ENIGMA II trial 2014.

Methods	Multicentre RCT
Participants	Setting: 45 participating centres from 10 countries Inclusion criteria: Adult males and females age ≥ 45 years, undergoing noncardiac surgery and general anaesthesia expected to exceed two hours. At increased risk of cardiac events, defined as any of History of coronary artery disease as defined by a history of any one of the following: i. angina ii. MI iii. segmental wall motion abnormality on echocardiography or a fixed defect on radionuclide imaging iv. a positive exercise stress test for cardiac ischaemia v. a positive radionuclide exercise, echocardiographic exercise, or pharmacological cardiovascular stress test for cardiac ischaemia vi. coronary revascularization (CABG or PTCA) vii. angiographic evidence of atherosclerotic stenosis > 50% of the diameter of any coronary artery viii. ECG with pathological Q waves in two contiguous leads; Heart failure; Cerebrovascular disease thought due to atherothrombotic disease; Aortic or peripheral vascular disease; Or three or more of the following risk factors: Age ≥ 70 years; Any history of congestive heart failure; Diabetes and currently on an oral hypoglycaemic agent or insulin therapy; Current treatment for hypertension; Preoperative serum creatinine > 175 µmol/L (> 2.0 mg/dL); Current or previous high cholesterol ≥ 6.2 mmol/L (> 240 mg/dL); History of a TIA (i.e. a transient focal neurological deficit that lasted less than 24 hours and thought to be vascular in origin); Emergency/urgent surgery (i.e. surgery which must be undertaken within 24 hours of acute presentation to hospital); High‐risk type of surgery (i.e. intrathoracic or intraperitoneal). Exclusion criteria: Having cardiac surgery. Marked impairment of gas‐exchange expected to require FiO2> 0.5 intraoperatively. Specific circumstances where nitrous oxide is contraindicated (e.g. volvulus, pulmonary hypertension, raised intracranial pressure) or the anaesthetist plans to use supplemental oxygen (e.g. colorectal surgery). Nitrous oxide unavailable for use. Participant numbers: 7112 randomly assigned; 6992 analysed
Interventions	Intervention: 70% nitrous oxide Control: no nitrous oxide
Outcomes	Primary outcomes: The primary endpoint is a composite of death and cardiovascular events (clinical and silent MI, cardiac failure, cardiac arrest, pulmonary embolism, and stroke) measured at 30 days after surgery. Secondary outcomes: Myocardial infarction: A typical rise of troponin or a typical fall of an elevated troponin with at least one value above the 99th percentile of the upper reference limit, detected at its peak‐post surgery in a patient without a documented alternative explanation for an elevated troponin (e.g. pulmonary embolism). This criterion also requires that 1 of the following must also exist: a) ischaemic signs or symptoms (i.e., chest, arm, neck, or jaw discomfort; shortness of breath, pulmonary edema); b) development of pathologic Q waves present in any two contiguous leads that are > 30 milliseconds; c) ECG changes indicative of ischaemia (i.e. ST segment elevation [> 2 mm in leads V1, V2, or V3; or > 1 mm in the other leads], ST segment depression [> 1 mm], or symmetric inversion of T waves > 1 mm) in at least two contiguous leads; d) coronary artery intervention (i.e. PCI or CABG surgery); e) new or presumed new cardiac wall motion abnormality on echocardiography or new or presumed new fixed defect on radionuclide imaging. Pathologic findings of an acute or healing myocardial infarction. Development of new pathological Q waves on an ECG if troponin levels were not obtained or were obtained at times that could have missed the clinical event. Wound infection At least one of the following: Purulent drainage from the incision. Positive microbial culture from the incision. Documentation of a wound infection in the medical record. Stroke New cerebral infarction or haemorrhage on CT scan, MRI or documented new neurological signs (paralysis, weakness or speech difficulties) lasting more than 24 hours or leading to earlier death (confirmed by a copy of the autopsy report or in the medical record). Severe nausea and vomiting At least two separate episodes of nausea or vomiting greater than six hours apart, or if requiring three or more doses of antiemetic medication, within three days after surgery. Pulmonary embolism A high probability VQ scan, spiral CT or documented on pulmonary angiogram; or pathological findings (with autopsy). Hospital stay
Notes	ClinicalTrials.gov identifier: NCT00430989
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was done with a computer‐generated code."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization sequence was accessed via an automated telephone voice‐recognition service."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The attending anaesthetists were aware of the patients' group assignments, but the patients, their surgical team were not."
Blinding of outcome assessment (detection bias) Inhospital case fatality rate/length of stay	Low risk	Quote: "The postoperative interviewers, and endpoint adjudicators were unaware of the patients' group assignments."
Blinding of outcome assessment (detection bias) Complications	Low risk	Quote: "The postoperative interviewers, and endpoint adjudicators were unaware of the patients' group assignments."
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 NCT00430989 and outcomes were reported.
Other bias	Low risk	No other potential sources of bias were detected.