Research

Original Investigation

Impact of Increasing Ondansetron Use on Clinical Outcomes

in Children With Gastroenteritis
Stephen B. Freedman, MDCM, MSc; Matt Hall, PhD; Samir S. Shah, MD, MSCE; Anupam B. Kharbanda, MD, MSc;
Paul L. Aronson, MD; Todd A. Florin, MD, MSCE; Rakesh D. Mistry, MD, MS; Charles G. Macias, MD, MPH;
Mark I. Neuman, MD, MPH

Editorial page 308

IMPORTANCE Ondansetron hydrochloride use in children with gastroenteritis is increasing Supplemental content at
rapidly; however, little is known about its impact on outcomes. jamapediatrics.com

OBJECTIVE To determine whether increasing emergency department ondansetron use has

resulted in a reduction in intravenous rehydration rates.

DESIGN, SETTING, AND PARTICIPANTS Retrospective observational analysis of eligible visits

included in the Pediatric Health Information System administrative database. Eligible
institutions included 18 emergency departments geographically distributed across the United
States, and participants included 804 000 patients aged 0 to 18 years who were diagnosed
as having gastroenteritis in an emergency department at an eligible participating institution
between January 1, 2002, and December 31, 2011.

INTERVENTIONS The presence or absence of oral ondansetron administration was identified

for each patient through database review. Visits were categorized based on institutional
ondansetron use: low (<5% administered ondansetron), medium (5%-25%), or high (>25%).

MAIN OUTCOMES AND MEASURES We conducted hospital-level analyses of the associations

between ondansetron use and 3 outcomes: intravenous rehydration (primary),
hospitalization, and emergency department revisits within 3 days. Time-series regression
models were used, adjusting for demographic characteristics, laboratory testing, diagnostic
imaging, and rotavirus infection.

RESULTS A total of 804 000 eligible patient visits were identified. Oral ondansetron use
increased from a median institutional rate of 0.11% (interquartile range, 0.04%-0.44%) of
patient visits in 2002 to 42.2% (interquartile range, 37.5%-49.1%) in 2011 (P < .001).
Intravenous rehydration was administered to 43 413 of 232 706 children (18.7%) during the
low ondansetron period compared with 59 450 of 334 264 (17.8%) during the high
ondansetron period (adjusted percentage change = −0.33%; 95% CI, −1.86% to 1.20%).
During the transition from low to high ondansetron use, we observed no change in the
hospitalization rate (adjusted percentage change = −0.33%; 95% CI, −0.95% to 0.29%), but
emergency department revisits decreased (adjusted percentage change = −0.31%; 95% CI,
−0.49% to −0.13%). The change in all 3 outcomes varied widely between low and high
ondansetron use categories at an institutional level. Oral ondansetron was provided to 13.5%
(95% CI, 13.3% to 13.7%) of children administered intravenous rehydration.

CONCLUSIONS AND RELEVANCE Although ondansetron use increased during the study period,
intravenous rehydration rates were unchanged. Most children administered intravenous
Author Affiliations: Author
fluids did not receive oral ondansetron. Our findings highlight the need to focus efforts to affiliations are listed at the end of this
administer ondansetron to children at greatest risk for oral rehydration failure. article.
Corresponding Author: Stephen B.
Freedman MDCM, MSc, Sections of
Emergency Medicine and
Gastroenterology, Department of
Pediatrics, Alberta Children’s Hospital
and Research Institute, University of
Calgary, 2888 Shaganappi Trail,
JAMA Pediatr. 2014;168(4):321-329. doi:10.1001/jamapediatrics.2013.4906 Calgary, AB T3B 6A8, Canada (stephen
Published online February 24, 2014. .freedman@albertahealthservices.ca).

