Rengarajan A, Savarino E, Della Coletta M, Ghisa M, Patel A, Gyawali CP. Mean Nocturnal Baseline Impedance Correlates With Symptom Outcome When Acid Exposure Time Is Inconclusive on Esophageal Reflux Monitoring. Clin Gastroenterol Hepatol. 2019 Jun 1.

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Авторы: Rengarajan A. / Savarino E.V. / Coletta M.D. / Ghisa M. / Patel A. / Gyawali C.P.

Mean Nocturnal Baseline Impedance Correlates With Symptom Outcome When Acid Exposure Time Is Inconclusive on Esophageal Reflux Monitoring

Arvind Rengarajan1, Edoardo Savarino2, Marco Della Coletta2, Matteo Ghisa2, Amit Patel3, C. Prakash Gyawali4

Author information
1 Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri.
2 Division of Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, Padua, Italy.
3 Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri; Division of Gastroenterology, Durham Veterans Administration Hospital, Duke University, Durham, North Carolina.
4 Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri. Electronic address: cprakash@ dom.wustl.e du.

Аннотация на русском языке

BACKGROUND & AIMS: Abnormal acid exposure time (AET) is associated with good outcomes of symptoms from antireflux therapy. Low esophageal mean nocturnal baseline impedance (MNBI) is an additional marker of reflux disease. We aimed to evaluate the value of MNBI when analysis of AET produces borderline or inconclusive results.

METHODS: We studied a retrospective cohort of 371 patients (mean age, 54.5 ± 0.7 y; 60.0% female) who had persistent reflux symptoms after treatment and underwent ambulatory pH-impedance monitoring off antisecretory therapy at 1 tertiary center in Europe or 1 in the United States. Total AET was determined from pH impedance studies (pathologic, >6%; physiologic, <4%; borderline or inconclusive, 4%–6%). Baseline impedance values were calculated at the 5-cm impedance channel at 3 nocturnal 10-minute periods and averaged to yield MNBI (abnormal, <2292 ohms). The primary outcome was response to antireflux therapy, defined as global symptom improvement of 50% or greater on patients’ answers on standardized visual analog scales.

RESULTS: Among the 371 patients, 107 (28.8%) had pathologic AET and 234 (63.1%) had abnormal MNBI. Low MNBI was concordant in 99.1% of patients with pathologic AET, in 91.2% with borderline AET, and in 33.7% with physiologic AET. During 38.7 ± 0.8 months of follow-up evaluation, 43.0% of patients had improved symptoms with medical therapy and 76.2% had improved symptoms with surgical antireflux therapy (P < .0001). When MNBI was low, response to medical therapy did not differ significantly between patients with borderline AET and patients with pathologic AET (P = .44), but did differ significantly when each group was compared with patients with physiologic AET, regardless of whether MNBI was normal or low (P < .0001 for each comparison).

CONCLUSIONS: When low, MNBI identifies patients with pathologic and borderline AET who respond to antireflux therapy. MNBI analysis complements AET in defining esophageal reflux burden. MNBI correlates with response of symptoms to antireflux therapy.

Keywords: GERD; pH-Impedance Monitoring; Baseline Impedance; Acid Exposure Time.

Abbreviations used in this paper. AET - acid exposure time. AUC - area under the curve. GERD - gastroesophageal reflux disease. LES - lower esophageal sphincter. MNB - Imean nocturnal baseline impedance. PPI - proton pump inhibitor

PMID: 31163276. DOI: 10.1016/j.cgh.2019.05.044.
What You Need to Know
Background. Abnormal acid exposure time (AET) is associated with good outcomes of antireflux therapy, however, low esophageal mean nocturnal baseline impedance (MNBI) is also a marker of reflux disease. We investigated the value of MNBI when analysis of AET produced borderline or inconclusive results.

Findings. When low, the MNBI identifies patients with pathologic and borderline AET who respond to antireflux therapy. MNBI correlates with response of symptoms to antireflux therapy.

Implications for patient care. MNBI might be used to complement AET in determining esophageal reflux burden and as a marker of symptom response to antireflux therapy.

