Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab')2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels

OBJECTIVE: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial. SETTING: One hundred fifty-seven intensive care units in the United States and Canada. PATIENTS: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels. INTERVENTIONS: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result. MEASUREMENTS AND MAIN RESULTS: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo. CONCLUSIONS: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels.     

Elevated growth-arrest-specific protein 6 plasma levels in patients with severe sepsis

OBJECTIVE: Growth-arrest-specific protein 6 (Gas6), an intracellular protein released by apoptotic cells, has been detected in normal plasma. As the Gas6 system has been implicated in mouse susceptibility to sepsis, and as leukocyte apoptosis is thought to play a major role in the physiopathology of human severe sepsis, we studied Gas6 plasma levels and possibly related variables in patients with severe sepsis. DESIGN: Matched case-control study. SETTING: Adult intensive care unit in a university hospital. PATIENTS: Thirty patients with severe sepsis, 30 patients with organ failure not related to infection, and 30 healthy subjects matched for age and gender. INTERVENTIONS: Blood draw. MEASUREMENTS AND MAIN RESULTS: Gas6 plasma levels were quantified using enzyme-linked immunosorbent assay. Whole-blood gas6 messenger RNA levels were measured by quantitative real-time polymerase chain reaction. Gas6 plasma levels were elevated (110 ng/mL [75, 139]; median values [interquartile range]) in severe sepsis patients compared with organ failure patients (85 ng/mL [56, 101]) and healthy subjects (54 ng/mL [49, 68]). In patients with severe sepsis, this increase correlated with the Acute Physiology and Chronic Health Evaluation II severity score, the organ failure Organ Dysfunction and Infection (ODIN) score, and the existence of a septic shock. Gas6 messenger RNA levels were increased in patients with severe sepsis and correlated specifically with the monocyte count. CONCLUSIONS: In severe sepsis, the recently described anti-apoptotic protein Gas6 was found at high levels in plasma and correlated well with the degree of organ dysfunction.     

Plasma levels of macrophage migration inhibitory factor are elevated in patients with severe sepsis

OBJECTIVE: To investigate the role of macrophage migration inhibitory factor (MIF) as a marker of severity of systemic inflammation in patients with severe sepsis and critically ill postsurgical patients. DESIGN: Prospective observational study in consecutive patients with severe sepsis, critically ill nonseptic postsurgical patients, and healthy blood donors. SETTING: A surgical intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: 19 patients with severe sepsis, 18 critically ill nonseptic postsurgical patients, and 10 healthy blood donors. MEASUREMENTS AND RESULTS: MIF plasma levels of patients and participants were measured. Interleukin 6 plasma levels were monitored as a control marker of inflammation. The median MIF plasma level was four to five times higher in patients with severe sepsis (2.70 ng/ml, range 0.31-19.59) and in critically ill nonseptic postsurgical patients (2.43 ng/ml, range 0.49-4.31) than in healthy blood donors (0.56 ng/ml, range 0.16-1.68). MIF plasma levels did not differ between the patient groups. CONCLUSIONS: MIF serves as a general marker for systemic inflammation in septic and nonseptic acute critical illness, but MIF does not discriminate for severity or differentiate between infectious and noninfectious origins of an acute critical illness.     

严重烧伤患者TNF、IL-6和IL-8水平的变化及相关性研究

目的 :研究烧伤后细胞因子的变化规律及其相关性 ,并探讨其临床意义。方法 :采用放射免疫法和ELISA法检测烧伤患者血中TNF、IL 6及IL 8水平。结果 :烧伤后血中TNF、IL 6及IL 8水平均显著高于正常对照组 (P <0 0 0 1) ,且持续时间较长 (4～ 5周 ) ,它们间呈正相关 (P <0 0 1) ;同时 ,IL 6与烧伤总面积呈正相关。结论 :细胞因子活性的检测有助于病情的评估及预后判断 ,尤其是大面积烧伤患者。     

Activated protein C improves survival in severe sepsis patients with elevated troponin

