Role of levosimendan in sepsis and septic shock

Bernardo Bollen Pintoa,b, Sebastian Rehberga, Christian Ertmera and

Martin Westphala
a
Department of Anesthesiology and Intensive Care,
University Hospital of Muenster, Muenster, Germany
and bDepartment of Anesthesiology, Critical Care and
Emergency, Hospital Geral de Santo António, Porto,
Portugal
Correspondence to Bernardo Bollen Pinto, MD,
Department of Anesthesiology and Intensive Care,
University Hospital of Muenster, Albert-Schweitzer-Str.
33, 48149 Muenster, Germany
Tel: +49 251 8347255; fax: +49 251 8348667;
e-mail: bollenpinto@gmail.com
Current Opinion in Anesthesiology 2008,
21:168–177
Purpose of review
To present the pharmacologic and biologic profile of levosimendan and discuss
potential indications in the treatment of sepsis and septic shock, with a special focus on
myocardial and pulmonary dysfunction.
Recent findings
In animal models of endotoxic shock, levosimendan improved both left ventricular
systolic and diastolic dysfunction, as well as ventriculovascular coupling. In addition,
positive effects have been reported on right ventricular performance and pulmonary
circulation. Two randomized, controlled trials in patients with septic shock revealed
levosimendan provided consistent beneficial effects on cardiopulmonary performance,
global oxygen transport, splanchnic perfusion and renal function. These effects have
been reported as superior to placebo and the classic inotropic agent dobutamine. Due
to its vasodilatory effects, combination with vasoconstrictor agents may be crucial in the
presence of arterial hypotension.
Summary
There is increasing evidence that levosimendan exerts beneficial effects in the treatment
of sepsis-induced myocardial and pulmonary dysfunction. Future large-scale multicenter
clinical trials are now needed to clarify whether levosimendan improves the overall
outcome of patients with sepsis and septic shock.

Keywords
global oxygen transport, levosimendan, myocardial dysfunction, pulmonary circulation,
right ventricle, sepsis, septic shock

Curr Opin Anesthesiol 21:168–177

ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907

Introduction Pharmacokinetics, metabolism and drug

Severe sepsis and septic shock are among the leading
causes of death in noncoronary intensive care units. In
recent years, incidence and mortality of sepsis has sub-
stantially increased [1–4]. In the presence of shock,
mortality may approach 70% [5,6]. Despite convincing
evidence for an intrinsic myocardial depression in sepsis,
there is still no consensus on the definition or the
epidemiology of septic myocardiopathy. In septic
shock patients, variable degrees of left ventricular
(LV) dysfunction have been reported to be present in
25–50% of cases [7
,8
,9,10]. Levosimendan is a new
inotropic and vasodilatory agent exerting beneficial
effects in the treatment of heart failure [11,12], particu-
larly in patients with acute heart failure (AHF)
[13,14,15
,16] and acute coronary syndromes (ACS)
[17]. The purpose of this review article is to characterize
the pharmacologic and biologic profile of levosimendan,
and to critically discuss potential indications in the
treatment of septic shock.
0952-7907 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
interactions of levosimendan
Levosimendan (Simdax; Abbott, Illinois, USA) is the
(-) enantiomer of {[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-
3-pyridazinyl)phenyl]hydrazono} propanedinitrile [18]. It
is commercially available as a powder, to be dissolved in a
solution of glucose 5% in water and administered as
intravenous infusion. The parent molecule has a short
elimination half-life of approximately 1 h, and is 95–
98% bound to plasma proteins [19]. It is fully metabolized
in the liver and intestine into both active and inactive
metabolites. OR-1896, the active metabolite, is approxi-
mately 40% bound to plasma proteins, has a longer half-
life (75 to 80 h) than levosimendan itself, and is respon-
sible for the persistence of hemodynamic effects for a
period of 7–9 days following a continuous infusion for
24 h [19].
The pharmacokinetic profile of levosimendan is similar
in healthy volunteers and patients with mild and severe

