxia that preceed the transition to overt organ dysfunctions [6, 31, 32] . Several investigators have pointed out that abnormalities in the relationship between DO2 and VO2 could unmask this oxygen debt [5, 17] . Pathologic oxygen supply dependency in which VO2 varies in the same direction with a change in DO2, even during hyperdynamic conditions, has been increasingly reported to underly cellular hypoxia in sepsis syndrome and ARDS and was suggested to herald MOF and to predict patient's outcome [5] . Thus, this abnormal dependence of VO2 on DO2 above the normal critical level of oxygen supply and its correlatives, defective oxygen extraction ability and increased blood lactate levels should porten obvious pathophysiologic, prognostic and therapeutic implications. In this prospective study, using directly measured VO2 before and after volume loading to increase DO2, we demonstrated that pathologic supply dependency was rather uncommon in 3 groups of patients whose clinical condition was believed to favour this dependence. In addition, neither measured oxygen extraction ratio nor arte- Results are expressed as mean +_ SEM * p < 0.05; * * p < 0.01; * * * p < 0.001 when baseline data were compared with values obtained after volume infusion. tp < 0.05; "M'p < 0.01; ttTp < 0.001 when differences between survivors and non-survivors were considered. Abbreviations as in Table 2 Results are expressed as mean -+ SEM * p<0.05; ** p<0.01; *** p<0.001 Abbreviations as in Table 2 rial lactate level did predict delivery dependence of VO 2 at the time of evaluation. Hence patient's outcome was unrelated to the relationship of VO 2 to DO 2. Several factors may account for the discrepancies between previous reports [5, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] and this study. Differences in methods used to change DO 2 could affect the behavior of VO2 due to the own drug-induced changes in metabolic rate and oxygen demand. This metabolic effect could account for a primary change in VO 2 and secondary compensatory change in DO 2 to match oxygen demand. Differences in patient population with respect to clinical diagnosis, hemodynamic status and microcirculatory condition at the time of evaluation are of paramount importance. Most studies on DO2/VO 2 relationship have been conducted in patients with sepsis syndrome and ARDS [5, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] . Since sepsis is a common cause and complication of ARDS these two conditions are closely associated [1, 2] . Whereas the effect of human sepsis on critical DO 2 is unknown, experimental animal models demonstrated that sepsis syndrome increased the critical DO E by increasing oxygen demand and by diminishing the ability of tissues to extract oxygen [33, 34] . Microembolisation, loss of autoregulation of microcirculatory blood flow and endothelial cells injury were mechanisms proposed to account for this extraction defect [31] . Therefore, inhomogeneous groups of patients, particularly in the ARDS population, might have critical-ly influenced the relationship between DO 2 and VO 2 depending on the coexistence of sepsis, the magnitude of peripheral extraction defect and the actual oxygen demand. In addition, in the setting of a dysfunctional microcirculatory environment, which is a common condition in many of these patients, "normal" dependence of VO 2 on DO 2 could have relied on an inadequately treated hypodynamic state and truly supply-driven ischemia as a result of hypovolemia or myocardial dysfunction. Therefore, to overcome these potential confounding variames care was taken in this study to assess the presence of oxygen supply dependency in homogeneous groups of patients with regards to clinical diagnosis, to alter DO 2 by an identical intervention and to provide all the patients with an adequate cardiac output. Finally, the method of VO 2 determination played a major role in the finding of oxygen supply dependency. The studies which addressed the issue of the dependence of VO 2 on DO 2 in sepsis syndrome and ARDS consistently demonstrated pathology supply dependency whenever VO2 was calculated [5, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . In contrast, when oxygen uptake was measured directly, VO 2 was usually not correlated with DO 2 either in sepsis syndrome or ARDS [16, [19] [20] [21] . In this study VO2 was systematically evaluated by calculation and direct measurement before and after volume loading. Whereas calculated data almost consistently led to pathologic supply dependency, the latter was supported by direct measurement of VO 2 in only 17~ of the tests. Unlike some previous studies in which supply dependence of VO2 was assessed using calculated VO2 [9, 11, 15, 35] neither EOEm nor arterial lactate level did predict delivery dependence of VO2 when measured oxygen consumption was considered. Similarly, Ronco et al. [21] reported that increased lactate did not predict dependence of measured VO 2 on DO 2 in patients with ARDS. Since blood lactate levels reflected the balance between peripheral production and hepatic elimination, elevation of blood lactate might not always be indicative of tissue hypoxia. In particular the 9 patients with arterial lactate > 2 mmol/1 at the time of evaluation had severe liver dysfunction due to either primary hepatic failure or as part of MOE So defective hepatic clearance rather than hypoxic driven-peripheral overproduction accounted for hyperlactacidemia in the subgroup. Further explanations for the lack of correlation between blood lactate and oxygen supply dependency include the inability of tissues to receive or use oxygen [36] and inactivation of pyruvate deshydrogenase which would increase both lactate and pyruvate in the same proportion without resorting to tissue hypoxia [8] . Although at the time of evaluation survivors had significantly greater DO E and VO2m and lower blood lactate than non-survivors [37] , unlike other investigators [5] we could not demonstrate any relation between patient's outcome and DO2/VO2 relationship. Oxygen flux test by volume loading did not reveal a supply dependency in the group of non-survivors. Nevertheless analysis of individual data on DO2/VO 2 relationship enabled the selection of 8 patients in whom pathologic supply dependency could be demonstrated. This subgroup did not differ from the whole population in terms of clinical diagnosis, outcome, baseline DO2 and arterial lactate. So, plateau levels of VO2m could be observed in the majority of the patients irrespective of clinical diagnosis, baseline lactate, EO2m and outcome. These data support that, provided a satisfactory DO2 was ensured to the patient, pathologic oxygen supply dependency as assessed by directly measured VO2 was uncommon in conditions which were suggested to favour this dependency and the emergence of MOF. Analysis of DO2/VO2 relationship based on calculated VO2 was flawed by mathematical coupling of shared variables. Reliance on EO2m and lactate level as a guide to assess tissue oxygenation and to tailor therapy and on DO2/VO2 relationship to predict patient's outcome may be misleading. 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