Advanced Studies in Medicine ■ S117 ABSTRACT Gastroesophageal reflux disease (GERD) is one of the most common acid-related disorders in US adults, occurring in approximately 20% of individuals according to a survey of residents from Olmsted County, Minn. Although GERD is not as well studied in the pediatric population, a high percentage of children aged 3 to 7 years have symptoms suggestive of this disease, without a history of acute illness or chronic medical or developmental disabilities. Nearly 15% of ado- lescents aged 10 to17 years and 25% of children aged 3 to 9 years report symptoms of abdominal pain; whether this is GERD or other etiologies is not clear. Among children with developmental disabilities or neurological injury, the risk for GERD and other feeding-related difficulties appears to be much higher than that of the gen- eral population. Recent studies demonstrate a high prevalence of significant GERD in children with asthma. Current treatment options for pedi- atric GERD include lifestyle changes initially, then pharmacologic therapy and, in selected cases, antireflux surgery. The drugs administered to decrease the symptoms of GERD and to heal ero- sive esophagitis are histamine type-2 receptor antagonists and proton pump inhibitors. After over a decade of use in adults and according to more recent studies published about use in children, the PPI class of agents has been found in studies to be safe, well tolerated, and highly effective. 1 (Adv Stud Med. 2003;3(3A):S117-S122) I t was once believed that gastroesophageal reflux disease (GERD) is a condition that may not end in childhood, but in fact may start, disap- pear, and then reappear in adulthood. However, in many cases, GERD can be a chronic disease in which the patient lives through peri- ods of exacerbated symptoms and periods that are pain free. Although many mechanisms have been investi- gated to determine the cause(s) of GERD, recent data support a transient lower esophageal sphincter relax- ation and esophageal body motility inhibition being present in children with documented GERD com- pared with normal controls (ie, those without GERD). 2 The symptoms and signs of pediatric GERD often may be very different than those exhibited in adults. The pathophysiology of pediatric GERD, how- ever, appears to be fairly similar to that seen in adults, as are the diagnostic and management tools. PROCEEDINGS GASTROESOPHAGEAL REFLUX DISEASE IN INFANTS, CHILDREN, AND ADOLESCENTS * — Benjamin D. Gold, MD † * This article is based on a presentation given by Dr Gold at the PRI-MED East Conference. † Associate Professor of Pediatrics and Microbiology, Director, Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Gastroenterology Service Line Chief, Egleston Children’s Hospital, Children’s Healthcare of Atlanta. Address correspondence to: Benjamin D. Gold, MD, Director, Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Emory University School of Medicine, 2040 Ridgewood Dr, NE, Atlanta, GA 30322. E-mail: ben_gold@oz.ped. emory.edu. S118 Vol. 3 (3A) ■ March 2003 PROCEEDINGS PREVALENCE OF GERD IN US CHILDREN More than 85% of premature infants have some evidence of GERD, with 3% to 10% of these patients having supraesophageal manifestations of the disease including bradycardia and apnea. Many former pre- mature infants will have GERD-induced exacerbation of bronchopulmonary dysplasia; the neonatal equiva- lent of adult chronic obstructive pulmonary disease and the result of prolonged ventilator support required by these prematurely born children shortly after birth. In the past, it was commonly believed that GERD completely resolved in infants by 3 months of age. However, there is now evidence to suggest the con- trary, because almost 100% of infants at the age of 3 months will have evidence of reflux. Whether true dis- ease, in one form or another, exists deserves further study. However, approximately 33% will seek medical attention and the regurgitation symptoms in most (>70%) of these children will resolve with minimal intervention and no diagnostic evaluation. In addi- tion, until recently, no long-term follow-up pediatric studies existed. Retrospective studies demonstrate that by 6 months of age, 20% of infants require further evaluation because of reported symptoms of GERD. In up to 40% of cases, pH monitoring reveals signifi- cant acid exposure (pH <4.0) to the distal esophagus for more than 5% of a 24-hour period (1.2 hours or longer). 