Laryngopharyngeal Re?ux:Trends in Diagnostic Interpretation Criteria
Brynn E.Richardson,MD,1Barbara M.Heywood,MD,1H.Steven Sims,MD,1Julie Stoner,PhD,2and Donald A.Leopold MD 1
1
Department of Otolaryngology–Head and Neck Surgery,and 2Department of Preventive and Societal Medicine,University of Nebraska Medical Center,Omaha,Nebraska,USA
https://www.doczj.com/doc/6c624825.html,ryngopharyngeal re?ux (LPR)is becoming recognized as a clinical entity with a variety of presentations distinct from those of gastroesoph-ageal re?ux disease (GERD).However,much uncertainty remains as to what is considered patho-logic versus physiologic re?ux.The aim of the study was to determine the normal range of pharyngeal re?ux (PR)occurring in healthy adults based on pH-monitoring parameters utilized in the DeMeester scoring system for GERD.We have reviewed the current pool of prospective literature examining ambulatory dual-channel pH-monitoring study data derived from hypopharyngeal proximal probes in normal adults.From our review we have identi?ed trends in several monitoring parameters based on the DeMeester scoring system for GERD.Our discussion recognizes and accepts the limitations imposed by small sample sizes and the number of healthy indi-viduals that would be required to determine the general adult physiologic range of PR.We also ex-plore the possible need for separate normal PR ref-erence intervals based on age or gender disparities.Additional discussion and the summary address fu-ture directions for LPR research notably,(1)identi-?cation of the most appropriate research paradigm for LPR (i.e.,pH 4vs.5),(2)establishing reproduc-ibility for the appropriate LPR research paradigm,and (3)complementary modalities to ambulatory dual-channel pH monitoring for the study of acid and nonacid bolus movement within the esophagus
Key words:Laryngopharyngeal re?ux —Pharyn-geal re?ux —Extraesophageal re?ux —Gastro-esophageal re?ux —Acid re?ux —Deglutition —Deglutition disorders.
Laryngopharyngeal re?ux (LPR)and extraesopha-geal re?ux (EER)are emerging as distinct clinical entities with a variety of presentations but our understanding of them is incomplete [1,2].Much uncertainty remains when one attempts to sharply de?ne the di?erence between physiologic episodes and pathologic events.There is relatively little data available to de?ne normal reference intervals for pH-monitoring modalities to assess events above the level of the upper esophageal sphincter.As a result,establishing guidelines to predict clinically relevant re?ux based on values obtained from pH monitoring while also considering probe placement remains a di?cult task [3].Equally arduous is the reconciliation of the intermittent nature of re?ux with the repro-ducibility of results.Day-to-day intrasubject vari-ability and the possibility of missing re?ux episodes during an arti?cially determined time period com-plicates attempts to establish norms.To assess upper aerodigestive complaints thought to be due to pha-ryngeal re?ux (PR),the otolaryngologist or gastro-enterologist must consider these factors when ordering and interpreting a pH-monitoring proce-dure.
We performed an extensive literature search to review the current pool of published,prospective studies correlating clinical LPR with pH-monitoring parameters in adults.
*Currently a?liated with Medtronic Xomed,Inc.,Jacksonville,Florida,USA
Correspondence to:Barbara M.Heywood,M.D.,981225Nebraska Medical Center,Omaha,NE,68198-1225,USA.Telephone:(402)559-7775,Fax:(402)559-8940,E-mail:
bheywood@https://www.doczj.com/doc/6c624825.html,
Dysphagia 19:248–255(2004)DOI:10.1007/s00455-004-0014-5
Purpose
The purposes of this article are(1)to brie?y sum-marize the historical background of pH monitoring, (2)to summarize the current results and document trends,and(3)to expose potential avenues for future investigation.
Historical Perspectives
Since its introduction by Tuttle and Grossman[4], esophageal pH monitoring has undergone a signi?-cant evolution in its technology and,consequently,its applications.Previously,esophageal pH monitoring was most often performed on an inpatient basis making it both very expensive and inconvenient.The development of equipment for ambulatory pH mon-itoring has reduced costs and inconvenience for pa-tients while maintaining diagnostic accuracy.Most recently,pH monitoring has expanded its utility to include application within the extraesophageal structures for study of re?ux conditions above the upper esophageal sphincter(UES).
