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Ondansetron, droperidol and their combination for the prevention of post-operative vomiting in children

Klockgether-Radke, A.*; Neumann, S.*; Neumann, P.*; Braun, U.*; Mühlendyck, H.

European Journal of Anaesthesiology: July 1997 - Volume 14 - Issue 4 - p 362–367
Original Paper
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In this study the antiemetic effects of droperidol, ondansetron and their combination were evaluated in 160 ASA Grade I and II children undergoing surgery for strabismus, who were randomly assigned to one of four groups: Group D received droperidol 75 μg kg−1, group O ondansetron 0.1 mg kg−1, group D + O received both droperidol 75 μg kg−1 and ondansetron 0.1 mg kg−1, and group N NaCl as placebo. Emesis within the first 24 h occurred in 95.0% of the children with placebo medication, compared with 32.5% (D), 40.0% (O) and 45.0% (D + O) in the groups with antiemetic prophylaxis. The differences between group N and all other groups were significant (P<0.001). However, there were no statistically significant differences between the groups D, O and D + O. It is concluded that droperidol (75 μg kg−1) and ondansetron (0.1 mg kg−1) both significantly reduce PONV in children undergoing surgery for strabismus. Neither ondansetron, nor the combination D + O were superior to droperidol alone.

*Department of Anaesthesiology, Emergency Medicine and Intensive Care and †Department of Strabology and Neuroophthalmology, Georg-August-University of Göttingen, Göttingen, Germany

Accepted September 1996

Correspondence: Dr A. Klockgether-Radke, Department of Anaesthesiology, Emergency Medicine and Intensive Care, Georg-August-University of Göttingen, Robert-Koch-Str. 40, D—37075 Göttingen, Germany.

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Introduction

Ondansetron, a selective 5-HT3 receptor antagonist, has been widely used for the prevention and therapy of chemotherapy-induced vomiting. Given in doses of 0.1 mg kg−1 intravenously (i.v.), ondansetron was more effective with less undesirable effects than high dose metoclopramide (3 mg kg−1) [1]. It was intriguing therefore to test ondansetron for the prevention of post-operative nausea and vomiting (PONV). Meanwhile, there is a wealth of evidence suggesting that the substance is effective when compared with placebo [2–5]. Over decades, droperidol has been a standard antiemetic drug, a substance which has proved to be highly effective. However, there is some concern about undesirable effects, e.g. sedation or acute dyskinesia [6]. It is interesting to note that until recently there were only a limited number of studies comparing ondansetron with other antiemetic substances, for example droperidol, in terms of PONV [7]. Meanwhile a greater number of such studies have been published with conflicting results [8–14]. Very little is known about interactions between ondansetron and droperidol when both substances are combined [15]. It was assumed that drugs acting at different receptor types (5-HT3 and D2) of the chemoreceptor trigger zone may exert additive antiemetic effects [16].

Our intention was to recruit a sufficiently large number of patients of a high-risk group regarding PONV for a randomized double-blind, placebo-controlled study to answer three questions:

  1. Is ondansetron more effective than droperidol in preventing PONV?
  2. Is a combination of both ondansetron and droperidol superior to a single drug therapy?
  3. Are there undesirable side effects as a result of ondansetron or droperidol medication?
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Methods

Following institutional approval and informed parental consent, 160 ASA Grade I and II children, aged 4–14 years, scheduled for surgery for strabismus, were randomly assigned to one of the following groups: Group D (n=40) received droperidol 75 μg kg−1 (max. 2.5 mg); Group O (n=40) received ondansetron 0.1 mg kg−1 (max. 4.0 mg); Group D + O (n=40) received droperidol 75 μg kg−1 and ondansetron 0.1 mg kg−1, and Group N (n=40) received NaCl 0.1 mL kg−1 0.9% as placebo.

