超滤for心衰现状未来20110621

超滤治疗心衰：现状与

未来研究中国中医科学院西苑医院CCU冯新庆背景需要住院的心衰患者，90%存在明显的引起呼吸困难等症状的钠水潴留；利尿剂是治疗心衰的基石,但利尿剂有诸多问题和缺陷；开发安全可行的利尿替代治疗意义重大。ADHERE注册研究

AllEnrolledDischargesover12months

n=52,047利尿治疗是基础：88%大部分CHF使用利尿剂InadequateDiuresisDuringADHFTreatmentNote:Forthechart,nrepresentsthenumberofpatientswhohavebothbaselineanddischargeweight,andthepercentageiscalculatedbasedonthetotalpatientsinthecorrespondingpopulation.Patientswithoutbaselineordischargeweightareomittedfromthehistogramcalculations.ADHERE®DatabaseAllEnrolledDischargesinOver12Months(01.01.2003–12.31.2003)WhoWereDischargedHome(includinghomewithadditionaland/oroutpatientcare)

TheNationn=26,757,68%ChangeinWeightFromAdmissiontoDischarge7%6%13%24%30%15%3%2%01020304050

Enrolled

Discharges(%)(<-20)(-20to-15)(-15to-10)(-10to-5)(-5to0)(0to5)(5to10)(>10)ChangeinWeight(lb)DespitetheUseofDiureticsin90%ofPatients,20%GainWeightonDischarge1Adamsetal.AmHeartJ.2005;149:209-216.FurosemideMonotherapyCauses

SignificantDeclineinRenalFunction(GFR)-25-20-15-10-505101505001000150020002500UrineOutput(mL)0–8hGFR(%Change)PlaceboIVfurosemideGottliebetal.Circulation.2002;105:1348.ChangeinGFRafterIVfurosemide80mginCHF利尿剂的问题3：GFR下降与死亡相关

Totalof1906patientsNYHA分级III(n=1138)III/IV(n=607)IV(n=161)GFRc=UsesCockroft- GaultEqn肾功能损害是死亡的强预测因素GFRc与死亡率相关（1,906CHF病人）HillegeHLetal.Circulation2000;102:203-10利尿剂量与死亡增加相关PRAISE研究(n=1153)大剂量利尿剂,低剂量ACEI

高死亡NeubergGWetal.AHJ2002;144:31-8.利尿剂的问题4：增加死亡？利尿剂的问题4：增加死亡？DiureticuseandRiskofMortalityinPatientswithLeftVentricularDysfunction:SOLVDDatabaseMortalityRiskbyDiureticUseatBaselineDiuretic(n=2901)NoDiuretic(n=3896)NIncidenceNIncidencepvalueDeath:allcause101312.85865.30.001CVDeath90311.45104.60.001SuddenDeath2413.11831.70.001CooperHAetal.Circulation,1999;100:1311DiureticsDilemma

Ourbesttoolfortheremovaloffluidfromthedyspneicvolumeoverloadedpatienthasself-limitingfeaturesthatworkcountertothegeneralgoalsofpatientcareandmayinfactengendercounterproductiveconsequences.

PeacockWF,CriticalPathwaysinCardiology;4:4:2005

利尿剂的尴尬境地利尿剂作为目前最好的缓解心衰患者容量负荷过重和呼吸困难症状的治疗措施，因为其自身药理性质的限制，有悖于总的治疗目标，实际上可能导致有违初衷的后果。ULTRAFILTRATIONallowsfortheproductionofplasmawaterfromwholebloodacrossasemipermeablemembraneinresponsetoatransmembranepressuregradientTheensuingfluidorultrafiltrate

isisotonictoplasmaRoncoetal.Cardiology.2001;96:155-168.

利尿替代：血液超滤UltrafiltrationcanremovefluidfromthebloodatthesameratethatfluidcanbenaturallyrecruitedfromthetissueThetransientremovalofbloodillicitscompensatorymechanisms,termedplasmaorintravascularrefill(PR),aimedatminimizingthisreduction1,2FluidRemovalbyUltrafiltration1.Laueretal.ArchInternMed.1983;99:455-460.2.Marenzietal.JAmCollCardiol.2001;38:4.

