Mechanisms Responsible for Gastroesophageal Reflux in Children

Transcription

1 GASTROENTEROLOGY 1997;113: Mechanisms Responsible for Gastroesophageal Reflux in Children HISAYOSHI KAWAHARA,* JOHN DENT, and GEOFFREY DAVIDSON *Department of Pediatric Surgery, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan; and Gastrointestinal Medicine, Royal Adelaide Hospital, and Gastroenterology Unit, Women s and Children s Hospital, Adelaide, South Australia, Australia Background & Aims: There is limited information about in most children with reflux disease 4 and there are the motor mechanisms responsible for gastroesopha- no reports of continuous measurements evaluating the geal reflux (GER) in children. The aim of this study was possible role of straining as a precipitant of reflux in to evaluate the relationship between esophageal body children. and lower esophageal sphincter (LES) motor events In adults with and without GER disease, most reflux and the occurrence of GER. Methods: Concurrent episodes occur during transient LES relaxation. 5 7 Tranesophageal manometry and ph monitoring was consient LES relaxation is distinct from the relaxation producted for 4 hours postprandially in 37 children referred for evaluation of suspected pathological GER. Presence duced by swallowing. Studies of the mechanisms of of esophagitis and/or abnormal esophageal acid expoopment of the position-tolerant sleeve sensor that moni- reflux in adults were only possible because of the develsure was used to classify patients into two groups: those with pathological GER (group A; n Å 24) and tors LES pressure for long periods, thus allowing reliable those in whom GER was not confirmed (group B; n capture of motor events associated with spontaneous Å 13). Results: GER occurred during LES relaxations reflux episodes. 8,9 Standard sleeve sensors are too bulky unassociated with swallowing within 5 seconds before for passage in most children. Consequently, this techand 2 seconds after the onset of LES relaxation in nique has been exploited very little for the study of 58% (group A) and 69% (group B) of the analyzable GER in children. The reported experience is limited to episodes. These swallow-independent sphincter relaxshort recording periods in a small number of chilations satisfied criteria for classification as transient dren. 10,11 These observations suggest that at least some LES relaxations. An additional 23% (group A) and 19% reflux episodes in children occur during periods of tran- (group B) of reflux episodes could have been a result of transient LES relaxation associated with swallowing sient LES relaxation, but the duration of these re- by chance. Persistent absence of LES tone was an cordings was not long enough to allow precise analysis infrequent association of reflux and was confined to of the motility of the LES and esophageal body during group A patients (8% of episodes). Conclusions: Transient LES relaxation is the most important cause of LES relaxation also differs from that of Cucchiara et spontaneous GER episodes. Our definition of transient GER in children. Absent basal LES pressure is a rela- al. 11 and is similar to that recently reported by Mittal tively infrequent cause of reflux and only in children et al. in adults. 7 This difference is crucial because the with pathological GER. pressure decreases defined as transient LES relaxation by Cucchiara et al. 11 included incomplete relaxations, which have been excluded from previous analysis of ymptomatic gastroesophageal reflux (GER) is a transient LES relaxations in adults. Scommon problem in infants and young children, The aim of this study was to define better the LES but the mechanical events that lead to its intermittent and esophageal body motor events associated with occuroccurrence are poorly understood. 1 It has been prorence of GER episodes by using a miniaturized sleeve posed that, in children, weak steady-state lower esophsensor for prolonged LES pressure recording, concurrent ageal sphincter (LES) pressure allows the sphincter to with monitoring of esophageal body motility and distal be overcome easily by spikes of intragastric pressure esophageal ph. generated by straining or that GER occurs because gastric contractions overcome a normally functioning Abbreviations used in this paper: CC, common cavity; GER, gastroantireflux barrier. 2,3 However, these hypotheses are not esophageal reflux. well supported, because sample measurements of LES 1997 by the American Gastroenterological Association pressure have failed to show convincing LES hypotonia /97/$3.00

2 400 KAWAHARA ET AL. GASTROENTEROLOGY Vol. 113, No. 2 Patients and Methods Patients Thirty-seven children, aged from 6 months to 16 years, were referred to one of the investigators (G.D.) at the Gastroenterology Unit of the Women s and Children s Hospital (North Adelaide, South Australia) for assessment of troublesome symptoms believed to be caused by GER. Approval for the studies was obtained from the Research Ethics Committee of the Women s and Children s Hospital, and informed consent was obtained from a parent or guardian. Children with neurological disease, those who had structural abnormalities of the esophagus other than hiatus hernia, or those who had any prior esophageal surgery were excluded. The 37 children were divided into two groups according to Figure 1. Arrangement of recording elements in the three manometric assemblies used in the study. the findings of endoscopy, esophageal mucosal histology, and 4-hour postprandial ph monitoring, the last procedure being conducted concurrently with the manometric study. When esophageal ph was õ4 for 5% or more during the second 2 minutes. Pulmonary aspiration was evaluated by scanning for hours after the meal, this was considered positive for pathologiof the presence of pulmonary activity 2 4 hours after ingestion cal reflux. Children in