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NEUROSURGICAL ANESTHESIA

A Randomized, Double-Blinded Comparison of Ondansetron, Droperidol, and Placebo for Prevention of Postoperative Nausea and Vomiting After Supratentorial Craniotomy

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina

Address correspondence to Cecil Borel, MD, Department of Anesthesiology, DUMC Box 3094, Duke University, Durham, NC 27710. Address e-mail to borel001{at}mc.duke.edu

	Abstract

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Nausea or vomiting occurs frequently after craniotomy. Because of the need for frequent postoperative neurological assessment, an effective antiemetic with minimal sedative side effects is needed. Therefore, we compared ondansetron to droperidol in a randomized, double-blinded, placebo-controlled study. A total of 60 adults requiring elective supratentorial craniotomy received standardized IV anesthesia with 4 mg of ondansetron, 0.625 mg of droperidol, or placebo at skin closure. The incidence of postoperative nausea, emesis, pain and sedation scores, and rescue antiemetic use were recorded at 0, 0.5, 1, 4, 8, 12, 24, and 48 h. All groups were demographically similar. Differences existed for cumulative 8, 12, and 24 h incidences of nausea (24 h, P = 0.03) and emesis (24 h, P = 0.04). Within 4 h, when maximal effect could be expected from treatment, 20% of the ondansetron group, 25% of the droperidol group and 50% of the placebo group received rescue antiemetic (P = 0.12). No differences in pain (P = 0.82) or sedation (P = 0.74) scores were detected. Both ondansetron and droperidol prevent nausea; however, only droperidol reduces emesis after supratentorial craniotomy. The dose of droperidol used was not more sedating than ondansetron. Sustained reduction in nausea and emesis over 24 h indicates a preemptive benefit of prophylactic antiemetic in this surgical population.

Implications: Nausea and vomiting after brain surgery are particularly troubling, because effective treatment may cause sedation, making postoperative neurological assessment difficult. Our study shows that both ondansetron and droperidol are effective in reducing nausea, and that droperidol is particularly effective in reducing vomiting. Neither drug caused more sedation than placebo.

	Introduction

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Nausea or vomiting affects 50% of individuals after craniotomy (1). In addition to causing patient discomfort, protracted postoperative nausea and vomiting (PONV) may cause dehydration, acid-based disturbances and electrolyte imbalance. The physical act of vomiting may increase intracranial or cerebral intravascular pressure, jeopardizing hemostasis and cerebral perfusion. However, management of PONV may confound patient assessment postcraniotomy if sedative side effects of antiemetics are present.

Ondansetron has minimal sedative properties. The efficacy of ondansetron in prevention and treatment of PONV has been demonstrated for many procedures (2). Other work, however, suggests that ondansetron is not superior to droperidol (3–10). In neurosurgical patients there are limited and conflicting reports (11–14). Ondansetron was effective in two cases of head injury (12) and when compared to placebo prophylaxis in patients undergoing infratentorial surgery (14). However, prophylactic ondansetron was of no benefit when compared to placebo, in pediatric (11), and with metoclopramide in adult craniotomy patients (13). Ondansetron has not been compared with droperidol in patients undergoing craniotomy. In this study, we compared the efficacy and side-effect profiles of ondansetron, droperidol, and placebo for prevention of PONV in patients undergoing supratentorial craniotomy.

	Methods

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We designed this study as a randomized, double-blinded, placebo-controlled, prospective trial. With institutional review board approval, 60 patients ages 18–75 yr scheduled for elective supratentorial craniotomy for mass lesion gave written, informed consent for participation in this study. Exclusion criteria were ASA physical status IV or V, antiemetic use pre- or intraoperatively, allergy to ondansetron or droperidol, pregnancy, breast feeding, morbid obesity, mental retardation, or psychiatric illness. For women of childbearing potential, a negative serum ß-hCG test was confirmed before enrollment.

Anesthetic technique was standardized: preinduction midazolam up to 2 mg IV, the induction of anesthesia by 3–5 mg/kg IV thiopental, 5 to 10 µg/kg IV fentanyl, and muscle relaxant of choice, followed by maintenance of anesthesia with 60% nitrous oxide, 40% oxygen, IV fentanyl, muscle relaxant and isoflurane as clinically indicated. Muscle relaxants included vecuronium, cisatracurium, and pancuronium. Muscle relaxants were reversed with neostigmine and IV glycopyrrolate. All patients received anticonvulsants perioperatively, and a large dose of dexamethasone intraoperatively.

Patients were randomly assigned to one of three groups. Group O received 4 mg of ondansetron diluted to 5 mL with 0.9% saline, Group D received 0.625 mg of droperidol in 5 mL of 0.9% saline, and the placebo group (Group P) received 5 mL of 0.9% saline. Study drugs were prepared by a pharmacist and administered by the anesthesia staff not involved in data collection. Study drugs were given IV on surgical commencement of skin closure. Postoperatively, patients were transferred to the recovery area, where IV analgesia (codeine) was nurse administered when necessary and assessments commenced.

Nausea was defined as a feeling of the urge to vomit, as solicited by the investigators during assessments. Vomiting was defined as expulsion of stomach contents through the mouth. Retching was defined as an attempt to vomit, not productive of stomach contents. An emetic episode was defined as a single vomit or retch or any number of continuous vomits or retches.

Assessments were made at 0, 30, and 60 min and at 4, 8, 12, 24, and 48 h. Nausea, emetic episodes, pain scores (6-point, linear numeric scale 0–5; the concept was explained to patients preoperatively), sedation scores (Ramsay scale) (15), and codeine use were recorded during these time intervals. The level of observation was equivalent for all subjects and constant over the 2 days of study.

