Gastroesophageal Reflux

REVIEW ARTICLE

Gastroesophageal reflux

Rocksane C. Norton1, Francisco J. Penna2

Abstract Objective: to discuss clinical, diagnostic and therapeutic aspects of gastroesophageal reflux. Method: we accomplished a literature review of the last 30 years, by means of Lilacs and Medline databases. Results: the gastroesophageal reflux is one of the most frequent causes of medical appointments with pediatric gastroenterologists. It represents a benign condition, characterized by regurgitations that can be resolved with general measures. Medical management with prokinetics and antacid agents controls clinical manifestations and prevents complications. Fundoplication is reserved to a minority of cases. Comments: some aspects of the clinical treatment have to be emphasized. Thickened/Solid diet and erect posture must be always recommended. Cisapride, the most commonly employed prokinetic agent, may prolong ventricular repolarization. Other prokinetic agents should be used in children. Bronchospasm or clinical manifestations of esophagitis indicate the use of antacid drugs.

J Pediatr (Rio J) 2000; 76 (Supl.2): S218-224: gastroesophageal reflux, child.

Introduction Gastroesophageal reflux (GER) can be defined as the not compromising the child’s growth and development. On retrograde and repetitive flux of gastric content for the the other hand, the pathological reflux presents clinical esophagus. It is frequent in children, and usually presents a repercussions, such as growth deficit, abdominal pain, benign evolution. It is characterized by the presence of irritability, digestive hemorrhages, bronchospasm, repeated regurgitations. Besides abdominal pain and intestinal pneumonia, or otorhinolaryngological complications, which constipation, it constitutes one of the main reasons of require capacity on the diagnosis and attention on the appointments with pediatric gastroenterologists. choice of the most adequate treatment to each case. Most part of the cases corresponds to physiological reflux, resulting from the immaturity of the antireflux barrier mechanisms. Although it is likely to evolve with life- Epidemiology threatening conditions, such as apnea crises, the GER is surely one of the main gastroenterological physiological reflux usually presents a satisfactory evolution, conditions among children. Although predominant in males, the difference between the sexes is not statistically significant.1 It is estimated that among children that present 1. Associate Professor of Pediatrics, Universidade Federal de Minas Gerais (UFMG) School of Medicine. regurgitation at a frequency that worries the parents, only 2. Professor of Pediatrics, UFMG School of Medicine. 2% will require investigation, and 0.4% will require surgery.1

S218 Gastroesophageal reflux - Norton RC et alii Jornal de Pediatria - Vol. 76, Supl.2, 2000 S219

GER classification intraluminal pressure of the esophagogastric junction and GER may be physiological or pathological, primary or impeding the reflux. secondary, and, still, occult. The angle of His is formed by the abdominal esophagus Physiological GER is more common in the first months and the gastric fundus. In normal conditions, this angle is of life. Among older children and adults, it may occur in the acute. So, the volume of gastric content increases the postprandial period, due to the transient lower esophageal pressure at the abdominal esophagus by extrinsic sphincter relaxation. Regurgitations arise between the birth compression, resulting from the stomach fund distension. and 4 months of age, usually presenting spontaneous In the newborn, this angle is obtuse. resolution up to 1 or 2 years of age.2,3 In these cases, the The gastric rosette, formed by concentric plicae of the child’s growth is normal, and there are no other symptoms gastric mucosa in the transition between the esophagus and or associated complications. The frequency of regurgitations the stomach, helps in the continence of the gastric content, decreases after 6 months of age, coinciding with the avoiding its passage to the esophagus. introduction of a solid diet and with the adoption of a more In young children, because of immaturity of some erect posture by the child. components of the antireflux barrier, vomits and Pathological GER may be suspected when the vomits regurgitations are common, but they tend to improve with and regurgitations do not improve after 6 months of age, aging. Adults also present reflux episodes in the postprandial when they do not respond to postural and dietetic measures, period, without any clinical repercussions. The reduction of and when clinical repercussions are present, such as growth regurgitations and vomits is expected to happen at the age stoppage or symptoms and signs that suggest esophagitis. of 4 to 6 months, with the introduction of solid food and the The reflux is denominated occult when respiratory, adoption of a more erect posture, resulting from the advance otorrinolaryngological, or esophagitis-indicating in the neuropsychomotor development. manifestations (irritability, constant cry) occur at the absence The reflux disease, or pathological disease, is of vomits and regurgitations. multifactorial and affects the LES function, the esophageal Primary GER results from dysfunction of the peristalsis, and the gastric emptying. esophagogastric junction. Secondary GER is associated The LES pressure is considered an important element of with specific conditions, such as esophageal congenital the antireflux barrier, although its hypotonia is not a frequent stenosis, tracheoesophageal fistula, esophageal atresia, cause of reflux.1 In a study involving children presenting deglutition disorders, hypertrophic pyloric stenosis, gastric reflux, a reduction of the LES tonus at 8% in cases of or duodenal ulcer, annular pancreas, intestinal esophagitis was shown.5 pseudoobstruction, cow’s milk allergy, urinary infection, intestinal parasitoses, genetic-metabolic diseases, asthma, Transient lower esophageal sphincter relaxation consists cystic fibrosis, and alterations in the central nervous system. of short episodes of abrupt reduction in the LES pressure. They are probably mediated by the action of inhibitory vasoactive peptides and/or of the nitric acid.1 Transient Pathophysiology lower esophageal sphincter relaxation lasting more than 35 The esophagogastric region presents several structures seconds and independent of normal peristaltic waves is 5,6 that contribute to the antireflux barrier: lower esophageal observed in 60 to 83% of reflux episodes. sphincter (LES), angle of His, phrenoesophageal ligament, Increase in the stomach volume, abnormal motor function crural diaphragm and gastric rosette. of the gastric fundus and retardation of its emptying may be LES is a circular smooth muscle segment at the terminal involved in the reflux etiopathogenesis. The gaseous gastric esophagus, adapted to generate a high-pressure zone, which distension is an important cause of transient lower esophageal 7 may range from 15 to 40 mmHg. LES maturation starts at sphincter relaxation, probably after vagal stimulus. the first weeks of intra-uterine life, and continues during the The retardation of esophagus emptying, possibly whole first year of life. Its extension measures around 2.5 to associated with the inefficacy of salivation and peristalsis, 3.5 cm in the adult, with equal supra and infradiaphragmatic seems to be important for the development of reflux portions. In the newborn, it measures 0.5 to 1.0 cm, and is esophagitis.8 Studies with animals showed that the lesion of predominantly located in the thorax. The characteristics the esophageal mucosa occurs when the pH remains below change after 3 months of age, with the development process. 4. The presence of gastric acid alters the esophageal defenses, The phrenoesophageal ligament is constituted by the and, consequently, causes mucosal lesion. Pepsin and bile subdiaphragmatic fascia, and its function is to impede that salts increase the gravity of damages.10 the LES is submitted to negative intrathoracic pressure. Hiatal hernias seem to have a relation with the gravity The diaphragmatic hiatus is formed by fibers of the right and refractivity to the clinical treatment of reflux esophagitis. crus of the diaphragm, the place through which the esophagus Permanent increase of the intra-abdominal pressure (obesity) penetrates the abdomen. During inspiration, the or its transitory increase (deep inspiration, coughing, physical diaphragmatic hiatus is contracted, increasing the exercises, Valsalva manoeuvre, constipation and others), S220 Jornal de Pediatria - Vol. 76, Supl.2, 2000 Gastroesophageal reflux - Norton RC et alii besides posture predominantly in decubitus, are factors that reactivity may rise the suspicion of GER.12 In some children, predispose to reflux. bronchospasm may be the only manifestation of the reflux GER may cause chronic respiratory disease through (occult GER). The clinical improvement of the three mechanisms11,12: aspiration of significant quantities bronchospasm with the antireflux therapy suggest the of gastric content (macroaspiration) into the superior airways association of both pathologies. In any patient with and lungs, causing aspiration pneumonia, more common in unexplainable recurrent pneumonia, the possibility of occult children who present deglutition disorders; aspiration of GER should be excluded. Apnea and GER may occur in the small quantities of gastric content (microaspiration), causing first 4 months of age, but the cause-and-effect ratio can secondary inflammatory reaction; and intratracheal rarely be established. When apnea occurs right after vomits, acidification, which, by the stimulus of nervous endings, it is possibly secondary to the reflux. Laryngospasm, induced may cause bronchospasm. by reflux, has been pointed as a possible causal factor of obstructive apnea in infants, explaining also recurrent stridors, acute hypoxia, and, possibly, the sudden death syndrome (SDS). There are evidences of resolution of Clinical status respiratory symptoms after the antireflux surgery.17 Depending on