Ambulatory reflux monitoring often is used to rule in or rule out gastroesophageal reflux disease (GERD) when esophageal symptoms persist despite treatment with antisecretory medications, especially in the absence of prior conclusive evidence of GERD (unproven GERD).1,2 Among metrics extracted from ambulatory pH- or pH-impedance monitoring, total acid exposure time (AET), the cumulative percentage of time when the distal esophageal pH is less than 4.0, predicts symptomatic outcome with antireflux therapy.3 By using available data and expert opinion, an international consensus of esophageal experts designated AET less than 4% as physiologic and greater than 6% as pathologic, and values between 4% and 6% were designated as borderline and inconclusive, requiring additional GERD evidence from alternate testing to determine the presence or absence of pathologic GERD.4

In addition to assessment of AET, pH-impedance monitoring provides a measurement of baseline esophageal impedance, which has been studied as a marker of esophageal mucosal integrity,5–7 and therefore is a potential marker for longitudinal reflux burden.8–11 When obtained from resting nocturnal periods, low mean nocturnal baseline impedance (MNBI) segregates reflux disease from functional syndromes and controls.12,13 Distal MNBI correlates with AET, but may not augment the diagnostic yield of pH-impedance testing when AET is increased pathologically.14 However, the clinical significance of MNBI when AET is inconclusive remains incompletely understood.

The primary aim of this study was to determine the additive value of MNBI in predicting symptomatic outcome with antireflux therapy, particularly when AET is borderline and therefore inconclusive.

This was a retrospective cohort study involving 2 tertiary medical centers (Washington University in St. Louis, MO, and University of Padua in Padua, Italy). All adult patients (age, >18 y) undergoing evaluation for persistent esophageal and extraesophageal symptoms suspicious for GERD with ambulatory pH-impedance monitoring performed off antisecretory medications were eligible for inclusion. Subjects were excluded if they had a history of previous foregut surgery, were diagnosed with major esophageal motor disorders, or if their studies were inadequate or incomplete. All subjects prospectively completed symptom questionnaires defining their symptoms and symptomatic state at presentation. Demographics and clinical presentation were abstracted from patient records. Eligible patients who completed reflux monitoring were contacted prospectively or evaluated at follow-up visits for administration of follow-up questionnaires to determine symptom response from medical and/or surgical antireflux therapy. Response was defined as at least 50% improvement in esophageal reflux symptoms on follow-up evaluation based on questionnaire data. This study protocol was approved by the Institutional Review Boards of both institutions.

pH-Impedance Studies and Metrics

Before ambulatory pH-impedance monitoring (Sandhill Scientific, Boulder, CO), patients were instructed to stop proton pump inhibitor (PPI) therapy at least 5 to 7 days before the study, and any H2 blocker, prokinetic agent, or antacid 3 days before the study; this is in compliance with recommendations from an international GERD consensus.1 Patients presented after an overnight fast. High-resolution manometry (Medtronic, Duluth, GA) was performed to localize the proximal margin of the lower esophageal sphincter (LES), to ensure placement of the distal pH sensor 5 cm proximal to the LES.15,16 Patients kept a dairy of food and beverage intake, as well as symptoms throughout the duration of the pHimpedance study. Total AET, defined as the fraction of the study time the distal esophagus was subjected to a pH less than 4.0, was extracted from pH studies after excluding meal times. Total AET was considered abnormal when higher than 6%, physiologic when less than 4%, and borderline/inconclusive if the AET was 4% to 6%.4

The MNBI was calculated using the method described by Martinucci et al,17 which involves extracting and averaging baseline impedance values at stable nocturnal 10-minute periods at 1:00 AM, 2:00 AM, and 3:00 AM. Previous reports have shown that distal MNBI (at the 3-cm and 5-cm markers) correlates with AET, but not proximal MNBI.9,14,17 For the purpose of this study, baseline impedance was calculated and averaged at the 5-cm channel to correspond to total distal AET, and was considered abnormal if les than 2292 ohms.

