Anesth Analg 2006;102:1387-1393
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000208967.94601.cd
AMBULATORY ANESTHESIA
Section Editor:
Peter S. A. Glass
The Use of Oral Granisetron Versus Intravenous Ondansetron for Antiemetic Prophylaxis in Patients Undergoing Laparoscopic Surgery: The Effect on Emetic Symptoms and Quality of Recovery
Paul F. White, PhD, MD*,
Jun Tang, MD
,
Mohamed A. Hamza, MD*,
Babatunde Ogunnaike, MD*,
Monica Lo*,
Ronald H. Wender, MD,
Robert Naruse, MD,
Alexander Sloninsky, MD,
Robert Kariger, MD,
Scott Cunneen, MD, and
Ted Khalili, MD
*Department of Anesthesiology and Pain Management, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas; Department of Anesthesiology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
Address correspondence and reprint requests to Paul F. White, PhD, MD, Professor and McDermott Chair of Anesthesiology, Department of Anesthesiology and Pain Management, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, F2.208A; Dallas, Texas 75390-9068. Address e-mail to paul.white{at}utsouthwestern.edu.
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Abstract
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Based on comparative studies in patients receiving emetogenic chemotherapy, it has been suggested that granisetron would be more effective than ondansetron for the prevention of postdischarge nausea and vomiting (PDNV). However, there have been no direct comparisons of these two popular 5-HT3 antagonists with respect to PDNV and quality of recovery. We designed this randomized, double-blind study to compare the antiemetic efficacy of oral granisetron (1 mg) to a standard IV dose of ondansetron (4 mg) when administered for antiemetic prophylaxis as part of a multimodal regimen in a laparoscopic surgical population. A total of 220 patients undergoing laparoscopic surgery with a standardized general anesthetic technique were enrolled in this prospective study at two major medical centers. Patients were randomly assigned to one of two prophylactic treatment groups: the control (ondansetron) group received an oral placebo 1 h before surgery and ondansetron, 4 mg IV, at the end of the surgery, and the granisetron group received granisetron, 1 mg per os, 1 h before surgery, and normal saline, 2 mL IV, at the end of the surgery. The early recovery profiles, requirement for rescue antiemetics, incidence of PDNV, and the side effects were recorded over the 48 h study period. In addition, nausea scores were assessed using an 11-point verbal rating scale at specific intervals in the postoperative period. The quality of recovery and patient satisfaction scores were recorded at 48 h after surgery. The demographic characteristics were similar in the two prophylaxis treatment groups, as well as the recovery times to patient orientation, oral intake, and hospital discharge. The incidences of PDNV, requirements for rescue antiemetics, and quality of recovery did not differ between the two study groups. The antiemetic drug acquisition costs to achieve comparable patient satisfaction with ondansetron and granisetron were US $25.65 and $47.05, respectively. Therefore, ondansetron (4 mg IV) was more cost-effective than granisetron (1 mg per os) for routine antiemetic prophylaxis as part of a multimodal regimen in patients undergoing either outpatient or inpatient laparoscopic surgery.
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Introduction
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Postdischarge nausea and vomiting (PDNV) can cause significant patient discomfort, electrolyte disturbances, and lead to delays in resumption of normal activities of daily living after elective surgery (1). According to Carroll et al. (2), up to 50% of all postoperative nausea and vomiting (PONV) after ambulatory surgery occurs in the postdischarge period. The deleterious effects of PONV are not limited to patients; it can also produce a negative financial impact on a surgical unit (3,4). Sennaraj et al. (5) reported that the use of prophylactic antiemetic therapy with ondansetron significantly increases satisfaction at less direct cost compared with simply treating emetic symptoms when they occur in the postoperative period.
Of the available 5-HT3 receptor antagonists, ondansetron is the most widely used for the prevention and treatment of emetic symptoms after elective surgery (6). Granisetron, a more selective 5-HT3 antagonist, has been alleged to produce a sustained antiemetic effect when used for prophylaxis (7,8). However, earlier studies involving prophylaxis with granisetron have only evaluated emetic symptoms during the first 24 h after surgery (8–12). Despite its higher cost than ondansetron, granisetron may be more cost-effective if it provided greater antiemetic efficacy in the postdischarge period. No comparative cost-efficacy studies have been performed evaluating these two 5-HT3 antagonists for preventing PDNV.
We designed this randomized, double-blind, and active-controlled study to evaluate the hypothesis that oral granisetron would be a cost-effective alternative to IV ondansetron for preventing PONV and/or PDNV and improving the quality of recovery when administered for antiemetic prophylaxis of patients undergoing laparoscopic surgery.
