GASTROESOPHAGEAL REFLUX DISEASE IN INFANTS, CHILDREN, AND ADOLESCENTS doc

ABSTRACT Gastroesophageal reflux disease GERD is one of the most common acid-related disorders in US adults, occurring in approximately 20% of individuals according to a survey of reside

ABSTRACT Gastroesophageal reflux disease (GERD) is

one of the most common acid-related disorders in

US adults, occurring in approximately 20% of

individuals according to a survey of residents

from Olmsted County, Minn Although GERD is

not as well studied in the pediatric population, a

high percentage of children aged 3 to 7 years

have symptoms suggestive of this disease, without

a history of acute illness or chronic medical or

developmental disabilities Nearly 15% of

ado-lescents aged 10 to17 years and 25% of children

aged 3 to 9 years report symptoms of abdominal

pain; whether this is GERD or other etiologies is

not clear Among children with developmental

disabilities or neurological injury, the risk for

GERD and other feeding-related difficulties

appears to be much higher than that of the

gen-eral population Recent studies demonstrate a

high prevalence of significant GERD in children

with asthma Current treatment options for

pedi-atric GERD include lifestyle changes initially, then

pharmacologic therapy and, in selected cases, antireflux surgery The drugs administered to decrease the symptoms of GERD and to heal ero-sive esophagitis are histamine type-2 receptor antagonists and proton pump inhibitors After over

a decade of use in adults and according to more recent studies published about use in children, the PPI class of agents has been found in studies to be safe, well tolerated, and highly effective.1

(Adv Stud Med 2003;3(3A):S117-S122)

I t was once believed that gastroesophageal refluxdisease (GERD) is a condition that may not

end in childhood, but in fact may start, disap-pear, and then reappear in adulthood However, in many cases, GERD can be a chronic disease in which the patient lives through peri-ods of exacerbated symptoms and periperi-ods that are pain free Although many mechanisms have been investi-gated to determine the cause(s) of GERD, recent data support a transient lower esophageal sphincter relax-ation and esophageal body motility inhibition being present in children with documented GERD com-pared with normal controls (ie, those without GERD).2The symptoms and signs of pediatric GERD often may be very different than those exhibited in adults The pathophysiology of pediatric GERD, how-ever, appears to be fairly similar to that seen in adults,

as are the diagnostic and management tools

GASTROESOPHAGEAL REFLUX DISEASE IN INFANTS, CHILDREN, AND ADOLESCENTS*

— Benjamin D Gold, MD †

* This article is based on a presentation given by Dr Gold

at the PRI-MED East Conference.

† Associate Professor of Pediatrics and Microbiology,

Director, Division of Pediatric Gastroenterology and N utrition,

Department of Pediatrics, Emory University School of Medicine,

Gastroenterology Service Line Chief, Egleston Children’s

Hospital, Children’s Healthcare of Atlanta.

Address correspondence to: Benjamin D Gold, MD,

Director, Division of Pediatric Gastroenterology and N utrition,

Department of Pediatrics, Emory University School of

Medicine, 2040 Ridgewood Dr, N E, Atlanta, GA 30322

E-mail: ben_gold@oz.ped emory.edu.

