Claude Chopin

Prognostic value of the dobutamine test in patients with sepsis syndrome and normal lactate values: a prospective, multicenter study.

To determine the oxygen supply (Vo2) and uptake (Vo2) responses to a 60-min dobutamine infusion in critically ill septic patients without circulatory shock and with normal blood lactate concentrations. Also, to determine whether these responses would predict outcome. Design:Prospective, cohort study. Setting:Five intensive care units in university-affiliated, city hospitals. Patients:Fifty critically ill patients with sepsis syndrome were studied from April 1990 to August 1991. Interventions:Pulmonary artery catheteriza-tion; fluid loading if pulmonary artery occlusion pressure was <10 mm Hg; and 10 μg/min/kg dobutamine infusion for 60 mins. Measurements and Main Results:Cardiac in-dex, Vo2, Vo2, and oxygen extraction ratio were determined immediately before and 1 hr after the onset of the dobutamine test. Using receiver operating characteristic curves, responders to the dobutamine infusion were identified by a >15% increase in Vo2 from the time immediately before to 1 hr after the onset of the dobutamine test. We identified 23 responders and 27 nonresponders. Groups differed significantly in age (responders 46 yrs vs. nonresponders 55 yrs) and associated chronic disease (responders one cancer vs. nonresponders six cancers). Significant changes in responders were: a) cardiac index increased 42.9%; b) systemic vascular resistance decreased 20.7%; and c) Vo2 increased 39.1% while Vo2 increased 40.8%, with no changes in oxygen extraction or blood lactate concentration. Significant changes in nonresponders were: a) cardiac index increased 14.2%; b) Vo2 increased 13.2%; and c) oxygen extraction decreased from 0.26 to 0.22. Lactate concentration increased significantly by 25.1% in nonresponders. The mortality rate in responders (8.7%) was significantly less than that rate in nonresponders (44.4%). Conclusions:Most of these septic patients without shock or hyperlactatemia responded to dobutamine infusion in one of two ways: with little increase in Vo2 and no increase in Vo2, or with significant increases in both Vo2 and Vo2 The latter response is typical of healthy volunteers given dobutamine. Because of the calorigenic effect of dobutamine, our results imply nothing about the presence or absence of oxygen supply limitation. Still, patients who had increases in Vo2 and Vo2 had a much higher survival rate than patients who did not. We speculate that the inability of some patients to respond to dobutamine and the associated higher mortality rate may be related to β-adrenoreceptor dysfunction. (Crit Care Med 1993; 21:1868–1875)

Ventricular Myocyte Caspases Are Directly Responsible for Endotoxin-Induced Cardiac Dysfunction

Background—Although most of the deleterious effects of sepsis-induced apoptosis have been attributed to increased lymphocyte cell death, caspase activation may directly alter cell function of different organ systems. We postulated that left ventricular (LV) cardiomyocyte caspase activation is directly involved in sepsis-induced heart contractile dysfunction. Methods and Results—LV cardiomyocytes isolated 4 hours after rat treatment with endotoxin injection (10 mg/kg) displayed major reductions in contractile reserve and myofilament response to Ca2+. Concomitantly, endotoxin also induced increases in LV cardiomyocyte caspase-3, -8, and -9-like activities, which were associated with sarcomeric structure destruction and cleavage of components of the cardiac myofilament. Interestingly, zVAD.fmk treatment of septic rat prevented LV cardiomyocyte contractile dysfunction, reductions in myofilament response to calcium, troponin T cleavage, and sarcomere destruction. Serum (10%) of endotoxin-treated rats induced contractile dysfunction, caspase-3–like activity increase, and troponin T cleavage of naive LV cardiomyocytes. The effects of septic serum were prevented in LV cardiomyocytes isolated from zVAD.fmk- or zDEVD.cmk-treated rats or LV cardiomyocytes preincubated with zVAD.fmk or zDEVD.cmk. Conclusions—The results show an important relationship between endotoxin-induced caspase activation and reduced contractile reserve and sarcomere disarray at the level of single LV cardiomyocytes.

