Granisetron and Ondansetron for Prevention of Nausea and Vomiting in Patients Undergoing Modified Radical Mastectomy

SUMMARY

Modified radical mastectomy is associated with a relatively high incidence of postoperative nausea and vomiting (PONV). This study was undertaken to evaluate the comparative profile and efficacy of ondansetron and granisetron to prevent PONV after modified radical mastectomy. In a randomized, double-blind, placebo-controlled trial, sixty female patients received ondansetron 4 mg, granisetron 1 mg or saline intravenously just before induction of anaesthesia (n=20 for each group). A standardized general anaesthetic technique was employed. The incidence of PONV and adverse events were recorded for the first 24h postoperatively. The incidence of PONV was 25% with ondansetron, 20% with granisetron and 70% with saline (P<0.05, Chi- square test with Yates' correction factor). The incidence of adverse events was comparable among the groups. Ondansetron and granisetron are both effective for reducing the incidence of PONV in female patients undergoing modified radical mastectomy.

Key Words: NAUSEA, VOMITING: postoperative, ondansetron, granisetron

Postoperative nausea and vomiting (PONV) are frequent and distressing adverse events after surgery performed under general anaesthesia, with female patients being particularly susceptible1. The overall incidence of PONV after general anaesthesia is approximately 20%2. Breast surgery performed with general anaesthesia has been found to have a very high incidence of PONV (60%-84%)3-8. Ondansetron and granisetron, selective 5-HT3 receptor antagonists reduce the incidence of PONV after breast surgery9,10. Studies have shown that granisetron (in contrast to ondansetron) produces irreversible block of 5HT3 receptor11,12 which may account for its longer duration of action. Furthermore, in studies comparing the potency of different 5-HT3 receptor antagonists, granisetron has been shown to have a greater potency than ondansetron13.

To our knowledge there have been no previous studies comparing the efficacy of granisetron with that of the more commonly used ondansetron following modified radical mastectomy. In the present study we conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and comparative profile of granisetron and ondansetron for preventing PONV in patients undergoing breast surgery.

MATERIAL AND METHODS

After Institutional Ethics Committee approval and informed consent, we studied sixty American Society of Anesthesiologists physical status 1 or 2 patients between the ages of 21 and 75 years, undergoing general anaesthesia for modified radical mastectomy. The study was conducted for a limited duration of six months in which the total of 60 cases were randomly divided into three groups. Group 1 received ondansetron 4 mg, group 2 received granisetron 1 mg, and group 3 received saline.

Patients with known stomach disorders, history of heart burn, motion sickness, previous PONV, lower oesophageal sphincter disorders, menstruation, uncontrolled hypertension, poorly controlled diabetics, or preoperative emesis less than 12 h prior to surgery were excluded from the study.

Patients were randomly allocated to receive one of three treatments in the same volume (i.e. 10 ml) administered intravenously just before induction. Randomization was achieved using a computer-generated random number list to assign patients into three equal groups (n = 20). Anaesthetists were blinded to the group to which the patients had been assigned.

All patients were premedicated with intramuscular injection of fentanyl 2 g/kg and glycopyrrolate 0.1 mg 30 minutes before surgery. The patients received diazepam 0.1 mg/kg orally on the night before surgery. Anaesthesia was induced with thiopentone sodium 2.5% 4-6 mg/ kg. Tracheal intubation was facilitated with vecuronium 0.1 mg/kg. After tracheal intubation, anaesthesia was maintained with 66% nitrous oxide and 1 to 3% (inspired concentration) isoflurane in oxygen. We adjusted the isoflurane concentration to maintain blood pressure and heart rate within 15% of preinduction values. Ventilation was mechanically controlled and was adjusted to keep the end-tidal CO2 between 35 and 45 mmHg. Before tracheal extubation, a nasogastric tube was inserted and suction was applied to empty the contents of the stomach. At the cessation of the surgical procedure, nitrous oxide and isoflurane administration were ceased. Residual neuromuscular blockade was antagonized with neostigmine 50 to 70 g/ kg with glycopyrrolate 8 to 10 g/kg, and the trachea was extubated when the patient was awake. All patients received intramuscular injection of diclofenac sodium 75 mg for postoperative pain relief. Postoperatively, all episodes of PONV were recorded for the first 24 hours (0-2, 2-6, 6-24 hours) by direct questioning by the attending anaesthetist or by spontaneous complaint by the patients.

All patients were evaluated by using a PONV numeric scoring system.

0=No nausea/vomiting

1=Nausea alone

2 = Vomiting once

3=Vomiting twice or more times in 30 minute interval.

A rescue antiemetic, ondansetron 4 mg intravenously, was given to all patients with PONV score =3.

Statistical analysis of data between the groups was performed using one-way analysis of variance (ANOVA). For the categorical data, Chi-square test with Yates’ correction factor was applied. A “P” value less than 0.05 was considered as statistically significant. All values were expressed as mean (standard deviation) or number or percentage.

RESULTS

There were no significant differences between the groups with regard to age, weight, ASA physical status, duration of anaesthesia, or intraoperative or postoperative analgesic requirements (Table 1).

