Evaluation of gastroesophageal reflux in children born with esophageal atresia using pH and impedance monitoring

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Evaluation of gastroesophageal reflux in children born with esophageal atresia using pH and impedance monitoring

Floor W.T. Vergouwe, MD

Michiel P. van Wijk, MD, PhD

Manon C.W. Spaander, MD, PhD

Marco J. Bruno, MD, PhD

Renй M.H. Wijnen, MD, PhD

Johannes M. Schnater, MD, PhD

Hanneke IJsselstijn, MD, PhD1

Department of Pediatric Surgery and Intensive Care Children, Erasmus MC University Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands,



Abstract

Objectives To evaluate acid and non-acid gastroesophageal reflux in infants and school-aged children with esophageal atresia (EA) using pH-impedance (pH-MII) monitoring.

Methods Between 2012-2017, all 24-hour pH-MII studies performed in infants (?18 months) and 8-year olds with EA were included. Anti-acid therapy was discontinued before study. Exclusion criteria were: isolated tracheoesophageal fistula; esophageal replacement therapy; tube feeding; and monitoring <18 hours. Automatically detected retrograde bolus movements (RBM) were manually reviewed and modified/deleted if necessary.

Results We included 57 children (51% male; 2% isolated EA; 44% thoracoscopic EA repair): 24 infants (median age 0.6 years) and 33 school-aged children (median age 8.2 years). Of the automatically detected 3,313 RBM, 1,292 were manually deleted from the tracings: 52% of non-acid RBM and 8% of acid RBM (mainly misinterpreted swallows or one event recognized as several events). In infants, median reflux index (RI;pH<4) was 2.6% (abnormal in n=2), median RBM was 61 (62% non-acid, 58% mixed) and median of the mean BCT was 11 seconds. In older children, median RI was 0.3% (abnormal in n=4), median RBM was 21 (64% non-acid; 75% mixed) and median of the mean BCT was 13 seconds.

Conclusions Most children with EA off medication have a normal RI, yet experience a significant number of non-acid RBM. After manual revision of the tracings a high percentage of RBM was deleted. Our data show that automated impedance analysis software needs refinement for use in infants and children with EA and question the need for standard antiacid therapy in these patients.

Keywords: acid reflux, pH-MII study, non-acid reflux, pH-metry, tracheoesophageal fistula esophageal atresia reflux



* Many esophageal atresia (EA) patients suffer from chronic gastroesophageal reflux. Only a few experience troublesome symptoms (e.g. heartburn, regurgitation and vomiting).

* Guidelines recommend reflux monitoring in EA patients around one year of age and during long-term follow-up in symptomatic children.

* Reference values for pH-impedance monitoring in children are absent.

What is new?

* We present pH-impedance data at the approximate ages at which reflux monitoring in EA patients is recommended.

* Most children have a normal reflux index, which questions the ESPGHAN-NASPGHAN recommendation for standard PPI therapy in the first year post-surgery.

* Automated software over-detects reflux events in EA patients.

List of abbrevations

BCT = bolus clearance time

EA = esophageal atresia

GER = gastroesophageal reflux

GERD = gastroesophageal reflux disease

IQR = inter-quartile range

ISFET = ion-sensitive field-effect transistor

MMS = Medical Measurement Systems

pH-MII monitoring = pH and impedance monitoring

PPI = proton pump inhibitor

RBM = retrograde bolus movements

RI = reflux index

SAP = symptom association probability

SD = standard deviations

SI = symptom index for reflux

TEF = tracheoesophageal fistula

Introduction

Esophageal atresia (EA) with or without a tracheoesophageal fistula (TEF) is a relatively common birth defect in which the continuity of the esophagus is interrupted (European prevalence: 2.43 per 10,000 births)(1). As a result of inborn deficient esophageal innervation and surgical nerve injury, EA patients suffer from esophageal dysmotility(2 ,3). Gastroesophageal reflux (GER; acid and non-acid) is a physiologic phenomenon. When GER causes troublesome symptoms interfering with daily life or complications it is referred to as GER disease (GERD) (4). GERD is thought to be common after surgical EA repair in both children and adults(5, 6). It results in respiratory and gastrointestinal problems in the short-term (e.g. aspiration pneumonia, apparent life-threatening events, dysphagia, feeding problems) and long-term (e.g. chronic respiratory symptoms, esophagitis, esophageal strictures, Barrett's esophagus, esophageal cancer)(6-10). Given the high prevalence of GERD in children with EA (up to 54% in some studies using the definition “fundoplication performed, pH-study positive or endoscopic esophagitis”), it is important to diagnose and manage GERD to reduce associated complications(5, 6).

