Alimentary
Pharmacology & Therapeutics
Review
Article: The Management of Acute Gastroenteritis in Children
M.
Pieścik-Lech, R. Shamir, A. Guarino, H. SzajewskaDisclosures
Aliment
Pharmacol Ther. 2013;37(3):289-303.
Abstract and Introduction
Abstract
Background
In 2008,
the European Society for Paediatric Gastroenterology, Hepatology and Nutrition
(ESPGHAN) and the European Society of Paediatric Infectious Disease (ESPID)
developed evidence-based guidelines for the management of acute gastroenteritis
(AGE) in children in Europe.
Aim To
summarise data published subsequently to the ESPGHAN/ESPID guidelines.
Methods
MEDLINE and
The Cochrane Library were searched in August 2012 for randomised controlled
trials (RCTs) or their meta-analyses published after 2008.
Results
Efforts to
improve the taste and/or efficacy of oral rehydration solution (ORS) continue,
and some interventions are promising. While standard (over 24 h) nasogastric
rehydration is still being used, new evidence confirms that rapid (over 4 h)
rehydration is also effective. For intravenous rehydration, new evidence is
available regarding rapid or ultrarapid and large-volume vs. standard-volume
rehydration; as the new evidence is not consistent, until more data are
available, the administration of 20 mL/kg seems appropriate. Convincing
evidence has accumulated showing that ondansetron reduces the risk for
vomiting; however, a clearance on safety in children is needed. New evidence
has reconfirmed that in Europe, where zinc deficiency is rare, there is no
benefit from the use of zinc. New data, although mainly from outside of Europe,
have reconfirmed that either smectite or racecadotril is an effective
adjunctive therapy to oral rehydration. There is a clear effect of using
certain probiotics, such as Lactobacillus GG or S. boulardii.
Conclusions
The update
of current ESPGHAN/ESPID recommendations is warranted.
Introduction
Acute
gastroenteritis (AGE), characterised by the sudden onset of diarrhoea with or
without vomiting, is one of the most common infectious diseases of childhood.
In Europe, it is estimated that the incidence of diarrhoea ranges from 0.5 to
1.9 episodes per child per year in children up to 3 years of age.[1] In low-
and middle-income countries, while the incidence of acute diarrhoea has
declined from 3.4 episodes/child year in 1990 to 2.9 episodes/child year in
2010, the incidence of AGE remains high, especially in infants aged 6–11 months
(4.5 episodes/child year).[2] Moreover, worldwide diarrhoea remains one of the
leading causes of mortality among children younger than 5 years.[3]
In 2008,
the European Society for Paediatric Gastroenterology, Hepatology and Nutrition
(ESPGHAN) and the European Society of Paediatric Infectious Diseases (ESPID)
developed evidence-based guidelines for the management of AGE for practitioners
at all levels of health care – primary care physicians, paediatricians and
family physicians – practising in Europe.[1] In addition, a number of national
guidelines have been developed, although their quality varies.[4] Perhaps the
best known among them are those developed by the National Institute for Health
and Clinical Excellence (NICE).[5]
Both
ESPGHAN/ESPID and the NICE guidelines largely agree on key issues in the
management of AGE. Oral rehydration therapy with a hypotonic solution remains
central to the management of AGE. Fast oral rehydration with rapid return to
regular food is recommended. The routine use of special or diluted formulas is
unjustified. Continuation of breastfeeding is strongly recommended. The
guidelines recommend against the routine use of antibiotics in otherwise
healthy children presenting with AGE. Regarding drugs, both sets of guidelines
recommend against the use of antiemetics, but they strongly emphasise the need
for further research. Compared with the NICE guidelines, the ESPGHAN/ESPID
guidelines make a stronger recommendation for the use of probiotics for the
management of AGE, particularly those with documented efficacy such as
Lactobacillus GG and Saccharomyces boulardii. The ESPGHAN/ESPID guidelines
state that treatment with racecadotril (an enkephalinase inhibitor) may be
considered in the management of AGE. Both sets of guidelines state that there
is evidence suggesting that smectite (a natural hydrated aluminomagnesium
silicate that binds to digestive mucus and has the ability to bind endotoxins
and exotoxins, bacteria and rotavirus) is an effective antidiarrhoeal agent,
but only the ESPGHAN/ESPID guidelines recommend that the use of smectite may be
considered in the management of AGE.
The
objective of this review was to summarise the more recent data on the
management of AGE published subsequently to the ESPGHAN/ESPID document, and to
find out whether this added information justifies revision of the guidelines.
We searched MEDLINE and The Cochrane Database of Systematic Reviews in August
2012 for randomised controlled trials (RCTs) or their meta-analyses (considered
the best study design for answering questions about the effectiveness of an
intervention) published in the last 5 years related to the management of AGE in
the paediatric population. No limit was imposed regarding the language of
publication. In particular, we searched for studies on the use of enteral (oral
or nasogastric) and intravenous rehydration therapy, antiemetics and
antidiarrhoeal drugs [such as probiotics, (dio)smectite, zinc, racecadotril]
compared with placebo or no intervention in children (for summary of evidence,
see Table 1). Studies related to the use of antimicrobials are not covered in this
review. We focused primarily, although not exclusively, on studies performed in
high-income populations. In the case of diarrhoeal diseases, consideration of
the study location is important, as factors such as pathogens, access to clean
water and sanitation, or comorbidities may have an impact on outcomes.
