double-blind placebo-controlled trial of omeprazole

DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL OF OMEPRAZOLE IN
IRRITABLE INFANTS WITH GASTROESOPHAGEAL REFLUX
DAVID JOHN MOORE,MBBS,FRACP,BILLY SIANG-KUO TAO,MBBS,FRACP,DAVID ROBIN LINES,MD,MBBS,FRACP,
CRAIG HIRTE,BSC (HONS), MARGARET LILA HEDDLE,RN,AND GEOFFREY PAUL DAVIDSON,MD,MBBS,FRACP
Objective To assess the efficacy of omeprazole in treating irritable infants with gastroesophageal reflux and/or esophagitis.
Study design Irritable infants (n = 30) 3 to 12 months of age met the entry criteria of esophageal acid exposure >5%
(n = 22) and/or abnormal esophageal histology (n = 15). They completed a 4-week, randomized, double-blind, placebocontrolled
crossover trial of omeprazole. Cry/fuss diary (minutes/24 hours) and a visual analogue scale of infant irritability as
judged by parental impression were obtained at baseline and the end of each 2-week treatment period.
Results The reflux index fell significantly during omeprazole treatment compared with placebo (-8.9% ± 5.6%,
-1.9% ± 2.0%, P < .001). Cry/fuss time decreased from baseline (267 ± 119), regardless of treatment sequence (period 1,
203 ± 99, P < .04; period 2, 188 ± 121, P < .008). Visual analogue score decreased from baseline to period 2 (6.8 ± 1.6,
4.8 ± 2.9, P = .008). There was no significant difference for both outcome measures while taking either omeprazole or placebo.
Conclusions Compared with placebo, omeprazole significantly reduced esophageal acid exposure but not irritability.
Irritability improved with time, regardless of treatment. (J Pediatr 2003;143:219-23)
Excessive crying and irritability is the most common reason for parents seeking
professional help for their infants in the first 3 months of life. 1 The underlying cause
is still not clear, but it is thought that gastroesophageal reflux (GER) may be
a frequent cause. 2,3 Heine et al 4 have recently demonstrated the presence of esophagitis in
26% of irritable infants, noting poor correlation with esophageal pH monitoring.
Treatment for GER in irritable infants is often implemented without formal
investigation. 5,6
Acid suppression is the principle pharmacologic treatment for symptomatic GER
disease in adults and children, with proton pump inhibitors the most effective agents, 7-9
recommended in the presence of documented esophagitis. There have only been two
placebo-controlled studies of their use in older children. 10,11 It can be hypothesized that if
irritability and excessive crying in infants are related to GER and esophagitis, then
expedient and effective reduction in acid exposure after treatment with a proton pump
inhibitor should lead to a reduction in crying and fussing. We have investigated the role of
omeprazole in irritable infants with significant GER in a double-blind, placebo-controlled,
crossover study.
METHODS
Subjects
Infants between 3 and 12 months of age were recruited to the study after referrals from
pediatricians, general practitioners, and postnatal clinics in South Australia. All infants
referred had a history of frequent spilling and irritability/crying at such a level that parents
GER Gastroesophageal reflux RI Reflux index
Group OP Treatment sequence omeprazole, then placebo VA Visual analog
Group PO Treatment sequence placebo, then omeprazole
See editorial, p 147.
From the Centre for Paediatric and
Adolesent Gastroenterology, Women’s
and Children’s Hospital, the Department
of Paediatrics, University of
Adelaide, the Department of Paediatrics,
Flinders Medical Centre, and the
Public Health Unit, Women’s and
Children’s Hospital, Adelaide, Australia.
This study was jointly funded by the
J.H. and J.D. Gunn Medical Research
Foundation and the Channel 7 Children’s
Research Foundation. The omeprazole
and placebo capsules were
supplied free of charge by Astra-
Zeneca Pty Ltd (Australia).
Submitted for publication July 25, 2002;
revisions received Dec 12, 2002, and
Mar 10, 2003; accepted Apr 3, 2003.
Reprint requests: David Moore,
MBBS, FRACP, Gastroenterology Unit,
Women’s and Children’s Hospital,
North Adelaide SA 5006, Australia.
E-mail: moored@wch.sa.gov.au.
