Aim: The aim of this study was to correlate the data obtained with multiple intraluminal esophageal impedance and pH (MII-pH) recordings in infants and children referred for suspected gastroesophageal reflux disease with esophageal histology.
Materials and Methods: In a prospective study, results of esophageal biopsies and MII-pH recording obtained in 45 children (mean age ± SD: 69 ± 55 months) were analyzed. Regarding the MII-pH data, an automatic (Autoscan Bioview Analysis Software, version 5.3.4, Sandhill Scientific Inc, Highlands Ranch, CO) and a manual reading were performed; an automatic pH analysis (meal included) was also performed.
Results: Acidic, weakly acidic, and alkaline reflux episodes accounted, respectively, for 48.7%, 49.5%, and 1.8% of the total number of reflux episodes detected by MII-pH. Esophagitis was present in 25 (56%) children. Concordance between classic pH-study analysis (alone) and esophageal histology was found in 19 of 45 (42%) children. According to the MII-pH analysis, the mean and median value of the pH were significantly higher in the group with esophagitis than in the group with normal esophageal histology. A longer clearance time was found in the group with esophagitis than in subjects with normal histology. Gas reflux episodes represented 21% of the total reflux episodes and were comparable in both groups.
Conclusions: Multiple intraluminal esophageal impedance and pH analysis does not provide a distinct parameter to predict esophageal mucosal injury in children. In our population, MII-pH shows comparable acidic, weakly acidic, alkaline, and gas reflux in children with and without esophagitis. Further research is needed to analyze clearance parameters.
Compared with pH monitoring, combined pH-multichannel esophageal impedance and pH recording (MII-pH) increases the detection of gastroesophageal reflux (GER) episodes because the technique allows one to identify all episodes of reflux regardless of its content (liquid, gas, and mixed) and its pH (acidic reflux [AR], weakly acidic reflux [WAR], and alkaline reflux [AlkR]) (1,2). Normal standards for MII-pH are not yet established in children. It remains unclear whether the detection of “more” reflux episodes is clinically relevant. The correlation between pH-metry results and esophageal histology was reported to be weak (2–4). Several factors, including the nature (content and pH) of the refluxate, have been suggested to determine the development of esophageal injury. The aim of this study was to compare the data obtained with MII-pH in children with and without histological esophagitis.
MATERIALS AND METHODS
A prospective study comparing results of histology of esophageal biopsies and MII-pH monitoring was performed in children consecutively referred between March 2005 and July 2007 because of gastrointestinal (n = 43, 83%) or respiratory (n = 9, 17%) symptoms suspected to be caused by GER disease. Patients with known neurological, allergic, and metabolic disease, acute or recent infection, cystic fibrosis, and previous esophageal or gastrointestinal surgery were excluded. Fifty-two subjects who underwent both MII-pH and esophageal biopsies were enrolled. Seven MII-pH tracings were discarded because of artefacts or technical problems, resulting in 45 children who could be included. A vast majority of the children (n = 40 of 45) were investigated before administration of any medical reflux treatment (acid suppression and/or prokinetics). Five of the 45 children had been treated with domperidone and ranitidine without improvement. Treatment was discontinued in these children at least 1 week before testing.
Combined MII-pH Monitoring
A single combined MII-pH flexible catheter with an outer diameter of 2.1 mm (Sandhill Scientific Inc) with 7 impedance electrodes (6 impedance channels) and 1 antimony pH sensor (located within the distal impedance channel) with external reference was used. Before the procedure, the probe was calibrated using buffered solutions of pH 4.0 and 7.0 as specified by the manufacturer. The probe was then inserted transnasally through the esophagus and the pH sensor was placed at 87% of the nares-lower esophageal sphincter distance (Strobel formula) and verified by fluoroscopy, at the third vertebra above the diaphragm. The 6 impedance channels were located at 1.5 or 2 cm distance from each other depending on the 2 different pediatric probes used, according to the child's height and the manufacturer's instructions. The catheter was connected to a data logger (Sleuth System; Sandhill Scientific Inc) that stores data from all impedance channels with a frequency of 50 Hz. Acidic beverages were not allowed during registration. The parents recorded in a diary the timing of the start and end of meals and position changes (awake, asleep). The timing was reported using the internal clock of the MII-pH device.
Data were downloaded and analyzed using dedicated software (Autoscan Bioview Analysis, version 5.3.4; Sandhill Scientific Inc). For each tracing, 2 automatic AR assessment reports were subsequently generated using either “pH monitoring alone” (pH-study) or “pH monitoring combined with impedance” (MII-pH). The “classic” pH-metry analysis takes AR during meals into account; the automatic impedance-pH analysis excludes reflux episodes during meals. Manual review analyzing segments using 2-minute screens including mealtime was also performed.