Re?nements in equipment have facilitated a transition from hospital-based procedures to ambu-latory pH monitoring.Advances in technology have produced portable battery-powered data recorders with buttons the patient can press with the onset of events such as heartburn,supine positioning,meals, or pain.Patients are also asked to complete written diaries as a backup data log.After a complete recording period,data may be downloaded and analyzed,using the appropriate software,on virtually any personal computer.Catheters with one or more pH electrodes(also called probes or sensors)are in-serted transnasally and positioned either through visualization with?exible nasopharyngoscopy or with manometry[5–8].
The?rst electrodes were constructed using glass and were quite bulky and sti?.Later,antimony monocrystalline probes were developed that were far less bulky and more pliable.Glass electrodes were believed to be superior to those made of antimony until the work of Richter et al.[9]documented the lack of signi?cant di?erences between the two elec-trode types.Thus,current equipment takes advantage of the greater?exibility of the antimony monocrys-talline probe without sacri?cing diagnostic accuracy.
The optimal position of a pH probe intended to measure distal esophageal acid exposure has pre-viously been de?ned as5cm proximal to the lower esophageal sphincter[10,11].In contrast,the best probe position from which LPR may be studied has become a more controversial topic.Three probe positions have been used to measure EER or PR. Probes have been placed just distal to the UES, within the UES,or just proximal to the UES [8,12,13].Further discussion regarding the rationale for probes placed proximal to the UES follows later in this article,but it is clear that the issue remains unsettled.
Commonly reported indices for the study of PR are adapted from a scoring system devised by Johnson and DeMeester[14]for the study of gas-troesophageal re?ux(GER)and include the percent total time at pH<4,percent time upright at pH<4, percent time supine at pH<4,total number of events,number of events lasting more than5minutes, and length of the longest event.The percent time at pH<4is also commonly referred to as the percent acid exposure time(%AET).In1991,Koufman[15] presented hypopharyngeal probe data from12con-trol patients demonstrating no pharyngeal re?ux events.On the basis of these results,pharyngeal re?ux was thought to be a rare event in normal individuals [15].Several studies performed since the Koufman report have documented pharyngeal acid exposure in subjects known to be without physical?ndings or symptoms suggestive of LPR[16–26].These?ndings are well recognized and support the existence of a physiologic range of pharyngeal re?ux.However,the histologic composition of the laryngeal and pharyn-geal mucosa is distinct from that of the esophagus.It is an accepted fact that the esophagus is better equipped to tolerate acid exposure than the mucosa lining the hypopharynx and larynx[27].So,there is still room for resolution of this issue as well.
Investigations in adults and children using a single,distal esophageal probe have shown excellent reproducibility and reliability in asymptomatic vol-unteers and GERD patients[28–30].Vaezi et al.[31] reported on32subjects undergoing two separate, dual-channel,ambulatory,24-h pH studies with a proximal and a distal esophageal probe.Having pa-tients serve as their own controls,Vaezi et al.[31] demonstrated that the reproducibility of results for a diagnosis of proximal esophageal acid re?ux was 55%.The speci?city of results was91%,however, sensitivity was less than ideal[31].One may logically infer from these results that a negative probe study does not exclude the possibility of proximal re?ux in subjects.In terms of speci?c monitoring parameters, the percent total and percent upright time with pH< 4emerged as the most reliable and reproducible indices in both healthy volunteers and GERD suf-ferers[31].To date,no authors have published a study that has examined the reproducibility of results
B.E.Richardson et al.:LPR:Trends in Diagnostic Criteria249
obtained using a hypopharyngeal probe,leaving assurances about a hypopharyngeal probe’s repro-ducibility uncertain to practitioners at large. Current Concepts
To adequately gauge PR it is necessary that the proximal probe in a pH study be located as close to the target organ or organs(i.e.,larynx and pharynx) as possible.The development of the thinner,more ?exible sensors has provided the capability of com-bining multiple sensors on one catheter and allowed placement in the hypopharynx without increasing patient discomfort or compromising diagnostic validity.Pseudore?ux events—acidi?cation of the hypopharyngeal milieu from sources other than gas-tric re?uxate—are a well-recognized phenomenon unique to pH monitoring within the hypopharyngeal space.Pseudore?ux artifacts can be minimized by correlating pharyngeal events with coincident esophageal data.Conversely,small,local?uctuations in acid concentration may be diluted within the relatively large volume of the hypopharynx.
Technological advances permit studies of the hypopharyngeal mucosa,and there is a growing body of data supporting the greater speci?city achieved to study extraesophageal manifestations of re?ux dis-ease[17,32–37].Shaker et al.[17]examined the esophageal distribution of gastric acid re?uxate in laryngitis patients and controls.Between study groups,subjects who reported laryngitis had approximately three times the number of episodes of pH<4and percent total time at pH<4when compared with normal controls[17].These di?er-ences were statistically signi?cant.We conclude that data obtained from a proximal esophageal probe may be insu?cient to support any assertions about re?ux episodes that breach the UES.Any estimation of the amount of hypopharyngeal acid exposure required to cause pathology is also susceptible to error for the same reason.
