Updatesinstressulcerprophylaxis:Is pharmacologicalprophylaxisstill indicated?

RubenDVillanueva,PharmD,BCCCP,BCPS Assistantprofessor OUHSCCollegeofPharmacy TraumaCriticalCare OUMedicalCenter

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Objectives

• Describethepathophysiologyofstressulcersinthe criticallyill

• Compareandcontrastcurrentstressulcerprophylaxis guidelines

• Summarizerecentstressulcerprophylaxisliterature

• Determineacriticallyillpatient’scontinuedneedfor stressulcerprophylaxis

2 PreͲAssessment

Whichofthefollowingistheunderlying pathophysiologicprocessforthedevelopmentof stressulcersintheICU? A) GIhypoperfusion B) Anemia C) Infection D) Hypersecretorystate

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PreͲAssessment

Whichofthefollowinghavebeenidentifiedas independentriskfactorsforclinicallysignificantGI bleedingincriticallyillpatients? A) Sepsis B) Organtransplant C) Vasoactivemedications D) Renalreplacementtherapy

4 PreͲAssessment

Enteralnutritionwouldlikelybesufficientforstress ulcerprophylaxisinwhichofthefollowingscenarios? A) Mechanicallyventilatedpatientreceivingcontinuous renalreplacementtherapywithanINRof2 B) MechanicallyventilatedTBIpatientwithout intracranialhypertension C) Mechanicallyventilatedpatientwithchronicliverand kidneydisease,COPD,andreceivingcorticosteroids D) Mechanicallyventilatedpatientwithoutsignificant PMH,anINRof1.9andonnorepinephrine

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UpdatesinStressUlcerProphylaxis BACKGROUND& PATHOPHYSIOLOGY

6 Background Stressrelatedmucosaldisease/damage • Representsacontinuum – Asymptomaticsuperficiallesionstoclinically significantGIbleeding(GIB) • Twotypes – Stressrelatedinjury – Stressulcers • EXCLUDES varicealbleeding StressͲrelatedmucosalbleeding Occult Guaiac+stoolorgastricaspirate Overt(OB) Hematemesis,hematochezia,melena Overt PLUS ш1:hemodynamicchanges, Clinically important(CIB) needfortransfusion,orљHgb >2g/dL

Plummer,M.P.,Blaser,A.R.,&Deane,A.M.(2014).Stressulceration:prevalence,pathology,andassociationwithadverseoutcomes.CriticalCare,18(213),1Ͳ 7. 7 Fennerty,M.B.(2002).Pathophysiologyoftheuppergastrointestinaltractinthecriticallyillpatient:Rationaleforthetherapeutic benefitsofacidsuppression.Crit CareMed,30,S351Ͳ S355.

Background

• Asymptomaticerosions(± occultbleeding) – Presentin74– 100%ofcriticallyillpatientswithin 72hrofadmissiontotheICUbasedonendoscopy

• Ratesofovertandclinicallysignificantbleeding depend onhowtheyaredefined – 2001reviewsuggestedovertbleedingmayoccurin ч25%ofICUpatientswithout pharmacologicSUP – OverallincidenceofclinicallysignificantGIbleeding inpatientswithout pharmacologicSUPreportedat3 –4%(0.6–5%)

Mutlu,G.M.,Mutlu,E.A.,&Factor,P.(2001).GIComplicationsinPatientsReceivingMechanicalVentilation.CHEST,119,1222Ͳ 1241. Bardou,M.,Quenot,J.ͲP.,&Barkun,A.(2015).StressͲrelatedmucosaldiseaseinthecriticallyillpatient.NatRevGastroenterolHepatol,12,98Ͳ 107. 8 Plummer,M.P.,Blaser,A.R.,&Deane,A.M.(2014).Stressulceration:prevalence,pathology,andassociationwithadverseoutcomes.CriticalCare,18(213),1Ͳ 7. Background

• Mortalityvariesbypopulation – Combineddatafrom2largestudies(N=1666)of mechanicallyventilated(MV)patients • Attributablemortalityofclinicallyimportantbleeding – Absoluterisk:20– 30% – Relativerisk(vsnoCIB):1–4

– Recentdatareported55.6%90dmortalityw/CIB

Cook,D.J.,Griffith,L.,Walter,S.D.,Guyatt,G.,O'Meade,M.,Heyland,D.,...Tryba,M.(2001).Theattributablemortalityandlengthof intesive careunitstayofclinicallyimportantgastrointestinalbleedingincriticallyillpatients.CriticalCare,5(6),368Ͳ 375. Krag,M.,Perner,A.,Wetterslev,J.,Wise,M.P.,Borthwick,M.,Bendel,S.,...Moller,M.H.(2015).Prevalenceandoutcomeof 9 gastrointestinalbleedinganduseofacidsuppressantsina cutelyilladultintensivecarepatients.IntensiveCareMed,41,833Ͳ 845.

