Department of Paediatrics
Academisch Ziekenhuis Kinderen
Vrije Universiteit Brussel
Clinica Pediatrica di Varese
Gastro-oesophageal reflux disease (GORD) can best be defined as manifestations of oesophageal or adjacent organ injury secondary to the reflux of gastric contents into the oesophagus or, beyond, into the oral cavity or airways. Determination of the exact prevalence of GORD at any age is virtually impossible because most reflux episodes are asymptomatic and symptoms are nonspecific, or due to self-treatment or lack of medical referral. Many factors influence the number of reflux episodes. Daily regurgitation is present in 50% of infants younger than 3 months, and in more than 66% at 4 months, but only in 5% at 1 year of age.(1,2) Approximately 5–9% of infants have (acid and troublesome) GORD.(3) Reflux oesophagitis is reported to occur in 2–5%. Barrett’s oesophagus is present in 0.1–3%, and refractory GORD requiring surgery in up to 6–13%.(4) At all ages, there is also a continuum between physiological GOR and GORD. The presenting symptoms of GORD differ according to age. Cow’s milk allergy (CMA) may overlap many symptoms of GOR, and may coexist or complicate GORD in up to 40% of infants.(5)
In infants and young children, verbal expression of symptoms is often vague or impossible, and persistent crying, irritability, back-arching, feeding and sleeping difficulties have been proposed as possible equivalents of adult heartburn. Infants with GORD learn to associate eating with discomfort. They subsequently tend to avoid eating and develop an aversive behaviour around feeds, although behavioural feeding difficulties are also common in control toddlers.(6) Unsurprisingly, the mother–child interaction is frequently affected.(7)
Diagnostic procedures are not discussed in detail here. Radiological contrast studies, scintiscanning and ultrasound are techniques evaluating only postprandial reflux; they also provide information on gastric emptying. Normal ranges are not (or not well) established for any of these procedures. Scintiscanning may show pulmonary aspiration, although this seems to occur in extremely seldom fashion. The results of ultrasound procedures are investigator-dependent. Endoscopy on preterm infants of less than 1,000g can be carried out using modern video-endoscopes. However, endoscopy shows anatomical malformations and oesophagitis, not reflux, and endoscopy-negative reflux disease is common. Biopsies of duodenal, gastric and oesophageal mucosa are mandatory to exclude eosinophilic infiltration and other causes of oesophagitis and/or GORD, such as allergy. Experience with spectrophotometric oesophageal probes to detect bilirubin is currently limited. Ambulatory 24-hour oesophageal pH monitoring measures the incidence and duration of acid reflux. Intraluminal oesophageal acid perfusion provoking chest pain (Bernstein test) or using other endpoints has found expanded use in practice and research in the USA, but not in Europe. Manometry does not demonstrate reflux, whereas impedancemetry measures electrical potential differences and is therefore not pH-dependent. The technique offers the possibility to distinguish between acid and nonacid reflux (in combination with pHmetry), and between liquid and gas reflux.
As reflux is common in infants, because there is no “golden standard” investigation and since investigations are invasive and expensive, interest has focused on the development of an “infant GOR questionnaire”.(1,8) The questionnaire offers the advantage of having an objective, validated and repeatable quantification of symptoms suggesting GORD, and thus offers the possibility to measure the impact of therapeutic intervention. Many studies have suggested a poor correlation between symptoms and the severity of reflux(/oesophagitis). From our experience, results of the questionnaire did not correlate with results of pH monitoring and endoscopy.(9)
The different treatment options available are presented in Box 1.
Complications of nonintervention
It is difficult to know the true natural history of GOR in infants and children because most patients get treatment. The paucity of long-term reports, the presence of multiple pathogenic factors and the absence of pathognomonic symptoms for complications make it currently impossible to predict, on an individual basis, which child will continue to have GORD into and during adult life. Recent observations suggest a decreased quality of life in regurgitating infants and their parents, even if the regurgitation has disappeared. Complications and side-effects of medication have to be considered in relation to the natural evolution of untreated GORD. A balanced approach considering the benefits of treatment, as well as its cost, risks of side-effects and complications of nontreatment, is recommended.
Nonpharmacological and nonsurgical therapies
The first approach should be a careful observation of feeding and handling of the infant during and after feedings.(10) Reassurance showing comprehension of 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. The data of 10 randomised controlled trials of nonpharmacological and nonsurgical interventions in GORD in healthy infants have not proven efficacy on reflux, although some may decrease the incidence of regurgitation.(11) Despite gravity, the upright seated position leads to significantly more and longer reflux episodes than the simple prone and 30(°) elevated prone positions, whether the infant is awake or asleep.(12) The supine (lying on the back) and right lateral positions are associated with the highest incidence of GOR, the prone position with the lowest, and the left lateral position with intermediate GOR.(12) The prone anti-Trendelenburg position (head elevated 30(°)) is the position with the lowest associated incidence of GOR. However, there is now ample evidence that the prone sleeping position is a risk factor for sudden infant death, independent of overheating, smoking or way of feeding.
