1、Diuretic Resistance in Heart FailureRobert J.DiDomenico,PharmDClinical Associate ProfessorAffiliate Faculty,Center for Phamacoeconomic ResearchUniversity of Illinois at ChicagoColleges of Pharmacy&MedicineCardiovascular Clinical PharmacistUniversity of Illinois Medical Center at ChicagoTo Pee or Not
2、 to PeeDisclosures Scios,Inc.Honoraria,consulting,research support Sanofi-Aventis/Bristol Myers Squibb Honoraria(c/o STRIVE network)The Medicines Company Honoraria(c/o University Pharmacotherapy Associates)Case54yo MPMH:CHF HTN CAD s/p CABG DL DM OSA(morbid obesity)Meds Furosemide 160mg bid Spironol
3、actone 25mg bid Enalapril 20mg bid Valsartan 80mg bid Digoxin 0.25mg daily ECASA 325mg daily Lovastatin 80mg qhs Insulin Advair TheoplyllineBP 113/73,HR 118,RR 4095%on 2L O2Phys exam Wt 117kg JVD 10cm B crackles at bases w/wheezing 2+LEE to kneesLabs 138 101 41(baseline 20)4.1 19 1.7(baseline 1.2)BN
4、P 414Initial Treatment(Med C)80mg IV furosemide in ED,then 80mg IV q12hResponse Urine output(18 hours)=980ml Increasing dyspneaTypical ADHF Treatment CourseADHERE Q1 2006 Final Cumulative Benchmark Report.Scios,Inc.:Sunnyvale,2006.Hauptman PJ,et al.JAMA 2006;296:1877-84.DiDomenico RJ,et al.April,200
5、7.Typical ADHF Treatment CourseADHERE Q1 2006 Final Cumulative Benchmark Report.Scios,Inc.:Sunnyvale,2006.Hauptman PJ,et al.JAMA 2006;296:1877-84.DiDomenico RJ,et al.April,2007.Typical ADHF Treatment CourseADHERE Q1 2006 Final Cumulative Benchmark Report.Scios,Inc.:Sunnyvale,2006.Hauptman PJ,et al.J
6、AMA 2006;296:1877-84.DiDomenico RJ,et al.April,2007.Diuretic Resistance Commonly referred to as Cardiorenal Syndrome Often associated with renal insufficiency(acute and/or chronic)Definitions vary Persistent edema despite adequate diuretic doses Diminished natriuretic response to repeated doses Dail
7、y furosemide doses 80mg1 Prevalence Chronic:35%1 Acute:unknown1Neuberg GW,et al.Am Heart J 2002;144:31-8.Diuretic Resistance&Mortality Eshaghian S,et al.Am J Cardiol 2006;97:1759-64.Diuretic ResistanceWhat About in ADHF?Greenhalgh E,DiDomenico RJ Retrospective analysis of ADHF admissions to UIMCC in
8、 2006 Inclusion 18yo,ADHF with volume overload,Tx with IV diuretic Exclusion Initial Tx doesnt include IV diuretic Use of IV vasoactives in 1st 24 hours N=264 Definition Urine output 500ml within 2 hours of IV furosemide Urine output 1000ml within 4 hours of IV furosemide Goals Characterize diuretic
9、 resistance in the acute setting Investigate if there are any reliable risk factors for diuretic resistance in ADHF Clinical characteristics Demographics,clinical presentation,NYHA FC LV Fxn,renal Fxn BP Dose of diuretic Home&inpatient Concomitant medsDiuretic ResistanceDiuretic Mechanism of Action&
10、Mechanisms of Diuretic ResistanceDiuretic Mechanism/Site of ActionDe Bruyne LKM.Postgrad Med J 2003;79:268-71.Mechanisms of Diuretic Resistance Diminished effect in heart failure&renal failure Stimulation of neurohormonal axes Hypertrophy of distal tubules impairs natriuretic response Post-diuretic
11、NaCl retention Venous congestion impairs renal tubular function?Normal patients Furosemide 40mg IVP 200 250mEq Na 3 4 L over 3 4 hrs CHF patients natriuretic response Absorption&peak effect delayed 1/3 1/4 that of normal patients Renal insufficiency(RI)1/5 1/10 furosemide secreted into renal tubules
12、 Free concentrations of diuretic may be in nephrotic syndrome due to protein bindingDiuretic PharmacodynamicsSodium&Water ExcretionBrater DC.New Engl J Med 1998;339:387-95.Diuretics Pharmacodynamics Sodium&Water ExcretionEllison DH.Cardiology 2001;96:132-43.Diuretics&NeurohormonesDiuretic Resistance
