gastroesophageal reflux evaluation in patients affected by chronic cough: restech versus...

The LaryngoscopeVC 2012 The American Laryngological,Rhinological and Otological Society, Inc.

Gastroesophageal Reflux Evaluation in Patients Affectedby Chronic Cough: Restech Versus MultichannelIntraluminal 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 gastricreflux (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 46.33 6 9.86 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 consideredsimultaneous.

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 monitoringmeasured 39 acid events; 17 (43.6%) were swallows according to MII, and 15 (38.5%) were not associated with MII or pHchange. Only seven episodes were detected simultaneously with both techniques (1.3% for MII vs. 18% for OP; P ¼ 0.0002).We found 49 pH-only refluxes at the pH sensor in the hypo-pharynx with MII/pH; only three (6.1%) correlated with OPreflux. 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 swallowsaccording to impedance. Time correlation between cough and reflux could not be demonstrated with OP pHmetry.

Key Words: Chronic cough, multichannel intraluminal impedance, pH monitoring, Restech.Level of Evidence: 4

Laryngoscope, 000:000–000, 2012

INTRODUCTIONAccording to recent evidence-based consensus state-

ments, gastroesophageal reflux disease (GERD) can becategorized in esophageal and extra-esophageal symp-toms.1,2 One of the most important proposedmechanisms of extra-esophageal manifestations is thepassage of gastric refluxate into areas above the protec-tion of the upper esophageal sphincter (UES), alsoknown as supra-esophageal gastric reflux (SEGR), caus-ing macro- and microaspiration.3 The group of patientswith extra-esophageal symptoms such as hoarseness,

cough, and sore throat, and who have signs of laryngealirritation on laryngoscopy, are considered to suffer lar-yngopharyngeal reflux (LPR).3 The laryngoscopicfindings in LPR, such as erythema and edema, are non-specific signs of laryngeal irritation. LPR is in manycases a diagnosis of exclusion.3 The association betweenreflux and extra-esophageal symptoms is well estab-lished,4,5 but proof of a clear, causal relationship hasfailed. Consequently, although SEGR is commonly impli-cated in patients presenting with symptoms suggestingextra-esophageal symptoms, formal diagnosis and man-agement remains clinically challenging.

Abnormal distal esophageal acid exposure on pHmonitoring can indicate the presence of pathologicGERD, but does not provide proof of causality for extra-esophageal symptoms.2 Extra-esophageal symptomsalone, or the analysis of classic pH-metry in the distalesophagus, are not suitable for the diagnosis of SGER.Several studies used proximal esophageal pH analysis asa diagnostic test of SGER.3,6,7 The measurement of dropsin proximal esophageal pH <4 has not been shown topredict therapy response.8

Current diagnostic methods are limited due to thelack of consensus regarding the optimal criteria for

From the Department of Pediatrics (D.U., B.H., Y.V.); the Departmentof Gastroenterology (L.V., B.R., D.U.), UZ Brussel, Brussels, Belgium; theDepartment of Pediatrics (D.UR.), University of Naples Federico II, Naples,Italy.

Editor’s Note: This Manuscript was accepted for publication onAugust 22, 2012.

The RestechVR company has donated the device for this research.Yvan Vanderplas, MD, is a consultant for United Pharmaceuticals andBiocodex. The authors have no other funding, financial relationships, orconflicts of interest to disclose.

Send correspondence to Yvan Vandenplas, MD, Department ofPediatrics, UZ Brussel, Vrije Unversiteit Brussel, Laarbeeklaan, 101,1090, Brussels, Belgium. E-mail: [email protected]

DOI: 10.1002/lary.23738

Laryngoscope 000: Month 2012 Ummarino et al.: Restech Versus MII/pH Metry

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SEGR. The minimum amount of supra-esophageal acidexposure needed to produce clinically significant patho-logic changes is unknown, but a SEGR event isconventionally defined as a drop in proximal pH < 4.0,in association with a preceding or simultaneous distalreflux event.3 Normal ranges for pH < 4.0 at the proxi-mal level have been established,9 but these have notbeen shown to predict therapeutic outcome.

