IAP Specialty Series on Pediatric Gastroenterology Ashish Bavdekar, John Matthai, Malathi Sathiyasekaran, SK Yachha
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Gastroesophageal Reflux1

John Matthai,
Sarah Paul
 
INTRODUCTION
Gastroesophageal reflux (GER) is the most common esophageal disorder in children. GER is defined as the involuntary passage of gastric contents into the esophagus with or without regurgitation and vomiting. The regurgitated gastric content may be saliva, ingested food, gastric secretions, pancreatic or biliary secretions.
Gastroesophageal reflux, which manifests as “bringing up” or “regurgitation” of feeds is physiological in most infants and needs no investigations or treatment. A few, however, have pathological symptoms and are referred to as having gastroesophageal reflux disease (GERD). Mothers often confuse between ”regurgitation” and “vomiting”. Vomiting is the forceful expulsion of gastric contents through the mouth and involves intense muscular activity of the respiratory and abdominal muscles. Regurgitation is passive and effortless and involves no muscular activity.
 
PREVALENCE AND NATURAL HISTORY
The prevalence of GER is high in western countries and is now being increasingly recognized in India. Formula feeding and restraining of infants in car seats are probable reasons in western countries. The prevalence of GERD in infants and children ranges from 1 to 8%.1 More than 85% of premature infants have GERD with up to 10% of them having extra intestinal manifestations like bradycardia and apnea. GER is an age-related problem in infants. Almost all babies will have some reflux at 3 months of age. However, only around 33% will be brought for medical attention at that age and it declines to 20% by 6 months of age. In most symptomatic infants, regurgitation decreases appreciably by 12 to 24 months of age.2 GERD changes in clinical character with advancing age. In a study on 1700 children followed from infancy to 21 years, it was noted that the predominant symptom changed from regurgitation in infancy to pain in adolescence. While 1.8% had heart burn by 9 years, 22% had epigastric pain or heart burn by 21 years. Older children with persisting regurgitation are unlikely to improve with age and may continue to remain symptomatic. Chronic untreated esophagitis can result in strictures, Barrett's esophagus and adenocarcinoma in adults. Data from US centers have shown a rise in incidence of Barrett's esophagus in children from less than 2% in 1997 to 4% in 2000.2
 
PATHOPHYSIOLOGY OF REFLUX
The esophagus is not under voluntary control. Distal to the mid-esophagus the muscular layer is composed of smooth muscle fibers. Peristaltic waves involving the external circular muscular layer propel the ingested food through the esophagus into the stomach. The lower esophageal sphincter is an area of thickened circular muscle that is tonically contracted at rest. A well-coordinated relaxation of the lower esophageal sphincter is essential for the transport of food into the stomach. Basal LES pressure is maintained above 4 mm Hg to prevent reflux. Pressure studies have disproved the earlier theory that infants with GER have abnormally low basal tone.
Reflux is now thought to occur due to transient LES relaxations (TLESR) in the absence of esophageal peristalsis and mediated primarily through vagal pathways via the brain stem.3 The pressure changes at the gastroesophageal junction are dependent on the volume-pressure relationship in the stomach as well as the proximal esophageal clearance of the refluxed material. Sensory pathways not only cause pain symptoms but also serve as the gastric afferent limb of the TLESR. The TLESR can thus be thought of as either a “belch equivalent” releasing gastric pressure (afferents being in the stomach) or as an “aborted swallow” (afferents in the esophagus).4 Nitric oxide and cholecystokinin are thought to mediate TLESR, because their antagonists reduce the frequency of reflux.
Relaxation of the LES may also be mediated by inhibitory neurotransmitters like vasoactive intestinal peptide (VIP) released from the enteric neurons.5 Thus, abnormal functioning of the CNS can result in abnormal gastric motor activity, retrograde peristalsis and relaxation of the LES. The crural diaphragm that surrounds the LES increases its tone especially during straining. Complex neural connections ensure that TLESRs are physiologically accompanied by coordinated crural relaxation. This explains the association of hiatus hernia with GERD.6 A recent study reported hiatus hernia in 6% of children with GERD.7 A genetic predisposition has been postulated in the etiology of hiatus hernia and complicated GERD. A locus for “Severe Pediatric GERD” has been identified on chromosome 13q14.8
Esophagitis does not occur in all children with reflux. The development of esophagitis depends on the frequency and duration of the reflux, the nature of the refluxate and the protective mechanisms in the esophageal mucosa.9
 
