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
Acute heart failure, clinical guidance,
inotropes
Correspondence
V. Bistola, Heart Failure Unit, 2nd
Department of Cardiology, Attikon University
Hospital, National and Kapodistrian University
of Athens, Athens, Greece.
Tel: +30-210-5832355; Fax: +30-210-5832351;
E-mail: vasobistola@yahoo.com
Funding Information
No funding information provided.
Continuing Cardiology Education, 2017;
3(3), https://doi.org/10.1002/cce2.59
Abstract
Acute heart failure (AHF) encompasses a wide range of clinical presentations,
from acute hypertensive heart failure (HF) to low cardiac output hypoperfusion
syndromes with cardiogenic shock at the extreme end of this side. Inotropes
are pharmacologic agents that enhance cardiac contractility, thereby augmenting
cardiac output. Currently, there are three classes of inotropes available in clini-
cal practice with distinct mechanisms of action: beta-adrenergic agonists, phos-
phodiesterase III inhibitors, and the calcium-sensitizer levosimendan. Inotropes
are indicated as short-term therapy in low cardiac output AHF and cardiogenic
shock (usually with coadministration of a vasoconstrictor) to increase cardiac
output, restore peripheral perfusion, and prevent end-organ dysfunction. Ino-
tropes can cause serious cardiovascular adverse effects, most commonly tach-
yarrhythmias and myocardial ischemia and are associated with increased
medium- and long-term mortality in HF. Therefore, intense monitoring is nec-
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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Introduction
Acute heart failure (AHF) is characterized by new onset or
change in the severity of symptoms and signs of HF [1].
Clinical presentation extends from gradually (over days or
even weeks) worsening dyspnea or peripheral edema to the
acute critical states of pulmonary edema or cardiogenic
shock. Accordingly, in-hospital mortality varies widely
between 2% in low-risk patients, who present with conges-
tion but adequate peripheral perfusion without end-organ
dysfunction, to 22% in high-risk patients (evidence of
hypoperfusion or frank cardiogenic shock) [2]. Currently,
no available pharmacologic strategies have proven efficacy
to reduce medium- and long-term morbidity and mortality
in AHF. Therefore, the treatment goals remain primarily eti-
ologic therapy when specific causes of AHF are recognized
(acute coronary syndrome, etc.) and concurrently/parallel
symptomatic relief with alleviation of congestion and hemo-
dynamic stabilization in order to preserve vital end-organ
function [3]. Loop diuretics are first-line agents for the relief
of dyspnea and edema; in hypertensive and normotensive
AHF, vasodilators are administered to reduce ventricular
afterload and indirectly increase cardiac output. Inotropes
and inodilators directly enhance cardiac contractility; there-
fore, they increase cardiac output, which is reduced acutely
in a subset of AHF patients. However, these agents have
been shown to induce adverse cardiovascular effects, includ-
ing myocardial ischemia, tachyarrhythmias, and have been
associated with increases in medium- and long-term mor-
tality. Therefore, their routine use in unselected AHF
patients is not recommended, while they may be considered
as short-term therapy in patients who display evidence of
low cardiac output and peripheral hypoperfusion [3, 4].
Conventional Inotropes
Three major classes of inotropes are currently available
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-
tors (milrinone), and the calcium-sensitizer levosimendan
(Table 1) [5, 6].
Beta-adrenergic agonists
Beta-adrenergic agonists mediate their cardiac inotropic
effect through stimulation of sarcolemmal beta-1 adrener-
gic receptors of cardiac myocytes. This in turn activates
the intracellular adenyl cyclase system leading to increased
formation of cAMP. cAMP stimulates sarcolemmal and
sarcoplasmic reticulum membrane-bound ionic channels
that ultimately promote the release of Ca2+ from the sar-
coplasmic reticulum through the Ca2+-induced Ca2+
release effect. The resultant increase of sarcoplasmic Ca2+
thereby augmenting myocardial contraction [6].
Dopamine
Dopamine is an endogenous molecule that stimulates
dopaminergic type 1 and 2 and beta-1 and alpha-1 adren-
ergic receptors. At low doses (up to 2.5 lg/kg per min),
dopamine causes renal and splachnic vasodilation through
the postsynaptic type 1 and presynaptic type 2 dopamin-
ergic receptors, respectively. Through this mechanism it
increases renal blood flow independently of cardiac out-
put enhancement. However, the clinical significance of
the renal effects of low-dose dopamine remains contro-
versial, since dopamine has not been shown to increase
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
not been demonstrated [7]. In DAD-HF-II study, low-
dose dopamine added to low-dose intravenous furose-
mide did not improve self-rated dyspnea scores, worsen-
ing renal function, short- and long-term mortality, or HF
hospitalizations compared to a strategy of single low-dose
furosemide treatment in acutely decompensated HF [8].
Moreover, ROSE-AHF trial showed no significant differ-
ence between placebo and low-dose dopamine or low-
dose nesiritide in 72-h urine volume as well as markers of
decongestion [9]. At moderate doses (3–5 lg/kg per
min), this agent primarily augments cardiac contraction
and chronotropy through stimulation of the cardiac
beta-1 receptors. At higher doses (>5 lg/kg per min), it
predominantly stimulates alpha-1 receptors producing
vasoconstriction. Dopamine side effects include tach-
yarrhythmias, which become more frequent at doses of
10 lg/kg per min and above, and hypertension.
