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DiureticResistanceinHeartFailure
RobertJ.DiDomenico,PharmDClinicalAssociateProfessorAffiliateFaculty,CenterforPhamacoeconomicResearchUniversityofIllinoisatChicagoCollegesofPharmacy&MedicineCardiovascularClinicalPharmacistUniversityofIllinoisMedicalCenteratChicagoToPeeorNottoPee…
DiureticResistanceinHeartF1DisclosuresScios,Inc.Honoraria,consulting,researchsupportSanofi-Aventis/BristolMyersSquibbHonoraria(c/oSTRIVE?network)TheMedicinesCompanyHonoraria(c/oUniversityPharmacotherapyAssociates)DisclosuresScios,Inc.2Case54yoMPMH:CHFHTNCADs/pCABGDLDMOSA(morbidobesity)MedsFurosemide160mgbidSpironolactone25mgbidEnalapril20mgbidValsartan80mgbidDigoxin0.25mgdailyECASA325mgdailyLovastatin80mgqhsInsulinAdvairTheoplyllineBP113/73,HR118,RR4095%on2LO2PhysexamWt117kgJVD10cmBcracklesatbasesw/wheezing2+LEEtokneesLabs13810141(baseline20)4.119
1.7(baseline1.2)BNP414InitialTreatment(MedC)80mgIVfurosemideinED,then80mgIVq12hResponseUrineoutput(18hours)=980mlIncreasingdyspneaCase54yoMBP113/73,HR118,R3TypicalADHFTreatmentCourseADHERE?Q12006FinalCumulativeBenchmarkReport.Scios,Inc.:Sunnyvale,2006.
HauptmanPJ,etal.JAMA2006;296:1877-84.DiDomenicoRJ,etal.April,2007.TypicalADHFTreatmentCourseA4TypicalADHFTreatmentCourseADHERE?Q12006FinalCumulativeBenchmarkReport.Scios,Inc.:Sunnyvale,2006.
HauptmanPJ,etal.JAMA2006;296:1877-84.DiDomenicoRJ,etal.April,2007.TypicalADHFTreatmentCourseA5TypicalADHFTreatmentCourseADHERE?Q12006FinalCumulativeBenchmarkReport.Scios,Inc.:Sunnyvale,2006.
HauptmanPJ,etal.JAMA2006;296:1877-84.DiDomenicoRJ,etal.April,2007.TypicalADHFTreatmentCourseA6DiureticResistanceCommonlyreferredtoasCardiorenalSyndromeOftenassociatedwithrenalinsufficiency(acuteand/orchronic)DefinitionsvaryPersistentedemadespiteadequatediureticdosesDiminishednatriureticresponsetorepeateddosesDailyfurosemidedoses>80mg1PrevalenceChronic:35%1Acute:unknown1NeubergGW,etal.AmHeartJ2002;144:31-8.DiureticResistanceCommonlyre7DiureticResistance&MortalityEshaghianS,etal.AmJCardiol2006;97:1759-64.DiureticResistance&Mortalit8DiureticResistance
WhatAboutinADHF?GreenhalghE,DiDomenicoRJRetrospectiveanalysisofADHFadmissionstoUIMCCin2006Inclusion>18yo,ADHFwithvolumeoverload,TxwithIVdiureticExclusionInitialTxdoesn’tincludeIVdiureticUseofIVvasoactivesin1st24hoursN=264DefinitionUrineoutput<500mlwithin2hoursofIVfurosemideUrineoutput<1000mlwithin4hoursofIVfurosemideGoalsCharacterizediureticresistanceintheacutesettingInvestigateifthereareanyreliableriskfactorsfordiureticresistanceinADHFClinicalcharacteristicsDemographics,clinicalpresentation,NYHAFCLVFxn,renalFxnBPDoseofdiureticHome&inpatientConcomitantmedsDiureticResistance
