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CLINICIANS CORNERCLINICAL REVIEW

Evaluation and Managementof Laryngopharyngeal RefluxCharles N. Ford, MD

LARYNGOPHARYNGEAL REFLUX

(LPR) is the result of retro-grade flow of gastric contents tothe laryngopharynx, where it

comes in contact with tissues of the up-per aerodigestive tract. It has been re-ported in up to 10% of patients pre-

senting to an otolaryngologists office,1

and more than 50% of patients withhoarseness have been foundto have re-flux-related disease.2 There is a dan-ger in failing to recognize LPR, whileoverdiagnosis of LPR can lead to un-necessary costs and missed diagnoses.When a medicalpractitioner fails to rec-ognize LPR, patients have prolongedsymptoms and delayed healing.3 In-flamed laryngeal tissues are more eas-ily damaged from intubation, have agreater risk of progressing to forma-tion of contact ulcers and granulo-mas, and often evolve to symptomaticsubglottic stenosis4 and lower airwaydisease. In a recent report, LPR symp-toms were found to be more prevalentin patients with esophageal adenocar-cinoma than weretypical gastroesopha-geal reflux symptoms, and they oftenrepresented the only sign of disease.5

Heightened awareness of LPR can leadto overdiagnosis of the condition be-cause the typical LPR symptoms (ex-cessive throat clearing, cough, hoarse-ness, and globus pharyngeus [a

sensation of a lump in the throat]) arenonspecific6 and can also be caused byinfections, vocal abuse, allergy, smok-ing, inhaled environmental irritants,and alcohol abuse.7

EVIDENCE ACQUISITIONThe PubMed database was systemati-cally searched using the natural lan-guage phrases laryngopharyngealreflux, laryngopharyngeal reflux fundo-plication, and laryngopharyngeal re-flux PPI treatment. These phrases were

CME available online atwww.jama.com

Author Affiliation: Department of Surgery,Division ofOtolaryngology, University of Wisconsin, Madison.Corresponding Author: Charles N. Ford, MD,Univer-sity of Wisconsin Clinical Science Center, 600 High-landAve, K4/714, Madison, WI 53792 ([email protected]).ClinicalReview Section Editor: Michael S. Lauer, MD.We encourage authors to submit papers for con-sideration as a Clinical Review. Please contactMichael S. Lauer, MD, at [email protected].

Context Laryngopharyngeal reflux (LPR) is a major cause of laryngeal inflammationand presents with a constellation of symptoms different from classic gastroesopha-geal reflux disease.

Objective To provide a practical approach to evaluating and managing cases of LPR.

Evidence Acquisition The PubMed database and the Ovid Database of System-atic Reviews were systematically searched forlaryngopharyngeal reflux, laryngopha-ryngeal reflux fundoplication, laryngopharyngeal reflux PPI treatment, and gastro-esophageal reflux AND laryngitis. Pertinent subject matter journals and reference listsof key research articles were also hand-searched for articles relevant to the analysis.

Evidence Synthesis Reflux of gastric contents is a major cause of laryngeal pathol-ogy. The pathophysiology and symptom complex of LPR differs from gastroesophagealreflux disease. Laryngeal pathology results from small amounts of refluxatetypicallyoccurring while upright during the daytimecausing damage to laryngeal tissues andproducing localized symptoms. Unlike classic gastroesophageal reflux, LPR is not usu-ally associated with esophagitis, heartburn, or complaints of regurgitation. There is nopathognomonic symptom or finding,but characteristic symptoms and laryngoscopic find-ings provide the basis for validated assessment instruments (the Reflux Symptom Indexand Reflux Finding Score) useful in initial diagnosis. There are 3 approaches to confirm-ing the diagnosis of LPR: (1) response of symptoms to behavioral and empirical medicaltreatment, (2) endoscopic observation of mucosal injury, and (3) demonstration of re-flux events by impedance and pH-monitoring studies and barium swallow esophagram.While pH monitoring remains the standard for confirming the diagnosis of gastroesopha-geal reflux, the addition of multichannel intraluminal impedance technology improves

