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Body Positioning and Medical Therapy for Infantile

Gastroesophageal Reflux SymptomsClara Loots, yStamatiki Kritas, Michiel van Wijk, y Lisa McCall, Laura Peeters,z Peter Lewindon, § Rob Bijlmer, § Ross Haslam, jj Jacinta Tobin, Marc Benninga,

yGeoffrey 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 (0–6 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 þLLP, PPI þ head of cot elevation (HE), antacid (AA) þ LLP, or AA þ 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 [2–26] weeks). PPI þLLP 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 ¼0.02). No treatment group showed

improvement in crying/irritability, although vomiting was reduced in AA þ

LLP (from 7 [2] to 2 [0] episodes P¼0.042). LLP compared with HE produced greater reduction in total GER (21 [4] vs 10 [4], P ¼0.056),

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, P¼0.043)

regardless of positional intervention. A post-hoc analysis using automated

analysis software revealed a significant reduction in crying symptoms in the

PPI þ LLP group (99 [65–103] to 62 [32–96] episodes, P ¼0.018).

Conclusions: ‘‘Symptomatic gastroesophageal reflux disease’’ implies

disease causation for distressing infant symptoms. In infants with

symptoms attributed to GER, LLP produced a significant reduction in

total GER, but did not result in a significant improvement in symptoms

other than vomiting; however, automated analysis appeared to identify

infants with GER-associated crying symptoms who responded to

positioning therapy. This is an important new insight for future research.

Key Words: diagnosis, gastroesophageal reflux, treatment

( JPGN 2014;59: 237–243)

G astroesophageal reflux (GER) is the retrograde flow of gastric contents into the esophagus. GER is a physiological

mechanism that occurs in all infants (1). Some infants present withtroublesome symptoms, such as irritability and crying, with or without excessive regurgitation. These infants are often diagnosed as having GER disease (GERD) once all other possible causes (eg,infection) have been excluded.

It has been well established that the underlying mechanism of nearly all GER episodes in infants is transient lower esophagealsphincter relaxation (TLESR) (2–7). TLESRs allow acidic (< pH 4)or nonacidic liquid, gas, or mixed GER episodes to occur. In older children and adults most GER symptoms and complications are

believed to be the result of excessive acid liquid GER. In infants,GER is more frequently not acidic owing to regular feeds with

potent buffers of gastric contents such as breast milk and formula;however, GER episodes in the shorter infant esophagus projectmore proximally, and evidence suggests that such GER episodes doalso cause symptoms (8–10).

The diagnosis of GERD in infants is fraught with difficulty

owing to the wide range of clinical presentations and the lack of diagnostic modalities and appropriate diagnostic criteria. Theseissues lead to failure of accurate GERD diagnosis.

The first steps in the therapeutic process are parental reas-surance and conservative nonpharmacological measures. Whenconservative therapy fails, often infants are empirically prescribed drugs that suppress gastric acid production. Despite widespread use(11), there is a paucity of evidence-based guidance on efficacyincluding appropriate dosing levels (12–14).

Although the therapeutic efficacy of proton-pump inhibitors(PPIs) in controlling symptoms has not been demonstrated, the

pharmacodynamic effect of PPIs on intragastric pH and acid GER has been well characterized (15,16). PPIs effectively reduce the

proportion of reflux episodes that are acidic; however, PPIs do notdecrease the overall number of GER episodes (15,17). This may

explain the lack of symptom efficacy, because experience suggests

Received October 24, 2013; accepted April 1, 2014.From the Pediatric Gastroenterology and Nutrition, Emma Children’s

Hospital, AMC, Amsterdam, The Netherlands, the ySchool of Medicine,Flinders University, Adelaide, zPediatric Gastroenterology, RoyalChildren’s Hospital, Brisbane, the § Neonatal Intensive Care Unit,

Women’s and Children’s Health Network, Adelaide, and the jj NorthWestern Academic Centre University of Melbourne, Melbourne,Australia.

