Kessing B.F., Bredenoord A.J., Weijenborg P.W., et al. Esophageal acid exposure decreases intraluminal baseline impedance levels. Am J Gastroenterol 2011; 106: 20932097.


: Kessing B.F. / Bredenoord A.J. / Weijenborg P.W. / Hemmink G.J.M. / Loots C.M. / Smout A.J.P.M.


Esophageal Acid Exposure Decreases Intraluminal Baseline Impedance Levels

Boudewijn F. Kessing, MD1, Albert J. Bredenoord, MD, PhD1, Pim W. Weijenborg, MD1, Gerrit J.M. Hemmink, MD, PhD2, Clara M. Loots, MSc3 and A.J.P.M. Smout, MD, PhD1



1 Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands;
2 Department of Gastroenterology, Sint Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands;
3 Department of Pediatric Gastroenterology and Nutrition, Emma Children Hospital, Academic Medical Center, Amsterdam, The Netherlands.

Correspondence: Boudewijn F. Kessing, MD, Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: b.f.kessing@ amc.uva.nl or bkessing@ gmail.com



Objectives: Intraluminal baseline impedance levels are determined by the conductivity of the esophageal wall and can be decreased in gastroesophageal reflux disease (GERD) patients. The aim of this study was to investigate the baseline impedance in GERD patients, on and off proton pump inhibitor (PPI), and in healthy controls.

Methods: Ambulatory 24-h pHimpedance monitoring was performed in (i) 24 GERD patients with and 24 without pathological esophageal acid exposure as well as in 10 healthy controls and in (ii) 20 patients with refractory GERD symptoms despite PPI, once on PPI and once off PPI. Baseline impedance levels in the most distal and the most proximal impedance channels were assessed.

Results: Median (interquartile range) distal baseline impedance in patients with physiological (2,090 (1,5372,547) Ω) and pathological (781 (6121,137) Ω) acid exposure was lower than in controls (2,827 (2,1273,270) Ω, P<0.05 and P< 0.001). A negative correlation between 24-h acid exposure time and baseline impedance was observed (r=− 0.7, P<0.001). In patients measured off and on PPI, median distal baseline impedance off PPI was significantly lower than on PPI (886 (7161,354) vs. 1,372 (9611,955) Ω, P<0.05) and distal baseline impedance in these groups was significantly lower than in healthy controls (P< 0.05 and P<0.001). Proximal baseline impedance did not differ significantly between the patients off PPI and on PPI (1,793 (1,3842,489) vs. 1,893 (1,6102,561) Ω); however, baseline impedance values in both measurements were signifi cantly lower than in healthy controls (3,648 (2,8153,932) Ω, both P<0.001).

Conclusions: These findings suggest that baseline impedance is related to esophageal acid exposure and could be a marker of reflux-induced changes to the esophageal mucosa.
INTRODUCTION
Ambulatory esophageal intraluminal impedance monitoring is used to detect gastroesophageal reflux by measuring changes in electrical impedance caused by gas and fluid reflux and swallows ( 1 ). Between reflux episodes and swallows, the esophageal lumen is collapsed and the resulting baseline impedance level is determined by the surrounding esophageal wall.

Reflux episodes as measured by esophageal impedance monitoring are defined as a > 50% drop from impedance baseline. Therefore, low-baseline impedance levels can lead to difficulties or even an inability to interpret impedance measurements ( 2 ). Acid reflux can result in macroscopic damage to the esophageal wall and baseline impedance levels can be decreased in patients with esophagitis ( 3 ). Other, more discrete reflux-induced changes to the esophageal wall are dilated intercellular spaces (DIS), which can occur without macroscopic damage to the esophageal wall ( 4 ). Farré et al. ( 5,6 ) demonstrated that DIS can be induced by esophageal acid exposure. Furthermore, most patients with DIS show a recovery of DIS after proton pump inhibitor (PPI) treatment ( 7 ). However, the effect of DIS on baseline impedance levels is not known.

In theory, reflux-induced changes to the esophageal wall could affect the resistance of the esophageal wall and thereby affect baseline impedance level. However, it is not known whether gastroesophageal reflux disease (GERD) patients are characterized by decreased baseline impedance levels and how this is affected by esophageal acid exposure.

