Gastroenteritis Therapies in Developed Countries: Systematic Review and Meta-Analysis

RESEARCH ARTICLE
Gastroenteritis Therapies in Developed

Countries: Systematic Review and Meta-
Analysis
Stephen B. Freedman1*, Dion Pasichnyk2, Karen J. L. Black3, Eleanor Fitzpatrick4,
Serge Gouin5, Andrea Milne2, Lisa Hartling2, Pediatric Emergency Research Canada
Gastroenteritis Study Group¶
1 Sections of Pediatric Emergency Medicine and Gastroenterology, Alberta Children’s Hospital, Alberta
Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta,
Canada, 2 Alberta Research Centre for Health Evidence, Department of Pediatrics, University of Alberta,
Edmonton, Alberta, Canada, 3 Division of Pediatric Emergency Medicine, BC Children’s Hospital, University
of British Columbia, Vancouver, British Columbia, Canada, 4 IWK Health Centre, Emergency Department,
Department of Emergency Medicine, Dalhousie University, Halifax, Nova Scotia, Canada, 5 Section of
Pediatric Emergency Medicine, Centre Hospitalier Universitaire Ste-Justine, Université de Montréal,
Montréal, Quebec, Canada
¶ The complete membership of the Pediatric Emergency Research Canada Gastroenteritis Study Group can
be found in the Acknowledgments
OPEN ACCESS * [email protected]
Citation: Freedman SB, Pasichnyk D, Black KJL,
Fitzpatrick E, Gouin S, Milne A, et al. (2015)
Gastroenteritis Therapies in Developed Countries:
Systematic Review and Meta-Analysis. PLoS ONE Abstract
10(6): e0128754. doi:10.1371/journal.pone.0128754
Academic Editor: Imti Choonara, Nottingham

University, UNITED KINGDOM
Context
Received: March 9, 2015
Gastroenteritis remains a leading cause of childhood morbidity.
Accepted: April 9, 2015
Published: June 15, 2015

Objective
Copyright: © 2015 Freedman et al. This is an open
access article distributed under the terms of the Because prior reviews have focused on isolated symptoms and studies conducted in devel-
Creative Commons Attribution License, which permits oping countries, this study focused on interventions commonly considered for use in devel-
unrestricted use, distribution, and reproduction in any
oped countries. Intervention specific, patient-centered outcomes were selected.
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are

Data Sources
within the paper and its Supporting Information files.
MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, trial registries, grey
Funding: This study was funded by the Canadian
Institutes of Health Research. The funders had no literature, and scientific meetings.
role in study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
Competing Interests: All authors have completed

Study Selection
the ICMJE uniform disclosure form at www.icmje.org/ Randomized controlled trials, conducted in developed countries, of children aged <18
coi_disclosure.pdf and declare: Dr. Stephen
years, with gastroenteritis, performed in emergency department or outpatient settings which
Freedman acknowledges receiving in-kind study
drug/placebo from GlaxoSmithKline, the evaluated oral rehydration therapy (ORT), antiemetics, probiotics or intravenous fluid
manufacturer of ondansetron for the conduct of an administration rate.
PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 1 / 21

Gastroenteritis Management in Developed Countries
unrelated study. Dr. Stephen Freedman has received Data Extraction

research grant support from Lallemand Health
Solutions to study a probiotic agent. All other authors The study was conducted in accordance with the Cochrane Handbook for Systematic Re-
declare no other support from any organization for views of Interventions and the PRISMA guidelines. Data were independently extracted by
the submitted work; no financial relationships with any multiple investigators. Analyses employed random effects models.
organizations that might have an interest in the
submitted work in the previous three years; no other
relationships or activities that could appear to have Results
influenced the submitted work. No individuals
31 trials (4,444 patients) were included. ORT: Compared with intravenous rehydration, hos-
employed or contracted by the funders (other than
the named authors) played any role in: study design, pitalization (RR 0.80, 95%CI 0.24, 2.71) and emergency department return visits (RR 0.86,
data collection and analysis, decision to publish, or 95%CI 0.39, 1.89) were similar. Antiemetics: Fewer children administered an antiemetic re-
preparation of the manuscript. This does not alter the quired intravenous rehydration (RR 0.40, 95%CI 0.26, 0.60) While the data could not be
authors' adherence to PLOS ONE policies on sharing
meta-analyzed, three studies reported that ondansetron administration does increase the
data and materials.
frequency of diarrhea. Probiotics: No studies reported on the primary outcome, three stud-
ies evaluated hospitalization within 7 days (RR 0.87, 95%CI 0.25, 2.98). Rehydration: No
difference in length of stay was identified for rapid vs. standard intravenous or nasogastric
rehydration. A single study found that 5% dextrose in normal saline reduced hospitalizations
compared with normal saline alone (RR 0.70, 95% CI 0.53, 0.92).
Conclusions
There is a paucity of patient-centered outcome evidence to support many interventions.
Since ORT is a low-cost, non-invasive intervention, it should continue to be used. Routine
probiotic use cannot be endorsed at this time in outpatient children with gastroenteritis.
Despite some evidence that ondansetron administration increases diarrhea frequency,
emergency department use leads to reductions in intravenous rehydration and hospitaliza-
tion. No benefits were associated with ondansetron use following emergency department
discharge.
Introduction
Gastroenteritis results in nearly 2 million pediatric emergency department (ED) visits in the
United States annually.[1] Although rotavirus vaccination has altered the epidemiology of
acute gastroenteritis (AGE),[2] emerging pathogens such as norovirus[3] continue to result in
symptoms prompting medical evaluation.[4]
While systematic reviews (SR) have evaluated treatment options,[5–11] they are often in-
conclusive or discordant. Recent guidelines published by European Society for Pediatric
Gastroenterology, Hepatology and Nutrition (EPGHAN) and the European Society of Pediat-
ric Infectious Diseases (ESPID)[12] and those issued by the National Institute for Health and
Clinical Excellence (NICE)[13] are vague regarding their recommendation regarding the use of
antiemetics, a therapy endorsed by other position papers and meta-analyses.[10,11,14] The
aforementioned guidelines also have differing recommendations regarding probiotics
(Table 1).[15] The most recent guidelines endorsed by the American Academy of Pediatrics
were published over a decade ago.[16]
Participant eligibility criteria in 'gastroenteritis' studies can vary significantly between stud-
ies. Since the diagnosis is made on clinical grounds, the precision is debatable. Most clinical tri-
als employ clearly defined clinical features to determine eligibility. As these studies reflect

