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ORIGINAL RESEARCH ARTICLE

Pediatr Drugs 2010; 12 (6): 405-410 1174-5878/10/0006-0405/$49.95/0

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Ondansetron Dosing in Pediatric Gastroenteritis


A Prospective Cohort, Dose-Response Study
Stephen B. Freedman,1,2 Elizabeth C. Powell,3 Alejandro A. Nava-Ocampo4,5,6 and Yaron Finkelstein1,4,7
1 Division of Pediatric Emergency Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 2 Division of Gastroenterology Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 3 Pediatric Emergency Medicine, Childrens Memorial Hospital, and Department of Pediatrics, Northwestern Universitys Feinberg School of Medicine, Chicago, Illinois, USA 4 Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada 5 PharmaReasons, Toronto, Ontario, Canada 6 Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada 7 Clinical Pharmacology Unit, Division of Emergency Medicine, Childrens Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA

Abstract

Background: Ondansetron is increasingly used to prevent emesis in children with acute gastroenteritis; however, the optimal dose is unknown. Objective: To determine if higher doses of oral ondansetron are associated with greater efficacy or side effects. Methods: We analyzed data from a prospective clinical trial performed between January 2004 and April 2005. Data were collected on 105 children with dehydration due to gastroenteritis who received an ondansetron oral disintegrating formulation. The following outcomes of efficacy were analyzed: number of vomiting episodes, volume of oral rehydration fluids consumed, percent weight gain, and the proportions of children who had ongoing vomiting, received intravenous rehydration, and were hospitalized. In addition, the number of episodes of diarrhea was evaluated to measure whether there were dose-dependent side effects. Results: Participants were aged 0.58.2 years and the dose ranged between 0.13 and 0.26 mg/kg. There was no significant association between the dose of ondansetron and the outcomes of number of vomiting episodes, volume of fluids consumed, increase in bodyweight, or number of diarrhea episodes/hour. The mean dose of ondansetron (mg/kg) administered was not different amongst those who did and did not have ongoing vomiting, undergo hospitalization, and receive intravenous rehydration. Conclusions: Within the dose range of 0.130.26 mg/kg, higher doses of ondansetron were not superior to lower doses, nor were they associated with increased side effects. Thus, ondansetron in this dose range was shown to result in a similar reduction in emesis in children with acute gastroenteritis.

Background Worldwide, gastroenteritis remains a leading cause of morbidity and mortality in children.[1] Among children in the US, acute gastroenteritis accounts for >1.5 million outpatient visits, and approximately 200 000 hospitalizations/year in children <5 years of age.[2] Nearly 70% of children with communityacquired gastroenteritis who are seen at a hospital experience vomiting prior to their Emergency Department (ED) visit,[3] and intractable vomiting is a common indication for admission

and inpatient care.[2] Inability of the caregiver to relieve their childs symptoms results in stress, fatigue, and frustration.[4] Although the exact pathophysiologic process resulting in emesis is incompletely understood, a major pathway involves serotonin release in the stomach and small intestine.[5] Consequently, selective serotonin receptor (5-hydroxytryptamine type 3 [5-HT3]) antagonists have been extensively studied. A recent advance in the treatment of pediatric gastroenteritis is the option of administering ondansetron, a 5-HT3 antagonist that is completely and rapidly absorbed from the gastrointestinal

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tract, to children with recurrent vomiting.[6-12] While other 5-HT3 antagonists have antiemetic effects, they have not been evaluated in children with gastroenteritis. Therefore, ondansetron, which is available as an oral disintegrating tablet (ODT; Zofran ODT; GlaxoSmithKline, London, UK), was the focus of our study. The ODT formulation can be administered to children who cannot tolerate oral fluids, refuse to swallow an elixir, or are too young to consume pills. Although there continues to be debate regarding the role of antiemetic agents in acute gastroenteritis, several clinical trials have documented the efficacy of ondansetron.[6-10] A recent meta-analysis concluded that ondansetron can reduce the need for intravenous rehydration and hospitalization.[12] Current reviews of the management of acute gastroenteritis have suggested ondansetron be used when treating children with vomiting secondary to acute gastroenteritis.[13-15] One potential concern regarding ondansetron use reported in clinical trials is that it may in fact increase the frequency of diarrheal episodes.[6,7,11] Additionally, the optimal oral ondansetron dose for treating acute gastroenteritis is unknown. While studies in children with gastroenteritis have evaluated doses between 0.10 and 0.26 mg/kg,[6,7,9] the accepted range in pediatric oncology patients can be as high as 0.6 mg/kg/dose intravenously.[16] Knowledge of the optimal dose to administer is crucial to maximize efficacy while minimizing side effects, such as diarrhea. Based on the pediatric anesthesia literature,[17-19] our hypothesis for this study was that higher doses of oral ondansetron are not associated with greater antiemetic efficacy nor increased diarrhea, amongst a group of otherwise healthy children who presented to an ED with vomiting due to gastroenteritis. Methods
Setting, Subjects, and Intervention

