TECHNICAL SKILLS © 2005 The Medicine Publishing Company Ltd 141 ANAESTHESIA AND INTENSIVE CARE MEDICINE 6:4 Circulating drugs are removed by distribution to peripheral tissues, metabolism and excretion. Thus, bolus doses exert transient effects and repeated doses are required for continuous effects. However, repetitive boluses produce peaks and troughs in blood concentra- tion and therefore varying effects. The most efficient method of maintaining a desired drug effect is by continuous infusion to achieve constant blood concentrations. Achieving steady-state drug concentrations in blood In 1968, Kruger-Theimer indicated how pharmacokinetic models can be used to design efficient dose regimens. This Bolus, Elimina- tion, Transfer (BET) regimen (Figure 1) administers: • a bolus dose calculated to fill the central (blood) compartment • a constant-rate infusion equal to the elimination rate • an infusion that compensates for transfer to the peripheral tissues: this initially rapid infusion declines asymptotically towards the elimination rate as tissues absorb drug. Approximations of BET infusions comprise stepped-down, constant infusions, as exemplified by the ‘10, 8 and 6’ regimen for propofol, intended to achieve blood concentrations of 3 µg/ml. A 1.5 mg/kg loading dose is followed by an infusion of 10 mg/ kg/hour that is reduced to rates of 8 and 6 mg/kg/hour at 10-min intervals. Target-controlled infusions by computer Using a pharmacokinetic model, a computer continuously calcu- lates the patient’s expected drug concentration and administers a BET regimen, adjusting pump speeds, typically at 10-second intervals. By specifying appropriate target concentrations, the anaesthetist uses the device in a similar fashion to a vaporizer. There are differences between predicted and actual concentra- tions, but these are not of great consequence, provided the true concentrations are within the drug’s therapeutic window, within which the clinician may adjust the targeted concentrations, accord- ing to patient response. Measured/predicted errors of about 30% are clinically acceptable. These devices simplify intravenous drug administration by relieving the clinician of tedious calculations and by eliminating errors. The benefits of BET and target-controlled infusions are listed in Figure 2. Anaesthetists need to associate blood drug concentrations with expected effects; for example, correlating alveolar partial pressures of inhaled anaesthetics to drug effect. The concept of minimum effective plasma concentration (EC 50 ) is identical to that of minimal alveolar concentration (MAC) for inhaled agents. Target- concentration guidelines for intravenous drugs and drug combina- tions are available from standard textbooks. However, no single targeted concentration suits all patients. Patient pharmacokinetics Principles of intravenous drug infusion Johan F Coetzee Johan F Coetzee is Associate Professor of Anaesthesiology at the University of Stellenbosch and Tygerberg Hospital, South Africa. He is Director of the Bureau for Biomedical Engineering at the University of Stellenbosch. Achieving a constant blood concentration of propofol using a BET regimen Infusion rate (µg/kg/min) Concentration (ng/ml) Exponentially declining infusion rate Bolus 0.75 mg/kg Time (min) Time (min) a b Computer simulation of propofol administered by a Bolus, Elimination and Transfer (BET) dose regimen to achieve and maintain a constant blood concentration of 3 µg/ml. a Administration of a bolus dose at time zero, calculated to establish the initial targeted concentration. This is followed by an infusion, which is initially rapid and then declines asymptotically to the maintenance rate. b The theoretical blood and effect-site concentrations. Note how the effect-site concentrations lag behind those in the blood. Blood Effect site 200 150 100 15 0 30 45 60 75 90 105 120 15 0 30 45 60 75 90 105 120 4000 3000 2000 1000 1