Gastroesophageal reflux (GER), defined as regurgitation of gastric contents into the esophagus, is a common physiological event. When symptoms or lesions occur as a result of reflux, this is referred to as gastroesophageal reflux disease (GERD) (1). The prevalence of GER varies according to age, particularly in children. Daily regurgitation is present in 50% of infants younger than 3 months, in >66% at 4 months, and 5% at the age of 1 year (2,3). Complete resolution of regurgitation occurs by 10 months in 55%, by 18 months in 60% to 80%, and by 2 years in 98% (4). Determination of the prevalence of GERD at any age is difficult because of increasing self-treatment and lack of medical referral. Children with GER symptoms present with esophagitis in 15% to 62%, with Barrett esophagus in 0.1% to 3%, and with refractory GERD requiring surgery in 6% to 13% (5–8).
A wide spectrum of clinical presentations of GERD exists, with important differences according to age (9). In children with GERD, regurgitation and vomiting occurred in 72%; epigastric pain, feeding difficulties, irritability, and Sandifer syndrome in 68%; failure to thrive in 28%; chronic respiratory symptoms in 13%; and recurrent apnea in 12%, with more feeding difficulties in toddlers and irritability in infants (7). Compared to adults, children report more regurgitation and vomiting and less heartburn, dysphagia, and chest pain (10).
The pathophysiology of GERD is multifactorial, and based on studies in adult patients, several contributing factors have been identified: esophageal motor dysfunction with lower esophageal sphincter (LES) incompetence (transient relaxations or permanently low LES pressure), failed peristalsis of the esophageal body, and hiatus hernia with cardia incompetence (11). In most patients, several mechanisms are likely to be present at the same time.
The literature suggests that transient LES relaxations (TLESRs) are the main mechanisms underlying reflux events in both adults and children (12,13). In adults with GERD, the most important motility abnormality in the esophageal body is referred to as “ineffective esophageal motility” (IEM). IEM is characterized by nontransmitted contractions and simultaneous contractions of reduced contraction amplitude (<30 mmHg) in the distal esophagus (14). These abnormalities are mainly found in adults with severe GERD and have been shown to impair esophageal clearance and contribute to the development of esophagitis (15,16).
In adults, there is an ongoing controversy as to whether impaired esophageal body motility in severe reflux disease is a primary disorder contributing to the pathogenesis of GERD, or whether it is a consequence of long-standing reflux or esophageal inflammation (17,18). The pediatric population offers the opportunity to study GERD and its complications in the earliest stages of the disease (19).
The purpose of this study is to determine the effect of age on the esophageal motility in GERD; to describe esophageal motility patterns in children with GERD, taking into account the presence of anatomical abnormalities and neurological impairment (NI); and to study the relation between esophageal manometry and GERD severity parameters (acid exposure and presence of esophagitis) in these children.
PATIENTS AND METHODS
The medical records of all pediatric patients referred to the University Hospital who underwent an esophageal manometry because of suspected GERD between 1998 and 2005 were reviewed retrospectively. At our hospital, children up to the age of 16 years are cared for by the pediatric division. In addition, children with severe psychomotor retardation (PMR) are often followed up at the pediatric division at ages beyond 16 years.
The main indication for the referral was to evaluate the severity of reflux disease and the need for a Nissen fundoplication. All of the patients were recruited by a single pediatric gastroenterologist (I.H.). To evaluate GERD severity, other investigations were also often performed, such as barium swallow, esophagogastroduodenoscopy, and esophageal pH monitoring.
Patients were classified by the presence of anatomical abnormalities, severity of endoscopic esophagitis, and neurological development (ND). The results of the barium swallow, esophagogastroduodenoscopy with biopsies, and pH monitoring, which were performed within 1 week in combination with an esophageal manometry, were noted. Patients and their parents were instructed to stop all medications known to affect gastroesophageal motility or secretion at least 2 weeks before the studies.
A barium swallow was performed to rule out a hiatal hernia, malrotation, or any other anatomical abnormality.