Address correspondence and reprint requests to Taher Omari, PhD, Flinders

Medical Science and Technology, School of Medicine, FlindersUniversity, South Australia, Adelaide, Australia (e-mail: [email protected]).

This study was supported by grants from the National Health and MedicalResearch Council (ID: 508053), the Financial Markets Foundation forChildren (grant no. 2009-112), the Dutch Digestive Disease Foundation(grant no. WO 07-07), the Channel 7 Children’s Research Foundation,and the Women’s & Children’s Hospital Foundation. Part of the equip-ment was kindly provided by AstraZeneca. None of these bodies had arole in the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article forpublication.

The authors report no conflicts of interest.

Copyright # 2014 by European Society for Pediatric Gastroenterology,Hepatology, and Nutrition and North American Society for PediatricGastroenterology, Hepatology, and Nutrition

DOI: 10.1097/MPG.0000000000000395

ORIGINAL ARTICLE: GASTROENTEROLOGY

JPGN Volume 59, Number 2, August 2014 237

mailto:[email protected]


http://dx.doi.org/10.1097/MPG.0000000000000395

http://dx.doi.org/10.1097/MPG.0000000000000395





that occurrence of GER rather than acidity causes symptoms.Presently there are no safe pharmacological approaches to reduceTLESRs and GER in children. We have shown in infants thatTLESRs and GER are significantly reduced in the left lateral

position (LLP) compared with right lateral position (RLP)(18–20). LLP has the ability to reduce all types of reflux during

the entire postprandial period but does not alter the proportion of acidic reflux episodes (pH< 4) (21).The present study evaluates an LLP regimen as a concept test

for the efficacy of therapies designed to treat GER-related symp-toms by reducing the rate at which reflux is triggered followingfeeding. We hypothesized that infants with a GER-symptom associ-ation (proven by impedance) demonstrate a symptom response toLLP owing to reduced GER episodes. The effect of PPI was alsoinvestigated as potential adjunct therapy.

METHODSInfants 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 Women’s and Children’s Health Network (WCHN) in Adelaide, Australia; the Royal Children’s Hospital inBrisbane, Australia; and the Emma Children Hospital, AcademicMedical Centre in Amsterdam, the Netherlands. Parents/guardiansprovided written consent before study procedures were started.Ethical approval was provided by the ethical committees of allparticipating hospitals. The study was registered with the AustraliaNew Zealand Clinical Trials Registry (ACTRN12609000988257).All of the authors had access to the study data and had reviewed andapproved the final article.

Inclusion and Exclusion Criteria

Term and preterm infants up to 6 months’ postnatal age wereenrolled in the study if the following inclusion criteria were met:parental/guardian written informed consent was given; any 2 of apnea/bradycardia/oxygen desaturations, vomiting/gagging, andirritability/pain were observed at least every second feed or at leasttwice every 8 hours; and clinical symptoms were present for at least5 days or increasing in frequency or severity for 3 days. Patientswith a history of acute life-threatening events, environmentalexposure to cigarette smoke, a history or a present need for resectionor reconstructive surgery of the gastrointestinal tract or with anycondition that may require surgery during the course of the study,any condition that would make performance of the study proceduresunsafe, or that would make it unlikely that the patient wouldcomplete the study procedures to the final day were excluded.

Study Protocol

Having satisfied inclusion criteria, infants underwent a base-line assessment with combined pH-impedance, physiologicalmonitoring, 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 topharmacological and nonpharmacological reflux therapies (13)(Fig. 1).

At baseline, infants were required to stop all of the medi-cation known to affect acid secretion or gastric motility for at least48 to 72 hours. Infants were studied in the supine nonelevatedposition. The occurrence of symptoms was recorded on the tracingin real time.

