NITROUS OXIDE CONTROVERSY - 'ENIGMA' TRIALS

Nitrous oxide and cardiovascular system-
Nitrous oxide inactivates vitamin B12 which inhibits methionine synthetase preventing conversion of homocysteine to methionine and thus increasing plasma homocysteine levels. Hyperhomocysteinemia in turn creates a milieu for acute coronary syndrome via endothelial dysfunction, atherogenesis and prothrombotic effects.

ENIGMA Study-
• 2000 unselected non-cardiac patients undergoing surgery for > 2 hours
• Randomised, double blind controlled trial, patients received either O2 30% & N2O 70% or O2 80% & N2 20%
• Primary outcome- length of stay

Results-
• Nitrous oxide was not associated with mortality
• ENIGMA demonstrated a trend to a lower risk of myocardial infarction in the nitrous oxide free group.
• The long term follow up over a median of 3.5 year further demonstrated a statistically significant increase in the risk of MI in patients exposed to nitrous oxide.
• ENIGMA also highlighted a significant increase in wound infection in patients exposed to nitrous oxide.

ENIGMA 2 Study –
• Involved 7000 patients at risk of coronary artery disease undergoing noncardiac surgery >2 hours duration
• It is a large multicentre randomised blinded clinical trial
• Patients randomly allocated to either a N2O containing (70%N2O in oxygen) or N2O-free (70%nitrogen in oxygen) anaesthetic,both groups FiO2 patients.
• The patients,health care providers except the anaesthesiologists,data collectors and outcome adjudicators were blinded to the study.
• Primary end point - death or cardiovascular events like clinical and silent MI, cardiac arrest, pulmonary embolism,and stroke measured at 30 days after surgery.
• Secondary end points - myocardial infarction, rest pulmonary embolism, stroke, wound infection, severe PONV, ICU stay, hospital stay.

Results-
• Follow up after 30 days showed no effect on primary outcome.
• One year follow up showed no difference in primary outcome

Strengths of study-
• Very large long-term studies in at risk patients
• Robust estimates of death and major complications
• Reliable data on impacts of nitrous oxide use

Limitations of study-
• Reliance on patient report of MI and stroke
• Number of covariates available for adjustment
• Missing data and limitations of inverse probability weighting

Conclusion-
Nitrous oxide can be safely administrated to patients with cardiovascular diseases undergoing non cardiac surgery.

- by Dr Amarja