British Journal of Anaesthesia 1998; 80: 725–732
Quantitative electroencephalographic analysis of the biphasic
concentration–effect relationship of propofol in surgical patients
during extradural analgesia
K. KUIZENGA, C. J. KALKMAN, P. J. HENNIS
Summary
We studied effects on the EEG of propofol
infused at a rate of 0.5 mg kg91 min91 for 10 min in
10 healthy male surgical patients under extradural analgesia. The EEG amplitude in six
frequency bands was related to arterial blood
propofol concentrations and responsiveness to
verbal commands. The EEG amplitude showed a
characteristic biphasic response to increasing
blood propofol concentrations in all frequency
bands. During the infusion, patients lost responsiveness when EEG amplitudes in the high
frequency bands were decreasing after having
reached a maximum. EEG changes were different during infusion and emergence. Pharmacodynamic modelling, using two effect compartments with dissimilar equilibration constants,
resulted in satisfactory fits. We conclude that
propofol exerts a biphasic effect on the EEG
amplitude in all frequency bands. The dissimilarity of EEG changes during infusion and during
emergence suggests that two effect compartments with different equilibration constants
exert opposing effects on the EEG. (Br. J.
Anaesth. 1998; 80: 725–732)
Keywords: monitoring electroencephalography; pharmacodynamics; propofol; biphasic modelling
Sedative doses of propofol significantly increase
amplitude and power in the beta region of the
EEG.1 2 Hypnotic doses of propofol, however, cause
slowing of the EEG, manifested by an increase in
delta power, reduced alpha and beta activity, and a
lowering of the median frequency and spectral
edge.3 This biphasic pattern of the EEG amplitude
in the beta band in response to an increasing blood
propofol concentration has been described
qualitatively,4 5 but has not been studied quantitatively.
The aims of the present study were, first, to quantify the biphasic relationship between propofol
concentration and EEG effects during the transition
from the awake state to hypnosis and during
subsequent emergence and second, to fit a pharmacodynamic model to the observed changes. The
study of EEG changes caused by hypnotics in anaesthetized surgical patients is hindered by the effects of
concurrently administered sedative and analgesic
drugs. As extradural analgesia with bupivacaine
appears to have no significant effect on the EEG,6 the
study was performed in surgical patients under
extradural analgesia, who received a 10-min propofol
infusion.
Patients and methods
The study was approved by the Medical Ethics Committee of the University Hospital of Groningen. After
obtaining written informed consent, we studied 10
healthy male patients, of mean (SD) age 28.4 (7.7) yr,
weight 81 (12) kg and height 1.82 (0.12) m, scheduled
for elective lower-limb surgery under extradural
analgesia. Patients with a history of recent drug intake,
an alcohol intake in excess of 30 g day91, neurological
disturbances, or extreme nervousness were excluded.
No oral intake was allowed after midnight preceding
the operation. No premedication was administered.
Before operation, an i.v. cannula was inserted and
0.9% saline 500 ml infused as fluid loading.
Extradural analgesia was achieved by giving 0.5%
bupivacaine 20 ml through an extradural catheter
inserted at L3–L4 5 min after a test dose of 0.5%
bupivacaine 3 ml with epinephrine 15 mg. Forty min
after the extradural administration of bupivacaine,
i.v. administration of propofol 0.5 mg kg91 min91 was
started with a constant-rate infusion for 10 min (total
dose 5 mg kg91). Surgery was started after the patient
lost responsiveness.
A 3-lead ECG, automatic noninvasive arterial
pressure, oxygen saturation and end-tidal carbon
dioxide concentration were monitored continuously.
If ventilation became insufficient during the infusion
of propofol, as indicated by SpO2 below 92%, an
obstructed airway, or an end-tidal carbon dioxide
concentration of more than 6%, ventilation was
assisted manually with a face mask and oxygenenriched air (40% O2).
Responsiveness was determined by testing the
response of the patient to simple commands from a
prerecorded tape (“raise your thumb”, “spread your
fingers”, and “clench your fist”), given via headphones every 30 s. It was noted when the patient
became unresponsive, and when responsiveness
returned after stopping the propofol infusion.
