Fujii Y, Tanaka H, Kawasaki T. Prophylaxis With Oral Granisetron for the Prevention of Nausea and Vomiting After Laparoscopic CholecystectomyA Prospective Randomized Study. Arch Surg. 2001;136(1):101-104. doi:10.1001/archsurg.136.1.101
Laparoscopic cholecystectomy is associated with a relatively high incidence of postoperative nausea and vomiting when no prophylactic antiemetic is given. This study assesses the efficacy and safety of oral granisetron hydrochloride for the prevention of nausea and vomiting after laparoscopic cholecystectomy.
A prospective, randomized, double-blind, placebo-controlled study.
University teaching hospital.
The study comprised 120 patients, 92 women and 28 men, undergoing laparoscopic cholecystectomy.
Patients received orally either placebo or granisetron at 3 different doses (1 mg, 2 mg, and 4 mg; n = 30 of each) 60 minutes before surgery. A standard general anesthetic technique and postoperative analgesia were used.
Main Outcome Measures
Emetic episodes were recorded during the first 24 hours after anesthesia.
The incidence of patients who were emesis-free 24 hours after anesthesia was 60% with 1 mg of granisetron (P = .40), 83% with 2 mg of granisetron (P = .01), and 83% with 4 mg of granisetron (P = .01), compared with placebo (53%). No clinically important adverse effects were observed in any of the groups.
Preoperative oral granisetron in doses higher than 2 mg is effective for the prevention of nausea and vomiting after laparoscopic cholecystectomy.
THE REPORTED incidence of nausea and vomiting after laparoscopic cholecystectomy with no antiemetic treatment varies from 25% to 42%.1,2 A variety of pharmacological approaches (antihistamines, butyrophenones, dopamine receptor antagonists) have been investigated for the prevention and treatment of postoperative nausea and vomiting, but adverse effects such as excessive sedation, hypotension, dry mouth, dysphoria, hallucinations, and extrapyramidal signs have been noted.3 Ondansetron hydrochloride, a serotonin type 3 receptor antagonist, reduces the incidence of nausea and vomiting after gynecologic surgery.4 Granisetron hydrochloride, another antagonist of serotonin receptors, is effective for the treatment of emesis in patients receiving cytotoxic drugs.5 Granisetron is more potent and has longer-acting properties against cisplatin-induced emesis than ondansetron.6 We have recently demonstrated that granisetron reduces the incidence of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy.7 However, granisetron ($33.40 for 1 mg) and ondansetron ($33.43 for 1 mg) are much more expensive than other commonly used well-established antiemetics, such as droperidol ($1.80 for 2.5 mg) and metoclopramide hydrochloride ($0.60 for 10 mg). In our institution, this may delay widespread use as an antiemetic. An oral granisetron preparation ($12.60 for 1 mg) that is less expensive and is effective for reducing emesis caused by cancer chemotherapy is now available.8 The purpose of this study was to evaluate the efficacy and safety of prophylaxis with oral granisetron for the prevention of nausea and vomiting after laparoscopic cholecystectomy.
After obtaining institutional review board approval and informed consent from each patient, we studied 130 patients who were classified as physical status 1 according to the American Society of Anesthesiologists. The group was composed of 98 women and 32 men, between 25 and 63 years old, undergoing general anesthesia for elective laparoscopic cholecystectomy. Indications for this surgical procedure in the current clinical trial are symptomatic cholelithiasis, chronic cholecystitis, and cholecystic polyp. Exclusion criteria were antiemetics given within 24 hours before surgery; active, acute cholecystitis in the 6 months prior to admission; regular corticosteroid therapy; serum γ-glutamyltransferase, alkaline phosphatase, or direct bilirubin levels twice normal; or laparoscopy replaced by laparotomy. Patients were randomly allocated via a computer-generated random numbers list to receive 1 of 4 treatment regimens (n = 30 of each): granisetron at 3 different doses (1 mg, 2 mg, or 4 mg) or placebo. These drugs were given orally 60 minutes before surgery. Identical-looking tablets containing either placebo, 1 mg of granisetron, 2 mg of granisetron, or 4 mg of granisetron were prepared according to randomization.
No patients received preanesthetic medication. Anesthesia was induced intravenously (IV) with thiopentone sodium at 5 mg/kg and fentanyl citrate at 2 µg/kg, and IV vecuronium bromide at 0.2 mg/kg was used to facilitate tracheal intubation. After intubation of the trachea, anesthesia was maintained with isoflurane at 1.0% to 3.0% (inspired concentration) and nitrous oxide at 66% in oxygen, with controlled ventilation adjusted to maintain an end-tidal carbon dioxide concentration between 35 and 40 mm Hg using an anesthetic/respiratory gas analyzer (Ultima; Datex, Helsinki, Finland). A nasogastric tube was inserted, and suction was applied to empty the stomach of air and other contents. Before extubation of the trachea, the nasogastric tube was again suctioned and then removed. Neuromuscular block was achieved with vecuronium. At the completion of the surgical procedure, isoflurane and nitrous oxide administration was stopped. Residual neuromuscular blockade was antagonized with IV atropine sulfate at 0.02 mg/kg and IV neostigmine methylsulfate at 0.04 mg/kg, and then the trachea was extubated. Rectal temperature was monitored and maintained at 37°C ± 1°C using a heating pad throughout surgery. Postoperatively, all patients were admitted to the hospital for 2 days. Postoperative analgesia was provided rectally with indomethacin at 50 mg for moderate pain and intramuscularly with pentazocine hydrochloride at 15 mg for severe pain.
