Gastroesophageal Reflux Evaluation in Patients Affected by Chronic Cough: Restech Versus Multichannel Intraluminal Impedance/pH Metry

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1 The Laryngoscope VC 2012 The American Laryngological, Rhinological and Otological Society, Inc. Gastroesophageal Reflux Evaluation in Patients Affected by Chronic Cough: Restech Versus Multichannel Intraluminal Impedance/pH Metry Dario Ummarino, MD; Liv Vandermeulen, MD; Bart Roosens, MD; Daniel Urbain, MD, PhD; Bruno Hauser, MD; Yvan Vandenplas, MD, PhD Objectives/Hypothesis: Oropharyngeal (OP) ph monitoring has been developed to detect supra-esophageal gastric reflux (SEGR). The results obtained with OP ph-metry and multichannel intraluminal impedance/ph monitoring (MII/pH) were compared. Study Design: Diagnostic study. Methods: Ten patients (age years) presenting with chronic coughing underwent simultaneous OP and MII/pH recording. A 2-minute interval was allowed between events detected with both techniques to be considered simultaneous. Results: A total of 515 reflux episodes were recorded with MII/pH (acid: 181; weakly acid: 310; weakly alkaline: 24); 180 (35%) reached the highest impedance channel (hypo-pharynx); 74/180 (41%) were not related to a change in ph, according to the antimony electrode of the MII/pH catheter located at the upper esophageal sphincter. The OP monitoring measured 39 acid events; 17 (43.6%) were swallows according to MII, and 15 (38.5%) were not associated with MII or ph change. Only seven episodes were detected simultaneously with both techniques (1.3% for MII vs. 18% for OP; P ¼ ). We found 49 ph-only refluxes at the ph sensor in the hypo-pharynx with MII/pH; only three (6.1%) correlated with OP reflux. Correlation in time between cough and reflux events was positive in 5/10 patients for MII (symptom index 5/10, symptom association probability 4/10), but in 0/10 patients according to OP ph metry. Conclusion: OP ph metry detected less reflux episodes than MII/pH; 35% of the OP events were swallows according to impedance. Time correlation between cough and reflux could not be demonstrated with OP ph metry. Key Words: Chronic cough, multichannel intraluminal impedance, ph monitoring, Restech. Level of Evidence: 4 Laryngoscope, 123: , 2013 INTRODUCTION According to recent evidence-based consensus statements, gastroesophageal reflux disease (GERD) can be categorized in esophageal and extra-esophageal symptoms. 1,2 One of the most important proposed mechanisms of extra-esophageal manifestations is the passage of gastric refluxate into areas above the protection of the upper esophageal sphincter (UES), also known as supra-esophageal gastric reflux (SEGR), causing macro- and microaspiration. 3 The group of patients with extra-esophageal symptoms such as hoarseness, From the Department of Pediatrics (D.U., B.H., Y.V.); the Department of Gastroenterology (L.V., B.R., D.U.), UZ Brussel, Brussels, Belgium; the Department of Pediatrics (D.UR.), University of Naples Federico II, Naples, Italy. Editor s Note: This Manuscript was accepted for publication on August 22, The Restech VR company has donated the device for this research. Yvan Vanderplas, MD, is a consultant for United Pharmaceuticals and Biocodex. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Yvan Vandenplas, MD, Department of Pediatrics, UZ Brussel, Vrije Unversiteit Brussel, Laarbeeklaan, 101, 1090, Brussels, Belgium. yvan.vandenplas@uzbrussel.be DOI: /lary cough, and sore throat, and who have signs of laryngeal irritation on laryngoscopy, are considered to suffer laryngopharyngeal reflux (LPR). 3 The laryngoscopic findings in LPR, such as erythema and edema, are nonspecific signs of laryngeal irritation. LPR is in many cases a diagnosis of exclusion. 3 The association between reflux and extra-esophageal symptoms is well established, 4,5 but proof of a clear, causal relationship has failed. Consequently, although SEGR is commonly implicated in patients presenting with symptoms suggesting extra-esophageal symptoms, formal diagnosis and management remains clinically challenging. Abnormal distal esophageal acid exposure on ph monitoring can indicate the presence of pathologic GERD, but does not provide proof of causality for extraesophageal symptoms. 2 Extra-esophageal symptoms alone, or the analysis of classic ph-metry in the distal esophagus, are not suitable for the diagnosis of SGER. Several studies used proximal esophageal ph analysis as a diagnostic test of SGER. 3,6,7 The measurement of drops in proximal esophageal ph <4 has not been shown to predict therapy response. 8 Current diagnostic methods are limited due to the lack of consensus regarding the optimal criteria for

