Patel A., Wang D., Sainani N., Sayuk G.S., Gyawali C.P. Distal mean nocturnal baseline impedance on pH-impedance monitoring predicts reflux burden and symptomatic outcome in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2016; 44:890898.


: Patel A. / Wang D. / Sainani N. / Sayuk G.S. / Gyawali C.P.


Distal mean nocturnal baseline impedance on pH-impedance monitoring predicts reflux burden and symptomatic outcome in gastro-oesophageal reflux disease

A. Patel, D. Wang, N. Sainani, G. S. Sayuk & C. P. Gyawali

Division of Gastroenterology, Washington University School of Medicine, Saint Louis, MO, USA.


Correspondence to: Dr C.P. Gyawali, Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8124, Saint Louis, MO 63110, USA. E-mail: cprakash@ wustl.edu

SUMMARY
Background. Mean nocturnal baseline impedance (MNBI), a novel pH-impedance metric, may be a surrogate marker of reflux burden.

Aim. To assess the predictive value of MNBI on symptomatic outcomes after anti-reflux therapy.

Methods. In this prospective observational cohort study, pH-impedance studies performed over a 5-year period were reviewed. Baseline impedance was extracted from six channels at three stable nocturnal 10-min time periods, and averaged to yield MNBI. Distal and proximal oesophageal MNBI values were calculated by averaging MNBI values at 3, 5, 7 and 9 cm, and 15 and 17 cm respectively. Symptomatic outcomes were measured as changes in global symptom severity (GSS, rated on 100-mm visual analogue scales) on prospective follow-up after medical or surgical anti-reflux therapy. Univariate and multivariate analyses assessed the predictive value of MNBI on symptomatic outcomes.

Results. Of 266 patients, 135 (50.8%) were tested off proton pump inhibitor (PPI) therapy and formed the study cohort (52.11.1 years, 63.7% F). The 59 with elevated acid exposure time (AET) had lower composite and distal MNBI values than those with physiological AET (P < 0.0001), but similar proximal MNBI (P = 0.62). Linear AET negatively correlated with distal MNBI, both individually and collectively (Pearsons r = -0.5, P < 0.001), but not proximal MNBI (Pearsons r = 0, P = 0.72). After prospective follow-up (94 patients were followed up for 3.10.2 years), univariate and multivariate regression models showed that distal MNBI, but not proximal MNBI, was independently pre dictive of linear GSS improvement.

Conclusions. Distal oesophageal MNBI negatively correlates with AET and, when assessed off PPI therapy, is independently predictive of symptomatic improvement following anti-reflux therapy.
INTRODUCTION
Ambulatory reflux monitoring is typically utilised when gastro-oesophageal reflux disease (GERD) symptoms persist despite empiric anti-secretory therapy.1 While acid exposure time (AET) remains the most consistent predictor of symptomatic outcomes with anti-reflux therapy,2 combining impedance with pH monitoring augments the assessment of reflux burden by increasing detection of reflux events,3 thereby improving confidence in a reflux mechanism for symptoms.2,4,5 However, reflux monitoring in general, especially 24-h catheter-based monitoring, offers cross-sectional assessment of reflux burden, and does not take day-to-day variation of reflux exposure into account.6,7

In contrast, baseline mucosal impedance is a novel pH-impedance-based metric that has shown promise as a longitudinal marker of reflux burden. Baseline distal oesophageal impedance may segregate acid exposure states from controls,8 and may represent a surrogate marker for reflux-induced mucosal changes and oesophageal mucosal integrity.8-10 Recent use of an endoscopic prototype for assessment of oesophageal mucosal impedance led to similar conclusions.11 Thus, these preliminary observations suggest that mean nocturnal baseline impedance (MNBI) can predict oesophageal acid injury and reflux burden, potentially augmenting the diagnostic yield of pH-impedance testing.12