PATHOGENESIS OF REFLUX DISEASE
GER in normal children occurs in the postprandial period, lasts less than 3 minutes and is asymptomatic. Physiologic reflux is uncommon in sleep. In children with GERD, nocturnal reflux is frequent.10 Reflux occurring at night is associated with increased complications, since the normal protective mucosal clearance, gravitational clearance and salivation are less effective during sleep.
The pathogenesis of reflux in premature infants is not well understood.11 They require good calorie intake but have limited gastric capacity. The refluxate tends to be of large volume and usually reaches the upper esophageal sphincter (UES). The response of the UES in most situations is to increase the sphincter pressure and protect the airway, but when esophageal pressure is excessive, it relaxes and allows the refluxate to escape. Gravitational force may, 3however, sometimes lead to aspiration into the lung. Laryngeal stimulation can also cause apnea in premature babies. The refluxate is usually not acidic in premature babies because frequent feedings buffer the gastric acid. Nasogastric tubes impair clearance of the refluxed material if they are of large size.12
Reflux is affected by environmental factors such as posture, activity, clothing and diet. Increased volume, acidity and osmolality of feeds are known to trigger regurgitation. In infants, supine and seated position (as in car seats) can result in reflux. Children with neurologic impairment, obesity, hiatus hernia and repaired esophageal atresia or achalasia are at high risk for chronic GERD.
 
SYMPTOMS AND MANIFESTATIONS
Some degree of reflux is normal in the first year of life and parents of healthy, thriving infants with reflux, should be reassured. “Regurgitating” or “bringing out” is the visible form of GER and can cause failure to thrive from loss of calories. Significant GERD can, however, exist even in the absence of this symptom.
Other manifestations of GERD include symptoms of esophagitis and respiratory tract related problems like apnea, acute life-threatening episode (ALTE), recurrent pneumonia or asthma.13 Reflux esophagitis may present as irritability (colic), failure to thrive, melena or hematemesis, in infants and young children. A symptom complex called “Sandifer's syndrome” has been seen in some infants with reflux and consists of abnormal posturing with tilting of the head to one side and bizarre contortions of the trunk. Older children with esophagitis complain of epigastric/retrosternal pain, dysphagia, odynophagia, belching or postprandial fullness. Anemia can result from chronic GI blood loss due to melena/hematemesis. Grading of lesions on endoscopy or biopsy does not correlate well with the severity of symptoms and proven severe esophagitis may have only minimal symptoms and vice versa.
There seems to be an association between GERD and dental erosions. Young children and children with neurologic impairment are at higher risk. There is no convincing evidence that GER is the primary cause of apnea and ALTE in most infants.14 However, in a subgroup of infants, it may play a significant role.15 Chronology of events, relationship with feeds, presence of feeds in the pharynx and evidence of chronic inflammation in the larynx indicate an etiological association. GERD has long been suspected to be responsible for asthma and recurrent pneumonia in infants. In the absence of well-designed controlled trials, it is not possible to conclude if reflux is the cause or an effect of the problem.16 Respiratory mucosa is very sensitive to acidic pH and exposure to gastric acid can result in inflammation leading to wheezing or infection. Reflux may also occur secondary to increased respiratory effect or persistent coughing in children with severe asthma. GERD may be considered as a possible cause of asthma in children who respond poorly to treatment/prophylaxis, infants with severe wheezing without a family history and in those without eosinophilia/elevated serum IgE. Neurologically abnormal children have more severe and complicated GERD than normal children. Increased gastric pressure due to spasticity, impaired refluxate clearance due to supine posture as well as inability to move and communicate predispose them to severe disease.174
 
EVALUATION
Detailed evaluation is necessary only in children with GERD. Available investigations have different goals and they include: documenting GER, excluding precipitating causes and associated anomalies, documenting tissue damage, or establishing a cause and effect relationship between GER and the symptom. Tests, therefore, need to be individualized, so that appropriate therapeutic decisions can be made. Standardized questionnaires for mothers are useful to diagnose and quantify the severity of regurgitation.18 It is a good objective assessment and repeated assessments can document improvement, stability, or worsening of disease.
 
