Prophylaxis with Oral Granisetron for the Prevention of Nausea and Vomiting After Laparoscopic Cholecystectomy a Prospective Randomized Study

ORIGINAL ARTICLE Prophylaxis With Oral Granisetron for the Prevention of Nausea and Vomiting After Laparoscopic Cholecystectomy A Prospective Randomized Study

Yoshitaka Fujii, MD; Hiroyoshi Tanaka, MD; Tsuneo Kawasaki, MD

Hypothesis: Laparoscopic cholecystectomy is associ- dard general anesthetic technique and postoperative ated with a relatively high incidence of postoperative nau- analgesia were used. sea and vomiting when no prophylactic antiemetic is given. This study assesses the efficacy and safety of oral Main Outcome Measures: Emetic episodes were re- granisetron hydrochloride for the prevention of nausea corded during the first 24 hours after anesthesia. and vomiting after laparoscopic cholecystectomy. Results: The incidence of patients who were emesis- Design: A prospective, randomized, double-blind, pla- free 24 hours after anesthesia was 60% with 1 mg of granise- cebo-controlled study. tron (P=.40), 83% with 2 mg of granisetron (P=.01), and 83% with 4 mg of granisetron (P=.01), compared with Setting: University teaching hospital. placebo (53%). No clinically important adverse effects were observed in any of the groups. Patients: The study comprised 120 patients, 92 women and 28 men, undergoing laparoscopic cholecystectomy. Conclusion: Preoperative oral granisetron in doses higher than 2 mg is effective for the prevention of nausea and Interventions: Patients received orally either placebo vomiting after laparoscopic cholecystectomy. or granisetron at 3 different doses (1 mg, 2 mg, and 4 mg; n=30 of each) 60 minutes before surgery. A stan- Arch Surg. 2001;136:101-104

HE REPORTED incidence of tron reduces the incidence of postopera- nausea and vomiting after tive nausea and vomiting in patients un- laparoscopic cholecystec- dergoing laparoscopic cholecystectomy.7 tomy with no antiemetic However, granisetron ($33.40 for 1 mg) and treatment varies from 25% ondansetron ($33.43 for 1 mg) are much toT 42%.1,2 A variety of pharmacological ap- more expensive than other commonly used proaches (antihistamines, butyrophe- well-established antiemetics, such as dro- nones, dopamine receptor antagonists) peridol ($1.80 for 2.5 mg) and metoclop- have been investigated for the preven- ramide hydrochloride ($0.60 for 10 mg). tion and treatment of postoperative nau- In our institution, this may delay wide- sea and vomiting, but adverse effects such spread use as an antiemetic. An oral granis- as excessive sedation, hypotension, dry etron preparation ($12.60 for 1 mg) that mouth, dysphoria, hallucinations, and ex- is less expensive and is effective for reduc- trapyramidal signs have been noted.3 On- ing emesis caused by cancer chemo- dansetron hydrochloride, a serotonin type therapy is now available.8 The purpose of 3 receptor antagonist, reduces the inci- this study was to evaluate the efficacy and dence of nausea and vomiting after gyne- safety of prophylaxis with oral granise- cologic surgery.4 Granisetron hydrochlo- tron for the prevention of nausea and vom- ride, another antagonist of serotonin iting after laparoscopic cholecystectomy. receptors, is effective for the treatment of From the Departments of emesis in patients receiving cytotoxic RESULTS Anesthesiology (Drs Fujii and 5 Tanaka) and Surgery drugs. Granisetron is more potent and has (Dr Kawasaki), Toride Kyodo longer-acting properties against cisplatin- Six women and 4 men were excluded from General Hospital, Toride City, induced emesis than ondansetron.6 We the study, according to the exclusion cri- Ibaraki, Japan. have recently demonstrated that granise- teria. Patient profile and information on