The UES is also actively involved in preven-tion of re?ux of gastric materials,providing further support for hypopharyngeal probe placement.Sev-eral recent works have focused on the known array of airway protective re?ex mechanisms as well as man-ometric studies in LPR patients and controls[17,32–37].Investigators have shown that pressure within the UES is quite variable.Most episodes of proximal re?ux occur in the upright position despite the fact that signi?cant decreases in UES pressure are noted during periods of calm and sleep[33].Additionally,resting UES pressures are signi?cantly lower in the elderly compared to the young[17,32].
UES response to esophageal acidi?cation is a controversial topic.Study of the esophago-UES contractile re?ex in controls and patients with re?ux esophagitis during episodes of spontaneous gastro-esophageal re?ux showed signi?cant UES pressure increases following34/35recorded re?ux events[37]. Gerhardt et al.[38]reported a similar response in subjects after intraesophageal acid infusion.Evidence to refute this relationship has also been presented [33,39].Vakil et al.[39]reported no change in UES pressure following spontaneous GER episodes.A study by Kahrilas et al.[33]also cited no signi?cant changes in UES pressure following spontaneous GER https://www.doczj.com/doc/6c624825.html,stly,access of gastric re?uxate to the airway is limited by the esophagoglottal closure re?ex which is known to produce vocal cord adduc-tion following abrupt esophageal distention[35]. Abnormal alterations in UES pressure or a lack of airway protective function may be at the root of PR causing some cases of clinical LPR.In healthy, asymptomatic adults with proper protective function, physiologic PR events are prevented from contacting extraesophageal structures and causing LPR.
Chief among arguable points is the amount of gastric acid re?ux present above the UES that com-prises physiologic PR.The remainder of this article is devoted to the discussion of identi?able trends in normal hypopharyngeal pH reference intervals and directions for future research in this?eld of study. Current Criteria
Two studies in healthy volunteers that evaluated24-h dual-channel pH monitoring utilizing a hypopha-ryngeal upper probe position to de?ne a normal pH reference interval for the adult population have been published[22,25].The experiments conducted by Bove et al.[25]and Vincent et al.[22]yielded helpful information.Bove et al.[25]studied40volunteers(20 male and20female;age range and mean:26–64years and43years,respectively)and Vincent et al.[22] reported on30healthy volunteers(13male and 17female;age range and median:18–53years and 28years,respectively.Each subject studied was neg-ative for symptoms of LPR/GER and had no?ndings of LPR/GER like posterior laryngeal edema or ery-thema on?exible nasopharyngoscopy[22,25].Sub-jects taking any gastrointestinal motility medications or any regular antacid or acid-suppressing medica-tion were not eligible for the studies[22,25].
250 B.E.Richardson et al.:LPR:Trends in Diagnostic Criteria
Conditions of pH monitoring were similar in that each patient was instructed to maintain typical activities and diet with the exception of avoidance of highly acidic or carbonated food or drink[22,25]. Analysis of the recorded data excluded meal periods (as recorded by the subject)in each study as well as an additional two minutes of the immediate postprandial period to allow for esophageal clearance in one of the studies[22].True pharyngeal acidi?cation was simi-larly de?ned between studies with each requiring a pH <4and simultaneous esophageal acidi?cation to qualify a pharyngeal event for analysis[22,25].Due to the skewed nature of the data distributions,data summaries were generally reported using medians and percentiles to act as measures of central tendency and variability and are summarized below(Table1).
Comparison of study design between the Bove et al.study and the Vincent et al.study reveals no major di?erences between the two protocols.Indi-viduals studied were of a similar age range as well as gender distribution and all were clinically and endo-scopically negative for LPR/GER[22,25].The only exception noted is the exclusion of an additional two minutes in the immediate postprandial period by Vincent et al.[22].
There is a striking similarity between the re-sults of these two studies that seems to be una?ected by any minor di?erences in study design or protocol. The95th percentile values summarized in Table1for the number of events and total and upright%AET are comparable between the two hypopharyngeal probe studies[22,25].Reported ranges for the total number of events for Bove et al.were0–15and0–10 for Vincent et al.[22,25].Reported ranges for total% AET for Bove et al.were0–1.1%and0–0.3%for Vincent et al.[22,25].
