Nitrous Oxide and Postoperative Morbidity and Mortality: An Update of the ENIGMA-II Trial

by Cameron Goertzen, MSc, DDS

Nitrous oxide is an odorless, colourless, inorganic gas that has been used in dental and surgical anesthesia since the mid-1800s. The combination of inhaled nitrous oxide and oxygen provides mild conscious sedation that can effectively manage dental anxiety. Beyond conscious sedation, nitrous oxide is commonly used in medical surgeries requiring general anesthesia in combination with vapours or intravenous agents. Despite the potential benefits, there is a concern that the use of nitrous oxide may increase perioperative cardiovascular risk.

In 2013, Dr. Michelle Wong published an article in Oral Health reporting the outcome of the Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia (ENIGMA) trial.1 The ENIGMA trial was first conducted to test the hypothesis that patients exposed to nitrous oxide for longer than two hours during non-cardiac surgery would be at greater risk of death, myocardial infarction, and stroke in subsequent years than would patients whose indexed anesthetic did not include nitrous oxide.2 In the first ENIGMA trial, there was a statistically significant increase in late myocardial infarction (4.5% to 6.4%, p=0.04; median follow up 3.5 years) in patients receiving nitrous oxide while under general anesthesia.2 Nitrous oxide did not increase the risk of stroke with adjusted odds ratio of 1.01, (CI: 0.55-1.87, p = 0.97). However, the first ENIGMA trial was not designed to evaluate cardiovascular complications and was underpowered due to enrollment of only 2,050 patients. In addition, most of these patients did not have cardiovascular risk factors. The outcome of this trial spurred a movement amongst anaesthesiologists to decrease the use of nitrous oxide due to concerns regarding cardiovascular morbidity and mortality. Since the publication of Dr. Wong’s article, a second ENIGMA trial (ENIGMA-II) has been published along with follow-up and subgroup studies.3 The purpose of this article is to provide an update on the ENIGMA-II trial findings with respect to the perioperative cardiovascular risk to patients exposed to nitrous oxide under general anesthesia.

The aim of the second ENIGMA trial (ENIGMA-II) was to establish whether the addition of nitrous oxide to the anesthetic regimen of a general anesthetic would increase the occurrence of death and cardiovascular complications in at-risk patients having non-cardiac surgery.4 To ensure adequate study power, 45 participating hospital centres from ten countries enrolled 7,112 patients between May 2008 and September 2013. The patients included in the study were over 45 years of age with cardiovascular risk factors (history of coronary artery disease, heart failure, cerebrovascular disease, or peripheral vascular disease, or older age [≥70 years] with other comorbidities) having non-cardiac surgery under general anesthesia, with an expected treatment time lasting more than two hours. Patients were randomly divided into two groups receiving general anesthesia. The first group of 3,543 patients were given 70% nitrous oxide and 30% oxygen. The second group of 3,569 patients received medical air-oxygen mixture with inspirate oxygen concentration of 30%. The main outcome investigated in the study was death or cardiovascular complications (myocardial infarction, stroke, cardiac arrest, pulmonary embolism, myocardial ischemia), and were similarly observed in both patient groups; 283 patients (8%) receiving nitrous oxide and 296 (8%) patients not assigned to receive nitrous oxide (relative risk [RR] 0.96, 95% CI 0.83-1.12; p=0.64). Similarly, no significant difference was observed in patients exposed to nitrous oxide for risk of other outcomes such as fever, PACU time, ICU admission rate, hospital admission length, surgical site infection, or sepsis. The only statistically significant outcome was severe nausea or vomiting following surgery in the first day in patients receiving nitrous oxide (RR 1.75, 95% CI 1.43-2.13; p=0∙001), which was negated if the patient received a prophylactic antiemetic before the end of surgery (RR 1.12, 95% CI 0.95-1.32). Based on these findings, the ENIGMA-II study concluded that use of nitrous oxide during general anesthesia did not increase the risk of cardiovascular complications.4

