Influence of Administration Rate on Propofol Plasma–Effect Site Equilibration

Background:The authors hypothesized a difference in plasma–effect site equilibration, depicted by a first-order constant ke0, depending on the injection rate of propofol. Methods:Sixty-one patients received 2.5 mg/kg propofol given as a bolus or as a 1-, 2-, or 3-min infusion. The Bispectral Index was used to monitor drug effect. Propofol predicted plasma concentration was calculated using a three-compartment model and the effect site concentration over time as the convolution between the predicted plasma concentration and the disposition function of the effect site concentration. The authors evaluated the influence of the infusion rate on the ke0 by comparing the model with one ke0 for all groups with models estimating different ke0 values for each group. The authors also assessed the accuracy of two pharmacokinetic models after bolus injection. Results:The best model based was a fixed (Bispectral Index ≥ 90) plus sigmoidal model (Bispectral Index < 90) with two values of ke0, one for the bolus (t½ ke0 = 1.2 min) and one for the infusions (t½ ke0 = 2.2 min). However, the tested pharmacokinetic models poorly predicted the arterial concentrations in the first minutes after bolus injection. Simulations showed the requirement for two ke0 values for bolus and infusion was mostly a compensation for the inaccurate prediction of arterial concentrations after a bolus. Conclusion:Propofol plasma–effect site equilibration occurs more rapidly after a bolus than after rapid infusion, based on the electroencephalogram as a drug effect measure, mostly because of misspecification of the pharmacokinetic model in the first minutes after bolus.

[1]  M. Struys,et al.  Comparison of Plasma Compartment versus Two Methods for Effect Compartment–controlled Target-controlled Infusion for Propofol , 2000, Anesthesiology.

[2]  M. Avram,et al.  Time-dependent distribution volume and kinetics of the pharmacodynamic effector site. , 1992, Journal of pharmaceutical sciences.

[3]  M. Avram,et al.  Intravascular mixing and drug distribution: The concurrent disposition of thiopental and indocyanine green , 1989, Clinical pharmacology and therapeutics.

[4]  C A Shanks,et al.  Recirculatory pharmacokinetic models of markers of blood, extracellular fluid and total body water administered concomitantly. , 1996, The Journal of pharmacology and experimental therapeutics.

[5]  R. Upton,et al.  The Effect of Altered Cerebral Blood Flow on the Cerebral Kinetics of Thiopental and Propofol in Sheep , 2000, Anesthesiology.

[6]  R N Upton,et al.  A physiological model of induction of anaesthesia with propofol in sheep. 1. Structure and estimation of variables. , 1997, British journal of anaesthesia.

[7]  R N Upton,et al.  Recirculatory model of fentanyl disposition with the brain as the target organ. , 2004, British journal of anaesthesia.

[8]  Anthony G. Doufas,et al.  Induction Speed Is Not a Determinant of Propofol Pharmacodynamics , 2004, Anesthesiology.

[9]  E. Kochs,et al.  Time Delay of Index Calculation: Analysis of Cerebral State, Bispectral, and Narcotrend Indices , 2006, Anesthesiology.

[10]  T. Kazama,et al.  Investigation of Effective Anesthesia Induction Doses Using a Wide Range of Infusion Rates with Undiluted and Diluted Propofol , 2000, Anesthesiology.

[11]  N. Morton,et al.  Pharmacokinetic model driven infusion of propofol in children. , 1991, British journal of anaesthesia.

[12]  L B Sheiner,et al.  Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. , 1980, Clinical pharmacology and therapeutics.

[13]  H. Schwilden,et al.  Closed-loop feedback control of propofol anaesthesia by quantitative EEG analysis in humans. , 1989, British journal of anaesthesia.

[14]  M. White,et al.  Effect-site modelling of propofol using auditory evoked potentials. , 1999, British journal of anaesthesia.

[15]  Steven L. Shafer,et al.  Measuring the predictive performance of computer-controlled infusion pumps , 1992, Journal of Pharmacokinetics and Biopharmaceutics.

[16]  H F Nicodemus,et al.  The Pharmacokinetics of Propofol in Children Using Three Different Data Analysis Approaches , 1994, Anesthesiology.

[17]  A. Lam,et al.  Propofol: Relation between Brain Concentrations, Electroencephalogram, Middle Cerebral Artery Blood Flow Velocity, and Cerebral Oxygen Extraction during Induction of Anesthesia , 2002, Anesthesiology.

[18]  Hugo Vereecke,et al.  Ability of the Bispectral Index, Autoregressive Modelling with Exogenous Input-derived Auditory Evoked Potentials, and Predicted Propofol Concentrations to Measure Patient Responsiveness during Anesthesia with Propofol and Remifentanil , 2003, Anesthesiology.

[19]  Steven L Shafer,et al.  Using the Time of Maximum Effect Site Concentration to Combine Pharmacokinetics and Pharmacodynamics , 2003, Anesthesiology.

[20]  Hugo Vereecke,et al.  Spectral Entropy as an Electroencephalographic Measure of Anesthetic Drug Effect: A Comparison with Bispectral Index and Processed Midlatency Auditory Evoked Response , 2004, Anesthesiology.

[21]  S L Shafer,et al.  A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect , 1997, Clinical pharmacology and therapeutics.

[22]  S L Shafer,et al.  The influence of age on propofol pharmacodynamics. , 1999, Anesthesiology.

[23]  S. Shafer,et al.  The Influence of Method of Administration and Covariates on the Pharmacokinetics of Propofol in Adult Volunteers , 1998, Anesthesiology.

[24]  E. Mortier,et al.  A comparison of bispectral index and ARX‐derived auditory evoked potential index in measuring the clinical interaction between ketamine and propofol anaesthesia , 2003, Anaesthesia.