A physiological model of induction of anaesthesia with propofol in sheep. Jinfei Yu 05/31/2006 R. N. Upton and G. L. Ludbrook

Significance Dose regimens —— to minimize adverse effects by matching the dose and injection rate. Dose regimens —— to minimize adverse effects by matching the dose and injection rate. Time courses of therapeutic and adverse effects —— closely related to time courses of the drug concentrations in blood. Time courses of therapeutic and adverse effects —— closely related to time courses of the drug concentrations in blood. Old models —— lack of a physiological basis. Old models —— lack of a physiological basis.

Goal of this paper To develop a physiologically realistic model of the kinetics and dynamics of induction of anaesthesia with propofol. To develop a physiologically realistic model of the kinetics and dynamics of induction of anaesthesia with propofol.

Overview of the model Moderately- perfused Poorly- perfused

Overview of the model Linear relationship

Overview of the model

Validation of the model ● : measured data ---: upper and lower 95% confidence limits ―: predicted data by model

Aterial concentration (mg/L) Brain concentration (mg/L) Low CO Normal CO High CO Low CO Normal CO High CO Bolus: 200mg, 20s Aterial concentration (mg/L) Brain concentration (mg/L) Low CO Normal CO High CO Low CO Normal CO Infusion: 200mg, 5 min High CO Quick Bolus VS Slow Infusion

Effect of injection rate Brain Artery ―2mg/L constant peak brain concentrations

Effect of injection rate ―100 mg constant dose 20s 30s 1min 2min 3min 4min 5min 20s 30s 1min 2min 3min 4min 5min Aterial concentration (mg/L) Brain concentration (mg/L) Given dose: 100 mg

Effect of injection rate ―stop infusion at 2 mg/L brain concentration by titration End of infusion 200 mg/min 100 mg/min 50 mg/min Brain concentration (mg/L)

Conclusion Faithful —— every aspect of the model validated extensively against published in vivo data set. Faithful —— every aspect of the model validated extensively against published in vivo data set. Not intuitive —— highly dependent on estimation of the large number of parameters comprising the model. Not intuitive —— highly dependent on estimation of the large number of parameters comprising the model. Valuable tool for designing induction of anaesthesia with propofol in humans. Valuable tool for designing induction of anaesthesia with propofol in humans.

Reference Upton RN, A model of the first pass passage of drugs from i.v. injection site to the heart ―parameter estimates for lignocaine in the sheep, British Journal of Anaesthesia 1996, 77: Upton RN, Ludbrook GL, A physiological model of induction of anaesthesia with propofol in sheep. 1. Structure and estimation of variables, British Journal of Anaesthesia 1997, 79: Ludbrook GL, Upton RN, A physiological model of induction of anaesthesia with propofol in sheep. 2.Model analysis and implications for dose requirements, British Journal of Anaesthesia 1997, 79:

Structural analysis of model Analysis Peak arterial (mg/L) Peak brain (mg/L) Onset time (min) Duration (min) Bolus Normal No recirculation No hepatic clearance Infusion Normal No recirculation No hepatic clearance