Role of clinical evaluation committees in sepsis trials: from 'valid cohort' assessment to subgroup analysis

In this issue of Critical Care, the study from Laterre and colleagues offers suggestions for the role of clinical evaluation committees (CECs) in future sepsis trials. Despite encouraging preliminary results, all randomized controlled trials (RCTs) devoted to potential compounds in severe sepsis have failed to show survival benefit. One of the reasons might be related to RCT-related factors that inevitably occur within a heterogeneous septic patient population. A patient population free from confounding events would seem to provide the most suitable platform upon which to judge therapeutic effect. To solve this issue, CECs have been introduced into RCTs in sepsis to ensure uniform data for analysis and to identify such 'optimal cohorts' for which the therapy was initially designed to treat. More recently, some RCTs have reported positive results in sepsis. The role of CECs has shifted to become a more integral part of the detailed analysis of drug safety and efficacy in large databases, and to identify subgroups of patients in which a therapy might be less or more effective and/or safe. As an example, the retrospective analysis by Laterre and colleagues focuses on patients with severe community-acquired pneumonia (sCAP) within a large, failed RCT (on recombinant tissue factor pathway inhibitor (rTFPI)). However, the results should be interpreted with great caution, and should be viewed as exploratory and a hypothesis-generating activity. This question of potential benefit of rTFPI in patients with sCAP will be definitively answered by the results of the recently completed RCP

Nonlinear Response and Fatigue Estimation of Surface Panels to White and Non-White Gaussian Random Excitations

In stochastic structural dynamics, the majority of analyses have dealt with linear structures under stationary, Gaussian, and band-limited white noise excitations. Although these simplifying assumptions may be justified, in many processes experimental data have shown quite frequently the non-stationary and non-Gaussian characteristics of the loads. An efficient finite element modal formulation has recently been developed to extend the analysis to nonlinear structural responses. Laminated plate theory and von Karman large displacement relations are used to derive the nonlinear equations of motion for an arbitrarily laminated composite panel subjected to combined acoustic and thermal loads. The nonlinear equations of motion in structural node degrees of freedom are then transformed to a set of coupled nonlinear equations in truncated modal coordinates with rather small degrees of freedom. Recorded B-1B flight acoustic pressure fluctuations have shown the non-white power spectral density (PSD) characteristics. This work presents for the first time the nonlinear large amplitude response and fatigue life estimation of arbitrary laminated composite panels subjected to non-white pressure fluctuations with or without a high thermal environment. The Palmgrem-Miner theory is combined with the rainflow counting cycles method in time domain, and with transformed Gaussian models in the frequency domain, to estimate the panel fatigue life. Equivalent band-limited White Noise Sound Pressure Level excitations (EWSPL), which have the same acoustic power within the bandwidth as the B-1B flight data, are generated. Nonlinear response and fatigue life are predicted for the identical panels subjected to EWSPL. Monte Carlo numerical simulation is used for the analysis of the EWSPL. Results show that the flight data with non-white PSD give higher stress characteristics and shorter fatigue life than the corresponding EWSPL

Diagnosis and treatment of severe sepsis

The burden of infection in industrialized countries has prompted considerable effort to improve the outcomes of patients with sepsis. This has been formalized through the Surviving Sepsis Campaign 'bundles', derived from the recommendations of 11 professional societies, which have promoted global improvement in those practices whose primary goal it is to reduce sepsis-related death. However, difficulties remain in implementing all of the procedures recommended by the experts, despite the apparent pragmatism of those procedures. We summarize the main proposals made by the Surviving Sepsis Campaign and focus on the difficulties associated with making a proper diagnosis and supplying adequate treatment promptly to septic patients

Risk factors for post-ICU red blood cell transfusion: a prospective study

INTRODUCTION: Factors predictive of the need for red blood cell (RBC) transfusion in the intensive care unit (ICU) have been identified, but risk factors for transfusion after ICU discharge are unknown. This study aims identifies risk factors for RBC transfusion after discharge from the ICU. METHODS: A prospective, monocentric observational study was conducted over a 6-month period in a 24-bed medical ICU in a French university hospital. Between June and December 2003, 550 critically ill patients were consecutively enrolled in the study. RESULTS: A total of 428 patients survived after treatment in the ICU; 47 (11% of the survivors, 8.5% of the whole population) required RBC transfusion within 7 days after ICU discharge. Admission for sepsis (odds ratio [OR] 341.60, 95% confidence interval [CI] 20.35–5734.51), presence of an underlying malignancy (OR 32.6, 95%CI 3.8–280.1), female sex (OR 5.4, 95% CI 1.2–24.9), Logistic Organ Dysfunction score at ICU discharge (OR 1.45, 95% CI 1.1–1.9) and age (OR 1.06, 95% CI 1.02–1.12) were independently associated with RBC transfusion after ICU stay. Haemoglobin level at discharge predicted the need for delayed RBC transfusion. Use of vasopressors (OR 0.01, 95%CI 0.001–0.17) and haemoglobin level at discharge from the ICU (OR 0.02, 95% CI 0.007–0.09; P < 0.001) were strong independent predictors of transfusion of RBC 1 week after ICU discharge. CONCLUSION: Sepsis, underlying conditions, unresolved organ failures and haemoglobin level at discharge were related to an increased risk for RBC transfusion after ICU stay. We suggest that strategies to prevent transfusion should focus on homogeneous subgroups of patients and take into account post-ICU needs for RBC transfusion

