A physiological model of inA physiological model of induction of anaesthesia witduction of anaesthesia wit

h propofol in sheep.h propofol in sheep.

Jinfei YuJinfei Yu05/31/200605/31/2006

R. N. Upton and G. L. LudbrookR. N. Upton and G. L. Ludbrook

SignificanceSignificance

• Dose regimens —— to minimize adverse Dose regimens —— to minimize adverse effects by matching the dose and injection effects by matching the dose and injection rate.rate.

• Time courses of therapeutic and adverse Time courses of therapeutic and adverse effects —— closely related to time courses effects —— closely related to time courses of the drug concentrations in blood.of the drug concentrations in blood.

• Old models —— lack of a physiological Old models —— lack of a physiological basis.basis.

Goal of this paperGoal of this paper

• To develop a physiologically realistic moTo develop a physiologically realistic model of the kinetics and dynamics of indudel of the kinetics and dynamics of induction of anaesthesia with propofol.ction of anaesthesia with propofol.

Overview of the modelOverview of the model

Moderately-perfused

Poorly-perfused

Overview of the modelOverview of the model

Linear relationship

Overview of the modelOverview of the model

Validation of the modelValidation of the model

●: measured data

---: upper and lower 95% confidence limits

―: predicted data by model

Ater

ial c

once

ntra

tion

(mg/

L)B

rain

con

cen

trati

on

(m

g/L

)

Low CO

Normal CO

High CO

Low CO

Normal CO

High CO

Bolus: 200mg, 20sAt

eria

l con

cent

ratio

n (m

g/L)

Bra

in c

on

cen

trati

on

(m

g/L

)

Low CONormal COHigh CO

Low CO

Normal CO

Infusion: 200mg, 5 min

High CO

Quick Bolus VS Slow Quick Bolus VS Slow InfusionInfusion

Effect of injection Effect of injection raterate

80

90

100

110

120

130

140

150

0 2 4 6 8 10

Duration of administration (min)

Dos

e (m

g)

0

2

4

6

8

10

12

0 2 4 6 8 10

Duration of administration (min)

Tim

e to

pea

k c

once

ntr

atio

n (m

in)

0

5

10

15

20

25

30

0 2 4 6 8 10Duration of administration (min)

Pea

k a

rter

ial

con

cen

trat

ion

(m

g/L

)

Brain

Artery

――2mg/L constant peak 2mg/L constant peak brain concentrationsbrain concentrations

Effect of injection rateEffect of injection rate―100 mg constant dose―100 mg constant dose

20s30s

1min

2min

3min

4min

5min

20s

30s

1min

2min3min

4min

5minAt

eria

l con

cent

ratio

n (m

g/L)

Bra

in c

on

cen

trati

on

(m

g/L

)

Given dose: 100 mg

Effect of injection rateEffect of injection rate―stop infusion at 2 mg/L brain ―stop infusion at 2 mg/L brain concentration by titrationconcentration by titration

0. 4

0. 5

0. 6

0. 7

0. 8

0. 9

1

1. 1

0 50 100 150 200

Infusion rate (mg/min)

Tot

al d

ose

(%)

End of infusion

200 mg/min

100 mg/min

50 mg/min

Bra

in c

on

cen

trati

on

(m

g/L

)

0

2

4

6

8

10

12

14

16

18

20

0 50 100 150 200

Infusion rate (mg/min)

An

aest

hes

ia t

ime

(min

)

ConclusionConclusion

• Faithful——every aspect of the model validated Faithful——every aspect of the model validated extensively against published extensively against published in vivoin vivo data set. data set.

• Not intuitive——highly dependent on estimatioNot intuitive——highly dependent on estimation of the large number of parameters comprisinn of the large number of parameters comprising the model. g the model.

• Valuable tool for designing induction of anaestValuable tool for designing induction of anaesthesia with propofol in humans.hesia with propofol in humans.

ReferenceReference

• 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: 764-772.

• 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: 497-504.

• 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: 505-513.

Structural analysis of Structural analysis of modelmodel

AnalysisPeak arterial

(mg/L)

Peak brain

(mg/L)

Onset time

(min)

Duration

(min)Bolus

Normal 39.33 4.07 1.14 12.55No recirculation 39.17 2.47 1.45 4.04No hepatic clearance 39.33 4.15 1.13 15.06

InfusionNormal 9 3.66 3.48 12.5No recirculation 5.95 2.77 3.83 5.94No hepatic clearance 9.39 3.80 3.47 15.44