diagnostic accuracy for describing LPR events. Ambulatory multichannel intraluminal im-pedance assessment allows for identification of gaseous as well as liquid refluxate anddetection of nonacid reflux events that are likely significant in confirming LPR. Al-though some patients respond to conservative behavioral and medical management, asis the case with gastroesophageal reflux, most require more aggressive and prolongedtreatment to achieve regression of symptoms and laryngeal tissue changes. Surgical in-tervention such as laparoscopic fundoplication is useful in selected recalcitrant cases withlaxity of the gastroesophageal sphincter.

Conclusions Laryngopharyngeal reflux should be suspected when the history andlaryngoscopy findings are suggestive of the diagnosis. Failure to respond to a 3-monthtrial of behavioral change and gastric acid suppression by adequate doses of protonpump inhibitor medication dictates need for confirmatory studies. Multichannel intra-luminal impedance and pH-monitoring studies are most useful in confirming LPR andassessing the magnitude of the problem.

JAMA. 2005;294:1534-1540 www.jama.com

1534 JAMA, September 28, 2005Vol 294, No. 12 (Reprinted) 2005 American Medical Association. All rights reserved.

by JohnStanton, on June 7, 2007www.jama.comDownloaded from
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used individually, with no language ordate restrictions. PubMed was thensearched using the Medical SubjectHeading terms gastroesophageal refluxand laryngitis. These terms were com-

binedusing theANDoperator andwerelimited by language to English, by daterange to 2001-2005, and by publica-tion type to randomized controlledtrial OR clinical trial. The Ovid ver-sion of the Cochrane Database ofSystematic Reviews was also searchedusing the key-word combination oflaryngitis.mp and reflux.mp.

All retrieval sets generated by thePubMed and Ovid searches were re-viewed for relevant citations address-ing core issues of diagnosis, assess-

ment, and management. The referencelists of all relevant citations were re-viewed for further material describingvalidationof diagnostic instruments andbasic science addressing pathogenesisand evolving technology. References inthe Cochrane Database of SystematicReviews protocol for reviewing acid re-flux treatment of hoarseness were par-ticularly useful.

EVIDENCE SYNTHESIS

Pathogenesis

Laryngopharyngeal reflux differs fromgastroesophageal refluxdisease (GERD)in that it is often not associated withheartburn and regurgitation symp-toms.8 The larynx is vulnerable to gas-tricreflux,so patients often present withlaryngopharyngeal symptomsin the ab-sence of heartburn and regurgitation.8

There are 4 physiological barriers pro-

tecting the upper aerodigestive tractfrom reflux injury: the lower esopha-geal sphincter, esophageal motor func-tion with acid clearance, esophagealmucosal tissue resistance, and the up-

per esophageal sphincter.1 The deli-cate ciliated respiratory epithelium ofthe posterior larynx that normallyfunc-tions to clear mucus from the tracheo-bronchial tree is altered when these bar-riers fail, and the resultant ciliarydysfunction causes mucus stasis.9 Thesubsequent accumulation of mucusproduces postnasal drip sensation andprovokes throat clearing. Direct reflux-ate irritation can cause coughing andchoking (laryngospasm) because sen-sitivity in laryngeal sensory endings is

up-regulated by local inflammation.9

This combination of factors can lead tovocal fold edema, contact ulcers, andgranulomas that cause other LPR-associated symptoms: hoarseness, glo-bus pharyngeus, and sore throat.1

