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AMBULATORY ANESTHESIA

A Comparison of the Costs and Efficacy of Ondansetron and Dolasetron in the Prophylaxis of Postoperative Vomiting in Pediatric Patients Undergoing Ambulatory Surgery

Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania

Address correspondence to Mehernoor F. Watcha, MD, Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104. Address e-mail to watcha{at}email.chop.edu

	Abstract

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Postoperative vomiting (POV) after ambulatory surgery remains a major problem. We designed this study to determine the smallest dose of dolasetron equivalent to the Food and Drug Administration approved dose of ondansetron 100 µg/kg IV, for the prophylaxis of POV in children undergoing surgery. In this double-blinded controlled study, 204 healthy ASA I–II children aged 2–12 yr, undergoing superficial ambulatory (day-case) surgery, were randomized to receive either ondansetron 100 µg/kg IV, or dolasetron 45, 175, 350, or 700 µg/kg IV during a standardized perioperative regimen. The primary end-point was the incidence of complete response, defined as the absence of POV symptoms. Costs were calculated from the perspective of the hospital using a previously described model. The incidence of early (0–6 h) and 24-h emesis was more frequent in the dolasetron 45 µg/kg group compared with the dolasetron 350 and 700 µg/kg groups and with the ondansetron group. Repeated POV occurred more often when dolasetron was used in a dose <350 µg/kg. There were no significant differences in emesis rates between the dolasetron 175, 350, and 700 µg/kg groups or between these groups and the ondansetron 100 µg/kg group. The smallest dose of dolasetron with acceptable equivalent efficacy and patient satisfaction scores to ondansetron 100 µg/kg was 350 µg/kg. Institutional costs for managing POV were less with dolasetron 350 µg/kg than with ondansetron.

IMPLICATIONS: This randomized double-blinded dose-ranging study concluded that dolasetron, 350 µg/kg IV, was the smallest dose that provided acceptable equivalent efficacy and patient satisfaction scores to ondansetron, 100 µg/kg IV, for the prophylaxis of postoperative vomiting in children undergoing outpatient surgery. However, with this dose, the costs to the institution for managing postoperative vomiting were less.

	Introduction

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Postoperative vomiting (POV) after ambulatory surgery remains a major cause of patient distress, delayed hospital discharge, unanticipated hospital admission, and increased use of resources leading to increased cost of care in both children and adults (1–5). The incidence of POV is more frequent in children than in adults (6), leading some anesthesiologists to recommend the routine administration of prophylactic antiemetics in high-risk children undergoing ambulatory surgery (7). The use of serotonin antagonists has become popular in pediatric ambulatory anesthesia because these drugs are more effective than older drugs (metoclopramide and droperidol) and free from sedative side effects (8–10). Although patients consistently state that POV is one of their major concerns (11), the routine use of antiserotonin drugs for POV prophylaxis is controversial in adults, because these drugs are not always effective (12,13).

Ondansetron is the prototype of this class of drugs. Dolasetron, another serotonin antagonist, was introduced into clinical practice after ondansetron had been widely used for some years. Dolasetron is at least as effective as ondansetron in preventing postoperative nausea and vomiting (PONV) in adults compared with placebo, but costs less (14,15). The drug was approved by the Food and Drug Administration (FDA) for use in children based on efficacy data for chemotherapy-induced emesis. The IV dose of dolasetron recommended for POV use in children (0.35 mg/kg) was based solely on pharmacokinetic data. There are no published data on the efficacy of this dose of dolasetron in preventing POV in children nor are there any dose-response data available that establish the best dose for this indication. The primary aim of this double-blinded, randomized controlled study was to establish the smallest dose of dolasetron with equivalent efficacy to the FDA-approved dose of ondansetron (100 µg/kg IV) in the prophylaxis of POV in the pediatric ambulatory surgery patient. The secondary aim was to compare costs of managing POV from the perspective of the health care institution, when prophylactic doses of ondansetron and the smallest equivalent dose of dolasetron were administered.

