eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Gastroesophageal Reflux

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Andre Hebra, MD, Chief, Division of Pediatric Surgery, Medical University of South Carolina; Professor of Surgery and Pediatrics, Medical University of South Carolina

Updated: May 13, 2009

Introduction

Background

Gastroesophageal reflux (GER) represents the most common gastroenterological disorder that leads to referral to a pediatric gastroenterologist during infancy. It refers to immaturity of lower esophageal sphincter (LES) function, manifested by frequent transient lower esophageal relaxations (tLESRs) that results in retrograde flow of gastric contents into the esophagus.

Although minor degrees of gastroesophageal reflux are noted in both children and adults, the degree and severity of reflux episodes are increased during infancy. Thus, gastroesophageal reflux represents a common physiological phenomenon in the first year of life. As many as 60-70% of infants experience emesis during at least one feeding per 24-hour period by age 3-4 months. The distinction between this "physiologic" gastroesophageal reflux and "pathologic" gastroesophageal reflux in infancy and childhood is determined, not merely by the number and severity of reflux episodes (when assessed by intraesophageal pH monitoring), but is most importantly determined by the presence of reflux-related complications, including failure to thrive, erosive esophagitis, esophageal stricture formation, and chronic respiratory disease.

Other complications noted in adults with gastroesophageal reflux, including Barrett esophagus and esophageal mucosal dysplasia, are uncommon in childhood. 

Gastroesophageal reflux is classified as follows:

• Physiologic (or functional) gastroesophageal reflux: These patients have no underlying predisposing factors or conditions. Growth and development are normal, and pharmacologic treatment is typically not necessary.
• Pathologic gastroesophageal reflux or gastroesophageal reflux disease (GERD): Patients frequently experience complications noted above, requiring careful evaluation and treatment.¹
• Secondary gastroesophageal reflux: This refers to a case in which an underlying condition may predispose to gastroesophageal reflux. Examples include asthma (a condition which may also be, in part, caused by or exacerbated by reflux) and gastric outlet obstruction.

Pathophysiology

Similarities between adults and infants

• For many years, gastroesophageal reflux during infancy and childhood was thought to be a consequence of absent or diminished LES tone. However, studies have shown that baseline LES pressures are normal in pediatric patients, even in preterm infants.
• The major mechanism in infants and children has now been demonstrated to involve increases in tLESRs. Factors that may promote gastroesophageal reflux during tLESRs include increased intragastric liquid volume and supine and "slumped" seated positioning.
• Likely because of reduced viscosity and increased gastric volumes, the fluid diet of the infant facilitates the process of regurgitation compared with solid meals ingested by older children and adults.
• Esophageal clearance is similar in infants and adults, although evidence of reduced peristaltic activity in preterm infants has been reported.

Differences between adults and infants

• The volume ratio of meal-stomach-esophagus differs. Necessary amounts of infant caloric requirements easily overwhelm gastric capacity. Reflux occurs when esophageal capacity is exceeded by refluxate.
• Decreased gastric compliance is believed to lead to LES relaxation at lower intragastric volumes in infants. This aspect, in conjunction with abdominal wall muscle contraction (if it occurs during periods of LES relaxation) propels refluxate into the esophagus with subsequent regurgitation.
• An association between gastroesophageal reflux and delayed gastric emptying is recognized. This is more common in premature infants.

Gastroesophageal reflux and respiratory symptoms in infants and children

• Gastroesophageal reflux has been associated with significant respiratory symptoms in infants and children.
• The infant's proximal airway and esophagus are lined with receptors that are activated by water, acid, or distension. Activation of these receptors can increase airway resistance, leading to development of reactive airway disease.²  
• In 1892, Osler first postulated a relationship between asthma and gastroesophageal reflux, manifested by a bidirectional cause and effect presentation. Accordingly, although gastroesophageal reflux may be involved in both the etiology and progression of reactive airway disease, the asthmatic condition (in addition to antiasthmatic medications) may play a role in exacerbation of gastroesophageal reflux.
• One postulated mechanism for gastroesophageal reflux–mediated airway disease involves microaspiration of gastric contents that leads to inflammation and bronchospasm. However, experimental evidence also supports the involvement of esophageal acid–induced reflex bronchospasm, in the absence of frank aspiration. In such cases, gastroesophageal reflux therapy using either histamine 2 (H₂) blockers or proton pump inhibitors has been shown to benefit patients with steroid-dependent asthma, nocturnal cough and reflux symptoms.

Gastroesophageal reflux and other conditions in infants and children

• Two major areas of controversy surround the relationship between gastroesophageal reflux and both apnea and otolaryngologic disease. Although early studies appeared to demonstrate a link between gastroesophageal reflux and obstructive apnea (including an association with apparent life-threatening events [ALTE]), recent work suggests a weak relationship between these disorders.³  
• Laryngeal tissues are exquisitely sensitive to the noxious effect of acid, and recent studies support a significant relationship between laryngeal inflammatory disease (manifested by hoarseness, stridor, or both) and gastroesophageal reflux.
• Conversely, no conclusive clinical evidence supports a link between gastroesophageal reflux and other supraesophageal problems, including otalgia, recurrent otitis media, and chronic sinusitis.

