Department of Pediatrics, Academic Hospital V.U.B., Brussels, Belgium
Yvan Vandenplas, MD, PhD, (e-mail: firstname.lastname@example.org).
Episodes of GER occur in normal children and adults (1). GER-disease (GERD) is one of the most common gastrointestinal diseases encountered in clinical practice. Since GER is both a physiologic event and a manifestation of disease, there is a lot of controversy on the topic. Primary GER results from a primary disorder of function of the upper gastrointestinal tract, due to an insufficiency at the level of the lower esophageal sphincter (LES) function. Secondary GER is caused by disease within or outside the gastrointestinal tract. Examples of diseases commonly causing secondary GER in infants are cow's milk protein (CMP) allergy and idiopathic pyloric hypertrophy. Treatment of the primary cause, elimination of CMP from the diet or pylorotomy, respectively, will make the symptoms disappear.
Because symptoms suggesting GERD are frequent and non-specific, especially during infancy, and because there is no ‘golden-standard’ diagnostic technique, many infants are exposed to anti-reflux treatment (2). Therapeutic intervention should always be a balance between intended improvement of symptoms and risk for side-effects (3). Untreated GERD may be associated with severe complications such as esophagitis, failure to thrive in children, esophageal stricture, Barrett esophagus and adenocarcinoma.
The first approach should be careful observation of feeding and handling of the child during and after feedings. Reassurance showing comprehension for the comfort problems and impaired quality of life of the infant and parents is of importance. Many infants are overfed or fed with an inappropriate technique. Non-pharmacological therapies for reflux do not have proven efficacy, although some may decrease the incidence of regurgitation. The supine and right lateral positions are associated with the highest incidence of GER; the prone position with the lowest, and the left lateral position with intermediate GER. The prone anti-Trendelenburg position (head elevated 30°C) is the position with the lowest GER-incidence.
Milk thickeners have been reported to reduce regurgitation in infants. Milk-thickening agents include bean gum, carboxymethylcellulose, cereals and starch from rice, potato, corn, etc. There are many different compositions of anti-regurgitation formula: casein-predominance, protein hydrolysates, etc. Although there is consistency in the finding of significant reduction in regurgitation, there is almost constant absence of evidence for a significant reflux-reducing benefit of thickened formula or thickening agents. One exception may be cornstarch; 2 independent studies with cornstarch-thickened formula indicate a decrease of esophageal acid exposure time; these observations need confirmation. Although the effect of thickened feeds is (only) cosmetic, this may help to bring reassurance to the parents and to improve the quality-of-life of infant and parents.
Prokinetic agents such as metoclopramide, domperidone and cisapride act on regurgitation through their effects on LES pressure, esophageal peristalsis or clearance and/or gastric emptying. Metoclopramide and domperidone also have anti-emetic properties due to their dopamine-receptor blocking action, while cisapride is a prokinetic mainly acting via indirect release of acetylcholine from the myenteric plexus. Use of metoclopramide in infants is limited because of severe adverse occurring in more than 20% of patients, including central nervous system effects and interactions with the endocrine system. Studies supporting efficacy of domperidone in improving GER in infants and young children are limited. Some efficacy of erythromycin has been suggested in gastric emptying and improving food tolerance, but there are no data on GER or reflux symptoms. A Cochrane review on cisapride in children concluded that there was a significant efficacy on “symptom present/absent” or on reflux index (4). However, cisapride can be considered as off market. Data with other prokinetic agents such as prucalopride, clebopride, itopride, etc., are disappointing or non-existing. Also, there are no pediatric data with ondansetron or tegaserod. Baclofen is a gamma-aminobutyric acid (GABA)-B receptor agonist, and decreased emesis in 6/8 children. Baclofen decreased significantly the number of acid reflux episodes, but did not change the reflux index (% of esophageal acid exposure time).
