reflujo gastroesofagico 2012

DOI: 10.1542/pir.33-6-2432012;33;243Pediatrics in Review

Jillian S. Sullivan and Shikha S. SundaramGastroesophageal Reflux

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Gastroesophageal RefluxJillian S. Sullivan, MD,*

Shikha S. Sundaram, MD

MSCI†

Author Disclosure

Drs Sullivan and

Sundaram have

disclosed no financial

relationships relevant

to this article. This

commentary does not

contain a discussion of

an unapproved/

investigative use of

a commercial product/

device.

Educational GapGastroesophageal reflux (GER) is common in healthy infants, children, and adults, but

when troublesome symptoms or complications occur, the patient is said to have GER dis-

ease (GERD). Clinicians should know the diagnostic techniques for distinguishing these

conditions as well as recommended management.

Objectives After completing this article, readers should be able to:

1. Understand the differences between benign GER and GERD.

2. Understand other diseases and conditions that may mimic GERD.

3. Understand methods of diagnosing GERD.

4. Describe therapeutic options for the treatment of GERD (including lifestyle

modifications, medical therapies, and surgical therapies).

IntroductionGastroesophageal re!ux (GER), de"ned as the passage of gastric contents into the esoph-agus, is a normal physiologic process in healthy infants, children, and adults but may causedistress for caregivers or patients. Gastroesophageal re!ux disease (GERD) is de"ned as thepassage of gastric contents into the esophagus that results in troublesome symptoms orcomplications for the infant, child, or adolescent, and not for the caregiver alone. (1) Re-gurgitation, commonly referred to as “spitting up,” is the effortless passage of gastric con-tents into the pharynx or mouth. Vomiting is the forceful expulsion of the gastric contents.In contrast, rumination is de"ned as voluntary, habitual, and effortless regurgitation of re-cently ingested food. Following this voluntary regurgitation, gastric contents are expulsedfrom the mouth or re-swallowed.

EpidemiologyGER is a common occurrence in healthy infants, children, and adults, most often in thepostprandial period. Fifty percent of infants younger than 3 months of age and 67% of infantsat 4 months of age will have at least one episode of regurgitation daily. (2) By 12 months ofage, however, only 5% experience episodes of regurgitation. (2) Re!ux symptoms (heartburn,epigastric pain, and regurgitation) affect up to 7% of school-age children and 8% of adoles-

cents. (3) Several pediatric populations are at increased risk forthe development of GERD, including patients who have neu-rologic impairment, obesity, lung disease (speci"cally cystic "-brosis), esophageal atresia, and prematurity.

PathophysiologyGER results from relaxation of the lower esophageal sphincter(LES). In healthy infants and children, relaxation of theLES is transient. In infants, gastric distention associated withlarge volume feeds (100–150 mL/kg per day compared tothe average adult intake of 30–50 mL/kg per day) portends

Abbreviations

ALTE: apparent life-threatening eventGER: gastroesophageal re!uxGERD: gastroesophageal re!ux diseaseH2RAs: histamine-2 receptor antagonistsLES: lower esophageal sphincterMII: multiple intraluminal impedancePPI: proton pump inhibitor

*Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Vermont Children’s Hospital, University of VermontCollege of Medicine, Burlington, VT.†Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Digestive Health Institute, Children’s HospitalColorado, University of Colorado School of Medicine, Aurora, CO.

Article gastrointestinal disorders

Pediatrics in Review Vol.33 No.6 June 2012 243



more frequent transient LES relaxations. Delayed gastricemptying also can increase the frequency of transient LESrelaxations. Esophageal clearance and mucosal defense (se-cretions) play a signi"cant role in prevention of esophagitis.Compromise of these functions contributes to the develop-ment of GERD. In neurologically impaired children, de-creased basal LES tone also is likely to contribute to GER.

Signs and SymptomsInfants

Regurgitation or spitting up is the most common presen-tation of infantile GER. Infants who have benign physiologicGER usually are described as “happy spitters.” Althoughmuch less common, infants can develop GERD, withfailure to thrive, feeding dif"culties, arching of the back,or irritability, the most common symptom noted by care-givers (Table 1). Irritability may, in addition to GERD,be associated with other factors, including the develop-ing nervous system in infants and exposure to tobaccosmoke. Rarely, extraintestinal signs of GERD occurin infants, including apparent life-threatening events(ALTEs), wheezing, recurrent cough, aspiration pneu-monia, and abnormal posturing or torticollis, knownas Sandifer syndrome.

ChildrenIn preschool and school-age children, regurgitation, vom-iting, abdominal pain, and feeding dif"culties are common

presentations of GERD. Extraintestinal signs can includechronic cough or pneumonia and dental erosions. In olderchildren, heartburn, regurgitation, and epigastric pain arethe most common signs associated with GERD. Similarlyto younger children, older youngsters may have GERD-associated chronic cough, recurrent pneumonia, and den-tal erosions. Severe in!ammation can cause hematemesisand anemia.

Other ConsiderationsOne of the challenges facing primary care providers is dis-tinguishing vomiting in patients due to GER or GERDfrom vomiting due to other causes. Worrisome signs andsymptoms in patients who have suspected GERD thatmay warrant further investigation are listed in Table 2.Table 3 summarizes common causes of vomiting not asso-ciated with GER or GERD. For the infant with uncom-plicated re!ux, reassurance by the primary care provideris appropriate. However, referral to a pediatric gastroenter-ologist is recommended if symptoms persist beyond 12 to18 months of age.