group A were required to have at least the label. Pathological reflux was diagnosed when scanning one of the following: probable or definite endoscopic esophagitis, showed two or more episodes. histological esophagitis, or a positive ph recording. Group B children had neither endoscopic nor histological esophagitis Methods and a negative ph monitoring study. The definition of esopha- Procedure for esophageal motility and ph recording. gitis and the procedure for ph monitoring are given below. Studies were started at approximately 10 AM after a 3-hour Before performance of combined esophageal motility and fast. Esophageal motility and ph were monitored for 4 hours ph studies, patient clinical details were recorded and baseline after food intake. No sedation was given. The miniature manoinvestigations were performed. Every attempt was made to metric assembly and ph electrode were passed transnasally. investigate each child with a barium swallow, upper gastroin- The ph electrode was attached to the assembly just above its testinal endoscopy, endoscopic esophageal biopsy, and gastro- bulb. In older children, the meal was preceded by a 20-minute esophageal scintigraphy. adaptation period after intubation. Feeds were offered directly Radiological studies were directed toward detection of ana- after intubation in infants because this often helped them to tomic abnormalities, but when at least a grade 2 reflux episode settle. The food given was not standardized, but foods or drinks occurred (as defined by McCauley et al. 12 ), this was recorded withaphofõ4 were excluded. If less than half of the meal as a positive result for radiologically demonstrated reflux. No was eaten, 180 ml of milk was introduced into the stomach maneuvers were used to provoke reflux during the radiological by the gastric manometric channel to ensure some nutrient examination. loading. Apart from during the meal, measurements were per- Endoscopic esophagitis was divided into two categories: formed with the child recumbent, either on a bed or on a (1) definite when erosions or ulceration were present; and (2) parent s lap. The child was kept awake with toys or a television probable when there were any of the following mucosal find- program so that sleep and its associated substantial effects on ings: increased friability or granularity, spontaneous bleeding, patterns of esophageal ph and motility were avoided. or leukoplakia. Recording methods. Three manometric assemblies Esophageal biopsy specimens were taken 3 4 cm above were used that had spans between the pharyngeal and gastric the gastroesophageal junction. Each specimen was cut and side holes of cm (Figure 1). These three assemblies examined at multiple levels, and the most severe change ob- covered the age-dependent range of esophageal lengths. LES served was the one recorded. Histological esophagitis was pressure was recorded with 3.5- or 4.0-cm long sleeve sensors, scored as present when intraepithelial eosinophils were noted the cross-sections of which were miniaturized in the two or if two of the following three findings were observed 13,14 : (1) shorter span assemblies (diameter, 3.5 and 3.0 mm) compared basal layer thickness ú 20% of total epithelial thickness; (2) with the longest span assembly (maximum diameter, 4.5 mm) papilla length ú 60% of total epithelial thickness ú 60; and used in older children. (3) number of squiggle cell lymphocytes per maximum high- Glass ph electrodes (model nos. MI 504 and 508; Micropower field (401) ú20 in at least one high-power field. electrodes Inc., Londonderry, NH), were used for distal esopha- Radionuclide scans were performed to test for reflux by geal ph recording. Their position relative to the sleeve was loading of the stomach to satiety with fluid labeled with 40 standardized by attaching them to the manometric catheter 3 mbq of technetium 99m, with subsequent scanning for 45 cm above the upper margin of the LES in children 10 years

3 August 1997 MECHANISMS OF GER IN CHILDREN 401 and 5 cm above the LES in children 10 years. Either a Beckman fiber junction (Beckman Instruments Inc., Fullerton, CA) or a Microelectrodes ceramic junction (Microelectrodes Inc., Londonderry, NH) external reference skin electrode was used, electrical skin contact being achieved with a conductive electrolyte gel. The manometric assembly was perfused with a low compli- ance infusion pump (Arndorfer Medical Specialties, Grove Tce, Greendale, WI). In the two assemblies for younger children, the sleeve was perfused at 0.4 ml/min, the gastric channel at 0.2 ml/min, and the esophageal body side holes at 0.1 ml/ min. The assembly used for the older children was perfused at 50% more than these rates. To avoid stimulation of swallowing, the pharyngeal manometric channel was water-filled but not perfused. Monitoring of occurrence of pharyngeal pressure waves with swallowing was usually adequate with this arrangement (see Results). The position of the sleeve relative to the LES was adjusted by pressure patterns seen in the respective recording side hole at the proximal and distal sleeve margin. 