Chest pain of unknown Chest pain of unknown origin (CPUO): role of the origin (CPUO): role of the

esophagusesophagus

Richard I. Rothstein, MDRichard I. Rothstein, MDChief, Section of Gastroenterology and HepatologyChief, Section of Gastroenterology and Hepatology

Dartmouth Hitchcock Medical CenterDartmouth Hitchcock Medical CenterProfessor of MedicineProfessor of Medicine

Dartmouth Medical SchoolDartmouth Medical School

Chest Pain of Unknown OriginChest Pain of Unknown Origin

Prognosis for angina-like pain with Prognosis for angina-like pain with normal coronary anatomynormal coronary anatomy

Chambers, Prog Cardiovasc Dis 1990

Kemp, Am J Med 1973

Functional Status – normal Functional Status – normal coronary anatomycoronary anatomy

Ockene N Engl J Med 1980

Reflux common in pts Reflux common in pts withwith coronary diseasecoronary disease

Singh, Ann Intern Med,1992; 117:824-30n = 30, 164 chest pain episodes

Abnormal esophageal motilityAbnormal esophageal motility

(n = 910) (n = 255)

Katz, Ann Intern Med, 1987; 106:593-7

Edrophonium TestingEdrophonium Testing

80 mcg/Kg IV

Diagnostic Yield of Esophageal Diagnostic Yield of Esophageal TestingTesting

Katz, Ann Intern Med, 1987; 106:593-7

Intraesophageal Balloon Inflation:Intraesophageal Balloon Inflation:Esophageal HypersensitivityEsophageal Hypersensitivity

n = 30 NCCP, 30 controls Richter, Gastroenterol, 1986; 91:845-52

Provocative TestingProvocative Testing

Barrish, Dig Dis Sci, 1986; 31:1292-8

WithWithEsophagealEsophagealSymptomsSymptoms

IsolatedIsolatedChestChestPainPain

Subgroups of Patients With Chest Subgroups of Patients With Chest PainPain

Anxiety/SomatizationAnxiety/SomatizationNeurosisNeurosis

• Rare for esophageal pathologyRare for esophageal pathology• Question the “non-cardiac”Question the “non-cardiac”• Reassurance, tincture of timeReassurance, tincture of time

Subgroups of Patients With Chest Subgroups of Patients With Chest PainPain

IsolatedIsolatedChestChestPainPain

• HeartburnHeartburn

• RegurgitationRegurgitation

• DysphagiaDysphagia

• Water brashWater brash

• NauseaNausea

• VomitingVomiting

Evaluate or treat for recognized esophageal disordersEvaluate or treat for recognized esophageal disorders

WithWithEsophagealEsophagealSymptomsSymptoms

Subgroups of Patients With Chest Subgroups of Patients With Chest PainPain

EndoscopyEndoscopy

Detection of Esophageal Disorders Detection of Esophageal Disorders Potentially Responsible for Potentially Responsible for

SymptomsSymptoms

pHpH • EGD-negative GERDEGD-negative GERD

Barium swallow ± Barium swallow ± manometrymanometry

• Esophageal stricture/webEsophageal stricture/web

• AchalasiaAchalasia

• Esophageal spasmEsophageal spasm

• Reflux esophagitisReflux esophagitis

• Infectious esophagitisInfectious esophagitis

• Pill esophagitisPill esophagitis

• Esophageal cancerEsophageal cancer

• Esophageal stricture/webEsophageal stricture/web

pH testing - Conventional pH testing - Conventional

Catheter Based:Catheter Based:

Patient IntolerancePatient Intolerance UncomfortableUncomfortable Pharyngeal and Throat Pharyngeal and Throat

DiscomfortDiscomfort Runny NoseRunny Nose

Artifact ProneArtifact Prone Alters Regular Diet and Alters Regular Diet and

ActivityActivity

                        

Catheter-Free pH Monitoring System

pH Capsule attached to the esophageal wall transmits data to pager-sized Receiver

Eliminates uncomfortable 24-hr trans-nasal catheter

Allows normal activities, showering and does not interfere with sleeping

Bravo pH System™Bravo pH System™

pH Capsule

Catheter

Handle

Bravo pH Capsule with Bravo pH Capsule with Delivery SystemDelivery System

Step 1

Position Bravo Capsule

Step 2

Apply Suction

Step 3

Advance Pin

Step 5

Begin pH Recording

Step 4

Release Capsule

Capsule Attachment

pH Capsule transmits data to pager-sized Receiver

pH Capsule

Receiver

Bravo pH ReceiverBravo pH Receiver

Use Digital Radio-Telemetry

Capsule measures pH every 6 sec and transmits data to receiver every 12 sec

Keep the receiver within 1m to prevent data loss (range up to 3m)

