Manual and Total Controlled Infusions

Total intravenous anaesthesia with propofol

• Propofol is a fast onset, short-acting intravenous anaesthetic
• Favourable pharmacokinetic properties allow accurate titration
• Suitable for both induction and maintenance of anaesthesia
• Propofol has a narrow therapeutic index (like most anaesthetics) which means it needs to be carefully administered
  • Underdosing will result in patient movement or awakening with possible recall
  • Overdosing can cause hypotension and respiratory depression
  • There is also evidence that excessive anaesthesia is bad for the brain – this applies to all anaesthetics
• Induction and maintenance of anaesthesia with propofol requires a bolus followed by a variable infusion to maintain an appropriate plasma level of propofol
• As there is significant interindividual variability in response to anaesthetics, titration is very important
  • Propofol TCI has a marked advantage over other anaesthetics in this regard
  • In adults, the plasma level (Cp) of propofol associated with sedation ranges from 0.5 – 2 mcg/ml and 1.5 – 3.5 mcg/ml for unconsciousness (anaesthesia)
  • Most studies suggest the median dose for anaesthesia is around 2.7 mcg/ml in healthy patients
  • Older and frailer patients may require significantly less
  • Propofol is NOT an analgesic and it is very important to use a powerful analgesic adjunct for surgical anaesthesia (e.g. remifentanil, alfentanil, regional block)
  • You only need to give enough propofol to produce loss of consciousness
  • Analgesia will be provided by your adjunct
  • If you only use propofol to produce surgical anaesthesia, you will require very large (excessive) doses which is not good for the patient
• Titration is the key to the safe delivery of intravenous anaesthesia

Manual Infusion

• This is called a time-variant system because the response to the same input varies with time
• Induction and maintenance of anaesthesia with propofol involves a loading dose followed by a variable infusion which needs to be adjusted according to the depth of anaesthesia required
• This is difficult, less accurate and less suitable for drugs with a narrow therapeutic range. Therefore, the use of processed EEG monitoring is advised
• When deepening of anaesthesia is required, a bolus dose with an increase in infusion rate is needed to raise the Cp
• Bristol manual infusion regime is an example which purports to produce a blood propofol concentration of 3 mcg/ml
  • Loading dose of 1 mg/kg followed by an immediate infusion of
  • 10 mg/kg/hour for 10 minutes
  • 8 mg/kg/hour for the next 10 minutes
  • 6 mg/kg/hour thereafter

Target controlled infusion (TCI)

• Computers and high-precision “smart” pumps have facilitated the development of target-controlled infusions (TCI) and these are readily available in most countries – except the USA! (Prof G Kenny says NIH = Not Invented Here)
• Complex pharmacokinetic models with multiple covariates are used. These represent diverse patient populations and incorporate features such as effect-site modelling to describe the time course of the pharmacodynamic effect in the brain
• These devices are similar in concept to using a vaporiser with inhalational drugs
  • You select a blood concentration in the same way as you would choose a vapour %
• They are time-invariant as the response to a change of target will be the same irrespective of the time at which the target is changed
• TCI systems are pre-programmed with pharmacokinetic data for a patient population
• The system determines the dose required to achieve and maintain a given blood or effect-site concentration based on a 3 compartment model, and will continuously adjust this
• The anaesthetist can then focus on the expected effect of the drug and the timing of the effect rather than the complex calculations required to produce it
• They are more accurate, less labour intensive and more intuitive and simple to use
• Recent models, such as the Eleveld, incorporate allometric scaling where adjustments are made for patient height, weight, sex and age

Developing TCI models

• Both non-population and population-based approaches can be used

Two-stage approach (traditional non-population methods)

• Small numbers of subjects intensively studied
• Sequential sample collection following bolus or infusion and the data is then used to construct a poly-exponential curve fitted to drug concentration vs. time
• Derived parameters from a group of subjects are averaged to create simple estimates of mean parameter values in that population
• TCI systems work the reverse way by using the PK model to calculate a drug dose
• Propofol models
  • Marsh
  • Schnider
  • Eleveld
  • Paedfusor
  • Kataria
• Remifentanil model
  • Minto
• Alfentanil
  • Scott
  • Maitre

Population pharmacokinetic methods

• These are based on a larger number of subjects
• Separately estimates fixed and random components
• Data is analysed as a population but patient individual identity is retained
• Parameters can be incorporated that influence PK, e.g. weight, age, sex
• The Eleveld Model is the latest example and has received favourable reviews

Open TCI systems

• TCI was initially restricted to proprietary drug preparations and pumps e.g. Diprifusor but these are rarely used now.
• Open TCI systems are smart pumps incorporating drug libraries with a choice of PK infusion models and a choice of drugs
• These systems allow non-tagged syringes containing generic drugs to be used