Abstract

Importance Observational studies have reported that statin use may be associated with improved outcomes of various infections. Ventilator-associated pneumonia (VAP) is the most common infection in the intensive care unit (ICU) and is associated with substantial mortality.

Objective To determine whether statin therapy can decrease day-28 mortality in patients with VAP.

Design, Setting, and Participants Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial performed in 26 intensive care units in France from January 2010 to March 2013. For power to detect an 8% absolute reduction in the day-28 mortality rate, we planned to enroll 1002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients.

Interventions Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.

Main Outcomes and Measures Primary outcome was day-28 mortality. Day-14, ICU, and hospital mortality rates were determined, as well as duration of mechanical ventilation and Sequential Organ Failure Assessment (SOFA) scores on days 3, 7, and 14.

Results The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naive to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2% [95% CI, 15.4% to 28.6%) than in the placebo group (15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83 to 2.51]); the between-group difference was 6.0% (95% CI, −3.0% to 14.9%). In statin-naive patients, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054) (between-group difference, 7.7% [95%CI, −1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in SOFA score.

Conclusions and Relevance In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.

Trial Registration clinicaltrials.gov Identifier: NCT01057758

Statins are widely used to lower cholesterol levels for prevention of cardiovascular disease. Statins also exert anti-inflammatory and immunomodulating effects, have been reported to counteract the deleterious effects of sepsis on coagulation,1,2 and may directly inhibit pathogenic microorganisms.3,4 Many clinical studies have been performed to evaluate whether these pleiotropic effects are beneficial in infections, although most used an observational design. A meta-analysis identified 20 studies, including only 1 randomized controlled trial, and found lower mortality (including pneumonia-related mortality) with statin use, defined as taking any statin for any reason.5 Another meta-analysis suggested efficacy of statins for treating and preventing infections,6 but a meta-analysis including only randomized controlled trials found no evidence of preventive efficacy.7

These data indicate a need for randomized controlled trials in uniform patient populations, distinguishing de novo from continued statin therapy. In the few such trials available, de novo atorvastatin therapy decreased the rate of progression to severe sepsis among ward patients with sepsis8; simvastatin decreased levels of tumor necrosis factor α and IL-6 in patients with acute bacterial infection9; continued atorvastatin therapy improved survival in patients with severe sepsis, although de novo atorvastatin therapy did not10; and de novo simvastatin therapy improved nonpulmonary organ dysfunction without affecting survival in patients with acute lung injury.11 Although these findings seem promising, the toxicities and renal excretion of statins in critically ill patients may differ from those in relatively healthy individuals, and very high peak plasma statin levels have been reported in critically ill patients.12 Thus, the risk-benefit ratio of statin therapy in the intensive care unit (ICU) remains unclear.

Ventilator-associated pneumonia (VAP) is diagnosed in approximately 8% to 28% of ICU patients receiving mechanical ventilation13,14 and remains associated with increased mortality rates and high health care costs.15 Thus, new adjunctive treatments are needed to improve the outcomes of VAP.

The primary objective of this trial was to determine whether adjunctive statin therapy decreased day-28 mortality among ICU patients with VAP.

Methods

Study Design

This 1:1 randomized, parallel-group, placebo-controlled, double-blind trial was monitored by an independent data and safety monitoring board (DSMB). A steering committee designed and executed the study, analyzed the data, interpreted the findings, wrote the manuscript, and holds the data. The study was conducted in accordance with the protocol and statistical analysis plan, which were approved for all centers by the ethics committee of the Nice University Hospital (Comité de Protection des Personnes Sud Méditerranée V). According to French law, written informed consent was obtained from the patients or their proxies either before study inclusion or, for patients not competent to provide consent and with no available proxies, at recovery of competence.