9 Calibration of the ph electrode was checked in buffer before and after each study. Drifts no greater than 0.5 ph units were accepted and corrected for on the assumption that such drift had occurred linearly through the study. A Devices M19 (Devices Ltd., Jersey, Channel Islands, United Kingdom) 8 channel polygraph recorded pressure and ph at a paper speed of 100 mm/min. The ph electrode was connected to a standard laboratory meter through an electrical isolation module. Bell and Howell pressure transducers were used. Data Analysis LES pressure. Mean values of end expiratory basal LES pressure were determined visually from every 15th minute of tracing, using intragastric pressure as the reference. If this segment of the tracing was uninterpretable because of crying or restlessness, the first interpretable minute after this was used. LES pressure was rarely uninterpretable for more than 15 minutes, in which case no value was derived for that period. Overall mean postprandial LES pressure was derived for each patient from these samples. Relationship of motility to reflux episodes. This anal- ysis was conducted at approximately the time of onset of the esophageal ph decrease caused by reflux. Reflux episodes were scored when esophageal ph decreased to õ4 for at least 4 seconds. Infrequently, intraesophageal ph drifted very gradu- ally to õ4. Such changes of ph were defined as ph drifts if the ph decreased by an average of õ1 ph unit/20 seconds. When intraesophageal ph was õ4, another reflux episode was also scored if there was a further abrupt decrease of at least 1 ph unit. The occurrence of common cavity (CC) episodes was also scored around the time of acid reflux episodes. These are abrupt elevations of basal intraesophageal pressure to intragastric pressure, which have been shown previously to be caused by flow of stomach content (either gas or liquid) into the esophagus. 15 Basal LES pressure just before reflux episodes was determined as a 10-second visual mean taken between 30 and 20 seconds before the onset of the decrease in ph. If LES pressure could not be interpreted during this period because of movement or frequent swallowing, a value was derived from the preceding 10 seconds. The time of onset of reflux was determined as accurately as possible, by either the onset of the ph decrease or the CC, whichever came first, because in some episodes, the onset of esophageal acidification was significantly later than the onset of the CC, the manometric indicator of reflux. When a clear CC did not occur in association with an episode of esophageal acidification, the onset of the ph decrease was defined as the time of onset of reflux. Esophageal acidification episodes were classified into six groups according to associated LES pressure patterns at the onset of reflux and their time relationship with swallowing. The flowchart in Figure 2 outlines this process and the criteria used. When the rate of decrease of LES pressure was 1 mm Hg/s, the decrease of LES pressure was defined as an LES relaxation. The time relationship of the pharyngeal manomet- ric swallowing signal to the onset of LES relaxation was then evaluated to distinguish between relaxations that were associ- ated with swallowing and those that occurred independently of swallowing. Episodes in which no swallow was scored within 5 seconds before and 2 seconds after the onset of LES relaxation were classified as type I LES relaxation. Episodes in which a single swallow was scored within that period were classified as type II LES relaxation. Episodes of decreases of LES pressure in which two or more swallows were scored within 5 seconds of the first swallow were classified as type III LES relaxation. The logic for classification of LES relaxation is explained in the Discussion section. The durations of complete LES relaxation were measured for the episodes of types I and II LES relaxation. The period of complete LES relaxation was defined as the time that LES pressure was 2 mm Hg. The duration of swallow-induced LES relaxation was also obtained in each patient from the average of the durations of three complete swallow-induced LES relaxations associated with normal primary peristalsis obtained mainly between 2 and 4 hours after food intake. Appropriate control swallows were defined as those that did not have any other swallow occurring in the 15 seconds before and after the test swallow. The intervals between the onset of complete LES relaxation and the onset of reflux as defined above were scored in the episodes of type I LES relaxation. The episodes of type I LES relaxation were divided into three subtypes according to the associated esophageal body motor events (Figure 3). Spontaneous type I LES relaxations were scored if there were no discernible esophageal body pressure waves other than respiratory changes within the 5 seconds before their onset. Post swallow cycle type I LES relaxations were defined as those that occurred just after swallowing that had resulted in LES relaxation and esophageal body peristalsis, in which basal LES pressure was not reestablished after the swallow-induced sphincter relaxation and contraction. Post esophageal body contraction LES relaxations were defined as those associated with a pressure wave of any size in the esophageal body that occurred in the 5 seconds before the onset of

4 402 KAWAHARA ET AL. GASTROENTEROLOGY Vol. 113, No. 2 LESP at the onset of acid reflux LESP 2 mm Hg LESP 2 mm Hg LESP 2 mm Hg throughout the preceeding 30 seconds? Reflux across a contracted LES Yes No Absent basal LES tone LESP decrease 1 mm Hg/s LES tone drift Time relationship of swallowing to onset of LES relaxation Any swallow within 5 to 2 seconds of onset of LES relaxation? Yes Single swallow Type II LES relaxation? transient LES relaxation? swallow-induced LES relaxation Two or more swallows within 5 seconds Type III LES relaxation repetitive swallowing No Type I LES relaxation Definite transient LES relaxation Figure 2. Flowchart for the method of analysis of the LES motor patterns associated with reflux Acid reflu episodes were classifie according to the patterns of LES pressure (LESP) before and at the time of reflux The relationship of swallowing to LES pressure changes was analyzed in detail to determine whether absence of LES pressure could be possibly explained by swallow-induced LES relaxation. of the esophageal body by swallowing was clearly within the duration of an established transient LES relaxation, that only a pure, single swallow test was evaluated, and that there was sufficient time for development of any esophageal body re- sponse within the time course of the transient LES