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:

·  Simplification of body composition

·  Failure to model intravenous induction

·  Inability to measure Ce

Logistical:

·  Processor maximum rate 1200mL/h

·  Inability to identify line disconnection

Kinetic:
Inaccurate estimates of:

·  V1: ∝ blood volume (↑ in pregnancy, ↓in haemorrhagic shock)

·  V2: ∝ musculature (↑ in athletes)

·  V3: ∝ adiposity (↑in obese)

·  Inter-compartmental rate constants: ∝ cardiac output (↓ in shock)

·  Elimination rate constant: ∝ clearance (↓ in liver failure)

Dynamic:

Highly variable Cp50:

·  Receptor polymorphism

·  Use of adjuvants

 

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 only as a qualifier)

Weight (adjust in obesity)

Age

Sex

Height          Calculates lean mass

Weight

Fixed

Rate constants

ke0 (0.26 or 1.2)

V1, V3

k13, k31

ke0 (0.456)

Variable

Volumes (by total mass)

V2, k12, k21 (by age)

k10 (by age, lean mass)

Compartment sizes (at 70kg)

V1 16L

V2 30L

V3 230L

V1 4.27L

V2 32L

V3 230L

Induction dose

Much higher

Much lower

Maintenance rate

Bit higher

Bit lower

Better setting

Plasma target
(loading dose not too big)

Effect target
(loading dose not too small)

Better patient

Young + robust

Old + frail

 

 

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