Primary care pediatricians often encounter gastrointestinal (GI) symptoms in infants and children, including recurrent vomiting and abdominal pain, for which they must consider a diagnosis of gastroesophageal reflux (GER). In fact, GER-related symptoms probably comprise the most common clinical GI problems of infancy that present to a pediatrician's office, as well as representing the most frequent cause of referrals to a pediatric gastroenterologist in the same age range.1"5 Clinical manifestations of GER may range from irritability or recurrent emesis during the first few years of life to heartburn or dysphagia in older children. Although these symptoms often resolve spontaneously, without either dietary modifications or acid reduction therapy, available data have shown that an adolescent or adult with GER disease (GERD) may have exhibited symptomatic GER during infancy or early childhood.1
GER is defined as the retrograde passage of gastric material into the esophagus.1'2 This phenomenon is physiologic and occurs throughout the day, most frequently after meals and at night. Although pathologic GER (ie, GER in which duration of esophageal acid exposure is greater than the physiologic normal value) may remain silent clinically, affected infants and children younger than 4 most frequently present with recurrent and persistent emesis (expulsion of gastric contents from the mouth), regurgitation (reflux into the oral cavity without expulsion), or both.3 Epidemiological studies suggest that recurrent emesis is noted in 60% to 70% of infants at ages 3 to 4 months.4 This phenomenon of "physiological" GER usually resolves spontaneously by age 1 . When symptoms of reflux during infancy result in clinical signs of GERD, to be discussed below, or when symptoms persists beyond age 18 months, GER should be considered as representing a pathologic condition, manifested by an increase in frequency and duration of reflux episodes, as well as by an impaired esophageal acid clearance mechanism.
Clinical Symptoms and Indications for Investigation in Infants and Children With Suspected GERD
The prevalence and natural history of GER in children and adolescents remain unknown. As noted above, GER is commonly encountered during infancy. Thus, published data indicate that approximately 50% of infants younger than 2 months are reported to have symptoms of reflux, defined clinically as more than two episodes per day of regurgitation or emesis. By age 4 months, these symptoms are reported in up to 70% of infants.4·5 By age 12 months, the prevalence of clinical GER falls to approximately 1% to 5%, with the greatest decline in emesis noted between ages 6 and 8 months.1'4'5
Despite the absence of longitudinal studies, children in whom reflux symptoms persist beyond age 18 months are more likely to experience symptomatic GER as adults.1 In children younger than 4 years, GER is likely to present in similar fashion to that noted during infancy, with predominant symptoms of emesis and regurgitation. After age 4, however, symptoms of reflux mimic the clinical spectrum of presentation in older children and adults, with a declining frequency of vomiting and increasing complaints of abdominal pain and heartburn.4'5 One retrospective study attempted to correlate GER in adults with evidence of reflux in early life. In the 379 patients examined, 63% of those with GER (n = 225) recalled more than one reflux symptom during childhood, while a similar history was obtained in 35% of those without GER (n = 154).6
Among children age 6 months to 18 years hospitalized in the United States in 2001, GERD was identified in 3.5% of all discharge diagnoses.3 Clinicians should be aware that certain conditions predispose children to a high prevalence of GERD, including neurological impairment, hiatal hernia, and repaired esophageal atresia.7"10 Several recent studies have described GERD as an important complicating disorder in those manifesting morbid obesity.11,12
Although the pathogenesis of GER is multifactorial, its primary causative mechanism likely involves inappropriate transient relaxations of the lower esophageal sphincter (TLESRs). 1>13"15 The lower esophageal sphincter (LES) is composed of a specialized band of smooth muscle that remains contracted to prevent the retrograde passage of gastric contents into the esophagus between meals, and relaxes during episodes of swallowing, belching, vomiting, and esophageal distention.13 At rest, normal LES tone is above 4 mm Hg. A TLESR is defined as a reduction in LES tone to the level of gastric pressure, or 0 to 2 mmHg, for more than 10 seconds.14
Esophageal injury secondary to GER develops as a consequence of LES failure to prevent gastric acid reflux into the esophagus, prolonged esophageal clearance of the gastric refluxate, and impaired (or overwhelmed) esophageal mucosal barrier function against back diffusion of acid. These combined phenomena result in pathologic esophageal complications such as esophagitis, often with significant blood loss, stricture formation, and Barrett's esophagus, a potentially pre-cancerous lesion.1,13,14 Predominant clinical symptoms of GERD, therefore, result from exposure of the esophageal mucosa to gastric acid, as well as from the increased stimulation of acid-sensitive sensory neurons.15
As noted above, GERD presents with a wide variety of clinical symptoms that differ in infants and children (Table, see page 260). Esophageal symptoms are caused by inflammation and visceral hypersensitivity to gastric refluxate, while extra-esophageal manifestations are caused primarily by direct acid-induced injury (supra-esophageal inflammation) and stimulation of airway reflexes by acid refluxate (GER-related reactive airway disease).13,14
Although GER clearly represents the most common diagnosis associated with recurrent emesis during infancy, this symptom is nonspecific. Thus, the astute clinician must be aware of an expanded differential diagnosis (Sidebar), not only in the infant with persistent vomiting but also in the infant with unexplained irritability.6 Many children with GERD past age 2, and certainly those past age 4, more often have symptoms related to heartburn, the consequence of esophageal irritation by gastric acid refluxate.15
Infants and older children also may present with different extra-esophageal manifestations of GERD.17 During infancy, Sandifer's syndrome is an uncommon condition, characterized by repetitive stretching and arching of the head and neck, that is often mistaken for a seizure or spastic torticollis.14 However, this maneuver likely represents a physiologic neuromuscular response, in which this unusual (and often frightening) positioning may prevent noxious refluxate from reaching the upper portion of the esophagus.13'14 The correlation between GERD and infant apnea (or apparent life-threatening events) remains a challenge.
