Professor Paul Myles (Alfred Health and Monash University)
Patients were enrolled between May 2008 and September 2013, at 45 centres in 10 countries.
Australia, New Zealand, United Kingdom, Hong Kong, Singapore, Malaysia, Geneva, Canada, United States and United Arab Emirates.
Our previous trial, ENIGMA, studied 2050 patients and identified some serious adverse effects, but most patients were not at risk of coronary artery disease (CAD) and so we could not reliably assess serious cardiac complications. We identified a non-significant increased risk of confirmed myocardial infarction in the N2O group, 1.3 per cent versus 0.7 per cent; adjusted P=0.19, and 10 post-operative deaths (1.0 per cent) in the N2O group compared with four (0.4 per cent) in the control group P=0.26.
Therefore, ENIGMA-II was designed as a large simple multi-centre randomised controlled trial to definitively evaluate the efficacy of removing N2O from the anaesthetic in moderate and high-risk patients undergoing non-cardiac surgery. There are about 20 million anaesthetics given each year in the US (1:10 of the population), with the majority receiving N2O. Approximately 25 per cent of patients undergoing major surgery have known coronary artery disease or risk factors for CAD. In 1990, approximately one million of the 25 million Americans who underwent non-cardiac surgery suffered a perioperative cardiac event, resulting in $20 billion in costs. N2O 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 N2O anaesthesia increases post-operative homocysteine levels. Chronic hyperhomocysteinaemia is associated with cardiovascular disease, and acute hyperhomocysteinaemia is known to cause endothelial dysfunction. Reducing post-operative myocardial infarction and death are important aims for those with CAD undergoing major surgery.
ENIGMA-II is one of the largest trials conducted in anaesthesia. It is an international, randomised, assessor- blinded trial in patients with known or suspected coronary artery disease having major non-cardiac surgery. Patients were randomly assigned to receive a general anaesthetic with or without nitrous oxide.
The primary outcome measure was a composite of death and cardiovascular complications (nonfatal myocardial infarction, stroke, pulmonary embolism or cardiac arrest) within 30 days of surgery. Secondary endpoints included surgical site infection, severe nausea and vomiting, and hospital length of stay.
Background
Nitrous oxide is commonly used in general anaesthesia but concerns exist that it might increase perioperative cardiovascular risk. We aimed to gather evidence to establish whether nitrous oxide affects perioperative cardiovascular risk.
Methods
We did an international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery. Patients were randomly assigned via automated telephone service, stratified by site, to receive a general anaesthetic with or without nitrous oxide. Attending anaesthetists were aware of patients' group assignments, but patients and assessors were not. The primary outcome measure was a composite of death and cardiovascular complications (non-fatal myocardial infarction, stroke, pulmonary embolism, or cardiac arrest) within 30 days of surgery. Our modified intention-to-treat population included all patients randomly assigned to groups and undergoing induction of general anaesthesia for surgery.
Findings
Of 10,102 eligible patients, we enrolled 7112 patients between May 30, 2008, and Sept 28, 2013. 3543 were assigned to receive nitrous oxide and 3569 were assigned not to receive nitrous oxide. 3483 patients receiving nitrous oxide and 3509 not receiving nitrous oxide were assessed for the primary outcome. The primary outcome occurred in 283 (8%) patients receiving nitrous oxide and in 296 (8%) patients not receiving nitrous oxide (relative risk 0·96, 95% CI 0·83–1·12; p=0·64). Surgical site infection occurred in 321 (9%) patients assigned to nitrous oxide, and in 311 (9%) patients in the no-nitrous oxide group (p=0·61), and severe nausea and vomiting occurred in 506 patients (15%) assigned to nitrous oxide and 378 patients (11%) not assigned to nitrous oxide (p<0·0001).
Interpretation
Our findings support the safety profile of nitrous oxide use in major non-cardiac surgery. Nitrous oxide did not increase the risk of death and cardiovascular complications or surgical-site infection, the emetogenic effect of nitrous oxide can be controlled with antiemetic prophylaxis, and a desired effect of reduced volatile agent use was shown.
Australian National Health and Medical Research Council; Australian and New Zealand College of Anaesthetists; Heart and Stroke Foundation of Quebec, Heart and Stroke Foundation of Ontario, Canada; General Research Fund of the Research Grant Council, Hong Kong Special Administrative Region, China.
Myles PS, Leslie K, Chan MT, Forbes A, Peyton PJ, Paech MJ, Beattie WS, Sessler DI, Devereaux PJ, Silbert B, Schricker T, Wallace S; ANZCA Trials Group for the ENIGMA-II investigators. The safety of addition of nitrous oxide to general anaesthesia in at-risk patients having major non-cardiac surgery (ENIGMA-II): a randomised, single-blind trial. Lancet. 2014 Oct 18;384(9952):1446-54.
ClinicalTrials.gov Identifier: NCT00430989
Professor Paul Myles presented the results at the Singapore annual scientific meeting (ASM) in May 2016.
The full abstract can be viewed on Pubmed