Vandenplas Yvan, Academisch Ziekenhuis Kinderen, Vrije Universiteit Brussel, Brussels, Belgium
Professor Yvan Vandenplas, male born on 1956-02-21 in Brussels, Belgium, graduated from the Free University of Brussels in 1981, and is now Head of the Department of Pediatrics, having more than 100 papers published.
Correspondence to: Vandenplas Yvan, MD, PhD., Academic Childre n＇s Hospital, Free University of Brussels, Laarbeeklaan 101, 1090 Brussels, Belgium
Telephone: 00-32-2-477-57-80/81, Fax. 00-32-2-477-57·83
Received: 1999-06-23

Subject headings: acid suppression; cisapride, endoscopy; esop hagitis; gastroesophageal reflux; H²-receptor antagonist, pH monitoring; proton pomp inhibitor

Vandenplas Y. Diagnosis and treatment of gastroesophageal reflux disease in infants and children.
World J Gastroentero, 1999;5(5):375-382

      Gastroesophageal reflux (GER) is a physiologic phenomenon occurring occasional ly in every human being, especially during the postprandial period. Regurgitatio n occurs daily in almost 70% of 4-month-old infants and about 25% of their par ents do consider regurgitation as “a problem”^［1,2］. Indeed, it seems against logic that the normal function of the stomach would reflux ingested material back into the esophagus. Whether all infants presenting with regurgitation need drug treatment is a controversial question.

DEFINITION
GER is best defined as the involuntary passage of gastric contents into the esophagus. The origin of the gastric contents can vary from saliva, ingested food and drinks, gastric, pancreatic to biliary secretions. Vomiting is used as a synonym for emesis, and means that the refluxed material comes out of the mouth “with a certain degree of strength” or “more or less vigorously”, usually involuntary and with sensation of nausea. Regurgitation is used if the reflux dribbles effortlessly into or out of the mouth, and is mostly restricted to infancy (from birth to 12 months)^［2,3］. Vomiting can be regarded as the top of the iceberg in its relation to the incidence of GER-episodes.

CLINICAL PRESENTATION
Symptoms of reflux may be observed in normal individuals, but in those cases they are only found incidentally, and they occur more often and are more severe in pathological situations. The usual manifestations and unusual presentations of GER(-disease) are listed in Table 1^［3］. Infants with a Roviralta Astoul syndrome have pyloric stenosis associated with hiatal hernia.
      Emesis and regurgitation are the most common symptoms of “primary” GER-diseas e but they are also a manifestation of many other diseases^［2,3］. Such “ secondary” GER-disease can be caused by infections (e.g. urinary tract inf ection, gastroenteritis, etc.), metabolic disorders and especially food allergy ^［2,4］. On clinical grounds, “secondary” reflux may be difficult to sep arate from “primary” reflux. “Secondary” reflux is the result of a stimulati on of the vomiting center in the dorsolateral reticular formation by all kinds o f efferent and afferent impulses (visual stimuli, the olfactory epithelium, laby rinths, pharynx, gastrointestinal and urinary tracts, testes, etc.). “Secondary ” GER is not further discussed in this paper. It is obvious that treatment of “primary” GER-disease should focus on motility and/or acid suppression, and that therapeutic management of “secondary” GER should focus on the etiolo gic phenomenon.

PATIENT GROUPS
The following approach is a generalization that, like all generalizations, may need to be modified for an individual patient^［3］. First, interest is focused on uncomplicated GER, mostly restricted to regurgitating infants. In a second paragraph, a proposal is made for optimal management in patients with complicated GER disease (symptoms suggestive of esophagitis). There is a continuum betw een normal infants with regurgitation and GER and those with severe GER which leads to disability, discomfort or impairment of function. An approach is proposed for the management of patients with atypical presentations of GER.

