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From the Departments of *Pharmacy, Anesthesiology, and Biostatistics, Scott and White Memorial Hospital and Clinic, Scott, Sherwood and Brindley Foundation, The Texas A&M University System Health Science Center College of Medicine, Temple, Texas
Address correspondence and reprint requests to Tricia Meyer, MS, FASHP, Scott & White Memorial Hospital, 2401 S. 31st St., Temple, TX 76508. Address e-mail to phatam{at}swmail.sw.org.
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Abstract |
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Introduction |
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Methods |
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All adult patients scheduled for outpatient surgery under general anesthesia (inhalation based with fen-tanyl for pain) were considered for enrollment in the study. Patients were excluded for any of the following reasons: 1) the patient declined participation, 2) the physician responsible for patient care considered the study not to be in the best interest of the patient for any reason, 3) the patient was allergic to either primary study drug, or 4) the patient was unable to understand the study.
The study received IRB approval, and informed consent was obtained from all participants. Patients were eligible if they experienced PONV. Inclusion criteria were patients 1) 
18 yr of age, 2) scheduled for day surgery, and 3) having general anesthesia. Consecutive eligible patients were interviewed by and gave consent to a research nurse coordinator in the Anesthesia Assessment Unit before surgery. A randomization schedule was provided by the Department of Biostatistics to Pharmacy Investigational Drug Services (IDS). The subset of consented patients who experienced PONV were entered into the treatment group and randomized to a single IV dose of either ondansetron 4 mg or dolasetron 12.5 mg. The random assignments were made sequentially from a confidential, computer-generated list of permuted blocks of varying size. This list provided equal probabilities for patients to receive one of the two study drugs treating PONV. None of the clinical personnel involved in the study had access to the randomization list other than the unblinded pharmacist from the IDS. The IDS labeled and prepared the blinded study syringes. The blinding was achieved by drawing up the contents of the dolasetron 12.5-mg/0.625-mL ampule and adding diluent to make a volume of 2 mL. This was placed in a 3-mL syringe. The ondansetron 4 mg was drawn to a volume of 2 mL (4 mg/2 mL) and placed in a 3-mL syringe. IDS delivered the blinded syringe containing the study drug to the postanesthesia care unit (PACU) or day-surgery step-down unit for the study participants experiencing nausea, vomiting, or both. The need for rescue medication was determined by patients experiencing one emetic episode or one nausea episode longer than 5 min or both. If patients did not experience PONV, they did not receive study drug and were not included in the analysis.
The primary outcome measurement in this study was the need for antiemetic rescue therapy in patients receiving either ondansetron or dolasetron as the initial treatment for PONV. Determination of the need for rescue antiemetic was assessed by the nurse in the Phase I or Phase II unit. The selection of the rescue antiemetic was at the discretion of the anesthesia care provider. Patients experiencing one emetic episode or one nausea episode longer than 5 min or both were allocated to receive postoperative treatment (a minimum of 20 min after study drug administration) until discharge. An additional objective was to determine the cost of the study drugs and rescue drugs used. Other additional outcome measurements included recovery time (defined as the time from the end of anesthesia until discharge criteria were met from the PACU and day-surgery unit) and episodes of PONV occurring within 24 h of surgery. Discharge criteria were based on the Aldreti score. In addition to the 24-h PONV follow-up, patients were queried for satisfaction outcomes.
Baseline characteristics included age, sex, number of prior surgeries, and history of PONV. Categorical variables including sex, history of PONV, receipt of prophylactic antiemetics, the need for rescue medication, type and dose of rescue medication, episodes of nausea and vomiting, and patient satisfaction with PONV treatment were compared by using Fisher’s exact test or the 
2 test, as appropriate. Continues variables including age and recovery time were compared by using Student’s t-test. The Wilcoxon nonparametric test was used to compare medians for continuous variables that were not normally distributed. P values <0.05 were considered statistically significant.
Sample size computation assumed a difference in proportion of 0.25 (specifically, 0.50 vs 0.25). On the basis of previous experience, the proportion of patients treated with ondansetron who were expected to continue vomiting and to need another rescue antiemetic, or another dose of ondansetron, was estimated to be approximately 25%. The sample size was expected to provide 80% power to show a statistically significant result if the proportion of patients whose treatment with dolasetron failed was 50%.
Additional assumptions used in estimating sample size included a criterion for significance (
) of 0.05 and an equal number in each study arm. With these assumptions, 92 (46 per group) randomized patients were required.
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Results |
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For patients who received either ondansetron or dolasetron, the proportion of men and women enrolled was similar between treatment groups (Table 1). Although the median age of patients treated with dolasetron was 10 yr older than those treated with ondansetron, this difference was not statistically significant. There were no statistically significant differences in baseline variables (prior surgery, history of PONV, postoperative vomiting, receipt of prophylactic drug, or admission to the hospital). Patient demographics and baseline characteristics are summarized in (Table 1. Types of surgical procedures were similar in both groups (Table 2).