13、&Renal FunctionProximal TubuleAT2 increases sodium reabsorbtionCollecting DuctHypertrophy of distal tubules.Aldosterone increases sodium reabsorbtionGlomerulusNorepinephrine,endothelin,AT2 decrease renal blood flow and GFRWeber KT.NEJM.2001;345:1689-1697.Francis GS et al.Ann Intern Med.1984;101:370-
14、377.Dzau VJ.Kidney Int.1987;31:1402-1415.Diuretic ResistanceNeurohormonal StimulationFrancis GS,et al.Ann Intern Med 1985;103:1-6.Baseline20 minutes*p0.01*Francis GS,et al.Ann Intern Med 1985;103:1-6.Baseline20 minutes3.5 hours2085+1035ml urine*p0.01*Diuretic ResistanceHemodynamic EffectsDoes Venous
15、 Congestion Impair Renal Function?Doty JM et al.J Trauma 1999;47:1000-3.Doty JM et al.J Trauma 1999;47:1000-3.Does Venous Congestion Impair Renal Function?Does Venous Congestion Impair Renal Function?Patel KP,Carmines PK.Am J Physiol Regulatory Integrative Comp Physiol 2001;281:R239-45.Treatment Opt
16、ions for Diuretic Resistance Change diuretics?Continuous infusion Combination of Loop diuretic+thiazide IV vasoactive drugs Combination hypertonic saline+Loop diuretic?Investigational therapies Vasopressin antagonists Adenosine antagonistsTreatment of Diuretic ResistanceAre All Diuretics Created Equ
17、al?More frequent dosing of furosemide&bumetanide may be necessary to overcome postdiuretic NaCl retentionBrater DC.New Engl J Med 1998;339:387-95.Treatment of Diuretic ResistanceContinuous Infusion of Diureticvs.Intermittent Bolus DosingTreatment of Diuretic ResistanceIV Bolus vs Continuous Infusion
18、Urine output(48hrs)IV bolus:3790mlCont inf:4490mlP0.01Lahav M,et al.Chest 1992;102:725-31.Treatment of Diuretic ResistanceIV Bolus vs Continuous InfusionDormans TPJ,et al.J Am Coll Cardiol 1996;28:376-82.Cumulative doses(area under the curve)of furosemide not significantly different 39 patients with
19、 ADHF 21 received IV bolus 18 received continuous infusion Daily urine output 65%greater with continuous infusion vs IV bolusTreatment of Diuretic ResistanceIV Bolus vs Continuous InfusionP=0.016Thomson MR,et al.HFSA 2007Abstract.Treatment of Diuretic ResistanceCombination Diuretic TherapyTreatment
20、of Diuretic ResistanceCombination Loop+ThiazideChanner KS,et al.Br Heart J 1994;71:146-50.Treatment of Diuretic ResistanceCombination Loop+ThiazideChanner KS,et al.Br Heart J 1994;71:146-50.26/40(65%)Treatment of Diuretic ResistancePractical Approach to Combination Therapy Start with low dose metola
21、zone(2.5 5mg daily)Long half-life negates need for more frequent dosing May give 1st dose 30 minutes prior to IV furosemide Not substantiated in literature May consider IV chlorothiazide 250 500mg Consider brief course(18yo,hospitalized for ADHF Dyspnea at rest or minimal activityPLUS Tachypnea OR p
22、ulmonary congestion on examPLUS+CXR OR BNP OR PCWP 20 OR EF V1a(30 times)urine output without sodium lossTreatment of Diuretic ResistanceRole for Conivaptan?Udelson JE,et al.Circulation 2001;104:2417-23.Treatment of Diuretic ResistanceRole for Conivaptan?Udelson JE,et al.Circulation 2001;104:2417-23
23、.New Drug ClassesAdenosine Receptor AntagonistsFuture Approaches for Diuretic Resistance in ADHFAdenosine Receptors and Function Other receptor subtypes:A2b,A3 Adenosine also responsible for sodium transport in proximal renal tubules(mechanism unknown)Adenosine levels increased in patients with hear
24、t failureAdenosine receptorLocationEffectA1Kidney(afferent arteriole)VasoconstrictionA2aHeartvasculatureVasodilationModlinger PS et al.Curr Opin Nephrol Hypertens.2003;12:497-502.Adenosine Antagonism in Heart FailureUrinary Output&Renal Function-25-20-15-10-505101505001000150020002500Urine Output(ml
25、)08 hoursGFR(%change)PlaceboIV Furosemiden=16(NYHA class III HFGottlieb SS et al.Circulation.2002;105:1348-1353.BG9719BG9719+IV FurosemidePROTECT Studies:Adenosine Receptor Antagonist,KW-3902Patients with ADHF and renal dysfunctionrequiring i.v.diureticIV KW-3902plusStandard therapyPlaceboplusStanda