Objective Multiple studies in sepsis have demonstrated that elevated troponin is associated with poor outcome. The elevated troponin in this situation is thought to be secondary to microthrombi. We hypothesized that recombinant human activated protein C (APC) treatment would improve outcomes in severe sepsis patients who have elevated troponin. Methods Patients with severe sepsis by consensus criteria in a university ICU were divided into a troponin elevated group (cTnI⁺) and a normal troponin (cTnI⁻) group. Outcome was compared using Fisher's exact test. APACHE II and MODS were calculated by standard methods. Patients We identified 105 patients with severe sepsis and troponin measured, of which 48 (46%) were in the cTnI⁺ group. The two groups were similar in terms of age and other comorbid conditions. Results APACHE II (28 ± 8 vs. 25 ± 8) was slightly higher and MODS (11 ± 4 vs. 9 ± 3) was significantly higher in the cTnI⁺ group. Mortality was 52% (25/48) in cTnI⁺ group and 30% (17/57) in cTnI⁻ group. Mortality was 30% in cTnI⁺ patients treated with APC and 72% in untreated cTnI⁺ patients. Conclusions Patients with severe sepsis who have elevated troponin have increased mortality. In patients with severe sepsis who have elevated troponin, treatment with APC improves outcome. Further study is needed to determine whether troponin can serve as a simple, readily available marker to identify which patients with severe sepsis will benefit from APC. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Antithrombin III in patients with severe sepsis: a pharmacokinetic study

Objectives: To evaluate the safety, pharmacokinetics, and the practicability of two different antithrombin III (AT III) high-dose regimens in patients with severe sepsis.¶Design: Prospective, open, randomized, 2 parallel groups, multinational clinical trial.¶Setting: Eleven academic medical center intensive care units (ICU) in Austria, Belgium, Denmark, Germany, Norway and Sweden.¶Patients: Thirty-three patients with severe sepsis who received standard supportive care and antimicrobial therapy, in addition to the administration of AT III.¶Interventions: Patients received an intravenous loading dose of 6,000 IU AT III followed by either intermittent bolus infusions of 1,000 IU AT III every 4 h or a continuous infusion of 250 IU AT III/h for 4 days, resulting in a total dose for both dosage regimens of 30,000 IU AT III.¶Measurements: All patients were evaluated for safety and all but one for pharmacokinetics.¶Results and conclusions: The administration of AT III was safe and well tolerated. The overall 28-day all-cause mortality was 30 % (43 % intermittent bolus infusions; 21 % continuous infusion). The mean probability of dying according to the SAPS II was 48 %. The difference in mortality between both groups was within the range of chance. AT III plasma levels were elevated from low baseline levels to above 120 % soon after onset of AT III therapy and remained at these levels for the treatment phase of 4 days. Functional and immunologic levels of AT III corresponded very well. With an overall median volume of distribution of 4.5 l (range: 2.4–6.5 l), AT III only moderately extended beyond plasma. The overall median elimination half-life was 18.6 h (range: 5.1–37.4). Overall, median response was 1.75 % per IU/kg (range: 1.14–2.8).¶The variability of elimination parameters was quite noteworthy (CV = 41–59 %), whereas distribution-related parameters showed a moderate variability (CV = 24 %). In spite of this variability, both high-dose IV regimens reliably provided AT III levels above 120 % for all but one patient. An increased mortality was observed for patients with a distribution volume exceeding 4.5 l (or a response < 1.7 % per IU/kg). AT III distribution volumes above 4.5 l might indicate a capillary leak phenomenon. The continuous infusion regimen was slightly preferred by the investigators with regard to practicability.     

血清降钙素原、C-反应蛋白及白细胞介素6在重症肺炎患者中的临床应用

目的观测血清降钙素原(PCT)、C-反应蛋白(CRP)及白细胞介素6(IL-6)在重症肺炎患者病程中的水平及变化趋势,探讨其临床意义。方法选择2010年12月至2011年6月行机械通气的重症肺炎患者42例作为观察组,其中存活组25例,死亡组17例,检测重症肺炎患者在入住重症医学科的第1、3、7天及转出ICU(或死亡)当天的血清PCT、CRP及IL-6水平及APACHEⅢ评分。结果第3天、第7天及转科或死亡当天,死亡组血清PCT水平分别为(15.06±4.16)μg/L、(16.18±3.78)μg/L及(19.50±2.09)μg/L,比存活组高(P值分别为0.049、0.041及0.039);第7天及转科或死亡当天,死亡组血清CRP水平分别为(94.87±11.67)mg/L,(117.56±11.43)mg/L,高于存活组(P值为0.025及0.019);观察期间存活组血清IL-6水平与死亡组无统计学差异(P值分别为0.183、0.371、0.843及0.424)。在观察期期间,存活组的血清PCT、CRP水平逐渐下降,死亡组逐渐上升;两组血清IL-6水平均逐渐下降。PCT、IL-6与APACHEⅢ评分呈直线相关(相关系数分别为0.447、0.602)。结论 PCT、CRP及IL-6在重症肺炎患者血清中水平升高,能反映病程严重程度;PCT与IL-6一定程度上与预后相关。     

