Gastroesophageal Reflux Disease: A Pediatric Perspective

From the 42nd Annual Advances and Controversies in Clinical Pediatrics, presented by the Department of Pediatrics, University of California, San Francisco, School of Medicine

Colin D. Rudolph, MD, PhD, Professor of Pediatrics, Medical College of Wisconsin, Medical Director, Gastroenterology and Vice Chair of Clinica, Children’s Hospital of Wisconsin, Milwaukee

Educational Objectives

The goal of this program is to improve the management of gastroesophageal reflux (GER) and GER disease (GERD) in in­fants and children. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the epidemiology and causative mechanisms of GER in infants.

2.   Distinguish between non-GER diagnoses and GERD when evaluating the infant with recurrent vomiting and/or re­gurgitation.

3.   Explain the difficulties in making a definitive diagnosis of GERD in infants and children.

4.   Discuss the recommended management approaches for common symptoms purported to result from infant GER, in­cluding irritability, feeding problems, and apnea.

5.   Summarize recommendations for the diagnosis and management of the child with erosive or nonerosive esophagitis, recurrent pneumonia, GER symptoms and asthma, and upper airway symptoms.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Rudolph and the planning committee re­ported nothing to disclose.

Acknowledgements

Dr. Rudolph lectured at the 42nd Annual Advances and Controversies in Clinical Pediatrics, held May 28-30, 2009, in San Francisco, CA, and sponsored by the Department of Pediatrics of the University of California, San Francisco (UCSF), School of Medicine. The Audio-Digest Foundation thanks Dr. Rudolph and the UCSF School of Medicine for their cooper­ation in the production of this program.

Gastroesophageal Reflux Disease in Infants

Introductory remarks: gastroesophageal reflux (GER) not disease (vomiting occurs ³1 time per day in »70% and >4 times per day in »20% of infants)

Mechanisms of GER: lower esophageal sphincter (LES; specialized smooth muscle) normally remains contracted, but re­laxes intermittently to allow belching or venting; surrounded by crus of diaphragm; transient LES relaxations (reduction in pressure in LES) allow reflux; intra-abdominal esophagus helps to prevent reflux

Mechanisms of GER in infant: short esophagus with limited capacity to hold liquid; relatively small stomach; prone posi­tion (keep infant in upright position or on stomach to prevent regurgitation)

GER vs GER disease (GERD): GER is normal physiologic process that causes few or no symptoms; GERD present when reflux of gastric contents causes troublesome symptoms and/or complications

Evaluation of patient: do complete history and physical examination (PE) of infant; warning signals suggestive of non-GER diagnosis  —  bilious or forceful vomiting; hematochezia; diarrhea; abdominal tenderness or distention; onset of vomiting after »6 mo of life; presence of atopia; fever, lethargy, hepatosplenomegaly, macrocephaly, or seizures; signs of GERD  —  growth fail­ure; esophageal symptoms (pain or irritability; feeding refusal [both questionable]; hematemesis; anemia); apnea; wheezing or asthma; recurrent pneumonia; upper airway symptoms

Recommendations for diagnosis and management of GERD in infant: diagnosis  —  history and PE excluding warning signs generally adequate to make diagnosis of uncomplicated GER in infants; management  —  in infant with uncompli­cated regurgitation, parental education, reassurance, and anticipatory guidance recommended; may consider thickening formula; in general, no other intervention necessary; no evidence that antisecretory or promotility agents improve physio­logic regurgitation; as regurgitation sometimes sole manifestation of cow’s milk protein allergy in otherwise healthy in­fant, can try 2-wk trial of protein hydrolysate or amino acid-based formula, or milk-free diet for breastfeeding mother; prone positioning not recommended because of association with sudden infant death syndrome (SIDS)

Irritability or pain: case example (»4 mo old male infant; spits up »4 times per day and cries »2 hr each day with back arching); crying within normal range for 4- to 6-mo old infant; diagnosis and treatment of GERD not indicated  without doing differential diagnosis (GERD not common cause of irritability in infants); study showed no correlation between duration of crying and amount of reflux time; proton pump inhibitor (PPI) therapy  —  double-blind placebo-controlled trials of omeprazole and lansoprazole in infants with GER reported no differences in vomiting, crying, fussing, and ir­ritability between patient groups; found PPI therapy has potential respiratory risks