WhatAbout9DiureticResistanceDiureticMechanismofAction&MechanismsofDiureticResistanceDiureticResistanceDiureticMe10DiureticMechanism/SiteofActionDeBruyneLKM.PostgradMedJ2003;79:268-71.DiureticMechanism/SiteofAct11MechanismsofDiureticResistanceDiminishedeffectinheartfailure&renalfailureStimulationofneurohormonalaxesHypertrophyofdistaltubulesimpairsnatriureticresponsePost-diureticNaClretentionVenouscongestionimpairsrenaltubularfunction???MechanismsofDiureticResista12NormalpatientsFurosemide40mgIVP200–250mEqNa3–4Lover3–4hrsCHFpatientsnatriureticresponseAbsorption&peakeffectdelayed1/3–1/4thatofnormalpatientsRenalinsufficiency(RI)1/5–1/10furosemidesecretedintorenaltubulesFreeconcentrationsofdiureticmaybeinnephroticsyndromeduetoproteinbindingDiureticPharmacodynamics
Sodium&WaterExcretionBraterDC.NewEnglJMed1998;339:387-95.NormalpatientsCHFpatientsDiu13DiureticsPharmacodynamics
Sodium&WaterExcretionEllisonDH.Cardiology2001;96:132-43.DiureticsPharmacodynamics
So14Diuretics&Neurohormones
DiureticResistance&RenalFunctionProximalTubuleAT2increasessodiumreabsorbtionCollectingDuctHypertrophyofdistaltubules.AldosteroneincreasessodiumreabsorbtionGlomerulusNorepinephrine,endothelin,AT2decreaserenalbloodflowandGFRWeberKT.NEJM.2001;345:1689-1697.FrancisGSetal.AnnInternMed.1984;101:370-377.DzauVJ.KidneyInt.1987;31:1402-1415.Diuretics&Neurohormones
Diur15DiureticResistance
NeurohormonalStimulationFrancisGS,etal.AnnInternMed1985;103:1-6.Baseline20minutes*p<0.01***DiureticResistance
Neurohormo16FrancisGS,etal.AnnInternMed1985;103:1-6.Baseline20minutes3.5hours2085+1035mlurine*p<0.01******DiureticResistance
HemodynamicEffectsFrancisGS,etal.AnnIntern17DoesVenousCongestionImpairRenalFunction?DotyJMetal.JTrauma1999;47:1000-3.DoesVenousCongestionImpair18DotyJMetal.JTrauma1999;47:1000-3.DoesVenousCongestionImpairRenalFunction?DotyJMetal.JTrauma1999;419DoesVenousCongestionImpairRenalFunction?PatelKP,CarminesPK.AmJPhysiolRegulatoryIntegrativeCompPhysiol2001;281:R239-45.DoesVenousCongestionImpair20TreatmentOptionsfor
DiureticResistanceChangediuretics?ContinuousinfusionCombinationofLoopdiuretic+thiazideIVvasoactivedrugsCombinationhypertonicsaline+Loopdiuretic???InvestigationaltherapiesVasopressinantagonistsAdenosineantagonistsTreatmentOptionsfor
Diureti21TreatmentofDiureticResistance
AreAllDiureticsCreatedEqual?Morefrequentdosingoffurosemide&bumetanidemaybenecessarytoovercomepostdiureticNaClretentionBraterDC.NewEnglJMed1998;339:387-95.TreatmentofDiureticResistan22TreatmentofDiureticResistanceContinuousInfusionofDiureticvs.IntermittentBolusDosingTreatmentofDiureticResistan23TreatmentofDiureticResistance
IVBolusvsContinuousInfusionUrineoutput(48hrs)IVbolus:3790mlContinf:4490mlP<0.01LahavM,etal.Chest1992;102:725-31.TreatmentofDiureticResistan24TreatmentofDiureticResistance
IVBolusvsContinuousInfusionDormansTPJ,etal.JAmCollCardiol1996;28:376-82.Cumulativedoses(areaunderthecurve)offurosemidenotsignificantlydifferentTreatmentofDiureticResistan2539patientswithADHF21receivedIVbolus18receivedcontinuousinfusionDailyurineoutput~65%greaterwithcontinuousinfusionvsIVbolusTreatmentofDiureticResistance