Group 1. Uncomplicated reflux: regurgitation
Regurgitation may occur in children who are normal and do not have complaints of GER-disease such as nutritional deficits, esophagitis, blood loss, structures, apnea or airway manifestations. There is no difference in the incidence of regu rgitation in breast-fed and formula-fed infants^［5］. But, infants with u ncomplicated regurgitation are frequently perceived by their parents as having a problem, and their parents often seek medical attention. The approach of the in fants presenting with “excessive” regurgitation and of their parents has to be well balanced, and cannot be subject to overconcern or disregard. This group of patients are mostly restricted to infants younger than 6 months, or at the most 12 months^［1,3,5］. A careful history, observation of feeding, and physic al examination of the infant are mandatory. Although the following statement has not been thoroughly validated because randomization is not possible (only anxio us parents seek medical help), it is rather unlikely that regurgitation will res ult in severe GER-disease. The effect of parental reassurance is suggested by m any placebo-controlled studies showing a similar efficacy of placebo and the tested intervention^［6,7］. If simple reassurance fails, dietary intervention is recommended, including restriction of the volume in clearly overfed babies, and change to a thickened “anti-regurgitation” formula^［5-7］. Larger food volumes and high osmolality increase the number of transient lower esophageal s phincter (LES) relaxations and drifts to almost undetectable levels of LES-pres sure^［8］.Both are well known pathophysiologic mechanisms provoking GER in infants, which might also explain why feed thickeners sometimes aggravate their symptoms. The thickening of the formula, with starch (e.g. from rice, potato, etc.) or non-nutritive thickeners (bean gum), decreases the frequency and volume of regurgitation^［5-7,9］ (Table 2). Some of these “anti-regurgitation” fo rmulae are casein-predominant (casein/whey 80/20%) to optimize the curd for mation, while others contain 100% whey (hydrolysate) enhancing gastric emptying. However, the effect of these formulae on GER-parameters, when measured with pH monitoring or scintigraphy are not convincing: most studies show that reflux pa rameters can improve, remain unchanged or worsen in approximately one third of i nfants for each possibility^［6,7,10］. In other words, “anti regurgitati on” formulae do what they claim to do: they reduce regurgitation^［5-7］but they do not influence (acid) GER. Thickened formula also increases the duration of sle ep^［5,6］. Therefore, anti-regurgitation formula should be considered as the first step in medical treatment, and should only be available on prescription^［3,5-7］. Anti-regurgitation formula and/or dietary intervention in gen eral should be nutritionally safe^［34］. However, regurgitation may be par t of the spectrum of symptom(s) of GER-disease, necessitating an effective inte rvention to decrease the number and intensity of the GER-episodes. In this situation, an intervention that is limited to alleviate the presenting manifestation (regurgitation) will not suffice. Differentiation between regurgitation and (pathologic) vomiting can be difficult on clinical grounds, since there is a continuum between both conditions^［5］. It is not always obvious in this patient group whether the parental complaints relate to physiological regurgitation or whether they suggest GER-disease. In practice, feed thickeners or special formula ca n not be given to breast-fed infants. Therefore, if the infant is breast-fed a nd/or in case of GER-disease, drug treatment with prokinetics should be consi dered prior to diagnostic procedures.
      It seems reasonable to add medication such as prokinetics to the treatment of cases that are refractory to dietary intervention. They reduce regurgitation via their effects on the LES pressure and motility, esophageal peristalsis and gastric emptying^［11］. For this reason, they interact with the pathophysiologic mechanisms of regurgitations in infants, which are related to immaturity of the gastroesophageal motor function^［12］. A link between cisapride and increased salivary secretion has been demonstrated^［13］. This indicates that, in combination with increased peristalsis and hence esophageal clearance, cisapride therapy may protect the esophagus via salivary components, such as bicarbonate and non-bicarbonate buffers, thus facilitating symptomatic relief and healin g of the esophagus.Metoclopramide and domperidone have anti-emetic properties due to their dopamine-receptor blocking activity, whereas cisapride is a prokinet ic acting through indirect release of acetylcholine in the myenteric plexus ^［11］. Although all three agents have been shown to reduce regurgitation in i nfants^［6,7］, data for cisapride are more convincing (Tables 3, 4). When compared to metoclopramide, cisapride appears to be more effective in reducing p H-metric^［14］, has a faster onset of action^［15］, and is better t olerated^［15］. Cisapride has also been shown to heal oesophagitis^{［16 ］}. Domperidone has been reported to be as effective as metoclopramide^{［17 ］} (less effective than cisapride). Extrapyramidal reactions and increased pro lactine levels are effects related to the dopamine-receptor blocking activity o f these drugs. In case of cisapride, which is devoid of dopamine- blocking prope rties at therapeutic doses, the most common adverse effects are transient diarrhea and colic (in about 2%)^［11,18］. The isolated reports of more serious adverse reactions, i.e., side-effects on the central nervous system, including extr apyramidal reactions and seizures (in epileptic patients), cholestasis (in extre me prematures) and cardiac interactions. Indeed, cisapride, which is metabolized by the cytochrome P450 3A4, has the potential to prolong the QT-interval^{［ 18］}. However, an extensive review of the literature resulted in reassuring sa fety consensus statements^［18］.To date, serious cardiac adverse reactions have not been reported in patients treated with a dosage within the recommended regimen (0.8mg/kg daily, max. 40mg/day) and in the absence of a dditional risk factors (Table 4). The association of cisapride with systemic or oral azole antifungals and with macrolides is contraindicated. Both azole-antif ungals and macrolides interact with the cytochrome P450 3A4, resulting in elevated cisapride plasma levels. In view of its mode of action, efficacy and safety, as well as its lower or equal cost when compared to other therapeutic agents for GER, cisapride is recommended when dietary treatment fails or in regurgitating breast-fed infan ts, if therapy is indicated. It merits consideration that prokinetics stimulate a physiologic activity (peristalsis), while acid-suppressive medication inhibit s a physiologic secretion.