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

heart failure [20,21]. Notably, pharmacokinetic proper-
ties are not influenced by age, race, gender, or frequent
comorbidities presented in patients with septic shock,
such as renal failure and hepatic dysfunction [20,21].
There is no evidence for a negative clinical interaction
with commonly used drugs in cardiac patients, such as
digoxin or warfarin [19]. On the contrary, a subanalysis of
the SURVIVE study [22] reports that levosimendan
reduces early mortality, as compared to dobutamine, in
the subgroup of patients suffering from heart failure and
taking b-blockers.
Pharmacodynamics and key biologic actions
Figure 1 illustrates the main mechanisms by which
levosimendan impacts on cardiovascular functions.
Calcium sensitizing effects
In the cardiac myocyte, levosimendan selectively binds
to the N-domain of cardiac troponin C (cTnC), thereby
stabilizing the calcium (Caþþ)-dependent interaction
between cTnC and cTnI [24,25]. The conformational
change in cTnC is an essential condition for the inter-
action between actin and myosin microfilaments necess-
ary to generate contractile force [26]. Levosimendan
binds to cTnC in a Caþþ-dependent manner [25,27]. It
dissociates from cTnC when Caþþ concentration
decreases during diastole, thereby acting only during
systole and not impairing diastolic myocardial relaxation
[25,27].
Figure 1 Mechanism of action of levosimendan on cardiovascular functions
BKCa channels, large conductance calcium-
activated potassium channels; KATP
channels, adenosine trisphosphate-sensitive
potassium channels; KV channels, voltage-
gated potassium channels; LV, left ventricle;
RV, right ventricle. Adapted from [23].
Circulation
Opening KATP,
Kv and BKCa
channels
Vasodilation
Periphery Kidney Gut
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Levosimendan in sepsis and septic shock Pinto et al. 169
‘Classic’ inotropes enhance muscle contraction by
increasing the level of cyclic adenosine monophosphate
(cAMP) and subsequently intracellular Caþþ concen-
tration [16,28]. b1-Adrenergic receptor agonists (e.g.
dobutamine, epinephrine) activate adenylate cyclase,
the enzyme responsible for cAMP production, and phos-
phodiesterase III (PDE III) inhibitors (e.g. milrinone,
amrinone) prevent cAMP degradation [16,28]. The use of
these drugs is therefore associated with increased myo-
cardial oxygen consumption and ventricular arrhythmias
[16,28]. Levosimendan also exerts a moderate inhibitory
effect on myocardial PDE III. Although this effect is only
reported at high (> 0.3 mM) tissue concentrations [29], a
small increase in cAMP concentrations may potentially
contribute to the lusitropic effect of the drug [29].
Acidosis has been shown in vitro to depress the positive
inotropic effect of levosimendan and OR-1896, mainly by
attenuating the effect on increasing intracellular Caþþ-
mobilization [30–32]. The drugs’ ability to increase
myofilament sensitivity to Caþþ is mainly unchanged.
In addition, there are no reports of impaired relaxation
under acidotic conditions [30].
With the recommended dosage for the treatment of
patients with AHF (see below), levosimendan exerts a
positive inotropic effect independent of cAMP pro-
duction, thereby leaving intracellular Caþþ-concen-
trations unaffected. Levosimendan therefore neither pro-
motes ventricular arrhythmias nor relevant increases in
myocardial oxygen consumption [14,28].
Levosimendan
Heart
Opening KATP ↑ Ca++ sensitivity of
contractile proteins
channels
+ +
inotropy lusitropy
Improved LV
Reduction of Protection performance
ischemia/ against
Lung Coronary
reperfusion myocordial
injury stunning Improved RV
performance
 170 Intensive care
Effects on potassium channel activity
Levosimendan interacts with potassium (Kþ)-channels in
the myocyte plasma membrane and in the mitochondria
[28]. In ventricular myocytes, levosimendan activates
adenosine trisphosphate (ATP)-dependent potassium
channels (KATP-channels) [33]. Notably, opening of
mitochondrial KATP-channels [34,35] appears to be
related to the drug’s beneficial effects in myocardial
ischemia [28,36,37]. Proposed mechanisms for this effect
are prevention of mitochondrial calcium overload, pres-
ervation of high energy phosphates and regulation of
mitochondrial volume [28,37].
In vascular smooth muscle cells, levosimendan activates
potassium channels in the plasma membrane [38
]. Levo-
simendan has also been reported to open KATP-channels
in mesenteric arteries of rats [39], canine and porcine
