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Ondansetron Dosing in Pediatric GastroenteritisA 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, Children’s Memorial Hospital, and Department of Pediatrics, Northwestern University’s Feinber

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, Children’s 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,

thenumber of episodes of diarrhea was evaluatedto measure whether there were dose-dependent side effects.

Results: Participants were aged 0.5–8.2 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 0.13–0.26mg/ 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 mor-

bidity 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 community-

acquired 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 thei

child’s symptoms results in stress, fatigue, and frustration.[4]

Although the exact pathophysiologic process resulting in

emesis is incompletely understood, a major pathway involve

serotonin release in the stomach and small intestine.[5] Con

sequently, selective serotonin receptor (5-hydroxytryptamin

type 3 [5-HT3]) antagonists have been extensively studied. A re

cent advance in the treatment of pediatric gastroenteritis is th

option of administering ondansetron, a 5-HT3 antagonist tha

is completely and rapidly absorbed from the gastrointestina

ORIGINAL RESEARCH ARTICLE Pediatr Drugs 2010; 12 (6): 405-4

1174-5878/10/0006-0405/$49.95

ª 2010 Adis Data Information BV. All rights reserve



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, ondan-

setron, 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 re-

views of the management of acute gastroenteritis have suggested

ondansetron be used when treating children with vomitingsecondary 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 hypo-

thesis for this study was that higher doses of oral ondansetron

are not associated with greater antiemetic efficacy norincreased

diarrhea, amongst a group of otherwise healthy children who

presented to an ED with vomiting due to gastroenteritis.

Methods

Setting, Subjects, and Intervention

Between January 2004 and April 2005, data were pros-

pectively collected on children aged 6 months–10 years who

presented to the ED of the Children’s Memorial Hospital,Chicago, IL, USA, with acute gastroenteritis and dehydration,

and were administered an ondansetron ODT as part of a pros-

pective clinical trial evaluating the efficacy of ondansetron.[6]

Eligibility criteria were the presence of non-bilious and non-

bloody vomitus and diarrhea secondary to acute enteritis, as de-

termined 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 dehy-

dration, weight <8 kg, underlying disease that might affect the

assessment of hydration status, or a history of abdominal surgery.

Since the ondansetron ODT is only commercially availabl

in 4 and 8 mg doses, subjects received a weight-based dose of th

preparation: 2 mg for children weighing 8–15kg, 4 mg fo

children weighing more than 15 kgand up to30 kg, and 8 mgfochildren weighing more than 30 kg. All children initially under

went a 60-minute oral rehydration therapy trial according t

a standard protocol[6] and were administered a single oral re

hydration solution (Enfalyte; Mead Johnson Nutritionals

Evansville, IN, USA). This study was approved by the Child

ren’s Memorial Hospital Institutional Review Board.

Outcomes

The primary outcome was the correlation between the dose o

ondansetron andthesuccess of oral rehydration therapy defined b

the volume of oral rehydration fluid consumed (mL/ kg/ h), percen

weight gain, and the frequency of vomiting. Secondary outcome

were the frequency of diarrhea, ongoing vomiting (dichotomou

variable), and the need for intravenous rehydration or hospital

ization following ondansetron administration.[7] To determine i

the length of stay played a role in weight gain, we additionall

evaluated the percent weight gain per hour of treatment in the ED

Standardized Patient Assessment and Data Collection

Datacollection forms werecompleted prospectively by traine

research nurses. Historical elements included the number oepisodes of vomiting and diarrhea in the proceeding 24 hours

age, sex, race, weight, presence of fever, frequency of urine out

put, andtime of initiation of oral rehydrationtherapy. A clinica

dehydration assessment was performed, as has been previousl

described.[6] Variables collected during ED treatment include

volume of oral rehydration fluids consumed, weight gain, an

number of episodes of diarrhea and vomiting. All data abstrac

tion and telephone follow-up were performed by a researc

assistant blinded to the dose of ondansetron administered.