Table 1 Symptoms of GER(-disease)

A number of these symptoms may also be caused by other mechanisms.

Table 2(PDF) Effect of special formula and milk-thickening products on GOR, gastric emptying (GE) and clinical parameters in infants with GOR disease (=: unchanged, ＜: worse, ＞: better)

^ameans of age in groups, ^bO: open, SB: single blind, XO: crossover, PA: parallel, ^cthickened meal (FT) vs unthickened meal (noFT) or vs baseline (B) or comparison of special formula, cn.d.: no data, N.S.: not significant.

Table 3(PDF) Effects of cisapride (CIS) on GOR disease in infants

^aAge: mean(s) of age in group(s); ^bO: open; DB: double bl ind; PA: parrallel; XO: cross-over with wash-out period; ^cCIS: cisapride ; PLA: placebo; MCL: metoclopramide; DO: domperidone; CIM: cimetidine; GAV: Gavi scon; AA: antacid; FT: feed thickener; B: baseline; CO: controls; bm: before mea ls/each feeding; afm: after meals; ^dDM: dietary measures; SD: standard diet; dex: dextrose; glu: glucose; CF: customary formula; SF: solid food started if not yet done so; PN: parenteral nutrition;
*prior therapeutic measures co ntinued (positional and/or dietary); e,f-Outcome: GOR, reflux parameter s on pH monitoring; GE, gastric emptying; ＞, better than; ＜, worse than; =, un changed, referring to the main/all parameters evaluated in paper; exceptions for single parameters are mentioned separately. Symptoms: if not specified, clinica l assessment including regurgitation and/or vomiting. PLES: pressure lower esoph ageal sphincter. n.d.: no data.

Table 4 Contraindications and risk factors for use of cisapride

      In the non-breast-fed infant, a change to a (thickened) hydrolysate or amino- acid formula should be considered, if regurgitation is resistant to a thickened formula with normal proteins and to prokinetics, since protein allergy may prese nt as therapy-resistant GER-disease.
      Non-drug treatment (positional therapy, dietary advice) can help convince the p arents of the physiologic nature of the regurgitations^［3］. The influence of position on the incidence and duration of GER episodes has been demonstrated in adults, children and infants both in asymptomatic healthy controls and sympt omatic individuals. The 30° prone reversed Trendelenburg position is nowadays generally recommended and accepted as an essential element of treatment^［3,6,7］. However, positional treatment is in practice very difficult to apply correctly in infants and rather unfriendly to the babies, since they have to be tied up in their beds or cot to prevent them from sliding down under the blankets, since an angle of 30° has to be achieved and maintained. The ample evidence that the prone sleeping position is a risk factor in sudden infant death, independent of overheating, smoking or way of feeding^［6］. Positional treatment remains, in view of its efficacy, a valid “adjuvant” treatment in patients not responding to other therapeutic approaches or beyond the age of sudden infant death^［6］.