Reviewing the information currently available, we have also summarized comparison studies exam-ining di?erences in pH measurements obtained from healthy volunteers.Subjects had a range of upper airway ailments as detailed below.
Several studies documenting controlled clini-cal experimental data have emerged from the Medical College of Wisconsin[17–21].pH-monitoring data obtained from patients with upper-airway disorders ranging from laryngotracheal stenosis,posterior lar-yngitis,and chronic sinusitis to GERD have been compared with values acquired from healthy volun-teers[17–21].Healthy volunteers ranged in age from 19to85years,reported no symptoms of LPR/GER, and were all negative on?exible nasopharyngoscopic exam for?ndings of re?ux[17–21].Asummary of pH-monitoring data for healthy volunteers from several of these studies is presented in Table2.
Additional comparative values are given in two studies conducted by the University of Wash-ington[16,26].Patients with respiratory symptoms such as cough,wheeze,or hoarseness were compared with healthy volunteers in each study[16,26].Healthy volunteers were sought using a symptom index questionnaire for absence of GER or LPR symptoms as an inclusion criterion[16,26].The?ndings of24-h dual-channel pH monitoring in healthy volunteers are also summarized in Table2.The age of the sub-jects was not available.
In1991,Koufman[15]presented comparative data from otolaryngology patients and12controls. In this study,no PR episodes were documented in controls.Demographic information concerning con-trols was unavailable.Finally,two studies by Ylitalo et al.[23,24]evaluated comparative data from pa-tients with either contact granuloma or posterior laryngitis and normal controls.Control subjects from these studies ranged in age from20to51years,were asymptomatic for LPR or GER,and were endo-scopically negative for re?ux?ndings in the larynx. Again,pH-monitoring?ndings for controls are summarized in Table2.
Table1.Summary of normative hypopharyngeal pH-monitoring data
No.of Events%AET
Hypopharyngeal probe N LPR prev Mean Median SD95th%Mean Median SD95th% Bove et al.[25]a4022/40(55%)
Total NR 1.0NR 6.1NR0.0NR0.2 Upright NR0.5NR 6.1NR0.0NR0.3 Vincent et al.[22]a2312/23(52%)
Total 2.0 1.0 2.7 6.9000.10.1 Upright 1.60.0 2.3 6.9000.10.2
N=number subjects,LPR prev=laryngopharyngeal re?ux prevalence,AET=acid exposure time,95th%=95th percentile,NR=not reported.
a Clinically and endoscopically negative for LPR
B.E.Richardson et al.:LPR:Trends in Diagnostic Criteria251
Signi?cant results were obtained comparing the patient population to controls for each parameter reported in Table2with the exception of patients su?ering chronic sinusitis alone[15–18,20–24,26]. When patients with chronic sinusitis were compared with controls,no signi?cant di?erences were found in the presented study[20].
Many studies detailed above excluded from data analysis meal periods recorded by the subject [15–18,20–24,26].Standard meals were consumed by subjects as part of the study protocol in several studies[17–21].Participants were asked to limit alcoholic and carbonated beverages and acidic food intake in some experiments[23,24].Overall,no major di?erences in study protocol with respect to de?nition of a PR event or probe position were noted.
Toohill et al.’s work presents several values germane to this discussion[18].Although minimal recorded data are reported in the body of the article, a few key items are remarkable.First,their study represents one of the larger pools of normal data (N=34)available within a single study.Second, from the reported number of events for each patient (range=0–3),we are able to calculate a95th per-centile value of2.3for the number of events[18].
The work of Smit et al.[8]merits further dis-cussion.They examined20healthy individuals(14 men and6women;mean age-32.5years;range-19–57years),identi?ed on the basis of re?ux symptom history,with dual-channel24-h pH monitoring.The proximal probe in their experiment was located within the mucosal con?nes of the UES as deter-mined by manometry.Subjects were asked to main-tain their daily routines and regular meals without restrictions.In their cohort,12subjects experienced re?ux events of pH4or less to the proximal probe (range1–17;mean number of events1.8;95th per-centile-3.72)[8].Based on these results,Smit et al. suggested that24-h pH-probe results with greater than0.1%of the total time or0.2%of the upright time at pH4or less should be considered patholog-ical[8].Their results also suggested that more than four re?ux episodes at pH4or less are considered pathological.The proximal probe position in the Smit et al.study represents a key divergence from the accepted standards for the proximal probe in a pH study for LPR[3,8].The possibility that the intra-sphincteric and hypopharyngeal probes are equiva-lent for diagnostic purposes is real;however,no head-to-head comparisons are as yet available to determine equivalency.