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There were no significant differences in the number of patients who actually vomited (11 [23%] of 47 for ondansetron versus 7 [16%] of 45 for dolasetron) (Table 3). Analysis of the primary outcome variable (need for rescue antiemetics; (Table 3) indicated that 70% (33 of 47) of patients receiving ondansetron required rescue antiemetic therapy, compared with 40% (18 of 45) of patients receiving dolasetron (P = 0.004). Although the dolasetron group was superior, both groups had a large number of patients who experienced PONV.
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Secondary outcomes included admission to the hospital for PONV, overall time until discharge-ready in the PACU, overall time until discharge-ready in day surgery, and evaluation of nausea and vomiting within 24 h of the procedure. Similarly, the overall median time spent in the PACU was the same between treatment groups (Table 3).
No difference was noted for time in the PACU. The overall median time spent in day surgery was larger for patients treated with ondansetron compared with dolasetron (158 versus 131 min, respectively; P = 0.17), although this was not statistically significant. Secondary outcome measurements are summarized in (Table 3. Follow-up information was collected for 37 patients treated with ondansetron and 37 patients treated with dolasetron. Data for 18 patients’ 24-h PONV incidences were not available. Of the available data, patients in the ondansetron arm experienced fewer episodes of nausea and vomiting within 24 h after surgery compared with those treated in the dolasetron arm (7 [19%] of 37 versus 17 [46%] of 37). Without data on the remaining 18 patients, the authors could not make a conclusion for the 24-h postdischarge PONV. Patients were asked whether they were satisfied with their treatment for PONV, and the response was that the dolasetron group was more satisfied (27 [71%] of 38) than the ondansetron group (23 [59%] of 39). Similarly, patient data on 15 subjects were unavailable for determination of satisfaction with the treatment; therefore, no conclusion could be made.
The type and number of doses of antiemetic rescue medications were recorded for each treatment group and compared to determine the total cost of rescue antiemetic therapy. Overall, 70% (33 of 47) of patients in the ondansetron treatment group required rescue antiemetic treatment, compared with 40% (18 of 45) of patients in the dolasetron treatment group. Rescue antiemetic use and the average cost of rescue therapy are summarized in (Table 4. The average wholesale price (from the Red Book on the drugs) was $19.55 for dolasetron and $26.71 for ondansetron.
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Discussion |
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A quantitative systematic review was published on antiemetics used for the treatment for established PONV (17). The authors noted the limited number of publications for treatment regimens for PONV; however. the 5-HT3 receptor antagonists were the drugs most often investigated. The group concluded that 5-HT3 receptor antagonists are effective to some extent as treatment for vomiting, however, they are less effective for treatment of nausea. The authors also noted that there were not many reports on direct comparisons of 5-HT3 receptor antagonists. The analysis conducted by this group relied on the indirect comparisons with these placebo-controlled studies. Our study directly compared two of the 5-HT3 receptor antagonists.
The purpose of our study was to compare the effectiveness of ondansetron 4 mg IV and dolasetron 12.5 mg IV for the treatment of PONV in patients undergoing day surgery. Both doses were selected from the Food and Drug Administration-approved package insert for treatment of PONV. An additional objective was to compare the cost of an overall treatment strategy for the antiemetic drugs when taking into consideration the cost of the primary 5-HT3 receptor antagonist drug and any required rescue antiemetic therapy.
A limitation of the study is the administration of a prophylactic antiemetic in 23 of the patients (14 patients in the ondansetron group and 9 patients in the dolasetron group). Twelve of the patients in this subset received metoclopramide 10 mg. Although categorized as a prophylactic antiemetic, this drug is often used for gastric emptying. Henzi et al. (18) found in a systematic review that the antiemetic activity of metoclopramide when used in standard clinical doses (10 mg IV) has no clinically relevant antiemetic effect for PONV prophylaxis. Therefore, the 12 patients who received metoclopramide may not be a limitation of this study. PONV before discharge and at 24 hours for patients receiving the prophylactic antiemetics versus patients not receiving the prophylactic antiemetics showed no difference between groups. Another limitation of the study was the failure to obtain information at the 24-hour follow-up. Eighteen patients’ data were unavailable for the postdischarge analysis.
In conclusion, treatment trials are more difficult to conduct than prevention trials. This may account for the lack of publications in this area. Our intent was to compare the most widely used 5-HT3 receptor antagonists in the United States for treatment of established PONV. Results of this trial suggest that, although dolasetron provides similar or greater efficacy compared with ondansetron for the treatment of PONV, the average cost of dolasetron therapy presents considerable cost incentives in the consideration of therapy strategies.
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Footnotes |
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References |
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