P REVALENCE OF GERD IN US C HILDREN

More than 85% of premature infants have some

evidence of GERD, with 3% to 10% of these patients

having supraesophageal manifestations of the disease

including bradycardia and apnea Many former

pre-mature infants will have GERD-induced exacerbation

of bronchopulmonary dysplasia; the neonatal

equiva-lent of adult chronic obstructive pulmonary disease

and the result of prolonged ventilator support required

by these prematurely born children shortly after birth

In the past, it was commonly believed that GERD

completely resolved in infants by 3 months of age

However, there is now evidence to suggest the

con-trary, because almost 100% of infants at the age of 3

months will have evidence of reflux Whether true

dis-ease, in one form or another, exists deserves further

study However, approximately 33% will seek medical

attention and the regurgitation symptoms in most

(>70%) of these children will resolve with minimal

intervention and no diagnostic evaluation In

addi-tion, until recently, no long-term follow-up pediatric

studies existed Retrospective studies demonstrate that

by 6 months of age, 20% of infants require further

evaluation because of reported symptoms of GERD

In up to 40% of cases, pH monitoring reveals

signifi-cant acid exposure (pH <4.0) to the distal esophagus

for more than 5% of a 24-hour period (1.2 hours or

longer).3-5

H OSPITALIZED C HILDREN

Overall, GERD is a significant problem in

hospi-talized children, with more males than females being

affected Review of a large, national pediatric hospital

database showed that in 1997 less than 2% of children

hospitalized in the United States had Barrett’s

esopha-gus, a specific columnar lining that may be a precursor

to esophageal cancer, as 1 of the top 5 discharge

diag-noses However, in 2000, the number of hospitalized

children with a discharge diagnosis of Barrett’s

esoph-agus increased to almost 4% According to data from

the same large database, the Pediatric Health

Information Survey, a consortium of approximately 37

children’s hospitals across the US, in the year 2000

3.5% of all pediatric hospital discharges were related

to GERD as 1 of the top 3 discharge diagnoses, and

$750 million in annual costs were incurred that were

related primarily to the surgical management of

chil-dren with GERD Specifically, there has been a

nation-al increase in the frequency of fundoplications

performed on children In another study, the diagno-sis of GERD in hospitalized infants increased 20-fold

in a single naval hospital from 1971 to 1995 It has not been determined whether these growing numbers are due to a rising prevalence of GERD, more awareness

of it and improved diagnostic testing, or both.6,7

Hospitalized and nonhospitalized children with a history of severe GERD symptoms suffer from a num-ber of esophageal complications such as erosive esophagitis, Barrett’s esophagus, and other esophageal-related maladies In some special populations, the numbers of children with GERD are particularly high For example, among children with a neurologic injury

or impairment such as cerebral palsy, 30% to 70% of children will eventually suffer from erosive esophagitis Other esophageal and supraesophageal complications

in severe pediatric GERD include esophageal stric-tures, laryngitis, sinusitis, pharyngitis, apnea, brady-cardia, seizures, and adenocarcinoma (primarily where there is concomitant neurologic injury or congenital abnormalities of esophagus) Approximately 27% of hospitalized children with GERD show signs of respi-ratory disease.4,7,8

Not only are the relative numbers of pediatric GERD cases increasing over the years, but the disease also appears to become more clinically relevant and change in character with advancing age Nelson reviewed the cases of more than 1700 children, track-ing them from newborn to adolescence, and noted that the presenting symptoms of reflux disease changes from a more regurgitant component (eg, vomiting) to one of a more pain-related type: a sig-nificant increase in the evidence of heartburn or epi-gastric pain as children age.4From ages 3 to 9 years, 1.8% of children show signs of heartburn; however, from ages 18 to 21 years, 22% of young adults expe-rience this symptom.4 In addition, one fourth of adults who have documented GERD will have had some evidence of childhood symptoms.5

The symptoms and manifestations of GERD in children vary and can be very distinct from those in adults (Table 1) In the pediatric population they include regurgitation, persistent vomiting that causes a failure to thrive, and signs of esophagitis Caregivers may report feeding difficulties such as the child refus-ing to eat, archrefus-ing and inconsolable cryrefus-ing,

hemateme-sis, and water-brash (spitting up) Other significant

physical manifestations of GERD that have been

docu-mented are anemia, weight loss, Sandifer’s syndrome

(which may cause head turning as a result of esophageal

inflammation), and stricture Older children may report

heartburn, dysphagia, and/or odynophagia

The supraesophageal manifestations of GERD in

children are similar to those found in adults These

include chronic sore throat and cough, hoarseness,

wheezing and asthma, and specific to the infant

popula-tion, apnea and bradycardia Dental erosions and

halito-sis may also be a result of chronic GERD in children

Two particularly troublesome conditions that appear

to be related to GERD in children are apnea and

dam-age to the laryngo-pharyngeal and vocal cords, called

laryngopharyngeal reflux disease It is still controversial

as to whether there is a true cause-and-effect relationship

between GERD and apnea However, in some children

being evaluated for suspected GERD-induced

apnea/bradycardia a definite relationship has been

shown; when esophageal pH drops below 4.0, there is a

cessation in nasal airflow and chest wall movement This

phenomenon is referred to as reflux-associated apnea.9,10

Clearly, intervention trials are needed to determine

whether infants are experiencing reflux-associated apnea,

in which case treatment may reduce episodes or

elimi-nate them completely

Another supraesophageal complication of GERD

observed among children is damage to the

laryn-gopharyngeal area and vocal cords Specifically, vocal

cords may develop a granular exudative surface with

induration and irregular contact edges and posterior

rugae—all as a result of chronic reflux of gastric

con-tents The inflammation and vocal cord damage

appears, in anecdotal cases, to completely resolve with

sufficient acid suppression Prospective pediatric

treat-ment trials in this population are definitely needed

D IAGNOSTIC T ESTING

In the diagnosis of pediatric GERD, the initial

workup—particularly in those children with

regurgita-tion predominant symptoms—should look for

anatomical abnormalities such as strictures, achalasia,

intestinal malrotation, or hiatal hernia Although these

abnormalities are often detected via an upper

gastroin-testinal (GI) contrast study, if the clinician uses the

upper GI solely to diagnose GERD, many

false-nega-tives and -posifalse-nega-tives will occur Upper GI endoscopy is

another useful test in the diagnosis of GERD It is an

especially valuable tool because it enables physicians to diagnose and rule out reflux esophagitis, Barrett’s dis-ease, and other types of inflammatory or infectious forms of esophagitis such as Crohn’s disease, herpes simplex virus, or candida

