Tropisetron (Navoban; Novartis Pharma, Basel, Switzerland) is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with potent antiemetic activities . Its elimination half-life (8-12 h) is longer than that of the other 5-HT3 antagonists (e.g., ondansetron 3.2-3.7 h, granisetron 3-4 h) [2,3], and a single dose of tropisetron may provide prolonged antiemetic effects. Tropisetron is effective in preventing postoperative nausea and vomiting (PONV) after laparoscopic cholecystectomy , and orthopedic , gynecologic [6-9], thyroid , and ophthalmic surgery . The recommended dose for PONV prophylaxis is a single 5-mg bolus of IV tropisetron. This regimen is derived from dose-finding studies after cancer chemotherapy . However, the emetic stimuli after surgery may be different from that after chemotherapy. Furthermore, the optimal doses for preventing PONV with ondansetron (4 mg), dolasetron (0.25 mg/kg), and granisetron (5 [micro sign]g/kg) are smaller compared with that required for chemotherapy-induced emesis (8 mg, 1.8 mg/kg, and 10 [micro sign]g/kg, respectively) [2,3,12]. Therefore, a smaller dose of tropisetron may be sufficient for prophylaxis against PONV. In this randomized, double-blind, placebo-controlled study, we compared the efficacy and safety of tropisetron 2 mg with tropisetron 5 mg for the prevention of PONV in patients receiving patient-controlled analgesia (PCA) after breast surgery.
The study was approved by the clinical research ethics committee. Written, informed consent was obtained from all patients. Based on the reported incidence of PONV after breast surgery , we calculated (beta = 0.10, alpha = 0.05) that at least 48 patients per group were required to demonstrate a decrease in the incidence of PONV from 60% to 30%. We studied 150 female patients with breast cancer undergoing modified radical mastectomy or lumpectomy with axillary dissection. All patients were ASA physical status I or II aged 18-75 yr. Patients were excluded if they had preexisting nausea or vomiting or had received opioids or drugs with known antiemetic properties in the 24 h before surgery. Pregnant patients and those with a history of esophageal reflux or opioid or alcohol abuse were also excluded. All patients were interviewed during the preoperative assessment. A history of motion sickness and PONV was noted. The day of the current menstrual cycle was also recorded. Preoperative electrocardiogram, full blood counts, and renal and liver function tests were performed. No preanesthetic medication was prescribed, and the patients fasted from midnight before surgery.
In the operating room, routine monitoring was applied. Patients were assigned to receive either tropisetron 5 mg (in 5 mL), tropisetron 2 mg (made up to 5 mL with saline), or placebo (saline 5 mL) according to a computer-generated random number concealed in an envelope. Study drugs were prepared by an anesthesiologist not otherwise involved in the study and were injected IV over 30 s. Arterial pressure and heart rate were recorded noninvasively immediately before and 1, 3, 5, and 10 min after the start of drug administration. Adverse reactions, including pain on injection, signs of allergy, dizziness, and chest or abdominal discomforts, were specifically sought.
Anesthesia was induced with morphine 0.15 mg/kg and thiopental 3-5 mg/kg. Vecuronium 0.1 mg/kg was administrated to facilitate tracheal intubation. Anesthesia was maintained with nitrous oxide 70% and isoflurane 0.5%-1.0% in oxygen. The lungs were mechanically ventilated, and the end-tidal carbon dioxide concentration was maintained between 5.0% and 5.5%. At the end of surgery, anesthesia was discontinued, and residual neuromuscular blockade was antagonized by using neostigmine 40 [micro sign]g/kg and atropine 20 [micro sign]g/kg. The trachea was extubated when the patient became fully awake. Anesthetic time was defined as the start of induction to the time when nitrous oxide was discontinued. The subsequent period until the patient responded to verbal command was recorded as the recovery time. Postoperative analgesia was provided by IV morphine using a PCA machine (Graseby 3300; Graseby Medical, Watford, UK) with standard settings (40-[micro sign]g/kg demand bolus and 10-min lockout intervals).
Postoperatively, all patients were monitored in the postanesthesia care unit for 2 h, after which time the patient returned to the ward. The incidence of nausea and emetic episodes (retching or vomiting), as well as the severity of nausea, pain, and sedation, were recorded at 30-min intervals for 2 h and then every 6 h for the next 46 h. Patient interviews were conducted in a standardized fashion by trained nurses who were blinded to the study drug. Retching or vomiting separated by at least 1 min was considered as separate emetic episodes. Severity of nausea and pain were graded using a 10-mm visual analog scale printed on a slide rule bar (Astra USA Inc., Westborough, MA). Sedation was scored as 1 = alert, 2 = asleep but alert after arousal, 3 = asleep and drowsy after arousal, 4 = asleep and difficult to rouse, 5 = unarousable. IM prochlorperazine 12.5 mg was given as rescue anti-emetic if there were two or more emetic episodes, if nausea persisted >10 min, or on the patient's request. Adverse reactions were also recorded. Preoperative laboratory tests and electrocardiogram were repeated at 24 h.
