• Guillaume Dumas, Sylvie Chevret, Marine Le Corre, Virginie Lemiale, Samir Jaber, and Elie Azoulay.
• Medical Intensive Care Unit, Saint-Louis Teaching Hospital, Paris, France; ECSTRRA team, Epidemiology and Clinical Statistics for Tumor, Respiratory, and Resuscitation Assessments, UMR 1153 (Center of Research in Epidemiology and Biostatistics), INSERM, Paris Diderot University, Paris, France.
• Chest. 2020 Sep 1; 158 (3): 986-998.

BackgroundRandomized controlled trials (RCTs) in patients with hypoxemic acute respiratory failure (ARF) often failed to show survival benefits and resulted in varying clinical end points.Research QuestionThis methodologic review was conducted of published RCTs on ARF, with a careful attention to whether the study results were positive or negative.Study Design And MethodsMEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science were searched for published RCTs in adult patients with ARF between January 1995 and December 2019. The objective was to investigate sources of heterogeneity and factors associated with a positive RCT (ie, with a significant difference on the primary end point). To determine the importance of the primary end point choice, end points were classified as follows: (1) respiratory event end points (corresponding to modification of the ventilation support); (2) physiologic/clinical end points (corresponding to oxygenation or clinical parameters); and (3) mortality. The Cochrane risk-of-bias tool was used to assess study quality.ResultsSeventy-four RCTs were included (57% were single-center RCTs) comparing mainly oxygenation/ventilation strategies (95%) in patients with various ARF causes (62%); studies were stopped prematurely in 20% of the trials. A standardized management of ARF was observed in 24 (32%) trials. Twenty-two distinct primary end points have been used, the first of which were those based on respiratory events (44 RCTs [49%]), namely intubation in 76% of the cases. Physiologic/clinical end points have been used in 21 trials (29%) and mortality in nine (12%). Overall, 42 (57%) RCTs were positive, 52% in studies with respiratory event end points, 76% in studies with physiologic/clinical end points, and 33% in studies with mortality end points. Adjusted for study quality (Cochrane risk-of-bias tool), factors associated with a positive RCT included clinically based primary end points (OR, 8.40; 95% CI, 1.35-65.79), the use of standardized ARF management (OR, 4.55; 95% CI, 1.02-22.88), and single-center trials (OR, 3.85; 95% CI, 1.25-13.11).InterpretationThe typology of published RCTs in patients with ARF could be used to frame future trial designs in this field and guide clinicians and researchers toward optimal research transfer to the bedside.Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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