CLINICAL REPORT Gastroesophageal Reﬂux: Management Guidance for abstracteqipp.aap.org/File Library/Courses/GER GERD/2013Lightdale... · CLINICAL REPORT Gastroesophageal Reﬂux:

CLINICAL REPORT

Gastroesophageal Reflux: Management Guidance forthe Pediatrician

abstractRecent comprehensive guidelines developed by the North AmericanSociety for Pediatric Gastroenterology, Hepatology, and Nutrition definethe common entities of gastroesophageal reflux (GER) as the physio-logic passage of gastric contents into the esophagus and gastroesoph-ageal reflux disease (GERD) as reflux associated with troublesomesymptoms or complications. The ability to distinguish between GERand GERD is increasingly important to implement best practices inthe management of acid reflux in patients across all pediatric agegroups, as children with GERD may benefit from further evaluationand treatment, whereas conservative recommendations are the onlyindicated therapy in those with uncomplicated physiologic reflux. Thisclinical report endorses the rigorously developed, well-referencedNorth American Society for Pediatric Gastroenterology, Hepatology,and Nutrition guidelines and likewise emphasizes important conceptsfor the general pediatrician. A key issue is distinguishing between clin-ical manifestations of GER and GERD in term infants, children, and ado-lescents to identify patients who can be managed with conservativetreatment by the pediatrician and to refer patients who require con-sultation with the gastroenterologist. Accordingly, the evidence basispresented by the guidelines for diagnostic approaches as well as treat-ments is discussed. Lifestyle changes are emphasized as first-line ther-apy in both GER and GERD, whereas medications are explicitly indicatedonly for patients with GERD. Surgical therapies are reserved for chil-dren with intractable symptoms or who are at risk for life-threateningcomplications of GERD. Recent black box warnings from the US Foodand Drug Administration are discussed, and caution is underlinedwhen using promoters of gastric emptying and motility. Finally, atten-tion is paid to increasing evidence of inappropriate prescriptions forproton pump inhibitors in the pediatric population. Pediatrics2013;131:1–12

INTRODUCTION

Gastroesophageal reflux (GER) occurs in more than two-thirds ofotherwise healthy infants and is the topic of discussion with pedia-tricians at one-quarter of all routine 6-month infant visits.1,2 In additionto seeking guidance from their pediatricians, parents often requestevaluation by pediatric medical subspecialists.3 It is, therefore, notsurprising that strongly evidence-based guidelines incorporating

Jenifer R. Lightdale, MD, MPH, David A. Gremse, MD, andSECTION ON GASTROENTEROLOGY, HEPATOLOGY, ANDNUTRITION

KEY WORDSgastroesophageal reflux, gastroesophageal reflux disease,pediatrics, guidelines, review, global consensus, reflux-relateddisease, vomiting, regurgitation, rumination, extraesophagealsymptoms, Barrett esophagus, proton pump inhibitors,diagnostic imaging, impedance monitoring, gastrointestinalendoscopy, lifestyle changes

ABBREVIATIONSGER—gastroesophageal refluxGERD—gastroesophageal reflux diseaseGI—gastrointestinalH2RA—histamine-2 receptor antagonistMII—multiple intraluminal impedancePPI—proton pump inhibitor

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave filed conflict of interest statements with the AmericanAcademy of Pediatrics. Any conflicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-0421

doi:10.1542/peds.2013-0421

All clinical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

PEDIATRICS Volume 131, Number 5, May 2013 1

FROM THE AMERICAN ACADEMY OF PEDIATRICS

Guidance for the Clinician inRendering Pediatric Care

state-of-the-art approaches to theevaluation and management of pedi-atric GER have been welcomed by bothgeneral pediatricians and pediatricmedical subspecialists and surgicalspecialists. GER, defined as the pas-sage of gastric contents into theesophagus, is distinguished fromgastroesophageal reflux disease(GERD), which includes troublesomesymptoms or complications associ-ated with GER.4 Differentiating be-tween GER and GERD lies at the crux ofthe guidelines jointly developed by theNorth American Society for PediatricGastroenterology, Hepatology, and Nu-trition and the European Society forPediatric Gastroenterology, Hepatol-ogy, and Nutrition.4 These definitionshave further been recognized as rep-resenting a global consensus.5 There-fore, it is important that allpractitioners who treat children withreflux-related disorders are able toidentify and distinguish those childrenwith GERD, who may benefit fromfurther evaluation and treatment,from those with simple GER, in whomconservative recommendations aremore appropriate.