IVBolusvsContinuousInfusionP=0.016ThomsonMR,etal.HFSA2007[Abstract].39patientswithADHFTreatment26TreatmentofDiureticResistanceCombinationDiureticTherapyTreatmentofDiureticResistan27TreatmentofDiureticResistance
CombinationLoop+ThiazideChannerKS,etal.BrHeartJ1994;71:146-50.TreatmentofDiureticResistan28TreatmentofDiureticResistance
CombinationLoop+ThiazideChannerKS,etal.BrHeartJ1994;71:146-50.26/40(65%)TreatmentofDiureticResistan29TreatmentofDiureticResistance
PracticalApproachto
CombinationTherapyStartwithlowdosemetolazone(2.5–5mgdaily)Longhalf-lifenegatesneedformorefrequentdosingMaygive1stdose30minutespriortoIVfurosemideNotsubstantiatedinliteratureMayconsiderIVchlorothiazide250–500mgConsiderbriefcourse(<3days)tominimizehypovolemia&electrolytedeficienciesMonitorvolumestatus,electrolytes,&renalfunctiondiligentlyTreatmentofDiureticResistan30TreatmentofDiureticResistanceIVVasoactiveTherapyTreatmentofDiureticResistan31AbrahamWT,etal.JACC2005;46:57-64.IVVasoactiveTherapyinADHF
ADHEREMortalityAnalysisAbrahamWT,etal.JACC2005;432IVVasoactiveTherapyinADHF
EarlyInitiationMayImproveOutcomesPeacockWF,etal.HFSA2006[Abstract].IVVasoactiveTherapyinADHF
33ASCEND-HFTrial
NesiritideinPatientswithADHFNesiritide+StdtherapyvsPlacebo+StdtherapyMinimumduration24hoursPrimaryendpointHFrehospitalizationorall-causemortalityReliefofdyspneaat6&24hrsN=7000UIMCC&JBVAareparticipatingsitesInclusion>18yo,hospitalizedforADHFDyspneaatrestorminimalactivityPLUSTachypneaORpulmonarycongestiononexamPLUS+CXROR
BNPORPCWP>20OREF<40%ASCEND-HFTrial
Nesiritidein34RationaleCreatesanosmoticgradient,mobilizingextracellularfluidintotheintravascularspacefollowedbyimmediateexcretionHypertonicsalinemayincreaserenalbloodflow,facilitatingdiureticactivityAdministrationIVfurosemide500–1000mgpreparedtogetherwithhypertonicsalinesolution1.4–4.6%Administeredas30minuteinfusionq12hAlsoadministeredIVKCltominimizehypokalemiaTreatmentofDiureticResistance
HypertonicSaline&IVDiureticsLicataG,etal.AmHeartJ2003;145:459-66.RationaleTreatmentofDiuretic35TreatmentofDiureticResistance
HypertonicSaline&IVDiureticsLicataG,etal.AmHeartJ2003;145:459-66.TreatmentofDiureticResistan36TreatmentofDiureticResistance
UltrafiltrationCostanzoMR,etal.JAmCollCardiol2007;49:675-83.TreatmentofDiureticResistan37TreatmentofDiureticResistance
UltrafiltrationCostanzoMR,etal.JAmCollCardiol2007;49:675-83.TreatmentofDiureticResistan38FutureApproachesforDiureticResistanceinADHFNewDrugClasses:VasopressinAntagonistsFutureApproachesforDiuretic39VasopressinReceptorAntagonistsV1areceptorFoundinvascularsmoothmusclecellsVasoconstriction→
peripheralvascularresistanceandafterloadMayinduceischemiaduetocoronaryvasoconstrictionV2receptorFoundonrenaltubularcellsMediatesfreewaterretentionthroughaquaporinchannelsVasopressinAntagonistsinDevelopmentConivaptan(Vaprisol?)DuelV1a&V2antagonistIVformavailablePOformindevelopmentTolvaptanV2>>V1a(30times)urineoutputwithoutsodiumlossVasopressinReceptorAntagonis40TreatmentofDiureticResistance