Esophagogastroduodenoscopy With Biopsies
A fiberoptic esophagogastroduodenoscopy with biopsies was performed in all of the patients, after sedation with midazolam 0.1 mg/kg (with a maximum of 5 mg) and pethidine 1 mg/kg (with a maximum of 10 mg) intravenously. The type and location of the mucosal injury were documented and the severity of the damage was graded according the Savary-Miller classification (20), which was still the basis for proton pump inhibitor reimbursement in Belgium at the time of the study. During the esophagogastroduodenoscopy, biopsies were obtained from the duodenum, the stomach (antrum), and the distal esophagus (21).
A Digitrapper MK III (Synectics Medical, Stockholm, Sweden) with unipolar antimony electrodes calibrated in test solutions (pH 7 and 1) was used for the pH monitoring. This assembly was introduced through the nose and positioned, under fluoroscopic control, 2 vertebrae above the diaphragm (22). The patients were admitted to the hospital for the duration of the study but were encouraged to carry out daily activities. Patients and their parents were asked to mark the sleeping, eating, and symptom periods by pressing a button on the data recorder. The ambulatory recording data were downloaded onto a personal computer and analyzed with the aid of commercially available software (Gastrosoft Inc, Synectics Medical, Irving, TX). Acid reflux was quantified with the following variables obtained from computerized analysis: number of reflux episodes, number of reflux episodes lasting longer than 5 minutes/hour, and percentage of time with pH 4 or less.
A water-perfused-type probe with 8 capillary tubes (0.5 mm) joined together around a larger central tube (0.75 mm) with the presence of a Dent sleeve (23) was used. The diameter of the entire catheter was 4.5 mm. Water-perfused catheters required a pneumohydraulic infusion pump to generate a constant pressure and flow rate through each lumen of the catheter. In the Arndorfer-type system, water was supplied from a chamber filled with sterile distilled water. Nitric oxide in a gas cylinder was used to pressurize the water chamber and then drive the water into the catheter via the capillary tubes and the pressure transducers. A pressure of 1000 mmHg (19.33 psi) generated a flow rate of 0.6 mL/min per channel (24).
The patient was asked to fast for 4 hours; no sedation was used (24). The pull-through technique at 1-cm steps was used with 1 to 5 mL water bolus swallows (wet swallow) at 20° to 25°C during every step. At least 20 seconds were allowed at each step. The level of the LES was assessed during the pull-through technique and was characterized by a step-up in the end-expiratory baseline pressure of >5 mmHg above gastric baseline. With the sleeve in position at the level of the LES, the catheter was secured to the patient's chin with tape. During the manometry study, the responses to 10 wet swallows were recorded with the registration of LES pressure, LES relaxation (second), velocity proximal and distal (centimeter/second), amplitude proximal, mid- and distal esophagus (millimeter of mercury), maximal amplitude proximal, mid- and distal esophagus (millimeter of mercury), duration contraction proximal, and mid- and distal esophagus (second).
Data and Statistical Analysis
Values were expressed as mean ± standard deviation or as median (interquartile range). Results were compared using the Student t test, with Bonferroni correction for multiple testing, or the Mann-Whitney U test. P values were considered to be significant if <0.05. The Pearson correlation coefficient between different age groups was calculated by linear regression analysis.
Esophageal manometry studies of 247 patients were available for analysis. Twenty-one studies were of minor quality due to crying and irritability of the child during the procedure and were excluded from the analysis. The evaluable study population consisted of 226 patients with a mean age of 6.7 ± 4.9 years (0.1–23.1), 92 girls and 134 boys. The patients were divided in 3 different groups based on the presence or absence of anatomical abnormalities as follows: group I: suspected GERD without anatomical abnormalities; group II: presence of a sliding hernia, and group III: esophageal atresia (EA) with primary repair. Group I consisted of 198 patients (78 girls, mean age 6.2 ± 4.9 years; 66 patients with NI (developmental disorders and cerebral palsy). Muscular and metabolic diseases were not included. Group II comprised 16 patients (10 girls, mean age 8.6 ± 6.0 years) and group III 12 patients (4 girls, mean age 5.5 ± 5.1 years; 11 patients with tracheoesophageal fistula).
