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5719
Although manual control of anesthesia is still the dominant practice during surgery, an increasing number of
studies have been conducted to investigate the possibility of automating this procedure. Several clinical studies
that compare closed-loop to manual anesthesia control performance have been reported. These studies used
proportional-integral-derivative (PID) controllers, as well as model-based controllers. However, there is a
need for a comprehensive evaluation of closed-loop systems, to establish their safety, reliability, and efficacy
for anesthesia regulation. This requires a detailed evaluation of promising and/or recent controllers for a
range of patients and conditions via simulation. The present study investigates the performance of singleloop PID, cascade, model-predictive, and RTDA (Robustness, set point Tracking, Disturbance rejection,
Aggressiveness) controllers for closed-loop regulation of hypnosis using isoflurane with bispectral index (BIS)
as the controlled variable. Extensive simulations are performed using a model that simulates patient responses
to the drug, surgical stimuli, and unexpected surgical events. Results of this comprehensive evaluation show
that model-predictive and RTDA controllers provide better regulation of BIS, compared to the other controllers
tested.
1. Introduction
Biomedical applications of process control have been
attracting the attention of researchers for several years now.1
One such application is the regulation of anesthesia, which
is a reversible pharmacological state where a patients
hypnosis, analgesia, and muscle relaxation are at the desired
levels. Automating anesthesia regulation enables anaesthetists
to pay more attention to critical signs of the patient during
surgery and it reduces risks due to fatigue, distraction, and
human error.2 The bispectral index (BIS) is a derivative of
the electroencephalogram (EEG), and is a noninvasive
measure of brain activity using electrodes attached onto the
subjects scalp.3 It is a dimensionless, empirically calibrated
index with a numerical value between 0 (deep coma) and
100 (awake state). BIS has been found to be a reliable
measure of sedation, irrespective of the type of anesthetic
drug, and has been successfully tested for propofol, isoflurane,
and midazolam.4 It also gives a better indication of the
patients response to incision than other EEG-derived parameters such as median frequency and 95% spectral edge
frequency.5
Several clinical trials on closed-loop hypnosis regulation
with isoflurane using BIS as the controlled variable have
already been conducted and reported in the literature.6-8
These studies used the ubiquitous proportional-integralderivative (PID) controllers, as well as advanced model-based
controllers. Because of the potential risks of such clinical
trials, they are often conducted on young, healthy patients
undergoing noncritical surgical procedures. As such, the
efficacy of controllers in the presence of extreme patient
sensitivities (e.g., that of a young child or an elderly person)
and unexpected surgical events (e.g., sudden loss of feedback
signal) cannot be fully evaluated. Without extensively
validating the performance of controllers under these sce* To whom correspondence should be addressed. Tel.: (65) 6516
2187. Fax: (65) 6779 1936. E-mail: chegpr@nus.edu.sg.
5720
[]
Cinsp
C1
C2
)
C3
C4
C5
where
-kR
k1R
k10
-k1
(
(
(
(
k12
k13
k14
k15
V1
V2
V1
V3
V1
V4
V1
V5
)
)
)
)
0
V2
k21
V1
0
V3
k31
V1
0
V4
k41
V1
0
V5
k51
V1
-k20 - k21
-k31
-k41
-k51
() () () ()
Q0 - Q + fR(VT - )
V
fR(VT - )
)
V
fR(VT - )
)
V1
kR )
k1R
k10
[ ][]
Cinsp
C1
C2
+
C3
C4
C5
Q0
V
0
0 [C0]
0
0
0
(1)
Ce
Ce + EC50
(2)
(3)
PD Parameters
fR
VT V1
ke0
EC50
(min-1) (L) (L) (min-1) (vol %)
25
25
10
10
4
4
4
4
10
25
25
10
4
4
4
4
1.2
1.2
0.6
0.6
0.8
0.8
0.3
0.3
0.6
1.2
1.2
0.6
0.8
0.8
0.3
0.3
1.60
1.60
2.31
2.31
3.02
3.02
3.02
3.02
2.31
1.60
1.60
2.31
3.02
3.02
3.02
3.02
3.4890
0.3853
3.4890
0.3853
0.3853
3.4890
0.3853
3.4890
0.0804
0.0804
0.0804
0.0804
0.0804
0.0804
0.0804
0.0804
0.5146
0.7478
0.5146
0.7478
0.7478
0.5146
0.7478
0.5146
1.0940
1.0940
1.0940
1.0940
1.0940
1.0940
1.0940
1.0940
steady-state
gain
0.7915
1.5340
0.7915
1.5340
1.5340
0.7915
1.5340
0.7915
2.9130
0.7915
2.9130
0.7915
2.9130
0.7915
0.7915
2.9130
82.8
81.1
74.1
70.7
67.0
66.5
62.2
61.9
60.2
58.8
58.3
54.2
40.1
35.1
30.1
20.9
a
Note: Nominal values of other parameters in the PK model are
given as follows.7,18 Rate constants: k12 ) 1.26 min-1, k13 ) 0.402
min-1, k14 ) 0.243 min-1, k15 ) 0.0646 min-1, k20 ) 0.0093 min-1, k21
) 0.210 min-1, k31 ) 0.0230 min-1, k41 ) 0.00304 min-1, and k51 )
0.0005 min-1; volume of compartments: V2 ) 7.1 L, V3 ) 11.3 L, V4 )
3.0 L, and V5 ) 5.1 L; physiological dead space: ) 0.15 L; losses of
the breathing circuit: Q ) 0.2 L/min; volume of respiratory system: V
) 5 L; and fresh gas flow: Q0 ) 1 L/min.
