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AMBULATORY ANESTHESIOLOGY

Haloperidol Plus Ondansetron Versus Ondansetron Alone for Prophylaxis of Postoperative Nausea and Vomiting

Loreta Grecu, MD^*, Edward A. Bittner, MD, PhD^*, Jay Kher, MD, Sarah E. Smith, BS, and Carl E. Rosow, MD, PhD^*

From the *Department of Anesthesia and Critical Care, Massachusetts General Hospital; Tufts New England Medical Center; and Boston University School of Medicine, Boston, Massachusetts.

Address correspondence to Carl Rosow, MD, PhD, Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. Address e-mail to crosow{at}partners.org.

Abstract

INTRODUCTION: Haloperidol 1 mg and ondansetron 4 mg are equally safe and effective for postoperative nausea and vomiting prophylaxis. We compared the combination to ondansetron alone in a mixed surgical population.

METHODS: Two-hundred and sixty-eight adults undergoing general anesthesia received 4 mg ondansetron plus 1 mg haloperidol or saline in this randomized, double-blind protocol. Efficacy and safety data were obtained until 480 min after postanesthesia care unit entry.

RESULTS: The combination had more complete responders (76.2% vs 59.2%), less nausea, less rescue, and longer time to rescue. Sedation, time to postanesthesia care unit discharge, and QTc prolongation were not different. No subject had dystonia, akathisia, or serious dysrhythmias.

CONCLUSIONS: Postoperative nausea and vomiting prophylaxis with both drugs is significantly more effective and longer lasting than ondansetron alone. There is no detectable increase in side effects.

Large trials of single-drug postoperative nausea and vomiting prophylaxis rarely indicate more than 65%–70% complete response.1,2 Combining droperidol and ondansetron generally improves efficacy,3–5 although some studies claim only a weak benefit6,7 or no benefit at all. Ondansetron is thought to suppress nausea less effectively than vomiting,8 and adding droperidol to ondansetron may reduce nausea.4 We have reported that PONV prophylaxis with 1 mg of haloperidol is comparable in efficacy to 4 mg ondansetron.9 The present study compares ondansetron alone with the combination of haloperidol and ondansetron in a mixed surgical population. We predicted the combination would be significantly more effective with decreased nausea and, possibly, a longer duration.

METHODS

This randomized, double-blind trial compared 4 mg IV ondansetron versus the combination of 1 mg haloperidol plus 4 mg ondansetron for PONV prophylaxis. Elective surgical patients gave written informed consent to participate in this IRB-approved protocol. The inclusion criteria were: Subjects 18 yr or older, ASA I–III, scheduled for general or combined epidural-general anesthesia. Unlike our first trial, those at high risk for PONV were included. We excluded those with adverse reactions to haloperidol or ondansetron, cardiac dysrhythmias, seizure disorder, Parkinson’s disease, and chronic treatment with dopamine antagonists or dexamethasone. At the request of the study sponsor, a screening electrocardiogram was obtained, and those with a QTc interval >450 ms were excluded.

Protocol
Approximately 1 h before the anticipated end of surgery, each patient received 4 mg of ondansetron plus the contents of a coded syringe containing either 1 mg haloperidol (5 mg/mL, Ben Venue Laboratories, Inc.) or 0.2 mL saline. Other prophylactic antiemetics, propofol infusions, and metoclopramide were not allowed, but there were no other restrictions on anesthesia, surgery, or postoperative care. Postanesthesia care unit nurses gave antiemetic rescue treatment for any episode of emesis or nausea score >2.

Efficacy Measurements
At PACU entry and every 30 min until discharge, we recorded nausea (11 point verbal scale, 0 = "none," 10 = "worst possible"), retching or vomiting, and rescue treatment. At 480 min after PACU entry, a phone call was made to the patient’s home or to the hospital ward to assess the later occurrence of PONV, need for treatment, and possible side effects. Complete response was considered no nausea, retching, emesis, or need for rescue. Time to rescue and/or PACU discharge were calculated from the time anesthetics were discontinued. The patient was eligible for PACU discharge when awake or arousable, vital signs stable (±15% of preoperative values), Spo₂ >90%, temperature >35.5°C, pain moderate or less, and a nausea score 3/10 or less. If the patient did not meet these criteria upon PACU entry, study personnel recorded which factor determined the time of discharge.

Safety Measurements
Sedation was measured categorically (1—awake, 2—arousable, 3—unarousable). Dysphoria and delirium were recorded as present/absent. We looked specifically for dystonia, akathisia, and other extrapyramidal signs. The QTc interval was determined automatically from pre- and postoperative electrocardiograms by machine algorithm using the Bazett transformation. QTc prolongation was defined as >450 ms for males and >470 ms for females.

