Preoperative and perioperative use of levosimendan in cardiac surgery

14 Pages·2015·0.71 MB·English

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InternationalJournalofCardiology184(2015)323–336
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International Journal of Cardiology
journal homepage: www.elsevier.com/locate/ijcard
Review
Preoperative and perioperative use of levosimendan in cardiac surgery:
European expert opinion
W.Tollera,⁎,M.Heringlakeb,F.Guarracinoc,L.Algotssond,J.Alvareze,H.Argyriadouf,T.Ben-Galg,V.Černýh,
B.Cholleyi,j,A.Eremenkok,J.L.Guerrero-Orriachl,K.Järveläm,N.Karanovicn,M.Kivikkoo,P.Lahtinenp,
V.Lomivorotovq,R.H.Mehtar,Š.Mušičs,P.Polleselloo,S.Rext,H.Rihau,A.Rudigerv,M.Salmenperäw,
L.Szudix,L.Tritapepey,D.Wyncollz,A.Öwallaa
aDepartmentofAnaesthesiologyandIntensiveCareMedicine,UniversityHospitalofGraz,Graz,Austria
bDepartmentofAnaesthesiology,UniversityofLübeck,Lübeck,Germany
cDepartmentofAnaesthesiaandCriticalCareMedicine,AziendaOspedaliero-UniversitariaPisana,Pisa,Italy
dDepartmentofCardiothoracicSurgery,SkånesUniversityHospitalLund,Lund,Sweden
eDepartmentofAnaesthesiologyandIntensiveCare,UniversityHospitalofSantiagodeCompostela,SantiagodeCompostela,Spain
fDepartmentofAnaesthesiologyandIntensiveCareUnit,AristotleUniversityofThessaloniki,AHEPATeachingHospital,Thessaloniki,Greece
gHeartFailureUnit,RabinMedicalCentre,PetachTikva,Israel
hDepartmentofAnaesthesiologyandIntensiveCare,UniversityHospitalHradecKralove,HradecKralove,CzechRepublic
iDepartmentofAnaesthesiologyandIntensiveCare,HôpitalEuropéenGeorgesPompidou,AP-HP,Paris,France
jUniversitéParisDescartes,Paris,France
k“B.V.Petrovsky”RussianNationalCentreofSurgery,Moscow,Russia
lDepartmentofCardio-Anaesthesiology,UniversityHospitalVirgendelaVictoriadeMalaga,Malaga,Spain
mHeartCentreandIntensiveCareUnit,TampereUniversityHospital,Tampere,Finland
nDepartmentofAnaesthesiologyandIntensiveCare,UniversityHospitalSplit,Split,Croatia
oOrionPharma,CriticalCare,Espoo,Finland
pDepartmentofAnaesthesiologyandIntensiveCare,KuopioUniversityHospital,Kuopio,Finland
q“E.N.Meshalkin”StateNovosibirskResearchInstituteofCirculationPathology,Novosibirsk,Russia
rDepartmentofInternalMedicineandCardiology,DukeUniversityMedicalCenterandDukeClinicalResearchInstitute,Durham,NC,USA
sDepartmentofCardio-Anaesthesiology,UniversityClinicalCentreLjubljana,Ljubljana,Slovenia
tDepartmentofAnaesthesiology,UZLeuven,CampusGasthuisberg,Leuven,Belgium
uCardiothoracicAnaesthesiologyandIntensiveCare,DepartmentofAnaesthesiologyandIntensiveCareMedicine,InstituteforClinicalandExperimentalMedicine,Prague,CzechRepublic
vInstituteofAnaesthesiology,UniversityHospitalofZürich,Zürich,Switzerland
wDepartmentofAnaesthesiology,IntensiveCare,EmergencyandPainMedicine,HelsinkiUniversityHospital,Helsinki,Finland
xDepartmentofAnaesthesiologyandIntensiveCare,GottsegenGyörgyNationalInstituteofCardiology,Budapest,Hungary
yDepartmentofAnaesthesiologyandIntensiveCare,Policlinico“UmbertoI”,“LaSapienza”UniversityofRome,Rome,Italy
zDepartmentofCriticalCare,St.Thomas'Hospital,London,UK
aaDepartmentofCardiothoracicSurgery,KarolinskaUniversityHospitalSolna,Stockholm,Sweden
a r t i c l e i n f o a b s t r a c t
Articlehistory: Incardiacsurgery,postoperativelowcardiacoutputhasbeenshowntocorrelatewithincreasedratesoforgan
Received12August2014 failureandmortality.Catecholamineshavebeenthestandardtherapyformanyyears,althoughtheycarry
Receivedinrevisedform9February2015 substantialriskforadversecardiacandsystemiceffects,andhavebeenreportedtobeassociatedwithincreased
Accepted21February2015
mortality.Ontheotherhand,thecalciumsensitiserandpotassiumchannelopenerlevosimendanhasbeen
Availableonline24February2015
showntoimprovecardiacfunctionwithnoimbalanceinoxygenconsumption,andtohaveprotectiveeffects
inotherorgans.Numerousclinicaltrialshaveindicatedfavourablecardiacandnon-cardiaceffectsofpreopera-
Keywords:
tiveandperioperativeadministrationoflevosimendan.Apanelof27expertsfrom18countrieshasnow
Cardiacsurgery
CABG reviewedtheliteratureontheuseoflevosimendaninon-pumpandoff-pumpcoronaryarterybypassgrafting
Valvesurgery andinheartvalvesurgery.Thispaneldiscussedthepublishedevidenceinthesevarioussettings,andagreedto
Lowcardiacoutputsyndrome voteonasetofquestionsrelatedtothecardioprotectiveeffectsoflevosimendanwhenadministeredpreopera-
Inodilator tively,withthepurposeofreachingaconsensusonwhichpatientscouldbenefitfromthepreoperativeuseof
Cardioprotective levosimendanandinwhichkindofprocedures,andatwhichdosesandtimingshouldlevosimendanbeadmin-
istered.Here,wepresentasystematicreviewoftheliteraturetoreportonthecompletedandongoingstudieson
⁎ Correspondingauthorat:DepartmentofAnaesthesiologyandIntensiveCareMedicine,UniversityHospitalofGraz,Auenbruggerplatz29,8036Graz,Austria.
E-mailaddress:[email protected](W.Toller).
http://dx.doi.org/10.1016/j.ijcard.2015.02.022
0167-5273/©2015TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
324 W.Tolleretal./InternationalJournalofCardiology184(2015)323–336
levosimendan,includingthenewlycommencedLEVO-CTSphaseIIIstudy(NCT02025621),andontheconsensus
reachedontherecommendationsproposedfortheuseofpreoperativelevosimendan.