Symptom Assessment

Before the initiation of pH monitoring studies, all patients were asked to assess their esophageal symptoms on validated esophageal questionnaires. Global symptom severity was assessed on a 100-mm visual analogue scale (“overall, how would you rate your symptoms in the past two weeks,” followed by a 100-mm horizontal line, anchored by “no symptoms” and “very bad symptoms” at the 2 ends), and was the primary outcome measure.3,18 Eligible patients who subsequently were enrolled and completed pH-impedance testing were contacted prospectively or evaluated at follow-up visits to determine if medical vs surgical antireflux therapy was pursued by their managing physician and for re-administration of the preprocedure symptom questionnaire. Response to either medical or surgical therapy was defined as at least 50% global improvement in esophageal symptoms at follow-up evaluation based on questionnaire data.

Data Analysis

Unless otherwise indicated, data are reported as means ± SEM. Continuous data were compared using the 2-tailed Student t test and categoric data were compared using the chi-squared test. Correlations between continuous variables were assessed using the Pearson correlation. Overall concordance between total AET and MNBI was determined. Symptom response was assessed, dichotomized based on medical vs surgical intervention, and compared in relationship with abnormal MNBI in the setting of abnormal, borderline, and normal total AET. Data were analyzed to assess concordance between total AET and MNBI and to assess symptom response in relationship to borderline AET and abnormal MNBI. Receiver operating characteristic plots were generated evaluating abnormal AET, abnormal MNBI, and either abnormal AET or MNBI in predicting 50% or more symptom improvement. In all cases, a P value less than .05 was required for statistical significance. All statistical and plots were performed using Microsoft Excel and R-Studio v2.11.
Baseline Characteristics

Between the 2 study centers, a total of 371 patients fulfilled inclusion criteria and were included in this study (Table 1). Although baseline characteristics were otherwise similar between the 2 centers, there was a higher proportion of female patients, patients with lower MNBI, and higher mean body mass index in the St Louis cohort, factors that potentially are inter-related. Patients were followed up for more than 3 years at both centers (median, 37 mo; range, 11–81 mo), with no statistically significant difference between the 2 study cohorts. There was a marginal difference in follow-up duration between responders and nonresponders (40.4 ± 1.2 vs 37.2 ± 1.0 mo, respectively; P = .05). Proportions of patients with physiologic, pathologic, and borderline AET were similar at both centers. A total of 41 patients received surgical intervention alone, 308 patients were managed medically, and 22 patients received initial medical therapy followed by surgical therapy.

Table 1. Demographics and Clinical Characteristics

(n = 371)

(n = 283)

St. Louis
(n = 88)

Age, y   54.5 ± 0.7   54.6 ± 0.8   54.1 ± 1.4   .76
Female   221 (59.7%)   160 (56.5%)   61 (69.3%)   .04
Body mass index   25.25 ± 0.3   24.4 ± 0.2   28.9 ± 0.7  <.001
Time to follow-up evaluation, mo   38.7 ± 0.8   39.0 ± 0.8   37.5 ± 2.0   .48
Total AET, mean   5.5 ± 0.4   5.7 ± 0.4   4.6 ± 0.5   .10
AET, <4%  196 (52.8%)  146 (51.6%)   50 (56.8%)   .40
AET, 4%–6%   68 (18.3%)   55 (19.4%)   13 (14.8%)   .35
AET, ≥6%  107 (28.8%)   82 (29.0%)   25 (28.4%)   1.0
MNBI, <2292 Ω  234 (63.1%)  167 (59.0%)   67 (76.1%)   .01
MNBI, ≥2292 Ω  137 (36.9%)   116 (41.0%)   21 (23.9%)  

AET, acid exposure time; MNBI, mean nocturnal baseline impedance.

Concordance Between Acid Exposure Time and Mean Nocturnal Baseline Impedance

When AET was pathologic (>6%), MNBI also was low in 99%. This contrasted with only 66% of physiologic AET (<4%) concordant with normal MNBI (Figure 1), because one third of patients with physiologic AET had low MNBI. When AET was borderline (4%–6%), MNBI was low in 91.2%, and normal only 8.8% of the time. As expected, overall MNBI decreased as total AET increased (Figure 1).

