Gastro-esophageal reflux disease and peptic esophagitis are associated with motor abnormalities of the esophagus. It has been suggested that an increase number of transient relaxations of the lower esophageal sphincter (TLERS) is responsible for gastro-esophageal reflux disease (GERD) in adults and children (1,2). However, some studies have found no difference in the number of TLERS in patients with GERD and controls (2). Thus, factors other than TLERS may play a role in the pathogenesis of GERD and reflux esophagitis. It is possible that abnormalities in esophageal motor function may promote GERD. In fact, failed or incomplete peristaltic waves, which result in delayed volume clearance from the esophageal body, are more prevalent in adult patients with mild to severe esophagitis (3,4).
In children, there is limited information on whether gastro-esophageal reflux disease and esophagitis are associated with abnormal esophageal motility. One study demonstrated non-specific motor defects (simultaneous, broad-based, double peak waves) in children with severe esophagitis (5). However, the measurements were for short periods and did not include physiologic events such as eating or sleeping. No previous studies in children have determined the extent of abnormal peristalsis during a reflux event, a moment when abnormal esophageal propulsion might result in delayed acid clearance (6). The development of equipment allowing combined ambulatory monitoring of esophageal manometry and pH (MP24) allows evaluation of esophageal motor events for extended periods of time throughout the day and during acid gastro-esophageal reflux episodes.
The aim of our retrospective study was to evaluate esophageal body contractions occurring during episodes of acid gastro-esophageal reflux using previously obtained combined ambulatory esophageal manometry and pH recordings (MP24) of children with gastroesophageal reflux with and without esophagitis.
PATIENTS AND METHODS
The medical records of all patients who underwent MP24 at the Motility Unit at Children's Hospital were reviewed. Patients were included if they had a) an upper gastrointestinal barium study without anatomic malformation; b) an upper endoscopy performed within 2 weeks of the MP24; c) no therapy administered between the MP24 and the upper endoscopy; and d) no history of congenital anomaly or gastric or esophageal surgery. Informed consent was obtained before all studies, and permission to conduct the study was approved by the investigational review board of Children's Hospital Boston.
MP24 was performed with a non-perfused solid state probe with 3 strain gauge pressure transducers separated by 5 cm from the distal end (Konisberg Instruments Inc., Pasadena, CA) as previously described (7). The probe had a pH electrode located 1 cm proximal to the distal pressure transducer with an external diameter of 5 mm. The probe was calibrated for both pH and pressure before placement. After an overnight fast, the probe was placed either without sedation, or with oral midazolam (0.5 mg/kg) for sedation if needed, in the Motility Unit in Children's Hospital Boston. Initially the gastric pH was documented, and then a standard stationary esophageal manometry was performed. This procedure included a slow pull through to determine the upper esophageal sphincter (UES) pressure, lower esophageal sphincter (LES) pressure and propagation of at least 10 wet swallows of water. After completion of the standard esophageal manometry, the probe was repositioned and taped with the pH electrode 3 to 4 cm above the LES.
During MP24, patients were allowed to conduct their normal activities and were instructed not to eat more frequently than every 4 hours. They were instructed to avoid acid containing food such as soda, apple juice, and lemonade. All activities and symptoms occurring during the study were recorded and included in the analysis. Data were recorded by a Synectics Microdigitrapper and analyzed by personal computer.
Data was analyzed as previously described (7) using a Synectics software package (Multigram Version 5.01 C2). Manometry and pH variables from the esophageal body were selected for analysis. The computer analysis program defined an acid reflux event as beginning when the pH dropped to <4.0 and ending when the pH returned to 4.1. The pH variables consisted of total percent of monitored time with esophageal pH < 4.0, total number of acid reflux episodes, duration of longest acid reflux episode and number of prolonged (>5 min) acid reflux episodes.
Upper esophageal sphincter (UES) pressure, upper esophageal contraction amplitude and duration, lower esophageal sphincter (LES) pressure, lower esophageal contraction duration and percent of normal swallows in the upper and lower esophagus during at least 10 wet swallows were analyzed with stationary manometry.
Motility variables obtained during MP24 were reported for the transducer in the lower esophageal body. Variables studied included: number of esophageal contractions, frequency of esophageal body contractions per minute of recording time, median contraction amplitude and duration, percentage of multi-peak contractions, percent of contractions >25 mm Hg, percent of contractions >180 mm Hg, percent of contractions >7 seconds in duration, percent of peristaltic, simultaneous and isolated contractions (contraction occurring only in a single channel for a period of greater than 0.8 sec).
