Gastroesophageal reflux disease (GERD) is a common ALIMENTARY TRACT

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: ALIMENTARY TRACT Use of Direct, Endoscopic-Guided Measurements of Mucosal Impedance in Diagnosis of Gastroesophageal Reflux Disease ELIF SARITAS YUKSEL,* TINA HIGGINBOTHAM,* JAMES C. SLAUGHTER, JERRY MABARY, ROBERT T. KAVITT,* C. GAELYN GARRETT, and MICHAEL F. VAEZI* *Division of Gastroenterology, Hepatology and Nutrition, Department of Biostatistics, Vanderbilt Medical Center, Nashville, Tennessee; Sandhill Scientific, Inc, Denver, Colorado; and Vanderbilt Voice Center, Nashville, Tennessee BACKGROUND & AIMS: Diagnostic tests for gastroesophageal reflux disease (GERD) are constrained because measurements are made at a single time point, so the long-term effects on the mucosa cannot be determined. We developed a minimally invasive system to assess changes in esophageal mucosal impedance (MI), a marker of reflux. We measured the extent of changes in MI along the esophagus and show that the device to assess MI can be used to diagnose patients with GERD. METHODS: A single-channel MI catheter composed of a unique sensor array was designed to easily traverse the working channel of an upper endoscope. We performed a prospective longitudinal study of patients with erosive esophagitis (n 19), nonerosive but ph-positive GERD (n 23), and those without GERD (n 27). MI was measured at the site of esophagitis as well as 2, 5, and 10 cm above the squamocolumnar junction. The MI values were compared among groups, at different levels along the esophageal axis. RESULTS: Median MI values were significantly lower at the site of erosive mucosa (811 ; range, ) than other nonerosive regions (3723 ; range, ; P.001), and were significantly lower at 2 cm above the squamocolumnar junction in patients with GERD (2096 ; range, ), compared with those without GERD (3607 ; range, ; P.008). There was a significant and graded increase in MI along the axis of the distal to proximal esophagus in patients with GERD that was not observed in individuals without reflux (P.004). CONCLUSIONS: Measurements of MI along the esophagus can be used to identify patients with GERD. Clinical- Trials.gov, number NCT Keywords: Mucosal Integrity; Chronic Reflux Damage; Acid; GERD. Gastroesophageal reflux disease (GERD) is a common chronic condition that results in a significant reduction in health-related quality of life and high costs to the US health care system. 1 3 GERD afflicts more than 100 million US adults and imposes more than $9 billion per year in total health care costs. 4,5 Empiric acid-suppressive therapy is the initial approach for patients with suspected GERD and diagnostic tests usually are reserved for those unresponsive to this approach. 6,7 Over the years, the demand for diagnostic testing has increased as the prevalence of patients with partial or no response to empiric therapy has grown. 8,9 The current diagnostic tests for GERD are suboptimal because of limited sensitivity and specificity, 10,11 and they are constrained by measurement of esophageal reflux during a single time point at a specified location. Esophageal mucosal injury detected by endoscopic evaluation is present in less than 30% of patients. 12 Ambulatory ph and impedance monitoring only measure reflux activity during the testing period (24 48 h), which often may be impacted by patient compliance to routine daily activity and is hampered by catheter discomfort. 5,13,14 These ambulatory reflux monitoring devices have acceptable sensitivity (77% 100%) and specificity (85% 100%) in patients with endoscopic esophagitis 10 ; however, they are less sensitive (0% 71%) among endoscopy-negative patients. 11 More importantly, these tests measure the presence of reflux but do not measure the long-term mucosal consequences of GERD, a significant limitation of existing platforms. The presence of dilated intercellular spaces within the esophageal squamous mucosa is suggested as a sensitive marker of GERD in patients with esophagitis 15,16 or in those with nonerosive reflux disease This observation is based on animal studies suggesting an increase in paracellular permeability of the esophageal lumen owing to exposure to acid and pepsin 18 as well as weakly acidic material. 