Diagnostic Approach to GERDHistory and Physical Examination

A thorough history and physical examination are centralelements of the evaluation of GERD and other conditions

Table 1. GERD Signs and SymptomsInfants

GI Extraintestinal

Regurgitation Failure to thriveFeeding difficulties WheezingHematemesis Stridor

Persistent coughApnea/ALTEIrritabilitySandifer syndrome

Children

GI Extraintestinal

Heartburn Persistent coughVomiting WheezingRegurgitation LaryngitisFeeding difficulties StridorDysphagia Chronic asthmaChest pain Recurrent pneumoniaHematemesis Dental erosions

Anemia

Table 2. Warning SignsNecessitating FurtherInvestigation in Infants andChildren Who Have VomitingBilious emesisGI bleedingFailure to thriveForceful or projectile emesisEmesis beginning after 6 mo of ageDifficulty swallowingHistory of food allergiesFeverDiarrheaConstipationAbdominal painHepatosplenomegalyLethargyAbnormal neurologic findingsBulging fontanelleAnxiety or disordered eatingSuspicion of genetic or metabolic disease

gastrointestinal disorders gastroesophageal reflux

244 Pediatrics in Review Vol.33 No.6 June 2012



that may mimic GERD. The history and examinationalone may be suf"cient to diagnose benign GER ina normally developed infant or young child. It is imper-ative to inquire about the nature of the vomiting,whether bile or blood is present in the emesis, if thechild seems irritable with emesis, if emesis is forcefulor projectile, or if emesis is associated with other symp-toms such as fever or lethargy. Feeding history shouldinclude volume and frequency of feedings, type of for-mula, preparation of formula, and positioning of the in-fant during the feeds. A history of dysphagia or foodsticking, eating slowly, cutting food into small pieces,or avoiding particular foods may be suggestive of eosin-ophilic esophagitis.

Past medical history should include inquiring aboutprematurity, neurologic problems, growth or developmental

concerns, past surgeries or hospitalizations, allergies(particularly to foods), and psychological disease. Reviewof systems should detail respiratory complaints and ear,nose, or throat symptoms. Pertinent family history includesinquiry about gastrointestinal (GI) diseases, includingGERD, and atopic disease.

Physical examination should include the patient’sgeneral appearance, measurements of weight andlength, pulmonary and cardiac evaluation, abdominalexamination (speci"cally noting the presence of abdom-inal distention, abdominal tenderness, bowel sounds,and hepatosplenomegaly), and a thorough neurologicassessment.

There is no symptom or constellation of symptoms thatis diagnostic for GERD in infants. However, in neuro-logically normal older children and adolescents, the clas-sic features (heartburn or chest pain, regurgitation, andepigastric pain) may be used to diagnose GERD. More-over, a detailed history and examination may provide clin-ical clues that suggest other causes of vomiting in additionto GERD (Table 3).

Diagnostic StudiesFor infants and children, history and physical examina-tion are suf"cient and further diagnostic testing is notnecessary to diagnose GER. A diagnostic evaluation shouldbe reserved for infants and children who have complica-tions related to GERD and to evaluate for other causesof vomiting. The evaluation must be tailored to individ-ual patients based on pertinent "ndings on history andexamination.

EMPIRIC TRIAL OF ACID SUPPRESSION. In a neurologi-cally intact older child (eg, older than 8 years of age) oradolescent who has classic symptoms of GERD (heart-burn, regurgitation, and epigastric pain), a positive re-sponse to an empiric trial of acid suppression with aproton pump inhibitor (PPI) can be used to diagnoseGERD. A 4-week trial is suggested, because 2 weeks ofPPI therapy may be insuf"cient to treat GERD. Referralto a pediatric gastroenterologist may be indicated if a4-week trial of PPI therapy and lifestyle changes are unsuc-cessful. There is no evidence, however, to support empirictreatment with PPIs in infants and young children as a wayto diagnose GERD.

BARIUM CONTRAST RADIOGRAPHY. An upper GI seriesis a !uoroscopic examination using barium to opacify theupper GI tract (Figs 1 and 2). This test, performed by ra-diologists, is helpful to de"ne the anatomy of the upperGI tract (esophagus, stomach, and small intestine). Anupper GI series should be used to evaluate for anatomic

Table 3. Nonreflux Causes ofVomitingInfections NeurologicSepsisMeningitisGastroenteritisUrinary tract infectionOtitis media

Increased intracranialpressure

Migraine

RespiratoryPosttussive emesisPneumonia

Anatomic/ObstructiveForeign body RenalPyloric stenosis Obstructive uropathyMalrotation Renal insufficiencyIntussusceptionSuperior mesenteric

artery syndromeCardiacCongestive heart failure

GastrointestinalEsophagitis Oncologic• Eosinophilic

esophagitisLymphoma, other solidtumors

• Pill esophagitis• Infectious

esophagitisDrugs and alcoholconsumption

AchalasiaGastritis Pregnancy• Peptic ulcer

disease• Helicobacter

pylori infectionPsychologic/BehavioralOverfeeding

Gastroparesis Self-induced emesisCholelithiasis Rumination syndromeHepatitisPancreatitisCeliac diseaseCrohn diseaseEosinophilic GI disease





causes of vomiting that may mimic GERD, includingesophageal web or stricture, achalasia, hiatal hernia, gas-tric outlet obstruction (antral web or pyloric stenosis),and intestinal malrotation. It should not be used to diag-nose GERD because nonpathologic re!ux frequently isdetected during this study.

