Considerable confusion has occurred in the past 20 years regarding what constitutes gastroesophageal reflux (GER). With the availability of 24-hour monitoring of the intraesophageal pH, it has been shown that there is a normal physiologic event in which gastric acid refluxes into the esophagus. When GER occurs more frequently with more than the usual volume or is not tolerated by the individual, a variety of gastroesophageal and respiratory symptoms may result. Chest pain, esophagitis, aspiration pneumonias, and failure to thrive are examples of such sequellae.
Gastroesophageal /reflux may be defined as the presence of gastric contents in the esophagus. Thus, any event such as rumination, vomiting, spitting up, or even eructation may be inchided under this broad definition. A term such as vomiting really applies more to the overt clinical observation of gastroesophageal reflux. Therefore, the term "gastroesophageal reflux" is a non-specific term to describe any episode in which gastric contents are returned to the esophagus. The presence of this condition may be either physiologic or pathologic.
Vomiting may be defined as the ejection of gastric contents from the mouth. Spitting up is a small episode of vomiting; reguritation represents an episode where gastric contents are brought into the mouth and might be either expectorated or swallowed. Rumination is the clinical observation of repeated pleasurable episodes of regurgitation. Common to all of the preceding definitions is gastroesophageal reflux.
CLINICAL MANIFESTATIONS OF GASTROESOPHAGEAL REFLUX
Gastroesophageal reflux may have a different prognosis and course depending upon the age of onset. In most reviews, it is generally accepted that both premature and term infants have an increased incidence of vomiting. Nearly all infants vomit or spit up in the early months of life. By the time solid food is introduced into the infant's diet - between four to six months of age - a general decrease is noted in the frequency of emesis.
Between six months and one year of age, the frequency of vomiting rapidly diminishes; fivtf- percent of children will vomit as frequently as once per week. ' Because of the increased incidence of vomiting that normally occurs in the early months of life, clinicians have been cautious in evaluating and treating such infants. Severe gastroesophageal reflux may result in failure to gain weight and grow, hematemesis, aspiration pneumonia, recurrent pneumonias, sudden episodes of cyanosis (particularly postprandially), near sudden infant death syndrome, iron deficiency anemia, and the Sandifer syndrome (Table I). Severe postprandial vomiting is the most common presentation of GER. Children who have strictures or who have severe reflux may be irritable, with difficulty swallowing and frequent emesis. Children between one and two years of age who have significant gastroesophageal reflux may present with similar signs of failure to gain weight and grow, dysphagia, esophageal obstruction, hematemesis, iron deficiency anemia, recurrent pulmonary infections, aspiration pneumonitis, and cyanotic or apneic episodes (Table 2).
SEQUELLAE OF GASTROESOPHAGEAL REFLUX IN CHILDREN
Children from five to ten years old may only complain of abdominal pain or will describe the classical symptoms of heartburn - which may be a sudden onset of continuous, retrosternal (midlJne) constant discomfort and may be associated with a bitter taste or water brash. Children of all ages, as well as adults, may complain that they find small amounts of emesis on the pillow or bed sheets when they wake in the morning. They may also have easilyinduced episodes of régurgitation or vomiting while bending over, during valsalva maneuvers, or following sufficient gastric distention with liquid or solid meals. Mentally retarded and neurologically damaged children may present with rumination, frequent emesis, and significant failure to thrive. In this group, frequent dysmotility of the esophagus and varying forms of bulbar palsies with swallowingdifficultiesare noted, contributing to the inability to prevent reflux-induced aspiration pneumonias. Children with tracheoesophageal fistula are at particular risk for aspiration pneumonia and reflux esophagitis, and have evidence of significant abnormalities in esophageal motility. A high incidence of gastroesophageal reflux has been found in varying subgroups of asthmatics, particularly those resistant to most forms of therapy and who quite frequently have recurrent pneumonias. Any severe asthmatic requiring continuous corticosteroids and in whom investigation for other etiologies of the asthma has proved unsatisfactory warrants evaluation for recurrent aspiration secondary to gastroesophageal reflux, particularly if the recurrent pneumonias show an aspiration-pneumonia pattern on chest radiograph.