19 However, the role of dilated intercellular spaces in the diagnosis of GERD remains unknown given the uncertainty of optimal biopsy site, the need for expensive and not widely available transmission electron microscopy, and recent contradictory findings. 20 Measurement of esophageal intraluminal potential difference by the multichannel intraluminal impedance technique recently has suggested low intraluminal impedance baseline for patients with GERD compared with controls. 21 However, this finding is based on measurements from the traditional catheter-based ambulatory 24-hour measurement of esophageal luminal impedance. This involves an indirect measure of mucosal conductivity and measurements are at a fixed location along the esophagus. There are no existing techniques to accurately, reliably, and directly measure the mucosal consequences of chronic esopha- Abbreviations used in this paper: EGD, esophagogastroduodenoscopy; DIS, dilated intercellular spaces; GERD, gastroesophageal reflux disease; IQ, interquartile range; MI, mucosal impedance; SCJ, squamocolumnar junction by the AGA Institute /$

2 October 2012 MUCOSAL IMPEDANCE 1111 geal exposure to injurious gastroduodenal agents. A simple, low-cost, accurate, and minimally invasive test is needed to assess the impact of GERD in endoscopic normal-appearing mucosa. Such a test could greatly improve medical management and quality of life, while potentially reducing health care costs. To that end, we conducted a study using an initial preprototype mucosal impedance (MI) catheter with a unique impedance sensor array, which was applied directly to the mucosal surface to reliably measure the esophageal MI pattern. Our aims were as follows: (1) to identify and directly measure the extent of MI changes along the esophageal axis; and (2) to show the feasibility of the MI device in differentiating between normal and damaged tissue in GERD from non-gerd populations. Materials and Methods This study was performed in accordance with the Declaration of Helsinki, Good Clinical Practice, and applicable regulatory requirements. The Vanderbilt Institutional Review Board approved this clinical trial (Institutional Review Board number ). Study Design and Patient Population We conducted a prospective longitudinal study to assess the clinical utility of a minimally invasive technology by directly measuring esophageal mucosal impedance during a routine esophagogastroduodenoscopy (EGD) in patients with objective GERD compared with those without GERD. Patients with upper gastrointestinal symptoms referred for the possibility of GERD as the etiology constituted the study population. Presenting symptoms included heartburn, regurgitation, epigastric pain, chronic cough, laryngitis, and asthma. Patients were excluded if they had dysphagia, Barrett s esophagus, history of prior esophageal surgery or gastrointestinal cancer, peptic ulcer disease, or if they did not discontinue the use of proton pump inhibitors 10 days before endoscopy and histamine-receptor antagonists 7 days before endoscopy. All participants completed a detailed questionnaire assessing current and past medical history; current medication use and demographic data (age, sex, and race); presence, severity, and frequency of GERD (heartburn/regurgitation); extraesophageal symptoms (cough, hoarseness, throat clearing, sore throat, globus sensation, heartburn, regurgitation, chest pain, and discomfort with phonation); history of smoking, and alcohol use. All participants subsequently underwent EGD and wireless ph testing to assess for esophagitis, to measure the degree of esophageal acid exposure over a 48-hour period, and to measure esophageal mucosal impedance while off acid-suppressive therapy. Before placement of the wireless ph capsule, the MI catheter was traversed through the working channel of the endoscope and direct contact mucosal impedance measurements were obtained by touching the MI