The software provided calculations of the number, duration, percentage, and content of all reflux episodes, the acid clearance time, and bolus clearance time. A (bolus) reflux episode detected by MII-pH was defined as a retrograde drop in impedance in the distal channels by at least 50% of baseline. Similarly, the end of a reflux episode occurred when the impedance value returned to at least 50% of the initial value. Bolus clearance time measures the duration of bolus reflux exposure in the most distal impedance channel (5,6). A pH only reflux is irrespective of bolus movement, whereas impedance reflux requires a retrograde bolus movement. Gas-only reflux was defined as an increase in impedance >3000 ohms in any 2 consecutive impedance channels with 1 site having an absolute value >7000 ohms (5). An AR episode was defined as a drop in pH to <4. The pH-only reflux events were defined as an AR in the absence of bolus reflux. Acid clearance time was calculated as the duration from any drop in pH to a pH < 4 to the time of its recovery to a pH > 4. The percentage of the total time of AR was expressed as the reflux index (RI) if calculated by pH study, or as a percentage of AR with bolus detected by MII-pH (% AR Bolus-Imp). The RI describes the duration of AR, the percentage of AR Bolus-Imp measures the duration of acidic bolus detection (5). As a consequence, the RI can be higher than the percentage of AR Bolus-Imp, because AR can occur without detection of bolus movement. Regarding nonacidic (pH > 4) reflux episodes, the version of the software distinguished WAR (pH > 4 but <7) and AlkR (pH > 7) according to the Porto classification (5).
Bolus exposure index (BEI) was calculated as the total percentage of time with bolus reflux detected by impedance (BEI [%] = AR Bolus-Imp [%] + WAR [%] + AlkR [%]). A separate analysis of the acidic and bolus exposure in the recumbent position was also performed.
We considered that the analysis of the pH-metry was abnormal if the RI was >10% in infants and more than or equal to 5% in children (7). The lack of pediatric normal values for impedance did not allow the determination of a clear-cut impedance threshold. However, because a BEI >1.4% has been proposed as an upper limit (95th percentile) of normal impedance in adults (8), this cutoff was used in the analysis of our results.
Endoscopy was performed before the MII-pH with an Olympus videoendoscope GIF XP 160 (Keymed, Essex, UK). The infants were sedated with midazolam intrarectally or intravenously. Esophageal grasp biopsies were taken at approximately 3 cm above the cardia. The diagnosis of esophagitis was made if any of the following European Society for Pediatric Gastroenterology, Hepatology, and Nutrition criteria were met: basal zone hyperplasia (>20%) and papillary lengthening (>50%) or the presence of many (>7) neutrophils, lymphocytes, or at least a few (4–6 per biopsy) eosinophils in the esophageal epithelium, lamina propria, or both (9). The hospital ethics committee approved the study.
Results were expressed as mean (±1 SD) and proportions and the comparison between the groups with normal histology and esophagitis was evaluated using the t test. A P value of <0.05 was considered to be statistically significant.
Demographic data and clinical presentation of the patients are shown in Table 1 and are comparable between the groups. Comparison between (mean) MII-pH data and histology results are listed in Tables 2 and 3. The incidence of esophagitis was comparable in the 2 groups presenting with gastrointestinal symptoms and with respiratory symptoms.
Esophagitis was diagnosed in 25 of 45 (56%) patients. No case with eosinophilic esophagitis or eosinophilic infiltration (>7 eosinophils per high-power field ) was detected. Concordance between classic pH-study analysis (alone) and esophageal histology was found in 19 of 45 (42%) (abnormal pH-metry in [only] 3 of 25 [12%] patients with esophagitis and normal pH-study in 16 of 20 patients with a normal biopsy).
The percentage of AR according to the MII-pH study was slightly smaller than the RI as calculated by classic pH-study analysis (3.2% ± 3.0% vs 3.0% ± 2.9%, respectively). The % AR Bolus-Imp represented roughly one third of total acid exposure (1.0% ± 1.1%). Overall, out of 3592 total impedance reflux episodes, the number of AR, WAR, and AlkR episodes were 1749 (48.7%), 1777 (49.5%), and 66 (1.8%), respectively. Alkaline reflux episodes occurred in 22 of 45 (49%) children (10 of 25 [40%] with esophagitis vs 12 of 20 [60%] with normal biopsy). The total number of AlkR episodes was (only) 40 in the esophagitis and 26 in the normal biopsy group (in 7 subjects only 1 AlkR episode was detected). In all except 4 patients (2 with esophagitis and 2 with normal biopsy who had 0.1% of AlkR), the percentage of AlkR exposure was 0%.
Gas reflux episodes were present in all of the patients except 1, and accounted for a total number of 753 (21%) reflux episodes. The great majority (79%) of these reflux episodes were WAR and comparable between the esophagitis and normal histology groups. The total number of reflux episodes during meal was 304 (8.5% of total impedance reflux episodes), also with no difference between children with and without esophagitis.