Since the ondansetron ODT is only commercially available in 4 and 8 mg doses, subjects received a weight-based dose of the preparation: 2 mg for children weighing 815 kg, 4 mg for children weighing more than 15 kg and up to 30 kg, and 8 mg for children weighing more than 30 kg. All children initially underwent a 60-minute oral rehydration therapy trial according to a standard protocol[6] and were administered a single oral rehydration solution (Enfalyte; Mead Johnson Nutritionals, Evansville, IN, USA). This study was approved by the Childrens Memorial Hospital Institutional Review Board.
Outcomes

The primary outcome was the correlation between the dose of ondansetron and the success of oral rehydration therapy defined by the volume of oral rehydration fluid consumed (mL/kg/h), percent weight gain, and the frequency of vomiting. Secondary outcomes were the frequency of diarrhea, ongoing vomiting (dichotomous variable), and the need for intravenous rehydration or hospitalization following ondansetron administration.[7] To determine if the length of stay played a role in weight gain, we additionally evaluated the percent weight gain per hour of treatment in the ED.
Standardized Patient Assessment and Data Collection

Between January 2004 and April 2005, data were prospectively collected on children aged 6 months10 years who presented to the ED of the Childrens Memorial Hospital, Chicago, IL, USA, with acute gastroenteritis and dehydration, and were administered an ondansetron ODT as part of a prospective clinical trial evaluating the efficacy of ondansetron.[6] Eligibility criteria were the presence of non-bilious and nonbloody vomitus and diarrhea secondary to acute enteritis, as determined by the supervising physician. Vomiting had to have occurred within 4 hours preceding triage and all children had mild to moderate dehydration. Exclusion criteria were severe dehydration, weight <8 kg, underlying disease that might affect the assessment of hydration status, or a history of abdominal surgery.
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Data collection forms were completed prospectively by trained research nurses. Historical elements included the number of episodes of vomiting and diarrhea in the proceeding 24 hours, age, sex, race, weight, presence of fever, frequency of urine output, and time of initiation of oral rehydration therapy. A clinical dehydration assessment was performed, as has been previously described.[6] Variables collected during ED treatment included volume of oral rehydration fluids consumed, weight gain, and number of episodes of diarrhea and vomiting. All data abstraction and telephone follow-up were performed by a research assistant blinded to the dose of ondansetron administered.
Power Calculations

Since this analysis employed data collected on a fixed sample size of 105 patients, sample size calculations were not performed. A power calculation determined that our sample size has 88% power to detect a correlation as small as 0.30 using a two-sided hypothesis test with significance set at 0.05.
Data Analysis

As outcomes of efficacy, the volume of oral rehydration solution consumed (mL/kg/h), percent weight gain, and percent
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weight gain per hour of ED treatment were analyzed as continuous variables employing Pearsons correlation coefficient. The correlation between the frequency of vomiting while in the ED and the dose of ondansetron administered was calculated using Kendalls tau rank correlation coefficient as a nonparametric test to measure the degree of correlation between two rankings. The number of diarrhea episodes, standardized for length of stay in the ED, was analyzed as a continuous variable employing Pearsons correlation coefficient. The relationship between the dose of ondansetron administered and the outcomes of vomiting, intravenous rehydration, and hospitalization were analyzed using the Independent Samples t-Test. All analyses were two-sided with significance set at p < 0.05. Unless otherwise specified, all analyses were performed with SPSS software (version 16.0) [SPSS Inc., Chicago, IL, USA].

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Percent weight change

10.0

5.0

0 r = 0.002 p = 0.98 0.10 0.15 0.20 0.25 Ondansetron dose (mg/kg) 0.30

5.0

Fig. 2. Linear regression analysis between the dose of ondansetron (mg/kg) and percent weight gain during Emergency Department oral rehydration therapy {([final weight initial weight]/final weight) 100}.