During the first 24 h, the number of patients who vomited twice or more within a 30 minute interval (PONV=3) was 5 in the ondansetron group, 4 in the granisetron group and 14 in the saline group respectively. Vomiting once only (PONV=2) was present in one patient in the ondansetron group, no patients in the granisetron group, and 3 patients in the saline group. Nausea only (PONV=1) was present in 2 patients in the ondansetron group, one in the granisetron group, and 3 in the saline group respectively.

TABLE 1

Patient demographics and underlying factors

The incidence of PONV=3 in patients who had received granisetron and ondansetron was lower than that in those who received saline (P=0.0016). This difference was statistically significant for both the two to six hour interval and overall (0 to 24 hours) (Table 2). However, there was no statistically significant difference in the incidence of PONV scores 1 or 2 between the groups.

Rescue antiemetic was required in 4 patients in the ondansetron group, 3 patients from the granisetron group and 8 patients from the saline group, while one out of 8 patients in the saline group required repeat dose of rescue antiemetic drug. No difference in the incidence of other adverse effects was observed among the groups.

DISCUSSION

The aetiology of PONV following breast surgery performed under general anaesthesia is complex and is dependent on a variety of factors which include age, gender, obesity, history of mountain sickness or previous PONV, phase of menstrual cycle, operative procedure, anaesthetic and analgesic technique and postoperative pain.

TABLE 2

Incidence and severity of PONV during the first 24 hours and rescue antiemetic requirement

TABLE 3

Incidence of adverse effects

In this study, the treatment groups were similar in regard to patient demographics, surgical procedure, anaesthetic administered and analgesic used postoperatively. Despite this, the saline group had an incidence of PONV=3 of 70%, compared to 25% in the ondansetron group and 20% in the granisetron group. The incidence of nausea only (PONV= 1), and vomiting once (PONV=2), appeared to be higher in saline group but the differences were not statistically significant. The difference in the incidence between the groups is likely to be due to the antiemetics administered. We cannot exclude a difference in the antiemetic efficacy of the two drugs for severe PONV due to the small sample size. For the same reason, we cannot comment on their effect on mild PONV

The incidence and severity of PONV in our study is comparable to previous studies, which have shown incidence of PONV in the range of 60 to 84% after breast surgery3-8. Fujii et al demonstrated 18% PONV after breast surgery after granisetron, which is similar to our study19. One previous study by Senthil et al had shown slightly higher incidence (33%) of PONV in patients receiving ondansetron7.

The complex act of vomiting involves coordination of the respiratory, gastrointestinal, and abdominal musculature and is controlled by the emetic centre, which is considered to be situated in the lateral reticular formation close to the tractus solitarius in the brainstem1,14. Stimuli from several areas within the central nervous system can affect the emetic centre. These include afferents from the pharynx, gastrointestinal tract and mediastinum, as well as afferents from the higher cortical centres (including the visual centre and the vestibular portion of the eighth cranial nerve) and the chemoreceptor trigger zone in the area prostrema. The area prostrema of the brain is rich in dopamine, opioid, serotonin and 5- hydroxytryptamine (5-HT3) receptors1.

Four majo\r neurotransmitter systems appears to play important roles in mediating the emetic response viz. dopaminergic, histaminic (Hl), cholinergic, and 5-HT3(1). As there are four different types of receptors, there are at least four sites of action of the antiemetic drugs. Antiemetic agents may have actions at more than one receptor but they tend to have a more prominent action at one or two receptors1,14. In current practice the 5-HT3 receptor antagonists have been used because of lack of side-effects such as sedation and extra pyramidal reactions. 5-HT3 receptor antagonists include ondansetron, granisetron, dolansetron and tropisetron. All 5- HT3 receptor antagonists have the same basic double nitrogen ring backbone for their chemical structure. This may be the chemical site of action of the 5-HT3 receptor antagonists15. 5-HT3 receptor antagonists are often used in current practice to reduce PONV following modified radical mastectomy surgery.

Granisetron and ondansetron have been proved to be effective in the reduction of emesis induced by cancer chemotherapy16, while Fujii et al have demonstrated that it also has a potent antiemetic effect on PONV after breast surgery17. Wilson et al compared different doses of intravenous granisetron in the prevention of PONV and found the optimal dose was 1 mg; therefore this dose was used in our studyls. Our results show that the incidence of severe PONV in patients who had received ondansetron or granisetron was less than those who had received placebo (P<0.05). These findings suggest that ondansetron and granisetron are effective in reducing PONV after breast surgery.

The adverse effects observed in this study were relatively mild, and there was no difference in the incidence of headache, dizziness, anxiety, insomnia, which was comparable with other studies.

In conclusion, both ondansetron and granisetron appear to be effective in reducing the incidence of severe PONV in female patients undergoing modified radical mastectomy. However, we cannot exclude a difference in the antiemetic efficacy between the two drugs or comment on their effect on mild PONV, due to the small sample size.