Contrast Studies
Barium study which has been in use for many decades has low sensitivity and specificity in diagnosis of GERD. It is now done to rule out structural abnormalities like a large hiatus hernia, esophageal stricture, duodenal web or atypical pyloric stenosis.19 Mere demonstration of reflux on a barium study has little significance, since it is normal in infants. Dynamic barium esophagography is used to identify abnormalities in pharyngeal, laryngeal and upper esophageal function.
 
Esophageal pH Studies
Esophageal pH monitoring has considerably improved our understanding of GER.20 Flexible pH probes can be placed in the esophagus while allowing the infant normal activity. A drop in intraesophageal pH < 4 is considered an acid reflux episode. A random pH probe study is of no value in the evaluation of GER disease. Ambulatory pH probes permit 24-hour monitoring while the infant carries on normal activities like sleep, food intake and change of position. Prolonged pH monitoring can determine the frequency of reflux, the time taken to clear the refluxate as well as the effect of feeding, body position and state of consciousness on GER.21 Correlation of episodic events like apnea in newborns, behavioral disturbances in infants and heart burn in older children, with acid reflux is also possible. A major drawback is that postprandial reflux may sometimes be missed, since foods neutralize gastric acidity and pH probes cannot detect non-acidic reflux. There is also no consistent correlation between the severity of acid reflux and the severity of symptoms and complications.
 
Nuclear Scintigraphy
This is also called “Milk Scan” wherein isotopes like 99mTC can be added to the infant's feed and monitored with a gamma counter. It is noninvasive and low in radiation but requires considerable expertise and experience. The gastric emptying time and the amount of radionucleotide refluxed into the esophagus or lungs can be studied. It is particularly useful in situations where GER is thought to be the cause of asthma or pneumonia. A negative test does not rule out possible pulmonary aspiration.
 
Endoscopy and Biopsy
Endoscopy allows direct visualization of the esophageal mucosa and the dynamics of the LES as well as provides a biopsy specimen for histopathology.22 Esophagitis always occurs in the lower 5part of the esophagus and can be recognized as redness of the mucosa with loss of the normal vascular pattern. The severity of the endoscopic esophagitis in children is graded according to the classification of Savary and Miller. A large majority of reflux esophagitis in children are restricted to grades 1 and 2. A good visual inspection must be done before multiple punch biopsies of the esophagus are taken. Histological criteria for the diagnosis of esophagitis have been graded. Basal cell zone hyperplasia of the esophageal squamous epithelium and increased stromal papillary length are the most commonly used criteria. Basal zone hyperplasia of more than 20% of the epithelial thickness and papillary height extending into the upper third of the epithelium are reliable criteria for histological diagnosis. It is important to recognize that esophagitis can occur from causes other than GERD. These include eosinophilic esophagitis, infections (Candida, herpes, CMV), Crohn's disease, caustic ingestion, etc. Longstanding untreated reflux esophagitis results in aberrant columnar epithelium lining the distal esophagus (Barrett's esophagus). The diagnosis requires multiple biopsies to show the transition from squamous to columnar epithelium. This is potentially malignant and aggressive medical or surgical therapy can reverse the mucosa to normal.
 
Empirical Acid Suppression as Diagnostic Test
Some experts recommend that in older children with typical pain symptoms of GERD, an empirical trial of PPIs for 4 weeks is justified. However, such an approach is not recommended for infants and young children in whom symptoms of GERD are nonspecific.
 