Digital Radio-TelemetryDigital Radio-Telemetry

Esophageal Testing in 123 Patients with Chest Pain Esophageal Testing in 123 Patients with Chest Pain and Normal Coronary Arteriogramsand Normal Coronary Arteriograms

TestTest% Abnormal% Abnormal

Ambulatory pH monitoringAmbulatory pH monitoring 8282

Esophageal motilityEsophageal motility 2929

Bernstein TestBernstein Test 1010

EdrophoniumEdrophonium 66

EndoscopyEndoscopy 55

Balloon distentionBalloon distention 44

Treadmill with pH monitorTreadmill with pH monitor 44

Chenan P, et al Dis Esophagus 1995; 8:129Chenan P, et al Dis Esophagus 1995; 8:129

Atypical presentations of Atypical presentations of GERDGERD

PulmonaryPulmonaryAsthmaAsthmaBronchitisBronchitisAspiration pneumoniaAspiration pneumoniaApneaApneaAtelectasisAtelectasisPulmonary fibrosisPulmonary fibrosis

ENTENTHoarsenessHoarsenessCoughCoughGlobusGlobusHalitosisHalitosisVocal cord granuloma Vocal cord granuloma Laryngeal stenosisLaryngeal stenosisLaryngeal cancerLaryngeal cancerLoss of dental enamelLoss of dental enamelSinusitis, otitisSinusitis, otitisChest PainChest Pain

Esophageal Chest Pain Work-UpEsophageal Chest Pain Work-Up

TraditionallyTraditionally EndoscopyEndoscopy pH probepH probe ManometryManometry Provocative testingProvocative testing

Emerging role for up-front Emerging role for up-front empiricismempiricism

Fass et al. Fass et al. GastroenterologyGastroenterology. 1998;115:42-49.. 1998;115:42-49.

GERD-PositiveGERD-Positive• n=23n=23• 78% response78% response

GERD-NegativeGERD-Negative• n=14n=14• 14% response14% response

PPI Trial in GERD Patients With PPI Trial in GERD Patients With Non-Cardiac Chest PainNon-Cardiac Chest Pain

37 patients with daily chest pain and negative cardiologic 37 patients with daily chest pain and negative cardiologic evaluationevaluation

Categorized as GERD+ or GERD- by EGD and pH studyCategorized as GERD+ or GERD- by EGD and pH study Randomized to omeprazole (40 mg q AM and 20 mg q PM for 7 Randomized to omeprazole (40 mg q AM and 20 mg q PM for 7

days) or placebo then crossed over after washoutdays) or placebo then crossed over after washout 50% reduction in symptoms constituted positive response50% reduction in symptoms constituted positive response

Characteristics of the PatientsCharacteristics of the Patients

Patients with NCCPPatients with NCCP

GERD-positiveGERD-positive GERD-negativeGERD-negative

Fass R, et al Gastroenterol 1998; 115:42-9Fass R, et al Gastroenterol 1998; 115:42-9

SubjectsSubjects 23231414

Age (yr)Age (yr) 58.2±58.2±2.32.3 61.6±61.6± 2.82.8

Range (yr) 35-76 47-83Range (yr) 35-76 47-83

Sex (M / F) 22 / 1 14 / 0Sex (M / F) 22 / 1 14 / 0

Upper endoscopy resultsUpper endoscopy results

Normal (grade 0-1)Normal (grade 0-1) 771414

Erosive esophagitis (grade 2-5)Erosive esophagitis (grade 2-5) 1616

Ambulatory 24-h esophageal pHAmbulatory 24-h esophageal pH

monitoring (%)*monitoring (%)*

MeanMean 9.6±9.6±1.81.8 1.2±1.2± 0.30.3

Range 0.5-29.1 0.0-2.9Range 0.5-29.1 0.0-2.9

*% total time pH<4*% total time pH<4

EnrollmentEnrollment

Upper endoscopy &Upper endoscopy &Ambulatory 24-hour esophageal pH Ambulatory 24-hour esophageal pH

monitoringmonitoring

GERD + GERD -GERD + GERD -

Baseline symptom assessmentBaseline symptom assessment

RandomizationRandomization

Placebo Placebo OmeprazoleOmeprazole(40 mg AM + 20 mg PM)(40 mg AM + 20 mg PM)

