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Continuing Cardiology Education

Inotropes in acute heart failure


V. Bistola1 & O. Chioncel2
1
Heart Failure Unit, 2nd Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
2
Institute of Emergency for Cardiovascular Diseases ‘Prof. C.C. Iliescu’, University of Medicine and Pharmacy Carol Davila, Bucuresti, Romania

Keywords Abstract
Acute heart failure, clinical guidance,
inotropes Acute heart failure (AHF) encompasses a wide range of clinical presentations,
from acute hypertensive heart failure (HF) to low cardiac output hypoperfusion
Correspondence syndromes with cardiogenic shock at the extreme end of this side. Inotropes
V. Bistola, Heart Failure Unit, 2nd are pharmacologic agents that enhance cardiac contractility, thereby augmenting
Department of Cardiology, Attikon University cardiac output. Currently, there are three classes of inotropes available in clini-
Hospital, National and Kapodistrian University
cal practice with distinct mechanisms of action: beta-adrenergic agonists, phos-
of Athens, Athens, Greece.
phodiesterase III inhibitors, and the calcium-sensitizer levosimendan. Inotropes
Tel: +30-210-5832355; Fax: +30-210-5832351;
E-mail: vasobistola@yahoo.com are indicated as short-term therapy in low cardiac output AHF and cardiogenic
shock (usually with coadministration of a vasoconstrictor) to increase cardiac
Funding Information output, restore peripheral perfusion, and prevent end-organ dysfunction. Ino-
No funding information provided. tropes can cause serious cardiovascular adverse effects, most commonly tach-
yarrhythmias and myocardial ischemia and are associated with increased
Continuing Cardiology Education, 2017;
medium- and long-term mortality in HF. Therefore, intense monitoring is nec-
3(3), https://doi.org/10.1002/cce2.59
essary during their administration, while long-term infusion is contraindicated
with the exception of advanced HF patients in whom inotropes may be used as
a bridge to a definitive therapy (transplantation or ventricular assist device
implantation) or as palliative treatment. Emerging inotropes acting through
novel pathways independent of those targeted by conventional agents may over-
come safety limitations of currently available agents.

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function [3]. Loop diuretics are first-line agents for the relief
Introduction
of dyspnea and edema; in hypertensive and normotensive
Acute heart failure (AHF) is characterized by new onset or AHF, vasodilators are administered to reduce ventricular
change in the severity of symptoms and signs of HF [1]. afterload and indirectly increase cardiac output. Inotropes
Clinical presentation extends from gradually (over days or and inodilators directly enhance cardiac contractility; there-
even weeks) worsening dyspnea or peripheral edema to the fore, they increase cardiac output, which is reduced acutely
acute critical states of pulmonary edema or cardiogenic in a subset of AHF patients. However, these agents have
shock. Accordingly, in-hospital mortality varies widely been shown to induce adverse cardiovascular effects, includ-
between 2% in low-risk patients, who present with conges- ing myocardial ischemia, tachyarrhythmias, and have been
tion but adequate peripheral perfusion without end-organ associated with increases in medium- and long-term mor-
dysfunction, to 22% in high-risk patients (evidence of tality. Therefore, their routine use in unselected AHF
hypoperfusion or frank cardiogenic shock) [2]. Currently, patients is not recommended, while they may be considered
no available pharmacologic strategies have proven efficacy as short-term therapy in patients who display evidence of
to reduce medium- and long-term morbidity and mortality low cardiac output and peripheral hypoperfusion [3, 4].
in AHF. Therefore, the treatment goals remain primarily eti-
ologic therapy when specific causes of AHF are recognized
Conventional Inotropes
(acute coronary syndrome, etc.) and concurrently/parallel
symptomatic relief with alleviation of congestion and hemo- Three major classes of inotropes are currently available
dynamic stabilization in order to preserve vital end-organ for clinical use for the management of patients with AHF:

ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: 10.1002/cce2.59 (107 of 116)
Inotropes in AHF V. Bistola & O. Chioncel

beta-adrenergic agonists (dobutamine, dopamine, epi- content enhances actin–myosin–troponin interaction,


nephrine, norepinephrine), phosphodiesterase III inhibi- thereby augmenting myocardial contraction [6].
tors (milrinone), and the calcium-sensitizer levosimendan
(Table 1) [5, 6].
Dopamine
Dopamine is an endogenous molecule that stimulates
Beta-adrenergic agonists
dopaminergic type 1 and 2 and beta-1 and alpha-1 adren-
Beta-adrenergic agonists mediate their cardiac inotropic ergic receptors. At low doses (up to 2.5 lg/kg per min),
effect through stimulation of sarcolemmal beta-1 adrener- dopamine causes renal and splachnic vasodilation through
gic receptors of cardiac myocytes. This in turn activates the postsynaptic type 1 and presynaptic type 2 dopamin-
the intracellular adenyl cyclase system leading to increased ergic receptors, respectively. Through this mechanism it
formation of cAMP. cAMP stimulates sarcolemmal and increases renal blood flow independently of cardiac out-
sarcoplasmic reticulum membrane-bound ionic channels put enhancement. However, the clinical significance of
that ultimately promote the release of Ca2+ from the sar- the renal effects of low-dose dopamine remains contro-
coplasmic reticulum through the Ca2+-induced Ca2+ versial, since dopamine has not been shown to increase
release effect. The resultant increase of sarcoplasmic Ca2+ glomerular filtration rate and a renal protective effect has

Table 1. Pharmacological properties of conventional inotropic agents.

Agents Dobutamine Dopamine Norepinephrine Epinephrine Levosimendan Milrinone

Mechanism b1 > b2 > a Dopaminergic > b; b1 > a > b2 b1 = b2 > a Calcium PDE inhibitor
of action high-dose a sensitizer;
high-dose
PDE inhibitor
Infusion dose 2–20 lg/kg <3 lg/kg per min: 0.2–10 lg/kg 0.05–0.5 lg/kg 0.05–0.2 0.375–0.75 lg/kg
per min renal effect per min per min lg/kg per min per min
No bolus dose 3–5 lg/kg per min: No bolus dose Bolus dose: 1 mg 12 lg/kg 25–75 lg/kg
inotropic IV every 3–5 min per min per min over
>5 lg/kg per min during resuscitation over 10 min 10–20 min
vasoconstrictor (optional, (optional)
No bolus dose not usually
preferred)
Inotropy ↑↑ ↑↑ ↑ ↑↑ ↑ ↑
Arterial ↑ ↑↑ (LD) 0 ↑ ↑↑ ↑↑
vasodilation
Vasoconstriction ↑ (HD) ↑↑ (HD) ↑↑ ↑ (HD) 0 0
Pulmonary ↑ or 0 ↓ or 0 (at ↓ or 0 (at high ↑↑ ↑↑
vasodilation high PVR) PVR)
Chronotropy ↑ 0 or ↑ ↑ ↑↑ 0 0
Blood pressure ↑ ↑ (HD) ↑ 0 or ↑ ↓ ↓
effect
Diuretic effect 0 ↑↑ (LD) ↑ 0 ↑ 0
Recommendation
class
ESC IIb IIb IIb IIb IIb IIb
ACC/AHA IIb IIb I (CS) I (CS) I (CS) Not licensed IIb
Level of C C C C C C
evidence
Adverse Tachyarrhythmias, Tachyarrhythmias, Tachyarrhythmias, Tachyarrhythmias, Hypotension, Tachyarrhythmias,
effects hypotension, hypertension, hypertension, headache, anxiety, atrial and hypotension,
headache, (rarely) myocardial headache cold extremities, ventricular headache
eosinophilic ischemia pulmonary edema, tachyarrhythmias,
myocarditis, cerebral headache
peripheral blood hemorrhage,
eosinophilia

HD, high dose; LD, low dose; PVR, pulmonary vascular resistances; CS, cardiogenic shock.