Miscellaneous Techniques
Esophageal manometry is used to assess pressure profile and dynamic changes. It can rule out achalasia and other motility disorders. Multiple intraluminal impedance monitoring is useful in demonstrating nonacidic reflux. It complements an esophageal pH study, but is difficult to perform and analyze.23
Bilirubin monitoring in the esophageal lumen is mostly of interest in research studies. Duodenogastric refluxate does not cause esophagitis except in the presence of acid.24 Surface electrogastrography records the myoelectrical activity generated by the pacemaker interstitial cells of Cajal. This is a non-invasive technique which may be useful in identifying motor abnormalities in the stomach that predispose to GERD. It may be of use in the evaluation of functional symptoms such as nausea, anorexia and dyspepsia, without an organic basis.25
Congenital abnormalities of the upper airway, e.g. Laryngeal clefts may result in aspiration during reflux or swallowing. Laryngobronchoscopy allows direct visualization of the area. It can also detect the presence of vocal cord erythema or nodules secondary to acid reflux. Polysomnography (sleep study), in association with esophageal pH study, is useful to identify apneic episodes that may be associated with acid reflux.
 
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of regurgitation in children is varied and requires a careful history and evaluation. Faulty feeding/overfeeding particularly in artificially fed infants is of particular concern. Cow's milk protein allergy is an important consideration in young infants who are 6exclusively formula-fed and are failing to thrive. In young infants with acute onset of symptoms, systemic infections should be ruled out. Gastrointestinal obstruction (malrotation/volvulus, pyloric stenosis, duodenal stenosis, stricture), achalasia, food intolerance and food allergy are other important differential diagnoses.
 
MANAGEMENT
Regurgitation being physiological in infancy, only those with pathological GER need to be treated. The risks and benefit of therapy should be carefully assessed in terms of age of the patient. In adolescents and adult GERD, esophagitis and consequently proton pump inhibitors are of prime importance. In infants the refluxate is less acidic and of large volume; and so positioning, consistency of feeds and probably prokinetics are more important.26
 
Lifestyle Measures
The “head elevated prone position” is clearly effective in reducing the reflux when compared to the supine or seated positions. However the risk of sudden infant death syndrome (SIDS) outweighs the benefits of prone or lateral positions and hence it is not recommended as a sleep position in infants less than 12 months.27 Positioning in an “infant chair” reclining at a 45 degree angle has not been shown effective. Small, frequent feeds are useful in reducing the reflux since they reduce the available volume in the stomach for reflux. Continuous nasogastric drip feeding is effective in reducing the reflux and improving weight gain in severe cases. Thickening of feeds does not improve the volume of refluxate, but decreases the number of episodes of ‘vomiting’.28 Thickened formula may, however, increase coughing during feeds. Thickening of feeds is usually achieved by adding rice cereal. In older children, positioning, control of obesity and avoidance of large meals may be beneficial.
 
Pharmacologic Therapy
Pharmacotherapy consists of acid–lowering agents, barrier agents and prokinetics. There is a paucity of data on the relative benefits of the various drugs in children.
 
Acid Lowering Agents
They are useful only in situations where the symptoms are acid related, like esophagitis, or heartburn. In order of increasing potency these include the conventional antacids, H2 receptor antagonists and proton pump inhibitors (PPI). Conventional antacids (1 ml/kg/dose qid) are not recommended now. Among the H2 blockers, Ranitidine (3–5 mg/kg/dose bd/tid) and Cimetidine (10–15 mg/kg/dose qid) have been used extensively, with the former being better tolerated and having lesser side effects.29 PPIs the most effective acid suppressants, covalently bond and deactivate the H+K+ ATPase pumps.30 They require acid for activation and should be administered 1 hour before breakfast. Omeprazole at 0.5–0.7 mg/kg/day is commonly used.31 Higher doses may be used in selected cases if esophageal pH studies show no response to treatment. For children unable to swallow the capsules, granules can be administered orally in weakly acidic foods such as apple juice or yogurt. Other PPIs like Lansoprazole (1.4 mg/kg/day), Pantoprazole 7and Rabeprazole are also effective. PPIs are superior to H2 blockers in relieving symptoms and healing esophagitis. Once daily dosing is sufficient in most children. In patients with nocturnal acid breakthrough, a morning dose of PPI and night dose of H2 blocker is used. No PPI has been approved for use in infants less than one year, even though they are widely prescribed.
 
Barrier Agents
Sucralfate and Alginate form complexes with the base of ulcers/erosions and is effective in settings where the esophageal epithelium has been severely damaged. The action is comparable to H2 receptor antagonists in adults but its safety and usefulness in children is unproven. While short-term use may be justified in older children with severe pain, chronic use is not recommended especially in infants.
 
