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12 authors, including:
Clara M Loots
Peter J Lewindon
University of Queensland
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Ross R Haslam
University of Melbourne
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Clara Loots, yStamatiki Kritas, Michiel van Wijk, yLisa McCall, Laura Peeters,
Peter Lewindon, Rob Bijlmer, Ross Haslam, jjJacinta Tobin, Marc Benninga,
y
Geoffrey Davidson, and yTaher Omari
ABSTRACT
Objective: Proton-pump inhibitors (PPIs) reduce acid gastroesophageal
reflux (GER) and esophageal acid exposure in infants; however, they do
not reduce total GER or symptoms attributed to GER. Reflux is reduced in
the left lateral position (LLP). We hypothesize that the effect of LLP in
combination with acid suppression is most effective in reducing GER
symptoms in infants.
Methods: In this prospective sham-controlled trial, infants (06 months)
with symptoms suggestive of gastroesophageal reflux disease were studied
using 8-hour pH-impedance, cardiorespiratory and video monitoring, direct
nurse observation, and a validated questionnaire. Infants demonstrating a
positive GER symptom association were randomized to 1 of 4 groups; PPI
LLP, PPI head of cot elevation (HE), antacid (AA) LLP, or AA HE.
HE and AA were considered sham therapies. After 2 weeks the 8-hour
studies were repeated on-therapy.
Results: Fifty-one patients were included (aged 13.6 [226] weeks). PPI
LLP was most effective in reducing GER episodes (69 [13] to 46 [10],
P < 0.001) and esophageal acid exposure (median [interquartile range] 8.9%
[3.1%18.1%] to 1.1% [0%4.4%], P 0.02). No treatment group showed
improvement in crying/irritability, although vomiting was reduced in AA
LLP (from 7 [2] to 2 [0] episodes P 0.042). LLP compared with HE
produced greater reduction in total GER (21 [4] vs 10 [4], P 0.056),
regardless of acid-suppressive therapy. Acid exposure was reduced on
PPI compared with AA (6.8 [2.1] vs 0.9 [1.4]%, pH < 4, P 0.043)
regardless of positional intervention. A post-hoc analysis using automated
Received October 24, 2013; accepted April 1, 2014.
From the Pediatric Gastroenterology and Nutrition, Emma Childrens
Hospital, AMC, Amsterdam, The Netherlands, the ySchool of Medicine,
Flinders University, Adelaide, zPediatric Gastroenterology, Royal
Childrens Hospital, Brisbane, the Neonatal Intensive Care Unit,
Womens and Childrens Health Network, Adelaide, and the jjNorth
Western Academic Centre University of Melbourne, Melbourne,
Australia.
Address correspondence and reprint requests to Taher Omari, PhD, Flinders
Medical Science and Technology, School of Medicine, Flinders
University, South Australia, Adelaide, Australia (e-mail: taher.omari
@flinders.edu.au).
This study was supported by grants from the National Health and Medical
Research Council (ID: 508053), the Financial Markets Foundation for
Children (grant no. 2009-112), the Dutch Digestive Disease Foundation
(grant no. WO 07-07), the Channel 7 Childrens Research Foundation,
and the Womens & Childrens Hospital Foundation. Part of the equipment was kindly provided by AstraZeneca. None of these bodies had a
role in the study design; the collection, analysis, and interpretation of
data; the writing of the report; and the decision to submit the article for
publication.
The authors report no conflicts of interest.
Copyright # 2014 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000000395
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Loots et al
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METHODS
Infants referred for evaluation of typical GERD symptoms
such as excessive vomiting, crying, irritability, feeding difficulties,
failure to thrive, and sleep disturbance were assessed for eligibility to
participate in the study. Patients were referred to the Department of
Gastroenterology of the Womens and Childrens Health Network
(WCHN) in Adelaide, Australia; the Royal Childrens Hospital in
Brisbane, Australia; and the Emma Children Hospital, Academic
Medical Centre in Amsterdam, the Netherlands. Parents/guardians
provided written consent before study procedures were started.
Ethical approval was provided by the ethical committees of all
participating hospitals. The study was registered with the Australia
New Zealand Clinical Trials Registry (ACTRN12609000988257).
All of the authors had access to the study data and had reviewed and
approved the final article.
