Anesth Analg 2007;104:1370-1373
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000261474.85547.8b
AMBULATORY ANESTHESIA
Section Editor:
Peter S. A. Glass
Granisetron Versus Ondansetron Treatment for Breakthrough Postoperative Nausea and Vomiting After Prophylactic Ondansetron Failure: A Pilot Study
Keith A. Candiotti, MD,
Fani Nhuch, MD,
Aimee Kamat, MD,
Krisnaprasad Deepika, MD,
Kristopher L. Arheart, EdD,
David J. Birnbach, MD, MPH, and
David A. Lubarsky, MD, MBA
From the Department of Anesthesiology, Perioperative Medicine and Pain Management, University of Miami School of Medicine, Miami, Florida.
Address correspondence to Keith A. Candiotti, MD, Department of Anesthesiology, University of Miami/Jackson Memorial Hospital, R-C370, 1611 NW 12th Ave., Miami, Florida 33101. Address e-mail to kcandiotti{at}miami.edu.
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Abstract
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INTRODUCTION: Patients with an increased risk of postoperative nausea and vomiting (PONV) are frequently given prophylactic doses of a selective 5-hydroxytryptamine-3 antagonist (5HT3). In chemotherapy patients, it has been demonstrated that after unsuccessful treatment with one 5HT3 administering a different 5HT3 alleviated symptoms. We hypothesized that we could define a benefit of a 5HT3, cross-over in a pilot study of PONV. Two-hundred-fifty female patients received prophylactic ondansetron 4 mg at the end of a surgical procedure requiring general anesthesia and were then followed postoperatively for 4 h.
METHODS: Eighty-eight women developed PONV and were randomly assigned to receive a repeat dose of ondansetron 4 mg (n = 30), granisetron 1 mg (n = 30), or granisetron 0.1 mg (n = 28) and then followed for 24 h.
RESULTS: Patients receiving the repeat dose of ondansetron showed a complete response of 57%. Those receiving 1 or 0.1 mg doses of granisetron had rates of 60% and 68%, respectively. This difference was not statistically significant (P = 0.773).
CONCLUSION: Unlike patients with chemotherapy-induced nausea and vomiting, perioperative patients who failed ondansetron prophylaxis did not have a significant response to cross-over dosing with granisetron.
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Introduction
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Patients with an increased risk of postoperative nausea and vomiting (PONV) are frequently given prophylactic treatment, often with a selective 5-hydroxytryptamine-3 (5HT3) antagonist (1). If breakthrough symptoms of PONV occur in patients who have received a prophylactic dose of a 5HT3 antagonist, various options are available, one of which is repeating a second dose of the same 5HT3 drug that was initially used for prophylaxis. However, it has been reported that repeating a second dose of ondansetron for PONV is no better than administering a placebo (2). In contrast, in chemotherapy patients, it has been demonstrated that a patient who has been unsuccessfully treated with one 5HT3 may benefit from the use of a different 5HT3 (3). This benefit may be due to any number of mechanisms, including differences in the metabolism of the drugs, which is one cause of therapeutic failures of 5HT3 antagonists in both chemotherapy and surgical patients (4,5). On the basis of the data from chemotherapy patients and the differences between the 5HT3 antagonists, we hypothesized that a postoperative patient who failed prophylactic ondansetron 4 mg would benefit more from a rescue dose of granisetron than a repeat dose of ondansetron.
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METHODS
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After obtaining approval from the University of Miami IRB (Miami, FL) and signed informed consent, 250 adult females between the ages of 18 and 64 with an ASA I–II status who were scheduled to undergo nonemergency surgery, requiring general anesthesia of at least 30 min duration, were enrolled. Patients provided medical histories; demographic information including, height, weight, age, ethnicity, tobacco use, second-hand smoke exposure, alcohol use, and menstrual history. Exclusion criteria were as follows: patients with known hypersensitivity to 5HT3 drugs; body mass index 
35; significant systemic disease; patients who had nausea or vomiting 24 h before the study and any patient taking antiemetics, steroids, H2 antagonists, anticholinergics, antihistamines, butyrophenones, phenothiazines, or metoclopramide within 24 h before surgery.
