A global evidence-based consensus has defined gastroesophageal reflux disease (GERD) as ‘a condition, which develops when the reflux of stomach contents causes troublesome symptoms and/or complications.’ The manifestations of GERD can be divided into esophageal and extraesophageal syndromes, and include vomiting, poor weight gain, dysphagia, abdominal or substernal/retrosternal pain, esophagitis and respiratory disorders. The extraesophageal syndromes have been divided into established and proposed associations: established would include cough, laryngitis, asthma and dental erosion ascribable to reflux, whereas proposed associations would include pharyngitis, sinusitis, idiopathic pulmonary fibrosis and recurrent otitis media. Uninvestigated patients with esophageal symptoms without evidence of esophageal injury would be considered to have asymptomatic esophageal syndromes, whereas those with demonstrable injury are considered to have esophageal syndromes with esophageal injury. Therefore, this allows symptoms to define the disease but permits further characterization if mucosal injury is found. Within the syndromes with associated injury are reflux esophagitis, stricture, Barrett's esophagitis and adenocarcinoma. This review will address definitions of GER and GERD-associated symptoms and treatment options.
Gastroesophageal reflux (GER), defined as passage of gastric contents into the esophagus, is a normal physiological process that occurs throughout the day in healthy infants, children and adults.1, 2 The North American Society for Pediatric Gastroenterology and Nutrition defines GER as passage of gastric contents into the esophagus, and GER disease (GERD) as symptoms or complications of GER.3 A global evidence-based consensus has defined GERD as ‘a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications;’ the level of agreement is A+, 81%.4 Manifestations of GERD can be divided into esophageal and extraesophageal syndromes and include vomiting, poor weight gain, dysphagia, abdominal or substernal/retrosternal pain, esophagitis and respiratory disorders. The extraesophageal syndromes have been divided into established and proposed associations:4 established would include cough, laryngitis, asthma and dental erosion ascribable to reflux, whereas proposed associations would include pharyngitis, sinusitis, idiopathic pulmonary fibrosis and recurrent otitis media. Uninvestigated patients with esophageal symptoms without evidence of esophageal injury would be considered to have asymptomatic esophageal syndromes, whereas those with demonstrable injury are considered to have esophageal syndromes with esophageal injury. Therefore, this allows symptoms to define the disease, but permits further characterization if mucosal injury is found. Within the syndromes with associated injury are reflux esophagitis, stricture, Barrett's esophagitis and adenocarcinoma. Complications of GER are listed in Table 1.
Gastroesophageal reflux is common during infancy and most often manifests as vomiting. Recurrent vomiting occurs in 50% of infants from 0 to 3 months, 67% in 4-month old (5%) in 10–12-month old infants.5 Vomiting generally resolves spontaneously in nearly all of these infants.6 Vomiting is usually not perceived as a problem unless it occurs frequently, is of large volume or if the infant cries a lot. Some infants may go on to develop GERD with symptoms, including anorexia, dysphagia, painful swallowing and arching of the back during feeds. In neonates, feeding refusal, but sucking on a pacifier, often suggests the presence of reflux that may be causing one of the above symptoms. GERD is one of the causes of acute life-threatening episodes in infants and has been associated with chronic respiratory disorders, including reactive airway disease, recurrent stridor, chronic cough and recurrent pneumonia in infants.
Population-based studies suggest that GERD is a common condition with a prevalence of 10 to 20% in Western Europe and North America.7, 8 The prevalence in Asia is reportedly variable but lower. The natural history is not clearly defined, but regurgitation resolves in most symptomatic infants by 12 to 24 months of age. Some of the infants may develop feeding problems later on and these can be aggravated by maternal smoking and are associated with maternal reflux symptoms. In preschool children, GER may manifest as intermittent vomiting, whereas older children may manifest adult-type pattern of chronic heartburn and regurgitation. Rarely, esophagitis in older children may present as stereotypical, repetitive stretching and arching movements that may be mistaken for atypical seizures or dystonia.9 More severe inflammation may cause chronic blood loss with anemia, hematemesis, melena or hypoproteinemia.10 Chronic inflammation may also result in replacement of distal esophageal mucosa with a metaplastic specialized epithelium known as Barrett's mucosa.11
Pathophysiological factors implicated in the causation of GER include inappropriate relaxation of the lower esophageal sphincter, reduced lower esophageal sphincter length and pressure, intrathoracic location and abnormal smooth muscle function. The Angle of His may be more obtuse and the length of the intra-abdominal esophagus may be short. The two most important anatomic factors preventing GER appear to be the length of the intra-abdominal esophagus and the angle at which it enters the stomach. Dietary factors, habitual postures and activity, and the presence of Helicobacter pylori may also contribute to GER similar to smoking. In a series of five families with severe pediatric GER an autosomal dominant form of inheritance associated with a chromosome 13q14 defect has been described.12
History and physical examination
There are no reports comparing history and physical examination to diagnostic tests. However, in most infants with vomiting and older children with regurgitation and heartburn, a history and physical examination are sufficient to reliably diagnose GER, recognize complications and initiate treatment strategies.