Copyright Ó 2003 Mosby, Inc. All rights
reserved.
0022-3476/2003/$30.00 + 0
10.1067/S0022-3476(03)00207-5
219

had sought help. Parents had received advice on the nonpharmacologic
management of GER, and all infants had been
given pharmacologic treatment for GER. No objective crying
and/or fussing criteria were used as a precondition to
enrollment. At entry, no infant had been investigated for
GER, and all were thriving. Those with a medical or surgical
condition other than GER were excluded from the study.
Approval for the study was obtained from the research ethics
committees of the Women’s and Children’s Hospital, Flinders
Medical Centre, and Child and Youth Health of South
Australia (an organization overseeing community child health
in the state). Informed consent was obtained from one or both
parents of each infant.
Study Design
All subjects underwent upper gastrointestinal endoscopy
under general anesthesia, with a biopsy specimen taken from
the lower esophagus 2 to 3 cm above the lower esophageal
sphincter, followed by 24-hour lower esophageal pH monitoring.
A calibrated antimony pediatric pH probe (Zinetics,
Medtronic Functional Diagnostics, Inc, Salt Lake City, Utah)
was inserted through the nose and positioned above the lower
esophageal sphincter by the Strobel method. 12 Continuous
intra-esophageal pH recordings were recorded for a minimum
of 21 hours. The output from the pH probe was recorded into
either an IBM-PC computer (92 studies) or a Synectics
Digitrapper (2 studies) (Medtronic Functional Diagnostics,
Inc). The settings for the IBM program were identical to the
Digitrapper criteria.
Significant GER for entry into the study was defined
as either a reflux index (percentage of total recording time pH
5%, or endoscopic biopsy evidence of esophagitis.
The biopsy criteria for esophagitis were intra-epithelial
eosinophils 13 or any two of the following criteria: basal cell
layer thickness of >20% of total epithelial thickness, papillary
length >60% of the total epithelial thickness, and >20
lymphocytes in at least one high-power field. 14,15
Infants who met the entry criteria commenced a randomized,
double-blind, placebo-controlled cross-over trial of
omeprazole (infants from 5 to 10 kg were given 10 mg daily
and >10 kg were given 10 mg twice daily) for 2 weeks and an
identical appearing placebo (supplied by AstraZeneca) for 2
weeks (periods 1 and 2). The omeprazole and placebo were
presented in a capsule as microspheres. The contents of each
capsule was emptied into a teaspoon of applesauce and administered
to the infant. A second 24-hour lower esophageal
pH recording was performed on all subjects at the end of
period 1. The patient code indicating the order of treatment
was broken at the completion of the study.
Parents reported infant behavior while on treatment in
two ways. The first was a diary as described by Barr et al, 16 in
which parents recorded infant behavior including crying and
fussing time over a period of 24 hours. The diary was kept for
a minimum of 5 days at baseline and during the second week of
each treatment period. The second was a visual analogue (VA)
score (ranging from 0 to 10) of parental impression of the
overall intensity of infant irritability at baseline and during
each treatment period. The scale ranged in severity from no
irritability (0) to the worst imaginable level of irritability (10).
A simple device was used, configured as a double-sided slide
rule with the side facing the parent showing two extremes of
‘‘no irritability’’ and ‘‘worst irritability’’ and the side facing the
investigator showing a linear scale of 0 to 10. By moving
a cursor between the two extremes, the parent indicated the
level of irritability of the infant while the investigator read the
score from the back of the slide rule.
Data Analysis
A sample size of 20 infants would detect an improvement
in cry/fuss time between omeprazole and placebo of 50%, with
a 2-sided significance level (a) of .05 and a power (1-b) of 80%.
The combined cry/fuss diary and visually assessed irritability
data were analyzed between (a) treatment groups (omeprazole
and placebo), and (b) treatment periods (1 and 2, 2 weeks
each). All data were expressed as mean ± SD. The Mann-
Whitney U test was used to compare distribution of variables.