GER is considered a normal physio-logic process that occurs severaltimes a day in healthy infants, children,and adults. GER is generally associatedwith transient relaxations of the loweresophageal sphincter independent ofswallowing, which permits gastriccontents to enter the esophagus. Epi-sodes of GER in healthy adults tend tooccur after meals, last less than 3minutes, and cause few or no symp-toms.6 Less is known about the nor-mal physiology of GER in infants andchildren, but regurgitation or spittingup, as the most visible symptom, isreported to occur daily in 50% of allinfants.7,8

In both infants and children, reflux canalso be associated with vomiting, de-fined as a forceful expulsion of gastric

contents via a coordinated autonomicand voluntary motor response. Re-gurgitation and vomiting can be fur-ther differentiated from rumination, inwhich recently ingested food is ef-fortlessly regurgitated into the mouth,masticated, and reswallowed. Rumi-nation syndrome has been identifiedas a relatively rare clinical entity thatinvolves the voluntary contraction ofabdominal muscles.9 In contrast, bothregurgitation and vomiting can beconsidered common and often non-pathologic manifestations of GER.

Symptoms or conditions associatedwith GERD are classified by the prac-tice guidelines as being eitheresophageal or extraesophageal.4 Bothclassifications can be used to definethe disease, which can be furthercharacterized by findings of mucosalinjury on upper endoscopy. Esopha-geal conditions include vomiting, poorweight gain, dysphagia, abdominal orsubsternal/retrosternal pain, andesophagitis. Extraesophageal con-ditions have been subclassifiedaccording to both established andproposed associations; establishedextraesophageal manifestations ofGERD can include respiratory symp-toms, including cough and laryngitis,as well as wheezing in infancy.10,11

Although older studies from the 1990ssuggested that GERD may aggravateasthma, recent publications havesuggested that the impact of GERD onasthma control is considerably lessthan previously thought.10,12–18 Otherextraesophageal manifestations in-clude dental erosions, and proposedassociations include pharyngitis, si-nusitis, and recurrent otitis media.Patients can be described clinically bytheir symptoms or by the endoscopicdescription of their esophageal mu-cosa. GERD-associated esophagealinjuries and complications found onendoscopy include reflux esophagitis,less commonly peptic stricture, and

rarely Barrett esophagus and adeno-carcinoma.

Although the reported prevalence ofGERD in patients of all ages worldwideis increasing,5 GERD is neverthelessfar less common than GER.Population-based studies suggestreflux disorders are not as commonin Eastern Asia, where the prevalenceis 8.5%,19 compared with WesternEurope and North America, where thecurrent prevalence of GERD is esti-mated to be 10% to 20%.20 New epi-demiologic and genetic evidencesuggests some heritability of GERDand its complications, including ero-sive esophagitis, Barrett esophagus,and esophageal adenocarcinoma.21–23

A few pediatric populations at highrisk of GERD have also been identified,including children with neurologicimpairment, certain genetic dis-orders, and esophageal atresia24,25

(Table 1). The prevalence of severe,chronic GERD is much higher in pedi-atric patients with these “GERD-pro-moting” conditions. These patientsmay be more prone to experiencingcomplications of severe GERD thanpatients who are otherwise healthy.26

Population trends hypothesized tocontribute to a general increase in theprevalence of GERD include globalepidemics of both obesity and asthma.In some instances, GERD can be im-plicated as either the underlying eti-ology (ie, recurrent pneumonia in thepremature infant exacerbated by

TABLE 1 Pediatric Populations at High Riskfor GERD and Its Complications

Neurologic impairmentObeseHistory of esophageal atresia (repaired)Hiatal herniaAchalasiaChronic respiratory disordersBronchopulmonary dysplasiaIdiopathic interstitial fibrosisCystic fibrosis

History of lung transplantationPreterm infants

2 FROM THE AMERICAN ACADEMY OF PEDIATRICS

GERD) or a direct repercussion (ie,obesity leading to GERD) of such con-ditions. In the great majority of cases,however, GERD and comorbidities areknown to occur simultaneously inpatients without a clear causal re-lationship.

CLINICAL FEATURES OF GERD

Troublesome symptoms or complica-tions of pediatric GERD are associatedwith a number of typical clinical pre-sentations in infants and children,depending on patient age5 (Table 2).Reflux may occur commonly in pre-term newborn infants but is generallynonacidic and improves with matura-tion. A full discussion of reflux inneonates and preterm infants is be-yond the scope of this report.

Guidelines have distinguished betweenmanifestations of GERD in full-terminfants (younger than 1 year) fromthose in children older than 1 year andadolescents. Common symptoms ofGERD in infants include regurgitationor vomiting associated with irritability,anorexia or feeding refusal, poorweight gain, dysphagia, presumablypainful swallowing, and arching of theback during feedings. Relying ona symptom-based diagnosis of GERDcan be difficult in the first year of life,especially because symptoms of GERDin infants do not always resolve withacid-suppression therapy.5,27 GERD in

infants can also be associated withextraesophageal symptoms of cough-ing, choking, wheezing, or upper re-spiratory symptoms.7 The incidence ofGERD is reportedly lower in breastfedinfants than in formula-fed infants.27

In line with the natural history ofregurgitation, GERD in infants is con-sidered to have a peak incidence ofapproximately 50% at 4 months ofage and then to decline to affect only5% to 10% of infants at 12 months ofage.7,8

Common symptoms of GERD in chil-dren 1 to 5 years of age include re-gurgitation, vomiting, abdominal pain,anorexia, and feeding refusal.28 Gen-erally, GERD causes troublesomesymptoms without necessarily in-terfering with growth; however, chil-dren with clinically significant GERD orendoscopically diagnosed esophagitismay also develop an aversion to food,presumably because of a stimulus-response association of eating withpain. This aversion, combined withfeeding difficulties associated withrepeated episodes of regurgitation, aswell as potential and substantial nu-trient losses resulting from emesis,may lead to poor weight gain or evenmalnutrition.