coronary arteries [36,40], feline pulmonary arteries [41],
and human portal and saphenous veins [42,43]. In
addition, it has been shown that levosimendan activates
voltage-gated potassium channels (KV-channels) and
large conductance calcium-activated potassium channels
(BKCa-channels) in rat and porcine large epicardial
arteries [38
].
Activation of Kþ-channels facilitates Kþ-efflux and pro-
motes cell hyperpolarization, which in turn diminishes
Caþþ-entry into the cytoplasm through voltage-gated
L-type Caþþ-channels and promotes Caþþ-efflux via
the 3 Naþ/Caþþ pump. The net effect is a lower intra-
cellular Caþþ concentration and, subsequently, vasodila-
tion. A currently accepted concept is that levosimendan
preferentially opens BKCa and KV-channels in large
conductance vessels (e.g. large epicardial arteries) and
KATP-channels in small resistance vessels (e.g. small
subendocardial coronary arteries) [38
,44]. That channel
distribution and physiologic regulation of vascular tone
within the different vascular beds contribute to this
selectivity cannot be ruled out, however.
Dose range considerations
For the treatment of acute decompensated heart failure
(ADHF), levosimendan is usually administrated as
a continuous infusion over a period of 24 h (0.05–
0.2 mg/kg/min) [12,19]. In these patients, levosimendan
infusion is commonly preceded by a loading dose of 6–
24 (12) mg kg1 over 10 min [12,19,17]. It has to be
considered, however, that bolus administration and
high dose infusion ( 0.4 mg/kg/min) may be associated
with increased heart rate (HR) and temporary arterial
hypotension [12,17,28,45]. In clinical settings, where
vasodilation is a relevant physiopathologic event (such
as in septic shock), it may be advantageous to withheld
bolus infusion and to restrict treatment to a continuous
infusion of 0.2 mg/kg/min [46,47
].
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Cardiovascular effects of levosimendan in
acute heart failure
Levosimendan has been reported to reliably increase
stroke volume (SV) and cardiac output, as well as to
improve LV diastolic function, LV filling pressures and
symptomatic relief in patients with ADHF [12,16]. In
addition, levosimendan typically reduces systemic vascu-
lar resistance (SVR) and mean arterial pressure (MAP),
hence decreasing LV afterload [28,45]. Notably, these
beneficial effects appear to be superior to placebo and
the classic inotropic agent dobutamine. The impact of
levosimendan on patient-centered outcome is less clear,
however. In this context, earlier studies reported a
reduction in the risk of death as compared with placebo
or dobutamine [11,12,16,17]. Surprisingly, however,
recent large-scale clinical trials, such as REVIVE-2 and
SURVIVE, failed to verify this benefit [12,16,22].
Besides enhancing LV function and global hemody-
namics, levosimendan has been shown to exert beneficial
effects on the right ventricle (RV) [48]. In canine and
porcine models of right heart dysfunction, where an
increased pulmonary artery pressure was induced by
temporary pulmonary artery constriction [49,50] or
repeated pulmonary embolism [51], levosimendan
induced pulmonary vasodilation and improved RV con-
traction and ventriculovascular coupling. To our knowl-
edge, the only clinical study that addressed the effects of
levosimendan on RV function was performed in the
setting of adult respiratory distress syndrome (ARDS)
and septic shock [47
].
Potential benefits in sepsis-induced
myocardial dysfunction
Sepsis-induced myocardial dysfunction represents a com-
plex array of events resulting in systolic and diastolic
dysfunction of both ventricles [7
,8
,9,10,52
]. Alterations
in sympathetic b-adrenergic signaling impair the myo-
cardial response to endogenous and exogenous catechol-
amines [53–55]. Several reports confirm that intracellular
Caþþ-trafficking is altered during systole and diastole
[8
]. Also, changes in the sensitivity of contractile myo-
filaments to Caþþ play a major role in diminishing
myocardial efficiency in sepsis [56–58].
Levosimendan exerts beneficial effects in the LV and
RV, which are independent of b-adrenergic signaling or
changes in intracellular Caþþ-concentration, by increas-
ing contractile myofilament sensitivity to Caþþ-ions.
Therefore, levosimendan represents an appealing drug
in the setting of sepsis-induced myocardial dysfunction
(Fig. 2). The most relevant experimental and clinical
studies supporting this notion are summarized below.
 Levosimendan in sepsis and septic shock Pinto et al. 171

