GERD in the Pediatric Patient: Management Considerations

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http://www.medscape.com/viewarticle/472765

A. Gremse, MD

Introduction

Gastroesophageal reflux (GER) is common in infants, children, and

adolescents.[1,2] Based on symptom surveys, recurrent vomiting is reported

in two thirds of 4-month-old infants, but is present in only 5% to 10% of

infants by 1 year of age.[2] Beyond infancy, up to one fourth of children

and adolescents have recurrent abdominal pain, whereas only 5% report

heartburn or epigastric pain.[2,3] Symptoms of gastroesophageal reflux

disease (GERD) are more common in adults, with heartburn occurring in 40% of

survey respondents.[4] In one study,[5] adults with GERD were more likely to

recall experiencing acid reflux symptoms in childhood, including abdominal

pain, heartburn, recurrent vomiting, dysphagia, chronic cough, or

hoarseness.[5] Symptoms of GERD vary with age. Common GERD symptoms in

infants are regurgitation, choking, gagging, irritability, opisthotonic

posturing, and excessive hiccups. GERD symptoms in young children are

similar to those experienced by adults, such as abdominal pain, vomiting,

excessive belching, and dysphagia. These results suggest that in some

individuals, GERD is a lifelong disease that may require aggressive therapy

early in life to reduce the risk of long-term sequelae, such as erosive

esophagitis or Barrett's esophagus. Therefore, because GER is common, it is

important to distinguish pediatric patients with pathologic reflux that may

lead to complications of GERD from those with physiologic GER who have a

better prognosis. The presence of associated symptoms such as poor weight

gain, excessive crying, disturbed sleep, and feeding or respiratory problems

distinguishes infants with GERD from those with physiologic gastroesophageal

reflux.

Diagnostic Evaluation of GERD in Children

Management of GERD in both adults and children is based on disease severity,

the degree of symptoms, and presence or absence of complications of GERD

determined by the diagnostic evaluation. Many diagnostic approaches are used

to evaluate GERD in pediatric patients. GERD can be diagnosed by typical

history and physical examination findings (Table 1

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1.> ) as a basis for a trial of therapy.[6] However, typical symptoms do not

always predict which patients will respond to treatment. In one study,[7]

there was poor correlation between irritability and positive esophageal

biopsy or esophageal pH study findings of GERD in infants. In the diagnostic

evaluation, the upper gastrointestinal series is neither sensitive nor

specific for the diagnosis of GERD, but can demonstrate anatomic causes of

vomiting, particularly congenital abnormalities in infants. Esophageal pH

monitoring can quantitate esophageal acid exposure by measuring the

frequency and duration of acid reflux events in children with suspected

GERD.[8] In the evaluation of GERD in pediatric patients, esophageal pH

monitoring determines the degree of esophageal acid exposure, whether a

temporal association exists between atypical symptoms and acid reflux, as

well as the adequacy of therapy in patients who respond poorly to

treatment.[8] Esophageal pH monitoring is particularly valuable in

correlating acid reflux and atypical symptoms of GERD in infants and

children, such as chronic cough, stridor, wheezing, apnea, irritability, or

opisthotonic posturing.

Esophagoscopy with biopsy can confirm the diagnosis of reflux esophagitis

and screen for other upper gastrointestinal disorders whose symptoms may

mimic those of GERD in children. Esophageal biopsy can provide additional

information beyond visual appearance, and thus is recommended in pediatric

endoscopy for evaluation of GERD because there is poor correlation between

endoscopic and histologic findings in infants and children.[9] Many of these

patients may have histologic evidence of reflux esophagitis despite the

appearance of grossly normal mucosa endoscopically, while other children

with esophagitis may have conditions that mimic GERD, such as eosinophilic

esophagitis. One endoscopic finding associated with GERD in children, as

opposed to eosinophilic esophagitis, is the presence of vertical red lines

in the distal esophagus (Figure 1).[10]

In addition to confirming the histologic features of reflux esophagitis,

esophageal biopsy can help diagnose atypical causes of vomiting, such as

eosinophilic esophagitis, which occurs in an estimated 10% to 15% of

children undergoing upper endoscopy for GERD symptoms.[6,11] The diagnostic

tests that are useful in the evaluation of suspected GERD in pediatric

patients are listed in Table 2

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2.> .

Eosinophilic esophagitis is characterized by an isolated, severe

eosinophilic infiltration of the esophagus. The presenting symptoms of

eosinophilic esophagitis are indistinguishable from GERD, and include

vomiting/regurgitation, abdominal pain, chest pain, heartburn, and

dysphagia. Choking, food impaction, and dysphagia may be more prominent

symptoms in these patients. However, these symptoms in children with

eosinophilic esophagitis do not respond to acid-suppression therapy. Many

infants with this condition respond to strict elimination diets and amino

acid-based formulas. Systemic or swallowed doses of inhaled corticosteroids

have been reported as treatments in older children or adolescents with

eosinophilic esophagitis.

