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48 Current Vascular Pharmacology, 2016, 14, 48-57

Inodilators in the Management of Low Cardiac Output Syndrome After

Pediatric Cardiac Surgery

Angela Ferrer-Barba1,*, Iria Gonzalez-Rivera1 and Victor Bautista-Hernandez2

1
Department of Pediatrics, Complexo Hospitalario Universitario de A Coruña. Instituto de investiga-
ción Biomédica de A Coruña (INIBIC). A Coruña, Spain; 2Department of Cardiovascular Surgery,
Complexo Hospitalario Universitario A Coruña (CHUAC), Congenital and Structural Heart Disease,
Instituto de Investigación Biomédica A Coruña (INIBIC), A Coruña, Spain

Abstract: Postoperative low cardiac output syndrome has been shown to have both a central and a pe-
ripheral vascular involvement. Therefore, inodilators which provide with a combination of positive
inotropic and vasodilating therapy, conceptually should be an ideal form of treatment. However, con-
tradictory data on these drugs exist. Phosphodiesterase inhibitors (e.g. milrinone) and more recently
Angela Ferrer-Barba
calcium sensitizers (e.g. levosimendan) have been most commonly used groups in the clinical setting.
This review will summarize the pharmacology of inodilators with a special foccus on current clinical evidence. This arti-
cle addresses the sixth of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduc-
tion in low cardiac output syndrome after pediatric cardiac surgery”.
Keywords: Cardiac output syndrome, inodilators, levosimendan, milrinone, pediatric cardiac surgery, pharmacology.

INTRODUCTION (e.g. adrenaline, dopamine, dobutamine and noradrenaline)

have been largely used. Their effects are mainly mediated
Morbidity and mortality associated with pediatric cardiac
through alpha and beta adrenergic receptors which promote
surgery has been reduced significantly in recent decades [1].
myocardial contractility [9]. However, catecholamines, espe-
However, low cardiac output syndrome (LCOS) remains
cially at high doses, show significant adverse events such as
common and occurs in up to 25% of children undergoing
increased myocardial oxygen consumption, which may in-
pediatric cardiac surgery [2]. LCOS has been related to pro-
duce myocardial ischemia, arrhythmias, diastolic dysfunction
longed mechanical ventilation and hospital stay as well as an and systemic and pulmonary vasoconstriction. Moreover,
increased risk of infection and death [3]. Several factors are
patients with a preoperative heart failure status may develop
involved in the development of postoperative LCOS, includ-
tachyphylaxis to catecholamines due to adrenergic receptor
ing preoperative myocardial dysfunction and heart failure,
desensitization [8, 10]. Furthermore, recent studies have re-
and intraoperative factors such as cardiopulmonary bypass
ported that LCOS is associated with significant increases in
and moderate or deep hypothermia. In addition, type of sur-
systemic and pulmonary resistance [2] Thus, drugs which
gical repair, deleterious effects of cardioplegia, myocardial may not only improve myocardial contractility but also
ischemia during aortic cross clamp, myocardial reperfusion
lower vascular resistances (systemic, pulmonary and coro-
injury, systemic inflammatory syndrome and changes in sys-
nary) may be key in preventing and treating LCOS [5, 11].
temic and pulmonary resistances have also been related to
LCOS [2, 4, 5]. Inodilators are pharmacologic agents, that have inotropic
and lusotropic effects on the myocardium. In addition, they
LCOS is characterized by the development of tachycar- also have vasodilatory properties involving the systemic,
dia, decreased renal output, decreased systemic perfusion,
pulmonary, and coronary vasculature. Consequently, they
and acidosis during the early postoperative period (i.e., 6-12
have become widely used in the treatment of LCOS in the
hours after surgery) [6]. Thus, early treatment and or preven-
pediatric patient undergoing heart surgery. Milrinone, an
tion of LCOS is crucial to avoid complications [7]. Never-
inhibitor of phosphodiesterase type III, and levosimendan, a
theless, no guidelines for the management of LCOS after
calcium sensitizer, are currently the most commonly used
pediatric cardiac surgery have been widely adopted [3]. In drugs for the treatment of LCOS. Furthermore, they have
general, optimization of preload and mechanical ventilation
been reported to prevent the development of perioperative
and the use of drugs like systemic and pulmonary vasodila-
LCOS in adult patients [12, 13]. The aim of this article is to
tors, inodilators and inotropes comprise standard care. How-
review the pharmacology of inodilators, specifically focusing
ever, the specific management of LCOS varies among insti-
on their use in the up-to-date management of LCOS after
tutions [8]. Regarding inotropic agents, catecholamines
pediatric cardiac surgery.