Recent investigations suggest thatvulnerable laryngeal tissues are pro-tected from reflux damage by the pH-regulating effect of carbonic anhy-drase in the mucosa of the posteriorlarynx.10 Carbonic anhydrase cata-lyzes hydration of carbon dioxide to

produce bicarbonate; this protects tis-sues from acid refluxate. In the esopha-gus, there is active production of bi-carbonatein the extracellular space thatfunctions to neutralize refluxed gas-tric acid. There is no active pumpingof bicarbonate in laryngeal epitheliumand carbonic anhydrase isoenzyme III,expressed at high levels in normal la-

ryngeal epithelium,wass absent in 64%(47/75) of biopsy specimens from la-ryngeal tissues of LPR patients.11

Diagnosis

History. It is important for physiciansto appreciate the potential signifi-cance of hoarseness and the relativenonspecificity of laryngitis. Laryngitisis a nonspecific designation of laryn-geal inflammation.12 Often, it is mildand resolves spontaneously. When per-sistent, laryngitis must be further de-fined based on probable etiologic fac-tors: viral or bacterial infection, allergy,vocal trauma, postnasal discharge, orLPR (TABLE). Persistent or progres-sive hoarseness lasting beyond 2 to 3

weeks requires examination of the la-ryngopharynx to rule out cancer andother serious conditions. This is gen-erally considered good practice; how-ever, laryngeal examination is particu-larly important in suspected LPRbecause of the apparent known asso-ciation of LPR and upper aerodiges-tive tract cancer.5,13

Laryngopharyngeal reflux should besuspectedwhenclinical history and ini-tial findings are suggestive. Failure toappreciateLPR as different from GERD

has been a major source of skepticismabout the diagnosis in the past. Kouf-man1 was the first to clearly distin-guish LPR from GERD, noting that ina combined reported series of 899 pa-tients, throat clearing was a complaintof 87% of LPR patients vs 3% of thosewith GERD, while only 20% of LPR pa-tients complained of heartburn vs 83%

Table. Clinical Clues to Distinguish LPR From Other Causes of Hoarseness

LPR InfectionRhinosinusitis

(Postnasal Drip) AllergyBenign

Vocal Fold LesionMalignant

Vocal Fold Lesion

Hoarsenesscharacteristic

Fluctuates Acute, resolves Acute/chronic orrecurrent

Fluctuates Constant Progressive

Throat pain Common (withcough, throat

clearing)

Yes Uncommon No From secondarymuscle tension

Late (local andreferred)

Laryngealfindings

Edema,granuloma,erythema,pseudosulcus

Erythema, edema Secretions (thick,discolored),edema

Edema, clearsecretions,bluish mucosa

Nodules, polyps,cysts, scars

Ulcerative or exophytic(red-white mass),stiff

Aggravatingfactors

Smoking, obesity,diet/lifestyle

Systemic infection,immunosuppression

LPR, allergy,smoking

Environment,seasonal

Smoking, vocaltrauma, LPR

Smoking (common),LPR, ethanolism

Abbreviation: LPR, laryngopharyngeal reflux.

MANAGEMENT OF LARYNGOPHARYNGEAL REFLUX

2005 American Medical Association. All rights reserved. (Reprinted) JAMA, September 28, 2005Vol 294, No. 12 1535


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in the GERD group. An internationalsurvey of American Bronchoesophago-logical Association members revealedthat the most common LPR symptomswere throat clearing (98%), persistentcough (97%), globus pharyngeus(95%), and hoarseness (95%).14 Basedon a careful study of pH probeconfirmed LPR cases, Belafsky et al15 de-veloped a useful self-administered tool,

the Reflux Symptom Index, that canhelp clinicians assess the relative de-gree of LPR symptoms during initialevaluation and after treatment. Pa-tients are asked to use a 0- to 5-pointscale to grade the following symp-toms: (1) hoarseness or voice prob-lem, (2) throat clearing, (3) excessthroat mucus or postnasal drip, (4) dif-ficulty swallowing, (5) coughing aftereating or lying down, (6) breathing dif-ficulties or choking spells, (7) trouble-some or annoying cough, (8) sensa-

