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Prophylactic Nesiritide Does Not Prevent Dialysis or All-Cause Mortality in Patients Undergoing High-Risk Cardiac Surgery.
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Permanent Link: http://ufdc.ufl.edu/IR00000599/00001
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Title: Prophylactic Nesiritide Does Not Prevent Dialysis or All-Cause Mortality in Patients Undergoing High-Risk Cardiac Surgery.
Series Title: The Journal of Thoracic and Cardiovascular Surgery. October 2009; 138(4):959-964.
Physical Description: Journal Article
Creator: Ayad K Ali
Publisher: Elsevier
Place of Publication: USA
Publication Date: July 3, 2009
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Abstract: Objectives Natriuretic peptides have been shown to improve renal blood flow and stimulate natriuresis. In a recent retrospective trial, we documented that prophylactic use of nesiritide was associated with a 66% reduction in the odds for dialysis or in-hospital mortality at 21 days in patients undergoing high-risk cardiac surgery; therefore, we designed a prospective trial. Methods This prospective, randomized, clinical trial included 94 patients undergoing high-risk cardiac surgery comparing a 5-day course of continuous nesiritide (at a dose of 0.01 μg · kg−1 · min−1 started before surgery) versus placebo. The primary end point was dialysis and/or all-cause mortality within 21 days; secondary end points were incidence of acute kidney injury, renal function, and length of stay. Results Nesiritide did not reduce the primary end point of incidence of dialysis and/or all-cause mortality through day 21 (6.6% vs 6.1%; P = .914). Fewer patients receiving nesiritide had acute kidney injury (defined as an absolute increase in serum creatinine ≥ 0.3 mg/dL from baseline or a percentage increase in serum creatinine ≥ 50% from baseline within 48 hours) compared with controls (2.2% vs 22.4%; P = .004), and mean serum creatinine was lower in the immediate postoperative period in the nesiritide group (1.18 ± 0.41 mg/dL vs 1.45 ± 0.74 mg/dL; P = .028). However, no difference in length of stay was noted (nesiritide 20.73 ± 3.05 days vs control 21.26 ± 4.03 days; P = .917). Conclusions These results do not demonstrate a benefit for prophylactic use of nesiritide on the incidence of dialysis and/or death in patients undergoing high-risk cardiac surgery. Although nesiritide may provide some renal protection in the immediate postoperative period, no effect on length of stay was observed.
Acquisition: Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Ayad Ali.
Publication Status: Published
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Source Institution: University of Florida Institutional Repository
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution.
System ID: IR00000599:00001

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Prophylacticnesiritidedoesnotpreventdialysisorall-causemortality inpatientsundergoinghigh-riskcardiacsurgeryA.AhsanEjaz,MD,aTomasD.Martin,MD,bRichardJ.Johnson,MD,a dAlmutG.Winterstein,PhD,cCharlesT.Klodell,MD,bPhilipJ.Hess,Jr,MD,bAyadK.Ali,PharmD,cElaineM.Whidden,ARNP,aNancyL.Staples,RN,bJamesA.Alexander,MD,dMaryAnnHouse-Fancher,ARNP,band ThomasM.Beaver,MD,MPHbObjectives: Natriureticpeptideshavebeenshowntoimproverenalbloodowandstimulatenatriuresis.Inarecentretrospectivetrial,wedocumentedthatprophylacticuseofnesiritidewasassociatedwitha66 % reductionin theoddsfordialysisorin-hospitalmortalityat21daysinpatientsundergoinghigh-riskcardiacsurgery;therefore, wedesignedaprospectivetrial. Methods: Thisprospective,randomized,clinicaltrialincluded94patientsundergoinghigh-riskcardiacsurgery