A two-compartment effect site model describes the bispectral index after different rates of propofol infusion

  • Marcus A. Björnsson
  • Åke Norberg
  • Sigridur Kalman
  • Mats O. Karlsson
  • Ulrika S. H. Simonsson
Article
  • 335 Downloads

Abstract

Different estimates of the rate constant for the effect site distribution (ke0) of propofol, depending on the rate and duration of administration, have been reported. This analysis aimed at finding a more general pharmacodynamic model that could be used when the rate of administration is changed during the treatment. In a cross-over study, 21 healthy volunteers were randomised to receive a 1 min infusion of 2 mg/kg of propofol at one occasion, and a 1 min infusion of 2 mg/kg of propofol immediately followed by a 29 min infusion of 12 mg kg−1 h−1 of propofol at another occasion. Arterial plasma concentrations of propofol were collected up to 4 h after dosing, and BIS was collected before start of infusion and until the subjects were fully awake. The population pharmacokinetic-pharmacodynamic analysis was performed using NONMEM VI. A four-compartment PK model with time-dependent elimination and distribution described the arterial propofol concentrations, and was used as input to the pharmacodynamic model. A standard effect compartment model could not accurately describe the delay in the effects of propofol for both regimens, whereas a two-compartment effect site model significantly improved the predictions. The two-compartment effect site model included a central and a peripheral effect site compartment, possibly representing a distribution within the brain, where the decrease in BIS was linked to the central effect site compartment concentrations through a sigmoidal Emax model.

