Review Articles

Stress ulcer, gastritis, and gastrointestinal bleeding prophylaxis in

critically ill pediatric patients: A systematic review
Ludovic Reveiz, MD, MSc; Rafael Guerrero-Lozano, MD; Angela Camacho, MD; Lina Yara, MD;
Paola Andrea Mosquera, Psi, MSc

Objective: To identify and evaluate the quality of evidence
supporting prophylactic use of treatments for stress ulcers and
upper gastrointestinal bleeding. Stress ulcers, erosions of the
stomach and duodenum, and upper gastrointestinal bleeding are
well-known complications of critical illness in children admitted
to the pediatric intensive care unit.
Data Sources: Studies were identified from the Cochrane Cen-
tral Register of Controlled Trials, PUBMED; LILACS; Scirus. We also
scanned bibliographies of relevant studies.
Study Selection: This systematic review of randomized con-
trolled trials assessed the effects of drugs for stress-related
ulcers, gastritis, and upper gastrointestinal bleeding in critically
ill children admitted to the pediatric intensive care unit.
Data Extraction and Synthesis: Two reviewers independently
extracted the relevant data. Most randomized controlled trials
were judged as having unclear risk of bias. When pooling two
randomized controlled trials, treatment was significantly more
effective in preventing upper gastrointestinal bleeding (macro-
scopic or important bleeding) compared with no treatment (two
studies ! 300 participants; relative risk, 0.41; 95% confidence
interval, 0.19 – 0.91; I2 ! 12%). Meta-analysis of two studies
found no significant difference in death rates among groups (two
randomized controlled trials ! 132 participants; relative
risk, 1.39; 95% confidence interval, 0.70 –2.79; I2 ! 4%). The rate
of pneumonia was not significantly different when comparing
treatment and no treatment in one study. When comparing rani-
tidine with no treatment, significant differences were found in the
proportion of mechanically ventilated children with normal gastric
mucosal endoscopic findings by histologic specimens (one ran-
domized controlled trial ! 48 participants; relative risk, 3.53; 95%
confidence interval, 1.34 –9.29). No significant differences were
found when comparing different drugs (omeprazole, ranitidine,
sucralfate, famotidine, amalgate), doses, or regimens for main
outcomes (deaths, endoscopic findings of erosion or ulcers, upper
gastrointestinal bleeding, or pneumonia).
Conclusions: Although pooled data of two studies suggested
that critically ill pediatric patients may benefit from receiving
prophylactic treatment to prevent upper gastrointestinal bleeding,
we found that high-quality evidence to guide clinical practice is
still limited. (Pediatr Crit Care Med 2010; 11:124 –132)
KEY WORDS: children; stress ulcer; gastrointestinal bleeding;
intensive care unit; critical care; prophylaxis; systematic review

S tress ulcers of the stomach and
duodenum as well as upper
gastrointestinal (UGI) bleeding
are well-known complications
of critical illness in children admitted to a
pediatric intensive care unit (ICU). The
prevalence of stress ulceration in criti-
cally ill adults and children may vary de-
pending on the severity of the illness and
methods used for diagnosis. A cohort of
1006 consecutive admissions enrolled in
a pediatric ICU reported that 10.2% of
pediatric participants had UGI bleeding
From the Research Institute (LR, PAM), Grupo de
Evaluación de Tecnologías, and the Department of
Pediatrics (RG-L, AC, LY), National University of Co-
lombia, Bogotá, Colombia.
The authors have not disclosed any potential con-
flicts of interest.
For information regarding this article, E-mail:
mmreveiz@hotmail.com
Copyright © 2010 by the Society of Critical Care
Medicine and the World Federation of Pediatric Inten-
sive and Critical Care Societies
DOI: 10.1097/PCC.0b013e3181b80e70
and 1.6% had clinically significant UGI
bleeding (1). Clinically important UGI
bleeding has an important attributable
morbidity and mortality in adults, asso-
ciated with a significant risk of death
(relative risk [RR], 4.1; 95% confidence
interval [CI], 2.6 – 6.5) and an excess
length of ICU stay of approximately 4 to 8
days (2). Clinically important UGI bleed-
ing is defined as macroscopic bleeding
that results in hemodynamic instability
and the need for red blood cell transfu-
sion and may lead to complications, such
as gastrointestinal perforations and sur-
gery (3, 4).
Prophylaxis against stress ulcers has
been recommended for the prevention of
UGI bleeding in critically ill adults pa-
tients. A systematic review published
more than one decade ago found that
prophylaxis with histamine2-receptor an-
tagonists decreases the occurrence of
overt gastrointestinal bleeding (odds ra-
tio [OR], 0.58; 95% CI, 0.42– 0.79) and
clinically important bleeding (OR, 0.44;
95% CI, 0.22– 0.88) (5). Another study
found that, among critically ill adult pa-
tients requiring mechanical ventilation,
those receiving ranitidine had a signifi-
cantly lower rate of clinically important
gastrointestinal bleeding than those
treated with sucralfate and no significant
differences were found in the rates of
ventilator-associated pneumonia, the du-
ration of the stay in the ICU, or mortality
(6). However, a more recent integrative
study found that ranitidine was ineffec-
tive in the prevention of UGI bleeding in
patients in intensive care compared with
placebo (OR, 0.72; 95% CI, 0.30 –1.70)
and might increase the risk of pneumonia
when compared with sucralfate
(OR, 1.35; 95% CI, 1.07–1.70) and that
studies on sucralfate do not provide con-
clusive positive results (7). A guideline on
stress ulcer prophylaxis published in
2006 recommended pharmacologic inter-
vention in adults admitted to the ICU
who have coagulopathy, require mechan-
ical ventilation for !48 hrs, have a his-

