751
ANESTH ANALG 3991;72:751-5
Prevention of Postoperative Nausea and Vomiting Using Ondansetron, a New, Selective, 5-HT3 Receptor Antagonist Jos Leeser, MD, and Harm Lip,
MD
LEESER J, LIP H. Prevention of postoperative nausea and vomiting using ondansetron, a new, selective, 5HT, receptor antagonist. Anesth Analg 1991;72:751-5.
The effect of ondansetron, a 5-HT3 antagonist, in prezlenting postoperative nausea and vomiting was investixatcd in a randomized, double-blind, placebo-controlled study of 84 patients undergoing gynecologic operation and receiving the same general anesthetic. The patients received premedication with eitker 16 m g oral ondansetron, or a matching placebo. The same medication was given postoperatively 8 h after the first dose. During the first hour after recovery from anesthesia, the frequencies of nausea and vomiting were
Nausea and vomiting are common after operative procedures requiring general anesthesia, with incidences that have remained unchanged over the last 30 yr (1). Ondansetron is a serotonin antagonist that selectively inhibits 5-HT3 receptors, with little or no activity on dopamine or other receptors (2). Both animal experiments (3) and studies in humans have shown ondansetron to be effective in preventing nausea and vomiting associated with cancer chemotherapy and radiation therapy (4-7). Because of its lack of activity at dopamine receptors, ondansetron has not been associated with extrapyramidal signs or symptoms often seen with antiemetics that act as dopamine antagonists, e.g., droperidol or metoclopramide. It may, therefore, have a potential benefit over such agents in the prevention of postoperative nausea and vomiting. The effect of oral ondansetron in preventing postoperative nausea and vomiting in patients undergoSupported in part by GIaxo Group Research, Greenford, Middlesex, U.K. Received from the Department of Anaesthesiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands; and the Department of Anaesthesiology, Sophia Ziekenhuis, Zwolle, The Netherlands. Accepted for publication February 6, 1991. Address correspondence to Dr. Leeser, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. 01991 by the International Anesthesia Research Societv 0003-2999/91/$3.50
52% and 40%, respectively, in patients given placebos.
01
the ondansetron group nausea and vomiting developed in 17% and 12%, respectively, values significantly difercnt from those with placebos ( P < 0.005). Similar differences were observed throughout the entire 24-h period after recovery, the incidence of nausea and vomiting being 67% and 60%, respectively, in the placebo group and 29% and 26% in the ondansetron treatment group. Ondansetron appears to be a promising antiemetic for the prevention of postoperative nausea and vomiting. Key Words: VOMITING, ondansetron.
ANTIEMETICS-
ing gynecologic operation under general anesthesia has, therefore, been investigated in a double-blind, randomized, placebo-controlled study.
Methods This randomized, double-blind study was carried out at two centers (Onze Lieve Vrouwe Gasthuis, Amsterdam, and Sophia Ziekenhuis, Zwolle) in The Netherlands, and the institutional ethics committees at both centers gave their approval for the conduct of the study. Each patient gave her written consent to take part in the study. A total of 84 patients, aged 18-65 yr, scheduled to have abdominal gynecologic operations under general anesthesia were included in the study. Patients who were pregnant or breast-feeding or who had evidence of clinically significant renal, hepatic, cardiovascular, metabolic, or endocrine dysfunction, or who had clinically significant abnormalities in laboratory screening tests, were excluded (patients of ASA physical status IV and V were thus excluded). In addition, patients who had received antiemetic medication in the 12 h before entering the study were excluded. Patients were randomly allocated to receive either ondansetron (Glaxo Group Research Limited, U.K.)
