Brower 2004.

Study characteristics
Methods	Multi‐centre randomised study conducted at 23 centres of the National Heart, Lung, and Blood Institute (NHLBI), USA Time period of study: October 1999 through February 2002
Participants	549 participants aged > 13 (23 centres) Included: ALI and ARDS (AECC) Excluded: ≥ 36 hours had elapsed since eligibility criteria were met, participation in other trials involving ALI within preceding 30 days, pregnancy, increased intracranial pressure, severe neuromuscular disease, sickle cell disease, severe chronic respiratory disease, body weight > 1 kg per centimetre of height, burns over 40% of body surface area, severe chronic liver disease, vasculitis with diffuse alveolar haemorrhage, coexisting condition associated with estimated 6‐month mortality rate > 50%, previous bone marrow or lung transplant, refusal to be included by attending physician Study authors estimated that a sample size of 750 patients would yield a statistical power of 89% to detect a reduction in mortality from 28% in the lower PEEP group to 18% in the higher PEEP group Interim analyses were designed to allow early termination of the trial if use of higher PEEP was found to reduce mortality, or if there was a low probability that the trial could demonstrate benefit from the use of high PEEP (futility stopping rule)
Interventions	Control (273) and intervention (276): MV:TV 6 mL/kg PBW, respiratory rate (breaths/min) 6 to 35 to achieve arterial pH ≥ 7.30, plateau pressure ≤ 30 cmH₂O, recruiting manoeuvres in first 80 participants (intervention group). Target ranges for oxygenation with PEEP/FIO₂ combination: PaO₂ between 55 and 80 mmHg or SpO₂ between 88% and 95% PEEP Control: PEEP/FIO₂ combination: mean PEEP values on Days 1 through 4 were 8.3 ± 3.2 cmH₂O Intervention: PEEP/FIO₂ combination (programming with higher levels of PEEP): mean PEEP values on Days 1 through 4 were 13.2 ± 3.5 cmH₂O
Outcomes	Primary: mortality before hospital discharge Secondary: VFD, days not spent in ICU, days free without organ failure Other outcomes: barotrauma, breathing without assistance by Day 28
Notes	In the first 171 participants (85 in control group, 86 in intervention group), the higher PEEP protocol was different from the other 378 participants, but adjusted mortality rates in both phases were small and were not significant Discontinued during the second interim analysis on the basis of specified futility‐stopping rule This study was supported by contract with NIHBS
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants randomly allocated because study authors used random permuted blocks (restricted randomisation)
Allocation concealment (selection bias)	Low risk	Centralised interactive voice system used
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Incomplete blinding (blinding of participants but not personnel) but primary outcome not influenced
Blinding of outcome assessment (detection bias) All outcomes	Low risk	No blinding but outcomes not influenced
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	High risk	Primary outcome (mortality before hospital discharge) was different from that given in the protocol (mortality at 28 days) Certain secondary outcomes in the protocol were not assessed in the study
Other bias	Low risk	Significant differences between the 2 groups in baseline characteristics for mean age and mean PaO₂/FIO₂, but after adjustment for differences in baseline variables, these differences did not change the main results