Although many children with EA are exposed to chronic GER, only a few experience troublesome symptoms. Results from pH-impedance (pH-MII) studies as well as endoscopic evaluations in children with EA show that asymptomatic children can have severe abnormalities(11-14). Therefore, the ESPGHAN-NASPGHAN Guideline (2016) recommends to routinely prescribe proton pump inhibitors (PPI) for the first year of life and monitor GER using pH-MII monitoring and/or endoscopy at time of discontinuation (regardless of symptoms) and during long-term follow-up in symptomatic children with EA(6).

We hypothesized that GER occurs frequently in children with EA, not only in infancy but even thereafter. Moreover, based on clinical interpretation of several pH-MII studies prior to this study we assumed that disturbed impedance patterns in EA patients leads to overdetection of reflux events in automated analysis. We aimed to evaluate and characterize acid and non-acid GER in infants and school-aged children with EA using pH-MII monitoring and to evaluate the rate of over-detection by automated software in this specific population.

Metods

Patients

All children with EA born in our hospital are offered a 24-hour pH-MII study at the age of 0.5 and 8 years as part of a longitudinal multidisciplinary follow-up program(15). As standard of care, all children receive PPI for at least six months after surgical EA repair. We retrospectively reviewed all pH-MII studies conducted in children with EA between September 2012 and October 2017 and included studies performed at age ?18 months or 7-9 years with a duration of ?18 hours. Exclusion criteria were: isolated TEF; esophageal replacement therapy (e.g. gastric pull-up, jejunal/colonic interposition); and use of tube feeding. The Medical Research Involving Human Subjects Act was considered not applicable to the study protocol (protocol ID MEC-2017-185).

Data collection

Data retrieved from patient records included baseline characteristics (e.g. gender, gestational age, type of EA, type of EA repair) and clinical data at time of pH-MII monitoring (e.g. symptoms, use of anti-reflux medication, z-scores height and weight-for-height)(16, 17). All 8-year old children were asked to fill in an online validated questionnaire for detecting GERD by Manterola et al.(18, 19). A cut-off score >3 was used.

Small for gestational age was defined as a birth weight two standard deviations (SD) below normal. Prematurity was defined as gestational age <37 weeks. Pulmonary infections were defined as lower respiratory tract infections requiring antibiotic therapy and/or hospital admission.

pH-MII monitoring protocol

Children were intubated with an age appropriate pH-MII catheter. We used two available types of pH-MII catheters to perform 24-hour pH-MII studies: Greenfield (Dover, USA) single use antimony pH-MII catheters (6.4 French, 6 impedance channels, 1-2 pH channels) and Laborie ion-sensitive field-effect transistor (ISFET) disposable pH-MII catheters (6 French, 6 impedance channels, 1 pH channel). A chest x-ray was performed to ensure correct pH channel position (three vertebrae above the diaphragm)(20). All anti-acid and prokinetic therapy was discontinued prior to the start of the pH-MII assessment (five and two days, respectively). Parents were asked to fill in a diary during pH-MII monitoring to monitor symptoms, body position and intake of food and beverages. Patients were instructed not to eat acid foods or drink carbonated beverages.

Manual correction of reflux events

Initial manual review was performed to ensure correct diary records and to delete artefacts. Then MMS database software 9.5 (Medical Measurement Systems B.V., Enschede, The Netherlands) was used for automated analysis (acid/alkaline limits: pH 4.0 and 7.0; minimum reflux duration pH- and MII-results: 5 seconds; air threshold: 5000Щ). All reflux events - identified as such by the software - were manually reviewed and modified (duration; number of impedance channels involved; liquid/mixed reflux content) by one researcher unaware of the clinical symptoms (FV). A second reviewer (MvW) examined inconclusive events. RBM were deleted in case both reviewers agreed the RBM was misinterpreted by the software.