Mean nocturnal baseline impedance has been evaluated in cross-sectional fashion in patients with PPI-responsive heartburn by Frazzoni et al., with segregation of erosive GERD and non-erosive reflux disease from healthy controls.12 However, to date, no outcome data exist to assess whether MNBI can predict symptomatic improvement with GERD therapy. In this study, we measured MNBI across all channels on pH-impedance tracings in an existing cohort of GERD patients with prospective outcome data, with the aims of assessing the relationship between this novel parameter and existing pH-impedance metrics, and evaluating its predictive value on symptomatic outcomes, taking contemporary metrics of oesophageal reflux burden into context.
METHODS
Subjects

Adults with persistent GERD symptoms referred for combined pH-impedance monitoring to Washington University in Saint Louis, Missouri between January 2005 and August 2010 were eligible for inclusion into this study. Subjects were excluded if they had previously undergone foregut surgery, were diagnosed with major oesophageal motor disorders or if their studies were inadequate (poor data quality precluding analysis) or incomplete (<14 h of recording time). Patients were then prospectively contacted for repeat symptom assessment; outcome data from this cohort has previously been published.2,4,5 This study protocol was approved by the Human Research Protection Office at Washington University in Saint Louis.

pH-Impedance and high-resolution manometry

pH-impedance testing at our centre is performed in an open-access fashion, ordered by academic and community gastroenterologists and gastrointestinal foregut surgeons, who in turn utilise pH-impedance results to individualise patient management at their discretion. When performed off therapy, patients are instructed to stop their PPI medications 57 days prior to the study, and any histamine-2 receptor antagonists, prokinetic medications and antacids 3 days prior to the study. After an overnight fast, an experienced nurse positions the pH-impedance catheter (Sandhill Scientific, Highlands Ranch, CO, USA) such that the distal oesophageal pH sensor is 5 cm proximal to the lower oesophageal sphincter (LES), measured using oesophageal high-resolution manometry (HRM). Throughout data acquisition, patients record their meals and activities on a paper diary; patients also log symptom events by pressing appropriate buttons on the data recorder. Upon return of the data recorder, diary events are reconciled and meal times are excluded.

Conventional pH-impedance and HRM metrics

Data uploaded from pH-impedance studies were analysed with dedicated software (Bioview Analysis; Sandhill Scientific), with automated calculation of AET, reflux events, symptom events and symptom-reflux association parameters. Each pH-impedance study was previously scrutinised manually by two reviewers (AP, CPG) to ensure the accuracy of automated capture of reflux events; any discrepancies between the reviewers were resolved by discussion. AET was calculated as the percentage of time the pH was below 4 at the distal oesophageal pH sensor. Per our institutional threshold, an AET <4.0% was designated as abnormal.2,4,13 Abnormal AET was further segregated into borderline (AET 46%) and elevated (AET>6%), while values <4% were designated physiological AET. Symptoms were considered associated with reflux events if they occurred within 2 minutes following a reflux event. Symptom association probability (SAP) was calculated using the Ghillebert probability estimate,14 and calculated separately for pH-detected reflux episodes (acid SAP) and impedance-detected reflux episodes (all SAP). SAP was designated positive if the likelihood of a chance association between symptoms and reflux events was <5%, corresponding to P < 0.05. HRM studies performed concurrently with the pH-impedance studies were analysed; proportions of ineffective swallows (distal contractile integral, DCI < 450 mmHg/cm/s) were determined according to Chicago Classfication 3.0 definitions.15

Acquisition of MNBI values

The existing pH-impedance tracings were further interrogated by one of the authors (DW) in a blinded fashion to calculate MNBI values. MNBI was calculated as described by Martinucci et al. (originally reported for the distal-most channel at 3 cm above the LES) by extracting baseline impedance values at each impedance channel (3, 5, 7, 9, 15 and 17 cm) across stable nocturnal 10-min periods (at or around 1:00 a.m., 2:00 a.m. and 3:00 a.m.) to avoid reflux events or swallows.10 The values from the three time periods for each channel were averaged to yield the MNBI for each channel. Distal MNBI was calculated as the average of MNBI values from the channels located at 3, 5, 7 and 9 cm above the LES; proximal MNBI was calculated as the average of MNBI values from the channels located at 15 and 17 cm above the LES.