Frequency

United States

• Symptoms of gastroesophageal reflux are most often directly related either to the consequences of emesis (eg, poor weight gain) or a result of exposure of the esophageal epithelium to gastric contents.
• Approximately 85% of infants vomit during the first week of life, and 60-70% manifest clinical gastroesophageal reflux at age 3-4 months.
• Symptoms abate without treatment in 60% of infants by age 6 months, when these infants begin to assume an upright position and eat solid foods. Resolution of symptoms occurs in approximately 90% of infants by age 8-10 months. 
• Symptoms that persist after age 18 months suggest a higher likelihood of chronic gastroesophageal reflux.⁴

Age

• Gastroesophageal reflux is most commonly seen in infancy, with a peak at age 1-4 months. However, it can be seen in children of all ages, even healthy teenagers.

Clinical

History

One must remember that the typical symptoms (eg, heartburn, vomiting, regurgitation) in adults cannot be readily assessed in infants and children. Pediatric patients with gastroesophageal reflux (GER) typically cry and report sleep disturbance and decreased appetite. The following are some of the common signs and symptoms of gastroesophageal reflux in the pediatric population:

• Signs and symptoms of gastroesophageal reflux in infants and young children
  • Typical or atypical crying and/or irritability
  • Apnea and/or bradycardia
  • Poor appetite
  • Apparent life-threatening event (ALTE)
  • Vomiting
  • Wheezing
  • Abdominal and/or chest pain
  • Stridor
  • Weight loss or poor growth (failure to thrive)
  • Recurrent pneumonitis
  • Sore throat
  • Chronic cough
  • Waterbrash
  • Sandifer syndrome (ie, posturing with opisthotonus or torticollis)
  • Hoarseness and/or laryngitis
• Signs and symptoms in older children - All of the above, plus heartburn and history of vomiting, regurgitation, unhealthy teeth, and halitosis

Physical

No classic physical signs of gastroesophageal reflux are recognized in the pediatric population (although an infant or toddler arriving in the office wearing a bib is often a sure tip off). One exception would be the relatively uncommon Sandifer syndrome, which is often misdiagnosed as spastic torticollis.

In toddlers and older children, excessive regurgitation may lead to significant dental problems caused by acid effects on tooth enamel. In the vast majority of cases, a diagnosis of gastroesophageal reflux is typically made once the primary care provider has obtained a clinical history that suggests this disorder.

• ALTEs that involve apnea associated with bradycardia, pallor, and/or cyanosis have been linked to gastroesophageal reflux, especially in premature infants. In these events, reflux into the hypopharynx is postulated to lead to laryngospasm and subsequent obstructive apnea. However, data suggest only a weak association between these phenomena. Any such relationship can only be objectively determined by esophageal pH monitoring performed in conjunction with pneumography and either nasal thermistor or pulse oximetry recording.
• Some patients have atypical symptoms (eg, nocturnal cough, wheezing, or hoarseness as the only major complaint). Gastroesophageal reflux is a complicating factor in asthma. The mechanism may include microaspiration, which leads to reflex bronchoconstriction. The association of gastroesophageal reflux and airway or respiratory tract disease is common. Cough, stridor, and pharyngitis have all been linked to gastroesophageal reflux. In addition, an association with rumination is commonly observed in patients with developmental delay.
• Regurgitation of food, one of the most common presenting symptoms in children, ranges from drooling to projectile vomiting. Most often, regurgitation is postprandial, although delays of 1-2 hours occur. One must also consider anatomic anomalies and protein allergy in a vomiting child, as well as inborn metabolic disorders (rare).
• Esophagitis may manifest as crying and irritability in the nonverbal infant. Failure to thrive can result from insufficient caloric intake secondary to repeated vomiting and nutrient losses in the emesis. Hiccups, sleep disturbances, and Sandifer syndrome (arching) have also been shown to be associated with gastroesophageal reflux and esophagitis.

Causes

Reflux after meals occurs in healthy persons; however, these episodes are generally transient and are accompanied by rapid esophageal clearance of refluxed acid. Some consider the small reservoir capacity of the infant's esophagus to be a predisposing factor to vomiting.

The causes and risk factors for gastroesophageal reflux in children are frequently multifactorial.

