title: The safety of addition of nitrous oxide to general    anaesthesia in at-risk patients having major non-cardiac   surgery (ENIGMA-II): a randomised, single-blind trial.
abstract: BACKGROUND
  Nitrous oxide is commonly used in general anaesthesia but concerns exist that it might increase perioperative cardiovascular risk. We aimed to gather evidence to establish whether nitrous oxide affects perioperative cardiovascular risk.
  
  
  METHODS
  We did an international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery. Patients were randomly assigned via automated telephone service, stratified by site, to receive a general anaesthetic with or without nitrous oxide. Attending anaesthetists were aware of patients' group assignments, but patients and assessors were not. The primary outcome measure was a composite of death and cardiovascular complications (non-fatal myocardial infarction, stroke, pulmonary embolism, or cardiac arrest) within 30 days of surgery. Our modified intention-to-treat population included all patients randomly assigned to groups and undergoing induction of general anaesthesia for surgery. This trial is registered at ClinicalTrials.gov, number NCT00430989.
  
  
  RESULTS
  Of 10,102 eligible patients, we enrolled 7112 patients between May 30, 2008, and Sept 28, 2013. 3543 were assigned to receive nitrous oxide and 3569 were assigned not to receive nitrous oxide. 3483 patients receiving nitrous oxide and 3509 not receiving nitrous oxide were assessed for the primary outcome. The primary outcome occurred in 283 (8%) patients receiving nitrous oxide and in 296 (8%) patients not receiving nitrous oxide (relative risk 0·96, 95% CI 0·83–1·12; p=0·64). Surgical site infection occurred in 321 (9%) patients assigned to nitrous oxide, and in 311 (9%) patients in the no-nitrous oxide group (p=0·61), and severe nausea and vomiting occurred in 506 patients (15%) assigned to nitrous oxide and 378 patients (11%) not assigned to nitrous oxide (p<0·0001).
  
  
  CONCLUSIONS
  Our findings support the safety profile of nitrous oxide use in major non-cardiac surgery. Nitrous oxide did not increase the risk of death and cardiovascular complications or surgical-site infection, the emetogenic effect of nitrous oxide can be controlled with antiemetic prophylaxis, and a desired effect of reduced volatile agent use was shown.
  
  
  BACKGROUND
  Australian National Health and Medical Research Council; Australian and New Zealand College of Anaesthetists; Heart and Stroke Foundation of Quebec, Heart and Stroke Foundation of Ontario, Canada; General Research Fund of the Research Grant Council, Hong Kong Special Administrative Region, China.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Myles
authors.forename: Kate
authors.initials: K
authors.lastname: Leslie
authors.forename: Matthew T V
authors.initials: MT
authors.lastname: Chan
authors.forename: Andrew
authors.initials: A
authors.lastname: Forbes
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Peyton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Paech
authors.forename: W Scott
authors.initials: WS
authors.lastname: Beattie
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Sessler
authors.forename: P J
authors.initials: PJ
authors.lastname: Devereaux
authors.forename: Brendan
authors.initials: B
authors.lastname: Silbert
authors.forename: Thomas
authors.initials: T
authors.lastname: Schricker
authors.forename: Sophie
authors.initials: S
authors.lastname: Wallace
mesh_terms: D000368:Aged; D000768:Anesthesia, General / Q000009:adverse effects* / Q000379:methods; D019162:Anesthetics, Combined / Q000009:adverse effects; D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000453:epidemiology; D003324:Coronary Artery Disease / Q000150:complications* / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009609:Nitrous Oxide / Q000009:adverse effects*; D011183:Postoperative Complications / Q000453:epidemiology; D020250:Postoperative Nausea and Vomiting / Q000139:chemically induced / Q000453:epidemiology; D011446:Prospective Studies; D018570:Risk Assessment / Q000379:methods; D016037:Single-Blind Method; D013530:Surgical Wound Infection / Q000453:epidemiology
chemical_list: D019162:Anesthetics, Combined; D018685:Anesthetics, Inhalation; D009609:Nitrous Oxide