Symptom assessment

Prior to pH-impedance monitoring, all patients completed symptom surveys to rate their oesophageal global symptomatic severity (GSS) on 100-mm visual analogue scales, as previously described.2,4 Eligible candidates for this study were prospectively contacted both to record what anti-reflux therapy (medical vs. surgical) was pursued by their managing physicians, and for outcome assessment by re-administering the pre-procedure symptom survey at nonstandardised time intervals based on when they could be successfully contacted. Linear as well as dichotomous (≥50%) improvements in GSS were calculated to quantify symptomatic outcomes. Responders were defined as those patients experiencing ≥50% improvement in GSS at follow-up. Existing outcome data previously reported were utilised for these calculations.2,4

Data analysis

Data are reported as the mean standard error of the mean (S.E.M) unless otherwise indicated. Categorical data were compared using the chi-squared test, and continuous data were compared using ANOVA or the two-tailed Students t-test, or nonparametric tests, as appropriate. Correlations between continuous variables were assessed using Pearsons correlation coefficient. Linear and logistic regression models were created to identify predictors of GSS improvement, with unstandardised coefficients (B) used to report effects of oesophageal physiological measures, including MNBI values, as independent predictors of symptomatic outcomes. In all cases, P < 0.05 was required for statistical significance. Statistical analyses were performed using IBM SPSS Statistics V.22.0 (Armonk, NY, USA).
RESULTS
Baseline clinical and HRM features

Of 266 patients who underwent pH-impedance testing during the study period, 135 (50.8%, 52.11.1 years old, 63.7% female) had studies performed off PPI, and formed the cohort for the current study. Of the 135 patients tested off PPI, 94 could be successfully reached for prospective follow-up after 3.10.2 years (range 1.16.7 years), and formed our outcome cohort. Of note, the patients tested off PPI (study cohort) and on PPI (remainder) had similar demographics (age and gender), symptom presentation, baseline GSS, mean DCI and numbers of ineffective swallows (P > 0.13 for all comparisons).

Conventional pH-impedance characteristics

Among patients tested off PPI, 76 patients (56.3%) had a physiological AET of <4.0%, and 59 patients had an elevated AET (19 with AET between 4% and 6%, and 40 with AET ≥6.0%). Those with elevated AET were older (P = 0.03), with higher symptom burden on GSS (P = 0.03, Table 1). Gender and distribution of presenting symptoms (typical vs. atypical) were similar regardless of oesophageal acid burden.

Table 1. Characteristics of study patients tested off PPI segregated by acid exposure time (AET)

  Physiological AET
<4.0% (n = 76)
Elevated AET
≥4.0% (n = 59)
P values*
Mean age (years)   50.01.5   54.91.7   0.033
Gender: Female (%)   50 (65.8)   35 (61.0)   0.57
Typical symptoms (%)   44 (57.9)   39 (66.1)   0.33
Baseline GSS   60.23.0   69.53.1   0.033
Composite MNBI   2499.789.4   2016.498.7  <0.0001
Distal MNBI   2484.7107.5   1718.7122.3  <0.0001
      MNBI at 3 cm   2310.2130.3   1360.1130.9  <0.0001
      MNBI at 5 cm   1984.091.9   1296.5100.0  <0.0001
      MNBI at 7 cm   3042.8140.4   2119.0148.4  <0.0001
      MNBI at 9 cm   2590.4135.1   2099.3163.1   0.21
Proximal MNBI   2532.3100.2   2611.8125.6   0.62
      MNBI at 15 cm   2033.885.4   2057.7106.2   0.86
      MNBI at 17 cm   3030.9124.9   3165.9160.2   0.50
Mean DCI   1034.799.3   943.1100.3   0.52
Ineffective swallows   2.40.4   2.40.4   0.99

* Two-tailed Students t-test for continuous variables, chi-square for categorical variables.
Heartburn, acid regurgitation.
Global symptom severity on 100-mm VAS.