• Anatomic factors that predispose to gastroesophageal reflux include the following:
  • The angle of His (made by the esophagus and the axis of the stomach) is obtuse in newborns but decreases as infants develop. This ensures a more effective barrier against gastroesophageal reflux.
  • The presence of a hiatal hernia may displace the lower esophageal sphincter (LES) into the thoracic cavity, where the lower intrathoracic pressure may facilitate gastroesophageal reflux. The presence of a hiatal hernia by itself does not predict gastroesophageal reflux. Many patients who have a hiatal hernia do not have gastroesophageal reflux.
  • Resistance to gastric outflow raises intragastric pressure and leads to reflux and vomiting. Examples include gastroparesis, gastric outlet obstruction, and pyloric stenosis.
• Other factors that predispose individuals to gastroesophageal reflux include the following:
  • Medications (eg, diazepam, theophylline)
  • Smoking
  • Alcohol
  • Poor dietary habits (eg, overeating, eating late at night, assuming a supine position shortly after eating)
  • Food allergies
  • Certain foods (eg, greasy, highly acidic)
  • Motility disorders (postulated to potentially cause reflux): These include antral dysmotility and delayed gastric emptying. Such disorders are considered functional problems and frequently do not have an identifiable anatomical or organic cause. 
  • Transient lower esophageal sphincter relaxation (tLESR): This is currently believed to be the main mechanism of gastroesophageal reflux, accounting for 94% of reflux episodes in children and adults. Poor basal LES tone was previously thought to be a cause.
  • Obesity: Obesity has been cited as a major risk factor for gastroesophageal reflux. In studies conducted with adult patients, weight loss was demonstrated to be one of the lifestyle modifications that can decrease the severity and frequency of reflux.
  • Supine position
  • Decreased gastric emptying and reduced acid clearance from the esophagus: These can cause abnormal reflux.
• Physiologic factors: Reflux is facilitated when an increase in intraabdominal pressure occurs. In some cases, and particularly in children with neurodevelopmental disabilities, the presence of a chronically lax LES associated with decreased or even absent  sphincter tone results in severe gastroesophageal reflux.

Differential Diagnoses

Other Problems to Be Considered

Vomiting is a symptom associated with many disorders. Accordingly, the diagnosis of gastroesophageal reflux (GER) cannot be assumed to be the primary problem in infants and children who present with history of emesis. Warning signals that herald the requirement for additional evaluation include the following:

• Bilious or forceful vomiting
• Hematemesis or hematochezia
• Vomiting with diarrhea
• Abdominal tenderness or distension
• Onset of vomiting after 6 months of life
• Fever, lethargy, hepatosplenomegaly
• Macrocephaly, microcephaly, seizures

Workup

Imaging Studies

In most cases of gastroesophageal reflux (GER), diagnosis can be made from the history and physical examination. Conservative measures can be started empirically. However, if the presentation is atypical or if response to therapy is minimal, further evaluation is warranted.

• Upper GI imaging series
  • This is used to evaluate the anatomy of the upper GI tract, but contrast imaging studies are neither sensitive nor specific for gastroesophageal reflux.
  • Imaging may be useful in the evaluation of gastric emptying time, which may be delayed in gastroesophageal reflux.
• Gastric scintiscan
  • This imaging study, using milk or formula that contains a small amount of technetium sulfur colloid, can assess gastric emptying and can reveal reflux (although not the degree or severity). However, its major diagnostic role is in the assessment of pulmonary aspiration.
  • A major error in performing scintigraphy is not performing a delayed scan over the pulmonary bed. Gastroesophageal reflux–related aspiration may occur as an early or late postprandial phenomenon. Accordingly, in addition to the "acute" (ie, 1 h) scintiscan, patients should be rescanned after 24 hours, in order to assess delayed pulmonary soilage by refluxed gastric contents.
• Esophagography
  • In cases of mild gastroesophageal reflux, diagnosis is made by clinical assessment and is confirmed by the response to therapy. This modality, conducted under fluoroscopic control, may reveal the integrity of esophageal peristalsis; however, it should not be used to assess the degree and severity of gastroesophageal reflux.
  • Strictures can be demonstrated by esophagography.
  • Chronic esophageal mucosal injury secondary to gastroesophageal reflux involves a mucosal/submucosal inflammatory cell infiltrate as well as basal cell hyperplasia. In severe cases, this may appear as a ragged mucosal outline on radiography.

Procedures

• Intraesophageal pH probe monitoring
  • A continuous esophageal pH probe in the distal esophagus documents the severity and frequency of reflux. Although a very sensitive technique, some controversy persists with respect to precise criteria for differentiating "physiologic" from "pathologic" gastroesophageal reflux. More recently, dual pH probe monitoring is being used to assess both distal and proximal esophageal reflux in an attempt to correlate gastroesophageal reflux with both laryngeal and pulmonary symptoms.
  • Although pH monitoring has become a widely overused modality, it remains the criterion standard for quantifying gastroesophageal reflux.
  • Advantages in using this procedure include quantification of reflux and the ability to establish a temporal relationship with atypical symptoms (eg, obstructive apnea) and reflux events.
  • Esophageal pH monitoring is not indicated in cases of obvious gastroesophageal reflux but is useful in demonstrating an association between reflux and symptoms in atypical presentations and in grading the risk of esophagitis.
• Manometry
  • This is becoming a more accessible tool for use in infants and children.
  • It is used to assess esophageal motility and lower esophageal sphincter (LES) function.
• Esophagogastroduodenoscopy
  • This modality is useful in patients who are unresponsive to medical therapy.
  • It allows for visualization of the mucosa for diagnosis of peptic ulcer disease, Helicobacter pylori infection, strictures, and peptic esophagitis. It provides access to obtain biopsies for histopathologic examination.
• Intraluminal esophageal electrical impedance (EEI).
  • This recently developed test is useful for detecting both acid reflux and nonacid reflux by measuring retrograde flow in the esophagus.
  • Gastroesophageal reflux episodes as brief as 15 seconds may be measured (see Media file 1).
    