Washout periodWashout period

Baseline symptom assessmentBaseline symptom assessment

Omeprazole Omeprazole Placebo Placebo (40 mg AM + 20 mg PM)(40 mg AM + 20 mg PM)

Week 1Week 1

Week 2Week 2

Week 3Week 3

Week 4Week 4

Week 5Week 5Fass R, et al Fass R, et al

Gastroenterol 1998; Gastroenterol 1998; 115:42-9115:42-9

Omeprazole Test in NCCPOmeprazole Test in NCCP

18/23 GERD-positive (78%)18/23 GERD-positive (78%) 2/14 GERD-negative (14%)2/14 GERD-negative (14%)

Sensitivity 78.3%Sensitivity 78.3% Sensitivity 85.7%Sensitivity 85.7%

59% reduction in number of diagnostic 59% reduction in number of diagnostic procedures procedures ($573 savings per patient evaluation)($573 savings per patient evaluation)

Fass R, et al Gastroenterol 1998; 115:42-9Fass R, et al Gastroenterol 1998; 115:42-9

Positive Positive OTOT

Results of Economic AnalysisResults of Economic Analysis

ConventionalConventionalwork-upwork-up OTOT DifferenceDifference % Change% Change

Cost ($)Cost ($) 20252025 1452145257357328 Reduction28 Reduction

No. of endoscopies/No. of endoscopies/ 1000 patients1000 patients 10001000 19019081081081 Reduction81 Reduction

No. of ambulatoryNo. of ambulatory 24-hr pH tests/24-hr pH tests/ 1000 patients1000 patients 650650 14014051051079 Reduction79 Reduction

No. of esophagealNo. of esophageal motility tests /motility tests / 1000 patients1000 patients 310310 470470-160-16052 Increase52 Increase

Total no. of diagnosticTotal no. of diagnostic procedures / procedures / 1000 patients1000 patients 19601960 8008001160116059 Reduction59 Reduction

Fass R, et al Gastroenterol 1998; 115:42-9Fass R, et al Gastroenterol 1998; 115:42-9

Omeprazole Test in NCCPOmeprazole Test in NCCP

Generalizability?Generalizability? Male, veteran populationMale, veteran population High % esophagitis, GERD symptomsHigh % esophagitis, GERD symptoms Pain pattern of frequent chest pain (≥ 3x/wk)Pain pattern of frequent chest pain (≥ 3x/wk) Small numbers, short course treatmentSmall numbers, short course treatment

Medication dosing, strengthMedication dosing, strength

Role of endoscopyRole of endoscopy Reassurance factorReassurance factor Once-in-a-lifetime Barrett’s checkOnce-in-a-lifetime Barrett’s check

IssuesIssues

LA Grade CLA Grade C LA Grade DLA Grade D

One or more mucosal breaks no longer than 5mm, not bridging the tops of mucosal folds

One or more mucosal breaks no longer than 5mm, not bridging the tops of mucosal folds

One or more mucosal breaks bridging the tops of mucosal folds involving <75% of the circumference

One or more mucosal breaks bridging the tops of mucosal folds involving <75% of the circumference

One or more mucosal breaks bridging the tops of mucosal folds involving >75% of the circumference

One or more mucosal breaks bridging the tops of mucosal folds involving >75% of the circumference

One or more mucosal breaks longer than 5mm, not bridging the tops of mucosal folds

One or more mucosal breaks longer than 5mm, not bridging the tops of mucosal folds

LA Grade BLA Grade BLA Grade ALA Grade A

Los Angeles (LA) Grade Los Angeles (LA) Grade Classification of Erosive EsophagitisClassification of Erosive Esophagitis

Lundell et al. Gut. 1999;45:172-180.Lundell et al. Gut. 1999;45:172-180.