comparinga5-daycourseofcontinuousnesiritide(atadoseof0.01 m g $ kg 1$ min 1startedbeforesurgery) versusplacebo.Theprimaryendpointwasdialysisand/orall-causemortalitywithin21days;secondaryend pointswereincidenceofacutekidneyinjury,renalfunction,andlengthofstay. Results: Nesiritidedidnotreducetheprimaryendpointofincidenceofdialysisand/orall-causemortality throughday21(6.6 % vs6.1 % ; P .914).Fewerpatientsreceivingnesiritidehadacutekidneyinjury(dened asanabsoluteincreaseinserumcreatinine 0.3mg/dLfrombaselineorapercentageincreaseinserumcreatinine 50 % frombaselinewithin48hours)comparedwithcontrols(2.2 % vs22.4 % ; P .004),andmeanserum creatininewaslowerintheimmediatepostoperativeperiodinthenesiritidegroup(1.18 0.41mg/dLvs1.45 0.74mg/dL; P .028).However,nodifferenceinlengthofstaywasnoted(nesiritide20.73 3.05days vscontrol21.26 4.03days; P .917). Conclusions: Theseresultsdonotdemonstrateabenetforprophylacticuseofnesiritideontheincidenceof dialysisand/ordeathinpatientsundergoinghigh-riskcardiacsurgery.Althoughnesiritidemayprovidesomerenalprotectionintheimmediatepostoperativeperiod,noeffectonlengthofstaywasobserved. Acutekidneyinjury(AKI)isamajorcomplicationofthe morethan200,000cardiovascularoperationsperformed onadultAmericansannually.1TheincidenceofAKIafter cardiacsurgeryisgenerallylow(1 % % )2butismuch higherinpatientswiththoracicaorticaneurysmandcardiacvalveoperations(AKI:25 % % ;perioperative mortality:8 % % ).3,4Whenthoracicaorticaneurysm surgeryiscomplicatedbyAKIrequiringrenalreplacement therapy(RRT),themortalityraterisesto50 % .5Thereare veryfeweffectiveinterventionalstudiesinthisgroupof patients. Natriureticpeptidesareattractiveagentstoconsiderfor renoprotectionowingtotheirabilitytocauserenalvasodilation,stimulationofnatriuresis,andpreservationofglomerularltrationrate(GFR).However,theliteratureonthe effectivenessofnatriureticpeptidesinthepreventionof AKIremainscontroversial.6Inalargeobservationalstudy (n 940)toevaluatetheclinicaleffectivenessofnatriuretic peptidesinthepreventionofAKIaftercardiovascular surgery,we7demonstrateda66 % reductionintheodds fordialysisorin-hospitalmortalityat21daysinsubjects whosebaselineserumcreatinine(SCr)valuewaslessthan 1mg/dL.Becausethislatterstudywasretrospective,we proceededwithaprospective,double-blindstudytoevaluate theeffectofnesiritideonrenaltissueinjury,renalfunction, andrequirementforRRTand/orall-causemortalityin patientsundergoinghigh-riskcardiacsurgery. METHODSThestudyisaprospective,double-blind,placebo-controlled,randomizedclinicaltrialconductedbythenephrologyandcardiovascularsurgery teamsatShandsHospitalattheUniversityofFloridainGainesville.The studywasapprovedbytheWesternInstitutionalReviewBoard,registered attheNationalInstitutesofHealths ClinicalTrials.gov (NCT00110201) Website,andwasfundedbyaninvestigator-proposedgrantfromScios, Inc. FromtheDivisionofNephrology,HypertensionandTransplantation,aDivisionof ThoracicandCardiothoracicSurgery,bandDepartmentofPharmaceuticalOutcomesandPolicy,cUniversityofFlorida,Gainesville,Fla;andRenalDiseases andHypertension,dUniversityofColoradoHealthSciencesCenter,Denver,Colo. Disclosures:Thestudywasconductedunderaninvestigator-proposedresearchgrant fromScios,Inc.Theauthorsdonothaveanyotherconictofinterest. Clinicaltrialsregistration: ClinicalTrials.gov NCT00110201. ReceivedforpublicationSept15,2008;revisionsreceivedFeb16,2009;acceptedfor publicationMay15,2009;availableaheadofprintJuly6,2009. Addressforreprints:A.AhsanEjaz,MD,DivisionofNephrology,Hypertensionand Transplantation,UniversityofFlorida,POBox100224,Gainesville,FL326100224(E-mail: ejazaa@medicine.u.edu). JThoracCardiovascSurg2009;138:959-64 0022-5223/$36.00 Copyright 2009byTheAmericanAssociationforThoracicSurgery doi:10.1016/j.jtcvs.2009.05.014TheJournalofThoracicandCardiovascularSurgerycVolume138,Number4959 PM Ejazetal PerioperativeManagement

