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original article
a bs t r ac t
Background
From the Division of Pediatric Emergency Vomiting limits the success of oral rehydration in children with gastroenteritis. We
Medicine, Hospital for Sick Children, Uni- conducted a double-blind trial to determine whether a single oral dose of ondanse-
versity of Toronto, Toronto (S.B.F.); the
Division of Pediatric Emergency Medicine tron, an antiemetic, would improve outcomes in children with gastroenteritis.
(M.A., E.C.P.) and the Mary Ann and
J. Milburn Smith Child Health Research Methods
Program (R.S.), Children’s Memorial Re-
search Center, Children’s Memorial Hospi- We enrolled 215 children 6 months through 10 years of age who were treated in a
tal, Chicago; and the Departments of Pedi- pediatric emergency department for gastroenteritis and dehydration. After being ran-
atrics (M.A., R.S., E.C.P.) and Preventive domly assigned to treatment with orally disintegrating ondansetron tablets or placebo,
Medicine (R.S.), Feinberg School of Medi-
cine, Northwestern University, Chicago. the children received oral-rehydration therapy according to a standardized proto-
Address reprint requests to Dr. Freedman col. The primary outcome was the proportion who vomited while receiving oral
at the Division of Pediatric Emergency rehydration. The secondary outcomes were the number of episodes of vomiting and
Medicine, Hospital for Sick Children, 555
University Ave., Toronto ON M5G 1X8, the proportions who were treated with intravenous rehydration or hospitalized.
Canada, or at stephen.freedman@
sickkids.ca. Results
N Engl J Med 2006;354:1698-705. As compared with children who received placebo, children who received ondanse-
Copyright © 2006 Massachusetts Medical Society. tron were less likely to vomit (14 percent vs. 35 percent; relative risk, 0.40; 95 percent
confidence interval, 0.26 to 0.61), vomited less often (mean number of episodes per
child, 0.18 vs. 0.65; P<0.001), had greater oral intake (239 ml vs. 196 ml, P = 0.001),
and were less likely to be treated by intravenous rehydration (14 percent vs. 31 per-
cent; relative risk, 0.46; 95 percent confidence interval, 0.26 to 0.79). Although the
mean length of stay in the emergency department was reduced by 12 percent in the
ondansetron group, as compared with the placebo group (P = 0.02), the rates of hospi-
talization (4 percent and 5 percent, respectively; P = 1.00) and of return visits to the
emergency department (19 percent and 22 percent, P = 0.73) did not differ signifi-
cantly between groups.
Conclusions
In children with gastroenteritis and dehydration, a single dose of oral ondansetron
reduces vomiting and facilitates oral rehydration and may thus be well suited for use
in the emergency department.
I
n the united states, gastroenteritis the study, a research assistant was contacted. Re-
accounts for more than 1.5 million pediatric search assistants were on call from 8 a.m. until
outpatient visits and 200,000 hospitalizations midnight, and overnight coverage was provided
annually.1 Although oral-rehydration therapy is by the principal investigator. A log was kept of
recommended for children with mild-to-moder- all children asked to enroll in the study, and any
ate dehydration,1 it remains underused. Clinicians reasons for refusal were recorded. Written in-
who provide care in emergency departments are formed consent was obtained from the parents
more likely to choose intravenous over oral rehy- or guardians of all children. All 33 supervising
dration when vomiting is a major symptom.2 In physicians working in the emergency department
one survey, 36 percent of pediatricians reported participated in screening, and 10 research assis-
that vomiting was a contraindication to oral rehy- tants were involved in the project.
