2-855 am...

Satish S. C. Rao, MD, PhD, FACG

GastroparesisGastroparesis: : New Tools & New ParadigmsNew Tools & New Paradigms

GastroparesisGastroparesis: : New Tools & New ParadigmsNew Tools & New Paradigms

Satish SC Rao, MD, PhD, FRCP, FACG, AGAFSatish SC Rao, MD, PhD, FRCP, FACG, AGAF

Professor of Medicine & Section ChiefProfessor of Medicine & Section Chief

Director, Digestive Health CenterDirector, Digestive Health Center

Medical College of GeorgiaMedical College of Georgia

Georgia Regents University, Augusta, GAGeorgia Regents University, Augusta, GA

OBJECTIVESOBJECTIVESOBJECTIVESOBJECTIVES

Physiology/PathophysiologyPhysiology/Pathophysiology

Clinical EvaluationClinical Evaluation

Diagnostic EvaluationDiagnostic Evaluation

TreatmentTreatment TreatmentTreatment

ACG Regional Postgraduate Course - Williamsburg, VA Copyright 2013 American College of Gastroenterology

1


Normal Normal Function Function -- StomachStomachNormal Normal Function Function -- StomachStomach


2


Case StudyCase Study

24 y/o female with 10 year history of IDDM. retinopathy, postural hypotension, dysautonomiawith labile blood pressure and orthostasiswith labile blood pressure and orthostasis. Gastroparesis since 2002

Poor glycemic control on insulin 8 hospitalizations in past 4 months with DKA,

weight loss and failure to thrive HgbA1c were >15%. Now, HgbA1c are still > 8%.

S t f t i f l t i l d Symptoms of gastroparesis for last year include severe nausea and vomiting, abdominal pain, abdominal bloating and dizziness

Failed multiple prokinetics and antiemeticsincluding metoclopramide, ondansetron, prochlorperazine


3


DefinitionsDefinitions

GastroparesisSymptomatic chronic disorder of the stomach Symptomatic chronic disorder of the stomach

characterized by delayed gastric emptying in thecharacterized by delayed gastric emptying in thecharacterized by delayed gastric emptying in the characterized by delayed gastric emptying in the absence of mechanical obstructionabsence of mechanical obstruction11. .

Symptoms are variable and include early satiety, Symptoms are variable and include early satiety, nausea, vomiting, bloating, and upper abdominal nausea, vomiting, bloating, and upper abdominal discomfort.discomfort.

Scintigraphy considered the Scintigraphy considered the ““gold standardgold standard””

Functional DyspepsiaFunctional DyspepsiaPain or discomfort centered in the upper abdomenPain or discomfort centered in the upper abdomenno structural or biochemical abnormality is identifiedno structural or biochemical abnormality is identifieddelayed gastric emptying in 25delayed gastric emptying in 25--50%50%

Parkman HP. Gastroenterol. 2005; 127:1592Hasler WL. J Clin Gastroenterol. 2005; 39(Suppl 3):S223

EpidemiologyEpidemiologyEpidemiologyEpidemiology

Diabetes Type 1Diabetes Type 1-- 40% (tertiary), 5% 40% (tertiary), 5% (Community)(Community)

Diabetes Type 2Diabetes Type 2-- 1010--20%(tertiary), 1% 20%(tertiary), 1% (community)(community)

Choung RS et al;Am J Gastroenterol 2011


4


GastroparesisGastroparesis -- Rising Incidence?Rising Incidence?18 fold increase over 10 yrs18 fold increase over 10 yrsProbably more awarenessProbably more awareness

GastroparesisGastroparesis -- Rising Incidence?Rising Incidence?18 fold increase over 10 yrs18 fold increase over 10 yrsProbably more awarenessProbably more awareness

Nusrat S ; Bielefeldt K; NGM 2013

PathophysiologyPathophysiology--GastroparesisGastroparesis

PathophysiologyPathophysiology--GastroparesisGastroparesis

AlteredAlteredAccommodationAccommodation

AntroAntro

PyloricPyloricDysmotilityDysmotility

DelayedDelayedIntragastricIntragastricTransportTransport

Abnormal TriturationAbnormal Trituration

Small Bowel /Small Bowel /Colonic DysmotilityColonic Dysmotility

DuodenalDuodenalCoordinationCoordination

Abnormal TriturationAbnormal TriturationAntral HypomotilityAntral Hypomotility

Tachy / Brady GastriaTachy / Brady Gastria


5


60% diabetics are hypersensitive to

Diabetic Gastroparesis-More than an emptying problem!

yp

gastric balloon distension.

90% diabetics have an impaired

accommodation response to a liquid

mealmeal.