Relationships between conventional metrics and MNBI

Linear AET negatively correlated with distal MNBI, both individually and collectively (Pearsons r = -0.5, P < 0.001), but not proximal MNBI (Pearsons r = 0, P = 0.72; Figure 1). Those with elevated AET≥4.0% had lower distal, but similar proximal, MNBI values compared to those with physiological AET (1718.7122.3 vs. 2484.7107.5 Ω, P < 0.001; 2611.8125.6 vs. 2532.3100.2 Ω, P = 0.62 respectively). There was a gradient of decline in MNBI as AET increased, with the lowest distal MNBI values recorded in patients with the highest AET (P < 0.0001; Figure 2). Patients with physiological AET <4% had significantly higher MNBI values at 3, 5, 7 and 9 cm compared to those with elevated AET ≥6% (P ≤ 0.001 for all comparisons; Figure 3). While numeric nonsignificant differences in distal MNBI were noted between physiological AET and borderline elevated AET of 46% (2177.8227.7 Ω, P = 0.21), statistically significant differences were seen with distal MNBI values between physiological AET and significantly elevated AET (610%: 1581.4170.7 Ω; >10%: 1363.9211.1 Ω, P < 0.0001 for each comparison, Figure 3). Proportions of patients below the Frazzoni et al. threshold of 2292 Ω12 also demonstrated a gradient: 41.9% with physiological AET <4%, 55.6% with borderline elevated AET (46%) and 81.6% with AET ≥ 6% (P < 0.0001 across groups).


Figure 1. MNBI averaged across proximal oesophageal channels (top; 15 and 17 cm above the LES) and distal oesophageal channels (bottom; 3, 5, 7 and 9 cm above the LES) plotted on the y-axis against AET (from left to right, 25% to 0%) on the x-axis, in patients tested off PPI therapy. When evaluated with Pearsons r, distal MNBI correlated modestly with AET (r = -0.5, P = 0.005), but not proximal MNBI (r = -0.03, P = 0.72).

Figure 2. Gradient of MNBI in relationship with AET in patients tested off PPI. Box (2575th percentile) and whiskers (595th percentile) plots on distal (left) and proximal MNBI values compared between physiological AET <4%, borderline elevated AET (46%) and elevated AET ≥6%. Distal MNBI was significantly lower with elevated AET (P ≤ 0.008 compared to other two groups), but not proximal MNBI (P = 0.721); distal MNBI in borderline elevated AET resembled that in physiological AET (P = ns).

Figure 3. Gradients of MNBI in distal channels in relationship with AET in patients tested off PPI. Boxand-whiskers plots on patients tested off PPI therapy, for individual MNBI values at 3, 5, 7 and 9 cm above the LES compared between physiological AET <4% and elevated AET ≥6%; MNBI comparisons were significantly different between these AET groups (P ≤ 0.001 for all comparisons). For AET between 4% and 6%, distal MBNI values differed from physiological AET at 3 cm (P = 0.03), and from elevated AET ≥6% at 5, 7 and 9 cm (P ≤ 0.03) but not other channels (P > 0.08).


When dichotomised using a reflux episode threshold of 57 episodes,16 similar composite, distal and proximal MNBI values were observed between those with ≥57 episodes compared to those not meeting this threshold (2257.9162.0 vs. 2303.474.9 Ω, P = 0.77; 1992.0189.4 vs. 2212.497.0 Ω, P = 0.27; 2788.0171.1 vs. 2485.585.9 Ω, P = 0.09) respectively. Numbers of effective swallows (P = 0.17, P = 0.95), IEM diagnosis (P = 0.93, P = 0.56) and numbers of reflux episodes (P = 0.14, P = 0.06) were not discriminative of distal or proximal MNBI respectively. Weak correlations were identified between numbers of effective wet swallows and MNBI at 3 cm (Pearsons r = 0.2, P = 0.02) and 5 cm (Pearsons r = 0.2, P = 0.046). At the remaining impedance locations, however, MNBI correlated poorly with peristaltic performance on HRM (P > 0.12 for each).