the patient’s age during the first symptoms, The esophagus acidification has been associated with GER may have several meanings and clinical courses. some other signs: hiccups, hoarseness, and dental erosion.18 There are two forms of presentation: in children and in adults. In the first case, the symptoms appear during the first months of life and improve up to 12-24 months in 80% of the cases.2,3 The second type may be a continuation of the Diagnosis first one, or appear later; it has persistent symptoms and The diagnosis of GER should start with the elaboration usually requires treatment.13 of the complete clinical history. Clinical history of The clinical manifestations may be: specific, such as regurgitations in young children, without other complaints rumination, vomits, regurgitations, eructation;14 related to and without alterations on the physical examination, suggests esophagitis, such as pain, anemia, and bleeding; respiratory, the diagnosis of physiological GER. In these cases, there is such as bronchospasm and repeated pneumonia; no need for any complementary examination, and clinical otorhinolaryngological, such as laryngitis, sinusitis, otitis, follow-up is recommended. Symptoms and signs such as and others. insufficient gain of weight, irritability, constant crying, evident or occult digestive bleeding, persistent Vomits and regurgitations are present in most children bronchospasm, repeated pneumonia, and recurrent with GER, mainly in the postprandial period. Regurgitation otorhinolaryngological symptoms may be manifestations may be defined as the involuntary return of a small quantity of pathological GER. For the confirmation, there are several of gastric or esophageal content to the pharynx and the complementary examinations available, and each of them mouth. It may be distinguished from vomit for the absence presents its specificity. of previous nausea, autonomic symptoms, abdominal pain or discomfort, or contraction of the thoracic musculature.15 Esophagus, stomach and duodenum radiograph The presence of esophagitis may be suspected through different ways, according to the child’s age. In infants, This is the most used examination for the assessment of excessive crying, irritability, sleep disorders, restlessness GER, for there are not more specific and sensitive procedures 19 and diet refusal are observed. Sandifer’s syndrome, available. It presents a sensitivity of 50 to 65%. It may be characterized by the association of esophagitis, anemia, and false positive due to the transient lower esophageal sphincter typical head posture in response to the reflux may be relaxation, which occurs after deglutition, during gastric identified in young children. Hematemesis, melena, occult distention, or during the performance of the examination. blood in feces and iron deficiency anemia may be present at The short period of observation is responsible for 10 to 15% any age. Older children may complain of dysphagia, pyrosis, of false negative results. It is useful for the detection of thoracic pain similar to angina, pain, and burning in the anatomic abnormalities, deglutition disorders, intestinal epigastric region, odynophagia, sialorrhea, and recurrent malrotation, intestinal obstruction, tracheoesophageal abdominal pain. fistula, hiatal hernia, and motility disorders. The dynamic study may show motility alterations and the presence of The compromising of growth may result from the loss of stomach spasms, which may be related to GER.20 nutrients due to the presence of esophagitis, from the increased energetic expense due to bronchospasm, from other respiratory manifestations, or, still, from feeding Manometry 16 difficulty. Esophageal manometry is difficult to be performed in Bronchospasm or nocturnal cough, inadequate response children, since it requires the patient’s collaboration. It does to the drug treatment of asthma, absence of familial history not diagnose the presence of GER, for a zone of high of atopia, and early beginning of the bronchial hyper- pressure at the LES does not assure the absence of reflux.21 Gastroesophageal reflux - Norton RC et alii Jornal de Pediatria - Vol. 76, Supl.2, 2000 S221

The LES pressure is normally higher than 15 mmHg; so, performance of pH-metry is necessary in patients with values below 6 mmHg may indicate the presence of GER. endoscopically proved esophagitis. The main indicators vary according to the predominant Scintigraphy symptomatology, but the rate of reflux (total % of the time Scintigraphy is performed after the oral administration during which pH was below 4) is considered highly important of technetium, obtaining images through a gamma counter. in almost all cases, being related to esophagitis and to cases It is not invasive, causes low exposition to radiation, and is of apnea. The area under the curve of pH<4 has been related 26 adequate to evaluate gastric emptying and the presence of to the presence of esophagitis. The values considered 27 pulmonary aspiration in late imaging. normal, according to Johnson & DeMeester, are presented in Table 1.

