Gastroesophageal Reflux in Children
Gastroesophageal reflux (GER) is defined as the involuntary retrograde passage of gastric contents into the esophagus with or without regurgitation or vomiting. It is a frequently experienced physiological condition occurring several times a day mostly postprandially and causing no symptoms. Gastroesophageal disease (GERD) occurs when reflux of the gastric contents causes symptoms that affect the quality of life or pathological complications.
Regurgitation is defined as effortless passage of gastric contents into the mouth. Other terms such as “spitting up” and “spilling” are also used for regurgitation. When regurgitation occurs in healthy, thriving, happy infants, it is always physiological.
The prevalence of GERD in infants and children is in the range of 1–10%. The prevalence of GER is age dependent. About 70–85% of infants have regurgitation within 2 months of life, and GER resolves without intervention in about 95% of infants by 1 year of age. Children with chronic respiratory and neurological diseases have a higher incidence of GERD.
Two major elements that compose the anti-reflux barrier are the lower esophageal sphincter (LES) and the crural diaphragm. The LES is a thickened ring of tonically contracted smooth muscle in the distal esophagus that generates a high-pressure zone at the gastroesophageal junction and serves as a mechanical barrier between the stomach and the esophagus. The right crura of diaphragm encircle the LES and provide additional support. Both structures generate a high-pressure zone in the distal esophagus. Failure of one or both mechanisms predisposes GER.
Transient lower esophageal sphincter relaxation (TLESR) is the predominant mechanism of GERD in all ages. TLESR is defined as an abrupt decrease in LES pressure to the level of intragastric pressure, unrelated to swallowing and of relatively longer duration than the relaxation triggered by a swallow. TLESR is a neural reflex, mediated through the brainstem, and the vagus nerve is the efferent pathway. Gastric distention and pharyngeal stimulation have been demonstrated to elicit relaxation. In addition to TLESRs, mechanical support of the hiatal crura, delayed esophageal clearance, and noxious characteristics of the refluxate contribute to GERD. Hiatal hernia is not as common in children as compared to adults but has been reported in cases of severe reflux, cystic fibrosis, and in children with neurological impairment.
Delayed gastric emptying has been associated with GERD in infants and children. Gastric emptying depends on the volume, osmolality, and caloric density of the meal consumed. The receptive relaxation of the fundus in response to a meal also impacts the occurrence of TLESRs. Recently, gastric emptying was shown to be delayed in patients with cow’s milk protein allergy in comparison with control subjects and infants with GER. It should be kept in mind that secondary GERD occurs with cow’s milk protein allergy and contributes to pathophysiology of GERD.
The refluxate (gas, liquid, or mixed contents) provokes esophageal distention or acidification, and this may trigger delayed esophageal clearance. The pathogenicity of the refluxate is determined by its constituents: acid, pepsin, and bile salts. Acid in combination with pepsin has been found to be the most noxious to esophageal mucosa. Esophageal mucosal injury in GERD occurs when mucosal defensive factors are overwhelmed by the refluxate.
There is a higher incidence of GER in infants, which is physiological. It is due to shorter esophagus, wider angle of His, frequent feedings, and more time in the supine position.
Regurgitation and vomiting
These are the most common symptoms of infant reflux. The typical presentation of uncomplicated infant GER is effortless, painless regurgitation in a healthy infant with normal growth – the so-called happy spitter. It is usually effortless and non-bilious with no or minimum irritability. A thorough history and physical examination with attention to warning signals suggesting other diagnosis is generally sufficient to establish a clinical diagnosis of uncomplicated infant GER.
Detailed feeding history including amount and frequency of formula or breast feeding, position during feeding, burping, and behavior during feeding should be obtained. Choking, gagging, coughing with feedings, or significant irritability can be warning signs for GERD or other diagnosis. If there is a forceful vomiting of gastric contents, laboratory and radiographic investigation (upper gastrointestinal series) is warranted to exclude other causes of vomiting.