K. KUIZENGA, MD; P.J. HENNIS, MD, PHD; Department of
Anaesthesiology, University of Groningen, Hanzeplein 1, Postbox
30.001, 9700 RB, Groningen, The Netherlands.
C.J. KALKMAN, MD, PHD, Department of Anaesthesiology,
University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam,
The Netherlands. Accepted for publication: 8 January 1998.
Correspondence to K. K.
726
British Journal of Anaesthesia
Table 1 Pharmacokinetic values expressed as mean (SD)
t1/2π (min91)
t1/2 (min91)
t1/2 (min91)
Vc (l kg91)
Vss (l kg91)
Cl (ml kg91 min91)
Three
compartments
(n:7)
Two
compartments
(n:3)
1.00 (0.52)
9.54 (4.34)
74.4 (19.1)
0.10 (0.04)
1.31 (0.30)
28.2 (5.39)
1.33 (0.31)
and related to the blood propofol concentrations, the
time at which the patient became unresponsive to
verbal command, and the time at which responsiveness was regained.
PROPOFOL KINETICS AND DYNAMICS
55.2 (12.4)
0.09 (0.09)
1.45 (0.83)
32.5 (6.11)
EEG RECORDING AND ANALYSIS
The EEG was recorded from bilateral mastoid to
prefrontal leads, M1–Fp1 and M2–Fp2, with Fpz as reference, using standard ECG electrodes (Red Dot) on
the skin, prepared with Omni-prep abrasive paste.
Electrode impedance was maintained below 5 k⍀. A
5-min baseline EEG was recorded before starting
extradural analgesia, with the patient supine and with
the eyes closed. After the onset of analgesia, the EEG
was recorded continuously from 5 min before the
start of the propofol infusion until the patient
regained consciousness and thereafter intermittently
for 5-min periods, coinciding with blood sampling,
until 190 min after the start of the infusion. The raw
EEG signal was stored on FM tape for off-line analysis. The EEG was processed with aperiodic analysis7
(Lifescan software version 4.3, Diatek, San Diego,
CA) to derive the amplitude and frequency characteristics of sequential EEG waves. Data recorded
from the nondominant hemisphere (defined on the
basis of the handedness of the patient) were used for
analysis. Amplitudes in six frequency bands (0–5,
6–10, 11–15, 16–20, 21–25, and 26–30 Hz) were
averaged over periods of 15 s. Periods containing
EMG artefact, manifest as an amplitude of more
than 15 mV s91 in the frequency band 26–30 Hz, were
excluded from analysis. The time course of the
amplitudes in the six frequency bands was studied
A 20 gauge cannula was inserted in a femoral artery
for sampling of arterial blood after the onset of extradural analgesia. This sample site was chosen to minimize patient discomfort. Blood samples of 3 ml were
taken at 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 25, 30,
40, 55, 70, 100, 130, and 190 min after the start of
the propofol infusion and mixed with EDTA. Blood
samples were stored at 4 ⬚C until determination of
whole-blood propofol concentrations with high
performance liquid chromatography (detection limit
5 ␮g l91, coefficient of variation 4.3%).8
Bi- and tri-exponential functions were fitted to
concentration vs time data using weighted (log
concentration) least-squares nonlinear regression
analysis (software package Multifit, J. H. Proost,
University of Groningen, The Netherlands). A bi-or
tri-exponential function was chosen on the basis of
the Schwartz criterion.9 The following pharmacokinetic parameters were derived using standard
equations: volume of the central compartment (Vc),
volume of distribution at steady state (VSS), plasma
clearance (Cl), distribution (T1/2π, T1/2␣) and elimination (T1/2␤) half-lives. Fitted data of individual
patients were used to calculate the time course of the
blood propofol concentration in each patient, to estimate the propofol concentrations at the time of loss
and return of responsiveness, and at the time of the
EEG amplitude maxima.