Data Analysis
A 15% difference in complete responders was considered clinically significant. Based on an anticipated 70% response to ondansetron alone, 119 subjects per group would give 80% power to detect such a difference ( >0.05, two-tailed). Student’s t-test or single-factor ANOVA was used to compare continuous variables. When normality failed (Kolmogorov–Smirnov test), the Wilcoxon’s ranked sum test was used. The ² test was applied for categorical data. Kaplan–Meier survival analysis was used to compare the elapsed times to antiemetic rescue. The log rank test was used to test for equality of the survivor functions. Statistical computations were performed with STATA 8.0 (College Station, TX, 2003) statistical software.

RESULTS

Two-hundred and sixty-eight subjects were enrolled, and 263 could be evaluated for efficacy. There were no significant differences between the groups for any demographic variable (Table 1). The difference in smokers (fewer for the combination) nearly reached significance (P = 0.07).

The combination was significantly more effective by almost every measure (Table 2). There was more complete response, less nausea, and less rescue. Persistent nausea determined eligibility for PACU discharge in 10 ondansetron subjects versus only one subject given the combination (P = 0.006). Emesis and retching were infrequent and not different between groups. Figure 1 shows that the time to rescue antiemetic was considerably longer for the combination (P = 0.005).

View larger version (8K): [in this window] [in a new window]   Figure 1. Survival curve showing the fraction of subjects not receiving antiemetic rescue vs time. Closed circles represent ondansetron, open circles represent ondansetron plus haloperidol. Time to rescue was significantly longer for the combination (P = 0.005).

Approximately 40% of patients in each group met discharge criteria upon PACU entry and the mean time to discharge was not different. Only 5 subjects were unarousable upon PACU entry; interestingly, none were among the 19 subjects >70-yr-of-age. One patient in the combination group experienced dysphoria and one patient in each group had delirium. There was no dystonia, akathisia, or other extrapyramidal effect. The average preoperative QTc was 417.5 ± 15.8 ms. There was no difference in the incidence of postoperative QTc prolongation (23.9% combination; 23.0% ondansetron), and no serious dysrhythmias occurred (Table 3).

DISCUSSION

A sizable fraction of the surgical population is at high risk for PONV and deserves prophylaxis with more than one antiemetic.10 One study used haloperidol as part of multimodal prophylaxis, but the contribution of individual drugs was not evaluated.11 Our data indicate that combining haloperidol with ondansetron has a substantial effect on early PONV. Over the first 8 h after surgery, we found a 17% absolute reduction in PONV compared with ondansetron alone (number-needed-to-treat = 5.88). Our study is limited by the short observation period and the lack of a standardized anesthetic or surgical population. On the other hand, the results appear to be broadly applicable. Since the conclusion of our two trials, we have incorporated haloperidol plus ondansetron as a part of routine PONV prophylaxis at our institution.

We have no evidence that haloperidol is any more effective than droperidol. The efficacy of the droperidol– ondansetron combination has been investigated in more than 20 trials, and the literature (through 1999) was reviewed in a meta-analysis by Eberhart et al.12 Surprisingly, that analysis found little evidence to suggest a statistical benefit of the combination (possibly because many of the trials were under-powered). The large factorial trial by Apfel2 estimated that ondansetron plus droperidol produced a 9% absolute reduction in PONV over 24 h compared with ondansetron alone. This corresponds to a number-needed-to-treat of more than 10, not a large effect. The haloperidol effect we measured might have been the same if we had collected data for a full 24 h.

In summary, we have found that haloperidol plus ondansetron significantly reduces PONV, and it nearly eliminates persistent nausea as a factor preventing discharge from the PACU. The timing of rescue medication indicates that the combination lasts longer than ondansetron alone. Our data suggest that haloperidol does not produce significant sedation or other toxicity, and the QTc effect (if any) is impossible to distinguish from other perioperative factors. Additional studies will be needed to determine the timing and safety of repeated doses.

ACKNOWLEDGMENTS

The authors acknowledge the invaluable assistance of the Massachusetts General Hospital Research Pharmacy and the nursing staff of our Post-Anesthesia Care Unit.

Footnotes

Accepted for publication October 26, 2007.

Supported, in part, by a grant from Glaxo Smith Kline Pharmaceuticals.

Reprints will not be available from the author.

REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Grecu, L. Articles by Rosow, C. E. Search for Related Content PubMed PubMed Citation Articles by Grecu, L. Articles by Rosow, C. E. Related Collections Ambulatory Complications Clinical Pharmacology Pharmacology