Management -- Lifestyle Changes for GERD in Children

The goals for treatment of GERD are to relieve symptoms, heal esophagitis if

present, maintain remission of symptoms, and manage or prevent

complications. Treatment options to achieve these goals include dietary or

behavioral modifications, pharmacologic intervention, and surgical therapy.

Recommendations regarding dietary and behavioral changes in the management

of pediatric GERD are age-dependent. For infants, dietary changes include

modifying infant feeding techniques and changing formula composition by the

addition of thickening agents or by changing the milk protein source. The

addition of rice cereal (1 tablespoon per ounce of formula) decreases the

volume and frequency of regurgitation, but does not reduce esophageal acid

exposure.[12] Alternatively, commercially available formula with osmotic

agents has also been reported to have similar effects as formula thickened

with rice cereal.[13] Because symptoms of milk protein allergy can overlap

those of GERD in infants, a 2-week trial of hypoallergenic formula can be

recommended in this age group.[6,11] Nonpharmacologic conservative therapy

improved symptoms of vomiting and irritability in approximately one fourth

of infants with GERD symptoms in one study.[14]

Lifestyle changes for management of GERD in adolescents are similar to adult

recommendations, and include dietary modification, weight reduction,

avoidance of alcohol, and smoking cessation (Table 3

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3.> ). Passive tobacco smoke exposure is a risk factor for esophagitis in

children; therefore, avoidance of tobacco smoke is recommended for a child

diagnosed with GERD.[15]

Management -- Pharmacologic Therapy for GERD in Children

Therapeutic agents that decrease gastric acid secretion are the most

effective treatment for management of GERD in children and adults.

Histamine-2 receptor antagonists (H2RAs) and proton-pump inhibitors (PPIs)

are recommended for antisecretory therapy of GERD.[6,16] Cimetidine and

nizatidine were found to be more effective than placebo in healing erosive

esophagitis in randomized controlled trials.[17,18] PPIs are more

cost-effective when compared with H2RAs because of their better treatment

outcome; PPIs are also less costly than surgical therapy in adults.[19]

Omeprazole and lansoprazole are approved by the US Food and Drug

Administration for pediatric use. Studies are currently being conducted or

are being planned to evaluate the safety and efficacy of the use of other

PPIs in children.

Two randomized, placebo-controlled trials of H2RA treatment for esophagitis

in children have been reported.[17,18] These trials involved use of

cimetidine administered at 30-40 mg/kg/day for 6 weeks[17] and nizatidine

given at 10 mg/kg/day[18] for 6 weeks; a 70% healing rate was achieved with

both cimetidine and nizatidine, compared with 15% for placebo. The safety

and efficacy of other H2RAs, including ranitidine and famotidine, have been

demonstrated in children in open-label studies.[6] The recommended dosages

of H2RAs and PPIs with FDA-approved pediatric indications are shown in Table

4

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4.> .

A previous study reported a similar outcome for high-dose antacid therapy

and cimetidine in children treated for esophagitis.[20] However, serum

aluminum concentrations approaching levels reported to cause osteopenia and

neurotoxicity were found in children taking aluminum-containing

antacids.[21] Thus, chronic antacid therapy is generally not recommended as

the primary therapy for the pediatric patient with GERD because safer and

more convenient alternatives exist.[6]

Although prokinetic or promotility agents are prescribed for the management

of pediatric GERD either in combination with an antisecretory agent or

alone, their efficacy is equivocal in controlled trials.[6] Metoclopramide

affects esophageal and gastric motility through an antidopaminergic

mechanism. However, its clinical efficacy for treatment of pediatric GERD

was equivocal in controlled trials, so little evidence exists to support

metoclopramide therapy for GERD in infants and children.[6] In patients with

a dysmotility disorder associated with GERD, such as significant

gastroparesis, erythromycin given in doses of 3-5 mg/kg/day may be

considered.[22] Cisapride was effective in decreasing symptoms and improving

results of esophageal pH monitoring in 6 controlled pediatric trials, but is

no longer available commercially in the United States. Based on available

evidence regarding the limited efficacy of prokinetics in the management of

GERD, more research is needed in the development of promotility agents that

are both safe and effective for use in the pediatric population.