Finally, the 24-hour intraesophageal pH study, par-ticularly if the child’s caregiver supplies a detailed diary

of the child’s symptoms to accompany the study, is a reli-able test to determine the presence of nocturnal silent reflux, the rapidity of esophageal acid clearance, and the adequacy of acid suppression This procedure, in which

a catheter is passed through the nose, into the back of the throat, and down towards the esophagus, is not deemed

to be necessary if the patient is vomiting.11

The primary goals in managing GERD are to elim-inate symptoms, heal esophagitis, prevent or manage complications, and maintain remission (Figure) Since GERD may be a lifelong disease, this condition and its long-term sequelae, which often appear in adulthood, may be most effectively handled if it is diagnosed and treated during childhood

Table 1 Symptoms and Manifestations of GERD

in Children

GERD = gastroesophageal reflux disease; GER = gastroesophageal reflux.

 Regurgitation (GER vs GERD; ie, physiologic vs pathologic?) – Vomiting (ie, “fat, happy spitter”) – most common

 Persistent vomiting – Failure to thrive

 Esophagitis – Feeding refusal, difficulties, resistance – Arching, crying (inconsolably) during initiation of feeds – Hematemesis

– Water-brash (“spit-up” burps) – Anemia, weight loss

– Sandifer’s syndrome (child presents with ‘head turning’ as a result

of esophageal inflammation) – Heartburn (“heartburn” symptoms reported in older child, adolescent)

– Dysphagia /odynophagia – Stricture

N ONSURGICAL M ANAGEMENT OF

M ILD TO M ODERATE GERD S YMPTOMS

Educating the caregivers of pediatric patients is

vital in managing mild GERD symptoms Specifically,

a change in the patient’s diet and lifestyle is often

nec-essary In infants, thickened feeds and sitting the child

upright for a period of 45 minutes to 1 hour after feeds

often lessens the number of regurgitation episodes In

addition, elevation of the crib or mattress at the head

of the bed often eases nighttime symptoms Obesity

can be a contributing factor to GERD, so weight

man-agement in older children is encouraged.11

If pharmacotherapy is necessary, antacids are

some-times helpful for symptom relief Anticholinergics may

be effective, but they are usually not recommended

due to the high incidence of side effects.11 On the

other hand, histamine type-2 receptor antagonists

(H2RAs) and proton pump inhibitors (PPIs) are

rec-ommended and have been approved for use in the

pediatric population by the US Food and Drug

Administration (FDA) Safety and dosing data have

been well established for medications such as

raniti-dine, famotiraniti-dine, lansoprazole, and omeprazole The

motility component of GERD is still not yet

adequate-ly addressed with currentadequate-ly available pharmacologic

agents Prokinetic drugs such as metoclopramide are also

sometimes employed in the treatment of GERD

However, safety issues are of concern with the use of

available prokinetic agents, particularly when

adminis-tered doses are high enough to achieve the desired

anti-regurgitant effect Cisapride has been withdrawn from

use by the FDA and metoclopramide has the potential

for irreversible central nervous system complications

Data indicate that the PPI, lansoprazole (15 to 30

mg qd), administered to children aged 1 to 11 years

with erosive esophagitis resulted in 78% of the subjects

being healed by week 8 of treatment and 100% of

sub-jects having their erosive esophagitis healed by week

12.12 Data regarding the 6-month efficacy of another

PPI, omeprazole, in children also demonstrated a

sim-ilar spectrum of symptom relief and esophagitis

heal-ing Hassall et al conducted an open multicenter study

of 57 children aged 1 to 16 years with a diagnosis of

erosive esophagitis.13 The children were administered

escalating doses of omeprazole in order to achieve an

optimal dose to maintain the duration of esophageal

acid reflux <6% in a 24-hour pH study In these

chil-dren, there was marked reduction in symptoms,

including heartburn, dysphagia, irritability, and

coughing, both at an interim visit 5 to 14 days into the study and at the healing visit on day 120.13