124 Pediatr Crit Care Med 2010 Vol. 11, No. 1

tory of gastrointestinal ulceration or
bleeding within 1 yr before admission, or
have at least two of the following risk
factors: sepsis, ICU stay of !1 wk, occult
bleeding lasting !6 days, and use of
!250 mg of hydrocortisone or the equiv-
alent (8). Unfortunately, there is still con-
flicting evidence concerning prophylaxis
for stress ulcers in children and we did
not find any systematic review on this
topic.
The aims of the systematic review pre-
sented here are to assess the best evi-
dence on the effects of interventions for
stress ulcer in children, to identify gaps
in the literature, and to suggest further
clinical investigation.
METHODS
Literature Search
Relevant randomized controlled trials
(RCTs) were identified from the Cochrane
Central Register of Controlled Trials (The Co-
chrane Library 2008, Issue 3), PubMed (1966
to June 2008), LILACS (1982 to June 2008),
and Scirus (June 2008). A search strategy to
locate studies on stress ulcer, UGI in children
was structured and adapted according to each
electronic database (Appendix A). The Interna-
tional Clinical Trials Registry Platform search
portal (http://www.who.int/trialsearch/De-
fault.aspx), the metaRegister of controlled tri-
als (www.controlled-trials.com) and http://
clinicaltrials.gov/ were searched for ongoing
trials. Eligible RCTs were included regardless
of the language of publication. We also
scanned bibliographies of relevant studies for
possible references to additional RCTs.
Study Selection
Two authors independently decided which
trials fit the inclusion criteria. Any disagree-
ments were resolved by discussion between
the reviewers, with referral to a third author if
necessary. Only RCTs of interventions for
stress ulcer in hospitalized children (studies
that included participants aged "18 yrs) were
considered in this systematic review. We con-
sidered any hospitalized children including
critically ill pediatric patients having or not
having mechanical ventilation, children ad-
mitted to pediatric ICUs or who underwent
surgery, preterm and full-term newborns
among others. Quasirandomized and nonran-
domized controlled studies were not discussed
further. We considered all doses and regimen
treatments as single or combined therapy used
as prophylaxis against stress ulcers. The com-
parators were placebo, no treatment, or an-
other active compound.
Pediatr Crit Care Med 2010 Vol. 11, No. 1
Data Extraction
At least two reviewers (L.R., L.Y., P.A.M.)
independently extracted the relevant data, us-
ing a predesigned data extraction form; dis-
agreement was resolved by consensus with all
authors. We extracted year of publication, pa-
tient population, number of patients (by in-
tention to treat), aspects of study quality, so-
ciodemographic, interventions (drug, dose,
duration of treatment), clinical, endoscopic,
and histologic outcomes and adverse effects.
Risk of Bias
Assessment/GRADE System
The Cochrane Collaboration recently pro-
posed a new tool having six domains to assess
the risk of bias of RCTs (namely, sequence
generation of randomization, allocation con-
cealment to prevent foreknowledge of group
assignment in an RCT, blinding, incomplete
outcome data, selective outcome reporting
and “other issues”). Therefore, a risk of bias
evaluation of each RCT was done for the as-
sessment of these features (9). Additional
quality information reported included also in-
formation of withdrawals, inclusion and exclu-
sion criteria, sample size calculation, and
baseline comparability of age, gender, relevant
clinical characteristics and diagnoses and du-
ration of complaint.
The tool for assessing risk of bias in each
RCT comprises a description and a judgment
for each entry in a “risk of bias” table. The
judgment for each entry involves answering a
question, with answers “Yes” indicating low
risk of bias, “No” indicating high risk of bias,
and “Unclear” indicating either lack of infor-
mation or uncertainty over the potential for
bias. A study should be considered as having
“low risk of bias” if all key domains were
judged as “Yes” and with unclear risk if the
reviewers judged “Unclear risk of bias” for one
or more key domains (9). We also used the
GRADE system for grading the quality of evi-
dence and the strength of recommendations
by two reviewers. A systematic approach for
grading the strength of management recom-
mendations can minimize bias and aid inter-
pretation of clinical practice guidelines. This
system takes into account study design, study
quality, consistency, and directness in judging
the quality of evidence for each important
outcome (10).
Definitions and Outcomes
The main outcomes considered were
death; presence of ulcers, gastritis, or UGI
bleeding; bleeding that requires transfusion;
bleeding associated with hemodynamic insta-
bility; gastrointestinal perforations; and pneu-
monia. In addition, endoscopic findings cate-
gorized according to the severity of UGI tract
lesions were also considered primary out-
come. We anticipated that diverse classifica-
tions could have been used by trialists. Other
outcomes were: delayed gastric emptying; bac-
teremia during the follow-up; mean patient’s
gastric aspirates pH during 24-hr monitoring,
pediatric ICU stay; duration of mechanical
ventilation hematologic test; cultures of gas-
tric and tracheal secretion, gastric and tra-
cheal colonization; and complicated postoper-
ative course. We only included data on adverse
events from RCTs; no further searches for
other types of studies were done (11).
Statistical Analysis
Statistical analyses were done with Review
Manager version 5.0 (Cochrane Collaboration)
software. The results expressed as RR and 95%
CI for dichotomous primary outcomes were
calculated by the Mantel-Haenszel fixed-
effects model. Weighted mean difference with
95% CI was used for continuous outcomes.
For the pooled analysis, we calculated the I2
statistic, which describes the percentage of
total variation across studies caused by heter-
ogeneity (9). Low, moderate, and high levels of
heterogeneity approximately correspond to I2
values of 25%, 50%, and 75%, respectively.
RESULTS
Description of Studies
A total of 294 citations were identified
from the diverse sources of information.
Of the 74 potentially RCTs screened, we
excluded 52 references because they were
guidelines, observational studies, or case
series reports. We identified 22 studies
assessing the effects of different thera-
peutic interventions for stress ulcers in
children (Fig. 1). However, we excluded
13 studies because they were nonran-
domized or noncontrolled or focused on
pharmacokinetics of drugs (12–24). One
study in Hungarian is pending for evalu-
ation (25). In total, we included and an-
alyzed eight RCTs evaluating the effects
of drugs for preventing stress ulcers in
children (26 –33). The main characteris-
tics of the eight included studies are de-
tailed in Table 1. Table 1: We could not
assess publication bias (e.g., funnel plot
or Egger regression test) because we
found less than nine RCTs and we could
not pool outcomes for more than three
studies.
Risk of Bias
Seven studies were open and we found
no RCT with low risk of bias. Overall six
125

