Randomized, placebo-controlled trial of combination antiemetic prophylaxis for day-case gynaecological laparoscopic surgery{dagger}

A. B. Ahmed1, G. J. Hobbs1,* and J. P. Curran2

1University Department of Anaesthesia and Intensive Care, Queen’s Medical Centre, Nottingham NG7 2UH, UK. 2Directorate of Anaesthesia, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK

{dagger}This article is accompanied by the Editorial.

Accepted for publication: July 3, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In a randomized, double-blind trial, we compared i.v. ondansetron 4 mg (control), i.v. ondansetron 4 mg and cyclizine 50 mg (combination) and i.v. saline 0.9% (placebo), given after induction of standardized anaesthesia, for the prevention of nausea and vomiting (PONV) after day-case gynaecological laparoscopic surgery. Compared with placebo, fewer patients in the control group vomited (9/20 versus 11/59, P=0.02) or needed rescue antiemetic (7/20 versus 9/59, P=0.06) before discharge. Compared with the control, fewer patients in the combination group (n=60) vomited (11/59 versus 2/60, P=0.01) or needed rescue antiemetic (29/59 versus 2/60, P=0.03) before discharge. The incidence of vomiting in the combination group was less than 5% overall. Compared with the control, the combination group had a significantly lower incidence (P=0.001) and severity (P<0.001) of nausea after discharge and more patients with no PONV at any time during the study (15/59 versus 27/60, P=0.03). Unlike the placebo and control groups, no patient receiving combination prophylaxis was admitted overnight for PONV management.

Br J Anaesth 2000; 85: 678–82

Keywords: vomiting, nausea, antiemetics; surgery, laparoscopy


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Postoperative nausea and vomiting (PONV) is associated with gender, motion sickness, opioids and previous PONV.13 Its reported incidence after day-case gynaecological laparoscopic surgery exceeds 50%.35 Postoperative nausea and vomiting is often the most distressing aspect of patients’ surgical experience,6 can increase pain and cause unplanned hospital admission.7 As more patients undergo surgery as a day case, the humanitarian and economic implications of PONV are becoming increasingly important.8

Prophylaxis of PONV often consists of a single antiemetic drug given during surgery. Of those available, ondansetron,4 5 9 cyclizine10 and droperidol11 reduce the incidence of PONV by approximately 50%. However, many patients continue to experience PONV. Therefore, a different strategy is required to solve this problem.

Before the advent of 5HT3 receptor antagonists, combinations of antiemetics were used for the management of patients at risk of chemotherapy-induced emesis.12 The success of 5HT3 receptor antagonists in the field of cancer chemotherapy has, unfortunately, not been repeated for PONV. However, combination antiemetic prophylaxis is a promising approach for inpatient surgery.13 14 We evaluated the efficacy of a combination of ondansetron and cyclizine for the prophylaxis of PONV in patients undergoing day-case gynaecological laparoscopic surgery.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
With hospital ethics committee approval and informed patient consent, we recruited patients aged 18 yr and over who were undergoing day-case gynaecological laparoscopy. Patients with a history of gastro-oesophageal reflux, taking medications with known antiemetic activity or who were pregnant or breastfeeding were excluded.

All received a standardized general anaesthetic. After induction with propofol 2–3 mg kg–1 and alfentanil 10 µg kg–1 and muscle relaxation with vecuronium 0.05–0.1 mg kg–1, a laryngeal mask airway was inserted and the patient’s lungs were ventilated mechanically to an end-tidal CO2 of 4.5–5.0 kPa. Anaesthesia was maintained with 35% oxygen in nitrous oxide with added isoflurane. After induction, each patient was given i.v. morphine 0.18 mg kg–1 to a maximum of 12.5 mg and rectal diclofenac 100 mg for postoperative analgesia. At the end of surgery, muscle relaxation was reversed with neostigmine 2.5 mg and glycopyrrolate 500 µg.

We planned to study 150 patients in a double-blind manner. Patients were allocated randomly, using a closed envelope technique, in blocks of 50 to three groups in a 2:2:1 ratio to receive ondansetron 4 mg and 0.9% saline (control), ondansetron 4 mg and cyclizine 50 mg (combination) or 0.9% saline (placebo). Each treatment was given as two 10 ml i.v. injections. These were prepared by a single investigator who took no part in data collection.

After surgery, increments of i.v. morphine for severe pain, oral dihydrocodeine 60 mg for moderate pain and a rescue antiemetic (i.m. prochlorperazine 12.5 mg) for nausea or vomiting were given as judged necessary by one of two recovery nursing staff. Patients were discharged from the day-case unit when they were able to take oral fluids and walk independently. This decision required the agreement of both patient and nurse. Patients were given oral diclofenac 75 mg sustained release to be taken 12-hourly and oral dihydrocodeine 60 mg to be taken 4-hourly as required at home for pain.