Oral Rehydration Therapy
Despite the
proven efficacy of oral rehydration therapy, it remains underused.[6, 7] The
main reasons for this are that an oral rehydration solution (ORS) neither
reduces the frequency of bowel movements and fluid loss nor shortens the
duration of illness, which decreases its acceptance. Moreover, the
unpalatability of regular ORS (strong salty taste) also decreases its
acceptance, although this is only an issue in infants and young children who
are not dehydrated.
ORS With Improved Taste
The study
by Freedman et al.[8] was a prospective, double-blind, randomised, 3-period,
3-treatment cross-over trial conducted in 66 children aged 5–10 years with
concerns unrelated to the gastrointestinal tract. The aim of the study was to
compare the palatability of 3 ORSs (i.e. Pedialyte and Pediatric Electrolyte,
which both contain sucralose, and Enfalyte, which contains rice syrup solid).
For each solution, children were instructed to drink as much as they wanted for
15 min. Then, the children rated the taste of the solution by marking a 100-mm
visual analogue scale (0 indicating the worst taste and 100, the best taste).
Children consumed similar amounts of all 3 solutions. The sucralose-sweetened
oral rehydration solutions were significantly more palatable than was the
comparable rice-based solution. For convenience, this trial on taste was
conducted in children who did not require oral rehydration. It is unclear
whether similar findings would be found in children (especially in infants and
young children) with AGE and dehydration. Similarly, another RCT documented
variations in the acceptance of different flavours of ORS. However, again this
study was carried out in healthy children aged 6–9 years.[9]
The
efficacy and safety of a hypotonic ORS with an apple taste compared with a
regular hypotonic ORS were recently assessed in 130 Polish children aged 4–48
months with AGE. The proportion of children with a resolution of signs of
dehydration in the experimental group compared with the control group was
similar at 24 h (P = 0.28). There were also no significant differences in
adequate weight gain (P = 0.48) and urine production at 24 h (P = 0.95) between
groups. There were no differences between groups in any of the secondary
outcome measures, including ORS intake. Thus, this study showed that in an
out-patient setting, both ORSs were equally effective and may be used
interchangeably.[10]
ORS With Zinc
One new RCT
that involved 500 boys aged 1–35 months from India compared the use of ORS with
zinc (40 mg/L) vs. use of ORS alone for the management of acute diarrhoea.
There was no difference in the median stool output (P = 0.25) or in the time to
recovery (HR: 1.06, 95% CI: 0.88–1.27) between groups. The results of this
study are in contrast to earlier evidence from this region. However, the
WHO-recommended daily dose of zinc for the management of diarrhoea was not
achieved in most of the children beyond the first day of treatment.[11] Considering
the study population and location, the results are not directly applicable to a
high-income population.
ORS With Zinc and Prebiotics
One RCT
performed in 119 Italian children aged 3–36 months with AGE and
mild-to-moderate dehydration found a benefit of administering a hypotonic ORS
containing zinc (1 mmol/L) and prebiotics (fructooligosaccharides and
xilooligosaccharides – both 0.35 g/L). Compared with use of ORS alone, the use
of ORS with zinc and prebiotics resulted in a higher rate of diarrhoea resolution
at 72 h (50% vs. 72.9% respectively; P = 0.01), greater ORS intake during the
first 24 h (50 mL/kg vs. 22 mL/kg respectively; P < 0.001), and a reduced
number of missed working days by parents (0.39 vs. 1.45 days respectively; P
< 0.001). While the results are promising, it is unclear which component –
zinc, prebiotics, or both – was effective.[12]
ORS With Polymers
It has been
postulated that glucose polymer-based ORS (e.g. that prepared using rice or
wheat) slowly releases glucose and may be superior to standard ORS. One new
Cochrane review[13] (search date: September 2008) assessed the efficacy of
using polymer-based ORS vs. glucose-based ORS for treating acute watery
diarrhoea. Thirty-four RCTs (n = 4214) of variable methodological quality were
available for analysis, among them 27 RCTs performed in children. Most compared
polymer-based ORS with ORS with an osmolarity ≥310 mOsm/L. Compared with
glucose-based ORS (ORS≥310 mOsm/L and ≤270 mOsm/L groups combined), there were
fewer unscheduled intravenous infusions in children in the polymer-based ORS
group (19 RCTs, n = 2235, RR: 0.75, 95% CI: 0.59–0.95). Adverse effects were
similar for those who received polymer-based ORS or glucose-based ORS. The
authors' conclusion was that polymer-based ORS shows some advantages compared
with glucose-based ORS (≥310 mOsm/L) for treating all-cause diarrhoea and
diarrhoea caused by cholera. Limited evidence favoured the polymer-based ORS
over the ORS ≤270 mOsm/L. Thus, for firm conclusions, further trials should compare
the efficacy of the current standard ORS ≤270 mOsm/L with a polymer-based ORS.
ORS With L-isoleucine
On the
basis of the hypothesis that L-isoluecine enhances the secretion of
antimicrobial peptides in the intestinal epithelium, Alam et al.[14] evaluated
the effects of L-isoleucine (2 g/L) added to standard ORS in a small RCT
carried out in 50 boys with acute diarrhoea who live in Bangladesh. Compared
with the standard ORS group, boys in the L-isoleucine-supplemented ORS group
experienced some beneficial effects in terms of a reduction in stool output and
ORS intake, although this was not consistent. No significant difference was
observed in the duration of diarrhoea between the study groups (74 ± 38 h vs.