The 135 patients tested off PPI therapy were stratified into phenotypes5 with elevated AET (43.0%), reflux hypersensitivity (RH; physiological AET but positive symptom-reflux association on SAP; 28.9%) and no reflux evidence (physiological AET and absent symptom-reflux association; 28.1%; Table 2). Although the pathological AET group had lower distal MNBI compared to the RH and no reflux evidence groups (P ≤ 0.001), the RH and no reflux evidence groups shared similar values for these metrics (P > 0.8). All three groups had similar proximal MNBI values (P = 0.497).

Predictive value for symptomatic outcomes

Of the 135 patients tested off PPI, 94 patients (53.91.4 years, 67% F, 64% with typical symptoms) were reached for prospective follow-up after 3.10.2 years to assess changes in GSS. Of the 88 with complete GSS data, 57 (64.8%) reported ≥50% GSS improvement (responders).2 The duration of follow-up did not correlate with change in symptom burden (GSS) (Pearson r = -0.06, P = 0.55), or was the duration of follow-up different between symptom responders and nonresponders (P = 0.51). When compared to those without ≥50% GSS improvement (nonresponders), responders had statistically nonsignificant but numerically lower distal MNBI values (1921.8127.1 vs. 2324.1197.1 Ω, P = 0.08) and similar proximal MNBI values (2577.9123.1 vs. 2505.3154.2 Ω, P = 0.72). On assessment for univariate predictors of linear GSS improvement on follow-up, lower distal but not proximal MNBI values predicted symptom improvement (P = 0.014 and P = 0.56 respectively). Moreover, analysis of individual channels for predictive value demonstrated similar findings, which validated grouping MNBI into distal (3, 5, 7 and 9 cm; individual P values of 0.05, 0.02, 0.008 and 0.05 respectively) and proximal (15 and 17 cm; individual P values of 0.34 and 0.79 respectively).

A multivariate regression model was created using data from the patients tested off PPI on whom follow-up symptomatic outcomes were available. This model included demographics (age and gender), symptom association data (SAP for acid-detected and all impedance-detected events), typical symptom presentation and distal MNBI (in thousands) as independent variables, with linear change in GSS as the outcome variable. In this model, only distal MNBI (B = -8.64, CI -0.65 to -16.64, P = 0.035) and SAP calculated with impedance-detected reflux events (B = 22.80, CI 3.6741.92, P = 0.020) remained as independent predictors of GSS (Figure 4). We have previously reported that AET predicts linear GSS improvement in similar regression models.2 However, when AET was introduced into these regression models, significance was lost, indicating that AET and distal MNBI represent co-variates.

Figure 4. Forest plots for univariate and multivariate linear regression models of independent predictors of linear GSS improvement in patients tested off PPI therapy. Prediction of linear risk is shown as risk ratios, with bars representing 95% confidence intervals; values not crossing the zero axis are significant (*). *P = 0.014 and 0.035 for distal MNBI and P = 0.009 and P = 0.020 for impedance SAP in univariate and multivariate models respectively.
DISCUSSION
In this study, we demonstrate the potential utility of MNBI from distal oesophageal impedance channels in complementing conventional ambulatory reflux monitoring parameters to predict symptomatic outcomes from anti-reflux therapy. In particular, distal but not proximal oesophageal MNBI values were lower as AET values increased. When assessing symptomatic outcomes, lower distal MBNI was a significant independent predictor of positive outcome following anti-reflux therapy, along with SAP calculated from impedance-detected reflux events. Our data suggest that MNBI values from 5 or 7 cm above the LES may be more discriminative than MNBI at 3 cm above the LES, the location at which the original reports of MNBI were focused.10 We conclude that MNBI can complement existing conventional parameters in adding confidence to a reflux diagnosis on ambulatory pH-impedance monitoring.

