dopamine dobutamine milrinone.pdf - Jacobi Medical Center

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Reassessment of Dobutamine, Dopamine, and Milrinone in the
Management of Acute Heart Failure Syndromes
Melike Bayram, MD,a Leonardo De Luca, MD,b M. Barry Massie, MD,c and
Mihai Gheorghiade, MDd,*
The appropriate role of intravenous inodilator therapy (inotropic agents with vaso-
dilator properties) in the management of acute heart failure syndromes (AHFS) has
longbeenasubjectofcontroversy,mainlybecauseofthelackofprospective,placebo-
controlledtrialsandalackofalternativetherapies.Theuseofintravenousinodilator
infusions,however,remainscommon,buthighlyvariable.Asnewoptionsemergefor
the treatment of AHFS, the available information should be reviewed to determine
which approaches are supported by evidence, which are used empirically without
evidence, and which should be considered inappropriate. For these purposes, we
reviewed data available from randomized controlled trials on short-term, intermit-
tent,andlong-termuseofintravenousinodilatoragents(dobutamine,dopamine,and
milrinone) in AHFS. Randomized controlled trials failed to show benefits with
current medications and suggested that acute, intermittent, or continuous use of
inodilator infusions may increase morbidity and mortality in patients with AHFS.
Their use should be restricted to patients who are hypotensive as a result of low
cardiac output despite a high left ventricular filling pressure. © 2005 Elsevier Inc.
All rights reserved. (Am J Cardiol 2005;96[suppl]:47G–58G)
Acute heart failure syndromes (AHFS) resulting in hospi- thatmayadverselyaffectpostdischargemorbidityandmor-
talization represent a major public health problem because tality.
of the high numbers of patients (1 million in the United Randomized controlled trials failed to show a benefit
States),postdischargemortalityandreadmissionrates(10% with the acute,4 intermittent,5 or continuous6 use of inodi-
and25%at60days,respectively),andsignificantassociated lators in patients with heart failure (HF). Despite these
costs ($27.9 billion per year).1 Most patients with AHFS negative results, dobutamine, dopamine, and milrinone are
presenttotheemergencyroomwitharelativelyhighblood often given to improve cardiac performance and to relieve
pressureandsystemiccongestionwithoutsignsofsystemic congestive symptoms of AHFS, even in patients with nor-
hypoperfusion (normal cardiac output). In addition, based malbloodpressureandrelativelypreservedcardiacoutput.
on the Acute Decompensated Heart Failure National Reg-
istry(ADHERE),almost50%ofthepatientsadmittedwith
AHFS had a relatively preserved systolic function (PSF).2 Use of Inodilator Therapy in Acute Heart Failure
These patients had a higher incidence of hypertension, left Syndromes Registries
ventricularhypertrophy,anddiabetesmellitusthanpatients
admitted with AHFS and systolic dysfunction.3 The ADHERE database was designed to study prospec-
HowwemanageAHFSisimportantbecauseselectionof tively the outcomes, characteristics, and management of
therapeutic agents, which are used for only days or hours, AHFS. In this registry, which currently comprises
may influence long-term mortality and morbidity. The ini- (cid:1)150,000 patients, (cid:2)3% presented with a systolic blood
tial therapy for patients with AHFS should improve symp- pressureof(cid:2)90mmHgandapproximately50%presented
tomsandhemodynamicswithoutcausingmyocardialinjury with relative PSF.3 Approximately 14% of the patients in
ADHERE were treated with (cid:1)1 acute infusions of inodila-
tor agents (dobutamine 6%, dopamine 6%, and milrinone
aDepartmentofMedicineResidencyTrainingProgram,Universityof 3%) in the hospital.7 Furthermore, among home discharges
Michigan,AnnArbor,Michigan,USA;bDepartmentofCardiovascularand
ofpatientswithapriorhistoryofHFduringthisperiod,1%
Respiratory Sciences, La Sapienza University, Rome, Italy; cSection of
weredischargedonchronicdobutamine,and1%onchronic
Cardiology,SanFranciscoVeteransAffairsMedicalCenterandSchoolof
Medicine,UniversityofCalifornia,SanFrancisco,SanFrancisco,Califor- milrinone infusion therapy.2
nia, USA; and dNorthwestern University Feinberg School of Medicine, Importantly, 15% of patients receiving inodilators had
Chicago,Illinois,USA. PSF.8Theinodilator-treatedpatientswithPSFhadahigher
*Addressforreprints:MihaiGheorghiade,MD,DivisionofCardiol-
mortality rate (19%) than all other inodilator-treated pa-
ogy,NorthwesternUniversityFeinbergSchoolofMedicine,Galter10-240,
tients (14%).8 Patients with PSF who were treated with
201EastHuronStreet,Chicago,Illinois60611.
E-mailaddress:[email protected]. inodilators also had a higher mortality rate than patients
0002-9149/05/$–seefrontmatter©2005ElsevierInc.Allrightsreserved. www.AJConline.org
doi:10.1016/j.amjcard.2005.07.021
48G TheAmericanJournalofCardiology(www.AJConline.org) Vol96(6A) September19,2005
withPSFwhowerenottreatedwithinodilators(19%vs2%, gest that (cid:1)50% of patients with chronic HF and coronary
respectively).8 Among the inodilator-treated patients, those artery disease (CAD) have hibernating myocardium, an
with PSF also had a longer hospital stay compared with all adaptive response to a sustained reduction in coronary va-
other inodilator-treated patients (mean, 12.9 vs 9.6 days).8 sodilator reserve in which the level of tissue perfusion is
Although these results may be confounded by unmeasured sufficienttomaintaincellularviabilitybutnotsufficientfor
differences in the patients and treatment settings in which normalcontractilefunction.15,16Thisprecariousbalancebe-
inodilatortreatmentswereused,theydoraisethepossibility tween perfusion and tissue viability, however, is not sus-
that these agents may be harmful, especially when used in tainedindefinitelyandwillprogresstomyocardialnecrosis
patients who are not appropriate for this therapy. unlessthebloodflowincreases.15,17–26Areasofhibernating
Recently, in a retrospective observational analysis of myocardium or contractile reserve may be adversely af-
ADHERE, Abraham and coworkers9 compared in-hospital fected by inodilator agents. In fact, inodilators may cause
mortality in a subset of 65,180 patients, 15,230 of whom worsening of ischemia by increasing myocardial oxygen
were receiving either intravenous vasodilator therapy (ni- demand through increased contractility and induction of
troglycerin or nesiritide) or inodilator therapy (dobutamine tachycardia. Schulz et al24 found that experimentally in-
or milrinone). Short-term vasodilator therapy was associ- creasing the contractility of hibernating myocardium by
ated with significantly lower in-hospital mortality than was using relatively low doses of an inodilator, such as dobut-
positive inodilator therapy in patients hospitalized with amine, for short periods can lead to myocardial necrosis.