©2015TheAuthors.PublishedbyElsevierIrelandLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND
license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.Introduction voting.Theresultsarepresentedhere,togetherwiththeevidenceofthe
pharmacologyoflevosimendan,andadiscussionoftheavailableclinical
Inpatientsundergoingcardiacsurgery,lowcardiacoutputsyn- data.
drome(LCOS)isadisastrouseventthatcanresultinlife-threatening
complications[1,2].WithLCOS,themortalityrateofthesepatients 2.Pharmacologyofthecardioprotectiveeffectsoflevosimendan
canbeashighas16.9%(versus0.9%withoutLCOS)[2].Preoperativere-
ducedleftventricularfunctionhasbeenrecognisedasthemainriskfac- Levosimendanischaracterisedbyatriplemechanismofaction
torforLCOS[3,4]. [8];i.e.,itactsviacalcium-dependentbindingtocardiactroponin
Cardiacsurgeryisalsousuallyaccompaniedbymulti-facetedeffects, C,andopenstheK channelsonsmoothmusclecellsinthevascu-
ATP
which include sympathetic activation, inflammation, and haemo- lature,andincardiacmitochondria.Thisbindingoflevosimendanto
dynamicchanges,andisthuslikelytopromoteorgandysfunction. troponinCandtheopeningofK channelsonsmoothmusclecells
ATP
Ofnote,acutekidneyinjury isfrequentlyobservedaftercardiac inthevesselsresultinitsinotropicandvasodilatoryeffects,respec-
surgery,andthisisassociatedwithincreasedlong-termmortality tively,whiletheopeningofK channelsincardiacmitochondriais
ATP
aftercardiothoracicsurgery[5].Postoperativeacutekidneyinjury believedtobeacardioprotectivepathway[15].Thedefinitionof
canbepartofcardiorenalsyndrome,whichisaclassicexampleof cardioprotection, however, is very broad, and it can be divided
organdysfunctionthatcanariseduetohypoperfusion,whichtrig- into atleast two categories ofeffects:short-termand long-term
gersasympathoadrenergicresponse,hyperglycaemiaandinflam- cardioprotection.Short-termcardioprotectionencompasseseffects
mation[6]. such as preconditioning, postconditioning, and anti-stunning, as
Inotropicsupportisfrequentlyinitiatedintheperioperativeperiod wellasanti-ischaemiceffects.Long-termcardioprotection,onthe
toimprovepost-bypassventricularfunction.However,inotropesin- otherhand,isoftenreferredtoashavinganti-remodelling,anti-
cludethepotentialriskofincreasedmyocardialoxygenconsumption, apoptoticandanti-inflammatoryeffects.
whichcanresultincardiacischaemia,withsubsequentdamagetohi-
bernatingbutviablemyocardium,andarrhythmias.Thishasprompted 2.1.Preconditioningeffectsoflevosimendan
anongoingdebateonthepotentialharmassociatedwithinotropicther-
apyincardiacsurgery.Indeed,theuseofperioperativeandpostopera- TheopeningofK channelsinthemitochondriahasapredomi-
ATP
tiveinotropeshasrecentlybeenfoundtobeassociatedwithincreased nantroleintheprotectionofthemyocardiumfromischaemiaandre-
mortalityandmajorpostoperativemorbidity[7]. perfusioninjury[16].Byattenuationofcalciumaccumulationinthe
Administrationofthecalciumsensitiserlevosimendan,whichhas mitochondriaandstabilisationofthemitochondrialinnermembrane
beenapprovedformanagementofacutelydecompensatedheartfailure, permeability,K channelopeningresultsinareductioninmyocardial
ATP
mightofferasolutiontothisunmetneed.Theeffectsoflevosimendanas cellnecrosisandapoptosisinducedbyischaemia–reperfusioninjury.
aninodilatorarebasedonatriplemechanismofaction[8]thatprovides Therefore,treatmentwiththeK channelopenerlevosimendanprior
ATP
positiveinotropywithaneutraleffectonoxygenconsumption[9],and tomyocardialischaemiawillmimicischaemicpreconditioning.According
withpreconditioning[10],cardioprotective[11],anti-stunning[12]and toex-vivodataobtainedbyToitandcolleagues,levosimendanprecondi-
anti-ischaemiceffects[13].Inarecentmeta-analysisofclinicaltrials, tioningcanreduceinfarctsizeby90%[11].Also,whencomparedwith
Harrisonandcolleaguesevaluatedtheeffectsoflevosimendanincardiac milrinoneinananimalmodelsetting,therewaslessmortalitywith
surgerypatientswithandwithoutpreoperativesystolicdysfunction[14]. levosimendan:afterocclusionandreperfusionofthecoronaryvessels,
Here,theyshowedthatmortalityandotheradverseoutcomes,suchas 70%ofdogstreatedwithlevosimendanbeforeischaemia–reperfu-
postoperativerenalfailurerequiringdialysis,postoperativeatrialfibrilla- sionsurvived,ascomparedto20%ofthosetreatedwithmilrinone
tion,andmyocardialinjury,werereducedwithlevosimendantreatment. [17].Inanothermodel,thelactate/pyruvateratiointheischaemic
Thesebenefitsweregreatestforthepatientswithdiminishedleftventric- areaswasreducedwithlevosimendantreatmentpriortoinduction
ularejectionfraction(LVEF). of ischaemia [18]. Finally, Kersten and co-workers also showed
Thecharacteristicsofthecardiacsurgerysettingdifferfromthe thatlevosimendanhasprotectiveeffectsagainstmyocardialischae-
conditionsinthecontextoflevosimendanuseinpatientswithacute miainadogmodel:withlevosimendantreatment,infarctsizewas
heartfailure.Factorsthatapplytocardiologypatientsarefrequently decreasedby50%[19].
notthesameasthosethatapplyperioperatively.Suspensionofstandard
therapy in the perioperative period, use of cardiopulmonary bypass 2.2.Anti-stunningeffectsoflevosimendan
(CPB),bloodloss,rapidintravascularandextravascularfluidshifts,and
systemic inflammatory response syndrome can affect the impact of Myocardialstunningoccurswhenacutemyocardialischaemialeads
levosimendantreatment.Thisindicatedtheneedforspecifichandlingof toatransientimpairmentofthecontractilefunction.Inpatientswith
levosimendanincardiacsurgerypatientswithrespecttothedefini- coronaryarterydisease,repeatedepisodesofdemandischaemiacan
tionofindications,modalityofadministration,andmanagementof leadtocumulativestunning,whichhasbeensuggestedtobeafactor
sideeffects. inthedevelopmentofchronicpost-ischaemicleftventriculardysfunc-
Therefore,27expertsfrom18countriesconvenedtoreviewtheliter- tion[20].
atureandtoagreeuponaseriesofrecommendations.Thepanellistsare Sonntagandco-workersdemonstratedtheanti-stunningeffectsof
allrecognizedspecialistsinthefieldsofcardiothoracicanaesthesiology, levosimendanin24patientswithacutecoronarysyndrome,whereby
cardiothoracicsurgery,cardiology,cardiovascularpharmacology,and ascomparedtoplacebo,thetotalnumberofhypokineticsegments
intensivecaremedicine.Theyextensivelydiscussedthepreoperative was significantly decreased with levosimendan treatment [21]. In
useoflevosimendan,andformulatedalistofquestions.Thereafter,the 30patientswithacutemyocardialinfarctionwhoexperiencedmyocar-
panellists received a questionnaire and responded through internet dialstunningafteremergencypercutaneouscoronaryintervention,
W.Tolleretal./InternationalJournalofCardiology184(2015)323–336 325
continuousinfusionoflevosimendan0.1μg/kg/minfor24hsignificant-
lyimprovedmyocardialfunction,ascomparedtoplacebo[22].Inare-
cent randomised, double-blind clinical trial with 61 patients who
developed clinical signs of heart failure within 48 h of primary
percutaneous-coronary-intervention-treatedSTEMI(includingcardio-
genicshock),25-htreatmentwithlevosimendanshowedsignificant-
ly greater improvement in their wall motion score index from
baselinetoday5,ascomparedtoplacebo[23].
2.3.Anti-ischaemiceffectsoflevosimendan
Inarodentmodelofhealedmyocardialinfarction,Levijokiand
co-workersshowedthattreatmentwithlevosimendancorrelated
with decreased mortality [13]. These preclinical data were con-
firmedmorerecentlyinanotherstudy[24].
3.Pharmacokineticandpharmacodynamicconsiderations
Levosimendanhasahalf-lifeforeliminationofabout1h.With- Fig.1.Strokevolume(SVI)atthestartofsurgery(base),15minaftertheendofcardiopul-
outaloadingdose,asteady-stateconcentrationcanbeachievedap- monarybypass(post-CPB),attheendoftheoperation(endsurgery),atarrivalinthe
proximately4hafterthestartofcontinuouslevosimendaninfusion. intensivecareunit(T0),and6(T6),12(T12),24(T24),and48(T48)hlater.