An analysis of contraction efficacy and peristaltic sequences in all three transducers was also included. Adequate amplitude was defined as amplitude of a wave >30 mm Hg in the lower channel, >25 mm Hg in the middle channel and >20 mm Hg in the upper channel. Contractions were defined as peristaltic between 2 adjacent recording sites if the onset of contraction at the distal site was 0.3 to 0.8 seconds after the onset of contraction at the proximal site. Intervals shorter than 0.3 seconds between contractions at adjacent sites were considered to represent simultaneous contractions. Propagated peristalsis was categorized as mechanically effective if both complete propagation and adequate amplitude were achieved as previously reported (4). A peristaltic sequence was classified as possibly effective if complete propagation without adequate amplitude was achieved. A sequence was classified as ineffective if neither complete propagation nor adequate amplitude were achieved. Peristaltic sequences were further subdivided in complete sequences (contractions occurring in all channels), dropped (contraction missing in the distal channel) or interrupted (contraction missing in the proximal or middle channel).
Esophageal body contractions occurring during episodes of gastroesophageal reflux (pH < 4) were also analyzed. Contractions were analyzed for the following periods: 30 seconds before the reflux event (GER-PRE), during the reflux event (GER) and 120 seconds after the reflux event (GER-POST). We chose to analyze these periods because Bumm et al. suggested that there is a period of induction and delayed response in which motor abnormalities occur when acid refluxes into the esophagus (8). Variables analyzed were frequency of contractions and the presence of isolated, hypertonic (>180 mm Hg) and prolonged (>7 sec) contractions. An analysis of manometric events during prolonged episodes of reflux (> 5 min) was also performed.
Patients were classified by evidence of gastro-esophageal reflux and esophagitis. Esophagitis was defined as histologic evidence of basal zone hyperplasia >20% of the total epithelial thickness or elongation of the epithelial papillae to >75% of the epithelial height and >3 but <15 eosinophils/HPF in the lower esophageal body. Patients without dysphagia, with grossly normal upper endoscopy, with no histologic evidence of esophagitis, with <6% time with esophageal pH < 4 and with no apparent gastrointestinal disease after 1 year of follow-up were considered controls, Group C. The manometric data on individuals in this group has been previously published (7). Patients without histologic esophagitis and a reflux index of >6% were designated as GERD without esophagitis (9,10), Group 1. Patients with histologic evidence of esophagitis and a reflux index of >6% were designated as GERD with esophagitis, Group 2. All individuals with >15 eosinophils/HPF and suspected of eosinophilic esophagitis based on symptoms being unresponsive to treatment with a proton pump inhibitor were excluded from this study (11).
A blinded investigator unaware of patient symptoms and evaluations analyzed the manometric findings. Statistical analysis was performed using SPSS (Chicago, Illinois). Qualitative values are expressed as mean ± SD. Comparisons of proportions were made with χ2. The Kruskal Wallace signed rank test was used to compare nonparametric data from the three different groups. Statistical significance was defined as a P < 0.05.
Patients and Symptoms
There were no significant differences in age and gender among the three groups (Table 1). No patients in Group C had dysphagia. There were no other differences in any presenting symptoms.
pH Probe Results
Results of pH probe studies are shown in Table 2. Among the groups, there were significant differences in the total number of reflux episodes, duration of longest episodes and episodes >5 minutes. Patients in Group C had the lowest frequency and duration of reflux episodes. Patients in Group 1 and 2 had a similar percent of time with esophageal pH < 4 and number of reflux episodes.
All patients had normal stationary esophageal manometry (12). There were no significant differences in the percent of normal swallows (Group C, 98%; Group 1, 96%; Group 2, 98%). There were no significant differences in the lower esophageal sphincter pressure (Group C, 24 ± 2 mm Hg; Group 1, 28 ± 4 mm Hg; and Group 2, 22 ± 2 mm Hg) or upper esophageal sphincter pressure (Group C, 116 ± 10 mm Hg; Group 1, 132 ± 7 mm Hg; and Group 2, 134 ± 13 mm Hg) of the groups.
During prolonged manometry there were no differences in the overall number of contractions, contraction frequency, duration of contractions, percent of multipeak, normal amplitude (>25 mm Hg) and prolonged contractions (>7 sec) (Table 3). There were no differences in the percent of peristaltic, simultaneous or isolated contractions or in the percentage of effective, ineffective, complete, dropped or interrupted propagations. There were significant differences in the percentage of hypertonic (>180 mm Hg) contractions with the lowest percent observed in Group C.