Keywords

Propofol Pharmacokinetics Pharmacodynamics Bispectral index NONMEM 

References

  1. 1.
    Gepts E, Camu F, Cockshott ID, Douglas EJ (1987) Disposition of propofol administered as constant rate infusions in humans. Anesth Analg 66:1256–1263CrossRefPubMedGoogle Scholar
  2. 2.
    Marsh B, White M, Morton N, Kenny GNC (1991) Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth 67:41–48CrossRefPubMedGoogle Scholar
  3. 3.
    Schnider TW, Minto CF, Gambus PL, Andresen C, Goodale DB, Shafer SL, Youngs EJ (1998) The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology 88:1170–1182CrossRefPubMedGoogle Scholar
  4. 4.
    Schüttler J, Ihmsen H (2000) Population pharmacokinetics of propofol. Anesthesiology 92:727–738CrossRefPubMedGoogle Scholar
  5. 5.
    Kazama T, Ikeda K, Morita K, Kikura M, Ikeda T, Kurita T, Sato S (2000) Investigation of effective anesthesia induction doses using a wide range of infusion rates with undiluted and diluted propofol. Anesthesiology 92:1017–1028CrossRefPubMedGoogle Scholar
  6. 6.
    Billard V, Gambus PL, Chamoun N, Stanski DR, Shafer SL (1997) A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect. Clin Pharmacol Ther 61:45–58CrossRefPubMedGoogle Scholar
  7. 7.
    Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, Youngs EJ (1999) The influence of age on propofol pharmacodynamics. Anesthesiology 90:1502–1516CrossRefPubMedGoogle Scholar
  8. 8.
    Struys MMRF, De Smeet T, Depoorter B, Versichelen LFM, Mortier EP, Dumortier FJE, Shafer SL, Rolly G (2000) Comparison of plasma compartment versus two methods for effect compartment-controlled target-controlled infusion for propofol. Anesthesiology 92:399–406CrossRefPubMedGoogle Scholar
  9. 9.
    Doufas AG, Bakhshandeh M, Bjorksten AR, Shafer SL, Sessler DI (2004) Induction speed is not a determinant of propofol pharmacodynamics. Anesthesiology 101:1112–1121CrossRefPubMedGoogle Scholar
  10. 10.
    Struys MMRF, Coppens MJ, De Neve N, Mortier EP, Doufas AG, Van Bocxlaer JFP, Shafer SL (2007) Influence of administration rate on propofol plasma-effect site equilibration. Anesthesiology 107:386–396CrossRefPubMedGoogle Scholar
  11. 11.
    Jeleazcov C, Ihmsen H, Schmidt J, Ammon C, Schwilden H, Shüttler J, Fechner J (2008) Pharmacodynamic modelling of the bispectral index response to propofol-based anaesthesia during general surgery in children. Br J Anaesth 100:509–516CrossRefPubMedGoogle Scholar
  12. 12.
    Upton RN, Ludbrook G (2005) A physiologically based, recirculatory model of the kinetics and dynamics of propofol in man. Anesthesiology 103:344–352CrossRefPubMedGoogle Scholar
  13. 13.
    Masui K, Kira M, Kazama T, Hagihira S, Mortier EP, Struys MMRF (2009) Early phase pharmacokinetics but not pharmacodynamics are influenced by propofol infusion rate. Anesthesiology 111:805–817CrossRefPubMedGoogle Scholar
  14. 14.
    Upton RN, Ludbrook GL, Grant C, Martinez AM (1999) Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration. Anesth Analg 89:545–552CrossRefPubMedGoogle Scholar
  15. 15.
    Peeters MYM, Aarts LPHJ, Boom FA, Bras LJ, Tibboel D, Danhof M, Knibbe CAJ (2008) Pilot study on the influence of liver blood flow and cardiac output on the clearance of propofol in critically ill patients. Eur J Clin Pharmacol 64:329–334CrossRefPubMedGoogle Scholar
  16. 16.
    Levitt DG, Schnider TW (2005) Human physiologically based pharmacokinetic model for propofol. BMC Anesth 5:4CrossRefGoogle Scholar
  17. 17.
    Minto CF, Schnider TW (2008) Contributions of PK/PD modelling to intravenous anesthesia. Clin Pharmacol Ther 84:27–38CrossRefPubMedGoogle Scholar
  18. 18.
    Dawidowicz AL, Fijalkowska A (1995) Determination of propofol in blood by HPLC. Comparison of the extraction and precipitation methods. J Chromatogr Sci 33:377–382PubMedGoogle Scholar
  19. 19.
    Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, Schwam EM, Siegel JL (1990) Validity and reliability of the observer’s assessment of alertness/sedation scale: study with intravenous midazolam. J Clin Psychopharmacol 10:244–251CrossRefPubMedGoogle Scholar
  20. 20.
    Beal SL, Sheiner LB, Boeckmann AJ (eds) (1989–2006) NONMEM users guides. ICON Development Solutions, Ellicott CityGoogle Scholar
  21. 21.
    Jonsson EN, Karlsson MO (1999) Xpose—an S-PLUS population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58:51–64CrossRefPubMedGoogle Scholar
  22. 22.
    Lindbom L, Pihlgren P, Jonsson EN (2005) PsN-toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed 79:241–257CrossRefPubMedGoogle Scholar
  23. 23.
    Karlsson MO, Holford N (2008) A tutorial on visual predictive checks. Abstract 1434, p 17. www.page-meeting.org/?abstract=1434
  24. 24.
    Upton RN, Ludbrook GL, Grant C (2001) The cerebral and systemic kinetics of thiopentone and propofol in halothane anaesthetized sheep. Anaesth Intensive Care 29:117–123PubMedGoogle Scholar
  25. 25.
    Peacock JE, Blackburn A, Sherry KM, Reilly CS (1995) Arterial and jugular venous bulb blood propofol concentrations during induction of anesthesia. Anesth Analg 80:1002–1006CrossRefPubMedGoogle Scholar
  26. 26.
    Dutta S, Matsumoto Y, Muramatsu A, Matsumoto M, Fukuoka M, Ebling WF (1998) Steady-state propofol brain: plasma and brain: blood partition coefficients and the effect-site equilibration paradox. Br J Anaesth 81:422–424PubMedGoogle Scholar
  27. 27.
    Ludbrook GL, Visco E, Lam AM (2002) Propofol: relation between brain concentrations, electroencephalogram, middle cerebral artery blood flow velocity, and cerebral oxygen extraction during induction of anesthesia. Anesthesiology 97:1363–1370CrossRefPubMedGoogle Scholar
  28. 28.
    Zamacona MK, Suárez E, García E, Aguirre C, Calvo R (1998) The significance of lipoproteins in serum binding variations of propofol. Anesth Analg 87:1147–1151CrossRefPubMedGoogle Scholar
  29. 29.
    Weaver BMQ, Staddon GE, Mapleson WW (2001) Tissue/blood and tissue/water partition coefficients for propofol in sheep. Br J Anaesth 86:693–703CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Marcus A. Björnsson
    • 1
    • 3
  • Åke Norberg
    • 2
  • Sigridur Kalman
    • 2
  • Mats O. Karlsson
    • 3
  • Ulrika S. H. Simonsson
    • 3
  1. 1.Clinical Pharmacology and DMPKAstraZeneca R&D SödertäljeSödertäljeSweden
  2. 2.Karolinska Institutet at Department of Anaesthesia and Intensive CareKarolinska University HospitalHuddingeSweden
  3. 3.Department of Pharmaceutical BiosciencesUppsala UniversityUppsalaSweden

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