Dobutamine
Dobutamine is a synthetic molecule that stimulates beta-
1, beta-2, and alpha-1 adrenergic receptors in order of
decreasing strength. By binding to cardiac beta-1 recep-
tors, dobutamine enhances cardiac contractility with
weaker chronotropic effects. Dobutamine also acts on the
vasculature to produce a net mild vasodilation due to the
combined agonist and antagonist effects on alpha-1 recep-
tors and stimulatory beta-2 effect. In the clinical setting,
dobutamine increases cardiac output with concomitant
mild vasodilation, which is encountered mostly at low
infusion doses (<5 lg/kg per min). However, at higher
doses peripheral vasoconstriction predominates through
vascular alpha-1 receptor stimulation. Dobutamine is
administered at doses starting from 1 to 2 lg/kg per min
up to 20 lg/kg per min, but occasionally doses as high as
40 lg/kg per min may be reached. Potential disadvantages
of dobutamine are its possible lower effectiveness in pre-
viously treated with beta-blocker patients and the devel-
opment of tolerance even after only a few days of therapy
[10]. Dobutamine can cause tachyarrhythmias at any
infusion dose.
Norepinephrine
Norepinephrine is the major endogenous neurotransmitter
released by post-ganglionic adrenergic neurons. It primar-
ily induces a prominent agonist effect on vascular alpha-1
adrenergic receptors inducing potent vasoconstriction.
However, its effect on cardiac beta-1 receptors is modest,
producing a less potent cardiac-positive inotropic effect.
In the clinical setting, norepinephrine markedly increases
systolic, diastolic, and pulse pressure with a minimal
impact on cardiac output. In AHF, norepinephrine is
ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: 10.1002/cce2.59 (109 of 116)
Inotropes in AHF
used in cardiogenic shock in conjunction with primarily
inotropic agents as well as in patients treated with
inodilators to avoid hypotension [3]. Moreover, its use
also applies in a wide spectrum of non-cardiogenic shock
etiologies, including septic, hypovolemic, and systemic
inflammatory response syndrome (SIRS)-related shock. In
a recent trial comparing norepinephrine to dopamine in
cardiogenic and non-cardiogenic shock, norepinephrine
was similarly efficacious in terms of 28 days mortality
albeit safer than dopamine, which was associated with
higher rates of arrhythmic adverse events and higher
mortality in the subgroup of cardiogenic shock [11].
Norepinephrine is usually prescribed at doses of 0.01–
0.03 lg/kg per min, which can be up-titrated to 1 lg/kg
per min to achieve the required levels of systolic blood
pressure. Prolonged infusions of norepinephrine can cause
direct myocardial toxic effects, through the induction of
cardiomyocyte apoptosis [12]. Norepinephrine adverse
effects include myocardial ischemia, arrhythmias, and
hypertension.
Epinephrine
Epinephrine is an endogenous catecholamine that stimu-
lates cardiac beta-1 and vascular beta-2 and alpha-1
adrenoreceptors. At low doses (<0.01 lg/kg per min),
beta-2-induced vasodilation predominates lowering arte-
rial blood pressure, while doses >0.2 lg/kg per min cause
a combined inotropic and vasoconstrictor effect that
results overall in increases of peripheral vascular resistance
and arterial blood pressure. Epinephrine also acts on the
pulmonary arterial and venous vasculature through stimu-
lation of beta-2/alpha-1 receptors, increasing pulmonary
arterial and venous pressure through vasoconstriction, and
increased pulmonary blood flow. In the clinical setting,
epinephrine is especially suitable when combined inotro-
pic/chronotropic and vasoconstrictor effects are urgently
required, as in resuscitation for cardiac arrest. In AHF, it
is used in cardiogenic shock. However, a recent open-label
randomized study comparing epinephrine versus a combi-
nation of norepinephrine/dobutamine in cardiogenic
shock has shown that although the two tested regimens
were comparably effective in improving global hemody-
namics, epinephrine was associated with unfavorable
metabolic (lactic acidosis), cardiac (higher heart rate and
arrhythmias), and peripheral organ function effects (inad-
equate gastric mucosa perfusion), suggesting that epi-
nephrine may be a less reliable and safe treatment option
than the combination of dobutamine/norepinephrine in
cardiogenic shock [13]. Infusion dose of epinephrine
ranges from 0.01 to 0.03 lg/kg per min, but doses as high
as 0.5 lg/kg per min may be reached to achieve hemody-
namic goals. Adverse effects include myocardial ischemia,
Inotropes in AHF
hypertension, ventricular tachyarrhythmias, pulmonary
edema, and cerebral hemorrhage.
Phosphodiesterase III inhibitors
Phosphodiesterase III inhibitors (PDEI) exert their inotro-
pic effect by increasing levels of cAMP in cardiomyocytes
through inhibition if its breakdown to AMP by the sar-
coplasmic reticulum-associated enzyme phosphodiesterase
III. Acting through the same mechanism in vascular
smooth muscle cells, PDEIs induce peripheral and pul-
monary vasodilatation, thereby reducing systemic arterial
blood pressure, pulmonary arterial and venous pressures,
and systemic and pulmonary vascular resistances. Due to
the mixed inotropic and vasodilator effects of PDEIs, they
are included in the group of inodilators. Because of their
independent mechanism of action from the beta-
adrenergic receptor pathway, PDEIs are effective in
patients chronically treated with beta-blockers [14].
