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Original Papers

Comparison of ondansetron and tropisetron combined with droperidol for the prevention of emesis in women with a history of post-operative nausea and vomiting

Koivuranta, M.*; Ala-Kokko, T. I.*; Jokela, R.; Ranta, P.*

Author Information
European Journal of Anaesthesiology: June 1999 - Volume 16 - Issue 6 - p 390-395

Abstract

Introduction

Ondansetron and tropisetron, which are selective 5-hydroxytryptamine receptor subtype 3 (5-HT3) antagonists, have proved to be effective in the prevention of post-operative nausea and vomiting [1-4]. Ondansetron, the anti-emetic efficacy of which has proved to be quite similar to that of droperidol [1], has been under extensive clinical research whilst tropisetron has received less attention in post-operative settings. The efficacy of tropisetron has been shown to be superior to placebo in patients undergoing gynaecological and ophthalmic surgery [3,5] and quite similar to droperidol in gynaecological incontinence surgery [4].

Possible differences in the relative potency and side effects between odansetron and tropisetron are still to be ascertained. There are some pharmacokinetic differences between these compounds. The mean elimination half-life of ondansetron is 3.5 h [6] while that of tropisetron is ≈8 h in volunteers classified as extensive metabolizers, increasing up to 30 h in poor metabolizers [7]. Because of its longer elimination half-life tropisetron is administered as a once daily dosage in comparison with ondansetron requiring multiple dosing for long lasting effects. It could be hypothesized that due to its longer lasting effects tropisetron might be more suitable than ondansetron for preventing post-operative nausea and vomiting (PONV) in high-risk patients. Female patients with a history of post-operative sickness, scheduled to have laparoscopic surgery, constitute a distinct high-risk population [8,9]. This patient population may benefit from the use of a multidrug approach or a 'balanced' regimen to prevent PONV [10-12]. Furthermore, longer drug effect might be especially advantageous for ambulatory patients. Consequently, the objective of the present study was to compare the anti-emetic efficacy, duration of action and tolerability of ondansetron and tropisetron in combination with a low dose of droperidol as double-agent regimens for women with a past history of PONV undergoing gynaecological laparoscopic surgery.

Methods

This prospective, randomized, double-blind trial was performed in the Departments of Anaesthesiology and Gynaecology of Oulu University Hospital and Lapland Central Hospital in Finland with the approval of the local institutional ethics committees and the national agency for medicines and performed according to the declaration of Helsinki. Only those female patients with a history of previous PONV, scheduled to have elective gynaecological laparoscopic surgery, aged over 18 years with an ASA Physical Status I-III were eligible. Patients who were pregnant or breast-feeding, had evidence of hepatic or other metabolic dysfunction, Parkinson's disease or those who had currently received opioids or medication with anti-emetic activity were excluded. Written informed consent was obtained from the participants.

Ninety patients were allocated in a random double-blind fashion to receive intravenously (i.v.), at the end of the laparoscopic procedure, either a slow injection of ondansetron 8 mg or tropisetron 5 mg, diluted to the same volume of saline. The treatment allocation codes were contained in sealed opaque envelopes and for each consecutive patient recruited the assisting nurses opened the next envelope in order and administered the study drug but did not participate in the post-operative assessment.

Anaesthesia was standardized throughout the study. Patients received premedication with midazolam 7.5 mg given orally 1 h pre-operatively. General anaesthesia was induced with glycopyrrolate 0.2 mg, propofol 1-2 mg kg−1 and fentanyl 2-4 μg kg−1. Muscle relaxation was produced with rocuronium 0.5 mg kg−1 and all patients had controlled ventilation via a tracheal tube with oxygen-enriched air. After the induction of anaesthesia, all patients received droperidol 0.75 mg i.v. Anaesthesia was maintained with end-tidal sevoflurane up to 2% and further increments of fentanyl 1-2 μg kg−1 were given as required. The recovery from neuromuscular blockade was without reversal agents. Peroperatively, the patients received 500-1000 mL 0.9% sodium chloride solution i.v. During surgery, the patients were monitored with ECG, non-invasive arterial pressure measurement, pulse oximetry and end-tidal carbon dioxide. Post-operatively, pain relief was provided by oxycodone, given at the request of the patient, 0.05 mg kg−1 i.v. in the recovery room and 0.1 mg kg−1 intramuscularly (i.m.) on the ward, and with paracetamol 1 g given orally at 8-h intervals. All patients were monitored for a period of at least 2 h in the recovery ward. Post-operatively supplementary anti-emetic treatment was provided with droperidol 0.75 mg i.v., given at the request of the patient.