ESOPHAGEAL PH MONITORING. Esophageal pH moni-toring measures the frequency and duration of acidicesophageal re!ux episodes, by using a transnasal catheterwith one or more pH electrodes along the length of thecatheter. A battery operated system (worn like a smallpurse) records output from the pH monitor, and patientsand caregivers are able to input meal times and times ofsupine positioning for data analysis. Wireless pH monitor-ing may be used in older children and may be toleratedbetter.

Based on data extrapolated from adults, acid re!ux isassociated with an intraesophageal pH <4.0. The pHprobe measures the total number of re!ux episodes,number of re!ux episodes lasting >5 minutes, durationof longest re!ux episode, re!ux index (percentage ofstudy during which the pH is <4.0), and symptom index(the number of times a particular symptom associatedwith acid re!ux occurs divided by the total number oftimes that particular symptom is recorded, eg, number

of coughs associated with acid re!ux divided by totalnumber of cough episodes recorded). A re!ux indexof >6% to 12% or a symptom index >30% to 50% is con-sidered abnormal. Using a compilation of this data,esophageal pH monitoring may be used to diagnoseacid re!ux. Esophageal pH monitoring is effective alsofor evaluating the ef"cacy of acid suppression therapy.In children who have a normal pH study but histolog-ically documented esophagitis, other conditions, such aseosinophilic esophagitis, must be considered.

There are several limitations to pH monitoring. Themonitor does not have the ability to measure nonacidre!ux, and the results (ie, re!ux index or symptom in-dex) do not always correlate with the severity of patho-logic acid re!ux. For infants or children who may feedevery 2 to 4 hours, it may be dif"cult to interpret a pHstudy, given that frequent feedings may buffer gastricacidity.

COMBINED MULTIPLE INTRALUMINAL IMPEDANCE ANDPH MONITORING. Combined multiple intraluminal im-

pedance (MII) and pH monitoring allows measurementof !uids, air, and solids in the esophagus, in additionto detecting nonacid and acid re!ux. This technology alsois able to distinguish between swallowed (antegrade) and

Figure 1. Esophageal stricture. Upper GI series demonstrat-ing a tapered circumferential mid and lower esophagealstricture. Figure 2. Achalasia. *Proximal esophageal dilation and **bird’s

beak appearance suggestive of achalasia.





regurgitated (retrograde) boluses,and the technique can be used whilea patient is on acid suppression ther-apy. This procedure also utilizes atransnasal catheter but has both pHand impedance electrodes, allowingcorrelation of documented symp-toms (for example, cough, chestpain, or ALTE) with episodes ofboth acid and nonacid re!ux. Thiscapability is particularly helpful inunderstanding extraintestinal symp-toms, with the caveat that such symp-toms must occur during the courseof the 24-hour study to be detected.Recent data suggest that theenhanced information provided bythe MII changes management(such as medication changes, useof fundoplication, and changesin feeding regimen) in 25% of pa-tients, compared with standardpH monitoring alone. (4)(5)

ESOPHAGEAL MANOMETRY.Esophageal manometry measuresesophageal function by assessingesophageal peristalsis and upper eso-phageal sphincter and LES pressures.Manometry is useful in diagnosingesophageal motility disorders, suchas achalasia (suboptimal relaxationof the LES). Many children who haveGERD will have abnormal manometric studies because ofesophageal injury or in!ammation. However, manometrycannot be used to diagnose GERD or predict success withtherapy because it cannot determine whether any re!ux(acid or nonacid) or esophagitis is present. In addition,access to physicians skilled in pediatric esophageal ma-nometry is limited, even among tertiary and quaternarycare pediatric centers.

ENDOSCOPYWITH BIOPSY.Upper intestinal endoscopywith biopsy allows for direct visual inspection and his-tologic examination of the esophagus, stomach, andduodenum (Figs 3 and 4). Endoscopy allows for identi-"cation of diseases that mimic re!ux, including eosino-philic esophagitis, esophageal stricture, pill esophagitis,infectious esophagitis, peptic ulcer disease, and Crohndisease. Therefore, endoscopy with biopsy may be rec-ommended for infants and children who have unex-plained refractory or recurring GERD symptoms to

assess for other conditions and evaluate for long-termcomplications of GERD.

SCINTIGRAPHY. Commonly known as a gastric emp-tying scan, this technique uses formula or food labeledwith 99technetium to measure gastric emptying. The scanmay identify esophageal re!ux and aspiration, althoughthe sensitivity (15%–59%) and speci"city (83%–100%)for the diagnosis of GERD as compared with esophagealpH monitoring are poor. Therefore, scintigraphy is notrecommended to diagnose or manage re!ux in infants orchildren.

Prognosis of GERUncomplicated GER carries a favorable prognosis be-cause most infants will “outgrow” regurgitation by 7 to12 months of age. Children who have neurologic im-pairment, obesity, interstitial lung disease, anatomic GI

Figure 3. Causes of esophagitis. A. Erosive esophagitis: severe erythema and edema withlinear ulcerations, associated with chronic GERD. (Provided courtesy of Dr Edwin deZoeten.) B. Eosinophilic esophagitis: white plaques, linear ridging, and trachealization ofthe esophagus consistent with eosinophilic esophagitis. (Provided courtesy of Dr GlennFuruta.) C. Infectious esophagitis (Candida): white plaques consistent with candidalesophagitis in a patient with Crohn disease. D. Infectious esophagitis (herpes simplexvirus): severe ulcerations consistent with herpes simplex virus infection.





abnormalities, malrotation, hiatal hernia, and prematuritycarry a higher risk for the development of GERD and itscomplications.