75 ± 42 h; P = 0.96). There was also no difference between groups in the
concentration of antimicrobial peptides in the stools.
ORS With Honey
Honey is
considered to have anti-inflammatory and antimicrobial properties. Researchers
in Egypt evaluated the effects of adding honey to ORS in an RCT that involved
100 infants and children with AGE. There was a significant reduction in
vomiting (P < 0.001) and diarrhoea frequency (P < 0.05) in the
honey-treated group compared with the control group (ORS alone). Also, the
recovery time (i.e. time from the initiation of the intervention to the passage
of the first normal stool, with normal hydration and satisfactory weight gain)
was significantly shorter in the honey-treated group compared with the control
group (P < 0.001).[15] Based on this single report, adding honey to ORS may
be of benefit.
In summary,
efforts to improve the taste and/or efficacy of ORS continue. While some
interventions are promising, no major breakthrough has been made since the
discovery of the scientific basis for oral rehydration and introduction of ORS
into everyday practice. Furthermore, most studies were carried out in
low-income countries, limiting their relevance to the Western world.
Early vs. Delayed Re-feeding
One
Cochrane review[21] (search date: May 2011) compared the efficacy and safety of
early (within 12 h of start of rehydration) and late (more than 12 h after
start of rehydration) reintroduction of feeding in children younger than 10
years with acute diarrhoea. The search identified 12 RCTs (n = 1283) of
variable methodological quality. Meta-analysis of the available data estimated
no significant difference between the two groups in the number of participants
who needed unscheduled intravenous fluids (6 RCTs, n = 813, RR 0.87, 95% CI:
0.48–1.59), who experienced episodes of vomiting (5 RCTs, n = 456, RR 1.16, 95%
CI: 0.72–1.86), and who developed persistent diarrhoea (4 trials, n = 522, RR
0.57, 95% CI: 0.18–1.85). The mean length of hospital stay was also similar
between groups (2 RCTs, n = 246). The authors of this meta-analysis stated that
there was no evidence that early reintroduction of feeds increases the risk of
unscheduled intravenous fluid use, episodes of vomiting and development of
persistent diarrhoea. Also, no conclusion could be made regarding the duration
of diarrhoea.
In summary,
recent evidence does support the current recommendation for early
reintroduction of regular feeding of children with AGE.
Nasogastric Rehydration
According
to current recommendations, when oral rehydration is not feasible, enteral
rehydration by the nasogastric route is as effective as, if not better than,
intravenous rehydration. In settings where nasogastric rehydration is common,
the results of a recent study from Australia are of interest. Children aged
6–72 months with viral AGE and moderate dehydration were recruited (n = 224).
Rapid (over 4 h) nasogastric rehydration was equally effective as a standard
(24 h) nasogastric rehydration. The primary failure rates (>2% weight loss
compared with the admission weight) were similar for the rapid rehydration
group and the standard rehydration group (11.8% vs. 9.2% respectively; P =
0.52). There were no statistically significant differences between the study
groups in persistent vomiting, dehydration scores, not tolerating the nasogastric
tube, or parental concern. Secondary treatment failure was more common in the
standard nasogastric rehydration group (P = 0.03). In general, rapid
nasogastric rehydration reduced the need for hospitalisation; however,
discharge from the emergency department failed in 27 of 132 (22.7%), and
another 9 (7.6%) children were readmitted to the hospital within 24 h in this
group.[16]
In summary,
rapid nasogastric rehydration for 4 h was effective in children with AGE. As
enteral rehydration, such as via nasogastric tube, is associated with
significantly fewer major adverse events (e.g. electrolyte imbalances, cerebral
oedema, phlebitis) than intravenous rehydration, the effectiveness of rapid
nasogastric rehydration is of clinical relevance.
Intravenous Rehydration
Intravenous
rehydration is the treatment of choice for severe dehydration and in cases of
failure of oral rehydration therapy. However, the most appropriate method is
still questionable. One of the discussions is focused on the volume and the rate
of administration of fluid used for intravenous rehydration. Previously, it has
been reported that evidence regarding rapid intravenous rehydration is lacking
and can be correlated with side effects.[17]
Ultrarapid vs. Rapid Large-volume Intravenous Hydration
In the US,
in a pilot trial carried out by Nager et al.,[18] 88 children aged 3–36 months
with vomiting and/or diarrhoea and moderate dehydration who failed oral
rehydration received either ultrarapid (50 mL/kg normal saline for 1 h) or
rapid ('standard') intravenous rehydration (50 mL/kg normal saline for 3 h).
Ultrarapid hydration for 1 h was comparable to standard 3-h hydration as
assessed by the mean emesis volume (69 mL/h in the ultrarapid group vs. 63 mL/3
h in the standard group), urine volume (93 mL/h in the ultrarapid group vs. 71
mL/3 h in the standard group), and stool output (45 mL/h in the ultrarapid
group vs. 75 mL/3 h in the standard group, P = 0.042). The two latter results
should be considered with caution because of the differences in the hydrating
time. There was no difference in the number of patients who needed to return to
the Emergency Department between the groups (7 vs. 6 respectively; P = 0.99).