RoleforConivaptan?UdelsonJE,etal.Circulation2001;104:2417-23.TreatmentofDiureticResistan41TreatmentofDiureticResistance
RoleforConivaptan?UdelsonJE,etal.Circulation2001;104:2417-23.TreatmentofDiureticResistan42NewDrugClassesAdenosineReceptorAntagonistsFutureApproachesforDiureticResistanceinADHFNewDrugClassesFutureApproac43AdenosineReceptorsandFunctionOtherreceptorsubtypes:A2b,A3Adenosinealsoresponsibleforsodiumtransportinproximalrenaltubules(mechanismunknown)AdenosinelevelsincreasedinpatientswithheartfailureAdenosinereceptorLocationEffectA1Kidney(afferentarteriole)VasoconstrictionA2aHeartvasculatureVasodilationModlingerPSetal.CurrOpinNephrolHypertens.2003;12:497-502.AdenosineReceptorsandFuncti44AdenosineAntagonisminHeartFailure
UrinaryOutput&RenalFunction-25-20-15-10-505101505001000150020002500UrineOutput(ml)0–8hoursGFR(%change)PlaceboIVFurosemiden=16(NYHAclassIIIHFGottliebSSetal.Circulation.2002;105:1348-1353.BG9719BG9719+IVFurosemideAdenosineAntagonisminHeart45PROTECTStudies:
AdenosineReceptorAntagonist,KW-3902PatientswithADHFandrenaldysfunctionrequiringi.v.diureticIVKW-3902plusStandardtherapyPlaceboplusStandardtherapyPrimaryendpoints:symptomaticreliefandrenalfunctionSecondaryendpoints:safety,medicalcostsExpectedenrollmentn=920.Identifier:NCT00354458&NCT00328692.Accessed10/12/06.PROTECTStudies:
AdenosineRec46DiureticResistance(HFSA)12.11Whencongestionfailstoimproveinresponsetodiuretictherapy,thefollowingoptionsshouldbeconsidered:SodiumandfluidrestrictionIncreaseddosesofloopdiureticContinuousinfusionofaloopdiuretic,orAdditionofasecondtypeofdiureticorally(metolazoneorspironolactone)orintravenously(chlorothiazide)Afifthoption,ultrafiltration,maybeconsidered(StrengthofEvidence=C)AdamsKF,etal.JCardFail2006;12:10-38.DiureticResistance(HFSA)12.147Vasodilators(HFSA)12.15Intheabsencesymptomatichypotension,intravenousnitroglycerin,nitroprusside,ornesiritide
maybeconsideredasanadditiontodiuretictherapyforrapidimprovementofcongestivesymptomsinpatientsadmittedwithADHF.Frequentbloodpressuremonitoringisrecommendedwiththeseagents.(StrengthofEvidence=B).AdamsKF,etal.JCardFail2006;12:10-38.Vasodilators(HFSA)12.15Inth48Vasodilators(HFSA)12.16Intravenousvasodilators(intravenousnitroglycerinornitroprusside)anddiuretics
arerecommendedforrapidsymptomreliefinpatientswithacutepulmonaryedemaorseverehypertension.(StrengthofEvidence=C)12.17Intravenousvasodilators(nitroprusside,nitroglycerin,ornesiritide)maybeconsideredinpatientswithADHFandadvancedHFwhohavepersistentsevereHFdespiteaggressivetreatmentwithdiureticsandstandardoraltherapies.(StrengthofEvidence=C)AdamsKF,etal.JCardFail2006;12:10-38.Vasodilators(HFSA)12.16Intra49InotropicAgents(HFSA)12.18(continued)Theseagentsmaybeconsideredinsimilarpatientswithevidenceoffluidoverloadiftheyrespondpoorlytointravenousdiureticsormanifestdiminishedorworseningrenalfunction.(StrengthofEvidence=C)WhenadjunctivetherapyisneededinotherpatientswithADHF,administrationofvasodilators