Prokinetic Agents
Since GERD has many features of intestinal motility disorders, prokinetic agents have been used in these patients. However, the potential side effects and toxicity have dampened the enthusiasm in their use. Bethanechol has no clear benefit and is not used. Metoclopranide has a narrow therapeutic range and extra-pyramidal side effects are not uncommon in children. Domperidone has not been proven effective in healing of reflux esophagitis in controlled trials. Cisapride (0.2 mg/kg/dose qih) a 5HT antagonist is thought to act by enhancing neurotransmitter release that stimulates smooth muscle contraction throughout the intestinal tract. It has been shown beneficial in reflux esophagitis, but not as dramatic as was earlier claimed. Studies comparing cisapride with other prokinetics have shown statistically significant better outcome with the use of cisapride in esophagitis—endoscopic assessment, duration of reflux episodes, esophageal clearance and improvement in symptoms. However, cardiotoxicity is the major side effect. The 2009 ESPGHAN/NASPGHAN consensus statement does not support the use of cisapride or any other prokinetic in GERD.32,33
 
Surgical Treatment
Surgery is indicated only in children with GERD which is refractory to adequate medical treatment— “Chronic relapsing GERD”. Indications include failure of optimal medical therapy, dependence on long-term medical therapy, non-adherence to medical therapy or recurrent pulmonary complications. Nissen Fundoplication is commonly done. Although efficacious in many children, side effects are common and often distressing.34 Moreover, surgery may not always be effective and some children will continue to require pharmacotherapy even after surgery. Complications may be attributed to many factors—“Bad patient” in whom surgery was technically challenging, “Bad diagnosis” in whom the symptoms which prompted surgery were actually not due to GERD, and “Bad therapy” due to defective surgical competence. Complications are more common in those with chronic neurologic or respiratory disease. A tight wrap may result in dysphagia or gas bloat presenting with nausea, vomiting, abdominal distension, retching and gagging. Laparoscopic fundoplication can be as effective as open fundoplication in children but requires expertise.358
 
Extraesophageal Manifestations
In these situations, therapy must be aggressive and for longer duration.36 Twice daily PPIs maintained for at least 3 months is recommended. Surgery may be considered early if symptoms are refractory to medical treatment, even though complications of surgery are greater in these patients.
 
SUMMARY
Gastroesophageal reflux is the involuntary passage of gastric contents into the esophagus. While in a majority of infants it is physiological, in some, it could be pathological (GERD). Reflux decreases by 12–24 months of age; even in those with severe symptoms. Reflux occurs due to transient lower esophageal sphincter relaxations and not due to an abnormally low basal tone of the LES as was earlier thought. Reflux can be triggered by posture (supine and seated), diet (increased volume, acidity and osmolality) and activity. Nocturnal reflux is usually pathological and associated with complications.
Children with GERD usually present with failure to thrive from loss of calories or symptoms of esophagitis. Apnea and acute life-threatening event can occur due to reflux in newborns. The association between asthma and recurrent pneumonia is unclear. Children with neurologic impairment, obesity, hiatus hernia and those who have had esophageal surgery are at high risk for chronic GERD.
Investigations in GER should be individualized. The mere demonstration of reflux in a barium study has little significance. Barium studies are done only to rule out structural abnormalities. Upper GI endoscopy and biopsy is the gold standard in diagnosis of esophagitis. 24-hour esophageal pH studies help to determine the frequency of reflux and correlate reflux with episodic symptoms. Nuclear scintigraphy is useful to demonstrate regurgitation into the respiratory tract.
Positioning in the “head elevated prone position” is beneficial, but carries an increased risk of sudden infant death. Thickening of feeds decreases the frequency of reflux. Acid lowering agents are useful in situations where acid is responsible for the symptoms. PPIs are most effective, but are still not approved in infants below 1 year of age. Prokinetics are not recommended in view of serious side effects. Fundoplication should be considered only in chronic relapsing GERD.
9
 
ACKNOWLEDGMENT
The authors wish to thank Mrs Dhanabaghyam for secretarial assistance.
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