Results One hundred and five children (59 males) met the study eligibility criteria and were included in the analysis. The age of participants ranged from 6 months to 8.2 years. The mean administered dose of ondansetron was 0.20 0.03 mg/kg (range 0.130.26 mg/kg).
Dose-Response Analysis

The dose of ondansetron administered (mg/kg) was not statistically associated with any of the pre-defined five parameters of efficacy that were evaluated. These included the volume of oral rehydration fluids (mL/kg/h) consumed (co-

30 Oral rehydration fluids (mL/kg/h) 25 20 15 10 5 0 0.10 0.15 0.20 Ondansetron dose (mg/kg) 0.25 r = 0.088 p = 0.36 0.30

Fig. 1. Linear regression analysis between the dose of ondansetron (mg/kg) and the volume of oral rehydration fluids consumed (mL/kg/h).
2010 Adis Data Information BV. All rights reserved.

efficient of correlation r = -0.088; p = 0.36) [figure 1], or percent weight gain (r = -0.002; p = 0.98) [figure 2]. Overall, 88% of study subjects (92/105) experienced no vomiting episodes, and there was no evidence of a dose-response relationship between those who vomited and those who did not or the frequency of vomiting during oral rehydration therapy in the ED (tau = 0.093; p = 0.24) [figure 3]. When weight change was analyzed per hour of ED treatment to take into account length of stay, the correlation with ondansetron dose administered (mg/kg) remained statistically non-significant (r = -0.063; p = 0.52). Visual analysis of the scatter plots did not suggest any nonlinear relationships between the dependent and independent variables included in the study. The dose of ondansetron administered was not correlated to the frequency of diarrheal episodes (standardized per hour) during ED stay (r = 0.062; p = 0.52) [figure 4]. No severe adverse effects of ondansetron (arrhythmias, hypersensitivity reactions, extrapyramidal reactions, liver failure, or pancreatitis) were seen during the ED treatment period nor reported during telephone follow-up 1 week later. The mean dose of ondansetron amongst children who did not receive intravenous rehydration was 0.20 0.03 mg/kg compared with 0.21 0.03 mg/kg amongst those who received intravenous rehydration (p = 0.12). The mean doses of ondansetron were nearly identical amongst those hospitalized and those who were discharged (0.20 0.02 vs 0.20 0.03 mg/kg, respectively; p = 0.95). Lastly, the mean dose of ondansetron was similar amongst those who had ongoing vomiting (0.21 0.03 mg/kg) and those who did not (0.20 0.03 mg/kg; p = 0.38).
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3.0 No. of ED vomiting episodes 2.5 2.0 1.5 1.0 0.5 0 0.10 0.15 0.20 Ondansetron dose (mg/kg) 0.25 0.30

Fig. 3. Kendalls rank correlation analysis between the dose of ondansetron (mg/kg) and the number of vomiting episodes during Emergency Department (ED) oral rehydration therapy (tau = 0.093; p-value adjusted for ties = 0.24).

Discussion To the best of our knowledge, this is the first study to evaluate the dose response of ondansetron amongst children with acute gastroenteritis. We found that higher doses of ondansetron, within the studied and commonly accepted dose range, were not associated with improved antiemetic efficacy. Children who received higher doses of ondansetron did not experience a greater reduction in vomiting or in the requirement for intravenous rehydration or hospitalization, and did not have increased oral fluid intake compared with children who received lower doses of ondansetron. The stability of the results in all evaluated parameters supports the robustness of our conclusions. Additionally, it was reassuring to note that higher doses were not associated with increased diarrhea, the main side effect attributed to ondansetron utilization in children with gastroenteritis. The optimal ondansetron dose in pediatric gastroenteritis has not been determined. The doses routinely studied in pediatric gastroenteritis of 0.100.15 mg/kg,[6-10] while effective, are significantly lower than those studied in pediatric oncology patients.[16,20] The standard antiemetic dose in children undergoing chemotherapy is 5 mg/m2 (approximately 0.17 mg/kg); however, this dose is often felt to be insufficient in such children.[20] Higher weight-based doses are suggested because of variations in pediatric pharmacokinetic parameters.[21] In fact, some clinical trials in oncology patients have evaluated doses as high as 0.6 mg/kg (18 mg/m2)[16] and the use of loading doses of 16 mg/m2.[20] In adults, ondansetron loading doses of 32 mg (approximately 0.40.5 mg/kg) administered intravenously have been reported to be safe and well tolerated.[22] However, the present analysis supports the use of lower doses of ondan 2010 Adis Data Information BV. All rights reserved.