    

    

    The image is a representation of concomitant intraesophageal pH and esophageal electrical impedance measurements. The vertical solid arrow indicates commencement of a nonacid gastroesophageal reflux (GER) episode (diagonal arrow). The vertical dashed arrow indicates the onset of a normal swallow.

    
    
  • In adult studies, impedance measurements have been used in conjunction with 24-hour intraesophageal pH monitoring in order to provide a more complete picture of bolus movement in the esophagus.
  • EEI has not been thoroughly validated, and normal values have not been determined in the pediatric age group.

Histologic Findings

• Histologic signs of peptic esophagitis include basal cell hyperplasia, extended papillae, and mucosal eosinophils.
• The number of mucosal eosinophils may be important because finding more than 20 per high-powered field (hpf) has recently been associated with eosinophilic (allergic) esophagitis rather than peptic esophagitis.

Treatment

Medical Care

• Because most cases are functional gastroesophageal reflux (GER), reassurance is the only treatment needed.
• Conservative measures may include upright positioning after feeding, elevating the head of the bed, prone positioning (infants >6 mo), and providing small, frequent feeds thickened with cereal.⁵
• Older children benefit from a diet that avoids tomato and citrus products, fruit juices, peppermint, chocolate, and caffeine-containing beverages. Smaller, more frequent feeds are recommended, as is a relatively lower fat diet because lipid retards gastric emptying. Proper eating habits are encouraged and weight loss and avoidance of alcohol and tobacco are recommended when applicable.
• Prone positioning may be recommended, at least for the first postprandial hour. However, the association of prone positioning with sudden infant death syndrome (SIDS) has brought its use into debate. Observations suggest that SIDS in the prone position is related to either suffocation or rebreathing carbon dioxide and is associated with puffy bedding material. Clearly, the use of the prone position during infancy must be based on a careful risk-to-benefit analysis. When it is advised, only very firm bedding material (no pillows) must be used. Bed elevations offer no added advantage to the prone position, and seated positions are not recommended.
• Thickening of formula provides a therapeutic advantage, particularly when excessive vomiting is associated with suboptimal weight gain. Even for infants with normal weight gain, thickened and reduced volume feedings may reduce the frequency and amount of vomiting episodes, ameliorating the concerns of an anxious caregiver. For formula-fed infants younger than 3 months, thickening is typically achieved by the addition of 1 tablespoon of rice cereal per 2 oz of formula. A recent meta-analysis examined the effect of thickened-feed interventions in gastroesophageal reflux.⁶
• Younger formula-fed infants may benefit from a prethickened, proprietary formula (Enfamil-AR; Mead-Johnson Nutritionals Inc, Evansville, IN). For breast-fed infants, aside from increasing feeding frequency, expressed breast milk may be thickened as described. Also, early introduction of rice cereal feedings (at age 3 mo) may be attempted. Recent work suggests that formula thickening is superior to positioning in promoting weight gain and reducing clinical symptoms in infants with gastroesophageal reflux.⁵
• Results of medical therapy are generally met with a better long-term response, leading to elimination of antisecretory medications (when prescribed) during infancy. This is primarily because normal development of GI motility includes resolution of physiologic gastroesophageal reflux by age 1 year (in most cases by age 6 mo). In mild, uncomplicated cases, more frequent thickened feeds and, in some cases, postprandial prone positioning may yield an excellent therapeutic response. In more severe cases, in addition to dietary management, pharmacologic intervention is directed at reducing gastric acid secretion. As pharmacotherapy has improved, the need for surgical therapy (fundoplication) has markedly decreased. Nevertheless, antireflux surgery remains one of the most common surgical procedures performed during infancy and early childhood.
• Current guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) involve the use of "step-up" and "step-down" therapy, which should be instituted under the guidance of a pediatric gastroenterologist.^7,8  
  • Media file 2 is a diagnostic and therapeutic algorithm to aid in the evaluation and management of gastroesophageal reflux. The diagram outlines the major points addressed in this article.
    
    

    

    Algorithm for evaluation and "step-up" management of gastroesophageal reflux (GER).

