Nausea and Vomiting following Balanced Xenon Anesthesia Compared to Sevoflurane: A Post-Hoc Explorative Analysis of a Randomized Controlled Trial

Abstract

Objective: Like other inhalational anesthetics xenon seems to be associated with post-operative nausea and vomiting (PONV). We assessed nausea incidence following balanced xenon anesthesia compared to sevoflurane, and dexamethasone for its prophylaxis in a randomized controlled trial with post-hoc explorative analysis.

Methods: 220 subjects with elevated PONV risk (Apfel score ≥2) undergoing elective abdominal surgery were randomized to receive xenon or sevoflurane anesthesia and dexamethasone or placebo after written informed consent. 93 subjects in the xenon group and 94 subjects in the sevoflurane group completed the trial. General anesthesia was maintained with 60% xenon or 2.0% sevoflurane. Dexamethasone 4mg or placebo was administered in the first hour. Subjects were analyzed for nausea and vomiting in predefined intervals during a 24h post-anesthesia follow-up.

Results: Logistic regression, controlled for dexamethasone and anesthesia/dexamethasone interaction, showed a significant risk to develop nausea following xenon anesthesia (OR 2.30, 95% CI 1.02-5.19, p = 0.044). Early-onset nausea incidence was 46% after xenon and 35% after sevoflurane anesthesia (p = 0.138). After xenon, nausea occurred significantly earlier (p = 0.014), was more frequent and rated worse in the beginning. Dexamethasone did not markedly reduce nausea occurrence in both groups. Late-onset nausea showed no considerable difference between the groups.

Conclusion: In our study setting, xenon anesthesia was associated with an elevated risk to develop nausea in sensitive subjects. Dexamethasone 4mg was not effective preventing nausea in our study. Group size or dosage might have been too small, and change of statistical analysis parameters in the post-hoc evaluation might have further contributed to a limitation of our results. Further trials will be needed to address prophylaxis of xenon-induced nausea.

Trial registration: EU Clinical Trials EudraCT-2008-004132-20 ClinicalTrials.gov NCT00793663.

Conflict of interest statement

Competing Interests: The authors of this manuscript had the following competing interests with Air Liquide Santé International during the time of performance and evaluation of the trial: Mark Coburn and Rolf Rossaint received lecture and consultant fees. Christian Stoppe received lecture fees. Astrid V. Fahlenkamp and Jan Cremer received a travel recompensation for an investigators meeting. Rolf Rossaint furthermore was a consultant for Baxter, a company selling the anesthetic Sevoflurane. None of the remaining authors declared any competing interests. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study procedure.

A simplified sketch of the study procedure is shown in Fig 1. After obtaining written informed consent and baseline examination, patients were first randomized to receive xenon or sevoflurane anesthesia for their individually scheduled surgery, then randomized to receive dexamethasone or placebo for prophylaxis of post-operative nausea. Within the first hour of anesthesia, the randomized prophylactic treatment was applied. Patients were monitored for 24h following anesthesia in fixed intervals (during PACU stay at 0, 5, 15, 30, 45, 60, 75, 105, 120 min until discharge as well as 2h, 6h, and 24h post anesthesia). The study-specific survey was completed 24h post anesthesia.

Fig 2. Consort flow chart.

A detailed flow chart depicts all patients enrolled in the trial including the reasons for study drop-out. 220 patients in total were randomized after written informed consent into one of the same-sized study groups. Pre-interventional drop out in the xenon group occurred in fifteen cases (¶): Five patients withdrew their consent; five were excluded after randomization for safety reasons. Two patients did not receive the scheduled surgery; three did not receive the allocated intervention for administrative reasons. Post-interventional drop-out in the xenon group occurred in two cases ($) by exclusion from data analysis due to study protocol violation. 93 patients in the xenon group received the allocated intervention and data analysis. Of these patients, 43 received dexamethasone as randomized prophylactic treatment, whereas 50 received placebo. Five patients (§) withdrew preterm because of severe nausea. Their data until the time of dropout was included into the final analysis. Pre-interventional drop-out in the sevoflurane group occurred in seven cases (Ұ): One patient withdrew his consent; two were excluded after randomization for safety reasons. Two patients did not receive the scheduled surgery; two did not receive the allocated intervention for administrative reasons. Post interventional drop-out in the sevoflurane group occurred in nine cases (&): One patient dropped out due to a serious adverse event not associated with the study intervention. Eight patients of the sevoflurane group were excluded from data analysis because of violation of the study protocol. 94 patients in the sevoflurane group received the allocated intervention and data analysis, with 44 cases of dexamethasone as randomized prophylactic treatment and 50 placebo. Two patients (#) did not complete the 24h-follow-up because of withdrawal due to severe nausea. Their data until the time of dropout was included into the final analysis.

Fig 3. Significant nausea during PACU surveillance.

The timed occurrence of nausea experienced by study participants during their PACU stay is depicted in Fig 3. Fig 3A shows the frequency of significant nausea in study participants, given as percent of total. The nausea intensity ratings of subjects experiencing significant nausea are presented in Fig 3B as medians and quartiles.

Fig 4. Frequency of nausea in the dexamethasone and placebo subgroups.

The timed frequency of significant nausea experienced by study participants during their PACU stay differentiated by randomized prophylactic is shown in Fig 4. Fig 4A shows nausea frequency in study participants following dexamethasone prophylaxis; Fig 4B depicts nausea frequency following placebo. All values are given as percent of subgroup and randomized anesthesia, accordingly.