ACKNOWLEDGEMENT

We are thankful to Dr Rajbir Singh and Dr S. N. Diwedi for their help in statistical analysis.

REFERENCES

1. Watcha MF, White PF. Postoperative nausea and vomiting, its etiology, treatment and prevention. Anesthesiology 1992; 77:162- 184.

2. Janknegt R, Pinckaers JWM, Rohof MHC et al. Double blind comparative study of droperidol, granisetron and granisetron plus dexamcthasone as prophylactic anti-emetic therapy in patients undergoing abdominal, gynecological, breast or otolaryngological surgery. Anaesthesia 1999; 54:1059-1068.

3. Oddhy-Muhrheck E, Jakobsson J, Andersson L, Askergren J. Postoperative nausea and vomiting. A Comparison between intravenous and inhalation anaesthesia in breast surgery. Acta Anaesthcsiol Scand 1994; 38:52-56.

4. Oddby-Muhrbeck E, Jakobsson J, Enquist B. Implicit processing and therapeutic suggestion during balanced anaesthesia. Acta Anaesthcsiol Scand 1995; 39:333-337.

5. Enqvist B, Bjorklund C, Engman M, Jakobsson J. Preoperativc hypnosis reduces postoperative vomiting after surgery of breasts. A prospective, randomized and blinded study. Acta Anaesthesiol Scand 1997; 41:1028-1032.

6. Reihner E, Grunditz R, Gicsecke K, Gustafsson LL. Postoperative nausea and vomiting after breast surgery: Efficacy of prophylactic ondansetron and droperidol in a randomized placcbocontrollcd study. Eur J Anasesthsiol 2000; 17:197-203.

7. Sadhasivam S, Saxsena A, Kathirvel S, Kannan TR, Trika A, Mohan V. The safety and efficacy of prophylactic ondansetron in patients undergoing modified radical mastectomy. Anesth Analg 1999; 8:1340-1345.

8. Can TJ, Ginsbcrg B, Grant AP, Glass PS. Double-blind randomized comparison of ondansetron and intraopcrative propofol to prevent postoperative nausea and vomiting. Anesthesiology 1996; 85:1036-1042.

9. Jakobsson J, Andersson L, Nilsson A, Davidson S, Askergren J. Premedication before elective breast surgery, a comparison between ketobemidone and midazolam. Acta Anaesthcsiol Scand 1991; 35:524- 528.

10. Mikawa K, Takao Y, Nishina K, Shiga M, Mackawa N, Obara H. Optimal dose of granisctron for prophylaxis against postoperative emesis after gynecological surgery. Ancsth Analg 1997; 85:652-656.

11. Newberry NR, Watkins CJ, Sporsen TS, Blackburn TP, Grahmc- Smith DG, Leslie RA. BRL 46470 potently antagonizes neural response activated by 5-HT3 receptors. Neuropharmacology 1993; 32:729-735.

12. Elliott P, Seemungal BM, Wallis DI. Antagonism of the effects of 5-hydroxytryptamine on the rabbit isolated vagus nerve by BRL 43694 and mctoclopramide. Naunyn-Schmiedcbergs Arch Pharm 1990; 341:503-509.

13. Marr HE, Davey PT, Bartlett AJ. Emerging differences between 5-HT3 receptor antagonists. Anti-Cancer Drugs 1991; 2:513-518.

14. Paxton DL, Mckay CA, Mirakin KR. Prevention of nausea and vomiting after day case gynaecological laparoscopy. Anaesthesial995; 50: 403-406.

15. Fujii Y, Tanaka H, Toyooka H. Optimal dose of prophylactic antiemetic dose of granisetron for preventing postoperative nausea and vomiting. Can J Anesth 1994; 41:794-797.

16. Gigillo CA, Soares H, Castro CP et al. Granisetron is equivalent to Ondansetron for prophylaxis of chemotherapy induced nausea and vomiting. Results of a meta analysis of randomized controlled trials. Cancer 2000; 89:2301-2308.

17. Fujii Y, Tanaka H, Toyooka H. Granisetron reduces incidence of nausea and vomiting after breast surgery. Acta Anaesthesiol Scand 1997; 41:746-749.

18. Wilson AJ, Diemunsch P, Lindeque BG Ct al. Single dose i.v. granisetron in the prevention of postoperative nausea and vomiting. Br J Anacsth 1996; 76:515-518.

19. Fujii Y, Tanaka H, Toyooka H. Prophylactic oral antiemetic therapy with a combination of granisetron and dcxamethasone in patients undergoing middle ear surgery. Br J Anaesth 1998; 81:754- 756.

N. DUA*, S. BHATNAGAR[dagger], S. MISHRA[double dagger], A. K. SINGHAL

Department of Anesthesiology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India

* M.D., Senior Resident.

[dagger] M.D., Associate Professor.

[double dagger] M.D., Assistant Professor.

M.D., Senior Research Associate.

Address for reprints: Dr S. Bhatnagar, 2, North Avenue, I.I.T., New Delhi, India.

Accepted for publication on July 22, 2004.

Copyright Australian Society of Anaesthetists Dec 2004