Figure 1. Correlation between mean nocturnal baseline impedance (MNBI) and acid exposure time (AET). The 2 metrics were almost perfectly concordant when AET was greater than 6%. Discordance (physiologic AET, low MNBI) was seen in a third of patients with physiologic AET, and in a small proportion (8%) when AET was borderline and MNBI was normal.

Symptomatic Outcomes

When defined as at least 50% symptom improvement, symptom response was highest when AET was pathologic (84 of 112; 75.0%), and lowest when AET was physiologic (55 of 208; 26.4%; P < .0001). Proportions with symptom improvement were most pronounced when comparing medical therapy between pathologic AET and physiologic AET (74.2% vs 21.1%, respectively; P < .005) (Figure 2A). Although numbers were small, response to surgical therapy was similar between AET cohorts. Response rates were comparable for patients with borderline AET because they appeared to improve with both medical and surgical therapy (Figure 2A), with statistically significant differences between borderline and physiologic AET in the medical management cohort (66.1% vs 21.1%; P < .005).

Figure 2. Proportion of patients with improvement of least 50% in global symptom severity assessed on a 100-mm visual analog scale after 38.7 ± 0.8 months of follow-up evaluation. (A) More patients improved with medical therapy when acid exposure time (AET) was pathologic (>6%) or borderline (4%–6%), compared with when AET was physiologic. Improvement with surgical management was similar across the 3 categories, but the number of patients undergoing antireflux surgery was small. (B) More patients improved from both medical and surgical therapy when mean nocturnal baseline impedance (MNBI) was low compared with normal MNBI. (C) Proportion of patients with symptom improvement with antireflux therapy was higher when MNBI was low, especially when AET was pathologic or borderline.

In evaluating responses by MNBI values, lower rates of symptom improvement were noted when MNBI was greater than 2292 ohms, compared with patients in whom MNBI was low (30 of 145 [20.7%] vs 160 of 234 [64.5%], respectively; P < .0001). Rates of symptom improvement were significantly higher with low MNBI compared with normal MNBI within the medical intervention cohort (60.1% vs 17.4%; P < .005) (Figure 2B). This same trend was evident within the surgical intervention cohort, although was not statistically significant (82.0% vs 53.8%; P = .06).

Figure 3. Receiver operating characteristic (ROC) curves showing that a low mean nocturnal baseline impedance (MNBI) has the best clinical value in predicting at least 50% symptom improvement when acid exposure time (AET) is less than 6%, where area under the curve (AUC) was 0.72 to 0.76. The image shows ROC curves for low MNBI in predicting at least 50% symptom improvement in 2 settings: when AET is 6% or higher, and when less than 6%, indicated by labels.

When the study cohort was grouped according to both AET and MNBI, patients with abnormal AET and low MNBI had significantly better symptomatic outcomes compared with those with physiologic AET, especially if MNBI also was normal (84 of 111 [75.7%] vs 28 of 138 [20.3%], respectively; P < .0001). When AET was borderline (ie, between 4% and 6%), response to antireflux therapy was similar to that seen with pathologic AET when MNBI was abnormal (49 of 67 [73.1%] vs 84 of 111 [75.7%], respectively; P = .725). In contrast, response was similar to that with physiologic AET when MNBI was normal (2 of 6 [33.3%] vs 27 of 70 [38.6%], respectively; P = 1.0). Thus, low MNBI correlates with improvement from therapeutic intervention when AET is borderline (Figure 2C).

We wanted to assess how AET alone, MNBI alone, or AET and/or MNBI would predict response in patients with pathologic AET, vs nonpathologic AET (ie, <6%). When constructing receiver operating characteristic curves evaluating abnormal AET, abnormal MNBI and either abnormal AET or MNBI in predicting at least 50% symptom outcome, the area under the curve (AUC) for each of these metrics was more profound when AET was nonpathologic (AUC, ≥ 0.72), and the curves were rather flat when AET was pathologic (AUC, ≤ 0.64). Combining AET with MNBI resulted in a more sensitive correlation with treatment response and a higher AUC (0.76) in patients with nonpathologic AET compared with pathologic AET (AUC, 0.63) (Figure 3). Performance characteristics of AET, MNBI, and the combination of abnormal AET and/or MNBI are described in Table 2. The gain in sensitivity and negative predictive value with the use of MNBI are offset by lower specificity and lower positive predictive value.

