Anaesthesia & Intensive Care Medicine Volume 14 issue 3 2013 [doi 10.1016%2Fj.mpaic.2013.01.006]...

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Total intravenousanaesthesiaChristopher Hawthorne

Nick Sutcliffe

Abstract Driven by better understanding of the pharmacokinetic principles

involved and improvements in infusion pump technology, total intrave-

nous anaesthesia (TIVA) has become more popular and has many poten-

tial advantages. Safe and effective use of TIVA requires the practitioner to

have a sound understanding of the pharmacokinetics involved and the

pharmacokinetic behaviour of many drugs can be described by a three-

compartment model. Mathematical modelling can be used to calculate

the blood and theoretical effect-site concentrations of anaesthetic

drugs for a given dosing regimen. Following consideration of the three-

compartment model, manual regimes were developed to permit TIVA,

but such regimes were insufficiently flexible to provide adequate anaes-

thesia for all patients in all circumstances. Target controlled infusion

(TCI) systems are computerized infusion systems capable of delivering

variable infusion regimes based on a complex mathematical solution to

the pharmacokinetic models. Such systems allow the anaesthetist to

achieve and maintain any desired target drug concentration appropriate

to an individual patient and level of surgical stimulation. TCI systems

have facilitated the increased use of TIVA over the past decade such

that this technique has become ‘mainstream’ throughout much of the

world.

Keywords Effect-site; pharmacokinetics; propofol; target controlled

infusion; three-compartment model; total intravenous anaesthesia

Royal College of Anaesthetists CPD Matrix: 1A02, 2A10

While intravenous induction of anaesthesia became widespread

following the discovery of barbiturates in the 1930s, maintenance

of anaesthesia using intravenous agents has only recently

become commonplace. Prior to the discovery of propofol in the

1970s, the intravenous hypnotic agents available were unsuitable

for maintenance of anaesthesia due to an undesirable pharma-

cokinetic profile (prolonged context sensitive half life), side-

effects or toxicity. However, a better understanding of the

pharmacokinetic principles involved, coupled with discovery of

the shorter-acting opioid analgesic agents such as alfentanil and

remifentanil, and improvements in infusion pump technology

facilitated development during the 1980s and 1990s of the tech-

nique of total intravenous anaesthesia (TIVA). TIVA, whereby

anaesthesia is administered exclusively via the intravenous route

has many potential advantages (Table 1).

Pharmacokinetics of drug delivery

Safe and effective use of TIVA requires the practitioner to have

a sound understanding of the pharmacokinetics involved.

Following intravenous administration of a drug, the drug issimultaneously subjected to dilution, elimination and distribu-

tion. The pharmacokinetic behaviour of many drugs can be

described by a three-compartment model (Figure 1), but it must

be understood that such compartments correspond to neither

anatomic boundaries nor organs, but are a theoretical construct.

It is inherent, however, that the blood volume lies within the

central compartment.

An intravenous drug is administered directly to the central

compartment; from this central compartment, the drug is redis-

tributed to peripheral compartments. Simultaneously, drug is

eliminated from the central compartment by metabolism and

excretion so it can be appreciated that, if the theoretical volumes

of the compartments are known, and the rates at which drugmoves between compartments can be determined, then mathe-

matical modelling can be used to calculate the drug concentra-

tion in the central compartment.

The administration of a bolus dose of a drug results in a peak

(central compartment) concentration, which then decreases

rapidly with time as the drug is redistributed into the peripheral

compartments. Although such a rapid onset of action is desirable

for the induction of anaesthesia with an intravenous agent,

recovery of consciousness would be rapid without some form of

maintenance. Repeated single bolus doses can be used to main-

tain a drug’s effect, but it is easy to understand how such ‘peaks

and troughs’ in drug concentration can result in both toxic and

subtherapeutic effects.When drugs are given by infusion at a constant rate, a steady-

state drug concentration can be achieved, but to achieve such

stability, a considerable time period is required. For instance,

propofol would have to be infused for more than 24 hours to

achieve steady state; a time frame clearly unsuitable for induc-

tion of anaesthesia! For many drugs used in anaesthesia, the

central compartment is not their site of action. Hypnotic anaes-

thetic drugs exert their clinical effects on the brain, and it is the

concentration at this ‘effect-site’, not the plasma concentration,

that is responsible for anaesthetic effect. The addition of this

fourth ‘effect-site’ compartment to the three-compartment model

(Figure 1), complete with a rate constant (ke0) for movement of

Learning objectives

After reading this article, you should be able to:

C describe what happens to a drug following intravenous

administration

C appreciate the potential advantages of total intravenous

anaesthesiaC understand the principles of target controlled infusion

Christopher Hawthorne MBChB FRCA is a Clinical Research Fellow at the

University of Glasgow, UK. Conflicts of interest: none declared.

