Postoperative nausea and vomiting (PONV), a major complication in children, is responsive to IV and oral ondansetron. Because these routes are not always available, we studied the acceptability and efficacy of ondansetron oral disintegrating tablets (ODT). In this double-blind, randomized, placebo-controlled study, 62 patients undergoing adenotonsillectomy, aged 5 to 11 years, preoperatively received ODT (4 mg) or placebo. Patients assessed the medication for taste and sensation. Anesthesia was induced with sevoflurane, maintained with desflurane, and supplemented with fentanyl 2.5 μg/kg and dexamethasone 0.5 mg/kg (maximum dose, 12 mg). An observer blinded to treat-ment evaluated patients for pain, agitation, and PONV. Postoperative treatment consisted of fentanyl 1 μg/kg for pain and agitation and metoclopramide 0.15 mg/kg (maximum dose, 10 mg) for PONV. There were no significant differences between study groups with regard to age, weight, recovery time, agitation, or pain. Approximately 90% of the subjects found the ODT to taste good. No subject rejected the study medication, but the ondansetron-containing tablets were found to be less palatable than the placebo. The incidence of vomiting was significantly less in the ondansetron-medicated group.
IMPLICATIONS: Ondansetron oral disintegrating tablets were accepted by school-age children undergoing adenotonsillectomy and decreased the incidence of postoperative vomiting.
Department of Anesthesiology, Children's National Medical Center, and George Washington University School of Medicine, Washington, DC
Supported by a grant from GlaxoSmithKline (Philadelphia, PA).
Presented in part at the annual meeting of the American Society of Anesthesiologists, Las Vegas, NV, October 2004.
Accepted for publication December 6, 2004.
Address correspondence and reprint requests to Ira Todd Cohen, MD, Department of Anesthesiology, Children's National Medical Center, 111 Michigan Ave. NW, Washington, DC 20010. Address e-mail to email@example.com.
Postoperative nausea and vomiting (PONV) continues to be a common complication in children undergoing general anesthesia and surgery. Although the use of 5-hydroxytryptamine-3 antagonists and guidelines for antiemetic prophylaxis may effectively decrease the incidence of PONV, at-home symptoms and unanticipated admission of ambulatory patients remain a concern (1–4). Effective treatments for PONV in children who no longer have IV access may be limited by their inability to swallow oral medications and by aversion to, and variable absorption of, rectal suppositories. Ondansetron oral disintegrating tablets (ODT), which do not require ingestion, may offer an acceptable alternative.
Children and other patients with PONV often have difficulty swallowing tablets. To address this problem, a novel method of preparing tablets that disintegrate rapidly in the mouth has been developed. Tablets with high porosity, allowing for rapid dissolving and absorption, can function as delivery devices (5). The objective of our study was to evaluate the effectiveness, safety, and acceptability of ondansetron ODT in children undergoing adenotonsillectomy. Although this population typically retains IV access, we hypothesized that we could demonstrate efficacy in the treatment group and allow for rescue in the control group.
After IRB approval was obtained, 62 children, 5–11 yr old, with an ASA physical status of I or II, who were scheduled for adenotonsillectomy, were enrolled in the study. Written, informed parental consent and patient assent, if applicable, were obtained in all cases. The study design was randomized, double blinded, and placebo controlled. Children who weighed <20 kg, who had a documented history of sleep apnea, or who received antiemetics, antihistaminics, or psychoactive drugs within 24 h before surgery were excluded. Also excluded were children who were developmentally delayed, required premedication, or were 150% more than their ideal body weight.
Children enrolled onto the study were randomly assigned to receive 1 of 2 treatments: ondansetron ODT (fixed dose of 4 mg) or placebo immediately before anesthesia induction. After the administration of study medication, each child was asked to evaluate the tablet according to taste, sensation, and willingness to take the medication in the future. General anesthesia was induced with sevoflurane in an oxygen/nitrous oxide mixture (30%/70%) by face mask with spontaneous ventilation. After induction, IV access was established. Fentanyl 2.5 μg/kg IV was administered for intraoperative and postoperative analgesia and to decrease the incidence of emergence agitation. Endotracheal intubation was facilitated with mivacurium 0.25 mg/kg IV or a deep sevoflurane inhalation technique. The amount of IV fluid administered was standardized to 20–25 mL/kg of lactated Ringer's solution during surgery, followed by a maintenance-rate infusion until hospital discharge. Anesthesia was maintained with 60%–70% nitrous oxide and desflurane 3%–5% adjusted to maintain heart rate and arterial blood pressure values within 20% of the baseline induction value. Each patient received dexamethasone 0.5 mg/kg (maximum dose, 12 mg) IV before the start of surgery (6).
