Correspondence  |   March 2011
Presenting Data versus  Predictions as Basic Scientific Information: Target-controlled Infusions versus  Microgram per Kilogram per Minutes
Author Notes
  • Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
Article Information
Correspondence   |   March 2011
Presenting Data versus  Predictions as Basic Scientific Information: Target-controlled Infusions versus  Microgram per Kilogram per Minutes
Anesthesiology 3 2011, Vol.114, 723. doi:10.1097/ALN.0b013e3182096b8e
Anesthesiology 3 2011, Vol.114, 723. doi:10.1097/ALN.0b013e3182096b8e
In Reply:
The letter by Kempen regarding two published articles1,2 raises several important issues. All of these can be reduced to the basic principle that drug administration based on dose is subject to more interindividual variability in response than is drug administration based on targeting plasma concentration or, even more optimally, effect-site concentration. For volatile anesthetics, the latter is easily accomplished because at pseudo–steady-state, the real time measured end-expiratory alveolar concentration reflects both the plasma concentration and the effect-site concentration.3 
Continuous real-time plasma concentration measurements of intravenously administered hypnotics and opioids would provide the anesthesiologist analogous information to help guide their administration. Unfortunately, such measurements are not practicable. Therefore, investigators have developed numerical solutions to pharmacokinetic models to calculate the infusion schemes required to target a desired plasma or effect-site concentration. In addition, these models can predict the time course of plasma and effect-site drug concentrations during and after drug administration. Although several of the better-known and more commonly used pharmacokinetic models have been shown to be significantly biased and inaccurate in predicting actual measured plasma drug concentrations during and after drug administration by boluses, short infusion, long infusion, or target-controlled infusion,4 they have clearly proven useful in guiding drug administration given the worldwide administration of more than 13 million target-controlled infusion propofol-based anesthetics.5 Therefore, reporting the predicted plasma or effect-site drug concentration and its associated effect, such as a processed electroencephalogram (e.g.  , bispectral index, entropy, etc.) effect, in clinical studies in which an intravenous anesthetic has been administered is as important and meaningful to many of the readers of Anesthesiology as is reporting the end-tidal anesthetic concentration in clinical studies in which a volatile anesthetic has been administered. In fact, simply reporting the infusion rate of an intravenous anesthetic is akin to reporting only the vaporizer dial setting of a volatile anesthetic without reporting the fresh gas flow, the alveolar ventilation, and the many other factors that influence uptake and distribution of volatile anesthetics.
Use of predicted plasma drug concentrations and measured drug effect to create a pharmacokinetic-pharmacodynamic model is another matter. The prediction of plasma drug concentrations is subject not only to the biases and inaccuracies of the commonly used pharmacokinetic models but also the interindividual variability in pharmacokinetics and physiologic changes that may affect the underlying pharmacokinetic model.6 Errors in the predicted plasma drug concentrations can lead to substantial errors in the pharmacodynamic model and erroneous conclusions.7,8 Therefore, it is highly desirable that pharmacokinetic-pharmacodynamic studies measure a sufficient number of plasma drug concentrations at times that will allow optimal characterization of pharmacokinetics, including early drug distribution,9 and subsequent accurate and precise estimation of the pharmacodynamic parameters.10 Such models could improve the accuracy of effect-site targeted target-controlled infusion8 more than is possible by reworking flawed existing models.
In conclusion, although reporting the predicted plasma or effect-site concentration at the time of important outcome assessments in clinical studies is better than reporting the dose, studies aimed at investigating the important physiologic covariates or drug-drug interactions that alter pharmacokinetics or pharmacodynamics should include measurements of plasma drug concentrations to prevent erroneously accounting for the variability caused by pharmacokinetic misspecification as pharmacodynamic variability.
Northwestern University, Feinberg School of Medicine, Chicago, Illinois.
Bandschapp O, Filitz J, Ihmsen H, Berset A, Urwyler A, Koppert W, Ruppen W: Analgesic and antihyperalgesic properties of propofol in a human pain model. Anesthesiology 2010; 113:421–8Bandschapp, O Filitz, J Ihmsen, H Berset, A Urwyler, A Koppert, W Ruppen, W
Rigouzzo A, Servin F, Constant I: Pharmacokinetic-pharmacodynamic modeling of propofol in children. Anesthesiology 2010; 113:343–52Rigouzzo, A Servin, F Constant, I
Gupta DK, Eger EI 2nd: Inhaled anesthesia: The original closed-loop drug administration paradigm. Clin Pharmacol Ther 2008; 84:15–8Gupta, DK Eger, EI
Masui K, Upton RN, Doufas AG, Coetzee JF, Kazama T, Mortier EP, Struys MM: The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: A comparison using bolus, continuous, and target-controlled infusion data. Anesth Analg 2010; 111:368–79Masui, K Upton, RN Doufas, AG Coetzee, JF Kazama, T Mortier, EP Struys, MM
Minto CF, Schnider TW: Contributions of PK/PD modeling to intravenous anesthesia. Clin Pharmacol Ther 2008; 84:27–38Minto, CF Schnider, TW
Henthorn TK, Krejcie TC, Avram MJ: Early drug distribution: A generally neglected aspect of pharmacokinetics of particular relevance to intravenously administered anesthetic agents. Clin Pharmacol Ther 2008; 84:18–22Henthorn, TK Krejcie, TC Avram, MJ
Fisher DM: Take it to the limit (one more time). Anesthesiology 2007; 107:367–8Fisher, DM
Struys MM, Coppens MJ, De Neve N, Mortier EP, Doufas AG, Van Bocxlaer JF, Shafer SL: Influence of administration rate on propofol plasma-effect site equilibration. Anesthesiology 2007; 107:386–96Struys, MM Coppens, MJ De Neve, N Mortier, EP Doufas, AG Van Bocxlaer, JF Shafer, SL
Avram MJ, Krejcie TC: Using front-end kinetics to optimize target-controlled drug infusions. Anesthesiology 2003; 99:1078–86Avram, MJ Krejcie, TC
Kuipers JA, Boer F, Olofsen E, Bovill JG, Burm AG: Recirculatory pharmacokinetics and pharmacodynamics of rocuronium in patients: The influence of cardiac output. Anesthesiology 2001; 94:47–55Kuipers, JA Boer, F Olofsen, E Bovill, JG Burm, AG