CriticalIllness

јCatecholamines Shockorhypotension Hypovolemia

Proinflammatory јVasoconstricƟon љCardiacoutput cytokinerelease

Splanchnicandmucosal hypoperfusion

љHCO3Ͳ љMucosal љProtecƟve AcidbackͲ љGIMoƟlity secretion bloodflow factors,i.e HSP,TFF diffusion

Mucosalvulnerability

GastricAcid

AcuteStressulcer 10 Bardou,M.,Quenot,J.ͲP.,&Barkun,A.(2015).StressͲrelatedmucosaldiseaseinthecriticallyillpatient.NatRevGastroenterolHepatol,12,98Ͳ 107. Buendgens,L.,Koch,A.,&Tacke,F.(2016).PreventionofstressͲulcerbleedingattheintensivescareunit:Risksandbenefitsofstressulcerprophylaxis.WorldJCrit CareMed,5(1),57Ͳ 64. UpdatesinStressUlcerProphylaxis RISKFACTORS

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Cooketal.,1994†RiskFactors Simonsetal.,1995‡ Cooketal.,1999† Design MCPro Obs (N=2252) Retro. (N=33,637) MCPro. RCT (N =1077) 60±15 years PolyͲtrauma Age~60years 17.4% onMV No breakdownof 100%onMV Patients 48.5%CVsurgery patientcharacteristics ~60%medical TBI <2.5% *EXCLUDEDburns* ~22% emerg.surgery Encouraged withholding SUP Ranitidine:50mg IVq8hr Intervent. EXCEPT certainpopulations N/A 30%onSUP Sucral:1gmPTq6hr CIB†:OBplusш1within24hrofonsetofbleeding(absentothercauses):љSBPby GIB 20mmHg,љSBPby10mmHgorјHRby20bpmonsiƫngup;љHgb >2mg/dL plus Definitions tx;tx afterwhichtheHgb didnotrisebynumberunitstx’d minus2mg/dL Severestressulcer/CIB‡:perforationorbleedingrequiring>2unitstx’d Mortality (%)9vs.48.5 Mortalityw/GIB(%)25 ICUmort.(%)19vs. 36.7 GIB:14±12dafteradmit GIB: 51%ч14dpinjury GIB:median3d(2–6d) Outcomes OB:4.4% o 40%onH2RA OB:4.7%(3.4–6) o 95%CI3.6–5.6% o 25%diet/gastricEN CIB:2.6%(1.6–3.6) CIB:1.5% OB:0.17% o 95%CI1–2.1% CIB:0.05% MC=multicenter,Pro=prospective,Obs = observational,Retro=restrospecitve,RCT=randomizedcontrolledtrial MV=mechanicalventliation,CV=cardiovascular,TBI=traumaticbraininjury GIB=gastrointestinalbleeding,OB=overtbleedingCIB=clinicallyimportantbleeding,tx =transfusion *Certainpopulations=TBI,burnsw/BSA>30%,pepticulcerdisease/gastritis,recentGIB,organtransplant 12 Cooketal.,1994* Simonsetal.,1995** Cooketal.,1999* Risk Univariate (OR) Univariate (RR) Univariate (RR) Factor HOTN: 25.5 TS<13:2.8 Plt <50k2.58(1.19– 5.57) CIB* Sepsis:7.3 AISheadш3:4.8 MaxScr 1.19(1.06– 1.35) GIB** Liverfx:6.5 >2Organfxs:49.4 MaxMOD1.11(1.01– 1.21) Renalfx:4.6 ARDS:30.1 RenalMOD1.46(1.14– 1.87) Steroids:3.7 RenalFx:45.5 Hep MOD1.37(1.04– 1.77) Organtxp:3.6 Liverfx:51 EN0.35(0.16– 0.76) Anticoagulationtx:3.3 Coagulopathy:26.3 H2RA0.4(0.18– 0.89) EN 3.8 Pneumonia20.4 Otherinfx:23.3

Independent (OR) Independent (OR) Independent (RR) MV>48hr:15.6 SCI:2 MaxScr 1.16(1.02– 1.32) Coagulopathy:4.3 ISSш16:12.6 EN0.3(0.13– 0.67) Age>55:2.5 H2RA0.39(0.17– 0.83) ***31/33CIBshadMV orcoagulopathy*** ***ALLCIBhadeitherSCI ***22/33CIBsw/BOTH orISSш16*** MVand coagulopathy*** ***2/1405CIBswith neither MVor coagulopathy*** OR=oddsratio,RR=relativerisk,txp =transplant,ACanticoagulant, tx =treatment,TS=truama score,AIS=abbreviatedinjuryseverity score,fx =failure,SCI=spinalcord,ISS=injuryseverityscore,MOD=multiͲorgandysfunctionscore,EN=enteralnutrition 13

RiskFactors:2000s

All(N=1034) ͲCIB(N=1007) +CIB(N=27) P Age, median(IQR) 63(48– 74) 64(48– 75) 58(51– 70) 0.324 SOFA,median(IQR) 6(4–8)6(4Ͳ 8) 10(7– 14) <0.001 Coagulop.atadmission, % 12.4 11.7 37 <0.001 Comorbidities, % 0 48.5 4.9 18.5 0.002 1 30.8 30.6 37 0.474 2 14.8 14.6 22.2 0.271 3 4.4 4.1 18.5 0.005 >3 1.5 1.5 3.7 0.347 Mechanical vent.atadmit, % 52.6 52.3 63 0.275 Circ.supportatadmit, % 45.4 44.7 70.3 0.009 RRTatadmit,% 6.8 6.1 33.3 <0.001 90dMortality, % 26.2 25.4 55.6 ͲͲ CIB=clinicallyimportantbleedingSOFA=sequential organfailureassessment,Coagulop =coagulopathy,Circ support= circulatorysupport(i.e.vasoactiveinfusions),RRT=renalreplacementtherapy