2 SEGR. The minimum amount of supra-esophageal acid exposure needed to produce clinically significant pathologic changes is unknown, but a SEGR event is conventionally defined as a drop in proximal ph < 4.0, in association with a preceding or simultaneous distal reflux event. 3 Normal ranges for ph < 4.0 at the proximal level have been established, 9 but these have not been shown to predict therapeutic outcome. Episodes with a ph < 4.0 have been proposed as the best discriminating factor between patients with and without heartburn caused by (acid) reflux. Whether episodes with a ph < 4.0 are an appropriate criterion to measure SEGR can be questioned. It has been observed that about 30% of acid refluxate has a ph > 4.0 when it reaches the proximal esophagus. 10 Data have shown that non-acid reflux with a ph between 4.0 and 7.0 (now called weakly acid reflux ) may contribute to airway and respiratory disease The traditional cutoff of ph <4 for SEGR may actually underestimate the presence of clinically significant reflux. Several recent studies have suggested using higher ph cutoffs for proximal ph monitoring. Ayazi et al. proposed to use ph < 5.5 in upright position and ph < 4.5 in supine position as cutoffs for SEGR. 14 Wiener et al. used a rapid (0.5 2 seconds) drop in oropharyngeal ph of at least 10% from the ph baseline as a definition for SEGR. 15 The Restech VR Dx-pH sensor is a transnasal catheter with an ion flow sensor able to measure the ph of both liquid and aerosolized droplets, and which is located in the posterior oropharynx (OP). The hypothesis is that direct measurement of OP ph may provide an accurate diagnostic tool for SEGR, compared with current methods. The aim of this study was to monitor OP ph with the Restech Dx-pH sensor in patients affected by chronic cough, and to evaluate the correlation between changes in OP ph and GER events detected by an antimony electrode placed at the upper esophageal sphincter (UES) region and with multichannel intraluminal impedance (MII-pH) monitoring. MATERIALS AND METHODS Participation in the study (simultaneous Restech and MII/ ph) was proposed to consecutive patients that were sent in for MII/pH because of unexplained chronic cough between January and July 2011, and in whom respiratory and cardiac problems had been excluded. Additional exclusion criteria included the inability to tolerate placement of two intranasal probes. Patients were not on reflux treatment. The study was approved by the local Ethical Committee of the UZ Brussel. Written informed consent was obtained from each patient prior to enrollment in the study. The MII/pH recording was performed with a portable data logger and a combined impedance-ph catheter (Sleuth ambulatory system, Sandhill Scientific, Inc; Highland Ranch, CO). The probe was placed transnasally; the location of the probe was determined with fluoroscopy. The six impedance channels were located 3, 6, 9, 12, 15, and 18 cm from the distal tip of the MII/ PH probe; the ph sensors were placed at the level of the UES and 5 cm above the diaphragm. TheRestechDx-pHprobe(Respiratory Technology Corp., San Diego, CA) is a transnasal, antimony tear-drop shaped ph sensor, designed to aid in maintenance of moisture saturation of the sensor from exhaled breath condensation on the tip surface. A colored light-emitting diode (LED) at the tip aids in transoral visualization during placement. Shortly after the esophageal MII-pH probe was placed, the Restech probe was inserted into the same nostril until the flashing LED was seen in the back of the patient s throat, and then positioned so that the LED was at the level of the uvula. Oropharyngeal ph tracings were also manually analyzed by the same investigator(d.ummarino).thenumberofrefluxepisodesaccording to the OP ph metry was analyzed using an OP ph drop < 5.5 as the definition for SEGR. 3 The internal clocks of both data loggers were synchronized just before the start to assure simultaneous monitoring of a 24- hour MII-pH and OP ph recording. All patients registered symptoms, meals and drinks, and position changes in a diary. After appropriate placement of both sensors, data recording was started. Subjects were discharged and were encouraged to maintain normal activities and sleep schedule, and to eat their usual meals (avoiding acid). All subjects tolerated the procedure well without incident or complications. All activities and symptoms were registered in a specific diary and on the data logger through specific markers. Once the esophageal and OP monitoring studies were completed, both catheters were removed. Data from both digital recorders were downloaded. The MII-pH data were analyzed by one author (D. Ummarino) with commercially available software (BioView Analysis, Sandhill