ENIGMA trial 2007.

Methods	Multi‐centre RCT
Participants	Setting: 19 hospitals from 6 countries Inclusion criteria: patients were aged 18 years or older, were scheduled to undergo general anaesthesia for surgery that included a skin incision and that was anticipated to exceed 2 h, and were expected to be in the hospital for at least 3 days after surgery Exclusion criteria: patients undergoing cardiac surgery, or thoracic surgery requiring one‐lung ventilation; patients that the anaesthesiologist considered that nitrous oxide was contraindicated (e.g. a history of post‐operative emesis or if the anaesthesiologist wanted to use supplemental oxygen for colorectal surgery) Participant numbers: 2050 randomly assigned; 2012 analysed
Interventions	Intervention: patients were administered a gas mixture of 70% nitrous oxide with 30% oxygen after induction of anaesthesia and until completion of surgery. Control: patients were administered a gas mixture of 80% oxygen with 20% nitrogen after induction of anaesthesia and until completion of surgery.
Outcomes	Primary outcomes: Inhospital case fatality rate Secondary outcomes: Pneumonia: radiologic infiltrate confirmed by chest x‐ray or computed tomography, in association with at least one of the following: temperature greater than 38°C, leukocyte count greater than 12,000/mL, or positive sputum culture that was not heavily contaminated with oral flora or that corresponded with positive blood cultures Pulmonary atelectasis: confirmed by chest x‐ray or computed tomography Myocardial infarction: confirmed by ECG and/or troponin or CK‐MB enzyme rise Stroke: a new neurological deficit persisting for 24 hours, confirmed by neurologist assessment and/or computed tomography scan or magnetic resonance imaging Severe nausea and vomiting: at least 2 episodes > 6 hrs apart, or if requiring > 2 doses of antiemetic medication Venous thromboembolism: symptomatic deep venous thrombosis, confirmed by venography, duplex ultrasonography, V‐Q scan or spiral computed tomography, or autopsy Wound infection: if associated with purulent discharge or a positive microbial culture Length of hospital stay Length of ICU stay
Notes	ClinicalTrials.gov identifier: NCT00164047
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly assigned using a computer‐generated code."
Allocation concealment (selection bias)	Low risk	Quote: "The random sequence was accessed via an automated telephone voice recognition service."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "All research staff, including those responsible for postoperative data collection and outcome assessment, were precluded by protocol from accessing the anaesthetic record and so were blinded to group identity."
Blinding of outcome assessment (detection bias) Inhospital case fatality rate/length of stay	Low risk	Quote: "All research staff, including those responsible for postoperative data collection and outcome assessment, were precluded by protocol from accessing the anaesthetic record and so were blinded to group identity."
Blinding of outcome assessment (detection bias) Complications	Low risk	Quote: "All research staff, including those responsible for postoperative data collection and outcome assessment, were precluded by protocol from accessing the anaesthetic record and so were blinded to group identity."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.
Selective reporting (reporting bias)	Low risk	Protocol was registered as NCT00164047 and outcomes were reported.
Other bias	Low risk	No other potential sources of bias were detected.