The study was conducted in 26 French ICUs from January 2010 to March 2013. Consecutive adults who had received mechanical ventilation in the ICU for at least 2 days were eligible if they had suspected VAP defined as a modified Clinical Pulmonary Infection Score (CPIS)16 of at least 5 and if they underwent quantitative bacteriological cultures of bronchoalveolar lavage (BAL) fluid, a protected telescopic catheter (PTC), or an endotracheal aspirate. The modified CPIS16 is based on body temperature, blood leukocyte count, amount and appearance of tracheal secretions, ratio of Pao 2 to fraction of inspired oxygen, acute respiratory distress syndrome (ARDS), and infiltrates on chest radiography. The total can range from 1 to 10 points. Patients were included only for the first episode of suspected VAP. Noninclusion criteria were statin therapy at intubation, previous VAP episode during the same hospitalization, known pregnancy, immunodepression with bone marrow aplasia, imminent death (Simplified Acute Physiology Score II of 75 or greater, calculated over the last 6 hours), treatment-limitation decisions, nothing-by-mouth order and no nasogastric tube, continuous gastric aspiration, known chronic intestinal malabsorption, known simvastatin hypersensitivity, acute hepatic failure,17 use of CYP3A4 inhibitors or cyclosporine, creatine kinase level greater than 5 times the upper limit of normal, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than 3 times the upper limit of normal (as recommended by the Agence Nationale de la Sécurité du Médicament from the French Ministry of Health), and enrollment in another trial within the previous 30 days.

Patients were randomly allocated to simvastatin (60 mg) or placebo given via a nasogastric tube or orally from study inclusion to ICU discharge, death, or day 28, whichever occurred first. Simvastatin or placebo was started on the same day as antibiotic therapy for suspected VAP. The simvastatin dosage was halved in patients with renal failure (creatinine clearance <30 mL/min). Randomization was stratified by center. A computer-generated random-number table was prepared by statisticians to assign patients in blocks of 4 to receive either simvastatin or placebo. Block size was unknown to the investigators, who enrolled the patients and then called the statistics department to obtain the randomization and treatment numbers after checking the inclusion and noninclusion criteria. To ensure blinding, placebo tablets identical to the simvastatin tablets were manufactured (same appearance, color, and time to dilution in 30 mL of water). Simvastatin or placebo was administered via the nasogastric tube or orally. Patients, clinicians, evaluators, monitors, and data analysts were blinded to the study treatment.

Definitions and Antibiotic Therapy

Definite bacterial VAP was defined as a positive pleural fluid culture or rapid cavitation of the lung infiltrate as determined by computed tomography, biopsy, or both, or an autopsy specimen showing histological evidence of pneumonia (consolidation with large numbers of neutrophils in the bronchioles and adjacent alveoli in several adjacent low-power fields, with or without tissue necrosis).18 Probable bacterial VAP was defined as a modified CPIS of 5 or greater, combined with BAL cultures with greater than 104 colony-forming units (CFU)/mL for at least 1 organism, PTC cultures with greater than 103 CFU/mL for at least 1 organism, or endotracheal aspirate culture with greater than 105 CFU/mL for at least 1 organism. Possible VAP was defined as absence of the above-listed criteria with a modified CPIS of 5 or greater. Adequate empirical therapy, ARDS, and septic shock are defined in the eMethods in the Supplement; the eMethods also describe the use of antibiotics.

Data Collection

We recorded demographic data, physiological variables, Simplified Acute Physiology Score II at admission and radiologic score,19 antibiotics used, and relevant diagnostic and therapeutic interventions in the ICU. The Sequential Organ Failure Assessment (SOFA) score20 and CPIS16 were calculated on the day of enrollment (day 1) and then on days 3, 7, and 14. Patients were monitored daily for evidence of infection. The duration of mechanical ventilation, length of ICU stay, and length of hospital stay were recorded. The occurrence of myocardial ischemia or infarction was assessed until day 28. Serum levels of creatine kinase, ALT, and AST were measured on days 1, 3, 7, 14, and 21.

Study Outcomes

The primary outcome was the day-28 mortality rate. Secondary outcomes were day-14, day-90 (exploratory), and ICU mortality rates; number of days outside the ICU between day 1 and day 28; mortality rates in the subgroups with definite and probable VAP; and number of ventilator-free days (after successful weaning) between day 1 and both day 28 and day 90 (exploratory). Successful weaning was defined as spontaneous breathing for at least 48 hours after disconnection of the ventilator. Other secondary outcomes were the SOFA score on days 3, 7, and 14, the occurrence of subsequent VAP episodes, bacteremia/fungemia, urinary tract infections (exploratory), and catheter-related infections (exploratory) from inclusion to day 28. All these outcomes were prespecified in the protocol except day-90 mortality, day-90 ventilator-free days, and incidences of urinary tract and catheter-related infections from inclusion to day 28, which were exploratory but nevertheless diagnosed and recorded prospectively. The main safety end points were the number of adverse events and the proportions of patients with alterations in creatine kinase levels, levels of ALT and AST, or both.