Table 1. Summary of differing recommendations of prominent gastroenteritis guidelines.
Antiemetics Probiotics
Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio Ondansetron, at the dosages used in the Administration of effective probiotic strains
A, Shamir R, Szajewska H European society for available studies and administered orally or reduce the duration of hospital stay and may
pediatric gastroenterology, hepatology, and intravenously, may be effective in young children be considered in children admitted with AGE
nutrition/european society for pediatric infectious with vomiting related to AGE. Before a final (II, B) (strong recommendation, low quality
diseases evidence-based guidelines for the recommendation is made, a clearance on evidence). Active treatment with probiotics, in
management of acute gastroenteritis in children safety in children is, however, needed (II, B) adjunct to ORS, is effective in reducing the
in europe: update 2014. J Pediatr Gastroenterol (strong recommendation, low-quality evidence). duration and intensity of symptoms of
Nutr 2014, 59:132–152. gastroenteritis. Selected probiotics can be used
in children with AGE (I, A) (strong
recommendation, moderate-quality evidence).
New evidence has confirmed that probiotics are
effective in reducing the duration of symptoms in
children with AGE (I, A) (strong recommendation,
moderate-quality evidence). The use of the
following probiotics should be considered in
the management of children with AGE as an
adjunct to rehydration therapy: L rhamnosus GG
and S boulardii (I, A) (strong recommendation,
low-quality evidence).
National Collaborating Centre for Women's and The guideline development group (GDG) There was evidence from a high-quality
Children's Health Diarrhoea and vomiting caused considered that evidence from randomised systematic review suggesting that probiotic
by gastroenteritis: diagnosis, assessment and controlled trials indicated that oral ondansetron treatment had a beneficial effect–shortening the
management in children younger than 5 years. could increase the success rate with oral duration of diarrhoea and reducing the stool
Commissioned by the National Institute for rehydration therapy. The GDG was concerned frequency. However, the available studies varied
Health and Clinical Excellence; Available at: that ondansetron might have adverse effects in quality, in the specific probiotics studied, in the
http://www.nice.org.uk/guidance/cg84/resources/ such as worsening diarrhoea. There was no treatment regimens used and in the outcomes
cg84-diarrhoea-and-vomiting-in-children-under-5- evidence to support other agents, including examined. Therefore, despite some evidence of
full-guideline2. Accessed October 15, 2014. metoclopramide and dexamethasone. The GDG possible clinical benefit, the GDG did not
concluded that administration of anti-emetics consider it appropriate to recommend the use
could not currently be recommended. of a probiotic at this time.
Cheng A, Canadian Paediatric Society—Acute Oral ondansetron therapy, as a single dose, Not applicable.
Care Committee Emergency department use of should be considered for infants and children
oral ondansetron for acute gastroenteritis-related six months to 12 years of age who present to
vomtiing in infants and children. Paediatr Child the ED with vomiting related to suspected acute
Health 2011, 16:177–179. gastroenteritis, and who have mild to moderate
dehydration or who have failed oral rehydration
therapy.
Piescik-Lech M, Shamir R, Guarino A, New evidence indicates that ondansetron, at the New evidence has confirmed that the
Szajewska H Review article: the management of dosages used in the studies and administered probiotics currently supported by ESPGHAN/
acute gastroenteritis in children. Aliment orally or intravenously, may be considered for ESPID–Lactobacillus GG and S. boulardii–are
Pharmacol Ther 2013, 37:289–303. use in young children with vomiting related to effective in reducing the duration of
AGE. However, before a final recommendation is diarrhoea. Current evidence clearly indicates
made, a clearance on safety in children is that these are not the only effective probiotic
needed. microorganisms; however, these are the most
studied. Probiotic effects are strain-specific, so
the efficacy and safety of each should be
established.
King CK, Glass R, Bresee JS, Duggan C No clear recommendation in report. Ondansetron, a serotonin antagonist, either by
Managing acute gastroenteritis among children: the oral or IV route, can be effective in
oral rehydration, maintenance, and nutritional decreasing vomiting and limiting hospital
therapy. MMWR Recomm Rep 2003, 52:1–16. admission. However, 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. Because acute diarrhea is a common
illness, cost-effective analyses should be
undertaken before routine pharmacologic
therapy is recommended.
doi:10.1371/journal.pone.0128754.t001

pragmatic considerations and employ randomization, they retain internal validity. However,
without careful consideration, their grouping together in SR and meta-analyses can be prob-
lematic. Consequently, significant variation has been documented in the management of AGE
in developed countries at institutional,[17] national,[18] and international levels.[19]. This is
in part explained by heterogeneity–population, setting, etiologic agents, and nutritional status.
Studies from low and middle income countries include more severe cases, organisms rarely
seen in developed nations, and malnourished children.[20,21] Outcome selection is increasing-
ly a concern with most SRs focusing on diarrhea duration–a single symptom which in addition
to being heterogeneous itself, also overlooks other key symptoms (e.g. vomiting). An analysis
of 138 pediatric AGE randomized clinical trials (RCT) identified 64 unique definitions of diar-
rhea, and 69 of “resolution.”[22]
Driven by recent evidence and uncertainties in practice, the efficacy of oral rehydration
therapy (ORT), antiemetics, probiotics and intravenous rehydration in developed countries
was evaluated.
Methods
A protocol (S1 File) was established a priori and followed standard SR procedures.[23] The
planned approach involved initially conducting a comprehensive search to identify all relevant
SRs performed to date to ensure that previously identified relevant studies were included in the
review. This was followed by a thorough search for additional studies. Lastly, the evidence fo-
cusing on studies of outpatient children in developed countries was re-examined.
Information Sources and Searches