    
    
  • In the case of pharmacologic intervention, "step-up" therapy involves progression from diet and lifestyle changes to H₂ receptor blockade medications (eg, ranitidine, nizatidine) to proton pump inhibitors (eg, omeprazole, lansoprazole).⁹  Both classes of acid antisecretory have proven safe and effective for both infants and children in reducing gastric acid output.
  • In combination with diet and lifestyle changes, this management guideline should obviate the need for surgery in the vast majority of cases. One important exception, however, may be children with moderate-to-severe neurodevelopmental disabilities who typically manifest both dysphagia and gastroesophageal reflux and are at high risk for aspiration. In these patients, conservative therapy alone may not be sufficient in preventing reflux-associated complications. However, careful monitoring under optimal nonsurgical therapy should be conducted before considering operative intervention.

Surgical Care

The goal of surgery for gastroesophageal reflux disease (GERD) is to reestablish the antireflux barrier, without creating obstruction to the food bolus. In general, the Nissen fundoplication, which is a complete 360° wrap, best controls the symptoms of gastroesophageal reflux;¹⁰ however, it may lead to more episodes of dysphagia (difficulty and discomfort with swallowing) and gas bloat than a partial wrap (see Media file 3).

Diagram illustrating the Nissen fundoplication. Note how the stomach is wrapped around the esophagus (360º wrap).

• The goals of medical therapy in gastroesophageal reflux are to decrease acid secretion and, in many cases, to reduce gastric emptying time. The "step-up" approach described herein is directed at decreasing acid content of the refluxate. However, other components of the refluxate (eg, bile, pepsin, trypsin) may also lead to esophageal mucosal injury, and these gastric fluid components may exert damaging effects even under conditions of gastric alkalinization. Thus, some patients under antisecretory treatment may have normal pH probe studies yet continue to have the symptoms of gastroesophageal reflux.^11,12 In these cases, the development of EEI as a diagnostic tool may prove invaluable.
• When rigorous "step-up" therapy has failed, or when complications of gastroesophageal reflux pose a short or long-term survival risk, the goal of surgical antireflux procedures is to "tighten" the region of the lower esophageal sphincter (LES) and, if possible, reduce hiatal herniation of the stomach (occasionally seen in patients with GERD).
• Surgical treatment of gastroesophageal reflux should be considered for the following patients:
  • Infants and children who have failed "step-up" therapy for gastroesophageal reflux (typically over 12 wk) and those who cannot be weaned off of acid-reducing medications should be considered for surgical treatment.
  • Those with an atypical presentation, especially respiratory, whose symptoms are clearly associated with gastroesophageal reflux (eg, obstructive apnea temporally associated with reflux during pH monitoring) should be considered for surgical treatment. However, a period of medical therapy (including acid blockade) under close monitoring conditions should be attempted in many cases prior to recommending a surgical approach
  • Patients with complications of gastroesophageal reflux, such as aspiration, stricture of the esophagus, or Barrett esophagus should be considered for surgical treatment. Patients with neurologic impairment that requires feeding gastrostomy who are found to have pathologic reflux and remain medication dependent should also be considered for surgery.
  • Patients with chronic reflux and recurrence of anastomotic stricture after repair of esophageal atresia should be considered for surgical treatment.
• Observations related to the possible need for gastrostomy include the following:
  • Small gastric volumes, decreased compliance in infants, and slow gastric emptying rate following the fundoplication procedure may necessitate a gastrostomy procedure to accompany a fundoplication.
  • Patients who are neurologically impaired or who have an inability to tolerate feeds also need an accompanying gastrostomy.
• For those who fail medical therapy, continuous intragastric administration of feeds alone (via nasogastric tube) is another option.¹³ This method is often used in preterm infants who have a significantly greater surgical risk. In these cases, adequate nutritional management, in conjunction with appropriate medical therapy, may permit the infant to "outgrow" reflux while optimizing weight gain.

Consultations

• In addition to pediatric gastroenterological referral, pulmonary consultation may be required to comanage respiratory complications (see Media file 2).
  
  

  

  Algorithm for evaluation and "step-up" management of gastroesophageal reflux (GER).

  
  
• Surgical consultation may be required if medical treatment is not successful.

Diet

• In infants, small, frequent feeds are recommended. Also, parents should thicken formula with rice cereal. One tablespoon of dry rice cereal added to 2 oz of milk formula increases the caloric intake to 24 calories per ounce instead of 20 calories per ounce. Feeding volumes should be reduced, in association with increased feeding frequency. For breast-fed infants, early introduction of rice cereal by spoon (at 3-4 mo) may provide a similar thickening effect (expressed breast milk may also be thickened as above). Constipation may be a troublesome consequence of cereal supplementation; however, specific therapy for this problem is not usually required.
• In children, small, frequent meals are also recommended. Greasy and spicy foods, which increase postprandial reflux by increasing gastric distention and slowing gastric emptying, should be avoided. Chocolate, peppermint, tomato products, citrus, and caffeine, which lowers LES pressure, should also be avoided.