sensors to the esophageal lining. Measurements were taken at 2, 5, and 10 cm above the squamocolumnar junction (SCJ) relative to the lesser curvature of the stomach and directly measured at the site of eroded mucosa if there was evidence of erosive esophagitis (Figure 1A). MI measurements were obtained continuously for 5 seconds at each location and the median of the measurements for each location was used for analysis. MI measurements were recorded without knowledge of the wireless ph results. Based on endoscopic and ph monitoring data, patients were divided into 3 groups, as follows: (1) erosive esophagitis (E ), (2) nonerosive mucosa with abnormal ph (E /ph ), and (3) nonerosive mucosa with normal ph (E /ph ). The MI values among the groups were compared with each other and at different levels along the esophageal axis (Figure 1A). Mucosal Impedance Measurements A newly designed MI catheter (Figure 1B) was engineered to measure electrical impedance of the esophageal lining by direct mucosal contact. A special sensor array composed of 360 circumferential sensing rings (Sandhill Scientific, Inc, Highlands Ranch, CO) was engineered and mounted on a 2-mm diameter catheter (Figure 1B) with the following specifications: (1) ring length of 2 mm, (2) ring separation of 2 mm, (3) end of distal ring mounted 1 mm away from the tip of the catheter, and (4) a soft catheter easily traversable through the working channel of an upper endoscope. The electrodes were connected to an impedance voltage transducer at the bedside via thin wires, which ran the length of the catheter. The voltage generated by the transducer was limited to produce at most 10 A of current. The frequency for the measuring circuit was set at 2 khz. Impedance measurements of the esophageal mucosa were expressed in ohms as the ratio of voltage to the current. Data were acquired with a stationary impedance data acquisition system (InSight; Sandhill Scientific, Inc) and were viewed and analyzed on BioView Analysis software (Sandhill Scientific, Inc). Unique specifications for the new catheter relative to the traditional multichannel esophageal impedance/ph catheter are highlighted in Figure 1B. Wireless ph Monitoring Ambulatory ph monitoring was performed for 48 hours using Bravo wireless ph monitors (Given Imaging, Duluth, GA). Study patients were instructed to discontinue all proton pump inhibitors for 10 days and histamine-receptor antagonists for 7 days before undergoing evaluation. Wireless capsules were calibrated by submersion in buffer solutions at ph 7.0 and ph 1.0 and then activated by magnet removal. Patients underwent EGD with deep sedation (propofol) for visual anatomic inspection and collection of distance measurements from the incisors to the SCJ. Wireless ph capsules then were placed as previously described. 22 Measurements of the total, upright, and supine percentage time when esophageal ph was less than 4 were determined over day 1 and day 2 of the wireless ph study. Acid exposure time (% time ph 4) greater than 5.3% per day was considered abnormal. 23 Statistical Analysis Data were collected and stored at the secure web-based Vanderbilt Digestive Disease Center REDCap database (Research Electronic Data Capture) (1 UL1 RR NCRR/ National Institutes of Health). There was strict control and supervision of the data entry and access to study data. To determine sample sizes for the groups, we used preliminary data to fit 3 multivariable linear regression models using the impedance value at the site of esophageal injury, at 2 or 5 cm above the SCJ, as the outcome of interest. All models included covariates for esophagitis status and controlled for impedance value at 10 cm to improve precision. From these models, we found that the root mean squared error from each