Milrinone
Milrinone is the most commonly prescribed PDEI for car-
diovascular indications. It is approved for intravenous use
in the United States and some European countries. Milri-
none is administered as short-term treatment in AHF
patients with evidence of low cardiac output who are not
severely hypotensive (e.g., SBP > 85 mmHg). It is partic-
ularly useful in cases where beta-adrenergic receptor
downregulation or desensitization is encountered, such as
in exacerbations in the setting of chronic HF and in
chronic beta-blockade treatment, since these patients
reportedly respond better to PDEIs than to beta-agonists
[14]. In patients with marginal SBP (e.g., 90–100 mmHg),
a vasoconstrictor (e.g., norepinephrine) should be admin-
istered concomitantly. Side effects of milrinone include
tachyarrhythmias and hypotension [15]. Caution is
needed when milrinone is prescribed in patients with
ischemic HF, since it has been shown to increase med-
ium-term mortality [16]. Because of the long half-life
(2.5 h) and its renal clearance, caution should be also be
exerted when milrinone is administered in patients with
impaired or rapidly fluctuating renal function.
Levosimendan
Levosimendan exerts a dual effect on the cardiovascular
system, acting simultaneously as a positive inotropic agent
and as a vasodilator (inodilator). Its positive inotropic
effect is mediated through sensitization of cardiac tro-
ponin to the prevailing level of intracellular calcium.
However, at high doses it may enhance inotropy by also
acting as a PDE III inhibitor. Vasodilatory effect of
Continuing Cardiology Education, doi: 10.1002/cce2.59 (110 of 116)
V. Bistola & O. Chioncel
levosimendan is exerted through opening of ATP-sensitive
potassium channels in the vascular smooth muscle cells
[17, 18]. Preliminary results from modest sized trials
suggested higher hemodynamic efficacy and improved
6-month outcomes of levosimendan over dobutamine in
patients with low-output AHF (LIDO study) [19] and
levosimendan over placebo in AHF with low cardiac
index complicating acute myocardial infarction (RUS-
SLAN trial) [20]. However, two large phase III trials in
severe low output AHF have failed to confirm previous
encouraging results of levosimendan over dobutamine
(SURVIVE trial) or over placebo (REVIVE-II trial). In
SURVIVE, 6-month mortality did not differ between
patients treated with levosimendan compared to dobu-
tamine [21]. In REVIVE-II, although levosimendan lead
to higher rates of symptomatic improvement than pla-
cebo, it was associated with a trend for increased mortal-
ity at 90 days after treatment. Furthermore, higher rates
of hypotension and ventricular arrhythmias were observed
in the levosimendan treatment arm [22]. Therefore, the
role of levosimendan in AHF remains controversial.
Levosimendan is available for clinical use only in Europe.
It is indicated for AHF patients with vital organ
hypoperfusion to reverse the effect of beta-blockade if
beta-blockade is thought to be contributing to hypoten-
sion with subsequent hypoperfusion [3]. It is adminis-
tered as an infusion at a rate of 0.05–0.2 lg/kg per min,
while a bolus initial dosing is not recommended since
it may cause excess hypotension and arrhythmias.
Levosimendan adverse effects include hypotension, ven-
tricular arrhythmias, atrial fibrillation, headache, and
hypokalemia.
Novel Inotropes
Omecamtiv mecarbil
Omecamtiv mecarbil is a novel molecule that increases
the efficiency of cardiac contraction by selectively activat-
ing specific isoforms of cardiac myosin. The movement of
myosin chains to bind onto actin filaments during cardiac
contraction is an energy-consuming mechanism, utilizing
the energy derived from ATP hydrolysis. Omecamtiv
mecarbil increases the rate of ATP turnover in cardiac
myocytes by accelerating actin-dependent phosphate
release and by slowing the rate of ADP release. By
increasing the availability of myosin energy substrate, OM
prolongs the occupancy time of myosin on the actin
molecule, increasing the number of myosin molecules
bound to actin, that is, the number of active cross-bridges
that participate in the generation of force during contrac-
tion [23]. Therefore, OM prolongs contraction by increas-
ing systolic ejection time without increasing the rate of
ª 2017 Hellenic College of Cardiology
V. Bistola & O. Chioncel
LV pressure development (dP/dt) [23, 24]. Moreover,
intracellular cAMP and free Ca2+ levels remain unaffected
by OM, suggesting that it may not induce myocardial
ischemia and arrhythmias, a common problem with con-
ventional inotropes [24]. Similar to levosimendan, beta-
blockade does not abrogate the inotropic effect of OM,
supporting a mechanism of action independent of adren-
ergic activation [23].
Omecamtiv mecarbil was the first molecule in the class
of cardiac myosin activators (CMA) to be tested in clini-
cal studies. Both in healthy volunteers and in patients
with chronic HF and reduced ejection fraction, OM com-
pared to placebo increased hemodynamical and echocar-
diographical indices of left ventricular systolic function
including systolic ejection time, stroke volume, fractional
shortening, and ejection fraction [25, 26]. However, in a
phase II, dose-escalating trial in patients with AHF and
reduced LVEF, OM failed to improve the primary end-
point of dyspnea relief compared to placebo, although it
increased systolic ejection time and LV end-systolic diam-
eter without increasing rates of ventricular and supraven-
tricular arrhythmias [27]. However, OM administration
was associated with a rise in troponin levels—although
without a clear dose relationship effect—which may be
related to the excessive increase in systolic ejection time
occurring at the expense of diastole, possibly impeding
ventricular and coronary filling [27, 28].