For diagnosis, we relied on a positive symptom associationprobability (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 anysymptom 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 periodand received a minimum once per week visit by a clinical trial nurseto ensure compliance with the treatment protocols. Treatmentgroups were as follows:

1. Group 1: Left-side positioning for 2 hours postprandially incombination with 1 mg kg1 day1 esomeprazole once daily(PPI þ LLP group).

2. Group 2: Head of cot elevation (HE) to 20 degrees for 2 hourspostprandially in combination with esomeprazole (PPI þ HEgroup).

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 dailyin infants 0 to 2, 2 to 4, and 4 to 6 months of age, respectively(AA þ LLP group).

4. Group 4: HE to 20 degrees in combination with antacid (AA þHE group).

The reasoning behind the decision to perform the trial shamcontrolled, rather than placebo controlled, was 3-fold: First, there isno evidence that HE and AA actually reduce GER frequency or acidexposure. Second, being used widely in the community, parentswere familiar with HE and AA and this allowed for better con-cealment of which treatments were hypothesized to be efficacious.Finally, by using sham therapies rather than a placebo, parents were

8 h study• pH-impedance

• Cardioresp

monitoring

• Sx monitored• Video

• GE breath test

• I-GERQ-R

Randomizaion

Positive symptom

assosiation (SAP > 95%)to symptoms of crying,

coughing or

regurgitation

8 h study

• pH-impedance

• Cardioresp monitoring

• Sx monitored

• Video

• GE breath test• I-GERQ-R

Eligibility

Exclusion

• GERD symptoms

• Informed consent

• ALTE

• Cigarette smoke

• Surgery

• Unsafe to enroll

TX 2 wk

Gr Med Pos

1 PPI LLP

2 PPI HE

3 AA LLP

4 AA HE

FIGURE 1. Study protocol. Overview of study procedures. AA ¼ antacid; ALTE¼acute life-threatening event; GE¼gastric emptying;

GERD¼gastroesophageal reflux disease; Gr ¼ group; HE ¼ head of cot elevation; I-GERQ-R¼ reflux questionnaire; LLP ¼ left lateral position;

PPI ¼ proton-pump inhibitor; SAP¼ symptom association probability; Sx ¼ symptoms.

Loots et al JPGN Volume 59, Number 2, August 2014

238 www.jpgn.org



reassured that, if not the trial treatment, a possible treatment wouldbe administered nevertheless.

PPI and AA therapies were administered double blind. Thatis, the medication was prepared by the hospital pharmacy, parentswere not advised as to what treatment had been given, and inves-tigators charged with analysis of studies had no knowledge of

therapies given. Body positioning interventions were performedsingle blind. That is, parents were not provided with specificinformation regarding which positioning treatment was predictedto be more effective.

After 14 days, combined pH-impedance, physiologicalmonitoring, video study, gastric emptying breath test, and theI-GERQ-R questionnaire were repeated on therapy and in theallocated body position. Adverse events were identified by askingparents/caretakers/hospital staff an open question about any healthissues during the study.

Precautions to Mitigate Sudden Infant DeathSyndrome Risk

The literature shows that side positioning (side unspecified)increases sudden infant death syndrome (SIDS) risk (23). It hasbeen suggested that the doubled risk of SIDS in the side-sleepingposition is probably because of the side position being relativelyunstable, resulting in infants turning to the prone position (24). Inaddition to the exclusion of infants who were exposed to cigarettesmoke in the home, we incorporated several additional precau-tionary measures into this study. To reduce the chance of accidentalprone positioning, parents were instructed to side position theirinfant with lower arm and shoulder forward using a purpose-designed pillow.

The following precautions were also taken for all of theinfants enrolled. All of the parents received instruction on SIDS-safe infant dressing and arrangement of bedding. Positioning pro-tocols were limited to the first 2 hours after a feed and only allowed

when parents were able to observe their infant. Finally, O2 satur-ation was continuously monitored during this period.