Esophagus ultrasonography This noninvasive examination has been recommended for the diagnosis of occult GER, neutral refluxes, and for the Table 1 - Reference values for the continuous monitoring of determination of gastric emptying time. It also allows the the esophagus in 24 hours (pH-metry) study of stomach motility. Its only inconvenience is the Data obtained through pH-metry Normal short period of observation used by the technique. values

Upper digestive endoscopy and esophageal biopsy No. of episodes with pH<4 in 24 h 50 % of time with pH<4 < 4.2% In children, this invasive examination requires sedation or anesthesia in order to be performed. It does not diagnose % of time with pH<4 in the erect position < 6.3% reflux, but the associated esophagitis. It may also identify % of time with pH<4 in the supine position < 1.22% stenosis zones, Barrett esophagus and hiatal hernia. There No. of episodes of reflux lasting for >5 minutes in 24 h < 3 are over 30 classifications for endoscopic alterations found Duration of the longest episode of reflux (pH<4) < 9.2 min in the esophagus, but none is universally accepted. The presence of erosions or ulcerations at the terminal esophagus confirms the endoscopic diagnosis of esophagitis. The esophagus biopsy should be performed in all the patients with suspicion of esophagitis, although some authors Alkaline GER prevalence is not known yet. Alkaline consider it unnecessary in cases without endoscopic GER is suspected in children that present pH values over 7 esophagitis.15,22 In 1970, Ismail-Beigi described on pH-metry. In these patients, an investigation directed to histological alterations resulting from gastroesophageal the alkaline GER should be performed. reflux: papillae growing longer than 60% of the epithelium thickness, small number of intraepithelial neutrophils and Modified Bernstein Test eosinophils (<5/field). A number of eosinophils superior to Bernstein’s test was originally used for the diagnosis of 15 per field of great enhancement suggests eosinophilic 23 esophagitis. The esophagitis symptoms were provoked in esophagitis Barrett esophagus, which is characterized by the patient through the instillation of acid and saline solution the presence of intestinal metaplasia at the esophagus, is a in the distal esophagus. The modified Bernstein test is premalignant condition, little frequent in the pediatric 24,25 useful to determine the relationship between GER and group. respiratory symptoms through the instillation of acid and saline solution in the esophagus.28 Esophagus pH monitoring (pH-metry) Normal esophageal pH ranges from 5 to 7; when it goes Intraluminal impedancemetry below 4, it suggests acid reflux. The esophageal pH This examination permits the determination of episodes monitoring documents the esophagus acidification during of physiological pH reflux. Together with pH-metry, it is prolonged periods, with the patient carrying out his/her worthwhile in the assessment of respiratory manifestations usual activities. The examination sensitivity ranges from 87 in gastroesophageal reflux.29 to 93%, and its specificity, from 92.9 to 97%. It is indicated in unusual presentations of GER, characterized by difficult- to-control chronic respiratory disease, rumination, Sandifer syndrome, apnea, risk of sudden death, growth deficit, Differential diagnosis difficult-to-control iron deficiency anemia, pharyngeal The clinical manifestations of GER are variable and itching, thoracic pain of noncardiologic origin, and less related not only to the digestive tract. This way, the common symptoms. It is also indicated to evaluate the differential diagnosis is extensive, and includes mechanical patient’s response to clinical and surgical treatment. The obstructions of the upper digestive tract, alimentary allergies, S222 Jornal de Pediatria - Vol. 76, Supl.2, 2000 Gastroesophageal reflux - Norton RC et alii especially to the cow’s milk protein, infectious and Drug treatment neurological diseases, bronchial hyperreactivity, peptic The use of drugs is reserved for the cases of pathological ulcer, colic, and other causes of irritability in the infant. reflux. In some situations, they may be used empirically and for short periods.1