Complications of GERDEsophageal Complications

Esophagitis, Barrett esophagus (presence of intestinalmetaplasia in the esophagus; Fig 4), strictures, and ade-nocarcinoma have been reported as consequences of se-vere GERD. Esophagitis (esophageal in!ammation) canoccur following chronic esophageal acid exposure andmust be diagnosed by upper endoscopy and histology.Barrett esophagus (presence of intestinal metaplasia inthe esophagus) can lead to the development of esopha-geal adenocarcinoma. Barrett esophagus is extremely rarein the pediatric population; it is present in<0.25% of chil-dren undergoing endoscopy. The condition is associatedwith older age (adolescence) and the presence of hiatalhernia. Of adults with Barrett esophagus, only 1% to 3%progress to adenocarcinoma. Esophageal strictures alsoare rare in children but have been reported in 5% of chil-dren who have chronic untreated GERD, so aggressivetreatment of GERD is warranted.

Extraintestinal ComplicationsRESPIRATORY SYMPTOMS. GERD is associated fre-

quently with asthma in pediatric patients. Proposedmechanisms include aspiration of gastric contents leadingto airway hyperresponsiveness and in!ammation and va-gally mediated bronchial or laryngeal spasm. The effect of

asthma on the severity of GERD has not been well stud-ied. Although GERD has been associated with asthma, itis not clear whether GERD contributes to asthma or ifGERD is a secondary phenomenon resulting from de-creased LES tone as a result of negative intrathoracicpressure from chronic hyperin!ation of the lung and dis-placement of the LES into the chest. (6) Patients whohave dif"cult-to-control asthma, nocturnal asthma symp-toms, or re!ux symptoms (heartburn, regurgitation) maybene"t from esophageal pH/impedance monitoring andre!ux therapy if appropriate.

Recurrent pneumonia is another potential compli-cation of re!ux, caused by aspiration of gastric con-tents. GERD may contribute also to exacerbations ofinterstitial lung diseases such as idiopathic pulmonary "-brosis or cystic "brosis because these diseases can resultin impaired airway protective mechanisms, which wouldnormally protect the lung against aspirated gastriccontents.

Several strategies have been postulated to predictwhich patients who have respiratory disease will respondto medical or surgical antire!ux treatment. Lipid-ladenalveolar macrophages on bronchoscopy have poor spec-i"city and sensitivity to detect re!ux-related respiratorydisease. Sputum pepsin concentrations are elevated inboth controls and patients who have re!ux becausehealthy individuals can aspirate small amounts of gastriccontents normally. In addition, normal pH/impedancestudies cannot rule out re!ux as a cause for pneumonia.Therefore, currently no test exists to predict response tomedical or surgical therapy. Consultation with a pediatricgastroenterologist may be indicated if persistent GERD issuspected in a patient who has dif"cult-to-control asthmaor interstitial lung disease. Medical therapy, gastrojejunalfeeding, and antire!ux surgery may be options for pa-tients who have respiratory complications of GERD, de-pending on the patient’s clinical course and the severityof lung disease.

UPPER AIRWAY SYMPTOMS. Descriptive studies havepostulated a link between re!ux and upper airway symp-toms such as hoarseness or chronic cough, as well as lar-yngoscopic "ndings such as upper airway edema, erythema,cobblestoning, and granulomas. Data are insuf"cient torecommend standard methods of diagnosis and manage-ment of these "ndings in children. Medications used totreat re!ux are unlikely to improve these symptoms inchildren.

DENTAL CARIES. GERD may be associated with dentalcaries in children. Other factors, however, such as con-sumption of juice, bulimia nervosa, and racial or genetic

Figure 4. Complications of GERD (Barrett esophagus). Barrettesophagus seen endoscopically by narrow band imaging(note change in epithelium). (Provided courtesy of Dr Edwin deZoeten.)





factors also may contribute to the development of caries.In addition, GERD may lead to the loss of tooth enamel.Although there are no standard recommendations for di-agnosis and management of GERD in patients who havecaries, care providers should perform a careful oral exam-ination in children who have known GERD.

ALTES. It is unclear if a relationship exists betweenGERD and ALTE. Combined pH monitoring and MIIstudies have revealed an association between re!ux andshort episodes of nonpathologic apnea, likely represent-ing normal protection of the airway during regurgitation.Although it is unlikely that GERD is contributing topathologic apnea in most infants who experience anALTE, infants who have a true ALTE obviously associ-ated with vomiting or regurgitation may be consideredfor antire!ux surgery. There are no data demonstratingef"cacy of medical or surgical therapy in patients whohave ALTE.

TreatmentLifestyle ModificationsINFANTS. Lifestyle modi"cations include changes in

nutrition, feeding practices, and positioning. Large vol-ume feeds can promote regurgitation in infants due togastric distention and an increase in transient LES relaxa-tion. Restricting volume, however, can result in insuf"cientenergy intake. Thus, increasing the caloric concentrationor density of feedings while decreasing the total volumeof the feedings may decrease GER. For example, an infantwho takes 32 oz of standard 20 kcal/oz infant formula,giving 640 calories per day, may be changed to 27 oz/dayof 24 kcal/oz formula or 24 oz/day of 26 kcal/ozformula.