Activity

• Appropriate weight management of overweight or obese children is important. Obesity has been cited as a risk factor in the development of gastroesophageal reflux.
• Infants and children diagnosed with gastroesophageal reflux should avoid the seated or the supine position shortly after meals. In addition, sleeping in the prone position has been demonstrated to decrease the frequency of gastroesophageal reflux; however, that same position has been shown to have an association with SIDS.
• Studies that monitored esophageal acid exposure after elevation of the head of the bed showed a decrease in reflux activity in adults. Placing blocks under the head of the bed or placing a foam wedge under the patient's mattress can accomplish this.

Medication

Therapeutic response for gastroesophageal reflux may take up to 2 weeks. If treatment is successful, weight increases and vomiting episodes decrease. Recurrent aspiration pneumonia or apnea is cause for decreased length of medical therapy. Note that the so-called "prokinetic agents" have been omitted from the following drug list. No currently available prokinetic drug (eg, metoclopramide) has been demonstrated to exert a significant influence in the number or frequency of reflux episodes.

Antacids

These agents are used as diagnostic tools to provide symptomatic relief in infants. Associated benefits include symptomatic alleviation of constipation (aluminium antacids) or loose stools (magnesium antacids).

Aluminum hydroxide (ALternaGEL, Amphojel)

Increases gastric pH >4 and inhibits proteolytic activity of pepsin, reducing acid indigestion. Antacids can initially be used in mild cases. No effect on frequency of reflux but decreases its acidity.

Dosing

Adult

5-15 mL/dose PO qd/qid

Pediatric

2.5-5 mL/dose PO qd/qid

Interactions

Decreases effects of tetracyclines, ranitidine, ketoconazole, benzodiazepines, penicillamine, phenothiazines, digoxin, indomethacin, isoniazid; corticosteroids decrease effects of aluminum in hyperphosphatemia

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in recent massive upper GI hemorrhage and infants; renal failure may cause aluminum toxicity; can cause constipation

Magnesium hydroxide (Phillips Milk of Magnesia)

Used as antacid to relieve indigestion. Also causes osmotic retention of fluid, which distends colon and increases peristaltic activity that provides laxative effect. Forms magnesium chloride in vivo after reacting with stomach hydrochloric acid.

Dosing

Adult

5-15 mL PO qid ac and hs

Pediatric

2.5-5 mL prn; not to exceed 4 doses per d

Interactions

Decreases effects of tetracyclines, digoxin, indomethacin, and iron salts

Contraindications

Documented hypersensitivity; colostomy, ileostomy, renal failure, fecal impaction, and appendicitis

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in severe renal impairment and infants; can cause diarrhea

H₂ Receptor Antagonists

Like antacids, these agents do not reduce the frequency of reflux but decrease the amount of acid in the refluxate by inhibiting acid production. All are equipotent when used in equivalent doses. They are most effective in patients with nonerosive esophagitis and are considered the drug of choice in children because of well-established pediatric doses and liquid forms.

Nizatidine (Axid)

Competitively inhibits histamine at the H ₂ receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.

Dosing

Adult

300 mg PO hs or 150 mg bid

Pediatric

<12 years: Not established; limited data suggest the following:
Neonates: 2-4 mg/kg PO q8-12h or 2 mg/kg IV q6-8h
Infants: 2-3 mg/kg/dose PO q8-12h
Children: 2-3 mg/kg/dose PO q6-8h
>12 years: Administer as in adults

Interactions

Absorption slightly decreased (10%) when coadministered with antacids containing aluminum and magnesium hydroxides; coadministration with high dose aspirin (ie, 3900 mg/d) increases serum salicylate level

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; may increase risk of necrotizing enterocolitis in premature infants

Cimetidine (Tagamet)

Inhibits histamine at H₂ receptors of gastric parietal cells, resulting in reduced amounts of gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Dosing

Adult

10-15 mg/kg/dose PO/IV/IM qid ac and hs; alternatively, 800 mg PO bid or 400 mg PO qid

Pediatric

Neonates: 5-20 mg/kg/d PO/IV/IM divided q6-12h
Infants: 10 mg/kg/d PO/IV/IM divided q6-12h; not to exceed 300 mg/dose
Children: 20-40 mg/kg/d PO/IV/IM divided q6h

Interactions

Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Elderly patients may experience confusional states; may cause impotence and gynecomastia in young males; may increase levels of many drugs; adjust dose or discontinue treatment if changes in renal function occur; adverse effects include headache and pancytopenia

Ranitidine (Zantac)

Inhibits histamine stimulation of the H₂ receptor in gastric parietal cells, which reduces gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Dosing

Adult

3.5 mg/kg/dose PO bid/tid ac and hs; alternatively, 150 mg PO bid or 75 mg PO bid

Pediatric

Neonates: 2-4 mg/kg PO q8-12h or 2 mg/kg IV q6-8h
Infants: 2-3 mg/kg/dose PO q8-12h
Children: 2-3 mg/kg/dose PO q6-8h

Interactions

May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; adverse effects include headache and malaise

Famotidine (Pepcid)

Competitively inhibits histamine at H₂ receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen ion concentrations.