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AbbreviationsandAcronyms AKI acutekidneyinjury AKI0.3mg/dL absoluteincreaseinserumcreatinine ofmorethanorequalto0.3mg/dL frombaseline AKI50 % increaseinserumcreatinineofmore thanorequalto50 % from baselinewithin48hours CI condenceinterval GFR glomerularltrationrate MDRD ModicationofDietinRenal Disease OR oddsratio RRT renalreplacementtherapy SCr serumcreatinine ParticipantsInitially,patientsundergoingsurgeryforthoracicaorticaneurysmwho wereolderthan18yearsofageandhadanSCrvaluegreaterthan1mg/ dLbutlessthan2mg/dLweredeemedtobeathighriskperreviewof theliterature2andwereeligibleforthestudy.Becauseoflowenrollment, aftertherst2patientswereenrolledtheinclusioncriteriaweremodied toincludepatientswithcardiacvalvesurgery,andtheSCrcriterionwasreplacedwithestimatedGFR(usingtheshortversionoftheModicationof DietinRenalDisease[MDRD]GFRcalculator)between30and90mL $ min 1$ 1.73m2 1tobetterreectrenalfunction.Patientswithahistory ofadversereactiontonesiritide,organtransplant,preoperativeintra-aortic balloonpump,orsymptomatic,acutedecompensatedcongestiveheartfailurewereexcluded.StudyProtocolEligiblepatientswererandomizedaccordingtorace,gender,anddiabetesstatustoreceivea5-daycourseofcontinuousnesiritide(atadoseof0.01 mg $ kg 1$ min 1)oranidenticalappearingplacebo,startingintheoperating roomimmediatelybeforetheoperation.Studydrugsweretitratedtoamaximumof0.03 mg $ kg 1$ min 1overa4-hourperiodtomaintainpostoperativeurineoutputgreaterthan1mL $ kg 1$ h 1.Patientswhodidnot achievetargeturineoutputafterthemaximumdoseofstudydrugorplacebo couldthenreceive1to5mgbumetanidebolusintravenously,followedby bumetanidecontinuousinfusionasrequired.Allpatientsreceivedroutine postoperativesupportivecarefortheirmedicalandsurgicalproblems,includingcareforAKI,optimizationofuidandnutritionalstatus,inotropic support,andadjustmentofdosesofmedicationasappropriateforpatients withrenaldysfunction.TheneedforRRTwasdeterminedindependently bythepatientstreatingnephrologistspercurrentstandardofcarecriterion, whichincludedbloodureanitrogengreaterthan80mg/dL,electrolyteor acid-basedisordersnotrespondingtomedicalmanagement,anddiureticunresponsivenesswithurineoutputlessthan0.5mg $ kg 1$ h 1andrefractory volumeoverloadasdenedbycentralvenouspressuresgreaterthan15mm Hg.PostoperativeGFRwascalculatedusingtheMDRDGFRcalculator andisinaccordancewithpreviouspublishedreports.8,9OutcomesTheprimaryendpointofthestudywastheincidenceofdialysisand/or all-causemortalitythroughday21.Thepredeterminedsecondaryendpoints includedtheincidenceofAKI,meanSCr,peakSCr,changefrombaseline topeakSCr,peakbloodureanitrogen,endofhospitalstay,orstudyday21; meanurineoutputperdaybyday5;andlengthofhospitalstay.AKIisdenedasanabsoluteincreaseinSCrofmorethanorequalto0.3mg/dLfrom baseline(AKI0.3mg/dL)oranincreaseinSCrofmorethanorequalto50% frombaselinewithin48hours(AKI50 %)aftersurgeryinaccordancewith theAcuteKidneyInjuryNetworkscriteria.10Posthocanalysesincluded thepercentchangeinpostoperativeGFRrelativetobaseline.SampleSizeandRandomizationThesamplesizewascalculatedonthebasisofaretrospectivestudythat examinedtheUniversityofFloridaexperiencewithnesiritideinpatientsundergoingcardiacsurgery7andhadan80 % powertodeclareefcacyorharm. Thestudyplanwasbasedonratesofcompositeendpointsof20 % (placebo) versus5 % (nesiritide).Thetargetedpopulationforthetrialhadanobserved oddsratio(OR)of0.21,similartothatreportedintheretrospectivestudy(OR 0.19).7Uptoatotalof164(was124)patientsundergoingthoracicaorticaneurysmsurgeryweretobeenrolledandrandomizedtoreceivenesiritideoran identicalappearingplacebodrug.RandomizationwasperformedbytheInvestigationalDrugProgramhousedinPharmacyattheShandsHospital. Thestudywasconductedasa2-stagegroupsequentialdesignwith92patients assignedtostageI(46patientsperarm)and72patientsassignedtostageII(36 additionalpatientsperarm).Thefollowinginferentialrulewasused:(1)Ifthe Z-testforproportions(pooledstandarddeviation)instageIfallsabove2.28in absolutevalue,haltthestudyanddeclareefcacy/harm.IfthisZ-testinstageI fallsbelow1.08inabsolutevalue,haltthestudyanddeclarefutility.IftheZtestinabsolutevalueatstageIfallsbetween1.08and2.28,continuetostage II.