Updatesinstressulcerprophylaxis:Is pharmacologicalprophylaxisstill indicated? RubenDVillanueva,PharmD,BCCCP,BCPS Assistantprofessor OUHSCCollegeofPharmacy TraumaCriticalCare OUMedicalCenter 1 Objectives • Describethepathophysiologyofstressulcersinthe criticallyill • Compareandcontrastcurrentstressulcerprophylaxis guidelines • Summarizerecentstressulcerprophylaxisliterature • Determineacriticallyillpatient’scontinuedneedfor stressulcerprophylaxis 2 PreͲAssessment Whichofthefollowingistheunderlying pathophysiologicprocessforthedevelopmentof stressulcersintheICU? A) GIhypoperfusion B) Anemia C) Infection D) Hypersecretorystate 3 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 5 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 11 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