3 1112 SARITAS YUKSEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 10 Figure 1. Schematic representation of MI catheter. (A) Two 2-mm long impedance sensing electrodes positioned 1 mm from the tip of a 2-mm soft catheter advanced through an upper endoscope. MI measurements obtained by direct mucosal contact of sensors at the site of esophagitis (if present) and 2, 5, and 10 cm above the SCJ. (B) Photograph of the MI catheter (inset photo) and schematic comparison of the MI catheter with the traditional multichannel impedance-ph catheter. model was 1201 (at the site of esophagitis), 1223 (2 cm above the SCJ), and 1513 (5 cm above the SCJ). To determine the appropriate sample size, we used the most conservative estimate of the standard deviation, 1513, while holding power constant at 80% and using a significance level of Thus, based on this model, 60 patients (20 patients in each group) provided 80% power to detect a difference of 1400 in impedance values between the groups (.025). Subject characteristics were described using medians and interquartile ranges for continuous variables and proportions for categoric variables. Statistical

4 October 2012 MUCOSAL IMPEDANCE 1113 Table 1. Demographic Data of the Study Population Erosive esophagitis Nonerosive (E ) (n 19) Abnormal ph (E /ph ) (n 23) Normal ph (E /ph ) (n 27) P a Age, y b 54 (38 62) 53 (46 60) 54 (44 63).94 Sex, % male Race, % white Body mass index b 30 (27 32) 29 (26 33) 26 (23 34).23 Complaints, % HB/regurgitation Chronic cough Hoarseness Throat clearing Time ph 4, % b Total 8.1 ( ) 8.7 ( ) 1.5 ( ).001 Upright 8 ( ) 10.9 ( ) 2.6 ( ).001 Supine 8.1 ( ) 6.1 ( ) 1.1 ( ).001 a According to the Kruskal Wallis test. b Median (interquartile range) shown. differences in outcomes among groups (E, E /ph, and E /ph) and different esophageal sites were assessed using the Kruskal Wallis test or the Pearson chi square test. Receiver operator characteristic (ROC) curves were used to summarize the sensitivity and specificity of MI to predict GERD (E or E /ph ) at all possible cut-off points. The area under the ROC curve was estimated with a 95% confidence interval to evaluate the predictive accuracy of mucosal impedance. Hypothesis tests were considered significant if the P value was less than.05. (811 ; ) than other nonerosive regions (3723 ; ) (Figures 2 and 3). In addition, the median (IQ) MI measurements were significantly (P.008) less at 2 cm above the SCJ for patients with objective evidence of reflux (E and E /ph ) (2096 ; ; and 2158 ; , respectively) than those with no objective evidence of reflux (E /ph ) (3607 ; )(Figure 3). A similar but not statistically significant trend (P.18) also was observed at 5 cm above the SCJ (Figure 3); however, the MI measurements were Role of Industry The protocol was an independent investigator-initiated study by the principal investigator (M.F.V.). Sandhill Scientific, Inc, helped design the novel mucosal impedance catheter used in this study. Their involvement in the study was limited to providing technical support and catheter design and had no role in the study protocol, conduct, statistical analysis, manuscript preparation, interpretation, or decision to submit the manuscript for publication. Results Demographics Sixty-nine patients constituted the study population: 19 with erosive esophagitis (E ) (LA grade A, 10; grade B, 6; grade C, 2; and grade D, 1); 23 with nonerosive mucosa and abnormal ph (E /ph ), and 27 with nonerosive mucosa and normal ph (E /ph ) (Table 1). There was no difference among the groups with respect to age, race, presenting symptoms, or body mass index status; however, patients with erosive esophagitis were more likely to be male (P.046). Patients with GERD (E and E /ph groups) had significantly (P.001) greater acid reflux exposure (total, upright, and supine % time ph 4) than those without GERD (E /ph group) (Table 1). Mucosal Impedance Median (interquartile range [IQ]) MI measurements were significantly (P.001) lower at the site of erosive mucosa Figure 2. Median (IQ) mucosal impedance measurements ( ) among the study groups. MI measurements were significantly (P.001) lower at the site of erosive mucosa than other nonerosive regions. In addition, the median (IQ) MI measurements were significantly (P.008) less at 2 cm above the SCJ for patients with objective evidence of reflux (E and E /ph ) than those with no objective evidence of reflux (E /ph ).