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 PATIENTS, MATERIALS, isoflurane and nitrous oxide administration was stopped. Residual neuromuscular blockade was antagonized with AND METHODS IV atropine sulfate at 0.02 mg/kg and IV neostigmine methylsulfate at 0.04 mg/kg, and then the trachea was After obtaining institutional review board approval and extubated. Rectal temperature was monitored and main- informed consent from each patient, we studied 130 tained at 37°C±1°C using a heating pad throughout patients who were classified as physical status 1 according surgery. Postoperatively, all patients were admitted to the to the American Society of Anesthesiologists. The group hospital for 2 days. Postoperative analgesia was provided was composed of 98 women and 32 men, between 25 and rectally with indomethacin at 50 mg for moderate pain 63 years old, undergoing general anesthesia for elective and intramuscularly with pentazocine hydrochloride at 15 laparoscopic cholecystectomy. Indications for this surgi- mg for severe pain. cal procedure in the current clinical trial are symptomatic Postoperatively, emetic episodes during the first 24 cholelithiasis, chronic cholecystitis, and cholecystic hours after anesthesia were recorded by nursing staff polyp. Exclusion criteria were antiemetics given within 24 blind to which treatment the patients had received. The hours before surgery; active, acute cholecystitis in the 6 nurses asked the patients if retching or vomiting had months prior to admission; regular corticosteroid therapy; occurred and if they felt nauseated. These nurses observed serum ␥-glutamyltransferase, alkaline phosphatase, or the patients at various intervals according to the normal direct bilirubin levels twice normal; or laparoscopy ward routine. Nausea was defined as the subjectively replaced by laparotomy. Patients were randomly allo- unpleasant sensation associated with awareness of the cated via a computer-generated random numbers list to urge to vomit; retching was defined as the labored, spas- receive 1 of 4 treatment regimens (n=30 of each): modic, rhythmic contraction of the respiratory muscles granisetron at 3 different doses (1 mg, 2 mg, or 4 mg) or without the expulsion of gastric content; and vomiting placebo. These drugs were given orally 60 minutes was defined as the forceful expulsion of gastric contents before surgery. Identical-looking tablets containing from the mouth.3 The details of any adverse effects were either placebo, 1 mg of granisetron, 2 mg of granisetron, noted throughout the study, whether obtained through or 4 mg of granisetron were prepared according to ran- general questioning of the patients by follow-up nurses, domization. through observation by these nurses, or spontaneously No patients received preanesthetic medication. Anes- mentioned by the patients. thesia was induced intravenously (IV) with thiopentone Patient demographic data were determined by analy- sodium at 5 mg/kg and fentanyl citrate at 2 µg/kg, and IV sis of variance with the Bonferroni adjustment for mul- vecuronium bromide at 0.2 mg/kg was used to facilitate tiple comparison or ␹2 test. The number of patients who tracheal intubation. After intubation of the trachea, anes- were emesis-free or experiencing nausea, retching, or vom- thesia was maintained with isoflurane at 1.0% to 3.0% iting and the incidence of adverse effects were compared (inspired concentration) and nitrous oxide at 66% in oxy- with the Fisher exact probability test. A P value less than gen, with controlled ventilation adjusted to maintain an .05 was considered significant. All values were expressed end-tidal carbon dioxide concentration between 35 and as mean (SD) or number (percentage). Power analysis was 40 mm Hg using an anesthetic/respiratory gas analyzer used to determine the number of patients in the current (Ultima; Datex, Helsinki, Finland). A nasogastric tube study based on the assumptions that the incidence of an was inserted, and suction was applied to empty the stom- emetic-free period (which was regarded as the primary end- ach of air and other contents. Before extubation of the tra- point) in patients receiving placebo would be 50%, an im- chea, the nasogastric tube was again suctioned and then provement between 50% and 80% was considered of clini- removed. Neuromuscular block was achieved with cal importance, and ␣=.05 and 1 − ␤=.8. Based on these vecuronium. At the completion of the surgical procedure, assumptions, 30 patients per group were required.