Measurement Methods

GER Monitoring GER episodes were recorded using a single-use infant pH-

impedance catheter with a pH sensor and 6 impedance channels.The pH sensor was placed at the third vertebra above the diaphragmand was confirmed by a thoracic x-ray. Depending on site pre-ference, a ComforTec MII/pH probe was used in combination with aSleuth system recording device (Sandhill Scientific, HighlandsRanch, 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 primaryanalysis by 1 investigator, who was experienced with the use of bothsoftware systems, each study was also checked for accuracy by asecond 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-minutetime window was used for GER-symptoms association. To assess

GER-symptom association, the SAP was calculated. A positivesymptom association is defined by a SAP 95% for any symptomtype (26).

Physiological Monitoring

One of 2 cardiorespiratory and video data acquisition sys-tems 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 systemcomputer (Philips Respironics, Best, the Netherlands). The 8hr

physiological and video data were synchronized and merged withGER data and analyzed in Bioview (Sandhill Scientific). In the

patients recruited in Amsterdam cardiorespiratory and video datawere acquired on the Embla polysomnography system with Remlo-gic analysis software (Broomfield, CO). pH-impedance tracingswere recorded on ambulatory Omega system and simultaneously onthe 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 (transcu-

taneous SaO2< 80%), and apnea (>20 seconds absence of nasalflow and concurrent desaturation). Videos were also manuallyreviewed 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 totaltime of irritability, crying, and fussing (total crying time) as a post-hoc measure of behavioral symptom severity.

Gastric Emptying Breath Test

Gastric half emptying time was measured with the 13C Na-octanoate (a stable isotope) breath test. 13C labeled Na-octanoate(50 mg) was added to the infants’ feed, and breath samples weretaken before and for 4 hours after feeding. The 13CO2 excretion rate

was used to calculate gastric emptying (gastric emptying half time,Tmax, and gastric emptying constant) using an established nonlinear regression model (27).

Analysis and Outcome Measures

Investigators analyzed the pH/impedance data blinded to thetreatment of the infants. Primary outcome was defined as the changein total aggregate number of symptoms and total crying time ontreatment. Secondary outcomes were the number of GER episodes(acid and weakly acid, liquid, mixed, and gas), the number of crying,coughing, and vomiting episodes (if present before treatment),I-GERQ-R scores, gastric emptying, and cardiorespiratory events.Additional post-hoc analysis was performed to assess the impact of patient selection criteria based on automated pH-impedance analysis(using autoscan) on symptomatic outcomes.

Statistical Analysis

Most variables were normally distributed and are presentedas mean (standard error of mean) unless otherwise stated. Primaryparameters at baseline were not significantly different (Studentt test). Consequently a paired t test was used to calculate thedifference between baseline and therapy per treatment group.The change between baseline and therapy was compared amongthe 4 treatment groups and for positioning intervention and medi-cation separately using an analysis of covariance, with the numberof events after treatment as the dependent and the number of eventsat baseline as a covariate. A Pearson correlation was used to

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investigate treatment effects in relation to GER change or gastricemptying change across all individual patients.

The additional post-hoc analyses of subgroups were per-formed using nonparametric tests because the groups were smalland not normally distributed. Wilcoxon signed rank test and Mann-Whitney U analyses were used to assess pre- and postdifferences

and differences between groups, respectively. Statistical analyseswere performed using SPSS Statistics 17.0 (SPSS, Chicago, IL).

RESULTSSixty-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 patientswere included in the study (27 boys, mean age 13.6 [range 2–26]weeks). Eleven patients were born prematurely (median [range]gestational age 32 [28–37] weeks). Twelve patients received treatment before enrolling in the study including PPIs, H2

antagonists, Mylanta, Gaviscon, Panadol, and Infacol (Glaxo-SmithKline, Brentford, UK). No patient had undergone surgery.Figure 2 shows the patient inclusion flowchart. After randomiz-ation, 6 patients were withdrawn, 3 patients were withdrawn beforethe start of therapy by their parents without further specification of motive, and 1 patient (randomized to AA therapy þ head elevation)was withdrawn by the parents after 9 days on therapy. One patient(randomized to PPI þ LLP) was withdrawn by the investigators

because of noncompliance. One patient (randomized to PPI þ HE)was withdrawn after admission to hospital because of feedingdifficulties and a request by the treating pediatrician for themedication 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 muscledysfunction was unremarkable and gave no indication that theinterventions were unsafe to the infants when performed during

the short study period.