All patients received midazolam 1–2 mg. Thiopental (3–5 mg/kg) was used for induction and succinylcholine (0.5–1 mg/kg), rocuronium (0.5–1.2 mg/kg), or vecuronium (0.07–0.1 mg/kg) were used to facilitate endotracheal intubation. Doses of muscle relaxants were repeated as needed. Maintenance of anesthesia was achieved with isoflurane <2.5%, nitrous oxide 50%–70%, and fentanyl (2–10 mcg/kg). All patients were tracheally intubated. Oxygen concentrations were maintained between 30% and 50%, except for anesthetic induction and just before tracheal extubation. Reversal of neuromuscular blockade was achieved with neostigmine (0.05 mg/kg) and glycopyrrolate (0.01 mg/kg), and every patient received reversal. All patients were given a prophylactic, open-label dose of IV ondansetron 4 mg approximately 30 min before extubation. All standard vital signs were monitored, and the use of gastric suction was noted. All patients were transported to the postanesthesia care unit (PACU) with supplemental oxygen. Both inpatients and outpatients remained in a recovery room setting for 4 h. All patients were asked on arrival in the PACU if they were nauseous or felt like vomiting. Episodes of retching were considered equivalent to vomiting. Any patient who complained of feeling nauseous or had an episode of vomiting within 4 h of extubation was considered to be a failure of prophylactic treatment. If a patient experienced PONV the patient was randomized, by a random number generator, to 1 of the 3 rescue arms: granisetron 0.1 mg, granisetron 1 mg, or ondansetron 4 mg. All patients who were randomized were followed for 24 h. Medications were given from prepackaged syringes. All syringes were admixed with normal saline to a volume of 2 mL and were given in a double-blind fashion. After rescue, patients were followed for 30 min at 10-min intervals and were asked about symptoms of PONV, pain scores and had vital signs taken. Repeat episodes of vomiting or retching at more than 1-min intervals were considered separate events. The intensity of nausea was graded on a numerical scale 0–10, with 0 being no symptoms and 10 being the worst possible nausea imaginable. Rescue efficacy was classified as one of two outcomes: complete response (no further PONV and no requests for further medication) or rescue failure (patient continued to have nausea or vomiting and/or requested rescue medication). Patients in the latter group were medicated at the discretion of the treating anesthesiologist with a drug of their choice.
After discharge from the PACU all patients were given diaries to record the recurrence of nausea or vomiting, medications taken and adverse events. All patients who were admitted to the hospital were visited 24 h after administration of the study drug while all outpatients had telephone interviews at 24 h. IV morphine (1–4 mg, doses repeated as needed) was used for postoperative pain management in all patients for the first 4 h of the postoperative period. While in the hospital pain scores were given as a verbal rating score with (0–10, 0 being no pain and 10 being the worst pain imaginable) and were tracked on all patients on arrival to PACU and every 15 min. Patients who later developed PONV were treated at the discretion of the primary service.
This study was planned as a pilot to evaluate the benefits of granisetron administration in patients who had developed symptoms of PONV despite ondansetron prophylaxis. Since we had no data on our target population to use for sample size calculations, we chose sample sizes that were used in a chemotherapy study that found a significant effect size of 0.46 (3). Data are presented as means ± sd for continuous data and absolute frequencies (n) and percentages for frequency data. For statistical analysis 
2 tests were used to compare proportions of patients and univariate logistic regression was used for continuous predictor variables. A repeated measures analysis of variance was used to analyze the nausea scores with contrasts to perform an omnibus test for differences among the treatment groups at each time. All tests performed were two-sided with the significance level set at P < 0.05.
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RESULTS
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A total of 243 patients completed the study with 88 patients requiring PONV rescue within 4 h of tracheal extubation, a breakthrough rate of 36%. Of the 250 patients enrolled seven patients were withdrawn due to protocol violations that might have influenced outcomes: One patient received the wrong induction drug; two patients received ondansetron more than 1 h before extubation; three patients failed to receive nitrous oxide or narcotics; and one patient was withdrawn due to protracted hypotension in the PACU. There were no statistically significant differences noted in the three rescue arms for body mass index, tobacco use, history of PONV and motion sickness, duration and type of surgery (the most common surgical procedures were gynecological followed by breast and abdominal surgeries), inpatient/outpatient status and morphine consumption. However, patients in the granisetron 1 mg arm were noted to be younger compared with those in the granisetron 0.1 mg arm, and both granisetron arms showed a smaller percentage of no alcohol use compared to ondansetron 4 mg (Table 1). Data for the subject's response to the rescue drug, in terms of complete response or rescue failure, are noted in Table 2. Complete response occurred in 57, 60, and 68% for the ondansetron 4 mg, granisetron 1 mg, and granisetron 0.1 mg groups, respectively (P = NS). There were no significant differences among the treatment groups at any time for nausea scores (Table 3). The breakthrough rate of vomiting with or without nausea in the 30 min after rescue was 37 of 88 (15%) and there were no statistical differences noted for efficacy between rescue arms once again related to vomiting (Table 4).
