Yves Le Tulzo

platelet-activating factor receptor antagonist Bn 52021 in the treatment of severe sepsis: A randomized, double-blind, placebo-controlled, multicenter clinical trial

Objective: To evaluate the safety and efficacy of a natural platelet‐activating factor receptor antagonist, BN 52021 (Ginkgolide B), in the treatment of patients with sepsis syndrome. Design: Prospective, randomized, placebocontrolled, double‐blind, phase III, multicenter clinical trial. Setting: Twenty‐one academic medical center intensive care units in France. Patients: Two hundred sixty‐two patients with sepsis syndrome who received standard supportive care and antimicrobial therapy, in addition to the administration of platelet‐activating factor receptor antagonist or placebo. Interventions: Patients received either a 120‐mg dose of platelet‐activating factor receptor antagonist intravenously every 12 hrs over a 4‐day period or placebo. Main Outcome Measurements: All patients were evaluated for 28‐day, all‐cause mortality. Results: The 28‐day mortality rate was 51% for the placebo group and 42% for the platelet‐activating factor receptor antagonist group ( p = .17). However, the efficacy of platelet‐activating factor receptor antagonist was significantly greater in patients with Gram‐negative sepsis (test for interaction, p = .03). In a separate analysis of patients with and without Gram‐negative sepsis, the 28‐day mortality rate was 57% for the patients receiving placebo (30 deaths of 53 patients) and 33% for patients receiving platelet‐activating factor receptor antagonist (22 deaths of 67 patients; p = .01). Platelet‐activating factor receptor antagonist also significantly ( p = .01) reduced the mortality rate among patients with Gram‐negative sepsis who were in shock at entry into the study (mortality rate was 65% for placebo vs. 37% for platelet‐activating factor receptor antagonist) and among patients >60 yrs of age (mortality rate was 74% for placebo vs. 31% for platelet‐activating factor receptor antagonist). A Cox proportional‐hazards model identified five independent prognostic factors: a) adequacy of antibiotic therapy; b) severity of illness; c) renal failure; d) hematologic failure; and e) hepatic failure at study entry. When the Gram‐negative sepsis population was stratified by age and these five prognostic factors were controlled for, the relative risk of death of the platelet‐activating factor receptor antagonist group was 0.61 (0.34 to 1.08, 95% confidence interval; p = .09). This risk corresponds with an adjusted reduction in mortality rate of 39% for patients receiving plateletactivating factor receptor antagonist. No differences in mortality rates were found between the placebo and the platelet‐activating factor receptor antagonist groups in the absence of Gram‐negative sepsis. There were no differences in adverse events between the placebo and the treated groups. Conclusion: The studied platelet‐activating factor receptor antagonist (BN 52021) seems to be a safe and promising treatment for patients with severe Gram‐negative sepsis. (Crit Care Med 1994; 22:1720–1728)

Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial

IMPORTANCEnDespite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia.nnnOBJECTIVEnTo test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis.nnnDESIGN, SETTING, AND PATIENTSnAn open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized.nnnINTERVENTIONSnHypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care.nnnMAIN OUTCOMES AND MEASURESnPrimary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients.nnnRESULTSnAfter inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; Pu2009=u2009.04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; Pu2009=u2009.13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; Pu2009=u2009.10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977).nnnCONCLUSIONS AND RELEVANCEnModerate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00774631.

Incidence of Pneumocystis jiroveci Pneumonia among Groups at Risk in HIV-negative Patients

BACKGROUNDnPneumocystis jiroveci pneumonia in human immunodeficiency virus (HIV)-negative immunocompromised patients is associated with high mortality rates. Although trimethoprim-sulfamethoxazole provides a very effective prophylaxis, pneumocystosis still occurs and may even be emerging due to suboptimal characterization of patients most at risk, hence precluding targeted prophylaxis.nnnMETHODSnWe retrospectively analyzed all cases of documented pneumocystosis in HIV-negative patients admitted in our institution, a referral center in the area, from January 1990 to June 2010, and extracted data on their underlying condition(s). To estimate incidence rates within each condition, we estimated the number of patients followed-up in our area for each condition by measuring the number of patients admitted with the corresponding international classification diagnostic code, through the national hospital discharge database (Program of Medicalization of the Information System [PMSI]).nnnRESULTSnFrom 1990 to 2010, 293 cases of pneumocystosis were documented, of which 154 (52.6%) tested negative for HIV. The main underlying conditions were hematological malignancies (32.5%), solid tumors (18.2%), inflammatory diseases (14.9%), solid organ transplant (12.3%), and vasculitis (9.7%). Estimated incidence rates could be ranked in 3 categories: 1) high risk (incidence rates >45 cases per 100,000 patient-year): polyarteritis nodosa, granulomatosis with polyangiitis, polymyositis/dermatopolymyositis, acute leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma; 2) intermediate risk (25-45 cases per 100,000 patient-year): Waldenström macroglobulinemia, multiple myeloma, and central nervous system cancer; and 3) low risk (<25 cases per 100,000 patient-year): other solid tumors, inflammatory diseases, and Hodgkin lymphoma.nnnCONCLUSIONSnThese estimates may be used as a guide to better target pneumocystosis prophylaxis in the groups most at risk.