Treatment Prokinetics The reflux, depending on the predominant form of Combined with dietetic and postural measures, the presentation, may require general measures, drug treatment, prokinetics are important therapeutic tools in the treatment or surgery. The objectives of the treatment are relief of of GER. They determine an increase in the LES pressure, symptoms, healing of the established esophageal lesions, as and stimulate esophageal peristalsis and gastric emptying. well as prevention of complications. General measures should be recommended in all cases. Drugs are indicated for Cisapride acts as a serotonine postganglionic agonist. It patients with the reflux disease (pathological reflux), or as is derived from benzamide, and its action seems to result in a testing treatment in some specific situations, for short the liberation of acetylcholine into the myenteric plexus. periods. Surgery should be left for cases that are refractory The use of cisapride was allowed in 1988, and it is available to the clinical treatment, or for situations that involve risk of in more than 90 countries since then.30 It has a half-life of death.1 7 to 19 hours, and it is metabolized by the hepatic enzymatic system (cytochrome P450 CYP3A4). Cisapride improves motility in all the gastrointestinal tract, facilitates General measures antroduodenal coordination, accelerates gastric emptying and increases LES pressure.15 Side effects are in general Orientation to parents transitory, and include colic, diarrhea, and cephalea.15 Regurgitations, when not accompanied by complications, There are reports of more serious reactions15: alterations in constitute a transitory process, related to the immaturity of the central nervous system (extrapiramidal reactions and the gastrointestinal tract. Families sometimes may consider seizures), cholestasis in preterms (preterms present it a serious problem. This way, the first step consists of decreased action of the cytochromes), cardiac alterations listening to the parents, without underestimating their (QT interval prolongation, characterizing prolonged complaints. They should receive simple explanations about ventricular repolarization). Although cisapride is the most the nature, natural evolution, prognosis, and treatment of used prokinetic in GER,15,31 recently, because of the adverse the disease. Sometimes, after an adequate orientation, the cardiovascular effects, the European Society of Pediatric regurgitation frequency decreases. Gastroenterology and Nutrition, and the North American Society of Pediatric Gastroenterology and Nutrition 30,32 Dietary recommendations published recommendations for its utilization: cisapride dosages should not be higher than 0.8 mg/kg/day (maximum The dietary modifications proposed to reduce the of 40 mg/day), and should be divided into three of four daily episodes of GER should respect the child’s nutritional administrations. It is contraindicated in the following needs. Among the recommended measures, milk thickening situations: use of macrolide antibiotics (clarithromycin, is greatly efficcacious.1 Solid diet is known to reduce the erythromycin, azithromycin), benzimidazoles (fluconazole, number of episodes of reflux. However, the duration of the ketoconazole, itraconazole), protease inhibitors longer episode may increase, making the efficacy of the (antiretroviral), phenotiazine (promethazine), esophageal emptying more difficult. In some patients with antiarhythmics, antidepressives, antipsychotics, and