the use of vasoactive drugs in the icu - armand vasoactive drugs 2007.pdf · the use of vasoactive...

The use of The use of vasoactivevasoactive drugs drugs in the ICUin the ICU

Prof. dr. Armand R.J. GirbesProf. dr. Armand R.J. GirbesIntensivist / Clinical PharmacologistIntensivist / Clinical Pharmacologist

Chairman department of Intensive CareChairman department of Intensive CareUniversity Hospital VUmcUniversity Hospital VUmc

Amsterdam, NLAmsterdam, NLwww.ArmandGirbes.comwww.ArmandGirbes.com

UseUse of of vasoactivevasoactive drugsdrugsNextNext 25 25 minutesminutes

•• General General remarksremarks•• ““OldOld”” vasoactivevasoactive drugsdrugs•• Focus Focus onon norepinephrinenorepinephrine•• Focus Focus onon brainbrain injuredinjured patientpatient•• ““NewNew”” vasoactivevasoactive drugsdrugs

–– LevosimendanLevosimendan–– AVPAVP–– TerlipressinTerlipressin

•• ConclusionsConclusions

HemodynamicsHemodynamics

•• Goals of hemodynamic therapyGoals of hemodynamic therapy

–– maintain sufficient maintain sufficient FLOWFLOW•• (oxygen rich blood)(oxygen rich blood)

–– maintain sufficient maintain sufficient PERFUSION PRESSUREPERFUSION PRESSURE

•• Continuous measurementsContinuous measurements•• Instantaneous action whenever necessaryInstantaneous action whenever necessary

HemodynamicsHemodynamicsIn the ICUIn the ICU

•• Assessment of preloadAssessment of preload•• Assess circulatory sufficiencyAssess circulatory sufficiency

–– not not ““highhigh””, not , not ““lowlow”” but but ““sufficientsufficient””

•• Target for Target for ““optimal preloadoptimal preload””–– DefDef**.: further increase of preload will not increase SV.: further increase of preload will not increase SV

•• Use of Use of vasoactivevasoactive drugsdrugs

* Girbes ARJ, Groeneveld ABJ. Clinical Intensive Care. 2000; 11:77-88


•• Physiological cardiac reservePhysiological cardiac reserve

Stro

ke v

olum

eSt

roke

vol

ume

LV End LV End DDiastiast VolumeVolume


Indication for fluid administrationIndication for fluid administration

Effect fluid administrationEffect fluid administration


•• Indices of "fluid responsiveness"Indices of "fluid responsiveness"–– In mechanically ventilated patientsIn mechanically ventilated patients–– Fluid administrationFluid administration

•• Favorable in steep partFavorable in steep part•• Unfavorable in flat partUnfavorable in flat part

HemodynamicsHemodynamicsHypovolemiaHypovolemia

•• Suspicion of Suspicion of hypovolemiahypovolemia–– NOT one single parameterNOT one single parameter

•• BP, HR, circulatory indices BP, HR, circulatory indices –– diuresis / physical examdiuresis / physical exam•• CVP (curve), [PAOP, CO / SV]CVP (curve), [PAOP, CO / SV]•• Arterial curveArterial curve

–– Signs of poor peripheral perfusion: lactate, SvOSigns of poor peripheral perfusion: lactate, SvO22

•• Effect of fluid administration Effect of fluid administration •• BP, HR, etcBP, HR, etc•• CVP (curve), [PAOP, CO / SV]CVP (curve), [PAOP, CO / SV]•• ArterialeArteriale curvecurve

–– Signs of peripheral perfusion, lactate, SvOSigns of peripheral perfusion, lactate, SvO22

HemodynamicsHemodynamicsVigilance Vigilance armarmééee & & permanentepermanente

•• Properties of heart change continuouslyProperties of heart change continuously–– Compliance (Compliance ( Starling curve)Starling curve)–– ContractilityContractility

•• Changing vascular bedChanging vascular bed•• Effects of mechanical ventilationEffects of mechanical ventilation•• Effects of changing body temperatureEffects of changing body temperature•• Fluid lossFluid loss

–– Diuresis Diuresis –– transpiration/ perspirationtranspiration/ perspiration–– AscitesAscites –– pleural fluidpleural fluid–– Capillary leakageCapillary leakage


•• Measure response on therapyMeasure response on therapy(fluid challenge)(fluid challenge)

–– Bedside!!!!Bedside!!!!–– Important role physician & ICU nurseImportant role physician & ICU nurse

HemodynamicsHemodynamicsVigilance Vigilance armarmééee & & permanentepermanente

•• Target: CVP 18 mm HgTarget: CVP 18 mm Hg

WRONGWRONG


Simple predictors of fluid responsiveness Simple predictors of fluid responsiveness bedsidebedside

