Inotropes in cardiac patients: update 2011
John T. Parissisa, Pinelopi Rafouli-Stergioua, Vassilios Stasinosa,
Panagiotis Psarogiannakopoulosa and Alexandre Mebazaab
a
Heart Failure Unit, Attikon University Hospital, Athens,
Greece and bDepartment of Anaesthesiology and
Critical Care Medicine, Hospital Lariboisière, APHP,
Université Paris Diderot Paris 7, U942 Inserm, Paris,
France
Correspondence to John T. Parissis, MD, Heart Failure
Clinic, Attikon University Hospital, University of Athens,
Athens, Greece
Tel: +30 210 6123720; fax: +30 210 5832195;
e-mail: jparissis@yahoo.com
Current Opinion in Critical Care 2010,
16:432–441
Introduction
Shock is a state of inadequate perfusion where oxygen
delivery to the tissues fails to meet oxygen tissue
demands. This serious clinical entity is the result of
several clinical pathologies. A shock state might emerge
from a reduction in oxygen tissue delivery (VO2), or an
increase in oxygen demands (DO2) [1]. Global oxygen
delivery is determined by the oxygen content of the
arterial blood and the body’s ability to circulate this
oxygen around the body. The formula below encom-
passes all the above, ignoring dissolved oxygen:
VO2 (ml O2/min) ¼ 1.39
cardiac output
arterial O2
saturation (%)
[Hb] g/l).
1070-5295 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Purpose of review
ICU patients frequently develop low output syndromes due to cardiac dysfunction,
myocardial injury, and inflammatory activation. Conventional inotropic agents seem to be
useful in restoring hemodynamic parameters and improving peripheral organ perfusion,
but can increase short-term and long-term mortality in these patients. Novel inotropes
may be promising in the management of ICU patients, having no serious adverse effects.
This review summarizes all the current knowledge about the use of conventional and
new inotropic agents in various clinical entities of critically ill patients.
Recent findings
In recent European Society of Cardiology guidelines, inotropic agents are administered
in patients with low output syndrome due to impaired cardiac contractility, and signs and
symptoms of congestion. The most recommended inotropes in this condition are
levosimendan and dobutamine (both class of recommendation: IIa, level of evidence: B).
Recent data indicate that levosimendan may be useful in postmyocardial infarction
cardiac dysfunction and septic shock through increasing coronary flow and attenuating
inflammatory activation, respectively. Furthermore, calcium sensitizing by levosimendan
can be effectively used for weaning of mechanical ventilation in postcardiac surgery
patients and has also cardioprotective effect as expressed by the absence of troponin
release in this patient population. Finally, new agents, such as istaroxime and cardiac
myosin activators may be safe and improve central hemodynamics in experimental
models of heart failure and heart failure patients in phase II clinical trials; however, large-
scale randomized clinical trials are required.
Summary
In an acute cardiac care setting, short-term use of inotropic agents is crucial for the
restoration of arterial blood pressure and peripheral tissue perfusion, as well as weaning
of cardiosurgery. New promising agents should be tested in randomized clinical trials.
Keywords
acute cardiac care, calcium sensitizers, inotropes, low output syndromes
Curr Opin Crit Care 16:432–441
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295
Cardiac patients are vulnerable in this clinical condition of
impaired cardiac output and peripheral tissue hypoperfu-
sion. Theoretically, inotropic agents can improve hemo-
dynamic parameters increasing cardiac output and redu-
cing left and right ventricular filling pressures. Therefore,
inotropes are indicated for the treatment of all cardiac
patients in clinical conditions characterized by peripheral
hypoperfusion and fluid retention resulting impaired car-
diac contractility. Although these agents benefit cardiac
patients by improving cardiac output, they have been also
associated with arrhythmogenesis, increased myocardial
demands, myocardial ischemia and damage. This review
focuses on all potential indications of using inotropic
agents in cardiac patients critically ill in an ICU.
DOI:10.1097/MCC.0b013e32833e10fb

Acute heart failure syndromes
Acute heart failure syndromes (AHFS) represent a
heterogeneous group of clinical entities with various
presentations, management strategies, and prognosis.
According to European Society of Cardiology (ESC)
guidelines, patients presented with AHFS are stratified
based on their SBP on admission [2]. In this classification,
hypotensive AHF (SBP <90 mmHg), including cardio-
genic shock, represents approximately 5% of the overall
AHF population and in-hospital mortality of these
patients exceeds 15% [3]. Furthermore, low SBP at
presentation is one of the most crucial prognostic factors
of adverse events (mortality or hospitalization) in AHF
patients, along with elderly subjects, renal dysfunction
[increased blood urea nitrogen (BUN) and serum creati-
nine], reduction of serum sodium, as well as an increase of
serum troponin and B-type natriuretic peptide (BNP) [4–
6]. In the Organized Program to Initiate Lifesaving
Treatment in Hospitalized Patients With Heart Failure
(OPTIMIZE-HF) registry, in-hospital death increased
21% for each 10 mmHg decrease of SBP below
160 mmHg [7]. Similarly, in Acute Heart Failure Global
Survey of Standard Treatment (ALARM-HF), the initial
systolic blood pressure had a highly significant influence
on in-hospital mortality, reaching 29.6% in patients with
SBP less than 100 mmHg, 11.7% in those with SBP 100–
120 mmHg compared with 5.3% in patients with SBP
higher than 120 mmHg. The need for treatment with
inotropic agents was also associated with higher mortality
(22.5 vs. 3.5% in patients without inotropes) [8].