Figure 1. Flow diagram of the process of identifying and including references.
RCTs were judged as having unclear risk
of bias mainly because the description of
the method used to generate the se-
quence of randomization and to conceal
the allocation was unclear (Table 2).
Some markers of quality in medical re-
search, such as performing a sample size
calculation, are unlikely to have direct
implications for risk of bias. However, the
majority of RCTs did not calculate the
sample size, which is a source of potential
imprecision. Overall the quality of the
reporting and design of the RCTs was
poor.
Effects of Interventions
Treatment Versus No Treatment
We found four studies that evaluated a
number of medications (cimetidine, al-
magate, ranitidine, sucralfate, and ome-
prazole) vs. no treatment or placebo for
different outcomes; data were not avail-
able in all RCTs for each outcome (26, 28,
30, 33).
When pooling two RCTs (Fig. 2),
“treatment” (which included almagate,
126
ranitidine, sucralfate, and omeprazole)
was significantly more effective in pre-
venting UGI bleeding (macroscopic or
important bleeding) compared with “no
treatment” (two studies # 300 partici-
pants; RR, 0.41; 95% CI, 0.19 – 0.91; I2 #
12%) (28, 30). However, no significant
difference was found when pooling both
studies of treatment vs. no treatment
with an additional RCT comparing treat-
ment vs. placebo (three studies # 340
participants; RR, 0.69; 95% CI, 0.41–1.17;
I2 # 63%) (26, 28, 30). In addition, meta-
analysis of two studies (30, 33) found no
significant difference in death rates
among groups (two RCTs # 132 partici-
pants; RR, 1.39; 95% CI, 0.70 –2.79; I2 #
4%). The rate of pneumonia was not sig-
nificantly different when comparing treat-
ment and no treatment in one study (30).
Summary of relevant findings for primary
outcomes of RCTs included in the review
are detailed in Table 3.
Ranitidine
One RCT (33) in mechanically venti-
lated preterm and full-term newborns
treated in a neonatal ICU showed that
rates of normal gastric mucosal endo-
scopic findings by visual inspection (one
RCT # 48 participants; RR, 3.04; 95%
CI, 1.30 –7.12) and histologic specimens
(one RCT # 48 participants; RR, 3.53;
95% CI, 1.34 –9.29) were significantly
higher in the ranitidine group compared
with no treatment groups. However, no
significant differences among groups
were found in the rates of patients with
erosions or ulceration, gastrointestinal
problems (bleeding from the gastrointes-
tinal tract and/or vomiting or delayed
gastric emptying), positive bacterial cul-
tures from the biopsy specimens, and the
risk for later suspected or proven bacte-
remia during the follow-up. An RCT of
children who needed mechanical ventila-
tion on admission (30) showed no signifi-
cant difference between groups in macro-
scopic bleeding, pneumonia occurrence,
duration of mechanical ventilation (days)
and pediatric ICU stay (days). Another RCT
of children admitted to a pediatric ICU (28)
did not show statistical difference in the
rates of patients with important UGI hem-
orrhage among groups. A significant differ-
ence favoring ranitidine was found in the
percentage of children with mean pH of !4
during !50% of study time compared with
no treatment (one RCT # 70 participants;
RR, 8.67; 95% CI, 2.89 –26.02).
Amalgate
An RCT (28) showed a significant dif-
ference favoring amalgate in the percent-
age of patients’ gastric aspirates with
mean pH of !4 during !50% of study
time (one RCT # 70 participants;
RR, 11.00; 95% CI, 3.72–32.56). No sig-
nificant difference was found among
groups regarding the rates of patients
with important UGI hemorrhage.
Sucralfate
In one RCT (28), a trend favoring su-
cralfate was found in the percentage of
patients’ gastric aspirates with mean pH
of !4 during !50% of study time (one
RCT # 70 participants; RR, 3.33; 95%
CI, 1.00 –11.09). However, no significant
difference between groups was found for
other outcomes, such as rate of patients
with important UGI hemorrhage. An-
other RCT (30) did not report significant
difference among groups in rates of mac-
roscopic bleeding, pneumonia, and
deaths as well as in the duration of me-
Pediatr Crit Care Med 2010 Vol. 11, No. 1
Table 1. Characteristics of randomized controlled trials included in the review
Study Methods Participants
Aanpreung et al (31) Open randomized Twenty critically ill pediatric patients
controlled trial aged 2 mos to 12 yrs. Severity of
disease was assessed using Zinner
index score.
Behrens et al (32) Open randomized Children who underwent corrective or
controlled trial palliative surgery for congenital heart
patients from the disease. Age, weight, cardiopulmonary
pirenzepine or bypass time, aortic cross clamp period,
famotidine group and mean interval between endoscopy
were and cardiac surgery were not
randomized. “No significantly different in the two
treatment group” groups.
vs. treatment
group was not
randomized.
Kuusela et al (33) Open randomized The study group was prospectively