We hypothesized that esophageal baseline impedance levels are decreased in GERD patients due to acid reflux. To test this hypothesis, we aimed to assess baseline impedance levels in GERD patients, in controls, and in patients measured with and without inhibition of gastric acid secretion.
METHODS
Subjects

In part A of the study, we included 24 GERD patients with physiological acid exposure, defined as an acid exposure time <6% (mean age 46 years, range 2068 years, 18 females) and 24 patients with pathological esophageal acid exposure, defined as an acid exposure time ≥6% (mean age 49 years, range 2174 years, 10 females) (Table 1). A history of reflux esophagitis was present in 10 GERD patients for which they were treated accordingly and no erosive damage was observed in 38 GERD patients (Table 1). No Barretts esophagus was observed in the included GERD patients. In all the patients, the indication for the 24-h reflux monitoring was the presence of typical reflux symptoms (heartburn, regurgitation). All the patients had a Symptom Association Probability ≥95%, indicative of a temporal correlation between their reflux symptoms and reflux episodes ( 8 ). We excluded patients with a history of upper gastrointestinal surgery. Furthermore, 10 healthy controls (mean age 48 years, range 2361 years, 7 females) defined as not having gastrointestinal symptoms or a history of major abdominal surgery were also studied.

In part B of the study, 20 patients were included who had typical reflux symptoms (heartburn, regurgitation, and/or chest pain) despite PPI therapy twice daily (b.i.d.) (mean age 45 years, range 2168 years, 10 females) (Table 1). A history of reflux esophagitis was present in 2 out of 20 patients with persistent symptoms despite PPI for which they were treated accordingly and no erosive damage was observed in 18 patients (Table 1). No Barretts esophagus was observed in the patients who were included in part B of the study. In these patients, the effect of gastric acid secretion on baseline impedance was measured. Patients from part B of the study were described previously and informed consent for the initial study was obtained ( 9 ). Approval by a medical ethical committee was obtained for both parts of the study.

1. Subject characteristics

  Pathological Physiological On vs. off patients Controls
  Number 24 24 20 10
  Age (years) 49 46 45 48
  Female 10 18 10 7
  Non-erosive 18 20 18  
  Esophagitis 6 4 2  
LA grade A 4 4 2  
LA grade B 1 0 0  
LA grade C 1 0 0  
  Barrets esophagus 0 0 0  

Esophageal pHimpedance measurements

In the GERD patients who were included in part A of the study and in the healthy controls, measurements were performed without inhibition of gastric acid secretion.

The research protocol in patients with symptoms despite PPI who were included in part B of the study consisted of ambulatory 24-h pHimpedance monitoring twice, once on PPI (double dose b.i.d.) and once after cessation of the PPI for 7 days, in a randomized order with an interval varying between 1 and 4 weeks.

Measurements were performed using a combined pHimpedance catheter assembly that consisted of six impedance segments and one ISFET pH electrode (Unisensor AG, Attikon, Switzerland), which was placed at 5 cm from the upper border of the of the manometrically localized lower esophageal sphincter. Impedance recording segments were located at 24, 46, 68, 810, 1416, and 1618 cm above the upper border. Impedance and pH signals were stored on a digital datalogger (Ohmega, Medical Measurement Systems, Enschede, The Netherlands), using a sampling frequency of 50 Hz.

Figure 1. Time period selection for measurement of esophageal impedance baseline levels. Mean impedance value during the selected period was considered baseline impedance for that time period and was calculated every 2 h.
Figure 2. Esophageal baseline impedance levels in gastroesophageal reflux disease (GERD) patients with pathological reflux, GERD patients with physiological reflux, and healthy control subjects.
Figure 3. Correlation between acid exposure time and distal baseline impedance levels in gastroesophageal reflux disease (GERD) patients.
Figure 4. Diurnal variations in esophageal impedance baseline levels in gastroesophageal reflux disease (GERD) patients, data are presented as mean and s.e.m.
Figure 5. Esophageal baseline impedance levels measured on and off proton pump inhibitor (PPI).


Data analysis

Baseline impedance levels were assessed every 2 h in the most distal impedance channel, situated at 3 cm above the lower esophageal sphincter, and in the most proximal channel, at 17 cm above the lower esophageal sphincter. A 30-s time period was selected (Figure 1), and the impedance baseline during this period was calculated by averaging the raw impedance values during the selected time period. Thereafter, the 2-hourly impedance baseline values were averaged to arrive at mean distal and proximal baseline impedance levels for the entire 24-h measurement. Investigators were blinded for the study group.