Dosing

Adult

10 mg PO bid

Pediatric

1-1.2 mg/kg/d PO divided q8-12h; not to exceed 80 mg/d
0.6-0.8 mg/kg/d IV divided q8-12h

Interactions

May decrease effects of ketoconazole and itraconazole; levels may increase with hydrochlorothiazide; fluconazole levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporine, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

If changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Proton pump inhibitors

These agents are indicated in patients who require complete acid suppression (eg, infants with chronic respiratory disease or neurologic disabilities). Administer with the first meal of the day. Children with nasogastric or gastrostomy tubes may have granules mixed with an acidic juice or suspensions; tubes must then be flushed to prevent blockage.

Lansoprazole (Prevacid)

Suppresses gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system (ie, proton pump) at the secretory surface of the gastric parietal cell. Blocks the final step of acid production. The effect is dose-related and inhibits both basal and stimulated gastric acid secretion, thus increasing gastric pH. Easy to administer to children because available as cap, PO disintegrating tab, and granules for PO susp.

Dosing

Adult

30 mg PO qd

Pediatric

<1 year: Not established; 1-2 mg/kg/d PO suggested as "step-up" therapy
1-11 years:
<30 kg: 15-30 mg PO qd or 1-2 mg/kg/d; not to exceed 30 mg qd; administer for up to 12 wk
>30 kg: 30 mg PO qd; administer for up to 12 wk
>11 years: Administer as in adults
Take before meals; do not chew or crush capsules

Interactions

Cytochrome P450 isoenzyme CYP2C19 and CYP3A3/4 substrate; increases theophylline clearance mildly (∼10%); may increase warfarin effects; may interfere with the absorption of ketoconazole, ampicillin, iron salts, and digoxin; sucralfate delays and decreases lansoprazole absorption by 30%; cranberry juice significantly reduces gastric pH and may reduce proton pump inhibitors effectiveness

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Consider adjusting dose in liver impairment; Prevacid SoluTabs contain aspartame, which is metabolized to phenylalanine and must be used with caution in patients with phenylketonuria

Omeprazole (Prilosec)

Decreases gastric acid secretion by inhibiting the parietal cell H⁺/K⁺ ATPase pump. Used for the short-term and long-term treatment (4-8 wk to 12 mo) of GERD.

Dosing

Adult

GERD: 20 mg PO qd

Pediatric

Wide dosage range of 0.7-3.3 mg/kg/d PO has been reported in the pediatric literature

Interactions

May decrease effects of itraconazole and ketoconazole; may increase toxicity of warfarin, digoxin, and phenytoin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Bioavailability may increase in elderly patients; adverse effects include headache, rash, diarrhea, hypergastrinemia, and polyps

Esomeprazole (Nexium)

S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H⁺/K⁺ -ATPase enzyme system at secretory surface of gastric parietal cells.
Used in severe cases of and patients not responding to H2 antagonist therapy.
Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers; may be used up to 8 wk to treat all grades of erosive esophagitis.

Dosing

Adult

20 mg PO qd for 4 wk

Pediatric

<1 year: Not established
1-11 years: 10-20 mg PO qd for up to 8 wk
12-17 years: 20-40 mg PO qd for up to 8 wk

Interactions

Extensively metabolized by CYP2C19 and CYP3A4, also inhibits CYP2C19; coadministration with CYP2C19 and CYP3A4 inhibitors (eg, voriconazole) may increase esomeprazole levels, but dosage adjustment is not normally required; may decrease atazanavir plasma levels; decreases diazepam clearance by 45%; postmarketing surveillance found coadministration with warfarin may increase INR and prothrombin time; amoxicillin or clarithromycin may increase plasma levels of esomeprazole when used concurrently; may reduce absorption of dapsone; may increase levels of diazepam and GI absorption of digoxin; may decrease absorption of iron, ketoconazole and itraconazole

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Symptomatic relief with proton pump inhibitors may mask symptoms of gastric malignancy; frequently occurring (>1%) adverse effects include headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and xerostomia

Follow-up

Complications

• Gastroesophageal reflux (GER) strictures typically occur in the mid-to-distal esophagus. Patients present with dysphagia to solid meals and vomiting of nondigested foods. As a rule, the presence of any esophageal stricture is an indication that the patient needs surgical consultation and treatment (usually surgical fundoplication). When patients present with dysphagia, barium esophagraphy is indicated to evaluate for possible stricture formation. In these cases, especially when associated with food impaction, eosinophilic esophagitis must be ruled out prior to attempting any mechanical dilatation of the narrowed esophageal region. 
• Barrett esophagus occurs when goblet cell metaplasia occurs. Risk of adenocarcinoma is increased 30-40 times. As with esophageal stricture, the presence of Barrett esophagus indicates the need for surgical consultation and treatment (usually surgical fundoplication).