Levosimendan(□)andMilrinone(▲).Dataaremean±standarddeviation.*,statistically
Aftertheinfusion,thelevosimendanserumconcentrationsdecrease
significantdifferencebetweengroupsforPb0.05.
relativelyrapidly.Levosimendan,however,hasanactivecirculating DatafromdeHertetal.[28].
metaboliteknownasOR-1896,whichhasahalf-lifeforelimination
ofapproximately80h[25].Inpatientswithheartfailure,OR-1896
reachesitspeaklevelapproximately2daysaftertheendofa24-h
infusion of levosimendan, and is removed from the circulation strategydescribedinFig.2,andgroupedaccordingtothetimingof
overthefollowing2weeks[25].Lillebergandcolleaguesshowed theuseoflevosimendanandthetypeofintervention,asinthefol-
thatlevosimendantreatmentofpatientswithheartfailurefor24h lowingsections(seeTable1).
improvescardiacoutputandreducespulmonarycapillarywedge
pressure (PCWP) for at least 1 week [26]. A reduction in the N-
terminal-pro-atrialnatriureticpeptidelevelswasobservedforat 4.1.Preoperativeuseinon-pumpcardiacsurgery
least2weeks.
Inthecardiacsurgerysetting,OR-1896canbefoundintheplasma, 4.1.1.Coronaryarterybypassgraftingsurgery
butcomparedtoheartfailurepatients,itsformationoccursataslower Inarandomised,double-blind,placebo-controlledtrialbyTritapepe
pace[27].Peaklevelsareobserved5daysto6daysafterthediscontin- andcoworkers,levosimendan24μg/kginfusionfor10minbeforeiniti-
uationoflevosimendaninfusion.Thisisprobablyduetopreoperative ationofcoronaryarterybypassgrafting(CABG)ledtosignificantreduc-
fastingandtotheuseofbroad-spectrumantibioticsincardiacsurgery. tionsintrachealintubationtime,lengthofIntensiveCareUnit(ICU)stay
ClinicaldataobtainedinpatientswithlowpreoperativeLVEF(≤30%) (Pb0.01forboth),andtheproportionofpatientsrequiringinotropic
scheduledforelectivecardiacsurgeryindicatedaprolongedeffectof supportforN12h(3.8%vs.18.0%forplacebo;P=0.021)[29].Ascom-
levosimendanonthestrokevolumeindex[28].Thepatientsreceived paredtoplacebo,levosimendan-treatedpatientshadsignificantlylower
either levosimendan 0.1 μg/kg/min infusion for 19 h or milrinone postoperativetroponinIlevels(Fig.3)andasignificantlyhighercardiac
0.5μg/kg/mininfusionfor83h.Withinthefirstfewhours,theeffects index(Pb0.0001each).
onstrokevolumeindexwerecomparableinbothgroups,butamore Thepreoperativeuseoflevosimendaninhigh-riskpatientswithse-
pronouncedeffectwasseenwithlevosimendanduringthefollow-up vereleftventriculardysfunction(LVEFb25%)scheduledforCABGwas
periodforupto48h,eventhoughlevosimendantreatmenthadalready assessedinarandomised,placebo-controlledtrial[30].Levosimendan
beendiscontinued(Fig.1). wasstarted24hbeforesurgery,withaloadingdoseof10μg/kginfusion
By overviewing the pharmacodynamic and pharmacokinetic for1hthatwasfollowedbycontinuousinfusionof0.1μg/kg/mininfusion
propertiesoflevosimendan,itbecomesclearthatitspreoperative, for23h.Overall,252patientsparticipatedinthestudy.Levosimendanre-
oralternativelyperioperative,usemighthaveeffectsthatarevery ducedmortalitycomparedtoplacebo(3.9%vs.12.8%;Pb0.05),and
different.Indeed,inthepreoperativesettings,thecardioprotective decreasedtheincidenceofLCOS(7.1%vs.20.8%;Pb0.05)andof
effectsoflevosimendanwouldhaveamajorrolealongwithitshae- complicated weaning from CPB (2.4% vs. 9.6%; P b 0.05). The
modynamiceffects(inotropicandvasodilatory),andlevosimendanmight levosimendan-treated group also showed lower requirement for
befurtherdifferentiatedfromotherinodilatory,haemodynamicallyactive other inotropes compared to placebo (7.9% vs. 58.4%; P b 0.05),
orvasoactivedrugs. andforvasopressors(14.2%vs.45.6%;Pb0.05),andloweruseof
anintra-aorticballoonpump(6.3%vs.30.4%;Pb0.05).
4.Publisheddataonthepreoperativeandperioperativeuse
oflevosimendan
4.1.2.CABGandaorticvalvesurgery
Inthesystematicanalysisoftheliterature,thedatasourcesused In24patientsundergoingcombinedaorticvalveandCABGsurgery,
werePubMed,IndexMedicus,ExcerptaMedica,ReferenceUpdate, preoperativelevosimendan12μg/kginfusionfor10minfollowedbya
BIOSIS,andScienceCitationIndex.Thepertinentstudieswereinde- continuous infusion of levosimendan 0.2 μg/kg/min infusion for
pendentlyidentifiedbytwotrainedinvestigators(updatedMarch 24hsignificantlyimprovedcardiacindexandstrokevolumeindex
27,2014).Thepapersandabstractsfoundbysearching([levosimendan throughoutthe4-daypostoperativeperiod(Pb0.05)[31].TheLVEF
ORSimdax]and[surgeryORbypassORvalveORCABGORanest*]) wasmaintainedinthelevosimendangroup,whereasitdecreasedinthe
were selected according to the PRISMA search and the inclusion controlgroup.
326 W.Tolleretal./InternationalJournalofCardiology184(2015)323–336
Fig.2.PRISMAflowdiagram[71]forsearchandinclusionofscientificinformationintosystematicreviewsappliedtothesearch((levosimendanORSimdax)and(surgeryORbypassOR
valveORCABGORanest*))updatedMarch27,2014.
4.2.Perioperativeuseinon-pumpcardiacsurgery aftersurgeryinthemilrinonegroup,butnotinthelevosimendangroup
(Pb0.05)despitesimilarfillingpressures.Totaldose,durationof
4.2.1.CABGsurgery inotropicdrugadministration,andnorepinephrinedosesweresig-
Arandomised,double-blindtrialassessedtheeffectsoflevosimendan nificantlylowerwithlevosimendan(Pb0.05).Moreover,thedura-
onhaemodynamics,coronarybloodflow,andmyocardialsubstrateuse tionoftrachealintubationwasshorterinthelevosimendan-treated
earlyafterCABG[32].Twodoseschedules(levosimendan8μg/kgor group(P=0.008).
