4. Target-Controlled Infusion (TCI)

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.

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

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

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 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 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 is metabolized mainly in the liver, undergoing conjugation to glucuronide and sulphate prior to renal excretion

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, 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 (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 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

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

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 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

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.

time taken for the plasma concentration to halve after an infusion designed to maintain constant blood levels is stopped. is different not only for dissimilar drugs but also for the same drug depending on the duration of infusion. The CSHT for remifentanil is about 4.5 minutes after 2 hours of infusion, and 9.0 minutes after 8 hours CSHT after 2 hours of infusion of 48 minutes, which extends after 8 hours to 282 minutes. The figures for alfentanil are 50 and 64 minutes, and for propofol 16 and 41 minutes. This makes it clear why remifentanil is such a suitable drug for administration in this way (Figure 4.7).

: the concept of the apparent Vd assumes that a drug is distributed evenly throughout a single compartment. (If, for example, 100 mg of a drug given intravenously yields a plasma concentration of 1 mg l−1, then the Vd is 100/1 = 100 litres larger. The volumes of distribution of drugs used in TCI are useful in explaining their clinical behaviour, being 800 litres for propofol and 30 litres for both alfentanil and remifentanil. Vd is, however, affected by such factors as pregnancy, age and volaemic status

one of several definitions of clearance is the rate of drug elimination per unit time per unit concentration. An alternative (and neat) model-independent method of determining clearance is to divide the dose of drug by the area under its concentration–time curve. The whole body clearance of propofol is 2,500 ml mi

This clearly will vary according to the procedure. For ‘conscious sedation’ a target plasma concentration below 1.0 μg ml− 1 might prove sufficient, whereas surgical anaesthesia might require upwards of 8.0 or 10.0 μg ml−1. In practice, the range is from around 2.0–8.0 μg ml−1. It is much lower if propofol is used in conjunction with remifentanil. This reflects the considerable pharmacokinetic and pharmacodynamic inter-patient variability. Influences include age, body weight, genetic factors, concurrent disease and administration of other drugs. Alfentanil, for example, reduces the distribution and clearance of propofol.

if a patient has to return to theatre soon after TCI has been discontinued, the microprocessor will no longer be storing the pharmacokinetic information. When the TCI is restarted, therefore, the system will deliver another bolus and rapid initial infusion as if there were no residual propofol in the body. The shorter the interval between cessation and resumption, the greater the risk of overdose