AProspectiveRandomisedTrialofEarlyLVVentingUsingImpellaCPforRecoveryinpatientswithcardiogenicshockmanagedwithVAECMO(REVERSE)Date:Dec202017NCTYettobereleased.PrincipalInvestigators:MichaelIbrahimMDPhD,ChristianBermudezMDInvestigators:EdwardRameMD,PavanAtluriMD,MichaelAckerMD,CardiologyHUP:EduardoRameMD,JoyceWaldMD,EdoYBiratiMD,SaifAnwarrudinMD,JayGiriMDCardiacSurgeryPPMC:MatthewL.WilliamsMD,WilsonSzetoMDCardiologyPPMC:SameerKhandaharMDLGH:JeremyMcGarveyMD,MarkEplerMD,JeffreyCopeMD,JahveriMD,DumasiaMD TableofContentsBackground 3ProposedMethods 5Inclusioncriteria 5Exclusioncriteria 6Cross-overbetweengroups 6Consent 7ECMO 7PrimaryEndpoint 10SecondaryEndpoints 10BaselineData 10Peri-proceduraldata 11Dataduringturndownstudies 13DataatpointofECMOremoval 14DischargeData 15REVERSELong-Termfollow-up 15SignificantAdverseEvents 16DataCollectionOverview 22ManagementofECMOplatform 25

Anticipatedoutcomes28Conclusions 28 BackgroundVeno-arterialextra-corporealmembraneoxygenation(VA-ECMO)isindicatedasahaemodynamicrescuestrategyindecompensatedacuteorchronicheartfailurepresentingascardiogenicshock1.Ithasbeenusedacrossaeitologiesincludingpost-myocardialinfarction,dilatedcardiomyopathy,acutemyocarditisandinpost-cardiotomyshock.VAECMOhasanumberofeffectsonthecirculationincludingimprovedend-organperfusionandpossiblyimprovedcoronaryperfusion,andisabridgetofurthertherapiesincludingpermanentadvancedmechanicalcirculatorysupport,cardiactransplantationandtocardiacrecovery.Leftventricularassistdevices(LVADs)providelong-termmechanicalcirculatorysupportandalsoprofoundlymechanicallyunloadtheleftventricle2.MultipleclinicalstudieshavedocumentedcardiacrecoveryusingLVADtherapy,witharatebetween10-60%inselectedpopulations2-8.Alargebodyofbasicsciencehasdocumentedthepivotalroleofmechanicalloadindeterminingventricularcontractileperformanceacrossspecies(amongstothers9-19).Thereforebothclinicaldataandbasiclaboratorystudiessupportthenotionthatprofoundventricularunloadingmayresultinimprovedcardiacperformancethroughavarietyofmechanismsrangingfromtriggereddenovocardiomyocyteproliferation10,subcellularcalciumhandlingreverseremodeling18,changestotheextracellularmatrixoftheheart20,reverseremodelingoftheneurohormalmilleu21,amongstmanyothers14,22,23.OneofthemajordeficienciesofperipheralVA-ECMOisitslackofleftventricularunloading,withassociatedpulmonarycongestion,whichcanderailclinicalimprovementandhampercardiacrecovery.Indeed,percutaneousVA-ECMOincreasesLVafterloadduetotheretrogradebloodflow,andbecauseofthelackofventing,theremaybeprogressiveLVdistension24,25.Theseconditionscanresultinacongested,pressure-overloadedventricle,evenintheabsenceofechocardiographicventriculardistension.Thismaybeamelioratedwiththeadditionofventricularmechanicalunloadingusingpercutaneoustherapiesincludingthepercutaneousleftventriculardevice,ImpellaCP.OntheplatformofVA-ECMO,theadditionofanImpelladevicetoreduceventricularloadingresultsinimprovedsurvivalandrecoveryofventricularperformanceinthesettingofcardiogenicshock26.Inanumberofsmallstudies,theuseofadditionalmeanstounloadtheventricle,principallyImpella,resultsincardiacrecoveryandlessventriculardistension27-29.Inchronicheartfailure,directventricularunloadingiscriticaltocardiacrecovery5,6,8,22.Objectives:TheobjectiveofthisrandomizedstudyistodeterminewhethertheadditionofearlydirectventricularunloadingusingImpellaCPleadstohigherratesofcardiacrecovery,definedas

survivalfreefrommechanicalcirculatorysupport,hearttransplantationorinotropicsupportatthirtydays.Thisstudywillalsoexaminetheclinical,biochemical,echocardiographicandradiologiceffectsofVAECMOwithandwithouttheadditionofImpellaCPtodirectlyventtheleftventricletoaddressadjunctimportantquestionssuchastheeffectsonpulmonarycongestion.ProposedMethodsPatientsattheTheHospitalofTheUniversityofPennsylvaniaandPennPresbyterianMedicalCenterwillbeplacedonVAECMOforclinicaldeteriorationtoprovidefullcirculatorysupportinthesettingofcardiogenicshock.FollowingtheinstitutionofVAECMO,eligiblepatientswhoenrollinthestudywillberandomizedtoeithernoLVventing(Control;48patients)orpercutaneousLVventingwithImpellaCP(48patients)30,31.PatientswillbeinformedofandconsentedfortheREVERSEstudybyamaximumof12hoursfromthetimeofECMOinstitution.Thepatientwillbescreenedforsignsoftermination/stabilizationofshockandmusthaveagrosslyviableneurologicalstatusincludingintactbrainstemreflexesandmovingextremitiestosomeextent.Randomisationwilloccuratanypointwhenthesecriteriahavebeenmetupto12hoursfromECMOinstitution,andImpellaCPwillbeinsertedwithin12hoursofrandomization–atamaximumof24hoursfromtimeofECMOinstitution.WewillfollowtheagreedpublishedinclusionandexclusioncriteriaforVA-ECMOatTheUniversityofPennsylvania(attached),inadditiontothestudycriteriaspecifiedasbelow.Inclusioncriteria1. Cardiogenicshock:Includingrefractorytoconventionaltherapy,includingsystolicBP<90mmHg,CardiacIndex<1.8oracardiacindex<2.0onmoderatetohighdosesofinotropesandvasopressorsforgreaterthan30mins,orsystemicsignsoftissuehypoxia.2. Post-acutemyocardialinfarctioncardiogenicshock:excludingmechanicalcomplicationsrequiringsurgicalinterventionafterECMOsuchaspost-ischaemicVSD.3. Drugoverdose-inducedcardiogenicshock.4. Earlygraftfailure:postorthotropichearttransplantationcardiogenicshock,excludingimmediateintra-operativefailure.5. Acuteonchroniccardiomyopathywithprogressiveshockanddecompensationunresponsivetomedicaltherapies.Exclusioncriteria1. Neurologicalinjuryincludingrecentcerebrovascularaccidentorsuspectedsevereneurologicinjury