*Address correspondence to this author at the Department of Pediatrics, LEVOSIMENDAN

Pediatric Intensive Care Unit, Hospital Materno-Infantil Teresa Herrera,
Xubias de Arriba nº 84, 2ª planta, 15006 A Coruña (Spain); Tel: + 34 981 Levosimendan is a newly discovered drug, which has
176 214; Fax: +34 981 178 196; E-mail: angela.ferrer.barba@sergas.es been used in the clinical setting since 2000 especially in the

1875-6212/16 $58.00+.00 © 2016 Bentham Science Publishers

Inodilators in the Management of Low Cardiac Output Syndrome
management of heart failure. Currently, it is likely the most
studied inotropic drug with about 83 controlled-randomized
studies in adults and 4 in children [14, 15]. Levosimendan
exerts its effects through two main mechanisms of action
within the cardiomyocyte: 1) calcium sensitizer and, 2) open-
ing of the K-dependent channels: which lead to positive
inotropy, lusotropy, vasodilation (systemic, pulmonary and
coronary) and cardioprotection. The utility of levosimendan
for the treatment of LCOS has been reported in adults and
children [7, 12, 14, 16-18]. However, levosimendan is rarely
utilized as first line of treatment due to its high cost when
compared to catecholamines and other inodilators [14].
Levosimendan is approved in Europe (12 countries), Asia,
South America and Australia but not in the USA [19]. No
formal indication exists in patients under 18 and thus, in
children it can only be prescribed off-label under compas-
sionate use and with informed consent [10, 19, 20].
Pharmacology
Levosimendan is the (-) enantimer of {[4-(1,4,5,6-
tetrahydro-4-methyl-6-oxo-pyridazinyl) phenyl]hydrazono}
propanedinitrile (Fig. 1) which is a derivate of the pyridazi-
none-dinitrile molecule. The pharmacokinetics of
levosimendan are complex and influenced by its main me-
tabolite, OR-1896, which exerts its cardiovascular effects
(Table 1).
Pharmacokinetics
Levosimendan is administered intravenously and is fully
metabolized by the liver with just traces being eliminated in
the urine and feces. 5% of the enteral dose is reduced by
intestinal bacteria into its active metabolite OR-1855, which
is progressively acetylated in the liver to the most active
form, OR-1896. The initial molecule is 98% protein-bound
while OR-1896 in 43% protein-bound. The half live of
levosimendan is 1-1,5 hours, while that of OR-1896 is 75-80
hours, which leads to a prolonged effect of up to 7-9 days
after 24 hours of continuous infusion [19, 21, 22]. Pharmo-
cokinetics are not altered in the presence of severe renal dys-
function or moderate hepatic dysfunction [22]. Some pre-
clinical studies show promising plasmatic levels of
levosimendan when administered po, although none of them
in the pediatric population.
Pharmacodynamics and Clinical Effects
Levosimendan binds to troponin C resulting in its in-
creased affinity for calcium and its subsequent stabilization,
thus resulting in increased inotropy. Unlike other inotropic
drugs, at therapeutic doses, levosimendan improves myocar-
dial contractility without increasing oxygen consumption or
raising intracellular cAMP or calcium concentrations (Fig. 2)
[22].
Levosimendan and its metabolite OR-1896 show vasodi-
latory properties on arteries and veins due to opening of
ATP-sensitive K+ channels and other other K+ channels re-
sulting in hyperpolarization and relaxtion of vascular smooth
muscle. Clinically, levosimendan and OR-1896 exert arterial
vasodilation (systemic, pulmonary and coronary) as well as
venous vasodilation (portal and saphenous) [21].
Current Vascular Pharmacology, 2016, Vol. 14, No. 1 49
Fig. (1). Structural formula of levosimendan.
Table 1. The three major mechanisms of levosimendan.
Papp Z et al. Levosimendan: molecular mechanisms and clinical implications: consen-
sus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2012;
159(2): 82-7. By permission of ELSEVIER.
As a consequence of inotropic and vasodilatory effects,
levosimendan also demonstrates a positive lusotropic effect,
with decrease of ventricular filing pressures and improve-
ment of diastolic dysfunction in the left and right ventricles
[11, 19, 21].
A cardioprotective effect of levosimendan has also been
reported. This action is associated with the decrease in pre
and post-load, coronary vasodilation and improved contrac-
tility, which facilitate myocardial perfusion [19, 21]. Similar
to milrinone, levosimendan inhibits phosphodiesterase III
and thus, increases intracellular calcium but at high doses
[23]. In addition, a preconditioning protective effect of
levosimendan has been related to opening of K+ channels in
the mitochondria [7] which would lead to a diminished oxi-
dative stress and ischemic and reperfusion injuries. These
effects could be especially beneficial in the setting of post-
operative LCOS. Furthermore, levosimendan seems to pro-
vide an antiapoptotic effect in the cardiomyocytes, poten-
tially improving cardiac remodeling. The cardioprotective
actions of levosimendan are thought to be systemic with the
subsequent benefits for other organs [21].
Levosimendan’s effects are independent of beta-
adrenergic receptors and the need for increased intracellular
calcium concentration, which reduces the activation of the
autonomous nervous system and subsequently reduces the
incidence of arrhythmias. Finally, levosimendan also exhib-
its an immunomodulatory effect, reducing the levels of pro-