Data analysis

Parameters analyzed in this study included number of pH changes to <4; reflux index (RI; acid exposure index (%)); number of long (>5 minutes) acid exposures; longest acid exposure (minutes); number of retrograde bolus movements (RBM); number of acid/non-acid (pH ?4) RBM; number of liquid/mixed RBM; mean bolus clearance time (BCT; seconds); number of proximal bolus exposures (reaching proximal impedance channel); symptom index for reflux (SI); and symptom association probability (SAP)(window of 120 seconds before and after a reflux event). An RI>7% was considered to be abnormal, <3% to be normal, and 3%-7% to be indeterminate(21). SI?50% and SAP?95% were considered positive(22). Data are presented as frequencies, mean (SD) or median (minimum; maximum; inter-quartile range (IQR)). Data were analyzed with SPSS 21.0 (SPSS Inc., Chicago, IL) using descriptive statistics. Non-parametric Mann-Whitney U test was used to compare continues variables and Pearson's chi-square test or Fisher's exact test for categorical variables. The two-tailed level of significance was set at p=0.05.

Results

Demographics (Table 1)

Of the 69 children born between 2011-2017 (aged ?18 months in study period), three children had died. Sixteen children fulfilled exclusion criteria, mainly because of tube feeding (Figure 1). We included 24/50 (48.0%) eligible infants (median age 0.6 (range 0.2-1.5) years). Reasons for not being included are listed in Figure 1. Of the 74 children born between 2004-2009 (aged 8 years in study period), six children had died. Nine children fulfilled exclusion criteria. We included 33/59 (55.9%) children (median age 8.2 (range 8.0-9.0) years) (Figure 1).



Figure 1: Flowchart of children included in study. a Deceased at a median age of 71 (range 3- 704) days.

Causes: multiple major anomalies (n=5), recurrent sepsis (n=1), reanimation complicated with sepsis and severe neurological impairment (n=1), acute apparent lifethreatening event based on intracerebral bleeding and ischemia (n=1), sudden death with unknown cause (n=1). b Inappropriate position of pH catheter (n=2) and software/electrode failure with negative pH values and impedance artefacts (n=2). c Clinical reasons for absence of pH-MII studies: absence of symptoms after a recent Nissen fundoplication (n=1); normal esophagus observed at endoscopy in an asymptomatic child treated with anti-reflux medical therapy (n=1); and expectative management in a child with a short esophagus, intrathoracic stomach and proven gastroesophageal reflux (n=1).

Примечания от редактора публикации на сайте GastroScan.ru. Символами a, b и с авторы статьи пометили: a - строки "Deceased" в левом и правом верхних скруглённых прямоугольниках (СП); b - строки "2 pH-MII study unreliable" в двух третих сверху в левом и правом столбцах СП; c - строку "3 clinical reason" в четвёртом сверху СП в левом столбце.

Demographics of the 57 included children and the 52 non-included children did not significantly differ (Supplementary Table 1, Supplemental Digital Content, htt p://links.lww.com/MPG/B702). In 43.9% of included children thoracoscopic EA repair was performed. Twenty-four children were using anti-reflux medication (91.7% of infants and 6.1% of older children), which was discontinued prior to pH-MII monitoring. Nissen fundoplication was previously performed in eight (24.2%) 8-year old children (median age 0.5 years).

Table 1: Patient demographics (N=57)

a Five children used Ranitidine and Domperidone. b Defined as lower respiratory tract infections requiring antibiotics and/or hospital admission since birth (infants) or in the previous year (8-year olds). c One infection in the previous year. d One (n=4) and 2-4 (n=4) infections in the previous year. e Vomiting unrelated to food intake/physical activity (n=1), frequent vomiting (n=1), ALTE (n=1), cough (n=1). f Regurgitation (n=2), acidic reflux (n=1), nausea (n=1), nausea/abdominal pain (n=1), foetor ex ore and abdominal pain related to food intake (n=1), night cough (n=2). g Median age of 5 (range 3-87) months at time of Nissen fundoplication.

pH-MII studies

Greenfield catheters were used in 30 (52.6%) and ISFET catheters in 27 (47.4%) of the 57 pH-MII studies. Of the 57 included pH-MII studies, we evaluated 52 complete pH-MII studies, three studies showed no reliable pH results due to pH-sensor malfunctioning and in two studies impedance results were not analyzed (after deleting artefacts, duration of the impedance tracing was <18 hours).