controlled trial collected from mechanically ventilated
preterm and full-term newborns
treated in a neonatal ICU. The
criterion for inclusion in the study
was the start of mechanical ventilation
during the first 2 hrs of life. Most of
the infants were preterm; the mean
gestational age was 32 wks (range #
24–41 wks) and the mean birth weight
was 1832 g (range # 620– 4550 g).
Twenty-nine of the neonates were
male and 24 were female. Altogether,
37 preterm infants of gestational age
of "33 wks and 16 infants of
gestational age of !33 wks were
enrolled in the study.
Lacroix et al (26) Double-blind Forty children from birth to 18 yrs old
randomized admitted to PICU. Inclusion criteria
controlled trial were that illness was severe enough to
preclude any oral or enteral nutrition
for at least 2 days. Exclusion criteria:
UGI bleeding, burns, or surgical
problems; need of oral or enteral
feeding; renal failure or cerebral
death; treatment requiring cimeridine
or antiacids. Mean & SD age was 1.85
& 3.25 yrs.
Lopez-Herce et al (27) Open randomized Forty patients admitted to PICU ranging Patients were randomized into four
controlled trial from neonate to 17 yrs old were
included.
Lopez-Herce et al (28) Open randomized 165 children admitted to PICU
controlled trial presenting at least one of the
following criteria: shock, acute renal,
cardiac respiratory or liver failure,
sepsis or serious focal infection,
coagulopathy, acute neurologic
dysfunction, multiple trauma, severe
metabolic acidosis post major surgery.
All patients had nasogastric tube
inserted. Severity of illness was
evaluated with three scores.
Pediatr Crit Care Med 2010 Vol. 11, No. 1
Interventions
Intravenous ranitidine 1.5 mg/kg every Patients’ intragastric pH was measured by
6 hrs and famotidine 0.4 mg/kg
every 8 hrs
The first 36 patients (group 1) were
not given treatment to prevent
lesions of the UGI tract. Later, 43
patients (group 2) were randomized
and treated either with pirenzepine,
an anticholinergic (21 patients) or
famotidine, a H2 antagonist (22
patients). Both drugs were given
intravenously at a dosage of 1 mg/
kg/day. In older patients, the drugs
were given as two doses; children
who weighed "10 kg were given
three doses.
Fifty-three mechanically ventilated
newborns were randomized into
either the treatment group
(prophylactic intravenous ranitidine
$5 mg/kg body weight/day% divided
into three doses throughout 4 days)
or the control group (no
prophylaxis). Prophylactic treatment
commenced immediately parallel to
mechanical ventilation. There was
no placebo treatment available.
Patients were randomized to
cimetidine 0.13 mL/kg/day
(ampoule 150/mg/mL) or placebo
every 6 hrs as long as 10 days.
groups. All of them received
ranitidine at different dosages: a) 2
mg/kg by nasogastric tube every 12
hrs; b) 4 mg/kg by nasogastric tube
every 12 hrs; c) 0.75 mg/kg iv every
6 hrs; d) 1.5 mg/kg iv every 6 hrs.
Participants were randomized to four Gastric pH evolution, UGI hemorrhage
groups: no treatment; almagate 0.25
mL/kg every 2 hrs; ranitidine 1.5
mg/kg iv every 6 hrs; and sucralfate
0.5 gr if weighing "10 kg and 1 gr
if weighing !10 kg every 6 hrs.
Outcomes
continuous pH monitoring digitrapper.
Intensity of UGI hemorrhage was
classified into three categories:
nonhemorrhage; slight; and important.
All patients had at least one endoscopic
examination performed by the same
examiner as the patients still required
mechanical ventilation. To assess the
severity of lesions of the UGI tract,
authors developed a score based on the
endoscopic findings: Normal findings 0;
Mild-to-moderate inflammation, few
petechiae or erosions 1; Pronounced
inflammation, multiple petechiae
erosions 2; Ulcer(s) 3. Additional
outcomes: continuous 24-hr
measurement of pH; tracheal and gastric
secretions culture; daily routine chest
radiographs on the first 3 postoperative
days and afterwards chest radiographs
were taken if indicated by the clinical
findings.
The primary outcome variable was mucosal
lesions detected endoscopically. The
procedure was planned for all patients at
the age of 3 to 6 days. The findings were
grouped into four categories: a) intact
gastric mucosa; b) mucosal friability; c)
erythema or gross blood; and d) erosions
or ulcers. Gastric mucosal biopsy
specimens were obtained for histological
and bacteriologic evaluation if there
were no contraindications. Alcian-blue-
periodic-acid-Schiff and modified Giemsa
stains were used to demonstrate fungi
and bacteria. Biopsy specimens were also
obtained for bacterial culture.
UGI bleeding noted from nasogastric tube.
Massive UGI bleeding was defined as
brown hemorrhage from nasogastric
tube and a decrease in arterial blood
pressure of !20 mm Hg or with an
acute decrease of hemoglobin of 2 mg/
dL pH measurements.
Treatment was considered successful when
gastric pH was !4 during !80% of the
study time on each patient.
occurrence rate, microscopic upper
gastrointestinal hemorrhage, mortality,
adverse events.
127
Table 1. —Continued