5721
23
tuning rules
original settings
final settings (with fine-tuning)
Kc
0.38Kcu
-0.21
-0.08
1.2Pcu
15.2
11.5
0.18Pcu
2.29
0.30
Kc
original
final (set 1)
final (set 2)
5.5
5.5
5.5
original
final
5.5
4
Master Controller
Kc
-0.020
-0.018
-0.018
5.4
6.0
12.0
0.4
0.1
0.1
-0.018
-0.025
6.0
6.0
0.1
0.05
PIDPI
Figure 2. Comparison of open-loop responses of all 972 patients (represented by black lines) with the 16 selected patients (represented by thick
red lines).
Kc
tuning rules
original settings
final settings (with fine-tuning)
(2c -0.46
-0.09
c2)/(Kc2)
PIDP
a
Note: IMC tuning for a PID controller is given as follows: Kc )
[ + (/2)]/{K[c + (/2)]}, I ) + /2, and D ) /(2 + ).
21
14
14
14
I
(2c - c2)/
48.0
12.0
takes the nominal patient model to a BIS value of 50. This step
change is small compared to the C0 value that is used to induce
hypnosis in a patient, and, hence, a long time is required to
attain steady state. Larger step changes in C0 results in the final
BIS value being well below 50.
Figure 2 clearly shows that the 16 selected PPs cover the
open-loop dynamics of the 972 patients. The values of the PK
and PD parameters for these 16 selected PPs are given in Table
1, which also includes the steady-state gain of each PP to the
step change of 0.7068 vol % in the input C0 value used for
Figure 2. These gains are calculated based on the ratio of the
difference between the initial value and the final steady-state
value of the output (BIS) to the given step input (C0, in units of
vol %). A high gain value in Table 1 indicates a sensitive patient
and a low gain indicates an insensitive patient. In the set of 16
profiles constructed, more emphasis is placed on insensitive
patients, because controller performance is expected to degrade
with decreased sensitivity. Notably, PP 15 and PP 16 represent
extremely insensitive patients who are atypical, and controller
performance is expected to be poor when tested on these PPs.
Because of the uncertainty in the model parameters, it is
useful to perform controllability, observability, and robustness
analysis. These analyses were performed on the linearized
patient model (linearized at the operating point, BIS ) 50). For
all 16 patient profiles, all seven states were determined to be
controllable and observable. Furthermore, controllability analysis
shows that the output (BIS) is controllable for all of the patient
profiles. Robustness analysis of the closed-loop system of the
patient model with the proportional-integral (PI) controller
shows that the system is robustly stable for the deviations in
the parameters considered. It furthermore shows that the system
is more sensitive to the parameters fR and EC50, which is
consistent with the open-loop sensitivity analysis.
3. Controller Design
Six controllerssidentified as PI, PID, cascaded PIDP,
cascaded PIDPI, MPC, and RTDAswere designed for closedloop administration of isoflurane to regulate hypnosis. All these
5722
Figure 4. BIS response with PI controller for all 16 patients for a set point
change from 100 to 50.
Figure 6. IAE values for the maintenance period for six controllers on 16
patients.
200
250
300
50 to 60
60 to 40
40 to 50
5723
Table 6. Controller Performance of Various Controllers for the Maintenance Period (t ) 100-350 min)
Value for the Controllera
performance criterion
PI
PID
PID-P
PID-PI
MPC
RTDA
IAE
MDPE
MDAPE
wobble
% time outside
(10 BIS
(5 BIS
TV
1767 (617)
-3.29 (4.38)
11.5 (5.79)
10.2 (4.11)
1801 (624)
-3.54 (4.46)
11.8 (5.98)
10.3 (4.01)
1542 (593)
-2.95 (3.43)
9.41 (4.95)
8.62 (4.30)
1719 (1017)
-4.11 (10.8)
10.8 (9.67)
8.51 (3.59)
1314 (229)
-0.87 (0.61)
7.40 (1.80)
7.24 (1.71)
1215 (219)
-0.79 (0.60)
6.59 (1.71)
6.95 (1.64)
24.6 (12.2)
51.4 (16.3)
45.42 (9.35)
25.4 (12.5)
52.4 (16.0)
44.66 (8.99)
19.4 (12.2)
43.6 (16.2)
53.56 (9.67)
22.2 (18.1)
43.8 (18.5)
47.58 (9.48)
15.3 (4.20)
37.2 (9.71)
60.16 (11.49)
13.5 (3.85)
34.6 (8.56)
63.25 (12.11)
Note: The mean and standard deviation (shown in brackets) of the criterion for each controller are given in Tables 6 and 7.
