REVIEW

CURRENT
OPINION Levosimendan: new indications and evidence for
reduction in perioperative mortality?
Antonio Pisano a, Giacomo Monti b, and Giovanni Landoni b,c

Purpose of review
In the last years, the perioperative use of levosimendan in cardiac surgery patients is spreading. Moreover,
newer indications have been suggested such as the treatment of sepsis-associated myocardial dysfunction.
In the present review, we discuss the most recent evidences in these settings.
Recent findings
Levosimendan has been seemingly confirmed to reduce mortality in patients undergoing cardiac surgery. In
particular, it appears to be the only inotropic drug to have a favorable effect on survival in any clinical
setting. Moreover, levosimendan has been shown to exert a cardioprotective action and to reduce acute
kidney injury, renal replacement therapy, and ICU stay in cardiac surgery patients. Finally, levosimendan
has been suggested to reduce mortality in patients with severe sepsis and to improve renal outcomes in
critically ill patients.
Summary
Although a strong rationale likely exists to use levosimendan in the setting of perioperative and critical care
medicine, evidence mainly comes from small and often poor-quality randomized clinical trials, whose
results acquire significance only when pooled in meta-analyses. Moreover, some aspects related to which
subgroups of patients may derive the most benefits from receiving levosimendan, to the optimal timing of
administration, and to the potential adverse effects need to be further clarified. Important insights will be
hopefully provided soon by the several large multicenter investigations which are currently ongoing.
Keywords
cardiac surgery, levosimendan, low cardiac output syndrome, mortality, sepsis

INTRODUCTION to have a direct cardioprotective (e.g., precondition-

Although it is still referred to as a new drug in most
studies, levosimendan was developed more than 20
&
years ago [1 ] and it entered clinical practice in 2000
[2]. Initially indicated for the treatment of acutely
decompensated chronic heart failure (ADHF) [3 ,4],
&
levosimendan is now increasingly used in different
& &
settings [3 ,4,5 ,6] such as repeated or intermittent
administration in patients with advanced heart fail-
ure [4] and perioperative use in patients undergoing
&
cardiac surgery [5 ]. The mechanism behind the sur-
vival benefit possibly exerted by levosimendan is
probably two-fold (Fig. 1): on the one hand, the
unique inotropic mechanism of calcium sensitizers
such as levosimendan (i.e., the increase in the sensi-
tivity of troponin C to calcium) allows us to improve
cardiac output without the most harmful side-effects
of other inotropes, especially catecholamines
(increased myocardial oxygen consumption, myo-
cardial ischemia, and ventricular arrhythmias)
& &&
[1 ,7 ]; on the other hand, levosimendan is thought
ing and antistunning) action through the activation
of adenosine triphosphate-sensitive potassium chan-
& &
nels (KATP) in cardiac mitochondria [1 ,5 ,8]. Levosi-
mendan also induces vasodilation because of the
opening of adenosine triphosphate-sensitive potass-
ium channels on smooth muscle cells in blood vessels
& & &
[1 ,3 ,5 ]: this may contribute to improve myocardial
function (through an increase in coronary blood
flow) but might also induce or worsen arterial
a
Cardiac Anesthesia and Intensive Care Unit, A.O.R.N. Dei Colli, Monaldi
Hospital, Naples, bDepartment of Anesthesia and Intensive Care, IRCCS
San Raffaele Scientific Institute and cVita-Salute San Raffaele University,
Milan, Italy
Correspondence to Giovanni Landoni, MD, Department of Anesthesia
and Intensive Care, IRCCS San Raffaele Scientific Institute, Via Olgettina
60, Milano, 20132 Italy. Tel: +39 02 26436158; fax: +39 02 26436152;
e-mail: landoni.giovanni@hsr.it
Curr Opin Anesthesiol 2016, 29:454461
DOI:10.1097/ACO.0000000000000357

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Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.

 Levosimendan: new indications and evidence Pisano et al.

evidence of a survival benefit in surgical patients.

