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Leslie K, et al. "Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial". Anesth Analg. 2011. 112(2):387-393.
PubMedFull text

Clinical Question

The use of Nitrous Oxide as part of an anesthetic plan for patient undergoing surgery is near-routine. The aims of this trial was to evaluate whether avoidance of nitrous oxide in the gas mixture for anesthesia could decrease the duration of hospital stay and reduce post-op complications when compared with a regimen that included nitrous oxide.

Bottom Line

Avoidance of nitrous oxide and the concomitant increase in inspired O2 concentration decreases the incidence of complications after major surgery but does not influence length of stay.

Major Points

Nitrous Oxide was first used as an anesthetic here in 1844, ever since that time it is widely used by anesthesiologists for various surgical procedures. Over the past 30 years there has been accumulating evidence of the risks of N2O have lead to clinicians questioning its routine use. Many of the adverse effects result from the irreversible inhibition of B12 which inhibits methionine synthase, folate metabolism and DNA synthesis. This mechanism explains the reports of: Megaloblastic anemia, neuro-toxicity,increased risk of teratogenicity, immunodeficiency and impaired healing. Increases in homocysteine levels may cause post-op CV complications. N2O impairs cerebral blood flow coupling and worsens air-space conditions. It is also a proven risk factor for nausea and vomiting.


No current guidelines available


  • Multicenter (19), blind (to analysis and surgery team), randomized, controlled trial
  • N=2,050 (4.035 screened)
  • Nitrous free (n=997);
  • Nitrous (n=200);
  • Setting: 19 US centers;
  • Enrollment: 2003-2004
  • Follow-up: 30 days
  • Analysis: Intention-to-treat
  • Primary outcomes:
  • Duration of hospital stay
  • Secondary outcomes:
  • ICU length of stay
  • Post-operative complications


Inclusion Criteria

  • Age ≥18 years
  • Pts scheduled for surgery including skin incision > 2h, LOS at least 3 days

Exclusion Criteria

  • Cardiac surgery, thoracic surgery requiring OLV
  • Anesthesiologist considered that N2O was contraindicated

Baseline Characteristics

  • Similar for both groups


  • Patients were randomly assigned to a group:
  • Nitrous oxide-free – 25-100% O2 and 0-20% N2O
  • Nitrous oxide – 70% N2O and 30% O2
  • If Hb oxygen saturation was deemed inadequate O2 concentration could be increased at any time


Presented as Nitrous-free vs. Nitrous

Primary Outcomes

Hospital Length of stay Median duration of stay 7.1 vs. 7.0 days

Secondary Outcomes

Length of ICU stay No significant difference in number of patients admitted to ICU between groups Median duration of stay was 1 day for both groups but Nitrous-free group was more likely to be discharged on any given day.

Post-operative Complications:

Patients in nitrous-free group had a significant lower incidence of complications including: Severe Nausea and Vomiting 104 vs. 229 Wound Infection 77 vs. 106 Fever 275 vs. 345 Pneumonia 15 vs. 30 Atelectasis 75 vs127 Any pulmonary or major complication Myocardial Infarction and Thromboembolism were diffent but not statistically significant


  • Complication detection bias
  • Subclinical adverse events may not be detected
  • Data not useful for minor surgery, pediatrics or labor anesthesia