Postoperative nausea and vomiting (PONV) is the most frequent side effect after anesthesia.¹ The incidence of PONV is variable; around 30% of unselected inpatients and up to 70% of high-risk patients are likely to be affected during the 24 hours after emergence from anesthesia.² Many patients rank PONV even above pain as the top undesirable outcome after surgery and anesthesia.³ In this March issue, Feng et al report their study on the use of intramuscular haloperidol 2 mg alone, intravenous ondansetron 4 mg alone, and intramuscular haloperidol 2 mg in combination with intravenous ondansetron 4 mg for PONV prophylaxis.⁴ This is a well designed and adequately powered study. It had strict control over a number of potential confounders, such as the same kind of surgical procedure, a standardized anesthetic technique, randomized groups, double-blindness of patients and investigators who collected the postoperative data, and a 24-hour follow-up. The authors compared complete response rates, incidence of PONV, nausea scores, the need for rescue medication, patient satisfaction scores, and adverse events among the three groups studied. The study also included patients at higher risk of PONV. The results confirmed that the combination of haloperidol and ondansetron had the highest antiemetic efficacy in comparison with either haloperidol or ondansetron alone. Patient’s satisfaction scores were significantly higher in the combination group than the groups given a single drug. It also revealed that the long half-life of haloperidol (18 hours) when used alone, did not result in better efficacy against PONV over 24 hours in comparison with ondansetron alone but the combination of the two drugs had greater effi cacy in terms of total incidence of PONV, nausea score, complete response rate and satisfaction score.

None of the antiemetics so far can completely pre vent PONV, principally because of patients having complex backgrounds, the influence of surgery, anesthesia-related factors and multiple mechanisms involving many innate physiologic receptors such as dopamine type 2, 5-HT type 3, histamine type 1, muscarinic cholinergic type 1, and neurokinin type 1. As we expected, this study did show that haloperidol combined with ondansetron had a better effi cacy than either haloperidol or ondansetron alone. The readers may ask whether haloperidol can replace droperidol as a better alternative for PONV prophylaxis. Haloperidol has been used in palliative care as an antiemetic for more than 40 years.⁵ It seems logical to choose haloperidol, an older member of the butyrophenone family and a major tranquilizer with a D2 receptor antagonistic effect. To anesthesiologists, low-dose droperidol (0.625−1.25 mg) has maintained a long and good record for its efficacy and safety in the management of PONV.⁶ However, according to a survey of members of the Society of Ambulatory Anesthesia, as cited by Habib and Gan in their report, the use of droperidol as an antiemetic has significantly declined after the FDA (Food and Drug Administration) “black box warning” in 2002.⁷ Droperidol was not available in Taiwan for a period of time since the original manufacturer stopped its production some years ago. In our recent survey of 15 sizable hospitals (> 1200 beds) in Taiwan, we found that generic droperidol was available for use in two thirds of these hospitals. It is not known whether droperidol is still widely used for PONV prophylaxis or only for the treatment of established PONV. In this study, the authors looked carefully for the potential adverse events of haloperidol, namely prolong ation of the QTc interval, over-sedation, extrapyramidal symptoms (EPS), and headache. The incidence of QTc longer than 470 ms was not significantly different among three studied groups. This might be relevant to patients who were younger or who had a low index number in ASA physical status.

It has been reported that haloperidol has many potential side effects, including akathisia, tardive dyskinesia, EPS, neuroleptic malignant syndrome, anti cholinergic effects and cardiac arrhythmias.⁸ It was not until September 2007 that similar warnings about haloperidol, as with droperidol, having the potential to cause QTc prolongation and torsade de pointes (TdP) when administered intravenously or in higher doses than recommended, were issued and caused much alarm.⁹ This may have led many practitioners to cast doubt on haloperidol as a safer alternative to droperidol. It has been reported that the inductive doses of intravenous haloperidol for TdP vary greatly.^8,10 From observation, it is suggested that a therapeutic alternative for haloperidol may be considered only in the elderly population.¹¹ All drugs known to cause significant QTc prolongation and TdP have the potential to block the potassium current, IKr.¹² The potential to cause clinically significant QTc prolongation depends on the selectivity for dopamine D2 or 5-HT2A receptors relative to the affinities of their human ether-a-go-go-related gene (HERG) channel.¹²

In this study, although no significant difference in the incidence of EPS and no untoward long-term consequences occurred in any of the studied groups, there were two cases where the EPS were related to the use of haloperidol. One more interesting finding was that the actual incidence of PONV was significantly less than the predicted incidence by Apfel et al’s risk score.¹³

In summary, this well designed study by Feng et al suggests that the combination of haloperidol (2 mg) and ondansetron (4 mg) can provide a higher complete response rate and greater patient satisfaction after laparoscopic cholecystectomy than either drug used alone.⁴

However, one should be particularly cautious in the use of haloperidol for PONV prophylaxis. A low dose via the intramuscular route is suggested, with avoidance of its use in patients with other QTc prolonging conditions such as hypokalemia, hypomagnesemia, cardiac arrhythmia, and in combination with other drugs which could also induce QTc prolongation.

Routine prophylactic use of antiemetics for PONV prevention is not widely accepted despite the increasing availability of newer and more expensive drugs. A single drug policy is usually suggested for mild- to moderate-risk (1−2 risk factors) patients and a combination of two antiemetics with different mechanisms is commonly recommended for highrisk (3−4 risk factors) patients.¹⁴ It is important that the benefits and adverse outcomes of PONV prophylaxis should be well balanced and the choice of antiemetic drugs would, therefore, depend on their efficacy, potential side effects, availability, cost, and patients’ physical status.

Yu-Chuan Tsai, MD

Professor of Anesthesiology

Department of Anesthesiology

Medical College and Hospital

National Cheng Kung University

Associate Editor, Acta Anaesthesiologica Taiwanica