A barium swallow revealed a sliding hernia in 16 patients, malrotation in 3 patients, and a distal esophageal stenosis in 2 patients. In the group with EA, 10 of 12 patients had a barium swallow, which did not reveal any other gastroesophageal congenital abnormality.
Endoscopy was performed in 131 of 198 patients in group 1, 16 of 16 patients in group II, and 10 of 12 patients in group III. The results are summarized in Table 1. No significant differences in the prevalence of esophagitis were found between the groups. A Barrett esophagus was present in 3 patients in group I, all with PMR.
Esophageal pH monitoring
pH monitoring was done in 120 patients in group 1, 9 patients in group 2, and 8 patients in group 3. Results are summarized in Figure 1.
Relation Between Age and Esophageal Manometry Findings
The children were divided in 4 age-range groups: <1 year (n = 27), 1 to 5 years (n = 78), 5 to 10 years (n = 48), and >10 years (n = 45). The manometry findings according to the age group are summarized in Table 2. The mean LES pressure and the velocity of propagation in the distal and proximal esophagus decreased with age in this group of patients with a high prevalence of GERD (all P < 0.01). A significant, inverse correlation was found between the age of the children and the resting LES pressure (Fig. 2) (R = −0.31, 95% confidence interval [CI] −0.43 to −0.18, P < 0.0001), distal velocity of propagation (R = −0.24, 95% CI −0.37 to −0.10, P < 0.001), and proximal velocity of propagation (R = −0.28, 95% CI −0.40 to −0.14, P < 0.0001). The prevalence of peristaltic wave progression tended to increase with age, but this correlation did not reach statistically significance (R = 0.05, NS).
Esophageal Motility in Children With Anatomical Esophageal Abnormalities
Table 3 compares esophageal motility parameters between the 3 groups. As can be expected, children with previous EA had severely disturbed esophageal motility.
Relation Between ND and Esophageal Manometry Findings
NI was present in 66 children (mean age 6.4 ± 4.7 years), whereas 132 had age-adequate ND (mean age 5.7 ± 4.7 years). The characteristics of esophageal manometry in these children are summarized in Table 4. Children with NI had a significantly lower occurrence of peristaltic waves, a lower velocity of propagation of the peristaltic wave in the distal esophagus, and a borderline increased duration of the peristaltic wave in the distal esophagus.
Relation Between pH Monitoring and Esophageal Manometry Findings
When patients were subdivided into 2 groups, based on normal or abnormal esophageal pH monitoring results, no difference was found between both groups (Table 4).
Relation Between Endoscopic Esophagitis and Esophageal Manometry Findings
Results of both esophageal manometry and gastroscopy were available for 125 children. The gastroscopy was abnormal in 111 children (78 with grade I and 33 with grade II esophagitis). Manometry findings according to endoscopy grade are summarized in Table 5. No significant differences in esophageal motor function were found according to endoscopic esophagitis grades.
The correlation between esophageal motility parameters and endoscopic findings was specifically analyzed in children with NI, because it was previously suggested that these have an increased prevalence of erosive esophagitis (8). Compared to children with ND and esophagitis, children with NI and esophagitis had a lower peristaltic amplitude in the proximal esophagus (48.7 ± 21.2 vs 38.7 ± 16.6 mmHg, P = 0.01) and lower proximal maximum amplitude (55.1 ± 26.3 vs 43.5 ± 19.8 mmHg, P = 0.01). In those with grade II esophagitis (14 patients with NI, 22 patients with ND), children with NI had a lower prevalence of peristaltic waves (96 ± 11% vs 67 ± 49%, P = 0.04) and significantly lower maximum amplitude of contractions in the proximal esophagus (58.4 ± 23.9 vs 43.1 ± 18.7 mmHg, P = 0.05). All of the other variables did not differ between ND and NI children with grade I or grade II esophagitis.