2. RecentSignificantPulmonaryEmbolus3. Moderatetosevereaorticvalveinsufficiency4. Ongoingsignificantsepsis5. Severepulmonaryhypertension&shock6. Hypothermia7. Post-cardiotomycardiogenicshock8. ContinuousCPR>20-30minutes,exceptifneurologicalstatusissatisfactory9. TransferfromoutsidehospitalonVAECMOorwithhistoryofCPR10. Listedforcardiopulmonarytransplantationorbeingevaluatedforcardiopulmonarytransplantationorpermanentmechanicalcirculatorysupport11. KnownorsuspectedchronicheartfailurewithechocardiogramdocumentingLVEDD>6.5cm12. KnownorsuspectedchronicheartfailurewithechocardiogramdocumentingLVEF<25%13. MechanicalAVR14. PresenceofLVthrombus15. Pre-existingImpella2.5,CP,3.5or5.016. Cardiogenicshockduetoprimaryrespiratoryfailure17. MechanicalcomplicationsrequiringsurgicalinterventionafterECMOsuchaspost-ischaemicVSD.18. SevereAI19. Severeliverfailure20. Activemalignancy21. Acuteaorticdissection22. IntracranialhemorrhagePresenceofapre-existingintra-aorticballoonpumpwillnotbeanexclusionorcross-overcriteria.Cross-overbetweengroupsInthepresenceofradiologicevidenceofseverepulmonarycongestion,cross-overfromthenon-ventedtovented(ImpellaCP)armwillbeallowedatthediscretionofthePI.Thisconsiderationismadeasthestandardofclinicalcareisthatinthepresenceofseverepulmonaryoedema,mostphysicianswouldadvocateadditionofanLVvent(surgicalorpercutaneous)forVAECMOpatients.ConsentWithin12hoursofinstitutionofVA-ECMO,alegallyauthorizedrepresentativewillbeproxyconsentedforenrolmentinthistrialtoincludeclinicalandlaboratorydatacollectionandechoturn-downstudies,andtheprimaryinterventionofLVventingwithImpellaCP.Inpatientswhoareawakeandorientated,thepatientwillbeconsented.ThiswillbeconductedincompliancewithFederalregulationsincluding45CFRPart46,HIPAAandICH-GCP.

Theconsentingprocesswilltakeaccountoftheimperativeofpatientcomfortandconfidentiality.AlldiscussionswillbeundertakeninaprivateroomintheHeartandVascularICUsuite.ECMOThestandardECMOset-uproutinelyusedattheUniversityofPennsylvaniawillbeemployed.Thistypicallyinvolvesa22-25FrenchVenouscannulainthefemoralveinanda15-19Frencharterialcannulainthefemoralartery.Adistalarterialperfusioncannulaisuniformlyused,oftenamicropuncture5-9Frenchperfusioncannula.Centralaorticandvenouscannulationwillnotbeused.AcentrifugalpumpsuchasMaquetRotafloworCentrimagplatformareusedonaconsolewithstandardMaquetbiolineheparinbondedcannulaeandQuadroxDoxygenator.TheImpellaCPsystemthatprovidesalowprofilethrougha16Frsheathwithflowupto3.0-3.5L/minona15Frmotorpumpsetup.ThemaximumouterdiameteroftheImpellaCPasitcrossestheiliofemoralsubclavianvesselsis5.8mm.Intheabsenceofsignificantperipheralvasculardisease,itwillbeinsertedviafemoralarteryusingtheSeldingeroropensurgicaltechniqueintheoperatingtheatreorcardiaccatheterisationlabunderfluoroscopicguidance,withitspositionre-adjustedunderechocardiographicguidance.Thesubclavianarteryrouteisalsowellestablishedandwillbeusedwhenmoreappropriatethanfemoralaccess.Angiographywillbeusedroutinelytoguideplacement.TheImpellaCPcatheterwillbepositionedneartheLVapexwiththedistalendofthecatheterbetween3-4cmfromtheaorticvalve.Inaddition,whereverpossible,allpatientswillreceiveaSwann-Ganzcatheter,whichisthestandardofcareinthemanagementofcardiogenicshock.RandomizationRandomisationwillbeperformedtoaimforanequalnumberofpatientswithsimilarage,sexandaetiologyofheartfailureinboththecontrolandtreatmentarms.AnticoagulationThestandardUniversityofPennsylvaniaECMOAnticoagulationprotocolwillbefollowed,asdescribedbelow.InitialHeparinBoluso 5,000unitsIVuponinitiation,priortocannulation• aPTTsentwithin1hourofinitialHeparinbolusHeparinInfusion