Treatment Effects on Gastroesophageal Reflux

Primary outcomes are presented in Table 1 for all of the patients per treatment group. Compared with baseline, the

combination of PPI þ LLP was most effective in reducing thenumber of GER episodes and esophageal acid exposure. Weaklyacid GER was reduced in the group treated with AA þ LLP, from32 [4] to 18 [3], P ¼ 0.03 on treatment. Esophageal acid exposurewas reduced in all groups treated with PPI (Table 1).

Treatment Effects on Symptoms

Symptomatic changes are shown in Table 2. Of patients whodemonstrated vomiting before treatment, vomiting was reduced inthe AA þ LLP group (Table 2). Furthermore LLP, regardless of medication, significantly reduced vomiting after treatment (from7 [2] episodes at baseline to 1 [1] episode on treatment, P ¼ 0.042).

None of the treatment groups showed a symptomatic improvementas measured by a decrease in total irritability, crying, and fussing(total crying time) (Table 2). Symptoms of cough and crying werenot reduced in any of the treatment groups either (Table 3).Parentally reported I-GERQ-R scores decreased in all of the groups,reaching statistical significance for both the PPI þ LLP group (from21 [1] to 18 [2], P¼ 0.02) and AA þ HE group from (24 [2] to

20 [2], P¼ 0.001).

Treatment Effects on Gastric Emptying

Gastric emptying results are shown in Table 3. Gastricemptying halftime was significantly delayed compared with base-line in LLP patients (39 [19] minutes slower) vs HE patients (10 [8]minutes faster, P ¼ 0.038) regardless of medication. Gastric empty-ing Tmax was significantly slower on therapy in the PPI þ LLPgroup (55 [5] minutes vs 78 [8] minutes pre- and posttreatment,respectively, P¼ 0.015).

Treatment Effect of LLP and PPI Independent

of Other Therapies

LLP overall produced a greater reduction in total GER whencompared with HE overall (Table 4). PPI therapy overall produced agreater reduction in reflux index compared with AA therapy overall(Table 4).

66 patients eligible

9 patients not randomized

6 patients withdrawn*

57 patients randomized

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 (N¼3), no compliance (N ¼1, PPI þ LLP), parents did not wish to

proceed after 9 days on therapy (N ¼1, AA þ HE), reduced oral intake, and hospital admission (N¼1, PPI þ HE). AA¼antacid; HE¼head of cot

elevation; LLP¼ left lateral position; PPI¼proton-pump inhibitor.


240 www.jpgn.org



Relation Between GER Change, GastricEmptying Change, and Symptom Change

Among all of the patients, an improvement in the number of symptoms overall did not correlate with the reduction in GER (total

number of GER r ¼ 0.13, P¼ 0.4, acid GER r ¼ 0.18, P¼ 0.26,

weakly acid GER r ¼ 0.005, P ¼ 0.96 and reflux index r ¼0.006,

P¼ 0.972). Reduced GER did not correlate with any specificsymptom subtype.

A relation between symptom improvement overall and aslowing of the gastric emptying rate was observed (r ¼0.54,

P< 0.001). Slower gastric emptying did not correlate with any

specific symptom subtype.

Post-Hoc Stratification Based on AutomatedImpedance Analysis

Impedance baseline recordings were reanalyzed by auto-mated 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 manualanalysis were found not to be SAP positive on automated analysis.When these patients were removed from the database, we were ableto observe some treatment effects in the remaining patients. In thePPI þ LLP–treated group (n¼ 7), crying in the (autoscan-deter-mined) SAP-positive infants reduced after treatment from 99

(65–103) to 62 (32–96) episodes (P¼ 0.018, Wilcoxon signed rank test) and in the PPI þ HE group (n¼ 5) vomiting reduced from17 (6–33) to 10 (1.5–20) (P¼ 0.042, Wilcoxon signed rank test).

