Gord McNeil MD, FRCPC

Current recommendation for antiemetics in pediatric
acute gastroenteritis (AGE).

Use of oral replacement therapy in pediatric AGE.

Why is ondansetron different?

Review of literature on ondansetron use in AGE.

Review side effects and costs of ondansetron.

Should there be a new consensus statement on
ondansetron in pediatric AGE?

Bottom line

5 year old boy, previous well with vomiting X 3,
diarrhea X 2 in last 24 hours. Clinically looks well
with minimal dehydration.

3 yr old female with vomiting X 7 and diarrhea X
8 in last 24 hours who “vomits every time we
give her anything”. Mild to moderate
dehydration.

18 month old boy with profuse watery diarrhea,
greater then 30 times with vomit X 10, lethargy
and hemodynamic instability.

They have adopted the recommendations
from the CDC: Managing Acute
Gastroenteritis Among Children.1
 Recommend supportive care using oral replacement
therapy for mild-moderate dehydration but no
pharmacologic treatment for vomiting.

“Reliance on pharmacologic agents shifts the
therapeutic focus away from appropriate fluid,
electrolyte, and nutritional therapy, can result
in adverse events, and can add unnecessarily
to the economic cost of illness.”1

“ORT is as effective as, if not better than,
intravenous fluid therapy for rehydration of
moderately dehydrated children and this has been
confirmed by two recent meta-analyses.”2

“ORT is associated with significantly fewer major
adverse events and a shorter hospital stay
compared with intravenous therapy, and is
successful in most children. As such, ORT should
be the treatment of choice in children with mild or
moderate dehydration.”2

Although ORT is successful in over 95% of cases, there
are certain contraindications to the use of ORT. These
include:

Protracted vomiting despite small, frequent feeding.

Severe dehydration with a shock-like state.

Impaired consciousness.

Paralytic ileus and monosaccharide malabsorption. 2
Should anti-emetics be used in
the pediatric AGE population?

Most anti-emetics in pediatrics are considered to have too
many side effects and are not recommended in the
pediatric population:
 Side effects of metoclopermide, prochlorperazine,
diphenhydarmine can include significant sedation and
extrapyramidal effects.3

“Studies of anti-emetics agents other than ondansetron
had small sample sizes, were of low methodological
quality and produced inconsistent results. Based on the
available literature, antiemetic agents other than
ondansetron should not be used for outpatients with
gastroenteritis “3

While physiologic pathways leading to emesis are
complex and not fully understood, evidence has
shown that one pathway entails serotonin release in
the stomach and small intestine to trigger the emetic
response.

Ondansetron is a serotonin 5HT3 receptor antagonist
with no dopmaine antagonist activity and therefore it
is unlikely to cause extrapyramidal symptoms.

Proven safety for kids older than 1 month

Easy to administer -iv, oral, disintegrating tablets.
If ondansetron is really the only
antiemetic for the pediatric
population, does it work for
pediatric acute gastroenteritis
(AGE)?
Review of 3 meta-analysis

Antiemetics for reducing Vomiting Related To Acute
Gastroenteritis in Children and Adolescents(Review)4
 Reviewed 3 papers
 Paper 1Cubeddu LX. Antiemetic activity of ondansetron in Acute
Gastroenteritis. Alimentary Pharmacology and Therapeutics, 1997;11;185-915
▪ Treatment failures (more than 2 episodes of vomiting in 90
minutes within 4 hours of drug admission)
▪ 17% in ondansetron vs. 42% with metoclopermide
▪ 67% ondansetron had diarrhea, 83% in maxeran and 16.7% in
placebo

Paper 2 Ramsook C. A Randomized clinical trial comparing oral ondansetron
with Placebo. Annals Emergency Medicine 2002:39:397-4036
 Compared ondansetron vs. placebo in ED for 2 days.
 Fewer emetic episodes and more did not vomit at all in ED
(87% vs. 65% p-0.04).
 No statistical difference at 48 hours.
 Fewer admissions and shorter length of hospital stays, but
had a higher rate of return visits for either persistent
vomiting or persistent diarrhea and higher mean incidence of
diarrhea.

Paper 3 Oral Ondansetron for Gastroenteritis in a Pediatric Emergency
Department, Freedman et al,NEJM 2006;354;1698-7057
 Less likely to vomit: 14% vs. 35%, NNT= 5
 Vomited less: 0.18 vs. 0.65
 Less likely to get IVF: 14% vs. 31%, NNT = 6
 Rates of hospitalization and return visits to the ED were
the same.

