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Keywords
global oxygen transport, levosimendan, myocardial dysfunction, pulmonary circulation,
right ventricle, sepsis, septic shock
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Levosimendan in sepsis and septic shock Pinto et al. 169
heart failure [20,21]. Notably, pharmacokinetic proper- ‘Classic’ inotropes enhance muscle contraction by
ties are not influenced by age, race, gender, or frequent increasing the level of cyclic adenosine monophosphate
comorbidities presented in patients with septic shock, (cAMP) and subsequently intracellular Caþþ concen-
such as renal failure and hepatic dysfunction [20,21]. tration [16,28]. b1-Adrenergic receptor agonists (e.g.
dobutamine, epinephrine) activate adenylate cyclase,
There is no evidence for a negative clinical interaction the enzyme responsible for cAMP production, and phos-
with commonly used drugs in cardiac patients, such as phodiesterase III (PDE III) inhibitors (e.g. milrinone,
digoxin or warfarin [19]. On the contrary, a subanalysis of amrinone) prevent cAMP degradation [16,28]. The use of
the SURVIVE study [22] reports that levosimendan these drugs is therefore associated with increased myo-
reduces early mortality, as compared to dobutamine, in cardial oxygen consumption and ventricular arrhythmias
the subgroup of patients suffering from heart failure and [16,28]. Levosimendan also exerts a moderate inhibitory
taking b-blockers. 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
Pharmacodynamics and key biologic actions contribute to the lusitropic effect of the drug [29].
Figure 1 illustrates the main mechanisms by which
levosimendan impacts on cardiovascular functions. Acidosis has been shown in vitro to depress the positive
inotropic effect of levosimendan and OR-1896, mainly by
Calcium sensitizing effects attenuating the effect on increasing intracellular Caþþ-
In the cardiac myocyte, levosimendan selectively binds mobilization [30–32]. The drugs’ ability to increase
to the N-domain of cardiac troponin C (cTnC), thereby myofilament sensitivity to Caþþ is mainly unchanged.
stabilizing the calcium (Caþþ)-dependent interaction In addition, there are no reports of impaired relaxation
between cTnC and cTnI [24,25]. The conformational under acidotic conditions [30].
change in cTnC is an essential condition for the inter-
action between actin and myosin microfilaments necess- With the recommended dosage for the treatment of
ary to generate contractile force [26]. Levosimendan patients with AHF (see below), levosimendan exerts a
binds to cTnC in a Caþþ-dependent manner [25,27]. It positive inotropic effect independent of cAMP pro-
dissociates from cTnC when Caþþ concentration duction, thereby leaving intracellular Caþþ-concen-
decreases during diastole, thereby acting only during trations unaffected. Levosimendan therefore neither pro-
systole and not impairing diastolic myocardial relaxation motes ventricular arrhythmias nor relevant increases in
[25,27]. myocardial oxygen consumption [14,28].
Opening KATP,
Opening KATP ↑ Ca++ sensitivity of
Kv and BKCa contractile proteins
channels
channels
+ +
Vasodilation inotropy lusitropy
Improved LV
Reduction of Protection performance
ischemia/ against
Periphery Kidney Gut Lung Coronary
reperfusion myocordial
injury stunning Improved RV
performance
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
170 Intensive care
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Levosimendan in sepsis and septic shock Pinto et al. 171
Sepsis
-?
Inflammation
-? -- -- -?
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.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
172 Intensive care
In two experimental models of porcine and ovine endo- (AVP, 0.5 m/kg/min) improved global and regional
toxemia, respectively, levosimendan increased systemic hemodynamics and resulted in a survival benefit as
oxygen delivery (DO2) [59,60] and consumption (VO2) as compared to AVP infusion alone or placebo in sheep
well as mixed-venous oxygen saturation (SvO2) [61] as with septic shock secondary to generalized peritonitis
compared with controls, thus supporting the view that [69].
levosimendan improves global oxygen transport.
In view of the studies referenced above, it should be kept
A report from an experimental study with LPS-treated in mind that the observed results are influenced by
pigs suggested an imbalance in myocardial oxygenation (a) differences in animal species, (b) etiology of shock
triggered by levosimendan infusion at a dosage of and differences from human septic shock, (c) time to
0.83 mg/kg/min [62]. In the same report, five of 6 animals observation of results (shock phase), (d) technology
died prematurely in the treatment group. Notwithstand- and methods used to determine hemodynamic variables,
ing these findings, it is important to notice that levo- (e) way and dose of levosimendan administration, or
simendan was not only infused at high concentrations (f) volume status. Major results from the most relevant
(0.83 mg/kg/min), but also without simultaneous adminis- experimental studies are summarized in Table 1.
tration of a vasopressor agent. In addition, it cannot be
ruled out that volume replacement was insufficient.