Modulation of sarcoplasmic reticulum Ca2+
ATPase
Sarcoplasmic reticulum Ca2+ATPase (SERCA2a) is an
enzyme that controls free calcium reuptake into the sar-
coplasmic reticulum at the end of systole, regulating both
myocardial relaxation and contraction [29]. SERCA2a is
downregulated in heart failure, contributing to contractile
dysfunction and arrhythmogenesis [30]. Preclinical studies
have shown that restoration of SERCA2a expression
through cardiac-specific adenoviral-mediated SERCA2a
gene delivery improved LV systolic function and reversed
adverse neurohormonal HF phenotype [31]. Therefore,
SERCA2a modulation could present a potential therapeu-
tic strategy in HF.
Genetic modulation of SERCA2a
SERCA2a gene therapy using recombinant adenoassoci-
ated virus serotype1 SERCA2a cDNA delivery [(AAV1)/
SERCA2a] has reached up to phase II clinical testing.
After phase I testing confirmed an acceptable safety pro-
file in patients with advanced heart failure [32], a phase
II trial (CUPID) confirmed the efficacy of intracoronary
SERCA2a gene delivery over placebo in 39 patients with
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Inotropes in AHF
advanced heart failure in terms of improvement of symp-
toms, exercise capacity, NT-proBNP levels, and LV end-
systolic volume at 6 months after the treatment. Clinical
improvement was accompanied by a reduction of cardio-
vascular hospitalizations at 6 and 12 months after therapy
[33]. The initial encouraging results from CUPID trial
prompted undertake of a phase IIb trial (CUPID-II),
which was designed to examine the efficacy of (AAV1)/
SERCA2a over placebo to increase time to HF-related
recurrent events including HF hospitalizations and ambu-
latory therapies for worsening HF. In CUPID-II, which
enrolled 250 ambulatory high-risk heart failure patients,
AAV1/SERCA2a failed to improve HF progression com-
pared to placebo, although no negative safety signals were
noted in the active treatment arm [34].
Istaroxime
Istaroxime exerts a dual mechanism of action in the car-
diac myocyte: (1) inhibition of sarcolemmal sodium–
potassium ATPase, and (2) stimulation of sarcoplasmic
reticulum calcium adenosine triphosphatase isoform 2a
(SERCA2a). Through the first mechanism it increases the
levels of intracellular Ca2+, thereby enhancing contractil-
ity. By the latter pathway it promotes the reuptake of free
Ca2+ into the sarcoplasmic reticulum during diastole,
improving myocardial diastolic function (lusitropy). In a
dose-finding, randomized, double-blind phase II study
(HORIZON-HF), istaroxime was superior to placebo in
reducing left ventricular filling pressures (PCWP) with an
associated rise in arterial systolic blood pressure and
lowering of heart rate, without increasing markers of
myocardial necrosis [35, 36]. Istaroxime remains under
investigation for the treatment of HF patients.
Indications for inotropes in AHF
Inotropes are indicated in AHF in the presence of
hypotension, low cardiac output, and peripheral hypoper-
fusion. Based on a large American registry database of
hospitalized HF (ADHERE), patients with the previous
characteristics constitute approximately 10% of the total
hospitalized HF population [37]. Although temporary
mechanical circulatory support devices are available for
the short-term support of severe cases, these devices are
not widely available, and even where they are available,
they are reserved for specific cases of AHF, such as
bridge-to-heart transplantation, bridge-to-bridge with
more durable devices, or bridge-to-decision for such
advanced therapies. Thus, short-term treatment with ino-
tropes is a common initial therapeutic measure to sup-
port critically compromised AHF patients. Goals of
inotropic therapy are to stabilize patient’s hemodynamic
Inotropes in AHF
condition (restore blood pressure and cardiac output)
and maintain vital organ function. A general rule guiding
treatment with inotropes is to use the lowest possible
doses to achieve treatment goals and for the shortest
duration of time.
AHF patients that usually receive inotropic therapy
belong to any of the following categories:
(1) Patients with cardiogenic shock.
(2) Patients with borderline blood pressure (e.g., 85–
95 mmHg) and signs of peripheral hypoperfusion, with-
out overt cardiogenic shock.
Tips and tricks for the administration of
inotropes in AHF
Cardiogenic shock
Cardiogenic shock (CS) is typically defined by severe
hypotension (<85 mmHg) that results from severely
reduced cardiac output (CI < 2.0 mL/min per m2), lead-
ing to high intra-cardiac filling pressures and vital organ
hypoperfusion, and is evidenced by findings as cold
extremities, altered mental status, low urine output, and
high plasma lactate concentrations. In CS, an inotrope
(e.g., dobutamine) should be initiated immediately to
improve patient’s hemodynamics and restore vital organ
perfusion until a definitive therapy is planned according
to the underlying cause of the shock. Usually, a vasocon-
strictor is administered concomitantly to ensure adequate
perfusion pressure. Norepinephrine or dopamine is pre-
ferred over epinephrine as a vasoconstrictor in cardio-
genic shock due to the association of the latter with
increased mortality, and higher levels of lactate, renal
impairment, and myocardial necrosis markers [38]. Com-
bination of an inotrope with a vasoconstrictor at moder-
ate doses is preferred over maximal dosing of a single
agent that would lead to excessive vasoconstriction and
increased left ventricular afterload increasing the risk of
myocardial ischemia and also to a higher risk of arrhyth-
mogenesis [39]. Mechanical circulatory support should be
considered in patients unresponsive to medical therapy.