Episodes with a pH < 4.0 have been proposed asthe best discriminating factor between patients with andwithout heartburn caused by (acid) reflux. Whether epi-sodes with a pH < 4.0 are an appropriate criterion tomeasure SEGR can be questioned. It has been observedthat about 30% of acid refluxate has a pH > 4.0 when itreaches the proximal esophagus.10 Data have shownthat non-acid reflux with a pH between 4.0 and 7.0 (nowcalled ‘‘weakly acid reflux’’) may contribute to airwayand respiratory disease.11–13 The traditional cutoff of pH<4 for SEGR may actually underestimate the presenceof clinically significant reflux. Several recent studieshave suggested using higher pH cutoffs for proximal pHmonitoring. Ayazi et al. proposed to use pH < 5.5 inupright position and pH < 4.5 in supine position as cut-offs for SEGR.14 Wiener et al. used a rapid (0.5–2seconds) drop in oropharyngeal pH of at least 10% fromthe pH baseline as a definition for SEGR.15

The RestechVR Dx-pH sensor is a transnasal catheterwith an ion flow sensor able to measure the pH of bothliquid and aerosolized droplets, and which is located inthe posterior oropharynx (OP). The hypothesis is thatdirect measurement of OP pH may provide an accuratediagnostic tool for SEGR, compared with currentmethods.

The aim of this study was to monitor OP pH withthe Restech Dx-pH sensor in patients affected by chroniccough, and to evaluate the correlation between changesin OP pH and GER events detected by an antimony elec-trode placed at the upper esophageal sphincter (UES)region and with multichannel intraluminal impedance(MII-pH) monitoring.

MATERIALS AND METHODSParticipation in the study (simultaneous Restech and MII/

pH) was proposed to consecutive patients that were sent in forMII/pH because of unexplained chronic cough between Januaryand July 2011, and in whom respiratory and cardiac problemshad been excluded. Additional exclusion criteria included theinability to tolerate placement of two intranasal probes.Patients were not on reflux treatment. The study was approvedby the local Ethical Committee of the UZ Brussel. Writteninformed consent was obtained from each patient prior toenrollment in the study.

The MII/pH recording was performed with a portable datalogger and a combined impedance-pH catheter (Sleuth ambula-tory system, Sandhill Scientific, Inc; Highland Ranch, CO). Theprobe was placed transnasally; the location of the probe wasdetermined with fluoroscopy. The six impedance channels werelocated 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 UESand 5 cm above the diaphragm.

The Restech Dx-pH probe (Respiratory Technology Corp.,San Diego, CA) is a transnasal, antimony tear-drop shaped

pH sensor, designed to aid in maintenance of moisture satura-tion of the sensor from exhaled breath condensation on the tipsurface. A colored light-emitting diode (LED) at the tip aids intransoral visualization during placement. Shortly after theesophageal MII-pH probe was placed, the Restech probe wasinserted into the same nostril until the flashing LED wasseen in the back of the patient’s throat, and then positioned sothat the LED was at the level of the uvula. Oropharyngeal pHtracings were also manually analyzed by the same investiga-tor (D. Ummarino). The number of reflux episodes accordingto the OP pH metry was analyzed using an OP pH drop < 5.5as the definition for SEGR.3

The internal clocks of both data loggers were synchronizedjust before the start to assure simultaneous monitoring of a 24-hour MII-pH and OP pH recording. All patients registeredsymptoms, meals and drinks, and position changes in a diary.After appropriate placement of both sensors, data recording wasstarted.

Subjects were discharged and were encouraged to main-tain normal activities and sleep schedule, and to eat their usualmeals (avoiding acid). All subjects tolerated the procedure wellwithout incident or complications. All activities and symptomswere registered in a specific diary and on the data loggerthrough specific markers. Once the esophageal and OP monitor-ing studies were completed, both catheters were removed. Datafrom both digital recorders were downloaded. The MII-pH datawere analyzed by one author (D. Ummarino) with commerciallyavailable software (BioView Analysis, Sandhill Scientific, High-lands Ranch, CO; DataView Lite, Respiratory TechnologyCorp.). Restech information was analyzed by the same coauthor(D. Ummarino) using a dedicated software program (AEMCInstruments, Foxborough, MA). Periods of meals and drinkswere excluded from the analysis.