(2)IfafterstageIItheZ-value(pooledstandarddeviation)exceeds2.00in absolutevalue,declareefcacy/harm.Otherwise,declarenosignicantdifference.Ifthereisindeednoadvantageforthedruginthetruetargetpopulation,thereisa5% probabilityoffalselydeclaringefcacyorharm(typeI error).Onthebasisofapilotstudy,theestimatedincidenceintheaneurysm/valvestratuminthecohortstudywas4.4 % fornesiritideversus 18.7 % fornonesiritide.Ifthetruefailureratesare5 % forthedrugand 20 % fortheplacebo,thestudyhasan80 % powertodeclareefcacy.Other endpointswillbestudiedusingtheZ-testforproportionsor t testsforquantitativeendpoints,butthestudyispoweredstrictlyonthebasisoftheprimary combinedendpoint.Thisdesignisminimaxinthesensethatno2-stagedesignwith80 % powerat P < .05hasasmallermaximumexpectedsample size.Theworst-casescenarioisanaveragesamplesizeof126patients,which occurswhentheactualtargetpopulationdifferenceis11 % ,ratherthan0 % (nullhypothesis)or15 % (alternatehypothesis).Asinglestagestudywould haverequired146patients.Theprimaryanalysisisbyintent-to-treat. PatientswereenrolledfromthecardiothoracicsurgeryserviceattheUniversityofFlorida.Informedconsentwasobtainedforallpatients.Random allocationsequencesweregeneratedbyblockstraticationbytheinstitutionalinvestigationaldrugservicesandconcealeduntilthestudywascompleted.Thestudyparticipants,physicians,nurses,anddataanalysisteams wereblindedtogroupassignment.StatisticalMethodsDemographiccharacteristics,perioperativevariables,andoutcomes werecomparedbyunivariateandmultivariateanalyses.Thechangefrom baselinetopostoperativepeakSCrwascomparedbyananalysisofcovariancemodel,withtreatmentgroupasqualitativefactorandbaselineSCr valueascovariate,aswellasusingnonparametrictests.Dataarepresented asmean standarderrorofmean.Univariatecomparisonsofthepresence ofriskfactorswerecomputedby c2andunpaired t testsforcategoricaland continuousvariables,respectively.StudyDesign,DataSafety,Analysis,andManuscript PreparationThestudyconception,design,execution,datacollection,analysis,and manuscriptpreparationwereperformedintheirentiretyandindependently bytheinvestigators.TheDataSafetyMonitoringBoardprovidedappropriateoversightandmonitoringoftheconductoftheclinicaltrialtoensurethe safetyofparticipantsandthevalidityandintegrityofthedata. PerioperativeManagement Ejazetal 960TheJournalofThoracicandCardiovascularSurgerycOctober2009 PM

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RESULTS Inaccordancewiththeaprioridetermination,thestudy wasstoppedaftercompletionofstageIinasmuchastheZtestwasbelow1.08inabsolutevalue.Importantly,theprimaryeventratewaslowinbothgroups(nesiritide3/45 [6.6 % ]vscontrol3/49[6.1 % ]),anditwasdetermined thatstatisticalsignicanceforadenitiveresultcouldnot beachievedduringthesecondstageofthestudy. PatientEnrollment Thenumberofsubjectsscreened,enrolled,anddropped outareshownin Figure1 .Onehundredthreepatientscompletedenrollmentbut9withdrewconsent.Theremaining94 patientsconstitutedthestudycohort. BaselineCharacteristics Meanageofthestudypopulationwas65.1 12years, 66 % ofthepatientsweremale,and92.5 % werewhite. MeanpreoperativeSCrwas1.17 0.29mg/dLwithacalculatedMDRDGFRof63.7 16.3.4mL $ min 1$ 1.73m2 1; andleftventricularejectionfractionwas49.4 % 9.4 % (n 