Patients

We included in the study adults who met the following criteria: ARDS, as defined according to the American–European Consensus Conference criteria12; endotracheal intubation and mechanical ventilation for ARDS for less than 36 hours; and severe ARDS (defined as a PaO 2 :FiO 2 ratio of <150 mm Hg, with an FiO 2 of ≥0.6, a PEEP of ≥5 cm of water, and a tidal volume of about 6 ml per kilogram of predicted body weight; the criteria were confirmed after 12 to 24 hours of mechanical ventilation in the participating intensive care unit [ICU]). Exclusion criteria are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org.

Trial Design

Patients were recruited from 26 ICUs in France and 1 in Spain, all of which have used prone positioning in daily practice for more than 5 years. Randomization was computer-generated and stratified according to ICU. Patients were randomly assigned to the prone group or supine group with the use of a centralized Web-based management system (Clininfo). The protocol, available at NEJM.org, was approved by the ethics committee Comité Consultatif de Protection des Personnes dans la Recherche Biomedicale Sud-Est IV in Lyon, France, and by the Clinical Investigation Ethics Committee at Hospital de Sant Pau in Barcelona. Written informed consent was obtained after the patients' next of kin read the informational leaflet. If patients were able to read the leaflet at some point after inclusion in the study, they were approached to confirm participation in the trial. An investigator at each center was responsible for enrolling patients in the study, following the protocol, and completing the case-report form. Centers were regularly monitored by research fellows. Data collectors were aware of the study-group assignments, but outcomes assessors were not.

The trial was overseen by a steering committee that met monthly. An independent data and safety monitoring board, comprising three experts in the field, was also set up (a list of board members is provided in the Supplementary Appendix). There was no commercial support. No one who is not listed as an author contributed to the writing of this manuscript. All authors vouch for the accuracy of the data and analysis and the fidelity of the study to the protocol.

Protocol

After a patient was determined to be eligible, a stabilization period of 12 to 24 hours was mandated. Inclusion in the study was confirmed only at the end of this period (Fig. S1 in the Supplementary Appendix).

Patients assigned to the prone group had to be turned to the prone position within the first hour after randomization. They were placed in a completely prone position for at least 16 consecutive hours. Participating centers were given guidelines (see the Supplementary Appendix) to ensure standardization of prone placement. Standard ICU beds were used for all patients. Patients assigned to the supine group remained in a semirecumbent position.

Mechanical ventilation13 was delivered in a volume-controlled mode with constant inspiratory flow, with tidal volume targeted at 6 ml per kilogram of predicted body weight13 and the PEEP level selected from a PEEP–FiO 2 table14 (Table S1 in the Supplementary Appendix). The goal was to maintain an end-inspiratory plateau pressure of the respiratory system (Pplat RS ), measured after a 1-second period of no air flow, of no more than 30 cm of water and an arterial plasma pH of 7.20 to 7.45. Physiological variables were measured at predetermined times in both groups. In the supine group, measurements were performed every 6 hours; in the prone group, measurements were performed just before the patient was turned to the prone position, after 1 hour of prone positioning, just before the patient was turned back to the supine position, and 4 hours after the patient was returned to the supine position. Adjustments of ventilator settings in specific situations are detailed in the Supplementary Appendix.

The criteria for stopping prone treatment were any of the following: improvement in oxygenation (defined as a PaO 2 :FiO 2 ratio of ≥150 mm Hg, with a PEEP of ≤10 cm of water and an FiO 2 of ≤0.6; in the prone group, these criteria had to be met in the supine position at least 4 hours after the end of the last prone session); a decrease in the PaO 2 :FiO 2 ratio of more than 20%, relative to the ratio in the supine position, before two consecutive prone sessions; or complications occurring during a prone session and leading to its immediate interruption. Complications leading to the immediate interruption of prone treatment included nonscheduled extubation, main-stem bronchus intubation, endotracheal-tube obstruction, hemoptysis, oxygen saturation of less than 85% on pulse oximetry or a PaO 2 of less than 55 mm Hg for more than 5 minutes when the FiO 2 was 1.0, cardiac arrest, a heart rate of less than 30 beats per minute for more than 1 minute, a systolic blood pressure of less than 60 mm Hg for more than 5 minutes, and any other life-threatening reason for which the clinician decided to stop the treatment.

