Impact of ENIGMA trials on nitrous oxide: a survey of Canadian anesthesiologists and residents

  • Davinder JainEmail author
  • Heung Kan Ma
  • Norman Buckley

To the Editor,

Nitrous oxide (N2O) has been part of anesthetic practice for almost 200 years. However, administration of the gas has declined dramatically over the last decade, perhaps because of an incidental finding of the N2O in the gas mixture for anesthesia (ENIGMA) trial.1 The ENIGMA trial results suggested a possible association between N2O use and cardiac morbidity following non-cardiac surgery (adjusted odds ratio, 1.59; 95% confidence interval [CI], 1.01 to 2.51). The ENIGMA trial was not designed or adequately powered to detect a difference in cardiac events and was criticized for having different inspired oxygen levels in the N2O and control groups. These concerns were specifically addressed in a follow-up trial (ENIGMA-II) that found no significant difference in cardiac events (relative risk, 0.96; 95% CI 0.83 to 1.12).2 The roles of these two studies in affecting practice and reasons for abandoning N2O were raised at one of our regular “Journal Club” discussions.

The purpose of this survey was to identify the current views on N2O among practicing anesthesiologists and trainees. Because there appeared to have been a decline in the use of N2O following ENIGMA, we specifically questioned the roles the ENIGMA and ENIGMA-II trials played in shaping practice. This study was approved by the Hamilton Integrated Research Ethics Board on 7 November 2016.

We developed an 11-item English-language questionnaire to collect demographics of respondents and perceptions of N2O as an anesthetic gas through various time periods between ENIGMA and ENIGMA-II (see the Electronic Supplementary Material for the instrument and full results). This survey was distributed through the Canadian Anesthesiologists’ Society mailing list of anesthesiologists and trainees across the country.

We received 383 responses to our survey with 365 of 1785 (20%) anesthesiologists and 16 of 634 (3%) residents. Of those responding, 330 of 383 (86%) completed their anesthesia training in Canada and 366 of 382 (95%) practiced anesthesia a minimum of two to three times per week (Table 1).
Table 1

Current perceptions of N2O

Survey question

Respondents (n = 383)

Frequency of N2O use after ENIGMA-II



 Every day



 2-3 times per week



 Few times a month



 Once a month



 Few times a year









Effect of ENIGMA-II on frequency of N2O use







 No change






Reasons if decreased or stopped use of N2O since ENIGMA (choose all that apply)

 PONV risk



 Environmentally unfriendly



 Lack of institutional support



 Lack of experience



 Inferior to newer agents



 Not convinced of current evidence of safety






Is there a current role for N2O in anesthesia?







ENIGMA = evaluation of nitrous oxide in the gas mixture for anesthesia; N2O = nitrous oxide; PONV = postoperative nausea and vomiting

Although prone to recall bias, ENIGMA appeared to have decreased the frequency of clinical N2O use. There was no resurgence of N2O use following publication of ENIGMA-II although it was a large, international trial. A total of 310 of 380 (82%) felt that the results of ENIGMA-II led to no change in their N2O usage. When asked, those who decreased or stopped using N2O following ENIGMA reported diverse reasons with postoperative nausea and vomiting (PONV) ranked the highest with 169 responses. This was despite the fact that the risk was almost completely mitigated by PONV prophylaxis in ENIGMA-II.3 Other responses included N2O being environmentally unfriendly (with an atmospheric lifetime of 114 years),4 being inferior to newer agents, and individuals being unconvinced of current evidence of safety. It is difficult to determine the extent that ENIGMA alone affected N2O use but our survey suggests that the results of ENIGMA-II did not strongly modify clinical practice.

While 318 of 380 (84%) surveyed felt there was still a role for N2O in anesthesia, it appears to be used infrequently. Only 121 of 381 (32%) respondents reported using N2O two to three times per week or more often. Qualitatively, many referred to its usefulness in obstetric and pediatric populations, which were not specifically addressed in our survey. We believe that though N2O usage has declined, it retains characteristics beneficial to patients and should remain in clinical practice. Our survey suggests that the previous association of N2O and cardiovascular complications is unlikely to have been the only factor driving the clinical decision to decrease its usage.


Conflict of interest

None declared.

Editorial responsibility

This submission was handled by Dr. Gregory L. Bryson, Deputy Editor-in-Chief, Canadian Journal of Anesthesia.



Supplementary material

12630_2018_1060_MOESM1_ESM.pdf (45 kb)
Supplementary material 1 (PDF 44 kb)


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Copyright information

© Canadian Anesthesiologists' Society 2018

Authors and Affiliations

  1. 1.Department of AnesthesiaMcMaster UniversityHamiltonCanada

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