KEY POINTS
 A growing body of evidence suggests that
perioperative administration of levosimendan may
reduce mortality in cardiac surgery patients.
 Among the newer possible indications, the treatment of
myocardial dysfunction in septic patients seems to be
the most promising.
 Since such evidences mostly come from meta-analyses
of small RCTs, the use of levosimendan in these settings
will be hopefully better defined after the publication of
large multicenter investigations which are
currently ongoing.
hypotension, limiting its use in some circumstances
&
[2,3 ,8]. Another advantage of levosimendan com-
pared with other inotropes is its long-lasting action
(up to 11.3 weeks after the end of a 24-h infusion)
because of the active metabolite OR1896
& & &
[1 ,3 ,5 ,8].
In the first international web-based consensus
conference on mortality reduction in the perioper-
ative period [9] and in its recent update [10],
levosimendan was reported to be one of the few
nonsurgical interventions with randomized
In particular, a small randomized clinical trial
(RCT) [11] and four meta-analyses of RCTs [12
15] found that levosimendan reduces mortality in
patients with low left ventricular ejection fraction
(LVEF) undergoing cardiac surgery. However,
although levosimendan is the most studied drug
ever among inotropes and vasopressors (Fig. 2)
&&
[7 ], evidence about its favorable effects only
comes from small single center RCTs [16], whose
findings should be regarded with caution (and
generally considered as hypothesis generating)
because of their limited external validity and high
risk of bias [17].
From the beginning of 2015 to date, many other
investigations reported favorable effects of levosi-
mendan on mortality or other important outcomes
in both patients undergoing cardiac surgery and
critically ill patients, including those with severe
sepsis and septic shock. In this review, we discuss
these recent evidences and seek to establish to what
extent they confirm the new indications that
emerged in the last few years (i.e., reducing perio-
perative mortality in cardiac surgery) and suggest
further indications such as the treatment of septic
shock and the improvement of renal outcome in
critically ill patients.

NC
N N NH
NC HN O

H 3C
Levosimendan

Actin
Tropomyosin Blood vessels
Ca2+

TnC Myosin head

KATP channels in
cardiac mitochondria
Ca2+-sensitization KATP channels on
(myocardium) smooth muscle cells

Inotropic action
Preconditioning and Vasodilation
without increased myocardial
anti-stunning effects
oxygen consumption

Cardiac protection
reduced mortality?

FIGURE 1. Mechanisms of action of levosimendan. TnC, troponin C.

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Drugs in anesthesia

performed a meta-analysis of seven RCTs (438

48
patients, overall) investigating the intermittent
use of levosimendan in advanced heart failure
patients and found that levosimendan significantly
32
reduced mortality [odds ratio (OR) 0.54, 95% CI
Number of RCTs

25 0.320.91, P 0.02], unlike other inotropes such

23
as dobutamine or phosphodiesterase-3 inhibitors
16 15 which were previously shown to have no impact
11 10 on mortality [30,31] or even increase it [32] in the
6 same clinical context. Together with a review of all
the 25 meta-analyses on levosimendan published so
&
far, Pollesello et al. [21 ] confirmed a reduction in
mortality with the administration of levosimendan
es

es
n

an ors

ne

xin

e
e

e
da

lu
in

in
gu

in
Do ami

go
t
en

eb
m

in patients with ADHF in a comparative meta-

l am
i
alo
ib

pa

ta

Di
sim

x
inh

len
pe

bu

ho
Do

analysis limited to the six phase II and III double-

vo

hy
Do

ec
-3

d
an
Le

et
E

at

blind RCTs which were taken into consideration by

PD

M
rc
sin

he

the regulatory authorities for the introduction of

es

Ot
pr

levosimendan into the market. A significant

so
Va

reduction in mortality was also recently found in

FIGURE 2. Number of randomized clinical trials (RCTs) septic patients receiving levosimendan (see below)
&

comparing any inotrope or vasopressor with no inotropic/
vasopressor therapy published from 1994 to 2015. PDE-3,
phosphodiesterase-3; other catecholamines include
ephedrine, epinephrine, isoproterenol, and phenylephrine.
Data from [7 ]. &&
[20 ]. The other four meta-analyses reporting a sur-
vival advantage with levosimendan deal with car-
diac surgery patients [16,18,19,22] and will be
discussed in the following section.