Older children and adolescents aremost likely to resemble adults in theirclinical presentation with GERD and tocomplain of heartburn, epigastricpain, chest pain, nocturnal pain, dys-phagia, and sour burps. When elicitinga history in school-aged children withsuspected GERD, it may be importantto directly ask patients themselvesabout their symptoms rather thanrelying strongly on parent report. In 1study, adolescents were significantlymore likely than their parents to re-port themselves to be experiencingsymptoms of sour burps or nausea.1

Extraesophageal symptoms in olderchildren and adolescents can includenocturnal cough, wheezing, recurrent

pneumonia, sore throat, hoarseness,chronic sinusitis, laryngitis, or dentalerosions. In a pediatric patient withGERD and dental erosions, the pro-gression of tooth structure loss maybe indicative that existing therapy forGERD is not effective. Conversely, sta-bility of dental erosions is 1 measureof adequacy of GERD management.

DIAGNOSTIC STUDIES

For most pediatric patients, a historyand physical examination in the ab-sence of warning signs are sufficientto reliably diagnose uncomplicatedGER in infants and initiate treatmentstrategies. Generally speaking, di-agnostic testing is not necessary. Thereliability of symptoms to make theclinical diagnosis of GERD is particu-larly high in adolescents, who oftenpresent with heartburn typical ofadults.29–31 Nevertheless, dedicating atleast part of a clinical visit to obtain-ing a clinical history and performinga physical examination are also es-sential to exclude more worrisomediagnoses that can present with refluxor vomiting (Table 3).

To date, no single symptom or clusterof symptoms can reliably be used todiagnose esophagitis or other com-plications of GERD in children or to

TABLE 2 Common Presenting Symptoms ofGERD in Pediatric Patients

Infant Older Child/Adolescent

Feeding refusal Abdominal pain/heartburn

Recurrentvomiting

Recurrent vomiting

Poor weightgain

Dysphagia

Irritability AsthmaSleep

disturbanceRecurrent pneumonia

Respiratorysymptoms

Upper airway symptoms(chronic cough,hoarse voice)

TABLE 3 Concerning Symptoms and Signs(“Warning Signs” in Figures) forPrimary Q:4Etiologies Presenting WithVomiting

Bilious vomitingGI tract bleedingHematemesisHematochezia

Consistently forceful vomitingFeverLethargyHepatosplenomegalyBulging fontanelleMacro/microcephalySeizuresAbdominal tenderness or distensionDocumented or suspected genetic/metabolicsyndrome

Associated chronic disease



predict which patients are most likelyto respond to therapy.21 Nonetheless,a number of GERD symptom ques-tionnaires have been validated andmay be useful in the detection andsurveillance of GERD in affected chil-dren of all ages. Kleinman et alQ:1 de-veloped a questionnaire for infantsthat was validated for documentationand monitoring of parent-reportedGERD symptoms.25 Another question-naire by Størdal et al32 for pediatricpatients 7 to 16 years of age com-pared favorably with results of pHmonitoring. As yet another example,the GERD Symptom Questionnaire de-veloped by Deal et al33 appears validfor differentiating children with GERDfrom healthy controls but has notbeen compared with objective stand-ards, such as pH monitoring or en-doscopic findings.

The strategy of using diagnostic test-ing to diagnose GERD may also befraught with complexity, because thereis no single test that can rule it in orout. Instead, diagnostic tests must beused in a thoughtful and serial mannerto document the presence of reflux ofgastric contents in the esophagus, todetect complications, to establisha causal relationship between refluxand symptoms, to evaluate the efficacyof therapies, and to exclude otherconditions. The diagnostic methodsmost commonly used to evaluate pe-diatric patients with GERD symptomsare upper gastrointestinal (GI) tractcontrast radiography, esophageal pHand/or impedance monitoring, andupper endoscopy with esophageal bi-opsy. Upper GI tract series are usefulto delineate anatomy and to occa-sionally document a motility disorder,whereas esophageal pH monitoringand intraluminal esophageal imped-ance represent tools to quantify GER.Upper endoscopy with esophageal bi-opsy represents the primary methodto investigate the esophageal mucosa

to both exclude other conditions thatcan cause GERD-like symptoms andevaluate for esophageal injury attrib-utable to GERD.4

