Oral Health Group

Nitrous Oxide and Postoperative Morbidity and Mortality: A Concise Literature Review of the ENIGMA Trials and New Evidence

February 1, 2013
by Michelle Wong, DDS

Nitrous oxide is a principal agent in the practice of conscious sedation and general anaesthesia. There has been a growing trend among anaesthesiologists to decrease the use of nitrous oxide because of concerns about cardiovascular morbidity and mortality. While the ENIGMA trials are quoted to further spur the movement for discontinuing nitrous oxide use, critical appraisal of these studies reveal some shortcomings. Dentists who practice conscious sedation should be aware of the evidence-based literature on nitrous oxide and its effects to better address questions from colleagues and patients. Discussions among medical and dental anaesthesia practitioners continue to debate the safety and use of nitrous oxide (N2O) in hospital and ambulatory practice.

Nitrous oxide is a weak inhalational general anaesthetic with a high minimum alveolar concentration value of 105, meaning surgical anaesthesia is unlikely to be achieved with N2O alone. Beginning at a level of 20% N2O accompanied by oxygen, N2O dosage is titrated to effect. Its rapid onset of action is attributable to its low solubility in the blood, thus it quickly achieves equilibrium between alveolar and arterial tensions. Upon reaching the site of action, the brain, its anxiolytic and sedative effects are achieved. By the reverse mechanism, it is rapidly eliminated unchanged in expired gas. In addition to anxiolysis and favourable pharmacokinetics, N2O reduces the dose of other anaesthetic drugs and has been a mainstay in inhalational induction in children. There are also mild analgesic properties associated with it.


While there are benefits of N2O use, there are also disadvantages. Nitrous oxide increases incidence of postoperative nausea and vomiting. Prolonged use has shown increased risk of megaloblastic anemia. Concerns for multisystem toxic effects have been raised in the literature including: hyperhomocysteinemia, increased platelet aggregation, myocardial ischemia, increased risk of hypoxia, myelopathy, peripheral neuropathy, increased intracranial pressure, expansion of air spaces (e.g. pneumothorax, bowel), immunosuppression, teratogenicity and spontaneous abortion. The agent also supports combustion, contributes to pollution and greenhouse gas.1

Contraindications for N2O use include patients who are uncooperative (e.g. cognitively impaired, claustrophic), have nasopharyngeal obstruction, conditions with closed tissue spaces, vitreoretinal surgery within 3 months, and recent bleomycin chemotherapy within the past year. The latter may predispose the patient to pulmonary fibrosis after high oxygen concentrations. Additionally, severe COPD patients may not tolerate the high inspired oxygen. Pregnancy is a relative contraindication for N2O use, but adverse events in pregnancy have not been proven.

The concerns about N2O causing cardiovascular morbidity and mortality stem from findings in the Evaluation of N2O in Gas Mixture for Anesthesia (ENIGMA) study.2 This prospective multicentred controlled trial randomized 2,050 patients into two groups. One group received 70% N2O: 30% O2 whereas the other group received 20% nitrogen: 80% O2. Both gas mixtures were supported by a total intravenous anaesthetic (TIVA). Myles et al. were primarily interested in the duration of hospital stays after noncardiac surgeries that exceeded 2 hours in duration. Subsequent analysis revealed incidences of myocardial infarction (the nitrogen group had 7 cases and the N2O group had 13 cases). Death within 30 days was also noted with 3 cases in the nitrogen group and 9 cases in the N2O group. The reported adjusted odds ratios (OR) were 0.58 (95% confidence interval: 0.22-1.50, p = 0.26) and 0.33 (95% confidence interval: 0.09-1.22, p = 0.098), respectively. While both odds ratios describe the nitrogen group having less likelihood of 30-day mortality and myocardial infarction (MI) than the N2O group, it is important to observe that there was no statistical significance found. Another major criticism is the large difference in the inspired oxygen fraction (FiO2), which makes for an unfair comparison.