VascularSpaceUFVascularSpaceInterstitialSpace(edema)NaNaNaNaKPH2OKPPRAHistoryofUltrafiltration

1979:Paganini

andothersreportedthepracticalapplicationofultrafiltrationinavolume-overloadedpatient41.SchneiersonSJ.AmJMedSoc.1949;298.2.Kolffetal.CleveClinQ.1954;21.3.Silversteinetal.NEnglJMed.1974;291:747-751.4.Paganinietal.AdvRenReplaceTher.1996;3:166-173.194019501960197019801949:SchneiersonproposedintermittentperitonealdialysisforrefractiveADHF1

1954:Kolffnotedthatultrafiltrationcouldbeusedfora“reductionofintractableedema”21974:Silversteindescribedsolitaryultrafiltrationon5ESRDpatientsviaamodifieddialysiscircuit3UltrafiltrationcanbedonesafelywithoutsignificantchangesinplasmavolumePlasmarefillratesmaydecreaseasvolumeremovalcontinuesMarenzietal.JAmCollCardiol.2001;38:963-968.

ChangesinPlasmaVolumeandRefillingRateDuringUltrafiltration

10–5–0––5––10–BeforeUF1liter2liter3liter4literAfterUF24hafterUFDPV(%)20–15–10–5–0–BeforeUF1liter2liter3liter4literAfterUF24hafterUFPRR(mL/min)HemodynamicEffectsofUFinCHFMarenzietal.JAmCollCardiol.2001;38:963-968.5.0–4.0–3.0–2.0–BeforeUF1liter2liter3liter4literAfterUF24hafterUFCO(L/m)70–60–50–40–30–BeforeUF1liter2liter3liter4literAfterUF24hafterUFSV(mL)25–20–15–10–5–0-BeforeUF1liter2liter3liter4literAfterUF24hafterUFRAP(mmHg)30–25–20–15–10-BeforeUF1liter2liter3liter4literAfterUF24hafterUFPWP(mmHg)UltrafiltrationinChronicCardiacInsufficiency:

FailureofFurosemidetoProvidetheSameResult

16stable,NYHAII–IIIchronicHFpatientsmatchedbyage,gender,andpeakVO2Randomizedtoisolatedultrafiltration(500mL/h)orIVfurosemideRemovalofthesameamountoffluidinbotharms(approximately1600mL)Measurementofhemodynamics,peakVO2,norepinephrine,PRA,andaldosteroneatbaseline,endoftreatment,and3monthsAgostonietal.AmJMed.1994;96:191-199.EffectsofUltrafiltrationvsIVFurosemideNeurohormonesTriangles=UltrafiltrationSquares=FurosemideAgostonietal.AmJMed.1994;96:191-199.+80–+40–%0–140–NEPRA+170–+80–+40–%0–-40-ALDd01d2d3d4d3m+80–+40–%0–140–d01d2d3d4d3md01d2d3d4d3mIsolatedUltrafiltrationProducesaSustainedDecreaseinBodyWeightinHFPatientsAgostonietal.AmJMed.1994;96:191-199.

UltrafiltrationFurosemide*P<.01vsbaseline†P<.01vsfurosemideB1d2d3d4d1m3mTime+2+10-1-2DBodyWeight(kg)EffectsofUltrafiltrationvsIVFurosemideLungWaterContentTriangles:UltrafiltrationSquares:IVFurosemideAgostonietal.AmJMed.1994;96:191-199.-

-3500

--2500

--1500mlFluidinputdiuresisplusultrafiltrate-3000--2000--1000–-mLFluidoutputb1d2d3d4d3m21-17-13-9-Chestx-rayscoreΔBodyWeightkg+2-+1-0--1--2-b1d2d3d4d1m3mEnhancedSodiumExtractionWithUltrafiltrationComparedWithIntravenousDiuretics15hospitalizedADHFpatientswithpresumeddiureticresistanceandclinicalevidenceofvolumeoverloadUrineelectrolyteconcentrationsmeasuredafteradoseofIVdiureticsUltrafiltrationwasthenbegunandultrafiltrateelectrolyteconcentrationsweremeasured8hlaterandcomparedwiththeinitialurinevaluesAlietal.JCardFail.2006;12(6suppl):114.UrinevsUFElectrolytesAfterIntravenousDiureticsorUltrafiltrationSodiumPotassiumMagnesium020406080100120140IVDUFP=.000025P=.000017P=.017mg/dLAlietal.JCardFail.2006;12(6suppl):114.UltrafiltrationandRenalFunctionJaskietalreportednodifferenceinmeancreatininebeforeUF(1.6mg/dL+/-0.6mg/dL)and24hafterUF

