Target controlled infusion (TCI)
Below you can find some useful information on the theory and principles of TCI infusions as well as the models in use on the Agilia SP TIVA.
Introduction
Target Controlled Infusion (TCI) is a way of delivering intravenous and specifically anesthetic drugs. The rationale for TCI is based on setting the desired target concentration which the device achieves and maintains in plasma or effect-site (biophase) [1, 2]. The target concentration is set a priori by the anesthesiologist to achieve a desired clinical effect.
Shüttler and col. first described the use of TCI systems in 1983 [3]. This delivery system, recently distributed for anesthesia practice, offers several advantages over conventional manually controlled infusions, which will be detailed in this review.
TCI conveys a better safety for use in anesthetic practice through a fine-tuning of predicted plasma and effect-site drug concentrations to anesthetic needs according to the level of surgical stimulus, the individual characteristics of the patient and the co-administered drug.
This technique allows more precise titration of anesthetic drugs, proceeding by successive concentration steps, thus taking into account the inter-individual pharmacokinetic (coefficient of variation around 30%) and pharmacodynamic variability [4]. The desired concentration plateau is reached and maintained by administering a calibrated bolus and further automatically changing the infusion rate. TCI provides a better adjustment between anesthetic drug concentrations and clinically required effects, which is of major interest in anesthesia practice, particularly during induction and to predict recovery [1, 5, 6].
Principle: Theoretical basis
This infusion technique converts a set target concentration into required amounts of drug by time unit, administered through a syringe pump. This conversion is automatically implemented by the microprocessor into the pump, programmed with an algorithm including the pharmacokinetic model of the infused drug [1] (fig. 1 [7]).
This algorithm iteratively calculates the infusion rate required to achieve the desired target concentration and transmits this order to the pump. It is based on the classical infusion regimen described in 1968 by Kruger-Thiemer [8] to quickly achieve and maintain a constant plasma concentration of an intravenous drug.
This regimen, known as the BET scheme consists in an initial Bolus to fill the central compartment, followed by a constant rate infusion to replace drug Eliminated from the body associated to an exponential decreasing infusion to replace drug Transferred to the peripheral tissues. Thus TCI allows the maintenance of the desired profile of target concentration and its adjustments to clinical needs (Fig. 2 [5]).
The development of TCI has coincided with recent advances in pharmacokinetic concepts applied to anesthetic drugs: the effect-site compartment associated to the blood/effect-site equilibration constant (Ke0), the time to peak effect, the context-sensitive half-time and the context-sensitive decrement time.
Principle: Effect-site compartment
A pharmacokinetic compartmental model is frequently used to describe the fate of a drug in the body; it is obtained from the mathematical analysis of the plasma concentration curves over time, plasma being, by definition, included in the central compartment of the model.
The relationships between pharmacokinetic and pharmacodynamic effects are mostly described from plasma concentrations. However, after transfer through the blood-brain barrier, anesthetic drugs act in the Central Nervous System (CNS) which represents their effect-site (biophase); so the effect-site concentration governs the effect of the drug. Even if the time of equilibration between blood and effect-site may be very short, it is not instantaneous and, after an intravenous bolus, there is a lag-time between blood concentration and central effect, due to the blood/effect-site equilibration time.
This lag-time can be estimated from the central pharmacodynamic effects, such as loss of consciousness, electroencephalographic responses, or evoked potentials.
Any change by the operator in the target concentration will be revealed in the effect-site compartment after a delay corresponding to the transfer of the drug from the blood to effect site (Fig. 3 [5]).
This delay can be mathematically described by the first-order rate constant ke0 [1] and its corresponding half-life (T1/2 ke0 = ln2.ke0 -1) which determines the time between changes in blood drug concentrations and changes in effect-site concentrations (Ce).
At equilibrium, when the infusion is maintained, the effect-site and blood concentrations become similar.
So, the effect-site concentration can be defined as the plasma concentration which gives, at steady state, a similar effect. Before reaching equilibrium (steady-state), the effect-site concentration closely precedes the central effects, its particular interest being to allow the visualization of the delay between changes in plasma concentration and related variations in central effects, and thus describe the time course of action of a drug.
The time to peak effect (maximum effect-site concentration) is independent of the pharmacokinetic model and can be measured through pharmacodynamic studies (in the example, the time to peak effect has been measured as 1.7 min for propofol, 1.5 to 2 min for alfentanil and remifentanil and 5 to 6 min for sufentanil and fentanyl). Corresponding values of ke0 (min-1) linked to the pharmacokinetic model have been calculated for propofol (0.456) [9], remifentanil (0.49) [10], alfentanil (0.77), sufentanil (0.112) [11] and fentanyl (0.147) [12].