LEVOSIMENDAN IN CARDIAC SURGERY

LEVOSIMENDAN AND MORTALITY
In 20152016 eight new meta-analyses confirmed a
possible role of levosimendan in reducing mortality
&&
in different settings [4,7 ,16,18,19,20 ,21 ,22].
&&
Belletti et al. [7 ] selected 177 trials (including
28 280 patients, overall) in which an inotropic
and/or vasopressor drug (see Fig. 2) was compared
with placebo or best available treatment (excluding
inotropes/vasopressors) in any setting, including
cardiac surgery, major noncardiac surgery, cardio-
logy (mainly acute or chronic heart failure), and
ICU, among others. They found that only levosi-
mendan (48 RCTs) was associated with a significant
reduction in mortality [risk ratio (RR) 0.80, 95%
confidence interval (CI) 0.680.94, P 0.008]. Inter-
estingly, the administration of inotropic drugs was
not associated with increased mortality, contrary to
what was suggested previously, especially in
patients with heart failure [2327] but also in those
undergoing cardiac surgery [28,29]. Conversely, a
significant reduction in mortality was found when
inotropes were used in the setting of vasoplegic
syndromes, sepsis, and cardiac surgery. These find-
ings suggest that there should be no hesitation to
use inotropes (when they are really needed), and
that levosimendan may become the drug of choice,
whenever it is possible, as it is the only inotropic
drug associated with improved survival across all
clinical settings. Silvetti and Nieminen [4] recently
For some years now levosimendan is part of the
pharmacological armamentarium of most cardiac
anesthesiologists and intensivists, especially to face
& &
the growing risk profile of their patients (e.g.,
patients with low preoperative left ventricle ejection
fraction undergoing coronary artery bypass surgery)
[8], but also to have available a drug with a more
favorable impact in terms of survival when inotropic
support is mandatory, such as for the treatment of
postoperative low cardiac output syndrome (LCOS).
The use of levosimendan in cardiac surgery has been
recently codified by a panel of 27 European experts
&
[5 ], whose main recommendations are reported in
Table 1.
Most of the investigations published soon after
this consensus paper seem to confirm the beneficial
effects of levosimendan on both survival and other
outcomes following cardiac surgery (Table 2).
Recent evidence of mortality reduction in
cardiac surgery patients
Despite the fact inotropes are used in up to 90% of
&&
cardiac surgery patients [7 ], few studies have
directly compared different inotropic drugs and
there is poor evidence about a possible survival
advantage with the one or the other drug. Greco
et al. [19] recently performed a Bayesian network
meta-analysis including 2647 patients from 46 RCTs

