Leung 2006.

Methods	Single‐centre RCT
Participants	Setting: University of California, San Francisco Medical Centre, USA Inclusion criteria: consecutive men or women who were > 65 years of age, undergoing non‐cardiac surgery, requiring general anaesthesia, who were expected to remain in the hospital after operation for > 48 h Exclusion criteria: patients who could not complete the neuropsychological testing such as those who were expected to remain intubated after operation; patients who not able to provide informed consent; surgical cases in which the use of nitrous oxide was contraindicated Participant numbers: 228 randomly assigned; 228 analysed
Interventions	Intervention: pre‐medication was limited to fentanyl up to 2 μg/kg intravenous. During operation, mechanical ventilation was initiated to maintain normocarbia and oxygen saturation > 95%. Anaesthetists were requested to control intraoperative heart rate and blood pressure to within ± 30% of preoperative baseline measurements. Intraoperative monitoring was not controlled by the study but was measured. Additional intravenous morphine sulfate or fentanyl was allowed to be titrated to maintain spontaneous ventilatory frequencies of 10 to 20 bpm and end‐tidal CO2 between 45 and 55 mm Hg while the inhalational agents were discontinued at the conclusion of surgery. The intraoperative anaesthetic management was consisted of nitrous oxide with oxygen plus a potent inhalational agent. In order to make the study clinically feasible, the study allowed the anaesthetists to adjust the percentages of inspired concentrations of oxygen during surgery as clinically indicated. Control: pre‐medication was limited to fentanyl up to 2 μg/kg intravenous. During operation, mechanical ventilation was initiated to maintain normocarbia and oxygen saturation > 95%. Anaesthetists were requested to control intraoperative heart rate and blood pressure to within ± 30% of preoperative baseline measurements. Intraoperative monitoring was not controlled by the study but was measured. Additional intravenous morphine sulfate or fentanyl was allowed to be titrated to maintain spontaneous ventilatory frequencies of 10 to 20 bpm and end‐tidal CO2 between 45 and 55 mm Hg while the inhalational agents were discontinued at the conclusion of surgery. The intraoperative anaesthetic management was consisted of oxygen plus a potent inhalational agent. In order to make the study clinically feasible, the study allowed the anaesthetists to adjust the percentages of inspired concentrations of oxygen during surgery as clinically indicated.
Outcomes	Primary outcomes: Inhospital case fatality rate Secondary outcomes: Length of hospital stay
Notes	—
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A computerized random number list was created to designate the two anaesthetic group assignments."
Allocation concealment (selection bias)	Low risk	Quote: "The assignment of the anaesthetic group for each study patient was contained in a sealed envelope."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	This was not reported.
Blinding of outcome assessment (detection bias) Inhospital case fatality rate/length of stay	Low risk	The outcome measurement is not likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias) Complications	Unclear risk	—
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing data.
Selective reporting (reporting bias)	Low risk	All outcomes described in methods section reported.
Other bias	Low risk	No other potential sources of bias were detected.