Pharmacokinetics and pharmacodynamics of esketamine during longterm sedation of children at the intensive care

Seriously ill children treated with long term sedative drugs develop tolerance,
which may be followed by abstinence symptoms after termination of the therapy.
In 2008 esketamine (Ketanest-S®) was introduced into the sedation protocol at
the AMC hospital PICU, for children sedated for more than 1 week. This protocol
is based on the sedation protocol of the Bristol Royal Hospital for Children in
the UK. According to this protocol children with artificial respiration are
sedated with continuous infusions of sedative drugs in order to facilitate the
respiration. In order to prevent symptoms of tolerance and abstinence a switch
takes place every week from one sedative drug to another, according to a strict
protocol. Recently the time to switch is shortened from 1 week to 5 days
because administration of morfine already produced symptoms of tolerance at day
6 and 7. During days 6 to 10 and days 16 to 20 of the sedation, esketamine is
administered intravenously with a rate of 1.2 mg/kg/hour in combination with
lorazepam 4 qd 0.05-0.1 mg/kg/day iv or orally, or 0.003 - 0.01 mg/kg/hour iv.
Routinely the degree of sedation is rated using the COMFORT-B score, validated
for this purpose.
The clinical practice has shown that the present dosage of esketamine 1,2
mg/kg/hour is not sufficient to achieve the aimed degree of sedation.
Nevertheless, due to the lack of evidence it is not known if it is possible to
increase the dosage of esketamine. More knowledge on the the pharmacokinetics
(PK) and the pharmacodynamics (PD) of continuously iv administrations of
esketamine could provide information for the development of a new dosage regime
which may be used to achieve a more adequate degree of sedation in children.

This explorative observational study aims to characterize the PK and PD of
esketamine during long term sedation of children at the PICU. The relationship
between the dosage and the plasma concentration of esketamine and norketamine
(active metabolite) is determined, together with the variation within and
between children (intra- and inter-patient variability). Furthermore the
relationship between the plasmaconcentrations and the degree of sedation, rated
using the COMFORT-B score, is studied. Based on the developed
concentration-effect relationship, a new dosage regime of esketamine can be
defined which may be used to obtain more adequate sedation in children.

This is an obsevational study aimed to characterize the PK and PD of esketamine
during long term sedation of children at the PICU of the AMC in Amsterdam.
Participating children are sedated according to clinical routine.

The patient receive standard clinical care. Participation in this study does
not have any influence on the therapy and patient care. As part of study 7
extra bloodsamples (0.5 ml) are collected during a period of 5 days (total 3.5
ml) from an arterial or central line that is allready present.
During the continuous intravenous administration of esketamine from day 6 till
10 of the sedation, a maximum of 7 bloodsamples of 0.5 ml each, is collected
during a 5-day period. Two of the samples are collected after stopping the
esketamine administration (1 and 4 hours after stopping). The other 5
bloodsamples are collected at random with an average of once a day, often in
combination with other samples (eg clinical chemistry).
If the sedation is applied for a period longer than 15 days, a second 5-day
period of esketamine administration starts with the same dosage as day 6 till
10. During this period blood samples will be collected as well similar as day 6
to 10.

The total volume of blood collected for the study will not exceed 7 ml per
patient. This is allways less than 5% of the circulating blood volume of the
child. Considering a newborn child of 4 kg with a circulating blood volume of
85 ml/kg, the collected blood samples will be 2% of the circulating blood
volume. Consequently, the volume of blood will not exceed the 5% limit which
makes it acceptable for children.