“The small number of included trials provided
some, abeilt weak and unreliable evidence which
appear to favour the use of ondansetron and
metoclopermide over the placebo to reduce the
number of episodes of vomiting due to
gastroenteritis.”4

“The increased incidence of diarrhea noted both
ondansetron and metoclopermide was considered
to be as a result of retention of fluids and toxins
that would otherwise have been eliminated
through the process of vomiting.”4

Four RCTs - Cochrane paper plus Reeves et al
 Ondansetron decreased vomiting
▪ RR: 1.3, 95% confidence interval (CI): 1.2–1.5,
▪ Number needed to treat (NNT): 5, 95% CI: 4–8,
 This effect was not observed at 24 h
▪ (RR 1.2, 95% CI: 0.9–1.7).

Ondansetron significantly reduced the risk of
intravenous rehydration.
▪ (RR 0.4, 95% CI: 0.3–0.7, NNT 7, 95% CI: 5–14).

No change in rates of hospitalization and
return emergency department visits.

Despite some clinical benefits, there is
insufficient evidence to recommend the routine
use of ondansetron.

Meta- analysis of 11 studies - looking at different antiemetics including 6 papers on ondansetron in AGE of
which 5 were conducted in the ED.

Include 2 of the 3 papers from the Cochrane review
(removed the Cubeddu paper ) and added 3 more
Reeves et al (up to 22 years of age)
Roslund et al
Stork et al

All studies were completed with assistance from the
pharmaceutical company who makes ondansetron.

They came to some different conclusions….

Cessation of Vomiting:
 AR 16.9% vs 37.8% (95% CI 0.33 -0.62)
 NNT was 5 (95%CI, 4-7)

Intravenous Fluid Administration:
 Decrease in IVF 13.9% vs. 33.9% (RR0.41 95%CI=
0.28-0.62)
 NNT to prevent IVF was 5 (95% CI 4-8)

Hospital Admission:
 Decrease in risk of hospital admission at time of
ED visit.
 7.5% vs. 14.6% (RR=0.52 CI 0.27-0.95)
 NNT - 14 children would need to be treated with
ondansetron to prevent 1 child from being
admitted to the hospital at their visit to ED.
(95%CI, 9-44)

Return visit:
 5 studies 612 patients
 No difference between the ondansetron and
placebo (RR 1.34 95% CI 0.77-2.35)

Overall hospital admission rates:
 4 studies reported whether children discharged
from the ED were admitted during follow-up.
 The RR of admission at any point during the
illness, not just at initial presentation to the ED
was not significantly different between either
group.

Adverse effects:
 Diarrhea- Most studies found increase in diarrhea
within the first 48 hours after administration.
 No other adverse event was systematically
evaluated and no other adverse effects were
common across studies, but data was to variable
to be pooled to investigate.

“Less likely to have ongoing vomiting, to be
prescribed IVF and to be admitted to the
hospital from the ED.”3

“The symptomatic relief and avoidance of
invasive therapies are important outcomes
that suggest a benefit of ondansetron
treatment in moderately ill children with
gastroenteritis”3

“The results cannot be applied reliably to
clinicians in other settings and those caring for
children with milder disease.”3

“ Although there is currently no evidence that
children with mild gastroenteritis benefit from
treatment with ondansetron, government
agencies and professional societies should
strongly consider amending current
gastroenteritis treatment guidelines to
incorporate the use of ondansetron for certain
children with gastroenteritis.”3

Why doesn’t the overall return visits or
admission rate decline?

“The included studies demonstrate variability in
the effect of ondanestron to reduce the risk of
hospital admission and the compiled data
demonstrate that the ability of single dose
ondansetron in the ED to reduces admission wanes
across time. “3

“A possible explanation is that the overall clinical
course and severity of gastroenteritis are largely
determined by the underlying disease or child host
and are not necessarily altered by short term relief
of symptoms. In addition, an increase in diarrhea
due to ondansetron may contribute to later
dehydration.”3

Attitude to illness ?
 Take a pill – everything is better and go home.
“Oh no, the vomiting started again or the diarrhea
increased. Better go back to the ED.”
OR
 “They really didn’t do anything for me except
teach me about ORT and I can do that at home so
I won’t go back.”

1. Vomiting from AGE is a distressing
symptom for children and parents. I should
do something and give them some
ondansetron.

2. Pediatric gastroenteritis is most commonly
a benign self-limited disease that can be
treated with ORT and time. Anti- emetics
have a limited role.