No patient had complications, such as overhydration, seizures, deteriorating mental
status, or laboratory abnormalities (although the study was underpowered for
assessing harms). The authors concluded that the new hydrating regimen is an
efficacious alternative, saves time, and allows earlier discharge of children
from the emergency department.
Large-volume vs. Standard-volume Intravenous
Rehydration
The
Canadian study by Freedman et al.[19] included 223 children aged 3 months–11
years with dehydration due to AGE, who had not responded to oral rehydration.
Compared with standard intravenous rehydration (20 mL/kg), rapid intravenous
rehydration (60 mL/kg), both with 0.9% saline over 1 h, resulted in similar
proportions of children with clinical rehydration 2 h after initiation of
treatment (30% vs. 36% respectively, P = 0.32, NNT = 15). There were no
differences between groups in any of the secondary outcomes, including
prolonged treatment (P = 0.18), emergency department length of stay >6 h (P
= 0.78), emergency department revisit resulting in admission (P = 0.77), and
adequacy of oral intake. The median time to discharge was significantly longer
in children rehydrated rapidly. Thus, this study documented that the current
recommendation of administering 20 mL/kg per hour is adequate. Of note, the
study methodology, especially the validity of the eight-point clinical
dehydration scale, has been questioned by at least one author.[20]
Overall,
new evidence regarding intravenous rehydration is not consistent. While there
is no clear advantage of alternative approaches such as large-volume, rapid
rehydration, future studies may contribute to resolving some uncertainties. In
the absence of clear evidence, it is reasonable to follow the current
recommendation of administering 20 mL/kg boluses.
Early vs. Delayed Re-feeding
One
Cochrane review[21] (search date: May 2011) compared the efficacy and safety of
early (within 12 h of start of rehydration) and late (more than 12 h after
start of rehydration) reintroduction of feeding in children younger than 10
years with acute diarrhoea. The search identified 12 RCTs (n = 1283) of
variable methodological quality. Meta-analysis of the available data estimated
no significant difference between the two groups in the number of participants
who needed unscheduled intravenous fluids (6 RCTs, n = 813, RR 0.87, 95% CI:
0.48–1.59), who experienced episodes of vomiting (5 RCTs, n = 456, RR 1.16, 95%
CI: 0.72–1.86), and who developed persistent diarrhoea (4 trials, n = 522, RR
0.57, 95% CI: 0.18–1.85). The mean length of hospital stay was also similar
between groups (2 RCTs, n = 246). The authors of this meta-analysis stated that
there was no evidence that early reintroduction of feeds increases the risk of
unscheduled intravenous fluid use, episodes of vomiting and development of
persistent diarrhoea. Also, no conclusion could be made regarding the duration
of diarrhoea.
In summary,
recent evidence does support the current recommendation for early
reintroduction of regular feeding of children with AGE.
Lactose Avoidance
The
protocol of a systematic review on lactose avoidance for acute diarrhoea in
children younger than 5 years has been published by The Cochrane Library.[22]
However, at the time of writing this review, a full report was not available.
In summary,
there is no basis to change the current ESPGHAN/ESPID guidelines stating that
children with AGE can safely continue to consume lactose-containing milk
formula.
Diosmectite
Two new
RCTs were published. However, neither of them was performed in a high-income
country. Dupont et al.[30] performed 2 parallel, double-blind studies of
diosmectite efficacy on stool reduction in 602 children (age range: 1–36
months) with acute watery diarrhoea from 2 countries (Peru and Malaysia).
Children who needed intravenous therapy, had gross blood in their stools, had a
fever >39ºC, or were undergoing current treatment with antidiarrhoeal or
antibiotic medications were excluded. Children randomly received diosmectite (6
g/day for children 1–12 months of age or 12 g/day for children 13–36 months of
age; given for at least 3 days, followed by half doses until complete recovery)
or placebo in addition to ORS. The results are presented separately for the two
populations, because of the differences in the definitions of some of the
outcomes. In Peru (n = 300), in the diosmectite group compared with the placebo
group, there was reduced 72-h cumulative stool output (102.0 ± 65.5 g/kg vs.
118.8 ± 92.5 g/kg respectively; P = 0.032) and a shorter duration of diarrhoea
(median, 68.17 h vs. 118.92 h respectively; P = 0.001). The positive effect of
diosmectite was confirmed in both rotavirus-positive and rotavirus-negative
children. In Malaysia (n = 302), the 72-h stool output was also significantly
less in children who received diosmectite than in controls (87.9 ± 81.2 g/kg
vs. 90.7 ± 94.0 g/kg respectively; P = 0.007). The median duration of diarrhoea
was significantly shorter in children who received diosmectite than in controls
(median, 25.1 h vs. 32.6 h respectively; P = 0.001); however, the beneficial
effect was observed in rotavirus-negative children only.
The more
recent open RCT carried out in India also found that diosmectite reduced the
duration of diarrhoea and prevented a prolonged course.[31] In this study, 117
children aged 2–5 years with watery diarrhoea for <48 h and mild-to-moderate
dehydration were randomised to receive ORS and diosmectite (1.5 g, three times
a day, for 5 days) or ORS only. In the diosmectite group compared with the
control group, the time for resolution of the diarrhoea was significantly
shorter (64.34 ± 14.86 h vs. 82.37 ± 21.43 h respectively; P < 0.001) as was
the total duration of diarrhoea (91.45 ± 17.53 h vs. 107.53 ± 25.68 h
respectively; P < 0.001).