Data collection and patient interviews with a structured questionnaire were completed on the ward on the first post-operative day up to 24 h after surgery. All observations were made without the interviewer being aware of the study treatment. The phase of menstrual cycle was recorded. The occurrence and intensity of nausea and vomiting, the time for additional anti-emetic treatment, the intensity of post-operative pain, the total dose of oxycodone administered, the level of sedation and any possible adverse events were recorded twice after the operation: at 2 h in the recovery room by trained nurses and at 24 h on the ward by the investigators. Nausea was graded by the patients as none, mild, moderate or severe and the number of doses of additional droperidol were recorded. Post-operative average pain during the 24 h study period was assessed by the patients using a verbal 11-point scale where 0 meant no pain at all and 10 represented worst pain imaginable. Post-operative sedation was objectively graded by the nurses after the first 2 h in the recovery room using a four point scale: 1=awake, 2=drowsy, 3=asleep, easily arousable and 4=fast asleep. The feeling of overall drowsiness during the whole study period was assessed by the patients with an 11-point scale from 0=alert and awake to 10=as drowsy as one could possibly feel.

The efficacy of the study treatments was measured by the incidence of nausea and that of vomiting as well as by the time of the first request for an additional dose of droperidol, respectively, during the 24-h period after surgery. The outcomes between the two treatment groups were statistically compared by calculating the 95% confidence interval (CI) for the differences in proportions using the CIA programme [8] and by calculating a P-value for the null hypothesis of no difference using the Fisher's exact test. The means of the measured variables were compared by the test statistic based on the t-distribution assuming unequal variances. The SPSS for Windows (version 6.1.3.) statistical package was used. A sample size of 45 patients per group was estimated to achieve a power of 0.8 (a=0.05) to detect a 30% difference in the main outcome measure between the groups.

Results

A total of 88 patients were studied: 45 received ondansetron and 43 tropisetron. Two patients were excluded from the final analysis because of a protocol violation. The ondansetron and tropisetron treatment groups were comparable as to the demographic and clinical characteristics (Table 1). Most of the study patients had a regular menstrual cycle, and there were no essential differences regarding the distribution of the patients to the separate physiological menstrual phases. Overall, approximately two-thirds of the patients underwent an ovarian or a tubal procedure.

Table 1
Table 1:
Patient characteristics in the two treatment groups

In the recovery room during the first 2 h post-operatively, the incidence of nausea was higher (16% vs. 9%, P=0.35) and the need for an additional dose of droperidol was more common after tropisetron than after ondansetron treatment (16% vs. 4%, respectively; P=0.11) but the differences did not reach statistical significance (Table 2). All rescued patients received only one dose. The level of sedation was similar in both groups after the first two observation hours: 49% of the patients in the ondansetron group vs. 40% in the tropisetron group were drowsy or sleeping.

Table 2
Table 2:
Incidence (%) of nausea and vomiting and the need for additional anti-emetic medication in the recovery room (0-2 h) and overall (0-24 h) in the two treatment groups (number of patients in parentheses)

During the entire 24 post-operative hours, the occurrence and severity of nausea as well as the incidence of vomiting were similar in both treatment groups (Table 2). However, there was a tendency towards a higher overall incidence of nausea in the tropisetron group (49% vs. 36%, P=0.28) although the difference was not statistically significant (Table 2). Two-thirds of the patients with nausea assessed it as mild and one-third of all nauseated patients vomited, mostly once or twice. Anti-emetics were administered equally often, the maximum number of doses being three in both groups. The mean time from the administration of the study drugs to the first additional dose of droperidol post-operatively was significantly shorter in the tropisetron than in the ondansetron group (3 h 18 min vs. 6 h 25 min, mean difference 3 h 7 min, 95% CI 55 min - 5 h 18 min, P=0.007).

There were no differences in the mean post-operative pain and sedation scores between the groups (Table 3). The consumption of oxycodone was also similar. A headache was significantly more common after ondansetron (42% vs. 14% after tropisetron; P=0.004). Otherwise the side effect profile did not differ between the groups, and no clinically severe side effects were observed during the whole study period.

Table 3
Table 3:
Post-operative oxycodone consumption (mg) (mean, range), pain and sedation scores (mean, SD), and the incidence (%) of adverse events in the two treatment groups

Discussion

Intravenous ondansetron and tropisetron, both with droperidol, appeared to be similar in the overall efficacy lacking deleterious side-effects. The only statistically significant difference in the primary outcome was the earlier onset of post-operative nausea/vomiting in the tropisetron group as determined by the time between the administration of the study drug and the first additional anti-emetic dose.