• HeparininfusionisinitiatedaspertheCT/Anesthesiaattendingphysicianandwillgenerallybestartedwithin12hoursofECMOinitiation.ReasonsfordelayinHeparininitiationinclude:o Chesttubeoutput>100ml/hro Hypothermiao ElevatedaPTTo Excessivebleedingatcannulationsites,pulmonaryhemorrhage,nasopharyngeal/GIbleedingo Hematomaformationatpuncturesites• InitialHeparininfusionrate–400-600units/hraspertheAnesthesia/CTattending• SendbaselineaPTTbeforestartingHeparininfusion• aPTTsentevery4hoursor4hoursafterHeparininfusiondosechange• Infusiontitrationguidelines-Standard:goalPTT56-70• aPTT<40.0–increaseby200units/hr• aPTT40.0-55.9–increaseby100units/hr• aPTT56.0-70.9nochange• aPTT71.0-79.9–decreaseby100units/hr• aPTT80.0-89.9–decreaseby200units/hr• aPTT90.0orgreater–holdHeparinforonehourandrecheckPTT• IfHeparininfusionincreased2timeswithoutanincreaseinPTTmayconsiderHeparinbolus1000-2000unitsIVPasperAnesthesia/CTattendingandbasedonamountofbleeding.• Infusiontitrationguidelines–Riskforbleeding:goalPTT40-55• aPTT<30.0–increaseby200units/hr• aPTT30.0-39.9–increaseby100units/hr• aPTT40.0-55.9nochange• aPTT60.0-69.9–decreaseby100units/hr• aPTT70.0-79.9–decreaseby200units/hr• aPTT80.0orgreater–holdHeparinforonehourandrecheckPTT• IfHeparininfusionincreased2timeswithoutanincreaseinPTTmayconsiderHeparinbolus1000-2000unitsIVPasperAnesthesia/CTattendingandbasedonamountofbleeding.• Ifplateletsdropbelow50,000orifplateletsdecreasemorethan50%frombaseline,heparinmayneedtobeadjustedordiscontinued.Providerteamwillexamineplateletcountdailyandmakeadjustmentsasneeded.Thiswillprovideappropriateanticoagulationlevelsrequired/recommendedbytheImpellaCPmanufacturer. PrimaryEndpointProportionofsubjectstreatedwiththisstandardizedECMOprotocolwitheither(i)noadditionaltherapyor(ii)ImpellaCPforLVmechanicalunloadingwhoexperiencemyocardial

recoverydefinedas:survivalfreefrommechanicalcirculatorysupport,hearttransplantationorinotropicsupportatthirtydays.SecondaryEndpoints1. Survivaltohospitaldischarge.2. Significantbetween-groupdifferencesininotropicscore,pulmonarycomplianceandradiologicmeasuresofpulmonarycongestionat24-72h.3. Significantbetween-groupdifferencesinechocardiographicmeasurements,biochemicalprofile,andhaemodynamics.4. Asingle5mlbloodsamplewillbetakenat3,6,9and12monthstoidentifybiomarkersofcardiacrecoveryinadditiontothosedefinedbelowinTable1.5. IncidenceofcrossoverBaselineData• DateInformedConsentobtained• Demographics(includingage,gender,race,ethnicity)• Medicalandsurgicalhistory• DiagnosisandhistoryofpresentillnessrequiringECMO• Cardiopulmonaryresuscitationhistory• Vitalsigns(temperature,heartrateandrhythm,bloodpressure[systolic,diastolic,mean])• Heightandweight• NYHAclass• INTERMACSprofileandmodifiers• Hemodynamics:CentralVenousPressure(CVP);PulmonaryArteryPressures:Systolic(PAS),Diastolic(PAD)andMean(PAM);PulmonaryCapillaryWedgePressure(PCWP);CardiacOutput(CO);CardiacIndex(CI);mixedvenousoxygensaturation(SVO2).• Ventilatorsettings:modeofventilation,tidalvolume,respiratoryrate,inspiratory/expiratory(I/E)rate(ratio),PEEP,ventilatorFiO2(%)• OxygenatorFiO2(%)andsweepgasflowrate(L/min)• Distalpulseassessmentincludingpresenceofdistalperfusioncannula• Criticalcareinterventions/assessments,including:levelofconsciousness(LOC),ContinuousRenalReplacementTherapy(CRRT)ordialysis,cardiopulmonaryresuscitation(CPR),urineoutput,intubated,ventilator,pulmonaryedema.• Othermechanicalsupportdeviceinuse;asapplicable• Routinemedicationsandmedicationsinlast24hours(ifdifferentfromroutine):Anticoagulants/Antithrombins,Anti-platelets,InhaledVasodilators/Prostaglandins,Inotropes,Thrombolytics,Vasopressors• Baselinelaboratorytestresults(asavailable):o Laboratorytestresults:§ WhiteBloodCellcount(WBC),RedBloodCellcount(RBC),Hematocrit(HCT),hemoglobin(HGB),Plateletcount(Plt),BloodUreaNitrogen(BUN),Creatinine(CR),Total

Bilirubin(TBili),AspartateAminotransferase(AST),AlanineAminotransferase(ALT),LacticDehydrogenase(LDH)o Coagulationlaboratorytestresults:§ ProthrombinTime/Internationalratio(PT/INR),PartialThromboplastinTime(aPTT)o Serumlactateo Arterialbloodgases(ABG):§ pH,pO2,HCO3,pCO2O2satPeri-proceduraldata• ECMOinsertionproceduredetailincluding:cannulatype,cannulationsites,circuitcomponents,durationofprocedureandanticoagulationadministered• ECMOdata:recordinitialsettingsfor:o Pumpspeed(inrevolutionsperminute[rpm])andflow(inlitersperminute[L/min])OxygenatorFiO2(%)andsweepgasflowrate(L/min)• Vitalsigns(temperature,heartrateandrhythm,bloodpressure[systolic,diastolic,mean])• Hemodynamics:RecordfirstsetofhemodynamicsassoonaspossibleafterECMOinsertion(oruponarrivalinCTSICU):o CVP;PulmonaryArteryPressuresifavailable:PAS,PAD,PAM;PCWP;CO;CI;SVO2.• Ventilatorsettings:modeofventilation,tidalvolume,respiratoryrate,I/Erate(ratio),PEEP,ventilatorFiO2(%)• Distalpulseassessmentanddetailsofdistalperfusioncannula• Criticalcareinterventions/assessments,including:LOC,CRRTordialysis,urineoutput,intubated,ventilator,pulmonaryedema.• Impellaparameters:Pspeed,flow,alarms,heparinflowrate• Medications:Anticoagulants/Antithrombins,Anti-platelets,InhaledVasodilators/Prostaglandins,Inotropes,Thrombolytics,Vasopressors• Laboratorytestresults(asavailable):o Coagulationlaboratorytestresults:recordimmediatelypriortoECMOinsertion,assoonaspossibleafterECMOinstitution(CTSICU):§ PT/INR,aPTT• SurgicalandotherproceduresproximatetotheECMOstarting• SeriousAdverseEvents• Transfusions(#packedRBC)meetingthedefinitionofMajorBleedingorMajorVascularAdverseEvent(recordonHematological/VascularEventDetailseCRF)• DeviceobservationsCoreDatawhileonECMOSupport• ECMOdata:Recordevery12hourswhileonECMOsupportandwitheachspeedchange.Recordforanyhemolysiseventandincludepumpcurrentspeed(rpm)andflow(L/min),OxygenatorFiO2(%)andsweepgasflowrate(L/min),transmembranegradients