3-5 HOSPITALIZED CHILDREN Overall, GERD is a significant problem in hospi- talized children, with more males than females being affected. Review of a large, national pediatric hospital database showed that in 1997 less than 2% of children hospitalized in the United States had Barrett’s esopha- gus, a specific columnar lining that may be a precursor to esophageal cancer, as 1 of the top 5 discharge diag- noses. However, in 2000, the number of hospitalized children with a discharge diagnosis of Barrett’s esoph- agus increased to almost 4%. According to data from the same large database, the Pediatric Health Information Survey, a consortium of approximately 37 children’s hospitals across the US, in the year 2000 3.5% of all pediatric hospital discharges were related to GERD as 1 of the top 3 discharge diagnoses, and $750 million in annual costs were incurred that were related primarily to the surgical management of chil- dren with GERD. Specifically, there has been a nation- al increase in the frequency of fundoplications performed on children. In another study, the diagno- sis of GERD in hospitalized infants increased 20-fold in a single naval hospital from 1971 to 1995. It has not been determined whether these growing numbers are due to a rising prevalence of GERD, more awareness of it and improved diagnostic testing, or both. 6,7 Hospitalized and nonhospitalized children with a history of severe GERD symptoms suffer from a num- ber of esophageal complications such as erosive esophagitis, Barrett’s esophagus, and other esophageal- related maladies. In some special populations, the numbers of children with GERD are particularly high. For example, among children with a neurologic injury or impairment such as cerebral palsy, 30% to 70% of children will eventually suffer from erosive esophagitis. Other esophageal and supraesophageal complications in severe pediatric GERD include esophageal stric- tures, laryngitis, sinusitis, pharyngitis, apnea, brady- cardia, seizures, and adenocarcinoma (primarily where there is concomitant neurologic injury or congenital abnormalities of esophagus). Approximately 27% of hospitalized children with GERD show signs of respi- ratory disease. 4,7,8 Not only are the relative numbers of pediatric GERD cases increasing over the years, but the disease also appears to become more clinically relevant and change in character with advancing age. Nelson reviewed the cases of more than 1700 children, track- ing them from newborn to adolescence, and noted that the presenting symptoms of reflux disease changes from a more regurgitant component (eg, vomiting) to one of a more pain-related type: a sig- nificant increase in the evidence of heartburn or epi- gastric pain as children age. 4 From ages 3 to 9 years, 1.8% of children show signs of heartburn; however, from ages 18 to 21 years, 22% of young adults expe- rience this symptom. 4 In addition, one fourth of adults who have documented GERD will have had some evidence of childhood symptoms. 5 SYMPTOMS AND MANIFESTATIONS OF GERD The symptoms and manifestations of GERD in children vary and can be very distinct from those in adults (Table 1). In the pediatric population they include regurgitation, persistent vomiting that causes a failure to thrive, and signs of esophagitis. Caregivers may report feeding difficulties such as the child refus- ing to eat, arching and inconsolable crying, hemateme- Advanced Studies in Medicine ■ S119 PROCEEDINGS sis, and water-brash (spitting up). Other significant physical manifestations of GERD that have been docu- mented are anemia, weight loss, Sandifer’s syndrome (which may cause head turning as a result of esophageal inflammation), and stricture. Older children may report heartburn, dysphagia, and/or odynophagia. The supraesophageal manifestations of GERD in children are similar to those found in adults. These include chronic sore throat and cough, hoarseness, wheezing and asthma, and specific to the infant popula- tion, apnea and bradycardia. Dental erosions and halito- sis may also be a result of chronic GERD in children. Two particularly troublesome conditions that appear to be related to GERD in children are apnea and dam- age to the laryngo-pharyngeal and vocal cords, called laryngopharyngeal reflux disease. It is still controversial as to whether there is a true cause-and-effect relationship between GERD and apnea. However, in some children being evaluated for suspected GERD-induced apnea/bradycardia a definite relationship has been shown; when esophageal pH drops below 4.0, there is a cessation in nasal airflow and chest wall movement. This phenomenon is referred to as reflux-associated apnea. 