•• Leg tilt Leg tilt -- effect on RR / HR / CVP / CO / SVeffect on RR / HR / CVP / CO / SV•• Systolic pressure variationSystolic pressure variation•• Pulse pressure variationPulse pressure variation

HemodynamicsHemodynamicsPulsePressurePulsePressure variationvariation

Michard et al. AJRCCM, 2000

Fluid resuscitation policyFluid resuscitation policy

•• PulsepressurePulsepressure variationvariation–– n=40 circulatory failure (in sepsis)n=40 circulatory failure (in sepsis)–– Response on 500 cc colloidResponse on 500 cc colloid

–– DistinguishDistinguish•• Responder = increase CI > 15%Responder = increase CI > 15%•• NonNon--responderresponder



•• PulsePulse--pressure variation (deltapressure variation (delta--PP)PP)–– DeltaDelta--PP (PPV) = PP max PP (PPV) = PP max –– PP min / PP meanPP min / PP mean

in %in %

–– PPV PPV ≥≥ 13% distinguishes (non13% distinguishes (non--) responders) responders•• Sensitivity 94%Sensitivity 94%•• Specificity 96%Specificity 96%



•• What if fluids are not enough?What if fluids are not enough?Problem brainProblem brainProblem heart Problem heart

post post resucitationresucitationpost coronary interventionpost coronary interventionpost cardiac surgerypost cardiac surgery

Problem kidney perfusionProblem kidney perfusionother? e.g. other? e.g. vasoplegiavasoplegia / sepsis / SIRS/ etc./ sepsis / SIRS/ etc.

Girbes ARJ. Resuscitation. 2000 Dec 13; 47(3): 339-342.


•• The organs needThe organs need–– flowflow–– perfusion pressureperfusion pressure

RelationRelation pressurepressure--perfusionperfusion

SpaanSpaan JAE, 1990JAE, 1990


•• Use of Use of inotropesinotropesDA1 DA2 alpha1 alpha2 bèta1 bèta2

Dobutamine 0 0 0-1* 0 2 1Dopamine 2 1 1-2* 0-1 1-2* 0-1*

Dopexamine 1 0-1 0 0 0-1 2Noradrenaline 0 0 2 1-2 1-2 1Adrenaline 0 0 2 1-2 1-2 2Isoprenaline 0 0 0-1* 0-1* 2 1Fenoldopam 2 0 0# 0 0 0


•• Use of Use of inotropesinotropes

–– Make the appropriate (hemodynamic) diagnosisMake the appropriate (hemodynamic) diagnosis–– Use what you needUse what you need

•• NB previous NB previous betablockerbetablocker use! PDEuse! PDE

–– And good is good enoughAnd good is good enough•• If good is good, more is not necessarily betterIf good is good, more is not necessarily better•• ““SupraSupra--normal goalsnormal goals”” -- obsoleteobsolete

HemodynamicsHemodynamicsVasoVaso--active drugsactive drugs

•• My personal experience:My personal experience:Norepinephrine allergic syndromeNorepinephrine allergic syndrome

–– specific effects of norepinephrine in the ICUspecific effects of norepinephrine in the ICU•• substantial increase in heart rate + BPsubstantial increase in heart rate + BP•• rise in temperaturerise in temperature•• aggressive behavioraggressive behavior•• rare cases: fighting behaviorrare cases: fighting behavior•• strangely: not in patientsstrangely: not in patients

Metabolic effectsMetabolic effectsVasoVaso--active drugsactive drugs

•• Norepinephrine allergic syndromeNorepinephrine allergic syndrome–– Epidemiology by experienceEpidemiology by experience

•• Dutch (cardiothoracicDutch (cardiothoracic--) surgeons) surgeons•• Dutch CardiologistsDutch Cardiologists

case of case of norepinephrinonorepinephrino--phobiaphobia

But: decreasing incidenceBut: decreasing incidence

The injured brain & The injured brain & HemodynamicsHemodynamicsNorepinephrineNorepinephrine

•• Norepinephrine is bad for the heartNorepinephrine is bad for the heart–– Deleterious effects on aerobic metabolismDeleterious effects on aerobic metabolism

•• Increases BPIncreases BP•• Increases Systemic Vascular ResistanceIncreases Systemic Vascular Resistance•• Induces vasoconstrictionInduces vasoconstriction•• Induces coronary vasoconstrictionInduces coronary vasoconstriction•• Induces ischemiaInduces ischemia

–– Is it this simple?Is it this simple?