surgery and anesthesia are summarized in Table 1. There COMMENT were no differences in patient demographics among the treatment groups. No differences were observed with Patients undergoing elective laparoscopic cholecystec- regard to the number of patients with either nausea, tomy have a relatively high incidence of postoperative retching, or vomiting. The only difference was found in nausea and vomiting.1,2 This problem is multifactorial the incidence of patients who were emesis-free up to 24 in origin, including patient demographics, nature of hours after anesthesia, which occurred in 16 (53%), 18 the underlying disease, type of surgery, anesthetic (60%), 25 (83%), and 25 (83%) of 30 patients who had technique, and postoperative care.3 The main patient- received placebo, 1 mg of granisetron, 2 mg of granis- related factors are age, sex, obesity, menstrual cycle, etron, and 4 mg of granisetron, respectively. Thus, an and history of motion sickness and/or previous post- emesis-free period was more common in patients who operative nausea and vomiting. Surgical factors had received granisetron at either 2 mg or 4 mg than in include the effect of intraperitoneal carbon dioxide those who had received placebo (PϽ.05). However, insufflation on residual stretching and irritation of the there was no difference between the patients who had peritoneum.2 In the current study, however, these fac- received 1 mg of granisetron and those who had tors were well balanced among the treatment groups, received placebo (Table 2). The clinically serious so differences regarding an emesis-free period for the adverse effects due to the study drug were not observed first 24 hours after anesthesia can be attributed to the in any of the groups. study drug.

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Placebo Granisetron, 1 mg Granisetron, 2 mg Granisetron, 4 mg Characteristic (n = 30) (n = 30) (n = 30) (n = 30) Mean (SD) age, y 48 (9) 46 (8) 46 (10) 48 (8) Sex (M/F) 7/23 8/22 7/23 6/24 Mean (SD) height, cm 158 (12) 158 (13) 156 (11) 158 (13) Mean (SD) weight, kg 55 (12) 56 (13) 55 (12) 56 (14) History of motion sickness, No. of patients 2 2 2 2 History of previous postoperative emesis, No. of patients 1 2 2 1 Median (range) days since last menstrual cycle [No.]* 16 (13-18) [20] 16 (14-18) [21] 16 (14-18) [21] 15 (13-19) [20] Mean (SD) duration of operation, min 85 (34) 88 (32) 85 (33) 87 (35) Mean (SD) duration of anesthesia, min 109 (35) 111 (34) 107 (32) 110 (35) Indication for laparoscopic cholecystectomy, No. of patients Symptomatic cholelithiasis 22 21 22 22 Chronic cholecystitis 3 3 3 3 Cholecystic polyp 5 6 5 5 Analgesic used postoperatively, No. of patients Indomethacin 18 17 18 17 Pentazocine 3 3 3 3

*Brackets indicate number of patients excluded because of menopause.

Table 2. Number of Patients Who Were Emesis-free or Experiencing Nausea, Retching, or Vomiting Up to 24 Hours After Anesthesia*

Symptoms Placebo Granisetron, 1 mg P Granisetron, 2 mg P Granisetron, 4 mg P Emesis-free 16 (53) 18 (60) .40 25 (83) .01 25 (83) .01 Nausea 7 (23) 6 (20) .5 3 (10) .15 3 (10) .15 Retching 2 (7) 1 (3) .5 1 (3) .5 2 (7) Ͼ.9 Vomiting 6 (20) 6 (20) Ͼ.9 2 (7) .13 1 (3) .05

*Data are presented as number (percentage) unless otherwise indicated.

