Use of nitrous oxide in contemporary anesthesia—an ongoing tug of war

Abstract

The role of nitrous oxide has been shaped by its use in the past 150 years of anesthetic practice. It is a readily available, inexpensive agent that produces anesthetic and analgesic-sparing effects. The use of nitrous oxide has, however, declined rapidly in the past quarter century after the discovery that irreversible inhibition of methionine synthase following nitrous oxide exposure may produce adverse cardiovascular events and immunosuppression. The decline was further accelerated by the findings of the Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia (ENIGMA) trial. In ENIGMA, 2,050 adults having major noncardiac surgery lasting[ two hours were randomized to receive nitrous oxide-based (nitrous oxide 70% in 30% oxygen) or nitrous oxide-free (20% nitrogen in 80% oxygen) anesthesia. Although the median length of hospital stay (the primary outcome) was not different between groups, there was an increase in the rate of postoperative nausea and vomiting, fever, pulmonary atelectasis, and infectious complications in the nitrous oxide group. In addition, the cost for managing these complications has offset any savings from a reduced consumption of other potent and more expensive anesthetic agents. It should be noted that the ENIGMA trial was underpowered for assessing secondary outcomes, and that the trial was not directly comparing nitrous oxide with nitrogen since the higher fraction of inspired oxygen concentration (FIO2) also differed between groups. Given the uncertainty on the safety profile of nitrous oxide, a subsequent ENIGMA-II trial was performed in 7,112 patients with known or at-risk of coronary artery disease having major noncardiac surgery. In contrast to the original ENIGMA trial, patients receiving nitrous oxide-free anesthesia in the ENIGMA-II trial had air-oxygen mixture with initial inspired oxygen concentration targeting at 30%. The results of the ENIGMA-II trial confirmed the safety of nitrous oxide. Nitrous oxide did not increase the risk of death or postoperative cardiovascular and infective complications. A similar safety profile was also shown in a long-term follow-up study of the ENIGMA-II cohort, where the incidence of mortality, myocardial infarction and stroke were not different among patients who did or did not receive nitrous oxide during their original index surgery, performed 12 months before. In addition, the risk of postoperative nausea and vomiting could be adequately managed with common antiemetic prophylaxis. This series of research highlights the importance of large randomized trials. In particular, reliable and definitive results can only be derived from appropriately designed and adequately powered trials. Nevertheless, the early safety concerns of nitrous oxide have been ingrained in our mind. In a recent survey of Canadian anesthesiologists and residents, only 16.5% of respondents used nitrous oxide on a daily basis, and 46.5% did not use the drug more than a few times a year. This shows another example of apophenia in anesthesia, whereby individuals are prone to accepting the results of high profile studies, newsworthy results, and positive trials. More importantly, there seems to be reluctance in changing practice despite the availability of definitive results. It remains unclear whether additional positive results on the potential benefits of nitrous oxide may help to overturn our prejudice against the drug in contemporary anesthesia. C. S. Chan, BSc M. T. V. Chan, MB BS, MMed, PhD, FANZCA, FHKCA, FHKAM (&) Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China e-mail: [email protected]