4/10/17

1

MedicalandSurgicalTreatmentsforShortBowelSyndrome

DouglasL.Seidner,M.D.VanderbiltUniversityMedicalCenter

CenterforHumanNutriHon

Disclosures

•  ShirePharmaceuHcals:Consultant

•  ZealandPharmaA/S:Consultant

•  VanderbiltOpHonCareInfusion:MedDir.DiscussionofofflabeluseofmedicaHonwillbenoted.

LearningObjecHves

•  ReviewkeyconceptstohelpunderstandthetreatmentofSBS

•  DiscusstheindicaHons,mechanismofacHon,andsideeffectofmedicaHonsusedforSBS

•  UnderstandtheroleofsurgeryinthemanagementofSBS

PathwaytoEnteralAutonomyinShortBowelSyndrome

Bowel Resection

* Intestinal Rehabilitation

Short Term TPN Long Term TPN

*Diet modification, enteral supplements, medications, intestinal trophic factors

Bowel Transplant

Autologous GI Reconstruction

GoalsofIRProgram/Process

•  RepletenutriHondeficiencies•  ControldiarrheaandmaintainhydraHon•  PromoteenteralautonomybyopHmizingabsorpHvefuncHon– DietandfluidmodificaHon– MedicaHonsforGIdiseaseandsymptoms–  SurgicalintervenHon

•  TreatandpreventcomplicaHons•  Improvequalityoflife

ShortBowelSyndrome

•  SevereintesHnalmalabsorpHonthatoccursaZerextensivesmallbowelresecHon

•  Clinicalfeaturesincludediarrhea,dehydraHon,electrolyteabnormaliHes,andmalnutriHon

4/10/17

2

NormalAdultGIAnatomyandSBS

SBlength:365-600cm

Duodenum:~30cm

Jejunum:~150to200cm

Ileum:~200to300cm

Colon:~150cm

ShortBowelSyndrome<200cmofjejunum-ileum(distaltotheLigamentofTreitz)

ShortBowelSyndromeMechanismsofMalabsorpHon

GastricAcidHypersecreHon

•  CommonaZerextensiveSBresecHon•  Transient,lasHng<4-6mo•  Pathogenesis:Hypergastrinemia•  Consequences– PepHculceraHon–  InacHvaHonofpancreaHcenzymes– PrecipitaHonofbilesalts– Metabolicalkalosisandhypokalemia

GastricAnHsecretoryMedicaHons

•  ProtonPumpInhibitor–  Esomeprazole,lansoprazole,omeprazole,pantoprazole,rabeprazole

–  Sideeffects:Abdominalpain,diarrhea,nausea,headache

•  Histamine-2receptorantagonists–  CimeHdine,famoHdine,nizaHdineraniHdine–  Sideeffects:Diarrhea,consHpaHon,abdominalpain,headache,gynecomasHa(cimeHdine),hepaHHs,lowplatelets

GIAnHsecretoryMedicaHons*

•  SomatostaHnanalogue–  OctreoHde(inhibitsGH,glucagon,insulinandothers)– MayinterferewithintesHnaladaptaHon–  Sideeffects:Abdominalpain,diarrhea,nausea,headache,dysrhythmias,hyper/hypoglycemia,hypothyroidism,gallstones

•  Alpha-2adrenergicreceptoragonist–  Clonidine–  Sideeffects:Hypotension,drymouth,abdominalpain,confusion,sleepdisorder,rash

*Offlabel

RapidGastrointesHnalTransit

•  ExtensiveSBresecHon;ileum&colon•  LossofneuroendocrinecellsthatsecretePYY,GLP-1,GLP-2andotherfactors

•  Absenceofileocecalvalve•  Consequences– Rapidgastricemptying– DecreasedintesHnaltransitHme–  IncreasedgastricsecreHons

4/10/17

3

AnHdiarrhealMedicaHonsMedicaNon Onedose StarNngdose Maxdose

Loperamide(Imodium)