other esophagitis or respiratory manifestations, this may intensify agents, even orange juice.33 So, preference should be given the symptomatology.15 Anyway, the buffer effect of the to the use of prokinetic drugs, which cause less adverse food over the gastric acidity would avoid the intensification effects. of the esophageal lesion. Foods and drugs that decrease the LES tonus or that Domperidone is a peripheral dopaminergic antagonist, increase the gastric acidity, such as fat foods, citric fruit, without cholinergic effects. It does not cause tomatoes, coffee, alcohol, smoking, as well as anticholinergic hematoencephalic reactions. Maximum concentrations of and adrenergic drugs, xanthine, prostaglandin and calcium the drug occur 10 minutes after oral administration. It channel blockers, for example, should be avoided whenever presents hepatic and intestinal metabolism, as well as renal possible. and intestinal excretion, with a half-life of approximately 7 hours. It increases esophageal peristalsis and accelerates gastric emptying, improving the antroduodenal motility. It Posture rarely causes side effects, such as dry mouth, cutaneous In general, the head is recommended to be elevated at 30 eruption, diarrhea, and transitory itching. It may cause degrees, and the child should be kept erect in the postprandial potent prolactin secretion, causing an enlargement of the period. No study has shown efficacy of lower elevations.15 mammas, galactorrhea, and amenorrhea. It is as efficacious Gastroesophageal reflux - Norton RC et alii Jornal de Pediatria - Vol. 76, Supl.2, 2000 S223 as metoclopramide, and has less side effects.15 The Surgical treatment recommended dosage is 0.2 to 0.6 mg/kg/dosage, three to The antireflux surgery (gastric fundoplication) is one of four times a day, before meals and when going to bed. Its the three most performed surgeries in children in the United highest efficacy may be reached after the 4th week of usage. States.14,37 The Nissen technique is the most used in the Metoclopramide acts peripherally, increasing the action world, and, more recently, videolaparoscopy has been of acetylcholine in muscarinic synapses, and antagonizing gaining adhesions, especially because of the lower risk for dopamine in the central nervous system. It increases LES complications and the shorter time of recovery. The antireflux pressure, facilitates gastric emptying, improves esophageal surgery should be reserved to patients that do not respond peristalsis, accelerates time and transit from the duodenum to clinical treatment and/or present life-threatening to the ileocecal valve, but it does not increase salivation and conditions. After the appearance of more potent prokinetic does not produce bronchospasm.34 Several side effects agents and acid secretion inhibitors, the role of surgery as a have been reported, and there is a small security margin definite therapeutic resource for the complicated reflux has between therapeutic and toxic dosages. Somnolence, been questioned.38 nervousness, tremors, nightmares, anxiety, and depression The best option for the long-term treatment of children may occur. Dystonic and neurological reactions have been with esophagitis, be it either surgery or clinical treatment, reported, as well as the increased level of prolactin and still has to be defined. Besides the high cost, surgery 34 ginecomasty. The recommended dosage is 0.1 mg/kg, presents high recidivism rates. On the other hand, the four times a day, 30 minutes before meals. clinical treatment demands adhesion and comprehension on the family’s part, and it also has associated side effects. Aiming to prevent complications, the therapeutic option Gastric acidity reductors may be always individualized, and the clinical follow-up should be prolonged. Antacids are compounds that neutralize the acidity of the gastric content, and, consequently, increase gastric motility through the action of gastrin. They increase the pressure at the lower portion of the esophagus and the esophageal depuration by an independent mechanism of gastrin. They are recommended for the symptomatic relief References in patients with light and moderate esophagitis. 