tion of something sticking or a lump inthe throat, and (9) heartburn, chestpain, indigestion,or stomach acid com-ing up. The Reflux Symptom Indexscore in untreated LPR patients wassig-nificantly higher than in controls (21.2vs 11.6; P.001). Since the 95% up-per confidence limit for controls was13.6, a Reflux Symptom Index score

greater than 13 is considered abnor-mal. When hoarseness is a prominentsymptom, acoustic voice analysis mea-suring frequency, intensity, perturba-tion, and signal-to-noise ratio pro-vides an objective way to document

symptom severity and progress of thedisease.2

Laryngoscopy. Nonspecific signs oflaryngealirritationand inflammationareusually seen, but several findings arehighly suggestive of LPR. Although notpathognomonic, thickening, redness,and edema concentrated in the poste-rior larynxposterior laryngitisisa common finding.7 Based on a coloranalysis, Hanson and Jiang9 quantifiedthe degree of erythema as a measure ofposterior laryngitis. Other laryngo-scopic findings have a strong associa-

tion with LPR. Contact granuloma wasfound to be associated with pH moni-toringconfirmed cases of LPR in 65%to 74% of patients.16,17 Frequently, themedial edge of the vocal fold appears tohave a linear indentation due to diffuseinfraglottic edema (FIGURE 1). Al-though this gives theillusion of a patho-logical condition of thevocal fold calledsulcus vocalis, in which there is a me-dial edge concavity of the vocal fold(sulcus) due to fibrosis and tissue loss,it lacks the fibrotic changes of patho-

logical sulcus vocalis.18

This finding istermed pseudosulcus and has been re-ported in as much as 90% of LPRcases.19 In a comparison of 30 LPR pa-tients and 30 controls, those with pseu-dosulcus were 2.5 times more likely tohave pH testingconfirmed LPR(P.001).20 Although the sensitivityand specificity of finding pseudosul-cus in LPR patients were only 70% and77%, respectively, pseudosulcus re-mains highly suggestive of LPR.

Since there is no pathognomonicLPR

finding, Belafsky et al

21

developed an8-item clinical severity scale for judg-ing laryngoscopic findings, the RefluxFinding Score, which appears to be use-ful for assessment andfollow-upof LPRpatients. They rated 8 LPR-associatedfindings on a variably weighted scalefrom 0 to 4: subglottic edema,ventricu-lar obliteration, erythema/hyperemia, vo-

cal foldedema, diffuse laryngeal edema,posterior commissure hypertrophy,granuloma, and thick endolaryngealedema. The results could range from 0(normal) to 26 (worst possible score).Based on their analysis, one can be 95%

certain that a patient with a Reflux Find-ing Score of 7 or more will have LPR.Confirming Reflux. There are 3 ap-

proaches to confirming the diagnosis:response of symptoms to behavioralandempirical medical treatment, endo-scopic observation of mucosal injury,and demonstration of reflux events bymultichannel impedance and pH-monitoring studies. Additional stud-ies, including radiography, esophagealmanometry, spectrophotometric mea-surement of bile reflux, andmucosal bi-opsy, can provide information useful in

targeting therapy.Because many patients respond well

to behavioral modification and initialmedical management, an acid suppres-sion trial is a frequently used ap-proach to initial diagnosis.22 The main-stay of empirical treatment is protonpump inhibitor (PPI) medication for atleast 3 months.

Endoscopic examination should in-clude flexible or rigid laryngoscopy inall suspected cases. Transnasal esopha-goscopy and esophagogastroduodenos-

copy (EGD) areuseful in detecting char-acteristic associated mucosal injury,esophagitis, and Barrett esophagus.Ov er al l , EG D and 2 4 - ho ur pH -monitoring studies have proven lessuseful in detecting LPR than in identi-fying GERD. While EGD reveals esoph-ageal lesions in 50% of typical GERDpatients, it is abnormal in less than 20%of LPR laryngitis patients.23

Demonstrationof reflux eventsis bestachieved with ambulatory multichan-nel intraluminalimpedance (MCII) and

pH-monitoring studies.

