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Monitoring the stress response during

general anaesthesia
(Invited paper for the session Modelling and Control in Anaesthesia and Intensive Care)

A.U. Schubert*, O. Simanski*, M. Janda**, R. Hofmockel**, B. Lampe*

* Institute of Automation, University of Rostock, Germany
** Clinic of Anaesthesiology and Intensive Care, University of Rostock, Germany

Abstract The major objectives of anaesthetists in the operating theatre are to maintain the hypnosis, the relaxation,
the analgesia, and the vital functions during the operation.
The aim of this paper is to present an overview of new developments regarding monitoring and control of stress
response during general anaesthesia. The applicability of
the main parameters to monitor the adequacy of analgesia
online will be discussed. Different models based on pharmacokinetic and pharmacodynamic effects in particular the
opioid remifentanil and the hypnotic propofol were developed. The response of these anaesthetics on heart rate,
different parameters of the heart rate variability and the
bispectral index during induction of general anaesthesia
were studied. Starting from these models, control strategies
in analgesia have been discussed. The developed environment for the assistant system for anaesthesia at the
University of Rostock is presented.

I.
INTRODUCTION
The main objectives during general anaesthesia are to
provide hypnosis, muscle relaxation, and analgesia of
patient. Anaesthetists apply various types of drugs to
induce and maintain adequate anaesthesia and the vital
functions while surgical manipulations and diagnostic
procedures. There are interactions between the three main
components of anaesthesia in different quantity.
Whereas gold standards are known to monitor automatically states of hypnosis and muscle relaxation there
is no standardized method to determine the state of analgesia. Analgesia is defined by the absence of pain in
response to stimuli which would be painful under nonanaesthetical conditions. Pain is an individual sensation and
during anaesthesia correlated with clinical signs. The
stress response to an external stimulus during anaesthesia
depends on the intensity of stimulus and the application
rate of analgesic drugs. The administration of hypnotic
agents is also stabilizing the state of analgesia and vice
versa. The anaesthetists control the drug rates with the
objective to achieve a balance between analgesia and
hypnosis.
The intensity of stimulus can not be standardized and
is a consequence of experience of physicians and the
sensitivity of patients. Therefore, the level of analgesia
can only be determined as a contemporary reaction on a
stimulus under known rates of anaesthetics. The quantification of the stress response is therefore restricted to a
comparison with the state of the patient without the influence of stimuli or with the response to other stimuli.
II. POTENTIAL MONITORING METHODS
In the clinical practice individual signs of inadequate
analgesia can be an increase in heart rate (HR) and arte-

rial blood pressure (ABP), mydriasis - widening of

pupils, sweating and lacrimation - tears flow. Analgesic
stability is defined according to haemodynamic stability
by lack of variation between 20% of the reference heart
rate or the arterial pressure [1]. The classically used endpoint in response to painful stimulation is the movement
of the patient [2].
In the last years different monitor methods have been
tested to quantify the stress response. The Bispectral
index (BIS) is a statistical evaluation of different frequency components in the electroencephalogram (EEG).
The BIS is used to monitor the depth of hypnosis as reaction on hypnotic drugs. There are also many studies to
consider the correlation of the BIS with sedation by the
combination of hypnotic and analgesic drugs. Without
using of opioids, the BIS predicts movement in response
to surgical stimulations [2]. The BIS during total intravenous anaesthesia (TIVA) shows reaction only on a
noxious stimulus and does not predict the movement of
patients [3].
In Ref. [4] skin conductance monitoring is compared
with the BIS to distinguish different clinical states of
patients while waking up after total intravenous anaesthesia (TIVA). Skin conductance varies with sympathetic
tone and the following sweat gland filling. The authors
consider that the BIS is a better predictor than skin conductance but it is characterized by slower response time.
The authors of this paper considered, that HR and ABP
are not applicable as predictor for arousal, but these parameters have been recorded every 2 min only.
The skin vasomotor reflexes measured by laser Doppler flowmetry detect a reduced skin blood flow induced
by noxious stimulation [5]. The pulse wave reflex detected by pulseplethysmography is a better predictor as
skin vasomotor reflex [6], but the sensitive suppression of
pulseplethysmography amplitude by nociceptive stimuli
is influenced by various other terms.
The pulse transit time (PTT) is a further parameter to
detect the response on nociceptive stimuli. The value of
PTT describes the time from the onset of ventricular
electrical activity to the start of the ejection into the aorta.
It can easily and continuously be measured using standard monitors in the operating theatre, electrocardiogram
(ECG) and pulse oximetery. In conclusion Singham et al.
resumed, that PTT reflects the autonomic response independently of HR [7].
None of the described monitor methods is standardized
for the use in the operating theatre. HR and ABP are the
classical parameters to register the adequacy of analgesia.
The known problem of big intra- and intervariability as
well as the dependency on the comprehensive state of