For pharmacokinetic–dynamic modelling of the
biphasic EEG effects of propofol the parametric
modelling technique of Mandema10 was applied. This
model assumes that the measured EEG effect of propofol is the result of effects of propofol on two different effect compartments. Increasing propofol concentrations in these two effect compartments have
opposing effects on the EEG amplitude, for example,
activation and inhibition. The formula of the
relationship between effect (E), and concentration is:


E max C1γ  1−
C2γ
E =  E0 +


γ
γ
γ
γ 
EC50 + C1   EC50 + C2 

where E0 is the baseline effect, Emax is the hypothetical
maximal increase of EEG effect when no EEG inhibition would occur, EC50 is the steady state
concentration at which half of Emax occurs, C1 is the
concentration in effect compartment 1, C2 is the concentration in effect compartment 2, and ␥ determines
the slope of the curves. The concentration in the
effect compartments was calculated using the following equation:
dCe
= keo (Cp − Ce)
dt
Figure 1 Measured blood propofol concentrations during the
first 35 min after the start of the propofol infusion. Infusion rate
0.5 mg kg91 min91. Duration 10 min (total dose 5 mg kg91). Linear
interpolation between measured data points was applied to draw
lines.
where Ce is the concentration in the hypothetical
effect compartment, Cp is the blood concentration,
and keo is a first-order rate constant, describing the
rate of equilibration between the plasma and the
effect site. Cp values were calculated using linear
Biphasic propofol concentration effect on the ECG
727
Figure 2 Typical analogue EEG recordings of a patient (no. 6) at representative moments during the propofol
infusion and emergence. First amplitude maximum, second amplitude maximum:times when maxima in the 11–15
Hz frequency band were reached: first, during infusion; second, during emergence.
interpolation between measured Cp values during
infusion and log–linear interpolation between the
measured Cp values after the infusion. In the present
study we allowed one or two values for keo during fitting. When only one keo is allowed the concentrations
in C2 and C1 are identical and the model could be
considered to consist of one effect compartment.
The quality of fit was expressed as the coefficient of
determination, R.
R =1−
2
∑(E
∑(E
observed
modelled
−E
−E
2
modelled
average
)
the morning of the operation, and on arrival at the
anaesthetic room). Shivering was observed in four
patients after the onset of extradural analgesia. All
patients required assisted ventilation from approximately 1 min after loss of responsiveness for 22 (16–
29) min (median and 25th–75th percentile). Patients
became unresponsive 2.8 (2.5–3.4) min after the
start of the propofol infusion and regained consciousness 21.5 (16.1–25.4) min after the infusion
was stopped. The blood propofol concentrations,
calculated on the basis of individual pharmacokinetic
2
)
STATISTICAL ANALYSIS
As it could not be ascertained if the EEG amplitude
data derived from aperiodic analysis in 10 patients
were normally distributed, EEG data are presented
as medians and 25–75 percentiles. Pharmacokinetic
data are expressed as mean (SD). Pharmacodynamic
data are expressed as mean (SD) and median and
25–75 percentiles. EEG data and the coefficients of
correlation, R2, of the pharmacodynamic fits using
one or two values for keo were compared using the
Wilcoxon signed ranks test. Blood propofol concentrations at which EEG amplitudes in the four
frequency bands from 0 to 20 Hz reach their
maximum were compared using the Friedman test.
P:0.05 was considered significant. The computer
program SPSS for Windows version 6.13 was used
for statistical calculations.
Results
Extradural analgesia was adequate in all patients
(sensory level to cold: T9 (T12—T5), median and
range). No patient developed bradycardia (:50 beats
min91) or hypotension (lowering of systolic blood
pressure by 925% from the average of the systolic
blood pressures measured at hospital admission, on
Figure 3 Representative time course of EEG amplitude in four
frequency bands in a patient (no. 9) in response to a 10-min
infusion of propofol 0.5 mg kg91 min91. All four frequency bands
show two amplitude maxima, one during the infusion and a
second during emergence. In each frequency band, there is a
difference in amplitude between the first amplitude maximum
and the second. This patient was unresponsive from 2.5 min until
24.5 min after the start of the infusion. Frequency bands:
▲:6–10 Hz; !:16–20 Hz; ■:0–5 Hz;  :11–15 Hz.
