Anaesthesia 2014, 69, 399–419
Editorial
What is the ke0 and what does it tell me about propofol?
Propofol is now the ‘gold standard’
intravenous anaesthetic drug and is
commonly used as the hypnotic
component of total intravenous
anaesthesia (TIVA) as it has a rela-
tively fast onset and short duration
of action, making it easy to titrate.
Like most anaesthetics, it has a nar-
row therapeutic ratio and significant
dose-dependent adverse effects. A
precise control of the anaesthetic
effect requires a good understand-
ing of the dose-effect relationship
and rational dose schemes. Effect-
compartment models are empirical
models that relate the dose of a
drug to its concentration (pharma-
cokinetic) and the concentration to
the effect (pharmacodynamic),
thereby assisting in titration of the
drug and its effects. These models
are being increasingly used in target
controlled infusion (TCI) devices to
facilitate administration of a num-
ber of drugs used in intravenous
anaesthesia.
Current controversy with
propofol effect-site
models
Since the concentration of propofol
in the brain cannot be measured,
effect-site models are derived using
repeated measurements of propo-
fol’s hypnotic effect. One of the
major problems of this approach is
that propofol’s hypnotic effect is not
easily measured [1]. Most studies
© 2014 The Association of Anaesthetists of Great Britain and Ireland
have used indices based on EEG
activity as surrogate measures of
propofol’s hypnotic effect. However,
discrepancies in these indices have
resulted in markedly different effect-
site elimination rate constant (ke0)
values [2], with different descrip-
tions of propofol’s effect-time pro-
file. In currently available TCI
pumps, it is possible to find two
very different Marsh effect-site
models: one with a slow ke0
(0.26 min 1) incorporated in the
DiprifusorTM (AstraZeneca, London,
UK); and one with a fast ke0
(1.21 min 1) used by the Base
Primea system (Fresenius-Kabi,
Brezins, France). The Schnider
model, also available in the base
Primea system, uses yet another ke0.
This has created confusion among
anaesthetists who must understand
the implications of these differences
in TCI model predictions. In addi-
tion, there is ongoing discussion
regarding the adequacy of available
effect compartment models to cha-
racterise propofol’s effect-time pro-
file [3, 4]. In this scenario, two
studies by Thomson et al., published
in this issue of Anaesthesia, add new
relevant information to this topic
[5, 6].
The principles of pharmacoki-
netic/pharmacodynamic modelling
have been explained in detail by
Rigby-Jones and Sneyd in this jour-
nal [7]. The aim of this editorial is
to help clinicians to understand
some important differences between
currently available propofol effect-
site models, focusing on the rele-
vance of the ke0. Since the ke0 is
critically dependent on the pharma-
cokinetic model, I will use the same
model (the Marsh model) with two
different ke0s in the simulated sce-
narios (manual bolus dose and
TCI).
Manual bolus dose
scenario
I will first use a simulated manual
bolus dose of propofol (2 mg.kg 1)
to analyse the time profile of propo-
fol effect and the predictions of the
two currently available Marsh
effect-site models (Fig. 1). In this
scenario, plasma propofol concen-
trations and propofol effect-site
concentrations are predicted by the
Marsh pharmacokinetic model [8]
using the slow and the fast ke0s.
The predicted effect will range from
10 (awake) to 0 (maximum propo-
fol hypnotic effect).
Plasma concentration to predict
the effect
Figure 1 shows that after the bolus
dose, predicted plasma concentra-
tion of propofol and the course of
the predicted effect do not follow
the same pattern. While the Marsh
pharmacokinetic model predicts an
initial peak plasma concentration
399
Anaesthesia 2014, 69, 399–419
(a)
(b)
Figure 1 Propofol concentrations and hypnotic effect after a manual bolus
dose predicted by the Marsh model using the slow (a) and the fast (b) ke0s.