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patient is evaluated by the anaesthesits with their experience. The non-invasive measured ABP is not suitable for
closed-loop control because it supplies the measured
values in intervals of several minutes only. The invasive
measured ABP is rarely available.
The different parameters of heart reate variability
(HRV) offer the possibility to support the autonomic
response in HR, without the induction of a further monitor. They visualize both parasympathetic and sympathetic
activities of the autonomic nervous system [8]. Our research group developed an online tool for calculating the
HRV under MATLAB. Based on the measured RRintervals of ECG, the tool supplies continuously parameters in time and frequency domains. First the RR-series
are detrended by the method of Tarvainen et al. [9]. Secondly, they are sampled with 4Hz. In the time domain
analysis of modified RR-series, the standard deviation of
the last minute is calculated in a sliding time window. In
the frequency domain the FFT of last 128s is used to
achieve the power of the low frequency range (0.04 0.15Hz) and of the high frequency range (0.15 0.4 Hz).
Also the ratio of both parameters is calculated, which is
considered to mirror the changing influence of parasympathetic or sympathetic systems respectively, i.e. the
sympatho/vagal balance. Nociceptive stimuli activate the
sympathetic system [8].
Similar to HRV, respiratory sinus arrhythmia (RSA)
was investigated as response to stress stimuli during general anaesthesia. The RSA describes the influence of
spontaneous respiration on HR subsequently of stimuli.
Blues and Pomfrett concluded, that RSA is related more
to depth of anaesthesia, i.e. hypnosis [10].
Experimental pain models were developed to quantify
the stimulus response by predetermined stimulus intensity
and drug level. Thermal, pneumatic, chemical or electrical inputs have been tested. However, the intensity of
experimental pain is not relevant for surgical stimuli,
because tissue damage has to be prevented. Therefore, in
preparation for control of analgesia, it should be helpful
to observe suitable parameters perioperative.
III. MODELS FOR ANAESTHETIC EFFECTS ON POTENTIAL
STRESS PARAMETERS

There are different options for modelling the body response to drug application. They all describe the
pharmacokinetic (PK) and pharmacodynamic (PD) of the
body drug response. The PK shows the distribution of
drug in the body and the PD summarizes the effects on
the body. Empirical models are the simplest models,
which formulate directly the reaction of the body on the
drug rate. Ordinarily, compartmental models are used,
which represent a division of the body into a minimal
number of compartments. One compartment is characterized by typical behavior in drug distribution. The
mamillary model is the most spreaded compartmental
model. It consists of a central compartment reflecting the
blood plasma and a different number of peripheral compartments, which are linked to the central compartment
only. The most accurate model type in anaesthesiology is
the physiological one using several compartments with
parameters directly related to the characteristics of the
different organs.
Data of HR, ABP, BIS, and HRV have been recorded
during induction of anaesthesia in studies at the University of Rostock to investigate the effect of the
anaesthetics and the response to different painful stimuli.

Therefore, empirical [11] and compartmental models

have been developed.
For compartmental models three compartments and an
additional effect compartment (Fig. 1) have been used,
with the parameters from Minto and Schnider [12] for the
analgesic drug remifentanil and with the parameters from
Schnider et al. [13] for the hypnotic drug propofol. A
software tool was developed under MATLAB for calculation of the plasma and the effect site concentration by
constant infusion rates and the target controlled infusion
(TCI) based on the method of Bailey and Shafer [14]. The
tool simulates the drug distribution in a patient with optional values in weight, age, height, and gender. The
application period of the manually administered bolus of
propofol was 10 seconds. The period between the application of the bolus and the start of the continuous
infusion of propofol was calculated as the mean value of
the recorded periods of patients with 25 sec.