Statistical analyses were performed with SPSS 6.1 (SPSS Ltd, Chicago, IL). Analysis was based on the intention to treat principle. Categorical data were compared among groups using chi squared analysis, and continuous data were analyzed by using the Kruskal-Wallis test. Intergroup differences were compared by using Fisher's exact test or the Mann-Whitney U-test. Severity of nausea during the initial 6 h was assessed by adding the nausea scores at 2 h and 6 h postoperatively. Similarly, the sum of the nausea scores at 12 and 18 h indicated the severity 6-18 h postoperatively. The aggregated totals during these two periods were then compared among groups using the Kruskall-Wallis test. A complete response was defined as no nausea, emetic episodes, or rescue antiemetic during the entire 48-h observation. The time to the first nausea or emetic episode was calculated using Kaplan-Meier analysis and was compared among groups using the log-rank test. The effects of variables that may influence the incidence of PONV were analyzed by Cox regression. A paired t-test was used to compare the hemodynamic variables before and after injection of the study drugs. A P value <0.05 was considered significant.
One hundred forty-eight patients completed the study (placebo, n = 50; tropisetron 2 mg, n = 49; tropisetron 5 mg, n = 49). One patient who received tropisetron 5 mg was excluded because of missing data. Another patient who received tropisetron 2 mg was erroneously given metoclopramide just before the end of surgery and was excluded from the study. This patient continued to suffer from PONV. Age, weight, height, and variables that may influence PONV did not differ among the groups (Table 1).
A complete response was observed in 16% of patients in the placebo group. This was significantly less than that in the tropisetron 2 mg group (36%, P = 0.001) or the tropisetron 5 mg group (67.3%, P < 0.001). The median time (95% confidence intervals) to the first PONV episode was shorter in the placebo group, 0.8 (0.0-3.9) h, compared with that in the tropisetron 2 mg group, 15.0 (8.3-21.7) h (P < 0.001), and the tropisetron 5 mg group, >48 h (P < 0.001) (Figure 1). Emetic episodes in the placebo group were reported frequently during the first 6 h after surgery. Both tropisetron 2 and 5 mg were effective in preventing emesis during this time period (P < 0.001, Figure 2). The incidence of emesis in patients who received tropisetron 2 mg increased significantly 6-18 h postoperatively compared with the initial 6 h (P = 0.01) and was similar to that in the placebo group (P = 0.43). In these 12 h, there were more emetic episodes in the tropisetron 2 mg and the placebo groups compared with the tropisetron 5 mg group (P = 0.001). Emetic episodes were rare in all three groups after the first postoperative day; the number was small and was not significant among groups.
Nausea was also common during the first 18 h after surgery (Figure 3), but the overall severity was low. In the first 6 h postoperatively, the median (range) aggregated nausea score in the placebo group, 6 (0-12), was significantly greater than that in the tropisetron 2 mg group, 0 (0-15) (P = 0.01) or the tropisetron 5 mg group, 0 (0-9) (P < 0.001). Despite an increase in the incidence of nausea during the next 12 h, the aggregated nausea score in the tropisetron 2 mg group remained low, 0 (0-18). This was similar to the score in the tropisetron 5 mg group, 0 (0-14) (P = 0.16) and the placebo group, 1 (0-20) (P = 0.06).
During the entire 48-h study period, more patients in the placebo group required rescue antiemetics (n = 39) compared with patients who received tropisetron 2 mg (n = 27; P = 0.015) or 5 mg (n = 12; P < 0.001). Furthermore, 15 of the 39 patients in the placebo group who required rescue antiemetics continued to experience PONV and received two or more rescue treatments, whereas only 8 patients in the tropisetron 2 mg group and 2 patients in the tropisetron 5 mg group required a second dose.
There was no difference in pain scores among the groups. The (mean +/- SD) 48-h morphine consumption in the placebo group (19.5 +/- 5.3 mg) was similar to that in the tropisetron 2 mg group (18.5 +/- 6.3 mg) and the tropisetron 5 mg group (17.1 +/- 4.5 mg). Multivariate analysis using the Cox regression model suggested that perioperative fluid therapy, postoperative morphine consumption, history of motion sickness, phase of menstrual cycle, operative variables, and recovery time did not affect the incidence of PONV. In contrast, history of PONV increased the likelihood of current PONV, odds ratio 3.3 (95% confidence interval, 1.3-8.3) (P = 0.01).