Nick Sutcliffe BSc MBChB MRCP FRCA is a Consultant Anaesthetist at the

Golden Jubilee Hospital, Clydebank, UK. Conflicts of interest: in the

past, received honoraria from GSK, AZ, Braun and GE.

PHARMACOLOGY

ANAESTHESIA AND INTENSIVE CARE MEDICINE 14:3 129 2013 Elsevier Ltd. All rights reserved.

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drug into and out of the compartment, allows the expected timecourse of any clinical effect to be modelled.

TIVA via manual regimens

By consideration of the three-compartment model the ‘BET’

(bolus, elimination, transfer) scheme was developed dictating

that to achieve TIVA three components would be required:

an initial bolus (B) dose e to ‘fill’ the central compartment

(and provide rapid induction of anaesthesia)

a constant final infusion rate e maintaining central

compartment concentration by matching the elimination

(E) of drug once redistribution is complete and drug

concentrations in peripheral and central compartments

have equilibrated

an interim infusion rate e maintaining central compart-

ment concentration by matching the rates of transfer (T) of

drug from central to peripheral compartments.

In 1988, Roberts et al.1 proposed such a regimen for the delivery

of propofol anaesthesia. This regimen consists of a bolus of

1 mg/kg followed by an infusion of 10 mg/kg/hour for 10 minutes,

reducing to 8 mg/kg/hour for a further 10 minutes, followed byan infusion of 6 mg/kg/minute for the duration of the surgery. It

is designed to achieve rapidly and maintain a steady-state plasma

propofol concentration of around 3 mg/ml.

Unfortunately, this regimen fails to provide adequate anaes-

thesia for all patients in all circumstances, risking excessive

doses in some and proving inadequate in others. Subtle phar-

macokinetic and pharmacodynamic variability between patients

dictate the clinical effect of any given drug concentration and

these differences, coupled with the need to vary depth of

anaesthesia to combat changing levels of surgical stimulation,

necessitate the ability to quickly and reliably titrate drug

concentration to effect.

Target controlled infusion

Target controlled infusion (TCI) systems are computerized infu-

sion systems capable of delivering variable infusion regimens

based on a complex mathematical solution to the pharmacoki-

netic models. These allow the anaesthetist to achieve and to

maintain any desired target drug concentration appropriate to an

individual patient and level of surgical stimulation. After entering

patient factors such as weight and age into the system, the

anaesthetist can select, and when necessary adjust, the ‘target’

drug concentration (Figure 2). This target can be either the

plasma or the effect-site concentration.

Effect-site TCI

As can been seen from Figure 2a, the delay for equilibration of

the effect-site concentration means that, although TCI delivers

rapid stepwise changes in blood concentration, the anaesthetic

effect on the patient is somewhat delayed. In clinical practice,

this can be ameliorated by selecting an initial high blood target

and thus ‘over-pressuring’ the system to achieve a rapid induc-

tion, before reducing the target to a maintenance value. This is

achieved automatically by adjusting the TCI algorithm in order to

target an effect-site concentration. This method allows the blood

concentration to rise transiently above the (effect-site) target

value during an increase in target and below the target during

Theoretical benefits of TIVA

Advantages of TIVA Comment

Separates provision of anaesthesia from ventilation Provides predictable anaesthesia in shared airway cases

Reduced incidence of PONV Well-demonstrated reduction in PONV e may even have antiemetic effects

Reduced atmospheric pollution Compared to volatile e both the local and general environment

Rapid, clear-headed recovery Of particular value in a day surgery setting

Easily titrated with TCI Allows rapid and predictable adjustments to depth of anaesthesia

Safe in malignant hyperthermia No reports of MH with propofol

Preservation of hypoxic pulmonary vasoconstriction Theoretical improvement in oxygenation during one-lung anaesthesia

Reduction in intracerebral pressure Reductions in cerebral metabolic rate and blood flow

resulting overall in reduced ICP

Little evidence of organ toxicity Liver, kidney and genetic damage seen with volatile anaesthetics

PONV, postoperative nausea and vomiting; MH, malignant hyperthermia; ICP, intracranial pressure; TCI, target controlled infusion; TIVA, total intravenous anaesthesia.