Figure 2 Effects of levosimendan in sepsis-induced organ dysfunction

Sepsis
-?

Inflammation

-? -- -- -?

Intrinsic myocardial depression

--
Blood Lung Mitochondrial Gut Kidney
Circulatory dysfunction Vasoconstriction Autonomic
Vasoconstriction Vasoconstriction
failure DIC ARDS Bacterial dysregulation
Microthrombosis ARF
-- -- translocation

Distributed Ca++ Adrenergic Myofibrillar

trafficking downregulation dysfunction

Cardiac dysfunction

Levosimendan has a positive effect on intrinsic myocardial depression and pulmonary and intestinal microcirculation probably due to its vasodilatory
actions. Effects on renal function, platelet aggregation and inflammatory mediators in sepsis remain to be investigated. Adapted from [8
]. ARDS, acute
respiratory distress syndrome; ARF, acute renal failure; DIC, disseminated intravascular coagulation.

some concerns were raised in view of possible derange-

Experimental data on levosimendan use in ments in the pulmonary microcirculation [63]. Conver-
endotoxemia and sepsis sely, in the study by Oldner et al. [59], no such events
Oldner et al. [59] were the first to have demonstrated the were noticed. In fact, arterial oxygen partial pressure
beneficial effects of levosimendan in lipopolysaccharide (PaO2) and shunt fraction were the same in both groups.
(LPS)-treated animals. In an endotoxic pig model,
levosimendan was administrated as a bolus infusion of Other studies reported more precise data concerning the
200 mg/kg followed by a 3 h continuous infusion of 3.3 mg/ effects of levosimendan on LV function of LPS-treated
kg/min. Compared with placebo, levosimendan induced animals [60,64,65
]. In isolated guinea pig hearts, incre-
a higher cardiac index (CI) and a nonsignificant increase mental concentrations of levosimendan induced
in stroke volume index (SVI). MAP and systemic vascular improvements in specific markers of systolic function,
resistance index (SVRI) were lower in the treatment with positive effects following concentrations above
group. With respect to the marked vasodilation noticed 0.03 mM [64]. In the same study, levosimendan induced
in response to levosimendan infusion, it has to be taken a direct coronary vasodilatory effect at higher concen-
into consideration that the drug was infused at a much trations (0.10 mM). Two rabbit endotoxic models in
higher dose than is recommended for clinical use. which levosimendan was infused at 3.0 or 3.3 mg/kg/
min (with no loading dose) consistently reported an
In all animal studies elucidating hemodynamic effects, increase in LV contractility versus baseline [60,65
].
levosimendan induced a decrease in MAP [59–62]. Importantly, changes were noticed in preload- and load-
Importantly, the observed reductions in MAP were small independent measurements [65
], thus suggesting a direct
in magnitude, and appeared to be beneficial in view of increase in contractility which is independent of volume
the corresponding decrease in LV afterload. status or changes in vascular properties. Ventriculovascular
coupling, a measure of ventricle contractile efficiency, was
In the experimental setting of swine endotoxemia, levo- also improved by levosimendan treatment [65
].
simendan likewise decreased mean pulmonary artery
pressure (MPAP) and pulmonary vascular resistance Levosimendan also proved being effective in ameliorat-
index (PVRI) [59]. Similarly, levosimendan infusion ing sepsis-induced diastolic dysfunction [64,65
]. In two
(loading dose of 100 mg/kg followed by a 2 h infusion of the models described above, both LV relaxation and
of 1.7 mg/kg/min) was associated with pulmonary vasodi- diastolic filling were improved after treatment. Notably,
lation and improvements in arterial blood oxygenation in there is no reported improvement in endotoxic diastolic
ovine endotoxemia [61]. Since levosimendan infusion dysfunction with infusion of the classic inotropes, such as
was linked to an increase in arterial carbon dioxide partial milrinone (10 mg/kg/min) or dobutamine (6 mg/kg/min)
pressure (PaCO2) as compared with baseline and controls, [65
].