setron in pediatric gastroenteritis, as no added benefit in any of the outcome parameters studied was detected amongst children who received higher doses. Similar findings have been reported amongst children undergoing anesthesia for minor surgical procedures associated with significant post-operative vomiting. Amongst 320 children randomized to receive intravenous ondansetron 0.05 mg/kg, 0.10 mg/kg, or 0.15 mg/kg or placebo, a clear reduction in postoperative emesis was observed amongst those administered ondansetron.[17] However, amongst the three doses of ondansetron evaluated, two of which were below the dose range used in our study, higher doses were not associated with a greater reduction in emesis. Similar results were found in a study that included 130 children undergoing sedation for ambulatory surgery who were randomized to receive placebo or intravenous ondansetron 0.01 mg/kg, 0.05 mg/kg, or 0.10 mg/kg.[19] Those who received the active medication vomited less frequently; however, the authors found that while a dose of 0.05 mg/kg was effective, increasing the dose to 0.10 mg/kg did not significantly reduce the frequency of emesis further. Additionally, amongst children undergoing strabismus surgery, the prophylactic use of intravenous ondansetron at a dose of 0.075 mg/kg was as effective as 0.15 mg/kg in preventing post-operative nausea and vomiting.[18] The discrepancy between the relatively low, yet effective, doses of ondansetron in the management of acute vomiting in children with gastroenteritis or post-surgery relative to the high doses required to control emesis in children undergoing chemotherapy needs attention; we speculate that this is due to a tachyphylaxis phenomenon (the rapid decrease in the response to a drug after repeated doses over a short period of time). Most
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Episodes of diarrhea in ED/h

r = 0.062 p = 0.52

0 0.10 0.15 0.20 Ondansetron dose (mg/kg) 0.25 0.30

Fig. 4. Linear regression analysis correlation between the dose of ondansetron (mg/kg) and the number of diarrheal episodes per hour during Emergency Department (ED) stay.
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leukemia and solid tumor treatment regimens include high doses of highly emetogenic chemotherapy agents that are typically administered over several weeks, in recurring treatment cycles. In a study of chemotherapy-naive children undergoing their first chemotherapy course, the use of low-dose intravenous ondansetron (0.15 mg/kg every 4 hours for four doses) was found to be as effective as the administration of a single high dose (0.6 mg/kg).[16] However, there is evidence that skipping a day of 5-HT3 antagonist therapy does not worsen delayed chemotherapy-induced nausea and vomiting, and may even reduce it by avoiding the development of tachyphylaxis to these antiemetic agents.[23] This is postulated to occur because of the continuous administration of a 5-HT3 antagonist, which subsequently results in the development of tolerance and receptor down-regulation and reduced effectiveness.[23] This phenomenon would not occur in children with acute gastroenteritis who are typically administered only a single dose of ondansetron.
Study Limitations

Acknowledgments
This study was accepted for presentation at the 2009 Pediatric Academic Society Annual Meeting, Baltimore, MD, USA, May 2009, and the Canadian Pediatric Society 86th Annual Conference, Ottawa, ON, Canada, June 2009. No sources of funding were used to conduct this study or prepare this manuscript. Dr Stephen Freedman receives research funding from Institut Rosell Lallemand Inc. Previous research support (2003) was provided by GlaxoSmithKline to Drs Freedman and Powell. None of the authors have any potential conflicts of interest to declare.