Unexplained crying and distressed behavior
These are nonspecific symptoms and associated with a variety of pathological and non-pathological conditions in infants. Healthy young infants fuss or cry an average of 2–2.5 h daily. Consideration should be given to individual variation of crying in infants and parental perception of the crying. Irritability coupled with arching in infants is thought to be a nonverbal equivalent of heartburn and chest pain in older children. Other causes of irritability including cow’s milk protein allergy, neurologic disorders, constipation, and infection should be ruled out. The presentation of cow’s milk protein allergy overlaps with GERD, and both conditions may coexist in 42–58% of infants.
Failure to thrive or poor weight gain
This can be the result of recurrent regurgitation and is a warning sign for GERD that alters clinical approach and management. A detailed feeding history should be obtained including the amount of intake, frequency of feedings, and description of infant sucking and swallowing behavior. Poor weight gain despite an adequate intake of calories should prompt evaluation for causes of regurgitation and weight loss other than GERD.
Heartburn is a symptom of GERD with or without esophagitis. Although older children can verbalize pain, the exact description may not be reliable until at least 8 years of age or later. In adolescents heartburn and regurgitation are reliable indicators of GERD. The guidelines recommend lifestyle changes initially, followed by 2–4-week empiric trial of acid suppression. If symptoms persist, then endoscopic evaluation is warranted to determine the presence of esophagitis and exclude other diagnosis such as eosinophilic esophagitis or infections.
Dysphagia can be the presentation of GERD; however, anatomic abnormalities, neurologic disorder, inflammatory conditions of mouth and esophagus, and psychological conditions should be ruled out. Imaging studies and endoscopic evaluation with histology can help to define the etiology.
Odynophagia or pain caused by swallowing
Odynophagia can occur in GERD and eosinophilic esophagitis but also can be seen in oropharyngeal inflammation.
Food refusal has often been a considered a symptom of GER, but there is no evidence that supports a causal relationship.
Extraesophageal Symptoms of GER
Dental erosions can be associated with acid reflux, especially on occlusive surfaces of posterior teeth. Dental erosion, also known as perimylolysis, is the irreversible loss of dental hard tissue by a chemical process in the absence of bacteria. This differentiates it from caries. It is characterized as a hard “dished out” area with a smooth, glistening base. Ingestion of acidic beverages and poor hygiene are the external contributory factors, but this usually affects anterior surfaces.
This is spasmodic torsional dystonia with arching of the back and opisthotonic posturing. It is an uncommon but specific presentation of GERD. Other neurological disorders including seizures, infantile spasm, and dystonia should be ruled out. The true pathophysiologic mechanisms of this condition remain unclear, but it is speculated to be secondary to vagally mediated reflex due to esophageal acid exposure. It responds well to anti-reflux treatment.
Apnea and apparent life-threatening events (ALTEs)
These are frequently considered extraesophageal manifestations of GERD in infants, but causality is rarely established. Apnea of prematurity (AOP) is a developmental sleep disorder which is yet to be completely understood. Feeding is an important trigger for AOP. While hypoxemia during feeding is most likely related to an immature coordination between sucking/swallowing and breathing, it is potentially due to an immature laryngeal chemoreflex. Hypoxemia after feeding may be caused by diaphragmatic fatigue, and GER only rarely plays a role. Although a clear temporal relation based on history suggests GER, the current evidence supports that GER is not related to apnea or to ALTEs. It is also reported that anti-reflux medications do not reduce the frequency of apnea in premature infants.
ENT presentations include stridor, chronic cough, hoarseness and lump in the throat, recurrent sinusitis, pharyngitis, and serous otitis media. Postglottic edema, vocal cord edema, arytenoid edema, and tracheal cobblestoning during laryngoscopy and bronchoscopy have been associated with GERD. There is no proven mechanism by which GER can cause these symptoms, although direct injury by the refluxate, neural reflexes mediated by intraesophageal acid, and stimulation of laryngeal chemoreceptors have been speculated. Pepsin has been identified in the middle-ear fluid of children with effusion.
Asthma and GER commonly coexist, and children with asthma were reported to have a high prevalence of GER. Sixty to eighty percent of children with asthma have abnormal pH or pH/impedance studies. Esophageal acidification in healthy individuals has minimal effect on pulmonary function; however, in patients with asthma, it can cause airway hyperresponsiveness and airway obstruction. Nocturnal wheezing appears related to GERD. Proposed mechanisms for GER inducing asthma are direct aspiration, vagally mediated laryngeal and bronchial spasm, and neurally mediated inflammation through the release of tachykinins.