Combined oesophageal pH-impedance monitoring debuted in the late 1990s with much promise of becoming the standard in reflux monitoring. The addition of impedance technology suggested the potential presence of mechanisms other than acid reflux in the generation of reflux symptoms.17 Moreover, impedance monitoring demonstrated that weakly acidic reflux events may represent a primary driver of reflux symptoms that occur despite PPI therapy.18 However, the technology has long suffered from the lack of a reliable impedance-based parameter predicting clinical outcomes.19 While impedance monitoring detects reflux events better than pH monitoring alone, confidence in numbers of impedancedetected reflux events alone in predicting therapeutic outcome remains in question,20 although the yield of symptom-reflux association is augmented by impedancedetected reflux events.2 Interest in impedance monitoring has been revitalised by the recognition that baseline mucosal impedance can be a marker for oesophageal mucosal integrity.12 MNBI, if further validated, might enhance cross-sectional data obtained from conventional pH-impedance parameters by providing longitudinal information regarding oesophageal mucosal changes induced by reflux over time.11 We demonstrate in this report that distal MNBI values are significantly different between cohorts with elevated AET and those with no reflux evidence. Recent work by Savarinos group has suggested that MNBI may help further distinguish hypersensitive oesophagus from functional heartburn,21 a finding our study could not replicate, likely because of heterogeneity in presenting symptoms in our cohort.

Interest in baseline oesophageal mucosal impedance stems from findings that acid exposure in the oesophagus can induce changes in the internal components of the oesophageal wall, such as impaired mucosal integrity that may result in decreased baseline impedance measurements.11 Baseline impedance values decrease with oesophageal acid perfusion in both animals and healthy human controls.22 AET has been previously reported to correlate with baseline impedance values, with lower baseline impedance as AET increases,8 a finding corroborated by our study. Furthermore, baseline impedance values discriminate reflux disease from functional heartburn, which we have also corroborated by demonstrating that GERD phenotypes with elevated AET can be segregated from those with physiological AET (reflux hypersensitivity, functional symptoms). Moreover, decreased baseline impedance is associated with dilated intercellular spaces, another finding suggestive of impaired mucosal integrity.23 Lower baseline impedance levels therefore add confidence to a reflux mechanism for heartburn, by enhanced segregation of patients with reflux from those without,11 and in turn patients that respond well to anti-secretory therapy.9,10

As assessment of baseline impedance can be impacted by swallows and artefacts during waking hours, the nocturnal period with the patient presumably asleep and less mobile provides an opportune time for assessment on pH-impedance monitoring. Similar to Martinucci et al., we recorded baseline impedance during three 10-min periods around 1 a.m., 2 a.m. and 3 a.m., and averaged these values to yield MNBI.10 There was a gradient in impedance values, with the lowest values recorded in the distal-most channels; recordings from channels at 7, 5 and 3 cm provided highest discrimination between normal and elevated AET. Based on the location of impedance electrodes on the catheter, we averaged values from the distal four electrodes to constitute distal MNBI, and those from the proximal two electrodes for proximal MNBI. There was a striking difference between distal and proximal MNBI measurements, with the distal values significantly lower in patients with elevated AET. Moving beyond observational data described in the literature, our findings have immediate clinical relevance, suggesting that reflux patients with lower distal MNBI values are more likely to respond to medical or surgical anti-reflux therapy over prospective follow-up.

Mean nocturnal baseline impedance may have value in further phenotyping GERD according to mucosal integrity parameters, although this concept has only been recently introduced with pH-impedance monitoring.5 Using threshold values for abnormal MNBI (<2292 Ω) obtained from healthy controls, Frazzoni et al. could segregate GERD phenotypes along a gradient from erosive oesophagitis through non-erosive GERD to healthy controls.12 These findings suggest that the emerging concept of baseline mucosal impedance, obtained during either pH-impedance testing12 or endoscopy11 could represent a benchmark for the identification of reflux-induced conditions or other inflammatory conditions like eosinophilic oesophagitis, and perhaps segregate these from true functional processes without oesophageal mucosal inflammation.19 When we applied these concepts to our cohort tested off PPI, patients with abnormal AET could be easily segregated from those with physiological AET using distal MNBI (Table 2). However, RH and nonreflux cohorts shared similar MNBI values.