Figure 1. Pharmacokinetics and Pharmacodynamics of a three compartment model

The mean of responses of 28 patients is used for modelling. The method for unconstrained nonlinear
optimization with a simplex search of Nelder and Mead
[15] was applied to find the models, starting at initial
estimate for determined model parameters. Therefore, the
signal is negated and scaled, so that the signal starts with
zero at the beginning of the infusion. Records of 240 sec
with a sampling time of 1 sec were analyzed.
When the infusion of remifentanil started, the patients
were awake. Therefore, the HR and the HRV were influenced by a number of impressions, such as excitement
and anxiety. It could visually be concluded, that the reactions of different HRV parameters and of the BIS on
continuous infusion of remifentanil with 0,4 g/kg body
weight/ min are not significant and able to deliver any
model. Therefore, HR has been tried to model with the
output of PK/PD-model as input (Figure 2). A gain K and
the time constants T1 and TV have been acquired by the
initial model structure in (1).

G (s) =

K (1 + sTV )
(1 + sT1 )

(1)

K=1.36
T1=1 s
TV=159.79 s
Propofol is a hypnotic drug and the patient falls to
sleep by its application. The body response to propofol
appears among the BIS, the parameter of hypnotic state,
in drop of ABP, HR and the HRV. The reaction of continuous measured standard deviation (SD) is shown in

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12

35
30
Infusion rate (mg/kg/min)
Effect site concentration (ng/ml)
Reference SD continuously (ms)
Model function for SDcont. (ms)

Infusion rate of remifentanil (g/kg/min)

Effect site concentration (ng/ml)
Reference HR (bpm)
Model function for HR (ms)

10

25
20
15
10
5

2
0

50

100

150

200

-5

250

50

100

Fig. 4 as an example for modelling the body response to

propofol. Firstly, a propofol bolus of 2 mg/ kg body
weight has been applied and than the continuous infusion
of 2 mg/ kg body weight/ h has been started. A slightly
signal increase was observed immediately after the beginning of bolus application in HR, the SD of time
domain analysis, and the low frequency component of
frequency domain analysis. It is probably caused by
stinging pain in vein during the beginning of propofol
application. It has been ignored for model optimization.
The commonly used limiter function for propofol is a
fractional sigmoid Emax model between the effect compartment concentration ce and the effect on the response
parameter [20]. The authors choose an arctangent function, where K1 and K2 are gains optimized also by
modelling. The pharmacodynamical model describing the
propofol model to changes in SD of HR is shown in
Fig.3, where the limiter function and second order model
with delay Td of body reaction are in series.
e sTd
(1 + sT1 )(1 + sT2 )

ce

200

250

SD
K1 arctan(K 2 ce ' )

Figure 3. Pharmacodynamical model for standard deviation of heart rate

associated with propofol

Figure 4. Modelling of standard deviation in response to propofol

infusion

anaesthesia. In Fig. 5 the mean values of the responses of

SD of the time domain analysis of HR for 14 patients
respectively to the intubation and to the insertion of laryngeal mask have been compared [16]. The effect of
intubation is significant higher compared with laryngeal
mask insertion.
The authors concluded from the results of modelling
and the reaction on different painful stimuli, that the
combination of HR and the continuously calculated SD of
HR will be a significant parameter setting for monitoring
analgesia. In the next investigations these parameters
should be observed perioperative to evaluate their capability for controlling of analgesia.
45
Intubation
Laryngeal mask
40
Standard deviation continuously (ms)

Figure 2. Modelling HR response to the infusion of

remifentanil

ce

150
Time (s)

Time (s)

35

30

25

20

15

50

100

150

200

250

Time (s)

The parameter set resulted from optimization for the

complex model as shown in Fig. 4 is given with:
K1= -9.105 K2=0.013
Td=22.5 s
T1=70.34 s
T2= 14.64 s.
Generally, it seems to be more useful to approach
models with an easier structure. First order models with
delay of body response have been attempted for modelling of the responses of HR, the low and high frequency
total power of frequency domain analysis to the application of propofol.
Fig. 5 demonstrates the evidence of HRV-parameters
to distinguish the intensity of stimuli during general anaesthesia. The patient is in steady state after the induction
of anaesthesia with the used anaesthetics. The insertion of
a laryngeal airway mask or the intubation follows to
enable artificial ventilation. The investigators considered
that the intubation is the most painful stimulus during

Figure 5. The SD response to intubation and to laryngeal mask airway

insertion

IV. CONTROL STRATEGIES FOR ANALGESIA

Up to now, a standard measurement for pain or state of
analgesia of the patient is not known. Only few relevant
approaches of closed-loop controllers for analgesia have
been established.
In Ref. [17] a multiple input multiple output predictive
controller was presented to regulate the invasive mean
ABP by infusion rate of alfentanil through a computercontrolled infusion pump based on TCI-models. The
predicted plasma concentration of alfentanil was involved
also as an output in the control strategy. The controller is
able to avoid under- and overdosing and to keep the ABP
on different reference values. A limitation of the method
is the application of invasive ABP, because it represents
an additional catheter, which is no routine in the operating theatre.