24μg/kgas5-mininfusionsafterCABG)werecomparedwithplacebo.Al- Levinandcolleaguescomparedlevosimendan(10μg/kgas1hinfu-
thoughlevosimendanimprovedcardiacperformancebyincreasingcardi- sion followedby 0.1 μg/kg/min infusion for24 h)anddobutamine
acoutputandcoronarysinusbloodflow,itdidnotincreasemyocardial (startingdose,5μg/kg/mininfusion)inarandomisedtrialwith137pa-
oxygenconsumptionorchangemyocardialsubstrateuse. tientswithLCOSaftersurgery[33].Patientstreatedwithlevosimendan
DeHertandco-workersconductedarandomisedstudywith30pa- experiencedsignificantbenefitsinthepostoperativeperiod,withim-
tientsscheduledforCABGwithpreoperativeLVEF≤30%[28].Inaddition provementsin haemodynamic parameters with levosimendan that
todobutamine,thepatientsreceivedeithermilrinone0.5μg/kg/min weregreaterandoccurredearlierthanwithdobutamine.Postoperative
infusionorlevosimendan0.1μg/kg/mininfusionimmediatelyafterthe
releaseoftheaorticcrossclamp.Theseinfusionswerecontinueduntil
weaningfrominotropicsupport.Thestrokevolumeindexdeclined12h
Fig.3.CardiactroponinIconcentrations(mean±95%confidenceintervals)inthe Fig.4.NeedforadditionalinotropicsupportinpatientswithLCOSaftercardiacsurgeryin
levosimendan(□)andplacebo(▲)groupsbeforesurgery(baseline),onarrivalinthe thestudybyLevinandcolleagues[33],withtreatmentwithlevosimendan(whitebars)
intensivecareunit(0),andafter6,24,and48h. anddobutamine(blackbars).*,statisticallysignificantdifferencebetweengroupsfor
DatafromTritapepeetal.[29]. Pb0.05.
W.Tolleretal./InternationalJournalofCardiology184(2015)323–336 327
mortalitywaslowerinthelevosimendangroupcomparedtodobuta- studycomparedtwodoseschedules(0.1μg/kg/minand0.2μg/kg/min
mine(8.7%vs.25%;Pb0.05),aswastheneedforvasopressors,second infusionsfor20min,afterinitialloadingdoseof12μg/kginfusionfor
orthirdinotropes,andintraaorticballoonpump(IABP)use(Fig.4). 10min)withplaceboin23patientsafteraorticvalvereplacementfor
Intherandomised,double-blindLEWEstudy,levosimendanfacili- aorticstenosis.Levosimendantreatmentshowedadose-dependentin-
tatedweaningfromCPBandreducedtheneedforadditionalinotropic creaseincardiacoutput(+28%;Pb0.001)andstrokevolume(+26%;
or mechanical circulatory support in patients with impaired LVEF P b 0.001), and a decrease in systemic vascular resistance (−22%;
(≤50%) undergoing CABG [27]. Sixty patients received either Pb0.001).TherewasatrendtowardsanincreaseinLVEF(12%;P=
levosimendanasa12μg/kgbolusfollowedby0.2μg/kg/mininfu- 0.058).Aftertheadministrationoflevosimendan,ascomparedtoplace-
sion,orplacebo,startedimmediatelyaftertheinductionofanaesthesia. bo,isovolumicrelaxationtimedecreased(−3%;Pb0.001),asdidthe
LevosimendansignificantlyfacilitatedprimaryweaningfromCPBascom- decelerationslopeofearlydiastolicfilling(−45%;Pb0.01).Bothpeak
paredwithplacebo(P=0.002;Fig.5).Fourpatientsintheplacebogroup earlydiastolicfillingvelocity(16%,Pb0.01)andpeaklatediastolicfill-
evenfailedthesecondweaningandhadtobesupportedbyIABP,ascom- ingvelocity(15%;Pb0.001)increasedsignificantly.
paredwithnoneinthelevosimendangroup(P=0.112).
4.2.4.CABGandmitralvalvesurgery
4.2.2.CABGandvalvesurgery Acase-matchedstudycomparedlevosimendanwiththeuseofan
Inarandomised,placebo-controlledtrial,Lahtinenandcolleagues IABPinheartfailurepatientsundergoingelectiveCABGwithoutor
demonstratedthatlevosimendantreatmentdiminishedtheincidence withconcomitantmitralvalvesurgery[37].Elevenpatientsreceived
ofheartfailureafterheartvalveorcombinedheartvalveandCABGsur- levosimendaninfusionatadoseof0.1μg/kg/minfor24h,whileanother
gery[34].Levosimendan24μg/kgover30minofinfusionfollowedby 11patientsreceivedpreoperativeIABP.ThelengthofstayattheICUwas
0.2μg/kg/mininfusionfor24h,orplacebo,wasadministeredafterin- significantlyreducedinthelevosimendan-treatedgroup,comparedto
ductionofanaesthesia.Fifteenpercentofpatientsinthelevosimendan IABPuse(2.5vs.5days;P=0.01).
groupand58%intheplacebogroupexperiencedpostoperativeheart
failure(Pb0.001).Accordingly,theuseofrescueinotropesandIABP 4.2.5.Mitralvalvesurgery
wassignificantlylessintheinterventionalarm(P=0.005andP= Gandham and co-workers compared the use of levosimendan
0.018,respectively).Thelevelofthemyocardialfractionofcreatineki- 0.1 μg/kg/min infusion with dobutamine 5 μg/kg/min infusion for
nase, which is indicative of myocardial damage, was lower in the weaningfromCPBin60patientswhowereundergoingmitralvalvere-
levosimendangrouponthefirstpostoperativeday,comparedtoplacebo pairorreplacementforseveremitralstenosis[38].Thepatientswhore-
(P=0.011).Incontrast,theuseofvasopressorswassignificantlyhigher ceivedlevosimendanshowedgreaterreductionsinsystemicvascular
inthelevosimendanarmduetoarterialhypotension(Pb0.001).Hospital resistanceindex,centralvenouspressure,andmeanarterialpressure,
mortalityratesand6-monthmortalityratesweresimilarinbothgroups. comparedtodobutamine.Therequirementofinotropesandvasocon-
strictorswasincreasedinthelevosimendan-treatedgroup.Compared
4.2.3.Aorticvalvesurgery todobutamine,therewasastatisticallysignificantincreaseincardiac
Twenty-fourpatientswithsevereaorticstenosisandleftventric- indexwithlevosimendan,even12hafterdiscontinuation.
ularhypertrophyundergoingaorticvalvesurgerywereincludedina
randomised,double-blindtrialbyJärveläandco-workers[35].In 4.3.Off-pumpcardiacsurgery
patientsreceivinga24-hinfusionoflevosimendan0.2μg/kg/min
startingaftertheinductionofanaesthesia,LVEFwasmaintained, Severalstudieshavetestedthehypothesisthatlevosimendantreat-
whileitdroppedintheplacebo-treatedgroup.Thisdifferencewas mentisassociatedwithbeneficialhaemodynamiceffectsduringand
notsignificant,however. afteroff-pumpCABGinpatientswithgoodpreoperativeleftventricular
Jörgensenandothersfoundthatinadditiontoitsinotropiceffects, function.Arandomised,four-times-masked,controlledstudyinvesti-
levosimendancanhaveapositivelusitropiceffectinpatientswithleft gatedlevosimendanattwodoseschedules:lowdose(12μg/kg)and
ventricularhypertrophy,asitshortenedisovolumicrelaxationtime highdose(24μg/kg)as10mininfusions[39].Thesetreatmentswere
andimprovedleftventricularfilling[36].Thisrandomised,blinded administrated20minbeforethestartofthesurgery.Comparedtopla-
cebo,significantincreasesincardiacoutputandLVEFoccurredafter
boththehigh-dose(Pb0.001andP=0.006,respectively)andthe
low-dose(P=0.001andP=0.002,respectively)treatments.Both
levosimendandosesproducedsignificantincreasesinstrokevolume
anddecreasesinsystemicvascularresistance.
Inadouble-blindrandomisedtrial,24patientsreceivedeitherplace-
boorlevosimendanatadoseof12μg/kgasaninfusionfor15minbe-
foreCABG[40].At10minand60minpost-infusion,thecardiacindex
andtheLVEFweresignificantlyhigherwithlevosimendanthanwith
placebo(P=0.018each).Thestrokevolumeindexwassignificantly
higherforlevosimendanat10min(P=0.018),but notat60min
(P=0.063).