• Distalpulseassessmentincludingdistalperfusioncannulae• Vitalsigns(temperature,heartrateandrhythm,bloodpressure[systolic,diastolic,mean])q1hour• Hemodynamics:RecordeveryhourwhileonECMOsupport.o CVP;PulmonaryArteryPressures:PAS,PAD,PAM;PCWP;CO;CI;SVO2.• Ventilatorsettings:modeofventilation,tidalvolume,respiratoryrate,I/Erate(ratio),PEEP,ventilatorFiO2(%)• Criticalcareinterventions/assessmentsdaily,including:LOC,CRRTordialysis,urineoutput,intubated,ventilator,pulmonaryoedema.• Impellaparameters:Pspeed,flow,alarms,heparinflowrate• Medications:Anticoagulants/Antithrombins,Anti-platelets,InhaledVasodilators/Prostaglandins,Inotropes,Thrombolytics,Vasopressors• Laboratorytestresults(asavailable):• Laboratorytestresults:Every12hourswhileonECMOsupport:• WBC,RBC,HCT,HGB,Plt,BUN,CR,TBili,AST,ALT,LDH• Coagulationlaboratorytestresults:Recordevery2hoursforthefirst6hoursandat12and24hourspost-ECMOinsertion;thenevery24hourswhileonECMOsupport.Alsorecord6hoursfollowinganticoagulationmedicationdosechange.§ PT/INR,aPTTo Serumlactateresults(recordavailableresults)every12hourso ABGresults:Recordallavailableresultsforthefirst24hourspost-ECMOinstitution,thenevery12hourswhileanoxygenatorisinthecircuit:§ pH,pO2,HCO3,pCO2O2sat,includesiteofsampling• Supportinterruptiondetails(dateandtimeinterruptedandresumed;reasonforinterruption)• Devicecomponentand/orextracorporealcircuitchanges• Surgicalandotherprocedures• SeriousAdverseEvents• Transfusions(#packedRBC)meetingthedefinitionofMajorBleedingorMajorVascularAdverseEvent(recordonHematological/VascularEventDetailseCRF)• DeviceobservationsDataduringturndownstudies• Dateandtimeofeachweaningattempt• TurndownstudieswillinvolveECMOweaningto1litre,modestinotropicsupport(epinephrine0.05mcg/kg/min,milrinone0.25mcg/kg/min)• ECMOdata:recordatthebeginningandendofeachweaningattemptandwitheachspeedchangeo Speed(rpm)andflow(L/min),OxygenatorFiO2(%)andsweepgasflowrate(L/min)• Impellaparameters:Pspeed,flow,alarms,heparinflowrate• Hemodynamicsasabove:recordatthebeginningandendofeachweaningattemptandwitheachspeedchangeo CO(L/min),SvO2(%),MAP(mmHg),OxygenatorFiO2(%)andsweepgasflowrate(L/min)

• Echocardiographytoguideweaning:o Dateandtime;EjectionFraction(EF)(%),LVEDD,LVESD• Surgicalandcardiacprocedures• SeriousAdverseEvents• DeviceobservationsDataatpointofECMOremoval• DateandtimeofECMOremovalo DurationofECMO(numberofECMOsupportdays)• Cannulasitehemostasisdetails• Remainingdevices• PriortoECMOremoval,record:o ECMOspeed(rpm)andflow(L/min),OxygenatorFiO2(%)andsweepgasflowrate(L/min),transmembranepressuresetco Hemodynamics:§ CVP;PulmonaryArteryPressures:PAS,PAD,PAM;PCWP;CO;CI;SVO2.o Ventilatorsettings:modeofventilation,tidalvolume,respiratoryrate,I/Erate(ratio),PEEP,ventilatorFiO2(%)o Distalpulseassessmento Criticalcareinterventions/assessments,including:LOC,CRRTordialysis,urineoutput,intubated,ventilator,pulmonaryedema.o Medications:Anticoagulants/Antithrombins,Anti-platelets,InhaledVasodilators/Prostaglandins,Inotropes,Thrombolytics,Vasopressorso Laboratorytestresults(asavailable):§ Coagulationlaboratorytestresults:• PT/INR,aPTT• Surgicalandcardiacproceduresperformed• Echocardiogram• SeriousAdverseEvents(per21CFR803MedicalDeviceReporting)willbecollected.• DeviceobservationsDischargeData• Dateofhospitaldischarge• VitalSigns(temperature,pulse,bloodpressure[systolic,diastolic])• NYHAClass• ICDorresynchronizationdeviceplacementpriortohospitaldischarge• DurableVADimplantorcardiactransplantafterECMOremoval• SAEsafterECMOremoval,onlyifSAE/injury/deathdirectlyattributabletoECMO(per21CFR803MedicalDeviceReporting).• Lengthofhospitalstay(totalnumberofhospitaldaysfromadmissiontodischarge)• LengthofICUstay(numberofICUdays)