321

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 Research Original Investigation
A
cute gastroenteritis (AGE) remains among the most
common illnesses for which children receive emer-
gency department (ED) care, accounting for more than
1.7 million ED visits each year.1 Treatment of AGE is dictated
by data supporting the equivalence of oral rehydration therapy
(ORT) and intravenous (IV) rehydration in moderately dehy-
drated children.2,3 Despite evidence supporting the use of ORT,
it remains underused, with 45% of physicians preferring IV re-
hydration over ORT in children with moderate dehydration.4,5
Vomiting, a key factor limiting the successful use of ORT,6
is present in approximately 70% of children with AGE.7 To po-
tentially overcome the impact vomiting has on the effective-
ness of ORT, clinical trials have evaluated the ability of ondan-
setron hydrochloride to optimize ORT success.8-10 Studies have
demonstrated efficacy of ondansetron in children with mild
to moderate dehydration who had initially failed ORT9,11 and
in those with multiple episodes of vomiting prior to ED
presentation.12 Although now administered to more than 50%
of children with AGE in US EDs,13 its administration is not rec-
ommended in guidelines endorsed by the American Acad-
emy of Pediatrics.14 There are concerns that indiscriminate use
may result in increased ED revisits, rates of misdiagnosis,15 and
health care costs. As ondansetron use has increased rapidly,15
an analysis of its effectiveness and potential for undesirable
consequences is warranted.16
Although randomized clinical trials (RCTs) have demon-
strated the efficacy (ie, the beneficial effects under optimal con-
ditions) of ondansetron use, its clinical effectiveness (ie, the
effects under real-world conditions)17 has only been evalu-
ated in a single-center study where use remained low.10 Thus,
we conducted a multicenter retrospective cohort study to de-
termine whether increasing ondansetron administration to
children with AGE is associated with a concomitant decline in
IV rehydration use.
Methods
Data Sources
Data for this time-trend, multicenter, retrospective cohort
study were obtained from the Pediatric Health Information Sys-
tem (PHIS). Participating hospitals, which provide resource uti-
lization data, are geographically dispersed across the United
States.13 Individual institutions provide deidentified data, along
with encrypted medical record numbers enabling the track-
ing of individual patients across hospital visits. The Chil-
dren’s Hospital Association, Overland Park, Kansas, and the
participating hospitals jointly ensure data quality.18 The Bos-
ton Children’s Hospital Institutional Review Board approved
this study with a waiver of informed consent given the study’s
retrospective design and large sample size.
Study Patients
Children who were younger than 18 years, treated in a partici-
pating ED between January 1, 2002, and December 31, 2011, and
diagnosed as having AGE based on their International Classi-
fication of Diseases, Ninth Revision primary discharge diagno-
sis code (eTable 1 in Supplement)18,19 were eligible. Children
322 JAMA Pediatrics April 2014 Volume 168, Number 4
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Ondansetron Use in Children With Gastroenteritis
with a primary diagnosis code of dehydration (276.51) were eli-
gible if they had a secondary diagnosis code for AGE. Chil-
dren transferred to the participating institution and those who
had a chronic comorbid condition (eg, malignant neoplasm,
sickle cell disease, epilepsy)19 were excluded. Hospital eligi-
bility required evidence of progression through an a priori–
defined range of ondansetron use (see Study Definitions and
Participant Characteristics). Hospitals that do not contribute
ED data and those that failed a standardized data quality evalu-
ation were excluded (eAppendix in Supplement).
Study Outcomes
The primary outcome was the proportion of children admin-
istered IV rehydration. Secondary outcomes included the pro-
portion of children hospitalized and the proportion experi-
encing an ED revisit within 3 days. We also evaluated the
proportion of children assigned a significant alternative diag-
nosis within 3 days and the changes in costs over time. Analy-
ses focused on differences between low and high ondanse-
tron use categories, with the medium use category serving as
an intervention introduction period enabling the conduct of
an interrupted time-series analysis.
Study Definitions and Participant Characteristics
The primary exposure was the administration of oral ondan-
setron. Receipt of IV rehydration was determined using bill-
ing codes (eTable 2 in Supplement). The exposure and out-
comes at each hospital were grouped into 3-month periods to
conduct time-series analysis. Because ondansetron use var-
ied by institution, instead of using an aggregated chronologi-
cal approach, each hospital served as its own control and was
evaluated through progression of increasing ondansetron use.
Thus, to reduce variability across hospitals and focus on the
impact of increasing ondansetron use, hospitals were in-
cluded only if they progressed through periods of low (<5% of
patients with AGE receiving ondansetron) to medium (5%-
25%) to high (>25%) ondansetron use. Category cut points were
selected based on the following: (1) extremely limited ondan-
setron use (<5%) prior to 2000; (2) the number needed to treat
to prevent 1 child from receiving IV rehydration (number
needed to treat = 5; 95% CI, 4-8)8; and (3) knowledge that ef-
ficacy studies may overestimate effectiveness by incorporat-
ing features maximizing the chance of finding a difference in
the shortest possible time at the lowest possible cost. Hence,
a significant increase in use may be required to see a clini-
cally significant reduction in IV rehydration rates.20 We de-
termined a priori that a 5-fold increase in ondansetron use
would be required to adequately evaluate changes in the out-
comes of interest. This would ensure adequate variation in on-
dansetron use and enable the establishment of a lag period,
which facilitates the detection of a change in outcomes in time-
series designs.10
Hospitalization was defined as admission to an observa-
tion (ie, short stay, 24 hours) or inpatient unit. For revisit out-
comes, a 3-day window, generally accepted as an ED quality
of care metric,21,22 was used because deterioration caused by
persistence or worsening AGE symptoms or that due to an al-
ternative diagnosis is expected to manifest within this pe-
jamapediatrics.com
 Ondansetron Use in Children With Gastroenteritis Original Investigation Research