In summary,
although both recent studies were carried out outside Europe, the findings
reconfirmed that diosmectite, as an adjuvant to standard rehydration therapy,
may provide benefit in the management of children with AGE.
Antiemetics
Ondansetron
The authors
of one meta-analysis (search date: 2008)[23] of 6 RCTs published subsequently
to the ESPGHAN/ESPID guidelines found that ondansetron therapy (0.15–0.30 mg/kg
for intravenous therapy or 2–8 mg orally) decreased the risk of persistent
vomiting (5 RCTs, RR 0.45, 95% CI: 0.33–0.62; NNT 5), reduced the need for
intravenous fluids (4 RCTs, RR 0.41, 95% CI: 0.28–0.62, NNT 5) and decreased
the risk of immediate hospital admission (5 RCTs, RR 0.52, 95% CI: 0.27–0.95,
NNT 14) in children with vomiting due to gastroenteritis. However, compared
with placebo, ondansetron significantly increased diarrhoeal episodes in
treated patients in 3 RCTs, and it did not have an effect on return to care (5
RCTs, RR 1.34, 95% CI: 0.77–2.35). The researchers concluded that future
treatment guidelines should incorporate ondansetron therapy for selected
children with gastroenteritis. They also suggested that given the costs related
to intravenous therapy or hospitalisation, ondansetron therapy is likely to be
cost-effective.
A more
recent Cochrane Review (search date: March 2012)[24] included 7 RCTs that
compared ondansetron (0.15–0.30 mg/kg intravenously or 2–8 mg orally) with
placebo therapy and out of these, 4 RCTs investigated oral administration.
Children younger than 18 years of age who presented with vomiting and had a
clinical diagnosis of gastroenteritis were included. Compared with placebo,
ondansetron significantly increased the proportion of children with cessation
of vomiting (oral administration: 4 RCTs, n = 574, RR 1.44, 95% CI: 1.29–1.61,
NNT 4, and intravenous administration: 3 RCTs, n = 186, RR 2.01, 95% CI: 1.49–2.71).
The use of ondansetron also reduced the need for intravenous therapy (oral
administration: RR 0.41, 95% CI: 0.29–0.59) and the immediate hospital
admission rate (RR 0.40; 95% CI: 0.19–0.83). In 3 RCTs, there was an increased
rate of episodes of diarrhoea in the ondansetron group (P < 0.05). The
authors of the Cochrane review concluded that healthcare policy makers should
consider the wider use of ondansetron.
On the
basis of evidence available, only the Canadian Pediatric Society[25]
recommended that oral ondansetron therapy, as a single dose, should be
considered for children aged 6 months–12 years with vomiting related to
suspected AGE, and who have mild-to-moderate dehydration or who have failed
oral rehydration therapy. The use of ondansetron was not recommended in
children with AGE manifested predominantly as moderate-to-severe diarrhoea, as
one of the most common side effects of ondansetron is increased frequency of
diarrhoea. Of note, although outside the context of diarrhoea, according to the
FDA black box alert published in September 2011, electrocardiogram monitoring
is recommended in patients receiving ondansetron with potential 'electrolyte
abnormalities' due to the risk of developing prolongation of the QT interval,
which can lead to an abnormal and potentially fatal heart rhythm, including
Torsade de Pointes.[26]
Other Antiemetics
Other
antiemetic interventions studied using a meta-analytical approach have included
administration of dexamethasone, dimenhydrinate, granisetron, and metoclopramide.[23,
24] From these, it can be concluded that there is no evidence to support the
use of dexamethasone or metoclopramide, and there is only limited evidence that
granisetron or dimenhydrinate stops vomiting. With regard to the latter, one
more trial published after the Cochrane review was identified. This
double-blind RCT confirmed that compared with placebo, oral dimenhydrinate had
no effect on the frequency of vomiting in children 1–12 years of age with
AGE.[27]
The
protocol for a new multicentre RCT comparing oral ondansetron vs. domperidone
for symptomatic treatment of vomiting during acute gastroenteritis in children
has been published that will shed light on the remaining uncertainties.[28]
In summary,
new evidence indicates that ondansetron, at the dosages used in the studies and
administered orally or intravenously, may be considered for use in young
children with vomiting related to AGE. However, before a final recommendation
is made, a clearance on safety in children is needed. There is no evidence to
support the use of other antiemetics.
Racecadotril
A recent
individual patient data meta-analysis[29] (search date: December 2010) assessed
the efficacy of the use of racecadotril as an adjunct to ORS compared with ORS
alone or with placebo. Raw data from 9 RCTs involving 1348 children aged 1
month to 15 years with AGE were available for the analysis. The experimental
treatment was compared with placebo, with no treatment (2 RCTs), or with
kaolin-pectin (2 RCTs; the latter was not in line with the authors'
objectives). There were 4 studies in the in-patient setting, and 5 studies in
the out-patient setting. Compared with placebo, racecadotril significantly
reduced the duration of diarrhoea after inclusion (2.81 vs. 1.75 days
respectively). Almost two times more patients recovered at any time in the
racecadotril group vs. the placebo group (HR 2.04, 95% CI: 1.85–2.32; P <
0.001). There were no interactions between treatment and dehydration, rotavirus
infection, type of study (out-patient/in-patient), or country. In the studies
evaluating in-patients, the ratio of mean stool output racecadotril/placebo was
reduced (0.59, 95% CI: 0.51–0.74; P < 0.001). In out-patient studies, the
number of diarrhoeal stools was lower in the racecadotril group (mean ratio
racecadotril/placebo: 0.63, 95% CI: 0.51–0.74, as per abstract;P < 0.001).