Conversely, asthma can induce GER. Chronic hyperinflation can flatten the diaphragms, alter crural function, reduce resting LES pressure, and change the angle of His. In patients where symptoms of asthma and GERD coexist, we can consider a 3-month trial of aggressive acid suppression.
In patients with persistent asthma and no GERD, 24-h pH probe and impedance study can be helpful in determining the presence of GERD for possible treatment with acid suppression.
Recurrent pneumonia and interstitial lung disease may be complications of GER due to the failure of airway defense mechanisms to protect the lungs against aspirated stomach contents. The most common cause of recurrent pneumonia in children is primary aspiration compared to GERD in 6% in reported series. Other causes of pneumonia in children (direct aspiration due to dysfunctional swallow, immune deficiencies, congenital heart disease, anatomic abnormalities, and asthma) are more common than GERD and should be ruled out first.
No test can determine whether GER is causing recurrent pneumonia. Lipid-laden alveolar macrophages have been used as indicator of aspiration, but the sensitivity and specificity are low. Elevated pepsin content of alveolar lavage fluid is reported from patients with GER; however, evidence is inconclusive for routine use. A trial of nasogastric feeding may be used to exclude aspiration during swallowing as a cause of pneumonia. A trial of nasojejunal feeding may help in determining whether surgical therapy is likely to be beneficial. In patients with severely impaired lung function, surgery can help to prevent further pulmonary damage despite lack of definite proof that GER is causative.
Barrett’s esophagus, esophageal strictures, and adenocarcinoma are the most important complications of chronic GERD.
Esophageal strictures are typically located in the distal third of the esophagus and should be distinguished from other causes of strictures. Chronic exposure to acid and pepsin, hiatal hernia, and esophageal dysmotility predispose to strictures. Reflux strictures are treated with a series of dilations in conjunction with aggressive medical therapy. Surgical therapy is reserved for recalcitrant strictures.
Barrett’s esophagus (BE)
Barrett's esophagus is the condition in which normal esophageal squamous epithelium is replaced by a metaplastic columnar epithelium with goblet cells that predisposes cancer development. It occurs in children with less frequency than in adults. Cystic fibrosis, severe neurological impairment, and repaired esophageal atresia are associated with BE in children. Symptoms are a poor guide to the severity of acid reflux and esophagitis. Aggressive acid suppression is recommended. Dysplasia surveillance is managed according to adult guidelines to help identify patients who may progress to develop dysplasia and adenocarcinoma.
Adenocarcinoma is extremely rare in childhood but has been reported in a child in the setting of Barrett's esophagus.
The diagnosis of uncomplicated GER is usually established with a detailed history and physical exam. In infants, there is no symptom which is diagnostic for GERD or predicts response to treatment. Because of these inconsistencies, parent-reported infant GERD questionnaires based on symptoms have been developed. The questionnaire has been shown to be reliable for documentation and monitoring of reported symptoms, but the correlation between the results of reflux investigation is poor. Atypical presentations, complicated GER, or failure to respond to empiric management are indications for further diagnostic evaluations. These include radiography, endoscopy with esophageal biopsy, esophageal pH monitoring, and combined pH and esophageal impedance measurements.
Fluoroscopic evaluation of the upper gastrointestinal tract has low sensitivity and specificity for diagnosing GERD, but it may be useful in identifying other anatomic abnormalities such as strictures, hiatal hernia, intestinal malrotation, or pyloric stenosis. Modified barium swallow studies can be helpful in diagnosing aspiration during swallowing in patients with airway symptoms.
Nuclear scintigraphy is generally utilized in infants to quantify gastric emptying and obtain information regarding reflux-related aspiration. The study in infants is performed using liquid labeled with technetium 99 m. In children and adults, the standard protocol involves a low-fat, egg-white meal with imaging at 0, 1, 2, and 4 h after meal ingestion. Gastric emptying may be delayed in some children who have GERD.