inflammatory cytokines IL-6 and TNF, and improving the
neurohormonal dysfunction present in heart failure scenarios.
Specifically, levels of blood B-type natriuretic peptide are
decreased after levosimendan infusion and therefore, could
be used as a biological marker of its effectiveness [19] in
treating congestive heart failure.
Clinical studies on the pharmacodynamics and pharma-
cokinetics of levosimendan in children are scarce and so the
50 Current Vascular Pharmacology, 2016, Vol. 14, No. 1
Fig. (2). Pharmacodynamics of levosimendan. Angadi U, Westrope C, Chowdhry MF. Is levosimendan effective in paediatric heart failure
and post-cardiac surgeries? Interact Cardiovasc Thorac Surg 2013; 17(4): 710-4. By permission of Oxford University Press.
data are usually extrapolated from adult experience. Never-
theless, three current studies have focused on pediatric pa-
tients. The first study involved an animal model mimicking
pediatric cardiopulmonary bypass and comparing
levosimendan versus milrinone [11]. 18 piglets underwent
cardiopulmonary bypass with aortic cross-clamp and car-
dioplegic arrest. Aftter 120 minutes, they were assigned to
control, milrinone, or levosimendan groups and were studied
for an additional 120 minutes. The major conclusion was that
milrinone and levosimendan prevented increased afterload
and exerted beneficial effects on pulmonary vascular resis-
tance and myocardial oxygen balance, although levosiman-
dan showed greater inotropic properties, just as shown in
adults studies. In the second study, 13 children with congeni-
tal heart disease undergoing preoperative cardiac catheteriza-
tion were enrolled and given a single loading dose of
levosimendan (12mcg/kg) over 10 minutes during the cathe-
terization [24], The results demonstrated a very similar
pharmacokinetic profile to that observed in adults, although
with a distribution volume 2 times larger in the pediatric
population. Thus, the authors recommended adjusting the
levosimendan dose according to body surface area in chil-
dren. The minimal hemodynamic effects observed after the
bolus dose was probably due to a small dose relative to the
body surface area. Recently, the third pediatric study by Pel-
licer et al. [25] compared milrinone and levosimendan in
neonatal patients with congenital heart disease undergoing
cardiac surgery in a phase I, randomized and blinded study.
Both drugs were administered in continuous infusions with
no bolus. Interestingly, levosimendan demonstrated similar
pharmacokinetics in neonates when compared to adults and
was well tolerated.
Dosage
The current doses of levosimendan for adult and pediatric
patients as recommended by The European Society of Cardi-
ology Guidelines in 2008 for the treatment of acute heart
Ferrer-Barba et al.
failure [26] (recommendation class IIa and evidence level B)
are shown in Table 2.
In patients having cardiac surgery, a loading dose of
levosimendan is usually avoided due to the low blood pressure
frequently observed in postoperative patients. Levosimendan
is thus commonly administered without a loading dose,in chil-
dren with postoperative LCOS [15, 18, 25], as recommended
in S3 guidelines for intensive care in cardiac surgery patients:
hemodynamic monitoring and cardiocirculatory system [27].
Adverse Events
The safety profile of levosimendan has been consistently
studied [28, 29]. LIDO (Levosimendan Infusion versus
Dobutamine) [28] and RUSSLAN (Randomized Study on
Safety and Effectiveness of Levosimendan in Patients with
Left Ventricular Failure after an Acute Myocardial Infarct)
[29] studies confirmed the safety of levosimendan in a large
cohort of patients. Levosimendan is usually well tolerated,
with the most common side effects being headache (8-7%),
hypotension (6-5%), hypokalemia (5%), and tachycardia.
Hypotension and tachycardia are usually managed by assur-
ing an adequate preload and the use of vasopressors (e.g.
noradrenaline). Controversial data also relate the use of
levosimendan to an increased incidence of atrial fibrillation
[28, 29]. Hypotension, tachycardia and hypokalemia are rela-
tively more frequent in children than adults [24, 25].
Toxicology
Animal data depicts no teratogenic effects of levosimen-
dan, although levosimendan affects bone metabolism and
fertility. In addition, levosimendan is eliminated in breast
milk [19].
Current Evidence and Research Issues
Levosimendan has been largely studied in adult patients
with heart failure [13]. In this population, levosimendan
Inodilators in the Management of Low Cardiac Output Syndrome
Table 2. Dosing guidance for levosimendan.
• Administration: only intravenous.
• Loading dose: 6 – 12 mcg/kg over 10 minutes.
• Maintenance infusion: 0,05 – 0,2 mcg/kg/min.
• Duration of infusion: 24 hours.
• Not loading dose if hypotension is not avoided
(fluid or vasopressors).
• Avoid hypokalemia
improves cardiac output, decreases left atrial filling pressures
and is less arrhythmogenic than other inotropes. “Classic”
studies such as LIDO [28], RUSSLAN [29], SURVIVE [30]
or REVIVE II [31] demonstrate that levosimendan is effec-
tive in patients with acute heart failure (primary or chronic
decompensated). More recent studies corroborated those data
and confirmed that levosimendan is well tolerated with little
side effects in adult patients [7, 12, 13, 15, 16]. The Euro-
pean Society of Cardiology has included levosimendan in the
current guidelines for the management of acute heart failure
