Impact of Feeding Strategies With Acid Suppression on Esophageal Reflexes in Human Neonates With Gastroesophageal Reflux Disease: A Single-Blinded Randomized Clinical Trial

Abstract

Introduction: Aims were to test hypothesis that esophageal provocation-induced reflexes are superior with acid suppression plus feeding modifications vs acid suppression alone among infants treated for gastroesophageal reflux disease (GERD).

Methods: Infants (N = 49, 41.3 ± 2.6 of postmenstrual age) with acid reflux index >3% underwent longitudinal motility testing (weeks 0 and 5) with graded midesophageal provocation to test randomly allocated therapies (4 weeks' proton pump inhibitor [PPI] ± feeding modifications) on sensory-motor aerodigestive reflexes. Feeding modification included restricted fluid volume <140 mL/kg per day, fed over 30 minutes in right lateral position and supine postprandial position. Primary motility outcome was frequency-occurrence of peristaltic reflex. Secondary outcomes included upper esophageal sphincter contractile reflex, lower esophageal sphincter (LES) relaxation reflex, respiratory change, and symptom characteristics.

Results: Treatment groups did not differ for primary outcome (odds ratio = 0.8, 95% confidence interval 0.4-1.6, P = 0.99) or secondary outcomes (all P > 0.05). For both treatment groups at follow-up, distal esophageal contraction and LES tone decreased, and LES relaxation reflex occurrence is less frequent (all P < 0.05). In a subgroup analysis, comparing infants with PPI washout (N = 40) vs with continued (N = 9) PPI therapy, no differences were noted for aerodigestive reflex response frequency-occurrence (all P > 0.05).

Discussion: In infants with GERD, feeding modification with acid suppression is not superior to acid suppression alone in modifying aerodigestive reflexes (frequency, sensation, or magnitude). Contiguous areas targeted by GER, i.e., LES and distal esophageal functions, worsened at follow-up for both groups despite PPI therapy. Maturation is likely the key factor for GERD resolution in infants, justifying the use of placebo in clinical trials for objectively determined GERD.

Trial registration: ClinicalTrials.gov NCT02486263.

Conflict of interest statement

Guarantor of the article: Sudarshan R. Jadcherla, MD, FRCPI, DCH, AGAF.

Specific author contributions: S.R.J.: developed proposal, obtained grant funding, conceptualized and designed the study, performed procedures and data acquisition, supervised data analysis, interpreted data, drafted the initial manuscript, edited and reviewed, and finally approved the final manuscript revision as submitted. K.A.H.: performed data acquisition, manometry data analysis and verification, interpretation of data, drafted the initial manuscript, and reviewed, and approved the final manuscript as submitted. I.K.G.: performed procedures and data acquisition, interpretation of data, edited and reviewed manuscript, and approved the final manuscript as submitted. R.H.: performed and verified manometry data analysis, verified data for statistical analysis, reviewed manuscript, and approved the final manuscript as submitted. H.I.: performed and verified manometry data analysis, verified data for statistical analysis, reviewed manuscript, and approved the final manuscript as submitted. V.Y.: performed independent statistical analysis, verification, interpretation, and manuscript writing, and approved the final manuscript as submitted. L.W.: supported with statistical study design, performed and guided with statistical analysis, reviewed and interpreted data, manuscript writing, and approved the final manuscript as submitted.

Financial support: Supported by the National Institutes of Health (R01 DK 068158 [to S.R.J.]) and the National Center for Advancing Translational Sciences (UL1TR002733 [to The Ohio State University Center for Clinical and Translational Science for REDCap support]).

Potential competing interests: None to report.

Trial registry: NCT02486263.

Figures

Figure 1.

Study flow diagram. †Clinical outcomes (feeding status and symptom scores) of this randomized controlled trial have been previously reported (36), while the focus of this current report is the motility outcomes of those infants who underwent longitudinal motility testing to determine the effect of conventional (proton pump inhibitor [PPI] alone) and study treatments (PPI + feeding modifications). Note of the 49 infants studied at week 5: 40 infants had 1 week of PPI washout as intended and were analyzed for all motility outcomes. Subanalysis was performed for the remaining 9 infants who did not receive washout due to parental refusal to discontinue medication.

Figure 2.

Impact of interventions (conventional or study) on airway and digestive support systems using supplemental oxygen and tube feeding, respectively. Conventional treatment: proton pump inhibitor (PPI) alone, study treatment: PPI + feeding modification bundle. *Denotes P < 0.05 over time. Note in (a) the need for supplemental oxygen decreases over time in conventional (P = 0.14) and in study (P = 0.03) group, and in (b) the need for tube feeding decreases over time in conventional (P = 0.01) and in study (P = 0.03). Maturation modifies the changes in airway and digestive needs and not the feeding modifications.

Figure 3.

Physiological characteristics of esophageal sphincters. Conventional treatment: PPI alone, study treatment: PPI + feeding modification bundle. For (a) and (b), comparisons were performed within and between groups; (a) UES and LES sphincter length increased with maturation in infants treated for GERD regardless of intervention type. (b) Differences were noted with UES basal tone across maturation, regardless of intervention. Also, note LES tone decreased across maturation in infants treated for GERD in both treatment groups. For (c) and (d), change was calculated as the difference between week 5 and week 0 for both intervention groups. (c) LES growth was greater in the study group. (d) UES tone increased in the conventional group and decreased in the study group, and LES tone decreased for both groups. GERD, gastroesophageal reflux disease; LES, lower esophageal sphincter; PPI, proton pump inhibitor; UES, upper esophageal sphincter.