Krag,M.,Perner,A.,Wetterslev,J.,Wise,M.P.,Borthwick,M.,Bendel,S.,...Moller,M.H.(2015).Prevalenceandoutcomeofgastrointestinalbleedingand 14 useofacidsuppressantsina cutelyilladultintensivecarepatients.IntensiveCareMed,41,833Ͳ 845. RiskFactors:2000s GI bleedingdefinitionsandoutcomes Overtbleeding(OB) ш1ofthefollowing:hematemesis,coffeeground emesis,melena,hematochezia,bloodyNGaspirate Clinicallyimportant bleeding(CIB) OBplusш1ofthefollowingwithin24hrofOBinthe absenceofothercauses:љBPш20mmHg,start of/increaseofvasopressorш20%,љHgb ш2g/dl,tx ш2unitsRBCsduringbleedingepisode Acid suppressiontherapy atadmit, % 37.4 PPI,%55 H2RA,%17 MediantimetoGIB,days(IQR) 3 (2–6) 21/27ч7dofICUstay OB(49/1034),%(95%CI) 4.7 (3.4Ͳ6) CIB(27/1034),%(95%CI) 2.6(1.6 – 3.6) ***27/27 receivingSUPattimeofbleed*** 90dMortality andCIB,% 55.6 OR 3.72(1.72 – 8.04)

aOR 1.70 (0.68– 4.28) 15

Krag,M.,Perner,A.,Wetterslev,J.,Wise,M.P.,Borthwick,M.,Bendel,S.,...Moller,M.H.(2015).Prevalenceandoutcomeofgastrointestinalbleedinganduseofacidsuppressantsina cutelyilladultintensivecarepatients.IntensiveCareMed,41,833Ͳ 845.

RiskFactors:2000s

Risk Factor OvertGIBleeding(aOR) CIB(aOR) SOFAscore 1.25(1.14–1.38) 1.37(1.22–1.55) Chronicliverdisease* 4.51(2.30–8.86) 7.64(3.32–17.57) Coagulopathy* 2.64(1.29–5.42) 4.22(1.74–10.23) Comorbidities 1 2.51(1.15–5.46) 3.03(1.00–9.25) 2 2.80(1.17–6.67) 3.22(0.94–11.06) 3 4.24(1.31–13.72) 9.29(2.34–36.94) >3 6.66(1.22–36.42) 8.88(2.74–28.80) Circulatorysupport atadmit 2.39(1.28–4.46) 2.31(0.99–5.40) RRTatadmit* 7.35(3.47–15.56) 6.89(2.72–17.48) Coagulopathy. atadmit* 4.06(2.16–7.63) 5.21(2.29–11.83) Anticoagulation at admit 2.25(1.04–4.87) 1.77(0.61–5.16) Acidsuppressivetx atadmit 2.95(1.44–6.06) 3.61(1.28–10.20 *Previously identifiedriskfactorsforCIB

16 Krag,M.,Perner,A.,Wetterslev,J.,Wise,M.P.,Borthwick,M.,Bendel,S.,...Moller,M.H.(2015).Prevalenceandoutcomeofgastrointestinalbleedinganduseofacid suppressantsina cutelyilladultintensivecarepatients.IntensiveCareMed,41,833Ͳ 845. RiskFactors:EnteralNutrition

• ProtectiveeffectsofEN – Increasedsplanchnicbloodflow – ENformulationsaretypicallyalkaline

• IndependentpredictoroflowerratesofCIBin MVpatientsonSUP:0.3(0.13– 0.67)

Cook,D.,Heyland,D.,Griffith,L.,Cook,R.,Marshall,J.C.,&Pagliarello,J.(1999).Rikfactorsforclinicallyimportantuppergastrointestinalbleedinginpatients requiringmechanicalventilation.Crit CareMed,27(12),2812Ͳ 2817. Hurt,R.T.,Frazier,T.H.,McClave,S.A.,Crittenden,N.E.,Kulisek,C.,Saad,M.,&Franklin,G.A.(2012).StressUlcerProphylaxisinIntensiveCareUnitPatientsand 17 theRoleofEnteralNutrition.JParenter EnteralNutr,36(6),721Ͳ 731.

RiskFactors:Summary

• SeveralriskfactorsforCIBhavebeenidentified – 1990sdata • Consistentunivariate riskfactors – MultiͲorganfailure,liverfailure,renalfailure,coagulopathy • Independent riskfactors – MV>48hr,coagulopathy,SCI,ISSш16,maximumScr – 2015data • Independent riskfactors – Highorganfailurescores(SOFA),chronicliverdisease, coagulopathy,ш3comorbidities,renalfailure • Enteralnutritionmayserveasaprotectivefactor – EffectsonGIbloodflowandpH – NegativeriskfactorinaPRCTofpharmacologicalSUP 18 UpdatesinStressUlcerProphylaxis GUIDELINES

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ASHP1999 EAST2008 SSC2016 Indications Indications(levelI) Indications o MV>48hrorcoagulopathy (C) o MV (strongrec,lowquality): o GIBorGIulcerinpastyear (D) o Coagulopathy o Sepsis/septicshock o TBIw/GCSч10(B) o TBI PLUS riskfactors o >35%BSAburns (B) o Majorburn o Mentioned“strongest o ш2offollowing(D): Indications(levelII) clinicalpredictorsof o Sepsis,ICU>7d,occult o Polytrauma GIBrisk”MV>48hr bleeding>6d,>250mgHC o Sepsis andcoagulopathy equivalents o Acute renalfailure o “…preexistingliver Indications(levelIII) disease,needforRRT, MAYBEindicated o ISS>15 andhigherorgan o Partial hepatectomy(C) o >250mgHCequivalents failurescoreswere o PolyͲtraumaw/ISSш16(D) o Select populationsnoppx is independent o Transplants(D) needed predictorsofGIBrisk” o Hepaticfailure(D) LevelII o SCI(D) Continueuntilextubatedorout Recommendagainst SUP ofICU inthosew/oriskfactors LevelIII (BPS) ContinueuntiltoleratingEN Choice shouldbeinstitutionspecific LevelI Either H2RAorPPI(weak InsufficientdataforPPI No differenceb/wH2RA, rec,lowquality) cytoprotectants,andsomePPIs LevelIII Enteralfeedingalonemaybe insufficient 20 UpdatesinStressUlcerProphylaxis:RecentPublications PROSPECTIVEANDRETROSPECTIVE