Alternatively, adding rice cereal to formula or humanmilk may decrease the amount of regurgitation by thick-ening the formula. Rice cereal will also increase the calo-ric density of the formula (1 tbsp per 2 oz of 20 kcal/ozformula will increase caloric density to 27 kcal/oz). Ahigher !ow nipple may be required to accommodate theincreased consistency of the formula. Antiregurgitant for-mulas (ie, formulas thickened with carob bean gum orother starches) have not been proven to decrease regurgi-tation when compared with standard infant formula or for-mula mixed with rice cereal.

Changing the type of formula does not positively af-fect GER symptoms. A casein hydrosylate or amino acidformula would, however, be of bene"t to infants whohave cow milk or soy protein allergy. Thus, primary careproviders may consider a 2-week trial of a casein hydro-sylate or amino acid formula in infants who have had

persistent vomiting or regurgitation and poor weightgain for >4 weeks. It is important to use the new formulafor at least 2 weeks before making additional changes be-cause symptoms of allergy (such as vomiting) may takeseveral days to improve while the GI mucosa heals. Ifpoor weight gain and vomiting persist, consultation witha pediatric gastroenterologist may be helpful.

Although prone positioning during sleep has beenshown to decrease the number of regurgitation eventsin infants, the American Academy of Pediatrics advocatessleeping in the supine position to reduce the risk for sud-den infant death syndrome.

CHILDREN AND ADOLESCENTS. For children and ado-lescents who have mild re!ux symptoms, lifestyle changesinclude dietary modi"cation (including avoidance ofmeals with high fat content at dinner time) and avoidanceof tobacco and alcohol. For obese patients, weight losshelps. Based on data extrapolated from adult studies,children and adolescents who have GER or GERD maybene"t also from avoidance of caffeine, chocolate, andspicy foods.

TRANSPYLORIC FEEDING. Nasojejunal or gastrojejunalfeedings may be considered, particularly in infants whohave recurrent pneumonia from aspiration and in neuro-logically impaired children. By providing a continuousrate of formula past the pylorus, the stomach does not"ll or distend, resulting in less GER. Similar rates ofpneumonia in neurologically impaired children are seenafter initiation of gastrojejunal feedings compared withneurologically impaired children after antire!ux surgery.

Pharmacologic TherapiesANTACIDS. Antacids act within minutes to buffer gas-

tric contents (Tables 4 through 6). Primarily validated inadults, antacids can be used in older children and adoles-cents for quick symptom relief. For optimal effect, antacidsshould be used after meals. Caution should be exercisedwhen administering aluminum-containing antacids becauseelevated aluminum levels can cause osteopenia, rickets,microcytic anemia, and neurotoxicity. In addition, ant-acids may interfere with absorption and ef"cacy of otherdrugs when taken concurrently.

HISTAMINE-2 RECEPTOR ANTAGONISTS. Histamine-2receptor antagonists (H2RAs) decrease acid productionby binding to the histamine-2 receptor on the gastric pa-rietal cell. Examples of these medications include raniti-dine, famotidine, cimetidine, and nizatidine. Ranitidinereaches a peak plasma concentration 2.5 hours afteringestion in children and has a half-life of 6 hours.





Although generally less effective than PPIs, H2RAs maybe used to heal esophagitis and treat symptoms of GERD.H2RAs are considered safe for use in children and are usedcommonly as "rst-line therapy in infants. However, insome infants, H2RAs may cause irritability, head banging,and headaches. Cimetidine use is associated with gyneco-mastia. Tachyphylaxis has been observed with chronicH2RA use.

PROTON PUMP INHIBITORS. PPIs suppress gastric acidproduction by irreversibly blocking H!, K! ATPase(commonly called the proton pump), the "nal step in pa-rietal cell acid secretion. PPIs are more effective thanH2RAs in blocking acid production. They must be ad-ministered on a daily basis before a meal and can take sev-eral days, once treatment is initiated, for maximal acidsuppression effect. Omeprazole, lansoprazole, and esome-prazole have been approved in the United States andEurope for pediatric use. However, no PPI is approvedcurrently for use in patients younger than 1 year of age.Yet PPI use in infants has increased dramatically in thelast decade. Studies, including a recent systematic re-view and a placebo-controlled trial, reveal no improve-ment in GERD-associated symptoms in infants whohave PPI use compared with placebo. (7)(8)

Generally considered safe for use in pediatrics, 12% to14% of children will have idiosyncratic reactions to PPIs,including headache, diarrhea, constipation, and nausea.Drug-induced hypergastrinemia may occur as a resultof blocking the proton pump. Acid suppression may re-sult in abnormal intestinal !ora and bacterial overgrowth.Adults on chronic PPI therapy have an increased riskfor respiratory infections, bacterial gastroenteritis, andClostridium dif!cile colitis. (9)(10) In neonates, acidsuppression is associated with a higher carriage rate ofCandida and a higher incidence of necrotizing enteroco-litis. In elderly patients, vitamin B12 de"ciency and an in-creased risk of hip fractures have been reported. The risksand bene"ts of long term PPI therapy should be consid-ered, particularly in infants, in whom the studies citedabove reveal no improvement of infantile GERD whencompared with placebo.

