Monitoring of the responsiveness to noxious stimuli during
anaesthesia with propofol and remifentanil by using RIII reflex
threshold and bispectral index
F. von Dincklage*, M. Hackbarth, R. Mager, B. Rehberg and J. H. Baars
Department of Anesthesiology, Charite´, Universita¨tsmedizin Berlin, Berlin, Germany
*Corresponding author: Charite´ Universita¨tsmedizin Berlin, Klinik fu¨r Ana¨sthesiologie mit Schwerpunkt operative
Intensivmedizin, Campus Mitte, Charite´platz 1, 10117 Berlin, Germany. E-mail: falk.von-dincklage@charite.de
Background. Movement responses are an important indicator of noxious perception in the
unconscious state. To allow for a continual monitoring of the responsiveness to noxious stimuli
during general anaesthesia, surrogate parameters are needed. Here we compare the perform-
ance of the bispectral index (BIS) and the RIII threshold in predicting reactions to noxious
stimuli during anaesthesia with propofol and remifentanil.
Methods. Twenty male volunteers were included. The first 10 subjects received constant con-
centrations of propofol while remifentanil concentrations were increased stepwise. The other
10 subjects each received high propofol concentrations combined with different low remifenta-
nil concentrations and also low propofol concentrations combined with different high remifen-
tanil concentrations. In all subjects, the reactions to an 80 mA 30 s tetanic stimulus were
tested every 5 min. BIS and RIII threshold were recorded continually in all subjects.
Results. Nineteen subjects completed the study. The population prediction probability for
reactions to the noxious stimuli amounted to 0.86 for the BIS and to 0.84 for the RIII
threshold in the first 10 subjects (P.0.05, PKDMACRO). In the other nine subjects, the pre-
diction probabilities amounted to 0.64 for the BIS and to 0.77 for the RIII threshold (P,0.05,
PKDMACRO). All population prediction probability values differed significantly from 0.5
(P,0.01, PKDMACRO).
Conclusions. RIII threshold and BIS are both influenced dose-dependently by remifentanil at
those concentrations that suppress reactions to noxious stimuli. The susceptibility of the par-
ameters to remifentanil concentration seems to be of a similar quality. Under different ratios
of propofol and remifentanil concentrations, the RIII threshold correlates with non-responsive-
ness better than the BIS.
Br J Anaesth 2010; 104: 201–8
Keywords: anaesthetics i.v., propofol; analgesics opioid, remifentanil; measurement techniques,
electrophysiology; monitoring, depth of anaesthesia; monitoring, electroencephalography
Accepted for publication: October 27, 2009
Anaesthetic depth can be defined as the probability of
a non-response to stimulation.
1
This non-response has to
be evaluated in the context of the strength of the stimulus,
the definition of the response, and the drug concentration
at the site of action that blunts responsiveness. In this
model, two components are further defined as necessary to
create the anaesthetic state: hypnosis created with drugs
such as propofol or inhalation anaesthetics and analgesia
created with opioids, nitrous oxide, or other means.
Simplified these components can be regarded to act
together in a hierarchical order where the net effect of
analgesics is to attenuate the transmission of painful sen-
sation to the cortex, reducing the amount of hypnotic
required to obtain the state of non-responsiveness.
As a difficulty for the application of this model, the
components hypnosis and analgesia cannot be measured
directly and therefore clinical relevant endpoints have to
be defined instead, such as the responsiveness to verbal
commands or the responsiveness to painful stimuli such as
laryngoscopy or surgical incision. Again, these endpoints
# The Author [2009]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournal.org
British Journal of Anaesthesia 104 (2): 201–8 (2010)
doi:10.1093/bja/aep357 Advance Access publication December 22, 2009

have the drawback that they can only be evaluated by
singular testing and therefore further parameters as
surrogates for these endpoints are needed to allow for a
continual monitoring. To act as a surrogate for the respon-
siveness to verbal commands, several rather precise par-
ameters have already been developed, such as indices
derived from the processed EEG like the bispectral index
(BIS). For the responsiveness to painful stimuli on the
contrary, no precise surrogate parameters exist.
Here we would like to propose the RIII reflex threshold
as a possible surrogate for the responsiveness to painful
stimuli. The RIII reflex as a component of the nociceptive
flexion reflex is a polysynaptic spinal withdrawal reflex
that is elicited by stimulation of nociceptive nerve affer-
ents. To assess the RIII reflex, biceps femoris muscle
activity is monitored using an EMG during the application
of electrocutaneous stimuli to the ipsilateral sural nerve.
