2019A Question 11
Describe the principles of how a computer-controlled infusion device targets and maintains a constant effect site concentration of propofol.
Examiner Report
28.2% of candidates achieved a pass in this question.
This question addresses a core pharmacology topic in anaesthesia. A good answer required a brief explanation of the principles of target-controlled infusions (TCI) and effect-site targeting of propofol.
A multi-compartment kinetic model for propofol is fundamental to understanding this question. The three-compartment model was frequently cited but the accompanying figures were often drawn incorrectly, particularly with respect to the effect site. In their discussion of the three-compartment model, many candidates mentioned drug distribution but then failed to apply this concept to the operation of TCI systems. Many answers discussed propofol TCI in terms of single-compartment kinetics, even after first presenting the multi-compartment model.
In basic terms, TCI devices deliver a variable-rate infusion to achieve and maintain a constant (calculated) target concentration. The initial component of the infusion is conceptualised as a bolus because it is rapid and brief. Importantly, bolus dose calculations are governed by the volume of the central compartment. Many answers failed to convey this point, while some answers incorrectly invoked the volume of distribution at steady state. Following the initial bolus, the ongoing infusion rate is calculated to take into account the loss of propofol from the central compartment due to both distribution and elimination. This results in an infusion rate that decreases over time (as long as the target concentration remains unchanged). There was a good deal of confusion in this area.
Good answers described the difference between plasma and effect-site targeting and correctly explained the concept of plasma overshoot.
Model Answer
Structure:
- TCI basics
- Compartment modeling
- Induction
- Maintenance
- Offset
- Model comparison
TCI Basics
| Property | Detail |
|---|---|
| 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 1-8μg/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
| Factor | Components |
|---|---|
| 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: - Time for Cp-Ce equilibration (some delay) - i.e. Pharmacobiophasics: ∆Ce/dt = k1eCp – ke0Ce - Time for drug-receptor interactions (minimal delay) - i.e. Pharmacodynamics: |
| 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)
- Highly variable Cp50: - Receptor polymorphism - Use of adjuvants |
Induction
| Property | Detail |
|---|---|
| TCI Induction Kinetics | - Poorly modeled - Loading dose = Cpt x VDC - At 70kg, VDC 0.45L/kg, Cpt 4μg/mL, dose = 126mg - Infusion rate (Q) max 1200mL/h in most machines |
| Alternative Induction Kinetics | 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) Time to peak Cp ∝: - 1/Cardiac output (note contradictory effects of cardiac output) - 1/Distance from injection site to heart |
Maintenance
| Phase | Detail |
|---|---|
| Formula | |
| Early | Early: High Q e.g. 100mL/h (distribution +++ metabolism ++) |
| Later | Later: Slow Q e.g. 50mL/h (metabolism ++ distribution +) |
| Steady state | Steady state: |
Offset
| Property | Detail |
|---|---|
| Distribution Phase | ; Rapid ↓ Cpt |
| Terminal Elimination Phase | Cpt ∝ Redistribution/metabolism; slower ↓ Cpt |
| Modeling | Multi-exponential decay curve () |
| Emergence | - Estimated to occur at ~1μg/mL - Highly variable |
Model Comparison
| Marsh | Schnider | |
|---|---|---|
| Inputs | Age (>16 only as a qualifier) Weight (adjust in obesity) |
Age Lean Body Mass: - Sex - Height - 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 |