The upper gastroenterology (GI) series is useful to detect anatomic abnormalities that may aggravate GER, such as hiatal hernia, or may detect problems, such as stricture or pyloric stenosis. The upper GI is neither specific nor sensitive for the diagnosis of GER when compared to esophageal pH monitoring. The sensitivity of the upper GI series varies from 31 to 86%, specificity 21 to 83% and positive predictive value 80 to 82% when compared with pH monitoring.13, 14, 15
Esophageal pH monitoring
pH monitoring is used widely as an index of esophageal acid exposure, and measures the frequency and duration of the episodes of acid reflux. An episode of acid reflux is defined as esophageal pH <4 for a minimum of 15 to 30 s. The percentage of the total time that the esophageal pH is <4 is called the reflux index and is considered the most valid measure of reflux. It is recommended that the upper limit of normal of the reflux index can be defined as up to 12% in the first year of life and up to 6% thereafter. The abbreviated 12-h test is less reproducible than the traditional 24-h test. Asymptomatic episodes of acid reflux can occur in normal infants, children and adults. The presence of endoscopic and histopathological esophagitis is strongly associated with abnormal esophageal pH monitoring. pH monitoring may also be useful to assess the adequacy of acid suppression and help guide therapy, and may also be useful to determine risk for upper airway complications of GER. In some studies, approximately 60% of children with asthma had abnormal pH monitoring studies.16, 17 Unfortunately, pH monitoring does not detect nonacid reflux episodes that occur frequently in infants. Multichannel monitoring that will detect nonacidic reflux as well is being recommended for neonates. The impedance technique will detect the nature of the reflux whether it is liquid, gas or mixed. It also defines the extent of migration of the refluxate as well as establishing temporal relationships between reflux and symptoms, such as coughing. Esophageal manometry as a diagnostic tool is still being defined.
Endoscopy and biopsy
These can determine the presence and severity of esophagitis, strictures and Barrett's esophagus. It can also detect the presence of eosinophils and neutrophils. However, criteria to define esophagitis and its severity have not been validated in the pediatric population. In addition, these procedures have not been routinely utilized in neonates and infants.
A trial of medical therapy is useful for determining whether GER is causing a specific symptom and is widely used, but has not been validated in pediatric patients. However, a short time-limited trial may be warranted before resorting to extensive additional diagnostic and therapeutic measures.
Feeding changes in infants
In most infants, change in formula does not decrease symptoms of GER, but is widely practiced. Formula-fed infants do have increased esophageal acid exposure compared with breast milk feedings. A subset of infants may benefit from the elimination of cow milk protein in the event they have true cow milk protein allergy, which is estimated to occur in about 5% of the population. Usually, the allergy is detected by other symptoms or the presence of a strong family history of atopy or allergy. There are no studies to support the use of soy protein formulas for GER; a recent study showed decreased regurgitation with a soy formula with added soy fiber compared with conventional formula.18 Meal thickening agents do not improve reflux index.19, 20 However, the use of thickened feeds has been shown to decrease several of the symptoms associated with GERD.21 The addition of rice cereal as the thickening agent, however, has some disadvantages: it increases caloric density, and therefore, energy intake leading to increased weight gain and contributing to obesity.22 However, it may be beneficial in infants who also have failure to thrive. More recently, prethickened formulas have been introduced and have shown significantly fewer regurgitations following feeding.23 It should be remembered that these formulas are considered ‘term’ infant formulas, and preterm infants will require specific nutrient supplementation with their use.