TABLE 1. Effect of different treatments upon GER variables

GER variables Pretreatment Posttreatment Difference

Total no. GER

PPI þ LLP 69 (13) 46 (10)

23 (5)

PPI þ HE 50 (6) 41 (6)

9 (3)

AA þ LLP 47 (6) 29 (3) 18 (6)

AA þ HE 55 (9) 44 (7) 11 (8)

Reflux index, %

PPI þ LLP 8.9 (3.1–18.1) 1.1 (0–4.4)

4 (12.9 to 0.2)

PPI þ HE 6.9 (2.1–21.8) 0.5 (0.1–2.2)

5.1 (21.2 to 0.1)

AA þ LLP 2.9 (0.6–6.9) 4.8 (0.8–9.0) 0.9 (2.0 to 2.8)

AA þ HE 5.8 (2.8–12.6) 1.1 (0.2–9.9) (0.066) 2.2 (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 paired t test or signed rank test (P values 0.05–0.10 shown in parentheses,

P<0.05,

P<0.01,

P< 0.001). P values for ANOVA across the 4 treatment

groups for pre-/posttreatment and difference were not significant. AA ¼ antacid; ANOVA¼ analysis of variance; GER ¼gastroesophageal reflux; HE¼head of cot elevation; IQR ¼ interquartile range; LLP¼ left lateral position; PPI¼ proton-pump inhibitor; SEM¼ standard error of mean.

TABLE 2. Effect of different treatments upon symptom assessments

Symptom assessments Pretreatment Posttreatment Difference

Total crying time, min

PPI þ LLP 92 (10) 92 (10) 1 (7)

PPI þ HE 71 (11) 81 (10) 9 (9)

AA þ LLP 106 (19) 88 (10) 17 (18)

AA þ HE 74 (20) 66 (13) 8 (13)

No. cough Sx

PPI þ LLP 22 (7) 25 (7) 4 (9)

PPI þ HE 23 (6) 25 (6) 2 (6)

AA þ LLP 30 (12) 31 (14) 2 (5)

AA þ HE 32 (9) 42 (12) (0.1) 11 (6)

No. vomit Sx

PPI þ LLP 7(2) 6 (2) 1 (1)

PPI þ HE 8 (3) 6 (2) 2 (3)

AA þ LLP 7 (2) 2 (0)

3 (1)

AA þ HE 3 (1) 2 (1) 0 (0) No. cry Sx

PPI þ LLP 48 (9) 48 (8) 5 (5)

PPI þ HE 30 (7) 49 (7)

17 (10)

AA þ LLP 60 (12) 54 (9) 7 (13)

AA þ HE 38 (10) 35 (7) 5 (10)

Mean (SEM) or median [IQR] and mean difference shown for eachtreatment group.

Pretreatment was significantly different from posttreat-

ment using paired t test or signed rank test (P values 0.05–0.10 shownin parentheses,

P<0.05,

P<0.01,

P<0.001). P values for ANOVA

across the 4 treatment groups for pre/post treatment and difference were notsignificant. AA ¼ antacid; ANOVA ¼ analysis of variance; GER ¼gastroesophageal reflux; HE¼head of cot elevation; IQR ¼ interquartilerange; LLP¼ left lateral position; PPI¼ proton-pump inhibitor; SEM¼standard error of mean; Sx ¼ symptoms.

