1University Department of Anaesthesia and Intensive Care, Queens Medical Centre, Nottingham NG7 2UH, UK. 2Directorate of Anaesthesia, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK
This article is accompanied by the Editorial.
Accepted for publication: July 3, 2000
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Br J Anaesth 2000; 85: 67882
Keywords: vomiting, nausea, antiemetics; surgery, laparoscopy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All received a standardized general anaesthetic. After induction with propofol 23 mg kg1 and alfentanil 10 µg kg1 and muscle relaxation with vecuronium 0.050.1 mg kg1, a laryngeal mask airway was inserted and the patients lungs were ventilated mechanically to an end-tidal CO2 of 4.55.0 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 kg1 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 (030 min), in the day-case ward (30120 min) and in the postoperative sitting room (120240 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.
|
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 Students t-test and ANOVA. Other data were analysed with the 2 and Fishers 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
=0.05. P<0.05 was taken as statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
|
|
|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 56 when the risk of PONV was high.25 The authors challenged the use of prophylactic ondansetron when riskbenefit 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 |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Palazzo M, Evans R. Logistic regression analysis of fixed patient factors for postoperative sickness: a model for risk assessment. Br J Anaesth 1993; 70: 13540[Abstract]
3 Kenny GNC. Risk factors for post-operative nausea and vomiting. Anaesthesia 1994: 49 (Suppl.): S25
4 McKenzie R, Kovac A, OConnor T, Duncalf D, Angel J, Gratk I, et al. Comparison of ondansetron versus placebo to prevent postoperative nausea and vomiting in women undergoing ambulatory gynecologic surgery. Anesthesiology 1993; 78: 218[ISI][Medline]
5 Malins AF, Field JM, Nestling PM, Cooper GM. Nausea and vomiting after gynaecological laparoscopy: comparison of premedication with oral ondansetron, metoclopramide and placebo. Br J Anaesth 1994; 72: 2313[Abstract]
6 Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treatment and prevention. Anesthesiology 1992; 77: 16284[ISI][Medline]
7 Gold BS, Kitz DS, Lecky JH, Neuhaus JM. Unanticipated admission to the hospital following ambulatory surgery. J Am Med Assoc 1989; 262: 300810[Abstract]
8 Watcha MF, White PF. Economics of anesthetic practice. Anesthesiology 1997; 86: 117096[ISI][Medline]
9 Pearman MH. Single dose intravenous ondansetron in the prevention of postoperative nausea and vomiting. Anaesthesia 1994; 49 (Suppl.): S115
10 Cholwill JM, Wright W, Hobbs GJ, Curran J. Comparison of ondansetron and cyclizine for prevention of nausea and vomiting after day-case gynaecological laparoscopy. Br J Anaesth 1999; 83: 6114
11 Tang J, Watcha MF, White PF. A comparison of costs and efficacy of ondansetron and droperidol as prophylactic antiemetic therapy for elective outpatient gynecologic procedures. Anesth Analg 1996; 83: 30413[Abstract]
12 Mitchell E, Schein P. Gastro-intestinal toxicity. In: Perry M, ed. Chemotherapy Source Book. Baltimore: Williams & Wilkins, 1992; 624
13 Lopez-Olaondo L, Carrascosa F, Pueyo FJ, Monedero P, Busto N, Saez A. Combination of ondansetron and dexamethasone in the prophylaxis of postoperative nausea and vomiting. Br J Anaesth 1996; 76: 83540
14 Wrench IJ, Ward JEH, Walder AD, Hobbs GJ. The prevention of postoperative nausea and vomiting using a combination of ondansetron and droperidol. Anaesthesia 1996; 51: 7768[ISI][Medline]
15 Simpson RB, Russell D. Anaesthesia for day case gynaecological laparoscopy: a survey of clinical practice in the United Kingdom. Anaesthesia 1999; 54: 726[ISI][Medline]
16 Kamath B, Curran J, Hawkey C, Beattie A, Gorbutt N, Guiblin H, et al. Anaesthesia, movement and emesis. Br J Anaesth 1990; 64: 72830
17 Pueyo FJ, Carrascosa F, Lopez L, Iribarren MJ, Garcia-Pedrajas F, Saez A. Combination of ondansetron and droperidol in the prophylaxis of postoperative nausea and vomiting. Anesth Analg 1996; 83: 11722[Abstract]
18 Foster PN, Stickle BR, Laurence AS. Akathisia following low-dose droperidol for antiemesis in day-case patients. Anaesthesia 1996; 51: 4914[ISI][Medline]
19 Kyriakides K, Hussain S, Harrison J, Webb A, Hobbs GJ. Comparison of ondansetron and cyclizine in the treatment of early postoperative nausea and vomiting [abstract]. Br J Anaesth 1998; 80: 96[ISI][Medline]
20 Peroukta SJ, Snyder SH. Antiemetics: neurotransmitter receptor binding predicts therapeutic actions. Lancet 1982; 1: 6589[ISI][Medline]
21 Alexander JI. Pain after laparoscopy. Br J Anaesth 1997; 79: 36978
22 Anderson R, Krohg K. Pain as a major cause of postoperative nausea. Can Anaesth Soc J 1976; 23: 3669
23 Jakobsson J, Davidson S, Andreen M, Westgreen M. Opioid supplementation to propofol anaesthesia for outpatient abortion: a comparison between alfentanil, fentanyl and placebo. Acta Anaesthesiol Scand 1991; 35: 76770[ISI][Medline]
24 Aspinall RL, Goodman NW. Denial of effective treatment and poor quality of clinical information in placebo controlled trials of ondansetron for postoperative nausea and vomiting: a review of published data. Br Med J 1995; 311: 8446
25 Tramer MR, Reynolds JM, Moore A, McQuay HJ. Efficacy, doseresponse, and safety of ondansetron in prevention of postoperative nausea and vomiting. Anesthesiology 1997; 87: 127789[ISI][Medline]