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 172 Intensive care
In two experimental models of porcine and ovine endo-
toxemia, respectively, levosimendan increased systemic
oxygen delivery (DO2) [59,60] and consumption (VO2) as
well as mixed-venous oxygen saturation (SvO2) [61] as
compared with controls, thus supporting the view that
levosimendan improves global oxygen transport.
A report from an experimental study with LPS-treated
pigs suggested an imbalance in myocardial oxygenation
triggered by levosimendan infusion at a dosage of
0.83 mg/kg/min [62]. In the same report, five of 6 animals
died prematurely in the treatment group. Notwithstand-
ing these findings, it is important to notice that levo-
simendan was not only infused at high concentrations
(0.83 mg/kg/min), but also without simultaneous adminis-
tration of a vasopressor agent. In addition, it cannot be
ruled out that volume replacement was insufficient.
In animal models of endotoxemia, there are conflicting
reports on arterial lactate concentrations and pH. Follow-
ing levosimendan infusion, lactate was either higher than
baseline [61], or remained unchanged as compared to
controls [59], baseline [60] or even both [62]. Likewise,
arterial pH remained unchanged in one study [59] and
decreased in two other reports [61,62]. A potential
explanation of these findings is that in a state of critical
organ perfusion, it may be harmful to administer only a
vasodilator (instead of a vasopressor or a combination
therapy), especially in the presence of hypovolemia and
in doses exceeding clinical recommendations.
Recently, Zager et al. [66] performed a comprehensive
study on the effects of levosimendan on the kidney of
LPS-treated mice. In several in-vivo, ex-vivo and in-vitro
experiments, levosimendan exerted a protective effect on
endotoxin-induced acute renal failure (ARF). Compared
to sham-treated animals, levosimendan decreased blood
urea nitrogen (BUN) and serum creatinine concen-
trations. Conversely, other studies in experimental sepsis
models showed no differences in renal blood flow [59,60]
or medullary to cortical flow re-distribution [60].
In animal models of endotoxemic shock, levosimendan
was associated with reduced gut vascular resistance,
increased portal venous [59] and superior mesenteric
arterial [61] blood flow, increased splanchnic DO2
[59,61] and VO2 [59], as well as increased mucosal O2
saturation and reduced mucosal PiCO2 [61]. These data
support beneficial effects of levosimendan on intestinal
blood flow and tissue oxygenation. This may be particu-
larly important, since splanchnic vasoconstriction and
cellular hypoxia play a pivotal role in the pathophysiology
of sepsis-associated organ failure [67,68].
In a recent study of our research group, addition of
levosimendan (0.2 mg/kg/min) to arginine-vasopressin
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
(AVP, 0.5 m/kg/min) improved global and regional
hemodynamics and resulted in a survival benefit as
compared to AVP infusion alone or placebo in sheep
with septic shock secondary to generalized peritonitis
[69
].
In view of the studies referenced above, it should be kept
in mind that the observed results are influenced by
(a) differences in animal species, (b) etiology of shock
and differences from human septic shock, (c) time to
observation of results (shock phase), (d) technology
and methods used to determine hemodynamic variables,
(e) way and dose of levosimendan administration, or
(f) volume status. Major results from the most relevant
experimental studies are summarized in Table 1.
Clinical evidence for the use of levosimendan
in septic shock
Administration of classic inotropic agents for the treat-
ment of shock may be associated with negative effects,
such as tachyarrhythmia or increase in myocardial oxygen
demand, stressing the need for alternative substances to
support the failing heart in critically-ill patients [23,70].
The use of levosimendan in patients with septic shock
was first described in a case report in 2005 [71]. Since
then, a few case reports and small case series reported
improvements of hemodynamics, global oxygen trans-
port, pulmonary circulation, metabolism or vasopressor
requirements, mostly in patients with long-lasting refrac-
tory septic shock [72,73].
Morelli et al. [46] published the first randomized con-
trolled clinical trial evaluating the effects of levosimen-
dan in septic shock patients (Table 2). Thirty patients
with septic shock with persistent left ventricular ejection
fraction (LVEF) <45% after 48 h of standard therapy
(volume substitution, norepinephrine and dobutamine)
were randomized to receive levosimendan (0.2 mg/kg/min
infusion without preceding bolus) or dobutamine infu-
sion (5 mg/kg/min) for 24 h. Norepinephrine was used to
maintain MAP at 70–80 mmHg. Volume substitution
with colloids was used to achieve a pulmonary artery
occlusion pressure (PAOP) above 12 mmHg. Pulmonary
artery catheter (PAC) and echocardiography measure-
ments were made before study drug infusion and 24 h
thereafter. Levosimendan increased SVI, CI, and LVEF
as compared to baseline. Levosimendan was also superior
to dobutamine in improving end-diastolic and end-sys-
tolic volume index (EDVI and ESVI) and left ventricular
stroke work index (LVSWI). Although a direct evaluation
of cardiac contractility was not performed, it can be
assumed that overall myocardial function was improved.
Interestingly, MAP and SVRI were similar between
groups, although comparable amounts of norepinephrine
 Levosimendan in sepsis and septic shock Pinto et al. 173

