Diagnosis and treatment of gastroesophageal reflux disease in infants and children

26D Can J Gastroenterol Vol 14 Suppl D November 2000 This mini-review was prepared from a presentation made at the World Congress of Gastroenterology, Vienna, Austria, September 6 to 11, 1998 Academisch Ziekenhuis Kinderen, Vrije Universiteit Brussel, Brussels, Belgium Correspondence and reprints: Dr Y Vandenplas, Academic Children’s Hospital, Free University of Brussels, Laarbeeklaan 101, 1090, Brussels, Belgium. Telephone +00-32-2-477-57-80, fax +00-32-2-477-57-83, e-mail yvan.vandenplas@az.vub.qc.bc Received for publication June 18, 1999. Accepted June 23, 1999 MINI-REVIEW

G astroesophageal reflux (GER) is a physiological phe- nomenon that occurs occasionally in every human being, especially during the postprandial period.Regurgitation occurs daily in almost 70% of four-month-old infants, and about 25% of parents consider regurgitation 'a problem' (1,2).It seems illogical that the normal function of the stomach would be to reflux ingested material back into the esophagus.Whether all infants presenting with regurgitation need drug treatment is a different question.

DEFINITIONS
GER is best defined as the involuntary passage of gastric contents into the esophagus.The origin of the gastric contents can vary and includes saliva, ingested foods and drinks, and gastric, pancreatic or 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.The term 'regurgitation' is used if the reflux dribbles effortlessly into or out of the mouth, and mostly is restricted to that occurring in infancy (from birth to 12 months) (2,3).Vomiting can be regarded as the tip of the iceberg in its relation to the incidence of GER episodes.

CLINICAL PRESENTATION
Symptoms of reflux may be observed incidentally in normal individuals; however, they occur more often and are more severe in pathological situations.The usual manifestations and unusual presentations of gastroesophageal reflux disease (GERD) are listed in Table 1 (3).
Emesis and regurgitation are the most common symptoms of primary GERD but are also manifestations of many other diseases (2,3).Secondary GERD can be caused by infections such as urinary tract infection, gastroenteritis, metabolic disorders and especially food allergy (2,4).Secondary reflux may be difficult to separate clinically from primary reflux.Secondary reflux is the result of a stimulation of the vomiting centre in the dorsolateral reticular formation by many efferent and afferent impulses such as visual stimuli, the olfactory epithelium, labyrinths, pharynx, gastrointestinal and urinary tracts, and testes.Secondary GER is not discussed further in this paper.Treatment of primary GERD should focus on motility and/or acid suppression, and therapeutic management of secondary GER should focus on the etiological phenomenon.

PATIENT GROUPS
The following approach is a generalization that, like all generalizations, may need to be modified for each individual patient (3).First, interest is focused on uncomplicated GER, mostly restricted to regurgitating infants.Optimal management in patients with complicated GERD (symptoms suggestive for esophagitis) is proposed.There is a continuum between normal infants with regurgitation and GER, and those with severe GER that leads to disability, discomfort or impairment of function.An approach for the management of patients with atypical presentations of GER is proposed.