728
British Journal of Anaesthesia
Figure 4 Hysteresis curves of EEG amplitude in the 11–15 Hz frequency band vs calculated blood propofol
concentrations during infusion and during emergence. The amplitude maximum is smaller when blood propofol
concentrations are increasing than when they are decreasing. Patient no. 10 showed only a minimal biphasic effect,
possibly because lower blood propofol concentrations were reached during the infusion. •:during infusion; ":after
infusion.
modelling, at the times when consciousness was lost
and regained were 6.45 (5.87–7.01) and 0.85 (0.64–
1.09) mg l91 respectively. The measured blood propofol concentrations in individual patients during the
infusion and the first 25 min after the infusion are
shown in figure 1. The calculated pharmacokinetic
parameters are shown in table 1.
The awake EEG was characterized by predominant activity in the 8–14 Hz frequency range. The
EEG pattern did not change after the onset of extradural analgesia, although amplitude in the highfrequency bands increased in the patients who were
shivering. After the start of the infusion, the
amplitude in the high-frequency bands increased initially. With further increases in blood propofol
concentration the EEG slowed and amplitude
decreased. At the end of the infusion, slow-wave
activity was present with spindles of high-frequency
Biphasic propofol concentration effect on the ECG
729
Table 2 EEG amplitude before, during and after a 10-min propofol infusion of 30 mg kg91 h91 and times of loss of responsiveness,
maximum EEG amplitude, and return of responsiveness. *Different from baseline value; †different from maximum during infusion;
††different from the time of loss of responsiveness. Data are expressed as median and 25th–75th percentile
Frequency band
0–5 Hz
6–10 Hz
11–15 Hz
16–20 Hz
EEG amplitude (V s )
Baseline
After epidural analgesia
Loss of responsiveness
Maximum during infusion
End of infusion
Maximum during emergence
Return of responsiveness
44 (24–69)
40 (35–62)
87* (46–99)
126* (71–190)
52* (29–119)
99*† (65–125)
45 (28–57)
51 (19–76)
40 (31–54)
43 (32–70)
71* (46–137)
34 (24–123)
93* (74–136)
31 (20–50)
42 (17–53)
42 (32–71)
86* (69–137)
106* (76–269)
43 (23–210)
242*† (163–477)
70* (32–142)
9 (2–27)
31* (7–38)
52* (19–84)
54* (20–99)
11 (4–20)
46* (17–96)
17 (5–85)
Time (min)
Loss of responsiveness
Amplitude maximum during infusion
Amplitude maximum during emergence
Return of responsiveness
2.8 (2.5–4.5)
4.8†† (3.5–9.0)
16.8 (10.5–20.8)
31.5 (23.8–39.5)
6.0†† (4.0–8.5)
17.0 (11.5–20.8)
3.8 (1.5–8.0)
19.3 (15.3–24.8)
2.5†† (0.5–4.0)
21.8 (14.8–30.5)
91
activity. During emergence, high-amplitude highfrequency activity reappeared, followed by a decrease
in amplitude until the patient became responsive
(fig. 2).
Quantitatively, marked amplitude changes occurred in the frequency bands between 0 and 20 Hz,
but amplitude in the frequency bands between 21
and 30 Hz was small and often contained obvious
muscle artefacts when patients were responsive.
Therefore data calculated from these bands were not
used in the calculations and are not shown in the
tables and figures. In all four frequency bands below
21 Hz, EEG amplitude showed a biphasic response
Figure 5 Box plots of calculated blood propofol concentrations
at the times of loss and regaining of responsiveness, and when
EEG amplitude maxima were reached in the frequency bands
0–5, 6–10, 11–15, and 16–20 Hz during infusion and emergence.
With increasing frequency the maxima occurred at lower blood
concentrations. Box plots represent median, 25th–75th percentile, 10th–90th percentile, and lowest and highest values (open
circles). *P:0.01 compared with loss of responsiveness to verbal
command. †P:0.01 compared with return of responsiveness to
verbal command.
to increase blood propofol concentration, that is,
EEG amplitude initially increased and subsequently
decreased to or beyond baseline values. When the
infusion was stopped, EEG amplitude again showed
a biphasic response: it increased to a maximum and
then decreased until the patient became responsive
(fig. 3).
The amplitude at the moment the patient became
responsive was similar to or just above baseline
values. The amplitude maxima reached during the
infusion and during emergence were dissimilar in the
0–5 Hz and 11–15 Hz bands (table 2).
Hysteresis of the EEG effect—blood concentration
curve was observed. Figure 4 shows individual
hysteresis curves of EEG amplitude in the 11–15 Hz
band and calculated blood concentrations during
and after the infusion.