5 1114 SARITAS YUKSEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 10 Figure 3. The median MI measurements for the study groups at each of the measured sites (mucosal injury, 2, 5, and 10 cm above the SCJ). MI measurements were lowest at the site of mucosal lesion followed by measurements at 2 cm above the SCJ for those with objective GERD (E and E /ph ). A similar but not statistically significant trend (P.18) also was observed at 5 cm above the SCJ for the 2 groups. However, the MI measurements were similar for the 3 groups at 10 cm above the SCJ. Patients without objective GERD (E /ph ) showed similar MI measurements at 2, 5, and 10 cm above the SCJ. similar for the 3 groups at 10 cm above the SCJ (E, 4339 ; ; E /ph, 4292 ; ; E /ph-, 3972 ; ). Importantly, there was a significant (P.004) and graded increase in median (IQ) MI axially along the esophagus from distal (2 cm above the SCJ) to proximal (10 cm above the SCJ) in patients with objective reflux (E and E / ph ) that was not present in those without reflux (E /ph ) (Figure 3). ROC analysis revealed a sensitivity of 88% and a specificity of 65% for MI threshold of 3200 for the diagnosis of objective GERD (abnormal ph and/or esophagitis). There were no complications associated with the MI catheter use and it added on average 2 additional minutes to the time needed to perform endoscopy. Discussion In this prospective study we showed the feasibility of an innovative MI measurement device in differentiating patients with GERD from those without GERD. Important observations from our study include the following: (1) eroded esophageal mucosa caused by GERD, on average, has nearly 80% lower MI than normal tissue, (2) nonerosive GERD patients show a similar pattern of MI along the axial distribution of the esophagus as those with erosive disease, and (3) this pattern does not exist in those without objective evidence of GERD. Based on the findings in our study, we propose that the mucosal changes associated with chronic GERD may occur in a graduated manner along the esophageal axis, which can be measured by our simple, minimally invasive MI device (Figure 4). Patients with severe reflux-causing esophageal mucosal erosions (Figure 4A) would be expected to have a more pronounced reduction in MI as a marker of decreased mucosal integrity. The findings would be expected to be similar, although attenuated, for those with reflux but without mucosal injury (Figure 4B). Patients without evidence of objective reflux whose symptoms may be caused by non-gerd factors would not be expected to have MI variation along the esophageal axis (Figure 4C). The distinct advantage of our proposed technique is its ability to measure the chronic impact of GERD on esophageal epithelial integrity via direct contact mucosal impedance measurements. Current clinically used diagnostic tests for GERD all rely on single time-point analyses for a condition that is chronic in nature. Endoscopic assessment of esophageal mucosa for possible erosion is highly specific; however, it lacks sensitivity because only 10% 30% of GERD patients show erosive disease. 8,10,24 In addition, given the widespread availability of acidsuppressive agents, many patients have normal-appearing mucosa at endoscopy. The current ambulatory reflux-detection tests including ph monitoring (catheter or wireless) and multichannel intraluminal impedance/ph monitoring are limited in that they measure reflux events only over a 1- to 2-day period and assess acid exposure at a single location (5 cm above the lower esophageal sphincter), thus providing only a snapshot measurement of esophageal luminal acid exposure. Most importantly, the catheter-based ph or impedance monitoring devices by their invasive and uncomfortable nature result in alteration of patient daily activity influencing the outcome they intend to measure. No existing techniques accurately and reliably measure the mucosal consequence of chronic esophageal exposure to injurious gastroduodenal agents. As such, our data lay the foundation for in-depth investigation into direct measurements of MI as an alternative and innovative method for detecting GERD and its chronic impact on esophageal mucosa. Figure 4. Proposed mucosal changes associated with chronic GERD based on MI measurements in this study. We speculate that esophageal mucosa exposed to chronic injurious gastroduodenal refluxate would show graduated changes along the esophageal axis, which can be measured by the simple, minimally invasive MI device. Patients with severe reflux-causing esophageal mucosal erosions (A) would be expected to have a more pronounced reduction in MI as a marker of decreased mucosal integrity. (B) The findings would be expected to be similar, although attenuated, for those with reflux but without mucosal injury. (C) Patients without objective reflux whose symptoms may be caused by non-gerd factors would not be expected to have MI variation along the esophageal axis.