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Methods
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After obtaining IRB approval at both the UT Southwestern Medical Center at Dallas and Cedars-Sinai Medical Center in Los Angeles and written informed consent, 220 patients undergoing surgery procedures (e.g., cholecystectomy, laparoscopic tubal ligation, gastric bypass) were enrolled in this prospective, randomized, double-blind multicenter clinical study. Exclusion criteria included a history of allergy to any of the potential study medications, pregnancy, breastfeeding, active menstruation, vomiting or retching within 24 h before the operation, administration of antiemetic or psychoactive medication within 24 h before surgery, a history of severe (or unstable) cardiovascular, respiratory, metabolic, endocrine or neurologic disease, active alcohol or drug abuse, as well as impaired renal or hepatic function.
All patients were assigned to one of two prophylactic treatment groups according to a computer-generated random numbers table. Patients in the ondansetron (control) group (n = 110) received an oral placebo 1 h before surgery and ondansetron, 4 mg IV, at the end of the surgery; whereas those in the granisetron group (n = 110) received granisetron, 1 mg per os, 1 h before surgery and normal saline, 2 mL IV, at the end of the surgery. The patients, the investigators collecting data, and the nurses involved in the postoperative care of the patients were blinded as to the content of the study medication, which were prepared by a research pharmacist at each hospital. The active and placebo pills were identical in appearance.
The patients were asked to provide a detailed medical history and demographic information (including age, weight, height, alcohol or drug consumption, and any history of smoking, PONV, or motion sickness). Patients were also asked to complete baseline verbal rating scales (VRS) for pain and nausea using an 11-point scale, with 0 = none to 10 = maximum. Immediately before leaving the preoperative holding area, patients were premedicated with midazolam, 20 µg/kg IV. On arrival in the operating room, standard monitoring devices were applied. The mean arterial blood pressure, heart rate, and hemoglobin oxygen saturation values were recorded at 5-min intervals throughout the operation. The inspired and end-tidal concentrations of oxygen, carbon dioxide, and desflurane were measured continuously using a calibrated infrared gas analyzer.
For all patients, we used a standardized general anesthetic technique. Anesthesia was induced with propofol, 1–2 mg/kg IV, and fentanyl 1–2 µg/kg IV, and tracheal intubation was facilitated with succinylcholine, 1 mg/kg IV. Dexamethasone, 4 mg IV, was given to all patients after induction for antiemetic prophylaxis. Anesthesia was maintained with desflurane 2%–6% inspired in combination with air (1 L/min) and oxygen (1 L/min). Cisatracurium, 0.025–0.05 mg/kg IV, was administered for muscle relaxation during the maintenance period. At the end of the surgical procedure, residual neuromuscular blockade was reversed with glycopyrrolate, 3 µg/kg IV, and neostigmine 30 µg/kg IV, desflurane was discontinued, and the inspired oxygen flow was increased to 5 L/min.
Anesthesia time (from induction of anesthesia to discontinuation of desflurane) and surgery time (from skin incision to placement of the wound dressing) were recorded. The times at which patients were able to open their eyes, follow a simple command (to squeeze the investigator’s hand), and were oriented to their name and place/date of birth, were assessed by a blinded observer at 1-min intervals after discontinuing the anesthetic. The duration of the postanesthesia care unit stay, and actual discharge times from the day surgery unit (outpatients) and hospital (inpatients) were also recorded.
Antiemetic efficacy was assessed by monitoring the incidences of nausea and vomiting (emesis or retching), as well as the need for "rescue" antiemetic medication. An emetic episode was defined as either a single episode or repeated episodes of vomiting or retching occurring within 1 min of each other. If the patient complained of feeling nauseated for more than 5 min, it was considered to be an episode of nausea. The VRS scores for pain and nausea were assessed at 30-min intervals and immediately before the patient receiving any rescue analgesic or antiemetic medication. Rescue antiemetic therapy was administered if the patients experienced 
2 emetic episodes or intractable nausea (i.e., VRS nausea score >6 for at least 5 min). Metoclopramide, 10 mg IV, was given as a rescue antiemetic. Postoperative pain was initially treated with boluses of fentanyl, 25 µg IV, and subsequently with hydromorphone, 0.25–0.5 mg IV. All adverse events and rescue medications administered during the 48-h study period were recorded.
Patients were contacted at 24 and 48 h after the operation by a blinded investigator to inquire about the number of episodes of nausea and/or vomiting, and the need for antiemetic rescue medication. Patients were also asked to evaluate their maximal degree of nausea during the 0- to 24-h and 24- to 48-h study periods using the 11-point VRS. For outpatients (e.g., laparoscopic tubal ligations, laparoscopic cholecystectomy), PDNV referred to the time period after discharge from the hospital. For inpatients (e.g., laparoscopic bariatric surgery), PDNV referred to the incidences after discharge from the recovery room. Complete responses referred to incidences when no emesis (vomiting/retching) and no rescue antiemetic drugs were required. Quality of life issues, including the patient’s ability to sleep, and their quality of recovery score (using a 9-item check list) (13), as well as the patient’s willingness to have the same treatment for the prevention of PONV in the future, were assessed at 48 h after surgery.