GROUP 1: UNCOMPLICATED REFLUX -
REGURGITATION Regurgitation may occur in children who are normal and do not have complaints of GERD such as nutritional deficits, esophagitis, blood loss, structures, apnea or airway manifestations.There is no difference in the incidence of regurgitation between breastfed and formula-fed infants (5).However, infants with uncomplicated regurgitation frequently are perceived by their parents as having a problem, and their parents often seek medical attention.The treatment approach of the infant presenting with excessive regurgitation and for his or her parents must be well balanced, and cannot be subject to overconcern or disregard.This group of patients is restricted mostly to infants younger than six months, or at the most 12 months (1,3,5).A careful evaluation of history, observation of feeding and physical examination of the infant are mandatory; however, the possibility has not been validated thoroughly because randomization is not possible (only anxious parents seek medical help).It is rather unlikely that regurgitation will result in severe GERD.Many parents who have a regurgitating infant are anxious about the pathophysiological mechanism and prognosis.Parents especially fear long term complications if the regurgitation is not stopped.Therefore, it is important to have a long discussion with the parents to learn the frequency and volume of Can J Gastroenterol Vol 14 Suppl D November 2000 27D Diagnosis and treatment of GERD feedings, how the baby is handled during and after feedings, etc.It is also very important to explain the normal, physiological origin of regurgitation.It has been observed in several studies, that just by reassuring the parents and giving them some very practical advice on how to feed the infant is helpful (6,7).The effects of parental reassurance have been suggested by many placebo controlled studies to show similar efficacies between the placebo and the tested intervention (6,7).If simple reassurance fails, dietary intervention is recommended, including restriction of the volume in overfed babies, and change to a thickened 'antiregurgitation' formula (5)(6)(7).Larger food volumes and high osmolality increase the number of transient lower esophageal sphincter (LES) relaxations and decrease LES pressure to almost undetectable levels (8).Both are well known pathophysiological mechanisms that provoke GER in infants, which may also explain why feed thickeners sometimes aggravate the symptoms.Thickening the formula with starch (eg, from rice or potato) or non-nutritive thickeners (bean gum) decreases the frequency and volume of regurgitation (5-7,9)(Table 2).Some of these 'antiregurgitation' formulas are caseinpredominant (casein/whey; 80%/20%) to optimize the curd formation, while others contain 100% whey hydrolysate to enhance gastric emptying.However, the effect of these formulas on GER parameters, when measured with pH monitoring or scintigraphy, is not convincing; most studies showed that reflux parameters improved, remained unchanged or worsened in approximately one of three infants for each possibility (6,7,10).In other words, 'antiregurgitation' formulas did what they claimed to do -they reduced regurgitation (5-7) but they did not influence acidic GER.Thickened formula also increased the duration of sleep (5,6).Therefore, antiregurgitation formula should be considered as the first step in medical treatment and should only be available by prescription (3,(5)(6)(7).Antiregurgitation formula and/or dietary intervention in general should be nutritionally safe (11).However, regurgitation may be part of the spectrum of symptoms of GERD, necessitating an effective intervention to decrease the number and intensity of the GER episodes.In this situation, an intervention that is limited to alleviating the presenting manifestation (regurgitation) will not suffice.Clinical differentiation between regurgitation and (pathological) vomiting can be difficult because 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 GERD.In practice, feed thickeners or special formula cannot be given to breastfed infants.Therefore, if the infant is breastfed and/or has GERD, drug treatment with prokinetics should be considered before 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 (12).For this reason, they interact with the pathophysiological mechanisms of regurgitation in infants, which are related to immaturity of the gastroesophageal motor function (13).A link between cisapride and increased salivary secretion has been demonstrated (14).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 nonbicarbonate buffers, thus facilitating symptomatic relief and healing of the esophagus.Metoclopramide and domperidone have antiemetic properties due to their dopamine receptor blocking activity, whereas cisapride is a prokinetic agent acting through indirect release of acetylcholine in the myenteric plexus (12).Although all three agents have been shown to reduce regurgitation in infants (6,7), data for cisapride are more convincing (Tables 3,4).Compared with metoclopramide, cisapride may be more effective in reducing pH-metric parameters (15), has a faster onset of action (16) and is better tolerated (16).Cisapride has also been shown to heal esophagitis (17).Domperidone has been reported to be as effective as metoclopramide (18) (and thus less effective than cisapride).Extrapyramidal reactions and increased prolactine levels are effects related to the dopamine receptorblocking activity of these drugs.In the case of cisapride, which is devoid of dopamine-blocking properties at therapeutic doses, the most common adverse effects are transient diarrhea and colic (in about 2%) (12,19).Isolated incidents of more serious adverse reactions such as side effects on the central nervous system, extrapyramidal reactions and seizures (in epileptic patients), cholestasis (in extreme premature infants) and cardiac interactions have been reported.Cisapride is metabolized by cytochrome P450 3A4 and has the potential to prolong the QT interval (19).However, an extensive review of the literature resulted in reassuring safety consensus statements (19).Serious cardiac adverse reactions have not been reported in patients treated with a dosage within the recommended regimen (0.8 mg/kg/day; 40 mg/day maximum) and in the absence of any of the additional risk factors (Table 4).Cisapride should not be taken with systemic or oral azole antifungals, or with macrolides.Both azole antifungals and macrolides interact with 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 compared with that of other therapeutic agents for GER, cisapride is recommended when dietary treatment fails or in regurgitating breastfed infants, if therapy is indicated.It merits consideration that prokinetics stimulate a physiological activity (peristalsis), while acidsuppressive medication inhibits a physiological secretion.
In the nonbreastfed 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 or to prokinetics, because protein allergy may present as therapy-resistant GERD.
Non-drug treatment (positional therapy, dietary advice) can help to convince parents of the physiological nature of 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 symptomatic individuals.The 30°p rone reversed Trendelenburg position generally is recommended and accepted as an essential element of treatment (3,6,7).However, positional treatment in practice is very difficult to apply correctly in infants and rather upsetting for the babies, because they must be tied up in their beds or cot to prevent them from sliding down under the blankets in or-der to achieve and maintain an angle of 30°.There is 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 syndrome (6).
Can J Gastroenterol Vol 14 Suppl D November 2000 31D Diagnosis and treatment of GERD