Scientific, Highlands Ranch, CO; DataView Lite, Respiratory Technology Corp.). Restech information was analyzed by the same coauthor (D. Ummarino) using a dedicated software program (AEMC Instruments, Foxborough, MA). Periods of meals and drinks were excluded from the analysis. Each MII-pH tracing was manually analyzed by one investigator (D. Ummarino). A bolus-liquid reflux is defined as a retrograde drop in impedance of at least 50% of the baseline in at least two distal impedance channels (3 consecutive rings). The end of a reflux episode is defined as the moment when the impedance value returned to at least 50% of the initial (baseline) value. Acid reflux is a reflux episode with a ph < 4.0; weakly acid reflux has a ph 4.0 but 7.0; the ph of weakly alkaline reflux is > 7.0. Swallows were defined as a rapid fall in impedance of > 50% that started at the highest channel. Gas-only reflux is characterized by an increase in impedance >3000 ohms in any two consecutive impedance sites, with one site having an absolute value >7000 ohms. Mixed reflux events are a combination of both liquid and gas patterns. Full-column reflux was defined as an episode that reached the highest pair of impedance sensors. For the MII-pH recording, a ph episode was defined as a fall in distal ph to < 4.0 lasting at least 5 seconds, detected by a ph sensor. Since the aim of the study was the comparison between both techniques, we did not make a group with normal and abnormal GER. The correlation between OP ph and esophageal MII-pH was determined based on the temporal relationship between OP and esophageal reflux events. The OP ph data were compared with the ph data recorded at the UES with the MII/pH in order to evaluate the correlation between the two ph sensors. The same comparison was done between the OP ph and impedance data. A time-interval of 2 minutes was allowed between Restech and MII/pH episodes to be considered simultaneous episodes. All symptoms recorded by the patients, written in the diary or recorded by pushing the event marker(s), were considered. Since chronic cough was the inclusion criterion, almost all symptoms referred to coughing episodes. To evaluate the correlation in time, we calculated the symptom index (SI). The SI is the percentage of GER-associated symptoms divided by the total 981

3 number of symptoms. A SI of 50% usually is used as the lower limit of significance. For the symptom association probability (SAP), the total measuring time is subdivided into 2-minute intervals, and a contingency table with four fields is established: 1) number of intervals with GER and symptom, 2) number of intervals with GER and without symptom, 3) number of intervals without GER and with symptom, and 4) number of intervals without GER and symptom. Fisher s exact test is then used for statistical analysis of correlation. A positive SAP (> 95%) is interpreted as a proof of a temporal association between GER and the recorded symptom. RESULTS We analyzed the MII/pH registrations in 10 consecutive patients (mean age 6 SD: years old; range years) with chronic unexplained cough send in for a MII-pH recording. The two probes were well tolerated by all patients. The mean duration of the recording was hours (range hours). In the 10 patients, MII/pH detected a total of 515 reflux episodes: 181 acid (35%), 310 weakly acid (60%) and 24 weakly alkaline (5%). Of these episodes, 180 (35%), of whom 106 (59%) were acid and 74 (41%) were weakly acid, were full-column and reached the highest impedance channel (hypo-pharynx). The 74 (41%) weakly acid reflux episodes could not be detected by the antimony electrodes of the MII/pH catheter. With the Restech technique, using an OP ph < 5.5 as cutoff, only 39 reflux episodes were recorded; 17 (43.6%) of these did correlate with swallows (and thus not with reflux), according to the MII recording, and 15 (38.5%) were not associated with MII/pH reflux. Out of all the reflux episodes detected, only seven were detected simultaneously with both techniques. Of these, three reflux episodes were characterised by a drop in ph (but ph > 4.0) in the hypopharynx (upper antimony sensor of MII/pH catheter). But, according to impedance data, these three episodes were not full column and no reflux reached channel 1. None of the full-column reflux events that corresponded with OP ph-metry detected reflux was non-acid. In one patient, two Restech episodes were of very long duration (2 and 4 hours, respectively). During these two periods, impedance recorded five and 13 reflux episodes, respectively. Five of these episodes were full column and reached channel 1. The number of simultaneous reflux episodes according to the different definitions is listed in Table I. If MII