Power Calculations

Since this analysis employed data collected on a fixed sampl

size of 105 patients, sample size calculations were not per

formed. A power calculation determined that our sample siz

has 88% power to detect a correlation as small as 0.30 using

two-sided hypothesis test with significance set at 0.05.

Data Analysis

As outcomes of efficacy, the volume of oral rehydratio

solution consumed (mL/ kg/ h), percent weight gain, and percen

406 Freedman et a

ª 2010 Adis Data Information BV. All rights reserved. Pediatr Drugs 2010; 12 (



weight gain per hour of ED treatment were analyzed as con-

tinuous variables employing Pearson’s correlation coefficient.

The correlation between the frequency of vomiting while in

the ED and the dose of ondansetron administered was calcu-lated using Kendall’s tau rank correlation coefficient as a non-

parametric 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 Pearson’s correlation coefficient. The re-

lationship between the dose of ondansetron administered and

the outcomes of vomiting, intravenous rehydration, and hos-

pitalization 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].

Results

One hundred and five children (59 males) met the study eli-

gibility 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

0.13–0.26 mg/ kg).

Dose-Response Analysis

The dose of ondansetron administered (mg/ kg) was not

statistically associated with any of the pre-defined five para-

meters of efficacy that were evaluated. These included the

volume of oral rehydration fluids (mL/ kg/ h) consumed (co-

efficient of correlation r=-0.088; p =0.36) [figure 1], or percen

weight gain (r =-0.002; p= 0.98) [figure 2]. Overall, 88% o

study subjects (92/ 105) experienced no vomiting episodes, an

there was no evidence of a dose-response relationship between

those who vomited and those who did not or the frequenc

of vomiting during oral rehydration therapy in the ED

(tau=0.093; p= 0.24) [figure 3]. When weight change was analyze

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 non

linear relationships between the dependent and independen

variables included in the study.

The dose of ondansetron administered was not correlated t

the frequency of diarrheal episodes (standardized per hour

during ED stay (r= 0.062; p= 0.52) [figure 4]. No severe advers

effects of ondansetron (arrhythmias, hypersensitivity reaction

extrapyramidal reactions, liver failure, or pancreatitis) wer

seen during the ED treatment period nor reported during tele

phone follow-up 1 week later.The mean dose of ondansetron amongst children who di

not receive intravenous rehydration was 0.20– 0.03 mg/ k

compared with 0.21 – 0.03 mg/ kg amongst those who receive

intravenous rehydration (p = 0.12). The mean doses of ondan

setron were nearly identical amongst those hospitalized an

those who were discharged (0.20– 0.02 vs 0.20 –0.03 mg/ kg

respectively; p= 0.95). Lastly, the mean dose of ondansetro

was similar amongst those who had ongoing vomitin

(0.21– 0.03 mg/ kg) and those who did not (0.20 –0.03 mg/ kg

p =0.38).

0.150.10

0

5

10

15

O r a l r e h y d r a t i o n f l u i d s

( m L / k g / h )

20

25

30

0.20

Ondansetron dose (mg/kg)

0.25 0.30

r = −0.088p = 0.36

Fig. 1. Linearregressionanalysis betweenthe doseof ondansetron(mg/ kg)

and the volume of oral rehydration fluids consumed (mL/ kg/ h).

0.150.10

−5.0

10.0

5.0

0 P e r c e n t w e i g h t c h a n g e

15.0

0.20


0.25 0.30

r = −0.002

p = 0.98

Fig. 2. Linearregressionanalysis betweenthe doseof ondansetron(mg/ kg

and percent weight gain during Emergency Department oral rehydratio

therapy {([final weight – initial weight]/ final weight)·100}.