Although no head-to-head pediatric comparative studies have been performed, data from H2RA and PPI treatment trials in similar patient populations demonstrate a superior efficacy of PPIs over H2RAs in the treatment of pediatric GERD For example, recent studies demonstrated that PPIs heal severe erosive esophagitis in up to 100% of the children in which they were administered.12PPIs were shown to be effec-tive even in patients whose GERD was refractory to other medications and who have failed surgery.12,13For short-term healing, PPIs in children have been shown

to be safe and effective However, PPI administration

in the pediatric population has been shown to require wider dosing ranges for treatment efficacy than is rec-ommended for adults Indeed, studies demonstrate that PPI doses used in the pediatric population are sometimes higher than those administered to adults due to the fact that children, in part, metabolize these medications faster than their older counterparts.13-16

There are a variety of formulations of PPIs available for use in pediatric GERD patients Both lansoprazole and omeprazole have been shown to be equally as effective in liquid suspension, and there is a lansopra-zole packet for suspension that is strawberry flavored Furthermore, PPI capsules can be opened and sprin-kled into food (eg, applesauce or ice cream) while

Figure.Treatment of Gastroesophageal Reflux Disease (GERD)

maintaining good bioavailability and similar efficacy.

In addition, there are other PPI formulations under

development including fast-dissolving tablets and

intravenous preparations

S URGERY

Antireflux surgery is another option for the

treat-ment of childhood GERD, particularly in those

patients with a significant motility or regurgitant

component to their disease Fundoplication is the

third most common procedure performed on children

today Between 1995 and 1999, approximately 25%

to 27% of hospitalized children with the primary

dis-charge diagnosis of GERD underwent

fundoplica-tion.7 However, caution and careful case selection

should be used as significant morbidity and mortality

can be associated with surgery, particularly in children

with neurologic injury (eg, the cerebral palsy

popula-tion) Thus, antireflux surgery is not recommended

for all pediatric patients The decision to move

for-ward with surgical intervention should be made

care-fully on a case-by-case basis Recent pediatric data

support previously published adult studies

demon-strating that those patients with GERD who respond

to medical therapy have better outcomes with

antire-flux surgery To date, no comparative outcome or

cost-effectiveness studies with PPI versus surgery have been

performed in the pediatric population

In summary, mild spitting and irritability often

characterize uncomplicated GERD in infants GERD

is most frequently diagnosed by history and physical

exam, and best approached by providing parental

guidance and reassurance, slight lifestyle changes, and

possible empiric treatment with prokinetic or

antise-cretory agents (H2RA/PPI) Refractory cases of infant

GERD should be referred to a specialist for

diagnos-tic testing (ie, upper GI) to rule out anatomic

abnor-malities such as hiatal hernia or achalasia, and pH

metry with an accompanying diary to demonstrate

reflux episode association with symptoms (Table 2)

Complicated GERD in infants often presents with

poor weight gain, dysphagia, apnea, respiratory

symp-toms, irritability, and hematemesis Diagnostic

options include endoscopy with biopsies and 24-hour

pH metry Recommended therapies include acid

sup-pression via H2RA/PPI, prokinetic medications,

change in formula, and increased caloric density,

although infants with complicated GERD often

require the expertise of a specialist

Table 2 GER in Infants:Management Approach

GER = gastroesophageal reflux; GI= gastrointestinal; H2RA = histamine type-2 recep-tor antagonist; PPI = proton pump inhibirecep-tor.

Table 3 GER in Older Children:Management Approach

GER = gastroesophageal reflux; GI= gastrointestinal; H2RA = histamine type-2 recep-tor antagonist; PPI = proton pump inhibirecep-tor.

Uncomplicated GER

“Happy spitter”/Mildly colicky

• Parental guidance/reassurance

• Lifestyle changes (elemental or thickened formula)

• Worsening symptoms or persistence >24 mo

• Upper GI contrast study

• Empiric treatment with prokinetic

or antisecretory (H2RA / PPI)

• Consider referral to specialist

Complicated GER

• Poor weight gain, dysphagia, apnea, respiratory symptoms, irritability, hematemesis

• Referral to specialist

• Diagnostic options: Endoscopy, pH probe

•

Rx options: Acid suppression, (H2RA/PPI), prokinetic, formula change, increase caloric density