The blood concentrations at which the EEG amplitude reached its maximum during infusion and emergence varied in different frequency band. EEG amplitudes in higher bands reached their maximum at lower
blood propofol concentrations than the EEG amplitudes in lower-frequency bands (P:0.01) (fig. 5).
Figure 6 Observed and estimated EEG amplitude in the
frequency range 11–15 Hz vs time in patient no.7. Estimated
values were obtained by fitting measured amplitudes to the
Mandema biphasic pharmacodynamic model, allowing either one
or two values for keo. o:observed effect. Allowing one keo resulted
in identical maximal EEG amplitudes during and after infusion
and an R2 of 0.78 (thin line). Allowing two values for keo resulted
in a smaller maximal EEG amplitude during infusion and an R2
of 0.87 (thick line).
730
British Journal of Anaesthesia
Table 3 Pharmacodynamic parameters of individual patients estimated with the Mandema model for the frequency band 11–15 Hz
allowing two values for keo. *P<0.01 vs keo1
Patient
R2
keo (min91)
keo2 (min91)
EC50 (mg l91)
E0 (V s91)
Emax (V s91)
1
2
3
4
5
6
7
8
9
10
0.91
0.87
0.89
0.91
0.82
0.87
0.87
0.83
0.89
0.92
0.06
0.16
0.21
0.15
0.22
0.05
0.27
0.07
0.13
0.17
0.08
0.25
0.27
0.21
0.21
0.07
0.34
0.16
0.18
0.22
4.0
4.1
2.0
2.4
3.6
4.7
3.6
3.1
3.4
4.9
10.8
4.2
3.8
5.3
3.7
16.4
4.8
4.1
3.5
5.6
39
62
21
26
25
79
39
52
37
46
1775
932
563
1995
525
4356
667
446
491
1686
0.88
0.03
0.88
0.87
0.91
0.15
0.07
0.16
0.07
0.21
0.20
0.08
0.21*
0.16
0.25
3.6
0.9
3.6
3.1
4.1
6.2
4.2
4.5
3.8
5.6
43
18
39
26
52
1344
1213
800
525
1775
Mean
SD
Median
25th Percentile
75th Percentile
Loss of responsiveness occurred immediately after
the initial amplitude maximum in the 16–20 Hz band
and before or simultaneously with the initial
amplitude maximum in the 11–15 Hz band. Patients
regained consciousness after the second amplitude
maximum in the 11–15 Hz band and the 16–20 Hz
band. As the EEG amplitude had a biphasic response
to blood propofol concentrations, responsiveness to
verbal command could not be related to an
amplitude value in any frequency band without
information on the time course of the value.
Calculated pharmacodynamic parameters derived
from EEG amplitudes in the 11–15 Hz band of individual patients allowing two values of keo are shown in
table 3.
The two-effect compartment model fitted the data
significantly better than the one-effect compartment
model in both the 11–15 Hz band and the 0–5 Hz
band (median R:0.88 vs 0.79 in the 11–15 Hz
band, and 0.78 vs 0.68 in the 0–5 Hz band, P:0.01).
Figure 6 shows an example of the one- and
two-compartment model fitted to the EEG data in
the 11–15 Hz frequency band.
EC50 was higher in the 0–5 Hz band: 4.2 (3.2–4.5)
mg l91 vs 3.6 (3.1–4.1) mg l91 in the 11–15 Hz band. In
the 0–5 Hz band keo1 was larger than keo2: 0.27
(0.22–0.33) min91. In the 11–15 Hz band, however,
keo was smaller than keo2: 0.16 (0.07–0.21) min91 vs
0.21 (0.16–0.25) min91.
Discussion
In this study, during a 10-min infusion of propofol,
we observed a biphasic EEG amplitude response to
an increasing blood propofol concentration in all frequency bands. EEG amplitude maxima were dissimilar during infusion and emergence in two of the four
frequency bands. The blood propofol concentration
at which the EEG amplitude maximum in a particular frequency band occurred was inversely related to
the frequency of this band.