There was no adverse event during the injection of tropisetron. Arterial blood pressure and heart rate did not change after drug administration. The postoperative hemoglobin concentration of all patients, 92 +/- 9 g/L, was less than that of the preoperative value, 118 +/- 11 g/L (P = 0.04), which corresponded to the amount of perioperative blood loss and hemodilution. No patient received a blood transfusion. Biochemical tests were not different from preoperative values. Sedation scores were similar among groups, and no patient had a score >2 during the entire 48 h. Two patients in the placebo group complained of dizziness, and another patient who received tropisetron 2 mg had a mild headache during the early postoperative hours. No other adverse effect was noted.
Our data do not support the use of a smaller dose of tropisetron for PONV. In patients after breast surgery, the antiemetic effect of the tropisetron 2 mg was shorter than that of tropisetron 5 mg. A single IV dose of tropisetron 2 mg failed to decrease the incidence of PONV 6 h postoperatively. This is in contrast to the findings of Capouet et al. , who reported that tropisetron 2 mg was as effective as tropisetron 5 mg in reducing PONV during the first 24 h after gynecologic surgery. Several factors may explain the difference. In the Capouet et al.  study, most patients underwent short laparoscopic procedures for which the emetic stimuli could have been brief. In addition, the incidence of PONV in their placebo group (55%) was less than that in the present study (84%), which suggests that the stimuli were less intense. Tropisetron 2 mg may be sufficient to cover the brief and mild stimulus associated with a surgery of shorter duration. However, emetic potential after major surgery requiring systemic opioids is more intense and prolonged. We recommend that the dose of tropisetron be titrated against the emetogenicity of the stimulus.
Pharmacokinetic variables also affect antiemetic efficacy. The clinical duration of action would be longer with a larger dose of tropisetron. Using a plasma tropisetron concentration of 3 ng/mL as the minimal effective concentration for 5-HT (3) block, the therapeutic concentration could be maintained for a longer period after tropisetron 5 mg (24 h) compared with tropisetron 2 mg (<3 h) (; data on file, Novartis Pharma, Basel, Switzerland). Our study confirmed that single-dose tropisetron 5 mg, not 2 mg, should be given during the first postoperative day to patients who are exposed to intense emetic stimuli.
We administered tropisetron immediately before the induction of anesthesia to maximize its potential preemptive antiemetic effect. However, a study comparing tropisetron 5 mg given with premedication or at the end of surgery did not reveal a significant difference in the incidence of PONV . Given its long elimination half-life, the preoperative administration of tropisetron should not decrease its antiemetic efficacy. Furthermore, the current timing of administration allowed us to assess the true hemodynamic effect after a rapid IV bolus of tropisetron.
Breast surgery is associated with a high incidence of PONV. Between 48% and 68% of patients undergoing mastectomy, breast reconstruction, and implantation suffer from PONV [13,15-17]. In this study, we found the incidence of PONV to be as high as 84% in the placebo group. Furthermore, 74% of all the PONV episodes occurred after the patients had returned to the ward. It is not clear why breast surgery causes PONV. We postulate that the characteristics of the typical middle-aged patient who is distressed at having breast cancer may predispose these patients to the greatest possible risk of PONV.
There are other factors that may influence PONV. Recent regression analyses [18-21] have identified postoperative opioid consumption and a history of motion sickness as important patient factors predicting postoperative sickness. In this study, we cannot associate these factors with a greater incidence of PONV, probably because of the small sample size. However, a history of PONV was the most consistent predictor and increased the risk of PONV in our patients by 3.3-fold. We believe that patients undergoing breast surgery, particularly those with a history of PONV, should receive prophylactic antiemetic therapy.
After receiving tropisetron 5 mg, one third of the patients continued to have PONV. We are uncertain as to the best treatment for these patients. Larger and repeated doses of tropisetron may reduce the incidence of PONV, but a useful guideline is lacking. Alternatively, combining tropisetron with other antiemetics of different modes of actions seems logical. Such combinations have been proven successful in chemotherapy-induced emesis ; however, their role in PONV has not been examined. Propofol-based anesthetics reduce PONV, and nitrous oxide contributes to both early and delayed emetic episodes [17,23,24]. Adding prophylactic tropisetron to an anesthetic technique that uses propofol as the maintenance anesthetic and omits nitrous oxide intraoperatively may further decrease the incidence of PONV.
In conclusion, a single dose of IV tropisetron 2 or 5 mg given for the prevention of PONV is well tolerated. The antiemetic efficacy of tropisetron 5 mg is superior to tropisetron 2 mg in patients undergoing breast surgery.
Tropisetron was kindly supplied by Novartis Pharmaceutical, Hong Kong.
1. Lee CR, Plosker GL, McTavish D. Tropisetron: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as an antiemetic. Drugs 1993;46:925-43.
2. Markham A, Sorkin EM. Ondansetron: an update of its therapeutic use in chemotherapy-induced and postoperative nausea and vomiting. Drugs 1993;45:931-52.