Manual correction of reflux events

In total 3,313 RBM were detected by MMS software of which 1,287 (39%) RBM were manually deleted from the tracings: 52% of all non-acid RBM (mainly swallows misinterpreted as being a RBM) and 8% of all acid RBM (mainly swallowing or a single event being recognized as several events by the software)(Supplementary Figure 1, Supplemental Digital Content, htt p://links.lww.com/MPG/B702). Median RI was 2.6% in infants and 0.6% in older children. Table 2 shows all other pH-MII parameters. In infants, pH results were abnormal in 2/22 (10%) evaluated pH studies; one of these had apparent life-threatening events suspected to be GER related. Indeterminate pH results were found in six (27%) infants, two of whom (33%) suffered from daily regurgitation/vomiting. Normal pH results were found in 14 (64%) infants, one was symptomatic (day and night cough). A median of 61 (range 0-134) RBM were observed. Four infants had >100 RBM/24 hours(22).

Table 2: Results from pH-impedance monitoring in children born with esophageal atresia after manual modification of reflux events

BCT: bolus clearance time; IQR: inter-quartile range; RBM: retrograde bolus movements. a Children aged ?18 months (n=24): results from 20 complete pH-MII studies, two studies without pH results and two studies without impedance results are shown. b Children aged 8 years (n=33): results from 32 complete pH-MII studies and one study without pH results are show

In older children, pH results were abnormal in 4/32 (12.5%) pH studies, three of them (75%) were symptomatic (regurgitation, acid reflux and night cough). None of the older children with abnormal pH results had undergone fundoplication surgery prior to the pH-MII study. Indeterminate pH results were found in two (6%) children, both asymptomatic, and pH results were normal in 26 (81%) children, five (19%) reported symptoms (regurgitation, nausea, nausea/abdominal pain, foetor ex ore/abdominal pain and night cough). A median of 21 (range 0-54) RBM were observed and none of the older children had >70 RBM/24 hours(22).

Symptoms

Prior to pH-MII monitoring, 12 children/parents spontaneously reported symptoms (16.7% of the infants and 24.2% of the older children) (Table 1). Diaries recorded during the measurement were missing in two children. Twenty-seven children did experience symptoms during pH-MII monitoring, of whom 21 reported non-specific and unlikely to be GER related (e.g. sneezing, hiccup) or very few (<3 times per 24 hours) symptoms. As a result, symptom analysis was performed in only four infants (coughing, belching and twice crying) and two older children (coughing and nausea/burping/regurgitation/vomiting). SI and SAP were positive in 1/6 (16.7%) and 3/6 (50.0%), respectively. If only acidic episodes were considered, SI and SAP were positive in 0/6 and 4/6 (66.7%), respectively. Without manual correction, only three of these latter four children had a positive SAP.

Questionnaire

Twenty-four (72.7%) 8-year old children completed the Manterola questionnaire (Supplementary Table 2, Supplemental Digital Content, htt p://links.lww.com/MPG/B702). Demographics, RI and number of RBM of these children did not significantly differ from the nine children who did not complete the questionnaire (Supplementary Table 3, Supplemental Digital Content, htt p://links.lww.com/MPG/B702). The score was suggestive for GERD in seven (29.2%) children. Nocturnal cough (n=7), regurgitation (n=6, weekly in four), dysphagia (n=5) and heartburn (n=5, weekly in one and daily in one) were the most frequently reported symptoms. In only 2/7 children abnormal pH results were found: an RI of 13% in a child with complaints of heartburn at least once a month and an index of 14% in a child with occasional chest pain. pH-MII parameters (automated or manual), SI and SAP did not differ significantly between children with a high (>3) or low (?3) score.

