Dellinger 1998.

Methods	Prospective, phase 2, multi‐centre, placebo‐controlled RCT ITT: yes Overall study quality: low risk of bias despite funding bias Sample size calculation reported. Not powered to show statistically significant benefit for any outcome
Participants	Included: 177 adults from 30 centres with ARDS < 72 hours before randomization. ARDS defined by American‐European Consensus Conference and minimal FiO2 of 0.5 and minimal PEEP of 8 cm H2O Exclusion criteria: pregnancy, < 18 years old, immunocompromised, sepsis‐induced ARDS, > 20% body surface burns, persistent hypotension (inotropic support) and multi‐system organ failure
Interventions	NO group: 120 participants at doses of 1.25, 5, 20, 40 or 80 ppm, for 28 days or until extubation Control group: 57 participants, placebo gas (nitrogen) Ventilation strategy and weaning of INO standardized (plateau airway pressure < 35 cm H2O; PEEP to optimize compliance; FiO2 minimized). No cross‐over of treatment failures
Outcomes	Primary outcomes: duration of mechanical ventilation Secondary outcomes: changes in oxygenation (PaO2, PaO2/FiO2, OI), percent responders, mortality, number of participants alive and off ventilator at 28 days, decrease in mean PA pressure, adverse events, methaemoglobin, hypotension, renal failure, pneumothorax
Notes	Country: USA Letter sent to study authors in June 2009. No reply received Follow‐up: 28 days. Treatment stopped before oxygenation threshold criteria were reached in 56 participants. 20 participants in INO group received steroids after day 6, and only 6 in the control group received steroids. Only 8 participants received 80 ppm INO; 80 ppm INO dose was eliminated mid‐study because international consensus suggests an unlikely advantage over lower concentrations. Data accounted for in analysis. Post hoc assessment for ventilator‐free days. Not stratified for origin Data on ventilator‐free days for the INO group provided by Dr. Neill Adhikari on the basis of his work on his recent systematic review in BMJ (Adhikari 2007) Study authors' conclusions: "Inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Blocked for each site, unclear method. Considered adequate
Allocation concealment (selection bias)	Low risk	Sealed, opaque envelopes
Blinding (performance bias and detection bias) All outcomes	Low risk	Clinicians and outcome assessors blinded during entire course of the trial. One unblinded investigator at each site, responsible for determining treatment allocation for each participant by using a supplied masked randomization code and daily recording of NO, NO2 and methaemoglobin concentrations. These values were kept strictly confidential
Incomplete outcome data (attrition bias) All outcomes	Low risk	Follow‐up: adequate, no post‐trial follow‐up
Selective reporting (reporting bias)	Low risk	Yes. Unable to compare with protocol but appears to be free of selective reporting
Other bias	Low risk	No apparent bias except funding bias (industry)