Kacmarek 2016.

Study characteristics
Methods	Multi‐centre pilot randomised controlled trial conducted in 20 ICUs from 6 countries (Chile, Brazil, Korea, Peru, Spain, United States) Time period of study: September 2007 through August 2013
Participants	Included: ARDS (AECC). During subsequent 12 to 36 hours after enrolment, patients were ventilated according to the ARDSnet protocol and then were reassessed (after blood gases were quantified) on specific ventilator settings for established moderate and/or severe ARDS (established ARDS): 18 patients were subsequently excluded because of PaO₂/FIO₂ ≥ 200 Excluded: patients with < 35 kg PBW, body mass index (BMI) > 50; intubation as a result of an acute exacerbation of chronic pulmonary disease such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, etc.; acute brain injury or elevated intracranial pressure (> 18 mmHg); immunosuppression from chemotherapy or radiation therapy; severe cardiac disease at class III or IV of the New York Heart Association; acute coronary syndrome; persistent ventricular tachyarrhythmias Sample size was estimated considering that approximately 600 patients would need to be randomised into the 2 groups ‐ ARDSnet protocol and OLA ‐ with α < 0.05 and β > 80%. Power analysis was based on expected 45% mortality (determined from a previous study: Villar 2006). Interim analyses were designed to allow early termination of the trial
Interventions	Control (101) and intervention (99): MV ventilator mode: volume control (control), pressure control (intervention). TV range 4 to 8 mL/kg PBW, plateau pressure ≤ 30 cmH₂O, respiratory rate (breaths/min) ≤ 35, pH ≥ 7.30 and ≤ 7.45. Target ranges for oxygenation: PaO₂ between 55 and 80 mmHg; SpO₂ between 88% and 95% PEEP Control: PEEP/FIO₂ combination: mean PEEP 11.1 cmH₂O during first 72 hours Intervention: recruiting manoeuvres followed by decremental PEEP titration according to best dynamic lung compliance. Mean PEEP 15 cmH₂O during first 72 hours
Outcomes	Primary: mortality at Day 60 Secondary: VFD, barotrauma, development of extrapulmonary organ failure, LOS in ICU, LOS in hospital, mortality in ICU and before hospital discharge
Notes	Discontinued during first interim analysis because of low rate of enrolment, precluding timely completion of original study size (600 patients who would be randomised into 2 groups) Dr Kacmarek received funding from Covidien, Venner Medical, and the Research Unit Hospital Dr Negrin Las Palmas from Gran Canaria (Spain). Dr Villar received funding from Maquet, Instituto de Salud Carlos III (Spain), and Asociación Científica Pulmón y Ventilación Mecánica (Spain). Dr Amato received funding from State Research Foundation and Brazilian Council for Scientific and Technological Development (Brazil), Maquet, Covidien, and Digital LTDA. Dr Suarez‐Sipmann received funding from Maquet. Remaining study authors have disclosed that they do not have any potential conflicts of interest
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about the sequence generation process
Allocation concealment (selection bias)	Low risk	Assignment performed by a Web‐based system
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Incomplete blinding (blinding of participants but not of personnel) but outcomes 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	Analysis on the basis of the intention‐to‐treat principle. Minor protocol violations in both groups: 13 out of 99 participants from intervention group and 12 out of 101 participants from control group. Study authors believe that these violations do not alter outcomes
Selective reporting (reporting bias)	Unclear risk	Certain secondary outcomes in the protocol not assessed in the study
Other bias	Low risk	During development of the study, changes were made to inclusion and exclusion criteria. Study authors believe that these changes did not alter outcomes