	Methods

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This study was approved by the IRB and written informed consent was obtained from the parents or legal guardians of healthy children (ASA physical status I or II) aged 2–12 yr scheduled to receive general, endotracheal anesthesia for superficial ambulatory surgery. Exclusion criteria included ASA physical status III or more, a previous history of gastroesophageal reflux, vomiting from organic causes, obesity (>95th percentile of weight for age), emergency surgery, antiemetic therapy within 24 h before surgery or the use of neuraxial anesthesia or drugs known to have antiemetic effects (e.g., steroids, propofol). Children undergoing tonsillectomy and adenoidectomy procedures were excluded from this study because they routinely receive steroids at our institution. A history of POV or motion sickness was noted during the preanesthetic evaluation but did not preclude enrollment.

After a minimal fast of 2 h (for clear liquids), all subjects received midazolam 0.5 mg/kg per os 15–30 min before induction with sevoflurane and nitrous oxide in oxygen via face mask. The child’s behavior during induction was assessed as asleep, calm, anxious but consolable or crying, and inconsolable. After the induction of anesthesia and the establishment of venous access, tracheal intubation was facilitated with 0.1 mg/kg IV vecuronium and anesthesia maintained with desflurane and nitrous oxide, along with 0.075 mg/kg IV morphine. The concentration of desflurane was adjusted to maintain blood pressure and heart rate within 15% of baseline values. The subjects were randomized on the basis of a computer-generated random number table to receive either ondansetron 100 µg/kg IV, or dolasetron in one of the following doses: 45, 175, 350, or 700 µg/kg IV within 15–20 min of the end of surgery. All study drugs were diluted to a fixed volume of 30 mL by health care professionals who were not otherwise involved in the subject’s anesthetic care in order to maintain the double-blinded nature of the study.

At the end of surgery, residual neuromuscular blockade was antagonized in all subjects with IV atropine (0.02 mg/kg) and neostigmine (0.07 mg/kg), the stomach was suctioned, and the trachea extubated when the patient was awake. In the postanesthesia care unit (PACU), pain was assessed using the Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS). Subjects with severe pain (CHEOPS scores >8) received IV morphine (increments of 0.05 mg/kg), whereas those with moderate pain (CHEOPS 5–8) received oral oxycodone (0.1 mg/kg). Mild pain (CHEOPS scores 3–5) was treated with oral acetaminophen 10–15 mg/kg. Subjects with postoperative emesis while still in the hospital received rescue antiemetics including IV ondansetron 0.05 mg/kg, metoclopramide 0.15–0.2 mg/kg, and droperidol 0.05 mg/kg for the first, second, and third episodes, respectively. If the IV access was no longer available, trimethobenzamide (Tigan^TM), 100–200 mg, was prescribed for rectal administration.

We recorded the nature and duration of surgery and anesthesia, all medications and IV fluids administered during the perioperative period, along with times from end of surgery to eye opening, response to commands, first oral intake, ambulation, and discharge readiness from phase 1 and phase 2 recovery areas. IV fluids were administered to replace preoperative deficits and intraoperative blood loss and to provide for normal maintenance requirements. Oral intake was permitted but not mandatory before discharge from the hospital, criteria for which included a fully awake patient who recognized the parents, had stable vital signs including oxyhemoglobin saturation >95% on room air, and who was free from persistent pain and emesis.

All postoperative emesis episodes (vomiting or retching) in the hospital were recorded, along with the resources used to manage this complication (e.g., number of blankets, linen, emesis basins, suction catheters, nursing time). Vomiting was defined as the forceful expulsion of gastric contents whereas retching was defined as spasmodic, labored, and rhythmic contraction of the respiratory muscles without the expulsion of gastric contents. Nausea, a subjective feeling of emesis, was not assessed in this study because of the young age of the patients. Emetic episodes separated by 2 min were considered as separate episodes. Phone interviews and questionnaires obtained at 24 h and 5 days respectively postoperatively determined the incidence of postdischarge emesis, the time the child’s appetite returned to normal, and when the child’s caretaker could return to daily routine duties without having to take care of the patient’s postoperative problems. Finally, the caretaker’s assessment of the patient’s tolerance of the first solid meal as well as overall satisfaction with the perioperative experience was noted, using an 11-point scale (from 0 = poor to 10 = excellent).