AHFS. Unadjusted in-hospital mortality varied widely, Regardless of whether the myocytes are hibernating be-
rangingfrom4.1%fortheentirecohorttoasmuchas14% cause of CAD or are alive but not contracting for other
for patients who received inodilators.9,10 reasons, as is the case in idiopathic cardiomyopathy, stim-
The Organized Program to Initiate Life-Saving Treat- ulation of these cells with an inodilator may result in cell
ment in Hospitalized Patients with Heart Failure (OPTI- death through necrosis or apoptosis, thereby further reduc-
MIZE-HF) study has been designed to improve medical ing contractility, creating a vicious cycle. For this reason,
care and education of hospitalized patients with HF.11 patients treated with inodilators may improve clinically in
Amongtheapproximately50,000patientswithHFenrolled the short term but may become more dependent on the use
to date, 4% received dobutamine, 4% received dopamine, of inodilators. Thus, despite the apparent clinical improve-
and 1% received milrinone during hospitalization.12 ment, there may be progression of HF in these patients.
In a recent OPTIMIZE-HF subanalysis investigating the
relationbetweenadmissionsystolicbloodpressureandout-
comes in hospitalized patients with HF, inodilators were
Mechanisms of Action and Effects of Inodilators
used in 5.5% of patients with and without hypertension
(admission systolic blood pressure between 119 and 200
Themostcommonlyusedinodilatoragentsworkthrougha
mm Hg), compared with 18.5% of those with relative hy-
common pathway of increased intracellular cyclic adeno-
potension(admissionsystolicbloodpressure(cid:2)119mmHg)
sine monophosphate (cAMP) and calcium concentrations.
(M. Gheorghiade et al, unpublished data, 2005).
These include (cid:2)-adrenergic agonists, endogenous cat-
echolamines, and phosphodiesterase inhibitors.
In Myocardial Viability Dobutamine—(cid:1)-adrenergic agonists:Dobutamine is a
racemic mixture that stimulates (cid:2)- and (cid:2)-receptors. The
1 2
HF often results in myocyte hypertrophy and/or myocyte negative enantiomer is also an agonist for (cid:2)-receptors,
1
apoptosisornecrosis.However,inHF,asignificantnumber whereasthepositiveenantiomerisaveryweakpartialagonist.
of patients with both ischemic and nonischemic cardiomy- Through its action on (cid:2)-receptors, dobutamine activates a
1
opathy and reduced systolic function have viable but non- guanine nucleotide regulatory cascade (via G proteins). This
contractile myocardium. This condition can occur for a leads to increased adenylate cyclase activity and increased
varietyofreasons,includingexcessiveandcontinuousneu- conversionofadenosinetriphosphate(ATP)totheintracellular
rohormonal stimulation, hemodynamic abnormalities, and second messenger cAMP. Intracellular cAMP causes release
chronic ischemia. The decrease in cardiac contractility that of calcium from the sarcoplasmic reticulum. The calcium is
occurs in HF has been hypothesized to be an important used by contractile proteins and results in increased stroke
compensatory mechanism that decreases energy use by the volume.27Inthevasculature,the(cid:3)-adrenergicagonisteffectof
failing myocardium and thereby improves long-term sur- the negative enantiomer appears to be counteracted by the
vival of cardiac myocytes.13 It has been suggested that partialagonismofthepositiveenantiomerandthevasodilatory
although augmentation of contractility by various drugs action caused by (cid:2)-receptor stimulation. This usually results
2
producesatemporaryimprovementincardiacperformance, in a modest decrease in systemic vascular resistances and
itmaydosoattheexpenseofincreasingmyocardialenergy venousfillingpressures.27
consumption and accelerating myocardial cell death.14 The rate of infusion doses of dobutamine needed to
Recentstudiesusingpositronemissiontomographysug- increasecardiacoutputusuallyrangesfrom2.5to15(cid:4)g/kg
Bayrametal/ReassessmentofDobutamine,Dopamine,andMilrinoneintheManagementofAHFS 49G
permin.Onsetofactioniswithin1to2minutes,butitmay plained tachycardia or arrhythmia in a patient receiving
take as long as 10 minutes to see the peak effect of a “low-dose” dopamine should make a clinician suspect an
particularinfusionrate.Theplasmahalf-lifeofdobutamine inaccurate estimation of lean body weight resulting in an
is 2 minutes. In studies with infusion periods (cid:1)24 to 72 inappropriately high dopamine infusion rate.27 The effects
hours, cardiac output was noted to return toward baseline of dopamine on cardiac function and energy metabolism
values in some study subjects, raising the concern of phar- have been compared with those of bucladesine.34 In this
macologic tolerance with prolonged infusion. setting, dopamine enhanced anaerobic metabolism at both
The overall effect of dobutamine on blood pressure is doses,withaconcomitantdecreaseinsystolicpressureand
variable, depending on the relative effects on the vascular coronary flow.
tone and cardiac output achieved. Heart rate is often de-
Milrinone—phosphodiesterase inhibitors:Phosphodi-
creasedbecauseofreflexwithdrawalofsympathetictonein
esteraseistheenzymethatbreaksdownintracellularcAMP
response to improved cardiovascular function. However,
to its inactive metabolite (5=AMP). Milrinone is a bipyri-
this is not always the case. The major side effects of do-
dine derivative that selectively inhibits the phosphodiester-
butamine include tachycardia, especially in patients with
ase III enzyme, leading to increased intracellular cAMP.27
atrial fibrillation, and atrial and ventricular arrhythmias.