9,10 Clearly, intervention trials are needed to determine whether infants are experiencing reflux-associated apnea, in which case treatment may reduce episodes or elimi- nate them completely. Another supraesophageal complication of GERD observed among children is damage to the laryn- gopharyngeal area and vocal cords. Specifically, vocal cords may develop a granular exudative surface with induration and irregular contact edges and posterior rugae—all as a result of chronic reflux of gastric con- tents. The inflammation and vocal cord damage appears, in anecdotal cases, to completely resolve with sufficient acid suppression. Prospective pediatric treat- ment trials in this population are definitely needed. D IAGNOSTIC TESTING In the diagnosis of pediatric GERD, the initial workup—particularly in those children with regurgita- tion predominant symptoms—should look for anatomical abnormalities such as strictures, achalasia, intestinal malrotation, or hiatal hernia. Although these abnormalities are often detected via an upper gastroin- testinal (GI) contrast study, if the clinician uses the upper GI solely to diagnose GERD, many false-nega- tives and -positives will occur. Upper GI endoscopy is another useful test in the diagnosis of GERD. It is an especially valuable tool because it enables physicians to diagnose and rule out reflux esophagitis, Barrett’s dis- ease, and other types of inflammatory or infectious forms of esophagitis such as Crohn’s disease, herpes simplex virus, or candida. Finally, the 24-hour intraesophageal pH study, par- ticularly if the child’s caregiver supplies a detailed diary of the child’s symptoms to accompany the study, is a reli- able test to determine the presence of nocturnal silent reflux, the rapidity of esophageal acid clearance, and the adequacy of acid suppression. This procedure, in which a catheter is passed through the nose, into the back of the throat, and down towards the esophagus, is not deemed to be necessary if the patient is vomiting. 11 MANAGEMENT OPTIONS The primary goals in managing GERD are to elim- inate symptoms, heal esophagitis, prevent or manage complications, and maintain remission (Figure). Since GERD may be a lifelong disease, this condition and its long-term sequelae, which often appear in adulthood, may be most effectively handled if it is diagnosed and treated during childhood. Table 1. Symptoms and Manifestations of GERD in Children GERD = gastroesophageal reflux disease; GER = gastroesophageal reflux.  Regurgitation (GER vs GERD; ie, physiologic vs pathologic?) – Vomiting (ie, “fat, happy spitter”) – most common  Persistent vomiting – Failure to thrive  Esophagitis – Feeding refusal, difficulties, resistance – Arching, crying (inconsolably) during initiation of feeds – Hematemesis – Water-brash (“spit-up” burps) – Anemia, weight loss – Sandifer’s syndrome (child presents with ‘head turning’ as a result of esophageal inflammation) – Heartburn (“heartburn” symptoms reported in older child, adolescent) – Dysphagia /odynophagia – Stricture NONSURGICAL MANAGEMENT OF MILD TO MODERATE GERD SYMPTOMS Educating the caregivers of pediatric patients is vital in managing mild GERD symptoms. Specifically, a change in the patient’s diet and lifestyle is often nec- essary. In infants, thickened feeds and sitting the child upright for a period of 45 minutes to 1 hour after feeds often lessens the number of regurgitation episodes. In addition, elevation of the crib or mattress at the head of the bed often eases nighttime symptoms. Obesity can be a contributing factor to GERD, so weight man- agement in older children is encouraged. 11 If pharmacotherapy is necessary, antacids are some- times helpful for symptom relief. Anticholinergics may be effective, but they are usually not recommended due to the high incidence of side effects. 11 On the other hand, histamine type-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are rec- ommended and have been approved for use in the pediatric population by the US Food and Drug Administration (FDA). Safety and dosing data have been well established for medications such as raniti- dine, famotidine, lansoprazole, and omeprazole. The motility component of GERD is still not yet adequate- ly addressed with currently available pharmacologic agents. Prokinetic drugs such as metoclopramide are also sometimes employed in the treatment of GERD. However, safety issues are of concern with the use of available prokinetic agents, particularly when adminis- tered doses are high enough to achieve the desired anti- regurgitant effect. Cisapride has been withdrawn from use by the FDA and metoclopramide has the potential for irreversible central nervous system complications. Data indicate that the PPI, lansoprazole (15 to 30 mg qd), administered to children aged 1 to 11 years with erosive esophagitis resulted in 78% of the subjects being healed by week 8 of treatment and 100% of sub- jects having their erosive esophagitis healed by week 12. 