Upper GI Tract Series

Upper GI tract contrast radiographygenerally involves obtaining a series offluoroscopic images of swallowedbarium until the ligament of Treitz isvisualized. According to the newguidelines, the routine performance ofupper GI tract radiographic imaging todiagnose GER or GERD is not justified,4

because upper GI tract series are toobrief in duration to adequately ruleout the occurrence of pathologicreflux, and the high frequency ofnonpathologic reflux during the ex-amination can encourage false-positive diagnoses. Additionally, ob-servation of the reflux of a bariumcolumn into the esophagus during GItract contrast studies may not corre-late with the severity of GERD or thedegree of esophageal mucosal in-flammation in patients with refluxesophagitis. It is recognized that up-per GI tract series are useful in theevaluation of vomiting to screen forpossible anatomic abnormalities ofthe upper GI tract.4 For example, ininfants with bilious vomiting, an upperGI tract series may be useful forevaluating for possible malrotation orduodenal web. Persistent, forcefulvomiting in the first few months of lifeshould be evaluated with pyloric ul-trasonography to evaluate for possi-ble pyloric stenosis. An upper GI tractseries should be reserved if theresults of the pyloric ultrasound areequivocal.

Esophageal pH Monitoring

Continuous intraluminal esophagealpH monitoring can be used to quantifythe frequency and duration of esoph-ageal acid exposure during a studyperiod. The conventional definition of

acid exposure in the esophagus is a pH<4.0, the pH most associated witha complaint of heartburn in adults.Esophageal pH metrics generally in-clude an absolute number of refluxepisodes detected during monitoring,the duration of reflux episodesdetected, and the reflux index, whichis calculated as the percentage ofa study period during which esopha-geal pH is <4.0. Although esophagealpH monitoring may be useful for as-sociating a temporal relationship be-tween a symptom and acid reflux andto evaluate the efficacy of pharmaco-logic therapy on acid suppression,mounting evidence suggests poor re-producibility of pH testing, as well asa clear continuum between pH find-ings in physiologic GER and pathologicGERD. In turn, esophageal pH moni-toring is losing value as a primarymodality for diagnosing or managingpediatric GERD.34

Multichannel IntraluminalImpedance Monitoring

Multiple intraluminal impedance (MII)is an emerging technology for detect-ing the movement of both acidic andnonacidic fluids, solids, and air in theesophagus, thereby providing a moredetailed picture of esophageal eventsthan pH monitoring.34 MII can be usedto measure volume, speed, and phys-ical length of both anterograde andretrograde esophageal boluses. Com-bined pH/MII testing is evolving intothe test of choice to detect temporalrelationships between specific symp-toms and the reflux of both acid andnonacid gastric contents. In particu-lar, MII has been used in recent yearsto investigate how GER and GERDcorrelate with apnea, cough, and be-havioral symptoms.35 According to thenew guidelines, MII and pH electrodescan and should be combined ona single catheter.4


Gastroesophageal Scintigraphy

Gastroesophageal scintigraphy scansfor reflux of 99mTc-labeled solids orliquids into the esophagus or lungsafter administration of the test mate-rial into the stomach. This nuclearscan evaluates postprandial refluxand can also quantitate gastric emp-tying; however, the lack of standard-ized techniques and age-specificnormal values limits the usefulness ofthis test. Therefore, gastroesophagealscintigraphy is not recommended inthe routine evaluation of pediatricpatients with GER.4

Endoscopy and Esophageal Biopsy

It is certainly preferable to pursueconservative measures for treatingGERD in children before consideringthe use of more invasive testing. Inparticular, any diagnostic benefits ofpursuing upper endoscopy in pediatricpatients suspected of having GERDmust also be weighed against minimal,but not entirely negligible, proceduraland sedation risks.36 Nevertheless, theperformance of upper endoscopyallows direct visualization of theesophageal mucosa to determine thepresence and severity of injury fromthe reflux of gastric contents into theesophagus.26 Esophageal biopsies al-low evaluation of the microscopicanatomy.24 Upper endoscopy withesophageal biopsy may be useful toevaluate inflammation in the esopha-geal mucosa attributable to GERD andto exclude other associated conditionswith symptoms that can mimic GERD,such as eosinophilic esophagitis. Re-cent data confirm that approximately25% of infants younger than 1 yearwill have histologic evidence ofesophageal inflammation.37 This testis indicated in patients with GERD whofail to respond to pharmacologictherapy or as part of the initial man-agement if symptoms of poor weightgain, unexplained anemia or fecal

occult blood, recurrent pneumonia, orhematemesis exist.