The impact of compliance with 6-hour and 24-hour sepsis bundles on hospital mortality in patients with severe sepsis: a prospective observational study

Introduction  

Compliance with the ventilator care bundle affects the rate of ventilator-associated pneumonia. It was not known, however, whether compliance with sepsis care bundles has an impact on outcome. The aims of the present study were to determine the rate of compliance with 6-hour and 24-hour sepsis bundles and to determine the impact of the compliance on hospital mortality in patients with severe sepsis or septic shock.     

Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study

Introduction

Cross-talk between the coagulation system and inflammatory reactions during sepsis causes organ damage followed by multiple organ dysfunction syndrome or even death. Therefore, anticoagulant therapies have been expected to be beneficial in the treatment of severe sepsis. Recombinant human soluble thrombomodulin (rhTM) binds to thrombin to inactivate coagulation, and the thrombin-rhTM complex activates protein C to produce activated protein C. The purpose of this study was to examine the efficacy of rhTM for treating patients with sepsis-induced disseminated intravascular coagulation (DIC).

Methods

This study comprised 65 patients with sepsis-induced DIC who required ventilatory management. All patients fulfilled the criteria of severe sepsis and the International Society on Thrombosis and Haemostasis criteria for overt DIC. The initial 45 patients were treated without rhTM (control group), and the following 20 consecutive patients were treated with rhTM (0.06 mg/kg/day) for six days (rhTM group). The primary outcome measure was 28-day mortality. Stepwise multivariate Cox regression analysis was used to assess which independent variables were associated with mortality. Comparisons of Sequential Organ Failure Assessment (SOFA) score on sequential days between the two groups were analyzed by repeated measures analysis of variance.

Results

Cox regression analysis showed 28-day mortality to be significantly lower in the rhTM group than in the control group (adjusted hazard ratio, 0.303; 95% confidence interval, 0.106 to 0.871; P = 0.027). SOFA score in the rhTM group decreased significantly in comparison with that in the control group (P = 0.028). In the post hoc test, SOFA score decreased rapidly in the rhTM group compared with that in the control group on day 1 (P < 0.05).

Conclusions

We found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC. Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.     

Haemodynamic study of patients with severe sepsis during haemodialysis

A study was perfomed in order to observe haemodynamic changes induced by haemodialysis in 14 patients with acute renal failure and severe sepsis. Left ventricular function, as assessed by changes in pulmonary wedge pressure and left ventricular stroke work index through plasma volume expansion, did not change during haemodialysis. Ultrafiltration-induced decreases in cardiac index provoked in 8 patients, with nearly normal initial systemic arteriolar resistance, had adequate and constant increase in their resistance (p<0.001), whereas 6 patients with low initial systemic arteriolar resistance did not increase their resistance and had a frequent (9/13 measurements) and significant (p<0.001) fall in mean aortic pressure. This abnormality of vascular tone is probably due to severe sepsis and explains why hypotension is a frequent occurrence during haemodialysis in such patients.     

Brachial artery reactivity in patients with severe sepsis: an observational study