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PropensityMatched JapaneseDatabaseCohortStudy DesignRecent CaseͲcontrolPublications Database Japanesediagnosis procedurecombinationdatabase Cases:severesepsis (sepsis+ш1organdysfunction) Patients Exposure:SUP(PPIorH2RAwithin2daysofadmission) Outcomes, % SUP(N= 16,651) Control(N= 16,651) PͲvalue GIB* 0.5 0.6 0.208 30dMortality 16.4 16.9 0.249 CDI 1.4 1.3 0.588 HAP 3.9 3.3 0.012

Significantsubgroupinteractionsfor30dmortality,%** Pvalue Pintx ICUadmissionwithin 2d 15.7 19.6 0.002 0.004 MVwithin2d† 20.5 23.1 0.005 0.010 Vasoactivemedsw/n 2d 17.6 19.6 0.002 0.002 ш2organfailures† 23.6 26.2 0.012 0.041 *Requiring endoscopichemostasiswithin30dofadmission,**Noothersubgroupinteractionsnoted †PreviouslyidenƟĮedriskfactors CDI=Clostridiumdifficileinfection,HAP=hospitalacquiredpneumonia 22 Sasbuchi,Y.,Matsui,H.,Lefor,A.K.,Fushimi,K.,&Yasunaga,H.(2016).RisksandBenefitsofStressUlcerProphylaxisforPatientswithSevereSepsis.Crit CareMed,44,e464Ͳ e469. RecentPublications • Design – International,multicenter,randomized,blinded,placeboͲ controlled • Interventions – IVpantoprazole40mgdailywhileonMVoruntilGIBvs. placebo(PBO) • DecisiontocontinuePPIafterextubationatphysiciandiscretion

OutcomesandInclusion/ExclusionCriteria OBPLUSш1within24hoursintheabsenceofanothercause: GIB outcomedefinition(CIB) љSBP/DBPш20mmHg,orthostaƟcјHRш20bpmorљSBP 10mmHg,љHgb ш2g/dL within24hours,tx ш2unitsPRBCs Inclusion Expectedmechanical ventilation(MV) >48hr MV ш72hrpriortorandomization,useofPPIduetoactivebleed orјriskofbleeding,dualanƟplatelettherapypriorto Exclusion randomization, palliativecare,ш2“dailydoseequivalents”ofppx H2RAorPPI

Alhazzani,W.,Guyatt,G.,Alshahrani,M.,Deane,A.M.,Marshall,J.C.,Hall,R.,...Cook,D.(2017).Witholding PantoprazoleforStressUlcerProphylaxisinCriticallyIllPatients:A 23 PilotRandomizedClinicalTrialandMetaͲAnalysis.Crit CareMed,45,1121Ͳ 1129.

RecentPublications Characteristics PPI(N=49) PBO(N=42) Age, median(IQR) 61.8(48.4– 73.5) 55.3(42.4– 65.6) Admissiontype, % Medical 79.6 73.8 Surgical 4.1 11.9 Trauma 16.3 14.3 APACHEII,median (IQR) 21(17– 26) 21.5(14– 27) Comorbidities,% Respiratoryfailure 10.2 7.1 Allothersч8% (CHF,ESRD,Immunocompromised) ͲͲ ͲͲ Medicationswithin3dofrandomization, % ASA 22.4 19 PPx UFH 16.3 14.3 PPx LMWH 24.5 26.2

Alhazzani,W.,Guyatt,G.,Alshahrani,M.,Deane,A.M.,Marshall,J.C.,Hall,R.,...Cook,D.(2017).Witholding PantoprazoleforStressUlcerProphylaxisinCriticallyIllPatients: 24 APilotRandomizedClinicalTrialandMetaͲAnalysis.Crit CareMed,45,1121Ͳ 1129. RecentPublications

PatientCharacteristicsrelevanttoSUP Characteristic PPI(N=49) PBO(N=42) Studyday1, % Mechanicalventilation 100 100 Vasoactive meds 44.9 57.1 Intermittenthemodialysis 0 2.4 Continuousrenal replacement 4.1 7.1 LowestHgb,mean(SD) 9.86(2.22) 10.4(2.21) HighestINR, mean(SD) 1.43(0.5) 1.32(0.4) Lowest plateletcount,mean(SD) 183.4(81) 197.3 (111.2) H2RA b/f randomization,%4.17.1 PPIb/f randomization,% 30.6 33.3 Durationofmech vent,median(IQR) 9(5– 17) 6.5(4– 14) Mediandaysoftreatment, N(IQR) 5(3– 15) 5(2– 11) *89%receiving ENduringinitial72hrofadmission

Alhazzani,W.,Guyatt,G.,Alshahrani,M.,Deane,A.M.,Marshall,J.C.,Hall,R.,...Cook,D.(2017).WithholdingPantoprazoleforStressUlcerProphylaxisin 25 CriticallyIllPatients:APilotRandomizedClinicalTrialandMetaͲAnalysis.Crit CareMed,45,1121Ͳ 1129.