Esophageal pH monitoring
Esophageal pH monitoring is widely accepted as a safe method of detecting acid reflux. GERD episode during pH monitoring is defined as a sudden decrease in intraesophageal pH to below 4.0. Based on the cutoff value of pH 4, several parameters can be defined to quantify the amount of GERD: number of episodes/ 24 h of drop in pH below 4, number of episodes of certain duration (i.e., above 5 min), and percentage of time during a 24-h period that esophageal pHis below 4. These parameters are also correlated to awakeness or state of sleep, meal time, and body position. The percentage of time in a 24-h study that the esophageal pH is less than 4, also called the “reflux index” (RI), is considered the most valid measure of reflux because it reflects the cumulative exposure of the esophagus to acid. Commonly, an RI greater than 11% is considered abnormal in infants, while RI greater than 7% is abnormal in older children. The greatest utility of pH monitoring is to correlate the specific symptom in relation to intraesophageal pH reading at the time of the “event” (apnea, stridor, or Sandifer’s syndrome) and to assess efficacy of antisecretory therapy.
Esophageal impedance monitoring
Esophageal impedance monitoring is a sensitive tool for evaluating overall GERD and particularly in detecting nonacid reflux episodes. Multichannel intraluminal impedance (MII) detects reflux episodes based on changes in electrical resistance to the flow of an electrical current between two electrodes on the probe when a liquid or gas bolus moves between them. When combined with esophageal pH monitoring, the MII test allows detection of both acid and nonacid episodes of GER.
Endoscopic evaluation with histology is the most accurate method of detecting esophageal injury by reflux and diagnosing Barrett’s esophagus. Macroscopic lesions associated with GERD include erosions, exudate, ulcers, strictures, and hiatal hernia. Histologic findings of reflux esophagitis include basal cell hyperplasia, increase papillary length, basal layer spongiosis (edema), and erosion and ulcerations in severe cases. None of the histologic findings listed are specific for reflux esophagitis. There is also a poor correlation between the severity of symptoms and presence and absence of esophagitis. There is insufficient evidence to support the use of histology to diagnose or exclude GERD.
For noncomplicated reflux, no intervention is required for most infants. Effective parental reassurance and educating parents regarding regurgitation and lifestyle changes are usually sufficient to manage infant reflux. This includes adjusting feeding regimens, positioning after feeds, and avoiding environmental smoke exposure. Review of 14 randomized controlled trials and practice guidelines summarized that thickening feeds does not seem to reduce measurable reflux, but it decreases the frequency of overt regurgitation and vomiting. It also increased the infant’s weight gain per day. Agents such as rice cereal (more popular in North America), corn or potato starch, carob-bean gum (also called locust-bean gum – more popular in Europe), carob-seed flour, and sodium carboxymethylcellulose are often used. Thickening a 20-kcal/oz formula with one tablespoon of rice cereal increases the caloric density to 34 kcal/ozwhich can cause excessiveweight gain in infants and may induce constipation.
A subset of infants with cow’s milk protein allergy have regurgitation and vomiting, mimicking GER. Forty percent of patients with GER were shown to have cow’s milk protein allergy. In these infants, symptoms decrease significantly within 2 weeks time after elimination of cow’s milk protein from the diet. In breast-fed infants, milk and milk products should be eliminated from maternal diet. In formula-fed infants, hydrolyzed or amino-acid-based formulas should be considered for 2–4-week trial. Studies have shown that prone positioning resulted in decreased frequency of reflux, but due to the risk of sudden infant death syndrome (SIDS), the American Academy of Pediatrics recommends that all infants younger than 12 months of age generally be placed in supine position for sleep even they have GERD.
In older children, mild symptoms of reflux without complications are often well managed by lifestyle changes such as weight loss, if appropriate, and by avoidance of fatty foods, caffeinated beverages, and chocolate and not eating before bedtime.
Pharmacotherapeutic agents used in GERD encompass antisecretory agents, antacids, surface barrier agents, and prokinetics. Antisecretory agents include histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs).