24

This ap-proach is based on changes in resis-tance to alternating current between aseries of metal electrodes produced byintraluminalgas,liquid,or bolus. Whencombined with pH transducers, itmakes it possible to give a more com-plete description of reflux events.25 Notonly can acid andnonacid reflux events

Figure 1. Reflux-Induced Granulomas andPseudosulcus

This rigid telescopic view shows a larynx with largebilateral granulomas based on the medial surfaces ofthe arytenoids(top). A prominent pseudosulcus is iden-

tified (arrowhead), representing typical infraglotticedema associated with laryngopharyngeal reflux.




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be detected but, also, liquid (de-creased impedance) as well as gaseous(increased impedance) events can beidentified. Although controversy ex-ists, an LPR event is evident when pHin the proximal sensor abruptly drops

to less than 4 during or immediately af-ter distal acid exposure (exposure nearthe lower esophageal sphincter) andLPR is confirmed when total acid ex-posure time (percentage of time dur-ing 24-hour monitoring when the sen-sor detects pH levels4) is more than1%.24 Reflux is often associated withesophageal dysmotility, including non-progressive (tertiary) contractions, in-creased amplitude and duration ofcontractions, and increased tone.1 Mul-tichannel intraluminal impedance soft-ware technology combined with ma-

nometry allows for graphic displays ofsimulated esophageal motility, sphinc-ter competence, andbolus transport, sothe use of barium swallow studies ismore limited in LPR assessment.

Treatment

Patient Education and BehavioralChange. Patients with LPR should beeducated as to the nature of the prob-lem and counseled on helpful behav-ioral and dietary changes.26 Importantbehavioral changes include weight loss,

smoking cessation, and alcohol avoid-ance. Ideal dietary changes would re-strict chocolate, fats, citrus fruits, car-bonated beverages, spicy tomato-based products, red wines, caffeine,andlate-night meals. Such behavioralchanges appear to be an indepen-dently significant variable in determin-ing response to medical therapy.27 Edu-cation should include the optimalschedule for taking PPI medications(omeprazole, esomeprazole, rabepra-zole, lansoprazole, and pantoprazole),

which work best when taken 30 to 60minutes before meals.Medical Management. There are 4

categories of drugs used in treating LPR:PPIs, H2-receptor antagonists, proki-netic agents, and mucosal cytopro-tectants. Proton pump inhibitors areconsidered themainstayof medical treat-ment,28 although there is some contro-

versyregarding their efficacy. A 3-monthempirical trial is a cost-effective ap-proach to initial assessment and man-agement.29,30 Responders canbeweaned,while nonresponders should undergostudies to confirm LPR.

Other drugs have been used to treatLPR. Ranitidine has proven a morepotentinhibitor of gastricsecretion thancimetidineandistheH2-receptorantago-nist of choice,31 although it has beenfound to be of limited value in treatingLPR.32 Prokineticagents that accelerateesophagealclearance andincreaseloweresophagealsphincterpressurehavefallenoutof favor because of reported adverseeffects of ventricular arrhythmias anddiarrhea.33 Cisapride has been discon-tinued because of such serious adverseeffects. Tegaserod is a prokinetic agent

that was recently demonstrated todecrease reflux and lower esophagealsphincter relaxationevents34 andthatwehave found useful in treating some LPRcaseswith associatedesophagealdyski-nesia. Sucralfate is a polysulfated salt ofsucrose that maybe helpful asanadjunctin protecting injured mucosa fromharmful effects of pepsin and acid.35,36