Thisresultsinincreasedintracellularcalciumconcentration
Patients taking a (cid:2)-blocker may have an attenuated initial
andmyocardialcontractilityaswellasaccelerationofmyo-
response to dobutamine until the (cid:2)-blocker has been
cardial relaxation. Increased cAMP peripherally produces
metabolized.
vasodilationinboththearterialandvenouscirculation.The
It has been hypothesized that the increased energy de-
end result is decreased systemic and pulmonary vascular
mands of the failing myocardium lead to a state of relative
resistances,decreasedleftandrightventricularfillingpres-
energy depletion through an initial compensatory phase of
sures, and increased cardiac output.
increased oxygen extraction.28,29 This paradigm suggests
Treatmentwithmilrinonemaybeinitiatedwithaloading
that further inodilator stimulation would impose further doseof50(cid:4)g/kgperminfollowedbyacontinuousinfusion
energy demands and ultimately accelerate myocardial cell of between 0.25 and 1.0 (cid:4)g/kg per min or as an infusion
death. Several investigators have attempted to demonstrate
without the loading dose. Most patients have improvement
this using a variety of methods to investigate myocardial
inhemodynamicfunctionin5to15minutesafterinitiation
oxygen consumption and a variety of in vitro and in vivo
of therapy. The elimination half-life is 30 to 60 minutes
models.Studiesinanimalmodelswithleftventriculardys- when tested in healthy individuals, but it is doubled in
function demonstrated that dobutamine infusion is associ- patients with severe HF.27
ated with an increase in myocardial oxygen consumption A major side effect of milrinone is hypotension, and
with a shift in myocardial metabolism, evidenced by an milrinoneisoftenadministeredwithoutaloadingdoseinan
increasedpreferenceforglycolyticsubstrates.30,31Studiesin attempt to minimize the decrease in blood pressure. Other
patients with ischemic or nonischemic dilated cardiomyop- side effects include increased atrial and ventricular ectopy
athy also suggested that dobutamine increases myocardial (eg, nonsustained ventricular tachycardia). The metabolic
oxygen consumption and the work-metabolic index.32,33 costofmilrinoneinpatientswithcongestiveHFisunclear,
particularly when compared with other inodilator agents.35
Dopamine—endogenous catecholamines:Dopamine
White et al36 determined the immediate effects of milri-
isanendogenoussubstancewithdose-dependenteffects.At
doses of (cid:5)2 (cid:4)g/kg per min, based on estimated lean body noneonexerciseperformancein14patientswithNewYork
HeartAssociation(NYHA)classIIItoIVcongestiveHF,in
weight, dopamine causes vasodilation by direct stimulation
a randomized, double-blind, placebo-controlled study.
of dopamine postsynaptic type 1 and presynaptic type 2
Compared with placebo, intravenous milrinone caused a
receptors in the splanchnic and renal arterial beds.27 Dopa-
higherpeakoxygenuptakeandoxygenuptakeattheanaer-
minealsohasdirecteffectsonrenaltubularepithelialcells,
obicthresholdwithaconcomitantdecreaseinbloodlactate
resulting in increased natriuresis.
Intermediateinfusionratesof2to5(cid:4)g/kgpermincause concentrations at matched submaximal exercise intensities.
directstimulationof(cid:2)-adrenergicreceptorsintheheartand
induce norepinephrine release from vascular sympathetic
neurons. This results in increased heart rate and cardiac Trials: Intravenous Inodilator Therapy
output. Infusion rates of 5 to 15 (cid:4)g/kg per min generally
stimulate (cid:2)- and (cid:3)-adrenergic receptors, leading to an in- There are several different regimens of intravenous inodi-
creased heart rate and peripheral vasoconstriction. lator therapy that have been used to treat patients with
A major side effect of dopamine is tachycardia, which congestive HF. These agents are used for short-term inpa-
tends to be much more pronounced with dopamine than tient therapy to treat AHFS. In this setting, patients are
dobutamine.27 Another concern when using dopamine is usually infused over several hours to a few days in combi-
correct dosing. Dopamine dose is based on lean body nationwithdiuretics.Acutetreatmentisdiscontinuedwhen
weight, which can be difficult to estimate. A new or unex- patients are clinically stable. However, some patients de-
50G TheAmericanJournalofCardiology(www.AJConline.org) Vol96(6A) September19,2005
Table1
Mortalityat1monthand6monthsintheCalciumSensitizerorInotropeorNonein
Low-OutputHeartFailureStudy(CASINO)
EndPoint Dobutamine Placebo Levosimendan
(n(cid:3)100) (n(cid:3)99) (n(cid:3)100)
1-momortality 14.0% 8.1% 6.0%*
6-momortality 42.0%† 28.3% 18.0%‡
*p(cid:3)0.04vsdobutamine.
†p(cid:3)0.02vsplacebo.
‡p(cid:3)0.0001vsdobutamineand0.03vsplacebo.
Adapted from Program and abstracts of the European Society of Cardiology, Heart
FailureUpdate200440andEurJHeartFail.41
compensate when intravenous inodilator infusions are compared with placebo. The CASINO trial suggests that
stopped, and they cannot be weaned off or switched to an short-term treatment with dobutamins is associated with
oral agent. In such cases, patients may need to be on con- increased postdischarge mortality.
tinuous intravenous infusions. This is usually done on an TheongoingSurvivalofPatientswithAcuteHeartFail-
outpatient basis. It has also been proposed to use intermit- ure in Need of Intravenous Inotropic Support (SURVIVE)
tent inodilator treatment to prevent rehospitalization. This trial will further analyze the effects of levosimendan com-
infusionscheduleinvolvesintermittentintravenoustherapy, pared with those of dobutamine on mortality during 180
usually given as a 4- to 6-hour pulse infusion for several days after the start of treatment.42
days per week or as a single 24- to 72-hour infusion once
Milrinone:Milrinone was approved for short-term in-
weekly.
travenous use in the late 1980s. Amrinone, the parent drug
ofmilrinone,however,hashadlimitedusebecauseithasa
10% rate of thrombocytopenia caused by reversible bone
Short-Term Use of Inodilator Treatment
marrow suppression. As mentioned before, oral milrinone
Dopamine and dobutamine:There are no randomized,
as a continuous treatment has been shown to increase mor-
controlledtrialsstudyingtheeffectsofshort-termdopamine
tality.43 Its intravenous use in the acute setting has been
infusion. Liang and associates37 studied the effects of con-
studiedinafewrandomizedcontrolledtrials.Thelargestof
tinuous infusion of dobutamine for 72 hours in 15 patients
thesetrialsistheOutcomesofProspectiveTrialofIntrave-
withNYHAclassIIItoIVHFwithafollow-upperiodof4
nous Milrinone for Exacerbations of Chronic Heart Failure
weeks. No deaths were observed in this 4-week period.