Use of capnography in diagnosis of pulmonary embolism during acute respiratory failure of chronic obstructive pulmonary disease

In chronic obstructive pulmonary disease (COPD) patients, there is a difference between Paco2 and endtidal partial pressure of CO2 (PetCo2). This gradient P(a-et)Co2 is due to ventilation/perfusion mismatching and deadspace, and is usually abolished by forced and prolonged expiration. We hypothesized that this gradient might not be canceled by forced expiration in the case of acute respiratory failure (ARF) related to pulmonary embolism (PE). Forty-four adult COPD patients were prospectively entered into this study; they were suspected of having ARF related to PE on the basis of clinical and biological data on admission. Maximum expired partial pressure of CO2 (Pemco2) was measured in mechanically ventilated and sedated patients by an interrupt of mechanical support. CO2 concentration was recorded during the following prolonged and passive expiration. The test was considered valid if an expiratory plateau was obtained. Pemco2 was measured in triplicate. Simultaneously, Paco2 was measured and the ratio, R = ([1 – Pemco2]/Paco2) × 100, was calculated. Pulmonary angiography was performed on the same day for all patients. Results showed that 17 patients had PE (PE+) and 17 had no PE (PE-). The two groups were comparable regarding mean age, severity of underlying chronic respiratory disease, Paco2, Pao2, and hemodynamic data on admission. P(aem)co2 and R were significantly different in PE+ and PE- patients at 12 ± 6.9 torr compared to 1 ± 2.4 torr and at 28 ± 14.8% compared to 2 ± 6.2% (p < .001), respectively. The positive predictive value of the test was 74%, but the negative predictive value 100% and the specificity was 65%, but sensitivity was 100%. We conclude that this test may be useful to rule out a diagnosis of PE during ARF of COPD patients. (Crit Care Med 1990; 18:353)

Calpain inhibitors improve myocardial dysfunction and inflammation induced by endotoxin in rats.

Excessive activation of calpains has been implicated in the pathophysiology of inflammation, trauma, and ischemia reperfusion injury. Here, we investigated the effects of calpain inhibition on myocardial dysfunction and inflammation induced by endotoxin in rats. Rats were treated i.v. with endotoxin (10 mg/kg) or endotoxin plus calpain inhibitors and were then prepared after 4 h for myocardial contractility assessment, detection of endothelium leukocyte interactions, and plasma TNF-α, nitrite/nitrate, and endocan levels. Compared with vehicle-treated rats, hearts from endotoxin-treated rats had reduced systolic performance that was partially prevented by calpain inhibitors, i.e., acetyl-leucyl-leucyl-arginal (leupeptin), carbobenzoxy-valyl-phenylalanial (calpain inhibitor III), and N-acetyl-leucinyl-leucinyl-norleucinal (ALLN). Leupeptin and calpain inhibitor III reduced plasma TNF-α levels in endotoxin-treated rats. ALLN reduced plasma TNF-α and nitrite/nitrate levels in endotoxin-treated rats. Endotoxin treatment increased mesenteric venule leukocyte rolling (10 ± 3 leukocytes/min vs. 44 ± 10 leukocytes/min; P < 0.01) and adhesion (2 ± 2 leukocytes/min vs. 15 ± 3 leukocytes/min; P < 0.01), which was reduced by calpain inhibitors. Attenuation of leukocyte endothelium interactions observed in calpain inhibitor-treated rats with sepsis was associated with increases in plasma anti-adhesion molecule endocan. In conclusion, calpain inhibitors improved endotoxin-induced cardiac dysfunction, which may be attributed to the modulation of endothelium leukocyte interactions in the inflamed vasculature.