A biphasic EEG response to increasing blood propofol concentrations was first described by Hazeaux
and colleagues,4 who reported an increase followed
by a decrease in alpha amplitude, and the appearance of theta and delta activity after an injection of
propofol 2.5 mg kg91 in 30 s. Borgeat and
co-workers5 described similar changes during induction of anaesthesia in children with a propofol bolus
of 3 or 5 mg kg91. They found a transient shift from
predominantly alpha (9–10 Hz) activity to beta (914
Hz) activity, followed by continuous delta activity.
Hazeaux and Borgeat did not quantify the EEG
changes or determine blood propofol concentrations
at which these phenomena occurred. In the presence
of sedative propofol blood concentrations, an
increase in beta activity accompanied by an
increased sedation level has been reported.1 2 In both
studies, propofol was given in doses sufficient to
achieve sedation, and the infusion rate was adjusted
to prevent unconsciousness. Beta activity was
increased throughout the procedure and showed no
biphasic response, probably because the patients did
not become unconscious and blood propofol
concentrations were 0.69 (0.34) mg l91 1 and 1.14
(0.39) mg l91.2 In the presence of anaesthetic propofol concentrations, Schwilden and colleagues3 used
the median frequency, calculated from the power
spectrum, as the EEG effect parameter for closedloop feedback control of propofol anaesthesia. They
described a monophasic response to propofol, that
is, a decrease of median frequency with increasing
blood concentrations. More recently, Forrest and
co-workers11 reported a biphasic shift of median frequency shortly after the start of a propofol infusion.
These authors were unable to quantify the maximum in median frequency because they collected
insufficient data in this concentration range.
The biphasic EEG amplitude response in the
11–15 Hz and the 16–20 Hz bands observed in the
present study is consistent with the increased beta
activity found by others during sedation,1 2 and the
decreased median frequency described during anaesthetic propofol concentrations.3 11
Although we were unable to demonstrate an influence of extradural analgesia on the EEG in a previous
study,6 in the present study we observed an increase
in amplitude of the 16–20 Hz band. As shivering
occurred in four patients, we suspect that this
increase in amplitude in the 16–20 Hz band is the
result of EMG artefact. EEG amplitude in the other
frequency bands was not different from baseline values. The 30 Hz low-pass filter probably eliminates
EMG artefacts caused by shivering in the other
frequency bands. Although extradural analgesia has
no effect on EEG amplitude itself, synergistic effects
of extradural analgesia with propofol on the EEG
amplitude cannot be excluded.
Biphasic propofol concentration effect on the ECG
Extradural analgesia might have influenced the
pharmacokinetics of propofol. Haemodynamic
changes, venous pooling and hepatic blood flow can
affect its distribution and clearance. In comparison
with the pharmacokinetic data reported by other
investigators12 13 14, we observed a shorter T1/2π and
T1/2␤ and a smaller Vss. In addition to the effects of
extradural analgesia, a short sampling period may
have been responsible for these differences. However,
changes in pharmacokinetic parameters had no
influence on the estimation of pharmacodynamic
parameters, as measured blood propofol concentrations were used to calculate effect compartment concentrations.
The sigmoid Emax model has been applied successfully for pharmacodynamic modelling of plasma
concentration–effect relationships of opioids15 and
hypnotics.3 16 However, modelling of biphasic effects
remains a major challenge. One might transform
EEG data in such a way that a sigmoid Emax model fits
the data. Greg and colleagues suggested semilinear
canonical correlation,17 18 which uses a summation of
log-transformed EEG power in several frequency
bins, which are multiplied by a weight factor to yield
effect data. When we applied this method to our
data, we achieved weight factors for individual
patients that resulted in good fits in nine of the 10
patients (R2:0.97 (0.95–0.97). However, when the
weight factors of all patients were averaged and the
average weight factor was applied to the EEG data,
the sigmoid Emax model could not be fitted satisfactorily (R2:0.78 (0.59–0.89). Ebling and colleagues19
have described the application of a nonparametric
approach to characterize biphasic EEG effects in
response to thiopentone in rats. The method
describes the relationship between the concentration
of drug in the effect compartment (Ce) and distinct
EEG effects including baseline effect, maximal
effect, 50% of baseline effect, and burst suppression.