(OPTIME-CHF).4,44Mostofthecontrolledtrials,including
Maximalexercisetimeandleftventricularejectionfraction
OPTIME-CHF, evaluated the effects of short-term use of
(LVEF) increased significantly in the dobutamine group.
milrinone (Table 2).4,44–47
NYHA functional class improved in 6 of 8 patients in the
The OPTIME-CHF investigators44 randomized 949 pa-
treatment group compared with 2 of 7 control patients.
tients(meanage,65years)admittedwithanexacerbationof
Recentrandomizedtrialshavecomparedtheeffectsofa
systolic HF with NYHA class III to IV HF and an LVEF
short-term intravenous infusion of dobutamine with levosi-
(cid:2)0.40(meanLVEF,0.23)tostudytheeffectofshort-term
mendan, a new calcium sensitizer and ATP-dependent po-
milrinoneinfusion(48to72hours)ontheprimaryoutcome:
tassiumchannelopener(seealsothearticlebyMebazaaand
cumulative days of hospitalization within 60 days of ran-
colleagues38 in this supplement). The Levosimendan Infu-
domization (the period with the highest risk of rehospital-
sion Versus Dobutamine (LIDO) study demonstrated the
ization48). They also studied the effects on secondary out-
acutehemodynamicbenefitsoflevosimendan(loadingdose
of 24 (cid:4)g/kg followed by an infusion of 0.1 (cid:4)g/kg per min comes,includingadverseeventsandmortality.Patientswho
for 24 hours) compared with dobutamine (started with a werejudgedtoneedinodilatortherapywereexcludedfrom
continuous infusion of 5 (cid:4)g/kg per min) in patients with the study (eg, for shock or severe hypotension) as well as
severe low-output HF.39 In addition, levosimendan was as- those who had myocardial ischemia in the last 3 months,
sociated with a significantly lower all-cause mortality and atrial fibrillation with poor rate control ((cid:1)110 beats per
readmission rate at 180 days. minute), or sustained ventricular tachycardia or ventricular
In the Calcium Sensitizer or Inotrope or None in Low- fibrillation. The study concluded that there were no signif-
Output Heart Failure Study (CASINO), dobutamine was icantdifferencesbetweenthetreatmentandplacebogroups
associated with lower 6-month survival compared with le- for the number of days hospitalized within the 60-day pe-
vosimendanorplaceboinpatientswithdecompensatedlow- riod, the number of rehospitalizations, the length of initial
output HF (Table 1).40,41 Moreover, this trial demonstrated stay, in-hospital mortality, or 60-day mortality (Table 3).
a survival benefit associated with levosimendan treatment Clinical status measured by an HF score was also similar
Bayrametal/ReassessmentofDobutamine,Dopamine,andMilrinoneintheManagementofAHFS 51G
Table2
Short-term(acute)infusions:milrinoneversusplacebotrials
Trial Milrinone Comparison Patient Number Follow- Outcome
Population up
Andersonetal 50(cid:4)g/kg Placebo NYHAclass 31 1hr Milrinonecausedsignificantincreasesin
198746,199145 loadingdose III–IVwith CI(41%)andSV(32%)and
followedby CI(cid:2)2.5 decreasesinPCWP(25%),SVR
infusionwith L/min/m2or (24%),andMAP(5%)at1hrof
0.5(cid:4)g/kg/min PCWP infusion.
(cid:4)1hr (cid:1)15mmHg
Seinoetal,199647 50(cid:4)g/kg Placebo Patientswith 52 1hr 37%decreaseinPAOP,39%decrease
loadingdose acuteheart inRAP,31%increaseinCI,and21%
followedby failurewith increaseinSVat15mincompared
continuous PCWP withdecreasedCIat60minandno
infusionwith (cid:1)18mmHg othersignificantchangesinplacebo
0.5(cid:4)g/kg/min group.Subjectivesymptomsalso
for6hr improvedcomparedwithno
improvementinplacebo.16%rateof
ventriculararrhythmiasinmilrinone
group.
Cuffeetal,200244 48–72-hr Salineplacebo NYHAclass 951 2mo Nosignificantdifferenceinnumberof
infusionwith III–IV;mean dayshospitalized,in-hospital
0.5(cid:4)g/kg/min LVEF(cid:3)0.23 mortality,60-daymortality,or
compositeincidenceofdeathor
re-admissions.
Felkeretal,20034 48–72-hr Salineplacebo NYHAclass 951 2mo Milrinone-treatedpatientswithischemic
infusionwith III–IV;mean heartdiseasetendedtohaveworse
0.5(cid:4)g/kg/min LVEF(cid:3)0.23 outcomesforthecompositeofdeath
andrehospitalizations.
CI (cid:3) cardiac index; LVEF (cid:3) left ventricular ejection fraction; MAP (cid:3) mean arterial pressure; NYHA (cid:3) New York Heart Association; PAOP (cid:3)
pulmonaryarteryopenpressure;PCWP(cid:3)pulmonarycapillarywedgepressure;RAP(cid:3)rightatrialpressure;SV(cid:3)strokevolume;SVR(cid:3)systemicvascular
resistance.
