Effect-compartment equilibrium rate constant (keo) for propofol during induction of anesthesia with a target-controlled infusion device

Abstract

The effect-compartment concentration (C(e)) of a drug at a specific pharmacodynamic endpoint should be independent of the rate of drug injection. We used this assumption to derive an effect-compartment equilibrium rate constant (k(eo)) for propofol during induction of anesthesia, using a target controlled infusion device (Diprifusor). Eighteen unpremedicated patients were induced with a target blood propofol concentration of 5 microg x ml(-1) (group 1), while another 18 were induced with a target concentration of 6 microg x ml(-1) (group 2). The time at loss of the eyelash reflex was recorded. Computer simulation was used to derive the rate constant (k(eo)) that resulted in the mean C(e) at loss of the eyelash reflex in group 1 being equal to that in group 2. Using this population technique, we found the k(eo) to be 0.57 min(-1). The mean (SD) effect compartment concentration at loss of the eyelash reflex was 2.39 (0.70) microg x ml(-1). This means that to achieve a desired C(e) within 3 min of induction, the initial target blood concentration should be set at 1.67 times that of the desired C(e) for 1 min, after which it should revert to the desired concentration.

The influence of target concentration, equilibration rate constant (ke0) and pharmacokinetic model on the initial propofol dose delivered in effect-site target-controlled infusion

“…Among the k e0 s determined to deliver initial doses of 2.0 mg.kg À1 , 1.75 mg.kg À1 and 1.5 mg.kg À1 propofol at the three effect site targets examined ( Table 2) the value of 0.59 min À1 delivering 1.75 mg.kg À1 with the Marsh model is very close to values of 0.61 min À1 and 0.57 min À1 reported in earlier studies [15,16]. The value of 0.61 min À1 with the Marsh model was determined as the value that had the greatest possibility of achieving a stable effect when the effect site target was fixed at the concentration indicated by this k e0 at the time when a desired degree of sedation was reached [15].…”

A novel technique to determine an ‘apparent ke0’ value for use with the Marsh pharmacokinetic model for propofol

“…An advantage of this approach is that propofol is administered by effect‐site TCI rather than by single bolus or infusion, as both the time to peak effect and k e0 may be influenced by the rate of injection . The k e0 value (0.57 min −1 ) from the currently available literature that is closest to our value was also derived in a study that used target‐controlled infusions of propofol and clinical endpoints .…”

“…Most studies have used electroencephalography (EEG)‐derived measures of effect, but these measures are complicated by time delays and the observed time of peak effect can be influenced by the monitor used . Other studies that are based on the hypothesis that the effect‐site concentration at loss of eyelash reflex should be independent of the method of administration have proposed values of 0.8 min −1 and 0.57 min −1 .…”

Influence of a modified propofol equilibration rate constant (ke0) on the effect‐site concentration at loss and recovery of consciousness with the Marsh model

“…There is no ideal method for obtaining the true k e0 of propofol, and a wide range of k e0 values, between 0.20 and 1.21 min −1 , has been reported . The k e0 value of 0.26 min −1 used in the Diprifusor was determined using auditory evoked potentials.…”

“…After intravenous administration, the plasma concentration of a drug gradually equilibrates with its effect‐site concentration. The rate of equilibration between plasma and effect‐site concentration depends on the rate of transfer of the drug from the plasma to the effect‐site . The time course of equilibration between plasma and effect‐site concentrations can be mathematically described by a first‐order rate constant, known as the plasma effect‐site equilibration rate constant (k e0 ), which can be used to estimate effect‐site concentration .…”