title: Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial.
abstract: BACKGROUND
  There is a plausible pathophysiologic rationale for increased long-term cardiovascular morbidity and mortality in patients receiving significant exposure to nitrous oxide. However, this relationship has not been established clinically. The ENIGMA trial randomized 2050 patients having noncardiac surgery lasting more than 2 hours to nitrous oxide-based or nitrous oxide-free anesthesia. We conducted a follow-up study of the ENIGMA patients to evaluate the risk of cardiovascular events in the longer term.
  
  
  METHODS
  The trial case report forms and medical records of all study patients were reviewed. The date and cause of death and occurrence of myocardial infarction or stroke were recorded. A telephone interview was then conducted with all surviving patients. The primary endpoint of the study was survival.
  
  
  RESULTS
  The median follow-up time was 3.5 (range: 0 to 5.7) years. Three hundred eighty patients (19%) had died since the index surgery, 91 (4.5%) were recorded as having myocardial infarction, and 44 (2.2%) had a stroke during the entire follow-up period. Nitrous oxide did not significantly increase the risk of death [hazard ratio = 0.98 (95% confidence interval, CI: 0.80 to 1.20; P = 0.82)]. The adjusted odds ratio for myocardial infarction in patients administered nitrous oxide was 1.59 (95% CI: 1.01 to 2.51; P = 0.04) and for stroke was 1.01 (95% CI: 0.55 to 1.87; P = 0.97).
  
  
  CONCLUSIONS
  The administration of nitrous oxide was associated with increased long-term risk of myocardial infarction, but not of death or stroke in patients enrolled in the ENIGMA trial. The exact relationship between nitrous oxide administration and serious long-term adverse outcomes will require confirmation by an appropriately designed large randomized controlled trial.
authors.affiliation: Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia. kate.leslie@mh.org.au
authors.forename: Kate
authors.initials: K
authors.lastname: Leslie
authors.forename: Paul S
authors.initials: PS
authors.lastname: Myles
authors.forename: Matthew T V
authors.initials: MT
authors.lastname: Chan
authors.forename: Andrew
authors.initials: A
authors.lastname: Forbes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Paech
authors.forename: Philip
authors.initials: P
authors.lastname: Peyton
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Silbert
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Williamson
mesh_terms: D000368:Aged; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D002423:Cause of Death; D016009:Chi-Square Distribution; D005260:Female; D005500:Follow-Up Studies; D006710:Homocysteine / Q000097:blood; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000209:etiology* / Q000401:mortality*; D009609:Nitrous Oxide / Q000008:administration & dosage / Q000009:adverse effects*; D016017:Odds Ratio; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000209:etiology / Q000401:mortality; D013514:Surgical Procedures, Operative; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018685:Anesthetics, Inhalation; D015415:Biomarkers; D006710:Homocysteine; D009609:Nitrous Oxide