The injured brain & The injured brain & HemodynamicsHemodynamicsnorepinephrinenorepinephrine

•• NorepinephrineNorepinephrine–– potent peripheral vasoconstrictor potent peripheral vasoconstrictor –– widely used in the ICUwidely used in the ICU

•• vasoplegicvasoplegic shockshock•• during cardiac shock ?!@during cardiac shock ?!@

–– restores perfusion pressurerestores perfusion pressure

–– e.g. can improve brain perfusion, renal functione.g. can improve brain perfusion, renal function

HemodynamicsHemodynamicsNNorepinephrine and the Heartorepinephrine and the Heart

•• Norepinephrine Norepinephrine –– cardiac effectscardiac effects–– induces coronary vasodilationinduces coronary vasodilation–– improves coronary circulationimproves coronary circulation–– improves oxygen deliveryimproves oxygen delivery–– improves improves endocardialendocardial oxygen deliveryoxygen delivery–– reduces infarct sizereduces infarct size

Sun et al. July 2002, CirculationSun et al. July 2002, CirculationHoffman & Hoffman & SpaanSpaan, 1990, 1990

Coronary Circulation and Coronary Circulation and NoradrenalineNoradrenaline

•• Effect of Effect of noradrenalinenoradrenaline on human coronary arterioleson human coronary arteriolesSun et al., Circulation, July 2002Sun et al., Circulation, July 2002

ProPro--ContraContra

•• NorepinephrineNorepinephrine–– TextbookTextbook

ProPro--ContraContra

•• TextbookTextbook GoodmanGoodman & Gilman& Gilman

NorepinephrineNorepinephrineEffectsEffects onon coronarycoronary bloodblood flowflow

VasoactiveVasoactive drugsdrugs

•• AnyAny newsnews? ?

My My selectionselection–– LevosimendanLevosimendan–– AVPAVP–– TerlipressinTerlipressin

LevosimendanLevosimendan

•• Hits: n=365Hits: n=365

–– Reviews:Reviews: 9292–– Human: Human: 250250–– RCT:RCT: 4141–– RCT + ICRCT + IC 22

InotropesInotropes

•• BackgroundBackground–– All positive inotropic drugs All positive inotropic drugs

detrimental effect longdetrimental effect long--term treatmentterm treatment–– PDE III inhibitorsPDE III inhibitors

high incidence of treatment related complicationshigh incidence of treatment related complicationsin shortin short--term treatment (AF, hypotension)term treatment (AF, hypotension)

InotropesInotropes

•• Side effectsSide effectsall drugs increase all drugs increase cAMPcAMPincrease intracellular increase intracellular cytosolcytosol Ca++Ca++

< < sarcoplasmicsarcoplasmic reticulumreticulum

•• New developmentsNew developments–– New approach to positive inotropic therapyNew approach to positive inotropic therapy

InotropesInotropes

•• New class New class –– new promisesnew promises–– Calcium sensitizerCalcium sensitizer

•• SensitisesSensitises troponintroponin C to CaC to Ca++++

increases effects of Caincreases effects of Ca++++

•• Increase cardiac contractilityIncrease cardiac contractility•• No increase in mvONo increase in mvO22

•• No No proarrhythmicproarrhythmic effectseffects


•• FavourableFavourable propertiesproperties–– Improves Improves hemodynamicshemodynamics

•• Improves cardiac performanceImproves cardiac performance–– SV increases, PAOP decreasesSV increases, PAOP decreases–– Not associated with increased myocardial Oxygen consumptionNot associated with increased myocardial Oxygen consumption–– Not Not dysrythmogenicdysrythmogenic–– Does not impair diastolic function (relaxation)Does not impair diastolic function (relaxation)

•• Induces vasodilationInduces vasodilation–– Coronary, pulmonary, renal, splanchnic, cerebral, systemic arterCoronary, pulmonary, renal, splanchnic, cerebral, systemic arteriesies–– Portal vein, systemic veinsPortal vein, systemic veins


•• RCT RCT –– double blind, placebo controlleddouble blind, placebo controlled•• CHF NYHA IIICHF NYHA III--IVIV

–– PCWP > 15 mm HgPCWP > 15 mm Hg–– CI < 2.5 L/min/mCI < 2.5 L/min/m22

•• N=146N=146•• Levosimendan infusion (0.1Levosimendan infusion (0.1--0.4 mcg/kg/min)0.4 mcg/kg/min)

–– Titrated in 4 hour infusionTitrated in 4 hour infusion

LevosimendanLevosimendanIntensive CareIntensive Care

•• Sepsis Sepsis studystudy–– Levosimendan Levosimendan vsvs dobutamine (5 dobutamine (5 mcgmcg/kg/min) /kg/min) –– 24 24 hrhr infusioninfusion–– PatientsPatients withwith sepsis sepsis relatedrelated LVD n=28LVD n=28–– EndpointsEndpoints: :