An a prior power analysis suggested that group sizes of 110 patients should be adequate to detect a 25%–30% difference in the incidence of PONV with a power of 0.8 (
= 0.05) assuming an incidence of 70% in patients undergoing similar laparoscopic procedures (14–17). Normally distributed continuous data were analyzed using Student’s t-test. Continuous data not normally distributed (e.g., pain scores) were analyzed by a Mann-Whitney U-test. Categorical data were analyzed using the 
2 test or Fisher’s exact test where appropriate. A P value of <0.05 was considered statistically significant. Data are presented as mean values ± sd, or median values (with interquartile ranges), numbers (n), and percentages (%).
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Results
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A total of 220 patients were enrolled in the study. However, 15 patients (9 patients in the ondansetron group and 6 patients in the granisetron group) were excluded from the final data analysis because of protocol violations and/or incomplete data. Demographic characteristics, including age, body weight, body mass index, smoking status, and history of PONV or motion sickness were comparable in both antiemetic treatment groups (Table 1). In addition, there were no differences in the durations of anesthesia and surgery or in the doses of preoperative medication, induction and maintenance anesthetics, muscle relaxant reversal drugs, and use of intraoperative (Table 1) and postoperative (Table 2) opioid analgesic medications in the ondansetron and granisetron groups.
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Table 1. Patient Demographic, Survey and Anesthesia Characteristics and Preoperative Nausea Score in the Two Antiemetic Groups
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With respect to the early recovery profiles and discharge times (Table 2), there were no significant differences between the two antiemetic prophylaxis groups undergoing inpatient or outpatient laparoscopic surgery (data not reported). More importantly, the incidences of nausea and vomiting and the need for rescue antiemetics in the first 24-h study period were not different in the two antiemetic groups (Table 3). Not surprisingly, outpatients received rescue antiemetics earlier than inpatients (73 ± 51 versus 296 ± 200 min) in the postoperative period.
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Table 3. The Overall Incidence of Postoperative Nausea and Vomiting (PONV), Postdischarge Nausea and Vomiting (PDNV), as well as the Need for "Rescue" Antiemetic Medication in the Two Treatment Groups
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During 48 h follow-up period after surgery, the incidences of PONV and PDNV, the maximum nausea score, as well as the quality of recovery were also comparable in both study groups (Table 3). An equally large percentage of patients in both antiemetic groups expressed a willingness to have the same antiemetic prophylaxis in the future (Table 2). Importantly, the other clinical outcome variables (e.g., ability to sleep normally, quality of recovery) were not different after ondansetron and granisetron prophylaxis at 48 h after surgery (Table 2). A subset analysis based on whether the laparoscopic procedure was performed on an inpatient or outpatient basis also failed to demonstrate any differences in postoperative emetic symptoms with granisetron versus ondansetron prophylaxis (Table 4).
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Table 4. The Incidence of Postoperative Nausea and Vomiting (PONV), as well as the Need for "Rescue" Antiemetic Medication in the Outpatient Versus Inpatient Subgroups
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Discussion
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Nausea and vomiting are the most frequently reported complaints after laparoscopic surgery (14,15). Patient concerns regarding PONV are often greater than their concern for avoidance of postoperative pain (18). For patients in the high-risk category (e.g., women, history of PONV and motion sickness, nonsmoking status, and use of postoperative opioid analgesics), PONV may occur in more than 70% of the cases (19). The duration of hospitalization in patients who experience PONV after major laparoscopic surgery is reported to be prolonged an average of 1 day longer than for those not experiencing PONV (15). However, the impact of PDNV on quality of recovery and patient satisfaction is less well understood.
A wide variety of antiemetic drugs (e.g., anticholinergics, antihistaminics, dopamine receptor antagonists, 5-HT3 antagonists, glucocorticosteroids, neurokinin-1 antagonists) are available to prevent postoperative emetic symptoms (1). However, their relative efficacy for preventing PDNV has not been extensively studied. Droperidol remains the most cost-effective antiemetic therapy despite concerns regarding extrapyramidal side effects and the potential for prolonging the electrocardiographic QT interval (20). Of interest, a recent placebo-controlled study evaluating the effects of small-dose droperidol (0.625–1.25 mg IV) on the QTc interval failed to demonstrate significant QT prolongation (21). Nevertheless, use of droperidol has dramatically declined because of medicolegal concerns regarding the Food and Drug Administration-imposed Black Box warning. Although an earlier dose-ranging study involving granisetron by Fujii et al. (11) suggested that only large doses (2 mg per os) were effective for the prevention of PONV after laparoscopic cholecystectomy procedures, we found that granisetron (1 mg per os) was comparable to ondansetron (4 mg IV) when administered as part of a multimodal antiemetic regimen. However, despite prophylaxis with these 5-HT3 antagonists in combination with the glucocorticoid steroid, the incidences of PDNV remained high at 26%–40% and 14%–21% during the 4- to 24-h and 24- to 48-h follow-up intervals, respectively.