Clinical assessments Comments
GROUP 2: OVERT GERD Patients with overt GERD either did not respond to previous approaches such as parental reassurance, dietary treatment and prokinetics, or presented with symptoms suggesting esophagitis (hematemesis, retrosternal and epigastric pain, etc) (Table 1).Therefore, an underlying anatomical malformation should be excluded, and endoscopy is the investigation of choice (3,20).Upper gastrointestinal endoscopy in infants and children should only be performed by experienced and qualified physicians, and should always be done as a duodenogastroesophagoscopy (20).If the question being asked is restricted to underlying anatomical malformations, upper gastrointestinal series may be considered (20).If symptoms and/or the esophagitis do not improve despite adequate medical treatment and controlled compliance, upper gastrointestinal series should be performed to exclude anatomical problems such as gastric volvulus, intestinal malrotation or annular pancreas.
Antacids have been reported to be effective in the treatment of GER ( 6), although experience with their use in in-fants is limited.Their capacity to buffer gastric acid is strongly influenced by the time of administration (21) and requires multiple doses.Gaviscon (SmithKline Beecham, USA), a combination of antacid and sodium salt of alginic acid, is as effective as antacids and appears to be relatively safe because 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 (1 g Gaviscon powder contains 46 mg sodium, and the suspension contains twice this amount of sodium) (6).
H 2 receptor antagonists, of which ranitidine is the most used, are effective in healing reflux esophagitis in infants and children (6).Many new drugs, such as misoprostil, sucralfate and omeprazole, have been developed.Of these, the proton pump inhibitors (PPIs) have been studied most effectively, although experience in infants and children is limited (22,23).PPIs are effective in suppressing the acidity in patients with gastric stress ulcers and also in neurologically impaired children.Even in patients with circular esophageal ulcerations, recent experience suggests a trial of PPIs before surgery (22).Omeprazole has been shown to be effective in cases of patients with severe esophagitis refractory to H 2 blockers (22).Sucralfate was shown to be as effective as cimetidine for esophagitis in children (24).
Immediate or early surgery is rarely indicated in life-threatening conditions where medical management is of no benefit.Surgery can be life-saving in severely affected patients (notably neurologically impaired children with recurrent and life-threatening aspiration).Before surgery, a full diagnostic workup including upper gastrointestinal series, endoscopy, pH monitoring, and 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 group 3 does not present with emesis and regurgitation (Table 1).Because these patients do not vomit, GERD is 'occult'.Before considering GER as a cause of the symptoms, classic causes of the manifestations such as allergy in a wheezing patient and tuberculosis in a patient with chronic cough must be excluded.
If GERD is suspected, pH monitoring of long duration (18 to 24 h) is the investigation of choice.In this group of patients, pH monitoring may need to be performed simultaneously with other investigations in order to relate pH changes to events (for example, polysomnography in 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 is identical).
If  (20,22).In this group, repeated pH monitoring under treatment conditions in combination with a clinical followup is mandatory.Depending on the unusual presentation, treatment can be stopped after six to 12 months because a possible mechanism for GER in association with unusual manifestations may be self-perpetuating GER (25).Once reflux occurs, acid gastric contents, containing pepsin and sometimes bile, come 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 restricted to the lower esophagus, impairs LES pressure and function, and favours GER (25).