relaxation. A testable single swallow was defined as one that occurred within 2 seconds after the onset and 10 seconds before the offset of LES relaxation, which was separated by at least 15 seconds from prior or subsequent swallows. Esophageal body responses to swallowing during transient LES relaxation were compared with responses to swallowing when transient LES relaxation was not occurring. These control swallows were identified by scanning the tracing backwards in time and taking the first swallow that occurred ú30 seconds before the start of the period of transient LES relaxation under review that satisfied the criteria given above. type I LES relaxation. Such pressure waves were, by definition, not swallow-related. The hypothesis that there is inhibition of the esophageal body during transient LES relaxation was tested by examining esophageal body motor responses to swallowing in type I LES relaxations lasting 20 seconds. Such periods of LES relaxation were scanned for occurrence of a testable single swallow. The criteria given below were chosen to ensure that the stimulation Statistical Analysis Data in the text are given as median values and interquartile ranges. Tests for statistically significant differences between groups of data were analyzed by Student s t test unless specified otherwise. A P value of õ0.05 was considered as significant in all analysis. Results Figure 3. Schema showing the three major subtypes of type I LES Group A Patients relaxation (definit transient LES relaxation) and their incidences in group A children. Synchronous non swallow-related esophageal body Clinical and ph data. Group A consisted of 24 contraction was associated with 21.7% of episodes, an isolated preschildren. Clinical findings are shown in Table 1. Vomsure wave seen in only one channel was seen in 3.9 episodes, and a secondary peristaltic pressure wave occurred in 2.6%. iting was the major clinical feature at presentation. Half

5 August 1997 MECHANISMS OF GER IN CHILDREN 403 Table 1. Major Presenting Features in Each Group to the analyzable 273 episodes. CCs were present in 213 episodes (78%). Group A Group B All of the measures of LES pressure around the time No. of patients of reflux showed that this was almost always associated Age (mo, range) 45 (13 108) 11 (9 68) Vomiting 18 (75%) 10 (77%) with LES relaxation. At the time of the earliest indication Respiratory symptom 11 (46%) 5 (38%) of reflux, LES pressure was 0 mm Hg and in 93% of Failure to thrive 9 (38%) 4 (31%) reflux episodes, LES pressure was within the range of 02 Heartburn 2 (8%) 2 (15%) Hematemesis 1 (4%) 0 (0%) and /2 mm Hg. If the onset of the ph decrease was Dysphagia 1 (4%) 1 (7%) used as the only indicator of the timing of the onset of flow from the stomach into the esophagus, then LES pressure was 0 mm Hg at this moment. When CCs occurred, LES pressure was 0 mm Hg at their onset. of the children had persistently troublesome respiratory None of these values differed significantly from each symptoms. In more than one third of the children, other (Kruskal Wallis test). LES pressure in the growth failure was an associated feature, although not seconds before reflux episodes was 9.0 mm Hg (range, the major presenting symptom ). LES pressure before reflux episodes and at Figure 4 summarizes the results of investigations in their onset of reflux (at the time of the earliest indication) each individual. Incidences of positive results in each differed significantly (P õ 0.01, Welch test), the values examination were 57% by histology, 30% by endoscopy, before reflux being similar to those of the 15-minute 75% from ph monitoring, 58% by upper gastrointesti- sample values. nal study, and 53% by scintigraphy. More detailed analysis of swallowing and other events Figure 5A gives the numbers of reflux episodes per 1 close in time to reflux episodes revealed the following. hour and Figure 5B the percentage of time of esophageal Of the 273 acid reflux episodes in which LES pressure ph õ4 in the second 2 hours after the meal. There were profiles were analyzable, 9 episodes did not have a techni- 3.8 (range, ) episodes of reflux per hour. The cally adequate swallowing signal in the pharyngeal tracpercentage of time of esophageal ph õ4 in the second ings. The patterns of swallowing and LES pressure change 2 hours after the meal was 9.0% (range, 6.7% 13.1%). associated with esophageal acidification were therefore Manometric data. Basal LES pressure showed examined in 264 episodes. The mix of patterns is shown substantial variation over time within individual chil- in Table 2. Of the acid reflux episodes, 84% met the dren. The median value of basal LES pressure for this criteria for LES relaxation (Figure 2). Episodes classified group was 11.9 mm Hg (range, ), and the me- as type I LES relaxation (definite transient LES relaxation) dian highest and lowest LES pressure values were 18 and were scored in more than half of analyzable episodes 6 mm Hg, respectively. (Table 2). The proportion of type I LES relaxations re- In 273 of 339 reflux episodes, the tracings could be sponsible for analyzable acid reflux episodes did not corevaluated for manometric events around the time of re- relate with the age of the patient (r Å 0.01; P Å 0.95). flux. Pressure changes caused by crying, straining, or The episodes classified as absent basal LES tone or reflux body movement obscured pressures generated by intrinsic across a contracted LES were infrequent. motor events in 66 episodes, making these episodes Durations of LES relaxation were 14.0 seconds (range, impossible to evaluate. The data presented below refer ) for type I LES relaxations and 11.0 seconds Figure 4. Results of investigations in each individual. For details of testing methods and criteria, see Patients and Methods., Definit positive;, negative;, not tested;, probable positive (endoscopic esophagitis).