RecentPublications

Outcome PPI(N=49) PBO(N=42) RR(95%CI) AnyGIB, % 8.2 7.1 1.14 (0.27– 4.82) MinorUGIB, % 2 2.4 0.86(0.06– 13.29) ClinicallyimportantGIB, % 6.1 4.8 1.29(0.23 – 7.33) GIBrequiringintervention,% 6.1 4.8 1.29(0.23 – 7.33) IncidentCDI, % 4.1 2.4 1.71(0.16– 18.24) VAP, % 20.4 14.3 1.43(0.57– 3.60) ICUmortality, % 22.4 23.8 ͲͲ (p=1) HospitalMortality, % 34.7 31 ͲͲ (p=0.824)

Alhazzani,W.,Guyatt,G.,Alshahrani,M.,Deane,A.M.,Marshall,J.C.,Hall,R.,...Cook,D.(2017).Witholding PantoprazoleforStressUlcerProphylaxisin 26 CriticallyIllPatients:APilotRandomizedClinicalTrialandMetaͲAnalysis.Crit CareMed,45,1121Ͳ 1129. Prospective/Retrospective:Summary

• Retrospectivedata:severesepsis/septicshock – NOassociationbetweenH2RA/PPISUPandreductioninGIBrequiring endoscopichemostasis – Subgroupswhomay benefit • Mechanicalventilation • MultiͲorganfailure • RecentplaceboͲcontrolleddata: – PPISUPDOESNOT appeartosignificantlyreduceclinicallyimportantGI bleedsinaMVpopulation • Caveats – Minimal coͲmorbidities – Not ondualantiplatelettherapy – No renalfailure – No coagulopathy – Early enteralnutrition(within72hrofICUadmission) – NumericallyhigherratesofCDIandVAP – Nodifferenceinmortality 27

UpdatesinStressUlcerProphylaxis:RecentPublications ENTERALNUTRITION

28 RecentPublications • Design – Singlecenter,randomized,blinded,placeboͲcontrolled • Interventions – IVpantoprazole40mgdailyuntilextubationor14dvs. placebo(PBO)

OutcomesandInclusion/ExclusionCriteria Primaryoutcome:clinically OBPLUSш1:љMAPш20mmHgwithin24hoursintheabsenceof importantGIbleeding anothercause,љHgb ш2g/dL within24hours,orneedfor (OB=overtbleeding) endoscopyorsurgerytoachievehemostasis Inclusion ExpectedMV>24hrandENTERNALNUTRITION (EN)within48hr AST priortoadmit,admittedw/GIB,hx PUD,>100mg prednisoloneequivalents,upperGIorcardiacsurgeryduring Exclusion currenthospitalization,Jehovah’sWitness,couldnotreceive studydrugwithin36hrofMV,palliativecare,readmittedtoICU

Selvanderan,S.P.,Summers,M.J.,Finnis,M.E.,Plummer,M.P.,Abdelhamid,Y.A.,Anderson,M.B.,...Deane,A.M.(2016).PantoprazoleorPlaceboforStressUlcer 29 Prophylaxis(POPͲUP):RandomizedDoubleͲBlindExploratoryStudy.Crit CareMed,44,1842Ͳ 1850.

RecentPublications

Characteristic PBO(N=108) Pantoprazole(N=106) Age(yr),mean(SD) 52(17) 52(18) APACHE III,mean(SD) 66(28) 66(26) IV/POSteroids,%148 Vasoactive infusions,%5349 Maxvasoactive dose 10(6– 18) 10(5– 21) (mcg/min),median(IQR) PrimaryICUdiagnosticgroup(N;nonoperative/operative) Trauma 32(20/12) 31(18/13) Neuro 26(18/8) 35(27/8) Respiratory 24(14/10) 19(15/4) Cardiovascular 14(13/1) 9(7/2) SourceofICUadmission, % Operatingtheatre 49 45 Emerg Dept 33 30 Generalward 11 16

Selvanderan,S.P.,Summers,M.J.,Finnis,M.E.,Plummer,M.P.,Abdelhamid,Y.A.,Anderson,M.B.,...Deane,A.M.(2016).PantoprazoleorPlaceboforStressUlcer 30 Prophylaxis(POPͲUP):RandomizedDoubleͲBlindExploratoryStudy.Crit CareMed,44,1842Ͳ 1850. RecentPublications

PatientCharacteristicsrelevanttoSUP PBO Pantoprazole PͲvalue Hemostaticdysfunction, % 32 37 0.50 INR>1.5 19 23 0.46 PTT>40s 25 20 0.36 Plt <100,000 17 19 0.78 Steroids,%22160.25 Enteral nutrition Numberwhoreceived, % 87 83 0.41 TimefromMVtoinitiation,hr 16(95%CI10– 25) 16(95%CI8 – 22) 0.37 Volume/day,ml(95%CI) 798(697Ͳ 898) 844 (729Ͳ 958) 0.55 ENintolerance,%39320.30 TimefromstartofMVto1st dose,hr 17(16– 19) 16(15– 18) 0.44 Mediannumberofdoses,days (IQR) 3 (2–7) 3(1–7) 0.58 ENintolerancedefinedasgastricresiduals>250mlatleast onceonanyday

Selvanderan,S.P.,Summers,M.J.,Finnis,M.E.,Plummer,M.P.,Abdelhamid,Y.A.,Anderson,M.B.,...Deane,A.M.(2016).PantoprazoleorPlaceboforStressUlcer 31 Prophylaxis(POPͲUP):RandomizedDoubleͲBlindExploratoryStudy.Crit CareMed,44,1842Ͳ 1850.