shouldbeconsidered
insteadofintravenousinotropes(milrinoneordobutamine).(StrengthofEvidence=B)AdamsKF,etal.JCardFail2006;12:10-38.InotropicAgents(HFSA)12.18(50ADHF(A)Signs&SymptomsofVOLUMEOVERLOAD(E)Moderate-SevereVolumeOverload(F)IVDiuretics+IVVasodilatorsIVfurosemideIffurosemidegivenpreviously,doublepreviousIVdose(max=360mg)Mayalsoconsidercontinuousinfusion(10–40mg/hr)Ifnofurosemidegivenpreviously&s/sofvolumeoverload,give40-180mgIVasdescribedabovePLUSNesiritide2g/kgIVpush,then0.01g/kg/mininfusionORNitroglycerin5-10g/mininfusionToachieve30-50%decreaseinPCWP,doseof140-160g/minmaybenecessaryDiDomenicoRJ,etal.AnnPharmacother2004;38:649-60.ADHF(A)Signs&SymptomsofVO51ADHF(B)Signs&SymptomsofLOWCARDIACOUTPUTDiDomenicoRJ,etal.AnnPharmacother2004;38:649-60.SBP>90mmHg?YesOna-blockerchronically?No(H)Milrinone(I)DobutamineADHF(B)Signs&SymptomsofDi5224681224Time(hours)frominitialEDphysicianevaluation0EstablishADHFdiagnosisInitiateIVADHFtherapyAssessresponse
toinitialtherapyReassessresponsetotherapyDeterminepatientdispositionTransferPatientInitialEDcontactDiDomenicoRJ,etal.AnnPharmacother2004;38:649-60.ImprovingTreatmentofADHF
TimingisEverything!24681224Time(hours)frominit53CaseRevisitedTreatmentcourseTransferCardiologyFurosemidedrip@10mg/hrDuration:96hoursIVNitroglycerindrip20mcg/minDuration:24hoursResponseInitialresponse1700mlurineovernext10hoursDevelopedintravasculardepletion,hypotension,WRFD/CfurosemideIVF+milrinonex2daysRenalfunctionCreatininepeakedat2.0(hospitalday2)Creatininereturnedtobaseline(1.2mg/dl)bydischargeDischargedonhospitalday13BP113/73,HR118,RR4095%on2LO2PhysexamWt117kgJVD10cmBcracklesatbasesw/wheezing2+LEEtokneesLabs13810141(baseline20)4.119
1.7(baseline1.2)BNP414InitialTreatment(MedC)80mgIVfurosemideinED,then80mgIVq12hResponseUrineoutput(18hours)=980mlIncreasingdyspneaCaseRevisitedTreatmentcourse54DiureticResistanceinHeartFailure
RobertJ.DiDomenico,PharmDClinicalAssociateProfessorAffiliateFaculty,CenterforPhamacoeconomicResearchUniversityofIllinoisatChicagoCollegesofPharmacy&MedicineCardiovascularClinicalPharmacistUniversityofIllinoisMedicalCenteratChicagoToPeeorNottoPee…
DiureticResistanceinHeartF55DisclosuresScios,Inc.Honoraria,consulting,researchsupportSanofi-Aventis/BristolMyersSquibbHonoraria(c/oSTRIVE?network)TheMedicinesCompanyHonoraria(c/oUniversityPharmacotherapyAssociates)DisclosuresScios,Inc.56Case54yoMPMH:CHFHTNCADs/pCABGDLDMOSA(morbidobesity)MedsFurosemide160mgbidSpironolactone25mgbidEnalapril20mgbidValsartan80mgbidDigoxin0.25mgdailyECASA325mgdailyLovastatin80mgqhsInsulinAdvairTheoplyllineBP113/73,HR118,RR4095%on2LO2PhysexamWt117kgJVD10cmBcracklesatbasesw/wheezing2+LEEtokneesLabs13810141(baseline20)4.119
1.7(baseline1.2)BNP414InitialTreatment(MedC)80mgIVfurosemideinED,then80mgIVq12hResponseUrineoutput(18hours)=980mlIncreasingdyspneaCase54yoMBP113/73,HR118,R57TypicalADHFTreatmentCourseADHERE?Q12006FinalCumulativeBenchmarkReport.Scios,Inc.:Sunnyvale,2006.