While some reports of simultaneous recordings of intraesophageal pH, heart rate, chest wall movement, and nasal airflow have demonstrated obstructive apnea preceded by GER episodes, this temporal relationship is not convincing and it has not been confirmed by more recent investigations.16"19 By contrast, a retrospective study of 688 children with nonseasonal asthma, 61% were reported to have abnormal 24-hour intraesophageal pH study results.16,17 Although GER in these patients could not be demonstrated to be either a primary diagnosis or secondary to asthma, clinical improvement in respiratory symptoms was reported following medical treatment for GERD.16,17
A thorough history and physical examination in most infants with recurrent emesis and in older children with heartburn are sufficient to diagnose GER and GERD, and to initiate appropriate, timelimited therapy2 When the diagnosis remains ambiguous, and when complications from GERD are suspected (Table), further investigations may be warranted. Accordingly, several diagnostic studies are available to document both the presence and severity of GER and acid-related injury.
Barium Upper Gastrointestinal Tract Study
This radiographic examination is employed to diagnose anatomic abnormalities such as a hiatal hernia, tracheoesophageal fistula, and esophageal atresia.13 The upper GI series does not provide any information about the physiologic function of the esophagus. In comparison to 24hour intraesophageal pH monitoring, the sensitivity, specificity, and positive predictive value of the upper GI series for GER (barium study versus pH monitoring) are 31% versus 86%, 21% versus 83%, and 80% versus 82%, respectively. Thus, the barium upper GI series is an unreliable test in the diagnosis of GER12,14,16
Figure 1. Schematic drawing of simultaneous intraesophageal pH and electrical impedance measurements. The onset of a "nonacid ic" GER episode is indicated by the solid vertical arrow at the bottom of the figure. Note the retrograde progression of impedance changes (diagonal arrow), indicating reflux of gastric contents while esophageal pH remains above 4.0 (the customary pH threshold for GER during intraesophageal monitori ng).The dashed vertical arrow indicates the onset of a normal swallow.
24-Hour Intraesophageal pH Study
A 24-hour intraesophageal pH monitoring study remains the gold standard in the diagnosis of GER. The reflux index (RI), defined as the percentage of total time that the esophagus is exposed to a pH lower than 4, is the most valid measure of gastric acid reflux.13'14 The mean upper limit of normal for the RI in several studies is 12% in infants, 5.4% in children up to age 9, and 6% in adults.18,20,23 These studies indicate both that physiologic acid reflux occurs with greater frequency and duration in normal infants (compared with older subjects) and that maturation of LES function is completed during early childhood.13 The diagnostic yield for pH monitoring increases when the study is performed in conjunction with a diary of symptoms.1,13,14 The pH study is useful to diagnose the presence or absence of GER, determine its severity, assess whether GER contributes to any pulmonary or otolaryngologic pathology (eg, asthma, stridor), and gauge the adequacy of acid suppression therapy. Esophageal pH monitoring is not required in children who manifest a clinical history consistent with GER and are without evidence of serious complications, or in cases where reflux esophagitis has been documented by upper GI endoscopy.1,13,14
Upper Gl Endoscopy and Biopsy
By examining mucosal biopsy specimens obtained during endoscopic evaluation, differentiation may be made between reflux-associated esophagitis and other etiologies of esophageal disease, including eosinophilic or infectious esophagitis. The presence of gastric and duodenal pathology also can be determined. However, the finding of normal esophageal histology does not necessarily indicate the absence of GER. Upper GI endoscopy and biopsy also is useful to diagnose complications of GERD such as Barrett's esophagus.1,13,14
Intraluminal Esophageal Electrical Impedance
This recently developed test is useful for detecting both acid and nonacid reflux by measuring retrograde flow in the esophagus, determined by electrical impedance measurements. Here, GER episodes as brief as 15 seconds may be measured (Figure I).24 In adult studies, impedance measurements have been used in conjunction with 24-hour intraesophageal pH monitoring to provide a more complete picture of bolus movement in the esophagus.24 Despite its potential utility, however, esophageal electrical impedance has not been validated thoroughly, and normal values have not been determined for the pediatric age group.