The hypersensitivity was often

associated with impaired

accommodation. Kumar, Rao et al;Neurogastro Mot 2007


6


NoneNone VeryVeryMildMild

MildMild ModeratModeratee

SeverSeveree

VeryVery

SevereSevere

Gastroparesis Cardinal Symptom Index (GCSI)

Gastroparesis Cardinal Symptom Index (GCSI)

Circle the number that best describes how severe the symptom has been during the prior 2 weeks

SevereSevere

Nausea 00 11 22 33 44 55

Retching 0 1 2 3 4 5

VomitingVomiting 00 11 22 33 44 55

Stomach FullnessStomach Fullness 00 11 22 33 44 55

Unable to finish normalUnable to finish normal--sized sized 00 11 22 33 44 55mealmeal

Feeling excessively full after Feeling excessively full after mealsmeals

00 11 22 33 44 55

Loss of appetiteLoss of appetite 00 11 22 33 44 55

BloatingBloating 00 11 22 33 44 55

Stomach or belly visibly largerStomach or belly visibly larger 00 11 22 33 44 55

Case StudyCase Study--Symptom Symptom profilesprofiles

Case StudyCase Study--Symptom Symptom profilesprofiles

NauseaNausea-- 55

VomitingVomiting--44

Postprandial fullness Postprandial fullness --44

Early Satiety Early Satiety --44

Wt lossWt loss--44

ConstipationConstipation

Abdominal PainAbdominal Pain--44


7


146 patients in a tertiary care146 patients in a tertiary care center

Soykan, McCallum. DDS 1998;43:2398Soykan, McCallum. DDS 1998;43:2398BILE GASTRITIS

PostPost--Viral Gastroparesis Viral Gastroparesis Criteria for clinical diagnosisCriteria for clinical diagnosis 1. 1. Previously healthy subjects with acute onset of viralPreviously healthy subjects with acute onset of viral--

illness illness with nausea, vomiting, diarrhea, fever, crampswith nausea, vomiting, diarrhea, fever, cramps

2. Persistence of symptoms (N, V, early satiety) for > 3 2. Persistence of symptoms (N, V, early satiety) for > 3 monthsmonths

3. Delayed gastric emptying3. Delayed gastric emptying 4. No evidence of obstruction, metabolic disease, systemic 4. No evidence of obstruction, metabolic disease, systemic

illnessillness

Potential viruses: CMV EBVPotential viruses: CMV EBV HerpesHerpes ZosterZoster Potential viruses: CMV, EBV, Potential viruses: CMV, EBV, HerpesHerpes--ZosterZoster Less severe symptoms than other idiopathic Less severe symptoms than other idiopathic

gastroparesisgastroparesis Good prognosis: Usually slow resolution of symptomsGood prognosis: Usually slow resolution of symptoms

BityutskiyBityutskiy, , SoykanSoykan, McCallum. AJG , McCallum. AJG 1997; 92: 1501.1997; 92: 1501.


8


Nuclear Scintigraphy

Tests of Gastric Sensori-Motor Function

Tests of Gastric Sensori-Motor Function

Nuclear Scintigraphy

Wireless Capsule Motility

Octanoic acid breath test

Electrogastrography

Antroduodenal manometry

Gastric barostat with sensation/Tone/compliance

Water load test

Gastric ultrasound

Standard MealStandard Meal

120 g 99Tc labeled egg substitute 120 g 99Tc-labeled egg substitute (Eggbeater)

2 slices of bread

30 g strawberry jam

120 ml water

255 kcal, 2% fat

Tougas G, Am J Gastroenterol 2000; 95: 1456.


9


Scintigraphic Images showing Delayed Scintigraphic Images showing Delayed Gastric EmptyingGastric Emptying

Scintigraphic Images showing Delayed Scintigraphic Images showing Delayed Gastric EmptyingGastric Emptying

NORMAL DUMPING

Gastric EmptyingGastric Emptying

Lag PhaseLag Phase

Liquidsfollow a simplefollow a simpleLag PhaseLag Phase

Mea

l R

emai

nin

gM

eal

Rem

ain

ing

30

40

50

60

70

80

90

100

Solids

follow a simple follow a simple exponential patternexponential pattern

mediated by fundic mediated by fundic tonetone

Solidslag phase lag phase

MinutesMinutes

% M

% M

0

10

20

30

0 20 40 60 80 100 120

Liquids

g pg pcorresponds to antral corresponds to antral triturationtrituration

followed by followed by exponential pattern of exponential pattern of emptyingemptying


10


Definitions:Rapid: <30% retention at 2 hrs.Slow: >10% at 4 hrs.