6 404 KAWAHARA ET AL. GASTROENTEROLOGY Vol. 113, No. 2 (range, ) for type II LES relaxations, both of Table 2. Patterns of LES Pressure Change Associated With which were significantly longer than the duration of the Acid Reflu LES relaxations in response to a single swallow (4.4 sec- Group A Group B onds; range, ) (analysis of variance [ANOVA]). Type I LES relaxation 152 (58.4) 36 (69.2) Duration of LES relaxation was ú5 seconds in 98% of Type II LES relaxation 66 (23.1) 10 (19.2) type I and 83% of type II LES relaxation episodes. Relax- Type III LES relaxation 4 (1.7) 3 (5.8) ations were frequently relatively prolonged because 49% LES tone drift 9 (3.4) 1 (1.9) of type I and 39% of type II LES relaxations lasted 15 Absent basal LES tone 18 (7.6) 0 (0.0) Reflu across contracted LES 15 (6.3) 2 (3.8) seconds. Total The interval between the onset of complete type I LES relaxation and the earliest indication of reflux was 3.0 seconds (range, ), being 5 seconds in 68% of episodes (Figure 6). There were 23 episodes of type I LES relaxation in which the duration of the relaxation was 20 seconds; of these, 7 episodes fulfilled the criteria for the evaluation of esophageal body motor responses to swallowing during transient LES relaxations (see Methods). In all of these episodes, the esophageal body pressure waves triggered by swallowing were confined solely to the uppermost esophagus. By contrast, all of the control swallows were followed by a normal peristaltic pressure wave that transversed the esophageal body in all instances in every patient. Incidences of subtypes of type I LES relaxation were 41% for spontaneous, 31% for post swallow cycle, and 28% for post esophageal body contraction. A sample tracing of spontaneous LES relaxation is shown in Figure 7. The durations of complete LES relaxation in each episode were not significantly different among the three subtypes of type I LES relaxation, all of which were significantly longer than swallow-induced LES relaxation (4.4 seconds; range, ) (ANOVA). Figure 5. Individual subject data for (A) numbers of reflu episodes and (B) percentage of time of esophageal ph õ 4 in the second 2 Figure 6. Interval between the onset of complete LES relaxation and hours after the meal, plotted separately for groups A and B. Horizontal the earliest indication of reflu in the episodes of type I LES relaxation bar indicates median value in each group. in group A.

7 August 1997 MECHANISMS OF GER IN CHILDREN 405 Group B Patients Clinical and ph data. Group B consisted of 13 children. Vomiting was also the major clinical feature at presentation (Table 1). No significant difference was noted in any findings of clinical symptoms between groups A and B (Fisher s Exact Test). Figure 4 gives the results of investigations in each individual. Incidences of positive results were 50% for upper gastrointestinal radiology and 71% for scintigra- phy. There were no significant differences in the incidences of positive findings for these two investigations between groups A and B (Fisher s Exact Test). Figure 5 gives data on patterns of reflux in this group. There were 1.5 (range, ) episodes of reflux per hour. The percentage of time of esophageal ph õ4 in the second 2 hours after the meal was 0.8% (range, 0% 3.4%). Manometric data. Similar to the children in group A, basal LES pressure showed substantial variation within individuals. The median value of basal LES pres- Figure 7. A sample tracing of spontaneous type I LES relaxation. Approximately 5 seconds before the onset of acid reflu there is an LES relaxation that occurs in the absence of swallowing; see pharyn- geal pressure tracing. The relaxation is substantially longer than swallow-induced relaxations also on the tracing. In association with esophageal acidification there is a CC elevation of basal esophageal body pressure, indicative of flo into the esophagus. sure of 16.4 mm Hg (range, ), was not significantly different from children in group A. Of the 93 acid reflux episodes, 29 of the manometric tracings could not be evaluated for motor events around that time because of pressures caused by straining. Esophageal body CCs were present in 59 episodes (92%). LES pressure before each acid reflux episode was 11.0 mm Hg (range, ). LES pressures at the onset of esophageal acidification, at CC onset, and at the earliest indication of reflux were 0 (range, 0 1.0), 0 (range, 0 1.0), and 0 (range, 0 1.0) mm Hg, respectively. None of these values differed significantly from each other, nor from the values for these analyses in group A children (Kruskal Wallis test). LES pressure before reflux episodes and at their onset of reflux (at the time of the earliest indication) differed significantly, as they did in group A (P õ 0.01, Welch test). The patterns of LES pressure change associated with episodes of esophageal acidification were examined in 52 episodes, because in 12 episodes, the swallow signal was technically inadequate. The mix of patterns is shown in Table 2. Of acid reflux episodes, 94% were related to LES relaxation. Episodes classified as type I LES relaxation (definite transient LES relaxation) were