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Schwilden and Stoeckel [18] developed a closed-loop

controller to maintain the median frequency of EEG at 24 Hz using the opioid alfentanil. The EEG is known to
reflect the hypnotic state of the patient more than his
analgesic state. Therefore, it is not an appropriate procedure for pain control.
The research group of Mahfouf and Nunes [19] linked
a multivariable fuzzy controller based on three rules with
a patient model. The patient model relates the HR, the
systolic ABP, and the auditory envoked potential features
with the effect concentrations of hypnotic drug propofol
and analgetic drug remifentanil. The effects of surgical
stimuli were involved in this model by Mamdani fuzzy
models using expert knowledge of anaesthesiologists.
The system is characterized by a very complex structure,
but so far there are no experiences with applications on
humans.
Stadler based the analgesia controller on a physiological PK model using alfentanil and the inputs HR and noninvasive mean ABP [20]. The measurement period of
ABP was reduced to the minimal value of 2 min, so that
no complication originates for the patient. Hence, the
haemodynamic changes in response to stimuli are more
rapid. The combined measurement of non-invasive ABP
and HR should replace the seldom available invasive
ABP. A modified cascade structure was used for the
controller. The inner cascade was a TCI system without
feedback from the patient. The outer loop influences the
target concentration of the inner loop by controlling the
changes of HR and ABP. The pain detection is defined by
exceeding a relative threshold value of HR, but the target
concentration is only increased, if this occurrence is accompanied by a high ABP. So far, the concept was
validated in pilot studies with less intense stimuli.
In the research group Anaesthesia Control at the University of Rostock an assistant system for anaesthesia
(ASYNARO) was developed [21]. The system controls
two major components of anaesthesia, the hypnosis and
the neuromuscular block. For controlling the depth of
anaesthesia a fuzzy-PD+I (P-proportional, D-differential,
I-integral part) controller calculates the amount of hypnotic drug propofol to minimize the error between the
actual measured BIS-value and the BIS set point of 40.
The developed fuzzy system, with integrated prefilter,
normalization and derivation, is composed of separate
PD- and I-part. Therefore, the number of rules was limited: 7 rules for the I-part and 43 for the PD-part. The
rules were modified together with the anaesthetists. The
fuzzy controller uses the Mamdani interference system.
For the control of muscle relaxation, an adaptive Generalised Predictive Controller (aGPC) was developed. The
controller strategy is divided into two periods. At the
beginning of control the patient behaviour is highly
nonlinear. Therefore, a modified on-off controller is used
to determine a bolus application of the relaxant to the
patient. The GPC takes the control in the second period
after identifying the linear model. The online identification of a third-order discrete-time ARX-model is
implemented to get the actual patient information. The
redundant sensor structure with parallel electromyographically and acceleromyographically measurement
advances the safety of the control procedure. The system
with both controllers was tested successfully for 51 patients during elective surgery under general anaesthesia.
The maintaining of haemodynamic and other vital
functions is the forth major objective during general an-

aesthesia. For neuro- or cardiac surgery it could be

beneficial to decrease the blood pressure to limit bleeding
and establish better surgical conditions. As mentioned
above, the blood pressure is influenced by anaesthetics
and could reflect the state of analgesia. Therefore, our
research group made an effort to create a blood pressure
control system [22]. Based on the model of Slate et al.
[23] a fuzzy gain scheduled PID controller for hypotension by the application of sodium nitroprusside was
developed.
The next step will be the development of ABP control
to keep the blood pressure on a determined level by application of two different drugs for hypotension and
hypertension. After integration of blood pressure control
into the assistant system for anaesthesia, further studies
will taking place in preparation of closed-loop control of
analgesia by the HR and the HRV-parameter SD with the
fast acting analgesic drug remifentanil and hypnotic drug
propofol. The BIS and the ABP are already controlled,
but the parameters are strongly influenced by the state of
analgesia. Therefore, a new control strategy has to be
conceived for a completion of the multiple input multiple
output (MIMO) structure of anaesthesia assistant system
described in Fig. 6.

Figure 6. MIMO structure for prospective assistant system for anaesthesia control

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