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.
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.
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.
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).
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.
Patel KK, Sun X, Cheng J, Schaller K, Tessitore E, Gondar R, Gaudet J, Myles PS, Leslie K, Nouri A. Safety of Nitrous Oxide Anesthesia in a Selected Group of Patients Undergoing Neurosurgery: An Exploratory Subgroup Analysis of the ENIGMA Trials. J Neurosurg Anesthesiol. 2022 Jul 1;34(3):306-312. doi: 10.1097/ANA.0000000000000771. Epub 2021 Apr 23. PMID: 33901062.
Haller G, Chan M, Combescure C, Lopez U, Pichon I, Licker M, Fournier R, Myles PS. The International ENIGMA-II substudy on postoperative cognitive disorders (ISEP): a randomised controlled trial. Sci Rep 2021; 11:11631. doi.org/10.1038/s41598-021-91014-8
Peyton PJ, Liskaser G, Ho A, Marsh H, Etherington C, Torlot F, Desai M, Perrett G, Chee B, Leslie K, Myles PS. Postoperative Pulmonary Complications in the ENIGMA II Trial: A Post Hoc Analysis. Anesthesiology. 2023 Apr 1;138(4):354-363. doi: 10.1097/ALN.0000000000004497. PMID: 36645804.
Beattie WS, Wijeysundera DN, Chan MTV, Peyton PJ, Leslie K, Paech MJ, Devereaux PJ, Sessler DI, Wallace S, Myles PS, on behalf of the ANZCA Clinical Trials Network and the ENIGMA-II Investigators. Survival after isolated post-operative troponin elevation. JACC 2017; 70:907-908.
Myles P. ENIGMA-II, and can an old dog be taught new tricks? South Afr J Anaesth Analg 2015;21:68.
Myles PS, Leslie K, Peyton P, Paech M, Forbes A, Chan MTV, Sessler D, Devereaux PJ, Silbert BS, Jamrozik K, Beattie S, Badner N, Tomlinson J, Wallace S, and the ANZCA Trials Group. Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) trial: rationale and design. Am Heart J 2009; 157:488-494.
Myles P, Chan MTV, Kasza J, Paech MJ, Leslie K, Peyton P, Sessler DI, Haller G, Beattie WS, Osborne C, Sneyd JR, Forbes A. Severe nausea and vomiting in the elimination of nitrous oxide in the gas mixture for anesthesia (ENIGMA-II) trial. Anesthesiology 2016; 124:1032-1040.
Chan MTV, Peyton P, Myles PS, Leslie K, Buckley N, Forbes A, Paech M, Beattie S, Sessler D, Kasza J, for the ENIGMA-II trial group and the ANZCA Clinical Trials Network. Chronic postsurgical pain in the evaluation of nitrous oxide in the gas mixture for anaesthesia (ENIGMA)-II trial. Br J Anaesth 2016; 117: 808-811.
Corcoran T, Kasza J, Short TG, O’Loughlin E, Chan M, Leslie K, Forbes A, Paech M, Myles PS. Intraoperative dexamethasone administration does not increase the risk of post-operative infection –a propensity score matched post-hoc analysis of the ENIGMA-II trial (EnDEX). Br J Anaesth 2017; 118:190-199.
Beattie WS, Wijeysundera DN, Chan MTV, Peyton PJ, Leslie K, Paech MJ, Sessler DI, Wallace S, Myles PS, on behalf of the ANZCA Clinical Trials Network for the ENIGMA-II Investigators. Implication of major adverse postoperative events and myocardial injury on disability and survival: a planned sub-analysis of the ENIGMA-II trial. Anesth Analg 2018; 127(5):1118-1126.