Continuing Cardiology Education, doi: 10.1002/cce2.59 (108 of 116) ª 2017 Hellenic College of Cardiology
V. Bistola & O. Chioncel Inotropes in AHF

not been demonstrated [7]. In DAD-HF-II study, low- used in cardiogenic shock in conjunction with primarily
dose dopamine added to low-dose intravenous furose- inotropic agents as well as in patients treated with
mide did not improve self-rated dyspnea scores, worsen- inodilators to avoid hypotension [3]. Moreover, its use
ing renal function, short- and long-term mortality, or HF also applies in a wide spectrum of non-cardiogenic shock
hospitalizations compared to a strategy of single low-dose etiologies, including septic, hypovolemic, and systemic
furosemide treatment in acutely decompensated HF [8]. inflammatory response syndrome (SIRS)-related shock. In
Moreover, ROSE-AHF trial showed no significant differ- a recent trial comparing norepinephrine to dopamine in
ence between placebo and low-dose dopamine or low- cardiogenic and non-cardiogenic shock, norepinephrine
dose nesiritide in 72-h urine volume as well as markers of was similarly efficacious in terms of 28 days mortality
decongestion [9]. At moderate doses (3–5 lg/kg per albeit safer than dopamine, which was associated with
min), this agent primarily augments cardiac contraction higher rates of arrhythmic adverse events and higher
and chronotropy through stimulation of the cardiac mortality in the subgroup of cardiogenic shock [11].
beta-1 receptors. At higher doses (>5 lg/kg per min), it Norepinephrine is usually prescribed at doses of 0.01–
predominantly stimulates alpha-1 receptors producing 0.03 lg/kg per min, which can be up-titrated to 1 lg/kg
vasoconstriction. Dopamine side effects include tach- per min to achieve the required levels of systolic blood
yarrhythmias, which become more frequent at doses of pressure. Prolonged infusions of norepinephrine can cause
10 lg/kg per min and above, and hypertension. direct myocardial toxic effects, through the induction of
cardiomyocyte apoptosis [12]. Norepinephrine adverse
effects include myocardial ischemia, arrhythmias, and
Dobutamine
hypertension.
Dobutamine is a synthetic molecule that stimulates beta-
1, beta-2, and alpha-1 adrenergic receptors in order of
Epinephrine
decreasing strength. By binding to cardiac beta-1 recep-
tors, dobutamine enhances cardiac contractility with Epinephrine is an endogenous catecholamine that stimu-
weaker chronotropic effects. Dobutamine also acts on the lates cardiac beta-1 and vascular beta-2 and alpha-1
vasculature to produce a net mild vasodilation due to the adrenoreceptors. At low doses (<0.01 lg/kg per min),
combined agonist and antagonist effects on alpha-1 recep- beta-2-induced vasodilation predominates lowering arte-