Figure 1. Change Over Time in Gastroenteritis Emergency Department Visits, Ondansetron Use,
Intravenous Rehydration Rates, and Hospitalization at 18 Hospitals

45 6000
Ondansetron use
Ondansetron Use, IV Rehydration, and Hospitalized, %

IV rehydration
40
Hospitalized
Mean No. of patients 5000
35

30 4000

Mean No. of Patients

25
3000
20

15 2000

10
Unadjusted annual proportions of
1000
children administered ondansetron,
5
administered intravenous (IV)
rehydration, and hospitalized, and
0 0
the mean numbers of emergency
2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 department visits per site
Year contributing data during a given year
(shown as mean number of patients).

riod. Alternative diagnoses were specified a priori based on institutions (range, October 2003 to October 2010), this ap-
prior research (eTable 3 in Supplement).15 proach also adjusts for changes in outcomes over time that may
be due to other external unmeasured factors (eg, introduc-
Statistical Analysis tion of rotavirus vaccination). Analyses were repeated exclud-
Bivariate analyses were used to explore the relationships be- ing children younger than 6 months to remain consistent with
tween potential covariates and ondansetron use categories (ie, the inclusion criteria used in earlier RCTs.9,12
low vs high) with the Kruskal-Wallis test for continuous vari- All aggregated analyses were clustered by hospital to ac-
ables, χ2 test for nominal multicategorical variables, and Coch- count for the decreased variability within hospitals com-
ran-Armitage trend test for binary variables. Costs were ad- pared with between hospitals and to enable us to better un-
justed to 2012 US dollars using the medical component of the derstand the changes in outcomes between ondansetron use
Consumer Price Index and are presented as index visit costs categories (ie, low to high) at the institutional level. Statisti-
as well as bundled (index visit ± revisit ± revisit with admis- cal analyses were performed using SAS version 9.3 statistical
sion). We constructed piecewise linear regression on the mean software (SAS Institute, Inc). P < .05 was considered statisti-
number of AGE ED visits per participating site with a break point cally significant; missing values were not imputed (institu-
at 2006 to determine changing trends in volumes. We se- tions with data quality issues were excluded).
lected 2006 because this year represented the point at which
the overall ondansetron use rate (Figure 1) reached the a priori–
defined moderate use range.
Multiple time-series regression models23 were used to as-
Results
sess the associations, at the hospital level, of ondansetron use Forty-two freestanding children’s hospitals contributed data to
category with the primary and secondary outcomes adjust- PHIS during the study period. Ten were excluded owing to data
ing for potential confounding by observed baseline character- quality issues (eAppendix in Supplement) and 14 institutions
istics identified in bivariate analysis (ie, age, sex, race, sea- had an inadequate range of ondansetron use; 4 lacked a low use
son, admission time, prior visit for AGE, laboratory testing, period, 7 lacked low and medium use periods, and 3 did not have
diagnostic imaging, and rotavirus diagnosis), including qua- a high use period. The final cohort included 18 institutions and
dratic terms when significant. Models were constructed by 804 000 patient visits. The demographic characteristics of chil-
hospital and also in aggregate by weighting the proportional dren at these institutions did not materially differ from ex-
contribution of each institution to the total number of cluded sites (eTable 4 in Supplement). Children in the high
encounters.24 We assessed the likelihood, expressed in terms (>25%) ondansetron use category were older, less likely to have
of percentage change, of experiencing the outcomes of inter- a prior ED visit for AGE during the preceding 7 days, and more
est based on an institution’s ondansetron use category. A mul- likely to have a diagnostic imaging study performed (Table 1).
tiple time-series approach was used, with adjustments made Although there was a modest increase in the mean num-
for observed differences in patient population characteris- ber of AGE ED visits per participating site between 2002 and
tics, to reduce the potential for bias from unmeasured con- 2006 (P = .05), the number of visits stabilized between 2006
founders. Because the transition from low to medium to high and 2011 (P = .98) (Figure 1). Overall, oral ondansetron use in-
ondansetron use category occurred at different times for all creased from a median institutional rate of 0.11% (interquar-