Kodalliandcolleaguescomparedlevosimendan0.1μg/kg/mininfu-
sionandplaceboafterinductionofgeneralanaesthesiainadouble-
blindmanner[41].Inpatientsreceivinglevosimendan,comparedto
placebo,thecardiacindexwassignificantlyhigherandthesystemic
vascularresistanceindexwassignificantlylowerat6,12,18and24h
afterCABG.Noimprovementswerenotedintermsofdurationofventi-
lationorICUlengthofstay.
Thedouble-blind,randomisedtrialbyShahandcolleaguestested
Fig.5.Weaningfromcardiopulmonarybypass(CPB).Firstweaningattemptwith preoperativelyadministeredlevosimendan200μg/kginfusionfor24h
levosimendan(whitebars)andplacebo(blackbars).Epinephrineaddedtosecond
againstplaceboforoff-pumpCABGin50patientswithleftventricular
weaningattempt.*,Weaningfailureledtouseofintra-aorticballoonpump.
DatafromErikssonetal.[27]. dysfunction(LVEFb30%)[42].Ascomparedtothecontrolgroup,the
328 W.Tolleretal./InternationalJournalofCardiology184(2015)323–336
levosimendan-treatedpatientshadhighercardiacindexandPCWPdur- low-cardiac-outputheartfailureaftercardiacsurgery,Labriolaand
ingtheoperativeandearlypostoperativeperiods.Also,requirements co-workersadministeredlevosimendanandobservedimprovedcar-
forinotropes,IABPandCPBsupportwerelowerforlevosimendan,and diacindexandPCWP.Atthesametime,themeanpulmonaryarterypres-
bothICUandhospitallengthofstaywerereduced. sureandrightarterialpressuredecreasedby13%(Pb0.001)and25%
(Pb0.001),respectively[50].
4.4.Effectsoflevosimendanonkidneyfunction
5.Pharmaco-economicconsiderations
Asrenaldysfunctionisanimportantcomplicationofcardiacsurgery,
severaltrialshaveinvestigatedthepotentialrenalbenefitsmediatedby
Health-andpharmaco-economicanalysesontheuseoflevosimendan
levosimendan.Inarandomised,placebo-controlledstudy,levosimendan
inacutedecompensatedheartfailurehaveshownthatitsuseiscost-
significantlyimprovedrenalparametersaftercardiacsurgerywithCPB
effective[51-53].Wedidnotfindintheliterature,however,systematic
[43].Levosimendanwasappliedasa0.1μg/kg/mininfusionfor1hafter
healtheconomicstudiesontheuseoflevosimendanincardiacsurgery.
aloadingdoseofa12μg/kginfusion.Whencomparedtoplacebo,this
Fromananalysisoftheavailabledata,itappearedtousthatlevosimendan
treatmentcausedasignificant12%increaseinrenalbloodflow,andasig-
positivelyaffectsthemajorelementswhicharelikelytoincreasethecosts
nificant21%increaseinglomerularfiltrationrate,whereasrenalvascular
oftreatmentincardiacsurgery:(1)theICUstayhasbeenreportedtobe
resistance decreased significantly by 18%. There were no significant
shorterinseverallevosimendanstudies[29,30];(2)thereislessneedfor
changesinfiltrationfraction,renaloxygenconsumption,orrenaloxygen
IABP(boththeactualnumberofthepatientsandtheduration)[28,30,33,
extraction.Theseeffectsclearlydifferedfromthoseofdopamine,which
34,54]; and (3) there is less need for renal replacement therapy in
alsoincreasedrenalbloodflow,butdidnotincreasetheglomerularfiltra-
levosimendantreatedpatients[14,30,33,44].Asitregardtheconcomitant
tionrate.
useofothervasoactivedrug,ahigherneedforvasopressorswhenusing
Baysalandco-workerscomparedlevosimendan(6μg/kginfusion
levosimendaniscompensatedbyalowerneedofinotropes.Overall,the
afterremovaloftheaorticcross-clamp,followedby24-hinfusionof
expectationisthatlevosimendantreatmentincardiacsurgerywouldbe
0.1μg/kg/min)withplaceboinadditiontostandardinotropictherapy
cost-effective[55],despiteitshighercostcomparedtodobutamine.
[44].Thecohortconsistedof128patientswithLVEF≤45%whowere
undergoingmitralvalvesurgery.Comparedwiththegroupofpa-
tientswhoreceivedonlystandardinotropictherapy,theaddition 6.Ongoingtrials
oflevosimendanimprovedpostoperativerenalclearanceondays1
and3.Atthesetimepoints,serumcreatininelevelswerelowerandthe AnumberofEuropeantrialsarecurrentlyassessingtheperiopera-
estimatedglomerularfiltrationrateswerehigherthaninthecontrol tiveuseoflevosimendan(seeTable3).TheLICORNstudyisinvestigat-
arm.Therewasatrendinfavouroflevosimendanregardingtheneed ingtheefficacyofpreoperativelevosimendaninpatientswithLVEF
forrenalreplacementtherapy. ≤40% undergoing CABG with or without valve replacement under
A meta-analysis by Harrison and colleagues also highlighted the CPB(studynumberP110138,France).Theprimaryendpointofthis
beneficialeffectsofperioperativelevosimendanonrenalfunction,asit placebo-controlledstudyisacompositethatincludestheuseofinotro-
showedsignificantreductionsintheneedfordialysisinlevosimendan- picagentsbeyond24haftertheendofstudydruginfusion,ortheneed
treatedpatients(P=0.003)[14].Aconsensuspaperontheoverall ofpostoperativemechanicalassistdevices(IABPorothers),ortheim-
renaleffectsoflevosimendanappearedalsorecentlyintheliterature[45]. possibilitytoweanthepatientsfromcirculatorysupportiftheywereal-
readyinusepreoperatively,ortheneedforrenalreplacementtherapy.
4.5.Effectsoflevosimendanonhepaticfunction Secondaryendpointsincludemortalityatdays28and180,eachitemof
theprimaryendpointseparately,andlengthofICUandhospitalstays.
Liverdysfunctionduetolowcardiacoutputaftercardiacsurgeryisas- Levosimendanisbeingadministeredasa0.1μg/kg/mininfusionfor
sociatedwithpoorprognosis.ArandomisedcontrolledstudybyAlvarez 24handisstartedatthetimeofanaesthesiainduction,without
andcolleaguescomparedtheeffectsofdobutamineandlevosimendan bolusapplication.Thestudypopulationwillinclude340patients.
onhepaticbloodflowinpatientswithlowcardiacoutputaftercardiac Arecentlycompleted(butnotyetpublished)double-blindstudyby
surgery[46].Atotalof25patientswererandomisedtoreceiveeither Argyriadouandco-workerswasaimedatconfirmationofthebenefitsof
levosimendan12μg/kginfusionfor15minfollowedby0.2μg/kg/min preoperativelevosimendaninpatientswithleftventriculardysfunction
infusionfor24h,ordobutamine7.5μg/kg/mininfusionfor24h.Ascom- (LVEF≤40%)routinelyscheduledforCABG(NCT01318460).Thirty-two
paredtodobutamine,levosimendanimprovedsystemicandhepatic patientswererandomisedtoeitherlevosimendan0.1μg/kg/mininfu-
haemodynamics(cardiacindex,portalveinflow,pulsatilityindex)at sionfor24hbeforesurgery,orplacebo.Apreliminaryanalysisofthe
24hand48h.Theyalsonotedthatlevosimendancanbeconsideredas datafavouredlevosimendantreatmenttoasignificantdegree:while
alivervasodilatorthatimproveshepaticbloodflowthroughboththe theplacebogroupshowednosignificantdifferencebetweenpreop-
hepaticarteryandtheportalvenoussystem.Incontrast,dobutamine erativeandpostoperativeLVEF,LVEFincreasedsignificantlyinthe
treatmentonlyaffectedportalvenousbloodflow. levosimendangrouponthe7thpostoperativeday.Moreover,cardi-
acindex,tissueperfusion,andPCWPweresignificantlyimprovedin
4.6.Effectsoflevosimendanonrightheartfunction theexperimentalarm.