Group 2. Overt GER-disease
Patients in this group did not either respond to the previous approach (parental reassurance, dietary treatment and prokinetics) or present with symptoms suggesting esophagitis (hematemesis, retrosternal, epigastric pain, etc.) (Table 1). Therefore, an underlying anatomic malformation should be excluded, and endoscopy is the investigation of choice^［3,19］. Upper gastrointestinal endoscopy in infants and children should only be performed by experienced and qualified physicians^［19］. If the question being asked is restricted to underlying anatomic malformations, upper gastrointestinal series can be considered^［19］. If symptoms and/or the esophagitis do not improve despite adequate medic al treatment and controlled compliance, upper gastrointestinal series should be performed to exclude anatomical problems such as gastric volvulus, intestinal ma lrotation, annular pancreas, etc.
      Antacids are reported to be effective in the treatment of GER^［6］, although experience is limited in infants. Their capacity to buffer gastric acid is strongly influenced by the time of administration^［20］, and requires multiple doses. Gaviscon (a combination of an antacid and sodium salt of alginic acid) is as effective as antacids and appears to be relatively safe, since only a limited number of side effects have been reported. Occasional formation of large bezoar-like masses of agglutinated intragastric material has been reported with the use of Gaviscon, and it can increase the sodium content of the feeds to an undesirable degree especially in preterm infants (1g Gaviscon-powder contains 46mg sodium, and the suspension contains twice this amount of sodium)^［6］.
      H²-receptor antagonists, of which ranitidine is by far the mostly used, are e ffective in healing reflux esophagitis in infants and children^［6］. Many new drugs have been developed (misoprostil, sucralfate, omeprazole, etc.). Of these, the proton pump inhibitors (PPIs) have been studied best, although experien ce in infants and children is limited^［21,57］. PPIs are effective in supp ressing the acidity in patients with gastric stress ulcer(s) and also in neurolo gically impaired children. Even in patients with circular esophageal ulcerations , recent experience suggests that PPIs should be given a chance prior to surgery^［21］. Omeprazole is known to be effective in patients with severe esophagitis refractory to H² blockers^［21］. Sucralfate was shown to be as ef fective as cimetidine for esophagitis in children^［22］.
      Immediate or early surgery is rarely indicated in life threatening conditions where medical management will be of no benefit. Surgery can be life-saving in severely affected patients (notably the neurologically impaired children with recur rent and life-threatening aspiration, etc.). Prior to surgery, a full diagnosti c work-up including upper gastrointestinal series, endoscopy, pH monitoring, eventually completed with manometry and gastric emptying studies is recommended.

Group 3. Patients with unusual presentations of GER
The most obvious difference between this patient group and groups 1 and 2, is that this patient group does not present with emesis and regurgitation (Table 1). Since these patients do not vomit, GER-disease is “occult”. Before considering GER as a cause of the symptoms, classic causes of the manifestations need to b e excluded, such as allergy in a wheezing patient, tuberculosis in a patient wit h chronic cough, etc.
      If GER-disease is suspected, pH monitoring of long duration (18-24 hours) is the investigation of choice. In this group of patients, pH monitoring may need t o be performed in simultaneous combination with other investigations in order to relate pH changes to events (e.g. polysomnography in the infants presenting with an apparent life threatening event). In patients suspected of pulmonary aspiration, a scintigraphy might prove the association (although a negative scintigraphy does not exclude reflux related aspiration, and the therapeutic approach will be identical).
      If pH monitoring is abnormal or if events are clearly related to pH changes, prokinetics, eventually in combination with H² receptor antagonists or PPIs, are indicated^［19,21］.In this group, repeat pH monitoring under treatment conditions in combination with a clinical follow-up is mandatory. Depending on the unusual presentation, treatment can be stopped after 6 to 12 months, since a possible mechanism for GER in association with unusual manifestations may be self-perpetuating GER^［23］. Once reflux occurs, acid gastric contents containing pepsin and sometimes bile comes into contact with the esophageal mucosa, which increases the esophageal permeability to acid and makes the esophageal mucosa much more susceptible to inflammatory changes. Esophageal inflammation, even res tricted to the lower esophagus, impairs LES pressure and function, and favors GE R^［23］.

Severely neurologically impaired children
The vast majority of neurologically impaired children suffer from severe GER- disease. Most of these children are under specialized follow-up, and only brief recommendations will be given here. The pathophysiological mechanism of GER-di sease in these children is particularly multifactorial: the neurological disease itself (which might cause delayed esophageal clearance and delayed gastric empt ying), the fact that most of these children are bedridden (gravity improves esop hageal clearance), many are constipated (which increases abdominal pressure and favors GER), etc.

CONCLUSIONS
The diagnostic approach of GER(-disease) in infants and children principally de pends on its presenting features. Infants with typical symptoms of uncomplicated GER (the majority of regurgitating babies) should be treated without prior investigations. Endoscopy, in specialized centers, is recommended if esophagitis is suspected. Long-term esophageal pH monitoring is the investigation of choice and occupies a central position in the diagnostic approach of the patient suspected of unusual or atypical presentations of GER- disease (“occult” GER-disease). Non-drug treatment (the importance of parental reassurance cannot be stressed enough) and dietary treatment are an effective and safe approach in infant regur gitation, but does not treat GER-disease. If the symptoms are refractory to thi s approach, or in reflux-disease, cisapride is the drug of choice. PPIs or H²-receptor antagonists, in combination with prokinetics, are recommended in (ulc erative) esophagitis. There is no excuse to persist with an ineffective manageme nt of a disease which might result in stunting, chronic illness, persistent pain , esophageal scarring or even death. Management of GER(-disease) in infants and children should therefore be well overthought, avoiding overinvestigations and o vertreatment of a self-limiting condition, but also avoiding underestimation of potential severe disease, accompanied by serious morbidity.

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