(1.7mg/dL+/-0.6mg/dL)1Bartetalreportedanaveragepre-UFcreatinineof

1.6mg/dLand48hpost-UFcreatinineof1.9mg/dL,whichwasnotstatisticallysignificant2Costanzoetalreportednochangeincreatininepre-andpost-UFinboththeEUPHORIA3andUNLOAD4trialsMarenzietalreportednochangeincreatininewhenutilizingUFinvolume-overloadedpatients5StudyNameStudyType&

InclusionCriteriaPtsConclusion(s)Pepi,BrHeartJ.1993;70(2):135-40.Randomized,controlled,FCII-III12/12Intheultrafiltrationgroup,variationsintheventricularfillingpattern,lungwatercontent,andfunctionalperformancepersistedforthreemonthsinallcases.Noneofthesechangeswasdetectedinthecontrolgroup.Agostoni,JAmCollCardiol.1993;21(2):424-31Randomized,controlled,FCII-III18/18Inpatientswithmoderatecongestiveheartfailure,ultrafiltrationreducestheseverityofthesyndrome.Marenzi,,AmJMed.1993;94(1):49-56Prospective,FCclassII-IV32RefractoryCHFrequirestheinterruptionofthehumoral-hemodynamicviciouscircle,andultrafiltrationisabletoaccomplishthat.Susuni,CritCareMed1990;18:14-18Prospective,FCIV,diureticresistant20UFmaybeconsideredaneffectivetoolforthetreatmentofacutepulmonaryedemarefractorytodrugtherapy,asanalternativetomechanicalventilation,andasaremedyforexcessiveextravascularlungwater.Rimondini,AmJMed.1987;83(1):43-8Prospective,caseseries,FCIV,diureticresistant11Hemofiltrationpromotedreliefofdyspneaandofclinicalandradiographicevidenceoflungcongestionandpleuraleffusion,andsubstantiallyreducedthedependentedemaandabdominalgirthFauchald,ActaMedScand.1986;219(1):47-52Prospective,caseseries,FCIII-IV,diureticresistant6Ultrafiltrationisasafemethodoffluidremovalinpatientswiththerapy-resistantcardiacedemaandcanbeusedaspreparationforcardiaccatheterizationorsurgery.血液滤过/超滤治疗心衰文献摘要StudyNameStudyType&