Prognosis

• Most cases of gastroesophageal reflux in infants and very young children are benign, and 80% resolve by age 18 months (55% resolve by age 10 mo). However, in refractory cases or when complications related to reflux disease are identified (eg, stricture, aspiration, airway disease, Barrett esophagus), surgical treatment (fundoplication) is typically necessary. The prognosis with surgery is considered excellent. The surgical morbidity and mortality is higher in patients who have complex medical problems in addition to gastroesophageal reflux.
• During infancy, the prognosis for gastroesophageal reflux resolution is excellent (developmental disabilities represent an important diagnostic exception), with most patients responding to conservative nonpharmacologic treatment. Some patients require a "step-up" to acid-reducing medications. Surgery is required in only a very small minority of patients. In patients whose gastroesophageal reflux persists into later childhood, long-term therapy with antisecretory agents is often required. Because symptomatic gastroesophageal reflux after age 18 months likely represents a chronic condition, long-term risks are increased.
• Methylxanthines exacerbate reflux secondary to decreased sphincter tone.
• Children with neurodevelopmental disabilities, including cerebral palsy, Down syndrome and other heritable syndromes associated with developmental delay, have an increased prevalence of gastroesophageal reflux. When these disorders are associated with motor abnormalities (particularly spastic quadriplegia), medical gastroesophageal reflux management is often particularly difficult, and suck and/or swallow dysfunction is often present. Infants with neurological dysfunction who manifest swallowing problems at age 4-6 months may have a very high likelihood of developing a long-term feeding disorder.

Patient Education

• See Diet and Activity for lifestyle changes.
• For excellent patient education resources, visit eMedicine's Heartburn/GERD/Reflux Center and Children's Health Center. Also, see eMedicine's patient education articles Spitting Up in Infants, Gastroesophageal Reflux Disease (GERD) FAQs, Reflux Disease (GERD), Understanding Heartburn/GERD Medications, and Sudden Infant Death Syndrome (SIDS).
• In addition, extremely useful patient information and provider-focused information can be accessed by visiting the NASPGHAN Web site.

Miscellaneous

Medicolegal Pitfalls

• Failure to recommend conservative diet and lifestyle changes before initiation of pharmacologic or surgical treatment
• Failure to realize that most cases of gastroesophageal reflux (GER) during infancy are self-limited and respond to conservative management
• Failure to understand the currently accepted clinical guidelines for gastroesophageal reflux management in children
• Failure to inform parents that patience is important, because the therapeutic response may take several weeks; and, during infancy, that the goals of therapy are to ensure normal growth and development and to avoid gastroesophageal reflux–related complications

Multimedia

Media file 1: The image is a representation of concomitant intraesophageal pH and esophageal electrical impedance measurements. The vertical solid arrow indicates commencement of a nonacid gastroesophageal reflux (GER) episode (diagonal arrow). The vertical dashed arrow indicates the onset of a normal swallow.

Media file 2: Algorithm for evaluation and "step-up" management of gastroesophageal reflux (GER).

Media file 3: Diagram illustrating the Nissen fundoplication. Note how the stomach is wrapped around the esophagus (360º wrap).

References

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Keywords

GER, gastroesophageal reflux disease, GERD, motility, heartburn, physiologic GER, lower esophageal sphincter, LES, esophagus, transient LES relaxation, tLESR, failure to thrive, erosive esophagitis, esophageal stricture formation, chronic respiratory disease, Barrett esophagus, esophageal mucosal dysplasia, asthma, gastric outlet obstruction, reactive airway disease, laryngeal inflammatory disease, otitis media, otalgia, chronic sinusitis, heartburn, apnea, bradycardia, pneumonitis, waterbrash, Sandifer syndrome, opisthotonus, torticollis, laryngitis, halitosis, pharyngitis, hiatal hernia, gastroparesis, pyloric stenosis, apparent life-threatening event, ALTE, treatment, diagnosis

Contributor Information and Disclosures

Author

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Coauthor(s)

Andre Hebra, MD, Chief, Division of Pediatric Surgery, Medical University of South Carolina; Professor of Surgery and Pediatrics, Medical University of South Carolina
Andre Hebra, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Surgeons, American Medical Association, American Pediatric Surgical Association, Association for Academic Surgery, Society of Laparoendoscopic Surgeons, South Carolina Medical Association, Southeastern Surgical Congress, and Southern Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Jayant Deodhar, MD, Associate Professor in Pediatrics, BJ Medical College, India; Honorary Consultant, Departments of Pediatrics and Neonatology, King Edward Memorial Hospital, India
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

B U K Li, MD, Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Director, Pediatric Fellowships and Gastroenterology Fellowship, Medical Director, Functional Gastrointestinal Disorders and Cyclic Vomiting Program, Medical College of Wisconsin; Attending Gastroenterologist, Children's Hospital of Wisconsin
B U K Li, MD is a member of the following medical societies: Alpha Omega Alpha, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition
Disclosure: Nothing to disclose.

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Jennifer DA Liburd, MD, to the development and writing of this article.

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