After fasting for at least 6 h all children received midazolam 0.5 mg kg−1 orally as premedication 30 min prior to the beginning of anaesthesia. On arrival in the anaesthesia induction room a venous cannula was placed in the dorsum of a hand, which had been prepared with EMLA™ cream 60 min earlier. After starting an i.v. infusion of ringer's lactate and appropriate preoxygenation via a facemask anaesthesia was induced following a standard technique using thiopentone 4–6 mg kg−1, alfentanil 0.02 mg kg−1, and atropine 0.01 mg kg−1. Vecuronium 0.1 mg kg−1 was given to facilitate endotracheal intubation. Patients were then ventilated with 66% N2O in O2 and halothane (0.8–1.5 vol% inspired concentration). All children were monitored with continuous ECG, blood pressure oscillometry, pulse oximetry, capnometry, and a rectal temperature probe. After induction of anaesthesia and before the start of eye surgery substance 1 was administered, containing droperidol 75 μg kg−1 (groups D and D + O), ondansetron 0.1 mg kg−1 (O) or NaCl 0.1 mL kg−1 0.9% (N). Fifteen min before the end of surgery substance 2 was administered, containing ondansetron 0.1 mg kg−1 in group D + O or NaCl 0.1 mL kg−1 0.9% in all other groups. All drugs were provided in neutral syringes adjusted to 0.1 mL kg−1 body weight. Neither the attending anaesthetist nor the patient or the observer in the recovery room knew which drugs had been administered. The oculocardiac reflex (OCR) was defined as a sudden drop in heart rate of at least 15% after manipulation of an eye muscle. At the end of surgery halothane and nitrous oxide were discontinued, and the endotracheal tube removed as soon as the patient had resumed spontaneous breathing and swallowing and coughing reflexes had returned. Neuromuscular block was not reversed at the end of surgery. The children were then transferred to the post-operative recovery room. Apart from basic monitoring by trained personnel, an assessment of recovery and of post-operative nausea and vomiting (PONV) was carried out by one of the authors (S.N.) using the following scores:

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Recovery score

Awareness

  • Fully aware: 4
  • Awake, drowsy: 3
  • Drowsy, arousable by shouting: 2
  • Drowsy, arousable by shaking: 1
  • Not arousable: 0
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Movements

  • Directed spontaneous movements: 4
  • Directed movements on demand: 3
  • Undirected spontaneous movements: 2
  • Undirected movements on demand: 1
  • No movements: 0

Figures for awareness and movements were combined to obtain the Recovery Score.

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Emesis score

  • No nausea or vomiting: 4
  • Slight nausea: 3
  • Heavy nausea: 2
  • Nausea and retching or vomiting: 1

These scores were calculated 30, 60, 90 and 120 min after arrival in the recovery room. Retching or vomiting were recorded as emetic episodes. 'Extubation time' was defined as the time following discontinuation of halothane until removal of the endotracheal tube. 'Time to opening of eyes' is the time from discontinuing halothane until the patient first opened his/her eyes. Having met discharge criteria the patient left the recovery room and was transferred to the surgical ward, where monitoring of nausea, retching and vomiting was continued until 24 h after surgery. Patients experiencing more than one emetic episode were given one dose of a rescue medication (dimenhydrinate 40 mg rectally). This dose was repeated if indicated.

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Statistics

Values are presented as mean±standard deviation, whenever applicable. Fisher's exact two tailed test and χ2-test were employed to compare the categorical data. Mann–Whitney U-test was used for the comparison of means. A P-value <0.05 was regarded as statistically significant.

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Results

The patients in the four groups were comparable with regard to the data shown in Table 1. However, operation and anaesthesia times in group D + O were higher compared with all other groups. In group N 38/40 (95.0%) of the patients vomited during the first 24 h, 13/40 (32.5%) in group D, 16/40 (40.0%) in group O, and 18/40 (45.0%) in D + O. The patients in group N experienced an average of 5.9 emetic episodes, compared with 1.0 (D), 1.4 (O), and 1.6 (D + O). The differences between group N and all other groups were significant (P<0.001). There were no statistically significant differences between the groups D, O and D + O. This applies to the number of children vomiting at least once, and also the number of emetic episodes. Mean time to onset of vomiting was 136min for patients with placebo medication, 404 min in group O, 501 min (D), and 775 min (D + O) (P<0.05 group N vs. all other groups). Group D + O children had the longest time to onset. If this figure is corrected for the operation time (substance 2 was given by the end of surgery), the difference is still significant compared with groups N and O (P<0.01). Of the patients without antiemetic medication (N) 42.5% received rescue medication vs. 17.5% (D), 15.0% (O), and 22.5% (D + O). The results of emesis scores calculated for the first 2 h in the recovery room are shown in Fig. 1. There were no significant differences between the four groups.

Table 1

Table 1

Fig. 1.

Fig. 1.

In a second step statistical analysis was carried out to elucidate the relation between vomiting and other variables shown in Table 1. No correlation could be found between emesis and sex, anaesthesia time, operation time, maximal halothane concentration, number of eye muscles repaired, and the occurrence of OCR. Younger children were more likely to vomit and had more emetic episodes than older ones. The subgroup of children under 50 months of age had a 100% incidence of vomiting, whereas the figure for those over 140 months was 21%. There was a negative correlation between age and the incidence of emesis (r=0.81, P<0.001).

The 30 min recovery scores were lower in group D + O children compared with group N (P<0.05) (Fig. 2). The values for time to extubation and time to opening of eyes are given in Table 2. Time to opening of eyes was longer in patients of group D + O compared with group N (P<0.05).

Fig. 2.

Fig. 2.