The total number of reflux episodes and the number of WAR episodes were slightly (but not statistically significant) higher in the esophagitis group. All other parameters related to both acid and bolus exposure (the percentage of RI pH-study, the percentage of AR MII-pH study, the percentage of AR Bolus-Imp, the percentage of BEI, mean acid clearance time [MACT], mean bolus clearance time [MBCT], and the longest impedance episode) were higher in the group with normal histology, with statistically significant difference only for the MACT. A statistically significant difference was also found for the mean and median value of the pH (lower in the normal histology group). The BEI was higher than 1.4% in 14 of 25 (56%) with esophagitis and in 9 of 20 (45%) with normal esophageal biopsy (P = NS). There is no individual relation between RI and BEI according to presence or absence of esophagitis, as shown in Figure 1. In the esophagitis group, the BEI was higher than the RI in 6 of 25 (24%) children. In the normal histology, this was observed in 3 of 20 (15%) (NS).
In the recumbent position, a statistically significant difference between both groups was found only for the MACT (MACT-recumb) and MBCT (MBCT-recumb) (data reported in Table 3).
Multiple intraluminal esophageal impedance and pH recording enables the detection and characterization of all types of reflux. Because many reflux episodes have a pH > 4.0, especially in infants and during postprandial periods, MII-pH is supposed to provide clinically useful additional information to pH-metry. AR indexes for pH-metry and MII-pH recordings are calculated in a different way by the “preset automatic system” because of the different definition criteria of acid episodes. In pH-metry, an acidic reflux is defined as any period with pH < 4 for more than 5 seconds, irrespective of the proximal extension of reflux. To be considered an acid reflux episode for MII-pH, the acid reflux episode needs to reach at least the 2 distal channels with a retrograde drop of the impedance baseline of more than or equal to 50%, irrespective of the duration. “Superimposed acid reflux,” a new acid reflux episode during a period when the pH is already below 4, is not considered in pH-metry analysis but is considered as a new episode in the pH-impedance analysis.
In this study, WAR and AlkR episodes accounted, respectively, for 49.5% and 1.8% of the total number of impedance reflux episodes, which results in a 2-fold increase of the number of episodes in comparison to the number of AR episodes according to the pH-only analysis. These data confirm previous pediatric reports in untreated patients (10,11). The role of WAR and AlkR in the pathophysiology of GER disease and esophagitis is not yet clear. Conversely, the duration of acid exposure detected with MII-pH is smaller than with pH-metry (12). This discrepancy, confirmed in this report, has been attributed to pH-only reflux events and/or to slow drifts of pH from baselines at approximately pH 5.0 to values <4.0, not accompanied by a typical impedance pattern of reflux (13). The bolus clearance of an AR episode is shorter than the chemical acid clearance. Chemical acid exposure often continues longer than bolus acid exposure. The clinical meaning of this observation is not clear yet.
In adults, the severity of esophageal injury has been attributed to esophageal acid exposure (14), and healing of reflux esophagitis has been directly correlated with the maintenance of the intragastric pH above 4.0 (15,16). However, recent reports failed to show a correlation between the results of a classic pH-metry and esophageal histology (17). The relation between reflux symptoms, endoscopic or histologic findings, and exposure of the esophagus to acid is considered to be complex (18). In pediatric patients the concordance between the results of pH-metry and esophageal histology has been debated, denied, or sustained (3,4,9,19–24). Our findings confirm the limited correlation between (classic) pH-study analysis and histology of esophageal biopsies, especially in children with esophagitis. A correlation between the results of the pH-metry (alone) and esophageal histology was found in less than half of the patients (19 of 45 [42%]) patients. Nonacid, mixed gastric and duodenal reflux and impaired esophageal clearance have been suggested to play a role in determining esophageal mucosal injury (25,26).
Multiple intraluminal esophageal impedance and pH quantifies the number, proportion, and duration of AR, WAR, and Alk reflux episodes and provides information about both acidic and bolus clearance time (MACT and MBCT, respectively). In adults, the duration of reflux and the incidence of AR and nonacid reflux episodes were similar in patients with and without esophagitis (18). However, in the supine position, patients with esophagitis showed a higher incidence of acid (P = 0.048) and liquid reflux episodes (P = 0.07) (18). Combined MII-pH and MII-esophageal manometry has recently demonstrated that patients with erosive esophagitis exhibit a significantly lower percentage of complete bolus transit and a longer MBCT compared with healthy controls and nonerosive reflux disease patients (27).
No study comparing MII-pH and esophageal histology in infants and children has been published so far. In our population, no MII-pH parameter was statistically significantly correlated to esophagitis except (unexpectedly) the mean and median pH values; conversely, acid, bolus exposure, and clearance time were higher (but significantly different only in the recumbent position) in the group with normal histology. It cannot be excluded that these findings are related to relatively small number of patients with esophagitis (n = 25). The relevance of gas reflux remains also a matter of future research. In our study no difference in gas reflux episodes was detected between patients with esophagitis and normal biopsy. In adults, gas reflux has been recently considered separately from liquid and mixed reflux episode in patients with GER symptoms (28).
In this pediatric population, MII-pH results failed to identify parameters correlating with the presence of histologic esophagitis. The duration and number of acidic, weakly acidic and alkaline, and gas reflux episodes were comparable in children with and without esophagitis.
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