scored in more than two thirds of analyzable episodes. On the other hand, there were no episodes classified as absent basal LES tone and very few that fitted the definition of reflux across a contracted LES (Table 2). The duration of LES relaxation was 14.5 seconds (range, ) in type I and 12.5 seconds (range, ) in type II LES relaxations. Comparison of these durations between groups A and B did not reveal significant differences (ANOVA). The distribution of the duration of complete LES relaxation was similar to that observed in group A. Duration of LES relaxation was ú5 seconds in 89% of type I and 90% of type II LES relax- ation episodes. One half of episodes of type I and 30% of episodes of type II LES relaxation lasted 15 seconds. In the episodes of type I LES relaxation, the interval between the onset of complete LES relaxation and the onset of reflux was 3.0 seconds (range, ), 83% of which were 5 seconds; the distribution of these values was similar to that seen in group A. Incidences of subtypes of type I LES relaxation were similar to group A children, being 42% for spontaneous, 39% for post swallow cycle, and 19% for post esopha- geal body contraction. Discussion The measurements made in the present study have allowed the first systematic analysis of the LES and esophageal body motor events associated with postprandial

8 406 KAWAHARA ET AL. GASTROENTEROLOGY Vol. 113, No. 2 repeated sampling showed wide variations of basal LES tone within individuals over time. It is therefore difficult to believe that a single or several pin-point in time samples of LES pressure obtained by the pull-through method could be adequately informative about the competence of the LES. The continuous recordings of LES, esophageal body, and stomach pressures made in the present study have allowed us to determine the patterns of function associated with GER episodes. We have found in the present study that the majority of acid reflux episodes occurred during complete LES relaxation. The pattern of events is very similar to that reported pre- viously for adults with symptomatic reflux. 5 Recording of swallowing showed clearly that the majority of these relaxations was not triggered by swallowing. The time pattern of these relaxations and the associated patterns of pharyngeal and esophageal body motility just before these relaxations had the distinctive pattern of transient LES relaxation, 7 which has been shown to be associated with belching 20 and reflux in humans with and without reflux disease 5 7 and in dogs. 21 Reliable recognition of this particular type of relaxation is a fundamental re- quirement for furthering understanding of this event. We have therefore endeavored to establish and apply unambiguous criteria for the events described in the present study. Definition of the time limits within which swallowing occurs just before or during LES relaxation is especially important for determination of whether any LES relaxation is possibly attributable to swallowing, or independent of it. 22 The analysis method used in the present study stipulated such time limits. The minimum intervals used to define LES relaxation as unrelated to swallowing removed any possibility that this category of relaxation could have been swallow-induced. The analysis of patterns of LES pressure change revealed that definite transient LES relaxation was the most common event associated with acid reflux in both group A and B pa- tients, regardless of the presence or absence of esophagitis or pathological esophageal acid exposure. However, it is notable that absence of basal LES pressure was completely confined to group A patients. The interpretation of these findings must acknowledge that a significant minority (20% in group A and 30% in group B) of reflux episodes could not be evaluated for sphincter activity because LES pressure was obscured by heavy strains from crying and body movement. Possibly a significant proportion of these episodes could have occurred because of absence of basal LES pressure. The duration of type I LES relaxations, i.e., definite transient LES relaxation, ranged from 4 to 38 seconds in the children we studied, which is similar to durations reported for adults with and without reflux disease. 5,6 As GER in children. The major finding is that LES relaxation unrelated to swallowing, i.e., transient LES relaxation, is the main mechanism of involuntary reflux of gastric contents into the esophagus in children, regardless of age. Analysis of patterns of esophageal body motility during transient LES relaxation showed clear-cut inhibition of esophageal body peristalsis, consistent with the hypothesis that transient LES relaxation associated with reflux is an active inhibition not only of the LES, but also of the esophageal body. The children studied were referred from primary care and specialist pediatric physicians to the only specialized pediatric gastroenterology service in South Australia. Consequently, the study group should be representative of children who present difficulties with management or diagnosis of reflux disease. The presence of histological esophagitis or erosive esophagitis is a widely accepted gold standard for the diagnosis of reflux disease. When these changes were seen, they were taken as establishing the diagnosis of reflux disease, but in keeping with other studies, definite endoscopic and/or histological esophagitis was seen only in a minority of children. The poor correlation between endoscopic findings and other marks of GER in children has been noted. 