Upper endoscopy may also be helpfulin the assessment of other causes ofabdominal pain and vomiting in pedi-atric patients, such as esophageal orantral webs, Crohn esophagitis, pepticulcer, Helicobacter pylori infection,and infectious esophagitis. Erosiveesophagitis is reported less often ininfants and children with GERD than inadults with GERD; however, a normalendoscopic appearance of the esoph-ageal mucosa in pediatric patientsdoes not exclude histologic evidenceof reflux esophagitis.5,8 Esophagealbiopsy is beneficial in evaluating forconditions that may mimic symptomsof GERD, such as eosinophilic esoph-agitis, infectious esophagitis (Candidaesophagitis or herpetic esophagitis),Crohn disease, or Barrett esopha-gus.24 Because endoscopic findingscorrelate poorly with histologic test-ing in infants and children, perform-ing esophageal biopsies duringendoscopy is recommended for theevaluation of GERD in children.4

MANAGEMENT

The new guidelines describe severaltreatment options for treating childrenwith GER and GERD. In particular,lifestyle changes are emphasized, be-cause they can effectively minimizesymptoms of both in infants andchildren. For patients who requiremedication, options include bufferingagents, acid secretion suppressants,and promoters of gastric emptyingand motility. Finally, surgicalapproaches are reserved for childrenwho have intractable symptoms un-responsive to medical therapy or whoare at risk for life-threatening com-plications of GERD.

LIFESTYLE CHANGES

Lifestyle Modifications for Infants

Lifestyle changes to treat GERD ininfants may involve a combination offeeding changes and positioningtherapy. Modifying maternal diet ifinfants are breastfed, changing for-mulas, and reducing the feeding vol-ume while increasing the frequency offeedings may be effective strategies toaddress GERD in many patients. Inparticular, the guidelines emphasizethat milk protein allergy can causea clinical presentation that mimicsGERD in infants. Therefore, a 2- to 4-week trial of a maternal exclusion dietthat restricts at least milk and egg isrecommended in breastfeeding infantswith GERD symptoms, whereas an ex-tensively hydrolyzed protein or aminoacid–based formula may be appro-priate in formula-fed infants.4,30 It isimportant to note that this recom-mendation applies to the subset ofinfants with complications of GER, andnot “happy spitters.”

In 1 study of formula-fed infants, GERDsymptoms resolved in 24% of infantsafter a 2-week trial of changing toa protein hydrolysate formula thick-ened with 1 tablespoon rice cereal perounce, avoiding overfeeding, avoidingseated and supine positions, andavoiding environmental tobaccosmoke.3 Feeding changes can also berecommended in breastfed infants,because it is well known that smallamounts of cow milk protein ingestedby the mother may be expressed inhuman milk. Indeed, several studieshave found that breastfed infants maybenefit from a maternal diet thatrestricts cow milk and eggs.38,39

The feeding management strategy thatinvolves the use of thickened feedings,either by adding up to 1 tablespoon ofdry rice cereal per 1 oz of formula30 orchanging to commercially thickened(added rice) formulas for full-term



infants who are not cow milk proteinintolerant, is recognized as a reason-able management strategy for other-wise healthy infants with both GERand GERDQ:2 .4 On the other hand, all pe-diatric clinicians should be aware ofa possible association between thick-ened feedings and necrotizing en-terocolitis in preterm infants.40 TheFood and Drug Administration issueda warning regarding a common com-mercially available thickening agent in2011, suggesting that “parents, care-givers and health care providers not...feed ‘SimplyThick’ to infants born be-fore 37 weeks gestation who arecurrently receiving hospital care orhave been discharged from the hos-pital in the past 30 days.”

Thickened feedings appear to de-crease observed regurgitation ratherthan the actual number of reflux epi-sodes. Little is known about the effectof thickening formula on the naturalhistory of infantile reflux or the po-tential allergenicity of commercialthickening agents. Excessive energyintake may occur with long-term use offeedings thickened with rice cereal orcorn. To this point, it is important torealize that thickening a 20-kcal/ozinfant formula with 1 tablespoon ofrice cereal per ounce increases theenergy density to 34 kcal/oz. Com-mercially available antiregurgitantformulae contain processed rice, corn,or potato starch; guar gum; or locustbean gum and may present an optionthat does not involve excess energyintake by infants when consumed innormal volumes. To date, there hasbeen little investigation into any re-lationship between use of added ricecereal or antiregurgitant formulae andchildhood obesity.

Lifestyle changes that may also benefitinfants with GERD include keepingthem in the completely upright posi-tion or even placing them prone. In-deed, a number of recent studies that

used impedance and pH monitoringhave confirmed older studies that usedpH monitoring to demonstrate signif-icantly less GER in infants in the flatprone position compared with the flatsupine position.41,42 However, theguidelines are unequivocal that therisk of sudden infant death syndromein sleeping infants outweighs thebenefits of prone positioning in themanagement of GERD and, therefore,that prone positioning should beconsidered acceptable only if the in-fant is observed and awake.4 Pronepositioning is suggested to be benefi-cial in children older than 1 year witheither GER or GERD, because the riskof sudden infant death syndrome isgreatly decreased in older agegroups.