Statistical Analysis

The DSMB requested a change in the statistical methodology initially chosen for analyzing the primary outcome. The DSMB further suggested that obtaining valid support for our hypothesis that simvastatin was superior over the placebo for the main objective required the use of an appropriate statistical methodology with a unilateral hypothesis and asymmetric boundaries. This change was made, and the final statistical plan was then approved by the ethics committee in May 2012. Two interim analyses were planned. Data management and analysis were each conducted in blinded fashion by 2 separate biostatistician teams.

Assuming a 28-day mortality rate of 30%, we needed 1002 patients (501 in each group) to obtain 80% power for detecting an 8% absolute reduction in the day-28 mortality rate (26.7% relative reduction) with a 1-sided α risk of .025 (SAS version 9.2 [SAS Institute Inc]).18,21 The study was monitored using group sequential testing; the stopping rules were efficacy (significant survival improvement with simvastatin) and futility (low probability of demonstrating such an improvement) according to O’Brien-Fleming–type asymmetric boundaries. Interim analyses of the primary outcome (day-28 mortality) were to be performed after enrollment of 251 and 502 patients. Asymmetric stopping boundaries were designed using α and β spending boundaries as described by Lan and DeMets.22 The efficacy stopping rules were an absolute decrease in day-28 mortality of at least 21.3% with simvastatin compared with placebo after enrollment of 251 patients and an absolute decrease at least 10.6% after enrollment of 502 patients; for the final analysis, an absolute decrease of at least 5.3% established efficacy. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of 251 patients and an absolute decrease in day-28 mortality no greater than 2.6% with simvastatin compared with placebo after enrollment of 502 patients. The independent DSMB conducted the first interim analysis in December 2012 based on data from the first 251 patients.

Continuous variables are reported as mean (SD) or median (interquartile range) and categorical variables as number (%). Between-group differences were assessed using t test, Wilcoxon test, χ2 test, or Fisher exact test, as appropriate. A Cox multivariate proportional hazards model was built using 5 predefined covariates: simvastatin use, baseline SOFA score, age, sex, and presence of a fatal underlying disease at hospital admission. We also planned to include all variables showing an imbalance between the 2 groups at baseline; the only such variable was antibiotic use within 3 days before inclusion. A Kaplan-Meier curve was plotted for time to death until day 28.

All analyses were performed using SAS version 9.2 (SAS Institute Inc) on an intention-to-treat basis. No patients were lost to follow-up for the main outcome or any of the outcomes related to mortality, duration of mechanical ventilation, stay lengths, or new infections. Variables with missing values (for determination of the SOFA score and for enzyme levels, both after day 3) were handled by confining the analyses to those patients with available data. P ≤ .05 (2-sided) was considered significant, except for the primary outcome, for which P ≤ .025 (1-sided) was considered significant.

Results

Patients and VAP Features

The trial was stopped for futility at the first scheduled interim analysis, based on results reported by the DSMB after breaking the randomization code.

Between January 2010 and December 2012, we screened 1303 patients for eligibility; of these, 300 were enrolled (Figure 1). All patients received at least 1 dose of statin or placebo. Consent was denied by 6 patients and withdrawn by 10; these patients were not included in the analysis. The only clinically significant baseline difference between groups was a higher proportion of patients receiving antibiotics in the simvastatin group (Table 1). Only 11 patients (7%) in the simvastatin group and 15 patients (11%) in the placebo group had received statins in the past month; statins were stopped at ICU admission (P = .33). VAP risk factors and preventive measures are listed in eTable 1 in the Supplement. In all patients, simvastatin or placebo was started within 24 hours after the first dose of antibiotics prescribed for VAP.

No patients had definite bacterial VAP. Probable VAP was diagnosed in 106 patients (73%) in the simvastatin group and 105 (76%) in the placebo group (P = .50) (eTable 2 in the Supplement). The diagnosis was based mainly on cultures of BAL fluid and PTCs, which recovered the organisms listed in eTable 3 in the Supplement. There were no between-group differences in the rates of multidrug-resistant or high-risk organisms. Adequacy of empirical treatment did not differ significantly between the 2 groups (86% for the simvastatin group and 77% for the placebo group).