Having satisfied inclusion criteria, infants underwent a baseline assessment with combined pH-impedance, physiological
monitoring, an 8-hour video study, direct nursing observation,
and a gastric emptying breath test. The primary caregiver completed
a validated infant GERD questionnaire (I-GERQ-R questionnaire),
which has been used to quantify symptomatic responses of infants to
pharmacological and nonpharmacological reflux therapies (13)
(Fig. 1).
At baseline, infants were required to stop all of the medication known to affect acid secretion or gastric motility for at least
48 to 72 hours. Infants were studied in the supine nonelevated
position. The occurrence of symptoms was recorded on the tracing
in real time.
For diagnosis, we relied on a positive symptom association
probability (SAP) as recommended by present North American/
European Society for Pediatric Gastroenterology, Hepatology,
and Nutrition guidelines for diagnosis of infantile GERD (22).
Infants who demonstrated a positive GER-symptom association
(SAP > 95%) to any symptom occurring >5 times were randomized
to undergo 14 days of treatment.
Patients were randomized to 1 of 4 treatment groups using a
randomization schedule generated by an independent monitor.
Patients were usually discharged home for the treatment period
and received a minimum once per week visit by a clinical trial nurse
to ensure compliance with the treatment protocols. Treatment
groups were as follows:
1. Group 1: Left-side positioning for 2 hours postprandially in
combination with 1 mg kg1 day1 esomeprazole once daily
(PPI LLP group).
2. Group 2: Head of cot elevation (HE) to 20 degrees for 2 hours
postprandially in combination with esomeprazole (PPI HE
group).
3. Group 3: Left-side positioning in combination with antacid
(AA) therapy, which consisted of at 1.5, 3, or 5 mL of Mylanta
(McNeil Consumer Healthcare, Ft Washington, PA) once daily
in infants 0 to 2, 2 to 4, and 4 to 6 months of age, respectively
(AA LLP group).
4. Group 4: HE to 20 degrees in combination with antacid (AA
HE group).
The reasoning behind the decision to perform the trial sham
controlled, rather than placebo controlled, was 3-fold: First, there is
no evidence that HE and AA actually reduce GER frequency or acid
exposure. Second, being used widely in the community, parents
were familiar with HE and AA and this allowed for better concealment of which treatments were hypothesized to be efficacious.
Finally, by using sham therapies rather than a placebo, parents were
8 h study
Randomizaion
GERD symptoms
Informed consent
pH-impedance
Cardioresp
monitoring
Sx monitored
Video
GE breath test
I-GERQ-R
Positive symptom
assosiation (SAP > 95%)
to symptoms of crying,
coughing or
regurgitation
ALTE
Cigarette smoke
Surgery
Unsafe to enroll
Study Protocol
Eligibility
Exclusion
TX 2 wk
Gr
Med
Pos
PPI
LLP
PPI
HE
AA
LLP
AA
HE
8 h study
pH-impedance
Cardioresp
monitoring
Sx monitored
Video
GE breath test
I-GERQ-R
FIGURE 1. Study protocol. Overview of study procedures. AA antacid; ALTE acute life-threatening event; GE gastric emptying;
GERD gastroesophageal reflux disease; Gr group; HE head of cot elevation; I-GERQ-R reflux questionnaire; LLP left lateral position;
PPI proton-pump inhibitor; SAP symptom association probability; Sx symptoms.
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Measurement Methods
GER Monitoring
GER episodes were recorded using a single-use infant pHimpedance catheter with a pH sensor and 6 impedance channels.
The pH sensor was placed at the third vertebra above the diaphragm
and was confirmed by a thoracic x-ray. Depending on site preference, a ComforTec MII/pH probe was used in combination with a
Sleuth system recording device (Sandhill Scientific, Highlands
Ranch, CO), or the Unisensor pH-MII infant catheter was used
in combination with the Omega ambulatory recording system
(Medical Measurement Systems, Enschede, the Netherlands).
Studies were manually analyzed for the occurrence of liquid, mixed,
and gas GER according to accepted criteria (25). Following primary
analysis by 1 investigator, who was experienced with the use of both
software systems, each study was also checked for accuracy by a
second investigator. Acid exposure time in the distal esophagus and
total reflux index (% time pH < 4) >24 hours were determined
using automated software (GERD Check; Sandhill Scientific and
Omega analysis software [Medical Measurement Systems]).