As stated above, H2RAs are frequently used as first-line therapy for

treatment of reflux esophagitis in pediatric patients,[23] but PPIs are

superior to H2RAs in healing of erosive esophagitis in adults[24] and

children.[25-27] PPIs are more potent inhibitors of acid secretion than

H2RAs in that they irreversibly bind to H+, K+ -ATPase in the gastric

parietal cell canaliculus and inhibit acid secretion.[16,23]

PPI Therapy

Pharmacokinetics studies have shown that the half-life of omeprazole and

lansoprazole is shorter in children than in adults.[25,28,29] Therefore,

higher weight-adjusted doses of PPIs per kilogram of body weight are needed

in children to achieve similar serum concentrations to those found to be

effective in adults.[16] In appropriate doses, the pharmacodynamics of

lansoprazole were found to be similar to those found in adults, based on

control of gastric acidity as measured by intragastric pH monitoring.[29]

Omeprazole given for 12 weeks resulted in resolution of moderate-to-severe

GERD symptoms, such as heartburn, epigastric pain, irritability, dysphagia,

odynophagia, coughing, wheezing, or vomiting, in all but 7% of pediatric

patients aged 1-16 years.[25] Erosive esophagitis was healed in 82% of

subjects treated with omeprazole. In another study[26] that used both PPI

and H2RA therapy in 153 patients aged 6-18 years, 70% of the patients with

peptic esophagitis responded to an 8-week course of ranitidine (4 mg/kg

dose, given twice daily or thrice daily). Of the 30% of patients who did not

improve, 87% responded to an 8-week course of omeprazole (20 mg/day), again

demonstrating improved response of children to PPI therapy compared with

H2RA therapy.[26] Similarly, lansoprazole given at a dose of 1.4 mg/kg/day

resulted in endoscopic healing of esophagitis in 80% of children (with a

median age of 3.5 years) after 4 weeks of therapy.[28] There was a 100%

healing rate for erosive esophagitis and abatement of symptoms of GERD in

80% of subjects treated with lansoprazole in a US multicenter study

involving 66 children aged 1-11 years.[27] Figure 2 demonstrates the

improvement in the median percentage of days with GERD symptoms over the

duration of treatment with lansoprazole in this latter study. As shown in

the figure, there was a 50% reduction in symptoms after 1 month of PPI

therapy in this age group, but an 80% reduction in symptoms was not achieved

until 12 weeks of therapy.[27] A short-term study in 63 adolescents aged

11-17 years receiving lansoprazole therapy reported improvement in GERD

symptoms in approximately 70% of patients after only 5 days of

treatment.[30]

Multiple pediatric clinical trials have demonstrated that PPIs are safe and

well tolerated in children of all ages.[25,28,30-32] The most commonly

reported adverse events (headache, constipation, diarrhea, and abdominal

pain) occurred in less than 5% of patients, which is similar to the

incidence of adverse events experienced with placebo in studies in

adults.[16] As in adults, some pediatric patients may require maintenance

therapy for treatment of GERD. However, there are limited data from

randomized, controlled trials of maintenance therapy for GERD in children.

Many dosing options are available for PPIs, including capsules, tablets,

suspensions, and an orally disintegrating tablet. For children who can

swallow pills, omeprazole and lansoprazole are available in capsules and

tablets. Omeprazole in oral suspension was safe and effective in pediatric

clinical trials conducted in infants aged 1-24 months, but is only available

after compounding by a local pharmacist. Lansoprazole is available in an

orally disintegrating tablet that is bioequivalent to capsules and can be

placed directly on the tongue or suspended in 5 mL of water and given via

oral syringe.[33]

Management -- Surgery for GERD in Children

Indications for surgical therapy of GERD are based on failed response to

medical therapy or recurrence of symptoms after weaning from medical

therapy.[6] Many adults with GERD symptoms who fail to respond to

acid-suppression therapy may have functional dyspepsia, in which case their

symptoms are unlikely to improve after surgery. In children, recurrent

vomiting is frequently a predominant symptom, and fundoplication has been

reported to be effective as treatment for the symptom of recurrent vomiting

in children with GERD. However, fundoplication is not required for

management of vomiting in the absence of other complications of GERD. In

contrast, potentially life-threatening complications of GERD, such as

respiratory symptoms associated with GER, are more likely in infants than

older children and may be an indication for surgery. Reports of complete

relief of GERD symptoms in children have ranged from 57% to 92% after

fundoplication.[6] Mortality rates for pediatric fundoplication have ranged

from 0% to 4.7%.[6] A review of 15 published reports involving over 11,000

children who had undergone fundoplication for GERD revealed that a weighted

average of the most common postoperative complications were GERD and

dysphagia, which occurred in approximately 6% of children.[34] However,

because the prognosis for resolution of GERD is better in infants than in

older patients, the need for surgery for GERD should be weighed against the

fact that only a small percentage of infants with GERD will have lifelong

disease.

Summary

As should be evident from the previous discussion, GERD is common in infants

and children. Identifying pediatric patients with complications of GERD,

such as erosive esophagitis, is important because effective treatment is

available in this age group, as it is in adults. Antisecretory therapy is

the most effective pharmacologic treatment for GERD, and PPIs in general

provide faster symptom relief and are effective in healing erosive

esophagitis in patients unresponsive to H2RAs. Surgical management of GERD

is an option for children in whom pharmacologic therapy is unsuccessful, but

the risks associated with surgical intervention must be considered against

the relatively better prognosis in infants without life-threatening

complications of GERD.