Study Methods Participants Interventions Outcomes

Osteyee et al (29) Open randomized Sixteen critically ill children.
cross over trial
Yildizdas et al (30) Open randomized 160 patients who needed mechanical
controlled trial ventilation on admission were enrolled
in the study. Patients were excluded if
any of the following circumstances
occurred in the first 48 hrs after
inclusion: extubation, death,
pneumonia, or new information that
the patient had received one of the
study drugs in the last 48 hrs before
admission.
Children in group 1 received bolus
dosing on day 1 and continuous
infusion of ranitidine on day 2.
Group 2 received the continuous
infusion on day 1 and bolus dosing
on day 2. Continuous infusion
regimen: ranitidine bolus of 0.15
mg/kg followed by continuous
infusion at 0.15 mg/kg per hour for
12 hrs. Bolus regimen: 1 mg/kg,
two doses 6 hrs apart.
Group S received sucralfate suspension Ventilator-associated pneumonia was
60 mg/kg/day in four doses via the
nasogastric tube that was flushed
with 10 mL of sterile water; group
R received ranitidine 2 mg/kg/day
intravenously in four doses; group
O received omeprazole 1 mg/kg/day
intravenously in two doses; and
group P did not receive any
medication for stress ulcer
prophylaxis.
Gastric pH.
defined as the occurrence of a new or
persistent radiographic infiltrate in
conjunction with one of the following:
positive pleural/blood culture with the
same organism recovered in the tracheal
aspirate or sputum, radiographic
cavitation, histopathologic evidence of
pneumonia; or at least two of the
following: fever; leukocytosis; and
purulent tracheal aspirate or sputum.
Pneumonia was considered to be
ventilator associated if it occurred after
a minimum of 48 hrs after the initiation
of mechanical ventilation. Respiratory
tract culture specimens were obtained
from tracheal aspirates. Hospital
mortality was defined as patient death
occurring in the PICU and hospital stay
was defined as the days in the PICU.

UGI, upper gastrointestinal; H2 antagonists, histamine H2-receptor antagonists; ICU, intensive care unit; PICU, pediatric intensive care unit; SD,
standard deviation.

chanical ventilation and pediatric ICU
stay.
Omeprazole
In one RCT (28), omeprazole was not
superior to no treatment in groups in
rates of macroscopic bleeding, pneumo-
nia, deaths, and in the duration of me-
chanical ventilation and pediatric ICU
stay.
Cimetidine
In one RCT (26), cimetidine was not
superior to placebo in rates of UGI
bleeding.
Drug Vs. Any Other Active
Compound
We found seven studies comparing di-
verse drugs, doses, and regimen (27–32).
Most studies did not report outcomes,
such as mortality, rates of UGI bleeding,
and pneumonia.
Pirenzepine Vs. Famotidine
No significant differences were found
between groups in one RCT of children
who underwent corrective or palliative
surgery for congenital heart disease con-
cerning rates of pneumonia and organ-
ism cultured from the stomach and from
tracheal secretion (32).
Ranitidine Vs. Sucralfate
One RCT (28) showed that ranitidine
had a significant effect in the rate of pa-
tients’ gastric aspirates with mean pH of
!4 during !50% compared with sucral-
fate (one RCT # 70 participants;
RR, 2.60; 95% CI, 1.49 – 4.55). However,
no significant differences were found in
the rates of patients with important UGI
hemorrhage (28) and macroscopic bleed-
ing, death and pneumonia, and in the
duration of mechanical ventilation and
pediatric ICU stay (29).
Ranitidine Vs. Amalgate
Ranitidine was significantly superior
to amalgate in the rate of patients’ gastric
aspirates with mean pH of !4 during
!50% of study time (one RCT # 70 par-
ticipants; RR, 0.79; 95% CI, 0.64 – 0.97).
No significant differences were found be-
tween groups in the rates of patients with
important UGI hemorrhage and gastroin-
testinal symptoms, such as nausea, vom-
iting, or diarrhea (28).
Amalgate Vs. Sucralfate
One RCT (28) showed that amalgate
had a significant effect in the rate of pa-
tients’ gastric aspirates with mean pH of
!4 during !50% compared with sucral-
fate (one RCT # 70 participants;
RR, 3.30; 95% CI, 1.94 –5.61). No signif-
icant differences were found between
groups in the rates of patients with im-
portant UGI hemorrhage and gastrointes-
tinal symptoms, such as nausea, vomit-
ing, or diarrhea (28).
Ranitidine Vs. Famotidine
No significant differences were found
between groups in one RCT (31) of criti-
cally ill pediatric patients in the rate of
patients’ gastric aspirates with mean pH
of !4 during !80% of study time.
Other Comparisons
No significant differences were found
between groups in one RCT (30) of pa-