•• HemodynamicsHemodynamics•• EchocardiographyEchocardiography•• GastricGastric tonometrytonometry•• LactateLactate


•• ResultsResults


•• ConclusionsConclusions


•• ARDS ARDS studystudy–– Levosimendan Levosimendan vsvs placebo (0.2 placebo (0.2 mcgmcg/kg/min)/kg/min)–– PatientsPatients withwith sepsis sepsis relatedrelated ARDS (n=35)ARDS (n=35)–– EndpointsEndpoints

•• HemodynamicsHemodynamics

–– ResultsResults•• ImprovementImprovement of RV performanceof RV performance


•• ConclusionsConclusions & & expectationsexpectations–– New New classclass of drugsof drugs–– May May improveimprove hemodynamicshemodynamics

•• PromisedPromised ((lacklack of) effect of) effect onon HR HR notnot provenproven

–– AdditionalAdditional valuevalue unclearunclear•• Studies Studies onon lowlow dosedose dobutaminedobutamine•• No studies No studies comparingcomparing PDIPDI•• PatientsPatients whowho benefit benefit notnot defineddefined

–– NotNot registratedregistrated in most in most countriescountries outsideoutsideScandinavianScandinavian countriescountries

–– In In AHFAHF: effect : effect onon mortalitymortality unknownunknown–– New trials New trials underwayunderway

VasopressinVasopressin

•• Potent Potent endogenousendogenous vasopressorvasopressor hormonehormone–– Most studies in ICU Most studies in ICU patientspatients –– allall categoriescategories

•• DecreaseDecrease needneed forfor NENE•• HR HR ↓↓ MAP MAP ↑↑ SV SV ↑↑ CO CO ↓↓

AdditionalAdditional valuevalue: : unclearunclear

RefRef: : DDüünsernser 2003 2003 CirculationCirculation/2002 /2002 ICMICM; ; LuchnerLuchner CCM 2005; CCM 2005; LauzierLauzier ICM 2006ICM 2006

EffectsEffects of AVP of AVP LucknerLuckner et al. CCM 2005et al. CCM 2005

SS=Septic Shock (n=103); PS=Postcardiotomy Shock (n=135); SIRS (n=78)

EffectsEffects of of TerlipressinTerlipressin

•• SyntheticSynthetic AVP AVP analogueanalogue•• VasoconstrictiveVasoconstrictive effectseffects

–– LowersLowers HRHR–– DecreasesDecreases COCO–– DecreaseDecrease needneed forfor NENE

•• Concern: effect Concern: effect onon intestinalintestinal ((mucosalmucosal) ) perfusionperfusion

•• AdditionalAdditional valuevalue: : unclearunclear


•• FinalFinal word word onon the the injuredinjured brainbrain–– TraumaTrauma–– PosthypoxicPosthypoxic–– Post SABPost SAB

The injured brain & The injured brain & HemodynamicsHemodynamics

•• Normal brainNormal brain–– Well developed Well developed autoregulationautoregulation

•• Maintenance of constant flow at different levels Maintenance of constant flow at different levels of perfusion pressureof perfusion pressure

•• Injured brainInjured brain–– More or less disturbed More or less disturbed autoregulationautoregulation

Flow

Perfusion pressure

The injured brain & The injured brain & HemodynamicsHemodynamics

•• The brainThe brain–– Does not forgive !! (like other organs)Does not forgive !! (like other organs)–– The mean or median does not count!!The mean or median does not count!!

•• If you do 10 weeks perfectly, but 5 minutes not,If you do 10 weeks perfectly, but 5 minutes not,only the 5 minutes will countonly the 5 minutes will count

•• Only a winner when you win all & always!!Only a winner when you win all & always!!

Use of Use of vasoactivevasoactive drugsdrugs

•• ConclusionsConclusions–– Make a hemodynamic diagnosisMake a hemodynamic diagnosis–– Maintain perfusion pressure AND flowMaintain perfusion pressure AND flow–– Sufficient is enough. Sufficient is enough. ““Better is the enemy of goodBetter is the enemy of good””–– Very Very veryvery close observation of close observation of hemodynamicshemodynamics–– Optimal preloadOptimal preload

•• PPV and other indicesPPV and other indices–– VasoVaso--actives based on hemodynamic profileactives based on hemodynamic profile

•• norepinephrine is not bad for the heartnorepinephrine is not bad for the heart

Thank you!Thank you!

Presentation available at:Presentation available at:

www.ArmandGirbes.comwww.ArmandGirbes.com(after the congress)(after the congress)

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