Histamine-2 receptor antagonists
Histamine-2 receptor anatagonists (H2RAs) decrease acid secretion by inhibiting histamine-2 receptors on gastric parietal cells. H2RAs (cimetidine, ranitidine, famotidine, and nizatidine) are effective in healing reflux esophagitis in infants and children. The fairly rapid development of tachyphylaxis in all H2RAs is a drawback for chronic use, and tolerance can be seen as early as 14 days of repeated administration. All H2RAs require dose adjustment in renal impairment. All can cause irritability and abnormal liver function tests. Gynecomastia and drug interactions have been reported with cimetidine.
Proton pump inhibitors (PPIs)
PPIs inhibit acid secretion by blocking Na+-K+-ATPase of the “proton pump” that performs the final step in the acid secretory process of the parietal cell. They thereby inhibit both basal and stimulated secretion of gastric acid, independent of the parietal cell stimulation. The superior efficacy of healing by PPIs is largely due to their ability to maintain intragastric pH at or above 4 for longer periods of time and to inhibit meal-induced acid secretion for which H2RAs do not have any effect. All PPIs are usually well tolerated; common adverse effects reported for all proton pump inhibitors include headache, diarrhea, rash, nausea, and constipation.
PPIs currently approved for use in children in North America are omeprazole, lansoprazole, and esomeprazole for above 1 year of age and pantoprazole above 5 years of age. At this time in Europe, only omeprazole and esomeprazole are approved. No PPIs have been approved for use in infants younger than 1 year of age. Although not approved, PPIs are commonly used for the treatment of infants with GERD. Multiple studies have shown that a trial of PPI in infants with reflux-like symptoms produced similar improvement in irritability while taking placebo or PPI, despite documented reduction of esophageal acidification in the PPI group. This concluded that PPI therapy is not beneficial for the treatment of infants with symptoms that were purported but not proven to be due to GERD. PPIs are highly efficacious and safe for the treatment of GERD-related symptoms and signs, including the most severe degrees of reflux esophagitis in older children and adolescents. Several open label treatment studies have found even higher rates of healing of erosive esophagitis in children compared with studies in adults. A failure to respond to PPI should raise consideration of insufficient dosing, improper administration, or incorrect diagnosis. Experience indicates that the most common error in PPI prescribing in children is underdosing. Another common error in prescribing PPIs in children is splitting the total daily dose into twice-daily dosing. The optimal administration mode for PPIs is once per day, just before the first meal of the day, since that is when acid pumps or proton pumps are generated and can then be efficiently blocked.
Antacids work by neutralizing gastric acid and decreasing the exposure of gastric acid to esophagus during episode of reflux. Most available products contain the combination of magnesium and aluminum hydroxide or calcium carbonate. The use of aluminum- containing antacids in infants can lead to elevated aluminum levels and cause osteopenia, microcytic anemia, and neurotoxicity as complications.
Surface barrier agents
These contain either alginate or sucralfate. Sodium alginate (Gaviscon) forms a surface gel that creates physical barrier against refluxate and protects the mucosa. It appears to be relatively safe, as only a limited number of side effects have been reported. Occasional formation of large bezoar-like masses of agglutinated intragastric material has been reported in infants with the use of Gaviscon. Sucralfate is a compound of sucrose, sulfate, and aluminum, which forms a gel in an acidic environment. North American and European Pediatric Gastroenterology Society (NASPGHAN/ESPGHAN) GER guidelines committee concluded that there is no adequate data of efficacy or safety of sucralfate in the treatment of infant GERD, especially with the risk of aluminum toxicity. In older children, its main use is in erosive and ulcerative esophagitis.
Prokinetic agents improve regurgitation via their effects on lower esophageal sphincter pressure, esophageal peristalsis, and acid clearance or promoting gastric emptying. The current NASPGHAN and ESPGHAN practice guidelines concluded that there is insufficient evidence to justify the routine use of prokinetic agents. Bethanechol seems to increase muscarinic cholinergic drive, resulting in increased LES tone and esophageal peristaltic amplitude and velocity. Because it is a cholinergic agonist, it increases salivary and bronchial secretions and may contribute to bronchospasm.
Domperidone is a peripheral dopamine-D2 receptor antagonist that facilitates gastric emptying and esophageal motility. NASPGHAN working group concluded that the effectiveness of domperidone is unproven. Cisapride is a benzamide derivative and is a non-dopaminereceptor- blocking, non-cholinergic prokinetic drug with 5HT4-antagonistic properties. It stimulates motility in lower esophagus, stomach, and small intestine by increasing acetylcholine release in the myenteric plexus. Despite the vast majority of the clinical trials, the efficacy of cisapride demonstrated that at least one of the end points changes favorably as a result of the intervention.