InNorthAmerica,arandomised,placebo-controlled,phaseIIIpivotal
Theefficacyoflevosimendaninincreasingrightventricularcontrac- trialinhigh-riskpatientsundergoingCABG(LVEF≤25%)and/ormitral
tilityandreducingrightventricularafterloadhasbeendemonstratedin oraorticvalvesurgery(LVEF≤35%)startedinthethirdquarterof2014
heartfailure,cardiogenicshockrelatedtoacutemyocardialinfarction, (NCT02025621).Atotalof760patientsin50cardiacsurgerycentres
andsepticshock(forreview,seeNieminenetal.[47]).Levosimendan acrossNorthAmericawillreceiveeitherlevosimendan0.2μg/kg/min
alsoprovedtobebeneficialinpatientswithpreoperativerightventric- infusionfor1hfollowedby0.1μg/kg/mininfusionfor23h,orplacebo.
ulardysfunctionwhowereundergoingimplantationofaleftventricular Infusionwillbestartedbeforesurgery.Co-primaryendpointscomprise
assistdevice[48].Similarly,inasmallretrospectivestudy,Theiss death,useofmechanicalassistdevices(IABP,leftventricularassist
andco-workersshowedsuperiortwelve-monthsurvivalcompared device),myocardialinfarction,anddialysis.Secondaryendpointsin-
toINTERMACSregistrydatainpatientswithrightventriculardys- cludepostoperativedurationofstayattheICUorcoronarycareunit,
functiontreatedwithlevosimendanbeforeleftventricularassist andincidenceofLCOS.Thesafetyendpointistheall-causemortality
deviceimplantation[49].Finally,inapilotstudyinpatientswith byday90.
W.Tolleretal./InternationalJournalofCardiology184(2015)323–336 329
Finally,thestudyoflevosimendaninhigh-riskpatientsundergoing Israel,Italy,Russia,Slovenia,Spain,Sweden,Switzerland,theU.K.,and
cardiacsurgery(HSR-LEVO)iscomparinglevosimendantoplaceboon theU.S.A.),allrecognizedspecialistsinthefieldsofcardiothoracican-
mortalityandmorbidityin1000patientsatriskofLCOS,andthisiscur- aesthesiology,cardiothoracicsurgery,cardiology,cardiovascularphar-
rentlyrecruiting(NCT00994825).Aninterimanalysisofthedatais macology,andintensivecaremedicine.Theywereinvitedtojointhe
plannedafterthefirst250patients. panelbythechairmen(WT,MH,FG),onthebasisoftheirexperi-
encewithpreoperativeandperioperativeuseoflevosimendandoc-
7.Compositionofthepanelandmodeofagreementon umentedintheliterature.
therecommendations Afterdiscussingtheavailableevidenceonpreoperativeandintra-
operativeuseoflevosimendan,thepanelfoundthattherationalefor
Thepanellistswere27expertsfrom18countries(Austria,Belgium, preoperativeuseoflevosimendanisprofoundlydifferentfromthat
Croatia,CzechRepublic,Finland,France,Germany,Greece,Hungary, foritsperioperative(orintraoperative)use.Indeed,intraoperatively,
Table1
Studiesonpreoperativeandperioperativeuseoflevosimendan.
FromPubMed.
Firstauthor Title Typeofstudy/comparator Numberof Levosimendandosing/timingof Results
patients dose
On-pumppreoperative
CABG
Tritapepe Levosimendanpre-treatment Randomised,double-blind/vs. 106(2×53) 24μg/kgfor10mininfusion Significantreductionsintracheal
[29] improvesoutcomesinpatients placebo beforetheinitiationofbypass intubationtime,lengthofICUstay
undergoingCABG andnumberofpatientsrequiring
inotropicsupportforN12hwith
levosimendan.Significantlylower
postoperativetroponinI
concentrationsandhighercardiac
index
Levin[30] Preoperativelevosimendan Randomised/vs.placebo 253(127vs. Loadingdose(10μg/kg),23h Levosimendangrouphadalower
decreasesmortalityandthe 125) infusion(0.1μg/kg/min) incidenceofcomplicatedweaning
developmentoflowcardiac fromCPB(2.4%vs.9.6%;Pb0.05),
outputinhigh-riskpatientswith decreasedmortality(3.9%vs.
severeleftventriculardysfunction 12.8%;Pb0.05)andalower
undergoingCABGwith incidenceofLCOS(7.1%vs.20.8%;
cardiopulmonarybypass(EF Pb0.05)comparedwiththe
b25%) controlgroup,lowerrequirement
forinotropes(7.9%vs.58.4%;Pb
0.05),vasopressors(14.2%vs.
45.6%;Pb0.05)andintra-aortic
balloonpumps(6.3%vs.30.4%;Pb
0.05)
Dogan[56] Levosimendanusedecreasesatrial Prospective,randomised/vs. 200(2× Levosimendanstarted6hbefore PostoperativeAFinlevosimendan
fibrillationinpatientsafterCABG: placebo 100) operation.Intheoperatingroom, groupwasreducedinpatients
apilotstudy levosimendancontinuedat24 withpoorleftventriclefunction
μg/kgasaslowdripthroughthe afterCABGoperations.C-reactive
centralvenouscatheterand proteinwashigher
stoppedbeforetheinitiationof postoperativelyinthecontrol
CPB.Duringtherewarmingperiod,
levosimendanwasstartedagain
viathecentralveinwiththesame
dose.
Eris[55] Preoperativeusesoflevosimendan Retrospective/levosimendan 40(4×10) (0.2μg/kg/mininfusion) IncreaseofLVEF;infusionof
inpatientsundergoingCABG infusionapplied12hbefore levosimendan12hbeforesurgery
(LVEFb30%) operation(G1),afterinduction producedlessmyocardialdamage
ofanaesthesia(G2),duringthe
pumpremoval(G3)andnon-LS
control(G4)
CABG+aortic
valve
Leppikangas Preoperativelevosimendan Randomised/vs.placebo 24(2×12) 12μgbolusfor10minfollowedby Highercardiacindexandstroke
[31] infusionincombinedaorticvalve 0.2μg/kg/mininfusionfor24h; volumeindexwithlevosimendan
andcoronarybypasssurgery treatmentwasstartedontheday forthe4-daypostoperativeperiod
beforesurgery (Pb0.05).LVEFmaintained(the
controlgroupshowedadecrease)
On-pumpperioperative
CABG
Lilleberg Effectsoflevosimendanon Randomised,double-blind/vs. 23(8,8,7) Twodoseschedules:8μg/kgor24 Heartrateincreasedsignificantly
[32] haemodynamics,coronaryblood placebo μg/kginfusionsafterCABP afterthehigherdose;cardiac
flow,andmyocardialsubstrateuse outputincreasedsignificantly
earlyafterCABG afterbothdoses,whilesystemic
andpulmonaryvascular
resistancedecreasedsignificantly.
Coronarysinusbloodflow
increasedafterbothdoses.