89);comorbiditiesarepresentedin Table1 .Therewasno signicantdifferencebetweenthe2studygroupswithrespecttobaselinedemographicandclinicalcharacteristics ( Table1).Mostpatients(76.6 % )underwentthoracicaortic aneurysmsurgery(ascendingaorticandarchreplacement, 57.5% ;descendingaorticreplacement,19.1 % ;valve only,23.4 % ).Differencesindurationofsurgery(nesiritide 424.66 16.26minutesvscontrol383.69 14.65minutes; P .065),durationofcardiopulmonarybypasssupport(nesiritide177.14 11.42minutesvscontrol158.41 9.29 minutes; P .207),andaorticcrossclamptime(nesiritide 109.70 7.97minutesvscontrol106.66 7.02minutes; P .776)werenotsignicantbetweenthegroups.Statisticallysignicantdifferenceswerealsonotobservedwithregardtothenumberofpatientswhounderwentcirculatory arrest(nesiritide53.3 % vscontrol42.9 % ; P .302;circulatoryarresttime:nesiritide20.77 2.90minutesvs14.90 2.16minutes; P .113),thoractomy(nesiritide31.1 % vs control30.6 % ; P 1.000),andmidlinesternotomy(nesiritide68.9 % vscontrol69.4 % ; P 1.000)betweenthe groups. PrimaryOutcome Therewasnostatisticallysignicantdifferencebetween thegroupswithregardtotheincidenceofdialysisand/or all-causemortalitythroughday21(nesiritide3/45[6.6 % ]; control3/49[6.1 % ]; P .914)( Figure2 ).Inthenesiritide group,1patientdiedonthesecondpostoperativedayof complicationsofcardiovascularsurgeryunrelatedtothe studydrug(asassessedbytheDataSafetyMonitoring Board)and2patientsrequiredcontinuousRRT.Inthecontrolgroup,2patientsrequiredhemodialysisand1patientreceivedtreatmentwithcontinuousRRT.RRTwasindicated inthenesiritidegroupprimarilyforvolumeoverloadanddecreasedurineoutput(preceding24-hoururineoutput:nesiritide1168.33 1050.44mLvscontrol4228.66 502.93 mL in patientswhounderwentdialysis; P .020),whereas theindicationinthecontrolgroupwasprimarilyforworseningrenalfunction(SCr:nesiritide1.83 0.15mg/dLvs control5.03 0.55mg/dL[ P .023]inthenesiritideand controlpatientsundergoingdialysis,respectively).Patient demographicsandclinicalcharacteristicswereotherwise notstatisticallydifferentbetweenthegroups. SecondaryOutcomes AKI50 %developedinfewerpatientsreceivingnesiritide thaninthecontrolgroup(nesiritide2.2 % [1/45]vscontrol Assessed for eligibility (n= 515) Excluded (n=412) Not meeting inclusion criteria (n=309) Refusing to participate (n=98) Other (n=5) Randomized (n=103) Allocated to intervention (n=49) Received intervention (n=45) Did not receive intervention (n=4) Lost to follow-up (n=0) Discontinued intervention (n=0) Analyzed (n=45) Excluded from analysis (n=0) Allocated to intervention (n=54) Received intervention (n=49) Did not receive intervention (n=5) Lost to follow-up (n=0) Discontinued intervention (n=0) Analyzed (n=49) Excluded from analysis (n=0) A nalysis Follow-up AllocationEnrollment FIGURE1. Flowofparticipants. Ejazetal PerioperativeManagement TheJournalofThoracicandCardiovascularSurgerycVolume138,Number4961 PM

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22.4 % [11/49]; P .004).Similarresultswereobserved whenadifferentcriterionforAKIwasapplied:AKI0.3mg/dLdevelopedinfewerpatientsreceivingnesiritidethaninthe controlgroup(nesiritide6.6 % [3/45]vscontrol28.5 % [14/49]: P .007,OR5.6,95 % CI[CI]1.4)( Figure3 ). ThedifferenceinAKIwasobservedinpatientswithSCr greaterthan1.2mg/dL(nesiritide7.1 % [1/14]vscontrol 43.7 % [7/16]; P .030,OR10.1,95 % CI1.1197)and inthosewhounderwentthoracicaorticaneurysmsurgery (nesiritide2.7 % [1/37]vscontrol25.7 % [9/35]; P .006,OR12.4,95 % CI1.4.5). The5-daycumulativeurineoutput(nesiritide8.6 7.3L vscontrol14.9 2.9L; P .269)wasnotdifferentbetween groups.Thefrequencyofadministrationofstandarddosesof diureticswasalsonotdifferent(nesiritide1.11 0.21vs control1.28 0.23);halfofthestudyparticipantsdidnot receiveanydiuretics(nesiritide23/45vscontrol24/49; P .807)intherst5postoperativedays. Lengthofhospitalstay(nesiritide20.73 3.05daysvs control21.26 4.03days; P .917)wasnotsignicantly differentbetweenthegroups.However,inthesubsetofpatientswhodidhaveAKI(n 17),thosereceivingnesiritide hadshortenedhospitalstay(nesiritide22.28 4.20daysvs control33 20.51days; P .017)comparedwiththecontrolgroup. PostHocAnalyses Byposthocanalyses,fewerpatientsinthenesiritide groupsustainedseverekidneyinjury(denedasarisein SCrof1mg/dLormore)comparedwithpatientsinthecontrolgroup(nesiritide1vscontrol11; P .004).PostoperativeGFRrelativetobaselinealsoincreasedinthenesiritide groupwhereasitdecreasedinthecontrolgroup(1.76 % 4.1 % vs 11.68 % 4.21 % ; P .026)( Figure4 .).ThedifferencesweremorepronouncedwhenanalyseswererestrictedtopatientswithbaselineGFRlessthan45mL $ min 1$ (1.73m2) 1( 2.24 % 13.41 % vs 33.17 % 8.03 % ; P .075;n 13).Inpatientswiththelargest decreaseinpostoperativeGFR( 30 % ;n 21),theuse ofnesiritidewasassociatedwithastatisticallysignicant decreaseintheincidenceofAKI50 %(22.2 % [2/9]vs 91.6 % [11/12]; P .002). SideEffects:HypotensionandNesiritide Nesiritidehasbeenassociatedwithhypotension,especiallyifgivenbybolus.6Inthistrial,episodesofhypotensionsolelyrelatedtotheadministrationofnesiritidewere notrecognized,inpartbecauseofthefrequentconcomitant requirementforvasopressorsinmanyofthepatients.However,thenumberofvasopressorsadministeredwashigherin thenesiritidegroup( P .023).Signicantdifferencesinabsolutechangeinmeanarterialpressuresbetweenthegroups werenotevidentthroughday5( P .858,.359,.914,.492, and.930,days1,respectively).Usageofdiureticsdidnot differamongthegroups. FIGURE2. Incidenceofprimaryevents. TABLE1.Baselinepatientcharacteristics Variable Nesiritide (n 45) Control (n 49) P value Demographics Age(y) 64.1 13.3165.91 10.76.484 Sex( % male) 64.4 67.3.820 Race( % ) White 88.9 96.147 AfricanAmerican 8.9 2.190 Other 2.2 21.000 Surgerytype( % ) TAA 82.2 71.4.235 Valves 17.8 28.6.217 Comorbidconditions( % ) Hypertension 68.9 63.3.666 CAD 33.3 40.8.524 PreviousCVsurgery 26.6 32.6.652 Diabetes 17.8 12.2.566 CVA 13.3 4.4.147 PVD 11.1 4.1.254 Renalfunction SCr(mg/dL) 1.16 0.291.18 0.30.702 MDRDGFR(mL $ min 1$ [1.73m2] 1) 64.4 16.7363.12 17.07.693 BUN(mg/dL) 22.17 14.3519.80 8.16.356 Cardiacfunction LVEF( % ) 48.56 1.2950.27 1.52.394 NYHAclassI( % ) 93.3 89.7.339 Meanarterial pressure(mmHg) 89.31 12.7492.94 13.22.178 ClevelandClinic ScoringSystem 3.40 0.223.51 0.23.735TAA, Thoracicaorticaneurysm; CAD, coronaryarterydisease; CV, cardiovascular; CVA, cerebrovascularaccident; PVD, peripheralvasculardisease; SCr, serumcreatinine; BUN, bloodureanitrogen; LVEF, leftventricularejectionfraction; NYHA, NewYorkHeartAssociation. PerioperativeManagement Ejazetal 962TheJournalofThoracicandCardiovascularSurgerycOctober2009 PM

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DISCUSSION AKIisaseriouscomplicationofcardiovascularsurgery andisassociatedwithmarkedlyincreasedratesofmortality andmorbidity.11-13ThepathogenesisofpostoperativeAKI iscomplexbutisthoughttobemediatedbyareductionin renalbloodowassociatedwithpersistentrenalvasoconstriction,mediatedinpartbythereleaseofproinammatory andvasoconstrictivemediators.14Althoughavarietyoftrialswithdifferentrenalvasodilatorshavebeennegative,15-18therehasbeenrecentinterestintheuseofnatriureticpeptidesowingtotheirabilitytocauseafferentrenalvasodilation,improveGFR,andantagonizetheproinammatory effectsofavarietyofcytokines.19,20Indeed,inarecentuncontrolledretrospectivetrial,ourgroup7reportedaremarkable80 % decreaseinAKIinsubjectsundergoingaortic aneurysmtherapythatreceivednesiritidetherapy.Other groupshavealsoreportedareductioninAKIusingeither