Antacids (sodium bicarbonate, alumi-num-, and magnesium-containingover-the-counter antacids) may relieveGERD symptoms but do not play a role

in LPR management.26

Surgery. When medical manage-ment fails, patients with demon-strable high-volume liquid reflux andlower sphincter incompetence are of-ten candidates for surgical interven-tion. Fundoplication, either complete(Nissen or Rossetti) or partial (Toupetor Bore), is the most common proce-dure performed, and the laparoscopicapproach is preferred.2 The goal of sur-gery is to restore competence of thelower esophageal sphincter, and the

outcome measures for LPR includedemonstration of reduced pharyngealreflux episodes. Excellent results havebeen reported in 85% to 95% of refluxcases37 but results with LPR are not asimpressive.22 Focusing on a carefullyscreened group of patients withdemon-strable extraesophageal reflux (LPR),Oelschlager et al38 reported a signifi-

cant decrease in pharyngeal reflux (7.9to 1.6 episodes per 24 hours; P.05)and esophageal acid exposure (7.5% to2.1%; P.05) following basic laparo-scopic Nissen fundoplication surgery.Fundoplication appears superior to

medicalmanagement in preventing Bar-rett metaplasia.39 Although there is in-terest in recent nonfundoplication en-doscopic techniques (Bard EndoCinchSystem for endoluminal plication, C. R.Bard, MurrayHill, NJ;Stretta System forradiofrequency-induced thermal in-jury, Curon Medical, Fremont, Calif;and Enteryx liquid polymer injection,Boston Medical, Natick, Mass) to im-prove lower esophageal sphinctericfunction, there are no controlled stud-ies and there is no long-term fol-low-up evidence to support their use.40

CONTROVERSIES

While there is an increased apprecia-tion of LPR as distinctfrom GERD,con-troversy remains regarding how to con-firm the diagnosis and what comprisesappropriate medical management. Inmild LPR cases, symptoms and physi-cal findings lack sufficient specificity;similar symptoms canresultfrom smok-ing, toxic inhalants, allergies, and post-nasal discharge. Assessing treatmentregimens is complicated because clini-

caltrials arevulnerableto placebo effect,uncontrolled behavioral changes, andthe variable natural history of LPR.23,41,42

Apparently, 25% of LPR patients expe-rience spontaneous resolutionof symp-toms and 50% have a chronic course ofdisease, with intermittent exacerba-tions and remissions.1

Physical Findings

Laryngoscopic findings can be mislead-ing,asshowninseveralstudiesinwhichasymptomatic participants revealed

findings similar to those seen in LPR-proven patients. Lundy et al43 foundposterior erythema in 73% of asymp-tomatic singing students and Hickset al41 found tissue changes associatedwith LPR in a group of more than 100asymptomaticvolunteers. Lackof a reli-able clinical marker has confoundedprogress in the diagnosis and treat-




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ment of LPR.23 Some trials based onclinical diagnosis have been misinter-preted because of lax inclusion crite-ria. The symptoms and physical find-ings of mild LPR can be confused withotherlaryngeal inflammationsand non-

pathological variations. Since patientswith advanced LPR and obvious pos-terior laryngitis probably differ frompatients with milder cases that mighthave alternative etiologies; future effi-cacystudiesshouldbe rigorous in theirexclusioncriteriaand/orstratify patientsin the treatment group.44 A break-through in LPR diagnosis may evolvefrom recent immunohistochemicalstudies of laryngeal biopsy specimensshowing concentration of pepsin and

depletion of carbonicanhydrase isoen-zyme III in documented LPR cases.45

pH Monitoring

Hydrogen ion concentration monitor-ing is considered the gold standard in

detecting GERD, but it is less reliable inconfirming LPR.46 Variability in testingmethods and lack of agreement on nor-mative values have raised questionsabout the sensitivity of pH-monitoringstudies for detecting LPR.44,47,48 In somestudies, the proximal probe was placedbelow the upper esophageal sphincterandin othersinthehypopharynx,whereit is considered closer to the site of in-jury.49 High placement of the proximalprobe is subject to spuriousdropsin pH

related to the wide-open pharynx andintermittent probe drying. The re-cently developed Bravo wireless pH-monitoring system (Medtronic Inc,Shoreview, Minn) allows for precise en-doscopic placement of the pH trans-

ducer at the upper esophageal sphinc-ter. A pinch of esophageal mucosa isused to securetheBravo capsule, andthepatient wears a pager-sized monitor dur-ing 48hours ofnormal activity. The cap-sule passes in 3 to 5 days with the su-perficial sloughing of mucosa. This hasbeen proven more effective in childrenand some adults who fail to tolerate anexternal catheter.50