Tougas G, Am J Gastroenterol 2000; 95: 1456.

MANOMETRY PROBE PLACEMENT UNDER

FLUOROSCOPY


11


Normal Fasting Gastric & Small Bowel Normal Fasting Gastric & Small Bowel MotilityMotility

Normal Fasting Gastric & Small Bowel Normal Fasting Gastric & Small Bowel MotilityMotility

Body

A tAntrum

Duodenum 2

Duodenum 1III IIIPhase

Jejumum 1

Jejumum 2

Antrum 1

Meal

TYPICAL UPPER GUT RESPONSE TO A MEAL

Figure 4

Antrum 2

Duodenum 1

Duodenum 2

Jejunum 1

Jejunum 2

1 hr 2hr 3hrMeal

Time


12


Gastric Barostat TestGastric Barostat TestGastric Barostat TestGastric Barostat Test

CASE

AccommodationAccommodation

ToneTone

SensationSensation

FundoFundo--antral antral R flR fl

Impaired

Decreased

Hypersensitive

Absent

CASE

ReflexReflex

The Wireless Motility Capsule (SmartPill) is anThe Wireless Motility Capsule (SmartPill) is an ingestible capsule that measures pH, pressure and

temperature using miniaturized wireless sensor technology.


13


GRT GRT --HealthyHealthyGRT GRT --

HealthyHealthyGRTGRT--

GastropareticGastropareticGRTGRT--

GastropareticGastroparetic


14


Relationship Between Scintigraphy and Relationship Between Scintigraphy and Capsule EmptyingCapsule Emptying

Relationship Between Scintigraphy and Relationship Between Scintigraphy and Capsule EmptyingCapsule Emptying

100 7 Non-digestible solid, emptied after the fed state by high amplitude

20

30

40

50

60

70

80

90

Mea

l lef

t in

th

e st

omac

h (

%)

1

2

3

4

5

6

pH

T 50%

T 90%

the fed state, by high amplitude contractions like the return of the fasting phase III MMCs

0

10

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

Time (hours)

0

1

Scintigraphic gastric emptying

Capsule pH recording

Correlation of T90% to GET: r=82%

WMC GET Comparison to WMC GET Comparison to Scintigraphy Scintigraphy

WMC GET Comparison to WMC GET Comparison to Scintigraphy Scintigraphy

Total Subjects Studied: 148 81 Healthy/67

Median Median T50 T50

Median Median T90 T90

Median Median GET GET

HealthyHealthy 88 min88 min 160 min160 min 215 min215 min

Total Subjects Studied: 148 81 Healthy/67 Gastroparetic

astric emptying scintigraphy

GastrosGastros 123 min123 min 237 min237 min 360 min360 min

SmartPill Correlation to Scintigraphy:SmartPill Correlation to Scintigraphy:T50T50 0.500.50T90T90 0.820.82

Kuo B et al APT 2006.


15


WMC compared to WMC compared to ScintigraphyScintigraphy

WMC compared to WMC compared to ScintigraphyScintigraphy

ParameterParameter GRT GRT Corr.Corr.

SensitivitySensitivity SpecificitSpecificityy

AUCAUC Cutoff Cutoff (Hrs)(Hrs)

T50T50 0.500.50 0.690.69 0.750.75 0.770.77 1.751.75

T90T90 0 820 82 0 900 90 0 720 72 0 850 85 2 922 92T90T90 0.820.82 0.900.90 0.720.72 0.850.85 2.922.92

GRTGRT 0.850.85 0.720.72 0.830.83 4.004.00

Kuo B et al APT 2006.

Strengths & Drawbacks of Current Strengths & Drawbacks of Current MethodsMethods

Strengths & Drawbacks of Current Strengths & Drawbacks of Current MethodsMethods

Scintigraphy WMC

Radiation ++ No

Invasive + No

GET & SBTT + +++

CTT No +++

WGTT No +++WGTT No +++

Myopathy/

Neuropathy

No ?