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Table 1. Main recommendations for the use of levosimendan in patients undergoing cardiac surgery by a panel of 27
European experts
Indications
Dosing
Timing
Monitoring
Association with vasopressors or other inotropes
&
Reproduced from [5 ].
in which an inodilator among dobutamine, enox-
imone, milrinone, and levosimendan was compared
with either placebo or one of the above inodilators
in cardiac surgery. These authors found that only
levosimendan was associated with a reduced
mortality as compared with placebo (posterior mean
of OR 0.48, 95% credibility interval 0.280.80),
suggesting that levosimendan carries the lowest risk
of mortality compared with dobutamine, phospho-
diesterase-3 inhibitors, and placebo. Lim et al. [16]
analyzed 11 RCTs reporting early mortality in
patients with reduced preoperative LVEF who were
randomized to receive levosimendan or either
placebo or other supportive therapies before,
during, or after cardiac surgery. Pooled in-hospital
mortality was 5.5% in the levosimendan group
(483 patients) and 9.1% in the control group
(482 patients) (OR 0.48, 95% CI 0.230.76,
P 0.004). In a random-effect meta-analysis of 13
trials (1345 patients, overall) investigating the
effects of levosimendan on renal outcomes after
cardiac surgery, Zhou et al. [22] found a significant
reduction in postoperative mortality (OR 0.41,
95% CI 0.270.62, P < 0.001). Finally, levosimen-
dan was found to reduce postoperative mortality
compared with either dobutamine (OR 0.40. 95%
CI 0.170.96, P 0.04) or milrinone (OR 0.20. 95%
CI 0.050.86, P 0.04), but not with placebo, in a
meta-analysis of 10 RCTs of high-risk cardiac sur-
gical patients with multiple organ dysfunction
syndrome (MODS) [18]. Interestingly, all the nine
meta-analyses published so far reporting a
mortality effect of levosimendan in cardiac surgery
agree that it significantly reduces mortality [21 ].
However, in addition to the acknowledged limita-
tions of meta-analyses (and, in particular, of net-
work meta-analyses), many of these investigations
are further limited by high risk of bias, suboptimal
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Levosimendan: new indications and evidence Pisano et al.
Preoperative administration in patients with impaired left or right ventricular function
0.1 mg/kg/min infusion for 24 h or up to the end of the vial
An initial bolus dose should be avoided when the drug is administered outside the
operating room but can be considered when the infusion is started during or after
induction of anesthesia
The day before surgery can be considered as the best time to start a preoperative
infusion of levosimendan
The patient should be under adequate hemodynamic monitoring during the infusion to
early detect and promptly treat side-effects such as hypotension
An infusion of norepinephrine or vasopressin should be added if excessive
vasodilation and hypotension occur
Dobutamine is the preferred drug if additional inotropic support is needed
quality and small sample size of the majority of
included RCTs.
Other possible favorable effects
In patients undergoing cardiac surgery, levosimen-
dan has been previously shown to provide cardiac
protection, improve cardiac performance in patients
with left ventricular hypertrophy and/or diastolic
dysfunction, favorably affect hepatic function and
renal outcomes, and reduce hospital and ICU length
&
of stay (LOS) [5 ,8]. Some of these effects have been
also found in recent investigations, though none of
particular strength (three of the abovementioned
meta-analyses [16,18,22], two retrospective studies
[33,34] and one small RCT [35]).
A lower troponin peak in patients receiving
levosimendan was found both in the meta-analysis
by Qiao et al. [18] and in a retrospective study on 146
patients with left ventricular systolic dysfunction
undergoing elective cardiac surgery from 2006 to
2013 [33]. In the latter cohort, the 13 patients who
received preoperative (within 72 h before surgery)
levosimendan had a postoperative peak troponin I
of 1.9  1.8 compared with 10.4  32 ng/ml in
patients not receiving it (P 0.02). Moreover, these
13 patients had a lower rate of LCOS (7.7 vs. 43.6%,
P 0.012) [33]. A lower incidence of LCOS (OR 0.24,
95% CI 0.150.36) was also found across the four
RCTs reporting data on it in the aforementioned
meta-analysis by Lim et al. [16].
Malik et al. [35] randomized 30 patients with
diastolic dysfunction and LVEF more than 55%
&
undergoing coronary artery bypass grafting on car-
diopulmonary bypass (CPB) to receive an infusion of
either levosimendan or nitroglycerin started before
skin incision and continued until ICU admission to
compare the effects of the two drugs on
www.co-anesthesiology.com 457
Drugs in anesthesia

Table 2. Summary of the investigations on levosimendan in cardiac surgery published from 2015