In adults, GERD can be associated with severe complications like Barrett esophagus, strictures, and esophageal adenocarcinoma, and esophageal motor function is more clearly impaired in those with more severe GERD manifestations. Epidemiological studies have shown that severe GERD complications are associated with a particularly long-standing history of reflux symptoms (26). If GERD early in life were associated with a long-lasting disturbance of esophageal motor function, it could be 1 of the factors that predispose to these complications later in life.
Studies in the literature differ with regard to the use of sedation and different types of sedation, and even general anesthesia makes it difficult to compare the studies and draw uniform conclusions. Although it was reported that midazolam does not change the LES pressure (24,25), we chose not to use any sedation to examine the motility by giving 10 wet swallows. In adults, it has been shown that liquid swallows are superior to dry swallows in inducing complete LES relaxation and contractions of normal amplitude (28,29). Crying and irritability of the child rendered 8.5% of manometries invaluable, a failure rate that is acceptable.
In the present study, we used wet swallows and a sleeve catheter at the level of the LES (27,28). Absence of sedation allowed every child to produce 10 wet swallows. It has previously been shown that 10 wet swallows are sufficient to obtain an accurate manometric diagnosis, and that 10 additional swallows change the diagnosis in only 2% (30). Ten wet swallows were possible and easy to give, whereas a higher number of swallows resulted in longer duration of the manometry with crying and irritability and a larger perfusion volume.
The issue of whether the LES tone is reduced at infancy has been the subject of many studies with conflicting findings (31–39). These studies used different techniques, with or without a sleeve sensor at the LES level. Studies by Omari et al (40) in very premature and premature infants with a Dent sleeve sensor revealed that, despite significant prematurity, the central motor control of the LES is fully developed during the intrauterine stage. All infants (PMA 33–38 weeks) had a high-pressure zone at the LES with a mean pressure of 20.5 ± 1.7 mmHg before and 13.7 ± 1.3 mmHg after feeding, and swallow-induced esophageal body motility showed a normal peristaltic progression. Mechanisms responsible for GER in children have been characterized by Kawahara et al, who found that TLESRs are the most important mechanism, whereas absent basal LES pressure is relatively infrequent (12). Similar results were published for premature infants (41). In the present study, we confirmed the presence of a resting LES pressure, even in the youngest patients. Surprisingly, LES pressure decreased with increasing age in the group of patients that was recruited in this study. This could reflect an aging and maturation effect. On the contrary, considering the high prevalence of GERD in the present group of children, it is also possible that the lower LES pressure and the shorter duration of distal contraction and decreased distal velocity of propagation reflects the impact of long-standing GERD, with or without inflammation, on esophageal motor function. The rise in proportion of peristaltic waves with increasing age is likely to represent a maturation effect. For ethical considerations, the performance of invasive testing in healthy, asymptomatic children is difficult. We therefore lacked a true control group for age-matched comparison, and such data are also not available from the literature.
EA is a common life-threatening congenital disorder occurring in approximately 1 of 3000 newborns. GER is considered the most frequent long-term complication, with an incidence of 40% to 70% (42,43). The literature concerning esophageal motility in children with EA is consistent with absence of peristaltic waves, low-amplitude contractions, and normal to low resting LES pressure. Different mechanisms have been proposed to explain the high prevalence of GER in EA. Morphological studies reported abnormalities of the myenteric plexus in the esophagus and stomach of these patients, suggesting a congenital origin of the motility disorders. However, surgical dissection and mobilization of the esophagus during EA repair may also contribute to disruption of its motor activity (44,45). In the present study, we confirmed significantly impaired esophageal motility in the EA group compared to the GER and hernia groups. All of the patients had absence of esophageal peristaltic waves and some had an LES pressure below 10 mmHg. This severely impaired motility and secondarily impaired clearance are likely to predispose to GER.
Contrary to our expectations, we found no significant difference in motility patterns in patients with a hiatal hernia compared to other patients investigated for GERD (although the hernia group was relatively small). Unlike what was reported for adults (46), the manometry did not reveal the presence of the hernia, which was demonstrated during radiology and endoscopy. The lack of detection on manometry probably reflects the small size of the sliding hernias, the limitations of a catheter with perfusion orifices at 3- or 4-cm intervals, and the position of the sleeve at the LES. Whether high-resolution manometry is more adequate in identifying hiatal hernia in children remains to be established.