Side effects:




CV: possible prolongation of the QT interval
GI: Constipation or diarrhea, abdominal pain
CNS: Headache -mild, lightheadedness
Hepatic: Transient increases of AST and ALT (not
dose or time related)
 Miscellaneous:- rash, bronchospasm, urticaria,
angioedema (rare), blurred vision: associated
with infusions of 30 mg in less than 15 minutes

Contraindications:
 -Hypersensitivity to ondansetron



8-15kg = 2mg
15-30 kg =4mg
>30 kg =8mg
Or

0.15mg -0.3mg/kg/ q8h

Ondansetron (generic) – out patient:
 4mg tabs po – 10 tabs – $93
 8mg tabs po– 10 tabs - $132

Zofran dissolving tabs (not generic) – out patient:


4mg tabs – 10 tabs - $155
8mg tabs – 10 tabs - $235

IV ondansetron (generic) – ACH pharmacy


4mg - $2.30 - $5.25
8mg - $4.58 – 10.50

5 year old boy, previous well with vomiting X 3,
diarrhea X 2 in last 24 hours. Clinically looks well
with minimal dehydration.

3 yr old female with vomiting X 7 and diarrhea X
8 in last 24 hours who “vomits every time we
give her anything”. Mild to moderate
dehydration.

18 month old boy with profuse watery diarrhea,
greater then 30 times with vomit X 10, lethargy
and hemodynamic instability.

Safe with few side effects and few contraindications
for patients >1 month and older.

Effectively reduces ongoing vomiting in pediatric
AGE.

May reduced IVF and admissions to hospital from the
ED.

There is not sufficient evidence to recommend the use
of ondanestron for pediatric GE in outpatient settings
or among children with mild disease.

Ondansetron works, but it is easily over
utilized.

It should never replace teaching parents how
to manage ORT.

Fewer lines and drugs, more teaching.

Severe dehydration – IV saline, ondansetron
and admit.

Moderate dehydration – Adequate trial of
ORT. If failure, then ondansetron and
potential for admission/close follow-up.

Mild dehydration – education of pediatric
AGE, the role of ORT and signs of severe
dehydration.
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
1. Managing Acute Gastroenteritis Among Children.
Oral Rehydration, Maintenance, and Nutritional Therapy . MMWR
Recommendations and Reports November 21, 2003 / 52(RR16);1-16

2. Oral rehydration therapy and early refeeding in the management of
childhood gastroenteritis. Nutrition Committee, Canadian Paediatric
Society (CPS).Paediatr Child Health 2006;11(8):527-31

3. Use of Antiemetic Agents in Acute Gastroenteritis. Decamp L,Arch
Pediatr Adolesc Med 2008;163(9):858-865

4. Antiemetics For Reducing Vomiting Related to Acute Gastroenteritis in
Children and Adolescents. (Review) Alhashimi D,Cochrane Database of
Systematic Reviews 2006, Issue 4. Art. No.: CD005506. DOI:
10.1002/14651858.CD005506.pub3.

5. Cubeddu LX, Trujillo LM, Talmaciu I; et al. Antiemetic activity of
ondansetron in acute gastroenteritis. Aliment Pharmacol Ther.
1997;11(1):185-191.

6. Ramsook C, Sahagun-Carreon I, Kozinetz CA, Moro-Sutherland
D. A randomized clinical trial comparing oral ondansetron with
placebo in children with vomiting from acute gastroenteritis. Ann
Emerg Med. 2002;39(4):397-403.

7. Freedman SB, Adler M, Seshadri R, Powell EC. Oral ondansetron
for gastroenteritis in a pediatric emergency department. N Engl J
Med. 2006;354(16):1698-1705.

8. Szajewska H, Gieruszczak-Bialek D, Dylag M. Meta-analysis:
ondansetron for vomiting in acute gastroenteritis in children.
Aliment Pharmacol Ther. 2007;25(4):393-400.

Stork CM, Brown KM, Reilly TH, Secreti L, Brown LH. Emergency
department treatment of viral gastritis using intravenous
ondansetron or dexamethasone in children. Acad Emerg Med.
2006;13(10):1027-1033.

Reeves JJ, Shannon MW, Fleisher GR. Ondansetron decreases
vomiting associated with acute gastroenteritis: a randomized,
controlled trial. Pediatrics. 2002;109(4)

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.
doi:10.1016/j.annemergmed.2007.09.010