Rescue antiemetics were administered at the discretion of the nurse or on request of the patient. IM trimethobenzamide (200 mg) was given followed by 4 mg of IV ondansetron 1 h later for rescue therapy, if symptoms were not controlled.

Power analysis indicated that 20 patients in each group would be sufficient to demonstrate a 30% difference in the incidence of PONV between any two groups at an of 0.05 and ß of 0.2. Binary data at each measured interval were analyzed by Fisher’s exact test and ordinal data by Kruskal-Wallis test. The repeated measures were analyzed by using a generalized estimating equations approach. Cumulative incidences of nausea and emesis were examined to eliminate confounding effects of the rescue antiemetic. A P < 0.05 was significant.

	Results

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A total of 60 patients (n = 20 per group) was enrolled. All groups were demographically similar, and there was no difference in duration of anesthesia or total fentanyl dose administered (Table 1). Dexamethasone was not different between groups.

View larger version (33K): [in this window] [in a new window]   Figure 1. Cumulative incidence of nausea and emesis by study group. *P < 0.05.

The use of rescue antiemetics within 4 h, when maximal effect could be expected from treatment, was not significantly different. In Group P, 10 of 20 (50%); Group O, 4 of 20 (20%); and Group D, 5 of 20 (25%) received rescue antiemetic (P = 0.119). Overall the 48-h incidence of rescue antiemetic administration was: P, 10 of 20 (50%); O, 8 of 20 (40%); and D, 8 of 20 (40%). After adjusting for rescue antiemetic and time, droperidol and ondansetron were significantly different from placebo with respect to cumulative nausea (D versus P, P = 0.009; O versus P, P = 0.013). However, only droperidol was significantly different from placebo for cumulative emesis (P = 0.0119). No difference in pain (P = 0.82) or sedation (P = 0.74) scores or codeine use was detected (See Figure 2).

View larger version (64K): [in this window] [in a new window]   Figure 2. Sedation scores by study group.

	Discussion

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PONV is a common problem and a potential cause of complications after craniotomy. The placebo group in our study experienced a similar incidence of nausea (70%) and vomiting (55%) to that previously reported from a retrospective analysis in adults (1) and a prospective study of children (11).

Two previous studies concluded that ondansetron is ineffective for prophylaxis of PONV after craniotomy (11, 13). In 1996, Pugh et al. (13) compared prophylactic metoclopramide and ondansetron in adults undergoing craniotomy. There was no placebo control group. Their primary end point was no PONV. By inference, some PONV was experienced by 44% of subjects receiving metoclopramide and 70% of those receiving ondansetron. Because we examined nausea and vomiting independently, our data are not directly comparable; however, the 70% incidence of PONV in the ondansetron group of Pugh et al. (13) is similar to our placebo incidence. We cannot explain the difference in observed drug effect. Possibly the control incidence in Pugh et al. (13) of postcraniotomy PONV exceeded 70%.

Furst et al. (11) examined 24-hour postcraniotomy emesis in a pediatric population. Their results are consistent with our findings in adults, that there was no significant reduction in emesis after prophylactic administration of ondansetron. However, during the same period, we demonstrated a significant reduction in nausea from prophylactic ondansetron. The disparate effects of ondansetron on nausea and emesis suggest different mechanisms for these two events after craniotomy. Droperidol blocks dopaminergic pathways and, to a lesser extent, blocks histamine and serotonin receptors, whereas ondansetron acts only at serotonin sites (16). Perhaps craniotomy causes emesis by some etiologies specific to the surgery, independent of the chemoreceptor trigger zone but amenable to blockade by droperidol.

We found less nausea in both treatment groups over 24 hours. However, there was no difference in rescue antiemetic use between ondansetron and placebo groups during this time. This suggests the benefit of ondansetron to be therapeutic rather than preemptive. This is consistent with the higher incidence of PONV in the placebo group during the first 4 hours resulting in the administration of rescue antiemetic. In contrast, the effect of droperidol may have been preemptive. Over time, the placebo group would receive ondansetron rescue and thereafter, behave in a similar fashion to the ondansetron treatment group. This may explain why there is no difference between these two groups. However, in the droperidol group, emesis remained at a lower incidence beyond the expected duration of the action of the drug. The mechanism for a preemptive effect is not apparent. Antiemetic administration on completion of surgery means that intraoperative factors were similar in all groups. The only events after antiemetic administration were reversal of muscle relaxant and emergence from anesthesia.

A potential cross-over treatment effect was introduced by using ondansetron as a rescue antiemetic. This would confound analysis of data by discrete time intervals because the groups may no longer be different. To control for the effect of rescue antiemetic, cumulative rates for nausea and emesis were analyzed. Each patient experiencing the first episode of nausea or emesis in a given time interval was added to the total number for the previous time interval. Thus, each patient was counted only once in the cumulative total. This approach also eliminated bias caused by individuals with refractory PONV.

Because of concern regarding sedation of postcraniotomy patients, we elected to study a small dose of droperidol. Previous work has demonstrated that up to 1.25 mg of droperidol was not more sedating than ondansetron (2). That there was no difference in sedation score over time between groups in our study confirms the safety of a dose of 0.625 mg.

We have demonstrated that prophylactic 0.625 mg of droperidol or 4 mg of ondansetron before emergence from anesthesia for craniotomy, effectively reduces postoperative nausea. The same dose of droperidol also reduces emesis without causing excessive sedation. This effect was sustained over 24 hours, indicating a preemptive benefit of prophylaxis. For these reasons we recommend 0.625 mg of droperidol be administered during closure of craniotomy.

	Acknowledgments

 
The authors gratefully acknowledge the contributions of John Guy, MD, in conceptualization and support for this work. The authors also acknowledge the work of Thangam Malaizoodum, MB, BS, in patient enrollment and data collection.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999