Although hypotension is the best marker for estimating
hypoperfusion and low cardiac output, there are also
some important clinical signs, such as sleepy sensorium,
hyponatremia, reduced pulse pressure, renal dysfunction,
liver dysfunction, intolerance to angiotensin-converting
enzyme (ACE) inhibitors and/or beta-blocking agents.
The indications for inotropic therapy in critically ill
cardiac patients are shown below [9].
(1) Hemodynamic impairment with low cardiac output
(i.e., cardiac index (CI) <2.0 l/min/m2) and increased
left and/or right ventricular filling pressures (i.e.,
Table 1 Useful ‘tips’ for proper administration of inotropic agents in AHFS
Inotropic agent Dobutamine
Initial IV dose (mg/kg) – 25–75
IV Infusion rate 2–20
(mg/kg/min)
Recommendation class IIa
Level of evidence B C
Adverse effects " Myocardial oxygen
consumption; myocardial
injury; arrhythmiogenesis;
" heart rate; tachyphylaxis
Adapted from [11].
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Inotropes in cardiac patients Parissis et al. 433
pulmonary capillary wedge pressure >18 mmHg and/
or right atrial pressure >10 mmHg)
(2) Clinical worsening despite optimal oral medical treat-
ment, including inhibitors of the renin–angiotensin
system, beta-blockers, aldosterone antagonists, when
tolerated, and diuretics and nitrates, when needed
(3) Critically ill patients characterized by abnormal
hemodynamics, and including any of the following:
(a) Severe exercise limitation
(b) Diuretic resistant fluid overload
(c) Kidney and/or liver dysfunction as shown by
abnormal laboratory exams (serum creatinine,
blood urea nitrogen, bilirubin, etc.)
Likewise, the ESC guidelines indicate inotrope use in case
of peripheral hypoperfusion with presence or not of con-
gestion or pulmonary edema that is refractory to optimal
doses of diuretics and vasodilators (class IIa, B for dobu-
tamine, and class IIa, B for levosimendan), as is described
in Table 1 [10,11]. Finally, according to American College
of Cardiology (ACC)/American Heart Association (AHA)
guidelines, inotropes are indicated in patients with AHFS
to improve symptoms and end-organ function in case of
low cardiac output, severe left ventricular systolic dysfunc-
tion (LVSD) and low SBP (<90 mmHg) despite adequate
filling pressures. A proposed inotrope treatment algorithm
in AHF is described in Table 2.
‘Conventional’ inotropic agents
The ideal inotropic agent should provoke stroke volume
increase without augmenting myocardial oxygen con-
sumption, have short half-life in order to be easily titra-
table, and not induce arrhythmias and tachyphylaxis.
Unfortunately, such an agent does not exist.
Regarding mechanisms of action, all inotropes improve
cardiac contractility through different pathways. In most
cases, these agents increase intracellular cyclic adenylate
monophosphate (cAMP) levels, which in turn induce an
augmentation in calcium release from the sarcoplasmatic
reticulum, hence enhance the contractile force gener-
ation by the contractile apparatus. The cAMP increase is
achieved by the beta-adrenergic-mediated stimulation of
Milrinone Enoximone Dopamine Levosimendan
0.25–0.75 – 12–24
0.375–0.75 1.25–7.5 2: Renal effect; 0.05–0.2
2–5: inotropic effect;
>5: vasoconstriction
IIb IIb IIb IIa
C C B
Hypotension; arrhythmio- " Heart rate; arrhythmias Hypotension; ventricular
genesis; " mortality in arrhythmias; headache
ischemic heart failure
 434 Cardiovascular system

Table 2 A proposed inotrope treatment algorithm in acute heart failure (AHF) syndromes
AHF syndromes

Edema (þ) Edema ()

Warm extremities Cool extremities

SBP >100 mmHg SBP 85–100 mmHg SBP  100 mmHg

IV Vasodilators (e.g., nitrates) þ Optimization of IV diuretics þ Volume correction if no response:

IV diuretics therapeutic
optimization; adjust ACEI/oral
vasodilator
Adapted from [11].