TABLE 3. Effect of different treatments upon gastric emptying vari-

ables

GE vari ables Pretreat ment Post treat ment Difference

GEt1=2

PPI þ LLP 53 (6) 92 (22) 39 (22)

PPI þ HE 46 (12) 29 (7) 16.8 (12)

AA þ LLP 57 (10) 96 (39) 39 (31)

AA þ HE 62 (11) 61 (14) 8 (11)

GEtmax

PPI þ LLP 55 (5) 78 (8)

22 (7)

PPI þ HE 65 (7) 52 (3) (0.051) 13 (6)

AA þ LLP 71 (4) 79 (13) 8 (12)

AA þ HE 66 (9) 77 (7) 12 (9)

Mean (SEM) or median (IQR) and mean difference shown for eachtreatment group. GEt1=2

: gastric emptying half time. GEtmax: gastric empty-

ing time to maximum 13

C concentration. GEGEC: gastric emptying constant.

Pretreatment was significantly different from posttreatment using paired t test or signed rank test (P values 0.05–0.10 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. AA¼ antacid;

ANOVA¼ analysis of variance;GER ¼gastroesophageal reflux; HE¼head head of cot elevation; IQR ¼ interquartile range; LLP¼ left lateral position;PPI¼ proton-pump inhibitor; SEM¼ standard error of mean.


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Adverse Events

During the study 5 patients experienced adverse events, of which 2 were serious. The adverse events were urinary tractinfection, constipation, diarrhea, and vomiting (following immu-nization). Of the 2 patients with serious adverse events, 1 patient(randomized to PPI þ HE) was admitted to hospital after 5 days of treatment and successfully treated for rotavirus infection. Another

patient (randomized to PPI þ 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.

DISCUSSIONIn this randomized sham-controlled study we assessed the

influence of body positioning and medical therapies on the fre-quency of GER and typical symptoms in infants with positive SAPfindings on pH-impedance monitoring. This is the first study to onlyinclude patients with a positive SAP and to assess the influence of therapies designed to reduce reflux triggering and reduce gastricacidity. LLP therapy reduced the number of impedance-detected GER episodes, and PPI therapy reduced acid GER. The use of boththerapies in combination was the most effective way of reducingtotal GER frequency and esophageal acid exposure; however,despite this potent effect on GER, there was no concomitantreduction 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 thatPPIs are ineffective for reducing typical GERD symptoms in theinfant group (13,15,16,28), the present trial addresses the possibilitythat PPIs may lack efficacy because acid suppression does notreduce 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 refluxand because pharmacological reflux inhibitor treatments, such as

baclofen, have adverse effects, which preclude use in infants 0 to6 months (18,19).

Despite use of therapies that clearly ameliorated the totalreflux burden, no objective symptomatic improvement was demon-strated in our patients. Parent reported I-GERQ-R scores improved in infants randomized to AA þ HE (sham þ sham group) as well as

PPIþLLP (active þ active group). The improvement in theI-GERQ-R score in the AA þ HE group, that did not show aconcomitant reduction in GER, appears counterintuitive. Thisfinding suggests that AA þ HE treatment was having a therapeuticeffect unrelated to GER or, alternatively, that parental familiaritywith this widely used conservative therapy could have influenced the subjective I-GERQ-R scores.

Possible explanations for the lack of a symptom responseoverall include the relatively short treatment period and the fact thatobjective symptom monitoring only occurred for 8 daytime hours.Patient selection required a positive SAP, but this may also have

been suboptimal. The SAP is recognized to be the strongeststatistical approach to determine whether GER episodes and symp-toms are causally related (8,26,29); however, SAP is problematic.SAP was originally conceived, designed, and validated (26) for theassessment of symptoms of (adult) heartburn. The number of symptoms typically recorded per infant study is much higher (120 [7] symptoms per patient) than the typical number of symp-toms of (adult) heartburn. The frequency of GER is also higher ininfants (30), and the combination of high numbers of symptoms and reflux episodes increases the chance that a GER episode and asymptom event are associated in time. Poor inter- and intrarater reliability of manual scoring of pH-impedance recordings may be

problematic (31). Interestingly, a post-hoc analysis of patientrecordings using automated analysis software yielded fewer

