ENIGMA-II Trial

More than 2.5 million anaesthetics are given each year in Australia (1:10 Australians), with the majority receiving nitrous oxide. Approximately 25% of patients undergoing major surgery have known coronary artery disease (CAD) or risk factors for CAD. In 1990, approximately 1 million of the 25 million Americans who underwent non-cardiac surgery suffered a perioperative cardiac event, resulting in $20 billion in costs.

Nitrous oxide interferes with vitamin B12 and folate metabolism. This impairs production of methionine (from homocysteine), used to form tetrahydrofolate and thymidine during DNA synthesis. It has been repeatedly demonstrated that nitrous oxide anaesthesia increases postoperative homocysteine levels. Chronic hyperhomocysteinaemia is associated with cardiovascular disease, and acute hyperhomocysteinaemia is known to cause endothelial dysfunction. One small trial has demonstrated an increased incidence of postoperative myocardial ischaemia in patients receiving nitrous oxide anaesthesia. Reducing postoperative myocardial infarction and death are important aims for those with CAD undergoing major surgery.

Our previous trial (ENIGMA) studied 2,050 patients and identified some serious adverse effects, but most patients were not at risk of CAD and so we could not reliably assess serious cardiac complications. This NHMRC-funded clinical trial involves 7,000 patients to provide a definitive evaluation of the safety of nitrous oxide anaesthesia. The primary endpoint is a composite of death and serious cardiovascular events within 30 days of surgery. To date we have enrolled over 1500 patients in 28 centres throughout the world (see www.enigma2.org.au ).