dration.3 Thus, a safe and effective method of con- A baseline dehydration score (Table 1) was
trolling vomiting is likely to increase the use and assigned to all children. The score could range
success rate of oral rehydration. from 6 to 21, with higher scores indicating more
In a previous study of oral ondansetron (Zofran, severe dehydration. Children under 24 months
GlaxoSmithKline) in children with gastroenteritis, of age were evaluated for all seven items used to
six doses of oral elixir or placebo were admin- determine the score, and those 24 months of age
istered over a period of 48 hours.4 Although vom- or older were evaluated for six (their ability to
iting was reduced among children receiving on- produce tears was not evaluated).7-14 It was de-
dansetron in the emergency department, the rates termined a priori that children under 24 months
of diarrhea and return visits to the emergency
department were increased.4 We conducted a study
to determine whether the administration of a single Table 1. Dehydration Score.*
orally disintegrating ondansetron tablet to chil- Normal or Mild Moderate Severe
dren with vomiting and dehydration as a result of Dehydration Dehydration Dehydration
gastroenteritis would control vomiting with mini- Variable (1 Point) (2 Points) (3 Points)
mal side effects. Pinch-retraction Immediate Slow (≤2 sec) Very slow
time† (>2 sec)
of age with scores of 10 to 17 and those 24 months the protocol specified the administration of 20-ml
of age or older with scores of 8 to 15 would be boluses of 0.9 percent normal saline per kilo-
considered to have mild-to-moderate dehydration gram of body weight, each given over a period of
and to be in need of rehydration. For analysis, 30 minutes.
dehydration scores for children 24 months of age
or older were standardized so that they were on Follow-up
the same scale as those for children under 24 On days 3 and 7 after randomization, a research
months of age. assistant telephoned the child’s family and asked,
using a standard script, whether the child had re-
Randomization turned to an emergency department, had received
The patients were randomly assigned in blocks of intravenous-fluid treatment, had had any addi-
six to receive ondansetron or placebo and were tional symptoms, or had been hospitalized. The
stratified according to the dose of medication. An records of Children’s Memorial Hospital were
independent statistician provided the code to the reviewed to confirm caregivers’ reports. If the re-
pharmacy, which dispensed in an opaque bag a search assistant was unable to reach a caregiver on
weight-appropriate dose of active drug or a pla- the designated day, attempts were continued daily
cebo of similar taste and appearance. The weight- for two weeks after enrollment of the child.
based dose was 2 mg for children weighing 8 to
15 kg, 4 mg for children weighing more than Outcome Measures
15 kg and up to 30 kg, and 8 mg for children The primary outcome was the proportion of chil-
weighing more than 30 kg. GlaxoSmithKline sup- dren in each group who vomited while receiving
plied the tablets but had no role in the conception, oral-rehydration therapy. A vomiting episode was
design, or conduct of the study or in the analysis recorded by the research assistant when the force-
or interpretation of the data. ful expulsion of stomach contents occurred. Epi-
sodes separated by no more than two minutes were
Study Intervention counted as a single episode. Nonproductive retch-
The bedside nurse administered the medication ing, spilling of oral contents, and drooling were
while the research assistant was outside the room not considered vomiting. The secondary outcomes
to ensure that the research assistant, physician, were the number of episodes of vomiting during
child, and caregivers remained unaware of the oral-rehydration therapy and the rates of intrave-
treatment assignment. A tablet was placed on the nous rehydration and hospitalization.
top of each child’s tongue, and the child was in-
structed to swallow five seconds later. Children who Adverse Events
were unable to adhere to these instructions were The research assistant, treating physician, and
assisted by the nurse until they swallowed. Since the nurses monitored patients for adverse events from
tablet dissolves in seconds and does not require the enrollment to disposition from the emergency
coadministration of liquids, aspiration was not con- department. A treatment-related adverse event was
sidered to be a risk. Children who vomited within 15 one considered by at least two of the three phy-
minutes after receiving the medication were giv- sician investigators to be possibly, probably, or
en a second dose. A 1-hour period of intense definitely related to the study drug. Although a
oral rehydration was initiated 15 minutes after significantly increased frequency of diarrhea in
administration of the medication; the oral rehy- the emergency department was considered an
dration period then continued until disposition adverse event, generalized symptoms related to
was determined (i.e., whether the child was ad- the underlying illness (fever, vomiting after dis-
mitted or sent home). In keeping with the World charge, diarrhea, or fatigue) were not considered to
Health Organization (WHO) recommendations be adverse events. A data and safety monitoring
on oral rehydration, the caregivers were instruct- board reviewed adverse outcomes in a blinded
ed to limit the amount of fluid given to 30 ml of fashion.