Perceived and actual benefits of seatedor semisupine positioning are alsoexplored in the new guidelines. Semi-supine positioning, particularly in aninfant carrier or car seat, may exac-erbate GER and should be avoidedwhen possible, especially after feed-ing.43 More recent data obtained withesophageal impedance–pH monitor-ing have confirmed that postprandialreflux occurs similarly when infantsare in car seats as when they aresupine but also suggests that being ina car seat for 2 hours after a feedingreduces reflux-related respiratoryevents.44

Lifestyle Modifications for Childrenand Adolescents

Lifestyle changes that may benefitGERD in older children and adoles-cents are more akin to recom-mendations made for adult patients,including the importance of weightloss in overweight patients, cessationof smoking, and avoiding alcohol use.Recommendations for conservativelymanaging GERD in older children andadolescents, likewise, may involve di-etary modification and positioning

changes, although the effectiveness ofthe latter as a treatment of GERD inolder children has not been as wellstudied as in infants. In terms of di-etary changes, older children andadolescents are advised to avoid caf-feine, chocolate, alcohol, and spicyfoods as potential symptom triggers.The guidelines also point out that 3independent studies have demon-strated decreased reflux episodes withpostprandial chewing of sugarlessgum.45–47

PHARMACOTHERAPEUTIC AGENTSFOR PEDIATRIC GERD

Several medications may be used totreat GERD in infants and children. The2 major classes of pharmacologicagents for treatment of GERD are acidsuppressants and prokinetic agents(Table 4). Growing evidence thatdemonstrates the former to be moreeffective than the latter has led to anincreased use of acid suppressants tomanage suspected GERD in pediatricpatients4,39; however, there is alsosignificant concern for the over-prescription of acid suppressants,particularly proton pump inhibitors(PPIs), and it is important to un-derstand the new guidelines formedication indications.

Acid Suppressants

The main classes of acid suppressantsare antacids, histamine-2 receptorantagonists (H2RAs), and PPIs. Theprinciples of using these medicationsin the treatment of pediatric GERD aresimilar to those in adults, other thanthe need to prescribe weight-adjusteddoses and the need to consider theform of the drug prescribed (ie, forease of ingestion in infants and chil-dren). Dosage ranges for drugs com-monly prescribed for pediatricpatients with GERD are listed in Ta-ble 4.


Antacids

Antacids are a class of medicationsthat can be used to directly buffergastric acid in the esophagus orstomach to reduce heartburn andideally allow mucosal healing ofesophagitis. There is limited historicalevidence that on-demand use of ant-acids can lead to symptom relief ininfants and children.48 Instead, al-though antacids are generally seen asa relatively benign approach to treat-ing pediatric GERD, it is important torecognize that they are not entirelywithout risk. Indeed, several studieslink aluminum-containing prepara-tions with aluminum toxicity and itscomplications in children.49–51 Simi-larly, milk-alkali syndrome, a triad ofhypercalcemia, alkalosis, and renalfailure, has been described in chil-dren receiving calcium-containingpreparations and adds to a note ofcaution. According to the new guide-lines, chronic antacid therapy is gen-erally not recommended in pediatricsfor the treatment of GERD.4 In addi-tion, the safety and efficacy of surfaceprotective agents, such as alginatesor sucralfate, an aluminum-containingpreparation, have not been adequatelystudied in the pediatric population. Assuch, no surface agent is currently

recommended as independent treat-ment of severe symptoms of GERD orerosive esophagitis in children.4

H2RAs

H2RAs represent a major class ofmedications that has completely rev-olutionized the treatment of GERD inchildren. H2RAs decrease the secretionof acid by inhibiting the histamine-2receptor on the gastric parietal cell.Expert opinion suggests little clinicaldifference between the various for-mulations of H2RAs. Randomizedplacebo-controlled pediatric clinicaltrials have shown that cimetidine andnizatidine are superior to placebo forthe treatment of erosive esophagitisin children.52,53 Pharmacokineticstudies in school-aged children sug-gest that gastric pH begins to in-crease within 30 minutes ofadministration of an H2RA and rea-ches peak plasma concentrations 2.5hours after dosing. The acid-inhibitingeffects of H2RAs last for approximately6 hours, so H2RAs are quite effective ifadministered 2 or 3 times a day.

However, H2RAs inherently have somelimitations. In particular, a fairly rapidtachyphylaxis can develop within 6weeks of initiation of treatment, lim-iting its potential for long-term use. In

addition, H2RAs have been shown to beless effective than PPIs in symptomrelief and healing rates of erosiveesophagitis. Although most of thesedownsides have been demonstratedmost clearly in adults, they are alsobelieved to affect children. It is alsoimportant to recognize that cimetidinehas specifically been linked to an in-creased risk of liver disease and gy-necomastia, and that theseassociations may be generalizable toother H2RAs.

PPIs

Most recently, PPIs have emerged asthe most potent class of acid sup-pressants by repeatedly demonstrat-ing superior efficacy compared withH2RAs. PPIs decrease acid secretion byinhibition of H+, K+-ATPase in the gas-tric parietal cell canaliculus. PPIs areuniquely able to inhibit meal-inducedacid secretion and have a capacity tomaintain gastric pH >4 for a longerperiod of time than H2RAs. Theseproperties contribute to higher andfaster healing rates for erosiveesophagitis with PPI therapy com-pared with H2RA therapy. Finally, un-like H2RAs, the acid suppressionability of PPIs has not been observedto diminish with chronic use.