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 Research Original Investigation Ondansetron Use in Children With Gastroenteritis

Table 1. Demographic Characteristics of Children With Gastroenteritis at 18 Sites

Ondansetron Use, No. (%)

Overall, No. (%) Low, <5% Medium, 5%-25% High, >25%
Characteristic (N = 804 000) (n = 232 706) (n = 237 030) (n = 334 264) P Value
Age, mean (SD), y 3.1 (3.9) 2.9 (3.8) 3.0 (3.9) 3.3 (4.0) <.001
Male 426 926 (53.1) 123 201 (52.9) 126 561 (53.4) 177 164 (53.0) .003
Race
Non-Hispanic white 253 841 (31.6) 71 778 (30.8) 65 666 (27.7) 116 397 (34.8)
Non-Hispanic black 186 416 (23.2) 58 574 (25.2) 52 648 (22.2) 75 194 (22.5)
Hispanic 262 058 (32.6) 68 118 (29.3) 79 921 (33.7) 114 019 (34.1) <.001
Asian 12 787 (1.6) 2529 (1.1) 4050 (1.7) 6208 (1.9)
Other 88 898 (11.1) 31 707 (13.6) 34 745 (14.7) 22 446 (6.7)
Payer
Government 202 881 (25.2) 52 580 (22.6) 61 565 (26.0) 88 736 (26.6)
Private 472 623 (58.8) 131 223 (56.4) 141 597 (59.7) 199 803 (59.8) <.001
Other 128 496 (16.0) 48 903 (21.0) 33 868 (14.3) 45 725 (13.7)
Census region
South 368 209 (45.8) 85 303 (36.7) 90 289 (38.1) 192 617 (57.6)
North Central 275 900 (34.3) 104 583 (44.9) 103 564 (43.7) 67 753 (20.3) <.001
West 159 891 (19.9) 42 820 (18.4) 43 177 (18.2) 73 894 (22.1)
Season
Spring 275 900 (34.3) 104 583 (44.9) 103 564 (43.7) 67 753 (20.3)
Summer 159 891 (19.9) 42 820 (18.4) 43 177 (18.2) 73 894 (22.1)
<.001
Fall 235 680 (29.3) 77 860 (33.5) 69 046 (29.1) 88 774 (26.6)
Winter 149 096 (18.5) 39 602 (17.0) 46 777 (19.7) 62 717 (18.8)
ED admission time
12 AM to 7:59 AM 180 658 (22.5) 43 229 (18.6) 52 647 (22.2) 84 782 (25.4)
8 AM to 3:59 PM 238 566 (29.7) 72 015 (31.0) 68 560 (28.9) 97 991 (29.3) <.001
4 PM to 11:59 PM 283 360 (35.2) 80 649 (34.7) 86 580 (36.5) 116 131 (34.7)
Rotavirusa 8761 (1.1) 3321 (1.43) 3116 (1.31) 2324 (0.7) <.001b
Prior AGE within 7 d 25 341 (3.2) 7360 (3.2) 8259 (3.5) 9722 (2.9) <.001b
Any prior visit within 7 d 61 946 (7.7) 18 117 (7.8) 19 009 (8.0) 24 820 (7.4) .07b
Any blood test performed 335 012 (41.7) 88 670 (38.1) 106 352 (44.9) 139 990 (41.9) <.001b
Any diagnostic imaging performed 128 264 (16.0) 30 576 (13.1) 39 004 (16.5) 58 684 (17.6) <.001b
Abdominal radiography 105 213 (13.1) 25 883 (11.1) 32 592 (13.8) 46 738 (14.0) <.001b
Abdominal ultrasonography 1821 (0.2) 327 (0.1) 525 (0.2) 969 (0.3) <.001b
Abdominal computed tomography 39 518 (4.9) 8211 (3.5) 11 364 (4.8) 19 943 (6.0) <.001b
ICU admission 1617 (0.2) 525 (0.2) 569 (0.2) 523 (0.2) <.001b

Abbreviations: AGE, acute gastroenteritis; ED, emergency department; ICU, intensive care unit.
a
International Classification of Diseases, Ninth Revision code 008.61 (enteritis due to a specified virus—rotavirus).
b
Cochran-Armitage trend test.