RecentPublications

Outcome PBO(N=108) Pantoprazole(N=106) PͲvalue Overtbleeding, % 5.6(95%CI2.1– 11.7) 2.8 (95%CI0.6–8) 0.5 Clinicallysignificant 0(upper97.5%CI 3.36) 0(upper 97.5%3.42) ͲͲ bleeding,N IVACorPNA, % 0.9(95%CI0.02– 5.1) 1.9(95%CI0.2 – 5.1) ͲͲ C.difficile,N0(upper 97.5%CI3.4) 1(95%CI 0.02–5.1) ͲͲ 90day mortality,% 23.1(95%CI15.6– 32.2) 28.3(95%CI20– 37.9) 0.88 IVAC =infectiveventilatorassociatedcomplications

Selvanderan,S.P.,Summers,M.J.,Finnis,M.E.,Plummer,M.P.,Abdelhamid,Y.A.,Anderson,M.B.,...Deane,A.M.(2016).PantoprazoleorPlaceboforStressUlcer 32 Prophylaxis(POPͲUP):RandomizedDoubleͲBlindExploratoryStudy.Crit CareMed,44,1842Ͳ 1850. RecentPublications • Design – Twosite,prospective,randomized,blinded, controlled • Interventions – Placebo/ENvs40mgIVpantoprazoledaily/EN

OutcomesandInclusion/ExclusionCriteria OB:coffeegroundNGaspirateoremesis,bloodysecretionsin Primaryoutcome:overt(OB) NGtubeorhematemesis,melenaorhematochezia orclinicallysignificant(CIB)GI CIB*:3pointљHct withina24Ͳhourperiod+signsofOB,orby bleeding anunexplained6pointљHct itina48Ͳhourperiod ExpectedMV>24hrandNO contraindicationstoENwithinfirst Inclusion 24hrofadmission GIBprior tostudyenrollment,admittedwithburninjury,TBIor Exclusion јintracranialpressure,hx ofpartial/completegastrectomy

ElͲKersh,K.,Jalil,B.,McClave,S.A.,Cavallazzi,R.,Guardiola,J.,Guilkey,K.,...Saad,M.(2018).Enteralnutritionasstressulcerprophylaxisincriticallyillpatients:Arandomized 33 controlledexploratorystudy.JournalofCriticalCare,43,108Ͳ 113.

RecentPublications

Characteristic PPI(N= 55) PBO(N=47) Medianage,(IQR) 62(49.5– 68) 58(40.5– 66.5) Median SOFAscore,(IQR) 7(6– 10) 7(6– 10) CHF, % 13 26 CKD, % 13 9 DM, % 25 36 OtherComorbidities, % 80 81 Admissiondx, % Neuro 20 19 Pulmonary 51 53 Sepsis 18 11 Other(%) 24 17

ElͲKersh,K.,Jalil,B.,McClave,S.A.,Cavallazzi,R.,Guardiola,J.,Guilkey,K.,...Saad,M.(2018).Enteralnutritionasstressulcerprophylaxisincriticallyillpatients:A 34 randomizedcontrolledexploratorystudy.JournalofCriticalCare,43,108Ͳ 113. RecentPublications

Characteristic PPI(N= 55) PBO(N=47) PreͲstudy medswithin1week,% NSAIDs 84 83 Corticosteroids 95 98 PPI 82 78 H2RA 95 91 DailyEN volume(ml),median(IQR) 699(539.5) 715.5 (434– 1081.9) TotalENvolumegiven(ml),median(IQR) 2540(880Ͳ 5493) 2914 (868– 4236.5) %GoalENdelivered, median(IQR) 55(36.6– 66.4) 64.4(40.2– 69.4) Pressorduring study,%5540 Hemostatic dysfx atanytime,%4547 MedianScr (mg/dL), median(IQR) 1(0.8– 1.8) 0.9 (0.8–1.4) DurationofMV(d),median(IQR) 4(2.2–7) 5(3–8) MediannumberofdosesPPI/PBO 3(2–7) 3(2–6)

ElͲKersh,K.,Jalil,B.,McClave,S.A.,Cavallazzi,R.,Guardiola,J.,Guilkey,K.,...Saad,M.(2018).Enteralnutritionasstressulcerprophylaxisincriticallyill 35 patients:Arandomizedcontrolledexploratorystudy.JournalofCriticalCare,43,108Ͳ 113.

RecentPublications

Characteristic PPI(N= 55) PBO(N=47) PͲvalue OvertGIB, % 1.82 2.13 0.99 CIBGIB,% 1.82 2.13 0.99 Incident CDI,% 1.82 6.38 0.33 CIB:3pointљHct withina24Ͳhourperiod+signsofovertGIbleeding,orbyan6pointљHct itina48Ͳhour period

ElͲKersh,K.,Jalil,B.,McClave,S.A.,Cavallazzi,R.,Guardiola,J.,Guilkey,K.,...Saad,M.(2018).Enteralnutritionasstressulcerprophylaxisincriticallyill 36 patients:Arandomizedcontrolledexploratorystudy.JournalofCriticalCare,43,108Ͳ 113. Retrospective reviewofSTICUpatientsreceivingEN Patients(N= 200);>95%trauma) Excluded primarycoagulopathy,continued SUPthroughoutICUstay,orintolerantofEN Medianage 42yr(IQR 29– 55) TBI(%) 73.5 ISS16– 25,%(severe) 40.6 ISS>26– 75, %(profound) 38 NSAIDS, % 31 MediantimetoEN(d) 1(IQR1–2) Gastric FTlocation,%94 MediandurationofSUP(d) 3 (IQR3–5;96.5%H2RA) MediandurationofMV(d) 14(IQR10– 20) MediandurationofMVw/oSUP(d) 10 (IQR4– 15) MedianICULOS(d) 15 (11– 21) ClinicallyimportantGIB,% (95%CI) 0.5 (0– 1.48) TBI(N=147) 0.68 (0–2)*ONLYGIBNOTED* VAP/1000days 1 CDI/1000days 0.2

Palm,N.,Mckinzie,B.,Ferguson,P.L.,Chapman,E.,Dorlon,M.,Eriksson,E.A.,...Fakhry,S.M.(2016).PharmacologicStressGastropathy ProphylaxisMayNot 37 BeNecessaryinAtͲRiskSurgicalTraumaICUPatientsToleratingEnteralNutrition.JournalofIntensiveCareMedicine,1Ͳ 6.