Table 1 Experimental trials on levosimendan in endotoxemia

Publication Subjects Intervention groups Main effects of levosimendan
Oldner et al., 14 endotoxemic (20 kg) pigs Levosimendan [bolus (200 mg/kg) Increase in CI; increase in DO2I
2001 [59] þ infusion (3.3 mg/kg/min)] and VO2I
Control (all effectsc) Decrease in MPAP and PVRI
No change in pH or Lart
No change in renal artery blood flow
Increase in portal blood flow and
decrease in gut VRI
Increase in gut DO2I and VO2I
Behrends et al., Isolated hearts from 17 Levosimendan in incremental Improvement in LV systolic function
2003 [64] endotoxemic guinea pigs concentrations (0.03; 0.10 and Improvement in LV diastolic function
(400g) vs. healthy animals 0.30 mM) (all effectsb) Increase in coronary blood flow
Faivre et al., Rabbits (2 kg) Set 1 and 3 (all animals): Levosimendan Improvement in LV systolic function
2005 [60] Set 1: 8 endotoxemic infusion (3.3 mg/kg/min) parametersb
rabbits vs. healthy animals Set 2: combined use of levosimendan No change in systolic or diastolic
Set 2: 26 endotoxemic rabbits (3.3 mg/kg/min), NE (1 mg/kg/min) renal blood flow
Set 3: 4 endotoxemic and AVP (0.005 U kg/min) No change in medullary to cortical
rabbits vs. healthy animals renal blood flow
No change in Lart
No improvement in AVP induced
detrimental effects in cardiac function
Zager et al., Endotoxemic and healthy Multiple in-vivo, ex-vivo and in-vitro After LPS induced ARF: reduction in
2006 [66] mice (30g) experiments (all effectsc) BUN and serum creatinine
Reduction in MC contraction after AII
No change in serum TNFa or MCP1
No change in serum NO
Dubin et al., 19 endotoxemic Levosimendan [Bolus (100 mg/kg) Increase in COc; increase in DO2c;
2007 [61] sheep (21 kg) þ infusion (1.7 mg/kg/min)] increase in SvO2c
Dobutamine (10 mg/kg/min) Decrease in MPAPc and PVRc
Control Increase in PaO2b,c and PaO2/FiO2c
Increase in mesenteric artery flowc,d,
gut DO2c,d and mesenteric SvO2c,d
Barraud et al., Rabbits (2 kg) Set 2: Levosimendan (3 mg/kg/min), Improvement in LV systolic function
2007 [65
] Set 1: 20 endotoxemic rabbits Dobutamine (6 mg/kg/min) parametersb
vs. healthy animals Milrinone (10 mg/kg/min) Improvement in LV diastolic function
Set 2: 20 endotoxemic rabbits parametersb
Cunha-Gonçalves 12 endotoxemic pigs (30 kg) Levosimendan (0.83 mg/kg/min) No change in CO; decrease in SVb,
et al., 2007 [62] Control LVb and RVb stroke work
Decrease in coronary perfusion
pressureb,c; increase in LGCVb
No change in DO2 and VO2; decrease
in SvO2b,c
Rehberg S et al., 21 endotoxemic sheep (40 kg) AVP (0.5 mU/kg/min)
2007 [69
] Levosimendan (0.2 mg/kg/min) þ Improved survivala,c
AVP (0.5 mU/kg/min)
Control
The letters in superscript indicate levosimendan’s statistically significant effects compared with AVP (a), baseline (b), control/vehicle (c) or dobutamine
(d). For more detail please refer to the text or original articles. AII, angiotensin II; ARF, acute renal failure; AVP, vasopressin; BUN, blood urea nitrogen;
CO/I, cardiac output/index; DO2I, systemic oxygen delivery index; FiO2, inspired oxygen fraction; Lart, arterial lactate; LGCV, great coronary vein lactate;
LV, left ventricle; MC, mesangial cell; MCP1, monocyte chemoattractant protein 1; MPAP, mean pulmonary arterial pressure; NO, nitric oxide; PaO2,
arterial oxygen partial pressure; PVRI, pulmonary vascular resistance index; RV, right ventricle; SV, stroke volume; SvO2, mixed venous oxygen
saturation; TNFa, tumour necrosis factor alpha; VO2I, systemic oxygen consumption index; VRI, vascular resistance index.

