TIVA and TCI

Dr Jim Hoyle FRCA FFICM

Consultant in Neuroanaesthesia and Neuro Critical Care

1A02

S
 Objectives

1. Benefits and priniciples of TIVA 1A02

2. Pharmacokinetics
3. Manual vs. TCI TIVA
4. Schnider vs. Marsh
5. Weight
6. Future improvements
Why TIVA

S
 Benefits of TIVA

S Rapid recovery of consciousness and psychomotor function

S Earlier recovery and discharge from PACU

S Use with neurophysiological monitoring

S Anti-emetic benefits

S No adverse effects on theatre personnel or the environment

S No Malignant Hyperthermia

S Preserves Hypoxic Pulmonary Vasoconstriction

TIVA principles

S
TIVA anaesthesia requirements:

S Rapidly achieve an appropriate blood and brain concentration

of Propofol
S Maintain that concentration of Propofol
S Adjust the level as required

S Can use manual or automated infusions

S How achieved requires some knowledge of Propofol

pharmacokinetics
Pharmacokinetics

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3 Compartment Model

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• Drug injected into Central compartment V1
• Initial volume of distribution
• Comparable to ‘plasma’
• Redistribution into second compartment (V2)
• “vessel-rich” or “fast”
• Redistribution into third compartment (V3)
• “vessel-poor” or “slow”
• Governed by rate constant / concentration
gradient
• Exponential process
• Elimination
• Fixed rate
 Achieving a constant plasma
level

S Initial bolus quite easy to calculate

= Concentration x Volume of distribution (V1)

S Maintenance infusion rate more difficult

S Has to match rate of decline of plasma Propofol level

S Initially high rate due to rapid redistribution

S Reduces over time as V2 & V3 fill up

S Ultimately just matches elimination

 Manual infusions

S Fixed rate infusions take 5 half-lives to reach steady state -

up to 24 hours for Propofol
 Bristol regime

3 mcg/ml
But:

S Changes to infusion rate will not lead to changes in blood

concentration for some time

S Manual boluses have to be given to rapidly change depth

S Size of bolus has to be ‘guestimated’

S May result in excessive side effects or awareness

S TCI systems automate the whole process

 TCI

S Target Controlled Infusions

S Multi-compartment pharmacokinetic models used to

calculate infusion rate required to achieve the target
concentration.

S “open-loop” systems

S Comprised of a user interface, a microprocessor and an

infusion device
Alaris Asena® PK (Alaris Base Primea (Fresenius)
Medical Systems)
 How does it work?

S Models have sizes and rate constants for the various

compartments programmed in

S Allows pump to calculate rate of Propofol redistribution and

elimination at a given time

S Initial bolus to achieve rapid rise in plasma level

S 3 superimposed infusion rates to match the rate at which drug is

being removed from the central compartment
 How does it work?

S If user wishes to increase the plasma level then pump will

calculate and give a bolus

S If user wishes to decrease the level then the pump will stop
and allow the level to fall before restarting
Plasma vs Effect site
Targeting

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S The clinical effect of Propofol is related to brain
concentration = effect site

S With plasma targeting there is a lag between achieving the

plasma level and the brain level catching up

S Therefore lag in induction and lag in changing depth of

anaesthesia
Equilibrium between blood and effect-site depends on several
factors:
• Rate of drug delivery to effect-site
• Pharmacological properties of the drug
• Mathematically described by Keo time constant
• Concentration gradient

Only factor we can control is concentration gradient

 Time to peak effect (TTPE)

S After a bolus, maximum effect-site concentration occurs at

the point where the blood and effect-site concentration
curves cross
 Time to peak effect (TTPE)

S After a bolus, maximum effect-site concentration occurs at

the point where the blood and effect-site concentration
curves cross.

S Time delay between bolus and this point is known as the

“time to peak effect” TTPE

S Independent of size of bolus

S Propofol TTPE is 1.6 minutes

 Time to peak effect (TTPE)

S By knowing the Keo and TTPE it is possible to ‘target’ the effect-

site concentration

Nomenclature of TCI:

Ce = Effect site concentration

Cp = Plasma concentration

t suffix = ‘Target’ Cet / Cpt

 Effect Site Targeting

S System manipulates the blood concentration to achieve the

effect-site target as quickly as possible

S “over-pressures” blood concentration to produce gradient

that results in fastest rise in effect-site level yet preventing
any overshoot

S Faster induction; faster changes in depth of anaesthesia

 Which to use ?

S No evidence that one method better than the other

S I would suggest that effect-site TCI is easier to use and closer to

drug physiology

S When using plasma targeting, be aware of the lag and

‘overpressure’ as required

S With effect-site targeting, bigger bolus given per dose increase

which may effect haemodynamics
Manual or TCI?