ABSTRACT: INTRODUCTION: Ultrasound measurements of brachial artery reactivity in response to stagnant ischemia provide estimates of microvascular function and conduit artery endothelial function. We hypothesized that brachial artery reactivity would independently predict severe sepsis and severe sepsis mortality. METHODS: This was a combined case-control and prospective cohort study. We measured brachial artery reactivity in 95 severe sepsis patients admitted to the medical and surgical intensive care units of an academic medical center and in 52 control subjects without acute illness. Measurements were compared in severe sepsis patients versus control subjects and in severe sepsis survivors versus nonsurvivors. Multivariable analyses were also conducted. RESULTS: Hyperemic velocity (centimeters per cardiac cycle) and flow-mediated dilation (percentage) were significantly lower in severe sepsis patients versus control subjects (hyperemic velocity: severe sepsis = 34 (25 to 48) versus controls = 63 (52 to 81), P < 0.001; flow-mediated dilation: severe sepsis = 2.65 (0.81 to 4.79) versus controls = 4.11 (3.06 to 6.78), P < 0.001; values expressed as median (interquartile range)). Hyperemic velocity, but not flow-mediated dilation, was significantly lower in hospital nonsurvivors versus survivors (hyperemic velocity: nonsurvivors = 25 (16 to 28) versus survivors = 39 (30 to 50), P < 0.001; flow-mediated dilation: nonsurvivors = 1.90 (0.68 to 3.41) versus survivors = 2.96 (0.91 to 4.86), P = 0.12). Lower hyperemic velocity was independently associated with hospital mortality in multivariable analysis (odds ratio = 1.11 (95% confidence interval = 1.04 to 1.19) per 1 cm/cardiac cycle decrease in hyperemic velocity; P = 0.003). CONCLUSIONS: Brachial artery hyperemic blood velocity is a noninvasive index of microvascular function that independently predicts mortality in severe sepsis. In contrast, brachial artery flow-mediated dilation, reflecting conduit artery endothelial function, was not associated with mortality in our severe sepsis cohort. Brachial artery hyperemic velocity may be a useful measurement to identify patients who could benefit from novel therapies designed to reverse microvascular dysfunction in severe sepsis and to assess the physiologic efficacy of these treatments.     

Effects of propofol on vasopressor use in patients with sepsis and severe sepsis: A pilot study

PurposePropofol is one of the most commonly used sedatives in the intensive care unit (ICU) despite its undesirable hypotensive effects. The purpose of this study was to determine the effects of continuous intravenous (CIV) propofol on vasopressor requirements in mechanically ventilated patients with sepsis.Materials and methodsA multicenter, retrospective, propensity-matched pilot study was conducted comparing patients with sepsis or severe sepsis who received CIV propofol for sedation to those who did not. The primary outcome was incidence of vasopressor support. Secondary outcomes included change in mean arterial pressure, mortality, and length of stay.ResultsA total of 279 patients (149 CIV propofol, 130 non-CIV propofol) were evaluated, with 174 patients matched 1:1 based on propensity score. There was no difference in vasopressor support requirements (49.4% vs 54%; P= .65) or in those experiencing a greater than 20% decrease in mean arterial pressure from baseline (58.6% vs 63.2%; P= .53) in the CIV propofol and non-CIV propofol groups. Furthermore, there were no differences in any secondary outcomes including hospital mortality (32.2% vs 33.3%; P= .87).ConclusionsContinuous intravenous propofol for sedation did not increase vasopressor requirements in this septic population. Furthermore, CIV propofol was not associated with significant differences in the use of multiple vasopressors, change in mean arterial pressure, length of stay, or mortality.     

Extravascular lung water in patients with severe sepsis: a prospective cohort study

Introduction  

Few investigations have prospectively examined extravascular lung water (EVLW) in patients with severe sepsis. We sought to determine whether EVLW may contribute to lung injury in these patients by quantifying the relationship of EVLW to parameters of lung injury, to determine the effects of chronic alcohol abuse on EVLW, and to determine whether EVLW may be a useful tool in the diagnosis of acute respiratory distress syndrome (ARDS).     

IL-1ra administration does not improve cardiac function in patients with severe sepsis

PURPOSE: The purpose of this study was to investigate the effects of interleukin-1 receptor antagonist (IL-1ra) on myocardial function in septic patients. MATERIALS AND METHODS: A subgroup of patients from a prospective, randomized, double-blind, placebo-controlled, multicenter trial was studied from 63 academic medical centers in the United States, Canada, and Europe. A subgroup of 71 patients with severe sepsis in whom vasoactive support was little altered during the study was included. The patients were randomized to receive either placebo (n = 29) or IL-1ra at a dose of 1 mg/kg/h (n = 20) or 2 mg/kg/h (n = 22). RESULTS: Hemodynamic measurements were taken at baseline, and 1, 2, 3, 4, 8, and 12 hours after placebo or IL-1ra administration. No significant differences in hemodynamic parameters were observed between the groups or over time during the study period. CONCLUSIONS: IL-1ra administration has no effect on cardiac function in septic patients.