Patients receiving nitrous oxide as part of general anesthesia for surgery may be at increased long-term risk of myocardial infarction (heart attack), reports a study in the February issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).
Based on follow-up from a previous randomized trial, the study finds no increased risk of death among patients receiving nitrous oxide, according to Dr. Kate Leslie of Royal Melbourne Hospital and colleagues. Experts emphasize the need for more research to clarify the true cardiovascular risks, if any, of using nitrous oxide for anesthesia.
ENIGMA Results Suggest Long-Term Increase in Myocardial Infarction Risk
In the ENIGMA trial, 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 ten patients not receiving nitrous oxide. There were also more deaths in the nitrous oxide group: nine versus three patients.
To see if there were any lasting harmful effects of nitrous oxide, Dr. Leslie and colleagues analyzed long-term outcome data on the ENIGMA patients. At a median follow-up of 3½ years, 19 percent of patients had died and 4.5 percent 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 percent 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: about two percent in both groups.
Could Homocysteine Levels Play a Role?
Among the many unanswered questions is how nitrous oxide anesthesia would lead to an increased myocardial infarction risk. 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 percent of patients with myocardial infarction had elevated homocysteine levels, compared to 11 percent 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 percent 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. "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 conclude.
Perhaps more familiar as a dental anesthetic, nitrous oxide is widely used in general anesthesia as well—it is commonly used to initiate anesthesia for surgery, before stronger anesthetics are given. Previous studies have linked nitrous oxide to an increased risk of infection and pneumonia, according to an accompanying editorial by Drs. W. Scott Beattie of University of Toronto and Neal H. Badner of University of Western Ontario.
"The article is undoubtedly intriguing," Drs. Beattie and Badner write. "However, it still does not answer several important safety aspects." They note that a new study, called ENIGMA-II, is now being performed to examine the effects of nitrous oxide anesthesia in patients at higher risk of cardiovascular disease.
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