CLINICAL ANAESTHESIA

Total intravenous
anaesthesia

Learning objectives
After reading this article, you should be able to:
C
appreciate the potential advantages of total intravenous
anaesthesia
C
describe what happens to a drug following intravenous
administration
C
understand the principles of target controlled infusion.

Ben Shelley
Nick Sutcliffe

Abstract
Driven by better understanding of the pharmacokinetic principles involved
and improvements in infusion pump technology, total intravenous
anaesthesia (TIVA) has become more popular and has many potential
advantages. Safe and effective use of TIVA requires the practitioner to
have a sound understanding of the pharmacokinetics involved. 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 anaesthesia 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.

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 is simultaneously subjected to dilution, elimination and distribution. 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
redistributed to peripheral compartments. Simultaneously, drug
is eliminated from the central compartment by metabolism and
excretion. It can be appreciated that, if the theoretical volumes of
the compartments are known, and the rates at which drug moves
between compartments can be determined, then mathematical
modelling can be used to calculate the drug concentration 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 maintain a drugs 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 steadystate drug concentration can be achieved. To achieve such
stability, however, 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 induction of anaesthesia! For many drugs used in anaesthesia, the central compartment is not their site of action.
Hypnotic anaesthetic 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 a fourth effect-site compartment to the threecompartment model (Figure 1), complete with a rate constant
(ke0) for movement of drug into and out of the compartment,
allows the expected time course of any clinical effect to be
modelled.

Keywords Effect site; pharmacokinetics; propofol; target controlled

infusion; three-compartment model; total intravenous anaesthesia

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 pharmacokinetic profile (prolonged context sensitive half life), sideeffects 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 technique of total intravenous anaesthesia (TIVA). TIVA, whereby

Ben Shelley MBChB DipPaed 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 and Clinical
Director of Anaesthesia at the Golden Jubilee Hospital, Clydebank, UK.
Conflicts of interest: in the past, received honoraria from GSK, AZ, Braun
and GE.

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CLINICAL ANAESTHESIA

Theoretical benefits of TIVA

Advantages of TIVA
Separates provision of anaesthesia from ventilation
Reduced incidence of postoperative nausea
and vomiting
Reduced atmospheric pollution
Rapid, clear-headed recovery
Easily titrated with TCI
Safe in malignant hyperthermia
Preservation of hypoxic pulmonary vasoconstriction
Reduction in intracerebral pressure
Little evidence of organ toxicity

Comment
Provides predictable anaesthesia in shared airway cases.
Well-demonstrated reduction in PONV e may even have antiemetic effects.
Compared to volatile e both the local and general environment.
Of particular value in a day surgery setting.
Allows rapid and predictable adjustments to depth of anaesthesia.
No reports of MH with propofol.
Theoretical improvement in oxygenation during one-lung anaesthesia.
Reductions in cerebral metabolic rate and blood flow resulting overall in reduced ICP.
Liver, kidney and genetic damage seen with volatile anaesthetics.

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

Table 1

TIVA via manual regimens

infusion of 6 mg/kg/min 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 anaesthesia for all patients in all circumstances, risking excessive
doses in some and proving inadequate in others. Subtle pharmacokinetic and pharmacodynamic variability between patients
dictate the clinical effect of any given drug concentration. These
differences coupled with the need to vary depth of anaesthesia to
combat changing levels of surgical stimulation necessitate the
anaesthetist to have the ability to quickly and reliably titrate drug
concentration to effect.

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:
1. An initial bolus (B) dose e to fill the central compartment
(and provide rapid induction of anaesthesia);
2. 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;
3. An interim infusion rate e maintaining central compartment
concentration by matching the rates of transfer (T) of drug
from central to peripheral compartments.
In 1988, Roberts et al1 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 min,
reducing to 8 mg/kg/hour for a further 10 min, followed by an

Target controlled infusion

Target controlled infusion (TCI) systems are computerized infusion systems capable of delivering variable infusion regimens
based on a complex mathematical solution to the pharmacokinetic models. This allows 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 is then able to select and when necessary adjust the
target drug concentration (Figure 2). This target can be either
the plasma or the effect-site concentration.

Three-compartment model
Drug input

Effect site

Effect-site TCI
Peripheral
compartment
C2

Central
compartment
C1

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 induction, before reducing the target to a maintenance value. This can
be achieved automatically by adjusting the TCI algorithm in
order to target an effect-site concentration. The system then
allows the blood concentration to rise transiently above the
(effect-site) target value during an increase in target and below
the target during a decrease in selected target concentration

Peripheral
compartment
C3

Elimination
Figure 1 Demonstrating handling of drug delivered to the central
compartment. A fourth effect-site compartment has been added
(dashed lines) to the traditional three-compartment model.

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CLINICAL ANAESTHESIA

New models and equipment

Initially, with the introduction of the Diprifusor, there was 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. 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 confusion
around the different pharmacokinetic models available for
propofol. A discussion of these models is beyond the scope of
this article, but the reader should be aware that prescribing
information and efficacy and safety data are only available for
TCI with the Marsh model in plasma control.

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
suited to use as part of a TIVA technique. TCI systems are now
available for alfentanil, sufentanil and remifentanil. Similarly 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 techniques. Their major limitation is the need to provide longeracting 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

Figure 2 Simulated changes in plasma propofol concentration and infusion rate during target controlled infusion e a; effect-site targeted TCI e
b. a The anaesthetist selects an initial target concentration (A), and the
control software then calculates and delivers a rapid infusion (essentially
a bolus) to achieve this target plasma concentration (red line), followed
by a constantly adjusting infusion regimen calculated to maintain the
target concentration. If a new higher target concentration is chosen (B),
the system will deliver a further rapid infusion followed by a new infusion
regimen. If a lower concentration is chosen (C), the control software will
stop the infusion until the new target concentration has been achieved
after which the system will control the infusion rate to maintain the new
target concentration. The effect-site concentration (green line) can be
seen to lag behind the plasma concentration. b Comparison should be
made with part a. Under effect-site control (with exactly the same targets
as in a) the desired effect-site concentration (green line) is more rapidly
achieved: A and B with the plasma concentration (red line) significantly
overshooting the target; C with the plasma concentration transiently
falling below the target.

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.
FURTHER READING
Absalom A, Struys MMRF. An overview of TCI & TIVA. 2nd edn. Gent:
Academia Press, 2006.
White PF. Textbook of intravenous anaesthesia. 1st edn. Baltimore:
Williams & Wilkins, 1997.

(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 is very little published data
concerning effect-site TCI. It is also important to recognize that
the transient peaks in plasma drug concentration caused by the
selection of an effect-site target may themselves have undesirable
effects.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:4

Acknowledgement
Figure 2a and b was produced using the Tivatrainer software. A
free trial of this excellent educational resource is available for
download from www.eurosiva.org.

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2010 Elsevier Ltd. All rights reserved.