E.
Mortier, MD, DSc; M. Struys, MD, PhD
Department
of Anaesthesiology, Ghent University Hospital, Ghent, Belgium.
Rational
dosing of anaesthetic drugs derives from an appreciation of both the
pharmacokinetics and pharmacodynamics of the compound in use (1).
Commercially
available target-controlled infusion (TCI) devices for propofol incorporate an
internal model of propofol pharmacokinetics to rapidly achieve and maintain a
constant drug concentration in the plasma (2). For anaesthetic agents, the site
of drug-effect is not the plasma (2). However, the concentration of the drug at
the site of action is not measurable (3). Nevertheless, the apparent rate of
drug flow into and from the site of action can be characterised by the time
course of drug effect (4). Knowing this time course, the drug concentration in
the biophase can be modelled with the introduction of an additional
compartment, the “effect compartment” (5). The effect compartment is defined as
being negligibly small (3). It is connected to the central compartment by a
first-order process (3). It is characterized by a first-order input rate constant (k1e) and a
first-order output rate constant (keo) (3). Assuming that the effect
compartment is negligibly small, k1e is an arbitrarily small
fraction of keo (4). Knowing kco, the apparent
concentration in the effect compartment can be calculated, since keo
will precisely characterize the temporal effects of equilibration between the
plasma concentration and the corresponding drug effect (6).
The
equilibration delay between the plasma compartment and the effect compartment
can be added to the pharmacokinetic model. There are several ways to do this.
First of all, one can introduce an effect site model using a keo
value from the available literature. However, since the value of keo
is influenced by the pharmacokinetic model, it may be inappropriate to mix the
keo from one published report with the pharmacokinetics from a
different study (7). However, a model-independent descriptor of blood-brain
equilibration exists. This is the time to peak efffect. It can be established
by giving a bolus and measuring the drug effect by means of an appropriately
sensitive parameter (8). A time to peak effect of 1.6 minutes has been reported
by the group of Schnider using EEG (8). When using the Marsh pharmacokinetics
this corresponds to a value of keo of 1.21 min–1 (9,10).
In one-hunderd twenty healthy female patients we tested the performance of
three TCI control algorithms (10). In all three groups the plasma
concentrations were calculated by means of the Marsh pharmacokinetics (9). In
group I, the plasma concentration was controlled (5.4 µg/ml). In groups II and
III, the effect site concentration was controlled.
In
group II the effect site was computed using a keo of 0.20 min–1
as reported by the group of Billard (11). In group III a keo of 1.21
min–1 corresponding to a time to peak effect of 1.6 minutes was
used. Patients lost consciousness more slowly when the TCI device targeted the
plasma. In group II, the largest doses of propofol were administered. In group
III, the induction dose was simular to that in group I (table 1). Group II was
associated with the largest overshoot in plasma propofol concentration.
Controlling the concentration in the effect compartment was more accurate in
producing the desired time course of propofol drug effect than when the plasma
compartment was controlled (table 2). However, mixing the keo from a
published report (Billard) with the pharmacokinetics of another report (Marsh)
was highly inappropriate.
Table
1: Observations at loss of consciousness (mean ±SD). The dose of propofol is
the amount of drug given up to the moment of loss of consciousness (10).
|
|
Group
I |
Group
II |
Group
III |
|
Time
(s) BIS CeCALC (µg/ml) Propofol
dose (ml) |
90
(44-601) 67±12 not
calculated 11.4±3.9D |
68
(45-101)* 78±11* 1.8±0.7 20.4±3.6D |
71(43-110)* 77±11* 4.7±0.6 11.7±2.0D |
CeCALC
= calculated effect-site concentration;
* = p< 0.05 compared to group I
= p< 0.05 between groups II and III; D = p< 0.05 between I and II and between II and III
Table
2: Model performance (10)
|
|
Group
I |
Group
II |
Group
III |
|
tpeak
(s) teq
(s) terror
(s) BIS
at tpeak CpMAX
(µg/ml) |
218±86 not
calculated not
calculated 39±11D 5.4
±0o |
116±21* 330±36 207±73 27±11D 14.2±0.4o |
120±21* 130±17 9±15 41±16D 7.5±0.2o |
tpeak = observed time necessary to reach maximal
drug effect; teq = calculated time necessary to reach equilibration
between plasma and effect site; terror = teq - tpeak ; CpMAX = calculated
maximum propofol concentration.
* =
p< 0.05 compared to group I; =
p< 0.05 between groups II and III
D = p< 0.05 between I and II and between II and III; o = p< 0.05 between all groups
1/ White M, Schenkels MJ, Engbers FHM,
Vletter A, Burm AGL, Bovill JG, Kenny GNC.
Effect-site modelling of propofol
using auditory evoked potentials
British Journal of Anaesthesia 1999;
82:333-339.
2/ Shafer SL.
Towards optimal intravenous dosing
strategies.
Seminars in Anesthesia 1993;
12:222-234.
3/ Schnider TW, Minto CF, Stanski DR.
The effect compartment concept in
pharmacodynamic modelling.
Anaesthetic Pharmacology Review
1994; 2:204-213.
4/ Shafer SL.
Principes of pharmacokinetics and
pharmacodynamics.
In : Longnecker DE, Tinker JH,
Morgan EC, editors
Principles and Practice of
Anesthesiology, St- Louis, 1998, Mosby-Yeark Book, Inc.
5/ Shafer SL, Gregg KM.
Algorithms to rapidly achieve and maintain stabel drug concentrations at
the site of drug effect with a computer-controlled infusion pump.
Journal of pharmacokinetics and
biopharmaceutics 1992; 20:147-168.
6/ Sheiner LB, Stanski DR, Vozek S, Miller
RD, Ham J.
Simultaneous modelling of pharmacokinetics and pharmacodynamics :
Application to d-tubocurarine.
Clinical Pharmacology and
Therapeutics 1979; 25:358-371.
7/ Gentry WB, Krejcie TC, Henthorn TK,
Shanks CA, Howard KA, Gupta KD, Awram MJ.
Effect of infusion rate on thiopental dose-response relationships.
Assessment of a pharmacokinetic-pharmakodynamic model.
Anesthesiology 1994; 81: 316-324.
8/ Schnider TW, Mimto CF, Shafer SL,
Gambus PL, Andresen C, Goodale DB, Youngs EJ.
The influence of age on propofol
pharmacodynamics.
Anesthesiology 1999; 90: 1502-1516.
9/ Marsh B, White M, Morton N, Kenny GN.
Pharmacokinetic model driven
infusion of propofol in children.
British Journal of Anaesthesia 1991;
67: 41-48.
10/ Struys
MRF, De Smet T, Depoorter B, Versichelen L, Mortier EP, Dumortier FJE, Shafer
SL, Rolly G.
Two methods for effect compartment
controlled target controlled infusion for propofol.
Anesthesiology 2000; 92: 399-406.
11/ Billard V, Gambus PL, Chamoun N, Stanski
DR, Shafer SL.
A comparison of spectral edge, delta power; and bispectral index as EEG
measures of alfentanil, propofol, and midazolam drug effect.
Clinical Pharmacology and
Therapeutics 1997; 61:45-58.