Blue lines, plasma concentrations; red lines, effect-site concentrations; green
lines, effect.
followed by a monotonic decay, the
hynotic effect reaches its maximum
(lowest values) shortly after the
bolus dose and shows a faster pro-
file with the fastest ke0 of
1.21 min 1. The delay between the
peak plasma concentration and the
peak effect is called hysteresis and
can be observed as a hysteresis loop
in a concentration-vs-effect plot
(not shown). The reason for this
delay between concentration and
effect is that plasma is not the site
of action of propofol and additional
time is required for the drug to
transfer to the brain (effect site). It
is clear, therefore, that, during
non-steady state conditions, plasma
concentrations do not adequately
characterise the time profile of
propofol’s effect. Figure 1 also
shows that there are important
pharmacokinetic model misspecifi-
cations during the initial distribu-
400
tion period, where the model
erroneously assumes an instanta-
neous mixing of propofol within
the central compartment (peak con-
centration at time zero). Early drug
distribution after a bolus dose is
not well characterised by traditional
compartment models and important
discrepancies exist between current
propofol pharmacokinetic models.
While the Marsh model has a large
initial volume of distribution (V1)
of 0.228 9 weight (kg) litres, the
Schnider model has a small fixed
V1 of 4.27 litres. This is important
to understand since erroneous
plasma concentration predictions
during this initial period will reduce
the capacity of all currently avail-
able effect-compartment models
adequately to characterise propofol’s
effect-time profile during the first
1–2 minutes after a bolus dose
[9].
© 2014 The Association of Anaesthetists of Great Britain and Ireland
Editorial
Effect-site concentrations to
predict the effect
In steady-state conditions, the
plasma concentrations of a drug can
be directly related to the drug
response using a pharmacodynamic
model. In the absence of equilib-
rium, when the drug response is not
apparently related to plasma concen-
tration, a link model (effect-com-
partment model) can be used to
remove the hysteresis. Since drug
concentration is not measured in the
effect-site organ, effect compartment
models are constructed adding a vir-
tual compartment that does not
affect drug distribution. This virtual
effect compartment is structurally
linked to the central compartment
by a first-order rate constant (ke0).
The ke0 is calculated based on
an analysis of plasma concentra-
tions and the corresponding time
profile of the measured effect. With
this parameter the pharmacokinetic
model can be used to predict the
dose-concentration relationship and
the course of the effect. The ke0 can
be expressed as a half-time ke0
(ln(2)/ke0), which is directly corre-
lated with the time of equilibration
between the central compartment
and the effect site. If plasma con-
centration is maintained stable, as
in the case of plasma TCI, the time
required for the effect-site concen-
tration to reach 50%, 75% or 87.5%
of plasma concentration can be esti-
mated by 1, 2 or 3 9 half-time ke0,
respectively .
Figure 1 shows that effect-site
concentration predicted by both
Marsh effect-site models (slow and
fast ke0s) allows a much better char-
acterisation of propofol’s effect-time
profile than plasma concentration.
Editorial Anaesthesia 2014, 69, 399–419

However, important differences
between effect-site predictions are
observed. While the small ke0 pre-
dicts a slower effect-time profile,
with a time to peak effect-site con-
centration (Tpeak) of 3.9 min, the
ke0 of 1.21 predicts a more rapid
onset and offset of propofol response
with a predicted Tpeak of 1.6 min. It
should be noted that Tpeak depends
not only on the ke0 but also on the
pharmacokinetic profile of the drug.
As an example, the Schnider phar-
macokinetic model requires a much
slower ke0 of around 0.4 min 1 to
predict a Tpeak of 1.6 [10, 11]. The
slower ke0 compensates for the faster
decay in plasma concentrations pre-
dicted by the Schnider model, which
has a much smaller V1 than that
present in the Marsh model. In
Fig. 1, it is also possible to see that
the magnitude of the effect-site con-
centration reached and its corre-
sponding predicted effect are
markedly different with these ke0s,
reaching higher peak effect-site con-
centrations and a more pronounced
predicted effect with the fast ke0. The
explanation for this is that equilib-
rium between the effect-site and
central compartment occurs more
rapidly with a fast ke0 when less prop-
ofol has been distributed or elimi-
nated from the central compartment.
to set a higher initial target (plasma
overshoot) to reach the desired effect
more rapidly. In the case of targeting
the effect site, peak plasma concen-
tration will always reach higher val-
ues than the target concentration
and the magnitude of plasma over-
shoot will depend on the ke0 value.
It should be noted that the Diprifu-
sor only allows propofol administra-
tion by plasma target mode and
therefore the slow ke0 incorporated
in this system is only used to predict
effect-site concentrations.