TABLE 4 Pediatric Doses of Medications Prescribed for GERD

Medications Doses Formulations Ages Indicated by the Foodand Drug Administration

Cimetidine 30–40 mg/kg/d, divided in 4 doses Syrup ≥16 yRanitidine 5–10 mg/kg/d, divided in 2 to 3 doses Peppermint-flavored syrup; Effervescent tablet 1 mo–16 yFamotidine 1 mg/kg/d, divided in 2 doses Cherry-banana-mint–flavored oral suspension 1–16 yNizatidine 10 mg/kg/d, divided in 2 doses Bubble gum–flavored solution ≥12 yOmeprazole 0.7–3.3 mg/kg/d Sprinkle contents of capsule onto soft foods 2–16 yLansoprazole 0.7–3 mg/kg/d Sprinkle contents of capsule onto soft foods or select juices 1–17 y

Administer capsule contents in juice through nasogastric tubeStrawberry-flavored disintegrating tabletOrally disintegrating tablet via oral syringe or nasogastrictube (≥8 French)

Esomeprazole 0.7–3.3 mg/kg/d Sprinkle contents of capsule onto soft foods 1–17 yAdminister capsule contents in juice through nasogastric tube

Rabeprazole 20 mg daily Oral tablet 12–17 yDexlansoprazole 30–60 mg daily Oral tablet No pediatric indicationPantoprazole 40 mg daily (adult dose) Oral tablet No pediatric indication



The timing of dosing most PPIs isimportant for maximum efficacy. Bothpediatricians and pediatric medicalsubspecialists must be diligent at ed-ucating their patients to administerPPIs, ideally, approximately 30 minutesbefore meals.7 All clinicians shouldalso recognize that the metabolism ofPPIs is known to differ in childrencompared with adults, with a trendtoward a shorter half-life, necessitat-ing a higher per-kilogram dose toachieve a peak serum concentrationand area under the curve similar tothose in adults.45 A fairly wide rangeof effective doses is evident in chil-dren. For example, an open-labelstudy of omeprazole in childrenrevealed an effective dosage range of0.7 to 3.3 mg/kg daily, on the basis ofimprovement in clinical symptomsand the results of esophageal pHmonitoring.47 Lansoprazole, 0.7 to 3.0mg/kg daily, improved GERD symp-toms and healed all cases of erosiveesophagitis in the treatment of 1- to12-year-old children with GERD.48

Other trials of PPI therapy support theefficacy of treatment of severeesophagitis and esophagitis re-fractory to H2RAs in children.4,45

As in adults, PPIs are considered safeand generally well tolerated with rel-atively few adverse effects. In terms oftheir long-term use, published studieshave reported PPI use for up to 11years in small numbers of children.16

The Food and Drug Administration hasapproved a number of PPIs for use inpediatric patients in recent years, in-cluding omeprazole, lansoprazole, andesomeprazole for people 1 year andolder and rabeprazole for people 12years and older. Nonetheless, the newguidelines strike a note of cautionwhen discussing the dramatic in-crease in past years in the number ofPPI prescriptions written for pediatricpatients, particularly infants, who may

FIGURE 1Approach to the infant with recurrent regurgitation and vomiting.


be at increased risk of lower re-spiratory tract infections.54–56

Overuse or misuse of PPIs in infantswith reflux is a matter for great con-cern. Placebo-controlled trials ininfants have not demonstrated supe-riority of PPIs over placebo for re-duction in irritability.57 Headaches,diarrhea, constipation, and nauseahave been described as occurring inup to 14% of older children and adultsprescribed PPIs.25,58 Although consid-ered a benign histologic change, en-terochromaffin cell hyperplasia hasrecently been demonstrated in up to50% of children receiving PPIs formore than 2.5 years.25 Finally, a grow-ing body of evidence suggests thatacid suppression, in general, with ei-ther H2RAs or PPIs, may be a riskfactor for pediatric community-acquired pneumonia, gastroenteritis,candidemia, and necrotizing entero-colitis in preterm infants.59,60

Prokinetic Agents

Desired pharmacologic effects ofprokinetic agents include improvingcontractility of the body of theesophagus, increasing lower esopha-geal sphincter pressure, and in-creasing the rate of gastric emptying.To date, efforts to design a prokineticagent with benefits that outweigh ad-verse effects has proven difficult. Evenmetoclopramide, the most commonprokinetic agent still available, re-cently received a black box warningregarding its adverse effects. Indeed,adverse effects have been reported in11% to 34% of patients treated withmetoclopramide, including drowsi-ness, restlessness, and extrapyramidalreactions. Although a meta-analysis of7 randomized controlled trials ofmetoclopramide in patients youngerthan 2 years with GERD confirmeda decrease in GERD symptoms, it wasclearly at the cost of such significantadverse effects.61 Other drugs in this

category include bethanechol, cis-apride (no longer available commer-cially in the United States), baclofen,and erythromycin. Each works asa prokinetic by using a differentmechanism. Nevertheless, after care-ful review, guidelines unequivocallystate that there is insufficient evi-dence to support the routine use ofany prokinetic agent for the treatmentof GERD in infants or older children.4