• Finallabdataasabove• EchocardiogramAllpatientswillbefollowedthroughremovalofECMOandathospitaldischarge,30days(+/-15days)and180days(+/-60days)afterinitialECMOinstitution.Followupoutcomesincludesurvivalandexitstrategystatus(e.g.durableVADimplant,cardiactransplant).PatientswillbecontactedbyphonetocollectsurvivalandVADorcardiactransplantstatus(datafromthepatient’smedicalrecord[chartreview]mayalsobeused,ifavailable).Qualityoflifeassessmentwithshortform36questionairrewillbecompleted.REVERSELong-Termfollow-upItisessentialtoassessthelong-termdurabilityofrecoveryinsurvivorsofboththecontrolandexperimentalarmsofthestudy.Weproposetofollowupat3,6,9and12months.Thisincludesavisitwithaheartfailurecardiologistforaclinicalhistoryandphysicalexamination,SF-36qualityoflifequestionnaire,transthoracicechocardiogram.Wewouldalsodrawasinglesampleofperipheralvenousbloodforstorageinaheartfailurebiomarkerbank.Atsixmonths,perthestandardofcare,patientswouldundergosubmaximalcardiopulmonaryexercisetestingusingsixminutewalktestwithmeasurementofVO2max(maximaloxygenconsumption).SignificantAdverseEventsSeriousAdverseEvents(SAEs)andanyunexpectedSAEswillbecollectedfromthetimeofECMOinsertionthroughremovalandhospitaldischarge.AllSAEswillbereportedusingmodifiedINTERMACSadverseevent(AE)categories.TheINTERMACSAEdefinitionshavebeenmodifiedtoexcludepediatricsandincludeSAEsrelatedtoextracorporealmechanicalassistdevices,includingpercutaneouscannulainsertion.SeriousInjuryDefinition:Aninjuryorillnessthat:• Islifethreatening;• Resultsinpermanentimpairmentofabodyfunctionorpermanentdamagetoabodystructure,or• Necessitatesmedicalorsurgicalinterventiontoprecludepermanent*impairmentofabodyfunctionorpermanentdamagetoabodystructure.*Permanentmeansirreversibleimpairmentordamagetoabodystructureorfunctionexcludingtrivialimpairmentordamage.

INTERMACSAdverseEventTermsandDefinitions(amendedforrelevance)MajorBleedingAnepisodeofSUSPECTEDINTERNALOREXTERNALBLEEDINGthatresultsinoneormoreofthefollowing: a.Death, b.Re-operation, c.Hospitalization, d.Transfusionofredbloodcellsasfollows: Iftransfusionisselected,thenapplythefollowingrules:Duringfirst7dayspost-insertion•Adults(≥50kg):≥4Upackedredbloodcells(PRBC)withinany24periodduringfirst7dayspost-insertion. After7dayspost-insertionthroughtoECMOremoval•Anytransfusionofpackedredbloodcells(PRBC)after7daysfollowinginsertionwiththeinvestigatorrecordingthenumberofunitsgiven.(recordnumberofunitsgivenper24hourperiod).Note:Hemorrhagicstrokeisconsideredaneurologicaleventandnotasaseparatebleedingevent.MajorVascularEventsAMajorVascularEventrelatedtotheECMOcannulationorImpella:• Anynewthoracicaorticdissection• Accesssiteoraccess-relatedvascularinjury(dissection,stenosis,perforation,rupture,arterio-venousfistula,pseudoaneurysm,haematoma,irreversiblenerveinjury,orcompartmentsyndrome)leadingtoeitherdeath,needforsignificantbloodtransfusions(>2units),unplannedpercutaneousorsurgicalintervention,orirreversibleend-organdamage(e.g.hypogastricarteryocclusioncausingvisceralischaemiaorspinalarteryinjurycausingneurologicalimpairment)• Distalembolization(non-cerebral)fromavascularsourcerequiringsurgeryorresultinginamputationorirreversibleorgandamageCardiacArrhythmiasAnydocumentedarrhythmiathatresultsinclinicalcompromise(e.g.,diminishedECMOflow,associatedwithunstablehemodynamics,oliguria,syncopeorrequirestreatment(drugtherapy,defibrillation,cardioversion,ICDtherapy[e.g.,shockoranti-tachycardiapacing)orarrhythmiaablationprocedure)occurringduringECMOsupport.Cardiacarrhythmiasareclassifiedas1of2types:

1)Sustainedventriculararrhythmiaresultinginclinicalcompromiseorrequiringdrugtreatment,defibrillationorcardioversion. 2)Sustainedsupraventriculararrhythmiaresultinginclinicalcompromiseorrequiringdrugtreatmentorcardioversion. PericardialFluidCollectionAPericardialFluidCollectionistheaccumulationoffluidorclotinthepericardialspacethatrequiressurgicalinterventionorpercutaneouscatheterdrainage.Thiseventwillbesubdividedintothosewithclinicalsignsoftamponade(e.g.increasedcentralvenouspressureanddecreasedcardiac/ECMOoutput)andthosewithoutsignsoftamponade.DeviceMalfunctionDeviceMalfunctiondenotesafailureofoneormoreofthecomponentsoftheECMOcircuitorImpellawhicheitherdirectlycausesorcouldpotentiallyinduceastateofinadequatecirculatorysupport(lowcardiacoutput)ordeathincluding:1. Suspectedorconfirmedpumpthrombus;visibleorwiththefollowing:a. Presenceofhemolysisb. Abnormalpumpcurrent2. Urgenttransplantation(immediate1Alistingfortransplant)3. Pumporcontrollerreplacement4. UrgentPumpremovalortransitiontoanothertemporaryordurablesupportdevice5. DeathHemolysisAplasma-freehemoglobinvaluegreaterthan20mg/dloraserumlactatedehydrogenase(LDH)levelgreaterthantwoandone-halftimes(2.5x)theupperlimitsofthenormalrangeattheimplantingcenterpost-implantandassociatedwithclinicalsymptomsorfindingsofhemolysisorabnormalpumpfunction.MajorHemolysisrequiresthepresenceofoneormoreofthefollowingconditions:o Hemoglobinuria(“tea-coloredurine”)o Anemia(decreaseinhematocritorhemoglobinlevelthatisoutofproportiontolevelsexplainablebychronicillnessorusualpost-VADstate)o Hyperbilirubinemia(totalbilirubinabove2mg%,withpredominatelyindirectcomponent)o Pumpmalfunctionand/orabnormalpumpparameters.HepaticDysfunctionNewonsetofanincreaseinanytwoofthefollowinghepaticlaboratoryvalues(totalbilirubin,aspartateaminotransferase/ASTandalanineaminotransferase/ALT)toalevelgreaterthanthreetimesthepatient’sbaselinevaluesintheabsenceofotherconfoundingconditionssuchasRightVentriculardysfunction.