Cardiac output monitoring in septic shock: evaluation of the third-generation Flotrac-Vigileo®

Continuous cardiac index (CI) monitoring is frequently used in critically ill patients. Few studies have compared the pulse contour-based device FloTrac/Vigileo® to pulmonary artery thermodilution (PAC) in terms of accuracy for CI monitoring in septic shock. The aim of our study was to compare the third-generation FloTrac/Vigileo® to PAC in septic shock. Eighteen patients with septic shock requiring monitoring by PAC were included in this study. We monitored CI using both FloTrac/Vigileo® and continuous thermodilution (PAC-CI). Hemodynamic data were recorded every hour or every 2xa0min during fluid challenges. The primary endpoint was the global agreement of all CI-paired measurements determined using the Bland–Altman method adapted to replicated data. We tested the linearity of the bias by regression analysis, and compared the reactivity of the 2 techniques during fluid challenges. A receiver operating characteristic (ROC) curve analysis tested the ability of FloTrac/Vigileo® to detect concordant and significative CI changes, using PAC-CI as the reference method. Overall, 1,201 paired CI measurements were recorded. The Bland–Altman analysis for global agreement of the 2 techniques showed a bias of −0.1xa0±xa02.1xa0Lxa0min−1xa0m−2 and a percentage error of 64xa0%. The overall correlation coefficient between PAC-CI and FloTrac/Vigileo® CI was 0.47 (pxa0<xa00.01), with r2xa0=xa00.22. The area under the curve of the ROC curve for detecting concordant and significant changes in CI was 0.72 (0.53; 0.87). In our study, third-generation Flowtrac-Vigileo® appears to be too inaccurate to be recommended for CI monitoring in septic shock.

Toward new insights on the white blood cell differential by flow cytometry: A proof of concept study on the sepsis model†

We sought to evaluate, on a model of sepsis, the clinical relevance of new parameters obtained on a white blood cell (WBC) differential by flow cytometry, implemented in the routine workflow of our hematology laboratory.

Interest of a simple on-line screening registry for measuring ICU burden related to an influenza pandemic

IntroductionThe specific burden imposed on Intensive Care Units (ICUs) during the A/H1N1 influenza 2009 pandemic has been poorly explored. An on-line screening registry allowed a daily report of ICU beds occupancy rate by flu infected patients (Flu-OR) admitted in French ICUs.MethodsWe conducted a prospective inception cohort study with results of an on-line screening registry designed for daily assessment of ICU burden.ResultsAmong the 108 centers participating to the French H1N1 research network on mechanical ventilation (REVA) - French Society of Intensive Care (SRLF) registry, 69 ICUs belonging to seven large geographical areas voluntarily participated in a website screening-registry. The aim was to daily assess the ICU beds occupancy rate by influenza-infected and non-infected patients for at least three weeks. Three hundred ninety-one critically ill infected patients were enrolled in the cohort, representing a subset of 35% of the whole French 2009 pandemic cohort; 73% were mechanically ventilated, 13% required extra corporal membrane oxygenation (ECMO) and 22% died. The global Flu-OR in these ICUs was only 7.6%, but it exceeded a predefined 15% critical threshold in 32 ICUs for a total of 103 weeks. Flu-ORs were significantly higher in University than in non-University hospitals. The peak ICU burden was poorly predicted by observations obtained at the level of large geographical areas.ConclusionsThe peak Flu-OR during the pandemic significantly exceeded a 15% critical threshold in almost half of the ICUs, with an uneven distribution with time, geographical areas and between University and non-University hospitals. An on-line assessment of Flu-OR via a simple dedicated registry may contribute to better match resources and needs.

EuroSCORE II underestimates mortality after cardiac surgery for infective endocarditis