However, there was a trend such that if the study sample size were larger, the ondansetron-droperidol combination would have been shown to be more effective. Although not statistically significant, there was a higher incidence of nausea at 0-2 h, during 0-24 h and need for early droperidol at 0-2 h in the tropisetron group. Furthermore, this was inspite of the fact that the patients in the ondansetron group had a higher incidence of motion sickness, received a longer anaesthetic and larger dose of fentanyl.

In this trial using double-agent prophylaxis, a relatively low incidence and severity of nausea and vomiting in a population with a very high probability of post-operative sickness was observed. We have previously shown in a clinical study that in these patients at high risk the incidence of PONV among women receiving placebo exceeds 80% [1]. Furthermore, prophylaxis using a single-agent therapy with droperidol or ondansetron has been demonstrated to have limited efficacy in the control of nausea and vomiting, particularly in patients with a past history of PONV [1,13].

The recommended dosage for tropisetron against emesis induced by chemotherapy has been 5 mg per day [7], which was chosen for our high-risk trial, too. However, there is also evidence that even a 2-mg dose would be sufficient for prophylaxis in post-operative patients [14]. In this study, with respect to the longer elimination half-life of tropisetron, unexpectedly tropisetron 5 mg seemed to be less effective than ondansetron 8 mg although due to the small sample size of this study statistical significance was not reached. The optimal i.v. dose of ondansetron for prevention is still not established. We chose 8 mg to achieve long-term efficacy, based on our previous findings of prophylaxis in women with a positive history of post-operative sickness [11], supported also by a recent review of efficacy and dose-response data of ondansetron by Tramèr et al.[15]. Although tropisetron has the advantage of a single daily dosage regimen and a longer elimination half-life, the present comparative study suggested that a dose of ondansetron 8 mg could have a longer drug effect compared with tropisetron 5 mg as judged from the earlier onset of nausea in the rescued patients in the topisetron group. This might be a result of differences in the affinity, selectivity and setting time for 5-HT3 receptors between these two compounds. It has been speculated that the anti-emetic efficacy of 5-HT3 antagonists correlates more with the duration and intensity of the inhibition of the receptor site rather than with their plasma levels [16].

There are limited data on the relative difference in efficacy between ondansetron and tropisetron in post-operative patients. In cancer patients, acute emesis induced by chemotherapy has been prevented effectively with ondansetron 8 mg, tropisetron 5 mg and granisetron 3 mg [17]. Naguib et al. has compared i.v. ondansetron 4 mg, tropisetron 5 mg and granisetron 3 mg with metoclopramide 10 mg and placebo in patients undergoing laparoscopic cholecystectomy [18]. In line with our study results there was a tendency to a better outcome in the ondansetron group. Although they observed no statistically significant differences in the incidence of post-operative nausea and vomiting (35% vs. 52%), nor in the onset of rescue medication between the ondansetron and tropisetron patients only ondansetron was a significantly better anti-emetic than placebo (72%). We confirm these findings in a selected patient population with a high risk of PONV.

The prophylactic anti-emetic treatments used in this study were well tolerated. The most frequently reported adverse effects of tropisetron have been mild headache, constipation, diarrhoea with abdominal pain, fatigue and dizziness [7]. A headache is a typical side effect of all 5-HT3 antagonists. In this study, it was significantly more commonly complained about by the patients given ondansetron, a frequent adverse effect associated with its use [11]. This could be related to the relatively high dose of ondansetron administered. Unfortunately the severity of the headache experienced was not assessed, which could have given more information concerning this adverse reaction of our two trial medications. The use of droperidol may account for the mild restlessness complained about by 11 patients, but serious extrapyramidal reactions were not observed in this study.

In conclusion, prophylactically administered ondansetron and tropisetron, when combined with low-dose droperidol intra-operatively, resulted in a similar incidence and low severity of PONV in a high-risk population. Although this was a relatively small study, it could also be concluded that ondansetron appeared to be more effective in preventing nausea in the early hours after surgery than tropisetron, but induced a headache more often during recovery.

Acknowledgments

We are grateful to Mr R. Leinonen, Programmer Analyst in the Computer Services Centre of the University of Oulu, for the statistical calculations.

References

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Keywords:

COMPLICATIONS, nausea, vomiting; ANTI-EMETICS, ondansetron, tropisetron; SURGERY, laparoscopic

© 1999 European Society of Anaesthesiology