atrialnatriureticpeptideorbrainnatriureticpeptideaftercardiovascularsurgery.8,21,22Thisledustodoaprospective, double-blind,controlledtrialtodeterminewhethernesiritide couldproviderenalprotectioninsubjectsundergoingcardiovascularsurgery. Thedesignofthestudywasbasedonselectingsubjectsat highriskforthedevelopmentofAKI.Wethereforestudied subjectsundergoingaorticaneurysmsurgeryand/orsubjects havingvalvereplacementwithorwithoutcoronaryartery bypassinwhomhigherratesofAKI(4 % % )canbe predicted.Furthermore,wealsoidentiedsubjectswith modest(GFR30mL $ min 1$ [1.73m2] 1)butnotseverechronickidneydisease,inasmuchasourretrospective studysuggestedthatthisisthegroupmostlikelytobenet fromnesiritideprophylaxis.Furthermore,inasmuchasanesiritideboluscaninducehypotension(reviewedinreference 6 ),weoptedtoinitiatenesiritideasacontinuousinfusion (withoutbolusadministration)for5daysbeginningimmediatelybeforesurgeryintheoperatingroom.Althoughnohypotensionattributabletonesiritidewasnoted,subjects randomizedtonesiritidewereadministeredpressorsmore frequently. Themajorndinginthisstudywasthattheprimaryend point,denedasdialysisordeath,wasnotdifferentbetween groups.Importantly,therewasnofavorableeffectofrandomizationtonesiritidewithregardtotheincidenceofdialysisand/orall-causemortalitythroughday21.Oneproblem wasthatfewerpatientsreachedthisendpoint(3subjectsper group)thananticipated,andthatindeedcontributedtothe futility.Thisdidnotdifferevenwhenthedatawereanalyzed withadifferentcriterion(needfordialysisdenedasSCr 4.5mg/dL)thatwasusedinastudythatreportedimproved dialysis-freesurvivalwithnatriureticpeptides(nesiritide4/ 45vs4/49; P 1.00).21ItwasofinterestthatAKInecessitatingRRTdevelopedinall3controlpatientswhereasthe2 nesiritide-treatedsubjectsreceivedRRTforclinicalevidenceofvolumeoverload.Nevertheless,thesenumbers aretoosmalltomakeanydenitivestatementsrelatedtopotentialdifferencesinreasonsthatpatientsachievedtheprimaryoutcome. Intermsofsecondaryendpoints,therewasnodifference inhospitallengthofstayineithergroup.However,wedid observesomeevidenceforrenoprotectionasnotedbyreducedAKIinthenesiritidegroupversustheplacebogroup. Itispossiblethatthismayrepresenttheknowneffectofnatriureticpeptidestocauserenalvasodilation,andhencethat theeffectonrenalfunctionsimplyreectsatransienthemodynamiceffect.Althoughthisremainsapossibility,theuse ofotherrenalvasodilators,suchasdopamineandfenoldopam,wasnotassociatedwithanybenetinrenalfunction intheacutepostoperativeperiod.16,17 FIGURE4. Percentchangeinpostoperativeglomerularltrationrate (GFR) comparedwithbaseline. FIGURE3. Incidenceofacutekidneyinjury (AKI) usingdifferent denitions. Ejazetal PerioperativeManagement TheJournalofThoracicandCardiovascularSurgerycVolume138,Number4963 PM

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Posthocanalysessuggestedthatnesiritidemayprovide greaterrenoprotectioninsubjectswithbaselinerenalinsufciency(estimatedGFR < 45mL $ min 1$ [1.73m2] 1).Futurestudiesmaybeindicatedtodeterminewhethertargeting thisspecicpopulationcouldresultindifferentoutcomes. Untilthisisshowninmulticenterrandomizedtrials,wedo notrecommendtheroutineuseofnesiritidefortheprophylaxisofpatientsundergoingcardiovascularsurgery.TheinvestigatorsacknowledgetheactivesupportofDSMB membersAbrahamHartzema,PharmD,MSPH,PhD,Meenakshi Devidas,PhD,EdwardA.Ross,MD,DanielF.Pauly,MD,PhD, andstudycoordinatorsAllanFinlay,RN,MichelleArmstrong, RN,KarissaRoberts,MaryAliceDennis,RN,andMichelleHunter duringthecourseofthestudy.References1.SocietyofThoracicSurgeons.Fall2007ReportAdultCardiacDatabaseExecutiveSummary: www.sts.org http://www.sts.org/sections/stsnationaldatabase/ publications/executive/article.html 2.ChertowGM,LevyEM,HammermeisterKE,GroverF,DaleyJ.Independentassociationbetweenacuterenalfailureandmortalityfollowingcardiacsurgery. Am JMed .1998;104:343-8. 