Table3
ResultsfromtheOutcomesofProspectiveTrialofIntravenousMilrinoneforExacerbationsofChronicHeartFailure(OPTIME-CHF)4
Outcome Placebo Milrinone pValue
(n(cid:3)472) (n(cid:3)477)
Cardiovascularhospitalizationwithin60days,meandays 12.5(cid:5)14 12.3(cid:5)14 0.71
Deathwithin60days 8.9% 10.3% 0.41
Deathorreadmissionwithin60days 35.3% 35.0% 0.92
Treatmentfailuresduringtheinfusionperiod 9.2% 20.6% (cid:2)0.001
Newatrialfibrillationorflutterduringindexhospitalization 1.5% 4.6% 0.004
Sustainedhypotensionduringindexhospitalization* 3.2% 10.7% (cid:2)0.001
*Definedasasystolicbloodpressure(cid:2)80mmHgfor(cid:1)30minutes,requiringintervention.
AdaptedfromJAMA.44
between the 2 groups, although patients treated with milri- termintravenousmilrinonetreatmentindecompensatedpa-
none subjectively reported feeling better at 30 days com- tients with HF.4 A total of 485 patients had ischemic HF
pared with the placebo group. The 2 groups, however, (defined as prior history of bypass grafting, percutaneous
differed in the treatment failures caused by adverse events coronary intervention, or myocardial infarction [MI]) com-
within 48 hours. There were more incidents of sustained pared with 464 patients in the nonischemic group. In each
hypotension, atrial fibrillation, atrial flutter, ventricular group,approximately50%ofthepatientswerefoundtobe
tachycardia, and ventricular fibrillation in the treatment randomizedinitiallytomilrinone.Thestudyconcludedthat
group.Theresultsfromthisstudydonotsupporttheuseof theresponsetomilrinonewasdifferentintheischemicand
short-term milrinone infusion in decompensated patients nonischemic groups. Patients with nonischemic HF bene-
who do not present with hypotension resulting from a low fited from short-term use of milrinone. The composite of
cardiac output. deathorrehospitalizationat60dayswassignificantlylower
The OPTIME-CHF investigators retrospectively evalu- in the treatment group compared with placebo (28% vs
ated the outcomes of the study to assess the interaction 35%, p (cid:3) 0.01), as well as the in-hospital mortality rate
between HF etiology (ischemic vs nonischemic) and short- (2.6% for milrinone compared with 3.1% for placebo, p (cid:3)
52G TheAmericanJournalofCardiology(www.AJConline.org) Vol96(6A) September19,2005
Figure1.Kaplan-Meiersurvivalcurvesforin-hospitalsurvivalto60daysbyheartfailureetiologyandtreatmentassignmentinaposthocanalysisofthe
OutcomesofProspectiveTrialofIntravenousMilrinoneforExacerbationsofChronicHeartFailure(OPTIME-CHF).(AdaptedfromJAmCollCardiol.4)
0.04). Mortality at 60 days was similar between the treat- require inodilator treatment as judged by their physicians.
mentandplacebogroups.Thetotalnumberofhospitaldays Nonetheless, data from the trial indicated that patients in
tendedtobelowerinthemilrinone-treatedgroupcompared this trial had severe HF, with event rates up to 35% within
withtheplacebogroup(10.9daysvs12.6days,p(cid:3)0.055). 60 days after discharge.44 Regarding the reanalysis of the
Incontrast,theischemicgroupwasadverselyaffectedby OPTIME-CHF study outcomes for ischemic versus non-
short-termintravenousmilrinonetreatment.4Themilrinone ischemicetiologyofHF,itshouldberememberedthatthis
treatment group trended toward prolonged hospitalizations is a retrospective study and can only be used to derive a
and increased mortality. Days hospitalized at 60 days was hypothesis, not a conclusion.4,44
13.6 for treated patients versus 12.4 days for placebo pa- Numerous studies compared milrinone with dobutamine
tients (p (cid:3) 0.055). The composite of death or rehospital- asanalternativetoreplacedobutamineintheacutesetting.
izationat60dayswassignificantlygreaterinthemilrinone A list of the randomized, controlled trials comparing the 2
group (42% compared with 36% for placebo, p (cid:3) 0.01). agents is shown in Table 4.49–52 All of these trials studied
In-hospital mortality was also significantly higher in the short-term infusion of dobutamine and milrinone, whereas
treatment group (Figure 1), whereas 60-day mortality rates in the study by Aranda and coworkers,53 the infusion was
were similar. continued until patients received cardiac transplant. The
Anderson,45 Anderson and colleagues,46 and Seino and follow-up periods were brief and mostly ended with com-
associates47 also studied the effects of short-term use of pletion of the infusion. Thus, no data were available com-
intravenous milrinone. However, they analyzed data only paring long-term effects on morbidity or mortality. It is
for the 1-hour period after infusion and did not analyze difficult to reach a common conclusion from these trials
long-termmortalityorworseningHF.Theyfoundthatmil- because the patient population in each trial varied broadly:
rinoneprovidedsymptomaticreliefcomparedwithplacebo. trials studied stable patients with HF,49,50 patients post-
However, there was also a tendency toward increased ven- MI,51 patients after cardiac surgery,52 and patients waiting
triculararrhythmiasassociatedwiththeuseofmilrinonein for cardiac transplantation.53 Overall, in these trials both
both studies. Transient occurrence of ventricular arrhyth- milrinoneanddobutamineseemedtobereasonableoptions
mias was observed in 16% and 12.2% of the milrinone- to be used in the acute setting. Biddle and colleagues49
treated patients in the placebo-controlled, double-blind foundthatsupraventriculararrhythmiasandsinustachycar-
studybySeinoandassociates47andinthemulticenterstudy dia occurred more frequently in the dobutamine group. In
by Anderson45 and Anderson and colleagues.46 So far, OP- thisstudy,nonsustainedventriculartachycardiaoccurredin
TIME-CHF investigators provided the largest randomized 2 patients in each group and resolved spontaneously. Also,
controlled trial and raised questions about the beneficial themilrinonegrouphad1patientwithventriculartachycar-
effects of short-term infusion of milrinone in decompen- dia requiring cardioversion and 1 patient with ventricular
sated patients with HF, especially in the presence of an fibrillation. Ventricular arrhythmias tended to occur in pa-
ischemicetiology.However,itisimportantthatthepatients tientsreceivinglargerbolusesofmilrinone.However,given
in OPTIME-CHF were not critically ill in that they did not the small number of patients studied in these trials, larger
Bayrametal/ReassessmentofDobutamine,Dopamine,andMilrinoneintheManagementofAHFS 53G
Table4
Short-term(acute)infusions:milrinonevsdobutaminetrials
Trial Milrinone Dobutamine Patient N Follow-up Outcome
Population
Biddleetal 50or75(cid:4)g/kg Incrementaldoses NYHAclass 79 48hr Nodifferenceinhemodynamiceffectsbetween
(1987)49 bolusthen of2.5–15(cid:4)g/ III–IV groups:SVincreased,HRincreased,SVR
Openlabel 0.5–1(cid:4)g/kg/ kg/min(cid:4)48hr (stablefor decreased,andPCWPdecreasedsimilarlyin
mininfusion (cid:1)2wk bothgroups.