Availability +++ ++

Rao SSC. Neurogastro Mot 2011


16


Gastroparesis-Principles of Management

Gastroparesis-Principles of Managementgg

Restoration of Metabolic Restoration of Metabolic EquilibriumEquilibrium

NutritionNutrition

Pain ManagementPain Management

ProkineticsProkinetics

AntiemeticsAntiemetics

Endoscopic / Surgical Therapy Endoscopic / Surgical Therapy

Electrical PacingElectrical Pacing

ProkineticProkinetic -- MetoclopramideMetoclopramideProkineticProkinetic -- MetoclopramideMetoclopramide

Camilleri et al;Am J Gastroenterol 2013


17


Dose 125 mg tid- IV or Syrup formulation


18


Camilleri et al;Am J Gastroenterol2013

Tegaserod on Gastric Emptying in Gastroparetic Patients (163 Gastroparetic Patients Randomized to 4 Treatments for 8 Weeks)


19


Ghrelin AgonistGhrelin AgonistGhrelin AgonistGhrelin Agonist

GhrelinGhrelin

Gut peptide hormoneGut peptide hormone

A i l d li i l d tA i l d li i l d t

TZPTZP--102 (Ghrelin 102 (Ghrelin agonist)agonist)

SS Animal and clinical data Animal and clinical data show that IV ghrelin show that IV ghrelin enhances gastric enhances gastric emptying* emptying*

Short plasma halfShort plasma half--life of 6 life of 6 to 12 minutesto 12 minutes

Selective, potent agonistSelective, potent agonist

Small moleculeSmall molecule

Prokinetic activity in an Prokinetic activity in an animal model of gastric animal model of gastric emptyingemptying

PK profile in human supportsPK profile in human supports

39

PK profile in human supports PK profile in human supports onceonce--daily oral dosing daily oral dosing

* Murray et al. Gut 2005;54(12):1693-8. Poitras et al. Peptides 2005;26(9): 1598-601. Tack et al. Gut 2006;55(3):327-33. Binn et al. Peptides 2006;27(7): 1603-6.

Improvement in Vomiting Severity over BL on Follow-up Day 30

Dosing Day 4 Improvement in N/V Subscale over Baseline

0

IV, TZPIV, TZP--101 (Ghrelin Agonist) Therapy 101 (Ghrelin Agonist) Therapy for Gastroparesisfor Gastroparesis

-3

-2

-1

0

Dose GroupGC

SI V

om

itin

g S

core

Imp

(PD

-BL

)

-4

-3

-2

-1

0

GC

SI N

/V S

ub

scal

e S

core

Imp

p=0.023 p=0.040

Dose Group

Placebo (n=8) All TZP-101 (n=12) 80 ug/kg (n=6)

Dose Group

Placebo (n=8) All TZP-101 (n=12) 80 ug/kg (n=6)

Wo et al Neurogastro Mot 2010


20


TZP-102 in gastroparesis: GCSI Scores, n=87

TZP-102 in gastroparesis: GCSI Scores, n=87

Nausea/Vomiting Subscale Score

0 2

0.0

0.2

ine

Treatment Post-Treatment

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2n

Cha

nge

from

Bas

el

p = 0.22

p = 0.02 p = 0.11

41

-1.8

-1.6

-1.4

Mea

n

PBO 20mg

Day: 0 8 2815 42 58

Wo et al Am J Gastro, ACG 2010

RMRM--131131-- Ghrelin Agonist Ghrelin Agonist (pentapeptide)(pentapeptide)

RMRM--131131-- Ghrelin Agonist Ghrelin Agonist (pentapeptide)(pentapeptide)

Shin A et al, Diabetes Care 2013; 36: 41-8.


21


Prokinetic Therapy for GastroparesisProkinetic Therapy for Gastroparesis

MetoclopramideMetoclopramide Dopamine (DDopamine (D22) receptor 10) receptor 10--20 20 mg,po,tidmg,po,tid

antagonist (central/peripheral)antagonist (central/peripheral)

ErythromycinErythromycin MotilinMotilin receptor receptor agonist 125 agonist 125 mg/mg/popo/Iv//Iv/tidtid

DomperidoneDomperidone Dopamine (DDopamine (D22) receptor ) receptor 1010--20 20 mg po.tidmg po.tid

antagonist antagonist (peripheral)(peripheral)

CisaprideCisapride 5HT5HT4 4 receptor agonist receptor agonist 1010--20 20 mg mg popo bidbid

TZP 102TZP 102 GhrelinGhrelin agonistagonist 20 20 mg mg popo

Gastroparesis Refractory to Medical Gastroparesis Refractory to Medical TherapyTherapy

Anti-emetics S.C or SL Metoclopramide Phenothiazines Avoid OndansetronMegase

Avoid Opiods for pain Visceral analgesicsMirtazapineMirtazapine Sertraline Buspirone Citalopram


22


Gastroparesis Refractory to Medical Gastroparesis Refractory to Medical TherapyTherapy

Improve Accommodationmirtazapinep

Hospitalization and IV Erythromycin/Azithromycin 125 mg tid-5 days Botox Injection NutritionEnteralParenteral

Dietary Considerations in Dietary Considerations in GastroparesisGastroparesis

Dietary modifications are aimed at promoting Dietary modifications are aimed at promoting GEGE