tile range, 0.04%-0.44%) of patient visits in 2002 to 42.2% (in-
terquartile range, 37.5%-49.1%) in 2011 (P < .001). At an
institutional level, use ranged from 1.3% in the low ondanse-
tron use category to 40.5% in the high category, representing
a 32-fold increase (P < .001) (Table 2). Overall, IV rehydration
was administered to 18.5% (95% CI, 18.4%-18.6%) of chil-
dren. While only 13.5% (95% CI, 13.3%-13.7%) of those admin-
istered IV rehydration received oral ondansetron, 54.1% (95%
CI, 53.8%-54.3%) received IV ondansetron.
The IV rehydration rates were lower during the high on-
dansetron use period compared with the low ondansetron use
period (17.8% vs 18.7%, respectively; mean difference = −0.9%;
95% CI, −0.7% to −1.1%) (Table 2). However, patients in the high
ondansetron use category had a higher rate of hospitalization
compared with children in the low ondansetron use category
(percentage change = 0.7%; 95% CI, 0.6% to 0.8%). Adjusted
median costs were higher in the high ondansetron use period
compared with the low use period (P < .001) but were greatest
during the medium use period. Further, children presenting
during the high ondansetron use period were less likely to re-
turn to the ED within 3 days after discharge (percentage
change = −0.7%; 95% CI, −0.6% to −0.8%) and to have a revisit
associated with hospitalization (percentage change = −0.4%;
95% CI, −0.4% to −0.5%). Among discharged children, the pro-
portion returning with a significant alternative diagnosis was
0.1% in all periods.

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 Ondansetron Use in Children With Gastroenteritis Original Investigation Research

Table 2. Treatment and Outcomesa

Ondansetron Use
Overall Low Medium High
Treatment or Outcome (N = 804 000) (n = 232 706) (n = 237 030) (n = 334 264)
Treatment, No. (%)
Ondansetron
Oral 178 016 (22.1) 2960 (1.3) 39 708 (16.8) 135 348 (40.5)
IV 80 436 (10.0) 14 113 (6.1) 29 076 (12.3) 37 247 (11.1)
Other antiemeticsb 13 839 (1.7) 5712 (2.5) 3890 (1.6) 4237 (1.3)
IV rehydration fluids 148 780 (18.5) 43 413 (18.7) 45 917 (19.4) 59 450 (17.8)
Admission to hospital, No. (%)
Inpatient or observation 53 460 (6.7) 13 839 (6.0) 17 365 (7.3) 22 256 (6.7)
Inpatient only 39 281 (4.9) 10 690 (4.6) 13 427 (5.7) 15 164 (4.5)
Observation only 14 179 (1.8) 3149 (1.4) 3938 (1.7) 7092 (2.1)
Total hospital costs, median (IQR), $c
All patients
Index visit 297 (165-585) 252 (136-492) 339 (165-643) 307 (186-606)
Episode of illnessd 315 (170-635) 260 (139-523) 349 (172-696) 325 (193-668)
Discharged patientse
Index visit 273 (155-496) 229 (130-431) 312 (154-542) 288 (181-514)
Episode of illnessd 289 (163-537) 241 (133-450) 330 (163-592) 300 (185-563)
Admitted patientsf
Index visit 3299 (2272-5199) 3022 (2089-4723) 3469 (2409-5393) 3352 (2293-5377)
Episode of illnessd 3373 (2303-5444) 3069 (2103-4841) 3549 (2436-5636) 3454 (2334-5668)
Revisit within 3 d, No. (%)g
Any 40 132 (5.4) 12 362 (5.7) 12 283 (5.6) 15 487 (5.0)
Limited to AGE ICD-9 codes 18 518 (2.5) 5835 (2.7) 5865 (2.7) 6818 (2.2)
Any with admission 11 282 (1.5) 3762 (1.7) 3554 (1.6) 3966 (1.3)
With admission limited to AGE ICD-9 codes 3067 (0.4) 1097 (0.5) 933 (0.4) 1037 (0.3)
d
Abbreviations: AGE, acute gastroenteritis; ED, emergency department; ICD-9, For episode of illness, total hospital costs are defined as all costs within 7 days
International Classification of Diseases, Ninth Revision; IQR, interquartile range; of the ED visit for gastroenteritis.
IV, intravenous. e
Refers to those who were discharged at the index visit. Such patients may
a
All P < .001 comparing all 3 categories of ondansetron use with the have had a repeated ED visit or hospitalization at a subsequent ED visit.
Kruskal-Wallis test for cost data and the Cochran-Armitage trend test for all f
Refers to those who were admitted at the index visit. Such patients may have
other analyses. had a repeated ED visit or hospitalization at a subsequent ED visit.
b
Includes dimenhydrinate, diphenhydramine hydrochloride, promethazine g
Denominator only includes patients discharged from the ED. Emergency
hydrochloride, domperidone, metoclopramide hydrochloride, granisetron department revisit includes patients who returned to the ED and were
hydrochloride, dolasetron mesylate, and palonosetron hydrochloride. discharged and those who were admitted to an inpatient or observation unit
c
Inflated to 2012 US dollars. bed.