For the purpose of accurate GER-symptom association,
symptoms suggestive of GER such as crying, irritability, fussing,
vomiting, burping, regurgitation, cough, sneeze, grimacing, and
back arching were continually observed by trained hospital staff and
recorded by direct input into the acquisition system. A 2-minute
time window was used for GER-symptoms association. To assess
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Physiological Monitoring
One of 2 cardiorespiratory and video data acquisition systems was used depending on site preference. In Adelaide and
Brisbane all cardiorespiratory and video data were acquired
simultaneously with GER monitoring on an Alice V sleep system
computer (Philips Respironics, Best, the Netherlands). The 8hr
physiological and video data were synchronized and merged with
GER data and analyzed in Bioview (Sandhill Scientific). In the
patients recruited in Amsterdam cardiorespiratory and video data
were acquired on the Embla polysomnography system with Remlogic analysis software (Broomfield, CO). pH-impedance tracings
were recorded on ambulatory Omega system and simultaneously on
the Remlogic system to ensure synchronization (GER analysis was
performed using the Omega software).
Cardiorespiratory tracings were analyzed for episodes of
bradycardia (heart frequency < 100/min), desaturation (transcutaneous SaO2 < 80%), and apnea (>20 seconds absence of nasal
flow and concurrent desaturation). Videos were also manually
reviewed to verify correct body positioning throughout the study
(ie, infant kept in randomized position for at least 50% of total time,
and at least 1 hour postprandially) and for the calculation of total
time of irritability, crying, and fussing (total crying time) as a posthoc measure of behavioral symptom severity.
Statistical Analysis
Most variables were normally distributed and are presented
as mean (standard error of mean) unless otherwise stated. Primary
parameters at baseline were not significantly different (Student
t test). Consequently a paired t test was used to calculate the
difference between baseline and therapy per treatment group.
The change between baseline and therapy was compared among
the 4 treatment groups and for positioning intervention and medication separately using an analysis of covariance, with the number
of events after treatment as the dependent and the number of events
at baseline as a covariate. A Pearson correlation was used to
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Loots et al
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RESULTS
Sixty-six infants were enrolled in the study between
September 2008 and May 2011 (16 patients in Amsterdam, 46
patients in Adelaide, and 4 patients in Brisbane). Fifty-one patients
were included in the study (27 boys, mean age 13.6 [range 226]
weeks). Eleven patients were born prematurely (median [range]
gestational age 32 [2837] weeks). Twelve patients received
treatment before enrolling in the study including PPIs, H2
antagonists, Mylanta, Gaviscon, Panadol, and Infacol (GlaxoSmithKline, Brentford, UK). No patient had undergone surgery.
Figure 2 shows the patient inclusion flowchart. After randomization, 6 patients were withdrawn, 3 patients were withdrawn before
the start of therapy by their parents without further specification of
motive, and 1 patient (randomized to AA therapy head elevation)
was withdrawn by the parents after 9 days on therapy. One patient
(randomized to PPI LLP) was withdrawn by the investigators
because of noncompliance. One patient (randomized to PPI HE)
was withdrawn after admission to hospital because of feeding
difficulties and a request by the treating pediatrician for the
medication to be changed. Baseline age and sex characteristics
per group are shown in Figure 2.
All of the patients were monitored for the risk of SIDS.
Physiological monitoring for apparent life-threatening events,
recurrent desaturations, brachio-/plagiocephaly, and neck muscle
dysfunction was unremarkable and gave no indication that the
interventions were unsafe to the infants when performed during
the short study period.
66 patients eligible
9 patients not randomized
57 patients randomized
6 patients withdrawn*
51 patients included for
analysis
Group 1
PPI and LLP
N = 12 (4 boys)
Age: 12(3) wk
Group 2
PPI and HE
N = 14 (9 boys)
Age: 12(3) wk
Group 3
Antacid and LLP
N = 13 (7 boys)
Age: 14(2) wk
Group 4
Antacid and HE
N = 12 (7 boys)
Age: 17(2) wk
FIGURE 2. Patient flowchart. Withdrawn patients: before start therapy (N 3), no compliance (N 1, PPI LLP), parents did not wish to
proceed after 9 days on therapy (N 1, AA HE), reduced oral intake, and hospital admission (N 1, PPI HE). AA antacid; HE head of cot
elevation; LLP left lateral position; PPI proton-pump inhibitor.