Figure 2 shows propofol concen-
tration and effect-time profiles when
the Marsh model with fast and slow
ke0s is used to administer the drug
using effect-site TCI (target =
3 lg.ml 1). It can be seen that the
slow ke0 determines a greater bolus
dose (1.9 mg.kg 1) to achieve the
target effect-site concentration as fast
as possible. Since the model assumes
a slow equilibration rate between the
(a)
(b)
effect-site and the plasma, a large
plasma overshoot is calculated in the
bolus dose given, to obtain the
desired effect-site concentration
rapidly. In contrast, a faster ke0 of
1.21 min 1 will result in a smaller
bolus dose (1.0 mg.kg 1) that results
in less plasma overdose for the
same effect-site target. Since both
models use the same pharmacoki-
netic parameters, the final predicted
effect will be of the same magnitude
but will be reached faster with the
fast ke0.
A new ke0 for the Marsh
model
The question now is: which of these
models better predict propofol’s
effects? In the current issue of
Anaesthesia, Thomson and col-
leagues derived a new ke0 for the
Marsh propofol model using an
alternative clinical measure of
propofol effect to avoid the use of

TCI scenario
If propofol is administered using
plasma TCI, the amount of drug
given to reach and maintain a con-
stant plasma concentration will
depend exclusively on the pharma-
cokinetic parameters of the drug and
Figure 2 Propofol concentrations and hypnotic effect after during effect-site
the desired target. Since we know TCI predicted by the Marsh model using the slow (a) and the fast (b) ke0s.
the plasma is not the site of effect of Blue lines, plasma concentrations; red lines, effect-site concentrations; contin-
propofol, in this modality it is usual uous green lines, predicted effect; dashed green lines, hypothetical real effect.

© 2014 The Association of Anaesthetists of Great Britain and Ireland 401

Anaesthesia 2014, 69, 399–419
surrogate EEG indices [5]. Their
method was based on a validated
clinical sign of sedation called visual
reaction time [12], which is classified
as stable, deepening, or lightening.
Using effect-site propofol TCI with
the Marsh model and different ke0
values, the authors assumed that the
best ke0 should be the one with the
greater probability of obtaining
stable reaction times when the target
was kept stable. In their results,
Thomson et al. show that a ke0 of
0.6 min 1 was best for the Marsh
model. Thomson et al.’s use of a pre-
viously validated clinical marker to
derive the ke0 is a clear strength of
this study, which also used a very
nice and novel modelling approach.
In the follow-up study [6], the
authors tested the adequacy of this
new ke0 in terms of speed of induc-
tion and side-effects when compared
with other currently available mod-
els. Unfortunately, since they used
speed of induction and side-effects
as the measured outcomes, both of
which are critically dependent on the
target selected, it is my opinion that
they cannot discriminate between
models but only test the adequacy of
the predefined selected target.
To understand the possible
implications of Thomson et al.’s
findings better, let us now assume
that the ke0 of 0.26 min 1 and
1.21 min 1 incorporated in the
Marsh model are both wrong, and
that the real propofol effect-time
profile is better described using this
new proposed ke0 of 0.6 min 1. In
this hypothetical scenario, the ‘real
effect’ is represented in Fig. 2 with a
dashed green line. In the case of
using propofol TCI with the Marsh
0.26 model, the bolus given would be
402
too large and, consequently, the real
effect would be more pronounced
and faster than that predicted by the
Marsh 0.26 model. In contrast, if
using the Marsh 1.21 model, the ini-
tial bolus dose would be too small
and would take more time to reach
the desired effect than that predicted
by the Marsh 1.21 model. In both
cases, differences between the mod-
els should be expected to occur only
during the first few minutes after set-
ting the target.
It is not the purpose of this edi-
torial to decide on which is the best
model to use, but to provide tools to
assist the interpretation of the mod-
els’ predictions. It is possible that in
the future, new integrated pharma-
cokinetic/pharmacodynamic models
derived from larger populations
might allow a better characterisation
of the propofol dose-effect relation-
ship and its variability. In the mean-
time, the most important message
for clinicians is the need to under-
stand the limitations of currently
available models and use them with
good clinical judgment and careful
titration to clinical effect.
Competing interests
No external funding and no com-
peting interests declared.
L. I. Cort
ınez
Associate Professor
Anaesthesia Department
Pontificia Universidad Catolica
de Chile
Santiago, Chile
Email: licorti@med.puc.cl
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doi:10.1111/anae.12642