Patients with AHF and peripheral hypoperfusion
without overt cardiogenic shock
Peripheral hypoperfusion due to low cardiac output is
manifested by significant hypotension. However, hypoper-
fused patients may not always present with significant
hypotension. Moreover, marginal blood pressure (90–
100 mmHg) does not always herald peripheral hypoperfu-
sion. The first scenario is observed in patients with AHF
in whom neurohormonal activation results in significant
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V. Bistola & O. Chioncel
vasoconstriction, while the latter is usually seen in
patients with previous chronic HF, who commonly exhi-
bit marginal arterial blood pressure due to chronic
vasodilator treatment (RAAS inhibitors/beta-blockers)
without presenting with acute decompensation. Therefore,
additional clinical evidence should be sought to confirm
hypoperfusion, including cool extremities, slowed menta-
tion, and decreased pulse pressure. Laboratory findings
implying hypoperfusion are worsening renal (increased
blood urea nitrogen and creatinine levels) and hepatic
function, hyponatremia, and elevated blood lactate. In
hypoperfused AHF patients, an inotrope or an inodilator
(milrinone or levosimendan) may be instituted to restore
adequate end-organ perfusion.
The choice of the specific agent depends on the specific
clinical and hemodynamic characteristics of each individ-
ual (Fig. 1). Inodilators are preferred in patients who are
peripherally vasoconstricted, while they are not indicated
as a monotherapy in patients with systolic blood pressure
<90 mmHg. Concomitant vasoconstrictor may be estab-
lished in case of development of hypotension with
inodilators. Inodilators may also be preferred for patients
on chronic beta-blockade, as mentioned earlier. However,
in a small, randomized trial that included 60 AHF
patients previously treated with beta-blockers (BEAT-CHF
trial), levosimendan was not superior over dobutamine in
decreasing PCWP and enhancing cardiac index after 24 h
of therapy [40].
Another patient subgroup in whom inodilators are
preferred over beta-agonists is patients with pulmonary
arterial hypertension, due to the pulmonary arterial
vasodilatory effect of both milrinone and levosimendan.
Such are patients listed for heart transplantation who
develop pulmonary hypertension during awaiting the pro-
cedure or patients who are excluded initially from listing
due to increased pulmonary vascular resistances. In such
patients, milrinone has been effective to reduce PVR. On
the contrary, milrinone is not indicated in patients with
ischemic heart disease because it may increase medium-
term mortality. Instead, levosimendan or dobutamine
could be used [16].
Patients with chronic intrinsic renal disease are possibly
better candidates for dobutamine due to its very short
half-life (~2 min) compared to milrinone (half-life 2.5 h)
or levosimendan (half-life of its active metabolite approxi-
mately 80 h). However, in patients with acute cardiorenal
syndrome, levosimendan may be preferred since it has
been shown to exert renoprotective effects by improving
renal blood flow [41].
Primary hepatic insufficiency is a contraindication for
levosimendan, because of its hepatic excretion. However,
in cardiohepatic dysfunction due to acute decompensa-
tion, levosimendan may be superior to dobutamine, since
ª 2017 Hellenic College of Cardiology
V. Bistola & O. Chioncel
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
than dobutamine [42].
In cardiopulmonary bypass surgery patients (CPB),
beta-agonists have been widely utilized for post-cardiot-
omy low cardiac output state, since their on–off pharma-
cokinetic profile is suitable in resuscitation settings.
Among adrenergic agonists, dobutamine appears most
favorable since it may enhance coronary blood flow and
cause less metabolic disturbances including hyperlac-
tatemia and hyperglycemia compared to dopamine and
epinephrine [43]. PDEIs have been shown to improve
hemodynamics with fewer rates of arrhythmias and post-
operative myocardial infarction compared to dobutamine
[44, 45]. Since they are a potent pulmonary arterial
vasodilator, PDEIs can also be used to reduce pulmonary
vascular resistances in cases with pulmonary hypertension,
often in combination with inhaled nitric oxide [46].
Levosimendan has been shown to confer a cardioprotec-
tive effect in the setting of cardiac surgery when it is
administered before the induction of CPB in patients at
risk for low cardiac output after surgery, by reducing
post-surgical troponin elevation [47]. This can be trans-
lated into clinical benefit with reduction of time to extu-
bation and length of intensive care unit and total hospital
stay [47, 48]. Combinations of beta-adrenergic inotropes
with levosimendan or PDEI can be administered in the
post-cardiotomy AHF setting. In this respect, the combi-
nation of levosimendan with dobutamine has been shown
to result in a more sustained enhancement of cardiac out-
put and shortened extubation time and length of hospital
stay [49].