Clinical evidence for the use of levosimendan
In animal models of endotoxemia, there are conflicting in septic shock
reports on arterial lactate concentrations and pH. Follow- Administration of classic inotropic agents for the treat-
ing levosimendan infusion, lactate was either higher than ment of shock may be associated with negative effects,
baseline [61], or remained unchanged as compared to such as tachyarrhythmia or increase in myocardial oxygen
controls [59], baseline [60] or even both [62]. Likewise, demand, stressing the need for alternative substances to
arterial pH remained unchanged in one study [59] and support the failing heart in critically-ill patients [23,70].
decreased in two other reports [61,62]. A potential
explanation of these findings is that in a state of critical The use of levosimendan in patients with septic shock
organ perfusion, it may be harmful to administer only a was first described in a case report in 2005 [71]. Since
vasodilator (instead of a vasopressor or a combination then, a few case reports and small case series reported
therapy), especially in the presence of hypovolemia and improvements of hemodynamics, global oxygen trans-
in doses exceeding clinical recommendations. port, pulmonary circulation, metabolism or vasopressor
requirements, mostly in patients with long-lasting refrac-
Recently, Zager et al. [66] performed a comprehensive tory septic shock [72,73].
study on the effects of levosimendan on the kidney of
LPS-treated mice. In several in-vivo, ex-vivo and in-vitro Morelli et al. [46] published the first randomized con-
experiments, levosimendan exerted a protective effect on trolled clinical trial evaluating the effects of levosimen-
endotoxin-induced acute renal failure (ARF). Compared dan in septic shock patients (Table 2). Thirty patients
to sham-treated animals, levosimendan decreased blood with septic shock with persistent left ventricular ejection
urea nitrogen (BUN) and serum creatinine concen- fraction (LVEF) <45% after 48 h of standard therapy
trations. Conversely, other studies in experimental sepsis (volume substitution, norepinephrine and dobutamine)
models showed no differences in renal blood flow [59,60] were randomized to receive levosimendan (0.2 mg/kg/min
or medullary to cortical flow re-distribution [60]. infusion without preceding bolus) or dobutamine infu-
sion (5 mg/kg/min) for 24 h. Norepinephrine was used to
In animal models of endotoxemic shock, levosimendan maintain MAP at 70–80 mmHg. Volume substitution
was associated with reduced gut vascular resistance, with colloids was used to achieve a pulmonary artery
increased portal venous [59] and superior mesenteric occlusion pressure (PAOP) above 12 mmHg. Pulmonary
arterial [61] blood flow, increased splanchnic DO2 artery catheter (PAC) and echocardiography measure-
[59,61] and VO2 [59], as well as increased mucosal O2 ments were made before study drug infusion and 24 h
saturation and reduced mucosal PiCO2 [61]. These data thereafter. Levosimendan increased SVI, CI, and LVEF
support beneficial effects of levosimendan on intestinal as compared to baseline. Levosimendan was also superior
blood flow and tissue oxygenation. This may be particu- to dobutamine in improving end-diastolic and end-sys-
larly important, since splanchnic vasoconstriction and tolic volume index (EDVI and ESVI) and left ventricular
cellular hypoxia play a pivotal role in the pathophysiology stroke work index (LVSWI). Although a direct evaluation
of sepsis-associated organ failure [67,68]. of cardiac contractility was not performed, it can be
assumed that overall myocardial function was improved.
In a recent study of our research group, addition of Interestingly, MAP and SVRI were similar between
levosimendan (0.2 mg/kg/min) to arginine-vasopressin groups, although comparable amounts of norepinephrine
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Levosimendan in sepsis and septic shock Pinto et al. 173
were infused. Therefore, a reduction in afterload was not improvement in global tissue oxygenation. In future
a major determinant of the observed improvement in clinical trials, additional markers of preload (e.g. dynamic
systolic function. Notably, patients received no bolus pressure assessments) and tissue perfusion/oxygenation
administration, but just a continuous infusion of 0.2 mg/ should be employed to judge these specific effects in
kg/min. In view of these results, it is conceivable that more detail. Another interesting finding of the latter
levosimendan infusion was linked with adequate preload study was the observation that levosimendan was
and organ perfusion. This assumption is in line with the superior to dobutamine in increasing urinary output
reported increase in VO2I and DO2I (vs. baseline) and the and creatinine clearance, thus showing improvements
decrease in arterial lactate (vs. baseline and dobutamine) in global renal function [46]. The authors also reported
observed 24 h after levosimendan infusion, suggesting an that levosimendan induced an increase in gastric mucosal
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
174 Intensive care
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.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Levosimendan in sepsis and septic shock Pinto et al. 175
since excessive activation of KATP-channels is associated 11 Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous
levosimendan compared with dobutamine in severe low-output heart failure
with vasodilation and vascular hyporesponsiveness to (the LIDO study): a randomised double-blind trial. Lancet 2002; 360:196–
catecholamines [83]. In several experimental septic 202.
shock models, KATP channel blockers have been reported 12 Mebazaa A, Barraud D, Welschbillig S. Randomized clinical trials with
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ing from Kþ-channel activation is counteracted by 14 Nieminen MS, Bohm M, Cowie MR, et al. Executive summary of the guidelines
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17 Moiseyev VS, Põder P, Andrejevs N, et al. Safety and efficacy of a novel
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Acknowledgements 21 Antila S, Kivikko M, Lehtonen L, et al. Pharmacokinetics of levosimendan and
The authors would like to thank Prof. Dr Hugo Van Aken (Muenster, its circulating metabolites in patients with heart failure after an extended
Germany) and Dr Andrea Morelli (Rome, Italy) for their contribution to continuous infusion of levosimendan. Br J Clin Pharmacol 2004; 57:412–
improve and revise the manuscript. 415.
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176 Intensive care
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