Subjects
RESULTS
Infants (n = 64) between 3 and 12 months of age were
recruited and investigated. Infants had all been given empirical
pharmacologic treatment for GER and irritability, which
included cisapride 87%, H2 receptor antagonist 73%, antacid
67%, and thickening agent 20%. None of the infants had been
given an empirical trial of proton pump inhibitor before to
recruitment. No infant had a history of hematemesis or
melena. Thirty-four infants met the entry criteria for the
therapeutic trial. Four were withdrawn from the study by their
parents during the first 2-week treatment period because of
persistent crying, leaving 30 infants (median age at endoscopy
4.8 months, range 3-10.2 months, mean age 5.4 ± 2.1 months,
boys 23, girls 7) who completed the study. None of the 64
infants had endoscopic changes of erosive or ulcerative
esophagitis; 29 infants had normal endoscopic findings in
the distal esophagus, whereas 35 infants demonstrated loss of
vascular pattern and/or an increase in friability after biopsy.
Fifteen met the endoscopic biopsy criteria, 22 satisfied the
esophageal acid exposure criteria, and 7 met both criteria.
Endoscopic biopsy findings were poorly correlated to pH
findings with increasing acid exposure not significantly related
to esophageal histologic changes (Table I). Eleven infants had
a reflux index >10%. There were no reports of adverse events
from treatment with omeprazole or placebo.
At the completion of the study, the randomization code
was broken, and it was found that 15 infants had commenced
treatment with omeprazole (group OP) and 15 with placebo
(group PO).
Reflux Index
There was a significant fall in reflux index from baseline
to the end of period 1 in the infants taking omeprazole
220 Moore et al The Journal of Pediatrics August 2003

Table I. Esophageal histology related to RI
Infants with RI # or [5%
Esophageal histology RI # 5% RI > 5%
Grade 0 30 *
15
Grade 1 2 (1) 1
Grade 2 2 (2) 5 (1)
Grade 3 4 1
Total 41 23
In parentheses, 4 infants who met the entry criteria and failed to complete
the trial included in the analysis.
Histological grading of esophageal biopsies: Grade 0 (no changes); Grade
1(basal cell hyperplasia >20% epithelial thickness and papillary lengthening);
Grade 2 (1-19 inflammatory cells per high powered field); Grade 3 ($20
inflammatory cells per high powered field); Grade 4 (erosive esophagitis).
Chi squared test P = .5 (for the analysis, 2 3 2 table used normal vs
abnormal histology and reflux index 5%).
*30 infants who did not meet the entry criteria.
Table II. RI in response to treatment with
omeprazole or placebo
RI (mean ± SD)
Baseline Period 1 % Change in RI
Omeprazole
(n = 15) 9.9 ± 5.8 1.0 ± 1.3 ÿ8.9 ± 5.6 *
Placebo
(n = 15) 7.2 ± 6.0 5.3 ± 4.9 ÿ1.9 ± 20 *
Total
(n = 30) 8.5 ± 5.9
*Omeprazole versus placebo P < .001.
compared with those taking placebo (n = 15, ÿ8.9% ± 5.6% vs
n = 15, ÿ1.9% ± 2.0%, P < .001) (Table II). All infants while
taking omeprazole had a reflux index 5% (range,
0.1-15.8%).
Cry/Fuss Score
There was no significant difference in the cry/fuss time
while taking either omeprazole or placebo (n = 30, 191 ± 120
min/d versus 201 ± 100 min/d, P = .400). However, there was
a significant fall in cry/fuss time from baseline to period 1
(n = 30, 267 ± 119 min/d versus 203 ± 99 min/d, P = .040)
and from baseline to period 2 (188 ± 121 min/d, P = .008).
There was no significant difference in cry/fuss time between
period 1 and period 2 (P = .330). When analyzed by treatment
order (groups OP vs PO, n = 15), there was no difference in
cry/fuss time for baseline (P = .481), period 1 (P = .604), or
period 2 (P = .534) (Table III).
The 15 infants who met the biopsy criteria for
esophagitis were compared with the 15 infants with normal
esophageal biopsy specimens, and no difference was found for
Table III. Cry fuss data in response to treatment
with omeprazole or placebo
Cry fuss time in min/24 h (mean ± SD)
Baseline Period 1 Period 2 Combined *
Omeprazole
(n = 15) 246 ± 105 203 ± 113 179 ± 129 191 ± 120
Placebo
(n = 15) 287 ± 132 204 ± 87 198 ± 115 201 ± 100
Total
(n = 30) 267 ± 119 yz 203 ± 99 y
188 ± 121 z
*Mean of the combined data from Period 1 and Period 2 (n = 30).
yBaseline versus Period 1, P = .040.
zBaseline versus Period 2, P = .008.
baseline cry/fuss time (265 ± 131 min/d versus 269 ± 109
min/d, P = .950). Furthermore, the 15 infants with abnormal
esophageal histology demonstrated no difference in response
to omeprazole vs placebo (182 ± 125 min/d versus 182 ± 92
min/d, P = .709).