[26]; (class of recommendation IIa; level of evidence B).
Moreover, levosimendan has been reported to provide a su-
perior effect in adults undergoing cardiac surgery when
compared to traditional inotropes. Specifically, in this popu-
lation levosimendan improves hemodynamics, reduces myo-
cardial damage, and shortens hospital stay [7, 17, 32, 33]. In
a recent meta-analysis on levosimendan administered intra-
venously postoperatively, Landoni et al. [13] analyzed 17
studies with a total of 1233 patients and reported a signifi-
cant reduction in mortality of those patients receiving
levosimendan compared to controls (5.8% vs. 12.9%; risk
ratio 0.52, 95% CI 0.35-0.76). In addition, levosimendan
could provide benefits when administered intraoperatively as
well as preoperatively due to its cardioprotective effects [7,
12]. Currently, perioperative levosimendan has been recom-
mended by experts consensus [14] and has been included in
the postoperative management guidelines of some scientific
societies [27].
In pediatric patients, current evidence with levosimendan
is limited to observational studies [8,18], case-reports [34,
35] or registry studies [10, 20, 36-39] with a few additional
randomized controlled trials [25, 40-42]. Those reports are
generally undertaken in pediatric patients in the ICU setting
and after pediatric cardiac surgery. The first case report was
communicated by Braun et al. in 2004. They observed left
ventricular function improvement with a decrease in the sys-
temic vascular resistances in a 2 month-old baby after car-
diac surgery [34]. Recently, Angadi et al. [18] reviewed the
literature on the use of levosimendan in pediatric patients
(Table 3) and reported that the inodilator improved cardiac
output and reduced the afterload of the left ventricle in pa-
tients with LCOS after heart surgery. Levosimendan was
also effective in reducing catecholamine doses and ICU stay.
In all the reported studies, levosimendan proved to be a safe
drug with good tolerance and few side effects. The authors
concluded that the inodilator serves as a promising second-
line drug for the treatment of LCOS after pediatric cardiac
Current Vascular Pharmacology, 2016, Vol. 14, No. 1 51
surgery. Nevertheless, they note the lack of cost-
effectiveness studies comparing levosimendan with other
drugs such as milrinone, which could be crucial because of
the high cost of levosimendan compared to classic inotropes.
After this review, Ebade et al. [42], published a randomized
double blind study comparing levosimendan vs. dobutamine
in children under 4 years of age having septal defects repair.
Levosimendan was more effective reducing pulmonary ar-
tery pressure and increasing cardiac output. Pellicer et al.
[25] reported the results of a double blind randomized com-
parison between levosimendan and milrinone in neonates
undergoing cardiac surgery. Interestingly, patients receiving
levosimendan had a higher pH, lower glycemic index, and
lower inotropic scores. In addition, levosimendan pharma-
cokinetics in neonates were very similar to that reported for
older children and adults.
In The European Survey EuLoCOS-Paed [3, 43], milri-
none was selected out as the inodilator of choice for LCOS
after heart surgery in children while levosimendan was the
preferred drug for adults. This discrepancy could be due to
the scarce clinical evidence involving levosimendan in the
pediatric population, the high cost of the drug, its utilization
off label and under compassionate use, and the lack of
world-wide authorization for clinical use. Finally, Ryerson
et al. [44] have recently suggested a rotational use of
inotropes in pediatric patients where weekly levosimendan is
one of the keys of this regimen.
Currently, we routinely use levosimendan not only in the
early postoperative period, but also intraoperative and even
preoperatively in pediatric patients at high risk to developing
LCOS after cardiac surgery.
CONCLUSION
In summary, levosimendan is an inodilator, that signifi-
cantly improves cardiac output, reduces afterload, decreases
catecholamine dosing, and shortens the length of ICU and
hospital length of stay in pediatric patients undergoing car-
diac surgery, with few clinical side effects. In our setting,
levosimendan can be administered off-label under compas-
sionate use for the treatment of perioperative LCOS. These
promising data need to be confirmed in larger randomized
pediatric clinical trials.
Milrinone
Despite the relatively high incidence of myocardial dys-
function and LCOS after pediatric cardiac surgery, no con-
sensus on the optimal inotropic strategies for its management
exists. Traditional treatment of LCOS in pediatric patients
entails the use of catecholamines. However this method of
support presents several drawbacks, such as excessive myo-
cardial oxygen consumption, increased afterload and down-
regulation of beta-adrenergic receptors with the subsequent
loss of efficacy of most inotropic drugs. Because of these
undesirable effects, inodilators like milrinone have been used
in postoperative cardiac surgery patients to treat and prevent
LCOS. The European Survey EuLoCOS-Paed is a question-
naire survey of European hospitals performing open heart
surgery (OHS), with the aim of characterizing the current
hospital practices for the prevention of LCOs [43, 45]. In the
52 Current Vascular Pharmacology, 2016, Vol. 14, No. 1 Ferrer-Barba et al.