SRandMAofICUPatients ReceivingEnteralNutrition Methods RCTs ofpatientsreceivingpharmacologicalSUPvsPBOornoSUP 2from2017,2from2016,2from1990s,1from1980s 4studiesw/PPIs,3w/H2RAs,1w/sucralfate;4/7usedPBO,3no Studies(N=7) ppx 3reportedclinicallysignificantGIB,6reportedovertGIB 4mixedICUs, 3MICUs;meanage50– 60s,2studies20– 40s 4studies100%receivingEN,allstudies>50% Patients(N=889) 5studies100%onMV,1>60%,120– 30% DurationofMVrangedfrom4– 21d GIB(RR) 0.8(0.49– 1.31),I2 =8% OvertGIB(N=589) 0.79(0.44– 1.39),I2 =24% Clinicallysig.(N=725) 0.63 (0.29– 1.37),I2 =25% No significantdifferencesnoted(PPI/H2RA/Sucral,yearpublished, Subgroups samplesize>100,blinded/unblinded,MICU/mixed,route) CDI(N= 407) 0.89(0.29– 1.39),I2=0% HAP(N=407) 1.53(1.04 – 2.27),I2=0% VAP(N=425) 1.24(0.72– 2.15),I2=0% Mortality(N=861) 1.21(0.94 – 1.56),I2=0%

Huang,H.ͲB.,Jiang,W.,Wang,C.ͲY.,Qin,H.ͲY.,&Du,B.(2018).Stressulcerprophylaxisinintensivecareunitpatientsreceivingenteralnutrition:asystematic 38 reviewandmetaͲanalysis.CriticalCare,22(20),1Ͳ 9 EnteralNutrition:Summary • PPISUPappearstoofferNObenefit inreducingCIBifMV patientstoleratingearlyenteralnutrition(i.e.ч24hr) – PENDING <100mgprednisoloneequivalents – NO upperGI/cardiacsurgery,burns,renalfailure, multiple/significantcomorbidities • Coagulopathy? – 30– 47%includedinprospectivedatasets • Hepaticdysfunction? – Casebycasebasis • TBI? – Casebycasebasis • PPISUPandCDI/VAP – Doesnotappeartobeasignificantincreasewhenusedshortterm

39

UpdatesinStressUlcerProphylaxis:RecentPublications METAͲANALYSES

40 RecentPublications

SystematicReviewandMetaͲanalysis:SUPvsNoSUP/PBO Design RCTS includingneurocritical carepatients 1from1980s,4from1990s,1from2000s,2after2010 7/8inICUsetting,1perioperative Studies 6usedH2RAs,1usedbothH2RAsandPPIs (N=8) Placebousedin7trials,1usednoppx **Notrialsmetthecriteriaofadequaterandomsequencegeneration, allocationconcealment,andblinding** N=829(288TBI,440intracerebral hemorrhage;remainderemergencyNES) Patients Meanagesrangedfrom29.6yr– 61yr MeanGCS5–9.8across6studies UpperGIBasdefinedineachindividualstudy Outcome ONLY 1evaluated CIB,remainderOVERT UGIB 11%vs.33% (N =8,829pts) RR0.31(0.2– 0.47);I2 45%(p=0.09) Mortality 23%vs.30% (N =5,381pts) RR 0.70(0.5– 0.98);I2 0%(p=0.62)

Liu,B.,Liu,S.,Yin,A.,&Siddiqi,J.(2015).Risksandbenefitsofstressulcerprophylaxisinadultneurocriticalpatients: asystematicreviewandmetaͲanalysisof 41 randomizedcontrolledtrials.CriticalCare,19(409),1Ͳ 13.

RecentPublications

Systematic Review andMetaͲanalysis ofPPIsvsH2RAs Methods RCTs ofcomparisonstudies 6Abstracts 10IV PPI,8POPPI Studies 10highriskofbias,3lowrisk;6unclear (N= 19,2117patients) 9inadequatelyblinded ***Noneevaluatedenteralnutritionstatus*** OvertGIB 4PRIORto2000,4AFTER2010(2/4ABSTRACT) PPIvsH2RA 0.48(0.34– 0.66),I2 =3% (N =17,1897pts) CIͲGIB 4PRIORto2000,3AFTER2010(2/3ABSTRACT) PPIvsH2RA 5WITHOUT clearlydefinedGIB, 2OVERTonly;othersw/variousdefs. (N=14,1679pts) RR0.39(0.21 – 0.71),I2 =0% PNA RR 1.12(0.86– 1.46),I2 =2% (N=13,1571pts) Mortality RR1.05 (0.87– 1.27),I2=0% (N=11, 1487)

Alshamsi,F.,BelleyͲCote,E.,Cook,D.,Almenawar,S.,Alqahtani,Z.,Perri,D.,...Alhazzani,W.(2016).Efficacyandsafetyofprotonpumpinhibitorsforstress 42 ulcerprophylaxisincriticallyillpatients:asystematicreviewandmetaͲanalysisofrandomizedtrials.CriticalCare,20(120),1Ͳ 12. SystematicReviewandMetaͲanalysis2018ComparingPharmacological SUP Design NetworkmetaͲanalysisofRCTs Comparison studiesofSUPpharmacotherapies Norestrictionsondose/route Studies 57eligiblestudies(18PPIvsH2RA;21H2RAvsPBP;18H2RAvsSucralf.) RiskofbiasHIGH in30studies,lowin16 ***MAJORITYdidnotreportonnutritionalstatus*** 20/31 PRIOR to2000,4AFTER 2010(2/4abstracts) CIͲGIB GIB+ш1:significanthemodynamicchanges,needforш2units transfusion,signiĮcantљHgb,+endoscopicfindings,needforsurgery H2RAvsPBO OR0.64(0.32– 1.30),moderate PPIvsPBO OR 0.24(0.10– 0.60),moderate PPIvsH2RA OR0.38(0.20– 0.73),moderate NosocomialPNA Per individualstudydefinition H2RAvsPBO 1.19(0.80– 1.78),moderate PPIvsPBO 1.52(0.95– 2.42)moderate PPIvsH2RA 1.27(0.96– 1.68),moderate Mortality Nosignificant differences(H2RAvsPPI,H2RAvsPBO,PPIvsPBO)