Table 1 shows the patient characteristics and the clinical outcome data collected during the study. Clinical outcome data were assessed during three periods after surgery but before discharge: in the recovery area (0–30 min), in the day-case ward (30–120 min) and in the postoperative sitting room (120–240 min). The assessments were made at the end of each timing interval, and the worst score during each interval for each symptom was recorded. The severities of nausea and pain were assessed by the patients, using standard four-point ordinal scales (none, mild, moderate, severe). The single worst scores for nausea and pain from any of the three time periods before discharge were used for analysis. Data from patients who completed the study up to hospital discharge or admission were included.


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Table 1 Patient characteristics and clinical outcome. BMI = body mass index; *major outcome measures
 
A telephone questionnaire was completed by the patients 24 h after surgery. This assessed the incidence of vomiting, the incidence and severity of nausea and pain, and analgesic requirements during the 24 h after hospital discharge, including the journey home. Similarly, the worst severity of nausea was taken to be the end-point in the post-discharge analysis. Data from patients admitted to hospital or receiving rescue antiemetic were excluded from the analysis of post-discharge data. All data were recorded by a single research nurse who remained blinded to the treatment groups throughout the study.

The major outcome measures were the incidences of vomiting before and after discharge, the need for rescue antiemetic before discharge and the frequency of a complete response (defined as the absence of any nausea and vomiting during the whole study period). Continuous data were analysed using Student’s t-test and ANOVA. Other data were analysed with the {chi}2 and Fisher’s exact sum tests if contingency tables had insufficient numbers. Pairwise comparisons of data before discharge were performed if there was an overall difference at the 5% level. After discharge, data from control and combination groups only were compared. Data were analysed using Minitab for Windows, release 10.1. Using previously published data from similar patient groups and local clinical audit, a 50% reduction in the incidence of vomiting after the combination treatment compared with the control, and control compared with placebo, would be demonstrated using a sample size of 150 patients in a 2:2:1 ratio respectively, with a power in excess of 0.8 at {alpha}=0.05. P<0.05 was taken as statistically significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
During the conduct of this study, we demonstrated in another study in a similar patient group that both cyclizine and ondansetron given singly were better than placebo for the prophylaxis of PONV.10 We therefore undertook interim analysis of the first 100 patients, which confirmed a significantly higher incidence of PONV in patients receiving placebo. Allocation to this group was therefore discontinued and 140 patients were finally enrolled in the study.

One patient who underwent laparotomy (control group) was withdrawn from the study. Data before discharge from 139 patients were analysed (Table 2). All groups were comparable for patient characteristics, pain and analgesic requirement. No patient required the administration of atropine or glycopyrrolate for intra-operative bradycardia. Eighteen patients (Fig. 1) received rescue antiemetic in hospital (seven in the placebo group, nine in the control group and two in the combination group). Seven were admitted overnight for management of PONV or four for other reasons (uncontrolled pain, surgical observation or social reasons). Table 3 gives the data for the remaining 110 patients who completed the telephone questionnaire at 24 h. Patient characteristics and analgesic data after discharge were comparable for the control and combination groups. There were more patients with moderate or severe pain in the control group, but this did not reach statistical significance. Two patients in this group received postoperative morphine, as did two in the combination group and none in the placebo group. This factor was, therefore, unlikely to be of significance.


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Table 2 Patient characteristics and clinical outcome before discharge. *Mean (SD), otherwise number (%) of patients. BMI=body mass index
 


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Fig 1 Primary outcome measures. Numbers over bars are number of patients. *Complete response = no nausea or vomiting at any time. The P values in the figure refer to comparisons between all groups. Combination compared with control: #P=0.01; {Phi}P=0.03; {psi}P=0.08.

 

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Table 3 Patient characteristics and clinical outcome data after discharge. *Mean (SD), otherwise number (%) of patients; §comparison between control and combination groups. BMI=body mass index
 
Figure 1 shows data for the major outcome measures. Compared with the placebo group, the control group had a significantly lower incidence of vomiting (P=0.02). Compared with the control group, the combination group had significantly less vomiting (P=0.01) and need for rescue antiemetic (P=0.03) before discharge, tended to vomit less after discharge (P=0.08) and had a significantly greater number of patients with a complete response (P=0.03). The incidence of vomiting in the combination group was less than 5% overall.

Compared with the control group, the combination group tended to have a lower incidence of moderate or severe nausea before discharge (P=0.06), and a significantly lower incidence and severity of nausea after discharge. No patients in the combination group required overnight admission for the management of PONV.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We have demonstrated, as have others,4 5 9 that in patients undergoing day-case gynaecological laparoscopy the prophylactic administration of ondansetron significantly reduces the problem of PONV. When cyclizine was combined with ondansetron, this reduction was even more striking, the effect extending into the period from discharge, through the journey home to the day after surgery.