Overall the strongest risk factor for PONV was a history of PONV (P < 0.0001). Factors such as a history of motion sickness (P = 0.1), no smoking history (P = 0.07), duration of surgery (P = 0.08), and no alcohol use (P = 0.10) approached, but did not reach, significance. For reasons that are not apparent morphine consumption was lower in the patients with PONV versus those without (6.3 ± 0.55 mg vs 9.4 ± 0.64 mg, P = 0.02).
Patients who were given a repeat 5HT3 drug were followed for 24 h and it was notable that after 6 h patients rarely vomited again but did have episodes of recurrent nausea. There were no statistical differences among the three treatment arms in terms of nausea and vomiting in the 24-h follow-up period.
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DISCUSSION
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The complete response of the three antiemetic treatments after ondansetron prophylaxis failures were noted to be 57, 60, and 68% for granisetron 0.1, granisetron 1 mg and ondansetron 4 mg, respectively. Although an actual placebo arm was not used, it was assumed that repeating ondansetron was not significantly different from placebo (2). Post hoc statistical analysis failed to show statistical significance among these three arms (P > 0.05). This study was designed with the intent to detect a magnitude of effect seen in chemotherapy-induced nausea and vomiting (CINV) patients. The magnitude of differential response to crossing over to a different 5-HT3 antagonist after failure with ondansetron did not approach that seen with CINV patients. It is possible that the mechanisms of nausea and vomiting are different in chemotherapy and general anesthesia. Chemotherapy has a significant direct effect on the chemoreceptor trigger zone and CINV appears to be primarily due to serotonin and substance P release, while PONV appears to be more multifactorial (6).
Our findings related to PONV were otherwise similar to previous reports in the literature. The overall rate of PONV breakthrough was 36% for the first 4 h after tracheal extubation. Since one-third of patients in this study developed PONV it appears that monotherapy may not be sufficient in high-risk patients. The rate of 57% complete response for patients who had breakthrough PONV after prophylactic ondansetron and were given a repeat 4 mg ondansetron dose as a rescue is similar but slightly less than that shown in the previous study by Kovac et al. (2), which found that repeating ondansetron was not significantly different from placebo.
It has been reported that using low dose granisetron 0.1 mg is effective in the treatment of PONV (7). We chose to evaluate the use of granisetron 0.1 mg for rescue of ondansetron failure and added the higher dose of 1 mg to evaluate the possibility that we were under-dosing patients during rescue. Our results showed no statistically significant difference for the rescue dose of granisetron 0.1 or 1 mg. This study supports the concept that patients who develop breakthrough PONV should not receive a rescue drug from the same class of drug as was used for prophylaxis, but rather a drug from a completely different class.
The study was originally powered to detect an effect size of 0.46 in the range of the 42% difference found in the CINV study (3). Post hoc power analysis of our study showed that it would have taken 492 patients to detect significance at the 0.05 level with 80% power because of the small effect size (0.14) found in this study. Cohen defines small, medium, and large effect sizes at 0.10, 0.30, and 0.50, respectively (8). With only 88 subjects, 0.33 is the smallest significant effect size where the null hypothesis would be rejected with 80% power. Because of the limited size of our study population we cannot exclude that there might be some cross-over benefit among 5HT3 antagonists (type-2 error) but it does not appear to be of the same magnitude as noted in CINV patients.
In summary, surgical patients who experience PONV after ondansetron prophylaxis do not appear to respond to other 5HT3 drugs as was noted previously in CINV patients.
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Footnotes
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Accepted for publication February 13, 2007.
This study was supported, in part, by a grant from Roche Labs Inc. (Nutely, NJ).
Reprints will not be available from the author.
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REFERENCES
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- Kovac AL, O'Connor TA, Pearman MH, et al. Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial. J Clin Anesth 1999;11:453–9.[Web of Science][Medline]
- de Wit R, de Boer AC, vd Linden GH, et al. Effective cross-over to granisetron after failure to ondansetron, a randomized double blind study in patients failing ondansetron plus dexamethasone during the first 24 hours following highly emetogenic chemotherapy. Br J Cancer 2001;85:1099–101.[Web of Science][Medline]
- Kaiser R, Sezer O, Papies A, et al. Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes. J Clin Oncol 2002;20:2805–11.[Abstract/Free Full Text]
- Candiotti KA, Birnbach DJ, Lubarsky DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology 2005;102:543–9.[Web of Science][Medline]
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- Taylor AM, Rosen M, Diemunsch PA, et al. A double-blind, parallel-group, placebo-controlled, dose-ranging, multicenter study of intravenous granisetron in the treatment of postoperative nausea and vomiting in patients undergoing surgery with general anesthesia. J Clin Anesth 1997;9:658–63.[Web of Science][Medline]
- Cohen J. Statistical power for the behavorial sciences. Hillsdale, NJ: Erlbaum, 1988.
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Abstract
Introduction