Intravenous granisetron is effective against emesis laparoscopic cholecystectomy and that increasing the dose induced by cancer chemotherapy.5 Recently, we have dem- to 4 mg provides no demonstrable benefit. onstrated both that this drug reduces the incidence of post- Granisetron does not cause the sedative, dys- operative nausea and vomiting in patients undergoing phoric, and extrapyramidal symptoms associated with laparoscopic cholecystectomy7 and that prophylactic nonserotonin type 3 receptor antagonists (eg, dro- therapy in combination with it is superior to droperidol peridol, metoclopramide).3,11 Adverse effects due to and metoclopramide for the prevention of nausea and granisetron observed in the present study were not vomiting after this procedure.9 An oral regimen of clinically serious in any group. Therefore, oral granise- granisetron is effective for the treatment of vomiting in tron at 3 different doses (1 mg, 2 mg, 4 mg) is consid- patients receiving cytotoxic drugs.8 In the current ered to be relatively free of adverse effects for the pre- study, the chance of an emesis-free period during the vention of nausea and vomiting after laparoscopic first 24 hours after anesthesia was greater in patients cholecystectomy. who had received 2 or 4 mg of granisetron than in those The results of this clinical study are important for who had received placebo (PϽ.05). The exact mecha- the potential reduction of therapy cost. Our hospital phar- nism of granisetron for the prevention of postoperative macy pays $25.20 for 2 mg of oral granisetron, which is nausea and vomiting remains unclear, but it has been the minimum effective dose and is less expensive than suggested that this drug may act on sites containing intravenous granisetron ($100.20 for 3 mg).7 The cost serotonin type 3 receptors with demonstrated anti- of oral granisetron is still high compared with other IV emetic effects.10 antiemetics, including droperidol ($1.80 for 2.5 mg) and We found no study to determine the minimum ef- metoclopramide ($0.60 for 10 mg). In the current study, fective dose of oral granisetron for the prevention of post- a cost-effective analysis, defined as the cost per unit of operative nausea and vomiting in patients undergoing success,12 was not performed. However, the use of dro- laparoscopic cholecystectomy. In this clinical trial, how- peridol and metoclopramide as antiemetics has been lim- ever, we demonstrated that antiemetic efficacy of 2 mg ited because these drugs occasionally cause excessive se- of granisetron was similar to that of 4 mg of granisetron dation and extrapyramidal signs.3 A decision about and that no differences existed in emesis-free periods be- antiemetics should not be limited to cost but should also tween patients who had received placebo and those who consider patient outcome. In conclusion, preoperative oral had received 1 mg of granisetron. These findings sug- granisetron, in doses higher than 2 mg, is effective for gest that granisetron at 2 mg may be an effective anti- the prevention of nausea and vomiting after laparo- emetic for the prevention of nausea and vomiting after scopic cholecystectomy.

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Corresponding author and reprints: Yoshitaka Fujii, MD, 5-hydroxytryptamine3 receptor antagonist BRL 43694. Br J Cancer. 1988;58: Department of Anesthesiology, University of Tsukuba In- 644-650. 6. Andrews PLR, Bhandari P, Davey PT, Bingham S, Marr HE, Blower PR. Are all stitute of Clinical Medicine, 2-1-1 Amakubo, Tsukuba City, 5-HT3 receptor antagonists the same? Eur J Cancer. 1992;28:S2-S6. Ibaraki 305, Japan. 7. Fujii Y, Tanaka H, Toyooka H. Granisetron reduces the incidence and severity of nausea and vomiting after laparoscopic cholecystectomy. Can J Anaesth. 1997; 44:396-400. REFERENCES 8. Maisano P, Adamo V, Settineri N, Pergolizzi S, Scimone A, Altavilla G. Efficacy of two oral dose regimens of granisetron. Anticancer Res. 1995;15:2287-2290. 1. Santon JM. Anaesthesia for laparoscopic cholecystectomy [letter]. Anaesthe- 9. Fujii Y, Saitoh Y, Tanaka H, Toyooka H. Anti-emetic efficacy of prophylactic granise- sia. 1991;46:317. tron, droperidol and metoclopramide in the prevention of nausea and vomiting 2. Iitomi T, Toriumi S, Kondo A, Akazawa T, Nakahara T. Incidence of nausea and after laparoscopic cholecystectomy: a randomized, double-blind, placebo- vomiting after cholecystectomy performed via laparotomy or laparoscopy [in Japa- controlled trial. Eur J Anaesthesiol. 1998;15:166-171. nese]. Masui. 1995;44:1627-1631. 10. Carmichael J, Cantwell BMJ, Edwards CM, et al. A pharmacokinetic study of granise- 3. Watcha MF, White PF. Postoperative nausea and vomiting: its etiology, treat- tron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation of anti- ment, and prevention. Anesthesiology. 1992;77:161-184. emetic response. Cancer Chemother Pharmacol. 1989;24:45-49. 4. Leeser J, Lip H. Prevention of postoperative nausea and vomiting using ondanse- 11. Yarker YE, McTavish D. Granisetron: an update of its therapeutic use in nausea tron, a new, selective, 5-HT3 receptor antagonist. Anesth Analg. 1991;72:751- and vomiting induced by antineoplasmic therapy. Drugs. 1994;48:761-793. 755. 12. Watcha MF, White PF. Economics of anesthetic practice. Anesthesiology. 1997; 5. Bermudez J, Boyle EA, Minter WD, Sanger GJ. The antiemetic potential of the 86:1170-1186.