Statistical analysis

Throughout the manuscript, baseline impedance levels ( Ω ) and total esophageal acid exposure time (% time pH<4) are presented as median (interquartile range), and upright and supine reflux are presented as mean s.e.m. Statistical analysis was performed using Prism software version 5 (Graph Pad, CA). Data distribution was evaluated using the Bartletts test for equal variances or KolmogorovSmirnov test. One-way analysis of variance followed by Tukeys post hoc analysis in the GERD patients and healthy controls analysis and Dunnets post hoc analysis in the patients with symptoms despite PPI and healthy controls analysis were used. Comparisons between distal and proximal baselines as well as baselines on and off PPI were analyzed using paired Students t-test or Wilcoxon signed rank test. Spearmans correlation statistics was used for correlation analysis. Differences were considered statistically signifi cant when P<0.05.
RESULTS
Part A: GERD patients

Acid exposure time was significantly higher in patients with pathological acid exposure (14.0 (10.817.0)%) than in patients with physiological acid exposure (2.7 (1.64.5)%, P<0.001) and healthy controls (1.8 (0.92.9)%). There was no significant difference between acid exposure times in patients with physiological acid exposure and controls. Upright acid exposure time was significantly higher than supine acid exposure time in all GERD patients (10.41.1 vs. 6.01.2%, P<0.05) and in patients with physiological acid exposure (4.50.6 vs. 0.80.3%, P<0.05) and a trend was observed in patients with pathological acid exposure (16.41.3 vs. 11.42.0%, P=0.07). Distal baseline impedance (781 (6121,137) Ω) was significantly lower in patients with pathological acid exposure than in patients with physiological acid exposure and controls (both P<0.001) (Figure 2). Distal baseline impedance in patients with physiological acid exposure (2,090 (1,5372,547) Ω) was significantly lower than in controls (2,827 (2,1273,270) Ω, P<0.05). Proximal baseline impedance values in patients with pathological acid exposure (2,544 (1,9803,473) Ω) and in patients with physiological acid exposure (3,014 (2,304 3,653) Ω) were higher compared with distal baseline measured at the same time periods in these patients (P<0.001 and P<0.001) and a trend to significance was observed in controls (3,648 (2,8153,932) Ω, P=0.07). Proximal baseline impedance was not significantly different between all the three groups (Figure 2). In GERD patients, a negative correlation between esophageal acid exposure and distal baseline impedance was observed (r=−0.7, P<0.001) (Figure 3). No statistically significant circadian patterns in baseline impedance were observed in these subjects (Figure 4).

Part B: measurements with and without inhibition of gastric acid secretion

Esophageal acid exposure time (% time pH<4) measured off PPI was significantly higher compared with the measurement on PPI (6.2 (2.315.7)% vs. 1.1 (0.65.2)%, (P<0.05). Distal baseline impedance in patients off PPI was significantly lower than in patients on PPI treatment (886 (7161,354) vs. 1,372 (9611,955) Ω, P<0.05) (Figure 5). In healthy volunteers, distal baseline impedance (2,827 (2,1273,270) Ω) was significantly higher than in patients off and on PPI (both P<0.05). Proximal baseline impedance did not differ significantly between the patients off PPI or on PPI (1,793 (1,3842,489) vs. 1,893 (1,6102,561) Ω) (Figure 5). However, proximal baseline impedance was higher off and on PPI compared with distal baseline impedance measured at the same time periods, P<0.05 and P<0.001. Proximal baseline impedance in healthy volunteers was significantly higher compared with patients off and on PPI (both P<0.001).
DISCUSSION
This is the first study in which esophageal baseline impedance levels were studied in detail. We specifically aimed to determine whether there is a difference in baseline impedance levels between GERD patients and controls and between measurements performed with and without inhibition of gastric acid secretion.

In this study, we show that distal baseline impedance levels in GERD patients with pathological acid exposure are markedly lower than those in healthy volunteers and GERD patients with physiological acid exposure. GERD patients with physiological acid exposure also have significantly lower impedance baselines, but the decrease is less pronounced than in patients with pathological acid exposure and an overlap exists.

We hypothesized that esophageal acid exposure correlates with baseline impedance. A negative correlation was observed between esophageal acid exposure time and distal baseline impedance, suggesting that acid exposure indeed affects baseline impedance. Furthermore, the distal baseline impedance levels in healthy controls, which were measured in this study, are comparable to levels reported by other studies ( 10,11 ).

Proximal baseline impedance levels were significantly higher than distal baseline impedance levels in GERD patients. This is in accordance with our hypothesis that acid exposure in GERD patients results in decreased baseline impedance levels since proximal acid exposure is lower than distal acid exposure ( 11 ). In healthy volunteers, we only observed a trend toward higher proximal baselines compared with distal impedance baselines, which could be due to the fact that in healthy controls there is a smaller proportion of reflux episodes that reaches the proximal esophagus than in GERD patients and less reflux in general ( 11 ). We expected to find a difference between proximal baseline impedance levels in GERD patients and healthy controls since GERD patients have more proximal reflux than healthy volunteers ( 11 ), but no significant difference between these groups was found.

Whereas acid exposure time in our patients decreased during the night, we did not find a clear diurnal trend in baseline levels during the 24-h measurement. These results, therefore, suggest that esophageal baseline levels in GERD patients do not recover during the night.