128 Pediatr Crit Care Med 2010 Vol. 11, No. 1

Table 2. Assessment of the risk of bias in randomized controlled trials included in the reviewa (9)

Blinding of Incomplete Free of

Sequence Allocation Participants, Personnel, Outcome Data/ Selective Other Sources of
Study Generation Concealment and Outcome Assessors Withdrawals Reporting? Bias/Commentaries Overall Risk

Aanpreung Unclear Unclear No Yes No Yes. Description of baseline Unclear risk of bias
et al (31) characteristics.
Behrens Unclear Unclear No Yes Unclear Yes. The clinical course of Unclear risk of bias
et al (32) patients in both groups
was similar. Similar
baseline characteristics.
Kuusela Unclear Unclear Unclear Yes Unclear Yes Unclear risk of bias
et al (33)
Lacroix Yes Unclear Unclear Yes Unclear Yes Unclear risk of bias
et al (26)
Lopez-Herce Unclear Unclear No Yes No No description of baseline High risk of bias
et al (27) characteristics.
Lopez-Herce Unclear Unclear No Unclear No Yes Unclear risk of bias
et al (28)
Osteyee et al Unclear Unclear No No No No description of baseline High risk of bias
(29) characteristics.
Yildizdas Yes Unclear No Unclear Unclear Yes. Baseline Unclear risk of bias
et al (30) characteristics and
primary diseases in the
patients were reported
for both groups.

Yes, low risk of bias; No, high risk of bias.

a
According to the Cochrane Collaboration Handbook. Sequence generation: Was the allocation sequence adequately generated? Allocation concealment:
Was allocation adequately concealed? Blinding of participants, personnel, and outcome assessors: Was knowledge of the allocated intervention adequately
prevented during the study? Incomplete outcome data/withdrawals: Were intention to treat analyses performed? Had participants withdrawn from the
study? Free of selective reporting? Other sources of bias: Was sample size calculated? Were inclusion/exclusion criteria and baseline characteristics defined?
Were conflicts of interests reported?

Figure 2. Meta-analysis of prophylaxis for preventing upper gastrointestinal bleeding (macroscopic or important bleeding) compared with no treatment.
M-H, Mantel-Haenszel; CI, confidence interval; df, degrees of freedom.

tients who needed mechanical ventilation
on admission concerning rates of macro-
scopic bleeding, deaths, pneumonia, and
the duration of mechanical ventilation
and pediatric ICU stay when comparing
omeprazole vs. ranitidine and omeprazol
vs. sucralfate.
Ranitidine Versus Ranitidine at
Different Doses and Regimen
One RCT (27) showed that intrave-
nous ranitidine at 2 mg/kg and 4 mg/kg
had a significant effect in the rate of pa-
tients’ gastric aspirates with mean pH of
!4 during !80% of study time compared
with ranitidine by nasogastric tube (one
RCT # 20 participants; RR, 0.25; 95%
CI, 0.07– 0.90 and RR, 0.25; 95%
CI, 0.07– 0.90, respectively). Another RCT
did not find significant difference in pa-
tients’ gastric aspirates pH when compar-
ing bolus dosing and continuous infusion
dosing of 4 mg/kg per day of intravenous
ranitidine (29).
DISCUSSION
The RCTs included in this review have
assessed a broad range of treatments that
resulted in limited opportunities to de-
scribe and pool useful data. Studies avail-
able for analysis are a highly heteroge-
neous group, with different drugs being
used and different methods for assessing
their efficacy (e.g., some used endoscopy
on all patients, others simply monitored
nasogastric output for bleeding). Fur-
thermore, because the majority of RCTs
had an unclear risk of bias, small sample
size, and did not reported relevant out-
comes, it was difficult to conclude
whether one treatment was more benefi-
cial than the comparator most of the
time. Most RCTs focused on secondary
outcomes, such as gastric pH control. In
addition, methods used for diagnosis of
UGI bleeding greatly varied across studies
and we could not integrate data for most
comparisons.
Pooled data of two studies suggested
that pediatric patients may benefit from
receiving prophylactic treatment for pre-
venting UGI bleeding. There was reason-
able evidence that ranitidine is better
than “no treatment” in mechanically ven-

Pediatr Crit Care Med 2010 Vol. 11, No. 1 129

Table 3. Summary of relevant findings for primary outcomes of randomized controlled trials included in the reviewa