oral electrolyte solution (Enfalyte, Mead Johnson
Nutritionals) every five minutes.15 After the oral- Statistical Analysis
rehydration period was completed, the treating We estimated that the enrollment of 214 children
physician resumed management. If the treating would provide the study with a statistical power
physician chose to administer intravenous fluids, of 90 percent to detect a change from 35 percent
cians (Fig. 1). One child did not meet the criteria
Table 2. Baseline Characteristics of the Patients.*
for dehydration after evaluation by the research
Ondansetron Placebo Group assistant, and one child was withdrawn by the
Characteristic Group (N = 107) (N = 107) supervising physician because of severe dehy-
Male sex — no. (%) 60 (56) 62 (58) dration. The caregivers of 26 children declined
Age — mo 26±21 30±20 to participate. A total of 215 children were ran-
Weight — kg 13.1±5.3 13.7±5.5 domly assigned to treatment, 108 to ondansetron
Heart rate — beats/min 141±20 140±17 and 107 to placebo. There were no significant dif-
ferences in baseline characteristics between the
Dehydration score — no. (%)†
groups (Table 2).
9–10 29 (27) 24 (22)
Three children in the ondansetron group were
11–12 51 (48) 58 (54) withdrawn before receiving study medication.
13–14 20 (19) 20 (19) Database analysis revealed that one child in the
15–16 7 (7) 5 (5) placebo group did not meet the eligibility crite-
Urinary measurements‡ ria. The only patient whose data were not ana-
Specific gravity 1.026±0.007 1.025±0.006
lyzed was a child who was accidentally assigned
to ondansetron before parental consent had been
Ketones 2.6±1.6 2.6±1.5
obtained and whose family chose not to par-
Vomiting — no. of episodes in preceding 9.0±6.0 9.3±6.8 ticipate.
24 hr
Five children who received ondansetron vom-
Diarrhea — no. of episodes in preceding 5.8±4.5 6.2±5.2
24 hr ited within 15 minutes. Each of these children was
given a second dose, which was tolerated. Three
Serum values at catheterization§
children who received placebo vomited within
Sodium — mmol/liter 138.8±6.7 136.8±2.9
15 minutes. The parents of two of these children
Potassium — mmol/liter 4.2±0.5 4.1±0.5 refused to allow a second dose to be given; the
Bicarbonate — mmol/liter 17.1±3.4 17.5±3.2 remaining child was given a second dose, which
Blood urea nitrogen — mg/dl 16.4±10.0 18.3±6.4 was tolerated.
Creatinine — mg/dl 0.49±0.12 0.54±0.14
Outcome
Glucose — mg/dl 91±24 92±24
Of the 107 children in each group whose data
* Plus–minus values are means ±SD. There were no significant differences be- were analyzed, 15 who received ondansetron vom-
tween the groups. ited while receiving oral-rehydration therapy, as
† Higher values indicate more severe dehydration.
‡ A total of 100 urine samples were obtained for analysis. Urinary ketone values
compared with 37 who received placebo (14 per-
are reported as 0 to 4+, with higher values indicating increasing ketonuria. cent vs. 35 percent, P<0.001) (Table 3). After ad-
§ The measurements were performed on serum samples obtained at the time justment for the type of physician providing care,
of insertion of the intravenous catheter in 48 patients (15 in the ondansetron
group and 33 in the placebo group). To convert values for blood urea nitrogen
the relative risk was 0.40 (95 percent confidence
to millimoles per liter, multiply by 0.357. To convert values for creatinine to interval, 0.26 to 0.61). The mean number of epi-
millimoles per liter, multiply by 88.4. To convert values for glucose to milli- sodes of vomiting was significantly lower among
moles per liter, multiply by 0.05551.
children who received ondansetron than among
those who received placebo (0.18 vs. 0.65, P<0.001).
Relative risks and 95 percent confidence in- This difference remained significant after ad-
tervals are presented for all results. Analyses were justment for the type of physician providing care
performed with SAS software (version 9.1) accord- (relative risk, 0.30; 95 percent confidence inter-
ing to the intention-to-treat principle. All P values val, 0.18 to 0.50).