At the conclusion of surgery, gastric contents were suctioned via an orogastric tube. The completion time of surgery was recorded as the time of the mouth-gag removal. Muscle-relaxant antagonists were not used. The trachea was extubated upon demonstration of a regular respiratory pattern and purposeful movement or grimacing.
Admission time to the postanesthesia care unit (PACU) was recorded, and an assessor, blinded to the treatment group assignment, recorded study variables, including vital signs, pain, agitation, PONV, and discharge criteria. Pain was evaluated with the Observational Pain Scale (7) until patients were able to report pain intensity orally. Emergence agitation was evaluated with a 1–3 scale (8). Patients were evaluated for pain and agitation every 5 min for the first 15 min and then every 15 min until they achieved a Steward Recovery Score of 6 and met discharge criteria (9). Fentanyl 1 μg/kg was given for a pain score ≥6 and for agitation scores of 3. The use of fentanyl was also recorded. Subsequent pain management was achieved with acetaminophen with or without codeine.
The incidence and time of PONV were recorded from the time of tracheal extubation to the following day. Within 24 h after surgery, all subjects were interviewed to assess the incidence of PONV, pain, agitation, and adverse events. Because nausea is difficult to assess in children, patients were asked to recall whether they experienced nausea, dizziness, and generalized discomfort. Episodes of vomiting occurring <5 min apart were considered a single episode. A rescue antiemetic consisting of metoclopramide 0.15 mg/kg IV (maximum dose, 10 mg) was administered if the children experienced one episode of retching and/or vomiting. If retching and/or vomiting occurred more than 3 times, IV ondansetron 0.1 mg/kg (maximum dose, 4 mg) was administered.
Patients were admitted to the short-stay recovery unit (SSRU) or the 23-h care unit for continued observation and care or were discharged. Subsequent needs for analgesics, antiemetics, and IV hydration were noted by the study nurse in the PACU, SSRU, and 23-h care unit. Variables documented in each case included age, sex, weight, height, duration of anesthesia, duration of PACU stay, pain scores, emergence agitation scores, analgesic requirements, incidence of retching and vomiting, and need for rescue antiemetics. A research nurse performed variable documentation in the PACU, SSRU, and 23-h unit. Guardians were given data-collection sheets for children who were discharged home before 23 h. A research nurse interviewed all participants after 24 h either in person or by phone. In addition, all patients were evaluated for the occurrence of adverse events.
Sample size was determined on the dichotomous outcome vomiting. For calculation of sample size, the placebo vomiting incidence rate was 75% (10), and the drug was deemed clinically effective if it decreased the incidence rate to 25%. The number of subjects needed in a two-sample (2 × 2 table) Fischer's exact test of significance of the difference between the change in incidence of vomiting (0.75 − 0.25 = 0.50) was determined. Each group required an n of 28. Sample size was increased by 11% for patient attrition or loss to follow-up, so that 31 patients were required in each group.
The study data were summarized by univariate summary statistics, such as means or medians, standard deviations, 95% confidence limits, and ranges. The continuous data were analyzed by the two-sample Student's t-test and/or Kruskal-Wallis test (the Wilcoxon-Mann-Whitney rank test). Discrete data, such as nominal and/or ordinal data, were analyzed by the χ2 test and/or Fisher's exact test for 2 × 2 contingency tables. The two treatment groups were analyzed by using proportions of PONV by the χ2 test and/or Fisher's exact test. For all tests of significance, a P value <0.05 was used as the level of significance.
Sixty-two patients were enrolled. Three patients were not included in the evaluation of the primary outcome, vomiting, because of protocol violations. Two patients received sevoflurane instead of desflurane for anesthetic maintenance, and one patient received rocuronium requiring reversal with neostigmine and atropine. All 62 patients were included for assessment of study drug acceptability and safety.
There were no significant differences between study groups with respect to age, sex, weight, height, intubation technique, or duration of anesthesia (Table 1). Also, no significant differences were seen with regard to emergence agitation, postoperative pain, the percentage of patients who received fentanyl in the PACU, or time to meet discharge criteria (Table 2). Four patients in each group received an additional dose of fentanyl in the PACU for pain. Adverse events consisted of one incident of intermittent oxygen desaturation in the study group and an increased temperature in the control group. Both were deemed not to be secondary to the ODT preparation.
Overall, children found the ondansetron ODT acceptable. None of the subjects rejected or spit out the study medication, but a significantly larger number of the subjects found the ondansetron-containing tablet to be not as “good” tasting as compared with the placebo group (12 versus 5; P = 0.043). All participants, except four in the ondansetron group, stated that they would be willing to take the medicine in the future.