PROKINETIC AGENTS. These medications are theorizedto improve GER by stimulating more rapid emptying ofthe stomach. They may be considered in patients whoshow evidence of delayed gastric emptying. Metaclopra-mide is an effective prokinetic, but it has a signi"cantadverse effect pro"le, including dystonic reactions,lethargy, irritability, gynecomastia, and permanent tardive

Table 4. Histamine-2 Receptor Antagonists

Drug Infant Dose Child Dose Adult DoseSpecialInstructions Adverse Effects

Cimetidine Not available Not available ‡16 y: 400–800mg PO BID

Not recommendedfor children <16 yof age, reducedose with renalinsufficiency

Headache, dizziness,constipation,diarrhea, irritability,gynecomastia, rash(including Stevens-Johnson syndrome)

Famotidine 1 mo–1 y: 1mg/kg perday PO Oq 12 h

1–12 y: 1 mg/kgper day PO Oq 12 h

‡12 y: 40–80mg/day PO Oq 12 h

Reduce dose withrenal insufficiency,may give with foodand antacids

Headache, dizziness,constipation,diarrhea, irritability

Nizatidine 6 mo–1 y: 5–10mg/kg per dayPO O q 12 h

1–12 y: 5–10mg/kg per dayPO O q 12 h

‡12 y: 150 mgPO BID

Limited data forchildren <12 y ofage, reduce dosewith renalinsufficiency, maygive with food andantacids

Headache, dizziness,constipation,diarrhea, irritability

Ranitidine 1 mo–1 y: 4–10mg/kg per dayPOO q 8–12 h

1–16 y: 4–10mg/kg per dayPO O q 8–12 h

‡16 y: 150 mgPO BID

Reduce dose withrenal insufficiency,may give with foodand antacids

Headache, dizziness,diarrhea,constipation,irritability

BID"twice daily; PO"by mouth; q"every.





dyskinesia. The risk of permanent tardive dyskinesia has re-sulted in a black box warning issued by the Food and DrugAdministration (FDA). Erythromycin also may be used inpatients who have delayed gastric emptying or gastroparesis.This drug, however, can cause a prolonged QT interval andshould be used cautiously. Bethanechol, baclofen, and dom-peridone also have been used to treat delayed gastric emp-tying; however, each of these medications carries potentialadverse effects. Thus, current guidelines do not recommendthe use of prokinetic agents for treatment of GERD.

SURFACE AGENTS. Sucralfate is a surface agent, con-sisting of sucrose, sulfate, and aluminum. When exposed

to acidic pH, it forms a gel that binds to eroded mucosa.Sucralfate has been shown in adults to improve symp-toms related to ulceration. Chronic use may result inaluminum toxicity or gastric bezoar formation. Therefore,sucralfate typically is prescribed for a maximum duration of7 to 10 days.

Surgical TherapyFUNDOPLICATION. Fundoplication decreases GER

by increasing the LES pressure and increasing the in-traabdominal length of the esophagus. Recently, mostfundoplication procedures have been performed

Table 5. Proton Pump Inhibitors

Drug Infant Dose Child DoseAdultDose

SpecialInstructions Adverse Effects

Esomeprazole 1 mo–1 y: 0.25–1mg/kg per dayPO

1–12 y: <20 kg:10 mg PO QD‡20 kg: 10–20mg PO QD

‡12 y: 20–40mg PO QD

FDA approved for‡1 y. Capsulesshould be swallowedwithout chewing ormay be opened andsprinkled on soft foodor in liquids.

Headache,diarrhea,nausea,infection

Lansoprazole <10 wk: 0.2–0.3mg/kg per dayPO, ‡10 wk: 1–2mg/kg PO QD

1–12 y: <30 kg:15 mg PO QD,‡30 kg: 30 mgPO QD

‡12 y: 30–60mg PO QD

FDA approved for ‡1 y.Capsules should beswallowed withoutchewing or may beopened and sprinkledon soft food or inliquids. Disintegratingtablets should beallowed todisintegratewithout chewing.

Headache,dizziness,diarrhea,nausea,infection

Omeprazole 1 mo–1 y: 0.7mg/kg perday PO

1–16 y: 5 kg to<10 kg: 5 mgPO QD, 10 kgto £20 kg: 10mg PO QD,>20 kg: 20 mgPO QD

‡16 y: 20–40mg PO QD

FDA approved for ‡1 y.Capsules should beswallowed withoutchewing or capsulesmay be opened andgranules can besprinkled on softfood or in liquids.


Pantoprazole Not available Not available 20–40 mgPO QD

Limited data on use inchildren. Tablet shouldbe swallowed withoutchewing.


Rabeprazole Not available ‡12 y: 20 mgPO QD

‡12 y: 20 mgPO QD

FDA approved for ‡12 y.Tablet should beswallowed withoutchewing.