3. Mikawa K, Takao Y, Nishina K, et al. Optimal dose of granisetron for prophylaxis against postoperative emesis after gynecological surgery. Anesth Analg 1997;85:652-6.
4. Naguib M, El Bakry AK, Khoshim MHB, et al. Prophylactic antiemetic therapy with ondansetron, tropisetron, granisetron and metoclopramide in patients undergoing laparoscopic cholecystectomy: a randomized, double-blind comparison with placebo. Can J Anaesth 1996;43:226-31.
5. Kaufmann MA, Rosow C, Schnieper P, Schneider M. Prophylactic antiemetic therapy with patient-controlled analgesia: a double-blind, placebo-controlled comparison of droperidol, metoclopramide, and tropisetron. Analg Anesth 1994;78:988-94.
6. Zomers PJW, Langenberg CJM, de Bruijn KM. Tropisetron for postoperative nausea and vomiting in patients after gynaecological surgery. Br J Anaesth 1993;71:677-80.
7. Capouet V, De Pauw C, Vernet B, et al. Single dose i.v. tropisetron in the prevention of postoperative nausea and vomiting after gynaecological surgery. Br J Anaesth 1996;76:54-60.
8. Alon E, Kocian R, Nett PC, et al. Tropisetron for the prevention of postoperative nausea and vomiting in women undergoing gynecologic surgery. Anesth Analg 1996;82:338-41.
9. Purhonen S, Kauko M, Koski EMJ, Nuutinen L. Comparison of tropisetron, droperidol, and saline in the prevention of postoperative nausea and vomiting after gynecologic surgery. Anesth Analg 1997;84:662-7.
10. Yilmazlar A, Yilmazlar T, Gurpinar E, et al. Anti-emetic efficacy of tropisetron and metoclopramide. J Int Med Res 1996;24:266-70.
11. Ali-Melkkila T, Kanto J, Katevuo R. Tropisetron and metoclopramide in the prevention of postoperative nausea and vomiting: a comparative, placebo-controlled study in patients undergoing ophthalmic surgery. Anaesthesia 1996;51:232-5.
12. Balfour JA, Goa KL. Dolasetron: a review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs 1997;54:273-98.
13. Oddby-Muhrbeck E, Jakobsson J, Andersson L, Askergren J. Postoperative nausea and vomiting: a comparison between intravenous and inhalation anaesthesia in breast surgery. Acta Anaesthesiol Scand 1994;38:52-6.
14. Suarez A, Stettler ER, Rey E, et al. Safety, tolerability, efficacy and plasma concentrations of tropisetron after administration at five dose levels to children receiving cancer chemotherapy. Eur J Cancer 1994;30A:1436-41.
15. Petru A, Kanakoudes F, Metaxari M, et al. The effect of tropisetron on postoperative nausea and vomiting after breast surgery. Br J Anaesth 1997;78(Suppl 1):85-6.
16. Jakobsson J, Andersson L, Nilsson A, et al. Premedication before elective breast surgery: a comparison between ketobemidone and midazolam. Acta Anaesthesiol Scand 1991;35:524-8.
17. Gan TJ, Ginsberg B, Grant AP, Glass PSA. Double-blind, randomized comparison of ondansetron and intraoperative propofol to prevent postoperative nausea and vomiting. Anesthesiology 1996;85:1036-42.
18. Palazzo M, Evans R. Logistic regression analysis of fixed patient factors for postoperative sickness: a model for risk assessment. Br J Anaesth 1993;70:135-40.
19. Haigh CG, Kaplan LA, Durham JM, et al. Nausea and vomiting after gynaecological surgery: a meta-analysis of factors affecting their incidence. Br J Anaesth 1993;71:517-22.
20. Cohen MM, Duncan PG, DeBoer DP, Tweed WA. The postoperative interview: assessing risk factors for nausea and vomiting. Anesth Analg 1994;78:7-16.
21. Koivuranta M, Laara E, Snare L, Alahuhta S. A survey of postoperative nausea and vomiting. Anaesthesia 1997;52:443-9.
22. Sorbe BG, Hogberg T, Glimelius B, et al. A randomised, multicenter study comparing the efficacy and tolerability of tropisetron, a new 5-HT3
receptor antagonist, with a metoclopramide-containing antiemetic cocktail in the prevention of cisplatin-induced emesis. Cancer 1994;73:445-54.
23. Divatia JV, Vaidya JS, Badwe RA, Hawaldar RW. Omission of nitrous oxide during anesthesia reduces the incidence of postoperative nausea and vomiting: a meta-analysis. Anesthesiology 1996;85:1055-62.
24. Tramer M, Moore A, McQuay H. Meta-analytic comparison of prophylactic antiemetic efficacy for postoperative nausea and vomiting: propofol anaesthesia vs omitting nitrous oxide vs total i.v. anaesthesia with propofol. Br J Anaesth 1997;78:256-9.