752
LEESER AND LIP
ANESTH ANALC 1991;72:731-5
or placebo according to the patient number taken from a predetermined randomization list. Study medication, either 16 mg ondansetron (two 8-mg tablets) or placebo (two tablets) was administered with premedication approximately 1 h before operation. A second dose of 16 mg ondansetron or placebo was administered postoperatively 8 h after the first dose. All patients were premedicated with 10 mg diazepam orally except for one patient who was given 5 mg diazepam. Anesthesia was induced with 4-5 mg/kg thiopental and maintained using 67% nitrous oxide in oxygen supplemented with 0.8%-2.5% isoflurane. Analgesia, if required, was maintained with alfentanil, using doses up to 7.5 mg, and vecuronium bromide was used as a muscle relaxant. If required, reversal of muscle relaxation was achieved with 1 mg atropine and 2 mg neostigmine except for two patients in the placebo treatment group, one of whom was given 2 mg atropine and 2 mg neostigmine, and the other who was given 0.5 mg atropine and 1 mg neostigmine. Postoperative analgesia was provided by morphine. All observations were made without knowledge of which treatment each patient received. Nausea and vomiting were assessed 1 h after recovery (as defined below), and again 24 h after recovery. Both nausea and vomiting were assessed separately, as present or absent. Nausea was assessed by a single individual at each center by asking whether the patient had experienced any nausea during the assessment period. The question was phrased in the same way for all patients. Records of patients who vomited were kept by the nursing staff. The severity of vomiting was not assessed. Retching was not assessed as a separate entity, and patients who reported retching were classified as nauseous. If patients experienced nausea or vomiting, they could request antiemetic treatment in the form of a 25-mg prochlorperazine maleate suppository. The duration of anesthetic administration and the time to recovery from anesthesia (patients were considered to have recovered from anesthesia when they first responded to spoken command) were assessed. Vital signs, including respiratory rate, blood pressure, and pulse rate, were monitored during the study. The patients were questioned about any possible side effects of the study medication 24 h after the operation and again after 5-7 days, when routine blood and urine samples were obtained for laboratory screening before discharge of the patient from the hospital. Laboratory tests included measurement of serum levels of sodium, potassium, calcium, total protein, albumin, urea, creatinine, bilirubin, alkaline
Table 1. Patient Demography Placebo
( n = 42) Age (Yr) Age range (yr) Weight (kg)
Ondansetron ( n = 42)
43 +- 11 23-61 69.6 t 10.2
44 i 10 21-60 65.2 ? 10.9
Values for age and weight are expressed as mean i SD.
phosphatase, alanine transaminase, aspartate transaminase, and y-glutamyl transpeptidase. Blood samples were also obtained for measurement of hemoglobin content, red blood cell count, packed cell volume, mean cell volume, platelet count, total white cell count, and differential white cell count. Urine was analyzed for pH and the presence of protein and glucose. The sample size chosen was designed to detect a decrease in nausea and vomiting from 65% after placebo treatment to 25% after ondansetron treatment assuming type I and type I1 errors to be 0.05. Analysis of the incidence of nausea and vomiting was carried out using logistic regression from which the relative risk of each event occurring was obtained for ondansetron relative to placebo. For the purposes of analysis, any patient who had requested and received prochlorperazine was deemed a treatment failure and considered to have vomited. All patients were included in the analysis. Differences in duration of anesthesia and the times to recovery were analyzed using the Wilcoxon ranksum test. Blood pressures and pulse rates were averaged during the maintenance of anesthesia, emergence from anesthesia, and the postoperative period. Analysis of covariance was applied to the single measurement recorded at induction of anesthesia and to the average values obtained during the maintenance of anesthesia and during the emergence and postoperative periods. Blood pressure and pulse rate measured at the time of premedication, before administration of study drug, was used as a pretreatment covariate in each analysis. Respiratory rate was averaged during the emergence and postoperative periods.
Results A total of 84 patients were entered into the study, 30 from one center and 54 from the other. The mean age and weight of the patients in the two treatment groups were not significantly different (Table 1).
ANESTH ANALG
ONDANSETRON AND POSTOPERATIVE EMESIS
753
1991:72:751-5
Table 2. Types of Operation Performed in Each Treatment Group Placebo Abdominal hysterectomy Abdominal laparotomy Vaginal hysterectomy
( n = 42)
Ondanse tron ( n = 42)
22 20 0
26 15 1
(28)
Ondansetron Placebo
Ondansetron Placebo
0 1 hour
024 hours
Figure 2 . The percentages of patients treated with ondansetron and placebo who vomited in the first hour and first 24 h after recovery. Actual numbers of patients in each group who vomited are shown in parentheses; n = 42 for both treatments. *Significantly different from placebo, P < 0.005.
unoanseuon riacew 0 1 hour
024 hours
Figure 1 . The percentages of patients treated with ondansetron and placebo who suffered nausea in the first hour and first 24 h after recovery. Actual numbers of patients in each group who suffered nausea are shown in parentheses; n = 42 for both treatments. *Significantly different from placebo, P < 0.001.