6 October 2012 MUCOSAL IMPEDANCE 1115 Simple and convenient means of measuring the chronic signature of reflux on the esophageal epithelium will advance the field of GERD diagnostics. Such a test may identify patients likely to benefit from GERD therapies, reduce unwarranted use of acid-reduction medications in those who do not have the disease, and could provide a simple way to monitor mucosal health pretherapy and post-therapy. Investigations into alteration of esophageal mucosal integrity owing to chronic reflux may play a key role in identifying such a tool. Healthy esophageal epithelium has low permeability to intraluminal materials as a result of integrity of cell membranes and tight junctions; however, injurious agents such as acid, pepsin, and/or bile acids may degrade epithelial integrity. Esophageal mucosal exposure to acid reflux is shown to decrease the potential difference and epithelial resistance while increasing small molecule permeability 25 with subsequent dilated intercellular spaces (DIS) detected by transmission electron microscopy. 17,19,26 30 Distal esophageal biopsy specimens from patients with GERD are reported to have significantly wider intercellular spaces compared with controls. 15 Subsequent studies also have suggested reversibility of DIS after acid-suppressive therapy. 28 However, several important constraints limit the use of this technique in GERD diagnosis. DIS is sensitive but not specific for GERD and can occur under stress, 31 in up to 30% asymptomatic healthy subjects, in the setting of food allergy, and in other esophageal disorders such as Candida infection. 32 A recent study has questioned the uniform presence of DIS in patients with GERD. 20 Furthermore, it is not distributed homogeneously in the esophagus of GERD patients because there is a radial and axial variation in its distribution. 30 Finally, the need for expensive and not widely available expertise-dependent technology of electron microscopy has limited the use of DIS in GERD to only academic centers with special interest in esophageal diseases. Impedance/pH monitoring traditionally has been used to determine the degree of acid and nonacid reflux in patients suspected of having GERD. The principle of impedance measurement depends on changes in resistance to an alternating current circuit between 2 metal electrodes (impedance measuring segments). The conventional impedance/ph catheters measure intraluminal impedance based on the presence of liquid or gas within the esophageal lumen using 4-mm sensor rings separated by 1.6 cm and measuring segments at 3, 5, 7, 9, 15, and 17 cm above the manometric lower esophageal sphincter. Initial studies using these catheters suggested that patients with intestinal metaplasia (Barrett s esophagus) or mucosal disruption (esophagitis) had lower intraluminal impedance values. 33,34 Moreover, recent studies suggested that baseline intraluminal impedance measurements may be related inversely to degree of esophageal acid exposure. 35 Most recently, a study of 8 patients with erosive esophagitis, 18 patients with nonerosive reflux, and 15 healthy volunteers suggested a lower intraluminal impedance in those with GERD than in healthy volunteers, suggesting a role for this device in monitoring mucosal integrity. 21 In addition, a recent study in infants with GERD suggested that intraluminal impedance increases after proton pump inhibitor therapy. 36 Taken together, these studies suggest reflux-related changes are detectable via intraluminal impedance in patients with GERD. However, we believe that the earlier-described observations performed crudely without confirmation of direct impedance sensor mucosal contact were indirect measurements of mucosal integrity. Our novel approach and technology provided confirmed and controlled mucosal impedance assessment via direct contact and short-duration MI performed during endoscopy without the need for 24-hour long, uncomfortable, catheter-based devices. An important limitation of this study should be highlighted. The catheter used in our study contained only 2 impedance rings, forming a single MI sensing channel. It provided measurements along the esophagus at each of the sites: esophagitis, 2, 5 and 10 cm above the SCJ. The catheter was repositioned manually from one site to the next along the esophagus, which may have resulted in measurement variability. This unavoidable shortcoming will be corrected by the next generation of MI catheters with many sensors positioned axially along the esophagus to measure the mucosal impedance simultaneously without the need for manual repositioning. Despite this limitation the sensitivity and specificity of the current device is similar to the available technology without the need for prolonged monitoring by uncomfortable catheter-based devices. The measurements can be taken during endoscopy while the patient is sedated. Future refinements are expected to improve both the sensitivity and specificity of the device, making it the diagnostic test of choice in GERD. In conclusion, we have developed a novel, minimally invasive, short-duration MI technique for detecting esophageal mucosal changes caused by chronic GERD without the need for 24- to 48-hour ambulatory impedance ph catheter placement. 