Management of irritability: available evidence does not support empiric acid-suppressive therapy for treatment of infants with irritability; if irritability persists with no explanation other than suspected GERD, practitioner may continue antic­ipatory guidance and parent training, or consider trial of hypoallergenic formula, esophageal impedance/pH monitor­ing, esophagogastroduodenoscopy to rule out Candida or other causes of esophagitis, or time-limited (2-wk) trial of PPI

Feeding problems and infant GER: study looked at »20 infants (age 5-7 mo) with >95th percentile acid exposure on 24-hr pH monitoring vs »20 controls; patients evaluated for feeding issues while on therapy; concluded infants with GERD more likely to have developmental delays that cause feeding difficulties  

Management approach for feeding difficulties: GERD itself not common cause of childhood odynophagia or infant feed­ing difficulties; evaluation of infants and children with feeding difficulties or dysphagia should include history, PE, and clinical observation of symptoms; radiographic contrast studies or endoscopy and biopsy might be indicated; empiric therapy not recommended except in older children capable of reporting symptoms of GERD

Airway protective mechanisms: small-volume esophageal distention causes upper esophageal sphincter (UES) to con­tract; large-volume distention causes series of vagal reflexes; refluxate enters pharynx; swallowing clears pharynx; respiration resumes

Apnea and apparent life-threatening events (ALTEs): apnea occurs in infants with laryngeal stimulation (in older child, same stimulus causes cough); GER associated with episodes of obstructive or mixed apnea that occur while infant awake, supine, and within »1 hr of feeding; however, studies have failed to show significant correlation between apnea and GER;  cannot assume diagnosis of GER; diagnosis and management  —   perform impedance pH recording in combination with polysomnographic recording to demonstrate relationship between GER and apnea; no data to support efficacy of pharmaco­logic treatment for GER-related apnea; apnea generally resolves spontaneously as infant matures, so surgical therapy not recommended

Conclusions: GER common in infants; differentiating GER from GERD challenging and cannot be based on typical symp­toms; GERD relatively uncommon and likely overdiagnosed and overtreated in infants; PPI therapy has potential risks which alter risk-benefit ratio of empiric treatment; best approach to diagnosis and management not always clear, but cur­rent practice patterns should be reassessed

Questions and Answers

When should physicians diagnose and treat GERD? speaker believes most physicians overtreating GERD; number of children with “classic signs” (eg, irritability, back arching) actually due to GERD very small; when infant referred with diagnosis of GERD, speaker recommends reassurance of family, rather than endoscopy; bottom line — huge increase in recognition of GERD because of availability of drug therapy (ie, due to pharmacologic marketing); good diagnostic tests presently lacking; avoid diagnosing GERD without differential diagnosis

Does possible relationship between acid-blocking agents and food allergy sensitization (per animal studies) further contraindicate use in children? no current data in humans; however, speaker finds ample reason to avoid acid-blocking (eg, dramatic increase in risk for pneumonia, poor acid clearance in patients with neurodevelopmental delay or cystic fi­brosis)

Gastroesophageal Reflux Disease in Children

Pathogenic mechanism of esophagitis: impaired acid clearance in esophagus (seminal study by Dodds et al); chewing gum least expensive acid-reducing agent

Esophagitis symptoms in childhood: pain; regurgitation; dysphagia; hematemesis; anemia

Prevalence of GERD symptoms in children: when questioned,  »8% of children 10 to 17 yr of age report having regurgi­tation, 5% report epigastric pain, and »5% report heartburn

Factors affecting diagnosis of GERD in children: children tend to answer questions in affirmative, making history less re­liable; ability to describe and localize pain highly variable; GERD symptom reports in young children not shown to pre­dict disease; many conditions with symptoms that overlap those of GERD in children; therefore, physician should not make positive diagnosis of GERD based on reported symptoms; in older children and adolescents, history and PE gener­ally sufficient to reliably diagnose GERD and initiate management; in infants, toddlers, and younger children, no symp­tom or group of symptoms can reliably diagnose GERD or predict treatment response