The authors of the ENIGMA trial performed a follow-up study three and a half years later.3 From the original ENIGMA sample, they performed a structured telephone interview on 1,290 patients to test the hypothesis that patients exposed to N2O during noncardiac surgery would be at greater risk of death, MI, and stroke in subsequent years than patients whose indexed anaesthetic did not include N2O. It was found that N2O did not increase the risk of death (Hazard Ratio 0.98, CI: 0.80 – 1.20, p = 0.82). For their secondary endpoints, it was determined that N2O was associated with increased long-term risk of MI with an adjusted OR of 1.59 (CI: 1.01-2.51, p = 0.04). Significant predictors of MI included increasing age, higher ASA physical status classification status, known coronary artery disease, anemia, and increasing duration of anaesthesia. Postoperative laboratory studies recorded hyperhomocysteinemia in a large proportion of patients with MI. It was suggested that elevated levels of serum homocysteine are both atherogenic and thrombogenic. Nitrous oxide did not increase the risk of stroke with adjusted OR of 1.01, (CI: 0.55-1.87, p = 0.97). Observing that there was statistical nonsignificance in their results, the issue of cardiovascular risk with nitrous oxide use remained ambiguous. For this reason, a further investigation by this research group is underway.

Currently in progress, Myles et al. are aiming to enroll 7,000 patients in the ENIGMA-II trial.(4) This multicentred international randomized controlled trial includes patients at risk of coronary artery disease who are undergoing noncardiac surgery. Their methodology blinds patients, health care providers, data collectors, and outcome adjudicators, with the exception of blinding the anaesthesiologist providing the anaesthetic. This trial clearly focuses their research question and improves upon the original ENIGMA trial by maintaining a consistent FiO2 of 30% while comparing 70% N2O to 70% nitrogen. The ENIGMA-II trial defines their primary outcome to be a composite of death and major nonfatal events (MI, cardiac arrest, pulmonary embolism, stroke) at 30 days after surgery. Updated information on this trial’s progress is available at www.enigma2.org.au.

Most recently published in Anesthesia and Analgesia, Turan et al hypothesized that N2O increases the odds of both 30-day mortality and major inpatient complications after noncardiac surgery.5 This retrospective cohort study screened and analyzed general anaesthetic records of 49,016 Cleveland Clinic patients spanning years 2005 to 2009. Exclusions included emergency cases, patients categorized as American Society of Anaesthesia Physical Status (ASA-PS) above class 4 (Table 2), and cases that did not undergo general anaesthesia. Propensity score matching was performed to rigorously, statistically match subjects in the nitrous and nitrous-free groups on multiple parameters. While the propensity score matching process excluded 27,524 patients, their final comparison sample remained substantial with 10,746 in each group. Interestingly, results demonstrated that the N2O group was less likely to have 30-day mortality (OR 0.67; CI: 0.46-0.97). The odds ratio of the common effect of all-cause in-hospital morbidity / mortality was reported to be 0.83 (CI: 0.74-0.92), indicating that N2O was favoured over the nonnitrous group. The precision of this result provides some answers to the question of N2O morbidity and mortality. Further analysis indicates that in-hospital mortality had an odds ratio of 0.50 (CI: 0.23 – 1.08) and pulmonary or respiratory complications had an odds ratio of 0.59 (CI: 0.44 – 0.78). Unlike the ENIGMA trial, the N2O concentration in this study was unknown. Anaesthetic records provided information on the dichotomous use of N2O, and thus dose-response could not be ascertained. The authors did speculate the
concentration to be approximately 55% N2O based on common practices at the Cleveland Clinic. As well, patients had general anaesthetics involving other inhalational agents such as desfluane and sevoflurane which differed from the ENIGMA’s TIVA protocol. The surgeries in the study by Turan et al. were of similar duration (>2 hr) to the ENIGMA trial.

Nitrous oxide continues to be a useful tool in dental practice for the dentally anxious. It may be used as a sole agent in minimal conscious sedation or as an adjunct in moderate conscious and deep sedation, as well as in general anaesthesia (Table 1). During the preoperative assessment that is required prior to any sedation, screening patients for the contraindications of N2O use is important. Besides the contraindications described above, methylenetetrahydrofolate reductase (MTHFR) deficient patients have been described in the literature where morbidity and mortality is postulated to be increased by N2O due to the hyperhomocysteinemia mechanism. Reduced MTHFR activity is common. The combined prevalence of two common polymorphisms is estimated to be approximately 20% in the Western European population.6 In these patients, N2O irreversibly inhibits vitamin B12 (cobalamin) which acts as a cofactor to methionine synthase, thereby negatively affecting homocysteine remethylation and the folate cycle. Hyperhomocysteinemia results elevate and “folate trapping” occurs since folate has a role in the conversion of homocysteine to methionine. Patients who have this MTHFR deficiency have protein and DNA synthesis problems, but are more prone to hyperhomocysteinemia which is postulated to increase atherogenic and thrombogenic events.3 It is unclear how clinically relevant the elevations of homocysteine levels are in the scope of dental use of N2O especially when treatment durations are within 2 hours. These MTHFR deficient patients are also susceptible to megaloblastic anemia from altered hematopoiesis. Oftentimes, these patients may not be identified, thus it is difficult to have defined recommendations for this population.