Infants with reflux index (RI) >5% (n = 22) were
compared with those infants with RI 5%, no significant difference was observed in response to
active versus placebo treatments (201 ± 130 min/d versus
196 ± 103 min/d, P = .787). Seven infants had both RI >5%
and abnormal esophageal histology; no significant difference
was seen in cry/fuss time while taking either omeprazole or
placebo (205 ± 163 min/d versus 145 ± 78 min/d, P = .848).
Infants with RI >10% (n = 11) were compared with
those infants with RI 10% between cry/fuss
time while taking omeprazole or placebo (189 ± 95 min/d
versus 201 ± 74 min/d, P = .554). There were only 3 infants
with both RI >10% and abnormal esophageal histology; the
numbers were considered too few for analysis of cry/fuss or
VA score.
Visual Analog Score
The VA score assessed by parents for the level of
irritability in their infants while taking omeprazole or placebo
was not significantly different (n = 30, 5.0 ± 3.1 versus
5.9 ± 2.1, P = .214). When analyzed independent of treatment,
there was a significant decrease in the VA score between
baseline and period 2 (n = 30, 6.8 ± 1.6 versus 4.8 ± 2.9,
P = .008) but not between baseline and period 1 (6.0 ± 2.3) or
between period 1 and period 2. When analyzed by treatment
order (groups OP versus PO, n = 15), there was no difference
in VA score for baseline (P = .262), period 1 (P = .724) or
period 2 (P = .105) (Table IV).
The 15 infants who met the biopsy criteria for esophagitis
were compared with the 15 infants with normal esophageal
Double-Blind Placebo-Controlled Trial of Omeprazole in
Irritable Infants with Gastroesophageal Reflux 221

Table IV. Visual analogue score by parents of the
level of infant irritability in response to treatment
with omeprazole or placebo
Visual analogue scale of infant
irritability (mean ± SD)
Baseline Period 1 Period 2 Combined *
Omeprazole
(n = 15)
Placebo
7.1 ± 1.4 5.9 ± 2.6 4.0 ± 3.3 5.0 ± 3.1
(n = 15)
Total
6.6 ± 1.7 6.0 ± 2.1 5.7 ± 2.2 5.9 ± 2.1
(n = 30) 6.8 ± 1.6 y
6.0 ± 2.3 4.8 ± 2.9 y
*Mean of the combined data from Period 1 and Period 2 (n = 30).
yBaseline versus Period 2, P = .008.
biopsy specimens, and no difference was found for baseline VA
score (6.6 ± 1.7 vs 7.0 ± 1.5, P = .868). Furthermore, the 15
infants with abnormal esophageal histology demonstrated no
difference in VA score in response to omeprazole versus
placebo (4.5 ± 3.2 versus 5.6 ± 2.4, P = .493).
Infants with RI >5% (n = 22) were compared with those
infants with RI 5%, no significant
difference in VA score was noted in response to omeprazole or
placebo treatment (5.5 ± 2.8 versus 5.7 ± 2.2, P = .953). Seven
infants had both RI >5% and abnormal esophageal histology;
no significant difference was seen in VA score while taking
either omeprazole or placebo (5.7 ± 2.6 versus 4.7 ± 2.5,
P = .223).
Infants with RI >10% (n = 11) were compared with
those infants with RI 10% between VA score while
taking omeprazole or placebo (6.1 ± 2.5 versus 6.4 ± 2.0,
P = .742).
DISCUSSION
GER and excessive crying are both common conditions
in infants; it is therefore not surprising that many irritable
infants may have both simultaneously. However, coexistence
of the two conditions does not establish a causal relation.