In sepsis-related myocardial dysfunction, dobutamine is
currently considered first-line inotrope after standard
fluid resuscitation and vasoconstrictors to maintain ade-
quate perfusion pressure [50]. However, accumulating
data suggest that levosimendan may have more favorable
hemodynamic, metabolic, and regional perfusion effects
ª 2017 Hellenic College of Cardiology
Inotropes in AHF
compared to dobutamine, by improving CI with less oxy-
gen consumption, decreasing lactate concentration, and
improving renal function and gastric mucosal perfusion,
and may even contribute to improved short-term out-
comes [51, 52].
Weaning of inotropes and long-term
inotropic therapy
Inotropes should be tapered gradually starting as soon as
adequate peripheral perfusion has been restored to
achieve improvement of end-organ function, while con-
gestion has resolved through adequate diuresis. During
tapering a careful adjustment of oral HF medications is
necessary, which is continued after inotrope discontinua-
tion. Most AHF patients can be weaned off inotropes
successfully. However, inotropic dependency may be
encountered in a subset of patients, in whom any attempt
to wean inotropes precipitates symptomatic hypotension,
recurrent symptoms, and signs of HF and end-organ dys-
function, most often worsening renal function. These
patients are considered inotrope dependent and are trea-
ted with inotropes for longer periods, while a definitive
treatment such as transplantation or left ventricular assist
device implantation is planned (bridge-to-transplant or
bridge-to-device), or while a decision for a definite ther-
apy is awaited in patients who are not yet candidates for
a definitive treatment but may become so in the future
(bridge-to-decision). In a subset of patients who do not
become candidates for any definitive therapy, inotropes
may be maintained as palliative treatment to reduce the
severity of HF symptoms at the end of life.
Conclusion
Patients with AHF who present with a low cardiac out-
put state need immediate diagnostic assessment and
Continuing Cardiology Education, doi: 10.1002/cce2.59 (113 of 116)
Inotropes in AHF
initiation of appropriate therapeutic measures to prevent
spiral deterioration and high mortality associated with
this state. Despite the unfavorable adverse effect profile
of inotropic agents and the option for temporary
mechanical circulatory support devices, inotropes remain
a frequently utilized first therapeutic measure in such
patients due to their wide availability, ease, and rapidity
of application. In order to limit adverse effects, mostly
arrhythmia and myocardial ischemia, short duration and
lowest possible doses of inotropic treatment should be
aimed for, coupled with close patient monitoring. Cur-
rent research focuses on the development of novel ino-
tropic molecules that would avoid the increase of
myocardial oxygen demand and the resulting myocardial
ischemia and arrhythmogenesis of conventional ino-
tropes, by acting through novel myocardial intracellular
pathways.
Conflict of Interest
Dr. Bistola reports honoraria from Novartis and
Dr. Chioncel has nothing to disclose.
References
1. Filippatos, G, and F Zannad. 2007. An introduction to
acute heart failure syndromes: definition and classification.
Heart Fail Rev 12:87–90.
2. Maggioni, AP, U Dahlstrom, G Filippatos, et al. 2010.
EURObservational Research Programme: the Heart Failure
Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 12:1076–1084.
3. Ponikowski, P, Voors, AA, and SD Anker et al. 2016 ESC
Guidelines for the diagnosis and treatment of acute and
chronic heart failure: The Task Force for the diagnosis and
treatment of acute and chronic heart failure of the
European Society of Cardiology (ESC)Developed with the
special contribution of the Heart Failure Association
(HFA) of the ESC. Eur Heart J 37:2129–2200.
4. Stevenson, LW. 2003. Clinical use of inotropic therapy for
heart failure: looking backward or forward? Part I:
inotropic infusions during hospitalization. Circulation
108:367–372.
5. Hasenfuss, G. Teerlink, JR.Cardiac inotropes: current
agents and future directions. Eur Heart J 32: 1838–1845.
6. Overgaard, CB, and V Dzavik. 2008. Inotropes and
vasopressors: review of physiology and clinical use in
cardiovascular disease. Circulation 118:1047–1056.
7. Bellomo, R, M Chapman, S Finfer, et al. 2000. Low-dose
dopamine in patients with early renal dysfunction: a
placebo-controlled randomised trial. Australian and New
Zealand Intensive Care Society (ANZICS) Clinical Trials
Group. Lancet 356:2139–2143.
8. Triposkiadis, FK, J Butler, G Karayannis, et al. 2014.
Efficacy and safety of high dose versus low dose
Continuing Cardiology Education, doi: 10.1002/cce2.59 (114 of 116)
V. Bistola & O. Chioncel
furosemide with or without dopamine infusion: the
Dopamine in Acute Decompensated Heart Failure II
(DAD-HF II) trial. Int J Cardiol 172:115–121.
9. Chen, HH, KJ Anstrom, MM Givertz, et al. 2013. Low-
dose dopamine or low-dose nesiritide in acute heart failure
with renal dysfunction: the ROSE acute heart failure
randomized trial. JAMA 310:2533–2543.
10. Metra, M, S Nodari, A D’Aloia, et al. 2002. Beta-blocker
therapy influences the hemodynamic response to inotropic
agents in patients with heart failure: a randomized
comparison of dobutamine and enoximone before and
after chronic treatment with metoprolol or carvedilol. J
Am Coll Cardiol 40:1248–1258.
11. De Backer, D, P Biston, J Devriendt, et al. 2010.
Comparison of dopamine and norepinephrine in the
treatment of shock. N Engl J Med 362:779–789.
