title: Does anaesthesia with nitrous oxide affect mortality or cardiovascular morbidity? A systematic review with meta-analysis and trial sequential analysis.
abstract: BACKGROUND
  The role of nitrous oxide in modern anaesthetic practice is contentious. One concern is that exposure to nitrous oxide may increase the risk of cardiovascular complications. ENIGMA II is a large randomized clinical trial currently underway which is investigating nitrous oxide and cardiovascular complications. Before the completion of this trial, we performed a systematic review and meta-analysis, using Cochrane methodology, on the outcomes that make up the composite primary outcome.
  
  
  METHODS
  We used conventional meta-analysis and trial sequential analysis (TSA). We reviewed 8282 abstracts and selected 138 that fulfilled our criteria for study type, population, and intervention. We attempted to contact the authors of all the selected publications to check for unpublished outcome data.
  
  
  RESULTS
  Thirteen trials had outcome data eligible for our outcomes. We assessed three of these trials as having a low risk of bias. Using conventional meta-analysis, the relative risk of short-term mortality in the nitrous oxide group was 1.38 [95% confidence interval (CI) 0.22-8.71] and the relative risk of long-term mortality in the nitrous oxide group was 0.94 (95% CI 0.80-1.10). In both cases, TSA demonstrated that the data were far too sparse to make any conclusions. There were insufficient data to perform meta-analysis for stroke, myocardial infarct, pulmonary embolus, or cardiac arrest.
  
  
  CONCLUSIONS
  This systematic review demonstrated that we currently do not have robust evidence for how nitrous oxide used as part of general anaesthesia affects mortality and cardiovascular complications.
authors.affiliation: Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Blegdamsvej 9, Copenhagen Ø DK-2100, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Imberger
authors.forename: A
authors.initials: A
authors.lastname: Orr
authors.forename: K
authors.initials: K
authors.lastname: Thorlund
authors.forename: J
authors.initials: J
authors.lastname: Wetterslev
authors.forename: P
authors.initials: P
authors.lastname: Myles
authors.forename: A M
authors.initials: AM
authors.lastname: Møller
mesh_terms: D000769:Anesthesia, Inhalation; D018685:Anesthetics, Inhalation; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology / Q000401:mortality*; D006323:Heart Arrest / Q000453:epidemiology; D006801:Humans; D009203:Myocardial Infarction / Q000453:epidemiology / Q000209:etiology / Q000401:mortality; D009609:Nitrous Oxide; D011183:Postoperative Complications / Q000453:epidemiology* / Q000401:mortality*; D011655:Pulmonary Embolism / Q000453:epidemiology / Q000209:etiology / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D040242:Risk Reduction Behavior; D020521:Stroke / Q000453:epidemiology / Q000209:etiology / Q000401:mortality; D016896:Treatment Outcome
chemical_list: D018685:Anesthetics, Inhalation; D009609:Nitrous Oxide
keywords: meta-analysis; nitrous oxide; review, systematic