On rare occasion, the media reports a case where a paediatric patient died when undergoing dentistry with N2O conscious sedation. This often results from an inadequate preoperative assessment of the patient’s airway and / or a lack of airway management skills intraoperatively where a patient progresses into moderate conscious or deep sedation levels. In these instances, the airway obstructs, and thus loses patency preventing adequate oxygenation. In such cases, nitrous oxide remains a safe option but only if the dentist recognizes the signs of airway difficulty and acts immediately and appropriately. A clinician should be mindful of the variability in patient response to N2O. As with all drugs, the distribution of patient response to a drug can be described by a Gaussian distribution or “bell-curve”. There is variability in the level of sedation achieved by a given dose concentration of nitrous oxide. Airway management must be respected in all levels of sedation and the nitrous oxide provider should be cognizant of emergency airway manoeuvres (e.g. head-tilt, chin-lift, jaw-thrust).7

The decision to exclude nitrous oxide from our armamentarium for sedation would greatly limit the conscious sedation options in dental practice. Upon reviewing the literature, the informed dentist should weigh the benefits and risks of nitrous oxide use in his or her sedation practice. Evaluation of the current literature suggests that continued nitrous oxide use does not appear to incur increased risk of cardiovascular events or mortality. It is important to note that these studies looked at noncardiac surgeries that used high concentrations (up to 70%) of N2O for durations of greater than 2hours, which is not recommended practice for the dental clinician who has been trained in mild to moderate conscious sedation. While the ENIGMA-II trial may offer additional data in the near future, long-term experience with N2O demonstrates its effectiveness and safety in dental practice.OH

Dr. Michelle Wong is a second-year resident in Dental Anaesthesia at the Faculty of Dentistry, University of Toronto.

Oral Health welcomes this original article.

1. Myles PS, Leslie K, Silbert B, Paech MJ, Peyton P. A review of the risks and benefits of nitrous oxide in current anaesthetic practice. Anaesthesia and intensive care [Internet]. 2004 Apr;32(2):165–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15957712

2. Myles, Paul S; Chen, Matthew TV; Forbes, Andrew; Paech, MJ; Peyton, Phillip; Silbert, BS; Pascoe EP the ETG. Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery. Anesthesiology. 2007;107:221–31.

3. Leslie K, Myles PS, Chan MT V, Forbes A, Paech MJ, Peyton P, et al. Nitrous oxide and long-term morbidity and mortality in the ENIGMA trial. Anesthesia and analgesia [Internet]. 2011 Feb [cited 2012 Aug 27];112(2):387–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20861416

4. Myles PS, Leslie K, Peyton P, Paech M, Forbes A, Chan MT V, et al. Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design. American heart journal [Internet]. 2009 Mar [cited 2012 Sep 28];157(3):488–494.e1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19249419

5. Turan A, Mascha EJ, You J, Kurz A, Shiba A, Saager L, et al. The Association Between Nitrous Oxide and Postoperative Mortality and Morbidity After Noncardiac Surgery. Anesthesia and analgesia [Internet]. 2012 Jul 19 [cited 2012 Aug 3];Published (July 19):1–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22822187

6. Nagele P, Zeugswetter B, Wiener C, Burger H, Hüpfl M, Mittlböck M, et al. Influence of methylenetetrahydrofolate reductase gene polymorphisms on homocysteine concentrations after nitrous oxide anesthesia. Anesthesiology [Internet]. 2008 Jul;109(1):36–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18580170

7. Becker DE, Haas D a. Recognition and management of complications during moderate and deep sedation part 1: respiratory considerations. Anesthesia progress [Internet]. 2011 Jan;58(2):82–92. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3198131&tool=pmcentrez&rendertype=abstract

8. Royal College of Dental Surgeons of Ontario. Standard of Practice: Use of Sedation and General Anesthesia in Dental Practice. Dispatch. 2012;(August/September):Supplement 1–32.