adjustment of standard therapy;
levosimendan (continuous
0.1–0.2 mg/kg/min) [If SBP
<85 mmHg after the initiation
of treatment, consider
0.05 mg/kg/min] or dobutamine
or milrinone (in nonischemic
HF) þ vasopressor to maintain
SBP >85 mmHg
IV vassopressors (dobutamine,
dopamine at vasoconstricting
dosing and/or norepinephrine)
If no response: mechanical support If necessary, addition of
hemofiltration levosimendan (continuous
0.05–0.1 mg/kg/min)

adenylate cyclase, which induces cAMP production, in
case of beta-agonists such as dobutamine, or by selective
inhibition of phosphodiesterase (PDE) III, the enzyme
that catalyzes the breakdown of cAMP in case of PDE-
inhibitors such as milrinone and enoximone. PDE inhibi-
tors also provoke vasodilation through inhibiting vascular
smooth muscle cells. It should be underlined that since
their action is exerted distal to the beta-adrenergic recep-
tor, PDE inhibitors maintain their effects during con-
comitant administration of beta-blocking agents [11].
Dobutamine and milrinone have similar hemodynamic
effects, but also some potentially important differences.
Those differences play an important role in everyday
clinical decision-making about the inotropic agent of
choice. Both lead to similar increases in cardiac output
and decreases of filling pressures, although milrinone
seems to have greater effect on lowering filling pressures
than dobutamine. Milrinone has significant vasodilatory
effects leading to greater decreases of systemic blood
pressure and systemic vascular resistance in comparison
with dobutamine. Both agents can cause tachycardia but
dobutamine provokes higher heart-rate states due to its
direct action on beta-adrenergic receptors. Additionally,
dobutamine seems to increase myocardial needs for
oxygen to a greater extent than milrinone. The alterations
of systemic and coronary pressures induced by either
dobutamine or milrinone are shown in Table 3 [12].
Although in the ESCAPE-trial invasive monitoring is
not recommended in routine use, pulmonary artery
catheterization may distinguish not only the patient with
a low output state who may gain benefit from inotrope
administration, but also the kind of inotropic agent that is
suitable for every different state [13].
In conclusion, milrinone is less indicated in clinical states
characterized by hypotension or renal insufficiency com-
pared with dobutamine. On the contrary, milrinone is
preferred if the use of beta-blocking agents is necessary
or in cases of increased pulmonary artery pressures.
Elevation of pulmonary artery pressure is a great issue
in patients listed for cardiac transplantation since it is
a strong relative contraindication to transplantation.
Milrinone must be administrated cautiously in patients
with renal failure as it has a relatively long half-life
(4–6 h) and is renally cleared. An initial dose of
0.125 mg/kg per min without bolus infusion is recom-
mended as hypotensive effect may be blunted.
In the Outcomes of a Prospective Trial of Intravenous
Milrinone for Exacerbations of Chronic Heart Failure
(OPTIME-CHF), 951 patients admitted for exacerbation
of chronic heart failure caused by left ventricular systolic
dysfunction were randomized to 48-h infusion of either
milrinone or placebo in addition to standard therapy. No
significant differences of in-hospital mortality were found
(2.3 vs. 3.8%, P ¼ 0.19) between the milrinone and
placebo cohorts, and the primary end-point concerning
a reduction of hospitalization for cardiovascular causes
was not reached (12.5  14 vs. 12.3  14.1 days for
placebo and milrinone, respectively, P ¼ 0.71). The dis-
continuation rate of infusion was higher in patients
randomized to the milrinone group compared to the
placebo group (20.6 vs. 9.2%, P ¼ <0.001). The milrinone
Table 3 Alterations of systemic and coronary pressures induced
by either dobutamine or milrinone
Dobutamine Milrinone
" CI þ þ
" HR þþ þ
# LVEDP þ þþ
# MPAP þ þþ
# PVR þ þþ
# SAP  þ
# SVR þ þþ
" CSBF þ –
" MOC þ –
CI, cardiac index; CSBF, coronary sinus blood flow; HR, heart rate;
LVEDP, left ventricular end-diastolic pressure; MOC, myocardial oxygen
consumption; MPAP, mean pulmonary artery pressure; PVR, pulmonary
vascular resistance; SAP, systolic arterial pressure; SVR, systemic
vascular resistance. Adapted from [12].

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group was characterized by higher rates of new-onset of
atrial fibrillation and flutter (4.6 vs. 1.5%, P ¼ 0.004),
ventricular arrhythmias (3.4 vs. 1.5, P ¼ 0.06), and sus-
tained hypotension (10.7 vs. 3.2%, P < 0.001). Posthoc
analysis of the OPTIME-CHF suggested that the increase
in mortality associated with milrinone administration was
more evident in patients with coronary artery disease
(CAD). The composite end-point of mortality and rehos-
pitalization occurred in 36 and 42% of ischemic patients
treated with placebo and milrinone, respectively, whereas
no significant differences between these two groups of
treatment were observed among nonischemic patients [9].
