PHARMACOLOGY

Principles of intravenous
drug infusion

Learning objectives
After reading this article, you should know that:
C
desired blood and effect-site drug concentrations can be achieved using a bolus, excretion and transfer (BET) dose regimen
C
pharmacokinetic simulation software can be used to drive infusion
pumps or to design manually controlled BET infusion regimens
C
recovery from the effects of prolonged infusions are best understood using context-sensitive decrement times
C
recovery times are determined by the concentrations achieved
as well as the dose history. Pharmacokinetic simulations help
clinicians to ascertain when to reduce or terminate infusions

Johan F Coetzee

Abstract
It is possible to establish and maintain targeted blood and effect-site drug
concentrations with reasonable accuracy using a bolus, elimination,
transfer (BET) infusion regimen. Simulation software that employs pharmacokinetic models can be used to drive infusion pumps or to design
manually controlled BET infusions. Prolonged infusions can result in prolonged recovery times. However, the elimination half-lives of infused lipid
soluble drugs have little or no relevance to rates of recovery because
elimination half-life does not take redistribution from peripheral compartments into account. A better method is to calculate the context-sensitive
decrement times (context-sensitive referring to the infusion duration).
These are not represented by a single number: they are a continuum of
time values that are a function of infusion duration and can be represented by a graph. Considering that decrement times depend on the concentrations achieved as well as the dose history, it is often difficult for
clinicians to anticipate a patients time to recovery. Pharmacokinetic simulation software continuously calculates and displays expected recovery
times, helping clinicians to ascertain when to reduce or terminate the
infusion.

Approximations of BET infusions comprise stepped-down,

constant infusions, as exemplified by the 10, 8 and 6 regimen
for propofol, intended to achieve blood concentrations of 3 mg/
ml. A 1.5 mg/kg loading dose is followed by an infusion of
10 mg/kg/hour that is reduced to rates of 8 and 6 mg/kg/hour at
10-minute intervals.
Target-controlled infusions by computer
Using a pharmacokinetic model, a computer continuously calculates the patients expected drug concentration and administers a BET regimen, adjusting pump speeds, typically at 10second intervals. By specifying appropriate target concentrations, the anaesthetist uses the device in a similar fashion to
a vaporizer. There are differences between predicted and actual
concentrations, but these are not of great consequence, provided the true concentrations are within the drugs therapeutic
window, within which the clinician may adjust the targeted
concentrations, according to patient response. Measured/
predicted errors of about 30% are clinically acceptable.
These devices simplify intravenous drug administration by
relieving the clinician of tedious calculations and by eliminating errors.
The advantages of BET and target-controlled infusions are
listed in Box 1. Anaesthetists need to associate blood drug concentrations with expected effects; for example, correlating alveolar partial pressures of inhaled anaesthetics to drug effect. The
concept of minimum effective plasma concentration (EC50) is
identical to that of minimal alveolar concentration (MAC) for
inhaled agents. Target-concentration guidelines for intravenous
drugs and drug combinations are available from standard textbooks. However, no single targeted concentration suits all patients. Patient pharmacokinetics and pharmacodynamics are
influenced by age, cardiac output, coexisting disease, smoking,
concurrent drug administration, body temperature and intensity
of noxious stimulation. These factors must be considered when
choosing target concentrations, and dose should be titrated according to clinical signs.
The first commercial target-controlled infusion device was the
Diprifusor (AstraZeneca), dedicated to propofol administration.
Newer systems can also administer remifentanil and sufentanil
as well as target the effect site. These devices can also operate in
tracking mode, when the anaesthetist operates the syringe

Keywords Anaesthesia intravenous methods; delayed emergence from

anaesthesia; infusions intravenous; infusion pumps
Royal College of Anaesthetists CPD Matrix: 1A02

Circulating drugs are removed by distribution to peripheral tissues, metabolism and excretion. Thus, bolus doses exert transient effects and repeated doses are required for continuous
effects. However, repetitive boluses produce peaks and troughs
in blood concentration and therefore varying effects. The most
efficient method of maintaining a desired drug effect is by
continuous infusion to achieve constant blood concentrations.

Achieving steady-state drug concentrations in blood

In 1968, Kruger-Theimer indicated how pharmacokinetic models
can be used to design efficient dose regimens. This bolus, elimination, transfer (BET) regimen (Figure 1) administers:
 a bolus dose calculated to fill the central (blood)
compartment
 a constant-rate infusion equal to the elimination rate
 an infusion that compensates for transfer to the peripheral
tissues: this initially rapid infusion declines asymptotically
towards the elimination rate as tissues absorb drug.