InclusionCriteriaPtsConclusion(s)Saltzberg,JCardFailure2003,9(5),Suppl.S46163Prospective,caseseries,FCIII-IV,DiureticResistant251)Safelyandeffectivelyremoveslargevolumesofexcessfluid2)Producessignificantsymptomaticandfunctionalimprovement3)Reducesneurohormonalactivationand4)ReducesLOSbyalmost2dayscomparedtothatobservednationallyinDHFpatientsreceivingconventionalheartfailuretreatment.Raman,IntJArtifOrgans.2003;26(8):753-7Randomized,caseseries,CVSurg61/57HemofiltrationduringCPBattenuatespostoperativeanemia,thrombocytopeniaandhypoalbuminemia,mayreducepost-operativebleedingandappearstodecreasepost-operativepulmonarycomplications.Jaski,JournalofCardiacFailure20039(3);227-231Prospective,caseseries,FCIII21Rapidremovalofextracellularandintravascularfluidvolumeexcesscanbesafelyachievedviaperipherallyinsertedultrafiltrationwithouttheneedforcentralvenouscatheterplacement.Marenzi,JAmCollCardiol2001;38:4:963-968Prospective,caseseries,FCIII24InpatientswithrCHF,subtractionofplasmawaterbyUFisassociatedwithhemodynamicimprovement.HypotensiondoesnotoccurwhenplasmarefillingrateisadequatetopreventhypovolemiaCanaud,NephrolDialTransplant1998,13[Suppl4]:51-55Prospective,SevereCHF,classIV52Veno-venousultrafiltrationhasthepotentialtoblockthedeleteriouseffectsofthecardiacandrenalinteractionssecondarytosevereCHF.Inasignificantproportionofpatients,itimprovescardiacperformanceandanumberofclinicalparameters.Blake,AdvRenReplaceTher.1996;3(2):166-73Referencedsummaryofclinicalworktodate.--UFrelievespulmonaryedema,reducesascitesandperipheraledema,enhancestheresponsetosubsequentdiuretictherapy,improvesoverallvolumestatus,normalizesfillingpressures,andreducesclinicalsymptoms,andoffersanimprovementinoverallqualityoflife.Agostoni,AmJMed.1994;96(3):191-9Randomized,UFvs.IVbolusLasix8/8Afterultrafiltration,thefavorablecirculatoryandventilatoryadjustmentsconsequenttothereabsorptionoflungwaterimprovedthefunctionalcapacityofthesepatients.Theimprovementcontinued3monthsaftertheprocedure血液滤过/超滤治疗心衰文献摘要SelectedUltrafiltrationStudiesSummaryInvestigatorPopulationUFRateConclusionsMarenzi,etal.(2001)JACC24NYHAClassIVPatientsinICU550ml/h4.9literstotalUFperformedsafelywithoutsideeffectsUrinaryoutputincrease,diureticdecreaseNYHAClassimprovementinallRonco,etal.(2001)Cardiology22patientstreatedwitheither4or24hourUFtherapy625ml/hvs100ml/h2.5literstotalBloodvolumemorestableinlowerUFrateHematocritmonitoringusefulCanaud,etal.(1998)NephroDialTransplant52NYHAClassIVPatientsUpto500ml/h75%improvedNYHAfunctionalclass46%improvedcardiacand/orrenalfunction(lasting>3monthsformost)Agostoni,etal.(1994)AMJMed16moderateCHF,randomizedtoUForfurosemide500ml//h1.7literstotalUF:improvedneurohormonalprofile,lastingfunctionalimprovement(at3months)Furosemide:continuedneurohormonalactivation,nochangeinfunctionalclass,recurringsymptomsAgostoni,etal.(1993)JACC36patients,randomizedtoUForfurosemide500ml//h1.9literstotalUF:improvementinhemodynamicstatus,neurohormonalprofileandexercisecapacityFurosemide:changesnotobservedRimondini,etal.(1987)AmJMed.11NYHAClassIVPatients500ml//h2-3literstotalEvidenceofcongestionreliefMaintenanceofCVstabilityUrineoutputincreasesubstantiallyESCCongress2005StockholmUltrafiltrationinCHF.Cardiology2002超滤与利尿剂比较利尿剂的缺点超滤的优点低张尿，排水>排钠等张超滤液，排水＝排钠量效关系差准确控制超滤量和超滤速度电解质紊乱对血浆电解质浓度无影响降低肾小球滤过率改善肾小球滤过率直接激活神经内分泌对神经内分泌无直接作用安全性和疗效没有随机对照试验验证随机对照试验证明安全有效，改善转归利尿替代－血液滤过实现的机械利尿自1986年，有近百篇零星报道;均是小样本研究，没有形成有说服力的证据;汇总结论：安全、有效，疗效体现在：1快速缓解呼吸困难等症状，2快速消除水肿，3改善心功能，4逆转利尿剂抵抗，5单次治疗，疗效持续3月，6改善神经内分泌状态，7改善血流动力学。没有心衰专用设备制约了超滤技术在心内科的应用Ultrafiltration~2%I/Vdiuretics~80%

I/Vdiuretics,inotropesCombination~20%

尽管临床研究表明超滤机械利尿安全、有效，但因为没有专用设备，大大限制了心内科的应用。现行的血液滤过/血液透析设备虽具备超滤功能，但不适用心衰的超滤治疗。心衰专用超滤装置的研发我们自己的经验和文献显示，现有的血滤设备不适用于心衰的治疗；研发新型设备是深入研究心衰超滤治疗的基础；历时5年；中科院电子所、声学所、环境所、计算所，清华大学、北京大学等通力合作；2009年研发成功，并用于临床；目前，全球有美国和我们两家生产同类设备。新型心衰专用超滤装置我们的设备CHFSolutionCo.USA使用新型设备的临床研究使用新型设备的临床研究Multicenter,prospectivestudy,21patients(25treatments)InitialUFwithin12hofhospitalizationandbeforeanysignificantadministrationofIVdiureticsand/orvasoactivedrugsPrimaryendpointofgreaterthan1Lfluidremovalinlessthan8hwasachievedin92%oftreatments(treatmentperiod6:43±1:47h:min)Onaverage,2611±1002mL(maximum3725mL)ofultrafiltratewasremovedpertreatmentPatientweightdecreasedfrom91.9±17.5to89.3±17.3kg(P<.0001)

afterultrafiltrationNomajoradverseeventsoccurredConclusion:RapidremovalofextracellularandintravascularfluidvolumeexcesscanbesafelyachievedviaperipherallyinsertedultrafiltrationwithouttheneedforcentralvenouscatheterplacementTheSAFEStudy Jaski.JCardFail.2003;9:227-231.ReliefforAcutelyFluidOverloadedPatientsWithDecompensated

