PERIOPERATIVE MEDICINE Anesthesiology 2010; 113:292–304
Copyright ? 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins
Propofol and Remifentanil Differentially Modulate Frontal
Electroencephalographic Activity
David T. J. Liley, M.B., Ch.B., Ph.D.,*
Nicholas C. Sinclair, B.Sc. (Medical Biophysics), B.E. (Electrical and Electronic) (Hons),†
Tarmo Lipping, Dr.Tech.,‡ Bjorn Heyse, M.D.,§ Hugo E. M. Vereecke, M.D., Ph.D.,

Michel M. R. F. Struys, M.D., Ph.D.#
ABSTRACT
Background: The purpose of this study was to evaluate a
new, physiologically inspired method for the analysis of the
electroencephalogram during propofol–remifentanil anes-
thesia. Based on fixed-order autoregressive moving-average
modeling, this method was hypothesized to be capable of
dissociating the effects that hypnotic and analgesic agents
have on brain electrical activity.
Methods: Raw electroencephalographic waves from a previ-
ously published study were reanalyzed. In this study, 45
American Society of Anesthesiologists status I patients were
randomly allocated to one of three groups according to a
specific target effect-site remifentanil concentration (0, 2,
and 4 ng/ml). All patients received stepwise-increased tar-
geted effect-site concentrations of propofol (Ce
PROP
). At
each step change in target Ce
PROP
, the Observer’s Assess-
ment of Alertness/Sedation score was evaluated. Raw electro-
encephalograph was continuously acquired from frontal
electrodes. Electroencephalography traces were analyzed us-
ing a fixed-order autoregressive moving average model to
give derived measures of Cortical State and Cortical Input.
Response surfaces were visualized and modeled using Hier-
archical Linear Modeling.
Results: Cortical State (a measure of cortical responsiveness) and
Cortical Input (a measure of the magnitude of cortical input) were
shown to respond differently to Ce
PROP
and effect-site remifentanil
concentration. Cortical Input decreased significantly with increas-
ing effect-site remifentanil concentration, whereas Cortical State
remained unchanged with increasing effect-site remifentanil con-
centration but decreased with increasing Ce
PROP
.
Conclusion: Because Cortical State responds principally to varia-
tions in Ce
PROP
, it is a potential measure of hypnosis, whereas the
dependence of Cortical Input on effect-site remifentanil concentra-
tion suggests that it may be useful as a measure of analgesic efficacy
and the nociceptive–antinociceptive balance.
* Associate Professor, Brain Sciences Institute, Swinburne Univer-
sity of Technology, Hawthorn, Victoria, Australia, and Chief Tech-
nology Officer, Cortical Dynamics Ltd., North Perth, Western Aus-
tralia, Australia. † Biomedical Research Engineer, Cortical Dynamics
Ltd. ‡ Professor, Department of Information Technology, Tampere
University of Technology, Pori, Finland. § Resident in Anesthesia,

Staff Anesthesiologist, Department of Anesthesia, Ghent Univer-
sity, Ghent, Belgium. # Professor and Chair, Department of Anes-
thesiology, University Medical Center Groningen, University of Gro-
ningen, Groningen, The Netherlands, and Professor, Department of
Anesthesia, Ghent University, Ghent, Belgium.
Received from the Brain Dynamics Research Group, Brain Sci-
ences Institute, Swinburne University of Technology, Hawthorn,
Victoria, Australia; Department of Anesthesia, Ghent University
Hospital, Ghent, Belgium; University Medical Center Groningen,
University of Groningen, Groningen, The Netherlands; and Depart-
ment of Information Technology, Tampere University of Technol-
ogy, Pori, Finland. Submitted for publication December 10, 2009.
Accepted for publication April 5, 2010. Supported by institutional
sources of Cortical Dynamics Ltd., North Perth, Western Australia,
Australia, and the Brain Sciences Institute, Swinburne University of
Technology, Hawthorn, Victoria, Australia, and by grant No. 7225
from Estonian Science Foundation, Tallinn, Estonia. Dr. Liley holds
an unvalued equity stake in Cortical Dynamics Ltd.
Address correspondence to Dr. Liley: Brain Sciences Institute,
Swinburne University of Technology, P.O. Box 218, Hawthorn,
Victoria 3122, Australia. dliley@swin.edu.au. Information on pur-
chasing reprints may be found at www.anesthesiology.org or on the
masthead page at the beginning of this issue. ANESTHESIOLOGY’s
articles are made freely accessible to all readers, for personal use
only, 6 months from the cover date of the issue.

This article is accompanied by an Editorial View. Please see:
Sleigh J: Disentangling Hypnos from his poppies. ANESTHESI-
OLOGY 2010; 113:271–2.
What We Already Know about This Topic
❖ Assessing depth of anesthesia by spontaneous electroen-
cephalographic activity is limited
❖ Neurophysiology-based processed electroencephalographic
monitoring in response to an arbitrary stimulus might improve
performance
What This Article Tells Us That Is New
❖ In 45 patients undergoing surgery, fixed-order time-series
modeling of electroencephalographic activity differentiated ef-
fects of the hypnotic propofol from those of the analgesic
remifentanil
❖ This approach might enable independent monitoring of hyp-
notic and analgesic drug actions
292 Anesthesiology, V 113 ? N o 2 ? August 2010