Table 1

Three-compartment model

Effect siteDrug input

Elimination

Central

compartment

C1

Peripheral

compartment

C2

Peripheral

compartment

C3

Figure 1

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a decrease in selected target concentration (Figure 2b). This will

result in more rapid changes in anaesthetic depth compared with

using the same pharmacokinetic model for plasma targeted TCI.

The apparent variation in effect-site equilibration seen between

subjects may, however, lead to problems with this dosing

strategy; there are very little published data concerning effect-site

TCI. It is also important to recognize that the transient peaks inplasma drug concentration caused by the selection of an effect-

site target may themselves have undesirable cardiovascular

effects.

New models and equipment

Following the introduction of the ‘Diprifusor’, there was just one

pharmacokinetic model available (Marsh2) for TCI of Diprivan

1% and 2%. Syringe tag recognition avoided drug errors with

both concentration and type of drug, but with the advent of open

TCI, we have gained the flexibility of TCI for a number of drugs

as well as different models for propofol, but we have lost the

safety features of syringe tag recognition and created confusionaround the different pharmacokinetic models available for

propofol.

Most open TCI systems provide the option of either the Marsh

or Schnider3 models for propofol and offer either plasma or

effect-site mode in adults. The Marsh model adjusts compart-

ment volumes based only on total body weight which means

there is the potential to overdose both obese patients and the

elderly. In practice, this can be corrected by selecting a reduced

weight in the obese and a slightly lower target in the elderly. The

Schnider model has the theoretical advantage of adjusting for the

covariates of age, gender and height as well as body weight.

However, the central compartment volume is fixed at 4.3 litres

which means that the Schnider model is not suitable for plasma

targeted TCI. There are also problems with the calculation of leanbody mass and complexities around dosing in effect-site targeted

TCI making the Schnider model unsuitable for use in obese

patients. Anaesthetists should therefore use the TCI system with

which they have most experience and always titrate to clinical

effect. Particular care should be taken in patient populations

outwith those from whom the models were derived.

Opioids

Opioids are a key component of intravenous anaesthesia. Their

ability to control the physiological responses to noxious stimuli

makes them an essential part of any balanced anaesthetic

technique.

The shorter-acting fentanyl derivatives are particularly suitedto use as part of a TIVA technique and TCI systems are now

available for alfentanil, sufentanil and remifentanil. Similar to

the benefits of TCI propofol over manual infusions, these systems

provide advantages in stability of effect and ease of titration

when compared to manual infusions or intermittent bolus tech-

niques. Their major limitation is the need to provide longer-

acting alternative analgesia before the infusion is discontinued.

This is particularly true of remifentanil, which has established

a position as ‘drug of choice’ for TIVA largely owing to its

‘ultrashort’ duration of action and context insensitive half life;

conferring rapid and predictable offset of effects. A

REFERENCES

1 Roberts FL, Dixon J, Lewis GTR, Tackley RM, Prys-Roberts C.

Induction and maintenance of propofol anaesthesia. Anaesthesia

1988; 43: 14e7.

2 Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven

infusion of propofol in children. Br J Anaesth 1991; 67: 41e8.

3 Schnider TW, Minto CF, Gambus PL, et al. The influence of method of

administration and covariates on the pharmacokinetics of propofol in

adult volunteers. Anesthesiol 1998; 88: 1170e82.

FURTHER READING

Absalom A, Struys MMRF. An overview of TCI & TIVA. 2nd edn. Gent:Academia Press, 2006.

Absalom AR, Mani V, De Smet T, Struys MM. Pharmacokinetic models for

propofoledefining and illuminating the devil in the detail. Br J Anaesth

2009; 103: 26e37.

White PF. Textbook of intravenous anaesthesia. 1st edn. Baltimore: Wil-

liams & Wilkins, 1997.

Figure 2

PHARMACOLOGY


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