Feed thickeners and antiregurgitation formulas
Milk thickeners are reported to reduce regurgitation in infants.(12) Although there is consistently significant reduction in regurgitation, there is no evidence for a significant reflux-reducing benefit of thickened formula or thickening agents.(13) A thickened formula leads to some improvement in oesophageal acid exposure in about one-third of infants; no difference is observed in another one-third, and oesophageal exposure is increased in the remaining one-third. Cornstarch may constitute an exception; independent studies with a cornstarch-thickened formula from two different companies indicate a decrease in oesophageal acid exposure time, although these observations need to be confirmed.(14) Commercial thickened formula is preferred to thickening agents added to formula at home; the nutritional content of the thickening agent and its effect on osmolality have been considered in the commercial formula. Studies of various thickening agents, including guar gum, carob bean gum and soybean polysaccharides, indicate the potential for decreased intestinal absorption of carbohydrates, fats, calcium, iron, zinc and copper.(15) Abdominal pain, colic and diarrhoea may ensue from fermentation of bean gum derivatives in the colon. Nevertheless, in view of their overall safety and efficacy in decreasing regurgitation, milk thickeners remain a valuable first-line measure in relieving regurgitation in many infants. Although their efficacy in GORD is questionable, they may help reassure parents and improve quality of life for both infant and parents.
Prokinetic agents such as metoclopramide, domperidone and cisapride act on regurgitation through their effects on lower oesophageal sphincter pressure, oesophageal peristalsis or clearance and/or gastric emptying. Metoclopramide and domperidone also have antiemetic properties due to their dopamine-receptor blocking action, whereas cisapride is a prokinetic agent acting mainly via indirect release of acetylcholine from the myenteric plexus.
Data supporting the efficacy of metoclopramide are limited to observations with intravenous administration.(16) Application in infants is limited because of severe adverse events that occur in more than 20% of patients, including central nervous system effects and interactions with the endocrine system.(16) Metoclopramide has been reported to induce torsade de pointes.(17) Although data in infants and children are limited, it is not recommended to investigate metoclopramide in children because of side-effects. Studies supporting the efficacy of domperidone in improving GOR in infants and young children are limited.(16) Most studies have been performed in older children or have investigated the effects of domperidone coadministered with other antireflux agents.(16) Domperidone is better tolerated than metoclopramide, as dystonic reactions (tremors) and anxiety are infrequent.(18) Domperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhythmic drugs.(16) Intravenous domperidone causes QT prolongation and ventricular fibrillation.(19) Because of the widespread use of domperidone in many countries, the absence of paediatric data and the unconvincing data in adults, a well-designed comparative trial with another prokinetic molecule is needed. Erythromycin has a prokinetic activity if it is administered intravenously. Some efficacy has been suggested on gastric emptying, but not on GOR or reflux symptoms. A Cochrane review on cisapride in children analysed data from seven trials including 236 patients and comparing cisapride with placebo for their effect on symptom presence and improvement.(20) Although there was a statistical difference for the parameter “symptoms present/absent”, no statistically significant difference for “symptom change” was observed between placebo and cisapride. The Cochrane review also concluded that cisapride compared with placebo significantly reduced the number and duration of acid reflux episodes, since there was a significant decrease in reflux index (the percentage of time that oesophageal pH is <4.0).(20) The most common adverse events are transient diarrhoea and colic (in about 2%). The effect of cisapride on relevant cardiac events such as QT prolongation and arrhythmia is dose- and risk factor-related. Cisapride possesses class III antiarrhythmic properties and prolongs the action potential duration, delaying cardiac repolarisation.(21) Torsades de pointes have been reported with cisapride.(22) Cytochrome P4503A4, which is involved in the metabolism of cisapride, is immature at birth and reaches adult activity by the age of 3 months.(23)
Prucalopride, a 5-HT(4) agonist, was forbidden in children because of extrapyramidal side-effects. Mosapride has limited effect, comparable to that of cisapride, on acid reflux variables and oesophageal motor function in patients with GORD. However, it also has cardiac side-effects, and was reported to induce torsades de pointes. Clebopride is another prokinetic agent; no placebo-controlled trials in peer-reviewed journals have been published. An open-label, noncomparative trial in 30 patients showed that itopride led to improvement in 73% of patients with nonulcer dyspepsia. The drug does not cause QT prolongation, as it does not involve the CYP3A4 system. Ondansetron is a 5-HT(3) receptor antagonist that accelerates gastric emptying, inhibits chemotherapy-induced emesis but prolongs colonic transit time.(24) The most frequently reported adverse events of ondansetron are mild-to-moderate headache, constipation and diarrhoea in patients receiving chemotherapy. Tegaserod is a partial 5-HT(4) agonist that has been mostly studied in constipation-predominant irritable bowel syndrome in adults.(25) Tegaserod was shown to accelerate small intestinal transit time and increase proximal colonic emptying. Tegaserod also improves gastric emptying and decreases GOR,(26) and may be a promising drug. However, no efficacy data in the treatment in paediatric GOR have yet been published. Baclofen is a gamma-aminobutyric acid B-receptor agonist used to reduce spasticity in neurologically impaired patients. Given orally, it has been shown to decrease GOR in healthy adults.(27) Administration in eight paediatric patients was reported to be safe.(28) Baclofen given to eight neurologically impaired children (age 2 months to 16 years) decreased emesis in six children.(29) Baclofen significantly decreased the number of acid reflux episodes but did not change the reflux index (percentage of oesophageal acid exposure time).(29) In addition, the oesophageal acid clearance time was increased in four out of eight children.(29) The banning of cisapride has caused a switch to (over)prescription of other prokinetic agents. Efficacy data for these other agents are either unknown or negative. Moreover, side-effects seem comparable (although poorly studied) to those of cisapride.