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Pretreatment
Posttreatment
Difference
69
50
47
55
(13)
(6)
(6)
(9)
46
41
29
44
(10)
(6)
(3)
(7)
8.9
6.9
2.9
5.8
(3.118.1)
(2.121.8)
(0.66.9)
(2.812.6)
1.1
0.5
4.8
1.1
(04.4)
(0.12.2)
(0.89.0)
(0.29.9) (0.066)
23
9
18
11
(5)
(3)
(6)
(8)
4
5.1
0.9
2.2
(12.9 to 0.2)
(21.2 to 0.1)
(2.0 to 2.8)
(8.9 to 0.2)
Mean (SEM) or median (IQR) and mean difference shown for each treatment group. Pretreatment was significantly different from posttreatment using
P < 0.001). P values for ANOVA across the 4 treatment
paired t test or signed rank test (P values 0.050.10 shown in parentheses, P < 0.05, P < 0.01,
groups for pre-/posttreatment and difference were not significant. AA antacid; ANOVA analysis of variance; GER gastroesophageal reflux; HE head
of cot elevation; IQR interquartile range; LLP left lateral position; PPI proton-pump inhibitor; SEM standard error of mean.
P < 0.001). Slower gastric emptying did not correlate with any
specific symptom subtype.
Pretreatment
Posttreatment
Difference
1
9
17
8
92
71
106
74
(10)
(11)
(19)
(20)
92
81
88
66
(10)
(10)
(10)
(13)
22
23
30
32
(7)
(6)
(12)
(9)
25
25
31
42
(7)
(6)
(14)
(12) (0.1)
4
2
2
11
(9)
(6)
(5)
(6)
6
6
2
2
(2)
(2)
(0)
(1)
1
2
3
0
(1)
(3)
(1)
(0)
48
49
54
35
(8)
(7)
(9)
(7)
5
17
7
5
(5)
(10)
(13)
(10)
7(2)
8 (3)
7 (2)
3 (1)
48
30
60
38
(9)
(7)
(12)
(10)
(7)
(9)
(18)
(13)
Mean (SEM) or median [IQR] and mean difference shown for each
treatment group. Pretreatment was significantly different from posttreatment using paired t test or signed rank test (P values 0.050.10 shown
P < 0.001). P values for ANOVA
in parentheses, P < 0.05, P < 0.01,
across the 4 treatment groups for pre/post treatment and difference were not
significant. AA antacid; ANOVA analysis of variance; GER
gastroesophageal reflux; HE head of cot elevation; IQR interquartile
range; LLP left lateral position; PPI proton-pump inhibitor; SEM
standard error of mean; Sx symptoms.
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Impedance baseline recordings were reanalyzed by automated analysis software. Differences in GER parameters based
on automated analysis were statistically similar to manual analysis;
however, 7 patients who were SAP positive based on manual
analysis were found not to be SAP positive on automated analysis.
When these patients were removed from the database, we were able
to observe some treatment effects in the remaining patients. In the
PPI LLPtreated group (n 7), crying in the (autoscan-determined) SAP-positive infants reduced after treatment from 99
(65103) to 62 (3296) episodes (P 0.018, Wilcoxon signed
rank test) and in the PPI HE group (n 5) vomiting reduced from
17 (633) to 10 (1.520) (P 0.042, Wilcoxon signed rank test).
TABLE 3. Effect of different treatments upon gastric emptying variables
GE variables
GEt1=2
PPI
PPI
AA
AA
GEtmax
PPI
PPI
AA
AA
Pretreatment
Posttreatment
Difference
39
16.8
39
8
(22)
(12)
(31)
(11)
22
13
8
12
(7)
(6)
(12)
(9)
LLP
HE
LLP
HE
53
46
57
62
(6)
(12)
(10)
(11)
92
29
96
61
(22)
(7)
(39)
(14)
LLP
HE
LLP
HE
55
65
71
66
(5)
(7)
(4)
(9)
78
52
79
77
(8)
(3) (0.051)
(13)
(7)
Mean (SEM) or median (IQR) and mean difference shown for each
treatment group. GEt1=2 : gastric emptying half time. GEtmax : gastric emptying time to maximum 13C concentration. GEGEC: gastric emptying constant.