PO"by mouth; QD"daily.





laparoscopically, which has decreased morbidity,length of hospital stays, and infections when comparedwith open fundoplication. However, both laparoscopicand open fundoplication have signi"cant postoperativecomplications, including gas-bloat syndrome (a constella-tion of symptoms including gagging, retching, nausea, andabdominal distention resulting from altered gastric accom-modation), dysphagia, and dumping syndrome (signi"cantrelease of gastric contents into the duodenum, which mayresult in hyper- and hypoglycemia). Children at the high-est risk of postoperative complications include neuro-logically impaired children and premature infants. (11)

Long-term outcomes after antire!ux surgery havebeen assessed in children and in adults. Up to 10% ofall children undergoing fundoplication will have compli-cations, and nearly 10% will require surgical revision. Inaddition, in neurologically normal children, there may beno improvement in the number of hospital admissions forpneumonia, respiratory distress or apnea, and failure tothrive after fundoplication. (12) Children who have neu-rological disorders were found to be at increased risk foradmissions for pneumonia (aspiration or other), respira-tory distress, and failure to thrive after fundoplication ina single study. (13) Another study revealed no change inadmissions for pneumonia in children who have neuro-logic impairment after fundoplication. (14) These "ndingscould be in part due to “preventative” fundoplications

performed in patients (particularly those with neurologicimpairment) without any evidence of GERD or misdiag-nosis of GERD. Given that these studies are retrospective,prospective trials are needed to investigate long term out-comes following antire!ux surgery.

Clinicians should be aware that fundoplication, partic-ularly in neurologically impaired children, is complicated.Careful analysis of the risks and potential bene"ts offundoplication should be considered before surgery.In adults, over 60% of patients continue to require acidsuppression medications after fundoplication. Thus, re-current symptoms after fundoplication are common.Investigation of recurrent re!ux symptoms after fundo-plication includes barium contrast radiography to deter-mine if the fundoplication remains intact and to detectstrictures, as well as pH-MII monitoring to determinethe functional capacity of the fundoplication.

Fundoplication may be considered in patients whohave con"rmed GERD who experience severe refractoryor recurrent symptoms or life-threatening complicationsof GERD. It is essential that primary care providers, gas-troenterologists, and surgeons educate families about thesigni"cant postoperative complications associated withfundoplication before pursuing surgery. This educationis even more critical in patients who have neurologic im-pairment because they have the highest postoperativecomplication rates.

Table 6. Antacids and Surface Agents

Drug Infant Dose Child Dose Adult DoseSpecialInstructions Adverse Effects

AntacidsCalciumchloride

Not available 400 mg/dose PO(maximum1,200–1,600 mgdaily)

750–1,500 mgPO prn(maximum9 g/24 h)

May use for 7–10 d.No dosingrecommendationsavailable inchildren £2.

Nausea,constipation,abdominalpain

Magnesiumhydroxide

Not available 2.5–5 mL/dosePO prn up toQID

5–15 mL prnup to QID

May use for 7–10 d.No dosingrecommendationsavailable inchildren £2.

Diarrhea,abdominalpain, nausea

Surface AgentsSucralfate Not available Not available 1,000 mg PO

QIDDosing is not wellestablished inchildren. Suspensionis the preferred formof administration andrecommended for7–10 d.

Constipation,nausea

PO"by mouth; prn"as needed; QID"four times daily.





Special ConsiderationsChildren Who Have Neurologic Impairment

GERD and its complications occur more frequently inchildren who have neurologic impairment. The rationalefor the increase in severity and complications of GERD inthis population is likely due to a combination of severalfactors, including chronic supine positioning, swallowingdysfunction, abnormal sensory integration, constipation,abnormal muscle tone, and skeletal abnormalities. It maybe dif"cult to diagnose GERD in neurologically impairedchildren, particularly those with atypical presentations,such as anxiety, dystonia, and self-injurious behaviors.In this population in particular, testing, such as bariumcontrast studies, pH-MII monitoring, and endoscopymay be necessary as part of the diagnostic evaluation.Medical therapies, such as long term PPI and prokineticuse, often are used to treat symptoms and esophagitis.Children who have neurologic impairment are morelikely to require gastrostomy feedings to support theirnutritional status. Antire!ux surgery often is consideredin this population; however, when compared with healthychildren, neurologically impaired children have twice therisk of postoperative complications, three times the riskof death, and four times the risk of needing surgicalrevision. (15)

References1. Sherman PM, Hassall E, Fagundes-Neto U, et al. A global,evidence-based consensus on the de"nition of gastroesophageal

