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PEDIATRIC ANESTHESIOLOGY

The Effects of Oral Ondansetron Disintegrating Tablets for Prevention of At-Home Emesis in Pediatric Patients After Ear-Nose-Throat Surgery

Peter J. Davis, MD^*, Kathleen M. Fertal, RN, CCRC, Karen R. Boretsky, MD^*, Gina M. Fedel, MD^*, Michael D. Ingram, MD^*, Susan K. Woelfel, MD^*, Paul C. Hoffmann, RPh, Harshad Gurnaney, MD^*, and Michael C. Young, MS^*

From the *University of Pittsburgh School of Medicine, Departments of Anesthesiology, and Pharmacy, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Address correspondence to Peter J. Davis, MD, Department of Anesthesiology, Children’s Hospital of Pittsburgh, 3705 Fifth Ave., Pittsburgh, PA 15213. Address e-mail to davispj{at}anes.upmc.edu.

Abstract

BACKGROUND: Tonsillectomy and adenoidectomy are associated with a frequent incidence of vomiting, both in the hospital and at home. We evaluated the effects of oral ondansetron disintegrating tablets (ODT) on the incidence of at-home emesis in children undergoing tonsillectomy with and without adenoidectomy and with and without bilateral myringotomy and tube insertion.

METHODS: All patients underwent inhaled mask induction with nitrous oxide, oxygen, and sevoflurane. Morphine, dexamethasone, and ondansetron were administered to all patients intraoperatively. Postoperative pain was treated with fentanyl or acetaminophen with codeine. Rescue antiemetics in the postanesthesia care unit or same day surgery unit were administered for three emetic episodes within 15 min, or upon patient or parent request. Patients were randomized for at-home administration of five doses of either ondansetron ODT or a placebo. All patients were followed for the first 3 days after surgery. At-home emesis was the primary outcome variable.

RESULTS: Two hundred and twenty-one patients were entered into the study, yielding 200 evaluable subjects. At-home emesis occurred in 15 (14.5%) of the 103 children who received ODT, and 31 (32%) of the 97 children in the placebo group, P = 0.004. Subgroup analysis demonstrated efficacy in patients who did not require rescue medication for nausea and vomiting while in the hospital, but did not demonstrate efficacy for patients who required rescue medication.

CONCLUSIONS: At-home use of ODT may prevent emesis in children during the first 3 days after tonsillectomy in children. Patients who require rescue after prophylactic treatment for nausea and vomiting in the hospital may not respond to prophylactic ondansatron ODT at home.

Tonsillectomy and adenoidectomy are associated with a 40%-80% incidence of postoperative emesis.1–10 Many therapeutic modalities have been reported with varying degrees of success. In pediatric patients, 5HT₃ receptor antagonists are commonly used for prophylaxis for postoperative vomiting. Ondansetron, a 5HT₃ receptor antagonist, has been shown to be an effective prophylactic drug when administered either IV or orally as in the form of the ondansetron disintegrating tablets (ODT).4,8,11–13 Surgical, patient, and anesthetic factors can affect the underlying incidence of postoperative emesis.14 In addition, the effectiveness of antiemetic drugs can also be a function of the time period that patients are monitored. Frequently, postoperative vomiting in ambulatory pediatric patients is only assessed during the hospitalization period and the first postoperative 24 h. After tonsillectomy or adenotonsillectomy postoperative vomiting can occur for days, since patients frequently require opioid analgesics. Effective postoperative vomiting treatment for children without IV access can be limited by a patient’s ability to swallow oral medication and by their aversion to rectally administered medication. Therefore, we studied home use of ODT in children undergoing tonsillectomy with or without adenoidectomy and with or without bilateral myringotomy and tube insertion. We hypothesized that administration of ODT during the patient’s first three postprocedure days would decrease the incidence of postoperative emesis at home.

METHODS

After granting of an investigator Investigational New Drug Number by the Food and Drug Administration, and approval by the University of Pittsburgh IRB, 221 pediatric patients were enrolled in this investigator-initiated, single-center, randomized, double-blind, placebo-controlled, parallel-group study. Evaluated patients were defined as those who were discharged from the hospital the same day of their operative procedure and remained compliant with the study medication administration throughout the study period. A placebo arm was justified, since pediatric patients undergoing tonsillectomy are routinely discharged home without medication to treat postoperative nausea and vomiting (PONV).

Potential study patients were screened the morning of their surgical procedure to determine eligibility. Eligible subjects were defined as patients who were ASA 1 or ASA 2, between 5- and 16-yr-of-age, weighed at least 25 kg, and were undergoing tonsillectomy with or without adenoidectomy and with and without bilateral myringotomy and tube insertion. Familial history of PONV was recorded. Patients with gastroesophageal reflux or other significant underlying medical conditions were excluded. Written informed consent was obtained from the parents of eligible subjects. Assent was also obtained from the child when appropriate, based on the age and maturity level.