12. Communal, C, K Singh, DR Pimentel, and WS Colucci.
1998. Norepinephrine stimulates apoptosis in adult rat
ventricular myocytes by activation of the beta-adrenergic
pathway. Circulation 98:1329–1334.
13. Levy, B, P Perez, J Perny, et al. 2011. Comparison of
norepinephrine-dobutamine to epinephrine for
hemodynamics, lactate metabolism, and organ function
variables in cardiogenic shock. A prospective, randomized
pilot study. Crit Care Med 39:450–455.
14. Lowes, BD, T Tsvetkova, EJ Eichhorn, et al. 2001.
Milrinone versus dobutamine in heart failure subjects
treated chronically with carvedilol. Int J Cardiol 81:141–
149.
15. Cuffe, MS, RM Califf, KF Adams Jr, et al. 2002. Short-
term intravenous milrinone for acute exacerbation of
chronic heart failure: a randomized controlled trial. JAMA
287:1541–1547.
16. Felker, GM, RL Benza, AB Chandler, et al. 2003. Heart
failure etiology and response to milrinone in
decompensated heart failure: results from the OPTIME-CHF
study. J Am Coll Cardiol 41:997–1003.
17. Parissis, JT, I Andreadou, V Bistola, et al. 2008. Novel
biologic mechanisms of levosimendan and its effect on the
failing heart. Expert Opin Investig Drugs 17:1143–1150.
18. Papp, Z, I Edes, S Fruhwald, et al. 2012. Levosimendan:
molecular mechanisms and clinical implications: consensus
of experts on the mechanisms of action of levosimendan.
Int J Cardiol 159:82–87.
19. Follath, F, JG Cleland, H Just, et al. 2002. Efficacy and safety
of intravenous levosimendan compared with dobutamine in
severe low-output heart failure (the LIDO study): a
randomised double-blind trial. Lancet 360:196–202.
20. Moiseyev, VS, P Poder, N Andrejevs, et al. 2002. Safety
and efficacy of a novel calcium sensitizer, levosimendan, in
patients with left ventricular failure due to an acute
myocardial infarction. A randomized, placebo-controlled,
double-blind study (RUSSLAN). Eur Heart J 23:1422–
1432.
ª 2017 Hellenic College of Cardiology
V. Bistola & O. Chioncel
21. Mebazaa, A, MS Nieminen, M Packer, et al. 2007.
Levosimendan vs dobutamine for patients with acute
decompensated heart failure: the SURVIVE Randomized
Trial. JAMA 297:1883–1891.
22. Cleland, JG, N Freemantle, AP Coletta, and AL Clark.
2006. Clinical trials update from the American Heart
Association: REPAIR-AMI, ASTAMI, JELIS, MEGA,
REVIVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail
8:105–110.
23. Malik, FI, JJ Hartman, KA Elias, et al. 2011. Cardiac
myosin activation: a potential therapeutic approach for
systolic heart failure. Science 331:1439–1443.
24. Shen, YT, FI Malik, X Zhao, et al. 2010. Improvement of
cardiac function by a cardiac Myosin activator in conscious
dogs with systolic heart failure. Circ Heart Fail 3:522–527.
25. Teerlink, JR, CP Clarke, and KG Saikali et al. Dose-
dependent augmentation of cardiac systolic function with
the selective cardiac myosin activator, omecamtiv mecarbil:
a first-in-man study. Lancet 378: 667–675.
26. Cleland, JG, JR Teerlink, and R Senior et al. The effects of
the cardiac myosin activator, omecamtiv mecarbil, on
cardiac function in systolic heart failure: a double-blind,
placebo-controlled, crossover, dose-ranging phase 2 trial.
Lancet 378: 676–683.
27. Teerlink, JR, GM Felker, JJ McMurray, et al. 2016. Acute
Treatment With Omecamtiv Mecarbil to Increase
Contractility in Acute Heart Failure: The ATOMIC-AHF
Study. J Am Coll Cardiol 67:1444–1455.
28. Meijs, MF, FW Asselbergs, and PA Doevendans. 2012.
Omecamtiv mecarbil: a promising new drug in systolic
heart failure. Eur J Heart Fail 14:232–233.
29. Kranias, EG, and RJ Hajjar. 2012. Modulation of cardiac
contractility by the phospholamban/SERCA2a regulatome.
Circ Res 110:1646–1660.
30. Mercadier, JJ, AM Lompre, P Duc, et al. 1990. Altered
sarcoplasmic reticulum Ca2(+)-ATPase gene expression in
the human ventricle during end-stage heart failure. J Clin
Invest 85:305–309.
31. Byrne, MJ, JM Power, A Preovolos, et al. 2008.
Recirculating cardiac delivery of AAV2/1SERCA2a
improves myocardial function in an experimental model of
heart failure in large animals. Gene Ther 15:1550–1557.
32. Jaski, BE, ML Jessup, DM Mancini, et al. 2009. Calcium
upregulation by percutaneous administration of gene
therapy in cardiac disease (CUPID Trial), a first-in-human
phase 1/2 clinical trial. J Card Fail 15:171–181.
33. Jessup, M, B Greenberg, D Mancini, et al. 2011. Calcium
Upregulation by Percutaneous Administration of Gene
Therapy in Cardiac Disease (CUPID): a phase 2 trial of
intracoronary gene therapy of sarcoplasmic reticulum
Ca2+-ATPase in patients with advanced heart failure.
Circulation 124:304–313.