SEVERELY NEUROLOGICALLY IMPAIRED CHILDREN
The vast majority of neurologically impaired children suffer from severe GERD.Most of these children are under specialized follow-up, and only brief recommendations are given here.The pathophysiological mechanism of GERD in these children is particularly multifarious: the neurological disease itself may cause delayed esophageal clearance and gastric emptying; most of these children are bedridden (gravity improves esophageal clearance); and many children are constipated (which increases abdominal pressure and favours GER).

CONCLUSIONS
The diagnostic approach of GERD in infants and children principally depends 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 centres, is recommended if esophagitis is suspected.Long term esophageal pH montoring is the investigation of choice and occupies a central position in the diagnostic approach for the patient suspected of unusual or atypical presentations of GERD, such as 'occult' GERD.Nondrug treatment (the importance of parental reassurance cannot be stressed enough) and dietary treatment are effective and safe approaches in infant regurgitation therapy but do not treat GERD.If the symptoms are refractory to this approach, or in reflux disease, cisapride is the drug of choice.PPIs or H 2 receptor antagonists, in combination with prokinetics, are recommended in ulcerative esophagitis.There is no excuse to persist with an ineffective management of a disease that might result in stunting, chronic illness, persistent pain, esophageal scarring or even death.Management of GERD in infants and children, therefore, should be thoroughly considered, avoiding overinvestigations and overtreatment of a self-limiting condition, but also avoiding underestimation of potential severe disease, accompanied by serious morbidity.

TABLE 2 Effects of special formulas and milk-thickening products on GOR, gastric emptying (GE) and clinical parameters in infants with GOR disease Author (reference) n Mean age (range) Study design Feed thickener/special formula GOR and GE parameters Clinical assessments Comments
CPF Casein formula; FT Thickened meal; GOR Reflux parameters on pH monitoring; HF/LC High fat/low carbohydrate; LF/HC Low fat/high carbohydrate; n Number of subjects; nd No data; noFT Unthickened meal; NS Not significant; O Open; PA Parallel; RI Reflux index; SB Single blind; SF Soy formula; WHF Whey hydrolysate formula; XO Crossover

TABLE 3 Effects of cisapride (CIS) on GOR disease in infants
Can J Gastroenterol Vol 14 Suppl D November 2000 29D Diagnosis and treatment of GERD 30D Can J Gastroenterol Vol 14 Suppl D November 2000 Vandenplas

TABLE 4 Contraindications and risk factors for the use of cisapride
pH monitoring parameters are abnormal or if events are clearly related to pH changes, prokinetics, eventually in combination with H 2 receptor antagonists or PPIs, are indi- 32DCan J Gastroenterol Vol 14 Suppl D November 2000Vandenplas *An electrocardiogram should be performed once before cisapride administration and two to three times after administration cated