Experience with antacids is limited in infants. Alginate-based raft-forming formulations usually contain sodium or potassium bicarbonate. Since alginate-based raft-forming formulations need to float on the gastric contents for effectiveness, the time at which this medication is taken is of great importance. Studies in infant and children remain limited (6 studies including at total 303 patients, only 1 double blind). Their efficacy in GERD is not convincing, although ‘clinical experience’ suggest some efficacy in ‘mild’ GERD. Several articles in adults and children report side effects on bone metabolism with the development of rickets with antacids. Other side effects include as well constipation as diarrhea with magnesium-rich preparations, and excessive absorption of aluminum in infants.
Acid suppressant therapy is recommended in esophagitis, but this does not rectify primary disordered motility. Ranitidine and nizatidine are the most popular, although poorly studied in children. In general, H2RAs are considered safe. There is a rapid development of tachyphylaxis or tolerance to H2RAs, limiting its long-term use.
PPIs can be considered prodrugs since in highly acidic environments, protonation of the molecule results in a series of reactions that ultimately produces the active form of the PPI. Omeprazole and lansoprazole have been best studied in children. In uncontrolled trials and case reports, omeprazole was used in dosage between 0.2-3.5 mg/kg/d for periods ranging from 14 days to 36 months. About 40% of children respond to a dosage of 0.73 mg/kg (equivalent to the adult dosage i.e. 17 mg/m2), 26% more respond to 1.44 mg/kg and 35% failed to respond to this doubled dosage. There is no relation between the dose and side effects (5). The following side effects have been reported: headache (±3%), neurologic and psychiatric side effects especially fatigue, dizziness and confusion in patients with hepatic diseases and/or advanced age; cutaneous reactions, generally rash and urticaria; hemolytic anemia, leucopenia and agranulocytosis; gynecomastia; subacute myopathy; gastrointestinal side-effects such as flatulence, constipation, diarrhea (±4%), dyspepsia and nausea (±2%), vomiting and abdominal pain; hepatic disorders, especially moderate elevation of aminotransferases; excessive urinary sodium loss. A prolonged period of hypochlorhydria may lead to gastric bacterial overgrowth. The clinical relevance of this overgrowth remains unclear, although an increase in nosocomial (respiratory) infections in critically ill patients has been reported.
GER and GERD are frequent conditions in infants, children and adolescents. Guidelines for treatment are difficult to establish, because they struggle with the fact that there is no prokinetic drug with a convincing efficacy profile and because the drugs available on the market differ from country to country (6). Treatment of regurgitation and moderate reflux diseases focuses on reassurance, dietary treatment and alginates. Proton pump inhibitors are the drug of choice in severe reflux. There is little or no information on how to best organize follow-up.
1. Salvatore S, Hauser B, Vandenplas Y. The natural course of gastro-oesophageal reflux. Acta Pediatr 2004;93:1063-9.
2. Hassall E. Decisions in diagnosing and managing chronic gastroesophageal reflux disease in children. J Pediatr 2005;146:S3-12.
3. Blumer JL, Heyman MB, Vandenplas Y, Ward RM. What safety data are needed for a medication to treat gastroesophageal reflux in premature infants? In children younger than 1 year of age? How to design a long-term safety registry for children? J Pediatr Gastroenterol Nutr 2003;37(Suppl. 1):S69-71.
4. Craig WR, Hanlon-Dearman A, Sinclair C, et al. Metoclopramide, thickened feedings, and positioning for gastro-oesophageal reflux in children under two years. Cochrane Database Syst Rev 2004:18;CD003502.
5. Scaillon M, Cadranel S. Safety data required for proton-pump inhibitor use in children. J Pediatr Gastroenterol Nutr 2002;35:113-8.
6. Rudolph CD, Mazur LJ, Liptak GS, et al. Guidelines for evaluation and treatment of gastroesophageal reflux in infants and children. Recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 2001;32(Suppl. 2):S1-S31.
© 2005 Lippincott Williams & Wilkins, Inc.