Dose Response of Ondansetron in Children 40




Discussion

To the best of our knowledge, this is the first study to eval-

uate the dose response of ondansetron amongst children with

acute gastroenteritis. We found that higher doses of ondanse-

tron, within the studied and commonly accepted dose range,

were not associated with improved antiemetic efficacy. Chil-

dren who received higher doses of ondansetron did not expe-

rience 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 re-

ceived lower doses of ondansetron. The stability of the results

in all evaluated parameters supports the robustness of our con-

clusions. Additionally, it was reassuring to note that higher

doses were notassociated 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 pe-

diatric gastroenteritis of 0.10–0.15 mg/ kg,[6-10] while effective,

are significantly lower than those studied in pediatric oncology

patients.[16,20] The standard antiemetic dose in children under-going chemotherapy is 5 mg/ m2 (approximately 0.17 mg/ kg);

however, this dose is often felt to be insufficient in such chil-

dren.[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

16mg/ m2.[20] In adults, ondansetron loading doses of 32 mg

(approximately 0.4–0.5 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-

setron in pediatric gastroenteritis, as no added benefit in any o

the outcome parameters studied was detected amongst childre

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 childre

randomized to receive intravenous ondansetron 0.05 mg/ kg

0.10 mg/ kg, or 0.15 mg/ kg or placebo, a clear reduction in post

operative emesis was observed amongst those administere

ondansetron.[17] However, amongst the three doses of ondan

setron evaluated, two of which were below the dose range use

in our study, higher doses were not associated with a greate

reduction in emesis. Similar results were found in a study tha

included 130 children undergoing sedation for ambulator

surgery whowere randomized to receive placebo or intravenouondansetron 0.01 mg/ kg, 0.05 mg/ kg, or 0.10 mg/ kg.[19] Thos

who received the active medication vomited less frequently

however, the authors found that while a dose of 0.05 mg/ kg wa

effective, increasing the dose to 0.10mg/ kg did not significantl

reduce the frequency of emesis further. Additionally, amongs

children undergoing strabismus surgery, the prophylactic use o

intravenous ondansetron at a dose of 0.075 mg/ kg was as ef

fective as 0.15 mg/ kg in preventing post-operative nausea an

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 hig

doses required to control emesis in children undergoing chemo

therapy needs attention; we speculate that this is due to

tachyphylaxis phenomenon (the rapid decrease in the respons

to a drug after repeated doses over a short period of time). Mos

0.150.10

0

0.5

1.0

1.5

N o . o f E D

v o m i t i n g e p i s

o d e s

2.0

2.5

3.0

0.20


0.25 0.30

Fig. 3. Kendall’s 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).

0.150.10 0.20


0.25 0.3

0

1

2

3

E p i s o d e s o f d i a r r h e a i n E D / h 4

5

r = 0.062

p = 0.52

Fig. 4. Linear regression analysis correlation between the dose of ondan

setron (mg/ kg) and the number of diarrheal episodes per hour during Eme

gency Department (ED) stay.

408 Freedman et a




leukemia and solid tumor treatment regimens include high

doses of highly emetogenic chemotherapy agents that are typ-

ically administered over several weeks, in recurring treatment

cycles. In a study of chemotherapy-naive children undergoingtheir first chemotherapy course, the use of low-dose intra-

venous ondansetron (0.15mg/ 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 re-

ceptor down-regulation and reduced effectiveness.[23]

Thisphenomenon would not occur in children with acute gastro-

enteritis who are typically administered only a single dose of

ondansetron.

Study Limitations

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 sig-

nificantly different, providing a greater dosage range and non-

overlapping 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 0.13–0.26 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 vomit-

ing and dehydration secondary to acute gastroenteritis. It was,

however, reassuring to note that higher doses were not asso-

ciated with increased side effects. Thus, the continued use of

ondansetron in this dose range to prevent emesis in children

with acute gastroenteritis is appropriate.

Acknowledgments

This study was accepted for presentation at the 2009 Pediatric Ac

demic Society Annual Meeting, Baltimore, MD, USA, May 2009, an

the Canadian Pediatric Society 86th Annual Conference, Ottawa, ON

Canada, June 2009. No sources of funding were used to conduct this stud

or prepare this manuscript. Dr Stephen Freedman receives researc

funding from Institut Rosell Lallemand Inc. Previous research suppo

(2003) was provided by GlaxoSmithKline to Drs Freedman and Powe

None of the authors have any potential conflicts of interest to declare.

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E-mail: [email protected]

410 Freedman et a




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