I. Introduction

Target-controlled infusion (TCI) is a new technique for the administration of intravenous agents based on real-time pharmacokinetic simulations. Its aim is to control and maintain a steady therapeutic level of drugs with narrow margin of safety. TCI is intended to be similar to the vaporizer of volatile anaesthetics. This technique is more and more used in adults thanks to the recent availability of a marketed system dedicated to propofol (Diprifusor®). Its use is much more limited in children due to scientific and practical limits.

II. Pharmacokinetics.

The performance of a TCI system is directly correlated to the appropriateness of the pharmacokinetic parameter set to a given patient. It is well known that body composition and function greatly vary during childhood and differ from adults. At first glance, volumes of distribution and metabolic clearance are inversely correlated to age for propofol. Thus specific pharmacokinetic sets are mandatory for TCI use in children. Pharmacokinetics of propofol, fentanyl and alfentanil have been validated in the litterature during TCI administration in children > 1 yr (1-4). All these pharmacokinetic models take into account some anthropometric data (age, weight, height) to individualize pharmacokinetic parameters. The performance of these pharmacokinetic sets (i.e. bias (MDPE) and precision (MDAPE)) are sufficient for a clinical use (MDPE<10%, MDAPE<20-30%).

III. Pharmacodynamics.

Pharmacodynamic data relevant to TCI administration are more scarce. Plasma concentrations required for maintenance of adequate anesthesia are rare. This can be explained by the fact that the goal of the few existing studies on TCI in children was to establish and validate pharmacokinetic models. However, propofol concentrations for maintenance and awakening seem to be similar to adults (5, 6). Delayed awakening may be related to greater context-sensitive half-time. More studies are necessary to determine optimal hypnotic-opioid combination, as it has been made in adults.

More, the value of the constant ke0, which adjust the time to equilibrium between the blood and the central nervous system during TCI administration, has not been yet reported for I.V. anaesthetics agents.

III. Practical problems.

Some practical problems may limit the use of TCI administration in a clinical setting. The placement of I.V. line in conscious children < 2-3 yr may be a challenge even with the use of EMLA cream. The placement of small catheters increase the risk to trigger untimely occlusion alarm, particularly during induction of anaesthesia. Induction times are longer due to limited infusion rate of the syringe pumps (i.e. 1200 – 1500 mL/h).

However at present, the main limit is the lack of a marketed device dedicated to children. The Diprifusor® can not be used in children < 16 yr and < 30 kg. Thus TCI administration in children requires « home–made » software and can be only dedicated to research.

In conclusion, TCI administration of I.V. anesthetic drug in children is technically possible. Before its use by the clinician anaesthesist, more studies are mandatory. TCI administration is a great opportunity to extend our knowledge of the pharmacokinetics and the pharmacodynamics of I.V. anaesthetics in children.

References

1. Fiset P, Mathers L, Engstrom R, Fitzgerald D, Brand SC, Hsu F, et al. Pharmacokinetics of computer-controlled alfentanil administration in children undergoing cardiac surgery. Anesthesiology 1995;83(5):944-55.

2. Marsh B, White M, Morton N, Kenny G. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 1991;67(1):41-8.

3. Ginsberg B, Howell S, Glass PS, Margolis JO, Ross AK, Dear GL, et al. Pharmacokinetic model-driven infusion of fentanyl in children. Anesthesiology 1996;85(6):1268-75.

4. Kataria B, Ved S, Nicodemus H, Hoy G, Lea D, Dubois M, et al. The pharmacokinetics of propofol in children using three different data analysis approaches [see comments]. Anesthesiology 1994;80(1):104-22.

5. Short TG, Aun CS, Tan P, Wong J, Tam YH, Oh TE. A prospective evaluation of pharmacokinetic model controlled infusion of propofol in paediatric patients. Br J Anaesth 1994;72(3):302-6.

6. Browne BL, Prys_Roberts C, Wolf AR. Propofol and alfentanil in children: infusion technique and dose requirement for total i.v. anaesthesia. British Journal of Anaesthesia 1992;69(6):570-6.