Avoidance of nitrous oxide for patients undergoing major surgery: a randomized controlled trial

Anesthesiology. 2007 Aug;107(2):221-31. doi: 10.1097/01.anes.0000270723.30772.da.


Background: Nitrous oxide is widely used in anesthesia, often administered at an inspired concentration around 70%. Although nitrous oxide interferes with vitamin B12, folate metabolism, and deoxyribonucleic acid synthesis and prevents the use of high inspired oxygen concentrations, the consequences of these effects are unclear.

Methods: Patients having major surgery expected to last at least 2 h were randomly assigned to nitrous oxide-free (80% oxygen, 20% nitrogen) or nitrous oxide-based (70% N2O, 30% oxygen) anesthesia. Patients and observers were blind to group identity. The primary endpoint was duration of hospital stay. Secondary endpoints included duration of intensive care stay and postoperative complications; the latter included severe nausea and vomiting, and the following major complications: pneumonia, pneumothorax, pulmonary embolism, wound infection, myocardial infarction, venous thromboembolism, stroke, awareness, and death within 30 days of surgery.

Results: Of 3,187 eligible patients, 2,050 consenting patients were recruited. Patients in the nitrous oxide-free group had significantly lower rates of major complications (odds ratio, 0.71; 95% confidence interval, 0.56-0.89; P = 0.003) and severe nausea and vomiting (odds ratio, 0.40; 95% confidence interval, 0.31-0.51; P < 0.001), but median duration of hospital stay did not differ substantially between groups (7.0 vs. 7.1 days; P = 0.06). Among patients admitted to the intensive care unit postoperatively, those in the nitrous oxide-free group were more likely to be discharged from the unit on any given day than those in the nitrous oxide group (hazard ratio, 1.35; 95% confidence interval, 1.05-1.73; P = 0.02).

Conclusions: Avoidance of nitrous oxide and the concomitant increase in inspired oxygen concentration decreases the incidence of complications after major surgery, but does not significantly affect the duration of hospital stay. The routine use of nitrous oxide in patients undergoing major surgery should be questioned.

Trial registration: ClinicalTrials.gov NCT00164047.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anesthesia Recovery Period
  • Anesthetics, Inhalation / administration & dosage
  • Anesthetics, Inhalation / adverse effects*
  • Anesthetics, Inhalation / therapeutic use
  • Female
  • Folic Acid / administration & dosage
  • Humans
  • Kaplan-Meier Estimate
  • Length of Stay / statistics & numerical data
  • Male
  • Nitrogen / administration & dosage
  • Nitrous Oxide / adverse effects*
  • Nitrous Oxide / therapeutic use
  • Odds Ratio
  • Oxygen / administration & dosage
  • Postoperative Complications / chemically induced
  • Postoperative Nausea and Vomiting / chemically induced
  • Risk
  • Surgical Procedures, Operative*
  • Treatment Outcome
  • Vitamin B Complex / administration & dosage


  • Anesthetics, Inhalation
  • Vitamin B Complex
  • Folic Acid
  • Nitrous Oxide
  • Nitrogen
  • Oxygen

Associated data

  • ClinicalTrials.gov/NCT00164047