Waleed,A.,Alshamsi,F.,BelleyͲCote,E.,HeelͲAnsdel,D.,BrignnardelloͲPetersen,R.,Alquraini,M.,...Guyatt,G.(2018).Efficacyandsafetyofstressulcerprophylaxisin 43 criticallyillpatients:anetworkmetaͲanalysisofrandomizedtrials.IntensiveCareMed,44,1Ͳ 11.

RecentPublications

SystematicReviewandMetaͲanalysis:PPISUPvsPBO Design RCTsofcomparisonstudies Studies N=6;1from1993,1from2004,1from2013,3from2016 N=713 Patients 1studiedICH,1studiedCABG, 1studiedSICU;othersmixedICU pops. Clinically importantbleedingasdefinedineachstudy Outcome VAPandCDIasdefinedineachstudy GIB(CIB) N=5(1from1993,1from2013,3from2016) OR0.96(0.24– 3.82);I2 =0%,ratedaslow qualityevidence VAP OR1.45(0.84– 2.50);I2 =0%,rated aslowqualityevidence CDI OR 2.10(0.31– 14.07);I2 =0%,rated aslowqualityevidence Mortality OR1.11(0.76– 1.61);I2 =0%,rated aslowqualityevidence

Alhazzani,W.,Guyatt,G.,Alshahrani,M.,Deane,A.M.,Marshall,J.C.,Hall,R.,...Cook,D.(2017).WithholdingPantoprazoleforStressUlcerProphylaxisin 44 CriticallyIllPatients:APilotRandomizedClinicalTrialandMetaͲAnalysis.Crit CareMed,45,1121Ͳ 1129. MetaͲAnalyses:Summary • NeurocriticalcarepatientsMAY benefitfromH2RAs – Reductioninovert bleeding – ?Mortalitybenefit – BasedmainlyondataPRIOR to2000

• PPIs>H2RAs??? – MajorityofincludedstudiesPRIOR to2000s – ш50%dataincludedafter2010inabstract form • PPIvsPBO – No significantbenefitforreducingCIBwhenmorerecentdata included – NodifferenceinPNA/CDI/Mortality • Upperlimitof95%CIforCDI14.5 • PNA/Mortality – Nosignificantdifferences – TrendstowardsincreasedriskofPNAforPPIsvsPBO/H2RAs 45

UpdatesinStressUlcerProphylaxis FINALSUMMARYAND RECOMMENDATIONS

46 FinalSummary

• Criticalillnessplacespatientsatincreasedriskfor stressrelatedmucosaldisease

• Guidelinesagreeonsomeriskfactors – Largestudiesconsistentlyidentifycertainriskfactors • Renalfailure,liverfailure,multiͲorganfailure,coagulopathy – Differencesinindependentriskfactors

• Recentliterature – SuggestnotallMVpatientsrequirepharmacologicalSUP • Enteralnutritionmaysuffice – Dataveryweakand outdated tosupportPPIsoverH2RAs

47

Final RecommendationsforSUP:MechanicallyVentilatedICUPatients Coagulopathy* Renal failure/renalreplacementtherapy(RRT) Liverfailure Chronicliverdisease Pharmacological SUP indicated MultiͲorganfailure Severeburns TBI* SCI Tolerating EARLY enteralnutritionandNONE of thefollowing: Dualantiplatelettherapy PharmacologicalSUPNOT indicated ш3comorbidities(i.e.<3) >100mgprednisoloneequivalents UpperGIorcardiacsurgery Renalfailure/RRTorhepaticfailure ISSш16 CaseͲbyͲcasebasis Coagulopathy* TBI* ***Considerstopping pharmacologicalSUPafterextubationinMOST patients*** 48 PostͲAssessment

Whichofthefollowingistheunderlyingphysiologic processforthedevelopmentofstressulcersinthe ICU? A) GIhypoperfusion B) Anemia C) Infection D) Hypersecretorystate

49

PostͲAssessment

Whichofthefollowinghasbeenidentifiedasan independentriskfactorforclinicallysignificantGI bleedingincriticallyillpatients? A) Sepsis B) Organtransplant C) Vasoactivemedications D) Renalreplacementtherapy

50 PreͲAssessment

Enteralnutritionwouldlikelybesufficientforstress ulcerprophylaxisinwhichofthefollowingscenarios? A) Mechanicallyventilatedpatientreceivingcontinuous renalreplacementtherapywithanINRof2.1 B) MechanicallyventilatedTBIpatientwithout intracranialhypertension C) Mechanicallyventilatedpatientwithchronicliverand kidneydisease,COPD,andreceivingcorticosteroids D) Mechanicallyventilatedpatientwithoutsignificant PMH,anINRof1.9,andonnorepinephrine

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Updatesinstressulcerprophylaxis:Is pharmacologicalprophylaxisstill indicated?

RubenDVillanueva,PharmD,BCCCP,BCPS Assistantprofessor OUHSCCollegeofPharmacy TraumaCriticalCare OUMedicalCenter

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