2019A11 Describe the principles of how a computer-controlled infusion device
targets and maintains a constant effect site concentration of propofol.

 

List:

·      TCI basics

·      Compartment modelling

·      Induction

·      Maintenance

·      Offset

·      Model comparison

 

TCI basics:

Aim

·  Achieve target rapidly and with minimal overshoot

·  Maintain target with minimal variability

Device

·  Pump + syringe

·  User interface

·  Microprocessor

Set up

·  Enter patient age, weight +/- height, sex

·  Enter desired Cpt or Cet (usually 1-8mcg/mL)

Functioning

·  Initial loading dose

·  Continuous infusion with q10 second rate adjustment

·  Desired concentration reached within 30-60 seconds

·  Rate increase: further bolus then increased infusion rate

·  Rate decrease: pause then decreased infusion rate

·  Allow overshoot and undershoot of Cpt if targeting Cet

Graph

 

TCI compartment modelling:

Diagramme

Cp (V1)

·  Small number of healthy volunteers

·  Propofol infusion at various rates for various duration

·  Serial blood sampling -> chromatography

·  Plot Cp vs time

·  Non-linear regression analysis -> tri-exponential decay curve, rate constants, compartment volumes

Ce (Ve)

·  Cannot measure directly

·  Derived from relationship between Cp and EEG data

·  Comprises:

o Time for Cp-Ce equilibration (some delay)

§ i.e. pharmacobiophasics: Ce/dt = k1eCp – ke0Ce

o Time for drug-receptor interactions (minimal delay)

§ i.e. pharmacodynamics: E = E0 + (Emax x Ceγ) / (EC50 + Ceγ)

Limitations

·  Fundamental oversimplification of body composition

·  Inability to measure Ce

·  Inaccuracy at induction

·  Inaccurate estimates of lean weight

·  Kinetic variability: e.g. blood volume

·  Dynamic variability: e.g. receptor polymorphism

·  Processor maximum rate 1200mL/h

 

Induction:

TCI induction kinetics

·   Poorly modelled

·   Loading dose = Cpt x VDC

·   At 70kg, VDC 0.45L/kg, Cpt 4mcg/mL, dose = 126mg

·   Infusion rate (Q) max 1200mL/h in most machines

Alternative induction kinetics

Time to LOC peak Cp / time to peak Cp

 

(A) Peak Cp

·   Dose size

·   Speed of injection

·   1/Cardiac output

·   1/Central blood volume (Central blood volume total blood volume)

·   Speed and extent of recirculatory second peak (important if bolus is slow)

(B) Time to peak Cp

·   1/Cardiac output (note contradictory effects of cardiac output)

·   1/Distance from injection site to heart

 

Maintenance:

 

·   Q distribution x metabolism

Early

·   Early: high Q e.g. 100mL/h (distribution +++ metabolism ++)

Later

·   Later: slow Q e.g. 50mL/h (metabolism ++ distribution +)

Steady state

·   Steady state: Css (mg/mL) = infusion rate (mg/min) / clearance (mL/min)

 

Offset:

Distribution phase

·   Cpt 1/(distribution x metabolism); rapid ↓Cpt

Terminal elimination phase

·   Cpt redistribution/metabolism; slower ↓Cpt

Modelling

·   Multi-exponential decay curve (C = Ae-at + Be-bt + Ge-gt)

Emergence

·   Estimated to occur at ~1mcg/mL

·   Highly variable

 

Model comparison:

 

Marsh

Schnider

Inputs

(Age >16 as a qualifier)

Total mass

Age

Sex

Total mass

Height

Fixed

Rate constants

ke0 (0.26 or 1.2)

V1 (4.27L), V3 (230L)

k13, k31

ke0 (0.456)

Variable

Volumes (by total mass)

At 70kg: V1=16L, V2=30L, V3=230L

V2 (at 70kg: 32L), k12, k21 (by age)

k10 (by height, total mass, lean mass)

Better setting

Plasma target (loading dose not too big)

Effect target (loading dose not too small)