Nitrous oxide may increase heart attack risk

Jan 30, 2011

Patients receiving nitrous oxide as part of general anesthesia for surgery may be at increased long-term risk of myocardial infarction, according to a new study in Anesthesia & Analgesia (February 2011, Vol. 112:2, pp. 387-393).

In the original Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia (ENIGMA) trial conducted in 2004, 2,050 patients undergoing noncardiac surgery were randomly assigned to receive anesthesia with or without nitrous oxide. In that study, an unexpectedly high number of myocardial infarctions occurred among patients receiving nitrous oxide -- 30 patients, compared to 10 patients not receiving nitrous oxide. There were also more deaths in the nitrous oxide group: nine versus three patients, according to the study authors.

In this follow-up study, designed to see if there were any lasting harmful effects of nitrous oxide, Kate Leslie, MBBS, MD, and colleagues at Royal Melbourne Hospital analyzed long-term outcome data on the ENIGMA patients. At a median follow-up of 3.5 years, 19% of patients had died and 4.5% had a myocardial infarction.

The results showed a persistently higher rate of myocardial infarctions among patients who received nitrous oxide. The odds of myocardial infarction were nearly 60% higher than in patients not receiving nitrous oxide, after adjustment for other risk factors such as age, history of heart disease, and length of surgery.

Despite the increased myocardial infarction rate, patients receiving nitrous oxide had no significant increase in the risk of death. There was no significant difference in stroke between the two groups: about 2% in both groups.

Among the many unanswered questions is how nitrous oxide anesthesia would lead to an increased myocardial infarction risk, Dr. Leslie noted. One possibility is increased levels of the amino acid homocysteine, which have been linked to an increased risk of heart attack.

In the ENIGMA study, 46% of patients with myocardial infarction had elevated homocysteine levels, compared to 11% of those without myocardial infarction.

However, no previous study has shown a link between nitrous oxide administration and long-term cardiovascular risk. Other mechanisms besides increased homocysteine levels are possible as well.

As a group, the patients enrolled in the ENIGMA study had a low risk of myocardial infarction. Only 11% had a history of heart disease. Although the new findings raise concerns, they are far from providing definitive evidence that nitrous oxide increases myocardial infarction risk, according to the researchers.

"The exact relationship between nitrous oxide administration and serious long-term adverse outcomes requires investigation in an appropriately designed large randomized controlled trial," Dr. Leslie and co-authors concluded.

A new study, ENIGMA-II, is now being performed to examine the effects of nitrous oxide anesthesia in patients at higher risk of cardiovascular disease.