Prone positioning has been recommended for the treatment and prevention of GER in infants.24, 25, 26 However, given that the risk of death from sudden infant death syndrome outweighs that from GER, in infants from birth to 12 months with GERD, supine position is recommended. Prone positioning is acceptable when the infant is awake and in the postprandial state. Prone positioning during sleep should be considered in unusual conditions where the risk of death from GERD outweighs that from SIDS; if this is performed advice against the use of soft bedding should be given. Studies have been conducted about body positioning effects on GER. In healthy premature infants, PMA 36 weeks, there was more liquid GER in the right lateral vs left lateral position. Gastric emptying was also faster.27 Using 24-channel multichannel impedance monitoring, Corvatlia et al.28 studied preterm infants with frequent regurgitation and found that placing premature infants prone or left lateral position in postprandial time decreases nonacid episodes, and prone position showed the lowest esophageal acid exposure.
Acid suppression therapies
In adults, acid-suppressive therapy has been evaluated in numerous randomized clinical trials. It has been shown that histamine-2 receptor antagonists (H2Ras) reduce GERD symptoms and promote healing of esophagitis.29, 30 Randomized studies in children have also shown that compared with placebo, H2RAs are effective for erosive esophagitis.31, 32 Proton pump inhibitors (PPIs) are superior to H2RAs in relieving symptoms and healing esophagitis.33 The current evidence supports the recommendation for the treatment of reflux esophagitis. The effectiveness of acid-reducing therapy for the other manifestations of GERD is not well documented. From 1999 to 2004, use of PPIs increased sevenfold with 0.5% being infants less than 1 year of age, despite the lack of supportive documentation of efficacy in this age group.34 Two double-blind studies found no significant differences despite documented decrease in acidity.35, 36
Transient relaxation of the lower esophageal sphincter not associated with an accompanied swallow is considered the most important pathophysiological mechanism of GER. Although prokinetic agents appear to increase lower esophageal sphincter pressure, a number of studies failed to show that these agents reduce the frequency of acid reflux episodes. The rationale for their use is based on evidence they enhance esophageal peristalsis and accelerate gastric emptying. There is evidence to support the use of cisapride when a prokinetic agent is indicated for the treatment of GERD. However, given the potential to cause serious cardiac arrhythmias, cisapride, is no longer in routine use. A recent meta-analysis concluded that the evidence is insufficient to support or to oppose the use of metoclopramide for GER in infants.37 Several side effects, including irritability, apnea and dystonia, have been described. Nonetheless, this drug is commonly used in most neonatal units.
These agents form a surface gel that decreases the regurgitation of gastric contents into the esophagus and protects the esophageal mucosa. There are conflicting data on the outcomes from their use and the data are inadequate to recommend their use in infants and children.
Surgery is often considered for the child with GERD who fails medical therapy. Fundoplication with the placement of a gastric feeding tube is the most common surgical approach. The potential risks, benefits and costs of successful prolonged medical therapy vs surgical therapy have not been well studied in infants and children with various GERD symptoms. Nonetheless, this approach is used especially when there is concommitant neurological injury.
Summary of approaches
The ‘happy spitter’
No tests are required and education and reassurance are the main stay of therapy. One can consider thickened formula or a trial of a hydrolysate. This usually resolves by 2 years of age, and if symptoms become bothersome or do not resolve, consider referral to a Pediatric GI specialist.
Vomiting and poor weight gain
Differential diagnosis must be reviewed and assure adequate calories. An upper GI, electrolyte panel and blood urea nitrogen (BUN) may assist in ruling out anatomic problems and assess current status. If abnormal, manage accordingly. If not, consider steps above or refer to Pediatric GI.
Chronic heartburn (older children)
Education and life style changes to be stressed including the role of smoking and alcohol. PPIs may be indicated and if there is no resolution refer to Pediatric GI.
Apnea is common in premature infants and GER is almost universal with about two-third of infants having documented reflux. Cause and effect relationship has yet to be established, and it is known that non-GER apnea is more common. Even in units where GER is aggressively treated, the incidence of apnea/bradycardia has not decreased.
In summary, GER and GERD are common disorders and present with a wide variety of symptoms. They are difficult to diagnose and manage and deserve a systematic approach as costs associated with these diseases are huge. Further clarification of this disease and treatment strategies will have important implications for prevention and treatment. The development of adenocarcinoma in under diagnosed or untreated disease is an important public health concern, and therefore, there is need for vigorous study of this common entity.
J Bhatia is a member of the speaker's bureau and a consultant for Dey, LP; on the speaker's bureau of Mead Johnson and Ovation Pharmaceuticals. A Parish has declared no conflict of interest. This study was on the basis of a talk presented at the Evidence vs Experience in Neonatal Practices Fifth Annual CME Conference that was supported by an unrestricted educational grand from Dey, LP.
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Pediatric Surgery International (2011)