Study Outcome Comparison (n) Relative Risk (95% CI) p Value/Heterogeneity

Lopez-Herce et al (28) UGI bleeding (macroscopic Treatment vs. (143) vs. no 0.38 (0.16–0.91)a .03; heterogeneity
or important bleeding) treatment (77) p # .35; I2 # 33%
Yildizdas et al (30)
Lacroix et al (26) UGI bleeding (macroscopic Treatment (162) vs. no 0.66 (0.23–1.85)b ns; heterogeneity
or important bleeding) treatment or placebo (98) p # .07; I2 # 63%
Lopez-Herce et al (28)
Yildizdas et al (30)
Lopez-Herce et al (28) UGI bleeding (macroscopic Sucralfate (73) vs. no 0.31 (0.09–1.09)a ns; heterogeneity
or important bleeding) treatment (77) p # .35; I2 # 33%
Yildizdas et al (30)
Kuusela et al (33) Deaths Treatment (141) vs. no 1.24 (0.68–2.28)a ns
treatment (67)
Yildizdas et al (30)
Yildizdas et al (30) Pneumonia Treatment (118) vs. no 1.11 (0.73–1.68) ns
treatment (42)
Kuusela et al (33) Rate of patients with normal Ranitidine (23) vs. no 3.04 (1.30–7.12) .011
visual endoscopic findings treatment (25)
Kuusela et al (33) Rate of patients with normal Ranitidine (23) vs. no 3.53 (1.34–9.29) .01
histological endoscopic findings treatment (25)

CI, confidence interval; UGI, upper gastrointestinal; ns, nonsignificant.

a
Relative risk and 95% CI for dichotomous primary outcomes were calculated by the Mantel-Haenszel fixed-effects model; brelative risk and 95% CI for
dichotomous primary outcomes were calculated by the Mantel-Haenszel random-effects model.

tilated preterm and full-term newborns Table 4. Risk factors significantly associated with gastrointestinal bleeding in severely ill pediatric
treated in a neonatal ICU in improving patients
rates of normal gastric mucosal endo-
Risk Factor Participants OR or RR (95% CI) Reference
scopic findings by visual inspection and
histologic specimens (33). In addition, ra- Mechanically ventilated NB in PICU OR # 4.06 (1.21–12.39) Kuussela et al (38)
nitidine, sucralfate, and amalgate were 1–15 yrs in PICU OR # 5.13 (1.86–14.12) Nithiwathanapong
also better than no treatment in improv- et al (40)
ing rates of patients’ gastric aspirates PRISM score !10 3–18 yrs in PICU OR # 13.4 (3.7–47.9) Chaibou et al (1)
with mean pH of !4 during !50% of Children in PICU RR # 2.87 (1.55–5.32) Lacroix et al (39)
Respiratory failure 3–18 yrs in PICU OR # 10.2 (1.3–82.8) Chaibou et al (1)
study time (28). However, we found no Coagulopathy 3–18 yrs in PICU OR # 9.3 (2.8–30.3) Chaibou et al (1)
evidence to support that prophylaxis Children in PICU RR # 5.37 (2.03–14.16) Lacroix et al (39)
medication is better than “no treatment” Thrombocytopenia 1–15 yrs in PICU OR # 2.26 (1.07–4.74) Nithiwathanapong
to decrease the rates of ulcers or erosion et al (40)
or deaths. Furthermore, no evidence was Shock NB–19 yrs in PICU OR # 17.39 (3.47–87.22) Cochran et al (34)
Surgery time !3 hrs NB–19 yrs in PICU OR # 3.57 (1.43–8.90) Cochran et al (34)
found to support that prophylaxis de- Trauma NB–19 yrs in Children OR # 20.92 (1.85–24) Cochran et al (34)
creases the duration of mechanical ven- in PICU
tilation or pediatric ICU stay. On the RR # 2.46 (1.14–15.33)
other hand, we did not find significant Lacroix et al (39)
increase in the rates of pneumonia or Pneumonia Children in PICU RR # 3.47 (1.21–9.9) Lacroix et al (39)
Enteral feeding Children in PICU RR # 4.16 (2.27–7.66) Lacroix et al (39)
adverse event. Finally, intravenous rani- Organ failure Mechanically ventilated RR # 2.85 (1.18–6.92) Deerojanawong
tidine was superior to ranitidine by naso- et al (35)
gastric tube in improving rates of pa- Corticoid administration NB RR # 1.90 (1.35–2.66) Halliday et al (36)
tients with mean pH of !4 during !80% RR # 1.74 (1.02–2.98) Halliday et al (37)
of study time.
OR, odds ratio, RR, relative risk; CI, confidence interval; NB, newborn; PICU, pediatric intensive
A meta-analysis evaluating the effect
care unit; PRISM, Pediatric Risk of Mortality.
of stress ulcer prophylaxis on gastrointes-
tinal bleeding, pneumonia, and mortality
in critically ill adult patients demon- phylaxis (OR, 1.25; 95% CI, 0.78 –2.00). ical ventilation. Authors also reported no
strates that prophylaxis with histamine2- However, sucralfate was associated with a significant differences in the rates of venti-
receptor antagonists decreases the occur- lower prevalence of nosocomial pneumo- lator-associated pneumonia, the duration
rence of overt gastrointestinal bleeding nia and reduced mortality rate when of the stay in the ICU, or mortality (6).
(OR, 0.58; 95% CI, 0.42– 0.79) and clini- compared with antacids and histamine2- A number of risk factors associated
cally important bleeding (OR, 0.44; 95% receptor antagonists (5). An additional with stress ulcers, gastritis, and gastroin-
CI, 0.22– 0.88). Authors also reported a RCT found that ranitidine had a signifi- testinal bleeding in severelly ill pediatric
trend toward an increased risk of pneu- cantly lower rate of clinically important patients have been described in observa-
monia associated with histamine2-recep- UGI bleeding than sucralfate in 1200 crit- tional studies (Table 4) (1, 34 – 40). A co-
tor antagonists as compared with no pro- ically ill adult patients requiring mechan- hort study found that respiratory failure,

