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The History of Target-Controlled Infusion

Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted (“target”) drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. We also describe the launch of the current clinically available systems.

The goal of every form of drug delivery is achieving and maintaining a therapeutic time course of drug effect, while avoiding adverse effects. IV drugs are usually given using standard dosing guidelines. Typically the only patient covariate that is incorporated into a dose is a metric of patient size, typically weight for IV anesthetics. Patient characteristics such as age, sex, or creatinine clearance are often not included because of the complex mathematical relationship of these covariates to dose. Historically there have been 2 methods of administering IV drugs during anesthesia: bolus dose and continuous infusion. Bolus doses are typically administered with a handheld syringe. Infusions are typically administered with an infusion pump.

Every anesthetic drug accumulates in tissue during drug delivery. This accumulation confounds the relationship between the infusion rate set by the clinician and the drug concentration in the patient. A propofol infusion rate of 100 μg/kg/min is associated with a nearly awake patient 3 minutes into the infusion and a highly sedated or asleep patient 2 hours later. By using well-understood pharmacokinetic (PK) principles, computers can calculate how much drug has accumulated in tissues during infusions and can adjust the infusion rate to maintain a stable concentration in the plasma or the tissue of interest, typically the brain. The computer is able to use the best model from the literature, because the mathematical complexity of incorporating patient characteristics (weight, height, age, sex, and additional biomarkers) are trivial calculations for the computer.1,2 This is the basis of a third type of anesthetic drug delivery, target-controlled infusions (TCI). With TCI systems, the clinician enters a desired target concentration. The computer calculates the amount of drug, delivered as boluses and infusions, required to achieve the target concentration and directs an infusion pump to deliver the calculated bolus or infusion. The computer constantly calculates how much drug is in the tissue and exactly how that influences the amount of drug required to achieve the target concentration by using a model of the PKs of the drug selected and the patient covariates.

During surgery, the level of surgical stimulation can change very quickly, requiring precise, rapid titration of drug effect. Conventional infusions cannot increase drug concentrations rapidly enough to account for abrupt increases in stimulation or decrease concentrations rapidly enough to account for periods of low stimulation. Conventional infusions cannot even maintain steady drug concentrations in the plasma or brain during periods of constant stimulation. By incorporating PK models, TCI systems can rapidly titrate response as necessary and similarly maintain steady concentrations when appropriate. The potential benefit to clinicians is the more precise titration of anesthetic drug effect.3

In this review, we describe the PK principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. Two accompanying review articles cover the global use and safety issues related to this technology.4,5

As TCI systems evolved, investigators chose idiosyncratic terms for the methodology. TCI systems have been referred to as computer-assisted total IV anesthesia (CATIA),6 titration of IV agents by computer (TIAC),7 computer-assisted continuous infusion (CACI),8 and computer-controlled infusion pump.9 Following a suggestion by Iain Glen, White and Kenny used the term TCI in their publications after 1992. A consensus was reached in 1997 among the active investigators that the term TCI be adopted as the generic description of the technology.10