Antacids do not change the course of GORD, as they chemically neutralise gastric acid. The key therapeutic advantage of antacids is their rapid onset of action (within minutes). Alginate-based raft-forming formulations have a different mode of action. In the presence of gastric acid, alginates precipitate, forming a gel. 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 (six studies, among which only one was double-blind, including a total of 303 patients). Their efficacy in GORD is not convincing, although clinical experience suggests some efficacy in mild GORD. Antacids, because of their aluminium content, should not be administered to infants and even toddlers, and given only for a short duration in older children. Gaviscon contains a considerable amount of sodium carbonate, increasing the sodium content of feeding to an undesirable level, especially in preterm infants. Algicon has a better taste than Gaviscon, a lower sodium load but a higher aluminium content. Some efficacy data for alginate-based raft-forming products in mild GORD in infants and young children have been published, but more placebo-controlled data are needed. Data on compliance (because these products have a very bad taste) are missing.
The coating agent sucralfate is a basic aluminium salt of sucrose octasulfate. There are no efficacy data in GORD in infants and young children, but extrapolation from adult data makes sucralfate unlikely to be effective in paediatric GORD.
H(2)-receptor antagonists (H(2)RAs)
Ranitidine and nizatidine are the most popular, although poorly studied, H(2)-receptor antagonists used in children.(30) Whether ranitidine may cause QT prolongation is still debated;(31) if it is given intravenously after autonomic blockage, the sinus cycle is prolonged and the systolic and diastolic blood pressures decrease.(32) The altered cardiac sympathovagal balance after oral administration of ranitidine indicates a shift toward sympathetic predominance in heart rate control.(33) Ranitidine modulates high-frequency power of heart rate, and this may be the underlying mechanism of cardiovascular side-effects.(34) Ranitidine alters the gastrointestinal flora(35) and causes significantly more pneumonias in patients in intensive care units.(36) There is a rapid development of tachyphylaxis or tolerance to H(2)RAs, limiting its long-term use.(37) Efficacy data on H(2)RAs in infants and children are lacking, but given the experience with H(2)RAs and proton pump inhibitors (PPIs) in adults, H(2)RAs should not be considered as a priority drug for further research in paediatric GORD.
Proton pump inhibitors
Omeprazole and lansoprazole have been best studied in children. Zimmerman and colleagues reviewed the literature on the use and administration of omeprazole in children.(38) In uncontrolled trials and case reports, omeprazole was used in dosages of 0.2–3.5 mg/kg/day for periods ranging from 14 days to 36 months. The antisecretory effect of PPIs is independent of plasma concentration but is correlated with the area under the plasma concentration–time curve. Most of the studies performed in children with GORD defined success of treatment by healing of oesophagitis. Overall, for both omeprazole and lansoprazole, currently available studies performed in children show that in patients with adequate acid suppression the healing rate of peptic oesophagitis is >75% after four to eight weeks of treatment; clinical symptoms improve in the same range. Failure to control symptoms with high-dose PPI treatment raises the likelihood of nonacid-related causes for the symptoms.
Lansoprazole, omeprazole and pantoprazole are metabolised by a genetically polymorphic enzyme, CYP2C19, absent in approximately 3% of Caucasians and 20% of Asians. Salivary secretion is decreased with omeprazole. PPIs are highly selective and effective in their action and have few short- and long-term adverse effects. There is no relationship between dose and side-effects. A prolonged period of hypochlorhydria may lead to gastric bacterial overgrowth. The safety of long-term administration of acid-blocking medication needs to be considered, and includes both abnormal gastrointestinal flora and enterochromaffin-like cell hyperplasia. Hypergastrinaemia occurs in nearly all patients. Fundic polyps and nodules have been reported in children on omeprazole for more than six months. Overall, long-term use of PPIs in children seems to be relatively safe, although these drugs have the potential to induce many side-effects.