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ARCHIVES OF INTERNAL MEDICINE Effects of Hormone Replacement Therapy on Bone Mineral Density in Postmenopausal Women With Primary Hyperparathyroidism: Four-Year Follow-up and Comparison With Healthy Postmenopausal Women Brandon J. Orr-Walker, MBChB; Margaret C. Evans, BSc; Judy M. Clearwater; Anne Horne, MBChB; Andrew B. Grey, MBChB; Ian R. Reid, MD Background: Long-term treatment of patients with asymptomatic primary hyperparathyroidism remains controversial, but the presence of osteoporosis is regarded as an indication for parathyroidectomy. Hormone replacement therapy (HRT) is a possible alternative therapy in osteopenic postmenopausal women with the disorder, and results of short-term studies suggest a beneficial effect on bone mass comparable to that achieved by parathyroidectomy. Longer-term data are required to further assess the efficacy of this treatment in chronic stable primary hyperparathyroidism. Methods: We report the results of the extension from 2 to 4 years of a randomized, placebo-controlled trial of HRT in postmenopausal women with primary hyperparathyroidism. Of 23 postmenopausal women with primary hyperparathyroidism, 11 received active HRT with conjugated equine estrogen, 0.625 mg/d, and medroxyprogesterone acetate, 5 mg/d, and 12 received placebo. Bone mineral density was measured throughout the skeleton at 6-month intervals using dual-energy x-ray absorptiometry in these women and in 50 normocalcemic age-matched control subjects. None of the 23 patients withdrew during the extension period. Results: Changes in bone mineral density were more positive in those taking HRT than placebo, with the between-group differences at 4 years being 4.6% in the total body, 7.5% in the lumbar spine, 7.4% in the femoral neck, 8.2% in the femoral trochanter, 6.8% in the legs, and 7.0% in the forearm (PϽ.01). At skeletal sites composed predominantly of cortical bone, there was a progressive divergence of the 2 groups. Biochemical markers of bone turnover remained lower throughout the study in women taking HRT. When rates of bone loss were compared between the placebo group and healthy women of comparable age, bone loss tended to be more marked throughout the skeleton in women with hyperparathyroidism, but only in the total body and its legs subregion was this difference significant. Conclusions: Hormone replacement therapy is efficacious in the long-term management of osteopenia in postmenopausal women with primary hyperparathyroidism and thus represents an important new therapeutic option for asymptomatic patients who do not have other indications for surgery. Bone loss seems to be accelerated in untreated primary hyperparathyroidism. (2000;160:2161-2166) Corresponding author: Ian R. Reid, MD, Department of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zea- land (e-mail: [email protected]).

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