Standard intravenous dose of dobutamine is 2.5–10 mg/kg
per min, and occasionally, up to 40 mg/kg per min. It is
rapidly cleared (half-life ¼ 2.4 min) and can be infused up
to 72 h with monitoring. In Flolan International Random-
ized Survival Trial (FIRST), 471 patients with advanced
heart failure were treated with (80 patients) or without
dobutamine. The dobutamine cohort had a higher occur-
rence of the first adverse event, including worsening of
heart failure, need for vasoactive medications, resusci-
tated cardiac arrest and myocardial infarction (MI), as
well as higher 6-month mortality rate.
On the contrary, dopamine is an agent of particular
interest as it bears a controversial dose-dependent mech-
anism [14]. At doses below 2 mg/kg per min, dobutamine
acts on peripheral DA1 and DA2 receptors causing
vasodilation predominantly in the renal, splanchnic,
coronary and cerebral vessels. Intermediate infusion rates
(2–5 mg/kg per min) cause direct stimulation of b-adre-
nergic receptors in the heart and induce norepinephrine
release from vascular sympathetic neurons. This results
in an elevated heart rate and cardiac output. Infusion
rates of 5–15 mg/kg per min stimulate a-adrenergic and
b-adrenergic receptors leading to an increase of heart rate
and peripheral vasoconstriction [15]. According to ESC
guidelines, dopamine is recommended as class IIb, level
of evidence C, and should be administrated cautiously
when heart rate exceeds 100/min (as dobutamine) due to
the risk of arrhythmia and tachycardia [2].
For many years, conventional inotropic agents have been
the cornerstones for the treatment of patients with low
output heart failure syndromes [11]. However, these
agents, especially in high doses, are associated with
adverse effects such as ischemia, increased myocardial
oxygen consumption, increased ventricular ectopy,
arrhythmias, and hypotension. Particularly, short-term
use of inotropic agents is associated with increased post-
discharge mortality in ischemic patients [16]. Recent
research is focused on the development of new agents
that may improve cardiac output safely and promptly in
order to stabilize critically ill patients as a ‘bridge’ to other
forms of destination therapy [11].
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Inotropes in cardiac patients Parissis et al. 435
‘Novel vogue’ of inotropic agents
The conventional inotropic agents may induce an adverse
long-term prognosis, despite the short-term clinical
and hemodynamic improvement. Therefore, new agents
have been used in AHF, which have cAMP-independent
mechanisms of action [17,18].
Istaroxime is an inhibitor of the sodium–potassium ade-
nosine triphosphatase pump, which also increases sarco-
plasmic reticular calcium adenosine triphosphatase iso-
form 2a activity (SERCA 2a) [19]. The HORIZON-HF
(Hemodynamic, Echocardiographic and Neurohomonal
Effects Of Istaroxime, a Novel Intravenous Inotropic
and Lusitropic Agent: A Randomized Control Trial in
Patients Hospitalized With Heart Failure) trial was con-
ducted at three European sites. Inclusion criteria were
left ventricular ejection fraction (LVEF) less than 35%,
SBP 90–150 mmHg, and AHFS that required hospital-
ization. A pulmonary artery catheter was placed within
48 h of admission. Overall, 120 patients were enrolled to
receive istaroxime or placebo via a 3 : 1 (istaroxime : pla-
cebo) randomization. Istaroxime was administrated at
doses of 0.5, 1.0, and 1.5 mg/kg per min for 6 h, and serial
hemodynamic assessment was performed. All three
doses of istaroxime decreased pulmonary capillary wedge
pressure (PCWP), the primary study end-point, by
3–5 mmHg. However, cardiac index (CI) increased only
in the highest dose and was not statistically different
at 6 h, whereas left ventricular end-diastolic volume
decreased significantly only at the highest dose. A favor-
able lusitropic effect, as assessed by increased mitral
deceleration time, occurred also only at highest dose.
Furthermore, no data concerning improvement of renal
function, circulation of neurohormones and dieresis were
presented [20]. The trial confirmed prior animal and
clinical studies that showed significant decrease in heart
rate and QTc interval (29 to 49 ms). There is more
than a glimmer of hope that istaroxime will prove to be
more safe and effective than currently utilized inotropic
agents in this challenging heart failure population [21].
However, the fate of istaroxime will depend on its effects
on in-hospital and postdischarge clinical outcomes,
especially in patients presented with low cardiac output
[22].
On the contrary, levosimendan is a pyridazinone-dinitrile
derivative molecule that increases troponine C affinity for
Ca2þ and stabilizes the conformation of troponine C.
Levosimendan has positive inotropic properties without
impairing ventricular relaxation or inducing cytosolic
Ca2þ overload, owing to improvement in sensitivity of
the contractile apparatus to intracellular calcium [23,24].