Esophageal motor abnormalities during gastro-esophageal reflux
Analysis of esophageal motility during acid gastroesophageal reflux events demonstrated significant differences in the total number of contractions per minute pre-, during and post-GER events (Table 4). Patients in Group C had a higher number of contractions per minute during the three periods compared to patients in Group 1 and 2, who displayed a similarly decreased number of contractions per minute. (Fig. 1). There were significant differences in the number of isolated contractions and esophageal body contractions >7 seconds during prolonged episodes of GER (>5 min) with more occurring inpatients classified in Group 1 and 2 compared to Group C (Table 4).
Although transient lower esophageal sphincter relaxations and abnormal esophageal body contractions during acid gastro-esophageal reflux have been implicated in the pathogenesis of GERD and esophagitis, the role of esophageal body contractions during gastro-esophageal reflux events has not been examined in children. We have demonstrated a significantly decreased number of esophageal body contractions per minute of gastro-esophageal reflux in children with GERD with or without esophagitis compared to controls. Patients in groups 1 and 2 also had a decreased number of contractions 30 seconds before and 120 seconds after reflux episodes.
We also found that patients with GERD had abnormal esophageal body contractions during reflux episodes. Control patients had a significantly fewer isolated and prolonged contractions (>7 sec) during prolonged reflux episodes (>5 min) compared to patients in the other groups. Thus in the present study, children with normal amounts of acid exposure have normal esophageal body contractions which are essential in esophageal acid clearance compared to patients with GERD with or without esophagitis. This suggests that children with gastroesophageal reflux disease may have impaired esophageal acid clearance due to decreased and abnormal esophageal body contractions.
In adults, esophageal motor abnormalities associated with gastro-esophageal reflux have been described (13). Bumm et al. found that irregular or high amplitude contractions were more prevalent in patients with gastro-esophageal reflux disease (8). Others have found that adults with GERD have more isolated, double-peaked contractions and simultaneous contractions than controls (14,15). The clinical significance of abnormal esophageal body motor contractions has been evaluated with simultaneous esophageal pH and fluoroscopic studies. Lumen obliterating, non-propulsive and repetitive contractions have been shown to result in delayed bolus clearance suggesting that abnormal esophageal contractions can produce delayed acid clearance (16). Kahrilas et al. demonstrated video-fluoroscopic escape of barium from a normal esophageal propulsion with an esophageal body contraction of <30 mm Hg (4).
It is unclear whether abnormal esophageal body contractions are the cause or consequence of peptic esophagitis. Experimentally, acid injury in the cat esophagus produces inflammatory changes and decreased lower esophageal sphincter pressure that return to normal after healing of the esophagus (17). Leukotriene D4 and peroxynitrite, a superoxide radial combined with nitric oxide, are inflammatory mediators implicated in altering smooth muscle contractions in the esophagus during inflammation (18,19). Cucchiara et al found that abnormal esophageal body contractions normalized in children after successful treatment of esophagitis (5). A limitation of our study is that we did not repeat prolonged manometry in our patients with esophagitis after treatment to see if the peristaltic abnormalities persisted after histologic cure. There are other studies, however, showing that abnormalities in peristalsis and lower esophageal sphincter pressure in patients with esophagitis do not improve after healing of the inflammation suggesting that manometric abnormalities in these patients may be a primary phenomenon (20). This possibility is also supported by the observation of a high relapse rate of esophagitis following discontinuation of acid blocking medication, omeprazole, suggesting continued acid exposure to the esophagus despite healing of the inflammation (21). Our Group 1 patients had the same decrease in esophageal body contractions during gastroesophageal reflux as Group 2 patients despite having no esophagitis. This observation suggests that esophageal body motor abnormalities occurred independent of esophagitis. However, prospective testing before and after treatment would be necessary to confirm this hypothesis.
In conclusion, patients with gastro-esophageal reflux disease with or without esophagitis have significantly fewer esophageal body contractions before, during and after reflux events compared to patients without GERD. This suggests that children with GERD with or without esophagitis have an impaired ability to clear esophageal body acid during reflux. Abnormalities in esophageal body contractions occur in children with GERD without esophagitis, which suggests that they may be due to an underlying disorder of the contractions of the esophageal body, and not due to inflammation.
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