On the basis of the observed EMG response, the stimulus
intensity required to elicit the RIII reflex can be used as
an objective measure of the individual nociceptive
threshold.
23
Recently, we have demonstrated that the prediction
probability of this RIII reflex threshold for reactions to
noxious stimuli during propofol mono-anaesthesia has a
comparable precision to that of the BIS.
4
Also the respon-
siveness of the RIII threshold to influences from analgesic
substances has been demonstrated in several studies.
5–12
Therefore, a susceptibility of the RIII reflex threshold to
both hypnotic and analgesic influences seems to be
evident, which can be regarded as the prerequisite for a
good performance as a surrogate for non-responsiveness to
painful stimuli since the non-responsiveness is usually a
product of the combination of these influences.
However, for a good performance as a surrogate par-
ameter, the parameter does not only have to be susceptible
to hypnotic and analgesic substances. Also the relative
susceptibility to each of the two substance classes has to
be similar to the influence of the substances on the
mechanisms producing the non-responsiveness to painful
stimuli. As an example, a parameter could respond in a
dose-dependent manner to both propofol and opioids. But
if the relative effect of the different substances on the par-
ameter would be in a different relative proportion as they
would affect the non-responsiveness to painful stimuli
itself, no conclusions can be drawn from the parameter to
the state of non-responsiveness.
In this study, we compared the performance of the RIII
reflex threshold and the BIS as surrogate parameters of the
non-responsiveness to painful stimuli by comparing their
prediction probabilities for the responsiveness to painful
electrical stimulation. The BIS was used in this study as a
comparison since even though it is not designed as a sur-
rogate of non-responsiveness to noxious stimuli, it can still
be regarded as the standard monitoring device of anaes-
thetic depth and which has to be outperformed by any
potential technique for monitoring immobility.
Methods
Subjects and setting
After approval of the local ethics committee (Berlin,
Germany) and obtaining written informed consent, the
study was performed in 20 healthy (ASA class I) male
volunteers, ranging in age from 23 to 35 yr. Only male
volunteers were included to reduce the variability of the
RIII reflex threshold. During the course of the study, the
subjects were comfortably rested in therapy beds with a
flexed leg-section to maintain angles of 1208 in the hip
and 1308 in the knee.
Automated RIII threshold tracking
To elicit the RIII reflex of the left biceps femoris muscle,
the left sural nerve was repeatedly stimulated at its retro-
malleolar pathway via surface electrodes (inter-electrode
distance: 30 mm). Stimuli were applied automatically at
randomized intervals of 8–12 s to avoid habituation, with
each stimulus consisting of a volley of five rectangular
electrical pulses of 1 ms duration each, at 200 Hz (DS5,
Digitimer Ltd, Hertfordshire, UK). To record the RIII
reflex of the left biceps femoris muscle, surface electrodes
were placed over its lateral tendon and over the muscle
itself, 10 cm proximal of the popliteal fossa. The recorded
signals were amplified (g.BSamp, g.tec, Schiedlberg,
Austria), digitized at a sampling rate of 5 kHz (Mikro
1401 mk II, CED Ltd, Cambridge, UK), rectified, and ana-
lysed using Signal 3.10 (CED Ltd).
In this study, the RIII reflex threshold was traced conti-
nually by an automated RIII threshold tracking system.
This system varies the stimulus intensity according to an
up–down-staircase algorithm with a variable step length
to estimate the stimulus intensity associated with a 50%
probability of RIII reflex occurrence, which is defined as
the reflex threshold.
13
RIII reflex occurrence was defined
as an interval peak z score higher than 10.32 in the post-
stimulation interval of 90–150 ms.
14
Testing procedure for reactions on verbal and
noxious stimuli
During the whole course of the study, the reactions on
verbal and noxious stimuli were tested every 5 min. The
testing sequence was performed in the following order:
one single verbal command, loudly repeated verbal com-
mands, trapezius squeeze of 10 s duration, electrical
tetanic stimulation in the area of the right ulnar nerve with
80 mA for 30 s. The different stimuli were applied
immediately one after another, with a maximum of 5 s in
between. Any verbal or movement reaction, regardless of
purposeful or not, was considered as a positive response
and the sequence of reaction testing was aborted.
von Dincklage et al.
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