A medical librarian (A.M.) developed the search strategy in collaboration with the research
team to identify previous SRs of: (1) ORT; (2) antiemetics; (3) probiotics; and (4) intravenous
fluid therapy (IVT). The following sources were searched: (a) MEDLINE (2000 to April 2012),
EMBASE (2000 to April 2012), and the Cochrane Database of Systematic Reviews (2005 to
April 2012) via the OvidSP platform; (b) appropriate journals and major, relevant scientific
meetings; (c) reference lists of relevant reviews; and (d) primary authors were contacted. The
search was not restricted by language or publication status. All studies contained in previous
relevant SRs were screened for inclusion. This approach is an economically efficient method of
identifying all prior relevant studies dating back to the origins of the search engines.
The librarian then searched the literature to identify trials published since the dates in-
cluded in the earliest SR identified. The search included electronic databases (i.e. MEDLINE,
EMBASE, Cochrane Central Register of Controlled Trials; S2 File) and the grey literature. The
latter search included clinical trials registries (clinicaltrials.gov, the World Health Organization
trials registry, and the Current Controlled Trials registry) and conference proceedings (Society
for Pediatric Research, American Academy of Pediatrics, Canadian Pediatric Society, Interna-
tional Conference on Emergency Medicine; 2010–2012). Reference lists were screened and ex-
perts contacted. No language restrictions were employed. The search was re-run in September
2014 to identify any recently published studies.
Inclusion Criteria
Search results were screened independently by two reviewers to identify potentially relevant ci-
tations. The full text of potentially relevant citations was assessed for inclusion by two indepen-
dent reviewers using predefined criteria. Disagreements were resolved by consensus. Eligible
RCTs involved children <18 years of age with AGE and evaluated: (1) any ORT regimen vs. in-
travenous or nasogastric rehydration; (2) any antiemetic medication vs. placebo or alternative;

(3) any probiotic agent vs. placebo or alternative; and (4) different rates and compositions of
intravenous fluid rehydration protocols. Studies were included if the condition evaluated was
consistent with AGE and the location was an ED or similar outpatient setting in a developed
nation as defined by the United Nations (i.e. Australia, Canada, European countries, Japan,
New Zealand, and the United States).[24]
Outcomes
The interventions and outcome measures were identified by clinician authors (SF, KB, EF, SG)
and knowledge users (DJ, FB, BH, MJ, TK) a priori based on clinical relevance incorporating
recommendations to employ outcomes of interest to parents, clinicians, and health systems
(Table 2).[25]
Data Extraction
As is commonly performed, one reviewer extracted data using a structured form with verifica-
tion performed by a second reviewer.[26–29] Items extracted were: study characteristics, par-
ticipants, interventions and comparisons, outcomes, funding source, and results. Data were
entered into Microsoft Excel (Microsoft, Redmond, WA). Disagreements were resolved by con-
sensus, or by a third reviewer.
Risk of Bias Assessment

The Cochrane Risk of Bias (RoB) tool[23] was applied, independently by two reviewers to as-
sess internal validity (S1 Table). Discrepancies were resolved by consensus or by involving a
third reviewer.
Table 2. Interventions and their specific outcomes evaluated.
Primary Outcome Secondary Outcomes

Oral Rehydration Therapy
Hospitalization Length of Stay
Return Visits
Adverse Effects
Antiemetic Agents
Administration of Intravenous Rehydration Hospitalization
Length of Stay
Return Visits
Adverse Effects
Probiotic Agents
Any Subsequent Healthcare Visit (7 days) Administration of Intravenous Rehydration
Hospitalization
Adverse Effects
Intravenous Fluid Therapy
Length of Stay Hospitalization
Return Visits
Dysnatremia*
*The term dysnatremia refers to the presence of a serum sodium value outside of the age accepted range
of normal values.

Grading the Body of Evidence

The quality of evidence was assessed using methods developed by the GRADE Working
Group.[30] For each comparison and outcome, the following were assessed: risk of bias, consis-
tency, directness, and precision. Overall quality was graded as high, moderate, low, or very low
by two reviewers with discrepancies resolved through discussion.
Statistical Analysis
Evidence tables to describe the studies were developed. A quantitative analysis synthesized nu-
merically the effectiveness of each intervention and investigated heterogeneity. Data was re-
ported for continuous outcomes as mean differences which were combined, where appropriate,
using a weighted mean difference and inverse-variance methods.[31] Data for dichotomous
outcomes are reported employing risk ratios (RR) or risk differences. The latter was employed
when there were zero events in one of the treatment arms of an individual study which contrib-
uted data to the meta-analysis (e.g. adverse events). Results are reported with 95% confidence
intervals. The primary analysis was based on a random effects model due to anticipated clinical
variability between studies.[32] Sensitivity analyses were conducted using a fixed effects model
and no differences were identified in the results. Heterogeneity was quantified using the I-
squared statistic.[33,34] When heterogeneity was substantial (I2 75%), pooling of studies was
not performed. Due to insufficient numbers pre-planned sensitivity analyses based on risk of
bias, intention-to-treat analysis, and funding source could not be conducted. Testing for publi-
cation bias was not performed due to insufficient numbers. Analyses were conducted using Re-
view Manager 5.0 (The Cochrane Collaboration, Copenhagen, Denmark).
Results
Sixty-six RCTS were relevant; 35 did not report any of the a priori identified outcomes of inter-
est, therefore, 31 RCTs involving 4,444 patients were included (Fig 1; Table 3). Four antiemetic
agents were studied along with 11 different probiotic strains. Overall risk of bias was low for
23% of trials (7/31), unclear for 74% (23/31), and high for 3% (1/31); S1 Table. Industry fund-
ing was identified in the following studies: ORT – 5 (50%); antiemetics – 3 (38%); probiotics – 2
(33%); IVT – 2 (33%).
Oral Rehydration Therapy (ORT)

Ten studies involving 599 patients compared ORT with IVT (S2 Table). Sample sizes ranged
from 24 to 111 (median 47, inter-quartile range 35 to 91). Five studies did not report dehydra-
tion severity; the remainder, with one exception,[35] included primarily children with mild
dehydration.
Three studies provided data on the effect for the primary outcome of hospitalization, which
in meta-analysis, showed no significant difference between groups (RR 0.80, 95% CI 0.24, 2.71,
I2 = 51%; Table 4; Fig 2). The quality of evidence was low owing to inconsistencies in effect esti-
mates across studies and imprecision in the pooled result. No difference was observed in the
secondary outcome of return to the ED. Six studies provided data on ED length of stay. Howev-
er, there was substantial heterogeneity across studies and results could not be pooled (I2 =
91%). Quality of the evidence was very low. The mean difference in length of stay reported by
individual studies, including time spent in hospital, ranged from 1.20 days less for ORT (95%
CI -2.16, -0.24) to 0.92 days longer (95% CI 0.31, 1.53). Five studies reported on adverse effects
(Table 5); no significant differences were identified.