These estimations allow the introduction, in the pharmacokinetic model, of an effect-site compartment in which it is possible to describe the time course of drug concentration. Thus, the effect-site concentration can be related to clinical effects, in order to determine Ce50 (response in 50% of patients) or Ce95 (response in 95% of patients) (Fig. 4 [13]).
With TCI it is possible to directly target the effect compartment, offering the major advantage in a clinical point of view to reach, as quickly as possible, the desired level of effect but without overshooting it.
Computer programs for TCI control
Various programs have been used to control TCI systems [7]. They are all conceptually similar.
A TCI program incorporates the pharmacokinetic model of the infused drug.
The anesthesiologist enters the desired (target) concentration which is chosen relative to the desired clinical effect. At frequent intervals (2 to 30 sec), the program calculates from the pharmacokinetic model the infusion rate required to achieve the desired concentration and transmits this rate to the infusion device. The latter then administers this rate to the patient and feeds back the computer with the amount of drug that the pump has really infused.
From the actual infusion rates and the pharmacokinetic model, the program calculates the predicted concentration reached in plasma (and in effect-site), compares it with the target concentration and adjusts the infusion rate to reach or maintain the desired concentration (Fig. 1 shown earlier).
TCI application in anaesthesia
During the past fifteen years, numerous studies have been performed with TCI, using various computer programs and TCI devices [5] with several hypnotic drugs[1, 4] such as propofol, midazolam, ketamine, and opioids such as fentanyl, alfentanil, sufentanil and remifentanil.
These studies have mainly been performed during surgical anesthesia, demonstrating better hemodynamic stability, better control on the level of anesthesia, particularly in spontaneous ventilation, and more rapid recovery, when compared to manual infusion modes [13, 14-18].
These advantages are particularly interesting in elderly patients [19], in whom anesthetic drugs pharmacokinetics are frequently modified and who have increased pharmacodynamic sensitivity to opioids.
TCI mode is also well adapted to neurosurgical procedures, allowing more precise control over the effect of anesthetic drugs on neurophysiologic parameters such as motor evoked potentials [20].
TCI mode can provide a rational approach for the treatment of post-operative pain with short onset time opioids like alfentanil or remifentanil [21, 22]. The flexibility of TCI mode allows more precise titration of the analgesic drugs to meet the large variability of analgesic needs during the post-operative period.
From the anesthesiologist point of view, the TCI mode, which is only a method for a rational adjustment of infused doses, retains all the properties and performances of the incorporated infusion device (maximal rate, the accuracy of the instantaneous flow rate, occlusion pressure,…).
The ability, for the anesthesiologist, to set the target concentration in a single step and to leave to the program the management of the iterative changes in infusion rates, allows better stability for anesthesia with fewer human interventions and a reduction in workload [23].
Pharmacokinetic models used in the Agilia SP TIVA
The pharmacokinetic models included in the pump have already been established and validated through clinical studies whose goal was to assess the model’s predictive accuracies in various groups of subjects.
All pharmacokinetic models included in the pump are 3-compartment models that can be represented as follows:
The pharmacokinetic models included in the Agilia SP TIVA were not developed specifically for the device but were established and validated by numerous clinical studies.
Be especially careful when using the Marsh and Schnider models for Propofol. These two models lead to different flow rate patterns, and the proper concentration can differ depending on the choice of model.
With TCI programming mode, drugs can be infused according to the target control modes below (TCI modes):
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Plasma Control Mode: control of plasma concentration
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Effect-site Control Mode: control of effect-site concentration
Effect-site control mode differs from plasma control mode by allowing an overshoot of the plasma concentration to rapidly achieve the effect-site concentration. Before using the effect-site control mode, you must evaluate the patient’s state of health. Be careful using the effect-site control on fragile (ASA 3 or 4) or elderly patients.
In TCI mode, it is always best to titrate the concentration. This involves finding the proper concentration for your patient by progressively increasing the target until you reach the desired effect.
Age
The TCI modes can be used on patients of ages 1 to 100 however this may be limited in certain models. You must be especially careful with the Marsh model since it does not take age into account. For patients aged 55 and older the Schnider model has proven to be more accurate.
Weight
The TCI modes can be used with patients weighing between 5 and 200kg. For morbidly obese patients, the pharmacokinetic model's accuracy has not been validated, and the TCI modes should be used with caution.
Additionally, the Schnider model is dependent on Lean Body Mass (LBM), and cannot be selected when the patient parameters give a calculated BMI (Body Mass Index) of more than 42 for male patients and 35 for female patients.
For more information on TCI please read the "Anesthetic agents used in TCI" book available on AgiliaASSIST HERE.
References
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* if patient age < 13 years
** if patient age is between 13 and 16 years
*** if patient age = 13 years
**** if patient age = 14 years
***** if patient age = 15 years
****** if patient age = 16 years