Study Design Population N Comparators Main findings

Greco et al. [19] network meta- cardiac surgery 2647 Dobutamine, Levosimendan was the only inodilator to
analysis patients enoximone, reduce mortality as compared with
milrinone, or placebo
placebo
Lim et al. [16] meta-analysis cardiac surgery 965 Placebo or other Levosimendan reduced early mortality,
patients with supportive therapies postoperative AKI, and ICU LOS
reduced LVEF
Zhou et al. [22] random-effect cardiac surgery 1345 Placebo or other Levosimendan reduced postoperative AKI,
meta-analysis patients inotropic drugs RRT need, postoperative mortality,
duration of MV, and ICU LOS
Qiao et al. [18] meta-analysis high-risk cardiac 440 Dobutamine, Levosimendan reduced postoperative
surgery patients with milrinone, or mortality as compared with dobutamine
MODS placebo or milrinone but not with placebo
Levosimendan also reduced cardiac Tn
release and AF
Avalos et al. [33] retrospective patients with LVSD 146 Patients not receiving Patients receiving levosimendan had
undergoing elective levosimendan reduced incidence of LCOS, lower Tn and
cardiac surgery Cr peak, and shorter MV
The incidence of new-onset atrial fibrillation,
hospital LOS, and 30-day mortality were
not significantly different
Treskatsch et al. retrospective cardiac surgery 159 Earlya vs. late start Late administration was associated with
[34] patients receiving of levosimendan increased in-hospital and 1-year mortality,
levosimendan infusion duration of MV, AKI incidence, and RRT
need
Malik et al. [35] RCT patients with diastolic 30 Nitroglycerin Levosimendan improved echocardiographic
dysfunction and markers of diastolic dysfunction
preserved LVEF
undergoing CABG
Juhl-Olsen et al. RCT patients with left 20 Placebo No differences in echocardiographic
[36] ventricular markers of both systolic and diastolic
hypertrophy and function
preserved LVEF
undergoing AVR
Salgado Filho et al. RCT CABG patients 81 Epinephrine As compared with levosimendan,
[37] epinephrine reduced post-CPB left ventricle
MPI and increased the rate of successful
weaning from CPB at the first attempt

AF, atrial fibrillation; AKI, acute kidney injury; AVR, aortic valve replacement; CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; Cr, creatinine;
ICU, intensive care unit; LCOS, low cardiac output syndrome; LOS, length of stay; LVEF, left ventricle ejection fraction; LVSD, left ventricle systolic dysfunction;
MODS, multiple organ dysfunction syndrome; MPI, myocardial performance index; MV, mechanical ventilation; RCT, randomized clinical trial; RRT, renal
replacement therapy; Tn, troponin.
a
Within 1 h after ICU admission.

(transesophageal) echocardiographic signs of dias- levosimendan on diastolic dysfunction. However,

tolic dysfunction evaluated at baseline, during left
internal mammary artery isolation, and during skin
closure. The levels of N-terminal fragment of pro-B-
natriuretic peptide (NT-proBNP) were measured at
baseline and 12 and 24 h after surgery. In the levo-
simendan group, isovolumic relaxation time and
deceleration time were significantly improved as
compared with both baseline and the same time
points in the nitroglycerin group. Moreover, the
increase in pro-B-natriuretic peptide levels was sig-
nificantly lower in patients receiving levosimendan,
further suggesting a potential beneficial effect of
such a favorable effect on diastolic function was not
confirmed in another small RCT in which 20
patients with left ventricular hypertrophy and LVEF
more than 45% undergoing aortic valve replace-
ment were randomized to receive an infusion of
either levosimendan or placebo from 4 h before
surgery until the end of it [36]. Of note, the trial
was stopped early because of a very high overall
incidence of postoperative atrial fibrillation. Echo-
cardiographic signs of both systolic and diastolic
function were not significantly different between
the two groups on the first day and up to 6 months