Due to reports of fatal cardiac arrhythmias or sudden death, from July 2000 in the USA and Europe, cisapride has been restricted to a limited access program supervised by a physician.
Metoclopramide has cholinomimetic and mixed serotonergic effects. Adverse effects of irritability, drowsiness, and extrapyramidal reactions can be seen up to 34% of children taking metoclopramide. Erythromycin, a macrolide antibiotic, also has prokinetic effects by its ability to act on motilin receptors and initiate phase 3 activity of the migrating motor complexes. Erythromycin does not have effects on esophageal or LES motility, but may improve gastric emptying in selective cases in infants and children. There is also a concern of development of infantile hypertrophic pyloric stenosis with use of erythromycin in newborn period, especially first 14 days of life. Baclofen is a gamma-aminobutyric acid B (GABA B) receptor agonist; it inhibits the occurrence of transient lower esophageal sphincter relaxations. Baclofen has been shown to decrease the frequency of emesis and improve reflux episodes in neurologically impaired children. Potential side effects include drowsiness and lowered seizure threshold.
Endoluminal gastroplication (EG) is emerging as a minimally invasive procedure for the treatment of gastroesophageal reflux disease in children. Endoscopic gastroplication using the EndoCinch endoscopic suturing device was developed by Swain and colleagues. The basis of this procedure is to construct plications in the gastric mucosa/submucosa below the lower esophageal sphincter with the intent to improve its function by augmenting the anti-reflux barrier. It is shown to reduce transient lower esophageal sphincter relaxations and slightly increase lower esophageal sphincter pressure. The largest pediatric series reported by one center followed up 16 children after endoluminal gastroplication. Four had recurrent symptoms requiring a repeat procedure within 2–24 months. Three years after procedure, nine patients were doing well with no medications. Other endoscopic GERD treatments have not been studied in children.
Despite the availability and proven efficacy of PPIs for severe GERD, anti-reflux surgery remains widely used in children. In the United States, fundoplication is among the most commonly performed operations by pediatric surgeons. The widely performed wrap is Nissen fundoplication which involves passage of gastric fundus behind the esophagus to encircle the distal esophagus. Laparoscopic Nissen fundoplication has largely replaced open Nissen fundoplication due to its decreased morbidity, shorter hospital stays, and fewer postoperative complications, but a somewhat higher reoperation rate is reported in laparoscopic Nissen fundoplication. A partial, 270 wrap (Toupet) is used in patients with severe esophageal motor dysfunction.
Fundoplication prevents GER by increasing LES pressure, increasing the length of the intra-abdominal esophagus, accentuating the angle of His, and reducing hiatal hernia if present. However, fundoplication has no impact on poor esophageal clearance or delayed gastric emptying and may cause dysphagia, bloating, and retching in these settings. In general, outcomes of fundoplication have been more carefully evaluated in adults than children.
Most of the literature on antireflux surgery in children with GERD consists of retrospective case series in which documentation of diagnosis and details of previous treatments are deficient, making it difficult to assess the outcome of surgery. The symptom improvement has been described between 60% and 90% of children, but also failure rate varies between 2% and 50% depending on reported series. Complications after surgery are due to alterations in fundic capacity and compliance that may persist from months to years. These include retching and gagging, gas-bloat syndrome, early satiety, and dumping syndrome.
The problems with anti-reflux surgery occur especially in children with neurologic impairment (NI), repaired esophageal atresia, or chronic lung disease and to a lesser degree in otherwise normal children. The children with NI have more than twice the complication rate, three times the morbidity, and four times the reoperation rate compared to otherwise healthy children.
Anti-reflux surgery may be of benefit in children with confirmed GERD who have failed optimal medical therapy or are dependent on medical therapy over a long period of time or who have life-threatening complications of GERD. Children with respiratory complications including asthma or recurrent aspiration are generally considered most likely to benefit from surgery when medical therapy fails, but additional studies are required to confirm this.
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