This calcium sensitizer has also peripheral vasodilatory
effects through opening of potassium ATP-sensitive
channels into vascular bed [24]. These inodilatory prop-
erties lead to a dramatic increase of cardiac output with a
 436 Cardiovascular system
concomitant reduction of cardiac filling pressures in the
failing hearts. However, levosimendan and its active
metabolite OR-1896, at high doses, are selective PDE
III inhibitors and may provoke moderate elevation of
intracellular cAMP [25]. Despite the fact that it does not
seem to induce ventricular arrhythmias and prolongation
of QT interval, levosimendan augments heart rate
(9 beats/min on average) and increases the incidence of
atrial fibrillation especially in case of high bolus dose or
prolonged administration (>48 h). In REVIVE-2 trial,
which is described below, patients with acutely decom-
pensated heart failure, treated with levosimendan, had
slightly higher incidence of ventricular arrhythmias com-
pared with placebo group, whereas in SURVIVE trial,
similar incidence of ventricular arrhythmias was observed
in both levosimendan and dobutamine cohort [26,27].
Finally, levosimendan may protect the failing myo-
cardium from further cardiomyocyte apoptosis through
activation of KATP mitochondrial channels [28].
According to recent ESC guidelines, levosimendan is
recommended as a second-line treatment in AHFS and
is approved in Europe, Asia, South America, and Australia
[2]. Short-term hemodynamic and clinical effects of
levosimendan have been verified by several studies
and trials, either compared to placebo, or to other ino-
tropes, such as dobutamine.
The Levosimendan Infusion vs. Dobutamine (LIDO)
study, a randomized double-blind trial, examined the
efficacy and safety of intravenous levosimendan compared
with dobutamine in 203 patients with severe low-output
heart failure. The patients who met the inclusion criteria
had LVEF less than 35%, CI <2.5 l/min per m2, and PCWP
higher than 15 mmHg. The levosimendan group received
an initial dose of 24 mg/kg per min and a continuous dose of
1 mg/kg per min for 24 h, whereas dobutamine group
received infusion 5 mg/kg per min without a loading dose.
The primary end-point of the study was the amelioration of
hemodynamic profile in levosimendan-treated patients,
defined as decline of PCWP more than 25%, and increase
of CI more than 30%. This target was reached in 28% of
levosimendan-treated patients and 15% of those treated
with dobutamine. The beneficial hemodynamic effects of
levosimendan were enhanced, and conversely, those of
dobutamine were reduced by the concomitant treatment
with beta-blockers [29].
The REVIVE study is a double-blind, placebo-controlled
trial that examined AHF patients with LVEF less than
35% and dyspnea at rest. The trial was divided into a pilot
study REVIVE-1 and a full-scale pivotal trial REVIVE-2.
Both studies revealed improvement of clinical and hemo-
dynamic profile, while REVIVE-2 reported reduced
length of stay at the hospital and decreased levels of
BNP [26].
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In the randomized study on safety and effectiveness of
levosimendan in patients with left ventricular failure
after myocardial infraction (RUSSLAN), levosimendan
did not increase ischemia or hypotension compared
with placebo in patients with cardiac systolic dysfunc-
tion due to an acute MI and the incidence of worsening
heart failure was less with levosimendan at 6 and 24 h
[30].
A great problem of all patients suffering from acutely
decompensated heart failure or cardiogenic shock is renal
function impairment as a result of several causes such as
pump failure, elevated central venous pressure, intra-
renal vasoconstriction due to catecholamines, endothelin,
vasopressin, as well as activation of the renin–angiotensin
pathway. Interestingly, an improvement in calculated
glomerular filtration rate (GFR) after a course of 72 h
continuous infusion of levosimendan has been observed,
while dobutamine had a neutral effect [31].
In another recent study, coronary blood flow and micro-
circulation in patients with AHF improved markedly
after 24 h continuous infusion of levosimendan, accom-
panied by improvement in cardiac performance and
neurohormonal activation [32].
Finally, cardiac myosin activators (CK-0689705, CK-
1122534, and CK-1827452) are recently discovered small
molecules that stimulate directly the activity of cardiac
myosin motor protein resulting in improvement of cardiac
contractility without alterations of intracellular calcium
concentration. This novel inotropic mechanism is in
contrast to that of beta-agonists and PDE inhibitors
which increase intracellular calcium in order to indirectly
activate cardiac myosin at the cost of adverse effects,
including increased oxygen consumption and arrhythmo-
genesis [33]. Healthy volunteers participated in a clinical
trial designed to estimate maximum tolerated dose of a
6-h intravenous infusion of CK-1827452, and evaluate
the effect on left ventricular function using serial echo-
cardiograms. This agent caused an increase in stroke
volume and cardiac contractility without affecting myo-
cardial oxygen consumption. These promising results
should be evaluated in large scale randomized trials
concerning patients with heart failure and impaired
cardiac contractility.