were infused. Therefore, a reduction in afterload was not
a major determinant of the observed improvement in
systolic function. Notably, patients received no bolus
administration, but just a continuous infusion of 0.2 mg/
kg/min. In view of these results, it is conceivable that
levosimendan infusion was linked with adequate preload
and organ perfusion. This assumption is in line with the
reported increase in VO2I and DO2I (vs. baseline) and the
decrease in arterial lactate (vs. baseline and dobutamine)
observed 24 h after levosimendan infusion, suggesting an
improvement in global tissue oxygenation. In future
clinical trials, additional markers of preload (e.g. dynamic
pressure assessments) and tissue perfusion/oxygenation
should be employed to judge these specific effects in
more detail. Another interesting finding of the latter
study was the observation that levosimendan was
superior to dobutamine in increasing urinary output
and creatinine clearance, thus showing improvements
in global renal function [46]. The authors also reported
that levosimendan induced an increase in gastric mucosal

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 174 Intensive care

Table 2 Clinical trials on levosimendan in septic shock

Publication Patients Intervention groups Main results

Morelli et al., 30 patients with septic shock Levosimendan (0.2 mg/kg/min) Increase in SIb and CIb; decrease
2005 [46] after 48h of ‘standard’ therapy þ Dobutamine (5 mg/kg/min) in EDVIb,d and increase in LVEFb
LVEF <45% Increase in DO2Ib and VO2Ib;
decrease in Lartb,d; decrease in
MPAPb,d; increase in urinary outputd
and creatinine clearanceb,d; increase
in gastric mucosal perfusiond
Morelli et al., 35 patients with septic Levosimendan (0.2 mg/kg/min) Increase in SIb and CIb; increase in LVSWIb
2006 [47
] shock and ARDS Control Decrease in PVRIb and MPAPb,c;
decrease in RVESVIb,c and increase
in RVEFb,c; increase in DO2Ib and SvO2b
The letters in superscript indicate levosimendan’s statistical significant effects compared with baseline (b), control/vehicle (c) or dobutamine (d). For
more detail please refer to the text or original articles. ARDS, adult respiratory distress syndrome; CI, cardiac index; DO2I, systemic oxygen delivery
index; EDVI, end-diastolic volume index; Lart, arterial lactate concentration; LVEF, left ventricular ejection fraction; LVSWI, left ventricular stroke work
index; MPAP, mean pulmonary arterial pressure; PVRI, pulmonary vascular resistance index; RVEF, right ventricular ejection fraction; RVESVI, right
ventricular end-systolic volume index; SI, stroke index; SvO2, mixed venous oxygen saturation; VO2I, systemic oxygen consumption index.