Postoperatively, emetic episodes during the first 24 hours after anesthesia were recorded by nursing staff blind to which treatment the patients had received. The nurses asked the patients if retching or vomiting had occurred and if they felt nauseated. These nurses observed the patients at various intervals according to the normal ward routine. Nausea was defined as the subjectively unpleasant sensation associated with awareness of the urge to vomit; retching was defined as the labored, spasmodic, rhythmic contraction of the respiratory muscles without the expulsion of gastric content; and vomiting was defined as the forceful expulsion of gastric contents from the mouth.3 The details of any adverse effects were noted throughout the study, whether obtained through general questioning of the patients by follow-up nurses, through observation by these nurses, or spontaneously mentioned by the patients.
Patient demographic data were determined by analysis of variance with the Bonferroni adjustment for multiple comparison or χ2 test. The number of patients who were emesis-free or experiencing nausea, retching, or vomiting and the incidence of adverse effects were compared with the Fisher exact probability test. A P value less than .05 was considered significant. All values were expressed as mean (SD) or number (percentage). Power analysis was used to determine the number of patients in the current study based on the assumptions that the incidence of an emetic-free period (which was regarded as the primary endpoint) in patients receiving placebo would be 50%, an improvement between 50% and 80% was considered of clinical importance, and α = .05 and 1 − β = .8. Based on these assumptions, 30 patients per group were required.
Six women and 4 men were excluded from the study, according to the exclusion criteria. Patient profile and information on surgery and anesthesia are summarized in Table 1. There were no differences in patient demographics among the treatment groups. No differences were observed with regard to the number of patients with either nausea, retching, or vomiting. The only difference was found in the incidence of patients who were emesis-free up to 24 hours after anesthesia, which occurred in 16 (53%), 18 (60%), 25 (83%), and 25 (83%) of 30 patients who had received placebo, 1 mg of granisetron, 2 mg of granisetron, and 4 mg of granisetron, respectively. Thus, an emesis-free period was more common in patients who had received granisetron at either 2 mg or 4 mg than in those who had received placebo (P<.05). However, there was no difference between the patients who had received 1 mg of granisetron and those who had received placebo (Table 2). The clinically serious adverse effects due to the study drug were not observed in any of the groups.
Patients undergoing elective laparoscopic cholecystectomy have a relatively high incidence of postoperative nausea and vomiting.1,2 This problem is multifactorial in origin, including patient demographics, nature of the underlying disease, type of surgery, anesthetic technique, and postoperative care.3 The main patient-related factors are age, sex, obesity, menstrual cycle, and history of motion sickness and/or previous postoperative nausea and vomiting. Surgical factors include the effect of intraperitoneal carbon dioxide insufflation on residual stretching and irritation of the peritoneum.2 In the current study, however, these factors were well balanced among the treatment groups, so differences regarding an emesis-free period for the first 24 hours after anesthesia can be attributed to the study drug.
Intravenous granisetron is effective against emesis induced by cancer chemotherapy.5 Recently, we have demonstrated both that this drug reduces the incidence of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy7 and that prophylactic therapy in combination with it is superior to droperidol and metoclopramide for the prevention of nausea and vomiting after this procedure.9 An oral regimen of granisetron is effective for the treatment of vomiting in patients receiving cytotoxic drugs.8 In the current study, the chance of an emesis-free period during the first 24 hours after anesthesia was greater in patients who had received 2 or 4 mg of granisetron than in those who had received placebo (P<.05). The exact mechanism of granisetron for the prevention of postoperative nausea and vomiting remains unclear, but it has been suggested that this drug may act on sites containing serotonin type 3 receptors with demonstrated antiemetic effects.10
We found no study to determine the minimum effective dose of oral granisetron for the prevention of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. In this clinical trial, however, we demonstrated that antiemetic efficacy of 2 mg of granisetron was similar to that of 4 mg of granisetron and that no differences existed in emesis-free periods between patients who had received placebo and those who had received 1 mg of granisetron. These findings suggest that granisetron at 2 mg may be an effective antiemetic for the prevention of nausea and vomiting after laparoscopic cholecystectomy and that increasing the dose to 4 mg provides no demonstrable benefit.
Granisetron does not cause the sedative, dysphoric, and extrapyramidal symptoms associated with nonserotonin type 3 receptor antagonists (eg, droperidol, metoclopramide).3,11 Adverse effects due to granisetron observed in the present study were not clinically serious in any group. Therefore, oral granisetron at 3 different doses (1 mg, 2 mg, 4 mg) is considered to be relatively free of adverse effects for the prevention of nausea and vomiting after laparoscopic cholecystectomy.
The results of this clinical study are important for the potential reduction of therapy cost. Our hospital pharmacy pays $25.20 for 2 mg of oral granisetron, which is the minimum effective dose and is less expensive than intravenous granisetron ($100.20 for 3 mg).7 The cost of oral granisetron is still high compared with other IV antiemetics, including droperidol ($1.80 for 2.5 mg) and metoclopramide ($0.60 for 10 mg). In the current study, a cost-effective analysis, defined as the cost per unit of success,12 was not performed. However, the use of droperidol and metoclopramide as antiemetics has been limited because these drugs occasionally cause excessive sedation and extrapyramidal signs.3 A decision about antiemetics should not be limited to cost but should also consider patient outcome. In conclusion, preoperative oral granisetron, in doses higher than 2 mg, is effective for the prevention of nausea and vomiting after laparoscopic cholecystectomy.
Corresponding author and reprints: Yoshitaka Fujii, MD, Department of Anesthesiology, University of Tsukuba Institute of Clinical Medicine, 2-1-1 Amakubo, Tsukuba City, Ibaraki 305, Japan.