re!ux disease in the pediatric population. Am J Gastroenterol. 2009;104(5):1278–1295, quiz 12962. Nelson SP, Chen EH, Syniar GM, Christoffel KK; PediatricPractice Research Group. Prevalence of symptoms of gastroesoph-ageal re!ux during infancy. A pediatric practice-based survey. ArchPediatr Adolesc Med. 1997;151(6):569–5723. Nelson SP, Chen EH, Syniar GM, Christoffel KK; PediatricPractice Research Group. Prevalence of symptoms of gastroesoph-ageal re!ux during childhood: a pediatric practice-based survey.Arch Pediatr Adolesc Med. 2000;154(2):150–1544. Mousa HM, Rosen R, Woodley FW, et al. Esophageal imped-ance monitoring for gastroesophageal re!ux. J Pediatr GastroenterolNutr. 2011;52(2):129–1395. Rosen R, Hart K, Nurko S. Does re!ux monitoring withmultichannel intraluminal impedance change clinical decision mak-ing? J Pediatr Gastroenterol Nutr. 2011;52(4):404–4076. Thakkar K, Boatright RO, Gilger MA, El-Serag HB. Gastroesoph-ageal re!ux and asthma in children: a systematic review. Pediatrics.2010;125(4). Available at: www.pediatrics.org/cgi/content/full/125/4/e9257. van der Pol RJ, Smits MJ, van Wijk MP, Omari TI, TabbersMM, Benninga MA. Ef"cacy of proton-pump inhibitors in childrenwith gastroesophageal re!ux disease: a systematic review. Pediatrics.2011;127(5):925–9358. Orenstein SR, Hassall E, Furmaga-Jablonska W, et al Multicen-ter, double-blind, randomized, placebo-controlled trial assessingthe ef"cacy and safety of proton pump inhibitor lansoprazole ininfants with symptoms of gastroesophageal re!ux disease. J Pediatr.2009;154(4):514–520.e49. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridiumdif"cile-associated disease. JAMA. 2005;294(23):2989–299510. Leonard J, Marshall JK, Moayyedi P. Systematic review of therisk of enteric infection in patients taking acid suppression. AmJ Gastroenterol. 2007;102(9):2047–2056, quiz 205711. Di Lorenzo C, Orenstein S. Fundoplication: friend or foe?J Pediatr Gastroenterol Nutr. 2002;34(2):117–12412. Lee SL, Sydorak RM, Chiu VY, Hsu JW, ApplebaumH, HaighPI. Long-term antire!ux medication use following pediatricNissen fundoplication. Arch Surg. 2008;143(9):873–876, dis-cussion 87613. Lee SL, Shabatian H, Hsu JW, Applebaum H, Haigh PI.Hospital admissions for respiratory symptoms and failure to thrivebefore and after Nissen fundoplication. J Pediatr Surg. 2008;43(1):59–63, discussion 63–6514. Srivastava R, Berry JG, Hall M, et al. Re!ux related hospitaladmissions after fundoplication in children with neurologicalimpairment: retrospective cohort study. BMJ. 2009;339:b441115. Pearl RH, Robie DK, Ein SH, et al. Complications ofgastroesophageal antire!ux surgery in neurologically impairedversus neurologically normal children. J Pediatr Surg. 1990;25(11):1169–117316. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al; NorthAmerican Society for Pediatric Gastroenterology Hepatology andNutrition; European Society for Pediatric Gastroenterology Hep-atology and Nutrition. Pediatric gastroesophageal re!ux clinicalpractice guidelines: joint recommendations of the North AmericanSociety for Pediatric Gastroenterology, Hepatology, and Nutrition(NASPGHAN) and the European Society for Pediatric Gastroen-terology, Hepatology, and Nutrition (ESPGHAN). J PediatrGastroenterol Nutr. 2009;49(4):498–547

Summary• Based on strong research evidence, (1)

gastroesophageal reflux in children is a commonconcern for both caregivers and health-care providers.

• Based on some research evidence as well as expertconsensus, (16) most infants have physiologic reflux, andreassurance and parenteral education are recommended.

• Based on some research evidence as well as expertconsensus, (16) judicious use of diagnostic testingshould be tailored to the history and physicalexamination of each patient.

• Based on strong research evidence, (7) medicaltreatment, including proton pump inhibitors,generally is effective in suppressing gastric acidproduction.

• Based on some research evidence as well as consensus,(16) antireflux surgery may be indicated in infants andchildren who have severe complications of reflux orsymptoms resistant to therapy.




http://www.pediatrics.org/cgi/content/full/125/4/e925

http://www.pediatrics.org/cgi/content/full/125/4/e925


PIR QuizThis quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Since January 2012, learners cantake Pediatrics in Review quizzes and claim credit online only. No paper answer form will be printed in the journal.

New Minimum Performance Level RequirementsPer the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and creditsystem, a minimum performance level must be established on enduring material and journal-based CME activities thatare certified for AMA PRA Category 1 CreditTM. In order to successfully complete 2012 Pediatrics in Review articles forAMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on thisassessment, which measures achievement of the educational purpose and/or objectives of this activity.

Starting with 2012 Pediatrics in Review, AMA PRA Category 1 CreditTM can be claimed only if 60% or more of thequestions are answered correctly. If you score less than 60% on the assessment, you will be given additionalopportunities to answer questions until an overall 60% or greater score is achieved.

1. The parents of a 4-month-old infant who spits up frequently but is otherwise well want to know why he doesso much spitting. You explain that the most common cause of gastroesophageal reflux in children is:A. delayed gastric emptying.B. hiatal hernia.C. impaired esophageal peristalsis.D. relaxation of the lower esophageal sphincter.E. salivary hypersecretion.

2. A 3-month-old otherwise well infant presents with the chief complaint of regurgitating four times per day.You counsel the family that there is a 95% chance the infant will “outgrow his reflux” by what age?A. 6 months.B. 9 months.C. 12 months.D. 18 months.E. 24 months.

3. You suspect that a 6-month-old girl has eosinophilic esophagitis rather than gastrointestinal reflux becauseshe manifests which symptom?A. apnea.B. dysphagia.C. epigastric pain.D. hematemesis.E. regurgitation.

4. You suspect that a teenage patient of yours has achalasia. Which of the following tests would be most useful inevaluation for that condition?A. endoscopy with biopsy.B. esophageal manometry.C. esophageal pH monitoring.D. MII with pH monitoring.E. radionuclide scintigraphy.

5. You see a 12-year-old overweight boy with heartburn and reflux symptoms in your clinic. After discussion ofweight loss and lifestyle modifications, you elect to start a proton pump inhibitor (PPI). Of the following, whichis a commonly reported idiosyncratic reaction to PPI therapy in children?A. anemia.B. B12 deficiency.C. headache.D. rectal bleeding.E. skin rash.





DOI: 10.1542/pir.33-6-2432012;33;243Pediatrics in Review

Jillian S. Sullivan and Shikha S. SundaramGastroesophageal Reflux

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