blood flow (accessed by laser-Doppler flowmetry) when

compared with dobutamine. This is in line with data from
experimental studies and strengthens the hypothesis that
levosimendan exerts a direct vasodilatatory effect within
the splanchnic microcirculation, independent of cardiac
output. This notion is supported by concomitant tono-
metry analysis showing a reduction in gastric to arterial
difference in PCO2 (Pg-aCO2), a surrogate marker of
gastric mucosal hypoxia.
Another recently published study was designed to estab-
lish the effects of levosimendan in septic shock in the
particular setting of ARDS and RV failure [47
] (Table 2).
Thirty-five patients with ARDS and septic shock were
assigned to either receive a 24 h infusion of levosimendan
(0.2 mg/kg/min infusion without bolus) or placebo.
Besides hemodynamic data collected from PAC, cardiac
magnetic resonance imaging (MRI) was used to deter-
mine right ventricular end-diastolic volume index
(RVEDVI), right ventricular end-systolic volume index
(RVESVI) and right ventricular ejection fraction (RVEF)
at baseline and after the 24-h infusion period. Similarly to
the previous study by Morelli et al. [46] global hemody-
namics were improved following levosimendan infusion.
In addition, levosimendan infusion contributed to a drop
in MPAP (probably by decreasing PVRI) and pulmonary
artery diastolic (PAD) to PAOP gradient as compared to
baseline and controls. The subsequent reduction in RV
afterload was associated with significant increases in
RVEF and decreases in RVESVI compared to the control
group. Although the above referenced study did not
investigate myocardial contractility itself, RV afterload
reduction was clearly associated with improvements in
systolic function of the RV in the treatment group.
Another clinically significant finding was that levosimen-
dan infusion increased DO2I and SvO2, thus strengthen-
ing previous findings that the drug exerts a beneficial
effect on global tissue oxygenation [46,47
].
Clinically relevant adverse effects
In patients with ADHF, levosimendan is generally well
tolerated [12]. The most significant adverse effects are
probably related to the drug’s vasodilatory properties and
include arterial hypotension, headache, dizziness and
nausea [12,28]. Particularly, bolus administration and
high dose infusion ( 0.4 mg/kg/min) are associated with
such unwanted effects [12,17,28,45]. In the two clinical
trials, however, in which levosimendan was administered
in septic shock patients, MAP and HR remained
unchanged [46,47
], most likely due to concomitant
adequate fluid replacement and norepinephrine infusion.
In addition, data from the same trials suggest beneficial
effects on global tissue oxygenation. Therefore, data from
the available clinical studies suggest that rational use of
levosimendan is a safe and effective alternative to
increasing dobutamine doses in treating the failing heart
of septic shock patients.
Economic considerations
In Europe, the average cost per patient for a 24-h infusion
of levosimendan approximates to s800 ($1100 US). In
the setting of ADHF, drug-related costs of dobutamine
are less than half of levosimendan [74]. Although there is
limited data in the current literature, differences in
material use, length of intensive care unit and hospital
stay may possible contribute to comparable cost-effec-
tiveness of levosimendan and dobutamine [74,75].
Due to the quite high costs and growing economic
pressure, it appears that levosimendan is rather used as
last resort treatment than as first line agent. Thus, levo-
simendan is typically given in shock states refractory to
‘classic’ inotropes, in a final attempt to save the patients’
lives. For many of them, however, this may be too late to
adequately reverse organ failure. Future large scale stu-
dies investigating the use of early vs. late levosimendan

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

infusion (as compared to standard inotropes) in septic
shock patients are urgently needed.
Considerations for the future
Challenging questions that might help clarifying the role
of levosimendan in treating patients with septic shock
remain to be answered (Fig. 2). As such, the effects of
levosimendan on platelet aggregation [76] or circulating
inflammatory mediators can only be extrapolated from
limited data [66,77–79]. In addition, more information is
needed to properly enlighten the effects of levosimendan
on the pulmonary microcirculation and renal function.
Another interesting target that remains to be elucidated
in this context is the mitochondria, especially since
mitochondrial dysfunction plays a pivotal role in the
pathophysiology of sepsis [80
,81]. Changes in architec-
ture and enzymatic activity are related to an inefficient
cellular respiration as well as cellular apoptosis [52
,80
].
Moderate opening of KATP-channels might protect mito-
chondrial function and prevent cellular apoptosis in sep-
sis [82]. To date, there are neither clinical nor exper-
imental reports on the use of levosimendan in the setting
of sepsis-related mitochondrial dysfunction. Taking into
consideration the modulatory effects on KATP-channels
[34,35], it may well be that levosimendan attenuates
septic myocardiopathy by opening KATP-channels in
myocardial mitochondria. Activation of KATP-channels
in septic shock may be a double-edged sword, however,
since excessive activation of KATP-channels is associated
with vasodilation and vascular hyporesponsiveness to
catecholamines [83]. In several experimental septic
shock models, KATP channel blockers have been reported
to induce peripheral vasoconstriction and improve global
hemodynamics [82,84]. Therefore, it is conceivable that
the levosimendan-induced systemic vasodilation result-
ing from Kþ-channel activation is counteracted by
specific inhibitors of vascular Kþ-channels [38
]. Further
research elucidating the interaction between levosimen-
dan and Kþ-channel blockers in sepsis is warranted.
Conclusion
Given that levosimendan is administered in fluid-resus-
citated patients in conjunction with a vasopressor agent,
the drug is safe and efficacious in the treatment myo-
cardial depression and pulmonary dysfunction related to
septic shock. Large prospective, randomized clinical
trials are now warranted to define precise clinical indica-
tions, most appropriate timing for levosimendan use and
overall outcome of septic shock patients.
Acknowledgements
The authors would like to thank Prof. Dr Hugo Van Aken (Muenster,
Germany) and Dr Andrea Morelli (Rome, Italy) for their contribution to
improve and revise the manuscript.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Levosimendan in sepsis and septic shock Pinto et al. 175
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