HauptmanPJ,etal.JAMA2006;296:1877-84.DiDomenicoRJ,etal.April,2007.TypicalADHFTreatmentCourseA58TypicalADHFTreatmentCourseADHERE?Q12006FinalCumulativeBenchmarkReport.Scios,Inc.:Sunnyvale,2006.
HauptmanPJ,etal.JAMA2006;296:1877-84.DiDomenicoRJ,etal.April,2007.TypicalADHFTreatmentCourseA59TypicalADHFTreatmentCourseADHERE?Q12006FinalCumulativeBenchmarkReport.Scios,Inc.:Sunnyvale,2006.
HauptmanPJ,etal.JAMA2006;296:1877-84.DiDomenicoRJ,etal.April,2007.TypicalADHFTreatmentCourseA60DiureticResistanceCommonlyreferredtoasCardiorenalSyndromeOftenassociatedwithrenalinsufficiency(acuteand/orchronic)DefinitionsvaryPersistentedemadespiteadequatediureticdosesDiminishednatriureticresponsetorepeateddosesDailyfurosemidedoses>80mg1PrevalenceChronic:35%1Acute:unknown1NeubergGW,etal.AmHeartJ2002;144:31-8.DiureticResistanceCommonlyre61DiureticResistance&MortalityEshaghianS,etal.AmJCardiol2006;97:1759-64.DiureticResistance&Mortalit62DiureticResistance
WhatAboutinADHF?GreenhalghE,DiDomenicoRJRetrospectiveanalysisofADHFadmissionstoUIMCCin2006Inclusion>18yo,ADHFwithvolumeoverload,TxwithIVdiureticExclusionInitialTxdoesn’tincludeIVdiureticUseofIVvasoactivesin1st24hoursN=264DefinitionUrineoutput<500mlwithin2hoursofIVfurosemideUrineoutput<1000mlwithin4hoursofIVfurosemideGoalsCharacterizediureticresistanceintheacutesettingInvestigateifthereareanyreliableriskfactorsfordiureticresistanceinADHFClinicalcharacteristicsDemographics,clinicalpresentation,NYHAFCLVFxn,renalFxnBPDoseofdiureticHome&inpatientConcomitantmedsDiureticResistance
WhatAbout63DiureticResistanceDiureticMechanismofAction&MechanismsofDiureticResistanceDiureticResistanceDiureticMe64DiureticMechanism/SiteofActionDeBruyneLKM.PostgradMedJ2003;79:268-71.DiureticMechanism/SiteofAct65MechanismsofDiureticResistanceDiminishedeffectinheartfailure&renalfailureStimulationofneurohormonalaxesHypertrophyofdistaltubulesimpairsnatriureticresponsePost-diureticNaClretentionVenouscongestionimpairsrenaltubularfunction???MechanismsofDiureticResista66NormalpatientsFurosemide40mgIVP200–250mEqNa3–4Lover3–4hrsCHFpatientsnatriureticresponseAbsorption&peakeffectdelayed1/3–1/4thatofnormalpatientsRenalinsufficiency(RI)1/5–1/10furosemidesecretedintorenaltubulesFreeconcentrationsofdiureticmaybeinnephroticsyndromeduetoproteinbindingDiureticPharmacodynamics
Sodium&WaterExcretionBraterDC.NewEnglJMed1998;339:387-95.NormalpatientsCHFpatientsDiu67DiureticsPharmacodynamics
Sodium&WaterExcretionEllisonDH.Cardiology2001;96:132-43.DiureticsPharmacodynamics
So68Diuretics&Neurohormones
DiureticResistance&RenalFunctionProximalTubuleAT2increasessodiumreabsorbtionCollectingDuctHypertrophyofdistaltubules.AldosteroneincreasessodiumreabsorbtionGlomerulusNorepinephrine,endothelin,AT2decreaserenalbloodflowandGFRWeberKT.NEJM.2001;345:1689-1697.FrancisGSetal.AnnInternMed.1984;101:370-377.DzauVJ.KidneyInt.1987;31:1402-1415.Diuretics&Neurohormones