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7 1116 SARITAS YUKSEL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No Vaezi MF, Schroeder PL, Richter JE. Reproducibility of proximal probe ph parameters in 24-hour ambulatory esophageal ph monitoring. Am J Gastroenterol 1997;92: Vaezi MF. Role of impedance/ph monitoring in refractory gerd: let s be careful out there! Gastroenterology 2007;132: Tobey NA, Carson JL, Alkiek RA, et al. Dilated intercellular spaces: a morphological feature of acid reflux-damaged human esophageal epithelium. Gastroenterology 1996;111: Caviglia R, Ribolsi M, Gentile M, et al. Dilated intercellular spaces and acid reflux at the distal and proximal oesophagus in patients with non-erosive gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2007;25: Caviglia R, Ribolsi M, Maggiano N, et al. Dilated intercellular spaces of esophageal epithelium in nonerosive reflux disease patients with physiological esophageal acid exposure. Am J Gastroenterol 2005;100: Orlando RC, Bryson JC, Powell DW. Mechanisms of H injury in rabbit esophageal epithelium. Am J Physiol 1984;246:G718 G Farré R, Fornari F, Blondeau K, et al. Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus. Gut 2010;59: Vaezi MF, Slaughter JC, Smith BS, et al. Dilated intercellular space in chronic laryngitis and gastro-oesophageal reflux disease: at baseline and post-lansoprazole therapy. Aliment Pharmacol Ther 2010;32: Farré R, Blondeau K, Clement D, et al. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 2011;60: Pritchett JM, Aslam M, Slaughter JC, et al. Efficacy of esophageal impedance/ph monitoring in patients with refractory gastroesophageal reflux disease, on and off therapy. Clin Gastroenterol Hepatol 2009;7: Pandolfino JE, Richter JE, Ours T, et al. Ambulatory esophageal ph monitoring using a wireless system. Am J Gastroenterol 2003;98: Falk GW. Refractory GERD: further insights into the cause of symptoms. Gastroenterology 2008;135: Tobey NA, Hosseini SS, Argote CM, et al. Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium. Am J Gastroenterol 2004;99: Carney CN, Orlando RC, Powell DW, et al. Morphologic alterations in early acid-induced epithelial injury of the rabbit esophagus. Lab Invest 1981;45: Orlando RC, Powell DW, Carney CN. Pathophysiology of acute acid injury in rabbit esophageal epithelium. J Clin Invest 1981; 68: Calabrese C, Bortolotti M, Fabbri A, et al. Reversibility of GERD ultrastructural alterations and relief of symptoms after omeprazole treatment. Am J Gastroenterol 2005;100: Calabrese C, Fabbri A, Bortolotti M, et al. Dilated intercellular spaces as a marker of oesophageal damage: comparative results in gastro-oesophageal reflux disease with or without bile reflux. Aliment Pharmacol Ther 2003;18: Edebo A, Vieth M, Tam W, et al. Circumferential and axial distribution of esophageal mucosal damage in reflux disease. Dis Esophagus 2007;20: Farré R, De Vos R, Geboes K, et al. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut 2007;56: van Malenstein H, Farré R, Sifrim D. Esophageal dilated intercellular spaces (DIS) and nonerosive reflux disease. Am J Gastroenterol 2008;103: Al-Zaben A, Chandrasekar V. Effect of esophagus status and catheter configuration on multiple intraluminal impedance measurements. Physiol Meas 2005;26: Vela MF. Multichannel intraluminal impedance and ph monitoring in gastroesophageal reflux disease. Expert Rev Gastroenterol Hepatol 2008;2: Kessing BF, Bredenoord AJ, Weijenborg PW, et al. Esophageal acid exposure decreases intraluminal baseline impedance levels. Am J Gastroenterol 2011;106: Loots CM, Van Wijk MP, Smits MJ, et al. Measurement of mucosal conductivity by MII is a potential marker of mucosal integrity restored in infants on acid-suppression therapy. J Pediatr Gastroenterol Nutr 2011;53: Reprint requests Address requests for reprints to: Michael F. Vaezi, MD, PhD, MSc(Epi), Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 1660 TVC, nd Avenue South, Nashville, Tennessee Michael.vaezi@vanderbilt. edu; fax: (615) Conflicts of interest This author discloses the following: Jerry Mabary is affiliated with Sandhill Scientific, Inc, which helped design the special mucosal impedance catheter used in this study. His involvement in the study was to provide technical support for the catheter design. He had no influence on the study design, conduct, analysis, or the final manuscript. Sandhill provided pilot feasibility funding for the conduct of this study. Vanderbilt University and Sandhill jointly hold a patent on the mucosal impedance concept and device. This was disclosed to patients. The remaining authors disclose no conflicts.