A one-year follow-up was conducted via a medical record review and telephone interview to determine if nitrous oxide exposure had any long-term effects on patients enrolled in the ENIGMA-II study.5 Of the 7,112 patients enrolled in ENIGMA-II, 5,844 patients were evaluated at one-year post-surgery. Exposure to nitrous oxide did not increase the risk of death (hazard ratio, 1.17; 95% CI, 0.97 to 1.43; P = 0.10), myocardial infarction (odds ratio, 0.97; 95% CI, 0.81 to 1.17; P = 0.78), or stroke (odds ratio, 1.08; 95% CI, 0.74 to 1.58; P = 0.70). Thus, this follow-up study concluded that nitrous oxide did not increase the risk of death or major cardiovascular events at one-year post-exposure in patients with cardiovascular disease, supporting long-term safety of nitrous oxide administration.5

Following the publication of the ENIGMA-I trial, administration of nitrous oxide in medical procedures requiring general anesthesia declined, possibly due to the suggested association between nitrous oxide and cardiac morbidity.2,6 Following the release of ENIGMA-II, a survey was conducted amongst Canadian anesthesiologists to determine if the views of practicing anesthesiologists changed.6 An 11-item questionnaire was completed by 365 anesthesiologists and 16 anesthesia residents. Despite the findings that nitrous oxide did not affect perioperative cardiovascular risk to patients, 81.6% of respondents said there was no change in their frequency of nitrous oxide use after ENIGMA-II. Of the respondents that said they decreased or stopped the use of nitrous oxide since ENIGMA-I, and have not changed the frequency of use following ENIGMA-II, the top answer cited was concern for risk of post-operative nausea and vomiting (169 respondents), despite ENIGMA-II demonstrating that the risk was almost completely mitigated by prophylaxis of an anti-emetic.4 The survey suggested that the decline of nitrous oxide use amongst medical anesthesiologists goes beyond the concern for cardiovascular complications and are most likely due to other factors such as environmental concerns or lack of experience with nitrous oxide use.6

In dentistry, nitrous oxide has shown itself to be a safe and effective agent to provide minimal conscious sedation for patients with dental anxiety, including younger children undergoing more invasive dental procedures.7 In addition to minimal sedation and anxiolysis, nitrous oxide also provides an additional benefit of mild analgesia and does so with very limited risk to patients. Its broad therapeutic range makes it an excellent adjunct to behaviour management for children, and it can be safely used in patients of all ages and with more complex medical histories. As with all pharmacological sedation agents, successful use of nitrous oxide for minimal sedation in the dental setting will depend strongly on the combination of appropriate case selection, including a thorough review of the patient’s existing medical conditions, adequate training of the clinician, appreciation for the benefits and risks of the sedation agent, and appropriate informed consent from the patient.

Oral Health welcomes this original article.


  1. Wong M. Nitrous Oxide and Postoperative Morbidity and Mortality: A Concise Literature Review of the ENIGMA Trials and New Evidence. Oral Health 2013
  2. Leslie K, Myles PS, Chan MT, et al. Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial. Anesthesia & Analgesia 2011; 112: 387-93
  3. Beattie WS, Wijeysundera DN, Chan MTV, et al. Implication of Major Adverse Postoperative Events and Myocardial Injury on Disability and Survival: A Planned Subanalysis of the ENIGMA-II Trial. Anesthesia & Analgesia 2018; 127: 1118-26
  4. Myles PS, Leslie K, Chan MT, et al. 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 (London, England) 2014; 384: 1446-54
  5. Leslie K, Myles PS, Kasza J, et al. Nitrous Oxide and Serious Long-term Morbidity and Mortality in the Evaluation of Nitrous Oxide in the Gas Mixture for Anaesthesia (ENIGMA)-II Trial. Anesthesiology 2015; 123: 1267-80
  6. Jain D, Ma HK, Buckley N. Impact of ENIGMA trials on nitrous oxide: a survey of Canadian anesthesiologists and residents. Canadian Journal of Anesthesia/Journal canadien d’anesthésie 2018; 65: 730-1
  7. Chi SI. Complications caused by nitrous oxide in dental sedation. J Dent Anesth Pain Med 2018; 18: 71-8

About the Author

Dr. Cameron Goertzen is a current second -year resident in the Dental Anesthesia program at the University of Toronto and is a U of T DDS graduate. He has a diverse background in research and has published articles in the fields of dental anesthesiology, breast cancer and oral cancer. Cameron is from the Niagara Region and together with his wife, Dr. Erin Goertzen, a pediatric dental resident at U of T, he hopes to practice in the Region following the completion of their respective studies.