Irritable infants are frequently subjected to empirical therapeutic
trials with little investigation and little rationale. 4,17
Many irritable infants have been given acid suppressing drugs
and motility agents such as cisapride (before the latter was
withdrawn from treatment of infants) in the belief that reflux
esophagitis was the cause of crying. With wide availability of
proton pump inhibitors, these medications will now predictably
be used more frequently in irritable infants. Their use
in adults and to a lesser extent in children has been widely
reported. This study was a double-blind, placebo-controlled
trial of a proton pump inhibitor (omeprazole) in an infant
population. In this trial of omeprazole, no adverse events were
recorded, and it was highly effective in reducing esophageal
acid exposure in infants 3 to 10 months of age.
The first finding of note from this study is the
dichotomy between effective esophageal acid suppression by
omeprazole and its failure to reduce infant crying and fussing
behavior. When parents were blinded to the therapeutic
agents, they reported no significant difference between the
active and placebo treatment groups. Furthermore, infants
with abnormal esophageal histology (n = 15), a baseline reflux
index of >10% (n = 11), or those positive for both histologic
and esophageal pH entry criteria (n = 7) also demonstrated no
significant reduction in irritability or visual analogue score
between the active and placebo groups. Despite effective acid
suppression in infants with GER, omeprazole failed to
suppress symptoms of irritability; it is possible that non-acid
reflux may be related to the irritability of some infants with
GER. Testing of this hypothesis awaits an effective antireflux
motility agent and possibly the correlation between non-acidrelated
reflux events and infant symptoms by using intraesophageal
impedance technology. 18 Hill et al 19 have suggested
that food protein intolerance in infants could be another cause
of esophagitis leading to infant distress. On the basis of our
findings, treatment of irritable infants with GER should not
include proton pump inhibitors unless esophagitis is evident.
The second finding from this study was the significant
improvement in irritability and visual analogue score during
the 4-week study period in infants >3 months of age, independent
of treatment. It is in agreement with the general
observation that infant irritability improves with time, which
could be a confounding factor in any study involving
therapeutic intervention of GER and infant irritability.
GER as a cause of infant irritability has been overdiagnosed
and overtreated. The results of this study support the
hypothesis that excessive crying in otherwise normal infants
with GER may be a self-limiting condition tending to
improve with time. None of the infants had erosive or
ulcerative esophagitis in which therapy with a proton pump
inhibitor would be indicated. Proton pump inhibitor treatment
in irritable infants without erosive esophagitis or
hematemesis but associated with a history of GER, reflux
index >5%, and/or abnormal endoscopic esophageal biopsy
findings is unlikely to significantly reduce cry/fuss behavior.
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It is commonly assumed that when infants ingest milk, lactose is degraded completely to glucose and galactose in the
gastrointestinal tract, and that the galactose that is absorbed is extracted in the first pass, by the liver, and converted to
glucose. This is far from the truth—a fact that is better known to older, than to contemporary, physicians. In the days when
urinary-reducing substances were determined in total, and separated by paper or thin layer chromatography, it was not
uncommon to find both lactose and galactose in the urine of children, particularly those with diarrhea or gastrointestinal
disturbances. The use of specific glucose measuring reagents has tended to obscure this fact for the modern physician. In
this paper, Hartman and his colleagues use the relatively crude and laborious methods available to them at the time to
demonstrate that in the infant who is taking formula every three to four hours, the galactose level in blood may be as high as
that of glucose, and in fact, could in certain circumstances, mask hypoglycemia if a specific measurement of glucose is not
made. In galactosemia, the ingestion of milk may lead to galactose levels as high as 110 mg/100 mL and actually depress
glucose levels in blood. Because galactose is metabolized in the liver, galactose levels were one way of measuring the severity
of liver dysfunction. Neither Hartmann et al nor I can speculate as to whether there are circumstances in which blood
galactose accumulation may have an adverse effect, even in patients who do not have inherited forms of deficient galactose
metabolism.
Stephen Cederbaum, MD
Departments of Psychiatry, Pediatrics, and Human Genetics
David Geffen School of Medicine at UCLA and
The Mattel Children’s Hospital
Los Angeles, CA 90024-1759
YMPD314
10.1067/S0022-3476(03)00277-4
Double-Blind Placebo-Controlled Trial of Omeprazole in
Irritable Infants with Gastroesophageal Reflux 223