Correspondence  |   July 2017
Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia II (ENIGMA II) Revisited: Patients Still Vomiting
Author Notes
  • University of Saskatchewan, Saskatoon, Canada (E.C.K.L.).
  • (Accepted for publication March 13, 2017.)
    (Accepted for publication March 13, 2017.)×
Article Information
Correspondence   |   July 2017
Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia II (ENIGMA II) Revisited: Patients Still Vomiting
Anesthesiology 7 2017, Vol.127, 204-205. doi:
Anesthesiology 7 2017, Vol.127, 204-205. doi:
To the Editor:
We read the secondary analysis of the Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia II (ENIGMA II) trial for severe postoperative nausea and vomiting (PONV) with great interest.1  Because PONV remains an often-cited risk in using nitrous oxide,2  the investigation of methods to mitigate PONV using existing data generated from randomized controlled trials is an important undertaking. We wish to respond to this thorough reanalysis.
The authors used a retrospective propensity score approach to investigate the effects of antiemetic prophylaxis on the nitrous oxide and non-nitrous oxide arms. The well-recognized limitations of this approach were openly acknowledged in the publication, including the inability to control for hidden covariates and the need to truncate available data.3  In the abstract, the authors conclude that the emetogenic effects of nitrous oxide are near eliminated by the addition of antiemetics. However, the results from the propensity score-matched analysis do not seem to support this conclusion, as the nitrous/antiemetic group had statistically higher odds of PONV compared with the non-nitrous/nonantiemetic group. In addition, administration of antiemetic prophylaxis among participants who did not receive nitrous oxide counterintuitively increased the odds of PONV. Although various clinical and scientific reasons may be hypothesized to explain this phenomenon, perhaps the simplest hypothesis is the presence of hidden covariates. Therefore, it is our opinion that the conclusion of negating PONV with antiemetics when nitrous is used is not supported by the results of this retrospective analysis, and the use of propensity score matching in this instance may not have resulted in a balanced comparison.
In light of the aforementioned results, another statistic (risk ratio, 0.74 [95% CI, 0.63 to 0.84]; P < 0.001) is quoted in the report1  to support the conclusion that PONV is not increased when antiemetics are used in conjunction with nitrous oxide. This risk ratio does not appear among the results generated by propensity score matching but appears to be the result of a subgroup analysis for the PONV outcome in the original ENIGMA II report for patients who received antiemetic prophylaxis.4  However, the lack of blinding of attending anesthesiologists to treatment allocation may have introduced selection bias into antiemetic prophylaxis, a possibility supported by the statistically significant difference in antiemetic administration between the nitrous and non-nitrous arms. If selection bias were present in antiemetic administration, the efficacy of this originally randomized subgroup analysis to equalize hidden covariates may have been compromised.5 
Although this secondary analysis1  of antiemetic prophylaxis on PONV has important limitations, we believe that the authors’ dose-effect analysis of nitrous oxide on PONV is very clinically relevant, although not emphasized in the abstract or report. The authors note in the report that nitrous oxide, when used for less than 2 h, did not seem to result in added PONV compared with the non-nitrous arm. This observation is congruent with existing literature,6  is a randomized comparison that carries with it the methodologic robustness of the original ENIGMA II trial, and has applicability in a wide variety of clinical settings. In closing, we thank the authors for their thorough reanalysis and presentation of the ENIGMA II data for the PONV outcome. This secondary analysis is revealing, but the conclusion that prophylaxis nearly eliminates PONV seems untenable.
Research Support
Support provided by the University of Saskatchewan, Saskatoon, Canada, for the salaries of Dr. Li, Dr. Balbuena, and Dr. Gamble.
Competing Interests
The authors declare no competing interests.
Edmond C. K. Li, M.D., Lloyd D. Balbuena, Ph.D., Jonathan J. Gamble, M.D. University of Saskatchewan, Saskatoon, Canada (E.C.K.L.).
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