Our findings are more consistent with the findings of Dua et al. (12), who demonstrated that ondansetron, 4 mg IV, and granisetron, 1 mg IV, given before induction of anesthesia were equally effective for reducing the incidence of PONV after mastectomy procedures. Another well-controlled comparative study (9) involving granisetron in patients undergoing laparoscopic cholecystectomy procedures suggested that even the use of a threefold larger dose (3 mg IV) failed to provide more effective antiemetic prophylaxis than ondansetron 4 mg IV. Given the expense of IV granisetron (US $136 for a 1 mg IV dose), we decided to evaluate the less costly oral formulation (US $48 for a 1 mg per os dose).
Granisetron has been alleged to possess a long duration of antiemetic activity (7,10,22). However, we failed to find significant differences in postdischarge emetic symptoms or in the need for rescue antiemetics with these two 5-HT3 antagonists at intervals up to 48 h after inpatient or outpatient laparoscopic procedures. The reduced time to rescue in the subpopulation undergoing outpatient laparoscopic surgery (e.g., tubal ligation procedures) was presumably related to their earlier ambulation compared with inpatients undergoing major laparoscopic procedures (e.g., gastric banding). Given the comparable efficacy of oral granisetron and IV ondansetron in the postoperative period, ondansetron would be preferable because it is more convenient (IV versus oral) and loss costly (US $25 versus US $47) for routine antiemetic prophylaxis.
A recent multicenter study involving a 5-HT3 receptor antagonist (ondansetron), dopamine antagonist (droperidol), and glucocorticoid steroid (dexamethasone), found that all three antiemetic drugs were equally effective for the prevention of PONV (23). This large multicenter study also demonstrated the advantage of using a combination of antiemetics (i.e., a multimodal regimen). Therefore, a multimodal strategy has been recommended for managing patients at increased risk for developing PONV (24). This approach ideally involves routine use of antiemetic prophylaxis, as well as the use of less emetogenic anesthesia techniques (25,26), aggressive IV hydration (27–29), and non-opioid analgesics for postoperative pain management (30). Scuderi et al. (25) confirmed the earlier findings of Tang et al. (14), suggesting that effective antiemetic prophylaxis improves patient satisfaction compared with symptomatic treatment of women undergoing laparoscopic surgery.
A deficiency of the current study design relates to our failure to include a placebo group. However, numerous previous studies have demonstrated that both ondansetron and granisetron were significantly more effective than a placebo for the prevention of PONV after laparoscopic surgery (9,11,14,15). Given the frequent incidence of emesis in patients undergoing laparoscopic surgery, we felt it was not ethical to deny these at risk patients the benefits of a multimodal prophylactic antiemetic therapy that included a 5-HT3 antagonist. Furthermore, the standard practice at the two institutions participating in this study was to administer a combination of three prophylactic antiemetics to all patients undergoing laparoscopic surgery. Finally, the study can be criticized because we failed to use a standard dose-ranging study design. Because 1 mg is the smallest oral dose of granisetron and 4 mg is the minimally effective IV dose of ondansetron for antiemetic prophylaxis (6), these were logical doses of the two 5-HT3 antagonists to compare in this cost-efficacy study. Furthermore, even a 3 mg IV dose of granisetron failed to provide more effective antiemetic prophylaxis than ondansetron 4 mg IV in a similar patient population (9).
In summary, there were no significant differences between granisetron (1 mg per os) and ondansetron (4 mg IV) with respect to their efficacy for preventing PONV and PDNV in patients undergoing either minor or major laparoscopic procedures. Given the lower cost of IV ondansetron to achieve a comparable quality of recovery and patient satisfaction, we concluded that it was a more cost-effective prophylactic antiemetic than oral granisetron for laparoscopic surgery.
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Footnotes
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Accepted for publication January 19, 2006.
Supported, in part, by the White Mountain Institute, a non-for-profit private educational and research foundation dedicated to art and medicine. Endowment funds from the Margaret Milam McDermott Distinguished Chair in Anesthesiology are used to support Dr. White’s academic activities.
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References
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Abstract
Introduction