Liquids empty better than solidsLiquids empty better than solids

Small, frequent, lowSmall, frequent, low--fat meals of complex fat meals of complex carbohydratescarbohydrates

Mechanically soft and low indigestible fiberMechanically soft and low indigestible fiber--limit chance of limit chance of bezoarbezoar formationformation

No carbonated beveragesNo carbonated beverages


23


Gastroparesis Refractory to Medical Therapy-2

Gastroparesis Refractory to Medical Therapy-2

Venting Venting gastrostomygastrostomy + Feeding + Feeding JejunostomyJejunostomy

Botox InjectionBotox Injection

Total parenteral nutritionTotal parenteral nutrition

Gastric electrical stimulation Gastric electrical stimulation

Partial RouxPartial Roux--enen--Y Y gastrectomygastrectomy

Programmer Pulse Generator

Gastric Electrical Stimulation for Gastroparesis:

ENTERRA Therapy

Lead


24


Wavess Study: SummaryWavess Study: SummaryWavess Study: SummaryWavess Study: Summary

Reduces frequency of vomiting & Reduces frequency of vomiting & improves nauseaimproves nausea

Improves QOLImproves QOL

Reduces hospitalizationsReduces hospitalizations

Improves Diabetic controlImproves Diabetic control

No change in GETNo change in GET

Efficacy of Long Term ENS In Efficacy of Long Term ENS In Idiopathic GastroparesisIdiopathic Gastroparesis

Efficacy of Long Term ENS In Efficacy of Long Term ENS In Idiopathic GastroparesisIdiopathic Gastroparesis

Mccallum et al NGM 2013


25


Long Term Clinical Utility of Long Term Clinical Utility of EnterraEnterraTotal Total Symptom ScoreSymptom Score--, n=188, 1, n=188, 1-- 10 yrs10 yrsnausea, vomiting, pain, bloating, satiety, PPF, nausea, vomiting, pain, bloating, satiety, PPF,

burning, 0burning, 0--44

Long Term Clinical Utility of Long Term Clinical Utility of EnterraEnterraTotal Total Symptom ScoreSymptom Score--, n=188, 1, n=188, 1-- 10 yrs10 yrsnausea, vomiting, pain, bloating, satiety, PPF, nausea, vomiting, pain, bloating, satiety, PPF,

burning, 0burning, 0--44

Di b ti Idi thi P tDiabetic, n=114

Idiopathic, n=43

Post-surgical,

n=31

Baseline 20 + 5 19 + 6 19 + 3

Follow up 9 + 6 10 + 8 11+ 7

% improvement

55% 47% 48%

Mccallum et al CGH 2011

CYCLIC VOMITING SYNDROME

Recurrent bouts of unexplained vomiting lasting 2-5 days with complete recovery in between episodesAssociated with intense abdominal pain, nausea Women>men Rising incidence inWomen>men, Rising incidence in adultsDysregulation of CRFCannabinoid syndrome !!!


26


CYCLIC VOMITING SYNDROME

Management: Hospitalization/prophylaxisManagement: Hospitalization/prophylaxis Antiemetics:Antiemetics:Antiemetics:Antiemetics: 55--HT3 antagonistsHT3 antagonists

AntiAnti--migraine treatments:migraine treatments: TriptansTriptans

BenzodiazepinesBenzodiazepines Tricyclic antidepressantsTricyclic antidepressants

A tiA ti il tiil ti AntiAnti--epileptics:epileptics:ZonisamideZonisamide

LevetiracetamLevetiracetam

AntiAnti--migraine treatments:migraine treatments:Beta blockersBeta blockers

CyproheptadineCyproheptadine

SUSPECTED GASTROPARESIS

History, Exam, Drugs, Metabolic Disorders, Surgery

Hb, U + Electrolytes, TFT, Abdo Xray, Glucose,HbA1C

Gastric Emptying TestGastric Emptying Test--Scintigraphy or WMCScintigraphy or WMC

EGD or Barium/CAT(Exclude Obstruction/Mucosal Disease)

Delayed Normal

-Ve

Gastric Barostat

Not Known

Gastroduodenal Manometry

Neuropathy Myopathy

Delayed

Etiology Known

Rx

Normal

VisceralHyperalgesia

Gastric Barostat

Impaired Accommodation


27


Eating should be a joyful Eating should be a joyful experienceexperience--Lets strive to restore itLets strive to restore it

Eating should be a joyful Eating should be a joyful experienceexperience--Lets strive to restore itLets strive to restore it


28

2-855 am...

Documents

Transcript of 2-855 am...