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Twenty-Four of Twenty-Seven Studies Show a Greater Incidence of Emesis Associated with Nitrous Oxide than with Alternative Anesthetics

Hartung, John PhD

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Abstract

Whether nitrous oxide (N2 O) increases the incidence of vomiting has been a contentious issue for at least 25 years. Fortunately, so many investigations have addressed the question [1-27] that a straightforward and simple analysis of their findings yields a conclusive answer.

Methods

Standard procedures (electronic search, follow-up on references, serendipity) were used to collect reports of the incidence of emesis in patients that received N2 O versus anesthetics or analgesics without N2 O. Each paper was classified as having found or not found more frequent vomiting in N2 O patients, and the statistical significance of each such finding was classified as P < 0.05 or not < 0.05. Studies for which the incidence of vomiting could not be distinguished from the incidence of nausea (e.g., [28]) were not included because the incidence of vomiting could not be determined, and one study was eliminated because "nausea requiring therapeutic intervention" was treated with antiemetics, which presumably altered the subsequent distribution of emesis [29].

The primary analysis consisted of calculating the binomial probability that chance could account for the number of studies in which emesis was more frequent in patients who received N2 O. Assuming that N2 O has no effect on vomiting (P = 0.5 that a study will show an increased incidence), this is like calculating the probability that an observed number of heads or tails would occur on any number of flips of a fair coin (ties were counted as evidence in favor of the null hypothesis).

For investigations that failed to find a statistically significant association between N2 O and emesis, the presence or absence of the minimum acceptable statistical power (1 - beta = 0.80) to detect a 20% difference in incidence was determined.

Results

Twenty-seven studies were found in which the incidence of emesis in patients who received N2 O with or without other anesthetics or analgesics could be compared to the incidence of emesis in patients who received anesthetics or analgesics without N2 O [1-27]. In 24 of those 27 investigations, patients who received N2 O had an absolutely higher incidence of vomiting (Table 1, P < 0.00005).

Table 1
Table 1:
Bionomial Analysis of N2 O and Emesis

Patients given N2 O did not have an absolutely higher incidence of emesis in three studies. In the first of those, a higher incidence of emesis was found in patients who received cyclopropane [2]. The second study was a tie, with 2 of 18 patients in a ketamine-only group vomiting and 2 of 18 patients in a ketamine-N (2) O group vomiting [4]. In the third study [10], 11 of 21 halothane-N2 O patients vomited (52.4%) versus 10 of 19 halothane-only patients (52.6%).

Of the 24 studies that evidenced more frequent emesis among patients who received N2 O, 12 found the association to be statistically significant. Among the investigations that failed to find a statistically significant association between N2 O and emesis, only two had statistical power >0.80 to detect a 20% effect size. One of those two included significantly more patients (P < 0.03) with a history of vomiting after anesthesia in its non-N2 O groups but still found an absolutely higher incidence of vomiting among its N2 O patients [13]. The other study [17] stated a directional hypothesis: "We studied the hypothesis that administration of nitrous oxide causes … vomiting." Although a directional hypothesis warrants a one-tailed statistical test, the authors chose to simultaneously test the hypothesis that N2 O has antiemetic properties, which increased their P value to 0.059 [17]. Had they performed a one-way Fisher's exact test, their observed association between N2 O and emesis would have been statistically significant at P < 0.036.

Discussion

The liability inherent in the methodology used here is that relevant studies may not have been obtained for examination. However, few such investigations are likely to have been missed, and the minimum number of studies required to dissipate the statistical significance of the current finding is 10--each of which would need to be an investigation in which patients receiving N2 O did not have a higher incidence of emesis.

Every statistical analysis makes a trade-off between power and robusticity. A powerful analysis is one that has a low probability of generating a false-negative inference (type II error) as a consequence of artifacts inherent in the analysis itself (primarily assumptions required by the analysis). In distinction, a robust analysis is one that has a low probability of causing a false-positive inference (type I error). The analysis used here has low power and high robusticity. In less formal terms, it is a crude instrument in the sense that it is likely to fail to detect a true but weak (small effect size) relationship. However, when a robust analysis does detect a relationship, as is the case here (P < 0.00005), one can be confident that such a finding is not an artifact of assumptions required by that analysis.

Meta-analysis, in contrast, is relatively powerful but lacks robusticity. That is, because meta-analyses require more potentially invalidating assumptions and decisions, they are more likely to generate false-positive inferences. Nevertheless, for the purpose of addressing subanalyses, such as which groups of patients or procedures are most susceptible to a drug or intervention that has been shown to have an effect, meta-analysis is indispensable. The above notwithstanding, for the purpose of addressing the primary question of whether a drug or intervention has an effect, the robusticity of a binomial probability cannot be surpassed.

The data imply that N2 O, perhaps the most ubiquitously used drug in anesthesiology, produces a greater incidence of emesis, perhaps the most common postoperative morbidity, than other currently used anesthetics (P < 0.00005). This relationship is undoubtedly variable according to context and circumstances. Those contexts and circumstances warrant investigation without hinderance from the prevailing premise that N2 O has not been shown to increase the incidence of emesis ([30,31] cf. [32]). That is, we need to move from the question "Does N2 O cause vomiting?" to "When, why, in whom, and under what circumstances does N2 O cause vomiting?"

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