MajorInfectionNewonsetofaclinicalinfectionaccompaniedbypain,fever,drainageand/orleukocytosisthatistreatedbyanti-microbialagents(non-prophylactic).Apositiveculturefromtheinfectedsiteororganshouldbepresentunlessstrongclinicalevidenceindicatestheneedfortreatmentdespitenegativecultures.Thegeneralcategoriesofinfectionarelistedbelow: LocalizedNon-DeviceInfection Infectionlocalizedtoanyorgansystemorregion(e.g.urinarytractinfection)withoutevidenceofsystemicinvolvement(seesepsisdefinition),ascertainedbystandardclinicalmethodsandeitherassociatedwithevidenceofbacterial,viral,fungalorprotozoalinfection,and/orrequiringempiricaltreatment.PercutaneouscannulasiteinfectionApositiveculturefromtheskinand/ortissuesurroundingthecannulacoupledwiththeneedtotreatwithantimicrobialtherapy,whenthereisclinicalevidenceofinfectionsuchaspain,fever,drainage,orleukocytosis.SepsisEvidenceofsystemicinvolvementbyinfection,manifestedbypositivebloodculturesand/orhypotension.NeurologicalDysfunctionAnynew,temporaryorpermanent,focalorglobalneurologicdysfunctionascertainedbyastandardneurologicalhistoryandexaminationadministeredbyaneurologistorotherqualifiedphysiciananddocumentedwithappropriatediagnostictestsandconsultationnote;oranabnormalityidentifiedbysurveillanceneuroimaging.Theexaminingphysicianwillclassifytheeventasacerebrovasculareventasdefinedbeloworasanon-vascularacuteneurologicevent.Aneurologiceventmayberecognizedbyaclinicallyevidentsignorsymptom,orbyclinically-silentelectrographicseizureactivity,orasaclinicallysilentlesiondetectedbysurveillanceneuroimaging.Eachneurologiceventshouldbeclassifiedbytheclinicalproviderfollowingcompleteneurologicassessmentasoneofthefollowingeventtypes:a. Transientischemicattack,definedasanacutetransientneurologicdeficitconforminganatomicallytoarterialdistributioncerebralischemia,whichresolvesin<24hoursandisassociatedwithnoinfarctiononbrainimaging(headCTperformed>24hoursaftersymptomonset;orMRI).b. Ischemicstroke,definedasanewacuteneurologicdeficit(oracuteencephalopathy***)ofanydurationassociatedwithacuteinfarctiononimagingcorrespondinganatomicallytotheclinicaldeficit.Ischemicstrokeshouldbesubclassifiedasduetoarterial-distributionischemiaorduetovenousthrombosis.

c. Acutesymptomaticintracranialhemorrhage,definedasnewacuteneurologicdeficit(oracuteencephalopathy***)attributabletoIntracranialhemorrhage(ICH).ICHsubtypeshouldbespecifiedasoneoracombinationofthefollowingtypes:subarachnoid,intraventricular,parenchymal,subdural.d. ClinicallycovertischemicstrokeorICH:infarctionorICHseenbysurveillanceimaging,withoutclinicalfindingsofstrokeorICHatthetimeofeventrecognition.e. Hypoxic-IschemicEncephalopathy:Acutenewencephalopathy***duetohypoxic-ischemicinjury(HIE),manifestasclinically-evidentsignsorsymptoms,orsubclinicalelectrographicseizuresfoundbycompleteneurologicaldiagnosticevaluationtobeattributabletoacuteglobalorfocalhypoxicorischemicbraininjurynotmeetingoneofischemicstrokeorICHeventsasdefinedabove.f. Acutenewencephalopathy***duetoothercauses,manifestasclinically-evidentsignsorsymptomsorsubclinicalelectrographicseizuresfoundbycompleteneurologicaldiagnosticevaluationtobeattributablecausesotherthanstroke,ICHorHIE,asdefinedabove.Thiscategoryof"other"acuteencephalopathyincludesneurologicsignsorsymptomsorsubclinicalseizuresfoundtobeattributabletootherconditionssuchasmeningitis,toxic-metabolicordrug-relatedprocesses.***Acuteencephalopathyisasignorsymptomofsomeunderlyingcerebraldisorder,andismanifestasdepressedconsciousnesswithorwithoutanyassociatednewglobalormultifocalneurologicdeficitsincranialnerve,motor,sensory,reflexesandcerebellarfunction. AcuteRenalDysfunctionNewonsetofabnormalkidneyfunction(frompost-ECMOinsertionthroughECMOremoval)requiringdialysis(includinghemofiltration)inpatientswhodidnotrequirethisprocedure(ortheprocedurewasnotpartofplannedinterventionforthediseasecoursepriortoECMOinsertion)orariseinserumcreatinineofgreaterthan3timesbaselineorgreaterthan5mg/dLsustainedover48hours.RespiratoryFailureNewonsetofimpairmentofrespiratoryfunction(frompost-ECMOinsertionthroughremoval)requiringreintubation,tracheostomyorventilatorsupportinpatientswhodidnotrequirethisprocedure(ortheprocedurewasnotpartofplannedinterventionforthediseasecoursepriortoECMOinsertion).Thisexcludesintubationforre-operationortemporaryintubationfordiagnosticortherapeuticprocedures. RightHeartFailureNewsymptomsandsignsofpersistentrightventriculardysfunction[centralvenouspressure(CVP)>18mmHgwithacardiacindex<2.3L/min/m2intheabsenceofelevatedleftatrial/pulmonarycapillarywedgepressure(greaterthan18mmhg),tamponade,ventriculararrhythmiasorpneumothorax]requiringRVAD;implantation;orrequiringinhalednitricoxide