Cost evaluations were made from the perspective of the Chief Financial Officer of the Children’s Hospital and based on a previously described model that included the incremental costs of resources, nursing labor, and drugs used for the prophylaxis and treatment of POV (15). Direct costs for the management of emesis included the costs for "emesis clean up," rescue antiemetics, management of the side effects of prophylactic and rescue antiemetic drugs, along with the acquisition costs of the drugs and materials used to administer them and the costs of labor involved (Table 1). In this model, all costs were based on the acquisition costs of drugs rather than on patient charges, and included the costs of wasted drugs. Single-dose vials were used for the study. Costs of materials used for emesis clean up were limited to those used in the hospital before discharge. Labor costs were adjusted according to the place of occurrence, with increased costs assigned to the more labor-intensive Phase 1 recovery area. These costs are listed in Table 1.

A group size of 68 was chosen for the ondansetron group based on the confidence intervals for the difference in response rates between dolasetron and ondansetron. It was assumed that the complete response rate with ondansetron would be similar to the rate in previously published studies in this patient population (8,18). A margin of 20% was considered to be equivalent, because this was less than the smallest difference in complete response rates between placebo and ondansetron in controlled clinical trials in this patient population (8,18).

A test for trends across proportions (logistic model) was used to compare the early, 24-h complete response rates and the proportion of patients with repeated POV among the 4 dolasetron groups. If a significant difference was noted, between-group comparisons were performed using the Fisher’s exact test. If no statistically significant difference was noted between two doses, the smallest effective dose was identified. The complete response rates and the proportion of patients with repeated POV were then compared between the smallest effective dose and the group receiving ondansetron. As mentioned above, a margin of 20% was considered to be equivalent.

The age, weight, duration of surgery and anesthesia, times from the end of surgery to tracheal extubation, arrival in the recovery area, eye opening, response to commands, and time to discharge were compared among the groups by a one-way analysis of variance. A Student-Newman-Keuls test was performed for intergroup comparisons if a significant difference was noted on the analysis of variance test. Parental assessment of the global perioperative experience and the subject’s tolerance of the first solid and liquid intake in the postoperative period were compared using a Kruskal-Wallis test. The subject’s sex, history of motion sickness, PONV, type of surgical procedures, incidence of emesis during the stay in the ambulatory surgery center and during the first 24 postoperative hours, and the number of patients requiring rescue antiemetic therapy were compared by Fisher’s exact and ² tests with a Yates’ continuity correction, as appropriate. All tests were two-tailed, with P values < 0.05 considered significant.

	Results

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The parents of 225 potential subjects were approached for consent for this study. Nine declined to participate. One subject was excluded from analysis after requiring additional surgery (evacuation of scrotal hematoma) before discharge from hospital. Eight subjects were excluded because of protocol violations (caudal epidural analgesia, additional intraoperative opioids or other antiemetics) and 3 subjects were lost to follow up. Data from the remaining 204 subjects were included in the analysis.

There were no significant differences among the study groups in age, sex, type and duration of surgery, incidence of previous motion sickness or POV, and inpatient behavior during separation from parents or during mask induction of anesthesia (Table 2). The doses of anesthetic drugs, duration of anesthesia, volume of perioperative fluids, intraoperative blood loss and the time interval from end of surgery to tracheal extubation, arrival in the PACU or duration of stay did not differ among the study groups. There were also no significant differences among the groups in the distribution of CHEOPS pain scores, requirement for rescue analgesia, and times to first oral intake during the postoperative period. There were no significant differences among the study groups by logistic regression analysis of factors known to affect POV. Similarly, there were no significant differences in the time to resumption of a normal diet, use of analgesic drugs, or need for additional medical attention (phone calls to physicians, visits to emergency department, or readmission to hospital) after discharge from the hospital. There were also no differences in the incidence of nonemetic adverse events (e.g., headache).

