Ferguson 2013.

Methods	Multi‐centre international RCT (39 centres in 5 countries) from July 2007 to August 2012
Participants	548 adults with ARDS; 16 ‐ 85 years of age; acute onset of respiratory failure, with fewer than 2 weeks of new pulmonary symptoms; tracheal intubation; hypoxaemia ‐ defined as PaO₂/FiO₂ ≤ 200 mmHg on FiO₂ ≥ 0.5, regardless of PEEP; bilateral alveolar consolidation (airspace disease) seen on frontal chest radiograph
Interventions	Intervention group: 3100B high‐frequency oscillatory ventilator using a lung‐open approach and an explicit protocol Control group: conventional ventilation using low tidal volumes (target tidal volume of 6 ml/kg, plateau pressure ≤ 35 cm H₂0) and a lung‐open approach according to an explicit protocol, with HFO only as rescue therapy
Outcomes	Hospital mortality; also ICU and 28‐day mortality, quality of life at 6 months. Other clinical and adverse outcomes including barotrauma, and treatment failure were also available.
Notes	After enrolment standardized ventilator settings were used for all participants: Tidal volume 6 ml/kg, FiO₂ of 0.60, PEEP of 10 cm H₂O or higher if needed for oxygenation. If PaO₂/FiO₂ remained ≤ 200 mmHg after 30 minutes, participants were randomized. Otherwise patients were reassessed daily for up to 72 hours Protocols for lung volume recruitment manoeuvres were used for both the HFO and CV group Steroids for ARDS were used in 93/275 and 96/273 of the HFO and CV groups respectively Paralysis was administered to 84/275 and 94/273 of the HFO and CV groups respectively 34 of 273 patients randomized to CV received "rescue" HFO for rescue hypoxaemia Partial industry support (CareFusion loaned 9 oscillators and provided technical support)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Computer generated randomisation schedule" (Study protocol, January 13 2010)
Allocation concealment (selection bias)	Low risk	"Randomization was performed in undisclosed block sizes of 2 and 4 with the use of a central Web‐based randomisation system, stratified according to centre"
Blinding (performance bias and detection bias) All outcomes	Low risk	Study investigators were blinded to overall results for the duration of the study Although blinding of caregivers, family members, and research co‐ordinators was not possible due to the nature of the intervention, the use of protocols for HFO and mechanical ventilation reduces the risk of performance bias due to lack of blinding Because the primary outcome was death, detection bias was unlikely
Incomplete outcome data (attrition bias) All outcomes	Low risk	No incomplete outcome data
Selective reporting (reporting bias)	Low risk	All primary and secondary outcomes were reported with the exception of quality of life at 6 months
Other bias	Unclear risk	The trial was terminated early because increased mortality was observed in the HFO group after an interim analysis of 500 participants (planned enrolment was 1200)