In the responder analysis (defined as a duration of diarrhoea of less than 2
days), the proportion of responders was significantly higher in the
racecadotril group compared with the placebo group (50.3% vs. 25.8%
respectively). By adjusting for dehydration and rotavirus, the absolute risk
difference was 24.7% (95% CI: 19.8–29.7), and the associated number needed to
treat was 4. The secondary need for care in out-patients was significantly in
favour of racecadotril in 2 studies. Also, the need for intravenous therapy was
lower in the racecadotril group compared with the placebo group. There was no
difference in the incidence of adverse events between the groups.
In summary,
the results of a recent meta-analysis based on individual patient data do
support the use of racecadotril, as an adjunct to ORS, for the management of
AGE in children
Diosmectite
Two new
RCTs were published. However, neither of them was performed in a high-income
country. Dupont et al.[30] performed 2 parallel, double-blind studies of
diosmectite efficacy on stool reduction in 602 children (age range: 1–36
months) with acute watery diarrhoea from 2 countries (Peru and Malaysia).
Children who needed intravenous therapy, had gross blood in their stools, had a
fever >39ºC, or were undergoing current treatment with antidiarrhoeal or
antibiotic medications were excluded. Children randomly received diosmectite (6
g/day for children 1–12 months of age or 12 g/day for children 13–36 months of
age; given for at least 3 days, followed by half doses until complete recovery)
or placebo in addition to ORS. The results are presented separately for the two
populations, because of the differences in the definitions of some of the
outcomes. In Peru (n = 300), in the diosmectite group compared with the placebo
group, there was reduced 72-h cumulative stool output (102.0 ± 65.5 g/kg vs.
118.8 ± 92.5 g/kg respectively; P = 0.032) and a shorter duration of diarrhoea
(median, 68.17 h vs. 118.92 h respectively; P = 0.001). The positive effect of
diosmectite was confirmed in both rotavirus-positive and rotavirus-negative
children. In Malaysia (n = 302), the 72-h stool output was also significantly
less in children who received diosmectite than in controls (87.9 ± 81.2 g/kg
vs. 90.7 ± 94.0 g/kg respectively; P = 0.007). The median duration of diarrhoea
was significantly shorter in children who received diosmectite than in controls
(median, 25.1 h vs. 32.6 h respectively; P = 0.001); however, the beneficial
effect was observed in rotavirus-negative children only.
The more
recent open RCT carried out in India also found that diosmectite reduced the
duration of diarrhoea and prevented a prolonged course.[31] In this study, 117
children aged 2–5 years with watery diarrhoea for <48 h and mild-to-moderate
dehydration were randomised to receive ORS and diosmectite (1.5 g, three times
a day, for 5 days) or ORS only. In the diosmectite group compared with the
control group, the time for resolution of the diarrhoea was significantly
shorter (64.34 ± 14.86 h vs. 82.37 ± 21.43 h respectively; P < 0.001) as was
the total duration of diarrhoea (91.45 ± 17.53 h vs. 107.53 ± 25.68 h
respectively; P < 0.001).
In summary,
although both recent studies were carried out outside Europe, the findings
reconfirmed that diosmectite, as an adjuvant to standard rehydration therapy,
may provide benefit in the management of children with AGE.
Zinc
To our
knowledge, there have now been at least 3 new meta-analyses on the use of zinc
for treating AGE in children. The first one (search date: November 2007;
published in 2008) identified 18 RCTs (11,180 participants). Use of zinc (15–40
mg/day depending on age) was associated with a significant reduction in
diarrhoea duration and the risk of diarrhoea lasting longer than 7 days, but no
significant reduction in stool volumes. The authors concluded that zinc
supplementation can be useful for treating AGE in children. However, most of
the studies were performed in developing countries where zinc deficiency is
common.[32]
The second
meta-analysis (search date: not stated) found that zinc supplementation reduced
the mean duration of acute diarrhoea by 19.7% (19 RCTs, n = 8,957) and the mean
duration of persistent diarrhoea by 15–30%; however, zinc supplementation had
no effect on stool frequency or stool output, and it increased the risk of
vomiting.[33]
The most
recent review[34] (search date: February 2012) identified 19 RCTs comparing
oral zinc supplementation (10–40 mg/day depending on age) with placebo in
children aged 1 month–5 years with acute diarrhoea, who were mainly from
developing countries where zinc deficiency is common. Interestingly, in
children younger than 6 months, zinc supplementation had no effect on the mean
duration of diarrhoea (2 RCTs, n = 1334, low-quality evidence, MD – 5.23 h, 95%
CI: –4 to 14.45), and it may increase the risk of diarrhoea persisting until
day 7 (1 RCT, n = 1074, moderate-quality evidence, RR 1.24, 95% CI: 0.99–1.54).