Cardiogenic shock
Cardiogenic shock is a clinical state of organ hypoperfu-
sion due to cardiac failure. The definition of cardiogenic
shock is based on hemodynamic parameters, such as SBP
less than 90 mmHg or mean arterial pressure (MAP)
30 mmHg lower than baseline, with severe reduction in
CI less than 1.8 l/min/m2 and adequate or elevated filling
pressures, left ventricular end-diastolic pressure

(LVEDP) higher than 20 mmHg, or when inotropes or
IABP are required in order to maintain SBP >90 mmHg
and CI higher than 1.8 l/min/m2 [34]. Clinically, hypo-
perfusion is expressed with cool extremities, oliguria and
alteration in mental status.
The incidence of cardiogenic shock is about 7% (5–8% in
STEMI [ST-elevation myocardial infarction] and 2.5% in
NSTEMI patients) [35]. MI (MI), especially anterior MI
evolving more than 40% of myocardial mass, is the most
common cause of cardiogenic shock. Any cause of acute,
severe left ventricular or right ventricular dysfunction can
lead to cardiogenic shock. According to SHOCK Trial
Registry, cardiogenic shock is also caused by mitral
impairment (8%), septal rupture (4%), isolated right
ventricular dysfunction (3.5%), cardiac rupture and tam-
ponade (1.7%), as well as other causes (7.5%) [36].
Left ventricular dysfunction is the primary reason, but it
is now accepted that systematic inflammatory response
syndrome (SIRS), neurohormones, inflammatory/apopto-
tic mediators and tissue microcirculation may contribute
to the pathogenesis of cardiogenic shock [37–39].
Mortality rates due to cardiogenic shock, despite early
vascularization, remain over 50% in most studies [40].
Data from the GUSTO-I trial demonstrated that 30-day
survivors of cardiogenic shock have a similar prognosis to
that of patients with MI uncomplicated with shock [41].
This finding underlines the importance of reperfusion,
mechanical and pharmacological support in the acute
phase.
Pharmacological support includes inotropes and vaso-
pressors. These agents are used in the early stabilization
of patients with cardiogenic shock to improve hemody-
namic profile, namely to increase cardiac output and
MAP and decrease PCWP, as a bridge to more definite
measures or until shock resolves. Despite their hemo-
dynamic benefits and the improvement in mitochondrial
function of noninfracted myocardium, inotropes increase
oxygen demand in a failing heart with limited supply,
and therefore, may provoke arrhythmias and lead to
cellular disruption and necrosis [12,42,43]. Thus, the
lowest doses of inotropes should be used in cardiogenic
shock patients.
According to the ACC/AHA guidelines, dobutamine is
recommended as a first-line agent if systolic blood pres-
sure ranges between 70 and 100 mmHg, in the presence
or not of symptoms and signs of shock.
In the case of either inadequate response to a medium
dose of dopamine or dopamine/dobutamine in combi-
nation, or if the patient has SBP less than 70 mmHg,
norepinephrine is suggested [44]. Evidence based data
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Inotropes in cardiac patients Parissis et al. 437
to support these recommendations are lacking. Some
studies from the 1980s showed that low doses of dopa-
mine improved CI in comparison with higher doses, while
combined therapy with both dopamine and dobutamine,
at doses of 7.5 mg/kg/min each, improved hemodynamic
profile with less side effects compared with each agent
alone at 15 mg/kg/min [45,46].
Interestingly, there was remarkable concern regarding
the use of dopamine in patients admitted to ICU, after
the publication of an observational study that concluded
that dopamine administration may be associated with
worse outcome of patients with shock regardless of etiol-
ogy [47]. A recent, multicenter, randomized trial com-
pared dopamine with adrenaline as first-line agents in
patients with circulatory shock. The primary end-point
was mortality rate at 28 days after randomization, while
secondary end-points included adverse events and
the number of days without need for organ support.
There was no significant difference with reference to
the primary end-point between patients who were trea-
ted with dopamine and those with norepinephrine. How-
ever, in the sub-group of patients with cardiogenic shock,
administration of dopamine was associated with an
increase in mortality rate [48]. The findings of this study
challenge ACC/AHA guidelines that recommend dopa-
mine as the initial inotropes, and support the use of
norepinephrine.
It is generally known that vasopressin levels decline
dramatically as shock progresses, resulting in refractory
cardiogenic shock with hypotension and hypoperfusion.
Only one small retrospective study showed that admin-
istration of vasopressin in patients with post-MI cardio-
genic shock increased MAP without negative impact on
CI and PCWP [49].
Furthermore, observational studies have shown that
levosimendan, compared with dobutamine, improved
LV hemodynamic function in patients with cardiogenic
shock, especially in patients with cardiogenic shock after
percutaneous coronary intervention (PCI) [50–52].
Similarly, it has been demonstrated that levosimendan
infusion for cardiogenic shock improved hemodynamic
parameters of right ventricular performance [53]. Further
large, randomized trials with long-term outcomes are
needed in order to establish the use of levosimendan
in cardiogenic shock.