are two-sided, with a P value of less than 0.05 used Fifteen children in the ondansetron group (14
to indicate statistical significance, without ad- percent) and 33 in the placebo group (31 percent)
justment for multiple comparisons. received intravenous rehydration (P = 0.003). The
interaction effect between treatment group and
R e sult s whether a child vomited was significant (P = 0.009);
thus, separate models were used for children who
Participants vomited and those who did not. Among the 92
During the study period, 243 potentially eligible children in the ondansetron group and the 70 chil-
patients were identified by the supervising physi- dren in the placebo group who did not vomit, in-
travenous hydration was less common in the on- was well tolerated and resulted in a reduction of
dansetron group (5 percent vs. 17 percent; P = 0.01; more than 50 percent in both the proportion of
relative risk, 0.32; 95 percent confidence inter- children who vomited during oral rehydration
val, 0.13 to 0.77). Although, overall, children in and the proportion treated with intravenous flu-
the ondansetron group received a larger volume ids. As compared with children who received pla-
of oral-rehydration fluid and a smaller volume cebo, children who received ondansetron had few-
of intravenous fluid and had a shorter stay in the er episodes of vomiting, greater oral intake of
emergency department, hospital admission rates fluids, and a shorter stay in the emergency de-
were similar in the two groups. partment.
To prevent vomiting in 1 child, 5 children had
Adverse Events to receive ondansetron (95 percent confidence
No cardiovascular or respiratory events occurred. interval, 3.2 to 10.6); to prevent 1 child from hav-
Urticaria developed in one child in the placebo ing to be treated by intravenous rehydration, 6 had
group. Children who received ondansetron had to receive ondansetron (95 percent confidence
more episodes of diarrhea while undergoing oral interval, 3.6 to 17.0). These benefits were also re-
rehydration than those who received placebo (1.4 ported in a previous study, which found that the
vs. 0.5, P<0.001), even after adjustment for the administration of liquid ondansetron three times
number of episodes occurring before arrival. Fol- daily for two days reduced vomiting in the emer-
low-up, which was completed for 96 percent of gency department, the use of intravenous fluids,
the children (Table 4), did not reveal any additional and the need for hospitalization among children.4
adverse events. Kawasaki’s disease was diagnosed However, that study did not report a reduction in
in one child in the ondansetron group six days vomiting after discharge, and children who were
after randomization. The disease was not attrib- given ondansetron had significantly more episodes
uted to treatment. of diarrhea and return visits to the emergency
department. We found that a single dose of oral
Dis cus sion ondansetron reduced vomiting and the need for
intravenous fluids without any clinically signifi-
We found that a single dose of ondansetron im- cant adverse events.
proves the success of oral rehydration in dehy- Although there are no established criteria in-
drated children with gastroenteritis. The oral dose dicative of a need for intravenous rehydration, we
characteristics in order to identify children with tion therapy might have been deemed successful
evidence of dehydration. The dehydration score in some of the children in whom it was consid-
was successful in this regard, since the ratio of ered to have failed if they had been observed for
blood urea nitrogen to creatinine exceeded 20 in four hours, as recommended by the WHO.15
96 percent of the children who underwent veni- We found that treatment with orally disinte-
puncture. A similar result was obtained in a previ- grating ondansetron tablets was beneficial in
ous study of intravenous rehydration: 82 percent children with vomiting and dehydration due to
of the children had a ratio of blood urea nitrogen gastroenteritis. The ondansetron tablet is easy
to creatinine of more than 20.19 to administer, has few side effects, and is safe
We chose not to use the WHO classification and effective. Therefore, it may be a useful thera-
of dehydration (no dehydration, some dehydra- py in the emergency department for children with
tion, and severe dehydration),15 because it does vomiting and mild-to-moderate dehydration as a
not work well as a research tool in settings in result of gastroenteritis.
which very few children are severely dehydrated. Supported by grants from the National Center for Research
Resources of the National Institutes of Health (M01 RR-00048)
It would not have allowed us to distinguish chil- and from GlaxoSmithKline.
dren with some dehydration who needed only No potential conflict of interest relevant to this article was
reassurance and minimal rehydration from chil- reported.
dren with some dehydration who required rehy- We are indebted to the emergency department nurses, clerical
staff, and physicians at Children’s Memorial Hospital for their
dration. assistance with patient recruitment and adherence to the proto-
The oral-rehydration period in the emergency col; to the pharmacy staff for promptly supplying the study medi-
department was limited to one hour to mimic cation; to the research assistants for their instrumental role in
patient enrollment; to Nancy Ryan for her administrative sup-
routine clinical practice, in which prolonged peri- port; and to Dr. Jennifer Thull-Freedman for her assistance
ods of observation are impractical. Oral-rehydra- throughout the study.
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