Primary End Point

Day-28 mortality was not significantly decreased by simvastatin therapy (21.2% [95% CI, 15.4% to 28.6%] vs 15.2% [95% CI, 10.2% to 22.1%]; P = .10; hazard ratio, 1.45 [95% CI, 0.83-2.51]) (Figure 2). The between-group difference in day-28 mortality was 6.0% (95% CI, −3.0% to 14.9%). Restricting the analysis to patients with probable VAP did not change the results: day-28 mortality was 22.6% (95% CI, 15.7% to 31.5%) with simvastatin vs 14.3% (95% CI, 8.9% to 22.2%) with placebo (P = .06; between-group difference, 8.3% [95% CI, −2.2% to 18.7%]). In the subgroup naive to statins at admission, day-28 mortality was 21.5% (95% CI, 15.4% to 29.1%) with simvastatin and 13.8% (95% CI, 8.8% to 21.0%) with placebo (P = .054; between-group difference, 7.7% [95% CI, −1.8% to 16.8%]). After adjustment, simvastatin was not significantly associated with day-28 mortality. Age, fatal underlying disease, and SOFA score were associated with day-28 mortality, but sex and baseline antibiotic therapy were not.

Secondary Outcomes

There were no significant between-group differences for day-14, ICU, or hospital mortality rates; mechanical ventilation duration; number of ventilator-free days by day 28; coronary events; or ARDS within 28 days after enrollment (Table 2). Neither did the groups differ regarding the course of organ dysfunctions (total SOFA score, SOFA subscores, and CPIS) or the development of kidney dysfunction (eTable 4 in the Supplement). At least 1 new nosocomial infection occurred after enrollment in 46 patients (31% [95% CI, 25% to 39%]) in the simvastatin group and 52 (38% [95% CI, 30% to 46%]) in the placebo group (between-group difference, 7% [95% CI, 5% to 17%]; P = .27) (eTable 5 in the Supplement). The mean number of antibiotic-free days was 12.5 (SD, 8.4) days in the simvastatin group and 12.5 (SD, 8.0) days in the placebo group (P = .99).

Tolerance of the Study Drug

Simvastatin (60 mg/d) was well tolerated, with no increases in rates of elevated creatine kinase, ALT, or AST levels (Table 3). There were no between-group differences in creatinine levels at days 3, 7, 14, or 21 (Table 3). No unexpected serious adverse reactions occurred during the study. The study treatment was interrupted for at least 24 hours because of an adverse event in 55 patients (19%) (31 [21%] in the simvastatin group and 24 [17%] in the placebo group).

Discussion

The use of simvastatin (60 mg) for the adjunctive treatment of VAP was not associated with a reduction in day-28 mortality in this trial. None of the secondary outcomes were significantly improved by simvastatin. Nonetheless, it should be emphasized that, although our study was not designed to test whether a placebo was superior to simvastatin, there was a nearly 6% absolute increase in day-28 mortality in the simvastatin group overall and a nearly 8% absolute increase in the statin-naive subgroup. Because de novo statin therapy does not constitute standard practice in ICU patients with infection, designing a study to test hypothetical superiority of a placebo over a statin would not have been relevant. We therefore tested the hypothesis that simvastatin was superior to a placebo. Our results do not support the use of adjunctive statin therapy in ICU patients with VAP, and this conclusion probably deserves to be extended to ICU patients with any type of nosocomial infection.

A large body of experimental data supports the use of statins in sepsis,4,23-25 and many clinical cohort studies suggest a role for adjunctive statin therapy in severe infections.26-30 Studies conducted among patients with community-acquired pneumonia have produced conflicting results.31-38 All of these studies used an observational design and evaluated the effects of statins prescribed for lowering lipid levels.

Three randomized controlled trials8,10,39 evaluated statins in infections, but only 1 was conducted in ICU patients and its primary outcome was the plasma IL-6 level, which was not significantly affected by statin therapy.39 To our knowledge, ours is the first randomized, placebo-controlled, double-blind trial evaluating adjunctive statin therapy in a specific infection. In a 2-center, randomized, open-label trial, pravastatin (40 mg/d) was compared with a placebo in patients receiving mechanical ventilation and having ICU stays longer than 48 hours.40 Six patients (8.45%) in the pravastatin group and 16 (19.85%) in the control group died during the 30-day treatment period (P = .06).40 The conflicting results reported to date may be related in part to differences in the proportions of patients taking statins at baseline, because statin discontinuation in the placebo group might explain the improved outcomes seen with statin therapy in some studies. Our choice of simvastatin, the statin on the market the longest, as the study drug may explain the results. We chose simvastatin because of its well-established immunomodulatory properties.41 Also, in a mouse model of acute Chlamydia pneumoniae infection, simvastatin decreased viable C pneumoniae counts and increased inflammatory cell infiltrates in lung tissue, suggesting not only immunomodulatory properties but also potential antimicrobial effects.42 The dose used in the present study may have been lower than required. However, in a study of healthy volunteers, plasma levels of inflammatory mediators were not significantly different between 40-mg and 80-mg simvastatin doses; consequently, using a higher simvastatin dose would probably not have changed our results.41