tors and stimulatory beta-2 effect. In the clinical setting, rial blood pressure, while doses >0.2 lg/kg per min cause
dobutamine increases cardiac output with concomitant a combined inotropic and vasoconstrictor effect that
mild vasodilation, which is encountered mostly at low results overall in increases of peripheral vascular resistance
infusion doses (<5 lg/kg per min). However, at higher and arterial blood pressure. Epinephrine also acts on the
doses peripheral vasoconstriction predominates through pulmonary arterial and venous vasculature through stimu-
vascular alpha-1 receptor stimulation. Dobutamine is lation of beta-2/alpha-1 receptors, increasing pulmonary
administered at doses starting from 1 to 2 lg/kg per min arterial and venous pressure through vasoconstriction, and
up to 20 lg/kg per min, but occasionally doses as high as increased pulmonary blood flow. In the clinical setting,
40 lg/kg per min may be reached. Potential disadvantages epinephrine is especially suitable when combined inotro-
of dobutamine are its possible lower effectiveness in pre- pic/chronotropic and vasoconstrictor effects are urgently
viously treated with beta-blocker patients and the devel- required, as in resuscitation for cardiac arrest. In AHF, it
opment of tolerance even after only a few days of therapy is used in cardiogenic shock. However, a recent open-label
[10]. Dobutamine can cause tachyarrhythmias at any randomized study comparing epinephrine versus a combi-
infusion dose. nation of norepinephrine/dobutamine in cardiogenic
shock has shown that although the two tested regimens
were comparably effective in improving global hemody-
Norepinephrine
namics, epinephrine was associated with unfavorable
Norepinephrine is the major endogenous neurotransmitter metabolic (lactic acidosis), cardiac (higher heart rate and
released by post-ganglionic adrenergic neurons. It primar- arrhythmias), and peripheral organ function effects (inad-
ily induces a prominent agonist effect on vascular alpha-1 equate gastric mucosa perfusion), suggesting that epi-
adrenergic receptors inducing potent vasoconstriction. nephrine may be a less reliable and safe treatment option
However, its effect on cardiac beta-1 receptors is modest, than the combination of dobutamine/norepinephrine in
producing a less potent cardiac-positive inotropic effect. cardiogenic shock [13]. Infusion dose of epinephrine
In the clinical setting, norepinephrine markedly increases ranges from 0.01 to 0.03 lg/kg per min, but doses as high
systolic, diastolic, and pulse pressure with a minimal as 0.5 lg/kg per min may be reached to achieve hemody-
impact on cardiac output. In AHF, norepinephrine is namic goals. Adverse effects include myocardial ischemia,

ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: 10.1002/cce2.59 (109 of 116)
Inotropes in AHF V. Bistola & O. Chioncel

hypertension, ventricular tachyarrhythmias, pulmonary levosimendan is exerted through opening of ATP-sensitive


edema, and cerebral hemorrhage. potassium channels in the vascular smooth muscle cells
[17, 18]. Preliminary results from modest sized trials
suggested higher hemodynamic efficacy and improved
Phosphodiesterase III inhibitors
6-month outcomes of levosimendan over dobutamine in
Phosphodiesterase III inhibitors (PDEI) exert their inotro- patients with low-output AHF (LIDO study) [19] and
pic effect by increasing levels of cAMP in cardiomyocytes levosimendan over placebo in AHF with low cardiac
through inhibition if its breakdown to AMP by the sar- index complicating acute myocardial infarction (RUS-
coplasmic reticulum-associated enzyme phosphodiesterase SLAN trial) [20]. However, two large phase III trials in
III. Acting through the same mechanism in vascular severe low output AHF have failed to confirm previous
smooth muscle cells, PDEIs induce peripheral and pul- encouraging results of levosimendan over dobutamine
monary vasodilatation, thereby reducing systemic arterial (SURVIVE trial) or over placebo (REVIVE-II trial). In
blood pressure, pulmonary arterial and venous pressures, SURVIVE, 6-month mortality did not differ between
and systemic and pulmonary vascular resistances. Due to patients treated with levosimendan compared to dobu-
the mixed inotropic and vasodilator effects of PDEIs, they tamine [21]. In REVIVE-II, although levosimendan lead
are included in the group of inodilators. Because of their to higher rates of symptomatic improvement than pla-
independent mechanism of action from the beta- cebo, it was associated with a trend for increased mortal-
adrenergic receptor pathway, PDEIs are effective in ity at 90 days after treatment. Furthermore, higher rates
patients chronically treated with beta-blockers [14]. of hypotension and ventricular arrhythmias were observed
in the levosimendan treatment arm [22]. Therefore, the
role of levosimendan in AHF remains controversial.
Milrinone
Levosimendan is available for clinical use only in Europe.
Milrinone is the most commonly prescribed PDEI for car- It is indicated for AHF patients with vital organ
diovascular indications. It is approved for intravenous use hypoperfusion to reverse the effect of beta-blockade if
in the United States and some European countries. Milri- beta-blockade is thought to be contributing to hypoten-
none is administered as short-term treatment in AHF sion with subsequent hypoperfusion [3]. It is adminis-
patients with evidence of low cardiac output who are not tered as an infusion at a rate of 0.05–0.2 lg/kg per min,
severely hypotensive (e.g., SBP > 85 mmHg). It is partic- while a bolus initial dosing is not recommended since
ularly useful in cases where beta-adrenergic receptor it may cause excess hypotension and arrhythmias.
downregulation or desensitization is encountered, such as Levosimendan adverse effects include hypotension, ven-
in exacerbations in the setting of chronic HF and in tricular arrhythmias, atrial fibrillation, headache, and
chronic beta-blockade treatment, since these patients hypokalemia.
reportedly respond better to PDEIs than to beta-agonists
[14]. In patients with marginal SBP (e.g., 90–100 mmHg),
Novel Inotropes
a vasoconstrictor (e.g., norepinephrine) should be admin-
istered concomitantly. Side effects of milrinone include
Omecamtiv mecarbil
tachyarrhythmias and hypotension [15]. Caution is
needed when milrinone is prescribed in patients with Omecamtiv mecarbil is a novel molecule that increases
ischemic HF, since it has been shown to increase med- the efficiency of cardiac contraction by selectively activat-
ium-term mortality [16]. Because of the long half-life ing specific isoforms of cardiac myosin. The movement of
(2.5 h) and its renal clearance, caution should be also be myosin chains to bind onto actin filaments during cardiac
exerted when milrinone is administered in patients with contraction is an energy-consuming mechanism, utilizing
impaired or rapidly fluctuating renal function. the energy derived from ATP hydrolysis. Omecamtiv
mecarbil increases the rate of ATP turnover in cardiac
myocytes by accelerating actin-dependent phosphate
Levosimendan
release and by slowing the rate of ADP release. By
Levosimendan exerts a dual effect on the cardiovascular increasing the availability of myosin energy substrate, OM
system, acting simultaneously as a positive inotropic agent prolongs the occupancy time of myosin on the actin
and as a vasodilator (inodilator). Its positive inotropic molecule, increasing the number of myosin molecules
effect is mediated through sensitization of cardiac tro- bound to actin, that is, the number of active cross-bridges
ponin to the prevailing level of intracellular calcium. that participate in the generation of force during contrac-
However, at high doses it may enhance inotropy by also tion [23]. Therefore, OM prolongs contraction by increas-
acting as a PDE III inhibitor. Vasodilatory effect of ing systolic ejection time without increasing the rate of