Table 7. Controller Performance of Various Controllers for the Surgical Stimuli Period (t ) 100-160 min)
Value for the Controllera
performance criterion
PI
PID
PID-P
PID-PI
MPC
RTDA
IAE
MDPE
MDAPE
wobble
% time outside
(10 BIS
(5 BIS
TV
618 (55)
-1.77 (5.38)
18.5 (2.35)
17.9 (2.13)
622 (62)
-1.86 (5.31)
18.7 (3.09)
18.3 (2.88)
569 (49)
-2.90 (5.00)
16.0 (2.35)
15.3 (2.55)
618 (200)
-0.21 (9.76)
17.4 (5.42)
16.7 (6.52)
571 (45)
-3.16 (5.10)
16.8 (2.41)
15.5 (2.57)
545 (41)
-2.85 (4.56)
15.2 (2.25)
14.1 (2.41)
45.2 (6.64)
72.1 (3.58)
22.96 (6.64)
45.6 (7.52)
71.8 (4.64)
21.89 (6.72)
39.4 (6.13)
68.7 (5.53)
30.41 (7.61)
41.3 (8.97)
69.1 (6.06)
23.1 (9.49)
41.7 (5.77)
69.2 (6.2)
30.75 (7.96)
37.2 (5.42)
64.8 (5.6)
33.29 (11.85)
Note: The mean and standard deviation (shown in brackets) of the criterion are given for each controller.
Figure 7. Percentage of the time that BIS is (5 units outside its setpoint
during the maintenance period.
min
uk,uk+1,...uk+M-1
J )
i)k+1
k+M-1
eTi Sei +
uTi Rui
(4)
i)k
(for
i ) k, k + 1, ...k + M)
5724
Figure 8. Performance of (a, b) PID, (c, d) MPC, and (e, f) RTDA controllers for PP 1, PP 4 (nominal), and PP 13.
5725
Figure 9. Performance of (a, b) PID, (c, d) MPC, and (e, f) RTDA controllers for the nominal (PP 4) and highly insensitive (PP 15 and PP 16) patients.
filter time constant to avoid introducing too much lag into the
closed-loop response. Lower and upper limits of 0 and 5 vol %7
were also placed on the controller outputs for all six controllers.
In this study, all the patient models, controllers and closedloop systems were implemented and simulated in SIMULINK.
The MATLAB and SIMULINK files that pertain to this work
will be made available to interested readers upon request.
Figure 3 shows a schematic representation of the closed-loop
setup for regulating hypnosis that uses BIS as the controlled
variable. Figure 4 shows the BIS response for all of the patient
sets reported in Table 1 with the PI controller (with settings
given in Table 2) for a set point change from 100 to 50. From
this figure, one can clearly observe that the second half of the
|e(t)| dt
t
(5)
5726
Figure 10. Effect of PD parameters on closed-loop performance during the loss of BIS signal (t ) 120-200 min): (a) effect of EC50, (b) effect of , and
(c) effect of ke0.
Table 8. Estimated EC50 Values for Selected PPs for All Six
Controllers
Estimated EC50 Value
controller
PP 1 (actual
EC50 ) 0.5146)
PP 7 (actual
EC50 ) 0.7478)
PP 13 (actual
EC50 ) 1.0940)
0.4986
0.4975
0.4752
0.4786
0.5055
0.5085
0.7285
0.7196
0.7289
0.7205
0.7401
0.7425
1.1105
1.1226
1.1195
1.1235
1.0885
1.0902
PI
PID
PIDP
PIDPI
MPC
RTDA
Large IAE values indicate responses that are more sluggish and
less desirable. However, they do not indicate the amount of
oscillatory behavior. The performance criteria based on the
performance error (PE), which were used by Struys et al.,27
were also employed.
PE )
(6)
(7)
(8)
(9)
|u
TV )
i+1
i)0
- ui
(10)
The TV value of u(t) is the sum of all the up and down control
moves. Thus, it is a good measure of the smoothness of the
manipulated input. The TV value should be as small as possible.
Controller performance was evaluated mainly for the surgical
stimuli and the maintenance phase of the surgery. Less emphasis
was placed on the induction period during which a patient is
brought into a hypnotic state. Induction is typically conducted
using open-loop intravenous injection of hypnotics to avoid the
undesirable slow-acting characteristic of volatile hypnotics such
as isoflurane. In fact, in clinical trials to evaluate controller
performance, such as those conducted by Morley et al.6 and
Struys et al.,28 the induction of anesthesia was done in openloop control and the controller was switched on only after
5727
Figure 11. BIS response and controller output in the absence of BIS signal from t ) 120-200 min for PP 3, using (a, b) MPC and (c, d) RTDA.
5728
Figure 12. Performance of MPC and RTDA controllers, in the absence of BIS signal in the period of t ) 120-200 min: (a, b) transient profiles for PP 1,
PP 7, and PP 13, using MPC, (c, d) transient profiles for PP 1, PP 7, and PP 13 using RTDA, and (e) IAE comparison for all patient models.
5729
5730
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