Table 3. Best evidence papers. Angadi et al. Is levosimendan effective in paediatric heart failure and post-cardiac surgeries? Inter-
act Cardiovasc Thorac Surg. 2013 Oct; 17 (4): 710-4. By permission of Oxford University Press.

Author, date, journal

and country Study Patient group Outcomes Key results Comments
type (level of evidence)

CI (as a primary end- CO and CI increased overtime in

point) the levosimendan group

Lechner et al. (2012), The study group did not

Haemodynamic parame- The other parameters were statis-
Pediatr Crit Care Med, include pre-existing
The study enrolled 40 infants ters tically insignificant heart rate (P
[43] congestive cardiac
comparing use of levosimendan = 0.172), systolic blood pressure
failure and complex
with milrinone (P = 0.62), lactate (P = 0.80)
Prospective double- congenital heart lesions
blind randomized study (single ventricle lesions)
Inotropic score, Inotropic score (P = 0.52), NIRS
(level I) NIRS, length of ICU (P = 0.42)
stay ICU stay (P = 0.72)

Authors noted
levosimendan is as
efficacious as milrinone

41 children in the age group 0–5
Momeni et al. (2010), years were randomized in a dou-
J Cardiothorac Vasc ble-blind fashion to a continuous
Anesth, Belgium [41] infusion of either levosimendan or
milrinone started at the onset of
Prospective randomized cardiopulmonary bypass 0.36
double-blind study patients completed the study
(level I)
Change in serum lactate was
Serum lactate at 4 h (as
insignificant
a primary endpoint)
Haemodynamic parame- Lower HR (<0.05) and a lower
ters
rate pressure index (P < 0.001)
were noted in the levosimendan
group
Limitations: Heteroge-
nous study group
No quantitative meas-
urement of cardiac
function done
No loading dose used
No risk stratification of
patient groups has been
stated

Levosimendan was well

tolerated with benefit on
haemodynamic and
metabolic parameters

Study of levosimendan in com-
Ricci et al. (2012),
parison to a standard inotrope
Intensive Care Med,
with risk stratification (RACHS
Italy [42]
3–4)
Case control study
The study involved 63 neonates
(level of evidence I)
(32 cases and 31 controls)
Limitations:
Better lactate levels (P = 0.015 at
Lactate levels The study was a pilot
ICU admission; P = 0.048 at 6 h)
open label uncommitted
trial
Better ionotropic scores in the
Inotropic score
levosimendan group (P < 0.0001)
Patients with only
biventricular anatomy
Length of mechanical ventilation
Ventilation days and included; RACHS 5–6
(5.9 ± 5 vs 6.9 ± 8 days, P = 0.54)
ICU stay not included
and ICU stay (11 ± 8 vs 14 ± 14
days, P = 0.26) though better was
Inadequate sample size
not statistically significant
(type II error)

Mortality (1 vs 3 patients, P =
Survival Conventional Inotropic
0.35)
score used which did
Side effects not take levosimendan
None reported
into consideration when
calculating

MAP not in the defini-

tion of LCOS was used
to guide ionotrope use
Inodilators in the Management of Low Cardiac Output Syndrome Current Vascular Pharmacology, 2016, Vol. 14, No. 1 53

Table (3) contd….