Each MII-pH tracing was manually analyzed by one inves-tigator (D. Ummarino). A bolus-liquid reflux is defined as aretrograde drop in impedance of at least 50% of the baseline inat least two distal impedance channels (3 consecutive rings).The end of a reflux episode is defined as the moment when theimpedance value returned to at least 50% of the initial (base-line) 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 weaklyalkaline reflux is > 7.0. Swallows were defined as a rapid fallin 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 onesite having an absolute value >7000 ohms. Mixed reflux eventsare a combination of both liquid and gas patterns. Full-columnreflux was defined as an episode that reached the highest pairof impedance sensors. For the MII-pH recording, a pH episodewas defined as a fall in distal pH to < 4.0 lasting at least 5 sec-onds, detected by a pH sensor. Since the aim of the study wasthe comparison between both techniques, we did not make agroup with ‘‘normal’’ and ‘‘abnormal’’ GER.

The correlation between OP pH and esophageal MII-pHwas determined based on the temporal relationship between OPand esophageal reflux events. The OP pH data were comparedwith the pH data recorded at the UES with the MII/pH in orderto evaluate the correlation between the two pH sensors. Thesame comparison was done between the OP pH and impedancedata. A time-interval of 2 minutes was allowed between Restechand MII/pH episodes to be considered simultaneous episodes.All symptoms recorded by the patients, written in the diary orrecorded by pushing the event marker(s), were considered.Since ‘‘chronic cough’’ was the inclusion criterion, almost allsymptoms referred to coughing episodes. To evaluate the corre-lation in time, we calculated the symptom index (SI). The SI isthe percentage of GER-associated symptoms divided by the total


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number of symptoms. A SI of 50% usually is used as the lowerlimit of significance. For the symptom association probability(SAP), the total measuring time is subdivided into 2-minuteintervals, and a contingency table with four fields is estab-lished: 1) number of intervals with GER and symptom, 2)number of intervals with GER and without symptom, 3) num-ber of intervals without GER and with symptom, and 4)number of intervals without GER and symptom. Fisher’s exacttest is then used for statistical analysis of correlation. A positiveSAP (> 95%) is interpreted as a proof of a temporal associationbetween GER and the recorded symptom.

RESULTSWe analyzed the MII/pH registrations in 10 consec-

utive patients (mean age 6 SD: 46.3 6 9.86 years old;range 33–66 years) with chronic unexplained cough sendin for a MII-pH recording. The two probes were well tol-erated by all patients. The mean duration of therecording was 23.24 hours (range 22.11–24.25 hours).

In the 10 patients, MII/pH detected a total of 515reflux 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%) wereweakly acid, were full-column and reached the highestimpedance channel (hypo-pharynx). The 74 (41%)weakly acid reflux episodes could not be detected by theantimony electrodes of the MII/pH catheter.

With the Restech technique, using an OP pH < 5.5as cutoff, only 39 reflux episodes were recorded; 17(43.6%) of these did correlate with swallows (and thus notwith reflux), according to the MII recording, and 15(38.5%) were not associated with MII/pH reflux. Out of allthe reflux episodes detected, only seven were detectedsimultaneously with both techniques. Of these, threereflux episodes were characterised by a drop in pH (butpH > 4.0) in the hypopharynx (upper antimony sensor ofMII/pH catheter). But, according to impedance data, thesethree episodes were not ‘‘full column’’ and no refluxreached channel 1. None of the full-column reflux eventsthat corresponded with OP pH-metry detected reflux wasnon-acid. In one patient, two Restech episodes were ofvery long duration (2 and 4 hours, respectively). Duringthese two periods, impedance recorded five and 13 refluxepisodes, respectively. Five of these episodes were full col-umn and reached channel 1. The number of simultaneousreflux episodes according to the different definitions islisted in Table I. If MII detected reflux is considered asthe ‘‘true’’ number of reflux episodes, 1.3% (95% CI 0.24–7.79) of all MII reflux episodes and 0% of the full-columnMIII reflux episodes are recorded simultaneously withboth techniques. If OP pH metry is considered as the tech-nique measuring the ‘‘true’’ number of reflux episodes,17.9% (95% CI: 12.25–27.28) of the episodes is recordedsimultaneously with MII-pH. Forty-nine pH reflux eventswere detected with the upper pH sensor at the UES withthe MII/pH; only three of these (6.1%) were simultane-ously recorded with OP pH metry.