PDE inhibitors, enoximone and milrinone, have been
shown to increase CI in patients with cardiogenic shock,
but there are no data supporting superiority of these
agents in comparison to catecholamines. In a prospective,
randomized, single-centre study, enoximone was com-
pared with levosimendan added on top to current
therapy, in patients with severe refractory cardiogenic
 438 Cardiovascular system
shock. A higher 30-day overall survival rate was found in
the levosimendan-treated cohort [54]. It is consequently
obvious that pharmacological treatments with vasopres-
sin, levosimendan and enoximone require further inves-
tigation in patients with cardiogenic shock.
Perioperative use of inotropic agents
Acute cardiovascular dysfunction is anticipated in 20% or
more patients in the perioperative period of cardiac
surgery [55]. Despite some degree of ischemic protec-
tion due to cardioplegia, the myocardium has to endure
subsequent periods of ischemia and reperfusion during
coronary artery bypass grafting (CABG) surgery. There-
fore, contractile myocardial dysfunction is a common
complication; hence, inotropic agents or mechanical sup-
port is necessary. The need for these management strat-
egies is associated with higher morbidity and mortality
[56]. The possible mechanisms leading to myocardial
damage are free radical formation, impairment of coron-
ary vasculature and calcium overload.
Recently, a clinical review summarized the indicators of
major perioperative risk, and the clinical risk factors. It
also underlined the importance of aggressively preserving
heart function and cardioprotective agents, such as
volatile anesthetics and levosimendan. The proposed
pharmacological treatment of myocardial dysfunction
after cardiac surgery included low-to-moderate doses of
dobutamine and epinephrine, milrinone, or levosimen-
dan. Optimal inotropic use perioperatively in cardiosur-
gery is still controversial and further large multicenter
trials are required [55].
Among classical inotropic agents, beta-agonists and
PDE inhibitors are the two main groups used for the
treatment of heart failure in cardiac operations.
Catecholamines are associated with a greater incidence
of tachycardia and tachyarrhythmia and PDE inhibitors
administration often requires co-administration of a
vasoconstrictor. Catecholamines such as dopamine,
epinephrine, and norepinephrine have no clear advan-
tages over dobutamine and may be associated with a
greater incidence of adverse effects. Epinephrine has
been used successfully for salvage therapy [57]. In a
placebo-controlled trial, patients treated with milrinone
were all successfully weaned from cardiopulmonary
bypass (CPB) contrary to the placebo group [58].
It has been found that a single dose of milrinone
50 mg/kg administered before separation from CPB,
increased significantly CI (43%), and decreased systemic
vascular resistance and catecholamine requirement com-
pared to placebo in 21 patients with preexisting cardiac
systolic dysfunction [59]. None of those inotropic agents
showed, in any study, an impact on major clinical out-
comes or survival in cardiac surgery patients.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Levosimendan was recently used for the successful treat-
ment of low cardiac output after cardiac surgery. Its
antiischemic effect, mediated by the opening of sarco-
lemmal and mitochondrial ATP-sensitive potassium
channels, suggests potential application in clinical con-
ditions where cardioprotection would be beneficial, such
as cardiac surgery. A double-blind trial studied 106
patients undergoing elective CABG who received pre-
operatively either levosimendan or placebo. The ICU
length of stay (primary end-point) and the duration of
tracheal intubation were significantly lower in levosimen-
dan cohort. Troponin I increased in both groups within
the first 24 h but was significantly lower in the levosi-
mendan group. There were significantly higher post-
operative values of MAP and CI, and lower systemic
vascular resistance in the levosimendan group (secondary
end-points). More patients from the placebo group
required inotropic support during the first 7 days than
those treated with levosimendan. Both cohorts had no
significant differences with respect to incidence of atrial
fibrillation, MI, kidney dysfunction, and mortality.
Finally, the effects of two different administration mod-
alities of levosimendan (initiation before CABG and at
the end of CABG) were compared with the standard
treatment with milrinone started at the end of CABG
in cardiac patient with a preoperative LVEF less than
30%, whereas in all patients additional dobutamine
(5 mg/kg/min) was initiated after the release of the aortic
cross-clamp. Initiation of levosimendan treatment before
the CABG was associated with a higher initial postopera-
tive stroke volume and a lower incidence of postoperative
atrial fibrillation, but had no effect on the extent of
postoperative troponin I release [60].
Beneficial effects on outcomes of inotropic agents, used
for the management of postoperative low cardiac output
syndrome, need to be confirmed in a large multicenter
study.
Septic shock
Septic shock is characterized by organ hypoperfusion due
to systemic inflammatory response to infection. Severe
sepsis and septic shock are among the most important
causes of morbidity and mortality in patients admitted to
the ICU. Formerly, septic shock was considered to
include two distinct clinical presentations, ‘hyperdy-
namic’ and ‘hypodynamic’, and the recommended
therapy was tailored according to this classification.