Table 2. Performance Characteristics of Reflux Metrics on pH-Impedance Monitoring in Predicting 50% Symptom Improvement From Antireflux Therapy

    Sensitivity   Specificity   PPV   NPV
  AET ≥ 4%   0.73 (0.65–0.79)   0.75 (0.68–0.81)   0.71 (0.66–0.76)   0.76 (0.71–0.80)
  AET ≥ 6%   0.46 (0.38–0.54)   0.86 (0.80–0.9)   0.74 (0.66–0.81)   0.65 (0.61–0.68)
  MNBI, <2292 Ω   0.85 (0.79–0.90)   0.56 (0.49–0.63)   0.62 (0.58–0.66)   0.81 (0.75–0.86)
  AET, ≥ 4%   0.86 (0.80–0.91)   0.53 (0.46–0.60)   0.61 (0.58–0.65)   0.82 (0.75–0.87)
  AET, ≥ 6%   0.85 (0.79–0.90)   0.55 (0.48–0.62)   0.62 (0.58–0.66)   0.81 (0.74–0.86)
          NOTE. Values in parentheses indicate 95% CIs.
          AET, acid exposure time; MNBI, mean nocturnal baseline impedance; NPV, negative predictive value;
          PPV, positive predictive value.
          aEither abnormal AET or abnormal MNBI.
In this study, using data collected from patients with esophageal symptoms refractory to PPI therapy from 2 international esophageal centers, we show that both pathologic AET and lowMNBI values are associated with better symptom response to antireflux therapy. In contrast, response to antireflux therapy was suboptimal when AET was physiologic, regardless of MNBI values. When AET was borderline, the low MNBI cohort showed symptom response comparable with the pathologic AET cohort, whereas the normal MNBI cohort resembled the physiologic AET cohort. MNBI therefore complements AET in defining esophageal reflux burden, and correlates with symptom response to antireflux therapy, especially when AET is borderline or pathologic.

The concept of using baseline impedance as a marker for esophageal mucosal integrity is not new. Farre et al5 used a perfused rabbit esophagus model to show correlation between esophageal transepithelial resistance and baseline impedance measurements, and to show that human esophageal baseline impedance values decrease after acid perfusion of the esophagus. Since then, other investigators have confirmed a relationship between baseline impedance and esophageal reflux burden and have hypothesized that this metric will be useful for GERD diagnosis and symptomatic assessment after therapy.19–21 The implication of these findings was that baseline impedance could represent a metric that indirectly assessed longitudinal reflux burden, in contrast to cross-sectional reflux burden assessed by pH monitoring, which is subject to significant day-to-day variation.22,23 Consequently, baseline impedance can be abnormal owing to abnormal mucosal integrity from intermittently increased acid burden, even when AET on a 24-hour pH monitoring study is normal or borderline, as shown by our findings.

Baseline impedance values are available on every pH impedance study, but accurate calculation can be influenced by swallows, reflux episodes, meals, and artifacts. To circumnavigate these confounding factors, Martinucci et al17 proposed the calculation of mean baseline impedance from 3 nocturnal sleep periods, when the baseline impedance values are stable. Mean values from three 10-minute measurement periods at 1 AM, 2 AM, and 3 AM, termed MNBI, have been shown to correlate well with AET.14 Although original reports used MNBI from 3 cm above the LES, values from 5 cm above the LES also correlate with AET, whereas impedance measurements from the proximal esophagus do not.14 MNBI has been shown to be a covariate with AET in predicting outcome from antireflux therapy,14 leading some to question how MNBI adds to the value of reflux monitoring above that from measurement of acid parameters such as AET.