(cid:4)48hr before
study)
Eichhornetal 50(cid:4)g/kgbolus 2.5–15(cid:4)g/kg/min NYHAclass 14 During 24%increaseinCIfrombaselineinbothgroups;
(1987)50 then0.5(cid:4)g/ (doseadjusted III–IV hemodynamic increaseinRVsystolicperformance.
kg/min toachieveequal and SignificantRVafterloadandPAESPreduction
increasesin radionuclide onlyinmilrinonegroup.
CO) recordings
Karlsbergetal 50(cid:4)g/kgbolus 24-hrinfusionof Within12hr 33 24hr CriteriafordecreaseinMPCWPweremetby
(1996)51 then24-hr 2.5–15(cid:4)g/kg/ to5days 94%ofthemilrinone-treatedpatientsand57%
Openlabel infusionof min(titratedup afteracute ofthedobutamine-treatedpatients(p(cid:3)0.03).
0.25–0.75 until(cid:1)30% MI MaximalreductioninMPCWPwasgreaterfor
(cid:4)g/kg/min increaseinCI themilrinone(53.2%vs31%,p(cid:3)0.01).Both
(titratedup or(cid:1)25% improvedglobalEF.
similarto decreasein
dobutamine) MPCWP)
Fenecketal 50(cid:4)g/kgbolus 10–20(cid:4)g/kg/min Patientswith 120 4hr DobutaminegrouphadgreaterincreasesinCI,
(2001)52 then0.5(cid:4)g/ infusion(cid:4)4hr lowCO MAP,andLVstrokeworkindex.Milrinone
Openlabel kg/min after grouphadgreaterdecreasesinMPCWP.
infusion(cid:4) cardiac Dobutaminegrouphadhigherincidencesof
4hr surgery hypertensionandatrialfibrillation;milrinone
grouphadhigherincidenceofsinus
bradycardia.
CI(cid:3)cardiacindex;CO(cid:3)cardiacoutput;EF(cid:3)ejectionfraction;HR(cid:3)heartrate;LV(cid:3)leftventricle;MAP(cid:3)meanarterialpressure;MI(cid:3)myocardial
infarction;MPCWP(cid:3)meanpulmonarycapillarywedgepressure;NYHA(cid:3)NewYorkHeartAssociation;PAESP(cid:3)pulmonaryarteryend-systolicpressure;
PCWP(cid:3)pulmonarycapillarywedgepressure;RV(cid:3)rightventricular;SV(cid:3)strokevolume;SVR(cid:3)systemicvascularresistance.
randomized controlled trials are needed to conclude which Intermittent Use of Inodilator Treatment
drug is better in which group of patients.
No randomized, controlled studies have been designed to
Concomitant use of milrinone and (cid:1)-blockers:The study the effects of using intermittent infusions of dopa-
mine.Arandomized,controlledtrial(theRandomizedOut-
increase in mortality associated with inodilator therapy
patient Milrinone Evaluation [ROME] trial) studying the
hasbeenattributedtoaproarrhythmiceffectandtodirect
effects of intermittent outpatient infusions of milrinone has
myocyte toxicity with acceleration of disease progres-
been terminated after enrollment of approximately 100 pa-
sion.54,55This toxicity may be related to cAMP-mediated
calcium overload.56,57 (cid:2)-Blockers have been shown to tients, and no data on the results are available yet.67 All of
the randomized, controlled trials retrieved in our search
attenuate these changes at a molecular and cellular
analyzed intermittent infusions of dobutamine (Ta-
level.58,59 For these and other reasons, these agents may
ble 5).68–73
be ideal in attenuating the undesirable side effects of
inodilators.60 Phosphodiesterase inhibitors, such as mil- Dobutamine:We identified 6 randomized, controlled
rinone, would be expected to retain their positive inotro- trials that analyzed the effects of intermittent infusions of
pic and vasodilator effects in the presence of a (cid:2)-blocker dobutamine.68–73 A review of the outcomes supports a ten-
because their site of action is beyond the (cid:2)-adrenergic dency for symptomatic improvement68,69,71 and increased
receptor.61 Several studies demonstrated that phosphodi- exercisetolerance68–72withdobutaminecomparedwithpla-
esterase inhibitors, in contrast to dobutamine and dopa- cebo. The Dobutamina nell’Insufficienza Cardiaca Estrema
mine, have continued positive inotropic effects in pa- (DICE)trial,however,foundnoimprovementinfunctional
tients with advanced HF receiving chronic (cid:2)-blocker status.72Therewasanonsignificanttrendtowarddecreased
therapy.62,63 Thus, the addition of a (cid:2)-blocker to a phos- hospitalizations in the DICE trial,72 whereas Elis and asso-
phodiesterase inhibitor would be expected to attenuate ciates73 found no difference in the number of hospitaliza-
the negative inotropic side effects of the former and the tions between groups at 6 months. Other prospective trials
long-term adverse effects of the latter.64–66 did not provide data on the number of hospitalizations.