Adjusted time-series analyses revealed that increasing on-

dansetron use was not associated with reductions in the rates
of IV rehydration or hospitalization (Table 3). High ondanse-
tron use was associated with a lower rate of 3-day ED revisits
compared with low use (mean difference = −0.4%; 95% CI, −0.6
to −0.2). In absolute numbers, this represents a reduction of
1337 revisits (95% CI, 668 to 2006) in our cohort of 334 264 ED
visits. Excluding children younger than 6 months (n = 89 250),
high ondansetron use was associated with lower IV rehydra-
tion rates compared with low ondansetron use (percentage
change = −0.27%; 95% CI, −0.45% to −0.09%) (eTable 5 in
Supplement).
The percentage change in the IV insertion, hospitaliza-
tion, and 3-day ED revisit rates between low and high use cat-
egories at an institutional level revealed that the relationship
between ondansetron use and each outcome varied by insti-
tution (Figure 2).
Discussion
In this multicenter study, we observed a dramatic increase in
the rate of ondansetron administration in children with AGE
during a 10-year period. In our adjusted time-series analysis,
the increase in ondansetron administration in pediatric EDs
was not associated with reductions in the rates of IV rehydra-
tion or hospitalization. However, some institutions did expe-
rience a significant reduction in IV rehydration use with in-
creasing ondansetron administration. Because the vast
majority (87%) of children administered IV rehydration did not
receive oral ondansetron, the lack of an identified beneficial
association may reflect an ondansetron use pattern that dif-
fers from the intended target population (eg, children who are
most likely to fail ORT) or the excessive use of our target out-
come (IV rehydration).