Continuing Cardiology Education, doi: 10.1002/cce2.59 (110 of 116) ª 2017 Hellenic College of Cardiology
V. Bistola & O. Chioncel Inotropes in AHF

LV pressure development (dP/dt) [23, 24]. Moreover, advanced heart failure in terms of improvement of symp-
intracellular cAMP and free Ca2+ levels remain unaffected toms, exercise capacity, NT-proBNP levels, and LV end-
by OM, suggesting that it may not induce myocardial systolic volume at 6 months after the treatment. Clinical
ischemia and arrhythmias, a common problem with con- improvement was accompanied by a reduction of cardio-
ventional inotropes [24]. Similar to levosimendan, beta- vascular hospitalizations at 6 and 12 months after therapy
blockade does not abrogate the inotropic effect of OM, [33]. The initial encouraging results from CUPID trial
supporting a mechanism of action independent of adren- prompted undertake of a phase IIb trial (CUPID-II),
ergic activation [23]. which was designed to examine the efficacy of (AAV1)/
Omecamtiv mecarbil was the first molecule in the class SERCA2a over placebo to increase time to HF-related
of cardiac myosin activators (CMA) to be tested in clini- recurrent events including HF hospitalizations and ambu-
cal studies. Both in healthy volunteers and in patients latory therapies for worsening HF. In CUPID-II, which
with chronic HF and reduced ejection fraction, OM com- enrolled 250 ambulatory high-risk heart failure patients,
pared to placebo increased hemodynamical and echocar- AAV1/SERCA2a failed to improve HF progression com-
diographical indices of left ventricular systolic function pared to placebo, although no negative safety signals were
including systolic ejection time, stroke volume, fractional noted in the active treatment arm [34].
shortening, and ejection fraction [25, 26]. However, in a
phase II, dose-escalating trial in patients with AHF and
Istaroxime
reduced LVEF, OM failed to improve the primary end-
point of dyspnea relief compared to placebo, although it Istaroxime exerts a dual mechanism of action in the car-
increased systolic ejection time and LV end-systolic diam- diac myocyte: (1) inhibition of sarcolemmal sodium–
eter without increasing rates of ventricular and supraven- potassium ATPase, and (2) stimulation of sarcoplasmic
tricular arrhythmias [27]. However, OM administration reticulum calcium adenosine triphosphatase isoform 2a
was associated with a rise in troponin levels—although (SERCA2a). Through the first mechanism it increases the
without a clear dose relationship effect—which may be levels of intracellular Ca2+, thereby enhancing contractil-
related to the excessive increase in systolic ejection time ity. By the latter pathway it promotes the reuptake of free
occurring at the expense of diastole, possibly impeding Ca2+ into the sarcoplasmic reticulum during diastole,
ventricular and coronary filling [27, 28]. improving myocardial diastolic function (lusitropy). In a
dose-finding, randomized, double-blind phase II study
(HORIZON-HF), istaroxime was superior to placebo in
Modulation of sarcoplasmic reticulum Ca2+
reducing left ventricular filling pressures (PCWP) with an
ATPase
associated rise in arterial systolic blood pressure and
Sarcoplasmic reticulum Ca2+ATPase (SERCA2a) is an lowering of heart rate, without increasing markers of
enzyme that controls free calcium reuptake into the sar- myocardial necrosis [35, 36]. Istaroxime remains under
coplasmic reticulum at the end of systole, regulating both investigation for the treatment of HF patients.
myocardial relaxation and contraction [29]. SERCA2a is
downregulated in heart failure, contributing to contractile
Indications for inotropes in AHF
dysfunction and arrhythmogenesis [30]. Preclinical studies
have shown that restoration of SERCA2a expression Inotropes are indicated in AHF in the presence of
through cardiac-specific adenoviral-mediated SERCA2a hypotension, low cardiac output, and peripheral hypoper-
gene delivery improved LV systolic function and reversed fusion. Based on a large American registry database of
adverse neurohormonal HF phenotype [31]. Therefore, hospitalized HF (ADHERE), patients with the previous
SERCA2a modulation could present a potential therapeu- characteristics constitute approximately 10% of the total
tic strategy in HF. hospitalized HF population [37]. Although temporary
mechanical circulatory support devices are available for
the short-term support of severe cases, these devices are
Genetic modulation of SERCA2a
not widely available, and even where they are available,
SERCA2a gene therapy using recombinant adenoassoci- they are reserved for specific cases of AHF, such as
ated virus serotype1 SERCA2a cDNA delivery [(AAV1)/ bridge-to-heart transplantation, bridge-to-bridge with
SERCA2a] has reached up to phase II clinical testing. more durable devices, or bridge-to-decision for such
After phase I testing confirmed an acceptable safety pro- advanced therapies. Thus, short-term treatment with ino-
file in patients with advanced heart failure [32], a phase tropes is a common initial therapeutic measure to sup-
II trial (CUPID) confirmed the efficacy of intracoronary port critically compromised AHF patients. Goals of
SERCA2a gene delivery over placebo in 39 patients with inotropic therapy are to stabilize patient’s hemodynamic

ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: 10.1002/cce2.59 (111 of 116)
Inotropes in AHF V. Bistola & O. Chioncel