Congestive

Heart

Failure

TheRAPID-CHFTrial

Bartetal.JAmCollCardiol.2005;46:2043-2046.RAPIDTrial:DesignMulticenter(7),randomized,controlledstudy(40patients)comparingthetreatmenteffectsofearlyultrafiltrationtreatmentstrategyof8h,todiuretictherapyforpatientswhoarehospitalizedfordecompensatedHFofanyetiologySingle8-hUFinterventioncomparedwithusualdiureticstrategiesArtificiallyconstrainedUFto8hTherapywasnottitratedagainstclinicalorbiochemicalmarkersofcongestion/edema/volumeBartetal.JAmCollCardiol.2005;46:2043-2046.RAPIDTrial:TotalFluidRemoval48hP=.028mL-11000-9000-7000-5000-3000-10001000UFUsualCareBartetal.JAmCollCardiol.2005;46:2043-2046.

RAPIDTrial:Conclusions

Ultrafiltrationissuperiortodiureticstrategiesinsaltand

waterremovalUltrafiltrationissafe,inavarietyofclinicalsitesThereisnoclinicaljustificationtodelayultrafiltrationtherapyuntildiureticsfailBartetal.JAmCollCardiol.2005;46:2043-2046.Early

UltrafiltrationinPatientsWithDecompensatedHFandObserved

ResistancetoInterventionWith

DiureticAgents

TheEUPHORIATrialCostanzoetal.JAmCollCardiol.2005;46:2047-2051.EUPHORIATrial:StudyEndPointsPrimaryefficacyendpointResolutionofsignsandsymptomsoffluidoverloadpermittingdischargein≤3daysPrimarysafetyendpointFeasibilityofachievingtheprimaryefficacyobjectivewithoutsymptomatichypotension,renalinsufficiency(≥25%increaseinserumcreatinine),orotheradverseeventsCostanzoetal.JAmCollCardiol.2005;46:2047-2051..EUPHORIATrial:PatientPopulationAge:74±8.5yearsGender:75%maleRace:95%CaucasianEtiologyofHF:75%ischemicLeftventricularejectionfraction:31±16%Costanzoetal.JAmCollCardiol.2005;46:2047-2051..EUPHORIATrial:ResultsNumberof8-hultrafiltrationcourses:

2.6±1.2Volumeremovedbyultrafiltration:

8653±4314mLCostanzoetal.JAmCollCardiol.2005;46:2047-2051.EUPHORIATrial:LengthofStay5743101234567Patients2Days3Days4Days5Days10DaysCostanzoetal.JAmCollCardiol.2005;46:2047-2051.VariablePre-UFDisch.30Days90DaysPValueWeight(kg)87±2381±2284±2180±18.006SBP(mmHg)120±17114±22120±26116±24.306Cr(mg/dL)2.12±0.62.20±0.82.38±1.12.18±0.7.532BNP(pg/mL)1236±747988±847816±494NA.03NYHAFCIV39%37%5%11%.063EUPHORIATrial:ClinicalandLaboratoryOutcomesCostanzoetal.JAmCollCardiol.2005;46:2047-2051.SerumSodium140139138137136135134133132131130129Pre-UF Discharge 30Day 90Day*Pre-UFtodischarge†Pre-UFto90daysNa(mg/dL)n=13ns*ns†n=7*P=.042†P=.017Earlyultrafiltrationinpatientswithfluidoverloadanddiureticresistancepermittedthedischargeof60%ofhighriskADHFpatientsin≤3daysAtreatmentstrategytouseultrafiltrationearlyinpatientswithvolumeoverloadandevidenceofdiureticresistanceresultsinreducedlengthofstayandimprovedclinicalstatusImprovementsinclinicalstatusarepreservedfor30–90daysfollowinghospitalizationsEUPHORIATrial:ConclusionsCostanzoetal.JAmCollCardiol.2005;46:2047-2051.UltrafiltrationversusIVDiureticsforPatientsHospitalizedforAcuteDecompensatedCongestiveHF:

AProspectiveRandomizedClinicalTrial

UNLOADTrialCostanzoMRetal.JAmCollCardiol.2007;49:675-683.UltrafiltrationversusIntravenousDiuretics

forPatientsHospitalizedforAcuteDecompensated

CongestiveHeartFailure(UNLOAD)UNLOADStudyDesign200subjectswithvolumeoverloadmanifestedby≥

2signsofHF:edema≥

2+;JVD≥7cm;CXRwithpulmonaryedemaoreffusion;enlargedliverorascites;PND/orthopneaorralesUltrafiltrationupto500ml/hr(Determinedbyphysician)NoIVdiureticsIVdiureticsasbolu