detected reflux is considered as the true number of reflux episodes, 1.3% (95% CI ) of all MII reflux episodes and 0% of the full-column MIII reflux episodes are recorded simultaneously with both techniques. If OP ph metry is considered as the technique measuring the true number of reflux episodes, 17.9% (95% CI: ) of the episodes is recorded simultaneously with MII-pH. Forty-nine ph reflux events were detected with the upper ph sensor at the UES with the MII/pH; only three of these (6.1%) were simultaneously recorded with OP ph metry. All subjects reported at least one symptom during the monitoring period. A total of 146 symptom events were recorded; of these, 33.5% were temporally associated with a MII-pH event and 2% were temporally TABLE I. Number of Reflux Episodes Detected Simultaneously by Impedance and Oropharyngeal ph Monitoring. Type of Reflux by MII-pH Total Number of Events N of Events with Corresponding Change in OP (%) All GER events (1.3%) Acid GER (1.6%) Non-acid GER (1.2%) Weakly acid GER (1.3%) Weakly alkaline GER 24 0 Full-column GER Full-column acid GER Full column weakly acid GER 74 0 Acid GER at UES (ph only) 49 3 (6.1%) associated with an OP ph event. Out of 515 GER events detected by MII-pH, 52 (10.1%) were associated with symptoms. Correlation in time (2 minutes time-interval) between cough and reflux events was positive in 5/10 patients for MII/pH metry. According to MII-pH, four out of 10 (40%) patients had a positive SAP. No patients had a positive SI or SAP for OP ph events. DISCUSSION The role of GER in extra-esophageal manifestations is supported by established associations, but is poorly defined and the causality between both remains unproven. The nonspecific nature of extra-esophageal symptoms and the lack of pathognomonic endoscopic or laryngoscopic features contribute to the confusion. The presence of abnormal distal or proximal acid reflux on ph monitoring has not been shown to predict the response of extra-esophageal symptoms to treatment. 8,16,17 In an effort to improve the diagnostic accuracy for refluxrelated respiratory and laryngeal symptoms, a (hypo)- pharyngeal ph sensor has been proposed. 18 In the past, OP ph monitoring has been characterized by many artifacts. 19 The Restech OP ph probe and sensor was developed to minimize these limitations. This probe has been insufficiently validated for the detection of SEGR. The aim of this study was to compare the results of simultaneously recorded ambulatory 24-hour esophageal MII-pH and OP ph in the detection of reflux reaching the hypopharynx, known as SEGR. SEGR can cause micro- and macroaspiration and has been implicated in the pathogenesis of respiratory symptoms. The analysis of the proximal ph could be useful to estimate the role of SEGR in the pathogenesis of respiratory symptoms. Simultaneous esophageal impedance and ph recording was done to validate if changes in ph detected by the Restech OP catheter were in association with either acid or non-acid GER episodes, or if changes in impedance were picked up by the OP ph recording. Overall, the proportion of acid, full-column reflux episodes which were simultaneously (6 2-minute time interval) recorded with both techniques was low (18% if the ph OP reflux 982

4 episodes are considered, and 1.3% if MII-pH reflux is considered). The latter (1.3%) is comparable to the 3.3% reported by Chiou et al. 3 The results of this study also indicate that the majority of acid and weakly acidic OP events had no temporal correlation with GER events detected by MII-pH monitoring. The clinical meaning of the drops in ph measured with the OP ph metry remains unknown at this moment. Finally, subjects were less likely to have a positive symptom correlation with OP ph monitoring than with esophageal MII-pH monitoring. Several studies suggested that the traditional cutoff of ph < 4.0 for SEGR may underestimate the presence of significant reflux because non-acid reflux with a ph between 4.0 and 7.0 may contribute to the pathogenesis of respiratory symptoms. 14,19,20 Choosing a drop in OP ph < 5.5 as cutoff for OP reflux detected by Restech, increases the number of reflux episodes compared to using ph < 4.0 as cutff. Recent studies have suggested other ph cutoffs for proximal ph monitoring. 13,14 Chiou et al. evaluated the sensitivity and specificity of other cutoffs for SEGR. 3 When the authors made the criteria less stringent for acid reflux detected by OP ph metry (ph < 4.5, ph < 5.0, ph < 5.5, > 10% drop in ph), the number of reflux episodes increased dramatically. 3 They reported only five OP episodes with a ph < 4.0 while they detected 170 episodes using ph < 5.5 as cutoff. 3 However, the correlation between reflux episodes detected with both techniques did not improve. 