Effects of a combined antithrombin III and protein C supplementation in porcine acute endotoxic shock

Antithrombin III (ATIII) and protein C (PC) are major inhibitors of the coagulation cascade and might regulate the cytokine network. We tested the possibility that a combined supplementation using these two inhibitors might have synergistic effects on sepsis-induced disseminated intravascular coagulation and shock. Hemodynamics, coagulation parameters, tumor necrosis factor (TNF) a, and interleukin 6 levels were measured in pigs submitted to a bolus infusion of Escherichia coli endotoxin (lipopolysac-charide). Four groups were studied: control lipopolysaccharide, ATIII (100 IU/kg), PC (50 lU/kg), and ATIII-PC (same doses). The endotoxin infusion resulted in a typical hypokinetic shock with disseminated intravascular coagulation in all animals. Compared with the control group, a significant improvement in mean arterial pressure and systemic vascular resistance was observed in the PC and ATIII-PC groups. The increase in lactate levels was almost completely blunted in the PC group. A significant lesser increase in TNFα levels was observed in the ATIII-PC group. No effects were seen on interleukin 6 levels. Coagulation and fibrinolysis parameters were not improved by ATIII and/or PC, except for a lesser decrease in prothrombin time in the ATIII-PC group. We conclude that in this acute endotoxic model, a combined supplementation using PC and ATIII concentrates has favorable effects on hemodynamic parameters and TNFα levels, independently from the anticoagulant actions of these inhibitors.

Effects of N omega-nitro-L-arginine methyl ester on the endotoxin-induced disseminated intravascular coagulation in porcine septic shock.

OBJECTIVES Nitric oxide is known to prevent platelet aggregation and clot formation. Inhibitors of nitric oxide synthase might promote or enhance endotoxin disseminated intravascular coagulation. The present study was designed to evaluate the effects of the arginine analog, N omega-nitro-L-arginine methyl ester (L-NAME), on the endotoxin-induced disseminated intravascular coagulation in a porcine model of septic shock. DESIGN Prospective, comparative, experimental study. SETTING Laboratory at a large university hospital. SUBJECTS Sixteen female piglets, weighing 20 to 28 kg. INTERVENTIONS Three groups of animals were studied: a control group (n = 6); a lipopolysaccharide (LPS)-treated group (n = 5) receiving Escherichia coli endotoxin (5 micrograms/kg/min over 30 mins); and an LPS + L-NAME group (n = 5) receiving endotoxin and, 1 hr after, a bolus of L-NAME (25 mg/kg). MEASUREMENTS AND MAIN RESULTS Hemodynamic changes, usual coagulation parameters, and plasma concentrations of thrombin-antithrombin complexes, antithrombin III activity (At III), tissue plasminogen activator, plasminogen activator inhibitor type 1, and von Willebrand factor were measured at baseline, and at 30, 60, 90, 120, 180, 240, and 300 mins. After euthanasia or death, lungs and kidneys were withdrawn for histologic study. The extent of microvascular thrombosis was assessed by a semiquantitative disseminated intravascular coagulation score. In both septic endotoxin group, administration of LPS resulted in hemodynamic changes typical of severe septic shock, with disseminated intravascular coagulation and histologic changes characterized by adult respiratory distress syndrome and kidney microthrombosis. L-NAME administration normalized mean arterial pressure with a dramatic increase in systemic vascular resistances and a marked decrease in cardiac index. The changes in usual coagulation parameters, AT III, tissue plasminogen activator, and plasminogen-activator inhibitor type 1 concentrations were not different between both septic groups. However, in the LPS + L-NAME group, thrombin-antithrombin complexes and von Willebrand factor were higher and associated with a higher histologic disseminated intravascular coagulation score. CONCLUSION In this model of endotoxin septic shock, L-NAME administration resulted in histologic and coagulation changes consistent with an increased activation of intravascular coagulation.