A nuclear scintiscan, also known as a milk scan, involves the use of 99Technetium-labeled milk or formula in children at risk for aspiration. Following consumption of the radiolabel, imaging studies performed up to 24 hours afterwards can determine whether aspiration had occurred.23,25 Scintigraphy can differentiate between aspiration of gastric contents from reflux versus aspiration from poor oropharyngeal muscle coordination.23,28 In addition, it may, in a nonquantitative manner, demonstrate nonacid gastric reflux and provide information on gastric emptying, which may be abnormal in children with GER. 13,2527
Esophageal manometry provides a qualitative and quantitative assessment of intraluminal pressures, coordination of pressure activity of the esophageal smooth muscle, and esophageal motility.29 Manometric studies often are performed when symptoms such as dysphagia, odynophagia, and noncardiac chest pain are suggestive of an esophageal motility disorder. In systemic disorders (eg, scleroderma), manometry is useful in assessing possible esophageal involvement.29 A manometric study also is indicated before antireflux surgery.29
The primary objectives in GERD management are the relief of symptoms, treatment and prevention of GERD complications, and mucosal healing.2 The treatment of GERD can be divided into lifestyle, medical, and surgical modalities.2
Lifestyle or Behavioral Treatment
Behavioral treatment can be implemented as the initial management of mild GERD. Avoidance of certain foods that exacerbate acid reflux (eg, caffeine, citrus, tomatoes, alcohol, peppermint, spicy/fried foods), lifestyle modification in children (eg, weight control where indicated, small meals, smoking cessation), and feeding maneuvers in infants (eg, thickened feeds, appropriate positioning) can improve mild reflux symptoms.
Figure 2. A simplified, algorithmic approach to the diagnosis and management of GER during infancy and childhood.
Of note, thickened feeds do not improve pH scores on 24-hour intraesophageal monitoring but may decrease the number of vomiting episodes. Studies have shown that prone positioning of infants decreases episodes of reflux as determined by pH intraesophageal monitoring.13 However, because prone positioning has been associated with a significantly increased risk of sudden infant death syndrome, it is only recommended with extreme caution when the risk of GERD complications exceeds the risk of sudden infant death syndrome.13,14 Hence, current positioning recommendations only suggest elevating the head of the bed to a maximum of 30 degrees.13'30 In addition, in terms of nonpharmacologic therapy, an empiric trial of hypoallergenic formula is supported in infants with recurrent emesis, particularly if conservative measures fail to ameliorate vomiting symptoms.13,30
Medical management of GER includes, as a cornerstone, the use of acid blocking medications. Both H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) may stimulate some increase in lower esophageal sphincter tone, mediated via the trophic effects of increased circulating gastrin levels following inhibition of the acid-regulated gastrin negative feedback loop. However, the primary effects of these agents involve reduced gastric hydrochloric acid secretion, and their major therapeutic role is to ameliorate dyspepsia, prevent acid-induced esophageal injury, and accelerate healing of esophagitis. 1A13
A suggested algorithmic approach to GER management during infancy and childhood is shown in Figure 2 (see page 263). Therapy may be initiated empirically, when acid-related symptoms or signs of complicated GERD are noted at any age. Acid reduction therapy is indicated clearly following establishment of the diagnosis of GERD using upper endoscopy and esophageal mucosal biopsy.13 In many cases, however, drug therapy is initiated after conservative management with dietary and lifestyle modifications has failed to reduce symptoms in mild (ie, uncomplicated) GER. Alleviation of symptoms and improvement in clinical status with treatment are noninvasive outcome measures used to monitor response to therapy.13,14
Clinicians may institute drug therapy for GERD either in a "step-up" or "step-down" approach. In the step-up approach, an H2RA is used as initial therapy, followed by a PPI, should the H2RA fail to achieve clinical improvement.31 For clinicians who prefer a stepdown approach, high doses of a PPI are administered initially, followed by either dose reduction of the PPI or changing to an H2RA to maintain clinical improvement. The step-down approach has been documented to be more cost effective in adults, but no clinical study has compared these two approaches in the pediatric population.32
Use of available prokinetic drugs (eg, urecholine, metoclopramide) remains controversial. To date, careful analyses of published data have failed to demonstrate clinical efficacy for these agents in significantly modifying the natural history or therapeutic outcomes of GER in childhood. In addition, the benefits of therapy with these drugs, in most cases, are outweighed clearly by their side-effect profiles. Accordingly, prokinetics are not recommended for routine GER management. (Cisapride, a once-promising prokinetic drug that exerts gastrointestinal motility changes mediated via 5-HT4 receptors or enhanced release of acetylcholine, is no longer available in the US, except as a compassionate-use agent, because of the drug's potential for cardiotoxicity.)