Fig 1. Flow diagram of study selection. SR, systematic review; PICO, Population, Intervention, Comparison, Outcome; RCT, randomized controlled trial.
doi:10.1371/journal.pone.0128754.g001
Antiemetics
Nine studies involving 1,691 patients evaluated three antiemetic agents: ondansetron (N = 6),
dimenhydrinate (N = 2), and granisetron (N = 1). Eight RCTs compared the antiemetic agent
with placebo; one RCT compared ondansetron with dexamethasone (Table 3; Fig 3; S3 Table).
Table 3. Overview of studies included in systematic review.
Comparison Number of Number of studies Number of studies Years of Countries of study Risk of
studies providing data for providing data for publication, (Numer of studies) bias
(Number of primary outcome secondary outcomes median (range)
patients) (Number of patients) (Number of patients)
Intravenous Therapy 10 (599) 3 (136) 10 (599) 1992 (1985– Australia (1), Canada 9 unclear,
vs. Oral Rehydration 2005) (1), Finland (1), USA 1 low
Therapy (7)
Any Antiemetic vs. 9 (1691) 7 (1043) 9 (1691) 2008 (2002– Australia (1), Canada 7 unclear,
Placebo 2014) (1), Germany (1), 2 low
Saudi Arabia (1),
USA (5)
Any Probiotic vs. 6 (1170) 1 (155) 6 (1170) 2009 (2007– Australia (1), Italy (2), 4 unclear,
Placebo 2012) Ukraine (2), USA (1) 2 low
Intravenous Fluid 6 (984) 2 (305) 4(644) 2011 (2006– Australia (2), Canada 3 unclear,
Rates & 2014) (1), USA (1) 2 low, 1
Compositions high

Table 4. Results for Primary and Secondary Outcomes.
Comparison Outcome Number of studies (Number of Risk Ratio (95% CI) I2 Quality of evidence based on
patients) (%) GRADE
IVT vs. ORT
Primary Hospitalization 3 (136) 0.80 (0.24, 2.71) 51 Low
Secondary Length of ED Stay 6 (308) Not pooled due to substantial 91 very low
heterogeneity
Return to ED 3 (193) 0.86 (0.39, 1.89) 0 moderate
Antiemetics
Any antiemetic vs. placebo
Primary IV Fluid Administration 5 (733) 0.40 (0.26, 0.60)† 30 High
Secondary Hospitalization 7 (1043) 0.44 (0.23, 0.82)† 27 High
Length of ED Stay 5 (991) Not pooled due to substantial 75 moderate
heterogeneity
Dimenhydrinate vs. placebo
Primary IV Fluid Administration 1 (144) 0.74 (0.29, 1.87) NA low
Secondary Hospitalization 2 (368) 0.72 (0.34, 1.53) 0 moderate
Ondansetron vs. dexamethasone
Primary Hospitalization 1 (93) 0.29 (0.06, 1.33) NA low
Secondary Return to ED 1 (56) 4.30 (1.00, 18.47)† NA low
Ondansetron vs. placebo
Primary IV Fluid Administration 3 (433) 0.38 (0.27, 0.54)† 0 High
Secondary Hospitalization 5 (613) 0.32 (0.18, 0.57)† 2 moderate
Return to ED 5 (609) 1.57 (0.70, 3.52) 36 Low
Length of ED Stay 4 (826) Not pooled due to substantial NA moderate
heterogeneity
Granisetron vs. placebo
Primary IV Fluid Administration 1 (156) 0.05 (0.00, 0.78) NA Very low
Secondary Hospitalization 1 (165) 3.04 (0.13, 73.46) NA Very low
Return to ED 1 (122) 3.09 (1.19, 8.05) NA Very low
Length of ED Stay 1 (165) -0.65 (-1.29, -0.01) NA Very low
Probiotics
Probiotic (Any) vs. Placebo
Primary Return to ED 1 (155) 0.78 (0.36, 1.67) NA Low
Secondary Hospitalization 3 (833) 0.53 (0.26, 1.07) 20 Low
IV Fluid Administration 1 (64) 1.13 (0.81, 1.57) NA Low
Probiotic (Combo) vs. Placebo
Secondary Hospitalization 1 (189) 0.47 (0.09, 2.53) NA very low
B. clausii vs. Placebo
E. faecium vs. Placebo
L. casei vs. Placebo
Secondary IV Fluid Administration 1 (64) 1.13 (0.81, 1.57) NA Low
L. paracasei vs. Placebo
Secondary Hospitalization 1 (107) 0.37 (0.18, 0.75)† NA Low
L. rhamnosus vs. Placebo
(Continued)