Johan F Coetzee BSc MbChB MMed (Anes) FCA(SA) PhD is Associate Professor of
Anaesthesiology at the University of Stellenbosch and Tygerberg Hospital, South Africa.

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PHARMACOLOGY

Advantages of BET dose regimens

C
Rapid achievement of desired blood concentrations
C
Avoidance of high peak concentrations that occur with a
manually delivered bolus and therefore a reduced risk of sideeffects
C
More accurate dosing and therefore:

Achieving a constant blood concentration of

propofol using a BET regimen

Infusion rate (g/kg/min)

200

150

Exponentially
declining
infusion rate






100
C

Bolus 0.75 mg/k g

C

15

30

45

60

75

90

105

120

Ability to maintain stable concentrations and therefore stable

effects
Ability to make proportional changes
Use is similar to that of a vaporizer; titrate to effect

Time (min)

Added advantages of computer-assisted BET infusions

C
Elimination of calculation errors
C
Compensation for any interruption to the infusion
C
Easy to assess the relationship between drug concentration
and effect
C
Display of effect-site concentrations
C
Prediction of time to recovery (context-sensitive decrement
time)
C
Ability to target the effect site (analogous to targeting endtidal partial pressures of volatile anaesthetics

4000

Concentration (ng/ml)

better haemodynamic control

reduced drug consumption
more rapid recovery
less postoperative depression

3000

2000

Blood
Effect site

1000

Box 1
0

15

30

45

60

75

90

105

120

Time (min)

computer control. Various pharmacokinetic simulator computer

programs, obtainable from the internet, enable anaesthetists to
use dosing regimens based on pharmacokinetic principles.
Various drugs and different pharmacokinetic parameter-sets can
be used (including those for paediatrics and patients in ICU).
Available software includes:
 TIVATRAINER (http://www.eurosiva.org)
 PKSIM
 RUGLOOP
 STANPUMP (http://www.anesthesia.stanford.edu/pkpd/)
 STELSIM (jfc@sun.ac.za).
The latter performs real-time simulations in the operating
room as efficiently as computer-controlled target-controlled
infusion. Figure 2 illustrates monitoring of a manually controlled
fentanyl infusion to estimate expected drug concentrations and
recovery times.

Computer simulation of propofol administered by a bolus,

elimination and transfer (BET) dose regimen to achieve and
maintain a constant blood concentration of 3 g/ml.
(a) Administration of a bolus dose at time zero, calculated to
establish the initial targeted concentration. This is followed by an
infusion, which is initially rapid and then declines asymptotically
to the maintenance rate. (b) The theoretial blood and effect-site
concentrations. Note how the effect-site concentrations lag
behind those in the blood.

Figure 1

pump manually. The pump software registers the doses and, by

using pharmacokinetic simulation, displays the concentrations
calculated and the expected time to recovery.

Recovery after intravenous infusions

Prolonged infusions can lead to prolonged recovery times. One
method for quantifying this phenomenon is to calculate the times
required for blood concentrations to decrease by a fixed fraction
after maintaining constant concentrations for various infusion
durations. These are termed context-sensitive decrement times
(context sensitive referring to the infusion duration) (Figure 3).

Target-controlled infusions by simulation

Target-controlled infusion devices are expensive and not universally available. Pharmacokinetic simulation software can be
used to develop manually adjusted BET infusion regimens that
approximate to the continuously changing infusions provided by

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PHARMACOLOGY

Monitoring a manually administered fentanyl infusion by simulation

a
Fentanyl concentration (ng/ml)

8
7

Plasma concentration

Effect-site concentration

Spontaneous
breathing

4
3
2
1
0
0

20

40

60

80

100

120

140

160

180

Time (min)

400

20
300
15
200

Spontaneous
breathing

10

100
5

Decrement time to 1.0 ng/ml (min)

Decrement time to 2.5 ng/ml (min)

25

Decrement time to
1.0 ng/ml
Decrement time to
2.5 ng/ml

0
0

20

40

60

80

100

120

140

160

180

Time (min)
The initial loading dose was 3 g/kg followed by an infusion of 5 g/kg/hour. After 60 minutes the infusion was reduced to 3.5 g/kg/hour for a further 60 minutes.