Disagreement about normative val-ues adds to the controversy. An abruptdecreaseinpH to lessthan4 inthe proxi-malprobefollowingor synchronouswith

a drop at the lower esophageal sphinc-ter is considered a default cutoffvalue,51

but this is largely based on lower esoph-ageal standardsapplied to GERD.In thehypopharynx, a drop to less than 5 isprobably a more reliable indicator ofproximalreflux becauseneutralizing fac-tors such as saliva and airway secre-tions can raise pH values.52 Failure todemonstrate clinical correlation in pHstudies can result from not recognizingthe minimal amount of gastric reflux-ate necessary to cause laryngeal inflam-

mation (in patients with LPR) or fromnotconsidering alternative sources of la-ryngealinflammation in controlgroups.48

An importantrecent meta-analysis of16 double pH-probe studies showedconsistencyand accuracy in distinguish-ing healthy persons vs those with LPRwhere techniques were tightly con-trolled.51 Upper probeplacementat 2 cmabove the upper esophageal sphincterwas considered critical; higher place-ment reduces contact of the sensor withmucosa, drying, and false-positive read-

ings, whereas events at or below thesphincter fail to correlate with LPRsymptoms. This study affirmed thatwhile healthy persons experiencedsomerefluxevents,theacidexposuretimeper-centage is very reliable in differentiat-ing persons with and without LPR. Us-ing a mixed-effects model, LPR wasfound to be a statistically significantrisk

Figure 2. Algorithm for Assessment and Management of LPR

6-mo Follow-up Assessment

3-mo Follow-up Assessment

Initial Assessment

Patient With Possible LPR

Empirical Therapeutic Trial

LifestyleDietPPI Therapy

Definitive Assessment (Perform 1 or More Studies)

Multichannel Impedance and pH Monitoring (Demonstrate Reflux)

TNE or EGD (Document Pathology)

Manometry (Assess Etiology)

Barium Swallow

Titrate PPITherapy

Titrate PPI Therapy Increase Dose of PPIContinue Lifestyle and

Diet Modifications

Reflux Symptom Index (History, Symptoms) >13and

Reflux Finding Score (Laryngoscopy) >7

Symptoms Improved

SymptomsResolved

Symptomsnot Resolved

Symptoms Resolved Symptoms Unchanged or Worse

When the history and clinical examination are suggestive of laryngopharyngeal reflux (LPR), patients areinstructed in lifestyle and dietary changes. Proton pump inhibitor (PPI) therapy is started and the patientis reassessed 3 months later. Failure to respond dictates a pathway to definitive assessment and continuedmonitoring. Those showing improvement proceed with more medical treatment, whereas those with resolu-tion of symptoms have PPI treatment tapered. TNE indicates transnasal esophagoscopy; EGD,esophagogastroduodenoscopy.




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factor for experiencing objective refluxevents (odds ratio, 9.19; 95% confi-dence interval, 5.4-15.4; P.001).

Another problem with standard pHprobemonitoringstudiesis failureto ac-count for bouts of potentially harmful

gaseous and/or nonacid refluxate. Thisis where impedance testing is supe-rior.24 Gaseous reflux events associatedwith small pH drops (1) have beenfound with significantly greater fre-quency in patients with LPR than inthose with GERD or in healthy con-trols. The ability to detect gaseous andmixed (gaseous-liquid) events is par-ticularly important in patientswithLPRbecause gasesaremorediffusibleandcanreach higher laryngeal structures. Fur-thermore, impedancetesting detectspo-tentially harmful nonacidic reflux. Pel-

legrini et al53 called attention to alkalinegastroesophageal reflux long ago, andGalli et al54 demonstrated laryngopha-ryngeal damage in patients whose gas-trectomy procedures resulted in ana-tomically predictable bile reflux. In arecent report, Sasaki et al55 demon-strated marked inflammatory histologi-cal changes in rat laryngeal mucosa ex-posed to bile salts in both acid andalkaline media; he suggested that bili-ary and acid reflux may exert a syner-gistic role in damaging esophageal mu-

cosa. This finding might also explainsome of the therapeutic failures of acidsuppression used as the sole treatmentfor LPR.