Table 2. Phenotypes of patients tested off PPI

  Elevated AET ≥4.0%
(n = 58)
RH*
(n = 39)
No reflux evidence
(n = 38)
P values
 Composite MNBI   2013.8100.5   2515.9124.2   2473.8127.2   0.002
 Distal MNBI   1712.5124.4   2457.2150.2   2501.5152.2 <0.001 
 Proximal MNBI   2616.4127.8   2635.9136.3   2418.5143.3   0.497

* Reflux hypersensitivity, physiological AET but positive symptom-reflux association by symptom association probability (SAP).
Physiological AET and absent symptom-reflux association by SAP.
ANOVA.


Confounders of this concept might include entities such as eosinophilic oesophagitis, other oesophageal mucosal inflammation, oesophageal body dilation and certain oesophageal motor disorders, which can independently result in low baseline impedance.11 Thus, MNBI is not perfect in identifying physiological acid burden; another factor affecting comparisons between AET and MNBI is the day-to-day variation in oesophageal reflux burden, as patients with normal AET on 24-h recordings can have elevated values on multiple-day pH monitoring.6 Therefore, without further well-designed outcome studies, we caution against the use of novel impedance-based parameters such as MNBI as replacements for conventional pH-impedance parameters, particularly AET, in guiding therapy. However, MNBI utilises existing data available in every pH-impedance study performed for evaluation of persisting reflux symptoms, and therefore represents information that could be easily extracted from the same studies where AET is calculated. We do not envision MNBI replacing AET, rather MNBI could complement AET in adding confidence to a reflux diagnosis where AET is not consistently elevated to make this conclusion.

A few limitations of our study design temper the strength of our findings. Although prospectively contacted for follow-up, patients were retrospectively identified from our pH-impedance database; however, 70% could be successfully followed up. Patients self-reported medical anti-reflux therapy prior to pH-impedance monitoring, as well as the nature (medical vs. surgical) of anti-reflux therapy on follow-up. Although the absence of protocolised management is acknowledged as a limitation, we feel that our approach allowing a combination of community and tertiary-care gastroenterology practices to make clinical decisions represents a real-world approach to reflux management. As noted, nonreflux inflammatory processes and motor disorders can affect basal impedance and oesophageal peristaltic performance; while major motor disorders were excluded, the oesophagus was not routinely or uniformly inspected by our group as part of this study. Therefore, we relied on information from our referring gastroenterologists and surgeons that conditions mimicking GERD were adequately excluded, and we could not consistently assess for the presence of erosive oesophagitis or Barretts oesophagus. Finally, other nonreflux factors (such as placebo effect or functional pain syndromes) were not evaluated in this study, and could have also influenced symptomatic outcomes.

In conclusion, MNBI is a novel impedance parameter that has clinical utility and adjunctive value in assigning confidence to reflux as a mechanism for symptoms. Decreased distal but not proximal oesophageal MNBI values are associated with increasing pathological oesophageal acid exposure, and lower distal MNBI values are associated with superior symptomatic outcomes. Therefore, MNBI has potential to complement AET, especially if AET alone is insufficient to make a conclusive diagnosis of reflux disease. Future prospective research can further refine the value of oesophageal MNBI as a measure of longitudinal reflux burden to complement cross-sectional reflux data currently available from conventional pH-impedance monitoring metrics.
AUTHORSHIP
Guarantor of the article: C. Prakash Gyawali.
Author contributions: AP: study design, data collection and analysis, manuscript preparation and review; DW, NS: data collection and analysis, critical review of manuscript; GSS: data analysis, critical review of manuscript; CPG: study concept and design, data analysis, manuscript preparation, critical review and final approval of manuscript. All authors have approved the final version of the manuscript.
ACKNOWLEDGEMENTS
Declaration of personal interests: CPG has received research funding from Medtronic, has served as a speaker and consultant for Medtronic, Allergan, Abbvie and Salix, and as a consultant for Quintiles and Torax. The other authors have no personal interests to declare.
Declaration of funding interests: This study was partially funded through NIH/NIDDK (T32 DK007130 AP; K23DK84413-4 GSS), and through the Washington University Department of Medicine Mentors in Medicine (MIM) and Clinical Science Training and Research (CSTAR) programs.
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