Table 3. Relative Risk of Experiencing Nausea or Vomiting During the First 24 h Postoperation on Ondansetron Compared With Placebo Time after recovery 0-1 h 0-24 h
The types of operations performed are presented in Table 2; the groups are well matched, with no important differences. One patient who had a vaginal hysterectomy was included in the analysis. The incidence of nausea and vomiting during the first 24 h after operation is shown in Figures 1 and 2. As might be expected, the incidence of nausea was somewhat higher than the incidence of vomiting because several patients experienced nausea without vomiting, whereas no patients experienced vomiting without nausea. Ondansetron treatment resulted in a significantly lower incidence of both nausea and vomiting during the study period. During the first hour after recovery, the incidence of nausea was 52% in placebo-treated patients compared with 17% in the ondansetron-treated group, and the incidence of vomiting was 40% in the placebo group and 12% in the ondansetron-treated group, respectively. Similar results were observed when nausea and vomiting were assessed over the whole of the first 24 h postrecovery. The overall incidence of nausea in the placebo group during the 24-h period was 67% compared
Relative risk of nausea' (95% confidence interval) 0.18 (0.07,O.SO) 0.20 (0.08,0.51)
Relative risk of vomiting" (95% confidence interval) 0.18 (0.06,0.58) 0.24 (0.10,0.61)
"Ondansetron compared with placebo.
with 29% in the ondansetron-treated group. Similarly, the incidence of vomiting during the whole 24-h period was 60% in the placebo-treated group and 26% in the ondansetron-treated group. When the relative risk of suffering emetic sequelae was calculated, patients were found to be approximately one-fifth as likely to experience nausea or vomiting after ondansetron treatment compared with placebo (Table 3 ) . The number of patients who required antiemetic treatment was less in the ondansetron-treatment group than in the placebo group. A total of 12 doses of prochlorperazine were administered to eight patients in the ondansetron group, compared with 33 doses administered to 22 patients in the placebo group. Patients in the first 24 h after recovery received postoperative analgesic medication with 10 mg intramuscular morphine with only a few exceptions (Table
754
ANESTH ANALG 1991:72751-5
LEESER AND LIP
Table 4. Analgesic Medication Administered During the First 24 h After Recoverv Number of patients receiving'
1 Dose 2Doses 3Doses 4Doses SDoses Total Placebo Ondansetron
5 5
1Sb 15'
11 15
8 46
0 1
40 40
"All patients received 10 mg intramuscular morphine, unless otherwise stated. "Includes one dose 10 mg piritramide and one dose 5 mg intramuscular morphine. 'Includes one dose 10 mg subcutaneous morphine. dIncludes two doses 5 mg intramuscular morphine.
4). Both the ondansetron-treated group and the placebo group were given similar amounts of analgesic medication (Table 4). A total of 102 doses of narcotic analgesics were administered to patients in the placebo group and 101 doses to those in the ondansetron-treated group. A total of 27 patients in the ondansetron-treated group had muscle relaxation reversed with atropine and neostigmine compared with 29 in the placebo group. The duration of anesthesia was comparable in both treatment groups, the mean period being 128 min (range, 35-290 min) in the placebo group and 125 min (range, 60-280 min) in the ondansetrontreated group. No significant differences in the time to recovery after anesthesia were observed, the mean time being 9 min (range, 4-30 min) after placebo treatment and 11 min (range, 0-55 min) after ondansetron treatment. No clinically important changes in blood pressure, pulse rate, or respiratory rate occurred during the study. No side effects considered to be related to study medication were reported. One patient who received ondansetron had delayed recovery from anesthesia, and another developed ileal stasis and a wound infection. None of these events were considered to have occurred as a result of ondansetron treatment. Occasional changes in laboratory values were seen postoperatively in both groups, 5-7 days after the operation, but in only four patients were these considered to be of any clinical significance. Three patients treated with ondansetron and one patient treated with placebo showed minor elevations in liver function tests.