condition (restore blood pressure and cardiac output) vasoconstriction, while the latter is usually seen in
and maintain vital organ function. A general rule guiding patients with previous chronic HF, who commonly exhi-
treatment with inotropes is to use the lowest possible bit marginal arterial blood pressure due to chronic
doses to achieve treatment goals and for the shortest vasodilator treatment (RAAS inhibitors/beta-blockers)
duration of time. without presenting with acute decompensation. Therefore,
AHF patients that usually receive inotropic therapy additional clinical evidence should be sought to confirm
belong to any of the following categories: hypoperfusion, including cool extremities, slowed menta-
tion, and decreased pulse pressure. Laboratory findings
(1) Patients with cardiogenic shock.
implying hypoperfusion are worsening renal (increased
(2) Patients with borderline blood pressure (e.g., 85–
blood urea nitrogen and creatinine levels) and hepatic
95 mmHg) and signs of peripheral hypoperfusion, with-
function, hyponatremia, and elevated blood lactate. In
out overt cardiogenic shock.
hypoperfused AHF patients, an inotrope or an inodilator
(milrinone or levosimendan) may be instituted to restore
adequate end-organ perfusion.
Tips and tricks for the administration of
The choice of the specific agent depends on the specific
inotropes in AHF
clinical and hemodynamic characteristics of each individ-
Cardiogenic shock ual (Fig. 1). Inodilators are preferred in patients who are
peripherally vasoconstricted, while they are not indicated
Cardiogenic shock (CS) is typically defined by severe
as a monotherapy in patients with systolic blood pressure
hypotension (<85 mmHg) that results from severely
<90 mmHg. Concomitant vasoconstrictor may be estab-
reduced cardiac output (CI < 2.0 mL/min per m2), lead-
lished in case of development of hypotension with
ing to high intra-cardiac filling pressures and vital organ
inodilators. Inodilators may also be preferred for patients
hypoperfusion, and is evidenced by findings as cold
on chronic beta-blockade, as mentioned earlier. However,
extremities, altered mental status, low urine output, and
in a small, randomized trial that included 60 AHF
high plasma lactate concentrations. In CS, an inotrope
patients previously treated with beta-blockers (BEAT-CHF
(e.g., dobutamine) should be initiated immediately to
trial), levosimendan was not superior over dobutamine in
improve patient’s hemodynamics and restore vital organ
decreasing PCWP and enhancing cardiac index after 24 h
perfusion until a definitive therapy is planned according
of therapy [40].
to the underlying cause of the shock. Usually, a vasocon-
Another patient subgroup in whom inodilators are
strictor is administered concomitantly to ensure adequate
preferred over beta-agonists is patients with pulmonary
perfusion pressure. Norepinephrine or dopamine is pre-
arterial hypertension, due to the pulmonary arterial
ferred over epinephrine as a vasoconstrictor in cardio-
vasodilatory effect of both milrinone and levosimendan.
genic shock due to the association of the latter with
Such are patients listed for heart transplantation who
increased mortality, and higher levels of lactate, renal
develop pulmonary hypertension during awaiting the pro-
impairment, and myocardial necrosis markers [38]. Com-
cedure or patients who are excluded initially from listing
bination of an inotrope with a vasoconstrictor at moder-
due to increased pulmonary vascular resistances. In such
ate doses is preferred over maximal dosing of a single
patients, milrinone has been effective to reduce PVR. On
agent that would lead to excessive vasoconstriction and
the contrary, milrinone is not indicated in patients with
increased left ventricular afterload increasing the risk of
ischemic heart disease because it may increase medium-
myocardial ischemia and also to a higher risk of arrhyth-
term mortality. Instead, levosimendan or dobutamine
mogenesis [39]. Mechanical circulatory support should be
could be used [16].
considered in patients unresponsive to medical therapy.
Patients with chronic intrinsic renal disease are possibly
better candidates for dobutamine due to its very short
Patients with AHF and peripheral hypoperfusion half-life (~2 min) compared to milrinone (half-life 2.5 h)
without overt cardiogenic shock or levosimendan (half-life of its active metabolite approxi-
mately 80 h). However, in patients with acute cardiorenal
Peripheral hypoperfusion due to low cardiac output is syndrome, levosimendan may be preferred since it has
manifested by significant hypotension. However, hypoper- been shown to exert renoprotective effects by improving
fused patients may not always present with significant renal blood flow [41].
hypotension. Moreover, marginal blood pressure (90– Primary hepatic insufficiency is a contraindication for
100 mmHg) does not always herald peripheral hypoperfu- levosimendan, because of its hepatic excretion. However,
sion. The first scenario is observed in patients with AHF in cardiohepatic dysfunction due to acute decompensa-
in whom neurohormonal activation results in significant tion, levosimendan may be superior to dobutamine, since

Continuing Cardiology Education, doi: 10.1002/cce2.59 (112 of 116) ª 2017 Hellenic College of Cardiology
V. Bistola & O. Chioncel Inotropes in AHF

Figure 1. A clinical guidance algorithm for the choice of the most appropriate inotrope according to the specific acute heart failure setting.
Modified from Ref [53]. CPB, cardiopulmonary bypass.

