Effect-site
One of the aims of target-controlled infusion (TCI) is to control
the pharmacological effects as adequately as the anesthesiologist
would like. The concentration in plasma or in blood had been thought
to be the target object for a long time after TCI had been developed.
However the pharmacological effect, such as the hypnotic one of
propofol, might be delayed for a short while compared to that
estimated by the plasma concentration just after the plateau is
reached. This is the fact we have experienced every day clinically.
In some anesthetics, their pharmacological effects can be monitored
by the EEG analysis. Stanski et. al. showed the hysteresis trajectory
could be seen when plotting the EEG response against the plasma
concentration on onset period and that on recovery period. This
phenomenon can be explained by the existence of the first-order
time delay between plasma concentration and its effect. The hypothetical
effect-site was introduced to incorporate this delay on time domain
into the disposition kinetic modeling and that is related to the
phase equilibration between plasma and effect-site and so that
it called bio-phase occasionally. The effect-site can be characterized
only by the rate constant from effect-site to outside of the body
(keo) and not by rate constant from central compartment to the
effect-site nor by volume of effect-site because the hypothetical
effect-site has the negligible small compartment in which net
mass transfer from central to effect can not be accounted. The
keo can be defined that the reciprocal of the time required decreasing
the response to -63.2 % of initial value and has dimension of
min-1. The t1/2keo is a response time to decrease half of initial
value, and equals 0.693/keo(min)
Keo
The anesthetics have different pharmacological effects and each
effect consists of different keo. For example, the keo(min-1)
of fentanyl has been reported as 0.105 (min-1) by Scott JC et.al.
and that of propofol was reported as 0.239 (min-1) by Shuttler
J et. al. The keo of fentanyl is about half that of propofol,
which means twice longer time required in the fentanyl to equilibrate
plasma concentration and the effect. As well as the different
anesthetics have its own keo, even in the same anesthetic there
are some different keos consisted in different pharmacological
effects. Propofol has a hypnotic effect mainly but has a hemodynamic
effect subsidiary. The keo for them are different. We have recently
studied propofol keo for hypnosis by measuring bi-spectral index
(BIS), and keo for hemodynamic effect by measuring the response
of the systolic blood pressure (SBP) against the concentration
of propofol. They were estimated as 0.300 (min-1) for BIS response
and 0.118 (min-1) for systolic pressure response in the patient
group aged 20 to 39 years (P<0.05). The equilibration time
between plasma and the effect-site, which is related with controlling
the systolic pressure, was three times longer than that related
with controlling the hypnosis.
Do these keos have dependency of the age of the patients? The keo for BIS did not have a significant difference between the group aged 20-39 and that of 70-85, however in keo for SBP had significant difference between these groups, 0.118 and 0.0678 respectively (p< 0.05).
Simulation
In usual clinical practice, suppose that we set the TCI target
concentration as 10mg/ml with fentanyl background (2ng/ml), we
might simulate that the intubation could be possible most adequately
after when 6.93min (3 times of t1/2keo (=87.5% response time)
of hypnotic) had passed from the plasma plateau had reached. The
t1/2keo for systolic blood pressure is 5.68 (min), then at the
time of intubation (estimated above) the blood pressure supposed
to be decreased about -55% of maximal amplitude of depression.
The dosing scheme and concentration time-course can be estimated by solving the pharmacokinetics compartment model and applying the concentration-effects relationship (pharamcodynamics) to this derived concentration time-course, we can estimate the pharmacological effects. However without the keo, which is a constant represented interrelation on time domain between Dconcentration and Deffects, the sudden change of concentration will make sudden change of effects and that response is far apart from the real response seen in clinical situations.
Automated control of the effects
The hypnotic index BIS can be used to the input signal of the
feedback source of the TCI system, and that might control hypnotic
response as constant as anesthesiologist requested. In its algorithm
a time response function expressed by the keo against unit-step
input function was consisted and may decrease the chance of becoming
unstable oscillating state.