Surgery for Pediatric GERD

Several surgical procedures can beused to decrease GER disorders in

children. Fundoplication, whereby thegastric fundus is wrapped around thedistal esophagus, is most common andcan be performed to prevent reflux byincreasing baseline pressure of thelower esophageal sphincter, de-creasing the number of transientlower esophageal sphincter relaxa-tions, and increasing the length of theesophagus that is intra-abdominal toaccentuate the angle of His and reducea hiatal hernia, if indicated.17,56,57 Totalesophagogastric dissociation is an-other operative procedure that israrely used after failed fundoplication.

FIGURE 2Approach to the infant with recurrent regurgitation and weight loss Q:3.



Both procedures are associated withsignificant morbidity and do not re-duce the risk of direct aspiration oforal contents. Careful patient selec-tion is one of the keys to successfuloutcome.17 Children who have failedpharmacologic treatment may becandidates for surgical therapy, asare children at severe risk of aspira-tion of their gastric contents. In mostpatients, if acid suppression with PPIsis ineffective, the accuracy of the di-agnosis of GERD should be reas-sessed, because fundoplication maynot produce optimum clinical results.Clinical conditions, such as cyclicvomiting, rumination, gastroparesis,and eosinophilic esophagitis, shouldbe carefully ruled out before surgery,because they are likely to still causesymptoms after surgery. If antirefluxsurgery is pursued, the new guide-lines also stress the importance ofproviding families with adequatecounseling and education before theprocedure so that they have a “re-alistic understanding of the potentialcomplications…including symptomrecurrence.”4

SUMMARY

The updated guidelines published in2009 are particularly rich withdescriptions of typical presentationsof GERD across all pediatric agegroups.4 With an emphasis onevidence-based, best practice, theypresent a number of algorithms thatcan be of great use to both generalpediatricians and pediatric medicalsubspecialists. The guidelines discussthe evaluation and management ofrecurrent regurgitation and vomitingin both infants and older children andthe importance of distinguishing GERDfrom numerous other disorders. Thefigures shown demonstrate the rec-ommended approaches for commonlyencountered presentations of GERD in

pediatric patients and are summa-rized here.

In the infant with uncomplicated re-current regurgitation, it may be im-portant to recognize physiologic GERthat is effortless, painless, and notaffecting growth (Fig 1). In this situa-tion, pediatricians should focus onminimal testing and conservativemanagement. Overuse of medicationsin the so-called “happy spitter” shouldbe avoided by all pediatric physicians.Instead, pediatricians are well servedto diagnose GER and provide signifi-cant parental education, anticipatoryguidance, and reassurance. In turn,they will provide high-value, high-quality care without risk to theirpatients or unnecessary direct andindirect costs.

Pediatricians must also be able torecognize infants with recurrent re-

gurgitation and troublesome symp-toms of GERD (Fig 2). The newguidelines emphasize weight loss asa crucial warning sign that shouldalter clinical management. Older chil-dren with heartburn may benefit fromempirical treatment with PPIs (Fig 3).In general, there is a paucity of stud-ies in pediatrics that demonstrate theeffectiveness of this approach. In-stead, it is essential to carefully followall patients empirically treated forGERD to ensure that they are improv-ing, because there are many clinicalconditions that may mimic its symp-toms. It cannot be overemphasizedthat pediatric best practice involvesboth identifying children at risk forcomplications of GERD and reassuringparents of patients with physiologicGER who are not at risk for compli-cations to avoid unnecessary

FIGURE 3Approach to the older child or adolescent with heartburn.


diagnostic procedures or pharmaco-logic therapy.62–64

LEAD AUTHORSJenifer R. Lightdale, MD, MPHDavid A. Gremse, MD

SECTION ON GASTROENTEROLOGY,HEPATOLOGY, AND NUTRITIONEXECUTIVE COMMITTEE, 2011–2012Leo A. Heitlinger, MD, ChairpersonMichael Cabana, MDMark A. Gilger, MDRoberto Gugig, MDJenifer R. Lightdale, MD, MPHIvor D. Hill, MB, ChB, MD

FORMER EXECUTIVE COMMITTEEMEMBERSRobert D. Baker, MD, PhDDavid A. Gremse, MDMelvin B. Heyman, MD

STAFFDebra L. Burrowes, MHA

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1—Kleinman et al is reference 30, not reference 25 as cited in the text. Please check.

2—Part of sentence that reads “for otherwise healthy infants with both GER and GERD”: Change to read “forotherwise healthy infants with either GER or GERD”?

3—Please verify that Figure 2 is complete.

4—Table 3 title, part that reads “(“Warning Signs” in Figures)”: I see “Warning Signs” in only 1 of the figures.

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