14,16 In addition to the findings of esophagitis, esophageal acid exposure val- ues were also used to divide the patients studied into two groups: those with pathological GER and those in whom this diagnosis was not clearly confirmed. Although the symptomatic assessment by an experienced pediatric gastroenterologist might be an important evaluation in the diagnosis of reflux disease in children, the finding of esophagitis and the amount of esophageal acid exposure were used to classify the children studied objectively. Pathological esophageal acid exposure, which is normally expressed as percentage of time of ph õ 4, is considered a useful determinant of reflux disease. 17 The period of ph monitoring was limited to the postprandial 4 hours. Because the second 2 hours after a meal has been sug- gested to be the most sensitive indication for pathological reflux 18 with such short-term ph monitoring, we used this time period to classify our patients as having normal or pathological esophageal acid exposure. Since GER was described by Berenberg and Neu- hauser 19 as a clinical entity in children, there has been considerable interest in the pathogenesis and the mecha- nism(s) responsible for the occurrence of GER. The preva- lent view has been that GER takes place in children because of the continuous absence of LES tone. It has been assumed that this absence of LES tone allows retrograde flow of gastric contents into the esophagus. 19 However, Moroz et al. 4 found that most children with pathological GER have normal basal LES pressure; also,

9 August 1997 MECHANISMS OF GER IN CHILDREN 407 in adults, the duration of transient LES relaxation in muscle esophagus, because transient LES relaxation was children was longer than the LES relaxations induced associated with total or partial esophageal body inhibi- by swallowing. However, most reflux episodes associated tion, in contrast to the responsiveness of the LES to with transient LES relaxation occurred within 5 seconds swallowing at other times. Transient LES relaxation is of onset of complete relaxation. This suggests that the the normal means for venting of gas from the stomach duration of LES relaxations is not the major factor that into the esophagus and is the prelude to a swallow- determines the occurrence of reflux. independent upper esophageal sphincter relaxation that The trigger for the type II LES relaxations associated allows gas to escape into the pharynx. 20 Such venting with reflux is debatable. Though these were associated may well fail if there was not associated suppression of with single swallows, their durations were mostly inconexpected esophageal body motility, because distention would be sistent with single swallow induced LES relaxation begeal to lead to early occurrence of secondary esopha- cause 83% (group A) and 90% (group B) of type II LES body peristalsis and return of refluxed gas to the relaxations lasted more than 5 seconds. Furthermore, the stomach before it can be vented across the upper esophaduration of type II LES relaxations did not differ signifiations, geal sphincter into the pharynx. Transient LES relax- cantly from type I relaxations. Consequently, it is likely including those unrelated to reflux episodes, need that the type LES II relaxations associated with reflux to be compared between children with and without are at least predominantly, if not solely, transient LES pathological GER in terms of their frequency and charac- relaxations that are associated with swallowing only by teristics in further study so as to explore more details of chance. If this is so, then the proportion of reflux episodes their contribution to GER disease. attributable to transient LES relaxations could be as high In conclusion, under the conditions of our study, tran- as 82% in group A children and 88% in group B. Defithe sient LES relaxation was the major factor that permitted nite resolution of the nature of type II relaxations requires occurrence of GER in children regardless of whether further study, possibly by performance of concurrent they had clearly established reflux disease. Specific subintraluminal recording of hiatal diaphragmatic electroated types of transient LES relaxation were defined by associ- myographic activity, as the hiatal diaphragm shows a esophageal body motor events, which were distinct distinctive, selective suppression during transient LES from a swallow-induced esophageal motor sequence, and relaxations. 