Table2.Summary of normative data derived from prospective controlled studies
No.of events%AET
Hypopharyngeal probe N LPR prev Mean Median SD95th%Mean Median SD95th% Eubanks et al.[26]b101/10(10%)
Total0.1NR0.3NR NR NR NR NR Upright0.1NR0.2NR NR NR NR NR Koufman[15]b120/12(0%)
Total00000000 Upright00000000 Oelschlager et al.[16]a102/10(20%)
Total0.200.4NR NR NR NR NR Upright0.200.4NR NR NR NR NR Shaker et al.[17]b122/12(17%)
Total0.200.4NR NR NR NR NR Upright0.200.4NR NR NR NR NR Toohill et al.[18]a347/34(21%)
Total NR0NR 2.3NR0NR NR Upright NR NR NR NR NR NR NR NR Ulualp et al.[19]a112/11(18%)
Total0.300.7NR0.8NR0.3NR Upright0.300.7NR0.8NR0.3NR Ylitalo et al.[24]a195/19(26%)
Total NR0NR8NR0NR0.1 Upright NR0NR6NR NR NR NR
N=number,LPR prev=laryngopharyngeal prevalence,NR=not reported,AET=acid exposure time,95th%=95th percentile.
a Clinically and endoscopically negative for LPR.
b Clinically negative for LPR.
252 B.E.Richardson et al.:LPR:Trends in Diagnostic Criteria
There is still a relatively small pool of studies for comparison.Interstudy comparison and meta-analysis are thwarted by incomplete demographic details in some studies,a lack of raw datasets,and small di?erences in protocol between studies.We appreciate the limitations imposed by small sample sizes;however,given the current level of variability in recording and reporting of data,it is not advisable to pool study results.Pooling the data would be possi-ble,but given the di?erences across studies in terms of design and data collected,the resulting normal limits would be di?cult to interpret.The most rea-sonable estimates of the upper limits for normal adult pH-monitoring reference intervals are based on the studies with the largest sample sizes and are sum-marized in Table3.
We appreciate the interesting di?erences be-tween the Bove et al.and the Vincent et al.studies relative to the Toohill et al.study[18,22,25].Spe-ci?cally,the range and95th percentile for the total number of episodes are much greater for the Bove and Vincent studies relative to the Toohill study [18,22,25].With such small sample sizes in each study,it is not clear if the di?erences are due to variance in the de?nition of‘‘normal’’subjects,the protocol followed,or if the intervals are equivalent given the large uncertainty in the interval estimates. In particular,the95th percentile for a sample with size39is the38th ordered observation.So,with the sample sizes of these three studies(40,23,and34), the percentile is de?ned to be essentially the largest measurement recorded.The reported studies pro-vide interesting,preliminary estimates of the upper limit of the normal reference range,but a much larger sample is required to provide a reliable esti-mate for the upper limit of the normal reference range.
Discussion
We conclude that it is di?cult to establish the range of adult physiologic PR using data available from the current prospective controlled and normative data studies relating to LPR.First,small sample sizes greatly limit the certainty of the normal ref-erence interval given the methods utilized to report pH-monitoring parameters.For example,when researchers use the percentile method to de?ne the normal reference interval,Linet[40]recommends a sample size of between125and700subjects, depending on the skew of the data distribution. Based on the data provided in the studies reported above,it appears that the distribution of PR observations among normal subjects is quite skewed and not representative of a Normal distribution.In addition,the largest normal sample available re-ports data from a sample of40subjects.To accu-rately proceed with the de?nition of a normal PR reference interval by the percentile method,it can be calculated that the minimum number of subjects needed to achieve a con?dence interval of±1.5% about the upper limit of normality would be approximately300subjects based on methods sug-gested by Linet and the characteristics of study data from Bove et al.[25,40].Narrowing the con?dence interval to±1%about the upper limit of normal-ity would increase the subject requirement to a minimum of approximately650.However,it should be noted by the reader that these conclusions are to be made carefully.The de?nition of normal subjects in the studies with the largest normal populations is presented in general terms and not explicitly de-?ned,leaving additional room for uncertainty [18,22,25].