SYMPTOMS OF GASTROESOPHAGEAL REFLUX IN CHILDREN
If a history is compatible with gastroesophageal reflux, the clinician must decide how extensive an evaluation of the gastroesophageal reflux is warranted. The evaluation may be divided into three purposes: 1) to evaluate the extent of the reflux and its relationship to the patient's clinical symptoms; 2) to evaluate the potential causes or contributing factors that produce gastroesophageal reflux; and 3) to determine the presence and severity of pathological sequellae. Table 3 summarizes these tests.
* Radiographie studies. The routine chest film may give evidence of recurrent aspiration-like pneumonias; a routine abdominal series may reveal evidence of an obstructed duodenum. A barium esophagram with an upper gastrointestinal series will allow evaluation of the stomach for pyloric stenosis, duodenal or pyloric channel ulcers, antral web, duodenal atresia, stenosis and antral dysmotility. This series may be routinely combined with a chest series. A videoesophagram or cineesophagram should be done to evaluate esophageal peristalsis and extent of reflux.2'3 If there is dysphagia, the patient should also be fluoroscopically monitored during swallowing. The effectiveness of antral movements and gastric emptying are evaluated and malrotation should be excluded. Various techniques to improve the radiologie evaluation have been advocated, such as the water siphon test (after the stomach is filled with barium, the patient is given small swallows of water).4 Unfortunately, large numbers of normal patients will reflux with the water siphon test, particularly since the lower esophageal sphincter (LES) relaxes normally with swallows.
CLINICAL DIAGNOSTIC EVALUATIONS OF GER
* Sclntographlc studies. Scintographic studies have been advocated to evaluate the extent and severity of gastroesophageal reflux. These tests are performed by mixing technitium with food or liquid.5'9 Scanning is done over the esophagus, stomach, and small intestine. The quantitation of gastric emptying may be assessed in cases where outlet obstruction is questioned, and reflux assessed by scanning over the esophagus. The degree of radiation exposure is equivalent to one chest film. This test is convenient and easily performed at any age as an outpatient. It is more physiologic in evaluating emptying disorders of both the esophagus and stomach. It is quantitative and may be used to monitor response to therapy. Scintographic studies have been used to assess aspiration10 but have not been successful in minor episodes.
* Esophageal manometry. A continuously-perfused multilumen catheter assembly is used to locate the lower esophageal sphincter area, as well as to assess peristalsis in the body of the esophagus and resting lower esophageal sphincter pressure.""13 Ineffective peristalsis of low amplitude may result from esophagitis, and either primarily or secondarily may contribute to prolonged stasis of acid in the esophagus with poor clearance. This may induce further injury to the esophageal mucosa. The amplitude, sequence, and duration of peristalsis in the esophageal body may be assessed by the use of manometry. If lower esophageal sphincter pressure (LESP) is below 10 mmHg, there is a high correlation with a continuously incompetent sphincter mechanism permitting frequent, massive reflux. When the LESP is greater than 20 mmHg, it may be intermittently incompetent or competent with other causes for GER.
* Intraesophageal pH monitoring. There are many versions of pH monitoring. The initial evaluation was described by Tuttle and Grossman,14 and subsequently, a standard acid reflux test was derived for both adults and children. This test proved useful in a short period of time to assess gross degrees of reflux. The standard acid reflux test15'16 is performed by instilling 300 ml of 0.1 N HCl per 1.73/ m2 body surface area into the stomach through a nasogastric tube. The tube is removed and a pH probe is positioned 5 cm above the lower esophageal sphincter in adults, or, in children, at a level above the LES 1 3 percent of the distance from the nares to the sphincter. (In most infants, the lower esophageal sphincter is located approximately 16 to 19 cm from the nares, and the pH probe is usually placed approximately 2 to 3 cm above it.) With the pH probe in place, once the patient has swallowed and cleared the acid from the esophagus, the patient is monitored for episodes of reflux (intraesophageal pH 4.0) and graded on a scale by the number of episodes which occur within one hour. Ninety percent of normal individuals will reflux less than twice in one hour. This test is extremely sensitive and patients with severe reflux usually yield positive results.