Over the past few years, there has been an international consensus effort to define GERD testing and diagnosis, and to refine AET thresholds used to designate pathologic GERD.1,4 By using a combination of existing data and expert opinion, this consensus process segregated AET thresholds into the 3 categories used in this report.4 Although MNBI was considered as an adjunctive parameter of value when AET is borderline, there was previously no literature describing the value of MNBI in this setting. Our report shows the clear value of MNBI when AET is borderline, in swaying clinical impression toward pathologic GERD when MNBI is low, and toward physiologic acid exposure when MNBI is normal. Furthermore, our data show that the combination of AET and MNBI can be used successfully in predicting symptomatic outcome from antireflux therapy, particularly medical therapy using acid suppressants. Within the borderline AET cohort, as many as three quarters of patients with low MNBI improved with antireflux therapy, in contrast to just a third when MNBI was normal, although numbers in the latter category were small.

Our data show that the vast majority of patients with borderline AET (>90% in our cohort) have low MNBI and likely have pathologic GERD. This is supported by the fact that three quarters of patients with borderline AET responded to antireflux therapy, likely reflecting the fact that the lower threshold for pathologic GERD proposed by the Lyon consensus (6%) may be too high. Our data also suggest that surgical therapy improves symptoms in at least 70% regardless of AET, especially when MNBI is low; in contrast, only 7 of 13 patients with normal MNBI reported symptom benefit with antireflux surgery when MNBI was normal. The latter finding further supports the need for prospective studies aimed to evaluate the role of MNBI in selecting patients for antireflux surgery.

The strengths of this study lie in the large patient numbers, and in the detailed assessment of patient symptoms and reflux parameters. Symptom data were collected clinically on a systematic basis using questionnaires without impacting decision making in GERD management, which was left to the treating physician, which reflects a real-world approach to GERD evaluation and management. Outcomes were similar in 2 separate tertiary referral centers on 2 continents, which adds to the value of this report. We acknowledge the lower MNBI values in the St. Louis cohort compared with the Padua cohort; our speculation is that these differences reflect higher reflux burden in the significantly more obese St. Louis population. It is well known that obesity is associated with a higher reflux burden, including erosive esophagitis,24 both of which can lower baseline impedance.

This report also had a few limitations that tempered the strength of the conclusions. Dosing of PPI was not influenced or monitored by the study, and instead was left to the treating physician. In addition to this approach reflecting real-world GERD management, this also could be considered a limitation because details regarding PPI regimens were not corroborated with response vs lack thereof. However, the main aim of the study was to determine the additive clinical value of MNBI values. Consequently, factors other than pH-impedance metrics and dominant symptoms were not factored into the analysis, which could have influenced some of the decisions regarding management. A fixed MNBI threshold was used, which was developed using limited healthy controls; furthermore, MNBI may be subject to variation based on the presence of motility disorders and esophageal dilation, which were not part of the study protocol. Normative MNBI thresholds also could vary between regions and ethnicities, and study conclusions could change if normal thresholds were different between Italy and US populations. Nevertheless, we believe our findings lend support to the clinical use of MNBI in solidifying the presence of GERD, especially when AET is borderline.

In conclusion, we show that MNBI can help segregate borderline AET into 2 categories based on whether MNBI is low or normal. Furthermore, management outcomes are impacted by whether MNBI is low or normal when AET is borderline. Further research will help define optimal AET and MNBI thresholds for designation of conclusive GERD.
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Reprint requests. Address requests for reprints to: C. Prakash Gyawali, MD, Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8124, St Louis, Missouri 63110. e-mail: cprakash@ dom.wustl.e du; fax: (314) 454-5107.

Acknowledgments. This article was presented at the United European Gastroenterology Conference, Barcelona, Spain, October 2017.

Conflicts of interest. This author discloses the following: Edoardo Savarino has consulted for AbbVie, Allergan, MSD, Takeda, Sofar, and Janssen; teaches and is a speaker for Medtronic, Reckitt-Benckiser, Malesci, Zambon, CPG, and Diversatek; and has consulted for Ironwood and Torax. The remaining authors disclose no conflicts.

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