Study Limitations

Strengths of our study include the multicenter design, which supports the external validity of our findings. Furthermore, VAP was diagnosed based on criteria used in many previous studies18 requiring bacteriological confirmation by quantitative cultures.

However, our study has several limitations. Because of the early trial termination recommended by the DSMB based on the interim analysis, we cannot completely rule out marginal benefits from simvastatin therapy in ICU patients with infection, given the CI for the between-group difference. However, it would have been ethically unacceptable to continue the trial after the interim analysis, which showed higher day-28 mortality in the simvastatin group, even though the increase was not statistically significant. The focus on VAP resulted in a uniform patient population, although it also limited the relevance of our findings to other infections. Statins are available only as oral preparations, and the pharmacokinetic profile of statins in ICU patients with sepsis, gastrointestinal intolerance, or both is unclear. However, all statins are absorbed rapidly after administration, with a time to peak plasma concentration of 4 hours.43,44 Very high plasma atorvastatin concentrations were documented in ICU patients with sepsis after a single oral dose of 20 mg.12 A study of the pharmacokinetics of simvastatin (60 mg) in ICU patients is in progress. In addition, our results may have limited relevance to non–ICU-acquired infections. Our patients received simvastatin (or placebo) after several days in the ICU and had at least 1 organ dysfunction. In contrast, many of the earlier studies focused on statin therapy to prevent severe sepsis or to reduce mortality after sepsis related to community-acquired infections.

Tolerance of the Treatment

We assessed levels of creatine kinase, ALT, and AST to evaluate the tolerance of simvastatin (60 mg/d) in ICU patients. No serious adverse events occurred, and the rates of elevated creatine kinase, ALT, and AST levels were comparable in the 2 groups. Similarly, in a randomized placebo-controlled trial of simvastatin (80 mg/d) in patients with acute lung injury, the rates of elevated creatine kinase, ALT, and AST levels were not significantly different between the 2 groups.11 Although simvastatin has been reported to improve sepsis-induced acute kidney injury via direct effects on the renal vasculature, reversal of tubular hypoxia, and a systemic anti-inflammatory effect,45 in our trial renal function was not better in the simvastatin group compared with placebo. The rates of adverse events requiring treatment discontinuation showed no significant differences between the 2 groups, in keeping with earlier data.11 High simvastatin doses did not appear to increase the risk of adverse effects in this population.

Conclusions

In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.

Back to top Article Information

Corresponding Author: Laurent Papazian, MD, PhD, Réanimation des détresses respiratoires et infections sévères, Hôpital Nord, Chemin des Bourrely, 13015 Marseille, France (laurent.papazian@ap-hm.fr).

Published Online: October 9, 2013. doi:10.1001/jama.2013.280031.

Author Contributions: Drs Baumstarck and Jouve had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Papazian, Roch, Baumstarck, Forel.

Acquisition of data: Roch, Charles, Perrin, Roulier, Goutorbe, Lefrant, Wiramus, Jung, Perbet, Hernu, Nau, Baldesi, Allardet-Servent, Moussa, Hraiech, Guervilly, Forel.

Analysis and interpretation of data: Papazian, Penot-Ragon, Baumstarck, Jouve.

Drafting of the manuscript: Papazian, Roulier, Wiramus, Jouve.

Critical revision of the manuscript for important intellectual content: Roch, Charles, Penot-Ragon, Perrin, Goutorbe, Lefrant, Jung, Perbet, Hernu, Nau, Baldesi, Allardet-Servent, Baumstarck, Moussa, Hraiech, Guervilly, Forel.

Statistical analysis: Baumstarck, Jouve.

Obtained funding: Papazian.

Administrative, technical, or material support: Papazian, Roch, Penot-Ragon, Roulier, Moussa, Forel.