12 Data regarding the 6-month efficacy of another PPI, omeprazole, in children also demonstrated a sim- ilar spectrum of symptom relief and esophagitis heal- ing. Hassall et al conducted an open multicenter study of 57 children aged 1 to 16 years with a diagnosis of erosive esophagitis. 13 The children were administered escalating doses of omeprazole in order to achieve an optimal dose to maintain the duration of esophageal acid reflux <6% in a 24-hour pH study. In these chil- dren, there was marked reduction in symptoms, including heartburn, dysphagia, irritability, and coughing, both at an interim visit 5 to 14 days into the study and at the healing visit on day 120. 13 Although no head-to-head pediatric comparative studies have been performed, data from H2RA and PPI treatment trials in similar patient populations demonstrate a superior efficacy of PPIs over H2RAs in the treatment of pediatric GERD. For example, recent studies demonstrated that PPIs heal severe erosive esophagitis in up to 100% of the children in which they were administered. 12 PPIs were shown to be effec- tive even in patients whose GERD was refractory to other medications and who have failed surgery. 12,13 For short-term healing, PPIs in children have been shown to be safe and effective. However, PPI administration in the pediatric population has been shown to require wider dosing ranges for treatment efficacy than is rec- ommended for adults. Indeed, studies demonstrate that PPI doses used in the pediatric population are sometimes higher than those administered to adults due to the fact that children, in part, metabolize these medications faster than their older counterparts. 13-16 There are a variety of formulations of PPIs available for use in pediatric GERD patients. Both lansoprazole and omeprazole have been shown to be equally as effective in liquid suspension, and there is a lansopra- zole packet for suspension that is strawberry flavored. Furthermore, PPI capsules can be opened and sprin- kled into food (eg, applesauce or ice cream) while S120 Vol. 3 (3A) ■ March 2003 PROCEEDINGS Figure.Treatment of Gastroesophageal Reflux Disease (GERD) Advanced Studies in Medicine ■ S121 maintaining good bioavailability and similar efficacy. In addition, there are other PPI formulations under development including fast-dissolving tablets and intravenous preparations. S URGERY Antireflux surgery is another option for the treat- ment of childhood GERD, particularly in those patients with a significant motility or regurgitant component to their disease. Fundoplication is the third most common procedure performed on children today. Between 1995 and 1999, approximately 25% to 27% of hospitalized children with the primary dis- charge diagnosis of GERD underwent fundoplica- tion. 7 However, caution and careful case selection should be used as significant morbidity and mortality can be associated with surgery, particularly in children with neurologic injury (eg, the cerebral palsy popula- tion). Thus, antireflux surgery is not recommended for all pediatric patients. The decision to move for- ward with surgical intervention should be made care- fully on a case-by-case basis. Recent pediatric data support previously published adult studies demon- strating that those patients with GERD who respond to medical therapy have better outcomes with antire- flux surgery. To date, no comparative outcome or cost- effectiveness studies with PPI versus surgery have been performed in the pediatric population. In summary, mild spitting and irritability often characterize uncomplicated GERD in infants. GERD is most frequently diagnosed by history and physical exam, and best approached by providing parental guidance and reassurance, slight lifestyle changes, and possible empiric treatment with prokinetic or antise- cretory agents (H2RA/PPI). Refractory cases of infant GERD should be referred to a specialist for diagnos- tic testing (ie, upper GI) to rule out anatomic abnor- malities such as hiatal hernia or achalasia, and pH metry with an accompanying diary to demonstrate reflux episode association with symptoms (Table 2). Complicated GERD in infants often presents