An alternative to estimating the normal ref-erence range based on percentiles is to transform the data to conform more closely to a Normal distribu-tion so that a reference interval could be calculated based on the Normal distribution.The uncertainty in a normal reference interval estimated from the Nor-mal distribution method is less than one based on the percentile method[40].It is also relevant to point out that neither the percentile nor the Normal probability distribution method accounts for di?erences that may exist in the normal reference ranges among study
Table3.Summary of normative data trends
Bove et al.[25](N=40)Vincent et al.[22](N=23)Toohill et al.[18](N=34)
Median Range95th%Median Range95th%Median Range95th% %AET total00)1.10.200)0.30.100)0.25NR
%AET upright0NR0.300)0.20.2NR NR NR No.of events10)15 6.110)10 6.900)3 2.25
N=number of subjects;95th%=95th percentile;AET=acid exposure time;NR=not reported.
B.E.Richardson et al.:LPR:Trends in Diagnostic Criteria253
populations de?ned by age,gender,or other con-founding factors.
Currently,it is unknown if separate reference intervals are required for gender or age subgroups. Based on described changes in UES physiology that occur with age,it can be reasoned that a set of age-speci?c reference intervals may be necessary[17,32]. Regression modeling could be used to de?ne sub-group-speci?c reference intervals that would be ad-justed for various subject characteristics such as age or gender.Estimation of subgroup-speci?c reference intervals would likely require a larger number of subjects than is required for a general adult reference interval.
Recently,there has been a call for an investi-gation into the appropriateness of utilizing pH4as the paradigm for PR pH-monitoring examinations since most of the information arising from studies utilizing pH￡4are focused in the esophagus.The sensitivity of laryngeal mucosa to acid is well docu-mented[15,41].However,PR events at pH￡4are relatively infrequent and shifting the paradigm to pH ￡5may provide a better model for PR research, especially since the enzyme pepsin is believed to ex-hibit some activity between pH4and5[27,42]. Establishing the most appropriate acid pH model for studying LPR is obviously important and should precede further e?orts to de?ne a normal adult ref-erence interval.Future directions for LPR research will likely focus on pilot work,animal and human, investigating alternative paradigms for acid re?ux events and enzymatic contributions to upper airway pathology.
As we stated,the degree of reproducibility for a pH-monitoring study utilizing a hypopharyngeal probe position remains inexact.Vaezi et al.[13]re-ported rather poor reproducibility for data derived from an upper esophageal probe,specially in GERD patients with proximal re?ux events.The assumption that reproducibility for a hypopharyngeal probe is similar to that of the upper esophagus yields an equally poor standard for the reliability of data accumulated from the hypopharynx.The most reproducible parameters from the Vaezi et al.study (total and upright%AET)are often missing from published normative data leaving the clinician to rely on parameters with poorer reproducibility,like the number of events,to interpret study?ndings[28–31].
Establishing dual–channel pH monitoring as the true gold standard of LPR diagnosis will require the completion of two tasks:(1)identi?cation of the most appropriate LPR research paradigm(i.e.,pH4 vs.5,etc.)and(2)veri?cation of the reproducibility of that model.
Multichannel intraluminal impedance moni-toring is noteworthy as the latest technology to emerge for the study of bolus movement within the esophagus.It is able to demonstrate the direction of bolus movement,the height achieved by retrograde bolus propagation,quanti?cation of volume clear-ance times,and discrimination between acid and nonacid re?ux when paired with pH monitoring[43–45].Clinical questions that may be answered by multichannel intraluminal impedance monitoring will likely focus on patients with persistence of symptoms despite adequate medical or surgical therapy as well as the contribution of alkaline or neutral re?uxate to patient symptoms.
