Development of a pharmacokinetic/pharmacodynamic model of dexmedetomidine, and the effect of repeated auditory stimulation on pharmacodynamics of dexmedetomidine.*

Dexmedetomidine is an α2-adrenoceptor agonist that has only recently been
registered for human use in Europe. It has sedative, analgesic and anxiolytic
properties, but patients remain arousable. This makes it an ideal drug for
procedures such as conscious sedation, awake craniotomies, and sedation in
Intensive Care Units (ICU). Pharmacokinetic models of (anaesthetic) drugs can
be used in target controlled infusions (TCI), to deliver stable plasma
concentrations of drug. There are several models available for dexmedetomidine
at this time, but the most often used models (Dyck and Talke) underpredict the
plasma concentration at higher concentrations. Also, plasma concentrations
aren*t what the clinician is interested in, but in the effect. Therefore,
pharmacokinetic/pharmacodynamic (PKPD) models can be developed to model the
concentration of the effect site (or a mathematical representation of the
effect site). This has been done for many anaesthetic drugs, but not for
dexmedetomidine. Additionally, we want to investigate the effect of stimulation
on the pharmacodynamics of dexmedetomidine. The reason for this is that
patients under dexmedetomidine sedation are arousable by noises or touch. An
operating room or ICU is never quiet, and there are always sounds of monitors,
alarms, and talking between team members or activity around another patient in
the same room, therefore the stimulation of the patient in such an environment
may have a profound effect on the sedative effect of dexmedetomidine.

To develop a PKPD dexmedetomidine model, and to assess the effect of continuous
auditory stimulation on dexmedetomidine pharmacodynamics.

Pharmacokinetic/pharmacodynamic modelling study.

Dexmedetomidine will be infused by target controlled infusion using the Dyck
model. The targets are, in order, 1, 2, 3, 4, 6 and 8 ng/ml. Each target step
will be maintained for 30 minutes. After 35 minutes at a target of 8 ng/ml, or
earlier if one of the dexmedetomidine cessation criteria is met,
dexmedetomidine infusion will cease.

Dexmedetomidine has been registered outside of the EU for over a decade, and is
safe to use in controlled settings, such as an operating room or intensive care
unit. The targets used in this study will be higher than the package insert
indicates, but our dexmedetomidine cessation criteria will prevent individuals
from reaching dangerously high concentrations. Other studies using similar
criteria have had individuals safely reaching measured concentrations of up to
14-16 ng/ml. Our maximum target concentration will be 8 ng/ml. An intravenous
line (drug and fluid infusion) and an arterial line (for blood sampling and
blood pressure/cardiac output monitoring) will be inserted before starting the
study. These lines will be inserted by a certified anaesthesiologist. Possible
risks include hematoma, infiltration, embolism and phlebitis, but these risks
are considered rare, especially in volunteers. All other monitoring will be
non-invasive, as in routine clinical care.