Consenting patients were randomized to one of two treatment groups, ODT (five doses) or placebo, using a randomization table. The anesthetic regimen was standardized for all study subjects. Administration of premedication (oral or nasal midazolam in standard preoperative doses) was left to the discretion of the attending physician. All patients underwent inhaled mask induction with nitrous oxide, oxygen, and sevoflurane. After securing IV access, propofol 2 mg/kg was administered before endotracheal tube placement. Anesthesia was maintained with nitrous oxide, oxygen, and isoflurane. Morphine (0.1 mg/kg), dexamethasone (0.5 mg/kg to a maximum dose 25 mg), and ondansetron (0.1 mg/kg to a maximum dose of 4 mg) were administered IV shortly after the induction of anesthesia. Upon emergence from anesthesia, patients were transferred to the Postanesthesia Care Unit and then the Same Day Surgery postoperative unit. Postoperative pain was treated with fentanyl and/or acetaminophen with codeine at the attending physician’s discretion. Subjects were continuously monitored by the research nurse for the occurrence of postoperative emesis and the administration of a rescue antiemetic (metoclopramide 0.1 mg/kg to a maximum dose 10 mg). Emesis was defined as expulsion of any stomach contents through the mouth. The criteria for rescue medication administration were the occurrence of three emetic episodes within a 15-min period, the physician’s discretion, or at the request of the parent or child. Nausea was not assessed as a separate entity because of the difficulty of assessing nausea in young patients.

Patients were discharged home after meeting the discharge criteria (stable vital signs, ability to swallow, absence of excessive pain, absence of bleeding, and absence of severe nausea). Parents were given routine discharge instructions for children undergoing these types of surgical procedures. The research nurse followed study patients through hospital discharge to monitor the incidence of emesis, provide study medication, and provide verbal instruction on taking study medication during the study period (approximately 60 h postoperatively). A 24-h contact number for questions or concerns was provided. Study blind was maintained by the research pharmacist who dispensed study medication (ondansetron ODT 8 mg or placebo ODT) in child-proof medication bottles labeled with detailed instruction for administering study drug. Both ondansetron ODT and placebo ODT were identical in appearance, taste, and texture. Parents were instructed to give their children one ODT or placebo as soon as they returned home on the day of surgery, followed by one ODT (or placebo) on the mornings and evenings of the first and second postoperative days. The incidence of vomiting after hospital discharge, fluid intake, other medications, times of study drug administration, satisfaction with study drug, and any concerns were recorded. The research nurse contacted parents by phone for three consecutive evenings to collect this information and respond to questions or concerns.

Sample size was determined on the dichotomous outcome of vomiting. For calculation of sample size, the control group was estimated to be 50% and the treatment group was estimated to be 30% with an of 0.05, β of 0.2, and 80% power. One hundred and three patients per group were estimated. Patient demographics were analyzed by summary statistics including Student’s t-test, Mann-Whitney, Fisher’s exact test, bivariate correlation, and regression, and a multivariate logistical regression.15 The outcome variable was at-home emesis, which was evaluated using a Fisher’s exact test for a 2 x 2 contingency table. A multivariate logistical regression involving all our data noted the modules were unstable and contained interactive terms without the corresponding primary effects and therefore was not reported.

RESULTS

Two hundred and twenty-one patients were enrolled in the study. Twenty-one patients (8 patients in the ODT group, 13 patients in the placebo group) were dropped from the study because of protocol violations or complications that resulted in hospitalization. Six patients in the ODT group were noncompliant (i.e., they did not complete the entire ODT regimen), and 2 patients returned to the hospital within the first 2 days after surgery for bleeding and vomiting. Five patients in the placebo group were noncompliant, and 8 patients were readmitted to the hospital during the study period (2 for bleeding, 1 for vomiting, 3 for airway issues, 1 for pain, and 1 for excessive somnolence). Of the 200 evaluable patients, 103 patients were randomized to the ODT group and 97 patients were randomized to the placebo group.

There was no statistical difference between the groups with regard to age, weight, gender, family history of postoperative vomiting, patient history of motion sickness, history of PONV, or types of surgery (Table 1). The incidence of analgesia use at home was not statistically different in both groups. Of the 200 patients, 197 children received opioids at home for analgesia, and 3 patients medicated themselves with acetaminophen. No patient received additional antiemetic therapy at home, other than the study medication or placebo.

The incidence of vomiting in the hospital and car is presented in Table 2. There were 15 patients in the ODT group, and 25 patients in the placebo group, who experienced emesis while in the hospital (P = 0.053). Similarly, there was a difference in the rate of rescue for the two groups while hospitalized: 10 patients in the ODT group versus 24 patients in the placebo group (P = 0.008). These patients had not yet received the study drug, and thus should have been indistinguishable in all predosing metrics.

At-home emesis was most severe on the day of surgery, occurring in 15 patients in the ODT group, and 24 patients in the placebo group. During the 3-day observation period, 15 children in the ODT group and 31 children in the placebo group experienced emesis (P = 0.004). Children receiving ODT experienced 25 episodes of vomiting, whereas those in the placebo group experienced 55 such episodes.