TO date depth of anesthesia monitoring has relied on a
range of heuristic measures to objectively assess depth of
anesthesia. The most successful existing methods are argu-
ably those derived from the analysis of spontaneous or time-
locked electroencephalographic activity.
1
In particular, the
Bispectral Index
®
(BIS
®
; Aspect Medical Systems, Nor-
wood,MA) has achieved a substantial level of routine clinical
use because of its reported efficacy in defining optimal levels
of hypnosis such that intraoperative awareness is mini-
mized.
2
Although reportedly enabling anesthesia to be more
optimally administered, it does so in the context of a number
of well-documented limitations: not all hypnotic agents are
reliably detected or monitored (nitrous oxide
3–6
and the
short-acting synthetic opioids
7–9
being quintessential exam-
ples), and the index admits of no clear physiologic interpre-
tation because it has been constructed to act as a quantitative
surrogate for an ostensibly subjective state. Although a range
of other processed electroencephalographic monitoring ap-
proaches have been developed in an attempt to circumvent
such limitations or to improve on the predictive ability of the
BIS in quantifying anesthesia, none has shown any clear ad-
vantage.
1
Such approaches include those based on spontane-
ous electroencephalographic activity, such as the Narcotrend
index (Narcotrend
®
; Schiller AG, Baar, Switzerland) and the
State Entropy and Response Entropy indices (M-entropy
®
module; GEHealthcare FinlandOy,Helsinki, Finland), and
those based on analyzing the morphology of the middle la-
tency auditory-evoked potential such as the A-Line ARX
index (AAI
®
; formerly Danmeter A/S, Odense, Denmark,
no longer trading). These indices, and a range of other em-
pirical measures that are based on assumed changes in the
complexity of the electroencephalogram signal with increas-
ing depth of anesthesia, are all heuristic constructs. Because
these measures are not derived from an understanding of the
mechanisms responsible for the genesis of dynamical activity
in the electroencephalogram, any anesthetic-induced electro-
encephalographic changes detected using such measures
must necessarily be of suboptimal sensitivity and specificity
and consequently will be of limited physiologic relevance.
Therefore, the development of physiologically more specifi-
cally motivated processed electroencephalographic ap-
proaches would be expected to result in improved perfor-
mance compared with existing methods. We outline one
such approach and show that it is able to differentiate the
effects of propofol and remifentanil on frontally recorded
electroencephalograms. This has the potential to pave the
way for monitoring the hypnotic effect of propofol indepen-
dent of the analgesic effect of remifentanil, a feature absent in
all existing processed clinical electroencephalogram-based
monitoring approaches.
10
The approach we will consider is based on a detailed the-
ory of mammalian cortical electrorhythmogenesis.
11–13
In
brief, it speculates that the rhythmic activity observed in the
electroencephalogram arises from the reverberant activity of
spatially distributed networks of excitatory and inhibitory
cortical neurons. This theory is able to account for a number
of electroencephalographic phenomena that are of relevance
to better understand and monitor anesthesia—the benzodi-
azepine-induced “
buzz,”
13
the proconvulsant effects of the
volatile general anesthetic agent enflurane,
14
and the bipha-
sic surge in total electroencephalographic power that typi-
cally accompanies anesthetic induction and emergence.
11,15
Although the full theory is mathematically elaborate, it does
suggest, to first approximation, that resting electroencepha-
lography may be regarded as a filtered pseudorandom linear
process. In particular, it posits that the electroencephalogram
can be regarded as arising from cortex linearly filtering sub-
cortical (thalamic) input. The direct empirical consequence
is that the electroencephalogram can be modeled as a fixed-
order autoregressive moving average (ARMA) process.
13
In
this manner, the estimated ARMA coefficients characterize
the properties of the “cortical” filter, whereas the estimated
amplitude of the white noise driving corresponds to the as-
sumedmagnitude of the subcortical (thalamic) input. In sub-
sequent analyses, a single scalar measure of the filter charac-
teristics is referred to as Cortical State (CS), whereas the
amplitude of the innovating noise is defined as the Cortical
Input (CI). From a functional point of view, CS can be
understood as characterizing the response of cortex to an
arbitrary stimulus or input. Because of this increase in phys-
iologic specificity, it was speculated that this fixed-order
ARMA analysis would be able to detect the effects of agents
not readily detected using other methods. Initial application
of this method to sevoflurane in the presence of varying levels
of adjuvant nitrous oxide
16
revealed that nitrous oxide, con-
sistent with its antinociceptive properties, reducedCI but left
CS unaffected.
To further investigate the relevance of fixed-order ARMA
modeling for monitoring depth of anesthesia, we sought to
determine whether the ultra–short-acting synthetic opioid
remifentanil, like nitrous oxide, exerted its principle cortical
effect by reducing CI. Even in the absence of specific noxious
stimuli, we would expect there to be a “background” of sub-
cortical input arising from ambient sensory stimulation that
will be ablated by opioid action. In the study reported here, it
is found that during propofol–remifentanil anesthesia CS
responds principally to variations in propofol effect-site
concentration (Ce
PROP
) and is therefore a likely measure
of hypnotic state, whereas CI responds dominantly to
changes in remifentanil effect-site concentrations (Ce
R
-
EMI) and therefore might represent a measure of analgesic
state (nociceptive–antinociceptive balance).
Materials and Methods
Patient Recruitment and Study Design
Raw electroencephalographic waves from a previously pub-
lished study were reanalyzed.
17
The original study was ap-
proved by the institutional ethics committee (Ghent Univer-
sity Hospital, Ghent, Belgium) and written informed
consent was obtained from 45 patients of American Society
of Anesthesiologists status I, aged 18–60 yr, and scheduled
Propofol and Remifentanil Differentially Affect EEG
Liley et al.
Anesthesiology, V 113 ? N o 2 ? August 2010 293