Endotoxin-induced myocardial dysfunction: Evidence for a role of sphingosine production

ObjectiveTo determine whether sphingomyelinase pathway activation would participate in myocardial depression induced by endotoxin. DesignRandomized, controlled trial. SettingExperimental laboratory. SubjectsMale Sprague-Dawley rats, isolated rat heart, and cardiac myocytes. InterventionsCardiovascular function was evaluated in rats injected with saline, endotoxin (10 mg/kg, intravenously), and N-oleoylethanolamine (NOE; 10 mg/kg, intravenously). In ex vivo experiments, isolated rat hearts were perfused with endotoxin (5 &mgr;g/mL). For pharmacologic intervention, NOE (1 &mgr;mol/L) was admixed to the perfusate 20 mins before endotoxin. In in vitro experiments, ventricular myocytes were incubated with sphingosine (20 &mgr;M). Myocyte cell shortening and calcium transient were measured. Mitochondrial membrane potential was measured using the cationic dye tetramethylrhodamine methylester fluorescence technique. Measurements and Main ResultsEndotoxin treatment at 4 hrs did not alter mean arterial pressure and abdominal blood flow compared with control rats. Left ventricle developed pressure (LVDP) and its first derivatives (i.e., maximal and minimal change in pressure over time [dP/dtmax and dP/dtmin]) were decreased after 4 hrs in endotoxin-treated rats compared with control rats. NOE (10 mg/kg) treatment largely prevented left ventricular systolic function alterations of endotoxin-treated hearts (n = 6 in each group). In isolated rat heart, endotoxin (5 &mgr;g/mL) caused increases in tumor necrosis factor-&agr; perfusate concentration and delayed depression of LVDP, dP/dtmax, and dP/dtmin after 60 mins, which was partially abrogated in the presence of the ceramidase inhibitor NOE (1 &mgr;mol/L). Sphingosine (20 &mgr;M) caused decreases in cell fractional shortening, calcium transient, and mitochondrial membrane potential of cardiac myocytes. ConclusionThese observations suggest that the sphingomyelinase pathway participates in endotoxin-induced myocardial depression.

Redox status of cytochrome a,a3: a noninvasive indicator of dysoxia in regional hypoxic or ischemic hypoxia.

OBJECTIVE Multiwavelength near infrared (NIR) spectrophotometry can monitor the redox state of cytochrome a,a3 (cyt a,a3) in vivo. Because cyt a,a3 is the most immediate reductant of oxygen, this technique has been proposed to evaluate tissue oxygenation. The purpose of this study was to examine the relationship between cyt a,a3 oxidation level as an indicator of dysoxia and oxygen uptake (VO2) when oxygen delivery (DO2) was progressively lowered in an in situ vascularly isolated hindlimb. DESIGN Prospective, randomized, laboratory study. SETTING University research laboratory. SUBJECTS Fourteen pigs. INTERVENTIONS Measurement of critical values for both VO2 and cyt a,a3 oxidation during ischemic and hypoxic hypoxia. MEASUREMENTS AND MAIN RESULTS The right hindlimb of anesthetized, paralyzed, and ventilated pigs was subjected to progressive ischemic or hypoxic hypoxia for 100 mins by ten stepwise decreases in DO2. In ischemic hypoxia (n = 7), arterial inflow (Q) from a pump-membrane oxygenator system was lowered from 50 to 0 mL/min, with PaO2 maintained at 100 mm Hg. In hypoxic hypoxia (n = 6), PaO2 was lowered from 100 mm Hg to 0 mm Hg. Hindlimb DO2 was calculated as the product of Q and arterial oxygen content, and VO2 as the product of Q and arteriovenous difference. The cyt a,a3 oxidation level was measured every 10 secs with a four-wavelength spectrophotometer. These parameters were measured 9 mins after each change of DO2. Critical values for both VO2 and cyt a,a3 oxidation level as a function of DO2 were determined in each animal by dual linear regression analysis. In ischemic and hypoxic hypoxia, a strong correlation was found between cyt a,a3 oxidation level and VO2 in both ischemic and hypoxic hypoxia (r2 =.90 and .87, respectively). Hindlimb vascular resistance increased in ischemic hypoxia and decreased in hypoxic hypoxia when DO2 reached critical DO2. CONCLUSIONS From these results, we concluded that monitoring the cyt a,a3 redox state by NIR spectrophotometry is, in this experimental setting, a sensitive indicator of dysoxia during regional hypoxic or ischemic hypoxia.

Inhaled nitric oxide modulates leukocyte kinetics in the mesenteric venules of endotoxemic rats.