3.CinaCS,LaganaA,BruinG,RicciC,DoobayB,TittleyJ,etal.Thoracoabdominalaorticaneurysmrepair:aprospectivecohortstudyof121cases. Ann VascSurg .2002;16:631-8. 4.GodetG,FleronMH,VicautE,ZubickiA,BertrandM,RiouB,etal.Riskfactors foracutepostoperativerenalfailureinthoracicorthoracoabdominalaorticsurgery:aprospectivestudy. AnesthAnalg.1997;85:1227-32. 5.SaHJ,HarlinSA,MillerCC,IliopoulosDC,JoshiA,MohasciTG,etal.Predictivefactorsforacuterenalfailureinthoracicandthoracoabdominalaorticaneurysmsurgery. JVascSurg .1996;24:338-44. 6.EjazAA,HeinigME,KazoryA,BihoracA,HobsonCE,BeaverTM.Theriseand fallofnatriureticpeptidesinacutekidneyinjury:amisunderstoodrelationship? RevCardiovascMed .2007;8:S32-7. 7.BeaverTM,WintersteinAG,ShusterJJ,GerhardT,MartinT,AlexanderJA,etal. Effectivenessofnesiritideondialysisorall-causemortalityinpatientsundergoing cardiothoracicsurgery. ClinCardiol .2006;29:18-24. 8.MentzerRMJr,OzMC,SladenRN,GraeveAH,HebelerRFJr,LuberJMJr, etal.NAPAInvestigators.Effectsofperioperativenesiritideinpatientswith leftventriculardysfunctionundergoingcardiacsurgery:theNAPATrial. JAm CollCardiol .2007;49:716-26. 9.CooperWA,OBrienSM,ThouraniVH,GuytonRA,BridgesCR,SzczechLA, etal.Impactofrenaldysfunctiononoutcomesofcoronaryarterybypasssurgery: resultsfromtheSocietyofThoracicSurgeonsNationalAdultCardiacDatabase. Circulation .2006;113:1063-70. 10.MehtaRL,KellumJA,ShahSV,MolitorisBA,RoncoC,WarnockDG,etal. AcuteKidneyInjuryNetwork.AcuteKidneyInjuryNetwork:reportofaninitiativetoimproveoutcomesinacutekidneyinjury. CritCare .2007;11:R31. 11.BoveT,Calabro`MG,LandoniG,AlettiG,MarinoG,CrescenziG,etal.Theincidenceandriskofacuterenalfailureaftercardiacsurgery. JCardiothoracVasc Anesth .2004;18:442-5. 12.VanDenNoortgateN,MoutonV,LamotC,VanNootenG,DhondtA, VanholderR,etal.Outcomeinapostcardiacsurgerypopulationwithacuterenal failurerequiringdialysis:doesagemakeadifference? NephrolDialTransplant 2003;18:732-6. 13.OstermannME,TaubeD,MorganCJ,EvansTW.Acuterenalfailurefollowingcardiopulmonarybypass:achangingpicture. IntensiveCareMed .2000;26:565-71. 14.DevarajanP.Updateonmechanismsofischemicacutekidneyinjury. JAmSoc Nephrol .2006;17:1503-20. 15.TumlinJA,FinkelKW,MurrayPT,SamuelsJ,CotsonisG,ShawAD.Fenoldopammesylateinearlyacutetubularnecrosis:arandomized,double-blind,placebo-controlledclinicaltrial. AmJKidneyDis .2005;46:26-34. 16.BoveT,LandoniG,Calabro`MG,AlettiG,MarinoG,CerchieriniE,etal.Renoprotectiveactionoffenoldopaminhigh-riskpatientsundergoingcardiacsurgery: aprospective,double-blind,randomizedclinicaltrial. Circulation .2005;111: 3230-5. 17.LauschkeA,TeichgraberUK,FreiU,EckardtKU.Low-dosedopamine worsensrenalperfusioninpatientswithacuterenalfailure. KidneyInt .2006; 69:1669-74. 18.LassniggA,DonnerE,GrubhoferG,PresterlE,DrumlW,HiesmayrM.Lackof renoprotectiveeffectsofdopamineandfurosemideduringcardiacsurgery. JAm SocNephrol .2000;11:97-104. 19.LaneseDM,YuanBH,FalkSA,CongerJD.EffectsofatriopeptinIIIonisolated ratafferentandefferentarterioles. AmJPhysiol.1991;261:F1102-9. 20.HoubenAJ,vanderZanderK,deLeeuwPW.Vascularandrenalactionsofbrain natriureticpeptideinman:physiologyandpharmacology. FundamClinPharmacol .2005;19:411-9. 21.SwardK,ValssonF,OdencrantsP,SamuelssonO,RickstenSE.Recombinant humanatrialnatriureticpeptideinischemicacuterenalfailure:arandomized placebo-controlledtrial. Crit Care Med .2004;32:1310-5. 22.ChenHH,SundtTM,CookDJ,HeubleinDM.BurnettJCJr.Lowdosenesiritide andthepreservationofrenalfunctioninpatientswithrenaldysfunctionundergoingcardiopulmonary-bypasssurgery:adouble-blindplacebo-controlledpilot study. Circulation .2007;116:I134-8. PerioperativeManagement Ejazetal 964TheJournalofThoracicandCardiovascularSurgerycOctober2009 PM


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