In children older than 6 months, the administration of zinc reduced the
duration of diarrhoea (5 RCTs, n = 2091, low-quality evidence, MD – 10.44 h,
95% CI: –21.13 to 0.25), and it reduced the risk of diarrhoea persisting until
day 7 (6 RCTs, n = 3865, moderate-quality evidence, RR 0.73, 95% CI:
0.61–0.88).
For the
European population, there was only one RCT carried out in 141 Polish children
with AGE aged 3–48 months. These children were randomised to receive zinc
sulphate (10 or 20 mg/day depending on age) or placebo for 10 days. There was
no significant difference in the duration of diarrhoea between groups
(P>0.05). Similarly, there was no significant difference between the groups
in secondary outcome measures, such as stool frequency on days 1, 2, and 3,
vomiting frequency, intravenous fluid intake, and the number of children with
diarrhoea lasting >7 days.[35]
At least
one large trial in a high-income country (US) on oral zinc for the treatment of
acute diarrhoea is currently in progress (clinicaltrials.gov NCT01198587).
In summary,
recent data provide further evidence that children older than 6 months living
in developing countries may benefit from the use of zinc in the treatment of
AGE. However, in regions where zinc deficiency is rare, no benefit from the use
of zinc was documented.
Probiotics
In an
update to a previously published Cochrane review, Allen et al.[36] pooled data
from 63 RCTs (N = 8014) that evaluated the efficacy of probiotics for the
treatment of acute infectious diarrhoea in subjects of all ages. Probiotics (as
a group) reduced the duration of diarrhoea (35 RCTs, n = 4555; MD -25 h; 95%
CI: 16–34) and the risk of diarrhoea lasting ≥4 days (29 RCTs, n = 2853, RR
0.41, 95% CI: 0.32–0.53).
The
majority of the trials (56 RCTs) were carried out in infants and young
children. Forty-six RCTs tested a single probiotic, and 17 RCTs tested a
combination of 2 to 8 probiotics. The 2 most commonly studied probiotics were
Lactobacillus GG (13 RCTs) and S. boulardii (10 RCTs). The remaining probiotics
or their combinations were evaluated in 5 or fewer studies. As pooling data on
different probiotics has been repeatedly questioned, evidence on each probiotic
strain (or their combinations) should be evaluated separately.[37]
Lactobacillus rhamnosus GG
LGG is considered
particularly effective in the management of AGE. This was confirmed by the
updated Cochrane review documenting that LGG reduced the duration of diarrhoea
(11 RCTs, n = 2072; MD: −26.69; 95% CI: −40.5 to −12.88), mean stool frequency
on day 2 (6 RCTs, n = 1335; MD: −0.76, 95% CI: −1.32 to −0.2), and the risk of
diarrhoea lasting ≥4 days (4 RCTs, n = 572; RR: 0.59, 95% CI: 0.40–0.87).[36]
Saccharomyces boulardii
At least 2
new RCTs[38, 39] and 3 systematic reviews have confirmed the beneficial effects
of S. boulardii. The updated meta-analysis[40] (search date: August 2009) of 9
RCTs (n = 1117), compared with 5 RCTs (n = 619) included in the original
meta-analysis,[41] confirmed that in otherwise healthy infants and children,
the use of S. boulardii reduces the duration of diarrhoea by approximately 1
day. In addition, a Cochrane review (search date: July 2010) documented that S.
boulardii reduced the risk of diarrhoea lasting ≥4 days (6 RCTs, n = 606, RR:
0.37; 95% CI: 0.21–0.65; NNT 3, 95% CI: 2–3).[36] Finally, the authors of the
most recent review (search date: October 2011) confirmed that use of S.
boulardii significantly reduced the duration of diarrhoea (approximately 24 h)
and hospitalisation (20 h). The authors' conclusion was that both effects
result in social and economic benefits.[42]
Lactobacillus reuteri
Previously,
the pooled results from 2 RCTs (n = 106) documented that L. reuteri ATCC 55730
reduced the duration of diarrhoea as well as the risk of diarrhoea on days 1, 2
and 3 of an illness.[43] As the L. reuteri ATCC 55730 strain was found to carry
potentially transferable resistance traits for tetracycline and lincomycin, it
was replaced by a new strain, L. reuteri DSM 17938, with no unwanted
plasmid-borne resistances.[44] Recently, one RCT evaluated the efficacy of
treatment with L. reuteri DSM 17938 (dose of 4 × 108 CFU) compared with placebo
in 74 Italian children aged 6–36 months hospitalised for acute diarrhoea.
Administration of L. reuteri DSM 17938 compared with placebo significantly
reduced the duration of watery diarrhoea (2.1 ± 1.7 vs. 3.3 ± 2.1 days
respectively; P < 0.03), the risk of diarrhoea on day 2 (55% vs. 82%
respectively; P < 0.01) and on day 3 (45% vs. 74% respectively; P <
0.03), and the relapse rate of diarrhoea (15% vs. 42% respectively; P <
0.03). The duration of hospital stay was similar in both groups.[45]
Other Probiotics
A number of
studies on various probiotics (single or in combinations) were published
subsequently to the ESPGHAN/ESPID guidelines.[46–49] Many reported a shortened
duration of diarrhoea in the probiotic(s)-treated group.