There were no significant differences in the complete response rates or the incidence of repeated POV between the groups receiving ondansetron 100 µg/kg or either of the 2 larger dolasetron doses (Table 3). The 24-h complete response rate with this dose of ondansetron was 78% (95% confidence intervals [CI] 67%–86%), which was similar to previously published data in this patient population (18). The 24-h complete response rates for the dolasetron 350 and 700 µg/kg groups were 73% (95% CI 56%–87%) and 73% (95% CI 57%–85%), respectively, and 73.5% (95% CI 64%–81%) for the combined 350 and 700 µg/kg dolasetron groups. The difference in the lower bound of the 95% CI of the 24-h complete response rates of these dolasetron and ondansetron groups was <10%. These doses were therefore considered to be equivalent in effect. In this study, dolasetron 350 µg/kg was the smallest dose with an efficacy similar to that of ondansetron 100 µg/kg in preventing POV.

	Discussion

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This randomized, double-blinded, dose-ranging trial demonstrated a clear relationship between dolasetron dosage across the range of 45–700 µg/kg IV and POV. The two largest doses were significantly better than the smallest dose. Although there were no statistically significant differences in the complete response between 175 µg/kg and either the 350 or 700 µg/kg doses, subjects receiving the 2 smallest doses of dolasetron were much more likely to have 2 or more episodes of POV. Because the observed differences would be considered clinically important, the smallest dose of dolasetron that we recommend for POV prophylaxis was 350 µg/kg IV. The complete response rate with this dose of dolasetron was similar to that with ondansetron 100 µg/kg (18).

The doses of dolasetron 350 µg/kg and ondansetron 100 µg/kg used in our study were based on the FDA-approved package insert recommendations for use in children. The doses of dolasetron 175 and 700 µg/kg were based on studies that show these were the minimally effective doses in adults when given at the end or the beginning of surgery respectively (12.5 and 50 mg for a 70-kg adult at the end or at the beginning, respectively) (17,19). The smallest dose of dolasetron (45 µg/kg) was arbitrarily chosen because the dose-response curve of antiserotonin drugs is steep, and smaller doses may be effective. There are some data to indicate that a dose of 1 mg of ondansetron may be effective in adults in certain situations (20). This dose is 25% of the usual dose of 4 mg. We chose 45 µg/kg of dolasetron for the smallest dose in the study, because it was approximately 25% of the next larger dose of 175 µg/kg. The dose of ondansetron in our study was based on the FDA-approved dose. Although there are some data showing that smaller doses may be effective, especially when combined with steroids, these studies were powered to detect efficacy compared with placebo and not to detect small differences in efficacy between the doses studied. Meta-analysis of pediatric studies show that there are more data with the FDA-approved dose than with other doses (12,18). We also submit that clinicians in private practice use the FDA-approved dose of most drugs including ondansetron.

Recently, Sukhani et al. (21) studied the efficacy of prophylactic dolasetron 500 µg/kg or ondansetron 150 µg/kg when administered along with dexamethasone 1 mg/kg for children undergoing tonsillectomy. They reported complete response rates of 76% and 74% for the dexamethasone-dolasetron and dexamethasone-ondansetron combinations, respectively. We obtained similar results in our study using single-drug prophylaxis with smaller doses of ondansetron (100 µg/kg) and dolasetron (350 µg/kg). However, we had excluded subjects undergoing tonsillectomy to avoid the confounding effects of steroids on POV. In a recent meta-analysis, Henzi et al. (22) concluded that "the best prophylaxis of PONV currently available is achieved by combining dexamethasone with a 5-HT3 receptor antagonist." It is possible that prophylaxis with a combination of a steroid and dolasetron may have achieved even greater efficacy in our study. It is also possible that prophylaxis with smaller doses of dolasetron in combination with dexamethasone may provide similar efficacy as monotherapy with the larger doses of dolasetron. There are data to suggest that, in children, prophylaxis with smaller doses of ondansetron (50 µg/kg) in combination with steroids are as effective as the large dose (150 µg/kg) used in the study by Sukhani et al. (21,23). Additional studies of the combination of steroids and 5-HT3 antagonists need to be performed in high-risk patient populations to determine the most cost-effective combination.