S
 Evidence for Manual vs. TCI

Cochrane review in 2008

S Looked at results of 20 poor quality trials

S 1759 patients

S No significant difference in quality of anaesthesia or

adverse outcomes

S Couldn’t recommend one over the other

Propofol TCI Models
Marsh vs. Schnider

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2 available models for Propofol TCI in adults:
S Marsh
S Schnider
 Marsh Model

S Published in 1991

S Model employed in the original Diprifusor®

S Based on study of 3 groups of 6 patients

S Detailed demographics never published

S Weight is only variable

S Effects size of V1, V2 & V3

S Age entered but has no effect on model

S Unless < 16 in which case pump wont run
 Marsh Model

S A ‘modified’ Marsh model was published by Struys et al in

2000

S This uses a faster Keo

S Results in less overshoot and undershoot when using Marsh

effect-site targeting

S Model used in modern TCI systems

S But PK pumps only allow plasma targeting

 Schnider Model

S Published in 1998

S Based on 24 volunteers (11 women, 13 men)

S Uses age, height, weight, age and gender

S V1 fixed - 4.27 L
S V3 fixed - 238 L
S V2 variable of age
S Elimination uses weight, height & LBM

S Uses a TTPE of 1.6 minutes and calculates a Keo for each

individual patient
70 kg man Marsh Schnider
V1 15.9 L 4.27 L (f)

V2 32.4 L 24.0 L

V3 202 L 238 L (f)

K10 0.119 (f) 0.384

K12 0.112 (f) 0.375

K13 0.042 (f) 0.196

K21 0.055 (f) 0.067

K31 0.0033 (f) 0.0035

Keo 0.26 (f) 0.456 (f)

TTPE (min) 4.5 (f) 1.69 (f)

Main differences

S
1. Time To Peak Effect

S Schnider model has faster TTPE (1.6 vs 4.5 min)

S Less ‘overshoot’ and ‘undershoot’ with Schnider effect-site

targeting than with Marsh
S Net effect is less Propofol administered with Schnider vs.
Marsh in effect-site targeting
S Probably safer in elderly and compromised patients

But: PK pumps do not allow Marsh effect-site targeting!!

2. Size of central compartment

S Schnider has fixed V1 (4.27 L)

S Marsh is a function of weight (15.9 L for 70kg)

S Striking differences in estimated plasma and effect-site

concentrations in first 10 minutes after the bolus
2. Size of central compartment

One minute after bolus:

S Marsh Cp = 4 mcg/ml Ce = 0.9 mcg/ml
S Schnider Cp= 8.2 mcg/ml Ce = 3.6 mcg/ml

S Differences less significant after 10 minutes

S After 30 minutes both estimate the same levels

S Net effect is Schnider administers less Propofol

3. Age

S Well described age related changes in Propofol PK and PD

S Volume of central compartment reduces with increasing age

S EC50 decreases by 50% from 25 to 75 years

S Marsh model doesn’t account for age

S Schnider does
Weight
 Marsh model

S Uses total body weight (TBW)

S Will tend to overdose in obesity

S Ideal Body Weight (IBW) best for induction

But….

S Maintenance infusion rate is TBW variable

Servin formula:

IBW + 0.4 (TBW-IBW)

 Schnider model

S Uses lean body mass (LBM)

S User enters TBW and pump calculates LBM

LBM = 1.1 x weight - 128 x (weight/height)2

S Accurate up to BMI of 42 in men and 37 in women - then get
paradoxical decrease in LBM
 Schnider model

S Schnider model will only allow entry of TBW up to BMI of 42 in

men and 37 in women

S Janmahasatian formula has been suggested as a better calculator of

LBM
 Janmahasatian Formula

Male = [9270 x weight (kg)] / [6680+216 x BMI]

Female = [9270 x weight (kg)] / [8780+244 x BMI]

Remifentanil

S
 Minto model

S Minto model 1997

S 3 compartment model

S Weight, height, gender and age

S Uses LBM calculated from TBW

S Keo adjusted for age

S Plasma vs Effect site is less of an issue due to rapid equilibrium

between plasma and brain

S Takes less than 5 minutes

Reducing the risk of
awareness

S
 Preventing awareness

Awareness arises because:

S Failure to deliver the correct amount of the correct drug to
the correct patient at the correct time
S Can be human or equipment failure - or both!

S Certain steps can be taken to minimise the risks

S SALG October 2009:

“Guaranteeing Drug Delivery in Total Intravenous

Anaesthesia”
 Preventing awareness

1. Infusion pumps
S Maintained
S Appropriate alarms
S Deliver the drug how you want to deliver it
S You are competent and trained in their use

2. Drugs
S Correct drug in correct concentration in correct pump
S Appropriate model and dosing selected
 Preventing awareness

3. Anti-syphon valve on every drug line

4. One way valve on any fluid line administered with TIVA

 Preventing awareness

3. Anti-syphon valve on every drug line

4. One way valve on any fluid line administered with TIVA

5. IV cannula site visible throughout the case and checked at

regular intervals

6. Avoid muscle paralysis when possible

7. Use depth of anaesthesia monitoring!

The Future….

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 Improving TCI

1. Closed loop systems

S Depth of anaesthesia monitoring
S End tidal Propofol
S Clinical sensitivity to Propofol

2. Multi-drug models
 Summary

1. TIVA rocks
2. Effect-site targeting rocks
3. Use Schnider for effect-site targeting
4. Use Marsh for plasma targeting
5. IBW + ‘a bit’ for Marsh model
6. TBW for Schnider and Minto models
7. Use BIS……