Diur69DiureticResistance
NeurohormonalStimulationFrancisGS,etal.AnnInternMed1985;103:1-6.Baseline20minutes*p<0.01***DiureticResistance
Neurohormo70FrancisGS,etal.AnnInternMed1985;103:1-6.Baseline20minutes3.5hours2085+1035mlurine*p<0.01******DiureticResistance
HemodynamicEffectsFrancisGS,etal.AnnIntern71DoesVenousCongestionImpairRenalFunction?DotyJMetal.JTrauma1999;47:1000-3.DoesVenousCongestionImpair72DotyJMetal.JTrauma1999;47:1000-3.DoesVenousCongestionImpairRenalFunction?DotyJMetal.JTrauma1999;473DoesVenousCongestionImpairRenalFunction?PatelKP,CarminesPK.AmJPhysiolRegulatoryIntegrativeCompPhysiol2001;281:R239-45.DoesVenousCongestionImpair74TreatmentOptionsfor
DiureticResistanceChangediuretics?ContinuousinfusionCombinationofLoopdiuretic+thiazideIVvasoactivedrugsCombinationhypertonicsaline+Loopdiuretic???InvestigationaltherapiesVasopressinantagonistsAdenosineantagonistsTreatmentOptionsfor
Diureti75TreatmentofDiureticResistance
AreAllDiureticsCreatedEqual?Morefrequentdosingoffurosemide&bumetanidemaybenecessarytoovercomepostdiureticNaClretentionBraterDC.NewEnglJMed1998;339:387-95.TreatmentofDiureticResistan76TreatmentofDiureticResistanceContinuousInfusionofDiureticvs.IntermittentBolusDosingTreatmentofDiureticResistan77TreatmentofDiureticResistance
IVBolusvsContinuousInfusionUrineoutput(48hrs)IVbolus:3790mlContinf:4490mlP<0.01LahavM,etal.Chest1992;102:725-31.TreatmentofDiureticResistan78TreatmentofDiureticResistance
IVBolusvsContinuousInfusionDormansTPJ,etal.JAmCollCardiol1996;28:376-82.Cumulativedoses(areaunderthecurve)offurosemidenotsignificantlydifferentTreatmentofDiureticResistan7939patientswithADHF21receivedIVbolus18receivedcontinuousinfusionDailyurineoutput~65%greaterwithcontinuousinfusionvsIVbolusTreatmentofDiureticResistance
IVBolusvsContinuousInfusionP=0.016ThomsonMR,etal.HFSA2007[Abstract].39patientswithADHFTreatment80TreatmentofDiureticResistanceCombinationDiureticTherapyTreatmentofDiureticResistan81TreatmentofDiureticResistance
CombinationLoop+ThiazideChannerKS,etal.BrHeartJ1994;71:146-50.TreatmentofDiureticResistan82TreatmentofDiureticResistance
CombinationLoop+ThiazideChannerKS,etal.BrHeartJ1994;71:146-50.26/40(65%)TreatmentofDiureticResistan83TreatmentofDiureticResistance
PracticalApproachto
CombinationTherapyStartwithlowdosemetolazone(2.5–5mgdaily)Longhalf-lifenegatesneedformorefrequentdosingMaygive1stdose30minutespriortoIVfurosemideNotsubstantiatedinliteratureMayconsiderIVchlorothiazide250–500mgConsiderbriefcourse(<3days)tominimizehypovolemia&electrolytedeficienciesMonitorvolumestatus,electrolytes,&renalfunctiondiligentlyTreatmentofDiureticResistan84TreatmentofDiureticResistanceIVVasoactiveTherapyTreatmentofDiureticResistan85AbrahamWT,etal.JACC2005;46:57-64.IVVasoactiveTherapyinADHF