Influence of Overweight on ICU Mortality* A Prospective Study

Study objective: Overweight patients seem to have a poorer outcome and a higher risk of complications during their stay in the ICU. We conducted a prospective study in order to examine the relationship between body mass index (BMI) and mortality among these patients. Design: Prospective clinical study. Setting: A 24-bed medical ICU in a university-affiliated hospital. Methods: All patients hospitalized in the ICU over a 1-year period were included except those dying or being discharged from the hospital within 24 h of admission. Overweight patients were defined as those having a BMI &gt; 75th percentile of this selected ICU population. Other data collected were demographic and ICU-related data. The Mann-Whitney test was used to compare numeric data between groups (ie, obese and nonobese populations). Variables that were significantly associated with ICU mortality by univariate analysis were entered into a multiple logistic regression model, allowing the determination of independent predictors. Results: Eight hundred thirteen patients were included in the study. The limit of the upper quartile of the BMI was 27. This value was used to separate obese (n ‫؍‬ 215) and nonobese (n ‫؍‬ 598) groups. Significant differences between obese and nonobese patients were observed in age, length of stay in the ICU, simplified acute physiology score (SAPS) II, and ICU mortality. The observed mortality of obese patients was significantly higher than that predicted by SAPS II (32% vs 18%, respectively; p ‫؍‬ 0.001). No difference was observed in frequency of nosocomial infection or duration of mechanical ventilation for mortality in ICU patients. Using a multivariate analysis, the predictive factors of mortality were SAPS II (p &lt; 0.0001) and BMI &gt; 27 (p &lt; 0.01). Conclusion: This is the first prospective study showing high BMI value as an independent prognostic factor of mortality for ICU patients. The prognostic scoring systems currently in use, which were designed to predict the mortality of ICU patients, do not include BMI or do not consider obesity. These may underestimate, therefore, the risk for the specific population of obese patients. (CHEST 2004; 125:1441-1445) Key words: body mass index; critical illness; mortality; obesity; overweight; prognostic index Abbreviations: APACHE ϭ acute physiology and chronic health evaluation; BMI ϭ body mass index; LOS ϭ length of stay; SAPS ϭ simplified acute physiology scor

Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome

INTRODUCTION: Protein C, because of its central role in hemostasis, plays an integral role in the host response to infection. Protein C depletion, resulting from increased consumption, degradation, and/or decreased synthesis, is characteristic of sepsis and has been shown to predict morbidity and mortality. The objective of this study was to determine whether early directional changes in protein C levels correlate with outcome. METHODS: Patients in the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) clinical trial were assessed and categorized by baseline protein C (n = 1574). Deficiency was categorized as: severe deficiency, protein C levels ≤ 40% of normal protein C activity (n = 615, 39% of patients); deficient, protein C levels 41–80% of normal protein C activity (n = 764, 48.5% of patients); and normal, >80% of normal protein C activity (n = 195, 12.4% of patients). Logistic regression analysis of 28-day mortality for placebo patients was used to investigate whether baseline and day 1 protein C levels were independent risk factors for mortality. The impact of treatment with drotrecogin alfa (activated) (DrotAA) was also assessed. RESULTS: Protein C levels at baseline and day 1 were independent risk factors in placebo patients. If baseline protein C levels of severely deficient placebo patients remained ≤ 40% at day 1 their odds of death increased (odds ratio = 2.75, P < 0.0001), while if levels improved to >40% by day 1 their risk of death decreased (odds ratio = 0.43, P = 0.03). If baseline protein C levels of placebo patients were >40% but decreased by ≥ 10% on day 1, their risk of death increased (odds ratio = 1.87, P = 0.02). DrotAA treatment improved protein C levels by day 1 compared with placebo (P = 0.008) and reduced the risk of death in severely deficient (≤ 40%) patients at baseline. Treatment also decreased the number of severely protein C deficient (= 40%) patients and decreased the number of deficient (41–80%) patients and normal (>80%) patients who had a ≥ 10% decrease in protein C levels by day 1. CONCLUSION: Baseline protein C levels were an independent predictor of sepsis outcome. Day 1 changes in protein C, regardless of baseline levels, were also predictive of outcome. The association of DrotAA treatment, increased protein C levels, and improved survival may partially explain the mechanism of action

Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]

INTRODUCTION: PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care). METHODS: Nineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism. RESULTS: Levels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin–antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days. CONCLUSION: Abnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups