title: Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design.
abstract: BACKGROUND
  Globally there are >200 million major surgical procedures undertaken annually, and about 20% of these involve patients who have coronary artery disease. Many receive nitrous oxide, which impairs methionine synthase, thus inhibiting folate synthesis and increasing postoperative homocysteine levels. Nitrous oxide anesthesia leads to postoperative endothelial dysfunction, and there is some evidence that it increases myocardial ischemia and, possibly, myocardial infarction. We have initiated the Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial to test the hypothesis that in inpatients undergoing anesthesia for major noncardiac surgery, avoidance of nitrous oxide will reduce the incidence of death and major cardiovascular events.
  
  
  METHODS
  ENIGMA-II is a 7,000-patient, international randomized trial involving patients at risk of coronary artery disease undergoing noncardiac surgery. The patients, health care providers (except for the anesthesiologists), data collectors, and outcome adjudicators are blinded to whether patients receive nitrous oxide-containing or nitrous oxide-free anesthetic. The primary outcome is a composite of death and major nonfatal events (ie, myocardial infarction, cardiac arrest, pulmonary embolism, and stroke) at 30 days after surgery.
  
  
  RESULTS
  At present, ENIGMA-II has randomized >1,000 patients in 22 hospitals in 5 countries. To date, patients' mean age is 70 years, 66% are men, 38% have a history of coronary artery disease, 19% have a history of cerebrovascular disease, and 84% have a history of hypertension. Most patients have undergone intra-abdominal 28%, vascular 32%, and orthopedic 16% surgery.
  
  
  CONCLUSIONS
  The ENIGMA-II Trial will be the largest study yet conducted to ascertain the benefits and risks of removing nitrous oxide from the gas mixture in anesthesia. The results of this large international trial will guide the clinical care of the hundreds of millions of adults undergoing noncardiac surgery annually.
authors.affiliation: Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Melbourne, Victoria, Australia. p.myles@alfred.org.au
authors.forename: Paul S
authors.initials: PS
authors.lastname: Myles
authors.forename: Kate
authors.initials: K
authors.lastname: Leslie
authors.forename: Philip
authors.initials: P
authors.lastname: Peyton
authors.forename: Michael
authors.initials: M
authors.lastname: Paech
authors.forename: Andrew
authors.initials: A
authors.lastname: Forbes
authors.forename: Matthew T V
authors.initials: MT
authors.lastname: Chan
authors.forename: Daniel
authors.initials: D
authors.lastname: Sessler
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Devereaux
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Silbert
authors.forename: Konrad
authors.initials: K
authors.lastname: Jamrozik
authors.forename: Scott
authors.initials: S
authors.lastname: Beattie
authors.forename: Neal
authors.initials: N
authors.lastname: Badner
authors.forename: James
authors.initials: J
authors.lastname: Tomlinson
authors.forename: Sophia
authors.initials: S
authors.lastname: Wallace
mesh_terms: D000368:Aged; D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000209:etiology*; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007902:Length of Stay; D008297:Male; D009609:Nitrous Oxide / Q000009:adverse effects*; D011014:Pneumonia / Q000453:epidemiology; D011183:Postoperative Complications / Q000453:epidemiology*; D012107:Research Design; D018570:Risk Assessment; D013514:Surgical Procedures, Operative; D013530:Surgical Wound Infection / Q000453:epidemiology; D014839:Vomiting / Q000453:epidemiology
chemical_list: D018685:Anesthetics, Inhalation; D006710:Homocysteine; D009609:Nitrous Oxide