2mg(5mL) 1to2tablets(5to10mL)POQID

8tablets(40mL)/d

Diphenoxylate(LomoNl)

2.5mg(5mL) 1to2tablets(5to10mL)POQID

8tablets(40mL)/d

CodeineelixirTylenol#3

15mL15,30,60mg

15to30mLPOQID15mgPOQID

180mL/d360mg/d

OpiumTincture 0.3mL(6drops) 6to20drops(0.3to1mL)POQID

120drops(6mL)/d

AnHdiarrhealmedsaremosteffecHveif½hrto1hrbeforemeals

AnHdiarrhealMedicaHons

•  Sideeffects:– Abdominalpain,distenHon,nausea,vomiHng– SedaHon,dizziness– AnHcholinergic(combinedwithdiphenoxylatetodiscourageabuse):xerostomia,tachycardia,mydriasis

SmallIntesHnalBacterialOvergrowth

•  Uncommonunless…– Blindloop,stricture,internalfistula–  IncreasedintesHnaltransit– Decreasedgastricacid,pancreaHcsecreHons– Absenceofileocecalvalve

•  Consequences– Bacteriaconsumeluminalnutrients– Mucosalinjury– D-lacHcacidosis

SIBOManagement

•  SurgicalintervenHon•  LimitanHsecretoryandanHdiarrhealmeds•  ProbioHcs(overthecounter)•  AnHbioHcs(offlabel)–7daycourse– Amox/Clavulanate500/125mgpoHd,#21,$63– Metronidazole250mgpoHd,#21,$24– Rifaximin550mgpobid,#14,$$$$$

Quigley,E.InfectDisClinNAm2010;24:943

OtherMedicaHonsandSupplements

•  Bileacidtherapy– Cholestyramine,colesHpol– Cholylsarcosine(NAinUS)– Oxbile(overthecounter)

•  PancreaHcEnzymeReplacementTherapy

HeydornSetal.ScanJGastroenterol1999:34;818Liple,KH.DigDisSci1992;37(6):929

Glucagon-LikePepHde2(GLP-2)&TedugluHde(TED)

•  SHmulatescryptcellproliferaHon,inhibitsenterocyteapoptosis

•  Increasesvillusheight/cryptdepth•  IncreasesnutrienttransporteracHvity•  IncreasesintesHnalbloodflow•  InhibitsgastricacidsecreHonandmoHlity

4/10/17

4

TedugluHdePivotalTrials

•  Two24wkinternaHonalrandomizeddouble-blindplacebocontrolledtrialsin83and86adults– Parenteralsupport>12months•  004trial:2:2:1-0.05mg/kg/dvs.0.10mg/kg/dvs.PBO•  STEPStrial:1:1-0.05mg/kg/dvs.PBO

– Primaryend-point=PSreducHonwasmetforbothtrials0.05gm/kg/d

JeppesenPB,Gut2011;60:902-914JeppesenPB,Gastroenterology2012;143:1473-81

FDARegulaHonofTedugluHde•  REMS:RiskEvaluaHonandMiHgaHonStrategy–  ImposedbyFDAtoensurethatbenefits>risks– Risks/precauHons:•  NeoplasHcgrowth•  IntesHnalobstrucHon•  BiliaryandpancreaHcdisease•  Fluidoverload•  IncreasedabsorpHonofconcomitantoralmedicaHon•  AdverseReacHons(>10%-n/v/abdominalpaindisteHon,URIsymptoms,HA,injecHonsite,fluidoverload)

hpps://www.gapex.com/hcp/rems.aspx

Prescribingandregulatoryissues

•  IndicaHon:AdultpaHentwithSBSonPS*•  DuraHonofPSisnotmenHoned

•  Prescribersmustpassanonlinecourse^•  Dispensedby5infusioncompanies^•  MaintainSBSregistry^(NCT01990040)•  Casemanagementsupportfromcompanytoassistwithdrugcost