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 Research Original Investigation
Table 3. Comparison of Changes in the Percentage of Outcomes Occurring Between Low, Medium, and High Ondansetron Use Periods
Outcome
Intravenous fluid rehydration
Low to medium ondansetron use
Medium to high ondansetron use
Low to high ondansetron use
Hospital admission
Low to medium ondansetron use
Medium to high ondansetron use
Low to high ondansetron use
ED revisit within 3 d
Low to medium ondansetron use
Medium to high ondansetron use
Low to high ondansetron use
Abbreviation: ED, emergency department.
a
Accounts for hospital clustering.
b
Adjusted for age, sex, race, season, admission time, prior gastroenteritis visit,
Our findings must be interpreted in the context of find-
ings from RCTs, which found a 20% absolute reduction in
the use of IV rehydration with the use of oral ondansetron
(number needed to treat = 5).8 Our study, in contrast, did not
identify a reduction. The reasons for our discrepant findings
are likely multifactorial and may highlight the distinction
between efficacy and effectiveness. To date, ondansetron
efficacy trials have used rigorous research designs as well as
stringent patient eligibility criteria and ORT protocols. One
must weigh the strength of high internal validity associated
with an RCT design against the potential weakness in exter-
nal validity or generalizability. In the real world, where many
ED physicians prefer to use IV rehydration in children with
moderate dehydration, it is unclear whether ondansetron is
being administered with the same intent and to similar
patients as those participating in the RCTs. We demonstrate
that ondansetron use has become more frequent, and those
administered IV rehydration are more often administered IV
ondansetron and are not given the opportunity to benefit
from oral ondansetron in conjunction with ORT.
Another possible explanation for the lack of an associa-
tion between increasing ondansetron use and a reduction in
IV use is the general trend over time for increased resource
utilization by ED physicians. This may include a trend for
increasing use of diagnostic testing (eg, laboratory studies or
diagnostic imaging)25 and treatments26 over time, which in
and of themselves may reflect increasing patient complexity
or acuity of illness. In nationally representative samples of
ED visits, there was a 60% increase in the use of diagnostic
imaging between 2001 and 200525 and an 84% increase in
the rate of antibiotic administration to patients with pneu-
monia from 1993 to 2008.26 Because IV rehydration is often
performed in conjunction with and while awaiting the
results of serum electrolyte tests in children with AGE, a
trend toward the increasing use of such diagnostic tests may
offset any potential benefit associated with ondansetron
administration. Supporting this notion is the fact that diag-
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Ondansetron Use in Children With Gastroenteritis
% Change (95% CI)
Unadjusteda Adjustedb
0.89 (−0.61 to 2.40) 0.01 (−1.20 to 1.22)
−1.88 (−3.27 to −0.49)c −0.32 (−0.92 to 0.28)
−0.99 (−2.83 to 0.86) −0.33 (−1.86 to 1.20)
0.54 (−0.24 to 1.32) 0.31 (−0.27 to 0.89)
−0.79 (−1.51 to −0.06)c −0.02 (−0.05 to 0.02)
−0.25 (−1.16 to 0.67) −0.33 (−0.95 to 0.29)
−0.10 (−0.42 to 0.22) −0.30 (−0.48 to −0.12)c
c
−0.57 (−0.87 to −0.28) −0.01 (−0.18 to 0.16)
−0.67 (−0.99 to −0.36)c −0.31 (−0.49 to −0.13)c
laboratory testing, diagnostic imaging, rotavirus diagnosis, and hospital
clustering.
c
Significant at P < .05.
nostic imaging increased by 34% in our study population
during the 10-year study period. By comparison, although
the performance of blood testing increased by 10% during
the study period, the unadjusted rate of IV rehydration
decreased by 5%. While the increased use of diagnostic
imaging continued between medium and high ondansetron
use categories, as ondansetron use approached 20%, the IV
rehydration rate plateaued. However, ondansetron adminis-
tration has continued to increase without evidence of fur-
ther improved outcomes, and excessive use is not without
potential consequences in terms of both cost and adverse
effects.27
The increase in costs observed in the medium and high on-
dansetron use periods is not surprising given its cost and the
lack of reduction in the use of IV rehydration. This contra-
dicts earlier economic evaluations conducted under the as-
sumption of clinical efficacy, which concluded that ondanse-
tron use was cost-effective.1,23 In light of the limited benefits
realized, the increase in diagnostic testing that occurred in the
high ondansetron use period and the rising costs of health care
in the United States (increase from 14% of national economy
in 2000 to 18% in 2010), our results are not unexpected.28 On
a positive note, during the high ondansetron use period, there
was a reduction in 3-day ED revisits. This finding, which has
not been incorporated into our economic model, has been iden-
tified in a prior retrospective cohort study 10 but not in
meta-analyses.8
Our findings must be considered in the context of the
population studied. While prior studies demonstrated the
efficacy of ondansetron,8 they primarily demonstrated ben-
efit with oral ondansetron in children aged 6 months and
older. Similarly, when we analyzed only children aged 6
months and older, while of minimal clinical significance, we
did document a small reduction in IV rehydration use associ-
ated with increased ondansetron administration. While we
identified a high rate of IV ondansetron use, this method of
administration has previously been shown to not reduce
jamapediatrics.com
 Ondansetron Use in Children With Gastroenteritis Original Investigation Research

Figure 2. Adjusted Change in Intravenous Rehydration, Admission, and 3-Day Emergency Department
Revisit Rates by Site Between Low and High Ondansetron Use Periods

A
15
Adjusted % Change in IV Rehydration Rate

10

–5

–10

–15

–20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Hospital No.
B
10
Adjusted % Change in Admission Rate

–5

–10

–15
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Hospital No.
C
7.5
Adjusted % Change in 3-d ED Revisit Rate

5.0

2.5

Adjusted change in intravenous (IV)

–2.5 rehydration rate (A), admission rate
(B), and 3-day emergency
department (ED) revisit rate (C) by
–5.0 site between low and high
ondansetron use periods. All models
were adjusted for age, sex, race,
–7.5 season, admission time, prior acute
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
gastroenteritis visit, laboratory
Hospital No. testing, and diagnostic imaging. Error
bars indicate 95% CIs.

hospitalization rates29; our findings were in keeping with the
results of this RCT.
Because the PHIS database lacks detailed clinical infor-
mation, we cannot discern whether the intensity of vomiting
or the severity of dehydration differed between ondansetron
use categories or whether ondansetron was being used with
an unmeasured objective in mind (eg, nausea reduction). In
addition, because IV fluids are overused in many institu-
tions, the effectiveness of ondansetron administration may be
better measured using outcomes that are not available in ad-