H2RAs are gastric acid-reducing drugs that act to decrease acid secretion by blocking the histamine-2 receptor on the surface of parietal cells in the stomach.14 Randomized clinical trials demonstrate that ranitidine, famotidine, Cimetidine, and nizatadine are superior to placebo for relief of symptoms and healing of esophageal mucosa.1,2,13 Tachyphylaxis to intravenous ranitidine (ie, escape from its acid inhibitory effect) has been observed after several weeks of administration.33,34 Also, H2RAs are unable to inhibit mealinduced acid secretion.2
PPIs selectively inhibit H+ secretion by blocking the gastric parietal cell H+, K+-ATPase pump.13,14 PPIs are actually prodrugs that require gastric acidity to convert the parent compound into the active metabolite.13'33 Maximum efficacy is achieved when a PPI is administered a half-hour before mealtime; concomitant dosing with an H2RA inhibits drug activity.13,33 Because gastric H+, K+-ATPase pumps are "recruited" in response to the first morning meal, once-daily dosing before breakfast is recommended and usually is sufficient to ameliorate GER symptoms. A second dose administered before supper may be considered in refractory cases.13,33,35
Currently, only two PPIs, omeprazole and lanzoprazole, are approved for children, with the latter approved for children as young as 12 months. In comparison with adults, children often require a higher relative dose of PPI (usually 1 to 2 mg/kg body weight), because of enhanced drug metabolic capacity during early childhood.36 Clinical trials in adults have demonstrated the superiority of PPIs when compared with H2RAs in treating GERD symptoms and effecting histological improvement. This is likely the consequence, at least in part, of the absence of PPI tachyphylaxis, as well as because of PPI inhibition of acid secretion during meals.2,13,33,34
Antireflux surgery is the second most common operation performed by pediatric surgeons in the US.37 Of the several different fundoplication techniques (including the Thai, Belsey, and Toupet procedures), the Nissen fundoplication, a 360-degree wrap of the fundus of the stomach around the base of the esophagus, is performed most commonly.13,38 Anti-reflux surgery may be recommended in patients who have failed medical therapy (either symptomatically or histologically), in those who seek to avoid lifelong gastric acid-reducing medications, and in those with potentially serious reflux-associated morbid complications (eg, Barrett's esophagus).13,38 Studies in the adult population have shown a better outcome following antireflux surgery for patients who clinically respond to PPIs.39
In children, the Pediatric Health Information Survey determined that 14% of patients hospitalized for GERD underwent a fundoplication without consultation with a pediatric gastroenterologist and without undergoing any formal diagnostic evaluation to establish GER conclusively as the etiology of clinical symptoms.2,13 This observation is particularly concerning, given the recent reports of high rates of failure and morbidity associated with surgery.40,41 Clearly, successful anti-reflux surgery is dependent upon selection of appropriate candidates, as indicated above, and is more likely with a history of clinical responsiveness to appropriate medical therapy.2,38
GER is a common reason for pediatric office visits and referrals to a pediatric gastroenterologist. This condition frequently is benign, and it is self-limited in most infants. Although a thorough history and complete physical examination usually are adequate to diagnose GER, a high index of suspicion must be maintained for other diagnoses associated with recurrent emesis, including metabolic disorders, as well as for other gastrointestinal conditions, such as pyloric stenosis and abnormalities of intestinal rotation.
Behavioral or lifestyle modification usually can be implemented empirically to diagnose and manage a suspected case of uncomplicated GER. When this fails, medical therapy can be initiated, employing either a step-up or step-down approach with a PPI or H2RA. With the proven efficacy of PPIs and their availability to children, medical treatment has become the mainstay of therapy in severely affected patients; nevertheless, anti-reflux surgery is still widely performed in children with GER.2
Pediatricians and other primary care providers often manage infants and children who have gastrointestinal complaints, prior to referral to a pediatric gastroenterologist. Hence, they have the responsibility to educate children and families about GER, its natural history, complications, and therapeutic options. A careful history and physical examination, informed use of diagnostic studies, and a consistent approach to medical treatment are important principles that are required to guarantee the success of GER management in infants and children.
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Clinical Symptoms and Indications for Investigation in Infants and Children With Suspected GERD