orinotropictherapyforadurationofmorethan1weekatanytimeafterECMOinsertionthroughremoval.ArterialNon-CNSThromboembolismAnacutesystemicarterialperfusiondeficitinanynon-cerebrovascularorgansystemduetothromboembolismconfirmedbyoneormoreofthefollowing: 1)standardclinicalandlaboratorytesting 2)operativefindings 3)autopsyfindingsThisdefinitionexcludesneurologicalevents.VenousThromboembolismEventEvidenceofvenousthromboembolicevent(e.g.deepveinthrombosis,pulmonaryembolism)bystandardclinicalandlaboratorytesting. OtherSeriousAdverseEventAseriouseventthatcausesclinicallyrelevantchangesinthepatient’shealth(e.g.limbischemia,skinbreakdownresultingfromimmobility).DataCollectionOverviewTable1specifiesindetailthedatacollectedatvarioustimepoints.Theseinvestigationsarecurrentlycollectedasthestandardofclinicalcare.Assessment Base-line ECMOInstitution OnECMO ECMOTurndown ECMORemoval Dis-charge 30Days 180DaysBaselinedataasabove X VitalSigns(Temp,heartrate/rhythm,B/P[S/D/M]) X X X X X X NYHAClass X X INTERMACsProfile,Modifiers X Hemodynamics X1 X1 X1 X1 X1 Ifavailable IfavailableVentilatorSettings) X3 X3 X3 X3 OxygenatorFiO2andSweepGasFlowRate(ifoxygenatorincircuit) X3 X3 X3 X3

DistalPulseAssessment X X X2 X2 CriticalCareInterventions/Assessments(LOC,urineoutput,CRRT/dialysis,Intubation,Ventilation,PulmonaryEdema) X X X2 X2 OtherMechanicalSupport;IABPparameters X X X X Medications X4 X4 X4 X4 X4 LaboratoryTests(WBC,RBC,HCT,HGB,Platelets,BUN,Creatinine,TotalBilirubin,AST,ALT,LDH,lactate,ABG,Coag) X Q1-4hourfor12hours X X X X X NIRSMicrocirculation X X5 ChestXraywithmodifiedMurrayindexofpulmonaryoedema X Daily X X X ECMOproceduredetails(cannulatype,cannulationsites,circuitcomponents,durationofprocedure,anticoagulationadmin.) X X5 ECMOparameters(speed,flow,FiO2,Sweep,transmembranegradientsandpost-oxygenatorgas)andImpellaparameters X X5 X5 X5 SupportInterruptiondetails;Devicecomponent/circuitchanges X ECMORemovaldetails(cannulasitehemostasis,anyremainingdevices) Echocardiogram(leftventricularend-diastolicdiameter;degreeofmitralregurgitation;LVEF;DegreeofRVdysfunction:degreeofTricuspidregurgitation X6 X6 X X X X Surgical/Cardiac/OtherProcedures X X X X X10 SAEs&DeviceObservations X11 X11 X11 X11,12 X11,12 HospitalandICULOS X Survival X X XDurableVAD,CardiacTransplant X X X1Includes:SBP,DBP,MAP,CVP,PAS,PAD,PAM,PCWP,CO,CI,SVO2.Collectatbaseline;thencollectthefirstsetofparametersassoonaspossibleafterECMOinsertion(oronarrivaltoCTSICU);theneveryhourwhileonECMOsupportandpriortoECMOremoval.Duringweaning,recordCO(L/min),SvO2(%),MAP(mmHg)atthebeginningandendofeachweaningattemptandwitheachspeedchange.2Every6hourswhileonECMOsupportandpriortoECMOremoval.ThetimeofImpellainsertionwillbecarefullydocumentedandwilltriggerrestartingalldatacollectionasifnewlyplacedonVAECMO.3Collectatbaseline,thencollectthefirstsetofparametersassoonaspossibleafterECMOinsertion(oruponarrivaltoCTSICU);thentheneveryhourswhileonECMOsupport.4Medicationsinthefollowingcategorieswillbecollected:Anticoagulants/Antithrombins,Anti-platelets,InhaledVasodilators/Prostaglandins,Inotropes,Thrombolytics,Vasopressors.Recordroutinemedications(meds)andmedswithin24hourspriortoECMOinsertion;proceduralmedsatECMOinsertion;medsevery6hourswhileonECMOsupportandmedsadministeredimmediatelyafterECMOremoval.Foranticoagulant/antithrombinmeds,recordassoonas

