Pharmacokinetics of Levosimendan in Children with Acute Heart Failure

Levosimendan, a calcium-sensitizer, is a relatively new inotropic drug with the
benefit over conventional inotropes that it does not increase myocardial oxygen
demand or lead to arrhythmias. Levosimendan has a relatively unique
pharmacokinetic profile, after a 24 hour infusion its clinical effects remain
for several days. This is achieved through the continuing haemodynamic effects
of its active metabolites, which have a half life of approximately 80 hours
compared to 1 hour of Levosimendan itself. Levosimendan has been extensively
studied in adults and is used in ischemic heart disease, acute heart failure,
chronic heart failure, following cardiac surgery, and in septic shock. Due to
the inotropic properties and its strong pulmonary vasodilatory effect,
Levosimendan could also be very useful as perioperative therapy in children
with congenital heart disease, low cardiac output, or pulmonary artery
hypertension.
Although experience with levosimendan in children is still scarce in the
literature, initial reports have been promising and Levosimendan is used more
and more often as a (rescue) therapy in children with heart failure. However,
current dosing regimens in children are based on adult pharmacokinetic
evidence. One pediatric report suggests that the pharmacokinetic profile of a
single loading dose of Levosimendan is probably similar in children older than
6 months compared to adults. The pharmacokinetic profile of a 24-hour infusion
of Levosimendan has not yet been studied in children. It is very important to
study the pharmacokinetics of this useful drug in different age groups because
of the diversity of the population due to age, volume of distribution, ontogeny
of the metabolizing enzymes, and the influence of disease state on
pharmacokinetics and pharmacodynamics.

To describe the pharmacokinetic profile of a 24 hour infusion of levosimendan
and its active metabolites in children with acute or chronic heart failure.

Observational study of Levosimendan levels in children treated with
Levosimendan because of heart failure.

1. During the first 24 hours, 4 levosimendan samples (each 0,5 ml EDTA) will be
taken using central or arterial lines already in situ. In, at least, 3 samples
we can use restblood taken for blood gas analyses which are part of standard
PICU-care. Furthermore we will take a small bloodsample for determining the
acetylator status of each patient. During the second 24 hours another 5 samples
will be taken (4 from restblood during standard blood gas analyses). After the
first 48 hours, a sample will be taken on day 3, 5, 8 and 12 (from restblood).
Therefore, a total of 13 samples will be taken from each patient with a total
of 6.5 ml over the duration of 12 days, which is < 2% of the total bloodvolume
in a 4 kg baby and therefore negligible. We estimate, based on our experience
with giving Levosimendan in 32 patients in two years, that 5-7 patients will
not have a sampling line in situ anymore because of their clinical improvement
and possible discharge to the ward. In these 5-7 children blood will be taken
preferably during routine blood sampling or they will need to have their bloods
taken especially for the study (we estimate 2-3 times), which is likely painful
(although local sedatives are always used) and therefore a burden.
2. Other blood samples (lactate, troponin, and pro-BNP) are all part of
standard ICU care in children with acute heart failure and therefore impose no
extra burden.
3. Echocardiography will be done 4-6 times during 12 days, which in most cases
is part of their routine care. Echocardiography is no burden for these children.
4. Known side-effects of Levosimendan are related to the vasodilating effect
and include hypotension, nausea and headache. As the study is purely
observational, taking part in the study does not increase this risk.
5. There will be no direct benefit for the patient by participating in this
pharmacokinetic observational study. They will receive Levosimendan anyway as
part of the treatment of heart failure.
6. The main endpoint of this study is to investigate the pharmacokinetic
profile of Levosimendan and its metabolites in children of different ages. In
our own experience of the last three years, more than 50% (12/22) of the
patients receiving levosimendan are younger than 6 months of age. Which is an
age group in which the pharmacokinetic profile of levosimendan is very likely
to be different compared to older children and adults.It is therefore
imperative to investigate the pharmacokinetics in these specific age groups.