Because of the need to improve and quantitate correlation between symptoms and episodes of gastroesophageal reflux, 24-hour monitoring of intraesophageal pH has been developed. 17~19 This test has been useful both to diagnose gastroesophageal reflux and to assess effectiveness of various therapies. The test is performed in a manner similar to the pH probe test. It is critical that the probe be placed accurately and must be checked during the monitoring period to assure it has not moved into the stomach or upward into the esophagus. The probe is calibrated against two buffers of pH 4 and 7, respectively, and remains taped to the nares for the duration of the study. Probes are available for infants and children and are the size of an 8 Fr, feeding tube. With a probe and a reference electrode connected to a bioisolator, or directly to a portable pH meter, the pH is continuously recorded by a recording device. Asymptomatic individuals have approximately one episode of reflux per hour and no reflux during sleep. Individuals with severe esophagitis are most frequently found to have the most severe and prolonged reflux and have poor acid clearance from the esophagus. Some individuals reflux 50 percent of the time monitored. Patients who have respiratory complaints or apneic episodes may have correlation between apnea and episodes of reflux. Recently, we evaluated an infant with episodes of severe cyanosis requiring resuscitation and paramedic transport to a hospital. During monitoring at the hospital, the infant was noted to have cyanotic crisis following a feeding, with good correlation between reflux and the time of cyanosis. A Nissen fundoplication was performed and this infant has had no further apneic or cyanotic spells for four months following the procedure.
Any episode of reflux - despite a relatively physiologic pattern - may be considered pathologic if it correlates with pathologic symptoms or sequellae such as cyanosis or severe apnea. Monitoring of pH is a more direct physiologic measurement of gastroesophageal reflux and esophageal clearance, but does not pinpoint the pathologic abnormality which is causing the reflux. It does, however, quantitatively assess the severity and degree of reflux and correlate these with the clinical symptomatology.
* Endoscopy and esophageal biopsies. In children, upper endoscopy with flexible fiberoptic endoscopes may be routinely performed safely without general anesthesia. The esophageal lumen is assessed for evidence of gross erythema, easily induced friability, loss of the normal vascular pattern, erosions, webs, ulcérations, and strictures. To confirm esophagitis, biopsies may be taken through the endoscope with the use of grasp forceps, and also may be submitted for fungal culture. It is important that the biopsy be taken at least 3 cm orad from the lower esophageal sphincter. The stomach, antrum, pylorus, duodenal bulb and duodenum may be assessed for evidence of webs, ulcers, inflammation, stenosis, or for any outlet obstruction that may also produce significant secondary gastroesophageal reflux.
The purpose of endoscopy is to evaluate abnormalities noted in the radiographie study. It also allows one to assess, with greater sensitivity, the prese nee of esophagitis, which may be the major sequella of significant gastroesophageal reflux leading to stricture formation, and Barrett's esophagus.
The esophageal biopsies are examined for the presence of polymorphonuciear cells infiltrating the mucosa, basal cell hyperplasia, change in the ratio of the rete pegs to the esophageal epithelial layer; observation of any of these is a sensitive indication of esophagitis.
DIFFERENTIAL DIAGNOSIS OF GASTROESOPHAGEAL REFLUX
The presentation of gastroesophageal reflux is variable and sometimes subtle. Its most common manifestation is postprandial vomiting. In a patient who presents with vomiting, all possible causes of it should be investigated. The age of onset, the nature of the vomiting, and the clinical history are extremely relevant. Metabolic, neuroJogic, and infectious causes should be initially excluded and are not included in this discussion.