The spectrum of heartburn frequency The spectrum of heartburn frequency and severity is similar in GERD patients and severity is similar in GERD patients

with and without esophagitiswith and without esophagitis

Severe

Moderate

Mild

Patients without esophagitisSeverity ofheartburn

Smout 1997

Patients with esophagitis

GERD Therapeutic OptionsGERD Therapeutic Options

ProkineticsProkinetics

OTC or prescription OTC or prescription H2RAsH2RAs

““First - aid” : Life-First - aid” : Life-style modifications style modifications

and antacidsand antacids

Endoscopic techniquesEndoscopic techniques

(plication, RF, implant)(plication, RF, implant)

SurgerySurgery

(Lap Nissen fundoplication)(Lap Nissen fundoplication)OTC or prescription PPIsOTC or prescription PPIs

TreatmentsTreatments

Life-style ModificationsLife-style Modifications

Reduce weightReduce weight

Elevate head of Elevate head of bedbed

Stop smokingStop smoking

Eat small meals, no Eat small meals, no late meals, reduce fatlate meals, reduce fat

Consider alternatives to reflux-Consider alternatives to reflux-promoting drugs e.g., theophilline, promoting drugs e.g., theophilline,

anticholinergicsanticholinergics

Avoid reflux-promoting agents e.g, alcohol, coffee; some Avoid reflux-promoting agents e.g, alcohol, coffee; some foodsfoods

Not evidence-basedNot evidence-based

ModificationsModifications

POSITION AND REFLUXPOSITION AND REFLUX

Rig

ht s

ide

dow

nL

eft s

ide

dow

npH

pH

0

0

4

4

8

8

(Katz,LC. Et al, J Clin Gastro 1994;18(4):280-3

GERD HEALING AND ACID CONTROLGERD HEALING AND ACID CONTROL

(Bell et al. Digestion. 1992;51(suppl 1):59-67.)(Bell et al. Digestion. 1992;51(suppl 1):59-67.)

Pa

tie

nts

Hea

led

(%

)P

ati

en

ts H

eale

d (

%)

Duration Intragastric pH >4.0 (Hours)Duration Intragastric pH >4.0 (Hours)

100100

8080

6060

4040

2020

0022 44 66 88 1010 1212 1414 1616 1818 2020 2222

Medical Rx OutcomesMedical Rx Outcomes(with H2RAs)(with H2RAs)

Relief of symptoms Relief of symptoms 50%50% Healing esophagitisHealing esophagitis <50%<50% Prevent complicationsPrevent complications --- --- RemissionRemission 25%25%

Medical Rx Outcomes (PPIs)Medical Rx Outcomes (PPIs)

Relief of symptoms Relief of symptoms 85-95%85-95% Healing esophagitisHealing esophagitis 85-95%85-95% Prevent complicationsPrevent complications 80%80% RemissionRemission 90%90%

GERD: Endoscopic TherapiesGERD: Endoscopic Therapies

Endoscopic suturing – i.e., Endocinch (this Endoscopic suturing – i.e., Endocinch (this leads to partial thickness plication)leads to partial thickness plication)

Full thickness plication – i.e., NDOFull thickness plication – i.e., NDO Radiofrequency ablation – i.e., StrettaRadiofrequency ablation – i.e., Stretta Injection therapy with augmentation of LES Injection therapy with augmentation of LES

– i.e., Enteryx– i.e., Enteryx Bulking procedures with augmentation of Bulking procedures with augmentation of

LES – i.e., GatekeeperLES – i.e., Gatekeeper

BARD EndoCinchBARD EndoCinch

Suction of tissue Suction of tissue just beneath z-linejust beneath z-line

Needle with Needle with pre-loaded pre-loaded suture advancedsuture advanced

Cinching/cutting Cinching/cutting catheter catheter advanced to advanced to tissuetissue

Final appearance Final appearance of plication in of plication in cardiacardia

NDO Plicator™NDO Plicator™

Plicator and gastroscope Plicator and gastroscope retroflexed retroflexed

Arms opened, tissue Arms opened, tissue retractor advancedretractor advanced

Gastric wall retracted, Gastric wall retracted, arms closed.arms closed.

Single, pre-tied implant Single, pre-tied implant deployed.deployed.