Change of anti-reflux treatment (Supplementary Table 4, Supplemental Digital Content, htt p://links.lww.com/MPG/B702)

The majority (22/24; 91.7%) of infants were using anti-reflux medication prior to the pH-MII study. In infants, medication was continued in three (one abnormal and two indeterminate pH results), discontinued in 18 (four indeterminate, twelve normal and two unreliable pH results), and discontinued in one infant with abnormal pH results who underwent Nissen fundoplication.

Of the older children, only 2/33 (6%) were using anti-reflux medication prior to the pH-MII study. Medication was discontinued in both (normal pH results). Upper endoscopy was performed in three children with abnormal pH results, in 2/3 PPI was started for mild esophagitis. In two children (one with abnormal pH results and one with night cough) medication was started without endoscopy.

Discussion

In this study we evaluated acid and non-acid GER using pH-MII monitoring in 57 children with EA in infancy and at school-age. Observed RBM were mainly non-acid boluses (infants: 62% of RBM, older children: 64% of RBM) and mixed boluses (infants: 58% of RBM, older children: 75% of RBM).

Compared to available reference values in children without EA (asymptomatic neonates or children with symptoms), we found similar results for RI, number of RBM (Figure 2A) and BCT(22-25).

Although several groups have published their pH-MII monitoring results in children with EA, reference values are lacking(2, 11, 12, 26-30). Differences in patient selection and study protocols makes comparing results difficult. For instance, one study in 35 children with EA continued PPI therapy, while medication was discontinued in other studies(26). Moreover, they included children of all ages (0.3-17.2 years) while two other studies focused on infants/toddlers(29) and school-aged children(11). In the latter study children with non-acid reflux were excluded(11). Compared to studies in children with EA, number of RBM in infants in our study was high compared to a small group of Dutch children, but similar to other cohorts(2, 11, 30). Results in 8-year old children were comparable. We found a lower RI in both infants (2.6% vs 5.8-6.1%) and older children (0.3% vs 2.5-8.3%) (Figure 2C). RI was similar in 35 Australian children (aged 0-17 years)(26).



Figure 2: pH-MII parameters (number of retrograde bolus movements (RBM) and reflux index) of study cohort compared to available reference values in A) children without esophageal atresia (asymptomatic neonates or children with gastrointestinal, pulmonary or neurological symptoms) and B) and C) children with esophageal atresia.

Symptom recording was insufficient for symptom association analysis as in 10/12 symptomatic children (spontaneously reported prior to pH-MII monitoring) symptoms were absent during pH-MII monitoring. A previous study in 20 children found a recording failure in 52% of coughs and a time lag of 11 seconds between the cough and the recording in the log(31).

The Manterola questionnaire(18) was suggestive for GERD in 29% of 8-year old children, but in only 2/7 an RI>7% was found. Compared to symptomatic 130 children without EA (aged 5-10 years) they had similar number of RBM (21 vs 24), but a lower mean BCT (11 vs 17 second)(22). We found similar pH-MII parameters in children with low and high Manterola scores, possibly due to a larger day-to-day variability of pH-MII studies in EA patients, or perhaps disturbed impedance patterns make pH-MII studies unsuitable for GER detection in EA patients(32). Dysphagia was scored positive by 5/7 children with a positive Manterola questionnaire, which may be the result of dysmotility, eosinophilic esophagitis or strictures rather than GER. Furthermore, regurgitation was also scored often (6/7) which - in children with EA - can also be regurgitation from the esophagus rather than the stomach. It may therefore be that the Manterola questionnaire is not suitable for EA patients.

After visual validation of RBM identified as such by the software, 39% was deleted from the tracings. These were mainly non-acid swallows, which the software incorrectly identified as RBM (Supplementary Figure 1, Supplemental Digital Content, htt p://links.lww.com/MPG/B702). Abnormal esophageal motility, stasis of fluids and gas caused disturbed patterns which were misinterpreted by the software. Stasis of fluids was mostly present in Z3-Z4, at the level of the esophageal anastomosis. The software did not recognize this stasis and measured a shorter BCT. This is in accordance with previous literature(33). In automated analysis, swallows following RBM were sometimes misclassified as proximal GER events. Air in the esophagus after a swallow showed a pattern that was recognized as GER by the software.