with poor weight gain, dysphagia, apnea, respiratory symp- toms, irritability, and hematemesis. Diagnostic options include endoscopy with biopsies and 24-hour pH metry. Recommended therapies include acid sup- pression via H2RA/PPI, prokinetic medications, change in formula, and increased caloric density, although infants with complicated GERD often require the expertise of a specialist. PROCEEDINGS Table 2. GERin Infants:Management Approach GER = gastroesophageal reflux; GI= gastrointestinal; H2RA = histamine type-2 recep- tor antagonist; PPI = proton pump inhibitor. Table 3. GERin Older Children:Management Approach GER = gastroesophageal reflux; GI= gastrointestinal; H2RA = histamine type-2 recep- tor antagonist; PPI = proton pump inhibitor. Uncomplicated GER “Happy spitter”/Mildly colicky • Parental guidance/reassurance • Lifestyle changes (elemental or thickened formula) • Worsening symptoms or persistence >24 mo • Upper GI contrast study • Empiric treatment with prokinetic or antisecretory (H2RA / PPI) • Consider referral to specialist Complicated GER • Poor weight gain, dysphagia, apnea, respiratory symptoms, irritability, hematemesis • Referral to specialist • Diagnostic options: Endoscopy, pH probe • Rx options: Acid suppression, (H2RA/PPI), prokinetic, formula change, increase caloric density Heartburn • Lifestyle changes • Trial PPI or H2RA for 2–4 weeks • Referral to specialist if symptoms persist or recur • Endoscopy and possible long-term treatment Complicated GER • Odynophagia, dysphagia, hematemesis, food lodged • Referral to specialist • Upper GI and endoscopy • Treatment with PPI for erosive esophagitis • Repeat endoscopy for erosive esophagitis In older children with complicated GERD, symp- toms can range from odynophagia to dysphagia to hematemesis. To diagnose complicated GERD, physi- cians commonly perform 24-hour pH metry and endoscopy with biopsies. (NOTE: A complete algorithm scheme for children of different ages with GERD is pro- vided in the recently published North American Society for Pediatric Gastroenterology and Nutrition clinical practice guidelines for GERD.) 11 The management approach taken in older children with GERD is slightly different than in younger children and infants. Often, older children with mild GERD first present with heart- burn as a key symptom. As with infants, lifestyle changes (particularly weight management) are often recom- mended. Administration of a PPI or H2RA for a period of 2 to 4 weeks is suggested. If systems persist, the older child with GERD should be referred to a specialist. Treatment with PPIs is recommended for all patients with erosive esophagitis diagnosed by the pediatric gas- troenterologist via upper endoscopy (Table 3). C ONCLUSION In conclusion, pediatric GERD is a more common problem than previously recognized, and its presenta- tion (ie, signs and symptoms) in the pediatric popula- tion may differ from GERD in adults. Early diagnosis and treatment may prevent lifelong GERD complica- tions. Effective therapies, such as PPIs, are safe, avail- able, and should be employed in the management of this common and chronic disease that causes signifi- cant morbidity and human suffering. REFERENCES 1. Managing Acid-Related Disorders Through the Ages of Man [abstract book]. PRI-MED East Conference; Nov 7, 2002; Boston, Mass. 2. Kawahara H, Dent J, Davidson G. Mechanisms responsible for gastroesophageal reflux in children. Gastroenterology. 1997;113:399-408. 3. Gibbons TE, Stockwell J, Kreh RP, McRae S, Gold BD. Population based epidemiological survey of gastroe- sophageal reflux disease in hospitalized US children. Gastroenterology. 2001;120(5):154. 4. Nelson SP, Chen EH, Syniar GM, Christoffel KK. 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Efficacy and safety of omepra- zole for severe gastroesophageal reflux in children. J Pediatr. 1993;123:148-154. 15. Hassall E and the International Pediatric Omeprazole Study Group. Omeprazole for maintenance therapy of erosive esophagitis in children. Gastroenterology. 2000; 118:A3610. 16. Andersson T, Hassall E, Lundborg P, et al. Pharmacokinetics of orally administered omeprazole in children. Am J Gastroenterol. 2000;95:3101-3106. S122 Vol. 3 (3A) ■ March 2003 PROCEEDINGS . diagnostic and management tools. PROCEEDINGS GASTROESOPHAGEAL REFLUX DISEASE IN INFANTS, CHILDREN, AND ADOLESCENTS * — Benjamin D. Gold, MD † * This article is. Studies in Medicine ■ S121 maintaining good bioavailability and similar efficacy. In addition, there are other PPI formulations under development including