^FDAREMS*PrescribinginformaHonfrompackageinsert

MedicaHonsforSBSIndicaNon MedicaNon

GastricacidhypersecreHon Protonpumpinhibitor

Histamine-2ReceptorAntagonist

GIsecreHon SomatostaHnanalogue*^

Alpha-2adrenergicreceptoragonist*

Diarrhea Opioidagonist

SmallIntesHnalBacterialOvergrowth ProbioHcs#/AnHbioHcs*

Bileaciddiarrhea Bileacidbindingresin

Bileaciddeficiency Bilesaltreplacement#

PancreaHcenzymedeficiency PancreaHcenzymereplacement

Parenteralsupportdependent GLP-2analogue

*Offlabel#Overthecounter^MayinhibitadaptaHon

SurgicalManagementofShortBowelSyndrome

•  AutologousGIReconstrucHon– RestoreintesHnalconHnuity

– Strictureplasty

SerialTransverseEnteroplasty

LongitudeIntesHnalLengtheningandTailoring

ReversedSegment

SurgicalManagementofShortBowelSyndrome

PlicaHon

Valve

4/10/17

5

IntesHnalTransplantaHonforSBS

a.  SmallIntesHneb.  Liver–SmallIntesHnec.  MulHvisceral(aboveplusstomachandpancreas)

IntesHnalTransplantaHonforSBS

•  FailureofHPN(alsoCMSindicaHonsforIT)–  Impending(bilirubin3-6mg/dL)orovertliverfailurefromPN–  Thrombosisof>2centralveins–  TwoormoreepisodesCRBSI/yrofsystemicsepsis,oneepisodeof

fungemia,sepHcshock,ARDS–  FrequentepisodesofseveredehydraHon

•  Highriskofdeath–  Invasiveintra-abdominaldesmoidtumor–  SevereSBS:gastroorduodenostomy,<20cmSBinadults(10cminfant)

•  HighmorbidityorpooracceptanceofHPN–  FrequenthospitalizaHon,narcoHcdependency,unabletofuncHon

(pseudoobstrucHon,highstomaoutput)–  PaHent’sunwillingnesstoacceptlong-termHPN.

IntesHnalFailurewith

PironiL,ArendsJ,BozzexF,etal.ClinNutr2016;35:247(recommendlisHngforTx)

IntesHnalTransplantaHonforSBS

GraZSurvival

TransplantVolume

GrantD,etal.AmJTranspl2015;15:210

ManagementofChronicIF-SBS

Diet-Hyperphagia

SurgeryMedicaHon

PaHentIntesHnalRehabilitaHon

References1.  KumpfVJ.PharmacologicmanagementofdiarrheainpaHentswithshortbowel

syndrome.JPENJParenterEnteralNutr2014;38(suppl1):38S-44S.2.  JeppesenPB.PharmacologicOpHonsforIntesHnalRehabilitaHoninPaHentswith

ShortBowelSyndrome.JPENJParenterEnteralNutr2014;38:45S-52S.3.  SchwartzLK,O'KeefeSJD,FujiokaK,etal.Long-termTedugluHdeforthe

treatmentofpaHentswithintesHnalfailureassociatedwithshortbowelsyndrome.ClinicalandtranslaHonalgastroenterology2016;7:e142.

4.  Seidner,DL,Schwartz,LK,Winkler,MF,etal.IncreasedintesHnalabsorpHonintheeraoftedugluHdeanditsimpactonmanagementstrategiesinpaHentswithshortbowelsyndrome-associatedintesHnalfailure.JPENJParenterEnteralNutr2013;37:201-11.

5.  PironiL,ArendsJ,BozzexF,etal.ESPENguidelinesonchronicintesHnalfailureinadults.ClinNutr2016;35:247-307.

6.  GrantD,Abu-ElmagdK,MazariegosG,etal.IntesHnalTransplantRegistryReport:GlobalAcHvityandTrendsAmJTranspl2015;15:210–19.