Table 4. (Continued)
Comparison Outcome Number of studies (Number of Risk Ratio (95% CI) I2 Quality of evidence based on
patients) (%) GRADE
Primary Return to ED 1 (155) 0.78 (0.36, 1.67) NA very low
Secondary Hospitalization 2 (347) 0.65 (0.08, 5.45) 43 very low
S. boulardii vs. Placebo
IV Fluids
Rapid IV vs. Standard IV
Primary Length of ED Stay >6 1 (226) 1.06 (0.74, 1.53) NA low
hours
Secondary Hospitalization 2 (318) 1.03 (0.44, 2.39) 23 low
Return to ED 2 (311) 0.88 (0.52, 1.48) 0 low
Rapid NG vs. Standard NG
Primary Length of ED Stay* 1 (228) -1.90 (-9.11, 5.31) NA very low
Secondary Hospitalization 1 (228) 0.69 (0.49, 0.97)† NA low
Isotonic IV Fluid vs. Hypotonic IV Fluid
Secondary Dysnatremia 1 (44) -0.23 (-0.41, -0.04)† NA very low
5% Dextrose in Normal Saline vs. Normal Saline
Primary Length of ED Stay 1 (188) 0.13 (-0.27, 0.53) NA Very low
Return visits 1 (80) 0.64 (0.30, 1.36) NA Very low
Plasma-Lyte A vs. 0.9% Sodium Chloride
IVT, Intravenous Therapy; ORT, Oral Rehydration Therapy; ED, Emergency Department; GRADE, Grading of Recommendations Assessment,
Development and Evaluation; IV, intravenous; NA, Not Applicable; NG, nasogastric; vs, versus.
† Statistically significant effect.
*Length of stay, as a continuous variable, is reported as mean difference (95% CI).
All five studies demonstrated a reduction in the primary outcome of intravenous rehydration
usage amongst children administered an antiemetic agent (Fig 3; RR 0.40, 95% CI 0.26, 0.60,
I2 = 30%; N = 733). Quality of evidence for this outcome was high. Pooled results demonstrated
that patients receiving an antiemetic agent were hospitalized less often (RR 0.44, 95% CI 0.23, 0.82,
I2 = 27%; N = 1043). There was substantial heterogeneity for length of stay results across studies
(I2 = 75%); therefore, data were not pooled. Mean length of stay reported in individual studies ran-
ged from 0.23 hours (95% CI -0.49, 0.03) to 1.0 hours (95% CI -1.34, -0.66) less for antiemetics.
There was no difference between groups in the proportions of children experiencing ED revisits.
Findings were similar when only those studies involving ondansetron were analyzed. No
significant differences were identified when studies involving dimenhydrinate were evaluated.
Three studies evaluating dimenhydrinate reported specific adverse events—drowsiness, head-
ache, rash, hyperactivity, gastrointestinal upset, and sedation; no differences were noted com-
pared with placebo (Table 5).
Diarrhea frequency was evaluated in several studies but due to the varying methods of re-
porting the findings, the results could not be combined. Following a single dose of ondansetron
or placebo, during ED ORT one study (N = 215) reported that ondansetron administration
resulted in a statistically significant increase in diarrhea frequency (1.4 vs. 0.5 stools; group
(P < 0.001).[36] Another study, which similarly evaluated single oral dose ondansetron vs. pla-
cebo, collected post-discharge diarrhea frequency information. In their cohort (N = 106), the

median number of episodes of diarrhea post-discharge was 0 in both groups; 93% of children
administered placebo and 80% of those administered ondansetron had < 3 episodes of diar-
rhea after discharge and the mean was 1.8 vs. 0.5 episodes of diarrhea respectively (no test of
significance provided).[37] A multi-dose ondansetron vs. placebo study (N = 145) reported no
difference in stool frequency while in the ED (mean 0.70 vs. 0.61 episodes respectively;
P = 0.62); however, following discharge there was a significant increase in stool frequency
amongst those administered ondansetron at both 24 (4.7 vs. 1.4; P = 0.002) and 48-hour (3.0
vs. 1.0; P = 0.02) outcome time points.[38] A study evaluating single dose, intravenous ondan-
setron (N = 107), reported that compared with placebo, there were no significant differences in
the proportion (41%—ondansetron; 40%—placebo; P = 0.93), frequency (median of 5 in both
groups; P = 0.87) or duration (60 hours in the ondansetron vs. 49 hours in placebo groups;
P = 0.72) of diarrheal episodes following the intervention.[39] Lastly, a multi-dose study of
granisetron (N = 165) reported a similar odds (OR 1.29, 95% CI 0.64, 2.60) and frequency of
diarrhea following medication administration (6.5 ± 6.1 vs. 5.8 ± 7.6; P = 0.51).[40]
Probiotics
Six studies, involving 1170 patients, examined different probiotics (Table 4; S4 Table); five
compared individual probiotic agents with placebo, one compared multiple and combination
products with placebo.
Fig 2. Meta-graph comparing oral rehydration therapy vs. intravenous fluid therapy. Results from meta-analysis of direct comparisons of oral
rehydration therapy vs. intravenous fluid therapy on the outcomes of admission to hospital from the emergency department and revisits to the emergency
departments, displayed employing Forest plots.

No studies reported findings related to any subsequent healthcare provider visits. One study
reported no difference between groups in terms of return for additional ED care (Fig 4 and
Table 4). Pooled results from 3 studies showed no difference between groups for hospitalization
within 7 days (RR 0.53, 95% CI 0.26, 1.07, I2 = 20%; N = 571). Based on one study, no differ-
ence was observed between probiotic and placebo groups in the need to administer intravenous
rehydration within 7 days.
When analyzed by individual probiotic product, most comparisons included a single RCT
and reported no significant differences between groups. The quality of evidence for all compar-
isons was low or very low. Specific adverse events were reported in only one study; no differ-
ences were found between groups (Table 5).
Intravenous Fluid Therapy (IVT)