Parents were most dissatisfied with control of POV when their child received dolasetron 45 µg/kg. Satisfaction scores did not differ between subjects receiving ondansetron or any of the other three doses of dolasetron. Prophylaxis with 350 µg/kg dolasetron provided similar efficacy and parental satisfaction at a smaller cost to the institution than with ondansetron 100 µg/kg or dolasetron 700 µg/kg. Fisher (24) has stated that these end-points are of greater clinical importance than the surrogate end-points related to the incidence of PONV.

Comparisons of costs are sensitive to the assumptions made in the cost model. Many pharmaco-economic studies in the anesthesiology literature can be criticized for limiting cost considerations to the acquisition costs of the drugs (25). The costs of drug strategies for prophylaxis should include the costs for managing failure of prophylaxis and non-drug-related costs (costs of resources used to clean up emesis, labor costs) (15,26). Although labor costs constitute a major component of health care costs, they are semi-fixed and do not necessarily increase unless additional nursing staff are hired or overtime payments are made (27). The costs of nursing labor and of PACU resources used for managing POV were not major factors in our study because the first emetic episode occurred in the hospital 11 times. Thus, inclusion or exclusion of these costs did not alter the overall conclusions that prophylaxis with dolasetron 350 µg/kg provided similar efficacy and parental satisfaction as ondansetron 100 µg/kg at a smaller cost. However, we are well aware that the acquisition costs of a single drug will vary with marketing strategies that are based on institutional purchasing power, time to patent expiry, and the effect of bundling the costs of a single drug with other drugs. In addition, many institutions will prefer to stock a single drug for the prophylaxis of both chemotherapy-induced and postoperative emesis. Although we used single-dose vials in the study, the conclusions would not be altered if a pharmacist drew up the drug from the same vial for multiple patients under a laminar flow hood. Savings from reduced drug wastage are offset by increased costs for the pharmacist’s labor (25).

The infrequent use of rescue antiemetics in this patient population despite the provision of prescriptions for rectal trimethobenzamide suggests that parents either fail to fill the prescription, are uncomfortable with this route of administration, or do not perceive the need to initiate treatment after just one episode of emesis. Some have questioned the role of prophylactic antiemetics and have recommended that we should wait for patients to develop POV symptoms before initiating treatment (28). Application of this policy to the pediatric ambulatory surgery patient population will result in a large number receiving no treatment for POV.

Although this study may be criticized for failing to use a placebo group, the dose-response component of the study was designed as a superiority trial. There are ethical reasons against denying effective therapy when it is available (21,29). Previous placebo-controlled studies of this patient population have consistently shown that the risk for POV without prophylaxis is 60% (6,18) and this can be reduced to 20%–30% with the prophylactic administration of ondansetron (8,12,13,18). Our study was therefore designed to determine a dose of dolasetron with equivalent effect as ondansetron 100 µg/kg. Equivalence studies have been criticized for their low assay sensitivity (30). The margin of equivalence in our study was determined a priori to be less than the smallest difference between placebo and ondansetron in controlled clinical trials. The fact that the two largest doses of dolasetron and the dose of ondansetron were associated with greater efficacy than the smallest dose of dolasetron demonstrates the internal validity to the conclusions. The finding that repeated emesis (two or more episodes) occurred more frequently with the smaller doses of dolasetron provides additional evidence of efficacy. As in other active control superiority trials, the magnitude of the effect in comparison to no treatment cannot be determined in our study. However, the incidence of emesis despite prophylactic ondansetron in our study is in keeping with previously published data, providing further validity to our conclusions.

In summary, this study has shown that the intraoperative administration of dolasetron 350 µg/kg or ondansetron 100 µg/kg provides equivalent control of POV after superficial surgery in children. Control of POV is not improved by increasing the dose of dolasetron to 700 µg/kg, but reducing the dose to 45 µg/kg is associated with decreased control and parental satisfaction. The institutional costs of prophylaxis with dolasetron 350 µg/kg are less than with ondansetron 100 µg/kg.

	Acknowledgments

 
We gratefully acknowledge the help provided by Lisa McCormick, BSN, RN, Anil Rajendra, BS, and Rosetta Chiavacci, RN, BSN, without whom this study would not have been completed. We also thank the PACU nurses and the operating room pharmacists at the Children’s Hospital of Philadelphia for their patience during this study.

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