Discussion Postoperative nausea and vomiting are troublesome complications of anesthesia that have proved difficult to prevent. A variety of agents with differing phar-
macologic properties are used in everyday practice, among the most popular being antihistamine, e.g., cyclizine, anticholinergic, e.g., scopolamine, and antidopaminergic drugs, e.g., droperidol. All the compounds available at present, however, have significant side effects that have frequently limited their use to the treatment of emesis rather than prophylactic use (8,9). The present paper describes the antiemetic properties of a novel class of compound, a 5-HT3 receptor antagonist, which appears to be devoid of many of the side effects known to be associated with existing antiemetics. Ondansetron has already proved to be an effective treatment for the prevention of nausea and vomiting induced by cancer chemotherapy and radiotherapy (4-7). The present study provides evidence that it is also effective in reducing the nausea and vomiting that occur after anesthesia. The fact that the relative risks of experiencing either nausea or vomiting after ondansetron treatment compared with placebo were similar demonstrates that the compound was equally effective, in proportional terms, against both symptoms. Many factors may influence the incidence of postoperative nausea and vomiting, and in the present study care was taken to ensure that the treatment groups were comparable in terms of type of patient, demography, surgical procedure, and type of anesthesia used. Similarly, the consumption of opiate analgesics was closely monitored to ensure that differences between the groups could not account for any difference in the incidence of emesis. It is concluded that oral treatment with ondansetron was effective in reducing the incidence of both postoperative nausea and vomiting in comparison with placebo treatment over the 24-h observation period. The site of action of ondansetron in the prevention of postoperative emesis is uncertain. It has been shown in animals that the area postrema and parts of the nucleus tractus solitarius, adjacent sites in the brain known to be associated with nausea and vomiting, contain large numbers of 5-HT3 receptors (lO,ll), and it is possible that ondansetron may act at these sites to reduce emesis. A peripheral action in the gastrointestinal tract at afferent vagal fibers known to possess 5-HT3 receptors cannot be ruled out. Further studies will be required to elucidate the exact site of action or, indeed, whether there are both central and peripheral actions involved in the control of emesis by 5-HT3 antagonists. Ondansetron would appear to be a promising agent for the prevention of postoperative nausea and vomiting, as it is both effective and devoid of many of the side effects associated with current therapies,
ONIIANSETRON AND POSTOPERATIVE EMESIS
including dopamine antagonists. Further studies will need to be performed to establish its optimal dosage. Glaxo Group Research Limited generously supplied ondansetron and matching placebo tablets, in addition to financial support for laboratory investigations and statistical analysis.
References 1. Palazzo MGA, Strunin L. Anesthesia and emesis. I. Etiology. Can Anaesth Soc J 1984;31:17%37.
2. Brittain RT, Butler A, Coates IH, et al. GR38032F, a novel selective 5HT, receptor antagonist. Br J Pharmacol 1987;90:87P. 3. Higgins GA, Kilpatrick GJ, Bunce KT, Jones BJ, Tyers MB. 5-HT3 receptor antagonists injected into the area postrema inhibit cisplatin-induced emesis in the ferret. Br J Pharmacol 1989;97:247-55. 4. Cunningham D, Hawthorn J, Pople A, et al. Prevention of emesis in patients receiving cytotoxic drugs by GR38032F, a selective 5-HT3 receptor antagonist. Lancet 1987;i:1461-3.