Six studies involving 984 patients compared different rates or compositions of intravenous flu-
ids (S5 Table). Two studies (N = 318) compared rapid (60 ml/kg and 50 ml/kg over 1 hour) vs
Table 5. Adverse Events.
Adverse Event Total number of Number of events/total (%) Risk Difference (95% Risk Ratio* (95% I2
patients CI) CI) (%)‡
IVT vs ORT
Periorbital 219 IVT 6/99 (6); ORT 8/120 (7) 0.03 (-0.07, 0.13) 1.30 (0.29, 5.87) 54
Edema
Hyponatremia 104 IVT 3/52 (6); ORT 4/52 (8) 0.02 (-0.08,0.12) 1.33 (0.31, 5.67) NA
Seizure 152 IVT 1/67 (1); ORT 1/85 (1) 0.00 (-0.07, 0.08) 0.70 (0.04, 11.94) 31
Phlebitis 52 IVT 0/17 (0); ORT 0/35 (0) 0.00 (-0.08, 0.08) - NA
Antiemetics
Headache 137 Dimenhydrinate 3/69 (4); Placebo 1/68 (2) 0.03 (-0.03, 0.08) 2.96 (0.32, 27.72) NA
Rash 137 Dimenhydrinate 4/69 (6); Placebo 0/68 (0) 0.06 (0.00, 0.12) - NA
Hyperactivity 137 Dimenhydrinate 4/69 (6); Placebo 0/68 (0) 0.06 (0.00, 0.12) - NA
GI Upset 137 Dimenhydrinate 3/69 (4); Placebo 3/68 (3) 0.00 (-0.07, 0.07) 0.99 (0.21, 4.71) NA
Sedation 208 Dimenhydrinate 22/106 (22); Placebo 18/102 0.03 (-0.08, 0.14) 1.18 (0.67, 2.06) NA
(19)
Exanthem 208 Dimenhydrinate 1/106 (1); Placebo 1/102 (1) 0.00 (-0.03, 0.03) 0.96 (0.06, 15.18) NA
Drowsiness 137 Dimenhydrinate 29/69 (46); Placebo 25/68 (37) 0.01 (-0.02, 0.22) 1.14 (0.75, 1.73) 0
Urticaria 214 Ondansetron 0/107 (0); Placebo 1/107 (1) -0.01 (-0.03, 0.02) - NA
Probiotics
Rhinitis 113 Escherichia coli Nissle 1/55 (2); Placebo 0/58 (0) 0.02 (-0.03, 0.07) - NA
Otitis Media 113 Escherichia coli Nissle 1/55 (2); Placebo 0/58 (0) 0.02 (-0.03, 0.07) - NA
Abdominal Pain 261 Escherichia coli Nissle 2/130 (1); Placebo 4/131 0.01 (-0.07, 0.05) 0.67 (0.06, 7.97) 60
(3)
Hypersensitivity 151 Escherichia coli Nissle 1/75 (1); Placebo 0/76 (0) 0.01 (-0.02, 0.05) - NA
Isotonic IV Fluids vs Hypotonic IV Fluids
Dysnatremia 44 Isotonic solution 0/20 (0); Hypotonic solution 5/ -0.23 (-0.41, -0.04)† - NA
22 (23)
Plasma-Lyte A vs. 0.9% Sodium Chloride
Dysnatremia 75 Plasma-Lyte A 1/38 (3)0.9% Sodium Chloride 1/ 0.00 (-0.07, 0.07) 0.97 (0.06, 15.00) NA
37 (3)
IVT, Intravenous Therapy; ORT, Oral Rehydration Therapy; GI, Gastrointestinal; IV, Intravenous; NA, Not Applicable.
* Risk ratio calculated where there was at least one incidence in each group
† Statistically significant difference between groups
‡ Based on risk difference

Fig 3. Meta-graph comparing any antiemetic therapy vs. placebo. Results from meta-analysis of direct comparisons of therapy with any antiemetic agent
vs. placebo on the outcomes of administration of intravenous hydration, admission to hospital from the emergency department and revisits to the emergency
departments, displayed employing Forest plots.

Fig 4. Meta-graph comparing any probiotic therapy vs. placebo. Results from meta-analysis of direct comparisons of therapy with any probiotic agent vs.
placebo on the outcomes of administration of revisits to the emergency department, admission to hospital from the emergency department, and intravenous
hydration, displayed employing Forest plots.
standard rehydration rates (20 ml/kg over 1 hour and 50 ml/kg over 3 hours, respectively); one
study compared rapid polyelectrolyte with rapid nasogastric (NG) rehydration (N = 254); one
study compared isotonic with hypotonic intravenous solutions (N = 124); one study compared
5% dextrose in normal saline solution with normal saline solution alone (N = 188); and, one
study compared Plasma-Lyte A with 0.9% sodium chloride (N = 100).
No difference in length of stay was identified for rapid vs. standard IVT or rapid vs. stan-
dard NG rehydration (Table 4). Two studies comparing rapid vs. standard IVT also identified
no difference between groups in admissions or ED revisits. Significantly fewer admissions oc-
curred with rapid compared with standard NG rehydration. The study comparing isotonic vs.
hypotonic IVT did not report on any of the outcomes of interest except for dysnatremia; signif-
icantly fewer cases occurred with isotonic intravenous hydration. A reduction in hospitaliza-
tions (RR 0.70, 95% CI 0.53, 0.92) was identified when 5% dextrose in normal saline was
compared with normal saline; however, no differences were found for length of ED stay or

return visits. Similarly, no differences were found for time to rehydration, hospitalization, or
incidence of dysnatremia in the study comparing Plasma-Lyte A with 0.9% sodium chloride.
Quality of evidence for all outcomes and comparisons was low or very low.
Discussion
Key treatment decisions were examined—route of rehydration, use of antiemetics and probiot-
ics, and methods of intravenous and nasogastric rehydration—in a single SR, with a unique
focus on children in developed countries in order to provide information needed by clinician
and knowledge users. Although, the use of antiemetics confers short term benefits in outpa-
tients by reducing intravenous rehydration administration and hospitalization, no difference
was identified in terms of ED revisits. Aside from individual studies which documented posi-
tive results, no other interventions evaluated were found to result in improved outcomes. This
must be interpreted with caution because most often there were insufficient numbers of eligible
studies evaluating the outcomes of interest.
The treatment of AGE was approached from a perspective which yielded a paucity of studies
from developed countries that reported on the a priori identified outcome measures. Conse-
quently the findings contradict those of prior reviews which endorse the use of probiotics
based on their ability to reduce the mean duration of diarrhea (by 25 hours), the likelihood of
diarrhea lasting 4 days (risk ratio 0.41; 0.32 to 0.53), and stool frequency on day #2 (mean dif-
ference 0.80 stools).[8] However, prior reviews included heterogeneous groups of children and
the importance of the outcomes evaluated has been questioned.[22] Because of the methodo-
logical limitations of many of the trials included in prior reviews of probiotics, it is suggested
that the evidence be viewed with caution.[41]
To minimize heterogeneity and maximize relevance the study focused on a well-defined
population, key interventions, and clinically important outcomes. This differs from other re-
views that “summarise the more recent data” and search only MEDLINE and The Cochrane
Database of Systematic Reviews.[15] Although a recent overview of reviews reported similar
findings, the methodologies, which differed significantly, resulted in the inclusion of different
studies.[42] Other prior meta-analyses have not restricted their populations to developed re-
gions and have struggled with the inclusion of studies with varying outcome measure defini-
tions (e.g. duration of diarrhea).[22] These two characteristics differentiate this review and
underlie the differences in the studies included compared with others.