Author, date, journal

and country Study Patient group Outcomes Key results Comments
type (level of evidence)

Improved CO in 50% of
Magliola et al. (2009), CO was the primary Successful in 9/18 (P = 0.004)
the interventions and no
Intensive Care Med, endpoint inotropic
Open, quasiexperimental cohort adverse effect reported
Spain [40] score Ionotropic score (P = 0.01) and
involving 14 children with refrac-
A-VDO2 (P = 0.029) showed
tory LCOS (18 opportunities) Limitations: Heteroge-
Prospective cohort study reduction, SvO2 showed im-
nous sample with no
(level II-2) Mixed venous saturation provement (P = 0.03)
risk stratification

Showed substantial
Reduced dose of dobutamine reduction in catecola-
(from 6.4 g/kg/min pre- mine use
Namachivayam et al. Effect on catecholamine levosimendan to 1.8 g/kg/min
5 children aged 7 days to 18 years
(2006), Pediatr Crit use on day 5 (P < 0.01) Limitations: Retrospec-
(median age 38 months) with
Care Med, Australia tive data; Heterogenous
severe myocardial dysfunction
[37] Hear rate, blood pressure and group
secondary to end-stage heart
Haemodynamic central venous pressure were
failure, or acute heart failure, who
Retrospective cohort parameters unchanged Inotropic score not
were inotrope-dependent (requir-
analysis commented
ing at least one catecholamine)
(level II-2) Ejection fraction Ejection fraction improved from
29.8 to 40.5% with levosimendan Diastolic myocardial
(P = .015) performance assessment
may have been useful

Osthaus et al. (2009),

Case series involving seven in- Lactate levels decreased
Eur J Pediatr, Small number of pa-
fants (body weight range 2.6–6.3
Germany [7] Haemodynamic tients
kg) with severe myocardial dys-
parameters
function after complex congenital Significant increase in central
Case series No risk stratification
heart surgery venous oxygen saturation
(level III)

The most common indication for

The indication of using
Analysis of data involving 293
Pertti et al. (2011), patients and 484 infusions (4 h 21
BMC Anesth, years age group) over 10 years
Finland [18]
Web-based questionnaire survey
Retrospective study concerning their clinical percep-
(level III) tions of levosimendan were also
evaluated
the use of levosimendan (94%)
was when the other inotropic
levosimendan agents were insufficient to main-
tain stable haemodynamics
Authors attributed
higher mortality for its
70.1% successfully weaned dur-
use in very sick children
ing study
Need for mechanical period
Limitations: Heteroge-
assist device
nous patient data
44% of respondents thought that
Retrospective study
the mechanical support had been
totally avoided in some patients
No risk stratification
61.1% of respondents felt that it
No data on haemody-
had saved the lives of some chil-
namic parameters evalu-
dren when the other treatments
ated
had failed

Survival 11% compared with overall mor-

tality of 2.3% in cardiac surgery
patients
54 Current Vascular Pharmacology, 2016, Vol. 14, No. 1 Ferrer-Barba et al.

Table (3) contd….

Author, date, journal

and country Study Patient group Outcomes Key results Comments
type (level of evidence)

NIRS showed increased intravas-

cular oxygenation but no change in
Levosimendan was used
tissue oxygenation index
as a rescue therapy
Bravo et al. (2011),
Reduced need of cardiovascular
Neonatology,
Cerebral and peripheral support and decreased serum
Spain [39] Case series study involving neo- Limitations: Small
intravascular oxygena- lactate levels
nates seven neonates group
tion
Prospective case series
Mixed linear model analysis
(level III)
identified blood pressure changes
Echocardiographic
and levosimendan as factors
performance lacking
independently associated with
cerebral oxygenation

Increase in mean blood pressure

[from 42 to 53 mmHg; (P <
Haemodynamic 0.05)]. Reduction in left atrial Authors recommend
Lobacheva et al. (2010), parameters pressure [from 25 to 17 mmHg; levosimendan as an
Anesteziol Reanimatol, (P < 0.05)] alternative to PDE III
Study of 75 cases with postopera-
Russia [38] CVP unchanged inhibitors in LCOS as
tive LCOS within the age group 3
LVEF by echocardi- well as a basic drug
days to 2 years 10 months
Cohort study ography LVEF increased from 21 to 27% during extracorporeal
(level II) circulation and after its
Side effects Systemic hypotension in first cessation
hour requiring fluid boluses and
epinephrine

Left atrial pressure decreased to 7

from
24 mmHg

Systolic arterial pressure in-

creased to 60 mmHg from 40
Lechner et al. (2007),
mmHg It is difficult to extrapo-
Pediatr Crit Care Med,
Single case report of premature 32 Single case report of late the results in a
Austria [36]
weeks premature 32 weeks Serum lactate level normalized to premature neonate to
(1.5 kg) (1.5 kg) 1.7 mmol/l from 14.8 mmol/l the haemodynamics of
Case report
older infants
(level III)
Mixed venous saturation in-
creased to 81 from 56%

