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Propofol Effect-Site Concentrations: Hunt the ke0

Glen, John B. BVMS, PhD, FRCA

doi: 10.1213/ANE.0b013e31829c653c
Letters to the Editor: Letter to the Editor

Glen Pharma, Knutsford, Cheshire, United Kingdom

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To the Editor

This letter makes a plea to authors and reviewers of articles describing calculated propofol effect-site concentrations1 to ensure that complete information is given on the pharmacokinetic model and either the blood–brain equilibration rate constant (ke0) or time to peak effect (tpeak) is used to determine these concentrations. The time of peak effect after bolus injection has been proposed as a model-independent method to link separate pharmacokinetic and pharmacodynamic studies.2 In the process of searching literature linking calculated propofol effect-site concentration to observed effects, this author found that a number of potentially relevant publications were of limited value in view of missing information on these details.3–5

Propofol may be administered in bolus or infusion doses or with a target-controlled infusion (TCI) device. The ke0 used with any model determines the extent to which the calculated effect-site concentration lags behind the calculated blood concentration. In addition, with TCI administration, the amount of drug delivered to achieve a particular target blood concentration is dependent on the pharmacokinetic model and to achieve a desired target effect-site concentration is influenced both by the pharmacokinetic model and ke0. The pharmacokinetic models described by Marsh et al.6 or Schnider et al.7,8 are most frequently used for the determination of predicted propofol effect-site concentration by computer simulation or for the administration of propofol by TCI. No pharmacodynamic data were obtained in the study by Gepts et al.9 which provided the basis for the Marsh model, but a ke0 of 0.26 min−1 is incorporated in “Diprifusor” TCI systems (AstraZeneca, London, United Kingdom) to provide a display of calculated propofol effect-site concentration. Commercial devices incorporating the Schnider model use a ke0 of 0.46 min−1 or tpeak of 1.6 minutes, values which are generally equivalent for this model.

With TCI administration, it is not sufficient to just describe the particular commercial device used as some of these provide a choice of pharmacokinetic model, ke0 or time to peak effect. There are also numerous research software systems that can be used. Of these, STANPUMP (developed by Steven L. Shafer, MD; Palo Alto, CA), RUGLOOP (written by Michel Struys, MD, PhD and Tom DeSmet, MSc; University of Ghent, Ghent, Belgium), and STELPUMP (written by J. F. Coetzee, MD; University of Stellenbosch Department of Anesthesiology, Tygerberg, South Africa) appear most frequently in publications. In most cases, these research systems also offer the user a choice of models with different ke0s. It is also important to note that these systems have evolved over the years as new information has become available. For the Marsh pharmacokinetic model, versions of STANPUMP before 1999 used a tpeak of 2.3 minutes (equivalent to a ke0 of 0.7 min−1) whereas since then a tpeak of 1.6 minutes is incorporated (equivalent to a ke0 of 1.2 min−1 for this model).

A computer simulation illustrating the influence of pharmacokinetic model and ke0 or tpeak on calculated effect-site concentration is shown in Figure 1. If a desired effect were to be noted 2 minutes after the administration of this bolus dose, the calculated effect-site concentration observed could range from 4.4 to 1.3 µg·mL−1. To avoid confusion and to allow comparison with earlier work, it is essential that in a study where calculated effect-site concentration for any drug is determined by pharmacokinetic simulation or by reading the value indicated by a TCI system, that detailed information is provided on the pharmacokinetic model and ke0 or time to peak effect.

Figure 1

Figure 1

John B. Glen, BVMS, PhD, FRCA

Knutsford, Cheshire, United Kingdom

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