34. Greenberg, B, J Butler, GM Felker, et al. 2016. Calcium
upregulation by percutaneous administration of gene
ª 2017 Hellenic College of Cardiology Continuing Cardiology Education, doi: 10.1002/cce2.59 (115 of 116)
Inotropes in AHF
therapy in patients with cardiac disease (CUPID 2): a
randomised, multinational, double-blind, placebo-
controlled, phase 2b trial. Lancet 387:1178–1186.
35. Gheorghiade, M, JE Blair, GS Filippatos, et al. 2008.
Hemodynamic, echocardiographic, and neurohormonal
effects of istaroxime, a novel intravenous inotropic and
lusitropic agent: a randomized controlled trial in patients
hospitalized with heart failure. J Am Coll Cardiol 51:2276–
2285.
36. Shah, SJ, JE Blair, GS Filippatos, et al. 2009. Effects of
istaroxime on diastolic stiffness in acute heart failure
syndromes: results from the Hemodynamic,
Echocardiographic, and Neurohormonal Effects of
Istaroxime, a Novel Intravenous Inotropic and Lusitropic
Agent: a Randomized Controlled Trial in Patients
Hospitalized with Heart Failure (HORIZON-HF) trial. Am
Heart J 157:1035–1041.
37. Abraham, WT, KF Adams, GC Fonarow, et al. 2005. In-
hospital mortality in patients with acute decompensated
heart failure requiring intravenous vasoactive medications:
an analysis from the Acute Decompensated Heart Failure
National Registry (ADHERE). J Am Coll Cardiol 46:57–64.
38. Tarvasmaki, T, J Lassus, M Varpula, et al. 2016. Current
real-life use of vasopressors and inotropes in cardiogenic
shock - adrenaline use is associated with excess organ
injury and mortality. Crit Care 20:208.
39. Richard, C, JL Ricome, A Rimailho, et al. 1983. Combined
hemodynamic effects of dopamine and dobutamine in
cardiogenic shock. Circulation 67:620–626.
40. Bergh, CH, Andersson, B, , and U Dahlstrom et al.
Intravenous levosimendan vs. dobutamine in acute
decompensated heart failure patients on beta-blockers. Eur
J Heart Fail 12: 404–410.
41. Rafouli-Stergiou, P, Parissis, JT, and M Anastasiou-Nana.
Inotropes for the management of acute heart failure
patients with renal dysfunction. Still an option? Expert
Opin Pharmacother 13: 2637–2647.
42. Nikolaou, M, J Parissis, MB Yilmaz, et al. 2013. Liver
function abnormalities, clinical profile, and outcome
in acute decompensated heart failure. Eur Heart J
34:742–749.
43. Fowler, MB, EL Alderman, SN Oesterle, et al. 1984.
Dobutamine and dopamine after cardiac surgery: greater
augmentation of myocardial blood flow with dobutamine.
Circulation 70:I103–111.
44. Feneck, RO, KM Sherry, PS Withington, and A Oduro-
Dominah. 2001. Comparison of the hemodynamic effects
of milrinone with dobutamine in patients after cardiac
surgery. J Cardiothorac Vasc Anesth 15:306–315.
45. Dupuis, JY, R Bondy, C Cattran, et al. 1992. Amrinone
and dobutamine as primary treatment of low cardiac
output syndrome following coronary artery surgery: a
comparison of their effects on hemodynamics and
outcome. J Cardiothorac Vasc Anesth 6:542–553.
Inotropes in AHF
46. Rathmell, JP, RC Prielipp, JF Butterworth, et al. 1998. A
multicenter, randomized, blind comparison of amrinone
with milrinone after elective cardiac surgery. Anesth Analg 50.
86:683–690.
47. Eriksson, HI, JR Jalonen, LO Heikkinen, et al. 2009. 51.
Levosimendan facilitates weaning from cardiopulmonary
bypass in patients undergoing coronary artery bypass
grafting with impaired left ventricular function. Ann 52.
Thorac Surg 87:448–454.
48. Tritapepe, L, V De Santis, D Vitale, et al. 2009.
Levosimendan pre-treatment improves outcomes in
patients undergoing coronary artery bypass graft surgery. 53.
Br J Anaesth 102:198–204.
49. De Hert, SG, S Lorsomradee, S Cromheecke, and PJ van
der Linden. 2007. The effects of levosimendan in cardiac
Continuing Cardiology Education, doi: 10.1002/cce2.59 (116 of 116)
V. Bistola & O. Chioncel
surgery patients with poor left ventricular function. Anesth
Analg 104:766–773.
Hunter, JD, and M Doddi. 2010. Sepsis and the heart. Br J
Anaesth 104:3–11.
Morelli, A, S De Castro, JL Teboul, et al. 2005. Effects of
levosimendan on systemic and regional hemodynamics in
septic myocardial depression. Intensive Care Med 31:638–644.
Zangrillo, A, A Putzu, F Monaco, et al. 2015.
Levosimendan reduces mortality in patients with severe
sepsis and septic shock: A meta-analysis of randomized
trials. J Crit Care 30:908–913.
Parissis, J, and V Bistola. 2016. When and how to use
inotropes? Pp. 108–118 in A Maisel and G Filippatos, eds.
Algorithms in heart failure. 1st ed. Jaypee Brothers
Medical Publishers, New Delhi.
ª 2017 Hellenic College of Cardiology