Patients undergoing day-case gynaecological laparoscopy have a number of risk factors for PONV, including female gender, the use of per-operative opioids15 and a journey home likely to lower the threshold to motion-induced emesis.16 Consequently, we believe that this group provides an excellent model for antiemetic studies.

Ondansetron has few unwanted side-effects.9 It has been given prophylactically in combination with dexamethasone in major gynaecological surgery13 and with droperidol in females using patient-controlled analgesia with morphine after abdominal surgery.14 17 These inpatient studies suggest that combination prophylaxis may be associated with significant improvements in PONV outcomes. However, the extrapyramidal side-effects of droperidol are of some concern, particularly in day-case patients,18 and many clinicians may be reluctant to give steroids primarily for managing PONV. Cyclizine is an alternative antiemetic and is efficacious for the prevention of PONV after day-case gynaecological surgery.10 When given sequentially for treating established PONV after major surgery, ondansetron and cyclizine together may be more effective than either drug alone.19 Cyclizine causes mild sedation, which is unlikely to be of significance, and tachycardia; the advantage of this is arguable because dangerous bradycardia may accompany the pneumoperitoneum that accompanies laparoscopy. It is an antagonist at muscarinic cholinergic and histamine-1 receptors.20 Its combination with a 5HT3 antagonist is entirely logical, given the multi-receptor aetiology of PONV.6 Cyclizine is also inexpensive.

Our study could be criticized on a number of grounds. First, we used morphine per-operatively, a recognized cause of PONV.3 However, gynaecological laparoscopy, particularly when clips are applied to the Fallopian tubes, causes pain.21 A departmental audit in this patient group indicated a higher risk of unacceptable pain before and after discharge when morphine was omitted from the analgesic regimen. Furthermore, there is an association between pain and PONV,22 and treating pain with opioids may relieve PONV.22 23 Our use of morphine was deliberate, and this accords with a recent survey of routine practice.15 Secondly, we did not stratify patients for the nature of the gynaecological procedure. We have previously suggested that the efficacy of single antiemetic prophylaxis may be influenced by the type of laparoscopic operation performed.10 However, the types of laparoscopy performed (diagnostic or sterilization) in our study were comparable between groups and this factor was unlikely to have influenced our results. Thirdly, we identified neither those at particular risk of PONV2 nor those who smoked. It was therefore inevitable that some patients who may not have suffered PONV received unnecessary antiemetic therapy. However, we believe the high risk of PONV in this group of patients justifies aggressive prophylaxis. Fourthly, we abandoned allocation to the placebo group when one of our studies10 demonstrated the superiority of both cyclizine and ondansetron over placebo when given prophylactically in a similar patient population. We felt obliged to perform interim analysis of the current study, and when it revealed a similar result we took advice and on ethical grounds stopped allocating to the placebo group. Some may also be critical of the use of placebo in studies of PONV.24 In order to validate our model of PONV and strengthen our study design, we considered it desirable to demonstrate concurrently the efficacy of single and combination prophylaxis. Finally, we did not collect side-effect data. It was the aim of this study to establish only the efficacy of combination prophylaxis after day-case surgery.

Many studies of antiemetics show significant reductions in the incidence of PONV, often of the order of 50%,4 5 9 11 but the outcomes associated with single antiemetic prophylaxis remain disappointing. A recent systematic review of the use of ondansetron compared with placebo for the prevention of PONV estimated the ‘number needed to treat’ (the number of patients that must be exposed to a treatment to prevent one PONV event) to be 5–6 when the risk of PONV was high.25 The authors challenged the use of prophylactic ondansetron when risk–benefit and cost– benefit arguments were considered. A randomized, double-blind, placebo-controlled study comparing the efficacy and costs of droperidol or ondansetron for PONV prevention in a patient group similar to that taking part in our study concluded that the use of low-dose droperidol was more cost-effective.11 However, the incidences of vomiting after low-dose droperidol were 12 and 27% before and after discharge respectively. The corresponding incidences after combination prophylaxis in our study were 3 and 4% respectively.

If our results are confirmed in other day-case studies, then combination therapy represents a major step forward in improving the outcome in these patients. It is important, especially in this group of patients, to have effective control of symptoms. Combination prophylaxis may also have important economic implications. These include reduced costs associated with nursing time spent managing PONV as well as the costs of delayed discharge or unplanned admission. Appropriate economic evaluations of these and alternative antiemetic combinations need to be performed for different patient groups, including the assessment of side-effect profiles, and there is a need to verify our results in day-case patients. Data concerning single antiemetic prophylaxis may therefore no longer be clinically relevant in patient groups at high risk of PONV.


    Acknowledgements
 
We are grateful to Claire Harvey RGN for assisting with data collection.


    Footnotes
 
* Corresponding author Back


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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