In summary,
new evidence has confirmed that the probiotics currently supported by
ESPGHAN/ESPID – Lactobacillus GG and S. boulardii – are effective in reducing
the duration of diarrhoea. Current evidence clearly indicates that these are
not the only effective probiotic microorganisms; however, these are the most
studied. Probiotic effects are strain-specific, so the efficacy and safety of
each should be established. The safety and clinical effects of 1 probiotic
microorganism should not be extrapolated to other probiotic microorganisms. The
role of probiotics in the treatment of AGE in the era of rotavirus vaccination
has yet to be established.
Synbiotics
Synbiotics
are defined as a combination of prebiotics and probiotics that beneficially
affect the host by improving survival and implantation of live microbial
dietary supplements in the gastrointestinal tract.[50] Previously, synbiotics
were not addressed in the ESPGHAN/ESPID guidelines due to a lack of data. Two
recent RCTs evaluated the efficacy of synbiotics for the management of AGE. In
the first RCT,[51] researchers from Belgium compared the efficacy of 5
probiotic strains (Str. thermophilus, L. rhamnosus, L. acidophilus, B. lactis,
B. infantis) and fructooligosaccharides in 111 children with acute diarrhoea
(median age: 40 months). Compared with the placebo group, the median duration
of diarrhoea was significantly shorter in the synbiotic group [3 days (IQR:
2–4) vs. 4 days (IQR: 4–5); P < 0.005]. In the synbiotic group compared with
the placebo group, the number of children with normalised stool consistency was
higher at day 2 (21% vs. 2% respectively; P < 0.001) and at day 3 (50% vs.
24%, P < 0.001). Moreover, in the synbiotic group, less additional
medications (antipyretics, antiemetics, antibiotics) were administered.
In the
second RCT,[52] researchers in Italy demonstrated that another synbiotic
combination (L. paracasei B21060 plus arabinogalactan and xilooligosaccharides)
also appears to offer benefit. In this study that involved 107 children aged
3–36 months with acute diarrhoea, the rate of resolution of diarrhoea at 72 h
was significantly higher in children who received the synbiotic combination
compared with placebo (67% vs. 40% respectively; P = 0.005). Moreover, compared
with the placebo group, children in the synbiotic group experienced a
statistically significant reduction in the total duration of diarrhoea (109.8 h
vs. 90.5 h respectively; P = 0.04), number of stool outputs from 48 to 72 h
after treatment (3.3 vs. 2.4 respectively; P = 0.005), and stool consistency
score from 48 to 72 h after treatment (1.3 vs. 0.6 respectively; P = 0.002).
The percentage of patients requiring hospitalisation, the percentage of parents
who missed at least one working day and the rate of use of adjunct medications
were also significantly lower in the synbiotic group compared with the placebo
group.
In summary,
the studies on synbiotics are promising. However, it would not be appropriate
to recommend use of any of the synbiotics studied thus far until confirmatory
data are available.
Synbiotics
Synbiotics
are defined as a combination of prebiotics and probiotics that beneficially
affect the host by improving survival and implantation of live microbial
dietary supplements in the gastrointestinal tract.[50] Previously, synbiotics
were not addressed in the ESPGHAN/ESPID guidelines due to a lack of data. Two
recent RCTs evaluated the efficacy of synbiotics for the management of AGE. In
the first RCT,[51] researchers from Belgium compared the efficacy of 5
probiotic strains (Str. thermophilus, L. rhamnosus, L. acidophilus, B. lactis,
B. infantis) and fructooligosaccharides in 111 children with acute diarrhoea
(median age: 40 months). Compared with the placebo group, the median duration
of diarrhoea was significantly shorter in the synbiotic group [3 days (IQR:
2–4) vs. 4 days (IQR: 4–5); P < 0.005]. In the synbiotic group compared with
the placebo group, the number of children with normalised stool consistency was
higher at day 2 (21% vs. 2% respectively; P < 0.001) and at day 3 (50% vs.
24%, P < 0.001). Moreover, in the synbiotic group, less additional
medications (antipyretics, antiemetics, antibiotics) were administered.
In the
second RCT,[52] researchers in Italy demonstrated that another synbiotic
combination (L. paracasei B21060 plus arabinogalactan and xilooligosaccharides)
also appears to offer benefit. In this study that involved 107 children aged
3–36 months with acute diarrhoea, the rate of resolution of diarrhoea at 72 h
was significantly higher in children who received the synbiotic combination
compared with placebo (67% vs. 40% respectively; P = 0.005). Moreover, compared
with the placebo group, children in the synbiotic group experienced a
statistically significant reduction in the total duration of diarrhoea (109.8 h
vs. 90.5 h respectively; P = 0.04), number of stool outputs from 48 to 72 h
after treatment (3.3 vs. 2.4 respectively; P = 0.005), and stool consistency score
from 48 to 72 h after treatment (1.3 vs. 0.6 respectively; P = 0.002). The
percentage of patients requiring hospitalisation, the percentage of parents who
missed at least one working day and the rate of use of adjunct medications were
also significantly lower in the synbiotic group compared with the placebo
group.
In summary,
the studies on synbiotics are promising. However, it would not be appropriate
to recommend use of any of the synbiotics studied thus far until confirmatory
data are available.
Conclusions
This review
summarised the most recent data on the management of AGE published subsequently
(i.e. after 2008) to the ESPGHAN/ESPID guidelines (Table 2). The update of
current recommendations is warranted.
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