All subjects reported at least one symptom duringthe monitoring period. A total of 146 symptom eventswere recorded; of these, 33.5% were temporally associ-ated with a MII-pH event and 2% were temporally

associated with an OP pH event. Out of 515 GER eventsdetected by MII-pH, 52 (10.1%) were associated withsymptoms.

Correlation in time (2 minutes time-interval)between cough and reflux events was positive in 5/10patients for MII/pH metry. According to MII-pH, fourout of 10 (40%) patients had a positive SAP. No patientshad a positive SI or SAP for OP pH events.

DISCUSSIONThe role of GER in extra-esophageal manifestations

is supported by established associations, but is poorlydefined and the causality between both remains unpro-ven. The nonspecific nature of extra-esophagealsymptoms and the lack of pathognomonic endoscopic orlaryngoscopic features contribute to the confusion. Thepresence of abnormal distal or proximal acid reflux on pHmonitoring has not been shown to predict the response ofextra-esophageal symptoms to treatment.8,16,17 In aneffort to improve the diagnostic accuracy for reflux-related respiratory and laryngeal symptoms, a (hypo)-pharyngeal pH sensor has been proposed.18 In the past,OP pH monitoring has been characterized by many arti-facts.19 The Restech OP pH probe and sensor wasdeveloped to minimize these limitations. This probe hasbeen insufficiently validated for the detection of SEGR.

The aim of this study was to compare the results ofsimultaneously recorded ambulatory 24-hour esophagealMII-pH and OP pH in the detection of reflux reachingthe hypopharynx, known as SEGR. SEGR can causemicro- and macroaspiration and has been implicated inthe pathogenesis of respiratory symptoms. The analysisof the proximal pH could be useful to estimate the roleof SEGR in the pathogenesis of respiratory symptoms.Simultaneous esophageal impedance and pH recordingwas done to validate if changes in pH detected by theRestech OP catheter were in association with either acidor non-acid GER episodes, or if changes in impedancewere picked up by the OP pH recording. Overall, theproportion of acid, full-column reflux episodes whichwere simultaneously (6 2-minute time interval) recordedwith both techniques was low (18% if the pH OP reflux

TABLE I.Number of Reflux Episodes Detected Simultaneously by

Impedance and Oropharyngeal pH Monitoring.

Type of Refluxby MII-pH

Total Numberof Events

N� of Events withCorrespondingChange in OP (%)

All GER events 515 7 (1.3%)

Acid GER 181 3 (1.6%)

Non-acid GER 334 4 (1.2%)

Weakly acid GER 310 4 (1.3%)

Weakly alkaline GER 24 0

Full-column GER 180 0

Full-column acid GER 106 0

Full column weakly acid GER 74 0

Acid GER at UES (pH only) 49 3 (6.1%)


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episodes are considered, and 1.3% if MII-pH reflux is con-sidered). The latter (1.3%) is comparable to the 3.3%reported by Chiou et al.3 The results of this study alsoindicate that the majority of acid and weakly acidic OPevents had no temporal correlation with GER eventsdetected by MII-pH monitoring. The clinical meaning ofthe drops in pH measured with the OP pH metry remainsunknown at this moment. Finally, subjects were lesslikely to have a positive symptom correlation with OP pHmonitoring than with esophageal MII-pH monitoring.

Several studies suggested that the traditional cutoffof pH < 4.0 for SEGR may underestimate the presenceof significant reflux because non-acid reflux with a pHbetween 4.0 and 7.0 may contribute to the pathogenesisof respiratory symptoms.14,19,20 Choosing a drop in OPpH < 5.5 as cutoff for OP reflux detected by Restech,increases the number of reflux episodes compared tousing pH < 4.0 as cutff. Recent studies have suggestedother pH cutoffs for proximal pH monitoring.13,14 Chiouet al. evaluated the sensitivity and specificity of other cut-offs for SEGR.3 When the authors made the criteria lessstringent for ‘‘acid’’ reflux detected by OP pH metry (pH <4.5, pH < 5.0, pH < 5.5, > 10% drop in pH), the number ofreflux episodes increased dramatically.3 They reportedonly five OP episodes with a pH < 4.0 while they detected170 episodes using pH < 5.5 as cutoff.3 However, the cor-relation between reflux episodes detected with bothtechniques did not improve.3 Thus, the other cutoff valuesfor SEGR proposed in literature do not result in a bettercorrelation between OP pH and MII-pH data.