130 Pediatr Crit Care Med 2010 Vol. 11, No. 1

coagulopathy, and a Pediatric Risk of
Mortality Score of !10 were independent
risk factors for clinically significant upper
GI bleeding, using multivariate analysis.
Based on those findings, authors recom-
mended that prophylaxis to prevent UGI
bleeding may be limited to patients who
present with at least two risk factors (1).
We have produced an updated cover-
age of RCTs of prophylactic treatments
for stress ulcers in children by summa-
rizing the best available data. Although
pooled data of two studies suggested that
critically ill pediatric patients may benefit
from receiving prophylactic treatment for
preventing UGI bleeding, the overall
quality of the evidence is low, leading to a
weak recommendation (using GRADE ap-
proach) (10). Although limited evidence
is available, some of the drugs studied
(histamine2 receptor antagonists, sucral-
fate, amalgate) have been replaced in
clinical use by proton pump inhibitors.
However, only one study including pa-
tients treated with omeprazole was found
(30). We need more evidence demonstrat-
ing the effectiveness and safety of differ-
ent prophylactic drugs and improved de-
sign and reporting of RCTs. We should
also investigate the use of proton pump
inhibitors in children.
ACKNOWLEDGMENT
We thank Dr. Rodrigo Pardo of the
Research Institute of the National Univer-
sity of Colombia for instructive commen-
taries to improve this manuscript.
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APPENDIX A
Search Strategy for PubMed
(Randomized controlled trial [pt] OR con-
trolled clinical trial [pt] OR randomized con-
132
trolled trials [mh] OR random allocation [mh]
OR double-blind method [mh] OR single-blind
method [mh] OR clinical trial [pt] OR clinical
trials [mh] OR (“clinical trial” [tw]) OR
((singl* [tw] OR doulb* [tw] OR tripl* OR
trebl* [tw]) AND (mask* [tw] OR blind* [tw]))
OR (“latin square” [tw]) OR placebos [mh] OR
placebo* [tw] OR random* [tw] OR research
design [mh:noexp] OR evaluation studies [pt]
OR follow-up studies [mh] OR prospective
studies [mh] OR crossover studies [mh] OR
control* [tw] OR prospectiv* [tw] OR volun-
teer* [tw]) NOT (animal [mh] NOT human
[mh]) AND (“Peptic Ulcer Perforation”[Mesh]
OR “Peptic Ulcer”[Mesh] OR “Duodenal Ul-
cer”[Mesh] OR “Stomach Ulcer”[Mesh] OR
“Peptic Ulcer Hemorrhage”[Mesh] OR Curl-
ing’s ulcer [tw] OR ((ulcer* [tw] OR bleeding
[tw] OR hemorrhage [tw] OR hemorrhage [tw]
OR ulceration [tw]) AND (Peptic [tw] OR Du-
odenal [tw] OR Stomach [tw] OR gastric [tw]
OR gastrointestinal [tw] OR gastro-intestinal
[tw]))) AND (stress [tw] OR critically ill [tw]
OR intensive care [tw] OR serious burns [tw]
OR mechanical ventilation [tw] OR ventila-
tor[tw] OR Critical Illness [mh] OR Ventila-
tors, Mechanical [tw] OR severely injured [tw]
OR PICU [tw] OR ICU [tw]) AND (“Anti-Ulcer
Agents”[Mesh] OR prophylaxis [tw] OR pre-
vention [tw] OR prevent [tw] OR Antacid* [tw]
OR Histamine H2 Antagonists [tw] OR sucral-
fate [tw] OR Proton-pump inhibitors [tw] OR
cimetidine [tw] OR omeprazole [tw] OR Es-
omeprazole [tw] OR ranitidine [tw] OR Cisa-
pride [tw] OR Famotidine [tw] OR lansopra-
zole [tw] OR pantoprazole [tw] OR rabeprazole
[tw] OR Acid suppression [tw]) AND (Child
[mh] OR children [tw] OR pediatric* [tw] OR
pediatric* [tw] OR Preschool OR Infant [mh]
OR infant* [tw] OR newborn [tw] OR perinatal
[tw] OR neonatal [tw] OR preterm [tw] OR
postnatal [tw] OR premature [tw] OR child-
hood [tw] OR neonate* [tw]).
Pediatr Crit Care Med 2010 Vol. 11, No. 1