Full-thickness plication Full-thickness plication completedcompleted

11 22 33

44 55

Antegrade techniqueAntegrade techniqueBalloon inflationBalloon inflation

Needle deploymentNeedle deployment1 cm above z-line1 cm above z-line

Injection at the Z-LineInjection at the Z-Line

Gatekeeper™ SystemGatekeeper™ System

Stabilize site

ExpansionDeliver prosthesis

Create pocket Access pocket

MAINTENANCE THERAPY OF GERDMAINTENANCE THERAPY OF GERDOmeprazole vs surgeryOmeprazole vs surgery

0102030405060708090

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Years

% in

rem

issi

on

Surgery (N=122)

Omeprazole (N=133)

(Lundel et al: J Am Col Surg, 192:172, 2001)

0

2

4

6

8

10

Sy

mp

tom

Sc

ore

Sy

mp

tom

Sc

ore

So et al. So et al. SurgerySurgery. 1998;124:28-32.. 1998;124:28-32.

Typical Symptoms Typical Symptoms (n=115)(n=115)

Improvement 6.2 points

Atypical Symptoms Atypical Symptoms (n=35)(n=35)

Improvement 4.4 points

Atypical Sx Atypical Sx ImprovementImprovement

• Overall 58% of patientsOverall 58% of patients

– Pulmonary 48%Pulmonary 48%

– Atypical chest pain Atypical chest pain 58%58%

– Pharyngo/Pharyngo/laryngeal 76%laryngeal 76%

Outcomes of Atypical GERD Outcomes of Atypical GERD Symptoms Treated by LNFSymptoms Treated by LNFPreoperative Postoperative

Esophageal Chest PainEsophageal Chest Pain

GERD relatedGERD related

Motility relatedMotility related

Esophageal hyperalgesiaEsophageal hyperalgesia

Esophageal HyperalgesiaEsophageal Hyperalgesia

““Irritable esophagus”Irritable esophagus”

Abnormal nociceptionAbnormal nociception

Lower threshold for painLower threshold for pain

Esophageal HyperalgesiaEsophageal Hyperalgesia

Noxious stimulus in esophagusNoxious stimulus in esophagus

Decrease in nociceptor thresholdDecrease in nociceptor threshold

Disorder of CNS nociceptive Disorder of CNS nociceptive pathwaypathway

Chest Pain - ImipramineChest Pain - Imipramine

50 mg nightly for 3 wks50 mg nightly for 3 wks 52% reduction in chest pain episodes52% reduction in chest pain episodes Suggested visceral analgesic effectSuggested visceral analgesic effect

Cannon R, et al. N Engl J Med 1994; 330:1411-7Cannon R, et al. N Engl J Med 1994; 330:1411-7

15 healthy male volunteers15 healthy male volunteers Balloon inflation volume at pain threshold Balloon inflation volume at pain threshold

higher on imipraminehigher on imipraminePeghini PL, et al. Gut 1998; 42:807-13Peghini PL, et al. Gut 1998; 42:807-13

NCCP Non-GERD NCCP Non-GERD Esophageal TherapiesEsophageal Therapies

Calcium channel blockersCalcium channel blockers AnticholinergicsAnticholinergics NitratesNitrates BotoxBotox Antidepressants (Imipramine, Trazodone)Antidepressants (Imipramine, Trazodone) OctreotideOctreotide BougienageBougienage 5 HT5 HT33 antagonists antagonists

Initial Perception Threshold (S1) Before and 40 Initial Perception Threshold (S1) Before and 40 Minutes after Octreotide InjectionMinutes after Octreotide Injection

BaseBase 40 min40 min00

1010

2020

3030

>30>30

CC

CC

pp < 0.02 < 0.02

Johnson BT, et al Am J Gastroenterol 1999; 94:65-70Johnson BT, et al Am J Gastroenterol 1999; 94:65-70

Maximally Tolerated Pain Threshold (S2) Before and 40 Maximally Tolerated Pain Threshold (S2) Before and 40 Minutes after Octreotide InjectionMinutes after Octreotide Injection

BaseBase 40 min40 min00

1010

2020

3030

>30>30

CC

CC

Johnson BT, et al Am J Gastroenterol 1999; 94:65-70Johnson BT, et al Am J Gastroenterol 1999; 94:65-70

Overlap Syndrome of Altered Pain Overlap Syndrome of Altered Pain SensitivitySensitivity

Approach to the NCCP PatientApproach to the NCCP Patient

Take a historyTake a history Exclude coronary / cardiac diseaseExclude coronary / cardiac disease Check for musculoskeletal diseaseCheck for musculoskeletal disease Look for GERDLook for GERD Check for dysmotilityCheck for dysmotility Consider esophageal hyperalgesiaConsider esophageal hyperalgesia Collaborative managementCollaborative management