References
1. Black RE, Morris SS, Bryce J. Where and why are 10 million children dying every year? Lancet 2003; 361: 2226-34 2. King CK, Glass R, Bresee JS, et al. Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy. MMWR Recomm Rep 2003; 52: 1-16 3. Forster J, Guarino A, Parez N, et al. Hospital-based surveillance to estimate the burden of rotavirus gastroenteritis among European children younger than 5 years of age. Pediatrics 2009; 123: e393-400 4. Mast TC, DeMuro-Mercon C, Kelly CM, et al. The impact of rotavirus gastroenteritis on the family. BMC Pediatrics 2009; 9: 11 5. Pascicha PJ. Prokinetic and antiemetic drugs. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilmans the pharmacological basis of therapeutics. 10th ed. Toronto (ON): McGraw-Hill Companies, Inc., 2001: 1029-33 6. Freedman SB, Adler M, Seshadri R, et al. Oral ondansetron for gastroenteritis in a pediatric emergency department. New Engl J Med 2006; 354: 1698-705 7. Ramsook C, Sahagun-Carreon I, Kozinetz CA, et al. A randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis. Ann Emerg Med 2002; 39: 397-403 8. Reeves JJ, Shannon MW, Fleisher GR. Ondansetron decreases vomiting associated with acute gastroenteritis: a randomized, controlled trial. Pediatrics 2002; 109: e62 9. Roslund G, Hepps TS, McQuillen KK. The role of oral ondansetron in children with vomiting as a result of acute gastritis/gastroenteritis who have failed oral rehydration therapy: a randomized controlled trial. Ann Emerg Med 2008; 52: 22-9 10. Stork CM, Brown KM, Reilly TH, et al. Emergency department treatment of viral gastritis using intravenous ondansetron or dexamethasone in children. Acad Emerg Med 2006; 13: 1027-33 11. Cubeddu LX, Trujillo LM, Talmaciu I, et al. Antiemetic activity of ondansetron in acute gastroenteritis. Aliment Pharmacol Ther 1997; 11: 185-91 12. DeCamp LR, Byerley JS, Doshi N, et al. Use of antiemetic agents in acute gastroenteritis: a systematic review and meta-analysis. Arch Pediatr Adolesc Med 2008; 162: 858-65 13. Manteuffel J. Use of antiemetics in children with acute gastroenteritis: are they safe and effective? J Emerg Trauma Shock 2009; 2: 3-5 14. Levine DA. Antiemetics for acute gastroenteritis in children. Curr Opin Pediatr 2009; 21: 294-8 15. Leung AK, Robson WL. Acute gastroenteritis in children: role of anti-emetic medication for gastroenteritis-related vomiting. Paediatr Drugs 2007; 9: 175-84 16. Sandoval C, Corbi D, Strobino B, et al. Randomized double-blind comparison of single high-dose ondansetron and multiple standard-dose ondansetron in chemotherapy-naive pediatric oncology patients. Cancer Invest 1999; 17: 309-13 17. Lawhorn CD, Kymer PJ, Stewart FC, et al. Ondansetron dose response curve in high-risk pediatric patients. J Clin Anesth 1997; 9: 637-42
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This was an unplanned observational study nested within a previously conducted clinical trial, resulting in a lack of clearly distinct dosage groups. It would have been ideal if there were two groups of children who received doses that were significantly different, providing a greater dosage range and nonoverlapping margins. As a result, our conclusions cannot definitively rule out any dose-response relationship, which may have been apparent if a high-dose spectrum, including doses that are used in oncology patients (0.6 mg/kg), were evaluated. However, our dose range was, in fact, relevant to our target population of patients with gastroenteritis, and as large as that employed in several prospective clinical trials of ondansetron conducted on patients undergoing surgical procedures.[17,18] Additionally, we analyzed numerous variables and found no evidence of a dose-response relationship for any of them. Conclusions We found that within the dose range of 0.130.26 mg/kg, higher doses of oral ondansetron were not superior to lower doses in preventing emesis and improving the success of oral rehydration therapy in otherwise healthy children with vomiting and dehydration secondary to acute gastroenteritis. It was, however, reassuring to note that higher doses were not associated with increased side effects. Thus, the continued use of ondansetron in this dose range to prevent emesis in children with acute gastroenteritis is appropriate.
2010 Adis Data Information BV. All rights reserved.

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18. Sadhasivam S, Shende D, Madan R. Prophylactic ondansetron in prevention of postoperative nausea and vomiting following pediatric strabismus surgery: a dose-response study. Anesthesiology 2000; 92: 1035-42 19. Watcha MF, Bras PJ, Cieslak GD, et al. The dose-response relationship of ondansetron in preventing postoperative emesis in pediatric patients undergoing ambulatory surgery. Anesthesiology 1995; 82: 47-52 20. Hasler SB, Hirt A, Ridolfi Luethy A, et al. Safety of ondansetron loading doses in children with cancer. Support Care Cancer 2008; 16: 469-75 21. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24: 2932-47 22. Seynaeve C, Schuller J, Buser K, et al. Comparison of the anti-emetic efficacy of different doses of ondansetron, given as either a continuous infusion or a

single intravenous dose, in acute cisplatin-induced emesis: a multicentre, double-blind, randomised, parallel group study. Ondansetron Study Group. Br J Cancer 1992; 66: 192-7 23. Lajolo PP, del Giglio A. Skipping day 2 antiemetic medications may improve chemotherapy induced delayed nausea and vomiting control: results of two pilot phase II trials. Support Care Cancer 2007; 15: 343-6

Correspondence: Dr Yaron Finkelstein, Division of Pediatric Emergency Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail: yaron.finkelstein@sickkids.ca

2010 Adis Data Information BV. All rights reserved.

Pediatr Drugs 2010; 12 (6)

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