Although ORT is the most fundamental and accepted treatment,[16] studies comparing ORT
to IVT generally provided inadequate descriptions of the severity of dehydration, which drives
treatment decisions.[16] The trials identified were small, often single-centre, and rarely re-
ported sample size calculations.[43] Children with mild dehydration were the typical target
population, reflecting the overuse of IVT in North America.[44] Although no difference in the
primary outcome of hospitalization was identified, in the context of the comparison evaluated
(ORT vs. IVT), this supports the use of ORT.
Although oral rehydration solution (ORS) use per se (i.e. we did not focus on the solution
used) was not evaluated, the conceptual approach of ORT as opposed to IVT was evaluated.
Since ORS remains the cornerstone of AGE management and is considered to be the one of the
top medical discoveries of the 20th century,[45] its effectiveness in children with moderate de-
hydration was not questioned. Given the paucity of studies identified in this review, to further
reduce IVT use in children with moderate dehydration in developed countries, quality im-
provement studies documenting the keys to successful knowledge translation in the target

environments, are needed.[46] Such studies have been called for to enhance the ability to trans-
late research findings into clinical practice to maximize the use of evidence-based therapies.
[47]
Antiemetics
Despite limited endorsement in most practice guidelines,[16] this intervention included the
largest number of children of the interventions included in this study. While the results fa-
voured the use of antiemetics as it relates to short-term outcomes, no difference was identified
in ED revisits. This finding is in keeping with the expectations of single dose use of a medica-
tion with relatively short half-life. Although prior reviews have been hesitant to recommend
ondansetron use in light of concerns related to its arrhythmogenic potential,[15] recent evi-
dence has reduced concerns related to single oral dose use in otherwise healthy children.[48]
Although we could not meta-analyze the available data on the impact of antiemetics on diar-
rhea frequency, the data we report does seem to indicate that ondansetron administration does
increase the frequency of diarrhea. The clinical relevance of this increase (range: 0.1–0.9 stools
while undergoing ORT) in the ED is minimal as reflected by the clinically relevant outcomes of
intravenous rehydration and admission which are both reduced amongst children adminis-
tered ondansetron relative to placebo. Following discharge, there similarly appears to be an in-
crease in the number of diarrheal episodes and this appears to be most pronounced with multi-
dose therapy. Given the lack of benefit seen with multi-dose therapy and the increased risk of
diarrhea, such regimens are not recommended,[49]
Probiotics
European guidelines state that probiotics “should be considered in the management of children
with AGE as an adjunct to rehydration therapy.”[12] Use in North America remains limited,
and has been reported to be as low as 1% amongst inpatients in large U.S. academic pediatric
centres.[50] Although over 60 studies have been conducted,[8] the current analysis raises con-
cerns as it relates to outcomes evaluated. No studies evaluated the primary outcome identified
as most important by our knowledge users—subsequent healthcare provider visits. This out-
come was deemed to reflect a clinically significant benefit to the child and family and extends
beyond simply measuring the absolute number of stools or time to last stool. Furthermore, the
quality of the evidence included was 'very low' or 'low' and a disproportionate number of stud-
ies (4 out of 6) emerged from Italy and Ukraine.
This review grouped all probiotic products into a single intervention for analytical purposes.
While not ideal, as not all probiotic preparations are equally effective,[51] it was necessary
given the paucity of studies performed with each individual strain. Additionally, a prebiotic
(nondigestible food that beneficially affects the host by selectively stimulating the growth/activ-
ity of colonic bacteria in the colon) plus probiotic (xilooligosaccharides plus arabinogalactan
and Lactobacillus paracasei B21060)[52] study was included in the analyses. Sensitivity analy-
ses, which were conducted when a minimum of two studies employing the same probiotic were
identified, did not produce any changes in the conclusions.
A trend towards reductions in future hospitalizations was detected; although this did not
achieve significance, one could interpret this as evidence of a possible clinical benefit associated
with probiotic use. However, it is challenging to generalize findings from probiotic clinical tri-
als with the most frequently studied strain (Lactobacillus GG) having its benefits confined to
studies conducted outside North America.[41] The only North American outpatient study em-
ploying Lactobacillus GG found no difference in the time to normal stool or the number of di-
arrheal stools.[53]