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after surgery. Similarly, there was no difference in the
indices of diastolic function in a recent RCT of 81
patients undergoing coronary artery bypass grafting
whose primary endpoint was to evaluate the effects of
levosimendan compared with epinephrine on the
left ventricle myocardial performance index (MPI)
[37]. Remarkably, these authors found a lower left
ventricle MPI in the post-CPB period in the epineph-
rine group compared with the levosimendan group
(0.26  0.15 vs. 0.39  0.17, P 0.0013), which trans-
lated into a higher rate of successful weaning from
CPB at the first attempt in patients receiving epineph-
rine compared with those receiving levosimendan.
These two small RCTs [36,37], although with their
important methodological limitations, are among
the first reports that discourage the routine use of
levosimendan in elective patients with preserved
LVEF undergoing cardiac surgery.
A reduced rate of postoperative acute kidney
injury (AKI) in patients receiving levosimendan
was found in the meta-analysis by Lim et al. [16]
(7.4 vs. 11.5%, OR 0.62, 95% CI 0.400.95) and in
that by Zhou et al. [22] (40/460 vs. 78/499, OR 0.51,
95% CI 0.340.76, P 0.001). The latter also showed
a reduced need for renal replacement therapy (RRT)
(22/492 vs. 49/491, OR 0.43, 95% CI 0.250.76,
P 0.002) [22]. A renal protective action of levosi-
mendan was also recently suggested by two obser-
vational investigations [33,34]. In the cohort of
patients studied by Avalos et al. [33], those who
had received preoperative levosimendan had a lower
peak serum creatinine (0.98  0.4 vs. 1.3  0.7 mg/
dl, P 0.03). Treskatsch et al. [34] analyzed data
from 159 cardiac surgery patients receiving levosi-
mendan and found a reduction in both the rate of
AKI (P 0.002) and the need for RRT (P 0.032) in
those receiving the drug early (perioperatively and
within 1 hour after ICU admission). Conversely, no
difference in the rate of AKI was found by Qiao et al.
[18].
Finally, a significant reduction in ICU and/or
hospital LOS was found by Lim et al. [16] and Zhou
et al. [22] but not by Qiao et al. [18] and Avalos et al.
[33].
Timing: preoperative in low left ventricular
ejection fraction or postoperative in low
cardiac output syndrome?
It is not necessarily a choice. As discussed earlier, in
fact, a rationale exists to use levosimendan in both
circumstances. However, according to expert
opinion the initiation of infusion 1 day before
surgery (especially in patients with left ventricular
systolic dysfunction) is the optimal timing (see Table
&
1) [5 ]. Only three recent investigations are weakly
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Levosimendan: new indications and evidence Pisano et al.
informative in this regard [16,33,34]. As discussed
previously, the retrospective investigation by Avalos
et al. [33] reported favorable effects with preoperative
preconditioning with levosimendan. In their meta-
analysis, Lim et al. [16] suggested the time of surgery
as the best time to start the infusion. Finally, Tre-
skatsch et al. [34] reported an increase in both in-
hospital and 1-year mortality and, as mentioned, in
AKI rate and RRT need, in patients receiving levosi-
mendan after the first hour of ICU admission as
compared with those receiving the drug earlier. Three
ongoing (LEVO-CTS, CHEETAH) or just completed
(LICORN) large RCTs are investigating either the
preoperative or postoperative use of levosimendan
in cardiac surgery and will probably provide import-
ant insights about this topic. In fact, the LICORN trial
(NCT02184819, France) and the LEVO-CTS trial
(NCT02025621, USA) involve patients with low LVEF
randomized to receive either levosimendan or
placebo at the time of anesthesia induction and
before surgery, respectively, whereas the CHEETAH
(HSR-LEVO) trial (NCT00994825, Italy) is randomiz-
ing mainly patients with postoperative LCOS [38].
Side-effects
As mentioned, levosimendan induces vasodilation
and may cause or worsen hypotension. Indeed, post-
hoc analyses of the REVIVE studies (which involved
ADHF patients receiving a bolus dose prior to
continuous infusion) showed that low baseline
blood pressure (systolic < 100 mmHg or diastolic
<60 mmHg) was associated with increased mortality
[2]. However, it is likely that this issue is less import-
ant in the surgical/ICU setting, where blood pressure
is strictly monitored and hypotension promptly and
easily managed.
In a retrospective analysis of a RCT of levosi-
mendan in patients undergoing cardiac surgery,
Lahtinen et al. [39] found an increased risk of post-
operative bleeding after valve surgery in patients
receiving levosimendan, possibly caused by an