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 Research Original Investigation Ondansetron Use in Children With Gastroenteritis

ministrative databases such as the frequency of vomiting, tol-
erance of ORT, and ED length of stay. Despite a lack of uni-
form benefit in outcomes, many institutions did experience a
decrease in IV rehydration and hospitalization during the study
period; some achieved a 10% reduction in IV rehydration rates.
These observations serve as a reminder that institutions must
evaluate their individual care patterns and outcomes to opti-
mize the care they provide.
Despite our attempts to adjust for severity of illness, re-
sidual confounding by indication may exist. Therefore, we ad-
justed the relationship of an institution’s ondansetron use pe-
riod to other testing including laboratory studies and diagnostic
imaging. If residual confounding by indication were present,
we would expect patients who presented during periods in
which greater severity of illness or diagnostic uncertainty ex-
isted to be more likely to undergo greater testing. Further, there
exists the potential for misclassification (ie, inclusion or ex-
clusion) of patient visits by our use of International Classifi-
cation of Diseases, Ninth Revision codes; however, misclassi-
fication is likely nondifferential and not any more likely at one
hospital over another or during specific periods. Lastly, our
findings may not be generalizable to non–children’s hospital
settings, as PHIS data are collected only from freestanding pe-
diatric hospitals.
Conclusions
Ondansetron use in children with AGE has increased dra-
matically in pediatric centers during the past decade without
a concomitant reduction in IV rehydration or hospitaliza-
tions. However, more than 85% of patients who received IV
rehydration for AGE were not given oral ondansetron, sug-
gesting an opportunity to better target its use to children at
greatest risk for failing ORT. Although tangible benefits asso-
ciated with ondansetron use in our cohort may have been
masked by the general trend of increased diagnostic testing
and treatment in EDs over time, future studies focusing on
other benefits such as patient satisfaction, ongoing vomit-
ing, and ED length of stay, which are currently unavailable in
the PHIS database, are needed. Lastly, individual institutions
need to assess the care they provide to children with AGE to
ensure that the interventions provided are achieving the
desired therapeutic aim.

ARTICLE INFORMATION
Accepted for Publication: October 28, 2013.
Published Online: February 24, 2014.
doi:10.1001/jamapediatrics.2013.4906.
Author Affiliations: Sections of Emergency
Medicine and Gastroenterology, Department of
Pediatrics, Alberta Children’s Hospital and Research
Institute, University of Calgary, Calgary, Alberta
(Freedman); Children’s Hospital Association,
Overland Park, Kansas (Hall); Divisions of Hospital
Medicine and Infectious Diseases, Cincinnati
Children’s Hospital Medical Center, University of
Cincinnati College of Medicine, Cincinnati, Ohio
(Shah); Division of Pediatric Emergency Medicine,
Children’s Hospitals and Clinics of Minnesota,
Minneapolis (Kharbanda); Section of Emergency
Medicine, Department of Pediatrics, Yale School of
Medicine, New Haven, Connecticut (Aronson);
Division of Emergency Medicine, Department of
Pediatrics, Cincinnati Children’s Hospital Medical
Center, University of Cincinnati College of Medicine,
Cincinnati, Ohio (Florin); Division of Emergency
Medicine, Department of Pediatrics, University of
Pennsylvania School of Medicine, Philadelphia
(Mistry); Section of Emergency Medicine,
Department of Pediatrics, Center for Clinical
Effectiveness, Baylor College of Medicine/Texas
Children’s Hospital, Houston (Macias); Division of
Emergency Medicine, Boston Children’s Hospital,
Boston, Massachusetts (Neuman).
Author Contributions: Dr Hall had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Study concept and design: All authors.
Acquisition of data: Freedman, Hall, Neuman.
Analysis and interpretation of data: Freedman, Hall,
Shah, Aronson, Florin, Macias, Neuman.
Drafting of the manuscript: Freedman, Hall,
Neuman.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Freedman, Hall, Neuman.
Administrative, technical, and material support:
Freedman, Neuman.
Study supervision: Freedman, Neuman.
Conflict of Interest Disclosures: Dr Freedman
acknowledges receiving in-kind study drug/placebo
from GlaxoSmithKline, the manufacturer of
ondansetron, for the conduct of an unrelated study.
No other disclosures were reported.
Disclaimer: Dr Shah is the JAMA Pediatrics Section
Editor for Clinical Challenges but was not involved
in the review process or the acceptance of the
manuscript.
Previous Presentation: This paper was presented
at the 2013 Annual Meeting of the Pediatric
Academic Societies; May 5, 2013; Washington, DC.
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