ANESTH ANALG 199 1;72:751-5
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5. Marty M, Droz JP, Pouillart P, Paule B, Brion N, Bons J . GR38032F, a 5-HT3 receptor antagonist, in the prophylaxis of acute cisplatin-induced nausea and vomiting. Cancer Chemother Pharmacol 1989;23:389-91. 6. Hesketh PJ, Murphy WK, Lester EP, et al. GR38032F (GR-C507174):a novel compound effective in the prevention of acute cisplatin-induced emesis. J Clin Oncol 1989;7:700-5. 7. Priestman TJ. Clinical studies with ondansetron in the control of radiation-induced emesis. Eur J Cancer Clin Oncol 1989; 2 5 ( S ~ p p l1):529-33. 8. Adriani J, Summers FW, Antony SO. Is the prophylactic use of antiemetics in surgical patients justified? JAMA 1961;175:66& 71. 9. Cookson RF. Mechanisms and treatment of post-operation nausea and vomiting. In: Davis CJ, Lake-Bakaar GV, GrahameSmith DG, eds. Nausea and vomiting: mechanisms and treatment. Berlin: Springer-Verlag, 1986:130-50.
10. Kilpatrick GJ, Jones BJ, Tyers MB. The distribution of specific binding of the 5-HT3 receptor ligand [3H]GR65630in rat brain using quantitative autoradiography. Neurosci Lett 1988;94: 156-60. 11. Pratt GD, Bowery NG. The 5-HT3 receptor ligand [,H]-BRL 46394, binds to presynaptic sites in the nucleus tractus solitarius of the rat. Br J Pharmacol 1989;97:414P.
ANESTH ANALG 3991;72:751-5
Prevention of Postoperative Nausea and Vomiting Using Ondansetron, a New, Selective, 5-HT3 Receptor Antagonist Jos Leeser, MD, and Harm Lip,
MD
LEESER J, LIP H. Prevention of postoperative nausea and vomiting using ondansetron, a new, selective, 5HT, receptor antagonist. Anesth Analg 1991;72:751-5.
The effect of ondansetron, a 5-HT3 antagonist, in prezlenting postoperative nausea and vomiting was investixatcd in a randomized, double-blind, placebo-controlled study of 84 patients undergoing gynecologic operation and receiving the same general anesthetic. The patients received premedication with eitker 16 m g oral ondansetron, or a matching placebo. The same medication was given postoperatively 8 h after the first dose. During the first hour after recovery from anesthesia, the frequencies of nausea and vomiting were
Nausea and vomiting are common after operative procedures requiring general anesthesia, with incidences that have remained unchanged over the last 30 yr (1). Ondansetron is a serotonin antagonist that selectively inhibits 5-HT3 receptors, with little or no activity on dopamine or other receptors (2). Both animal experiments (3) and studies in humans have shown ondansetron to be effective in preventing nausea and vomiting associated with cancer chemotherapy and radiation therapy (4-7). Because of its lack of activity at dopamine receptors, ondansetron has not been associated with extrapyramidal signs or symptoms often seen with antiemetics that act as dopamine antagonists, e.g., droperidol or metoclopramide. It may, therefore, have a potential benefit over such agents in the prevention of postoperative nausea and vomiting. The effect of oral ondansetron in preventing postoperative nausea and vomiting in patients undergoSupported in part by GIaxo Group Research, Greenford, Middlesex, U.K. Received from the Department of Anaesthesiology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands; and the Department of Anaesthesiology, Sophia Ziekenhuis, Zwolle, The Netherlands. Accepted for publication February 6, 1991. Address correspondence to Dr. Leeser, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands. 01991 by the International Anesthesia Research Societv 0003-2999/91/$3.50
52% and 40%, respectively, in patients given placebos.
01
the ondansetron group nausea and vomiting developed in 17% and 12%, respectively, values significantly difercnt from those with placebos ( P < 0.005). Similar differences were observed throughout the entire 24-h period after recovery, the incidence of nausea and vomiting being 67% and 60%, respectively, in the placebo group and 29% and 26% in the ondansetron treatment group. Ondansetron appears to be a promising antiemetic for the prevention of postoperative nausea and vomiting. Key Words: VOMITING, ondansetron.
ANTIEMETICS-
ing gynecologic operation under general anesthesia has, therefore, been investigated in a double-blind, randomized, placebo-controlled study.