Summary
In conclusion,the current bodies of work that examine normal adults and the pH4paradigm to de?ne standards of physiologic PR do not conclu-sively establish a range of the number of pharyngeal acidi?cation events or the fraction of time in a24-h period that is compatible with physiologic re?ux.We are able to identify only trends in normal monitoring parameters like the%acid exposure time and the number of events per24hours at this time. References
1.Barbero GJ:Gastroesophageal re?ux and upper airway dis-
ease:Acommentary.Otolaryngol Clin North Am29:27–38, 1996
2.Wong RK,Hanson DG,Waring PJ,Shaw G:ENT mani-
festations of gastroesophageal re?ux.Am J Gastroenterol 95(Suppl):s15–22,2000
3.Koufman JA,Aviv JE,Casiano RR,Shaw GY:Laryngo-
pharyngeal re?ux:position statement of the committee on speech,voice,and swallowing disorders of the American Academy of Otolaryngology–Head and Neck Surgery.Oto-laryngol Head Neck Surg127(1):32–35,2002
4.Tuttle SG,Grossman MI:Detection of gastroesophageal
re?ux by simultaneous measurement of intraluminal pressure and pH.Proc Soc Exp Biol Med98:225–227,1958
5.Postma GN:Ambulatory pH monitoring methodology.Ann
Otol Rhinol Laryngol109:10–14,2000
6.Richter JE:Ambulatory esophageal pH monitoring.Am J
Med103(5a):131s–134s,1997
7.Dhiman RK,Saraswat VA,Naik SR:Ambulatory esopha-
geal pH monitoring:technique,interpretations,and clinical indications.Dig Dis Sci47:241–250,2002
8.Smit CF,Tan J,Devriese PP,Mathus-Vliegen LMH,
Brandsen M,Schouwenburg PF:Ambulatory pH measure-ments at the upper esophageal https://www.doczj.com/doc/6c624825.html,ryngoscope 108:299–302,1998
9.Richter JE,Bradley LA,DeMeester TR,Wu WC:Normal
24-hour ambulatory esophageal pH values:in?uence of
254 B.E.Richardson et al.:LPR:Trends in Diagnostic Criteria
study center,pH electrode,age and gender.Dig Dis Sci 37:849–856,1992
10.Dobhan R,Castell DO:Normal and abnormal proximal
esophageal acid exposure:results of ambulatory dual-probe pH monitoring.Am J Gastroenterol88:25–29,1993
11.Kahrilas PJ,Quigley EMM:Clinical esophageal pH
recording:a technical review for practice guideline develop-ment.Gastroenterology110:1982–1996,1996
12.Jacob P,Kahrilas PJ,Herzon G:Proximal esophageal pH-
metry in patients with‘‘re?ux laryngitis.’’.Gastroenterology 100:305–310,1991
13.Wiener GJ,Koufman JA,Wu WC,Cooper JB,Richter
JE,Castell DO:Chronic hoarseness secondary to gastro-esophageal re?ux disease:documentation with24-hour ambulatory pH monitoring.Am J Gastroenterol84:1503–1508,1989
14.Johnson LF,DeMeester TR:Twenty-four hour pH monitor-
ing of the distal esophagus.Aquantitative measure of gas-troesophageal re?ux.Am J Gastroenterol62:325–332,1974 15.Koufman JA:The otolaryngologic manifestations of gas-
troesophageal re?ux disease:a clinical investigation of225 patients using ambulatory24-h pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal https://www.doczj.com/doc/6c624825.html,ryngoscope101(4Pt2 Suppl53):1–78,1991
16.Oelschlager BK,Eubanks TR,Maronian N,Hillel A,Ole-
ynikov D,Pellegrini CA:Laryngoscopy and pharyngeal pH are complementary in the diagnosis of gastroesophageal–laryngeal re?ux.J Gastrointest Surg6(2):189–194,2002 17.Shaker R,Milbrath M,Ren J,Toohill R,Hogan WJ,Li Q,
Hofmann CL:Esophagopharyngeal distribution of re?uxed gastric acid in patients with re?ux laryngitis.Gastroenterol-ogy109(5):1575–1582,1995
18.Toohill RJ,Ulualp SO,Shaker R:Evaluation of gastro-
esophageal re?ux in patients with laryngotracheal stenosis.
Ann Otol Rhinol Laryngol107(12):1010–1014,1998
19.Ulualp SO,Toohill RJ,Ho?man R,Shaker R:Possible rela-
tionship of gastroesophagopharyngeal acid re?ux with path-ogenesis of chronic sinusitis.Am J Rhinol13(3):197–202,1999 20.Ulualp SO,Toohill RJ,Shaker R,Ulualp SO,Toohill RJ,
Shaker R:Pharyngeal pH monitoring in patients with pos-terior laryngitis.Otolaryngol Head Neck Surg120(5):672–677,1999
22.Vincent DAJr,Garrett JD,Radiono?SL,Reussner LA,
Stasney CR:The proximal probe in esophageal pH moni-toring:development of a normative database.J Voice 14(2):247–254,2000