In all ages, particular attention should be directed to any evidence of a more distal obstruction involving the outlet of the stomach or smail bowel. This produces secondary gastroesophageal reflux. In infancy, stenoses, webs, and atresias of the upper intestinal tract must be investigated by contrast studies prior to instituting other evaluations for gastroesophageal reflux. Congenital hypertrophie pyloric stenosis should be ruled out during differential diagnosis, as it is a common cause of early and severe gastroesophageal reflux and postprandial nonbilious vomiting. Functional disorders, such as antral dysmotility, may produce a significant amount of gastroesophageal reflux. Diagnosis of these entities is confirmed by contrast and gastric emptying studies21 and may cause elevated or normal lower esophageal sphincter pressures.
Incompetence of the lower esophageal sphincter is felt to be a major contributing factor to gastroesophageal reflux. The neurohumeral control of the LES is a physiologically complicated entity affected by both cholinergic and noncholinergic mediators. Basal resting tone may be affected by the location of the LES, and theoretically in the case of hiatal hernia, could be weakened as it is pulled into the chest, where intrathoracic pressure may be negative. At the diaphragm or below, intragastric and intra-abdominal pressures increase LES pressure. Basal resting pressure, as indicated in the previous discussion of manometry, is directly correlated with the continuous competence of the LES. Periodic relaxation of this sphincter, particularly at inappropriate times22 or during sleep, may induce significant reflux, producing sequellae, even when these episodes are infrequent. Additionally, drugs or surgery may decrease lower esophageal sphincter competence.
* Hiatal hernia. The relationship of hiatal hernia to gastroesophageal reflux has been vigorously debated. Many feel that there is a direct relationship between hiatal hernia and gastroesophageal reflux; however, other studies refute this and emphasize the importance of the lower esophageal sphincter." Weakening of the LES by its intrathoracic location is an important concept. However, many patients who have hiatal hernia are essentially asymptomatic and have no significant gastroesophageal reflux; thus, the true relationship between hiatal hernia and gastroesophageal reflux still remains unclear. Furthermore, the diagnosis of hiatal hernia, by both endoscopy and barium studies, is frequently argued among radiologists and, therefore, small hiatal hernias and their contributions to reflux are even more controversial. It is, however, accurate to say that the diagnosis of hiatal hernia alone is insufficient to establish a diagnosis of gastroesophageal reflux.
* Esophageal disorders. Ineffective peristalsis of the body of the esophagus may result in poor acid clearance. This may be primary or secondary. Diseases affecting the musculature of the esophagus, such as myotonia dystrophica, intestinal pseudo-obstruction, scleroderma, and achalasia, are examples of primary disorders. In such cases, the esophagus may become dilated and static; even a single brief episode of reflux may result in prolonged acid in the esophagus causing significant injury to the body of the esophagus over a long period of time. Webs, strictures. Barren's esophagus, and infections of the esophagus may result from prolonged presence of gastric contents in the esophagus.