patients who were SAP positive and a significant improvementin crying symptoms in infants randomized to the PPI þ LLP group.These findings in relation to automated analysis clearly warrant

further exploration.Across all of the patients randomized to the 4 differenttreatment arms, an inverse relation was demonstrated betweengastric emptying rate and symptom change. Although our obser-vation that slower gastric emptying may improve symptomsseems counterintuitive, because delayed GE is thought to exacer-

bate vomiting, it may also contribute to satiety. There is alsoevidence in the neonatal literature showing that recommended doses of the prokinetic drug cisapride may slow or leave GEunchanged, rather than accelerate it (22,32). We have published several articles on the influence of lateral positioning on TLESRsand GER showing in LLP that GER is reduced while gastricemptying is paradoxically delayed (18–20). Clearly the relation

between gastric emptying, GER, and typical symptoms requiresfurther investigation.

TABLE 4. Differences in GER, GE, and symptom variables in relation to body positioning or acid-suppression therapy

LLP vs HE PPI vs AA

Difference LLP HE PPI AA

GER variables

Total no. GER 21 (4) 10 (4) (0.056) 16 (3) 15 (5) No. acid GER 10 (3) 9 (3) 12 (3) 6 (3)

No. WA GER 11 (3) 0 (4) (0.052) 4 (3) 7 (5)

Reflux index (%) 3.4 (2.1) 4.5 (1.7) 6.8 (2.1) 0.9 (1.4)

GE variables

GE 1/2 time 39 (19) 10 (8)

8 (13) 24 (17)

Sx assessments

Total ICF, min 8 (9) 1 (8) 4 (6) 12 (11)

No. cough Sx 3 (5) 6 (4) 3 (6) 6 (4)

No. vomit Sx 2 (1) 1 (1) 2 (1) 2 (1)

No. cry Sx 1 (7) 5 (7) 11 (5) 6 (8) (0.09)

Data presented as mean (SEM).

Treatments were significantly different using t test (P values 0.05– 0.10 shown in parentheses,

P<0.05,

P< 0.01,

P<0.001). AA¼ antacid; GER ¼ gastroesophageal reflux; HE¼head of cot elevation; IQR ¼ interquartile range; LLP¼ left lateral position;PPI¼ proton-pump i nhibitor; SEM¼ standard error of mean; Sx ¼ symptoms; WA¼Weakly acidic.


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It is important to recognize that LLP was used in this clinicaltrial as a ‘‘concept test’’ for pharmacological reflux inhibition,which may emerge from future drug development. We presentevidence that LLP may reduce vomiting symptoms; however,caution needs to be exercised because side-positioning contravenesSIDS-safe guidelines and may contribute to plagiocephaly and neck

muscle dysfunction. We undertook several measures to eliminateany potential for these outcomes, including the use of a brace pillowto prevent rolling to the prone position and careful control and monitoring of the interventions used. The requirement for suchmeasures, and the widespread availability of safe treatments for regurgitation and vomiting, precludes lateral positioning from beingrecommended for use in the community under any circumstances.

In conclusion, ‘‘symptomatic GERD’’ implies a diseasecausation for distressing infant symptoms that provokes a targeted therapeutic response. We present the first sham-controlled trial inGER-symptom– positive infants, which used therapies designed toreduce total GER triggering and acid exposure. A reduction in totalGER and/or esophageal acid exposure did not result in a significantimprovement in symptoms other than vomiting; however, auto-mated analysis appeared to identify infants who responded to

positioning therapy. This is an important new insight for futureresearch owing to the inherent advantages of automated analysis inreducing the time and costs associated with administration of pH-MII tests.

Acknowledgments: The authors thank Jan James, Ros Lontis,Louise Goodchild, Amanda Warden, Rosa Katsikeros, and Julia vande Pol for their help and support with conducting this study, and theUniversity of Pittsburgh for access to the I-GERQ-R.

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