(continuedonnextpage)
330 W.Tolleretal./InternationalJournalofCardiology184(2015)323–336
Table1(continued)
Firstauthor Title Typeofstudy/comparator Numberof Levosimendandosing/timingof Results
patients dose
Nijhawan Levosimendanenhancescardiac Prospective,randomised, 18(3×6) Twodoseschedules:18(low Placebopatientsexperienced
[57] performanceafter double-blind/vs.placebo dose)or36(highdose)μg/kg significantincreasesinheartrate
cardiopulmonarybypass:a bolusand0.2(lowdose)or0.3 anddecreasesinsystemicvascular
prospective,randomised (highdose)μg/kg/mininfusion. resistance15minafterCPB,aswell
placebo-controlledtrial Administrationstartedbefore aslaterincreasesinmeanarterial
separationfromCPBandwas pressureandcardiacoutputand
continuedfor6hafterCPB. decreasesinstrokevolumeand
pulmonaryvascularresistance.
Heartratewasgreaterinpatients
receivinghigh-dosebutnot
low-doselevosimendanversus
placeboimmediatelyafterCPB.
Meanarterialpressurealsowas
lowerinpatientstreatedwitheither
levosimendandosecomparedwith
placeboafterCPB.Levosimendan
increasedcardiacoutputand
decreasedsystemicvascular
resistance.
Alvarez[58] Hemodynamiceffectsof Randomised/vs.dobutamine 30(2×15) Loadingdose18μg/kgin15–20 Heartrateandcardiacindex
levosimendanfollowingcardiac mininfusionfollowedby24-h increasedinthelevosimendan
surgery infusionof0.2μg/kg/min grouponly(Pb0.05).MAP,
systemicandpulmonaryvascular
resistancedecreasedsignificantlyin
thelevosimendangroup(Pb0.05)
only.
Alvarez[59] Hemodynamiceffectsof Randomised/vs.dobutamine 41(20vs.21) Loadingdose12μg/kginfusion Levosimendanimprovedcardiac
levosimendancomparedwith followedby24-hinfusionof0.2 indexmorethandobutamine(2.4
dobutamineinpatientswithlow μg/kg/min [0.2]vs.2.9[0.3]l/min/m2,
cardiacoutputaftercardiac respectively,at24h;Pb0.05)and
surgery reducessystemicandpulmonary
vascularresistance,decreases
systemicarterial,pulmonary
arterial,pulmonarycapillarywedge,
andcentralvenouspressure
Al-Shawaf Levosimendanormilrinoneinthe Randomised/vsmilrinone50 30(14vs.16) 12μg/kgbolusfor10minfollowed Significantlyhighercardiacindex
[60] type2diabeticpatientwithlow μg/kgfor10minfollowedby0.3 by0.1to0.2μg/kg/mininfusion andmixedvenousoxygen
LVEFundergoingelectivecoronary to0.5μg/kg/mininfusionfor24 for24h saturationwithlevosimendan;
arterysurgery h significantlylowerpulmonary
capillarywedgepressure,systemic
vascularresistanceandoxygen
extractionratios
Akgul[54] Levosimendanforweaningfrom Prospective 15 12–24μg/kgloadingdosefor10 Allpatientsshowedevidenceof
cardiopulmonarybypassafter mininfusionfollowedby0.1–0.2 hemodynamicimprovementwith
CABG μg/kg/mininfusionfor24h thestartofLSinfusion,and93.3%
weresuccessfullyweanedfromCPB.
53.3%experiencedsignificant
increasesincardiacindexandblood
pressure,leadingtoalesseningof
theneedforcatecholaminesupport.
DeHert[28] Theeffectsoflevosimendanin Randomised/vs.milrinone0.5 30(2×15) 0.1mg/kg/mininfusionstarted Strokevolumedeclined12hafter
cardiacsurgerypatientswithpoor mg/kg/mininfusion immediatelyafterthereleaseof surgeryinthemilrinonegroupbut
leftventricularfunction theaorticcrossclamp,continued notintheLSgroup(Pb0.05)
untilweaningfrominotropic despitesimilarfillingpressures.
support. Totaldose,durationofinotropic
drugadministrationand
norepinephrinedosewerelower
withlevosimendan(Pb0.05).The
durationoftrachealintubationwas
shorterwithlevosimendan(P=
0008).Threepatientsinthe
milrinonegroupbutnoneinthe
levosimendangroupdiedwithin30
daysofsurgery.
Levin[33] Levosimendangivessuperior Randomised/s.dobutamine5 137(69vs. 10μg/kgloadingdosefollowedby Improvementofhemodynamic
resultstodobutaminein μg/kg/mininfusion 68) 0.1μg/kg/mininfusionfor24h parameterswasgreaterwith
postoperativelowcardiacoutput levosimendanandoccurredearlier.
syndrome Postoperativemortalitywaslower
(8.7%vs.25%;Pb0.05),aswere
majorpostoperativecomplications.
Theneedforadditionalinotropic
drugtreatment,vasopressor
therapyorballoon
counterpulsationwaslower.
Levosimendan-treatedpatients
experiencedshorterICUstay.
W.Tolleretal./InternationalJournalofCardiology184(2015)323–336 331
Table1(continued)
Firstauthor Title Typeofstudy/comparator Numberof Levosimendandosing/timingof Results
patients dose
Eriksson Levosimendanfacilitatesweaning Prospective,randomised, 60(2×30) 12μg/kgbolusfor10minfollowed Levosimendansignificantly
[27] fromcardiopulmonarybypassin double-blind/vs.placebo by0.2μg/kg/mininfusionfor24h; enhancedprimaryweaningfrom
patientsundergoingCABGwith administrationwasstarted CPBcomparedwithplacebo(P=
impairedleftventricularfunction immediatelyafterinductionof 0.002).Fourpatientsinthe
anaesthesia placebogroupfailedthesecond
weaningandunderwentIABP
comparedwithnoneinthe
levosimendangroup(P=0.112).
Lomivorotov Levosimendanversusintra-aortic Randomised/vs.preoperative 40(2×20) 12μgbolusfor10minfollowedby Significantlylowerlevelsof
[61] balloonpumpinhigh-riskcardiac IABP 0.2μg/kg/mininfusionfor24h; troponinIat6haftersurgerywith
surgery treatmentwasstartedafter levosimendan,significantly
inductionofanaesthesia. shorterintensivecareunitstay
Lomivorotov Levosimendanversusan 90(3×30) Levosimendancaused
[62] intra-aorticballoonpumpin significantlyincreasedcardiac
high-riskcardiacpatients index5minafterCPB,attheend
oftheoperation,and2hand4h
afterperfusion.Significantly
lowerleveloftroponinI6hafter
surgery,significantlyshorterstay
attheintensivecareunit
CABG+valve
Tasouli[63] Efficacyandsafetyof Randomised:duringorafter 45 0.1μg/kgminwithoutloading ICUstayandhospitalstaywere
perioperativeinfusionof open-heartsurgery dosefor24–48h significantlydecreasedwhen
levosimendaninpatientswith levosimendanwasstartedinthe
compromisedcardiacfunction operatingtheatrealreadyrather
undergoingopen-heartsurgery: thanattheICU.
importanceofearlyuse
Lahtinen Levosimendanreducesheart Prospective,randomised/vs. 200(99vs. 24μg/kgbolusover30min Levosimendanledtoareduced
[34] failureaftercardiacsurgery:a placebo 101) followedby0.2μg/kg/mininfusion incidenceofheartfailure,butwas
prospective,randomised, for24h associatedwitharterial
placebo-controlledtrial hypotensionandincreased
requirementofvasopressor
agentspostoperatively.
Järvelä[35] Levosimendaninaorticvalve Prospective,randomised, 24(2×12) 0.2μg/kg/mininfusionfor24h LVEFwasmaintainedwith
surgery:cardiacperformanceand double-blind/vs.placebo beginningaftertheinductionof levosimendanbutdroppedwith
recovery anaesthesia placebo(n.s.).