Intravenous Fluid Therapy

Few studies evaluating IVT were identified, and limited evidence supporting the use of rapid
rehydration therapy was found. The limited evidence of benefit may relate to the inaccuracy of
dehydration assessment[54] or a delay in the timing between intravascular rehydration and
clinical improvement. As it relates to choice of maintenance IV hydration solution, a single,
low quality study, reported that dysnatremias are more frequent amongst children adminis-
tered hypotonic fluids.
Overall
Investigators should conduct more sophisticated studies that answer clinically relevant ques-
tions employing outcomes of importance to end-users. Pragmatic, comparative effectiveness
trials using factorial or non-inferiority designs and valid outcome measures[55] answering key
questions such as the success of ORT in children with moderate dehydration would significant-
ly enhance the uptake of ORT. Such work is needed to confirm and convince knowledge-users
(if positive) of the utility of interventions such as probiotics. Although multiple meta-analyses
have identified some benefits to be associated with the latter,[8,41] their uptake has been limit-
ed. Antiemetics have been investigated employing clinically important outcome measures and
consequently uptake has occurred rapidly.[56] The use of patient-centered outcomes and well
defined patient populations to minimize heterogeneity and maximize clinical applicability re-
sulted in the exclusion of many reports which highlights the need for further investigations em-
ploying outcomes established as important to parents and children.[22] While diarrhea
remains a concern with ondansetron administration the clinical impact appears to be negligible
with single dose regimens, however when multiple doses are administered this becomes more
of a concern.
This review has adhered to the latest methodological standards. Relevant evidence was
searched for extensively and this review included all studies regardless of language of publica-
tion. Although not all possible interventions were considered, this review focused on common
clinical intervention options and represents a comprehensive synthesis incorporating two key
perspectives: 1) patient-centered outcomes, and 2) developed countries.
This review has several limitations. It is limited by the challenges of synthesizing unrelated
outcomes which resulted in a limited body of evidence. Since this review focused on outpatient
studies, the results cannot be applied to the care of children managed at home by caregivers for
whom very limited data exists, or to the care of hospitalized children. The latter group, which
represents a fraction of children with AGE, has been the focus of most clinical trials. While the
ED setting may differ significantly from other outpatient settings and this might be a source of
heterogeneity, within each therapy the location was very consistent (e.g. ondansetron studied in
ED; probiotics studied in primary care). Since participant ages varied across the studies, planned
sub-analyses (i.e. < 5 years vs. 5 years) could not be conducted. Additionally, the only inter-
ventions evaluated are those currently being considered for routine use in developed countries;
interventions that are primarily considered for use only in developing nations (e.g. antibiotics,
zinc) were not evaluated. Although "exp Diarrhea/” was included in the original search strategy
(S2 File) data related to the duration and frequency of diarrhea was not abstracted originally as
these were not included in the a priori defined outcome measures. However, in the context of an-
tiemetic evaluation, they were deemed to be important and thus were included in the current ver-
sion of the SR. Lastly, despite attempts to minimize heterogeneity amongst different studies, it
could not be completely eliminated as studies included almost certainly varied in terms of infec-
tious etiology, seasonality, and local factors influencing clinical decision making. Nonetheless,
the knowledge gaps identified can serve to guide future research efforts.

Conclusions
Although some clinical practice guidelines endorse probiotic use, there is a paucity of support-
ing evidence for their use in developed countries. Routine probiotic use appears unjustified at
present and future studies employing patient-centered outcomes are needed. While further evi-
dence supporting ORT is needed to expand its use, such studies may be challenging to justify
as expert opinion overwhelmingly supports its use as first-line therapy in children with AGE.
Ondansetron has a strong evidence base supporting use and the key will be ensuring that ad-
ministration is directed at the populations included in the RCTs. It should be noted that
ondansetron use is not associated with reduction in ED revisits and it has the potential to in-
crease diarrheal episodes. Moving forward, studies focusing on important outcomes and pa-
tient populations are needed to build a stronger evidence base to guide therapy for this
extremely common condition.
Supporting Information
S1 File. Protocol.
(PDF)
S2 File. Search Strategy.
(DOC)
S1 Table. Risk of Bias.
(DOC)
S2 Table. Baseline Characteristics—Intravenous vs Oral Rehydration Therapy.
(DOC)
S3 Table. Baseline Characteristics–Antiemetics.
(DOC)
S4 Table. Baseline Characteristics–Probiotics.
(DOC)
S5 Table. Baseline Characteristics—Intravenous Fluids.
(DOC)
S6 Table. PRISMA Checklist.
(PDF)
Acknowledgments
Data Access
Drs. Stephen Freedman and Lisa Hartling had full access to all of the data (including statistical
reports and tables) in the study and take responsibility for the integrity of the data and the ac-
curacy of the data analysis.
Contributorship
We thank the following for their contributions to this project: Drs. Bob Hilliard, Francois
Belanger, Mona Jabbour and Terry Klassen for their contributions as knowledge users. We
thank David Johnson for his assistance with protocol development and critical review of the
manuscript. We thank the following staff from the Alberta Research Centre for Health

Evidence: Melanie Muise for assistance with data extraction and quality assessment, Jennifer
Seida for assistance grading the quality of evidence, Ben Vandermeer for advice on the statisti-
cal analysis, and Robin Featherstone for re-running the search.
Members of the Pediatric Emergency Research Canada Gastroenteritis Study Group: Ste-
phen Freedman (Lead), David Johnson, Karen Black, Robert Robert, Gary Joubert, Serge
Gouin, Quynh Doan, Janie Williamson, Lynell Aucoin, Eleanor Fitzpatrick, Mona Jabbour,
Terry Klassen.
Data sharing
The authors are prepared to provide the data on which the manuscript is based for examination
by the editors or their assignees if requested.
Meetings
Presented at 2014 Pediatric Academic Society Meeting in Vancouver, Canada, May 5, 2014.
Author Contributions
Conceived and designed the experiments: SF KB EF SG LH. Performed the experiments: AM
SF DP KB EF SG. Analyzed the data: LH DP. Wrote the paper: SF LH. Interpreted the data,
critically revised the draft manuscript, and gave final approval of the version to be published:
SF DP KB EF SG AM LH.
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Gastroenteritis Therapies in Developed Countries: Systematic Review and Meta-Analysis

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RESEARCH ARTICLE

Gastroenteritis Therapies in Developed

Academic Editor: Imti Choonara, Nottingham

Published: June 15, 2015

Data Availability Statement: All relevant data are

Competing Interests: All authors have completed

PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 1 / 21

unrelated study. Dr. Stephen Freedman has received Data Extraction

PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 2 / 21

Table 1. Summary of differing recommendations of prominent gastroenteritis guidelines.

PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 3 / 21

Information Sources and Searches

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Risk of Bias Assessment

Table 2. Interventions and their specific outcomes evaluated.

Primary Outcome Secondary Outcomes

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Grading the Body of Evidence

Oral Rehydration Therapy (ORT)

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Table 3. Overview of studies included in systematic review.

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Table 4. Results for Primary and Secondary Outcomes.

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Intravenous Fluid Therapy (IVT)

Table 5. Adverse Events.

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PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 13 / 21

Oral Rehydration Therapy

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PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 15 / 21

Intravenous Fluid Therapy

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PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 18 / 21

PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 19 / 21

PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 20 / 21

PLOS ONE | DOI:10.1371/journal.pone.0128754 June 15, 2015 21 / 21

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