The recalled incidence of nausea and/or dizziness was similar between the two groups. The incidence of vomiting, severe vomiting (more than 2 episodes), and late vomiting (6–24 h) was significantly less in the ondansetron-medicated group as compared with those who received the placebo (Table 3). The relative risk reduction for vomiting (single incident) was 50% (95% confidence interval, 44.3%–55.7%). The number needed to treat of 2.86 (95% confidence interval, 2.62–3.1) predicts that the use of ODT in 3 patients would result in 1 fewer patient experiencing posttonsillectomy emesis.
All patients (n = 33) who experienced vomiting received metoclopramide 0.15 mg/kg (maximum dose, 12 mg). Of these patients, 17 continued to experience emesis, and 10 had multiple episodes. The use of oral analgesics was similar between groups. Of the 5 patients who were discharged before 23 h, vomiting occurred in 2—1 in ondansetron group and 1 in the control group. Both emetic episodes occurred when the patient was at home and not during transport.
This study demonstrated that ondansetron ODT administered before adenotonsillectomy was accepted by children and significantly reduced the incidence of PONV. IV ondansetron has been shown to be effective in treating PONV both prophylactically and acutely in children (11–13). Ondansetron ODT has been shown to be effective in adults undergoing chemotherapy, radiotherapy, and ambulatory surgery but not in patients undergoing outpatient laparoscopic surgery (4,11–16). This initial evaluation of ondansetron ODT in children found the medication to be effective in reducing the overall incidence, repeated episodes, and late (after PACU discharge) emesis.
Nausea in the pediatric population is difficult to assess. Of the subjects who participated in this study, only two (one in each group) complained of nausea without vomiting while in the PACU. In this study, we attempted to discern this symptom by interviewing patients within 24 hours after surgery and by adding other descriptors. The incidence of nausea, dizziness, or both reported (30%–38%) was similar between the ondansetron-treated and control groups. Although this lack of response to treatment may reflect methodological problems, recall bias, or both, we believe that it confirms previous findings that 5-hydroxytryptamine-3 antagonists are less effective in alleviating nausea than they are in preventing vomiting (17).
Previous studies have found that the postdischarge incidence of PONV in all children having undergone ambulatory surgery ranges from 13% to 20% (1–3). An acceptable and easily administered antiemetic in children who no longer have IV access would be helpful in treating symptoms and reducing readmissions. Ondansetron ODT was accepted by 100% of our study participants; only 4 of 31stated that they would not want to use it in the future. The taste of ondansetron-containing preparation was scored lower than that of the placebo, as previously reported (14). The masking of the medicinal flavor is apparently only partially successful.
The ondansetron ODT is a fixed-dose preparation, and patients in this study weighing <26.7 kg were receiving more than the recommended nonfixed oral dose of 0.15 mg/kg (18). Although bioavailability may differ, both the traditional and ODT optimal fixed oral dose in the adult population is 8–16 mg (14,15,19). Our dosing is consistent with these guidelines. A post hoc examination (linear regression) of weight versus incidence of vomiting demonstrated no relationship be-tween dose and outcome. In our study, a fixed dose of 4 mg resulted in a relative risk reduction of 50% and a number needed to treat of 2.86.
Although each patient received dexamethasone 0.5 mg/kg IV (maximum, 12 mg), approximately 75% of children in the control group, as in our previous study, experienced PONV (10). The literature reports a significant decrease in PONV in children undergoing tonsillectomy with similar doses of dexamethasone (5,20–22). The reason for this disparity may lie in the anesthetic technique. Metoclopramide, which was administered after one episode of emesis, did not effectively prevent further episodes. More than half of the patients treated went on to have at least one repeat episode, and a third had multiple episodes. This finding supports the recommendation to select other antiemetics over metoclopramide as a first-line rescue medication for PONV in children (1).
This study did not evaluate the effect of ondansetron ODT in children who already had nausea and vomiting. Although IV ondansetron has been shown to be equally effective prophylactically and therapeutically, we cannot, with certainty, assume that the same is true for the ODT preparation. Further investigation is indicated to assess how receptive and responsive a child already experiencing nausea and/or vomiting will be to this medication. Of note, this study examined children undergoing a high-risk procedure for vomiting; therefore, these results should not be extrapolated to the general population.
In conclusion, ondansetron ODT was found to be a successful prophylactic antiemetic in children undergoing adenotonsillectomy. This preparation of ondansetron may be a useful alternative in preventing nausea and vomiting in children who lack IV access and are unable to take oral medications.
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