Figure 2

Propofol and sufentanil have context-sensitive half-times (50%

decrement times) that increase gradually with infusion duration.
In contrast, the context-sensitive half-times of thiopental, fentanyl and midazolam are markedly dependent on infusion duration
and become inordinately prolonged after infusions that last
longer than 1 hour. Clinically, 50% concentration decrements of
propofol and the three opioids often represent recovery from
moderate clinical effects; however, there are also circumstances
in which a 20% or an 80% plasma-concentration decrease is
required for recovery.
In Figure 3, conservative dosing, achieving blood concentrations that require only 20% decrements for recovery, leads
to rapid recovery times, even after prolonged infusions. In
contrast, when large concentration decrements are required for
recovery (80%), context-sensitive recovery times show steep
increases even after brief infusions. Figure 3 illustrates that
sufentanil is a good choice for opioid administration by

ANAESTHESIA AND INTENSIVE CARE MEDICINE 16:12

infusion, because it has short, predictable context-sensitive

half-times. Remifentanil is rapidly hydrolysed by tissue esterases so that the 50% and 80% context-sensitive decrement
times are 3 and 12 minutes, regardless of infusion duration
because there is virtually no accumulation of drug in peripheral
compartments.
The rate at which drug concentration decreases after an
infusion is determined by the rate at which it is irreversibly
removed from the body, as well as the rate of redistribution to
peripheral tissues. Therefore, recovery after an infusion has little
relevance to the elimination half-life of a drug because the
elimination half-life does not take redistribution into account. For
example, propofol and sufentanil have long elimination half-lives
but short context-sensitive half-times. Note that context-sensitive
decrement times are not represented by a single number: they are
a continuum of time values that are a function of infusion
duration and can be represented by a graph.

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PHARMACOLOGY

Considering that decrement times depend on the concentrations achieved as well as the dose history, it is often difficult for
clinicians to anticipate a patients time to recovery. Pharmacokinetic simulations continuously calculate and display expected
recovery times, helping clinicians to ascertain when to reduce or
terminate the infusion.
Figure 2 illustrates that by maintaining moderate fentanyl
concentrations (e.g. 3e4 ng/ml to supplement 0.6e0.8 kPa
end-tidal isoflurane [fentanyl, 1.67 ng/ml, reduces the MAC of
isoflurane by 50%]), it is possible to achieve a reasonably short
recovery time to concentrations at which spontaneous breathing occurs (2e3 ng/ml). This simulated, 19-minute decrement
time for a 29% concentration decrease, is partly due to early
continued redistribution of fentanyl. The further 60% decrement to the minimum analgesic concentration of 1 ng/ml
is protracted (Figure 3b). Theoretically, the patient should
experience the analgesic effects of fentanyl for several more
hours.

Computer simulations of the context-sensitive

decrement times of various hypnotics and opioids
Alfentanil

Propofol

Fentanyl

Sufentanil

Midazolam

Thiopental

20% decrement time

(min)

20

15

10

60

120

180

240

300

360

420

480

Infusion duration (min)

Relationship between drug concentration and effect

50% decrement time

(min)

240

Most drugs exert their effects at a distant site and the circulation transports drug molecules to their site of action. Whereas
steady-state blood concentrations correlate with drug effects,
when blood concentration is changing, or has recently
changed, there is a time-lag between changing blood concentrations and changing effects (Figures 1 and 2). The timerelated hysteresis between dose and effect is described in the
further reading.
Limited space precludes a detailed discussion of the relationships between blood and effect-site concentrations. Recent
research has quantified these relationships, especially the way in
which hypnotics and opioids interact synergistically.
A

180

120

60

60

120

180

240

300

360

420

480

Infusion duration (min)

80% decrement time

(min)

1200

900

600

FURTHER READING
Absalom A, Struys MRF. An overview of TCI and TIVA. 2nd edn. Gent:
Academia Press, 2000.
Glass PSA, Shafer SL, Reves JG. Intravenous drug delivery systems. In:
Miller RA, ed. Anesthesia. 7th edn. New York: Churchill Livingstone,
2010 (Previous editions of this textbook also contain similar chapters
by the same authors.).
Short TG. Using response surfaces to expand the utility of MAC. Anesth
Analg 2010; 111: 249e51 (This editorial article provides a short
overview of the techniques used to quantify the interactions between
hypnotics and opioids.).

300

60

120

180

240

300

360

420

480

Infusion duration (min)

Note the different timescales on the ordinates of the three
graphs.
Figure 3

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2015 Elsevier Ltd. All rights reserved.