Study supervision: Papazian, Roch, Penot-Ragon, Moussa, Forel.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Wiramus reported receiving travel expenses from Fresenius Kabi and MSD. Dr Jung reported receiving payment for lectures from Merck France and Pfizer. Dr Guervilly reported receiving travel expenses from Gilead and MSD. Dr Papazian reported receiving payment for providing expert testimony from Faron and receiving travel expenses from Air Liquide Santé. No other authors reported disclosures.

Funding/Support: This study was supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2007).

Role of the Sponsor: The study sponsor (Assistance Publique–Hôpitaux de Marseille) took full administrative responsibility but had no role in the recruitment of patients; the management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript. The French Ministry of Health had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Data and Safety Monitoring Board: J. Chastre (Service de Réanimation Médicale, Institut de Cardiologie, Hôpital Pitié-Salpêtrière, Paris, France); J. Pugin (Service de Réanimation, Hôpitaux Universitaires de Genève, Genève, Suisse) ; P. Auquier (Laboratoire de Santé Publique, Faculté de Médecine, Aix-Marseille Université, Marseille, France).

Group Information: Members of the STATIN-VAP Study Group: Corsica: Réanimation CH Ajaccio, Ajaccio (B. Lecomte, M. Mattys); Réanimation CH Bastia, Bastia (P. Mercury). France: Réanimation médicale, CHU Hôpital Edouard Herriot (Lyon L. Argaud; S. Conrozier); Réanimation Centre Ambroise Paré, Marseille (J.-M. Seghboyan); Réanimation médicale, CHU Hôpital Bocage, Dijon (P.-E. Charles); J.-P. Quenot; T. Devaux Réanimation Centre Clairval, Marseille (M. Codde); Réanimation chirurgicale, CHU Hôtel Dieu, Clermont-Ferrand (J.-M. Constantin); Réanimation polyvalente, CH Aix En Provence (O. Baldesi); Réanimation HIA, Toulon (P. Goutorbet, H. Boret); Réanimation CH Aubagne, Aubagne (C. Agostini, D. Almosnino, O. Darchen, G. Grossmith); Réanimation chirurgicale Hôpital Saint-Roch, Nice (C. Ichai); Réanimation CH Cannes, Cannes (A. Freche); Réanimation chirurgicale, CHU Hôpital Caremeau, Nïmes (J.-Y. Lefrant, G. Louart, L. Muller, S. Lloret); Réanimation polyvalente CHU Conception, Marseille (F. Heraud); Réanimation CHU Nord, Marseille (M. Leone, C. Martin, J. Textoris); Réanimation des Urgences et Médicale, CHU Timone, Marseille (G. Perrin); Réanimation CH Salon de Provence, Salon de Provence (A. Mofredj); Réanimation Institut Paoli-Calmettes, Marseille (D. Mokart); Réanimation HIA Laveran, Marseille (A. Nau); Réanimation chirurgicale, CHU Saint-Eloi, Montpellier (F. Belafia, S. Jaber, A. Prades); Réanimation CH Perpignan, Perpignan (P. Roulier); Réanimation CHU Hôpital Roger Salengro, Lille (L. Robriquet); Réanimation Hôpital Desbief, Marseille (J.-M. Seghboyan); Réanimation chirurgicale CHU Pontchaillou, Rennes (P. Seguin, D. Deborah); Réanimation Médicale, Hôpital Nord, CHU Saint Etienne (P. Dominique); Réanimation des Détresses Respiratoires et Infections Sévères, Hôpital Nord, Marseille (F. Xeridat, M. Castanier, M. Adda, S. Dizier); CPCET, Marseille (E. Charles, J. Micaleff); Laboratoire de Santé Publique, Faculté de Médecine de Marseille (A. Loundou); Direction de la Recherche et de l’Innovation APHM, Marseille (J.C. Reynier, A. Giuliani, M. Seux, P. Sudour).

Additional Contributions: We are indebted to Antoinette Wolfe, MD, for assistance in preparing and reviewing the manuscript. Dr Wolfe is a self-employed independent medical writer with no affiliations to any public or private institutions or corporations. She was paid for her work on our manuscript by the ADEREM, a French nonprofit donation-funded organization that supports medical research. We are also indebted to Didier Raoult, MD, PhD (Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, Faculté de Médecine, Aix-Marseille Université), for his helpful comments during the preparation of the study. Dr Raoult received no compensation for his contributions. We are grateful to all medical staff, staff nurses, and research nurses at the 26 sites, who contributed greatly to the successful conduct of the study.