Since we hypothesized that acid reflux lowers baseline impedance levels, we expected that PPI would increase baseline impedance levels. The results from this study confirm that baseline impedance is indeed higher on PPI, which further suggests that baseline impedance is affected by acid exposure.

Despite the fact that these results are in accordance with our hypothesis, it is still possible that a low-baseline impedance is caused by coating of the esophageal wall with gastric content that has a high ionic content. A study that used scintigraphy to visualize the position of postprandial acid pocket demonstrated that coating of the esophageal wall can be detected by a pH electrode. This suggests that esophageal acid coating is unlikely without a concurrent pH drop ( 12 ). We therefore limited the effect of esophageal coating by only determining baseline impedance during periods without reflux or a pH drop. Furthermore, the finding that baseline impedance during the night, even hours after the last reflux episode, is stable and comparable to baseline impedance during the day is suggestive of a mechanism other than coating of the esophageal wall with acidic content. One could also argue that low-baseline impedance is due to altered esophageal motility. Blonski et al. ( 13 ) described that baseline impedance levels in patients with ineffective esophageal motility are lower than those found in healthy controls. However, no information about esophageal acid exposure was presented in that study and, given that impaired motility is associated with pathological acid exposure, the latter could be the true explanation for the observed low impedance levels. Furthermore, baseline impedance values just before swallows and after liquid and viscous swallows were not different, suggesting that these low baselines are more likely to be caused by discrete esophageal changes due to ineffective acid clearing after reflux.

A limitation of our study is that the design did not incorporate systematic assessment of macroscopic or microscopic mucosal changes during the measurement but only presents historical endoscopic and histological data. Therefore, a relation between changes in the esophageal wall and baseline impedance could not be demonstrated. However, several previous studies have demonstrated that DIS can be induced by gastroesophageal reflux, that PPI therapy results in a decrease in DIS, and that macroscopic changes are more common in patients with increased acid exposure (57,14). The patients who were assessed in this study were therefore expected to have reflux-induced changes in the esophageal wall. Furthermore, the first results from a study that links DIS to baseline impedance levels show decreased baseline impedance levels in rabbit esophagus in which DIS was present ( 10 ).

The results from this study warrant further research in which baseline impedance levels are correlated to macroscopic and microscopic changes to the esophagus, such as DIS, to determine the extent to which baseline impedance reflects structural changes to the esophagus. Furthermore, due to the great overlap between the groups and the relatively small number of healthy controls, a lower limit of normal could not be established in this study. Future studies will therefore clarify whether baseline impedance levels can be clinically useful.

Tissue impedance is a technique that aims to measure structural changes in the esophageal wall by measuring its electrical conductivity. These results therefore suggest that the use of tissue impedance in GERD patients could, in theory, provide useful information regarding changes in the esophageal mucosa. Finally, although there is a great overlap between the groups, the change in baseline impedance before and during therapy could, in theory, be a marker for response to therapy. Future studies are warranted to assess whether baseline impedance levels could be a marker for predicting response to therapy.

In conclusion, baseline impedance is related to esophageal acid exposure and baseline impedance levels are often decreased in GERD patients even without pathological esophageal acid exposure. These results suggest that esophageal baseline impedance could be a marker for acid reflux-induced changes to the esophageal mucosa.
Acknowledgments
We thank Mr Jac. Oors for his experienced assistance in the impedance studies.
Conflict of interest
Guarantors of the article: Boudewijn F. Kessing, MD and A.J.P.M. Smout, MD, PhD.

Specific author contributions: Study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analysis, and approval of final submitted draft B.F. Kessing; study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content, and approval of final submitted draft: A.J. Bredenoord; acquisition of data, critical revision of the manuscript for important intellectual content, and approval of final submitted draft: P.W. Weijenborg and G.J.M. Hemmink; study concept, critical revision of the manuscript for important intellectual content, and approval of final submitted draft: C.M. Loots; study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content, and approval of final submitted draft: A.J.P.M. Smout.

Financial support: A.J.B. was supported by the Netherlands Organisation for Scientific Research (NWO).

Potential competing interests: None.
Study Highlights
What is current knowledge
  • Low esophageal baseline impedance levels can lead to diffculties in the interpretation of impedance measurements.
  • Acid infusion in the esophagus results in a decreased baseline impedance level.
What is new here
  • Esophageal acid exposure time correlates with intraluminal baseline impedance levels.
  • Symptomatic gastroesophageal reflux disease (GERD) patients have lower baseline impedance levels than healthy controls, even if acid exposure times are in the physiological range.
  • Baseline impedance levels increase.
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