PPIs are priority drugs for further research in infants and children. Although efficacy data in adults are convincing, more data are needed in young children and infants because of the different metabolic rate in this age group. Moreover, attention should be given to long-term safety aspects, especially regarding gastric atrophy, polyps, gastrointestinal flora and risk for infections or nutritional consequences.
Therapeutic endoscopic procedures
In recent years, new endoscopic techniques to improve the function of the antireflux barrier have been developed.(39–42) Although experience is too limited to recommend broad use, the theoretical concept of these procedures is interesting.
Gastro-oesophageal fundoplication is currently one of the three most common major operations on infants and children in the USA.(43) While antireflux surgery in certain groups of children may be of considerable benefit, mortality and failure rates are also associated with surgery.(43) Ninety percent of patients remain free from significant reflux symptoms after laparoscopic Nissen, although side-effects occur in up to 22% of patients.(44) Failure rates of 5–20% were found after objective postoperative follow-up.(44)
- Orenstein SR, et al. Clin Pediatr 1996;35:607-14.
- Nelson SP, et al. Arch Pediatr Adolesc Med 1997;151:569-72.
- Vandenplas Y, et al. Pediatrics 1991;88:834-40.
- Lee WS, et al. J Paediatr Child Health 1999;35:568-71.
- Salvatore S, et al. Pediatrics 2002;110:972-84.
- Nelson SP, et al. Pediatrics 1998;102:e67.
- Mathisen B, et al. J Pediatr Child Health 1999;35:163-9.
- Kaynard A, et al. Postgrad Med 2001;110:42-4.
- Salvatore S, et al. J Pediatr Gastroenterol Nutr In press.
- Arguin Al, et al. Pediatr Nurs 2004;30:45-51.
- Carroll AE, et al. Arch Pediatr Adolesc Med 2002;156:109-13.
- Vandenplas Y, et al. Eur J Pediatr 1997;156:343-57.
- Craig W, et al. Cochrane Database Syst Rev 2004;4:CD003502.
- Xinias I, et al. J Gastroenterol Hepato (in press).
- Aggett PJ, et al. J Pediatr Gastroenterol Nutr 2002;34:496-8.
- Vandenplas Y. Eur J Gastroenterol Hepatol 1998;10:871-81.
- Chou CC, et al. Chang Gubng Med J 2001;4:805-9.
- Patterson D, et al. Am J Gastroenterol 1999;94:1230-4.
- Drolet B, et al. Circulation 2000;102:1883-5.
- Augood C, et al. Cochrane Database Syst Rev 2000;3:CD002300.
- Tonini M, et al. Aliment Pharmacol Ther 1999;13:1585-91.
- Hill SL, et al. Pediatrics 1998;101:1053-6.
- Semama DS, et al. Dis Child Fetal Neonat Ed 2001;84:F44-6.
- Culy CR, et al. Paediatr Drugs 2001;3:441-79.
- Wagstaff A, et al. Drugs 2003;63:1101-20.
- Kahrilas PJ, et al. Aliment Pharmacol Ther 2000;14:1503-9.
- Ciccaglione AF, et al. Gut 2003;52:464-70.
- Wiersma HE. Ther Drug Monitor 2003;25:93-8.
- Kawai M. J Pediatr Gastroenterol Nutr 2004;38:317-23.
- Sabesin SM. Aliment Pharmacol 1993;7 Suppl 2:S35-40.
- Alliet P, et al. Eur J Pediatr 1993;152:933-4.
- Hu WH, et al. Zhonghua Yi Xue Za Zhi 1997;60:1-5.
- Nault MA, et al. Anesthesiology 2002;96:336-41.
- Ooie T, et al. Heart Vessels 1999;14:137-42.
- Cothran DS, et al. J Perinatol 1997;17:383-8.
- Messori A, et al. BMJ 2000;321:1103-6.
- Huang JQ, et al. Best Pract Res Clin Gastroenterol 2001;15:355-70.
- Zimmermann AE, et al. Clin Ther 2001;23:660-79.
- Mahmood Z, et al. Gut 2003;52:34-9.
- Wolfsen HC, et al. J Laparoendosc Adv Surg Tech A 2002;12:395-402.
- Johnson DA, et al. Am J Gastroenterol 2003;98:250-8.
- Galmiche JP, et al. Lancet 2003;361:1119-21.
- Fonkalsrud EX, et al. J Pediatr Surg 1999;34:527-31.
- Norrashidad AW, et al. J Paediatr Child Health 2002;38:156-9.