Since low baseline impedances are observed in esophagitis and motility disorders(27) it is not surprising that children with EA have baseline impedances that are approximately 75% lower than in symptomatic patients without EA(12). Even in EA patients without esophagitis baseline impedances are 44% lower than in control patients with esophagitis(28). Low baseline impedances impair bolus detection, resulting in an underestimation of the reflux burden in EA patients. This is a major limitation of pH-MII in EA patients.

Previous studies show high inter- and intra-observer variability in pH-MII analysis(34, 35). The high percentage of deleted RBM raises the question how accurate pH-MII analysis in EA patients is. We believe this number is too high to ignore and to perform automated analyses without manual revision. Manual revision, however, carries the risk of greater inter-observer variability. Refinement of automated software is needed to identify impedance reflux patterns in patients with complex motility disorders such as EA.

The recent ESPGHAN-NASPGHAN Guideline recommends to treat all EA patients with anti-acid treatment in the first year of life and to monitor GER with pH-MII monitoring and/or endoscopy at time of discontinuation (regardless of symptoms) and during long-term follow-up in symptomatic children(6). However, no studies have been performed to show benefit of routine pH-MII monitoring in EA patients and a recent SR showed evidence - - albeit of low quality - that prophylactic anti-reflux medication does not prevent stricture formation after EA repair(36). As discussed above reflux in our patients was mainly nonacid. These non-acid reflux events would be missed on pH monitoring without impedance tracing. Impedance tracing has additional benefits to correlate extra/esophageal symptoms with reflux events(6). In infants, symptoms were mainly associated with non-acid RBM, while symptoms in older children were mainly associated with acid RBM(29). Treatment options of non-acid GER are limited. A small double-blinded placebo controlled RCT in children showed that Baclofen inhibits transient lower esophageal sphincter relaxation and accelerates gastric emptying, but is dissuaded in guidelines as a first-choice therapy in children because of known side effects in adults(4, 37). Surgical anti-reflux procedures are available, but have side effects and it is unclear which patients would benefit. Further research is needed to determine the optimal duration of anti-acid therapy after EA repair.

The strengths of our study are the manual evaluation of RBM, the inclusion of both symptomatic as well as asymptomatic children with EA, and both infants and older children. International guidelines recommend to monitor GER at time of discontinuation of anti-acid treatment (around one year) and during long-term follow-up in symptomatic children with EA(6). Our study is the first to show pH-MII results in these two age-groups. Still, some limitations need to be mentioned. First, two different pH electrodes were used. Although significant differences have been found in acid exposure times between ISFET, glass and antimony electrodes, our results from both catheters were similar(38). Second, only 52% of eligible children of our follow-up program were included. Since demographics did not differ and the majority (79%) was asymptomatic, selection bias does not seem to be a major factor influencing our results. Third, only RBM recognized by the software were manually reviewed and modified. This method might have resulted in underreporting of reflux events. Although the software is designed to over-detect reflux events, we cannot exclude the option that episodes were missed. This is important to realize and manual revision of pH-MII tracings should be considered in all EA patients, especially in case of unexplained symptoms or persistent growth impairment. Last, due to the lack of longitudinal data we did not compare results between infants and older children. Infants seem to have worse pH-MII parameters compared to older children, however differences in type of feeding (liquid vs solid food), body position during feeding, and other demographics (i.e. thoracoscopic surgery, use of antireflux medication and history of fundoplication surgery) would have made the comparison unreliable.

In conclusion, most infants and school-aged children with EA off medication have a normal RI, yet experience a significant number of non-acid RBM. After manual revision of the tracings a high percentage of RBM was deleted. These were mainly non-acid swallows which the software incorrectly identified as RBM. Our data show that automated impedance analysis software needs refinement for use in infants and children with EA and question the need for standard anti-acid therapy in these patients.

Acknowledgements

The authors thank Marja van Schaik, Alwin van der Geer, Marjolein Spoel and Saskia Gischler of the pediatric surgical long-term follow-up team of our hospital for acquisition of data. Ko Hagoort provided editorial advice.



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