Methods This randomized, double-blind study was carried out at two centers (Onze Lieve Vrouwe Gasthuis, Amsterdam, and Sophia Ziekenhuis, Zwolle) in The Netherlands, and the institutional ethics committees at both centers gave their approval for the conduct of the study. Each patient gave her written consent to take part in the study. A total of 84 patients, aged 18-65 yr, scheduled to have abdominal gynecologic operations under general anesthesia were included in the study. Patients who were pregnant or breast-feeding or who had evidence of clinically significant renal, hepatic, cardiovascular, metabolic, or endocrine dysfunction, or who had clinically significant abnormalities in laboratory screening tests, were excluded (patients of ASA physical status IV and V were thus excluded). In addition, patients who had received antiemetic medication in the 12 h before entering the study were excluded. Patients were randomly allocated to receive either ondansetron (Glaxo Group Research Limited, U.K.)
752
LEESER AND LIP
ANESTH ANALC 1991;72:731-5
or placebo according to the patient number taken from a predetermined randomization list. Study medication, either 16 mg ondansetron (two 8-mg tablets) or placebo (two tablets) was administered with premedication approximately 1 h before operation. A second dose of 16 mg ondansetron or placebo was administered postoperatively 8 h after the first dose. All patients were premedicated with 10 mg diazepam orally except for one patient who was given 5 mg diazepam. Anesthesia was induced with 4-5 mg/kg thiopental and maintained using 67% nitrous oxide in oxygen supplemented with 0.8%-2.5% isoflurane. Analgesia, if required, was maintained with alfentanil, using doses up to 7.5 mg, and vecuronium bromide was used as a muscle relaxant. If required, reversal of muscle relaxation was achieved with 1 mg atropine and 2 mg neostigmine except for two patients in the placebo treatment group, one of whom was given 2 mg atropine and 2 mg neostigmine, and the other who was given 0.5 mg atropine and 1 mg neostigmine. Postoperative analgesia was provided by morphine. All observations were made without knowledge of which treatment each patient received. Nausea and vomiting were assessed 1 h after recovery (as defined below), and again 24 h after recovery. Both nausea and vomiting were assessed separately, as present or absent. Nausea was assessed by a single individual at each center by asking whether the patient had experienced any nausea during the assessment period. The question was phrased in the same way for all patients. Records of patients who vomited were kept by the nursing staff. The severity of vomiting was not assessed. Retching was not assessed as a separate entity, and patients who reported retching were classified as nauseous. If patients experienced nausea or vomiting, they could request antiemetic treatment in the form of a 25-mg prochlorperazine maleate suppository. The duration of anesthetic administration and the time to recovery from anesthesia (patients were considered to have recovered from anesthesia when they first responded to spoken command) were assessed. Vital signs, including respiratory rate, blood pressure, and pulse rate, were monitored during the study. The patients were questioned about any possible side effects of the study medication 24 h after the operation and again after 5-7 days, when routine blood and urine samples were obtained for laboratory screening before discharge of the patient from the hospital. Laboratory tests included measurement of serum levels of sodium, potassium, calcium, total protein, albumin, urea, creatinine, bilirubin, alkaline
Table 1. Patient Demography Placebo
( n = 42) Age (Yr) Age range (yr) Weight (kg)
Ondansetron ( n = 42)
43 +- 11 23-61 69.6 t 10.2
44 i 10 21-60 65.2 ? 10.9
Values for age and weight are expressed as mean i SD.
phosphatase, alanine transaminase, aspartate transaminase, and y-glutamyl transpeptidase. Blood samples were also obtained for measurement of hemoglobin content, red blood cell count, packed cell volume, mean cell volume, platelet count, total white cell count, and differential white cell count. Urine was analyzed for pH and the presence of protein and glucose. The sample size chosen was designed to detect a decrease in nausea and vomiting from 65% after placebo treatment to 25% after ondansetron treatment assuming type I and type I1 errors to be 0.05. Analysis of the incidence of nausea and vomiting was carried out using logistic regression from which the relative risk of each event occurring was obtained for ondansetron relative to placebo. For the purposes of analysis, any patient who had requested and received prochlorperazine was deemed a treatment failure and considered to have vomited. All patients were included in the analysis. Differences in duration of anesthesia and the times to recovery were analyzed using the Wilcoxon ranksum test. Blood pressures and pulse rates were averaged during the maintenance of anesthesia, emergence from anesthesia, and the postoperative period. Analysis of covariance was applied to the single measurement recorded at induction of anesthesia and to the average values obtained during the maintenance of anesthesia and during the emergence and postoperative periods. Blood pressure and pulse rate measured at the time of premedication, before administration of study drug, was used as a pretreatment covariate in each analysis. Respiratory rate was averaged during the emergence and postoperative periods.