Management of possible esophagitis in children: older child or adolescent who presents with typical symptoms of GERD (heartburn, regurgitation)  —  consider empiric therapy, lifestyle changes, or treatment with PPI; if symptoms resolve, wean from therapy and observe; if symptoms recur or persist, do endoscopy and biopsy (findings of erosive esophagitis and biopsy consistent with GERD considered definitive diagnosis); if symptoms recur intermittently, consider on-demand therapy; younger children (<8-12 yr of age)  —  consider pH monitoring and endoscopy to confirm diagnosis

Erosive esophagitis: traditionally, pediatric erosive esophagitis presumed to be chronic relapsing disease requiring long-term PPIs or antireflux surgery; however, recent study suggests that there may be pathophysiologic mechanisms causing erosive esophagitis in children other than chronic and relapsing reflux; weaning from PPIs after 3 mo, observation, and retreatment only with symptomatic recurrence now recommended

Pathology of GERD: in children, classic histologic parameters of esophageal inflammation, even when considered to­gether, have poor correlation with symptoms, endoscopic findings, and esophageal pH monitoring, both qualitatively and quantitatively; endoscopic biopsy important to identify or rule out other causes of esophagitis, and to diagnose and moni­tor Barrett’s esophagus and its complications, but not reliable for diagnosis of GERD

Nonerosive reflux disease: consider empiric therapy in child reporting symptoms; if symptoms resolve, wean from therapy and observe; with endoscopy and abnormal biopsy, GERD possible but not definitive

Recurrent pneumonia: real symptom of reflux; in child with recurrent pneumonia who has been diagnosed with GERD, determine whether aspiration associated with swallowing or with reflux; reflux not most common cause of recurrent pneumonia; look for differential diagnosis

Evaluation of infant or child with recurrent pneumonia: GER-related aspiration pneumonia may arise in absence of esophagitis; normal esophageal pH does not exclude GER as cause of aspiration pneumonia; combination of tests may aid in diagnosis

PPI treatment of patients with GER and neurodevelopmental delay: treatment associated with significant decrease in vomit­ing and pneumonia; double-blind placebo-controlled trials needed in normal and neurologically abnormal children

Outcomes of surgery for children with pulmonary disease: recent study looked at »1142 patients who had antireflux sur­gery; »52% had respiratory-related events (RRE) before surgery; surgery decreased rate of RRE in patients <1 yr of age and 1 to 3 yr of age, but not in those 4 to 18 yr of age; developmental delay was risk factor for increased RRE ad­missions after surgery

Conclusions: no controlled studies show benefit of medical therapy for reflux-related aspiration; potential benefits of sur­gery must be balanced against potential complications

GER and asthma: share pathogenic mechanisms; symptoms of GER extremely common in children with asthma

Affect of PPI treatment on asthma in: adults  —  double-blind placebo-controlled trial of esomeprazole in adults with moder­ate-to-severe persistent asthma; only improvement seen in small subgroup of patients with nocturnal GER and asthma symptoms; children  —  placebo-controlled study of omeprazole in children with GER and asthma symptoms showed no difference in symptom scores at »12 wk; pulmonary function tests (PFTs) and use of bronchodilators similar

Management of infant or child with asthma (guidelines): in patient with GER symptoms and moderate-to-severe asthma,  trial of PPI therapy reasonable, but efficacy may be expected only in patients with nocturnal asthma symptoms; previ­ous guidelines recommended pH probe to guide treatment, but evidence lacking to support this recommendation; if treatment initiated, outcome variables such as symptoms, medication use, and pulmonary function test (PFT) changes should be monitored; role of both medical and surgical therapy remains poorly defined

Laryngopharyngeal reflux disease (LPRD): symptoms usually occur in absence of classic symptoms of GER; upper en­doscopy and pH monitoring often normal; laryngoscopic findings primary diagnostic criteria (yet unreliable); esomepro­zole for chronic posterior laryngitis in adults  — in large placebo-controlled study, no difference between groups

Diagnosis and management of pediatric upper airway symptoms (guidelines): several studies report presence of GERD in children with either chronic or recurrent laryngeal symptoms; laryngoscopy indicated to rule out other pathology; no uni­form interpretation of laryngeal findings for GER in children and adults; findings may be due to other etiologies (eg, allergy, voice abuse); PPI therapy of limited (if any) value for all diagnoses, with possible exception of chronic cough; available data inadequate to allow recommendations for diagnosis or treatment of possible GER-related cough, hoarseness, stridor, vocal cord nodules, or poor surgical healing in pediatric patients; therefore, caution should be exercised in establishing GER as sole diagnosis in patients with chronic laryngeal symptoms; surgery should not be expected to improve symptoms in patients who do not respond to PPI therapy