54G TheAmericanJournalofCardiology(www.AJConline.org) Vol96(6A) September19,2005
Mortality data were provided in 5 of the prospective stud- who really need the continuous infusions would not be
ies.68–70,72,73 Adamopoulos and coworkers71 reported no enrolled in placebo-controlled, randomized trials. Indeed,
deathsineithergroup.Mortalitywasincreasedinthetreat- there are no data from randomized, controlled trials study-
mentgroupsinthetrialbyDiesandcolleagues,69whichwas ing the effects of continuous administration of intravenous
stopped because of increased mortality in the dobutamine inodilator drugs prospectively compared with placebo ef-
group. In the dobutamine group, death was more common fects. Reports in the literature indicate that the use of con-
amongpatientswith(cid:1)4episodesofventriculartachycardia tinuous inodilator treatment has a significant impact on
per day at baseline, although dobutamine did not seem to qualityoflifeandisassociatedwithanincreasedmortality
increase the frequency of arrhythmias. The study by Elis rate. In the past, several large-scale trials were designed to
and associates73 and the DICE trial72 did not find a signif- studytheeffectsoflong-termoralinodilatoruseinHFand
icant difference in mortality between the dobutamine and showed increased mortality with these agents.43,74–76 The
placebo groups (3 of 19 in the placebo group vs 5 of 19 in Prospective Randomized Milrinone Survival Evaluation
the dobutamine group). However, in the DICE trial, 2 pa- (PROMISE) analyzed 1,088 patients with severe chronic
tientsinthedobutaminegroupunderwentcardiactransplan- HF (NYHA class III or IV). Compared with placebo, mil-
tation and 1 patient discontinued the protocol because of rinone increased hospitalizations, mortality from all causes
severeventriculararrhythmias.Inthistrial,dobutaminewas by 28%, and cardiovascular mortality by 34%.43 This in-
not associated with an increased number of ventricular ar- creaseinmortalitywasparticularlyevidentinpatientswith
rhythmias. No adverse effects on mortality were observed verysevereHForclassIVHF.Thisfindingarguesagainst
by Leier and coworkers68 or Erlemeier and colleagues70 (1 the common belief that these agents are most useful for
deathin10patientsintheplacebogroupvs1deathin10in patients with the most advanced stage of HF.
the dobutamine group). A meta-analysis by Thackray and Other agents that have been studied are pimobendan, a
colleagues5 included 6 trials37,69,70,72,73 and calculated an phosphodiesterase inhibitor with calcium-sensitizing prop-
oddsratioof1.5(95%confidenceinterval,0.51to3.92)for erties74;ibopamine,anoraldopaminergicagonistwithrenal
all-causemortalityinthedobutaminegroupcomparedwiththe and peripheral vasodilatory effects75; and vesnarinone, a
controlgroup.Itischallengingtoderiveconclusionsbasedon phosphodiesterase inhibitor with effects on sodium ion
theresultsofthesecontrolledtrialsforseveralreasons:(1)the channels.76 All 3 agents increased mortality when used in
smallnumbersofpatientsenrolledineachofthesetrialsonly patients with advanced HF. Vesnarinone appeared to im-
allowdetectionoflargedifferencesbetweenthetreatmentand
provethequalityoflifeattheexpenseofincreasingtherisk
controlgroups;(2)theinfusionpatternsofdobutaminevaried
of death.76
widelybetweendifferenttrials(eg,theaveragerateofinfusion
In contrast to oral inodilator agents, no large-scale trials
byDiesandcolleagues69washigh[8.1(cid:4)g/kgpermin],which have been designed to study the effects of long-term intra-
may have played a role in the increased mortality associated
venous inodilator therapy. There are no randomized con-
withdobutamine);(3)patientpopulationsstudiedinthesetrials
trolledtrialslookingattheeffectsofcontinuousinfusionsof
werenotalwayscomparable(Liangandassociates37excluded
dopamine.Forintravenoususeofmilrinone,Arandaetal53
patientswithischemicheartdisease,whereasElisandassoci-
studied 36 patients awaiting cardiac transplantation who
ates,73 Erlemeier and colleagues,70 and the DICE trial72 en-
wererandomizedtoreceiveeithermilrinoneordobutamine,
rolledpatientswithCADorischemicHF);and(4)follow-up
andfollowedthemuntildeath,transplantation,orplacement
durationwasvariedbetweentrials.However,untilmorecon-
ofmechanicalcardiacsupport.Nodifferencebetweenthe2
clusive trials are conducted analyzing the safety of using do-
groupswasobservedinrightheartdynamics,death,orneed
butamineinHF,thisinodilatoragentshouldbeavoidedwhen-
for other inodilator/vasodilator treatment or for mechanical
everasaferoptionisavailable.
cardiac support.53 Similar to other inodilator agents, there
are no data from prospective, randomized controlled trials
Continuous Inodilator Treatment on chronic intravenous infusion of dobutamine. A retro-
spective analysis of the Flolan International Randomized
Many patients with advanced HF are hospitalized because
SurvivalTrial(FIRST)istheonlysourceofdatalookingat
ofexacerbatedofcongestivesymptoms.Theuseofoptimal
chronicinfusionofthisagent.6Cautionmustbeexercisedin
HFtherapydoesnotsufficeforsymptomaticreliefinsome
interpreting the results of this post hoc analysis because a
ofthesepatients,andintravenousinodilatortherapyiscom-
higher proportion of the dobutamine patients had NYHA
monly used. Of patients who are started on intravenous
class IV HF.
inodilators for refractory HF symptoms, some cannot be
successfullyweanedoffafterbeingstabilizedclinicallyand Dobutamine:In FIRST, 471 patients with NYHA class
become dependent on inodilator therapy. In this setting, III to IV HF were enrolled initially to study the effects of
continuousinodilatorinfusionsareusedeitherasabridgeto conventionaltherapywithandwithoutintravenousepopro-
cardiac transplantation or for palliative purposes. At this stenol. The results of the study showed a trend toward
stage,patientshavenootheroption,regardlessoftheeffect increased mortality rate in the epoprostenol group.77 The
of continuous inodilator infusions on survival. Thus, those data from this trial were later analyzed to compare the
Bayrametal/ReassessmentofDobutamine,Dopamine,andMilrinoneintheManagementofAHFS 55G
Table5
Intermittentinfusions:dobutamineversusplacebotrials
Trial Dobutamine Control Patient Number Follow-up Outcome
Population
(NYHAclass)
Leieretal IVinfusionfor4hr Matched III–IV 26 24wk NosignificantchangeinCIorrestingLVEF.