Results A total of 84 patients were entered into the study, 30 from one center and 54 from the other. The mean age and weight of the patients in the two treatment groups were not significantly different (Table 1).
ANESTH ANALG
ONDANSETRON AND POSTOPERATIVE EMESIS
753
1991:72:751-5
Table 2. Types of Operation Performed in Each Treatment Group Placebo Abdominal hysterectomy Abdominal laparotomy Vaginal hysterectomy
( n = 42)
Ondanse tron ( n = 42)
22 20 0
26 15 1
(28)
Ondansetron Placebo
Ondansetron Placebo
0 1 hour
024 hours
Figure 2 . The percentages of patients treated with ondansetron and placebo who vomited in the first hour and first 24 h after recovery. Actual numbers of patients in each group who vomited are shown in parentheses; n = 42 for both treatments. *Significantly different from placebo, P < 0.005.
unoanseuon riacew 0 1 hour
024 hours
Figure 1 . The percentages of patients treated with ondansetron and placebo who suffered nausea in the first hour and first 24 h after recovery. Actual numbers of patients in each group who suffered nausea are shown in parentheses; n = 42 for both treatments. *Significantly different from placebo, P < 0.001.
Table 3. Relative Risk of Experiencing Nausea or Vomiting During the First 24 h Postoperation on Ondansetron Compared With Placebo Time after recovery 0-1 h 0-24 h
The types of operations performed are presented in Table 2; the groups are well matched, with no important differences. One patient who had a vaginal hysterectomy was included in the analysis. The incidence of nausea and vomiting during the first 24 h after operation is shown in Figures 1 and 2. As might be expected, the incidence of nausea was somewhat higher than the incidence of vomiting because several patients experienced nausea without vomiting, whereas no patients experienced vomiting without nausea. Ondansetron treatment resulted in a significantly lower incidence of both nausea and vomiting during the study period. During the first hour after recovery, the incidence of nausea was 52% in placebo-treated patients compared with 17% in the ondansetron-treated group, and the incidence of vomiting was 40% in the placebo group and 12% in the ondansetron-treated group, respectively. Similar results were observed when nausea and vomiting were assessed over the whole of the first 24 h postrecovery. The overall incidence of nausea in the placebo group during the 24-h period was 67% compared
Relative risk of nausea' (95% confidence interval) 0.18 (0.07,O.SO) 0.20 (0.08,0.51)
Relative risk of vomiting" (95% confidence interval) 0.18 (0.06,0.58) 0.24 (0.10,0.61)
"Ondansetron compared with placebo.
with 29% in the ondansetron-treated group. Similarly, the incidence of vomiting during the whole 24-h period was 60% in the placebo-treated group and 26% in the ondansetron-treated group. When the relative risk of suffering emetic sequelae was calculated, patients were found to be approximately one-fifth as likely to experience nausea or vomiting after ondansetron treatment compared with placebo (Table 3 ) . The number of patients who required antiemetic treatment was less in the ondansetron-treatment group than in the placebo group. A total of 12 doses of prochlorperazine were administered to eight patients in the ondansetron group, compared with 33 doses administered to 22 patients in the placebo group. Patients in the first 24 h after recovery received postoperative analgesic medication with 10 mg intramuscular morphine with only a few exceptions (Table
754
ANESTH ANALG 1991:72751-5
LEESER AND LIP
Table 4. Analgesic Medication Administered During the First 24 h After Recoverv Number of patients receiving'
1 Dose 2Doses 3Doses 4Doses SDoses Total Placebo Ondansetron
5 5
1Sb 15'
11 15
8 46
0 1
40 40
"All patients received 10 mg intramuscular morphine, unless otherwise stated. "Includes one dose 10 mg piritramide and one dose 5 mg intramuscular morphine. 'Includes one dose 10 mg subcutaneous morphine. dIncludes two doses 5 mg intramuscular morphine.