1. Orenstein SR. Gastroesophageal reflux. In: Hyman PE, DiLorenzo Histamine H2-receptor antagonists compete with the C, eds. Pediatric gastrointestinal motility disorders. New York: histamine for H2-receptors, inhibiting the gastric secretion Academy Professional Information Services; 1994. p.55-88. of acid induced by histamine or other H2 agonists (muscarinic 2. Carré IJ. The natural history of partial thoracic stomach (hiatus agonists and gastrin). The H2-receptor antagonists available hernia) in children. Arch Dis Child 1959; 34:344-53. 3. Shepherd RW, Wren J, Evans S, Ong TH, Lander M. to use are cimetidine, ranitidine, famotidine, and nizatidine. Gastroesophageal reflux in children; clinical profile course and These drugs are almost totally absorbed orally. The outcome with active therapy in cases. Clin Pediatr 1987; 26:55- recommended dosages are 5 to 10 mg/kg of cimetidine, four 60. times a day before meals and before going to bed, and 5 mg/ 4. Werlin SL, Dodds WJ, Hogan WJ. Mechanisms of kg of ranitidine, twice a day. There has not been enough gastroesophageal reflux in children. J Pediatr 1980; 97:244-9. experience with the prolonged use of famotidine yet. 5. Kawahara H, Dent J, Davidson GP. Mechanisms responsible for gastroesophageal reflux in children. Gastroenterology 1997; H+ channel blockers represent a class of drugs as safe 113:339-408. as the H2-receptor antagonists. They are the most potent 6. Dent J, Davidson GP, Barnes BE, Freeman JK, Kirubakan C. The inhibitors of acid secretion. mechanism of gastroesophageal reflux in children. Austr Pediatr Omeprazole is a benzimidazole that inhibits the enzyme J 1981; 17:125. 7. Cox MR, Martin CJ, Westmore M. Effect of general anesthesia responsible for the transportation of hydrogen ions to the on transient lower esophageal sphincter relaxation in the dog. stomach light. They have a prolonged action, even when Gastroenterology 1987; 92:1357. blood levels are not detectable anymore. One only dosage 8. Sonnenberg A, Steinkamp U, Weise A. Salivary secretion in may eliminate over 90% of the acid secretion in 24 hours. reflux esophagitis. Gastroenterology 1982; 83:889-95. Dosages of 0.7 to 3.3 mg/kg/day, with an average dosage of 9. Watanabe Y, Catto SAG. The clinical significance of prolonged 1.9 mg/kg/day, have been recommended.35 It is a labile stable pH around 4.0 in 24 h pH monitoring. J Pediatr Gastroenterol drug, composed by granules of enteric absorption, with 1- Nutr 1994; 19:50-7. 10. Iacono G, Carrocio A, Cavataio F, Motalto G, Soresi M, Campagna 2 mm diameter, which dissolve at pH>6, allowing duodenal 36 P et al. IgG anti-betalactoglobulin: its use in diagnosis of cows absorption. The maximum plasmatic concentrations occur milk allergy. Ital J Gastroenterol 1995; 27:355-60. 1 to 3 hours after oral medication, so that the administration 11. Donald OC, Peter FS. Gastroesophageal reflux disease and is recommended to happen before the first meal in the asthma. Sem Gastroenterol Dis 1992, 3:139-50. morning. In case of pediatric administration, the granules 12. Simpson WG. Gastroesophageal reflux disease and asthma: are separated and administrated with acid fruit juice. diagnosis and management. Arch Inter Med 1995; 155:798-803. S224 Jornal de Pediatria - Vol. 76, Supl.2, 2000 Gastroesophageal reflux - Norton RC et alii