Jörgensen Effectsoflevosimendanonleft Prospective,randomised, 23(12vs.11) Twodoseschedules:0.1or0.2 Levosimendangaveriseto
[36] ventricularrelaxationandearly blinded/vs.placebo μg/kg/mininfusionfor20min dose-dependentincreasesin
fillingatmaintainedpreloadand afterinitialloadingdosesof12 cardiacoutput(28%;Pb0.001)
afterloadconditionsafteraortic μg/kginfusionfor10min andstrokevolume(26%;Pb
valvereplacementforaortic 0.001)aswellasdecreasesin
stenosis systemicvascularresistance
(−22%;Pb0.001).Trendforan
increaseinLVEF.Decreasesin
isovolumicrelaxationtimeand
decelerationslopeofearly
diastolicfilling;increasedpeak
earlydiastolicfillingvelocity
andpeaklatediastolicfilling
velocity
CABG+mitral
Severi[37] Levosimendanversusintra-aortic Case-matched/vs.preoperative 22(2×11) 0.1μg/kg/mininfusionfor24h ShorterdurationofICUstay
balloonpumpinhigh-riskcardiac IABP withlevosimendan(2.5vs.5
surgerypatients days;P=0.01)
Mitral
Gandham Acomparisonofhemodynamic Randomised/vs.dobutamine5 60(2×30) 0.1μg/kg/mininfusionwhile Increasedvasodilationandlesser
[38] effectsoflevosimendanand μg/kg/mininfusion weaningoffCPB inotropicactivitywith
dobutamineinpatients levosimendan,statistically
undergoingmitralvalve significantincreaseincardiac
repair/replacementforsevere indexevenafter12hof
mitralstenosis discontinuation.Increased
requirementofinotropesand
vasoconstrictors
Off-pump
Barisin[39] Levosimendaninoff-pump Randomised,four-times 31(11,10, Twodoseschedules:lowdose(12 Significantincreasesincardiac
coronaryarterybypass:a masked/vs.placebo 10) μg/kg),highdose(24μg/kg)over outputandLVEFoccurredafter
four-timesmaskedcontrolled 10min;treatmentwasgiven20 high-dose(Pb0.001;P=0.006)
study minbeforestartofsurgery andlow-doselevosimendan(P=
0.001;P=0.002).Both
levosimendandosesproduced
significantincreasedstroke
volumeanddecreasedsystemic
vascularresistance.
(continuedonnextpage)
332 W.Tolleretal./InternationalJournalofCardiology184(2015)323–336
Table1(continued)
Firstauthor Title Typeofstudy/comparator Numberof Levosimendandosing/timingof Results
patients dose
Husedzinović Levosimendanasanewstrategy Randomised,double-blind/vs. 24(2×12) 12μg/kgbolusfor15minbefore CardiacindexandLVEFwere
[40] duringoff-pumpCABG: placebo surgery significantlyhigher10minand60
double-blindrandomised min(P=0.018forall)after
placebo-controlledtrial levosimendanadministration.After
60min,cardiacindexincreased
from2.18to2.84l/min/m2.Stroke
volumeindexwassignificantly
higherat10min(P=0.018),but
notat60min(P=0.063).
Kodalli[41] Effectoflevosimendanon Randomised/vs.placebo 30(2×15) 0.1μg/kg/mininfusionduring Significantincreaseofcardiac
hemodynamicchangesinpatients surgery indexandsignificantdecreaseof
undergoingoff-pumpCABG:a vascularresistanceindexwith
randomisedcontrolledstudy levosimendanat6,12,18and24
haftersurgery.Nooutcome
benefitintermsofdurationof
ventilationorICUstay
Shah[42] Levosimendanduringoff-pump Randomiseddouble-blind/vs. 50(2×25) 200μg/kginfusionin24h Levosimendanincreasedcardiac
CABGinpatientswithLV placebo indexduringoperativeandearly
dysfunction operativeperiod.
Levosimendan-treatedpatients
hadlessrequirementfor
inotropes,IABP,CPN,ICUstayand
hospitalstay.
Mainlydescribingrenalfunction
Ristikankare Effectsoflevosimendanonrenal Prospective,randomised, 60(2×30) 12μg/kgbolusfor10minfollowed Nosignificantchangesinplasma
[64] functioninpatientsundergoing double-blindsubstudy/vs. by0.2μg/kg/mininfusionforthe creatinine,serumcystatinC,and
coronaryarterysurgery placebo next23hand50min urineNAGatanyofthemeasuring
points
Bragadottir Effectsoflevosimendanon Prospective,randomised/vs. 30(2×15) 0.1μg/kg/mininfusionfor1hafter Increasesincardiacindex(22%),
[43] glomerularfiltrationrate,renal placebo aloadingdoseof12μg/kg strokevolumeindex(15%)and
bloodflow,andrenaloxygenation heartrate(7%)with
aftercardiacsurgerywith levosimendanoverplacebo,
cardiopulmonarybypass:a decreasedsystemicvascular
randomisedplacebo-controlled resistanceindex(21%).Significant
study increasesinrenalbloodflow(12%,
Pb0.05)andglomerularfiltration
rate(21%,Pb0.05),decreasedrenal
vascularresistance(18%,Pb0.05).
Baysal[44] Levosimendanimprovesrenal Randomised/vs.placeboontop 280(2×64) Loadingdose(6μg/kg)afterremoval Valvesurgeryimproved
outcomeincardiacsurgery:a ofstandardinotropictherapy aorticcross-clamp,24hinfusion immediatepostoperativerenal
randomisedtrial (0.1μg/kg/min)inadditionto function(eGFR)andreducedneed
standardinotropictherapy forrenalreplacementtherapy.
Mainlydescribingliverfunction
Alvarez[46] Acomparisonofdobutamineand Randomised/vs.dobutamine7.5 25 Levosimendan(12μg/kginfusion) Thesystemicandhepatic
levosimendanonhepaticblood μg/kg/mininfusionfor24h over15min+infusionof0.2 haemodynamicsat24hand48h
flowinpatientswithalowcardiac μg/kg/minfor24h wereallbetterafterlevosimendan
outputstateaftercardiacsurgery: thandobutamine.Levosimendan
arandomisedcontrolledstudy isselectivelivervasodilatorand
improveshepaticbloodflow
throughboththehepaticartery
andportalvenoussystem.
Mainlydescribingrightheartfunction
Sponga[48] Preoperativetreatmentwith Consecutive 21 Levosimendan0.1to0.2 Levosimendanimproves
levosimendanincandidatesfor mg/kg/mininfusionfora preoperativehemodynamic
mechanicalcirculatorysupport maximumof48hwithoutbolus conditionsinLVADcandidates
withborderlinerightventricular
function.
Labriola[50] Haemodynamiceffectsof Consecutive 11 Levosimendan12μg/kgover10 Levosimendanimprovescardiac
levosimendaninpatientswith min,followedbyacontinuous index,andreducesPCWP,mean
low-outputheartfailureafter infusionof0.1μg/kg/minfor12h pulmonaryarterypressureand
cardiacsurgery rightarterialpressure.
Theiss[49] Preconditioningwith Retrospective,consecutive 9 Levosimendancontinuous Levosimendanimprovedclinical
levosimendanbeforeimplantation infusionof0.1μg/kg/minfor24h outcomeandsurvivalwhenused
ofleftventricularassistdevices aspretreatmentinpatientswith
rightheartinsufficiencypriorto
LVADimplantation.
levosimendan is primarily used for its inodilatory effects, which cardioprotectivepropertiesthatcomeintoeffectlaterduringthein-
canbeachievedwithoutanynegativeimpactonmyocardialoxygen traoperativeperiod.
balance.Incontrast,inthepreoperativesetting,levosimendanis Forthesakeofclarity,thepaneldecidedtodiscussthesetwoappli-
used also in an attempt to provide patient benefit through its cationsoflevosimendanseparately.Thepanelrecognizedthattheuseof