MII/pH detects acid and non-acid reflux, morereflux episodes were detected with impedance (515reflux events, resulting in only 1.4% of the MII/pHreflux events that correlated in time with Restechdetected 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 pediatricpatients.3 Since the impedance-pH catheter has an anti-mony sensor at the level of the upper esophagealsphincter (UES), we compared the ‘‘acid reflux detectedwith the upper antimony electrode at the level of theUES’’ (n ¼ 106) with Restech reflux episodes: we foundonly three pH episodes that were recorded simultane-ously with both techniques. An important observationwas that 24/39 (61%) of the acid reflux events detectedby OP pH-metry did correlate in time with an imped-ance recorded event, but 17/24 (71%) OP events didcorrelate with a swallow according to impedance, andnot with an acid reflux episode. Events detected by Rest-ech do not separate reflux from swallows.

When the conventional threshold of pH <4 wasused, we demonstrated very little OP acid exposure.This is consistent with recent studies using the Restechprobe in normal adult volunteers, in which both the me-dian number of OP events with pH <4 and medianpercent time pH <4 were also found to be zero.13,14,20

The optimal time interval allowed between refluxepisodes recorded with two different techniques to be con-sidered ‘‘simultaneous’’ is also always debated. Inaccordance with Chiou et al., we doubt that a prolongeddelay (>2 min) between an episode of GER and subse-

quent acidification of the oropharynx would account forthe lack of correlation.3 The high proportion of noncorre-lating OP pH events seen in our study is consistent withother investigations employing pharyngeal and esopha-geal pH monitoring. Williams et al. found that 92% ofpharyngeal 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 hypo-pharyngeal pH drops <4.0 were likely due to artifacts.20

Other studies that combined the Restech pH probe withesophageal pH monitoring also found inconsistenciesbetween OP and distal esophageal pH data. Chheda et al.observed a high rate of false positive and non-correspond-ing pharyngeal events occurring in supine position inasymptomatic, normal adult volunteers.21 Golub et al.reported a trend for the OP pH probe to register progres-sively lower pH levels and more non-correlating pHevents during sleep, and suggested that data obtainedduring sleep should be excluded from Op pH analysis.22

Limitations of the study design need to be acknowl-edged. Full-column impedance reflux does notnecessarily extend above the upper esophageal sphinc-ter, and thus is not exactly the same as supra-esophageal reflux. This limitation may cause an under-estimation of the sensitivity of the Restech probe forfull-column acid reflux. But it cannot explain the lowspecificity: only seven of the 39 episodes detected withthe OP Restech recording were simultaneously detectedwith MII. Restech detects of course only acid reflux,whereas MII detects acid and nonacid reflux. The num-ber of patients included is small (n ¼ 10); however, theabsence of correlation between both techniques is soobvious that a larger number of patients is extremelyunlikely to influence the conclusions.

CONCLUSIONThe passage of gastric refluxate into areas above the

protection of the upper esophageal sphincter, also knownas supra-esophageal gastric reflux, causing macro- andmicroaspiration, may cause extra-esophageal symptomssuch as hoarseness, cough, and sore throat. However, cau-sality has not been proven. The Restech Dx-pH sensor is atransnasal catheter that has an ion flow sensor able tomeasure the pH of both liquid and aerosolized droplets,which is located in the posterior oropharynx, and seemstherefore of major interest in this indication. However,combined esophageal multichannel intraluminal imped-ance and pH monitoring is now considered as the ‘‘gold’’standard to measure GER. The results show absence ofany correlation between the results obtained with bothtechniques. Therefore, the value of the Restech Dx-pHsensor should be further tested (e.g., with double-blindplacebo-controlled therapeutic trials). Up to now, theRestech Dx-pH sensor cannot be recommended as a vali-dated diagnostic tool for supra-esophageal reflux.

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gastroesophageal reflux evaluation in patients affected by chronic cough: restech versus...

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