Nowadays, it is known that these are phases of a single
process, which starts with warm sepsis and evolves to cold
sepsis. Myocardial function is depressed in sepsis despite
hemodynamic measurements showing increased cardiac
output [61]. Variable degrees of left ventricular dysfunc-
tion have been observed in 25–50% of septic shock
patients [62].

According to 2008 Surviving Sepsis Guidelines, nor-
adrenaline and dopamine are recommended as first
choice agents for the maintenance of MAP 65 mmHg
or more. Dobutamine is indicated in states of low cardiac
output despite fluid administration and inotropic therapy.
Second-line agents, such as phenylephrine and vasopres-
sin, may be used when adrenaline or dopamine fail to
restore an adequate organ perfusion (ScVO2 < 70% or
CI < 2.0) [63]. A systematic review of seven randomized
trials that compared the action of inotropes in septic
shock, published in 2004, was unable to determine super-
iority of a vasopressor agent [64]. Studies from the 1990s
have shown improvement in hemodynamic parameters
for patients with septic shock receiving noradrenaline
[65]. Adrenaline, despite vasoconstriction in end organs,
improves renal function in patients with sepsis after 24 h
from the initiation of the infusion [66].
On the contrary, dopamine is indicated as an alternative
agent to noradrenaline. As it is known, dopamine increases
renal blood flow in doses of 1–3 mg/kg/min in normal
volunteers [67]. However, this beneficial effect of low or
‘renoprotective’ dose of dopamine is controversial, despite
supportive data from several studies [68,69]. Observational
studies suggested that treatment with dopamine may be
detrimental particularly in patients with essential hyper-
tension [70]. Investigators from the SOAP study, a multi-
center European observational study, reported higher ICU
and hospital mortality rates with dopamine administration
in a subgroup of patients with septic shock [47]. A recent
randomized trial tried to evaluate the choice of norepi-
nephrine over dopamine as the first-line agent among
patients with septic shock. This trial included 1044 septic
shock patients, 542 in dopamine group and 502 in norepi-
nephrine group, and did not reveal significant differences
in the 28-day mortality rates [48].
Furthermore, it has been proposed that dobutamine
improves low cardiac output in severe sepsis, despite
dopamine/noradrenaline infusion, but data supporting
this recommendation are scant [62]. The EGDT trial
was the mainstay for this recommendation [71].
Vasopressin, an endogenously released peptide hormone,
is recommended for patients with severe septic shock as an
adjunct to catecholamines, since a relative vasopressin
deficiency is apparent in patients with sepsis [72]. Evi-
dence for the use of vasopressin in septic shock has been
described in two small randomized trials that showed
improvement in hemodynamic parameters and renal func-
tion in patients treated with vasopressin [73,74]. VASST
trial was a multicenter, randomized double-blind trial that
compared vasopressin with norepinephrine in sepsis. This
trial found no significant difference in 90-day mortality rate
or rate of organ dysfunction [75]. A small randomized,
controlled, open-label trial has been recently published
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Inotropes in cardiac patients Parissis et al. 439
comparing vasopressin doses in advanced vasodilatory
shock, and found that higher supplementary dose restores
cardiovascular function more effectively [76]. Terlipressin
is a vasopressin analogue that seems to be advantageous in
sepsis, either as a single agent or with concomitant use of
inotropes [77,78]. In an Italian randomized pilot study,
TERLIVAP, this agent was found to be effective in
improving arterial pressure and reducing norepinephrine
requirements [79].
Phenylephrine, a pure alpha-adrenergic agonist, may be
useful when tachycardia or arrhythmias preclude ino-
tropes with beta-adrenergic activity. A prospective
randomized trial that compared phenylephrine with nor-
adrenaline, as a first-line agent in septic shock, found no
differences in terms of hemodynamic parameters and
cardiopulmonary performance; however, larger random-
ized trials are needed regarding the use of phenylephrine
in sepsis [80].
Finally, the calcium sensitizer levosimendan has been
investigated in animal models of endotoxic shock where
it appeared to improve organ perfusion, left ventricle
(LV) and right ventricle (RV) function [81–83]. Never-
theless, only a few small, randomized trials evaluated
levosimendan in septic patients, thus, large-scale multi-
center clinical trials are necessary.
It is remarkable that according to a recently published
study, management of early sepsis varies between
specialities and countries, and the responses do not
always follow SSC guidelines [84].
Conclusion
Short-term use of inotropic agents is recommended for
the alleviation of symptoms, restoration of peripheral
organ perfusion, and reduction of abnormal filling pres-
sures in patients with low output syndromes due to
cardiac contractile dysfunction. The use of inotropes in
serious clinical conditions of ICU patients such as post-
MI cardiogenic shock, postcardiac surgery low output,
and septic shock may be beneficial at the lowest doses but
require more clinical data. New drugs with novel mech-
anisms of inotropic action may be more safe but ongoing
trials will confirm their safety and efficacy in daily
clinical practice.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 517).
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