GERD can be a serious disorder with a higher complication rate in neurologically impaired children (47–49). GER is common in neurologically handicapped children and does not seem to be related to any specific finding on computed tomography or magnetic resonance imaging of the brain (50). Several studies confirmed the high prevalence of reflux esophagitis and pathological pH monitoring in NI children (47–52). Abnormalities of esophageal motor function (low LES pressure, low-amplitude contractions, and abnormal motor response to swallowing) have been reported in this subgroup, especially in those with moderate or severe esophagitis (35,51,53), and a poor response to medical therapy was observed in those with a basal LES pressure below 10 mmHg (51). In the present study, we found statistically significant differences between children with normal and abnormal development for the proportion of peristaltic waves, the propagation velocity of the peristaltic wave, and the duration of the distal esophageal contraction. The proximal amplitude, the proximal maximum amplitude, and the proportion of peristaltic waves in children with esophagitis grade II were statistically different in children with ND and NI. The difference in proximal amplitude was not reported previously and its relevance to GERD is unclear. The abnormal distal motor responses suggest an important role for impaired motility and acid clearance, which makes the children with NI more vulnerable to GERD. In children with NI, symptoms suggestive of reflux should be sought, and a low threshold for further investigation is appropriate because of the underlying motor abnormalities with an increasing risk of esophagitis.
The relation between esophageal motility disturbances and esophagitis in children and adults remains controversial. Several studies have shown that TLESRs are the predominant mechanism for GER in premature children, older children, and adults, with the proportion of TLESRs accompanied by acid being significantly higher in patients with GERD than in normal subjects (12,41,54). Low resting LES pressure is found mainly in adults with severe manifestations of GERD. In children, little information is available on whether GERD is associated with low esophageal sphincter pressure and abnormal esophageal body motility. In a study by Berezin et al (55), esophageal motility was studied in 31 patients with mild to moderate esophagitis and in 48 patients without esophagitis, revealing no difference in LES pressure and esophageal contractions. Cucchiara et al (56) stated that motor dysfunctions of both LES and esophageal body are the major factors predicting refractoriness of GERD in children. The highest predictive values for the refractoriness of the reflux disease were TLSERs and esophageal sphincter pressure drift (57). In a study in which both 24-hour manometry and stationary manometry were performed, Chitkara et al found no significant difference in LES pressure (58). During prolonged manometry, no differences were found in the overall number of contractions, contraction frequency, duration of contractions, normal amplitude and prolonged contractions, and proportion of peristaltic contractions. There were significant differences in the total number of contractions per minute pre-, during, and post-GER events in children with GERD with or without esophagitis. These abnormalities occurred in all children with GERD, regardless of the presence or absence of esophagitis and may reflect an underlying motility disorder rather than a consequence of inflammation. In the present study, we recorded only 10 wet swallows, but the results are in line with this observation. We found no statistically significant differences in esophageal motor function between children with or without esophagitis, and no difference in distal esophageal body function or LES pressure in mild or moderate esophagitis grades with the use of the water-perfused probe and during 10 wet swallows. Somani et al reported a negative correlation between esophageal acid exposure and LES pressure and between the amplitude of distal esophageal contractions and more severe esophagitis (37). We could not confirm such correlation in the present study, and only found a significant increase of distal contraction amplitude in NI children with pathological pH monitoring. The underlying mechanism is unclear, but one could hypothesize that this represents an early compensatory mechanism of mucosal protection against acid reflux.
In conclusion, LES pressure and esophageal velocity decreased with increasing age. Esophageal manometry is severely impaired in children with EA and PMR. No specific esophageal motor abnormalities related to the presence of mild or moderate endoscopic esophagitis or abnormal pH monitoring were found. Further studies are needed to understand the interaction between esophageal manometry findings and GERD in the pediatric population, especially in patients with NI and in severe esophagitis. In this latter group, the influence of the spastic component of striated muscle, the neurological maturation defect, the underlying etiological disease, and medication should be investigated in depth.
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