OBJECTIVESnTo better select for patients who most likely will benefit from cardiac surgery among those with infective endocarditis (IE), we aimed to identify preoperative markers associated with poor outcome after cardiac surgery for IE, and to evaluate the accuracy of European System for Cardiac Operative Risk Evaluation (EuroSCORE) II to predict mortality.nnnMETHODSnWe enrolled all adult patients who underwent cardiac surgery during the acute phase of definite IE (Duke Criteria) in two referral centres for cardiac surgery. Patients were identified through intensive care unit (ICU) electronic databases, and data were collected from medical charts on standardized questionnaire.nnnRESULTSnBetween 2002 and 2013, 149 patients (117 males), with a median age of 64 years [interquartile range 52-73], fulfilled the inclusion criteria. Main complications before surgery were left ventricular dysfunction (23%), central nervous system symptomatic events (34%) and septic shock (24%). Most patients (95%) presented with valve regurgitation, and 49% had perivalvular abscess. Surgery was performed with a median delay of 12 days [5-24] after IE diagnosis, and mean EuroSCORE II was 15.8 (13.4-18.1). In-hospital mortality was 21%. Preoperative variables associated with mortality in multivariate analysis were obesity [odds ratio (OR) 3.67 [1.10-12.19], P = 0.03], vegetation >15 mm (OR 6.72 [1.46-30.98], P = 0.01), septic shock (OR 4.87 [1.67-14.28], P = 0.004) and mechanical prosthetic valve IE (OR 4.99 [1.72-28.57], P = 0.007). EuroSCORE II underestimated mortality in patients with predicted mortality over 10%.nnnCONCLUSIONnFactors independently predictive of mortality after cardiac surgery for IE are obesity, septic shock, large vegetation and a mechanical prosthetic valve IE. EuroSCORE II underestimates post-cardiac surgery mortality in patients with IE.

Chronic alcohol exposure, infection, extended circulating white blood cells differentiated by flow cytometry and neutrophil CD64 expression: a prospective, descriptive study of critically ill medical patients.

BackgroundA history of prolonged and excessive consumption of alcohol increases the risk for infections. The goal of this study was to investigate circulating white blood cells (WBC) differentiated by flow cytometry and neutrophil CD64 expression in excessive alcohol drinkers versus abstinent or moderate drinkers, and in those with or without infection, in medical patients admitted to the intensive care unit (ICU).MethodsAll patients admitted between September 2009 and March 2010 with an ICU-stay of 3 days or more were eligible for inclusion. Upon admission, hematological exams were conducted by flow cytometry.ResultsOverall, 281 adult were included, with 37% identified as at-risk drinkers. The only significant difference found in circulating WBC between at-risk and not-at-risk drinkers was a lower number of B lymphocytes in at-risk drinkers (Pu2009=u20090.002). Four groups of patients were defined: not-at-risk drinkers with no infection (nu2009=u200966); not-at-risk drinkers with infection (nu2009=u2009112); at-risk drinkers with no infection (nu2009=u200953); and at-risk drinkers with infection (nu2009=u200950). Whilst the presence of infection significantly reduced levels of noncytotoxic and cytotoxic T lymphocytes and significantly increased levels of CD16– monocytes in not-at-risk drinkers, with variation related to infection severity, infection had no effect on any of the variables assessed in at-risk drinkers. Post-hoc comparisons showed that B-lymphocyte, noncytotoxic, and cytotoxic T lymphocyte and CD16– counts in at-risk drinkers were similar to those in not-at-risk drinkers with infection and significantly lower than those in not-at-risk drinkers without infection. Neutrophil CD64 index varied significantly between groups, with variations related to infection, not previous alcohol consumption.ConclusionsThese results show that chronic alcohol exposure has an impact on the immune response to infection in critically ill medical patients. The absence of significant variations in circulating WBC seen in at-risk drinkers according to the severity of infection is suggestive of altered immune response.

Iterative Thoracentesis as First-Line Treatment of Complicated Parapneumonic Effusion

Rationale Optimal management of complicated parapneumonic effusions (CPPE) remains controversial. Objectives to assess safety and efficacy of iterative therapeutic thoracentesis (ITTC), the first-line treatment of CPPE in Rennes University Hospital. Methods Patients with CPPE were identified through our computerized database. We retrospectively studied all cases of CPPE initially managed with ITTC in our institution between 2001 and 2010. ITTC failure was defined by the need for additional treatment (i.e. surgery or percutaneous drainage), or death. Results Seventy-nine consecutive patients were included. The success rate was 81% (nu200a=u200a64). Only 3 patients (4%) were referred to thoracic surgery. The one-year survival rate was 88%. On multivariate analysis, microorganisms observed in pleural fluid after Gram staining and first thoracentesis volume ≥450 mL were associated with ITTC failure with adjusted odds-ratios of 7.65 [95% CI, 1.44–40.67] and 6.97 [95% CI, 1.86–26.07], respectively. The main complications of ITTC were iatrogenic pneumothorax (nu200a=u200a5, 6%) and vasovagal reactions (nu200a=u200a3, 4%). None of the pneumothoraces required chest tube drainage, and no hemothorax or re-expansion pulmonary edema was observed. Conclusions Although not indicated in international recommendations, ITTC is safe and effective as first-line treatment of CPPE, with limited invasiveness.

Constipation is independently associated with delirium in critically ill ventilated patients.

Delirium is a central nervous system (CNS) dysfunction reported in up to 80 % of intensive care unit (ICU) patients associated with negative short- and long-term outcomes [1, 2]. Gastrointestinal motility disorders are frequent in ICU patients leading to frequent delayed passage of stools [3]. Because there is a bi-directional communication between the CNS and the digestive tract [4], we believed it relevant to test the hypothesis that constipation and delirium are related in ICU patients.