Heartburn

• Lifestyle changes

• Trial PPI or H2RA for 2–4 weeks

• Referral to specialist if symptoms persist or recur

• Endoscopy and possible long-term treatment

Complicated GER

• Odynophagia, dysphagia, hematemesis, food lodged

• Referral to specialist

• Upper GI and endoscopy

• Treatment with PPI for erosive esophagitis

• Repeat endoscopy for erosive esophagitis

In older children with complicated GERD,

symp-toms can range from odynophagia to dysphagia to

hematemesis To diagnose complicated GERD,

physi-cians commonly perform 24-hour pH metry and

endoscopy with biopsies (NOTE: A complete algorithm

scheme for children of different ages with GERD is

pro-vided in the recently published North American Society

for Pediatric Gastroenterology and Nutrition clinical

practice guidelines for GERD.)11 The management

approach taken in older children with GERD is slightly

different than in younger children and infants Often,

older children with mild GERD first present with

heart-burn as a key symptom As with infants, lifestyle changes

(particularly weight management) are often

recom-mended Administration of a PPI or H2RA for a period

of 2 to 4 weeks is suggested If systems persist, the older

child with GERD should be referred to a specialist

Treatment with PPIs is recommended for all patients

with erosive esophagitis diagnosed by the pediatric

gas-troenterologist via upper endoscopy (Table 3)

In conclusion, pediatric GERD is a more common

problem than previously recognized, and its

presenta-tion (ie, signs and symptoms) in the pediatric

popula-tion may differ from GERD in adults Early diagnosis

and treatment may prevent lifelong GERD

complica-tions Effective therapies, such as PPIs, are safe,

avail-able, and should be employed in the management of

this common and chronic disease that causes

signifi-cant morbidity and human suffering

REFERENCES

1 Managing Acid-Related Disorders Through the Ages of Man

[abstract book] PRI-MED East Conference; N ov 7, 2002;

Boston, Mass.

2 Kawahara H, Dent J, Davidson G Mechanisms responsible

for gastroesophageal reflux in children Gastroenterology.

1997;113:399-408.

3 Gibbons TE, Stockwell J, Kreh RP, McRae S, Gold BD Population based epidemiological survey of gastroe-sophageal reflux disease in hospitalized US children.

Gastroenterology 2001;120(5):154

4 N elson SP, Chen EH, Syniar GM, Christoffel KK.

Prevalence of symptoms of gastroesophageal reflux during

childhood Arch Pediatr Adolesc Med 2000;154:2.

5 W aring JP, Feiler MJ, Hunter JG, Smith CD, Gold BD Childhood gastroesophageal reflux symptoms in adult

patients J Pediatr Gastroenterol N utr 2002;35:334-338.

6 Callahan CW The diagnosis of gastroesophageal reflux in

hospitalized infants: 1971-1995 J Am Osteopath Assoc.

1998;98(1):32-34.

7 Gibbons TE, Stockwell J, Kreh RP, et al Population-based epi-demiologic survey of gastroesophageal reflux disease in

hospi-talized US children Gastroenterology 2001;120:154.

8 Hassall E Co-morbidities in childhood Barrett’s esophagus.

J Pediatr Gastroenterol N utr 1997;25:255-260.

9 Herbst JJ, Minton SD, Book LS Gastroesophageal reflux causing respiratory distress and apnea in newborn infants

J Pediatr 1979;95:763-768.

10 W enzl TG, Schenke S, Peschgens T, Silny J, Heimann G, Skopnik H Association of apnea and nonacid gastroe-sophageal reflux in infants: investigations with the

intralumi-nal impedance technique Pediatr Pulmonol 2001;31:

144-149

11 Rudolph J, Mazur LJ, Liptak GS, et al Guidelines for evalua-tion and treatment of gastroesophageal reflux in infants and children: recommendations of the N orth American Society

for Pediatric Gastroenterology and N utrition J Pediatr Gastroenterol N utr 2001;32(suppl 2):S1-S31.

12 Tolia V, Ferry G, Gunasankeran T, Huang B, Keith R, Book

L Efficacy of lansoprazole in the treatment of

gastroe-sophageal reflux disease in children J Pediatr Gastroenterol

N utr 2002;35(suppl 4):S308-S318.

13 Hassall E, Israel D, Shepherd R, et al Omeprazole for treatment of chronic erosive esophagitis in children: A multi-center study of efficacy, safety, tolerability and dose

require-ments J Pediatr 2000;137:800-807

14 Gunasekaran TS, Hassall E Efficacy and safety of omepra-zole for severe gastroesophageal reflux in children

J Pediatr 1993;123:148-154.

15 Hassall E and the International Pediatric Omeprazole Study Group Omeprazole for maintenance therapy of

erosive esophagitis in children Gastroenterology 2000;

118:A3610.

16 Andersson T, Hassall E, Lundborg P, et al Pharmacokinetics

of orally administered omeprazole in children Am J Gastroenterol 2000;95:3101-3106