it improves cholestatic enzyme elevations more effectively compared to dobutamine, by improving CI with less oxy-
than dobutamine [42]. gen consumption, decreasing lactate concentration, and
In cardiopulmonary bypass surgery patients (CPB), improving renal function and gastric mucosal perfusion,
beta-agonists have been widely utilized for post-cardiot- and may even contribute to improved short-term out-
omy low cardiac output state, since their on–off pharma- comes [51, 52].
cokinetic profile is suitable in resuscitation settings.
Among adrenergic agonists, dobutamine appears most
Weaning of inotropes and long-term
favorable since it may enhance coronary blood flow and
inotropic therapy
cause less metabolic disturbances including hyperlac-
tatemia and hyperglycemia compared to dopamine and Inotropes should be tapered gradually starting as soon as
epinephrine [43]. PDEIs have been shown to improve adequate peripheral perfusion has been restored to
hemodynamics with fewer rates of arrhythmias and post- achieve improvement of end-organ function, while con-
operative myocardial infarction compared to dobutamine gestion has resolved through adequate diuresis. During
[44, 45]. Since they are a potent pulmonary arterial tapering a careful adjustment of oral HF medications is
vasodilator, PDEIs can also be used to reduce pulmonary necessary, which is continued after inotrope discontinua-
vascular resistances in cases with pulmonary hypertension, tion. Most AHF patients can be weaned off inotropes
often in combination with inhaled nitric oxide [46]. successfully. However, inotropic dependency may be
Levosimendan has been shown to confer a cardioprotec- encountered in a subset of patients, in whom any attempt
tive effect in the setting of cardiac surgery when it is to wean inotropes precipitates symptomatic hypotension,
administered before the induction of CPB in patients at recurrent symptoms, and signs of HF and end-organ dys-
risk for low cardiac output after surgery, by reducing function, most often worsening renal function. These
post-surgical troponin elevation [47]. This can be trans- patients are considered inotrope dependent and are trea-
lated into clinical benefit with reduction of time to extu- ted with inotropes for longer periods, while a definitive
bation and length of intensive care unit and total hospital treatment such as transplantation or left ventricular assist
stay [47, 48]. Combinations of beta-adrenergic inotropes device implantation is planned (bridge-to-transplant or
with levosimendan or PDEI can be administered in the bridge-to-device), or while a decision for a definite ther-
post-cardiotomy AHF setting. In this respect, the combi- apy is awaited in patients who are not yet candidates for
nation of levosimendan with dobutamine has been shown a definitive treatment but may become so in the future
to result in a more sustained enhancement of cardiac out- (bridge-to-decision). In a subset of patients who do not
put and shortened extubation time and length of hospital become candidates for any definitive therapy, inotropes
stay [49]. may be maintained as palliative treatment to reduce the
In sepsis-related myocardial dysfunction, dobutamine is severity of HF symptoms at the end of life.
currently considered first-line inotrope after standard
fluid resuscitation and vasoconstrictors to maintain ade-
Conclusion
quate perfusion pressure [50]. However, accumulating
data suggest that levosimendan may have more favorable Patients with AHF who present with a low cardiac out-
hemodynamic, metabolic, and regional perfusion effects put state need immediate diagnostic assessment and

ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: 10.1002/cce2.59 (113 of 116)
Inotropes in AHF V. Bistola & O. Chioncel

initiation of appropriate therapeutic measures to prevent furosemide with or without dopamine infusion: the
spiral deterioration and high mortality associated with Dopamine in Acute Decompensated Heart Failure II
this state. Despite the unfavorable adverse effect profile (DAD-HF II) trial. Int J Cardiol 172:115–121.
of inotropic agents and the option for temporary 9. Chen, HH, KJ Anstrom, MM Givertz, et al. 2013. Low-
mechanical circulatory support devices, inotropes remain dose dopamine or low-dose nesiritide in acute heart failure
a frequently utilized first therapeutic measure in such with renal dysfunction: the ROSE acute heart failure
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lowest possible doses of inotropic treatment should be agents in patients with heart failure: a randomized
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rent research focuses on the development of novel ino- after chronic treatment with metoprolol or carvedilol. J
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pathways.
1998. Norepinephrine stimulates apoptosis in adult rat
ventricular myocytes by activation of the beta-adrenergic
Conflict of Interest pathway. Circulation 98:1329–1334.
13. Levy, B, P Perez, J Perny, et al. 2011. Comparison of
Dr. Bistola reports honoraria from Novartis and
norepinephrine-dobutamine to epinephrine for
Dr. Chioncel has nothing to disclose.
hemodynamics, lactate metabolism, and organ function
variables in cardiogenic shock. A prospective, randomized
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