After patients in the prone group were turned to the supine position, the prone session could be resumed at any time before the planned assessment at 4 hours in the supine position if the criteria for oxygen saturation level, PaO 2 , or both were met. The prone-positioning strategy was applied every day up to day 28, after which it was used at the clinician's discretion. Patients in the supine group could not be crossed over to the prone group except as a rescue measure in case of life-threatening hypoxemia when all the following criteria were met simultaneously: a PaO 2 :FiO 2 ratio of less than 55 mm Hg, with an FiO 2 of 1.0; maximal PEEP according to the PEEP–FiO 2 table; administration of inhaled nitric oxide at a concentration of 10 ppm; infusion of intravenous almitrine bismesylate at a dose of 4 μg per kilogram per minute; and performance of respiratory recruitment maneuvers to increase the amount of aerated lung.

Weaning from mechanical ventilation was conducted in the same way for both groups (see the Supplementary Appendix). Details regarding the management of sedation and the use of neuromuscular blocking agents are also provided in the Supplementary Appendix. The investigators assessed patients at least every morning until day 28 or discharge from the ICU.

Data Collection

At the time of admission, we recorded data on age, sex, the setting from which the patient was admitted to the ICU, the context for admission to the ICU, McCabe score14 (which ranges from A to C, with A indicating no underlying disease that compromises life expectancy, B an estimated life expectancy with the chronic disease of <5 years, and C an estimated life expectancy with the chronic disease of <1 year), ventilator settings, time from intubation to randomization, height, predicted body weight, and the Simplified Acute Physiology Score (SAPS) II15 (which ranges from 0 to 164, with higher scores indicating greater severity of symptoms). We also recorded the number of lung quadrants involved on chest radiography, results of measurements of arterial blood gases, Pplat RS , arterial blood lactate levels, the cause of ARDS, the Sepsis-related Organ Failure Assessment (SOFA) score16 (which ranges from 0 to 24, with higher scores indicating more severe organ failure), the lung injury score (which ranges from 0 to 4, with higher scores indicating more severe lung injury),17 and the time at which the first prone session was started.

The following events were recorded daily until day 28: attempts at extubation, administration of inhaled nitric oxide, infusion of almitrine bismesylate, use of extracorporeal membrane oxygenation (ECMO), infusion of sedatives and neuromuscular blockers, complications, and the SOFA score. Ventilator settings, Pplat RS , static compliance of the respiratory system, and the results of measurements of arterial blood gases were recorded daily during the first week as indicated above. Data quality was verified by the research fellows, and data were stored in a database (Clininfo) that was specifically developed for the study with the use of Epi Info software, version 3.4.3.

Outcome Measures

The primary end point was mortality at day 28. Secondary end points were mortality at day 90, the rate of successful extubation, the time to successful extubation, the length of stay in the ICU, complications, the use of noninvasive ventilation, the tracheotomy rate, the number of days free from organ dysfunction, and ventilator settings, measurements of arterial blood gases, and respiratory-system mechanics during the first week after randomization.

Successful extubation was defined as no reintubation or use of noninvasive ventilation in the 48 hours after extubation. In patients who had undergone a tracheotomy, successful weaning from the ventilator was defined as the ability to breathe unassisted through the tracheostomy cannula for at least 24 hours.

Statistical Analysis

The expected 28-day mortality in the supine group was 60%. We estimated that with a sample of 456 patients, the study would have 90% power to detect an absolute reduction of 15 percentage points (to 45%) with prone positioning, at a one-sided type I error rate of 5%.

An interim analysis was planned 28 days after half the patients had been enrolled, and two analyses were scheduled, each with a type I error rate set to 2.5% to maintain an overall type I error rate of 5%. The statistician sent the data from the interim analysis to the data and safety monitoring board, which had to decide whether to continue or discontinue the trial. An absolute difference in mortality of 25 percentage points or more between groups at the time of the interim analysis was the only criterion for early trial termination. There was no stopping rule for futility.

The analysis was performed on an intention-to-treat basis. Continuous variables were expressed as means with standard deviations. Data were compared between groups with the use of the chi-square test or Fisher's exact test and analysis of variance as indicated. Patient survival was analyzed with the use of the Kaplan–Meier method and compared between groups with the use of the log-rank test. Cox proportional-hazards regression, with stratification according to center, was planned to adjust the between-group differences in mortality at day 28 and day 90 for significant baseline covariates. The statistical analysis was performed with the use of SPSS software (SPSS for Windows, version 17.0). The investigators had no access to the database until the study was completed. All reported P values are two-sided, and have not been adjusted for multiple comparisons. A P value of less than 0.05 was considered to indicate statistical significance.