Questions and Answers

Is overdiagnosis of GERD in children with upper airway disease related to regional training of otolaryngologists? speaker believes problem international (not regional); moving away from overdiagnosing GERD will require major shift in otolaryngologists’ thinking; problem caused by physicians’ difficulty in managing these children

Is pacifier protective in erosive esophagitis? unknown; infants tend to swallow saliva; unclear whether pacifier increases salivary secretions

Suggested Reading

Adler J, Dickinson CJ: Thickened formula is only moderately  effective in the treatment of gastroesophageal reflux in healthy infants. J Pediatr 154:774, 2009; Balistreri WF: The reflex to treat reflux--let's be conservative regarding gastroesophageal re­flux (GER)! J Pediatr 152:A1, 2008; Bhatia J, Parish A: GERD or not GERD: the fussy infant. J Perinatol 29 Suppl 2:S7, 2009; Croxtall JD et al: Esomeprazole: in gastroesophageal reflux disease in children and adolescents. Paediatr Drugs 10:199, 2008; De Boeck K et al: Lipid-laden macrophage index and gastroesophageal reflux-related respiratory disease in children. Pediatrics 122:680, 2008; Diaz DM et al: Knowledge, attitudes and practice styles of North American pediatricians regarding gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 45:56, 2007; Dodds WJ: The pathogenesis of gastro­esophageal reflux disease. AJR Am JRoentgenol 151:49, 1988; Goldin AB et al: Do antireflux operations decrease the rate of reflux-related hospitalizations in children? Pediatrics 118:2326, 2006; Horvath A et al: The effect of thickened-feed interven­tions on gastroesophageal reflux in infants: systematic review and meta-analysis of randomized, controlled trials. Pediatrics 122:e1268, 2008; Noronha AC et al: Gastroesophageal reflux and obstructive sleep apnea in childhood. Int J Pediatr Otorhi­nolaryngol 73:383, 2009; Orenstein SR: Crying in infant GERD: acid or volume? Heartburn or dyspepsia? Curr Gastroen­terol Rep 10:433, 2008; Orenstein SR et al: Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pedi­atr 154:514, 2009; Orenstein SR et al: Natural history of infant reflux esophagitis: symptoms and morphometric histology during one year without pharmacotherapy. Am J Gastroenterol 101:628, 2006; Orenstein SR, Hassall E: Infants and proton pump inhibitors: tribulations, no trials. J Pediatr Gastroenterol Nutr 45:395, 2007; Orenstein SR, McGowan JD: Efficacy of conservative therapy as taught in the primary care setting for symptoms suggesting infant gastroesophageal reflux. J Pediatr 152:310, 2008; Owayed AF et al: Underlying causes of recurrent pneumonia in children. Arch Pediatr Adolesc Med 154:190, 2000; Putnam PE: Stop the PPI express: they don't keep babies quiet! J Pediatr 154:475, 2009; Rosen R et al: Lipid-laden macrophage index is not an indicator of gastroesophageal reflux-related respiratory disease in children. Pediatrics 121:e879, 2008; Rudolph CD: Are proton pump inhibitors indicated for the treatment of gastroesophageal reflux in infants and children? J Pediatr Gastroenterol Nutr 37 Suppl 1:S60, 2003; Rudolph CD et al: Guidelines for evaluation and treatment of gastro­esophageal reflux in infants and children: recommendations of the North American Society for Pediatric Gastroenterology and Nutrition. J Pediatr Gastroenterol Nutr 32 Suppl 2:S1, 2001; Savino F, Castagno E: Overprescription of antireflux medica­tions for infants with regurgitation. Pediatrics 121:1070, 2008; Sondheimer J: Non-pharmacologic therapy may be effective for infants with gastroesophageal reflux. J Pediatr 153:441, 2008; Tipnis NA, Rudolph CD: Treatment Options in Pediatric GERD. Curr Treat Options Gastroenterol 10:391, 2007.