7 these findings suggest that transient LES relaxation is Cucchiara et al. 11 recently concluded that transient associated with total or partial inhibition of the LES and LES relaxation is the most common mechanism of reflux the esophageal body. in children, but the only other mechanism of reflux they described was gradual LES pressure drift. However, our References data show that 20% of GER occurred during LES relax- 1. Orenstein SR. Controversies in pediatric gastroesophageal reflux ation associated with swallowing. The difference noted J Pediatr Gastroenterol Nutr 1992; 14: Hebra A, Hoffman MA. Gastroesophageal reflu in children. Pedibetween both studies might be related to the study conatr Clin North Am 1993; 40: ditions or to differing definitions of transient LES relax- 3. Boix-Ochoa J. The physiologic approach to the management of ation. We used ordinary food as a test meal, whereas gastric esophageal reflux J Pediatr Surg 1986; 21: Moroz SP, Espinoza J, Cumming WA, Diamant NE. Lower esopha- Cucchiara et al. used apple juice (15 ml/kg) to keep the geal sphincter function in children with and without gastroesophaph in the stomach õ4. Cucchiara et al. included de- geal reflux Gastroenterology 1976; 71: creases of LES pressure to a nadir 4 mm Hg (so-called 5. Dent J, Holloway RH, Toouli J, Dodds WJ. Mechanisms of lower incomplete transient LES relaxation 7 ) as transient LES oesophageal sphincter incompetence in patients with symptom- atic gastroesophageal reflux Gut 1988; 29: relaxation. There is some controversy with regard to in- 6. Dent J, Dodds WL, Friedman RH, Sekiguchi T, Hogan WJ, Arncomplete transient LES relaxation, 7 and to avoid this we dorfer RC, Petrie DJ. Mechanism of gastroesophageal reflu in only scored transient LES relaxation when the nadir LES recumbent asymptomatic human subjects. J Clin Invest 1980; 65: pressure reached 2 mm Hg. This highlights the need 7. Mittal RK, Holloway RH, Penagini R, Blackshaw LA, Dent J. Tranfor use of standard scoring criteria so that the findings sient lower esophageal sphincter relaxation. Gastroenterology of different studies can be compared. 7, ; 109: Dodds WJ, Stewart ET, Hogan WJ, Stef JJ, Arndorfer RC. Effect Our evaluation of esophageal body motor events just of esophageal movement on intraluminal esophageal pressure before and during transient LES relaxation gives support recording. Gastroenterology 1974; 67: to the belief that transient LES relaxation occurs because 9. Dent J. A new technique for continuous sphincter pressure mea- of sustained neural inhibition. 7 These findings are essensurement. Gastroenterology 1976; 71: Werlin SL, Dodds WJ, Hogan WJ, Arndorfer RC. Mechanisms of tially identical to a similar evaluation in adults. 5 We gastroesophageal reflu in children. J Pediatr 1980; 97:244 have concluded that this inhibition includes the smooth 249.

10 408 KAWAHARA ET AL. GASTROENTEROLOGY Vol. 113, No Cucchiara S, Bortolotti M, Minella R, Auricchio S. Fasting and 19. Berenberg W, Neuhauser EBD. Cardio-oesophageal relaxation postprandial mechanism of gastroesophageal reflu in children (chalasia) as a cause of vomiting in infants. Pediatrics 1950; 5: with gastroesophageal reflu disease. Dig Dis Sci 1993; 38: Wyman JB, Dent J, Heddle R, Dodds WJ, Toouli J, Downton J. 12. McCauley RGK, Darling DB, Leonidas JC, Schwartz AM. Gastro- Control of belching by the lower oesophageal sphincter. Gut esophageal reflu in infants and children: a useful classificatio 1990; 31: and reliable physiologic technique for its determination. AJR 21. Patrikios J, Martin CJ, Dent J. Relationship of transient lower 1978; 130: esophageal sphincter relaxation to postprandial gastroesopha- 13. Shub MD, Ulshen MH, Hargrove CB, Siegel GP, Groben PA, Askin geal reflu and belching in dogs. Gastroenterology 1986; 90: FB. Esophagitis: a frequent consequence of gastroesophageal reflu in infancy. J Pediatr 1985; 107: Holloway RH, Penagini R, Ireland AC. Criteria for objective defini 14. Groben PA, Siegal GP, Shub MD, Ulshen MH, Askin FB. Gastro- tion of transient lower esophageal relaxation. Am J Physiol 1995; esophageal reflu and esophagitis in infants and children. Perspect 268:G128 G133. Pediatr Pathol 1987; 11: McNally EF, Kelly JE Jr, Ingelfinge FJ. Mechanism of belching: Received November 10, Accepted April 4, effects of gastric distention with air. Gastroenterology 1964; 64: Address requests for reprints to: Hisayoshi Kawahara, M.D., De partment of Pediatric Surgery, Osaka Medical Center for Maternal 16. Hyams JS, Ricci A Jr, Leichtner AM. Clinical and laboratory corre- and Child Health, 840 Murodo-cho Izumi, Osaka, Japan Fax: lates of esophagitis in young children. J Pediatr Gastroenterol (81) Nutr 1988; 7: Supported by project grant funds from the National Health and 17. Evans DF, Robertson CS, Ledingham SJ, Kapila L. Esophageal Medical Research Council of Australia. ph monitoring for gastroesophageal reflux a United Kingdom The authors thank Dr. G. Binns, Department of Histology, Women s study. J Pediatr Surg 1991; 26: and Children s Hospital, for histological analysis; Ms. Beverley E. 18. Jolley SG, Herbst JJ, Johnson DG, Matlak ME, Book LS, Pena A. Barnes and Dr. C. Kirubakaran for technical and clinical assistance Postcibal gastroesophageal reflu in children. J Pediatr Surg with the studies; and Professor Akira Okada, Department of Pediatric 1981; 16: Surgery, Osaka University, for his continuous support to H.K.