(1982)68 weekly(cid:4) control Improvedfunctionalclassification(p(cid:2)
24wk group 0.05);increasedexercisetolerance(p(cid:2)
0.05).2of15diedindobutaminegroupvs
1of11incontrolgroup.
Diesetal IVinfusionfor48 Placebo III–IV, 60 8wk Increasedtreadmilltimes;improvedsymptom
(1986)69 hr/wk(cid:4)24wk EF0.20(cid:5)0.11 scores.Increasedmortalityintreatment
group(44%vs17%inplacebogroup).
Erlemeieretal 8(cid:4)24-hrinfusions 5% IV 20 3daysafterlast Increasedexercisedurationontreadmilltest;
(1992)70 overa4-wk dextrose infusion decreasedbodyweight.1deathintreatment
periodwithat solution group(1/10)and1death(1/10)incontrol
least3daysin group.
between
Adamopoulos IVinfusion4days/ Usual MostlyIII,EF 20 6wkafter Increasedexercisetoleranceat3and6wk;
etal(1995)71 wk(cid:4)3wkto activity 0.23(cid:5)0.03 intervention increasedchronotropicresponsivenessto
raiseHRto70%– only exercise;improvedsymptoms;increased
80%maximum (cid:2)-receptordensity.Noclinicallysignificant
for30min/day arrhythmiasandnodeathsreported.
Olivaetal Infusionfor48hr/ Optimal III–IV,EF 38 8wkforCI;6 Didnotimprovefunctionalstatus;non-
(1999)72 wk(cid:4)6mo standard (cid:2)0.30 moforother significanttendencytowarddecreased
treatment outcomes hospitalizations.Nonsignificanttrendto
improveexercisetolerance.Noincreasein
ventriculararrhythmias.Didnot
significantlyincreasemortality.
Elisetal 24-hrinfusionevery Placebo III–IV,EF0.30 19 Untildeathor Nodifferenceinnumberofhospitalizations
(1998)73 2wk(cid:4)6wk (ischemia- Dec.1996 betweengroupsat6mo.Nosignificant
thenevery3wk inducedHF) (survival differencebetweensurvivalcurvesat32
(cid:4)6mo analysisat32 mo(p(cid:3)0.7)
mo)
CI(cid:3)cardiacindex;EF(cid:3)ejectionfraction;HF(cid:3)heartfailure;HR(cid:3)heartrate;IV(cid:3)intravenous;LVEF(cid:3)leftventricularejectionfraction;NYHA
(cid:3)NewYorkHeartAssociation.
outcomes in 2 patient groups: patients who were receiving nousdobutaminetreatment,nottoshort-termorintermittent
intravenous continuous dobutamine at the time of random- intravenous treatment.
ization for the initial study versus patients who were not
receiving dobutamine at the time of randomization.6 There
were 391 patients in the no-dobutamine group and 80 pa-
Indications for Inodilators in Current Guidelines
tients in the dobutamine group. The median age, ratio of
men to women, and etiology of HF were similar in the 2
The current guidelines on chronic HF from the American
groups. However, more patients in the dobutamine group
CollegeofCardiologyandtheAmericanHeartAssociation
had NYHA class IV HF. The median dose of dobutamine
accept the use of continuous intravenous inodilator infu-
administeredwas9(cid:4)g/kgpermin(5to12(cid:4)g/kgpermin)
sions for stage D patients (those with HF refractory to
and the median duration of treatment was 14 days (7 to 52 therapy) as a palliative treatment or as a bridge to cardiac
days).Thisstudyconcludedthatthedobutaminegrouphad transplantation,onlyafterallalternativeattemptstoachieve
a higher occurrence of first events and a higher mortality stabilityhavefailed(classIIbrecommendation:usefulness/
rate compared with the no-dobutamine group. Caution is efficacy is less well established by evidence/opinion).78
warranted when interpreting these results, given the limita- These guidelines do not approve of using intermittent or
tions of a retrospective study. It is not possible to identify continuous intravenous inodilator therapy in stage C pa-
what proportion of the increased mortality was attributable tients(thosewithsevereHFwhoappeartorespondtoother
to dobutamine versus the baseline characteristics of the therapies; long-term intermittent infusions of a positive in-
dobutamine group. However, the investigators concluded odilator drug in these patients is considered a class III
that even when the baseline differences were adjusted for, recommendation [conditions for which there is evidence
thetreatmentgrouphada2-foldincreaseinmortalityrate.6 and/or general agreement that a procedure/therapy is not
The results of this study apply only to continuous intrave- useful/effective and in some cases may be harmful]), or in
56G TheAmericanJournalofCardiology(www.AJConline.org) Vol96(6A) September19,2005
stage D patients who can be successfully weaned from 6. O’ConnorCM,GattisWA,UretskyBF,AdamsKFJr,McNultySE,
inodilator therapy (routine intermittent infusions in these GrossmanSH,McKennaWJ,ZannadF,SwedbergK,GheorghiadeM,
CaliffRM.Continuousintravenousdobutamineisassociatedwithan
patients are considered a class III recommendation). Con-
increasedriskofdeathinpatientswithadvancedheartfailure:insights
versely,theEuropeanSocietyofCardiologyguidelinessug-
fromtheFlolanInternationalRandomizedSurvivalTrial(FIRST).Am
gest the use of inodilator agents in the presence of periph- HeartJ1999;138:78–86.
eral hypoperfusion (hypotension, decreased renal function) 7. FonarowGC,YancyCW,HeywoodJT,fortheADHEREScientific
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to diuretics and vasodilators at optimal doses (class IIa heartfailurequality-of-careindicatorsinUShospitals:analysisofthe
ADHEREregistry.ArchInternMed2005;165:1469–1477
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