4. Target-Controlled Infusion (TCI) Flashcards
Pharmacokinetic Principles Relevant to Target-Controlled
Infusion (TCI) Systems
computer-controlled infusion pump (with
safety features to prevent the risk of overdose), which is programmed with a
pharmacokinetic model specific to the drug that is being infused
microprocessor
computes the infusion rate that is required to maintain a predicted blood concentration
and an adequate concentration of drug at the effector site throughout the
duration of the procedure.
Infusion systems:
The
pump types are not interchangeable because they use differently modified versions of
the pharmacokinetic models. The Alaris offers the original Marsh or the Schnider
models, whereas the Base Primea offers a different version of the Schnider and a
modified Marsh model. These differences are not academic
Pharmacokinetic modelling
decay in blood concentrations
following a bolus dose or a continuous infusion of a drug is typically identified by a three-compartment model
distribution, redistribution and clearance.
starting target concentration, a bolus dose fills the central intravascular
compartment V1.
This is then followed by an initial high-infusion rate which
compensates for rapid distribution into the ‘vessel rich’ compartment V2
Redistribution into the ‘vessel-poor’ compartment V3 is much slower
Steady state
Thereafter, the rate decreases to maintain the steady state.
The microprocessor employs continuous calculations of the concentrations in the different compartments by employing
pharmacokinetic information about the elimination and distribution of the drug.
There is of course a fourth additional compartment, V4, which is the effector site –
the brain – with a rate constant Keo.
The maintenance infusion
The maintenance infusion rate has to compensate for clearance and
for redistribution to the peripheral compartments which is governed by different rate constants:
K10, which is the elimination rate constant from the central compartment;
and K12, K21, K13 and K31,
which are the rate constants governing movement of drug between the peripheral compartments (V1, 2 and 3).
Distribution
distribution to other compartments is the most important of
the factors which decrease drug effects.
With the highly lipophilic propofol, for
example, the initial distribution half-life,
α, is short (2–3 minutes),
whereas intermediate distribution, β1, takes 30–60 minutes.
The terminal phase decline, β2, is less
steep, and takes 3–8 hours.
The immediate volume of distribution is 228 ml kg
the steady state volume of distribution in healthy young adults is around 800 litres
Propofol
Propofol is metabolized mainly in the liver, undergoing conjugation
to glucuronide and sulphate prior to renal excretion
Plasma and effect-site targeting
If the plasma concentration is targeted as in the Marsh model
there will be an inevitable delay in attaining the effect-site (brain) concentration.
Achieving equilibrium with this fourth compartment depends on the
pharmacokinetic properties of the drug, the rate constant Keo (from plasma to brain)
With effect-site targeting, as in the Schnider model
the programme increases the blood concentration rapidly
and with it the effective concentration gradient,
this being the only extrinsic factor over which the anaesthetist has any control
This obviously involves an overshoot in the plasma concentration,
and its degree will depend on the size of k12 (decline in concentration in the
central compartment) and keo
The latest modification to the Marsh model incorporates
a faster keo so there is a smaller overshoot.
If a smaller keo is determined by the programme (as in Schnider),
then there will be a larger plasma overshoot in order to
generate the necessary concentration gradient between plasma and brain
Marsh model
Marsh model, the rate constants as described earlier are fixed,
but the entered weight alters the size of the three compartments V1, V2 and V3,
and the clearances.
The estimated plasma concentrations in V1 vary with the patient’s
weight, whereas the fixed rate constants
mean that the estimated rate of decline is the same in all patients.
This original Marsh model targets only plasma concentrations.
Modified Marsh
Modified Marsh (1): This incorporated a rate constant keo (plasma/effect site) of
0.26 min–1 to allow effect-site targeting, and is used in the Alaris pumps.
Modified Marsh (2): This changed the rate constant keo to 1.2 min–1 and is used in
the Base Primea pumps.
The ‘Diprifusor’ and ‘Open’ systems:
The original Diprifusor used the Marsh model
for the infusion of propofol and had two main disadvantages. The fixed pharmacokinetic
model targeted only plasma concentration, and the pumps could only use proprietary (and therefore more costly) radio-labeled syringes containing propofol
1% or 2%. In later iterations, the processors incorporated a value for keo which
allowed an estimation of effect-site concentration
Schnider model
age, gender, weight and height
size of the compartments V1 and V3 are fixed
(4.27 and 238 litres, respectively
as are the rate constants k13 and k31.
V2 is adjusted according to age along with k12 and k21
K10 is adjusted according to
calculated lean body mass, total body weight and height. The fixed V1 compartment
size means that the model assumes the same peak plasma concentration for all
patients, regardless of body habitus or age.
the rate of decrease in plasma
concentration as the drugs redistributes into V2 is dependent on age (in contrast to
the Marsh model discussed earlier
Weight, height and lean body mass are used to
determine the rate of elimination by metabolism (k10) and thereby the rate of
propofol infusion to replace that loss
Minto model for remifentanil:
This is a three-compartment model and also
uses age, gender, weight and height.
Keo is age adjusted, but the very rapid plasma–brain equilibration
which is achieved within 5 minutes means that the issue of plasma or
effect-site targeting is not important.
Its rapid metabolism by non-specific esterases means that its pharmacokinetics
are consistent with a duration of action of 5–10 minutes,
a very short context-sensitive half-life, and minimal accumulation even after prolonged infusion
Marsh and Schnider, practical differences
Marsh models determine a variable volume for V1, in this example of
15.9 litres, whereas in Schnider V1 this is fixed at 4.27 litres
the original Marsh plasma target is used the pump will deliver larger volumes
of propofol, and in subjects of approximately normal weight this difference in
infusion rates will persist until the calculated curves approach each other at around
10 minutes.
By 30 minutes after the start of the infusion the models predict the same
plasma and effect-site concentrations (assuming that a modified Marsh model
This increase in the mass of propofol delivered in the early stages is
more likely to cause hypotension, and because the Marsh models do not incorporate
age this may be significant in the elderly
To give an indication of this difference, if
the target concentration is set at 4 μg ml–1 for a patient weighing 70 kg, Marsh will
deliver a bolus of 172 mg, whereas Schnider which will give only 77 mg
Problems
Obesity
Obesity represents a problem for both models.
If the Marsh model programmes in the total body weight,
then the initial or induction dose will be excessive.
Lean body weight can be used
(as a guide this only rarely exceeds 70 kg in females and 90 kg in males),
but this will then lead to under-dosing during continuous infusion, because the
requirement for propofol in the obese during maintenance shows a proportionate
increase
Problems with the Schnider model relate primarily to the calculation of lean
body mass (LBM). The formula that is used means that LBM increases proportionately
with total body weight (TBW) up to a body mass index of 37 kg m−2 in females
and 42 kg m−2 in males. Thereafter it decreases with the result that the calculated k10
(the elimination rate constant from the central compartment) increases and with it
the infusion rate to match the estimated drug metabolism.