ADHEREMortalityAnalysisAbrahamWT,etal.JACC2005;486IVVasoactiveTherapyinADHF
EarlyInitiationMayImproveOutcomesPeacockWF,etal.HFSA2006[Abstract].IVVasoactiveTherapyinADHF
87ASCEND-HFTrial
NesiritideinPatientswithADHFNesiritide+StdtherapyvsPlacebo+StdtherapyMinimumduration24hoursPrimaryendpointHFrehospitalizationorall-causemortalityReliefofdyspneaat6&24hrsN=7000UIMCC&JBVAareparticipatingsitesInclusion>18yo,hospitalizedforADHFDyspneaatrestorminimalactivityPLUSTachypneaORpulmonarycongestiononexamPLUS+CXROR
BNPORPCWP>20OREF<40%ASCEND-HFTrial
Nesiritidein88RationaleCreatesanosmoticgradient,mobilizingextracellularfluidintotheintravascularspacefollowedbyimmediateexcretionHypertonicsalinemayincreaserenalbloodflow,facilitatingdiureticactivityAdministrationIVfurosemide500–1000mgpreparedtogetherwithhypertonicsalinesolution1.4–4.6%Administeredas30minuteinfusionq12hAlsoadministeredIVKCltominimizehypokalemiaTreatmentofDiureticResistance
HypertonicSaline&IVDiureticsLicataG,etal.AmHeartJ2003;145:459-66.RationaleTreatmentofDiuretic89TreatmentofDiureticResistance
HypertonicSaline&IVDiureticsLicataG,etal.AmHeartJ2003;145:459-66.TreatmentofDiureticResistan90TreatmentofDiureticResistance
UltrafiltrationCostanzoMR,etal.JAmCollCardiol2007;49:675-83.TreatmentofDiureticResistan91TreatmentofDiureticResistance
UltrafiltrationCostanzoMR,etal.JAmCollCardiol2007;49:675-83.TreatmentofDiureticResistan92FutureApproachesforDiureticResistanceinADHFNewDrugClasses:VasopressinAntagonistsFutureApproachesforDiuretic93VasopressinReceptorAntagonistsV1areceptorFoundinvascularsmoothmusclecellsVasoconstriction→
peripheralvascularresistanceandafterloadMayinduceischemiaduetocoronaryvasoconstrictionV2receptorFoundonrenaltubularcellsMediatesfreewaterretentionthroughaquaporinchannelsVasopressinAntagonistsinDevelopmentConivaptan(Vaprisol?)DuelV1a&V2antagonistIVformavailablePOformindevelopmentTolvaptanV2>>V1a(30times)urineoutputwithoutsodiumlossVasopressinReceptorAntagonis94TreatmentofDiureticResistance
RoleforConivaptan?UdelsonJE,etal.Circulation2001;104:2417-23.TreatmentofDiureticResistan95TreatmentofDiureticResistance
RoleforConivaptan?UdelsonJE,etal.Circulation2001;104:2417-23.TreatmentofDiureticResistan96NewDrugClassesAdenosineReceptorAntagonistsFutureApproachesforDiureticResistanceinADHFNewDrugClassesFutureApproac97AdenosineReceptorsandFunctionOtherreceptorsubtypes:A2b,A3Adenosinealsoresponsibleforsodiumtransportinproximalrenaltubules(mechanismunknown)AdenosinelevelsincreasedinpatientswithheartfailureAdenosi
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