1

NEGATIVE ENDOSCOPY,PPI REFRACTORY REFLUX:PPI REFRACTORY REFLUX:

What is the Diagnosis and Treatment?

Michael F. Vaezi, MD, PhD, MSc, FACGProfessor of Medicine

Clinical DirectorDivision of Gastroenterology, Hepatology and Nutritiongy, p gy

Vanderbilt University Medical Center

STEP DOWN

PPI - BID

H2RA’s - BID

H2RA’s-q dayA t id

PPI’s - q day

AntacidsLife Style Modification

2

ACID SUPPRESSIONH2RA

– Cimetidine (Tagament)• 400 mg BID

PPI’s

– Omeprazole (Prilosec)• 20 mg QD

• 400 mg BID– Ranitidine (Zantac)

• 150 mg BID– Famotidine (Pepcid)

• 20 mg BID– Nizatidine (Axid)

BID

– Lansoprazole (Prevacid)• 30 mg QD

– Rabeprazole (Aciphex)• 20 mg QD

– Pantoprazole (Protonix)• 40 mg QD

– Esomeprazole (Nexium)QD

DR

• 150 mg BID • 40 mg QD– Omeprazole + bicarb (Zegerid)

• 40 mg QD– Dexlansoprazole (Dexilant)

• 60 mg QD

IR

DDR

3

100

80

PPI

H2RA

Placebo

ENDOSCOPIC HEALING WITH PPI'SMETA-ANALYSIS

7635 i

85%

60

40

20

% T

otal

hea

led 7635 patients

Grade II-IV52%

28%

00 2 4 6 8 12

Weeks

Earnest et al. AJG - November, Suppl., 1999.Chiba et al Gastroenterology 1997; 112:1798-810

GERD

Symptoms Esophagitis Barrett’s

4

Response to Acid-Suppressive Therapy

Moayyedi et al Gastroenterology 2004; 127:1329-37

“Refractory GERD”Refractory GERD

Poor response to bid PPI

5

Refractory Reflux SymptomsComplianceDosingZEPPI resistance

InadequateAcid

Suppression

RuminationAerophagia

PPI resistanceNAB

RefractorySymptoms

NOT

Vaezi, AJG 2004

Motility disorder(achalasia)

FunctionalDGEEoE

RegurgitationBileNon-acid

NOTReflux

Related

Non-acidReflux

Rumination

• Rare• Often confused with GERD• Often confused with GERD• Persistent regurgitation of ingested food• Remastication and swallow• No nausea

D t d t PPI• Does not respond to PPI

6

RUMINATION: MII-EM

Tutuian and Castell. CJG 2004; 2:340-343

Aerophagia

• Belching (up to 20 / min)• Excessive air swallow• Excessive air swallow• Gastric• Subpragastric• Often confused with GERD

P t PPI• Poor response to PPI

7

Air SwallowImpedance-manometry

Bredenoord et al Gut 2004; 53:1561-1565

Air Swallow

• Gastric Supra-gastricBredenoord et al Gut 2004; 53:1561-1565

8

Achalasia0

5

PharynxPharynx

8080

1001009090

mmHgmmHg

10

15

20

25

30

CmCm

7070

4040

202015151010

5050

3030

55

6060

30

35 StomachStomach

SecondsSeconds0 5 10 15 20 25

00

--1010

55

EoE

9

pH monitoring in symptomatic patientson PPI therapy

pH <

4

25

30%

Dis

tal T

otal

Tim

e p

5

10

15

20

Upper limit of normal

(69%) (93%) (70%) (99%)

5.5

Vaezi. Am J Gastroenterol 2005;100:283-289.

0

QD

ATYPICAL GERD(n = 115)

BIDQD BID

TYPICAL GERD(n = 135)

ComplianceAliment. Pharmacol ther 2006- 23:1473-7

• 100 pts with persistent GERD100 pts with persistent GERD– 54% not dosed appropriately

• 39% qhs ppi use• 4% prn

The gallup Organization 2000

• 52% pts reported qhs ppi use

10

Impedance-pH

Antegrade Bolus Movement

11

Retrograde Bolus Movement

Impedance-pH in GERDRefractory to PPI BID

Symptomatic pts(N 144)(N=144)

Abnl Non-acid reflux(37%)

Inadequate Acid Supp(Distal acid > 1.6%)

(11%)

Normal(52%)

Mainie et al. Gut 2006; 55:1398-1402.

12

Abnormal Impedance ON therapy =Abnormal pH OFF therapy

Pts Refractory Sx on BID PPI

Impedance

Sx on BID PPI

Normal

N=25

Abnormal

N=14

Wireless pH

Stop PPI

64% 36%

93%p

Normal Abnormal

Pritchett and Vaezi, CGH 2009

Post-Fundoplication Predictor of Response:HB/Regurg; Abnormal pH; Hiatal hernia

NOT IMPEDANCE

Francis and Vaezi, Laryngoscope 2011

-HB/Acid +HB/-acid -HB/+acid +HB/acid

13

+ Reflux

-NSS

R-S-R-S+R-

R+S-R+S+R+

Symptom

+ -

SI/SAP Depend on Degree of Reflux

NS-S+

Slaughter and Vaezi, CGH 2011

OTHER THERAPIES• More PPI’s over the counter• Additional PPI enantiomers

R b l ?– Rabeprazole ?• PPI + other agents• TLESR inhibitors

– Baclofen– mGluR5 antagonist ?

• ?PCABs/CCK2-receptor antagonists• Sensory inhibition**

14

Suspected LPR PatientsN=72

BID PPI 4-monthsRespondersN=47

Non-respondersN=25

- Abnormal baseline pH- Normal pH on BID PPI- Continued signs/symptomsContinued signs/symptoms

Surgery Continued(Fundoplication) BID PPI

N=10 N=15

Surgery Does not Improve Symptom

100

7%10%25

50

75

12-month response

7%

0

Surgery Group Medical Group

Swoger and Vaezi, CGH 2007

15

Refractory Reflux SymptomsInadequate

AcidSuppression

ComplianceDosingZEPPI resistance

RefractorySymptoms

NOT

RuminationAerophagia

PPI resistanceNAB

NOTReflux

Related

Non-acidReflux

Vaezi, AJG 2004

Motility disorder(achalasia)

FunctionalDGEEoE

RegurgitationBileNon-acid

Algorithm

GERD

PPI PPI qdqd (bid) (bid)

EGDAlarmSx’sChange PPI’s

qq ( )( )11––2 months2 months

Symptoms Symptoms persistpersist

SymptomsSymptomsimprove

Empiric therapyEmpiric therapyPain modulatorsPain modulators

TitrateTitrate

MII/pHMII/pHmonitoringmonitoring

(on Therapy)(on Therapy)

Impedance/pHImpedance/pHavailableavailable

negativenegative“positive”

????????????????

bloatingbloatingearly satietyearly satiety

(TCA, SSRI’s,(TCA, SSRI’s,Trazedone)Trazedone)

CAUTIONCAUTIONOff tx testing:Off tx testing:

EGD/pHEGD/pHSurgerySurgeryCarafateCarafate

GastroparesisGastroparesisDietDiet

Low bulk/fatLow bulk/fatPromotilityPromotility

motilinmotilin//reglanreglan