TREATMENT OF GASTROESOPHAGEAL REFLUX
Before treatment of gastroesophageal is instituted, a concerted effort must be made to elucidate the cause and identify the sequellae. In the first six months of life, evaluation of gastroesophageal reflux must be carefully undertaken only when significant sequellae occur such as listed in Table I. Once the diagnosis of gastroesophageal reflux has been confirmed by two or more positive tests, therapy may be initiated. Upright positioning and thickened feedings will not change the physiologic abnormalities. They may, however, diminish the overt amount of reflux and, in cases of less severe reflux, may permit postponement of any further therapy until a later date. Such delay could be advantageous, since, with maturity, the patient may outgrow his degree of vomiting. This treatment may be used empirically when the only complaint is frequent vomiting, and evaluation reveals that sequella of gastroesophageal reflux. The upright position must be maintained for at least two hours following each meal and may be necessary nearly continuously. Bethanecol at a dose of 9 mg/m2 may be useful in some infants, and may allow a sufficient period for maturity.24-26
If any patient has significant sequellae- particularly severe failure to thrive, gross esophagitis, recurrent apnea, cyanosis or pneumonia - surgical intervention is warranted. The Nissen fund o pii cation is preferred by many institutions. In this procedure, the gastric fundus is wrapped around the distal esophagus. By continuous pH monitoring, surgical therapy has been demonstrated to result in even less reflux than in controls.27 If the infant under six months of age is having no significant sequellae but continues to vomit, the surgical decision may be postponed; careful monitoring for any developing sequellae should, however, continue. Success of therapy or improvement of GER may also be evaluated by repeat intraesophageal pH monitoring.
Another modality of treatment for gastroesophageal reflux is antacids. They are taken when symptoms occur. Alginic acid (Gaviscon), a substance which coats the esophagus and promotes salivation to neutralize acid reflux, is also useful to relieve heartburn.28 In addition, cimetidine has been used,29 although not approved in children for gastroesophageal reflux. It may be taken at a dose of 20 to 40 mg/kg/day, in a maximum of four divided doses for continuous coverage, or once at bedtime to ensure adequate antacid protection during recumbency. Cimetidine and antacids may relieve the pain of heartburn; they may not, however, prevent continued injury to the body of the esophagus.
Numerous surgical operations are available to prevent gastroesophageal reflux. One of the more popular is the Nissen fundoplication as described above. Additional procedures include the Belsey and HiH procedures, which provide lesser degrees of fundoplication and gastropexy. In all of the techniques, fixation of the lower esophageal sphincter below the diaphragm and creation of a longer narrowing of the distal esophagus are mechanisms which may contribute to improved LES competence.
Attention to the correction of antral dysmotility in infants should be mentioned. As discussed, occasionally a funnel-shaped antrum and delayed gastric emptying are found on both barium study and gastric emptying studies;10 the lower esophageal sphincter remains normal. Surgery of choice in this instance is a long myotomy, similar to the Ramstedt procedure, with extension of the myotomy over the antrum. This may relieve the obstruction in some children, resulting in resolution of vomiting and significant gastroesophageal reflux.
The diagnosis of gastroesophageal reflux requires careful consideration of the patient's clinical history and initial evaluation of presenting symptoms. In cases where overt vomiting is noted, the initial evaluation should include a barium esophagram and upper gastrointestinal series. The diagnosis of gastroesophageal reflux may not be established by one test alone, but may require many tests to confirm the presence of significant reflux and to assess its sequellae,31-33 It is imperative to demonstrate that the extent and timing of GER is not merely physiologic.
Continuous intraesophageal pH monitoring has proven to be the most sensitive test for gastroesophageal reflux and better identifies its frequency, duration, and relationship to other symptoms. Manometry assesses the competence of the lower esophageal sphincter and integrity of esophageal peristalsis. The standard acid reflux test is a provocative test of gastroesophageal reflux. Gastric outlet obstruction, both organic and functional, may be primary causes of gastroesophageal reflux, and may be evaluated with barium contrast studies and scintographicstomach-emptyingstudies. Pooresophageal transit and clearance are contributingfactors which promote esophagitis.
Treatment of gastroesophageal reflux requires identification of the primary cause, and selection of the therapeutic modality appropriate to the severity of reflux and its associated sequellae. In those patients with severe clinical sequellae, the most effective treatment for gastroesophageal reflux is surgical fundoplication.
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SEQUELLAE OF GASTROESOPHAGEAL REFLUX IN CHILDREN
SYMPTOMS OF GASTROESOPHAGEAL REFLUX IN CHILDREN
CLINICAL DIAGNOSTIC EVALUATIONS OF GER