Improvement in left ventricular

function (FS increased from 10–
25%)

Braun et al. (2004),

Eur J Cardiothorac
Surg,
Improved left ventricular function
Berlin [35] Case report of a 2 month baby Survival Single case
and decreased vascular resistance

Case report
(level III)

A-VDO2: Arterio-Venous Difference in O2-content; CI: Cardiac Index; CO: Cardiac Output; CVP: Central Venous Pressure; FS: Fractional Shortening; HR: Heart Rate; ICU: Inten-
sive Care Unit; LCOS: Low Cardiac Output Syndrome; LVEF: Left Ventricle Ejection Fraction; MAP: Mean Arterial Pressure; NIRS: Near Infrared Spectroscopy; PDE: Phosphodi-
esterase; RACHS: Risk Adjustment for Congenital Heart Surgery.
Inodilators in the Management of Low Cardiac Output Syndrome
EuLoCOS-Paed milrinone was reported in 70.7% of all drug
regimens, and a combination of milrinone with another drug
was used in up to 64% of all reports [43, 45].
Pharmacological Issues and Dosage
Milrinone’s mechanism of action involves inhibition of
phosphodiesterase type 3 (PDE3), which results in increased
concentration of intracellular cyclic adenosine monophos-
phate (cAMP). This cAMP activates protein kinases, in-
crease extracellular calcium influx and trans-sarcolemal cal-
cium flux which results in activation of contractile proteins
and increased myocardial contractility (inotropic effect). The
activation of the phospholamban by cAMP accelerates re-
moval of calcium from cytosol, shortening contraction time
and leaving more time for myocardial relaxation in each car-
diac cycle (lusitropic effect). The effect on the peripheral and
coronary circulation is secondary to the increment of cGMP
in vascular smooth muscle cells (vasodilator effect). These
changes improve myocardial performance without raising
myocardial oxygen consumption or increasing afterload.
These effects are independent of alpha and beta receptors.
Milrinone’s inotropic and vasodilator effects are concen-
tration-dependent (and dose-related). Several studies have
reported the therapeutic range for milrinone in adults and
children, and the effective plasma concentration is the same
for all ages (100-300ng/ml) [46, 47]. However, pharmacoki-
netics studies of milrinone showed that metabolism, volume
of distribution, protein binding, and clearance are influenced
by age [48-50], which in turn may affect plasma concentra-
tion. The relationship between pharmacokinetic parameters
(clearance, volume of distribution) and weight was directly
proportional, so there are no changes in dose prescribed by
weight; consequently milrinone is usually administered on a
per kilogram basis [46, 51].
The clearance of milrinone is greater in pediatric patients
than in adults (2 ml/kg [48]. However, milrinone clearance in
neonates is decreased by about 25% when compared to older
children and increases linearly as the patient thrives. In addi-
tion, the volume of distribution of milrinone is higher in
neonates when compared to adults (0.3L/kg) [48] and, thus,
it takes longer to reach the therapeutic blood concentration in
neonates when milrinone is prescribed at the same infusion
rate per kilogram, unless a bolus dose is administered.
In summary, neonates are dependent on loading doses to
reach the steady-stead concentration and achieve therapeutic
blood concentrations. However, as a result of decreased
clearance in small patients, the infusion rate should be re-
duced to maintain the same plasma concentration. The
Table 4. Milrinone usual dosage.
MILRINONE USUAL DOSAGE
Effective plasma concentration
Bolus
Continuous infusion rate 0.50 - 0.75 mcg/kg/min
Current Vascular Pharmacology, 2016, Vol. 14, No. 1 55
reported therapeutic blood levels of milrinone range from
100 to 300ng/ml for children and adults [46-48, 51]. Garcia
Guerra et al., in a prospective cohort study of milrinone
blood levels in children after cardiac surgery, reported a sig-
nificant association between the absolute variation of the
Milrinone Blood Level with the development of LCOS and
arrhythmia. They included 63 patients with a total of 220
blood samples looking at milrinone levels. Despite using a
recommended therapeutic dose (0.5mcg/kg/min of median
dose) overall 114 (52%) were outside the therapeutic range,
(16% were in supratherapeutic range and 36% were in sub-
therapeutic range). The use of milrinone to prevent LCOS is
not standardized and depends on institutional protocols and
physician´s preference. In general, studies report a usual
dosage consisting on a bolus in the operating room, followed
by a continuous infusion during 24-72h. Most frequent doses
for boluses are 50-75 mcg/kg [46, 47, 52, 53] but some stud-
ies describe therapeutic milrinone blood levels using
