Influence of nitrous oxide anesthesia, B-vitamins, and MTHFR gene polymorphisms on perioperative cardiac events: the vitamins in nitrous oxide (VINO) randomized trial

Anesthesiology. 2013 Jul;119(1):19-28. doi: 10.1097/ALN.0b013e31829761e3.


Background: Nitrous oxide causes an acute increase in plasma homocysteine that is more pronounced in patients with the methylenetetrahydrofolate reductase (MTHFR) C677T or A1298C gene variant. In this randomized controlled trial, the authors sought to determine whether patients carrying the MTHFR C677T or A1298C variant had a higher risk for perioperative cardiac events after nitrous oxide anesthesia and whether this risk could be mitigated by B-vitamins.

Methods: The authors randomized adult patients with cardiac risk factors undergoing noncardiac surgery, to receive nitrous oxide plus intravenous B-vitamins before and after surgery, or to nitrous oxide and placebo. Serial cardiac biomarkers and 12-lead electrocardiograms were obtained. The primary study endpoint was the incidence of myocardial injury, as defined by cardiac troponin I increase within the first 72 h after surgery.

Results: A total of 500 patients completed the trial. Patients who were homozygous for either MTHFR C677T, or A1298C gene variant (n=98; 19.6%) had no increased rate of postoperative cardiac troponin I increase compared with wild-type and heterozygous patients (11.2 vs. 14.0%; relative risk 0.96; 95% CI, 0.85-1.07; P=0.48). B-vitamins blunted the rise in homocysteine, but had no effect on cardiac troponin I increase compared with patients receiving placebo (13.2 vs. 13.6%; relative risk 1.02; 95% CI 0.78 to 1.32; P=0.91).

Conclusions: Neither MTHFR C677T and A1298C gene variant, nor acute homocysteine increase are associated with perioperative cardiac troponin increase after nitrous oxide anesthesia. B-vitamins blunt nitrous oxide-induced homocysteine increase but have no effect on cardiac troponin I increase.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anesthesia, Inhalation / adverse effects*
  • Anesthetics, Inhalation / adverse effects*
  • Double-Blind Method
  • Endpoint Determination
  • Female
  • Genotype
  • Heart Diseases / epidemiology
  • Homocysteine / blood
  • Humans
  • Intraoperative Complications / epidemiology
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Middle Aged
  • Nitrous Oxide / administration & dosage*
  • Perioperative Care
  • Perioperative Period
  • Polymorphism, Genetic / genetics
  • Postoperative Complications / epidemiology
  • Postoperative Complications / genetics
  • Risk
  • Sample Size
  • Treatment Outcome
  • Vitamin B Complex / adverse effects
  • Vitamin B Complex / therapeutic use*
  • Vitamins / adverse effects
  • Vitamins / therapeutic use*


  • Anesthetics, Inhalation
  • Vitamins
  • Homocysteine
  • Vitamin B Complex
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Nitrous Oxide