26、rd therapyPrimary endpoints:symptomatic relief and renal functionSecondary endpoints:safety,medical costsExpected enrollmentn=920http:/www.clinicaltrials.gov.Identifier:NCT00354458&NCT00328692.Accessed 10/12/06.Diuretic Resistance(HFSA)12.11 When congestion fails to improve in response to diuretic t
27、herapy,the following options should be considered:Sodium and fluid restriction Increased doses of loop diuretic Continuous infusion of a loop diuretic,or Addition of a second type of diuretic orally(metolazone or spironolactone)or intravenously(chlorothiazide)A fifth option,ultrafiltration,may be co
28、nsidered(Strength of Evidence=C)Adams KF,et al.J Card Fail 2006;12:10-38.Vasodilators(HFSA)12.15 In the absence symptomatic hypotension,intravenous nitroglycerin,nitroprusside,or nesiritide may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients
29、admitted with ADHF.Frequent blood pressure monitoring is recommended with these agents.(Strength of Evidence=B).Adams KF,et al.J Card Fail 2006;12:10-38.Vasodilators(HFSA)12.16 Intravenous vasodilators(intravenous nitroglycerin or nitroprusside)and diuretics are recommended for rapid symptom relief
30、in patients with acute pulmonary edema or severe hypertension.(Strength of Evidence=C)12.17 Intravenous vasodilators(nitroprusside,nitroglycerin,or nesiritide)may be considered in patients with ADHF and advanced HF who have persistent severe HF despite aggressive treatment with diuretics and standar
31、d oral therapies.(Strength of Evidence=C)Adams KF,et al.J Card Fail 2006;12:10-38.Inotropic Agents(HFSA)12.18(continued)These agents may be considered in similar patients with evidence of fluid overload if they respond poorly to intravenous diuretics or manifest diminished or worsening renal functio
32、n.(Strength of Evidence=C)When adjunctive therapy is needed in other patients with ADHF,administration of vasodilators should be considered instead of intravenous inotropes(milrinone or dobutamine).(Strength of Evidence=B)Adams KF,et al.J Card Fail 2006;12:10-38.ADHF(A)Signs&Symptoms of(E)Moderate-S
33、evere Volume Overload(F)IV Diuretics+IV VasodilatorsIV furosemideIf furosemide given previously,double previous IV dose(max=360 mg)May also consider continuous infusion(10 40 mg/hr)If no furosemide given previously&s/s of volume overload,give 40-180 mg IV as described abovePLUSNesiritide 2 g/kg IV p
34、ush,then 0.01 g/kg/min infusion ORNitroglycerin 5-10 g/min infusion To achieve 30-50%decrease in PCWP,dose of 140-160 g/min may be necessaryDiDomenico RJ,et al.Ann Pharmacother 2004;38:649-60.ADHF(B)Signs&Symptoms of DiDomenico RJ,et al.Ann Pharmacother 2004;38:649-60.SBP 90 mmHg?YesOn a -blocker ch
35、ronically?No(H)Milrinone(I)Dobutamine24681224Time(hours)from initial ED physician evaluation0Establish ADHF diagnosisInitiate IV ADHF therapyAssess response to initial therapyReassess response to therapyDetermine patient dispositionTransfer PatientInitial EDcontactDiDomenico RJ,et al.Ann Pharmacothe
36、r 2004;38:649-60.Improving Treatment of ADHFTiming is Everything!Case RevisitedTreatment course Transfer Cardiology Furosemide drip 10mg/hr Duration:96 hours IV Nitroglycerin drip 20mcg/min Duration:24 hoursResponse Initial response 1700ml urine over next 10 hours Developed intravascular depletion,h
37、ypotension,WRF D/C furosemide IVF+milrinone x 2 days Renal function Creatinine peaked at 2.0(hospital day 2)Creatinine returned to baseline(1.2mg/dl)by dischargeDischarged on hospital day 13BP 113/73,HR 118,RR 4095%on 2L O2Phys exam Wt 117kg JVD 10cm B crackles at bases w/wheezing 2+LEE to kneesLabs 138 101 41(baseline 20)4.1 19 1.7(baseline 1.2)BNP 414Initial Treatment(Med C)80mg IV furosemide in ED,then 80mg IV q12hResponse Urine output(18 hours)=980ml Increasing dyspnea