25mcg/kg [48], or 100mcg/kg [50]. Continuous infusion
rates are usually from 0.50mcg/kg/min to 0.75mcg/kg/min;
[3, 51] however, Ramamoorthy et al. did not found differ-
ences in plasma levels or in the incidence of side effects in
patients treated with 0.25mcg/kg/min compared with
0.75mcg/kg/min. Milrinone clearance is lower in neonates
than in older children and thus, an infusion rate of 0.2
mcg/kg/min has been recommended in neonates [50]. Actu-
ally, Zuppa et al. found high milrinone blood levels in 16
neonates after stage I reconstruction for Hypoplasic Left
Heart Syndrome using a perfusion rate of 0.5mcg/kg/min
(Table 4).
Current Evidence and Research Issues
Different studies have consistently reported on the posi-
tive hemodynamic effects of milrinone after pediatric cardiac
surgery. These effects include increasing cardiac index, de-
creasing systemic and pulmonary vascular resistance as well
as atrial pressure [46, 53]. In addition, Chang et al, in 1995,
reported an increase in heart rate without altering the myo-
cardial oxygen consumption in a cohort of 10 neonates
treated with milrinone after cardiac surgery. In 2003,
Hoffman et al. reported the results of the first double-blind
placebo-controlled trial to evaluate the efficacy and safety of
prophylactic milrinone in pediatric patients after cardiac sur-
gery [51]. The 238 treated patients were randomized to three
groups: placebo, low dose of milrinone and high dose of
milrinone, and the results showed that use of high dose of
milrinone after pediatric congenital cardiac surgery reduced
the risk of LCOS without significant differences in the inci-
dence of adverse events. After this report, milrinone use was
100-300 ng/ml
Specially in neonates
50 - 75 mcg/kg
If hemodynamic stability in operating room
In neonates consider low dose: 0.25-0.5 mcg/kg/min
56 Current Vascular Pharmacology, 2016, Vol. 14, No. 1
widespread in pediatric postoperative cardiac care. With the
recent emergence of levosimendan as an effective drug to
improve cardiac function and hemodynamics some recent
studies have compared milrinone with levosimendan in the
prevention of LCOS in children after corrective open-heart
surgery. Momeni et al. [40], in 2011, randomized 41 pediat-
ric patients to milrinone or levosimendan infusion in a dou-
bled-blind randomized controlled trial and concluded that
levosimendan is as effective as milrinone in preventing
LCOS. Similar results have been described by Lechner 2012
and Pellicer 2012 in randomized double-blind studies [25,
41].
Toxicity and Side Effects Associated with Milrinone
One of the most important adverse effect described using
milrinone is hypotension, [53]. However, lower mean blood
pressure can also be considered as a therapeutic effect of
milrinone in LCOs (afterload reduction) [51]. Tachycardia is
another side effect of milrinone. Nevertheless, controversial
reports on this side effect exist [46, 47, 51, 53, 54]. Paradisis
et al., hypothesized that milrinone-induced tachycardia could
be mediated by increased cAMP. There is no consistent evi-
dence of increased incidence of tachyarrhythmias associated
with milrinone treatment [47, 53, 55]. Ramamoorthy et al.
reported tachyarrhythmia in two out of 19 patients (11%)
treated with milrinone. One of them had high blood levels of
milrinone (345 ng/ml). Smith et al. in a prospective review
of 603 children underwent cardiac surgery report an inci-
dence of tachyarrhythmia of 50%, however, in this cohort
33% of patients had arrhythmia preoperatively. Thrombocy-
topenia with the use of milrinone was not observed in PRI-
MACORP or Paradisis studies. Ramamoorthy et al. reported
on this side effect and recommended platelet monitoring
during milrinone infusion, however, thrombocytopenic effect
of milrinone could not be clearly separated from that of CPB
itself. Other reported side effects of milrinone include sei-
zures, feed intolerance and slow closure of the ductus arte-
riosus in preterm infants [54, 56, 57].
CONCLUSION
Milrinone is the drug most commonly used in the preven-
tion and treatment of LCOS in postoperative patients follow-
ing pediatric cardiac surgery, but 10 years after the PRIMA-
COR study, the actual incidence of LCOS may be lower than
previously demonstrated given the advances in surgical tech-
nique, improvements in intraoperative support (including
shorter CPB times), and advances in anesthesia and postop-
erative critical care. It is, thus, important to reevaluate the
risk and incidence of LCOS in the current era which in order
to best inform the best possible pharmacologic strategies.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.
Ferrer-Barba et al.
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