Table 2

Table 2

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Discussion

This study, carried out in 160 children after surgery for strabismus, yielded three major results:

  1. Droperidol (75 μg kg−1), ondansetron (0.1 mg kg−1) and a combination of both were effective in preventing PONV when compared with placebo.
  2. The incidence of PONV was lowest in the droperidol group. Neither ondansetron nor a combination of both were superior to droperidol.
  3. There were no major undesirable side effects (acute dyskinesia, prolonged sedation) related to droperidol or ondansetron. There were no significant differences in post-operative sedation.

Patients undergoing strabismus surgery are a high-risk group for PONV. In patients without antiemetic prophylaxis, vomiting is common (43–85%) [17]. Compared with other studies, a rate of 95% in the placebo group of the present study is fairly high. This may be because of the fact that our survey was carried out on an in-patient basis, and all children were carefully monitored for a complete 24-h period. An explanation for the high percentage of PONV in poststrabismus patients is speculative; the factors influencing nausea and vomiting after eye muscle repair are not, as yet, understood properly.

Droperidol given in doses of 75 μg kg−1 in paediatric anaesthesia is effective, though not completely successful in preventing PONV. Droperidol is believed to act at different receptor sites of the chemoreceptive trigger zone (acetylcholine, histamine, dopamine). The main antiemetic effect is probably a result of its antidopamine (anti-D2) activity [18]. Droperidol seems to be superior to metoclopramide [17] and other antiemetic substances. However, there is some concern regarding post-operative sedation and the risk of acute dyskinesia [6]; neither of these was observed in the present study.

Ondansetron has been used for the prevention of post-operative nausea and vomiting. In children, 0.1–0.15 mg kg−1 were used successfully [13,14]. Until recently only a few studies were published comparing droperidol and ondansetron for the prevention of PONV. Alon and Himmelseher found a superior effect of ondansetron (13% vomiting) compared with 45% for droperidol and 54% for metoclopramide [7]. These results could not be confirmed by the same author, when using a reduced dosage of ondansetron [8]. In this study, droperidol prevented PONV in 80% of the cases, compared with 40% for ondansetron (P<0.05). A number of other studies have also been published with conflicting results [8–14]. The only study revealing a significant advantage for ondansetron compared with droperidol seems to be the one by Furst et al.[9]. Our study is in accordance with those of the majority of other authors that ondansetron is not superior to droperidol in its capacity to prevent PONV. Obviously there is a substantial difference in the pathogenesis of chemotherapy-induced and post-operative nausea and vomiting. In the first case a certain amount of 5-HT is thought to be released by the enterochromaffine cells of the gut as a result of chemotherapy. Ondansetron is believed to act both as a central and a peripheral 5-HT3 blocking agent. Hence, the emetic effects of serotonin may be suppressed at two sites, at the chemoreceptor trigger zone, and at the gut mucosa. However, the pathogenesis of PONV is much more complicated. Several factors are known to influence PONV, and a number of receptor sites are believed to be involved. These include the opioid receptor as well as histamine, serotonin, acetylcholine, and dopamine receptors [18]. It is thus unlikely that PONV can be eliminated by blocking only one of the different receptor sites involved. This may explain the poor effect of a 5-HT3 blocking substance in this study. The purpose of this study was to test the effect of a combination of droperidol and ondansetron, thereby blocking at least two different receptors involved in PONV. In one study [15], a group of adult patients receiving droperidol and ondansetron had less PONV than patients treated with either of these drugs alone. However, our results in children are disappointing in terms of an antiemetic drug combination. Patients receiving both droperidol and ondansetron experienced even more PONV than those treated with one of the drugs alone. This may be explained by the fact that anaesthesia and operation times were longer in group D + O compared with the other groups. However, there is one aspect of the combination group worth mentioning. Children having received both drugs had the longest delay before onset of vomiting (775 min (D + O) vs. 136 min (N), P<0.05). This may encourage us to give at least one of the drugs in a second dose at the end of the first day. Obviously the antiemetic effects of both drugs are too brief, when given on a single-dose basis during anaesthesia. It is our impression that the emetic effects elicited by anaesthesia and eye muscle surgery are still active at the end of the operation day and during the following night, a time when the residual antiemetic effects of droperidol and ondansetron are very weak.

There were no major differences regarding sedation scores between the groups, a result which was unexpected. Obviously the anaesthetic drugs themselves have a greater impact on post-operative sedation than the antiemetic drugs administered.

In conclusion, droperidol, ondansetron and a combination of both reduced PONV in children undergoing surgery for strabismus when compared with placebo. Neither ondansetron nor the combination were superior to droperidol. Droperidol resulted in the lowest rate of PONV in all the groups studied while at the same time incurring the lowest costs.

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Keywords:

Vomiting; Strabismus Surgery; Droperidol; Ondansetron

© 1997 European Academy of Anaesthesiology