4). Both the ondansetron-treated group and the placebo group were given similar amounts of analgesic medication (Table 4). A total of 102 doses of narcotic analgesics were administered to patients in the placebo group and 101 doses to those in the ondansetron-treated group. A total of 27 patients in the ondansetron-treated group had muscle relaxation reversed with atropine and neostigmine compared with 29 in the placebo group. The duration of anesthesia was comparable in both treatment groups, the mean period being 128 min (range, 35-290 min) in the placebo group and 125 min (range, 60-280 min) in the ondansetrontreated group. No significant differences in the time to recovery after anesthesia were observed, the mean time being 9 min (range, 4-30 min) after placebo treatment and 11 min (range, 0-55 min) after ondansetron treatment. No clinically important changes in blood pressure, pulse rate, or respiratory rate occurred during the study. No side effects considered to be related to study medication were reported. One patient who received ondansetron had delayed recovery from anesthesia, and another developed ileal stasis and a wound infection. None of these events were considered to have occurred as a result of ondansetron treatment. Occasional changes in laboratory values were seen postoperatively in both groups, 5-7 days after the operation, but in only four patients were these considered to be of any clinical significance. Three patients treated with ondansetron and one patient treated with placebo showed minor elevations in liver function tests.
Discussion Postoperative nausea and vomiting are troublesome complications of anesthesia that have proved difficult to prevent. A variety of agents with differing phar-
macologic properties are used in everyday practice, among the most popular being antihistamine, e.g., cyclizine, anticholinergic, e.g., scopolamine, and antidopaminergic drugs, e.g., droperidol. All the compounds available at present, however, have significant side effects that have frequently limited their use to the treatment of emesis rather than prophylactic use (8,9). The present paper describes the antiemetic properties of a novel class of compound, a 5-HT3 receptor antagonist, which appears to be devoid of many of the side effects known to be associated with existing antiemetics. Ondansetron has already proved to be an effective treatment for the prevention of nausea and vomiting induced by cancer chemotherapy and radiotherapy (4-7). The present study provides evidence that it is also effective in reducing the nausea and vomiting that occur after anesthesia. The fact that the relative risks of experiencing either nausea or vomiting after ondansetron treatment compared with placebo were similar demonstrates that the compound was equally effective, in proportional terms, against both symptoms. Many factors may influence the incidence of postoperative nausea and vomiting, and in the present study care was taken to ensure that the treatment groups were comparable in terms of type of patient, demography, surgical procedure, and type of anesthesia used. Similarly, the consumption of opiate analgesics was closely monitored to ensure that differences between the groups could not account for any difference in the incidence of emesis. It is concluded that oral treatment with ondansetron was effective in reducing the incidence of both postoperative nausea and vomiting in comparison with placebo treatment over the 24-h observation period. The site of action of ondansetron in the prevention of postoperative emesis is uncertain. It has been shown in animals that the area postrema and parts of the nucleus tractus solitarius, adjacent sites in the brain known to be associated with nausea and vomiting, contain large numbers of 5-HT3 receptors (lO,ll), and it is possible that ondansetron may act at these sites to reduce emesis. A peripheral action in the gastrointestinal tract at afferent vagal fibers known to possess 5-HT3 receptors cannot be ruled out. Further studies will be required to elucidate the exact site of action or, indeed, whether there are both central and peripheral actions involved in the control of emesis by 5-HT3 antagonists. Ondansetron would appear to be a promising agent for the prevention of postoperative nausea and vomiting, as it is both effective and devoid of many of the side effects associated with current therapies,
ONIIANSETRON AND POSTOPERATIVE EMESIS
including dopamine antagonists. Further studies will need to be performed to establish its optimal dosage. Glaxo Group Research Limited generously supplied ondansetron and matching placebo tablets, in addition to financial support for laboratory investigations and statistical analysis.
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