3 Thus, the other cutoff values for SEGR proposed in literature do not result in a better correlation between OP ph and MII-pH data. MII/pH detects acid and non-acid reflux, more reflux episodes were detected with impedance (515 reflux events, resulting in only 1.4% of the MII/pH reflux events that correlated in time with Restech detected reflux). Using the definition for SEGR of ph < 5.5 for a ph determined reflux episode Chiou et al. reported 19% of simultaneous events in pediatric patients. 3 Since the impedance-ph catheter has an antimony sensor at the level of the upper esophageal sphincter (UES), we compared the acid reflux detected with the upper antimony electrode at the level of the UES (n ¼ 106) with Restech reflux episodes: we found only three ph episodes that were recorded simultaneously with both techniques. An important observation was that 24/39 (61%) of the acid reflux events detected by OP ph-metry did correlate in time with an impedance recorded event, but 17/24 (71%) OP events did correlate with a swallow according to impedance, and not with an acid reflux episode. Events detected by Restech do not separate reflux from swallows. When the conventional threshold of ph <4 was used, we demonstrated very little OP acid exposure. This is consistent with recent studies using the Restech probe in normal adult volunteers, in which both the median number of OP events with ph <4 and median percent time ph <4 were also found to be zero. 13,14,20 The optimal time interval allowed between reflux episodes recorded with two different techniques to be considered simultaneous is also always debated. In accordance with Chiou et al., we doubt that a prolonged delay (>2 min) between an episode of GER and subsequent acidification of the oropharynx would account for the lack of correlation. 3 The high proportion of noncorrelating OP ph events seen in our study is consistent with other investigations employing pharyngeal and esophageal ph monitoring. Williams et al. found that 92% of pharyngeal ph decreases of 1 2 ph units and 66% of ph <4 events were independent of esophageal acidification. 19 Harrell et al. reported that approximately 80% of hypopharyngeal ph drops <4.0 were likely due to artifacts. 20 Other studies that combined the Restech ph probe with esophageal ph monitoring also found inconsistencies between OP and distal esophageal ph data. Chheda et al. observed a high rate of false positive and non-corresponding pharyngeal events occurring in supine position in asymptomatic, normal adult volunteers. 21 Golub et al. reported a trend for the OP ph probe to register progressively lower ph levels and more non-correlating ph events during sleep, and suggested that data obtained during sleep should be excluded from Op ph analysis. 22 Limitations of the study design need to be acknowledged. Full-column impedance reflux does not necessarily extend above the upper esophageal sphincter, and thus is not exactly the same as supraesophageal reflux. This limitation may cause an underestimation of the sensitivity of the Restech probe for full-column acid reflux. But it cannot explain the low specificity: only seven of the 39 episodes detected with the OP Restech recording were simultaneously detected with MII. Restech detects of course only acid reflux, whereas MII detects acid and nonacid reflux. The number of patients included is small (n ¼ 10); however, the absence of correlation between both techniques is so obvious that a larger number of patients is extremely unlikely to influence the conclusions. CONCLUSION The passage of gastric refluxate into areas above the protection of the upper esophageal sphincter, also known as supra-esophageal gastric reflux, causing macro- and microaspiration, may cause extra-esophageal symptoms such as hoarseness, cough, and sore throat. However, causality has not been proven. The Restech Dx-pH sensor is a transnasal catheter that has an ion flow sensor able to measure the ph of both liquid and aerosolized droplets, which is located in the posterior oropharynx, and seems therefore of major interest in this indication. However, combined esophageal multichannel intraluminal impedance and ph monitoring is now considered as the gold standard to measure GER. The results show absence of any correlation between the results obtained with both techniques. Therefore, the value of the Restech Dx-pH sensor should be further tested (e.g., with double-blind placebo-controlled therapeutic trials). Up to now, the Restech Dx-pH sensor cannot be recommended as a validated diagnostic tool for supra-esophageal reflux. BIBLIOGRAPHY 1. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:

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