However, nonparametric estimation of keo, needed to
calculate the effect site concentrations, is based on
the assumption that the effect during increasing and
decreasing effect compartment concentrations is
similar.20 21 As the magnitude of EEG effects during
and after the infusion in the present study was
dissimilar in the 0–5 Hz band and the 11–15 Hz
band, nonparametric estimation of keo and effect site
concentrations was not possible. Accordingly, we did
not attempt to use this method to model the effect of
propofol.
It could be that we observed dissimilar EEG
amplitude maxima during infusion and during emergence in the present study because the 15 s averaging
epoch used was too long to detect a transient increase
in amplitude in response to a rapidly changing
propofol concentration. This could explain the lower
EEG maximum during infusion in the 11–15 Hz
band, when concentrations changed rapidly. However, the amplitude maximum in the 0–5 Hz band
was highest during infusion, in spite of the same
rapid concentration changes. Another argument
against this explanation is that the amplitude maxima
in the 11–15 Hz band did not change and remained
smallest during infusion after reanalysis of the data
using 2 s epochs.
The dissimilar EEG amplitude maxima during
infusion and emergence suggest that more than one
731
effect compartment may exist. One might hypothesise two compartments with different equilibration
constants exerting opposing effects: inhibition and
activation. Applying this concept to the EEG amplitude in, for example, the 11–15 Hz range results in
the following sequence: during an increasing blood
propofol concentration, the concentration will rise
faster in the “inhibiting” effect compartment than in
the “activating” compartment, and therefore inhibition will dominate soon after the start of drug
administration. However, after stopping the propofol
infusion, the concentration in the “inhibiting” effect
compartment will decrease more rapidly, thus allowing the “activating” effect to become clinically apparent.
Because dissimilar effects during increasing and
decreasing blood concentrations preclude modelling
with nonparametric models, we chose the simplest
parametric model proposed by Mandema (with the
least number of parameters to be estimated) to fit our
data.10
Although the Mandema model is a simplification
of the summation of two sigmoid Emax curves, it was
possible to model the data consistently according to
this method with good results.
The findings that using two values for keo resulted
in significantly better fits than using one, and that
there were significant differences between keo1 and
keo2 supports the hypothesis that assuming two effect
compartments with unequal equilibration constants
might explain the dissimilar EEG amplitudes observed during infusion and emergence in the 0–5 Hz
and the 11–15 Hz band.
One might hypothesize that differences in regional
cerebral blood flow could be a physiological explanation for these differences. An alternative explanation
might be that there are differences in the affinity or
dissociation rate of propofol for receptors on either
excitatory or inhibitory neurons. A third explanation
might be that in either the excitatory or the inhibitory
neuron, after initial occupation of the receptor, a secondary pathway must become activated, which
requires additional time before an effect becomes
apparent.
Because of the biphasic character of the EEG
response to propofol, a particular EEG amplitude
may correspond to more than one propofol concentration. This finding makes it difficult to use the EEG
amplitude as an indicator of the level of consciousness. Estimation of the level of consciousness
requires additional information about the time
course of the EEG amplitude and the time course of
the EEG amplitude in other frequency bands. For
use as a control parameter of the level of consciousness one might try to maintain the EEG amplitude in
the 0–5 Hz band at its maximal value, as these
maxima correspond to propofol concentrations at
which patients are unresponsive. When EEG amplitude decreases from the maximal value one can
determine the direction of change of propofol
concentration from the changes of EEG amplitudes
in other frequency bands.
In conclusion, the propofol concentration—EEG
effect relationship is biphasic in all EEG frequency
bands. The present study demonstrates that the EEG
effects during infusion and emergence are dissimilar,
which suggests the existence of at least two effect
732
compartments with different equilibration constants
exerting opposing effects on EEG amplitude. Modelling of the blood propofol concentration—EEG
relationship was possible using a biphasic parametric
model.
Acknowledgements
Determination of the blood propofol concentrations was funded
by a grant from Zeneca Pharma, Ridderkerk, The Netherlands.
References
1. Veselis RA, Reinsel RA, Wronski M, Marino P, Tong WP,
Bedford RF. EEG and memory effects of low-dose infusions
of propofol. British Journal of Anaesthesia 1992; 69: 246–254.
