Gastric motility abnormalities in pediatric gastroesophageal reflux disease: A comprehensive review of mechanisms and therapeutic implications

Table 1 Key medical management points of gastroesophageal reflux disease in children

No.	Key medical management points
1	Use of thickened feeding for visible regurgitation/vomiting in infants with GERD
2	Modification of feeding volumes and frequency according to age and weight to minimize overfeeding
3	Use of a 2-4-week trial of extensively hydrolyzed protein-based (or amino-acid-based) formula in infants when optimal pharmacological management failed to improve symptoms
4	Use of head elevation and left lateral positioning in children, not in infants
5	Providing parental/patient educational material and support
6	Use of PPI as first-line treatment of reflux-related erosive esophagitis in infants and children with GERD for 8 weeks
7	Use of H2RAs in the treatment of reflux-related erosive esophagitis when PPIs are not available

GERD: Gastroesophageal reflux disease; H2RA: Histamine-2 receptor antagonists; PPI: Proton pump inhibitor.

Table 2 Gastroprokinetic agents, their mechanisms of action and clinical relevance in pediatric gastroesophageal reflux disease

Drug	Mechanism of action	Effects on gastrointestinal motility	Use in pediatric GERD	Key limitations
Domperidone	D-2 receptor agonist	Increased GE, increased LES tone	Common	QT prolongation
Metoclopramide	D-2 and 5HT4 receptor agonist	Increased GE, increased LES tone	Limited	Neurological side effects
Erythromycin	Motilin receptor agonist	Increased MMC, increased GE	Off label	Tachyphylaxis
Buspirone	5HT1A receptor agonist	Increased gastric accommodation, increased esophageal motility	Emerging	Limited pediatric data
Acotiamide	A muscarinic receptor antagonist	Decreased postprandial symptoms, enhanced accommodation and antral motility	Emerging	Mostly adult data
Camicinal	Small molecular motilin receptor agonist	Increased gastrointestinal motility and GE	Emerging	No pediatric data
Relamorelin	Ghrelin receptor agonist	Increased GE	Emerging	No pediatric data

D-2: Dopamine-2; GE: Gastric emptying; GERD: Gastroesophageal reflux disease; LES: Lower esophageal sphincter; MMC: Migrating motor complexes.

Table 3 Clinical trials assessing the efficacy of domperidone in the treatment of gastroesophageal reflux disease in children

Ref.	Participants, n (age range)	Cases/controls	Design	Outcome	Comments on the study
De Loore et al[111], 1979	47 (3 weeks to 8 years)	Children with regurgitation/vomiting	Blinded RCT with placebo-controlled arm; domperidone vs metoclopramide vs placebo	Domperidone was superior to a placebo. Domperidone proved to be superior in reducing symptoms compared to metoclopramide	Assessment of symptoms of younger children, especially regurgitation, may have been problematic
Carroccio, et al[112], 1994	80 (1-18 months)	GERD with no erosion. All children were assessed with upper GI endoscopy and pH study	Blinded RCT: Group 1: Domperidone with magnesium hydroxide + aluminium hydroxide; Group 2: Domperidone with alginate; Group 3: Domperidone; Group 4: Placebo, duration 8 weeks	Group 1 showed significant improvement of symptoms and reflux index compared to Groups 2 and 3 (P < 0.018 and P < 0.034 respectively). The domperidone group reported fewer reflux episodes (59 vs 48.5, P < 0.009) and improvement in clinical score before and after treatment (P < 0.04)	A well-conducted study with real-life use of domperidone combined with antacids or alginates. The control group was also appropriate. Assessment was done with pH
Bines et al[113], 1992	17 (5 months to 12 years)	GERD is unresponsive to non-pharmacological treatments and confirmed with pH studies	Blinded RCT with domperidone and placebo arms for 8 weeks	No significant difference in symptom improvement. Only 25% reduction in postprandial reflux episodes in children on domperidone	A small number of patients; age range varies widely, and it could be difficult to assess symptoms in younger children; randomization was not clear; some patients had other diseases
Grill et al[114], 1985	15 (3-13 months)	Babies with symptoms of GERD, like vomiting, spitting, coughing, irritability, and choking, after 2 weeks of non-pharmacological interventions	Open-label study with domperidone for 6 weeks	Improvement of the mean symptom score at 3 weeks and 6 weeks. Reduction of post-prandial reflux time and peristaltic esophageal contractions	The study's open-label design makes it difficult to interpret the results
Hegar et al[115], 2009	20 (2-9 months)	Symptomatic GERD not responding to conservative interventions	Randomized, investigator-blind, open label trial domperidone vs cisapride for 4 weeks	Both drugs were equally effective in reducing the daily frequency of regurgitation, reducing the trends of reflux index, and the number of refluxes/24 hours. No statistical difference between drugs	The open-label nature of the prescription makes it difficult to interpret results. However, the authors have randomized the population, and the investigators are blinded
Cresi et al[116], 2008	26 term and preterm neonates	Symptomatic GERD not responding to non-pharmacological interventions	Open-label, randomized, placebo-controlled trial. Domperidone was given at 8 hours and 16 hours during a 24-hour pH recording with a meal	Increase in reflux frequency and reduction in reflux duration in the group receiving domperidone	The open-label nature of the study makes it difficult to interpret the results. Assessment of symptoms in preterm babies could have been misinterpreted

GERD: Gastroesophageal reflux disease; RCT: Randomized controlled trial; GI: Gastrointestinal.