Define Nitrous oxide

Nitrous oxide and long-term morbidity and mortality in the ENIGMA trialAnesth Analg 112:387-393
Leslie K, Myles PS, Chan MTV, Forbes A, Paech MJ, Peyton P, Silbert BS, Williamson E


Purpose The purpose of this study was to examine the incidence of death, myocardial infarction (MI), and stroke following anesthetics greater than two hours long with vs. without nitrous oxide. MI was defined by cardiac enzyme changes and either ECG changes, a procedure to improve coronary circulation, or pathologic findings of an MI. Stroke was defined as a new deficit lasting at least 24 hours.

Background Long term cardiovascular morbidity and mortality may be increased in patients with significant exposure to nitrous oxide. While a cause and effect link has not been established, a credible scientific rational can be described. Nitrous oxide inhalation

results in the inactivation of methionine synthase and a dose-dependent increase in homocysteine that persists for some time after an anesthetic level exposure to nitrous oxide has ended. Bench science studies suggest that homocysteine may be thrombogenic. Elevated homocysteine levels may also result in immunosuppression and atelectasis. Excessive levels of plasma homocysteine impair vascular dilation and may “destabilize” coronary artery plaques. Previous studies have suggested that nitrous oxide may be associated with postoperative myocardial ischemia and other cardiovascular events.

The original analysis of the ENIGMA trial revealed that postoperative 30 day mortality and myocardial infarction were each higher in the group that received 70% nitrous oxide, but not statistically significantly. Plasma homocysteine was elevated in all patients who received nitrous oxide.

Methodology This was a secondary analysis of a prospective, multi-center, multi-national, randomized controlled trial. The secondary analysis was performed in an attempt to better assess the effects of nitrous oxide use on the incidence of postoperative death, MI, and stroke. In the original study, 2, 050 patients having noncardiac procedures lasting longer than two hours were randomized to receive a general anesthetic with either 70% nitrous oxide and 30% oxygen or 80% oxygen and 20% nitrogen. In

In this secondary analysis, statistical methods were used in an attempt to prevent patient variables and differences in anesthetic technique from obscuring the differences in cardiovascular morbidity and mortality between groups. Patient variables included age, weight, ASA physical status, anemia, emergency surgery, and type of surgery. Differences in anesthetic technique included specific drugs used (other than nitrous oxide), MAC level of inhalation agent used intraoperatively, and duration of anesthesia.clusion and exclusion criteria did not consider cardiovascular risk factors. Other aspects of the anesthetic were not controlled, but up to the discretion of the anesthesia provider.

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