2. Seifert HA, Blouin RT, Conard PF, Gross JB. Sedative doses
of propofol increase beta activity of the processed electroencephalogram. Anesthesia and Analgesia 1993; 76: 976–978.
3. Schwilden H, Stoeckel H, Schuttler J. Closed-loop feedback
control of propofol anaesthesia by quantitative EEG analysis
in humans. British Journal of Anaesthesia 1989; 62: 290–296.
4. Hazeaux C, Tisserant D, Vespignani H, Hummer-Sigiel M,
Kwan-Ning V, Laxenaire MC. Retentissement electroencephalographique de l’anesthésie au propofol. Annales
Françaises d’Anesthésie et Réanimation 1987; 6: 261–266.
5. Borgeat A, Dessibourg C, Popovic V, Meier D, Blanchard M,
Schwander D. Propofol and spontaneous movements: an
EEG study. Anesthesiology 1991; 74: 24–27.
6. Kuizenga K, Hennis PJ. Does lumbar epidural analgesia with
bupivacaine affect the EEG? In: Bonke B, Bovill JG,
Moerman N, eds. Memory and Awareness in Anaesthesia III.
Assen, The Netherlands: Van Gorcum BV, 1996; 202–206.
7. Gregory TK, Pettus DC. An electroencephalographic
processing algorithm specifically intended for analysis of
cerebral electrical activity. Journal of Clinical Monitoring 1986;
2: 190–197.
8. Plummer GF. An improved method for the determination of
propofol using HPLC fluorescence. Journal of Chromatography
1987; 421: 171–176.
9. Schwartz G. Estimating the dimension of a model. Annals of
Statistics 1978; 6: 461–464.
British Journal of Anaesthesia
10. Mandema JW, Danhof M. Pharmacokinetic–harmacodynamic modelling of the CNS effects of heptobarbital using
aperiodic EEG analysis. Journal of Pharmacokinetics and
Biopharmaceutics 1990; 18: 459–481.
11. Forrest FC, Tooley MA, Saunders PR, Prys-Roberts C. Propofol infusion and suppression of consciousness: the EEG and
dose requirements. British Journal of Anaesthesia 1994; 72:
35–41.
12. Shafer A, Doze VA, Shafer SL, White PF. Pharmacokinetics
and pharmacodynamics of propofol infusions during general
anesthesia. Anesthesiology 1988; 69: 348–356.
13. Kay NH, Uppington J, Sear JW, Douglas E, Cockshott I. The
pharmacokinetics of propofol in patients undergoing surgery.
A comparison in men and women. British Journal of Anaesthesia 1986; 58: 1075–1079.
14. Gepts E, Camu F, Cockshott ID, Douglas EJ. Disposition of
propofol administered as constant rate intravenous infusion in
humans. Anesthesia and Analgesia 1987; 66: 1256–1263.
15. Scott JC, Cooke JE, Stanski DR. Electroencephalographic
quantification of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology 1991; 74: 34–42.
16. Schüttler J, Schwilden H, Stoeckel H. Infusion strategies to
investigate the pharmacokinetics and pharmacodynamics of
hypnotic drugs: etomidate as an example. European Journal of
Anaesthesiology 1985; 2: 133–142.
17. Gregg KM, Varvel JR, Shafer SL. Application of semilinear
canonical correlation to the measurement of opioid drug
effect. Journal of Pharmacokinetics and Biopharmaceutics 1992;
20: 611–635.
18. Gambus PL, Gregg KM, Shafer SL. Validation of the
alfentanil canonical univariate parameter as a measure of
opioid effect on the electroencephalogram. Anesthesiology
1995; 83: 747–756.
19. Ebling WF, Danhof M, Stanski DR. Pharmacodynamic characterization of the electroencephalographic effects of thiopental in rats. Journal of Pharmacokinetics and Biopharmaceutics
1991; 19: 123–143.
20. Hull CJ, Beem van HBH, McLeod K, Sibbald A, Watson MJ.
A pharmacodynamic model for pancuronium. British Journal
of Anaesthesia 1978; 50: 1113–1122.
21. Fuseau E, Shiener LB. Simultaneous modeling of pharmacokinetics and pharmacodynamics with a nonparametric
pharmacodynamic model. Clinical Pharmacology and Therapeutics 1984; 35: 733–741.