13. Treem WP, Hyams L. Gastroesophageal reflux in the older child 28. Berenzin S, Medow MS, Glassman M.S. Esophageal chest pain presentation response to treatment and long term follow up. Clin in children with asthma. J Pediatr Gastroenterol Nutr 1991; Pediatr 1991;30:435-40. 12:52-5. 14. Fonkalsrud EW, Ament ME. Gastroesophageal reflux in 29. Wenzel TQ, Silny J, Schenke S. Gastroesophageal reflux and childhood. Curr Probl Surg 1996; 33:1-70. respiratory pneumonia in infants: status of the intraluminal 15. Vandenplas Y, Belli D, Benhamou PH, Boige N, Heymans H, impedance technic. J Pediatr Gastroenterol Nutr 1999; 28:423-8. Benatar A, et al. Current concepts and issues in the management 30. Vandenplas Y, Belli DC, Benatar A. The role of cisapride in the of regurgitation of infants: a reappraisal. Acta Paediatr 1996; treatment of pediatric gastroesophageal reflux. JPediatr 85:531-4. Gastroenterol Nutr 1999; 28:518-28. 16. Alvarez-Ruiz JA. Refluxo gastroesofágico en pediatria. Bol 31. Vandenplas Y. Asthma and gastroesophageal reflux. J Pediatr Assoc Med PR 1982; 74:129-33. Gastroenterol Nutr 1997; 24:89-99. 17. Jolley SG, Halpern LM, Tunell WP, Leonard C. The risk of 32. Schulman RJ, Boyle JT, Colletti RB. The use of cisapride in sudden infant death from gastroesophageal reflux. J Pediar Surg children. J Pediatr Gastroenterol Nutr 1999, 28:529-33. 1991; 26:691-6. 33. Food and drug administration. Talk paper. FDA updates warning 18. Mahajan L, Wyllie R, Oliva L. Reproducibity of 24 hour for cisapride. FDA Home page. January 24, 2000. intraesophageal pHmonitoring in pediatric patients. 34. Kaplan B, Koppelo K. The treatment of gastroesophageal reflux Pediatrics1998;101:260-3. disease. West Virg Med J 1994; 90:510-7. 19. Foglia RP. Gastroesophageal disease in the pediatric age group. 35. Gunasekaran TS, Hassal EG. Efficacy and safety of omeprazole Chest Surg Clin North Am 1994, 4:785-809. for severe gastroesophageal reflux in children. J Pediatr 1993; 20. Vandenplas Y, Belli D, Boige N, Benhamou PH, Heymans H, 123:148-54. Benatar A, et al. A standardized protocol for the methodology of 36. Israel DM, Hassal E. Omeprazole and other proton pump inibitors: esophageal pH monitoring and interpretation of the data for the pharmacology, efficacy and safety, with special reference to use diagnosis of gastroesofageal reflux. J Pediatr Gastroenterol Nutr in children. J Pediatr Gastroenterol Nutr 1998; 27:568-79. 1992; 14:467-71. 37. Fonkalsrud EW, Foglia RP, Ament ME. Operative treatment for 21. Baswell DL, Lebenthall E. Gastroesophageal reflux. In: Lebenthal gastroesophageal reflux syndrome in children. J Pediat E. Textbook of Gastroenterology and Nutrition in Infancy. New Gastroenterol Nutr 1989:24:525-9. York: Raven Press; 1981. p.911-20. 38. Hassall E. Wrap session: is the Nissen sliping? Can medical 22. Hassall E. Macroscopic versus microscopic diagnosis of reflux treatment replace surgery for severe gastroesophageal reflux esophagitis: erosions or eosinophils? J Pediatr Gastroenterol disease in children? Am J Gastroenterol 1997;90:1212-20. Nutr 1996; 22:321-5. 23. Liacouras CA. Failed Nissen fundoplication in two patients who had persistent vomiting and eosinophilic oesophagitis. J Pediatr Surg 1997; 32:1504-6. 24. Spechler SJ, Goyal RK. Barrett’s esophagus. N Engl J Med 1986; 315:326-71. 25. Beddow EC, Wicox DT, Drake DP, Peirro A, Kiely E, Spitz L. Correspondence: Surveillance of Barrett’s esophagus in children. J Pediatr Surg Dra. Rocksane C. Norton 1999; 34:88-91. Dep. Pediatria – Faculdade de Medicina da UFMG 26. Vandenplas Y. “Area under pH4”advantages of a new parameter Av. Alfredo Balena 190 - Santa Efigênia in the interpretation of esophageal pH monitoring data in infants. CEP 30130-100 – Belo Horizonte, MG, Brazil J Pediatr Gastroenterol Nutr 1989; 9:34-9. 27. Johnson LF, DeMeester TR. Twenty-four hour pHmonitoring of Fax: + 55 31 248.9772 the distal esophagus: a quantitative mesasure of gastroesophageal E-mail: [email protected] reflux. Am J Gastroenterol 1974; 62:325-32.