Efficacy of PPI Treatment

Unlike with GERD, response to PPItherapy in patients with LPR has beendescribed as highly variable.22 Thisis inpart because LPR requires more aggres-sive and prolonged therapy thanGERD.56 Clinical trials have failed toquell the controversy because studies

have had different inclusion criteria,failed to stratify populations based onLPR severity, lacked adequate con-trols,and, often,used inappropriate dos-ageor durationoftherapy.27,29,42,57,58 Con-founding factors can undermineconclusions; for example, in a class 1randomized, placebo-controlledtrial de-signedto demonstrate theefficacy of PPI

therapy for LPR, Steward et al27 foundthat lifestylemodification for 2 months,with or without PPI therapy, signifi-cantly improved chronic laryngitissymptoms. In a recent open-labeled, pro-spective cohort study, Park et al56 shed

somelightonthecontroversy. They con-cluded that twice-daily dosing of PPIre-sulted in significantly higher symptomrelief than daily dosing (P =.03) andnoted that nonresponders improvedwhen twice-daily dosage was extendedfrom2 to 4 months. Like Fackler et al,32

they found that the addition of H2-antagonist therapy at bedtime was of noadded benefit. Further clarificationis an-ticipated based on the Cochrane Data-base of Systematic Reviews protocol thatwill focus on clinical trials with atten-tion to randomization, selection bias,

blinding process, and outcome assess-ment in reviewing acid reflux treat-ment of hoarseness.2

RECOMMENDATIONSAND CONCLUSIONS

The algorithm in FIGURE 2 summa-rizes an approach to assessment andmanagement of LPR-induced hoarse-ness. It begins with clinical evaluationand progresses to an empirical trial oflifestyle and dietary changes and ini-tiation of PPI therapy. Although most

patients can experience symptomaticimprovement in 3 months, it oftentakesat least 6 months for the laryngealsymptoms and related physical find-ings to resolve.9 Unlike GERD, treat-ment for LPR must be more aggressiveandprolonged in many cases to achieveresolution.8,56 Patients whose LPR hasresolved should have drugs titratedoff,while others who show signs of im-provement should be treated withomeprazole, 40 mg (or an equivalentPPI), twice daily 30 to 60 minutes be-

fore meals.Cases that fail to substantially im-prove with aggressive medical manage-ment over 3 months require definitiveassessment. Ambulatory MCII with pHmonitoring is currently the most effec-tive way to demonstrate LPR. Wheresuch technology is not available, mul-tichannel pH monitoring remains a

well-tested option. Mucosal injury, hia-tal hernia, and other esophageal pa-thology such as Barrett esophagusshould be documented by esophagos-copy (transnasal esophagoscopy orEGD). Barium swallow esophagos-

copy, manometry, and MCII with ma-nometry can be helpful in demonstrat-ing pathology, describing dysmotilityproblems, and guiding the surgeon inplanning fundoplication surgery. Pa-tients whose LPR fails to resolve afterdefinitive medical or surgical treat-ment must be followed indefinitelywithcareful examination of the upper aero-digestive tract for signs of complica-tions and malignancy.5

Financial Disclosures: None reported.Acknowledgment: I thankEricA. Gaumnitz,MD, Gas-troenterologySection, Universityof Wisconsin, for hiscareful reading of an early version of the manuscript

and helpful suggestions.

REFERENCES

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