ArticlesThe 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
Introduction
At least 5% of the 230 million people worldwide who have major surgery each year will have a major perioperative cardiovascular complication. These complications prolong hospital stay, are a threat to disability-free survival, and greatly increase health-care costs,1 contributing an estimated US$20 billion to costs for hospital care and long-term care annually in the USA alone.2 The postoperative period is associated with increased myocardial oxygen demand,3 hypotension, and a procoagulant state.4 Patients with coronary artery disease are at high risk of cardiovascular complications in this setting.
Nitrous oxide is a commonly used anaesthetic that has been given to billions of patients in the past 150 years. That nitrous oxide increases the risk of postoperative nausea and vomiting is well established, but whether it causes more serious complications is unclear. Concern persists because nitrous oxide increases postoperative plasma homocysteine concentrations and impairs endothelial function.5, 6, 7, 8 Both consequences are exposure-dependent and are probably greater in at-risk patients.8
Chronic hyperhomocysteinaemia is associated with cardiovascular disease, but efforts to decrease this risk by reduction of homocysteine concentrations have had mixed results.9, 10, 11, 12, 13, 14, 15 Whether nitrous oxide is associated with myocardial injury during and after surgery is uncertain.5 In our previous multicentre trial—the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA) trial16—we observed a non-significant increase (from 0·7% to 1·3%, p=0·26) in ischaemic cardiac complications within 30 days of surgery,16 and a significant increase in late myocardial infarction (from 4·5% to 6·4%, p=0·04; median follow-up 3·5 years)17 in patients receiving nitrous oxide. However, the ENIGMA trial was not designed to assess cardiovascular complications, and enrolled only 2050 patients, most of whom were not at high risk of a cardiovascular complication. The trial was thus underpowered for cardiovascular outcomes.18
The aim of the present trial (ENIGMA-II) was to establish whether addition of nitrous oxide to the anaesthetic regimen would increase occurrence of death and cardiovascular complications in at-risk patients having non-cardiac surgery.
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Study design and participants
We have published the design and rationale of the prospective, multicentre, international randomised ENIGMA-II trial.19 The study was approved by the ethics committee at each site. The steering committee members vouch for the accuracy of the dataset, and adherence to the protocol and analysis plan.
Eligible participants included adults aged at least 45 years who were at risk of cardiovascular complications and who were having non-cardiac surgery under general anaesthesia that was expected to
Results
The 45 participating centres from ten countries in the ENIGMA-II Trial enrolled patients between May 30, 2008, and Sept 28, 2013. Of 10 102 eligible patients, 7112 patients were enrolled and randomly assigned: 3543 to receive nitrous oxide and 3569 not to receive nitrous oxide; 7011 patients underwent induction of anaesthesia and were included at baseline, and 6992 patients were assessed for the primary endpoint (figure 1). Study patient mean age was 69 years, and about two-thirds of patients
Discussion
In patients having general anaesthesia for major non-cardiac surgery, addition of nitrous oxide to the gas mixture did not affect the risk of death and major cardiovascular complications (panel). Nitrous oxide did not increase the risk of surgical-site infection, but, consistent with previous studies,16, 26 we noted an increased risk of severe postoperative nausea and vomiting with nitrous oxide administration. Quality of recovery scores was slightly reduced in patients given nitrous oxide
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2022, British Journal of AnaesthesiaCitation Excerpt :There are several potential explanations for this finding: (i) fewer women may have presented for surgery at recruiting centres because of lower incidences of relevant surgical conditions, such as those related to smoking, or lower rates of referral for treatment and scheduling for surgery in women than in men3,13; (ii) fewer women may have met the study inclusion criteria. Cardiovascular disease and cardiovascular intervention17,18,20,22–26 were inclusion criteria in seven of the 11 studies. Although the incidence of cardiovascular disease is lower in women,13,29 there is some evidence that women are underdiagnosed and undertreated with respect to cardiovascular disease, because presentation is delayed,30 their symptoms are not typical of those in men,31 and fewer diagnostic and interventional procedures and secondary prevention medications are prescribed.4,30