Pretreatment was significantly different from posttreatment using paired
t test or signed rank test (P values 0.050.10 shown in parentheses,
P < 0.05, P < 0.01,
P < 0.001). P values for ANOVA across the
4 treatment for the difference in GEtmax was 0.061. AA antacid;
ANOVA analysis of variance; GER gastroesophageal reflux; HE head
head of cot elevation; IQR interquartile range; LLP left lateral position;
PPI proton-pump inhibitor; SEM standard error of mean.
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TABLE 4. Differences in GER, GE, and symptom variables in relation to body positioning or acid-suppression therapy
LLP vs HE
Difference
PPI vs AA
LLP
GER variables
Total no. GER
No. acid GER
No. WA GER
Reflux index (%)
GE variables
GE 1/2 time
Sx assessments
Total ICF, min
No. cough Sx
No. vomit Sx
No. cry Sx
21
10
11
3.4
(4)
(3)
(3)
(2.1)
39 (19)
8
3
2
1
(9)
(5)
(1)
(7)
HE
10
9
0
4.5
(4) (0.056)
(3)
(4) (0.052)
(1.7)
10 (8)
1
6
1
5
PPI
(8)
(4)
(1)
(7)
16
12
4
6.8
AA
15
6
7
0.9
(3)
(3)
(3)
(2.1)
8 (13)
4
3
2
11
(5)
(3)
(5)
(1.4)
24 (17)
12
6
2
6
(6)
(6)
(1)
(5)
(11)
(4)
(1)
(8) (0.09)
Data presented as mean (SEM). Treatments were significantly different using t test (P values 0.050.10 shown in parentheses, P < 0.05, P < 0.01,
P < 0.001). AA antacid; GER gastroesophageal reflux; HE head of cot elevation; IQR interquartile range; LLP left lateral position;
PPI proton-pump inhibitor; SEM standard error of mean; Sx symptoms; WA Weakly acidic.
Adverse Events
During the study 5 patients experienced adverse events, of
which 2 were serious. The adverse events were urinary tract
infection, constipation, diarrhea, and vomiting (following immunization). Of the 2 patients with serious adverse events, 1 patient
(randomized to PPI HE) was admitted to hospital after 5 days of
treatment and successfully treated for rotavirus infection. Another
patient (randomized to PPI HE) was admitted because of reduced
oral intake and weight loss. None of the adverse events were judged
to be related to the study therapies by the treating pediatricians.
DISCUSSION
In this randomized sham-controlled study we assessed the
influence of body positioning and medical therapies on the frequency of GER and typical symptoms in infants with positive SAP
findings on pH-impedance monitoring. This is the first study to only
include patients with a positive SAP and to assess the influence of
therapies designed to reduce reflux triggering and reduce gastric
acidity. LLP therapy reduced the number of impedance-detected
GER episodes, and PPI therapy reduced acid GER. The use of both
therapies in combination was the most effective way of reducing
total GER frequency and esophageal acid exposure; however,
despite this potent effect on GER, there was no concomitant
reduction in symptoms other than vomiting.
The purpose of this study was to determine the effect of
known reflux-reducing interventions on GER and typical symptoms
that would, in present clinical practice, lead to the prescription of
antireflux therapies. With overwhelming clinical trial evidence that
PPIs are ineffective for reducing typical GERD symptoms in the
infant group (13,15,16,28), the present trial addresses the possibility
that PPIs may lack efficacy because acid suppression does not
reduce the total reflux burden of combined acid, weakly acidic, and
nonacidic episodes (15,17). LLP was chosen based on previously
published observations that LLP significantly reduces total reflux
and because pharmacological reflux inhibitor treatments, such as
baclofen, have adverse effects, which preclude use in infants 0 to
6 months (18,19).
Despite use of therapies that clearly ameliorated the total
reflux burden, no objective symptomatic improvement was demonstrated in our patients. Parent reported I-GERQ-R scores improved
in infants randomized to AA HE (sham sham group) as well as
242
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