Objective: to determine whether inhaled nitric oxide (NO) would alter leukocyte kinetics in the septic microvasculature. Design: Randomized, controlled trial. Setting: Experimental laboratory. Subjects: Male Sprague Dawley rats. Interventions: Rats were treated with either saline or endotoxin (10 mg/kg, iv) and then allowed to breathe either air or air plus NO (10 ppm). Measurements and Main Results: After a 4‐hr period, rolling, firm adhesion, and emigration of leukocytes and endothelial dysfunction were monitored in mesenteric venules by using intravital videomicroscopy. Compared with controls, endotoxemic rats exhibited a profound influx in mesenteric venule rolling leukocytes (55 ± 17 vs. 70 ± 19 leukocytes/min; p < .05), associated with a reduction of leukocyte rolling velocity (83 ± 14 vs. 34 ± 3 μm/sec; p < .05). In endotoxemic rats, venular endothelium leukocyte firm adhesion (1.15 ± 0.32 vs. 4.08 ± 0.96 leukocytes/100 μm; p < .05) and emigration (0.84 ± 0.47 vs. 4.23 ± 1.2 leukocytes/100 μm; p < .05) increased compared with controls. Inhaled NO had no effect on leukocyte kinetics in control rats. Inhaled NO significantly attenuated endotoxin‐induced venular endothelium leukocyte adhesion (4.08 ± 0.96 vs. 1.86 ± 0.76 leukocytes/100 μm; p < .05) and emigration (4.23 ± 1.2 vs. 1.68 ± 0.72 leukocytes/100 μm; p < .05). Compared with control rats, macromolecular (FITC‐dextran) vascular leakage, expressed as the perivenular/intravenular fluorescence intensity ratio, increased in endotoxemic rats (0.56 ± 0.02 vs. 0.81 ± 0.05; p < .01). Endotoxin‐induced macromolecular vascular leakage increases were partially prevented by inhaled NO (0.66 ± 0.01 vs. 0.56 ± 0.02; p < .05). Conclusion: These observations suggest that inhaled NO reduces leukocyte adhesion and the degree of vascular permeability dysfunction in mesenteric venule of endotoxemic rats.

Escherichia coli endotoxin reduces cytochrome aa3 redox status in pig skeletal muscle.

ObjectiveTo assess the effect of endotoxin on cytochrome aa3 (C aa3) redox status in a controlled blood flow preparation of pig isolated hindlimb, at a constant oxygen delivery (˙Do2limb) (constant flow period) and during progressive ischemia (decreasing flow period). DesignRandomized, controlled experimental study. SettingUniversity hospital experimental laboratory. SubjectsTen piglets. InterventionsHindlimb blood flow was restricted to the femoral vessels. The arterial femoral blood flow coming from the carotid artery was controlled by a roller occlusive pump. The femoral venous blood flow was returned to the jugular vein. During the first 100 mins, the hindlimb blood flow was maintained at a normal level and then decreased stepwise. Animals were randomized to receive 150 &mgr;g/kg endotoxin lipopolysaccharide (LPS; n = 5) or saline (control; n = 5). Measurements and Main ResultsHindlimb muscle C aa3 redox status was monitored by near-infrared spectroscopy. Hindlimb ˙Do2limb and oxygen consumption (&OV0312;o2limb) were calculated. In the LPS group, a rapid reduction of C aa3 redox status was observed after LPS administration, whereas the hindlimb blood flow remained normal with no change in ˙Do2limb and &OV0312;o2limb. A progressive simultaneous decrease in ˙Do2limb and &OV0312;o2limb was observed during the decreasing flow period with no further reduction in C aa3 redox status. In the control group, no change was observed in C aa3, ˙Do2limb, or &OV0312;o2limb during the constant flow period. During the decreasing flow period, C aa3 redox status was reduced as ˙Do2limb and &OV0312;o2limb decreased. ConclusionOur results suggest that endotoxin may induce a reduction of C aa3 redox status independently of ˙Do2 and &OV0312;o2.