possibleafterECMOinsertion(oruponarrivaltoCTSICU);thenevery2hoursforthefirst6hoursandat12and24hourspost-ECMOinsertion;thenevery24hourswhileonECMOsupportandpriortoECMOremoval.RecordadditionalmeddetailsforanticoagulationmedsadministeredduringtheECMOinsertionprocedure.5Every12hours,andatanyspeedchange6Ideallypre-ECMOifpossible,thenfollowingECMOinstitution(within24hours),duringturndownstudiesasdictatedbyICUteam,at30daysandatdischarge.Otherechocardiogramsmaybeorderedbyclinicalteamasrequired.RadiationexposureThisstudydoesnotinvolveanymorechestxraysthanisthecurrentstandardofcare. ManagementofECMOplatformMultiplebroadphasesofmechanicalunloadinginducedrecoveryhavebeendescribed8,23.First,shockmustbeterminated.Earlyon,maximalunloading(anddrugtherapy)aimstoinducemaximalreverseremodeling.Laterphasesfocusoninducingphysiologicalhypertrophy,intheircase,usingclenbuterolwithgradedweaningofmechanicalsupportastolerated.FollowingrandomizationtocontrolorImpella(andinstitutionofImpella),eitheratthetimeofECMOinstitutionorshortlyafter,aperiodoffullhaemodynamicsupportwillbeusedtoterminateandreversesystemicsequelaeofshock,“Stabilisation”.Thisalsoisapowerfulimpetusforreverseremodeling,andmayindeedmimictheeffectsofanumberofcardiovascularpharmacologicapproaches12,24-26.Terminationofshockwillbedeterminedbysubstantiveimprovementsinhemodynamicsandassociatedsustainedimprovementsinendorganfunctionincludinglactate,renalandliverfunction.Followingthis,the“recovery”phasewhenlactateisclearing,andend-organfunctionisimproving,involvesaperiodofpartialsupportofvaryingextentswillbeusedtoiterativelyre-loadtheLV.ThebenefitsofpartialsupportoftheLVareemergingattheclinicalandbasiclevels27-29,andthisphasepromotesphysiologicalhypertrophywithsequentialreloading,culminatinginde-cannulation.Theextentofpartialsupportandtheundertakingofturndownstudies(whereECMOsupportisweanedandhaemodynamicandechocardiographicdataarecollected)willbeagreedwiththeICUandcardiacsurgeryattendingresponsibleforthepatient.ThegeneralguidelineswillbetoweantomaintainCVP,PAdiastolicandmeanarterialbloodpressureatbaseline±10%withoutrequiringsignificantescalationofvasopressorsorinotropes.LikewisethedecisiontoproceedtodecannulationwillbemadewithICUandcardiacsurgeryattending,butwillgenerallybeguidedbyhaemodynamic,laboratoryandechocardiographicstabilityonminimalsupport.Thiscanbedefinedbroadlyasthefollowingfeaturesonamoderatedoseofinotropicsupport:

Turndownat1L,fullanticoagulation:• EchocardiogramLVEF>25• CVP<15-18• PAD<20orWedge<18• CI>2.2• AbsenceofgreaterthanmoderateMR• MAP>65Decannulationmayproceedwhentheheartteambelievesthepatientisabletosupporttheircirculationbasedonthesefactors.ItmaybenecessarytophaseremovalofthedevicessothatECMOisremovedbutImpellaremainsforaperiodoftime.Thesedecisionsareatthediscretionoftheclinicalteam.ThePspeedofImpellawillbedirectedbytheICUteamandgenerallybetweenP2-P8aimingforadequateventingoftheLVonechocardiographywithadecompressedventricle,LVEDD<6cmintheabsenceofgreaterthanmoderateMR.RemovalofECMOandImpellaToassurethehigheststandardofsafety,ECMOdecannulationandImpellaremovalwillbeperformedintheoperatingroom.While“pullingandholdingpressure”hasbeenusedtoremoveImpella,thisexposespatientstoahigherriskofvascularinjuryorsubsequentbleeding.Directlyvisualizedremovalandprimaryrepairofthearteryassuresthepatientleavestheoperatingroomwithanintactandworkingartery.Thiswillbeperformedbyeithercardiacorvascularsurgerydependingonavailabilityasbothclinicalgroupsarehighlyexperiencedinthisprocedure. PHASETIMEPOINT ECMOSUPPORT MEDICALTHERAPY GOALSDECISIONNODEP1STABILIZATION Institution Full Inotropes&vasopressorsModeratedoses:epinephrine0.05mcg/kg/hr,milrinone0.25mcg/kg/hr,dopamine2-8mcg/kg/hr MAP>60mmHgMaintainECMOflowatCI>2.2L/min/m2 Hasshockbeenterminated?Appropriateforturndownstudies?Appropriateforpartialsupport?Evidenceofcardiacrecovery?P2

RECOVERY Daily PartialsupportasagreedwithICUteamandaccordingtoprotoco Weaningofinotropesandvasopressors Lactatefallingandbelow5mmol/LwithimprovingLFTandserumcreatinine. TitrationofpharmacologicsupportTitrationofECMOsupportP3RECOVERED Daily Minimalsupport Minimalvasopressors&inotropesDiuresis Turndownat1L,fullanticoagulation:• echocardiogramLVEF>25,• CVP<15-17• PAD<20orwedge<18• CI>2.2• AbsenceofgreaterthanmoderateMR Appropriatefordecannulation?P4DECANNULATION Day1postVAECMO Inotropes,Vasopressors, ReverseremodelingagentsastoleratedACEinhibitorsBetablockers Activemonitoringofhaemodynamicsandend-organfunction. Recoverystable?AnticipatedoutcomesThisstudywillprovidevaluabledataonthechangesatmultiplelevelswithfullanditerativelyreducedmechanicalcirculatorysupport.Itwillserveasafocusedattempttoactivelyseekoutcardiacrecovery,withtheworkingassumptionthatitcouldbepossibleinamajorityofpatients.Itwillservetocarefullydocumenttheconsequencesoffull,thenpartialmechanicalcirculatorysupportonkeyhaemodynamicandechocardiographicindices.Storedtissuesampleswillbeusedtoinvestigatebiologicmarkersofrecovery.Insummaryitwillprovidedataonthefollowingquestions1. IsdirectmechanicalunloadingoftheventricleusingpercutaneousLVventinganeffectivestrategyforinducingcardiacrecoveryonVA-ECMO.Thisstudyisthefirstrandomizedtestofthisquestion.2. Whataretheclinical,haemodynamic,imagingandbiochemicalchangesinpatientsonVAECMOmanagedwitharecoveryorientatedstrategywithfullthenpartial,gradedsupport.Retrospectiveanalysisofthesedatawillalsoprovidenewinsightsintoidentifyingthosepatientswiththegreatestpotentialforcardiacrecovery,usingreadilyavailableindices.3. Atwhatratecancardiacrecoverybeanticipatedwithaprogramwhichisaggressivelymonitoringforandpromotingcardiacrecovery.Forexample,atwhatratecansupportbeweanedfollowingthegeneralguidelinesoutlined.

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