A factorial trial of six interventions for the prevention of postoperative nausea and vomiting

Abstract

Background: Untreated, one third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown.

Methods: We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly.

Results: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent. Propofol reduced the risk by 19 percent, and nitrogen by 12 percent; the risk reduction with both of these agents (i.e., total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients' baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients' baseline risk.

Conclusions: Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be used first. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients.

Fig. 1

Trial profile. Due to the factorial design, patients were simultaneously randomized to several interventions. One center each was unable to randomize for nitrogen (n=424), remifentanil (191), or both (181). A total of 4123 patients were thus factorially randomized to all six primary factors with 4086 providing analyzable data.

Fig. 2

Percentage of patients with PONV (± 95% confidence intervals) according to the various combinations of antiemetic drugs based on 5161 patients. Filled circles show the means of all patients given 0, 1, 2, or 3 antiemetics. Plus symbols (#) represent patients who received ondansetron; section symbols (§), those who received dexamethasone; and daggers (†), whose who received droperidol.

Fig. 3

Percentage of 4086 patients randomized to all interventions with PONV (± 95% confidence intervals) according to the combinations of anesthetic strategies and the number of anti-emetic treatments given. Because remifentanil did not contribute significantly to the PONV risk, it is not displayed in this figure. Although the figure suggests there is an interaction between nitrogen and propofol in patients with no antiemetics, statistical analyses did not confirm this impression.