impairment of platelet function because of phos-
phodiesterase inhibition [8]. To our knowledge,
there have been no other reports in this regard.
Although levosimendan has been reported to be
associated with an increased incidence of atrial
fibrillation in heart failure patients [8], a meta-
analysis found a significantly reduced risk in cardiac
surgery patients receiving levosimendan [12]. A
lower incidence of atrial fibrillation in patients
receiving levosimendan was also found in the
meta-analysis by Qiao et al. [18], whereas there
was no difference in the retrospective analysis by
Avalos et al. [33]. Finally, as mentioned, the RCT by
Juhl-Olsen et al. [36] was stopped prematurely
www.co-anesthesiology.com 459
Drugs in anesthesia
because of an overall excessive rate of atrial fibrilla-
tion, with a trend toward increased incidence in the
levosimendan group. The ongoing large trials will
hopefully shed some light also on this controversial
topic.
LEVOSIMENDAN IN ICU PATIENTS
Although its mechanisms are not well known, it is
now clear that a myocardial dysfunction is present
in up to 50% of patients with severe sepsis [40].
&
Zangrillo et al. [20 ] performed a meta-analysis of
seven RCTs (246 patients, overall) comparing levo-
simendan vs. standard inotropic drugs (such as
dobutamine) in septic patients and found a signifi-
cant reduction in mortality in patients receiving
levosimendan (47 vs. 61%, RR 0.79, 95% CI 0.63
0.98, P 0.03). Also blood lactate levels were signifi-
cantly lower in the levosimendan group. Of note, no
difference in mean arterial pressure and norepi-
nephrine use was shown. A beneficial effect of lev-
osimendan on both myocardial dysfunction and
inflammatory markers was recently confirmed in
an animal model of sepsis [41], and may be
explained by both the inotropic and pleiotropic
(including anti-inflammatory) effects of levosimen-
dan [40,41]. A large multicenter RCT investigating
the effects of a 24-h infusion of levosimendan in
patients with septic shock (LeoPARDS trial) has just
completed enrollment in the UK [42].
Besides that in cardiac surgery patients, a sig-
nificant reduction in both the rate of AKI (RR 0.79,
95% CI 0.630.99, P 0.048) and the risk for RRT
(RR 0.52, 95% CI 0.320.86, P 0.01) was also found
in a meta-analysis including 3879 critically ill
&
patients from 33 RCTs [43 ]. This topic deserves
further investigation.
Finally, a beneficial role of levosimendan has
been suggested in the setting of aneurysmal subar-
achnoid hemorrhage [44], but the evidence is
currently scarce.
COST-EFFECTIVENESS
A main concern about the use of levosimendan is its
high cost. However, two recent pharmacoeconomic
studies (both with representatives of the company
that produces levosimendan among authors)
suggest that levosimendan may lead to money sav-
ing, mainly because of reduced hospital LOS, in both
the cardiology [45] and cardiac surgery [46] settings.
CONCLUSION
There is a growing bulk of evidence suggesting a
beneficial role of levosimendan on several
460 www.co-anesthesiology.com
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
outcomes, including mortality, in both cardiac
surgery and critically ill (especially septic) patients.
However, this evidence mainly comes from small
and often poor-quality RCTs, whose results acquire
significance only when pooled in meta-analyses.
Even though it seems to exist a strong rationale to
use levosimendan, especially before cardiac surgery
in patients with myocardial dysfunction, we look
forward to the results of the three ongoing large
multicenter RCTs, as it is not uncommon to see the
findings of previous single center studies and meta-
analyses not being confirmed or being even over-
turned by subsequent large multicenter investi-
gations, especially in the complex field of
perioperative and critical care medicine [17]. It can-
not be excluded, for example, that the observed
effects are overestimated and related to protocols
and volumes of activity of individual centers, or
limited to specific subgroup of patients.
Although it is likely that, if confirmed, similar
favorable effects could also apply to noncardiac
surgery, evidence in this setting is so far anecdotal,
with a few case reports of preoperative or postoperative
administration of levosimendan, for example, in high-
risk elderly patients undergoing emergent abdominal
&
surgery [3 ]. Future adequately designed trials are to be
performed also in the noncardiac surgery setting.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
G.L. received speaker fees from AbbVie, Orion and
Tenax.
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Volume 29  Number 4  August 2016

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