23.Ylitalo R,Ramel S:Extraesophageal re?ux in patients with
contact granuloma:a prospective controlled study.Ann Otol Rhinol Laryngol111(5Pt1):441–446,2002
24.Ylitalo R,Lindestad PA,Ramel S:Symptoms,laryngeal
?ndings,and24-hour pH monitoring in patients with sus-pected gastroesophago-pharyngeal re?https://www.doczj.com/doc/6c624825.html,ryngoscope 111(10):1735–1741,2001
25.Bove M,Ruth M,Cange L,Ma nsson I:24-H pH monitoring
in healthy volunteers:a normative study.Scand J Gast-roenteroul35(3):234–241,2000
26.Eubanks TR,Omelanczuk PE,Maronian N,Hillel A,Pope
CE II,Pellegrini CA:Pharyngeal pH monitoring in222pa-tients with suspected laryngeal re?ux.J Gastrointest Surg 5(2):183–190,2001
27.Axford S,Sharp N,Ross PE,Pearson JP,Dettmar PW,
Panetti M,Koufman JA:Cell biology of laryngeal defenses
in health and disease:preliminary studies.Ann Otol Rhinol Laryngol110(12):1099–1108,2001
28.Hampton FJ,MacFadyen UM,Simpson H:Reproducibility
of24hour oesophageal pH studies in infants.Arch Dis Child 65(11):1249–1254,1990
29.Jamieson JR,Stein HJ,DeMeester TR,Bonavina L,Schw-
izer W,Hinder RA,Albertucci M:Ambulatory24-h esoph-ageal pH monitoring:normal values,optimal thresholds, speci?city,sensitivity,and reproducibility.Am J Gastroen-terol87(9):1102–1111,1992
30.Wiener GJ,Morgan TM,Copper JB,Wu WC,Castell DO,
Sinclair JW,Richter JE:Ambulatory24-hour esophageal pH monitoring:Reproducibility and variability of pH parame-ters.Dig Dis Sci33:1127–1133,1988
31.Vaezi MF,Schroeder PL,Richter JE:Reproducibility of
proximal probe pH parameters in24-h ambulatory esopha-geal pH monitoring.Am J Gastroenterol92(5):825–829,1997 32.Bardan E,Xie P,Brasseur J,Dua K,Ulualp SO,Kern M,
Shaker R:E?ect of aging on the upper and lower oesopha-geal sphincters.Eur J Gastroenterol12(11):1221–1225,2000 33.Kahrilas PJ,Dodds WJ,Dent J,Haeberle B,Hogam WJ,
Andofer RC:E?ect of sleep,spontaneous gastroesophageal re?ux and a meal on upper esophageal sphincter pressure in normal human volunteers.Gastroenterology92:466–471,1987 34.Knight RE,Wells JR,Parrish RS:Esophageal dysmotility as
an important cofactor in extraesophageal manifestations of gastroesophageal re?https://www.doczj.com/doc/6c624825.html,ryngoscope110(9):1462–1466, 2000
35.Shaker R,Dodds WJ,Ren J,Hogam WJ,Arndorfer RC:
Esophagoglottal closure re?ex:a mechanism of airway pro-tection.Gastroenterology102:857–861,1992
36.Shaker R:Protective mechanisms against supraesophageal
GERD.J Clin Gastroenterol30(3Suppl):s3–8,2000
37.Torrico S,Ren J,Sui Z,Hofmann C,Shaker R:Upper
esophageal sphincter function during gastroesophageal re?ux events[abstract].Gastroenterology114(4):G3481
38.Gerhardt DC,Shuck TJ,Bordeaux EA:Human upper
esophageal sphincter.Response to volume,osmotic and acid stimuli.Gastroenterology75:268–274,1978
39.Vakil N,Kahrilas PG,Dodds W,Vanagunas A:Absence of
an upper esophageal sphincter response to acid re?ux.Am J Gastroenterol84:606–610,1989
40.Linet K:Two-stage transformation systems for normaliza-
tion of reference distributions evaluated.Clin Chem33:381–386,1987
41.Delahunty JE,Cherry J:Experimentally produced vocal cord
https://www.doczj.com/doc/6c624825.html,ryngoscope78:1941–1947,1968
42.Panetti M,ReVille J,Clyne S,et al.:Clinical implications of
the functional stability of pepsin.Presented at the annual meeting of the American Academy of Otolaryngology–Head and Neck Surgery,September1998,San Antonio,TX 43.Shay SS,Bomeli S,Richter J:Multichannel intraluminal
impedance accurately detects fasting,recumbent re?ux events and their clearing.Am J Physiol Gastrointest Liver Physiol283(2):G376–G383,2002
44.Castell DO,Vela M:Combined multichannel intraluminal
impedance and pH-metry:an evolving technique to measure type and proximal extent of gastroesophageal re?ux.Am J Med111(Suppl8A):157S–159S,2001
45.Srinivasan R,Vela MF,Katz PO,Tutuian R,Castell JA,
Castell DO:Esophageal function testing using multichannel intraluminal impedance.Am J Physiol Gastrointest Liver Physiol280(3):G457–G462,2001
B.E.Richardson et al.:LPR:Trends in Diagnostic Criteria255