Because of the differences in rescue medication before study drug administration, we performed a secondary subgroup analysis based on whether or not the patient received rescue medication (Table 3). Of the 93 patients in the ODT group who did not receive rescue medication, only 7 (7.5%) had emesis at home. Of the 73 patients in the control group who did not receive rescue medication, 19 (26%) had emesis at home (P = 0.002). In the subgroup of patients who experienced in-hospital rescue, 8 of 10 patients in the ODT group (80%) vomited at home compared with 12 of 24 (50%) patients in the placebo group (P = 0.14).

DISCUSSION

This study demonstrated that ODT can reduce the overall incidence of at-home postoperative vomiting. The interpretation of the results is complicated by the statistically significant difference in vomiting and rescue between the two groups during hospitalization, before study drug administration. This represents a failure of the blinded randomization to evenly divide the risks of postoperative emesis between the two groups. The study also suggests that ODT may not be effective in children who have received prophylactic ondansetron and dexamethasone intraoperatively, and who subsequently require rescue treatment in the hospital.

Although ODT have been shown to be highly effective in adult studies of chemotherapy-induced nausea and vomiting, the results of adult PONV ODT studies are mixed. Thagaard et al. have shown in 96 patients undergoing laparoscopic surgery that 8 mg of ODT administered twice a day for 3 days was similar in effect to placebo.16 Gan et al., in a study of 60 patients undergoing outpatient gynecological laparoscopic procedures, noted that patients who received two doses of 8 mg of ODT 12 h apart had a markedly decreased incidence of postdischarge vomiting compared with patients who received placebo (3% vs 23%).17 ODT were also found to be effective in hospitalized adult patients undergoing acoustic neuroma surgery. In this study, Hartsell et al. noted that ODT administered twice a day for 72 h resulted in less frequent rescue therapy compared with patients receiving placebo.18

There are few data describing ODT in children.19,20 In pediatric cancer patients, Corapcioglu and Sarper noted that ODT were safe, well tolerated, and cost-effective compared with IV ondansetron.20 Pediatric PONV studies of ODT are extremely limited. In pediatric patients undergoing adenotonsillectomy, Cohen et al. administered ODT as prophylactic antiemetics before induction of anesthesia and combined them with IV dexamethasone. In this study, ODT significantly decreased the incidence of emesis (37.9%) compared with children who received placebo (73%).19

The present study demonstrates that with multimodal prophylactic antiemetic therapy involving dexamethasone and ondansetron, the incidence of in-hospital vomiting is about 17%. In addition, for those pediatric patients who do not vomit or require rescue therapy in the hospital, the at-home use of ODT is associated with a decreased incidence of emesis. However, in patients who require rescue medication in the hospital, about one-half of these patients will vomit at home, and the use of ODT at home did not have a beneficial effect in this study. The fact that ODT did not work on this subgroup of patients is consistent with the findings of Kovac et al., who demonstrated that repeat doses of ondansetron are not an effective rescue for adult patients who have failed prophylactic ondansetron.21 It appears that the role of ODT may be more beneficial for those patients who have no in-hospital emesis and do not receive in-hospital rescue.

Although our study suggests some benefit to ODT, the study has a few potentially limiting factors.1 Because nausea in children can be very difficult to quantify, we chose not to measure this. We likely under-estimated the rate of PONV. However, in older children who complained of nausea, rescue medication was administered.2 Although younger children may not have reliably expressed the feeling of nausea, we felt compelled to treat nausea in those patients who did report it. We nevertheless performed a subgroup analysis (Table 3) of patients requiring rescue in the Postanesthesia Care Unit or Same Day Surgery Unit.3 We did not collect information on the individual total opioid doses administered at home. However, almost all of our patients (197 of 200) received oral opioids at home. In view of the possible dose-response relationships of IV morphine and vomiting after day-surgery, tonsillectomy patients,22 there may be the same relationship for oral opioid use at home. Consequently, differences in opioid consumption may have been a factor between the two groups.4

The biggest limitation is the unexpected difference in vomiting and in-hospital rescue rates between the two groups before drug administration. We have no explanation for these differences. We addressed this by including a subgroup analysis based on whether the patient required rescue medication. This analysis demonstrated efficacy of ODT prophylaxis in those patients who did not require rescue, but a lack of efficacy in those who did require it.

In summary, ODT reduced the incidence of at-home emesis in patients undergoing tonsillectomy with or without adenoidectomy and with or without bilateral myringotomy and tube insertion. However, its effectiveness may be limited in those patients who require rescue after receiving intraoperative prophylaxis with ondansetron and dexamethasone.

ACKNOWLEDGEMENT

The authors thank Susan Danfelt for her secretarial assistance.

Footnotes

Accepted for publication December 17, 2007.

Supported, in part, from an unrestricted education grant from GlaxoSmithKline.

Dr. Peter J. Davis, Section Editor for Pediatric Anesthesiology, was recused from all editorial decisions related to this manuscript.

Reprints will not be available from the author.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Davis, P. J. Articles by Young, M. C. Search for Related Content PubMed PubMed Citation Articles by Davis, P. J. Articles by Young, M. C. Related Collections Complications Clinical Pharmacology Pediatrics Pharmacology