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Ind. Eng. Chem. Res.

2009, 48, 57195730

5719

A Comprehensive Evaluation of PID, Cascade, Model-Predictive, and RTDA


Controllers for Regulation of Hypnosis
Yelneedi Sreenivas, Tian Woon Yeng, G. P. Rangaiah,* and S. Lakshminarayanan
Department of Chemical & Biomolecular Engineering, National UniVersity of Singapore, Singapore 117576

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.

A preliminary version of this paper was presented at ADCONIP


2008, Canada.

narios, the application of such closed-loop systems remains


limited. Recently reported simulation studies for regulation
of hypnosis with isoflurane are limited to the nominal
patient.9-11 Therefore, it is important to conduct a comprehensive evaluation of promising and/or recent controllers for
a range of patients and conditions via simulation.12,13
The present study has two main objectives. One objective
is to apply and evaluate the promising model predictive
control (MPC) and the recent RTDA (Robustness, set point
Tracking, Disturbance rejection, Aggressiveness) approaches
for hypnosis regulation using BIS as the controlled variable
by manipulating isoflurane infusion. MPC is a popular control
scheme that has been used by process industries for many
years, for the optimal, constrained control of complex
multivariable processes.14,15 Recently, this controller has been
used for the regulation of hypnosis with propofol.16 RTDA
is the most recent control scheme used for single-input-singleoutput (SISO) systems.17 Another objective is to extensively
assess and compare the performance of single-loop PID,
cascade, MPC, and RTDA controllers for hypnosis control.
The performance comparison of six controllers is conducted
by testing the robustness (considering parameter variations
in the patient model to account for patient-model mismatch),
set point changes, and disturbances during the surgery. For
realistic assessment, measurement noise is added to the BIS
signal in the simulations.
2. Patient ModelsModeling Hypnosis
The response of a patient to the hypnotic drug is modeled
with a pharmacokinetic (PK)/pharmacodynamic (PD) model.
The PK model describes the drug distribution within the body,
and the mammillary compartmental model of Yasuda et al.18
(shown in Figure 1) was adopted for this study. Mass balance
about the various compartments gives the following sixth-order
linear PK model:7

10.1021/ie800927u CCC: $40.75 2009 American Chemical Society


Published on Web 05/18/2009

5720

[]

Cinsp
C1
C2
)
C3
C4
C5

where

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

-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)

k1 ) k10 + k12 + k13 + k14 + k15


The values of these parameters are given in Table 1.
The PD model describes the drug effect and is comprised of
a first-order lag and a static Emax model.13 They respectively
account for time taken for the drug to distribute to the effectsite and the relationship between BIS and the effect-site
concentration (Ce). The first-order lag and Emax models are given
as
dCe
) ke0(C1 - Ce)
dt
BIS ) 100 - 100

Ce
Ce + EC50

(2)

(3)

where ke0 is the equilibration constant of the effect compartment,


EC50 the effect-site concentration of the drug at half-maximal
effect (i.e., the concentration corresponding to a BIS value of
50), and a measure of nonlinearity.
Patient variability in drug responses was simulated by varying
important parameters in the PK and PD models. Open-loop
simulations (by varying each parameter independently) showed

Figure 1. Mammillary compartmental model (from Yasuda et al.18)

that the dominant PK parameters are breathing frequency (fR),


tidal volume (VT), and lung volume (V1). In the PD model, all
three PD parameters (EC50, ke0, and ) were determined to be
important. Hence, these three PK and three PD parameters were
varied over three levels (except VT, which was varied over four
levels) within their ranges reported in Yasuda et al.18 and
Gentilini et al.,7 and then combined to give many PK and PD
models with different drug sensitivities. From these, 16 patient
profiles (PPs) with different combinations of the PK and PD
models were chosen, based on decreasing sensitivity to the
drug.19 Figure 2 shows the open-loop responses of all 972 (4
35) patients, along with those of the 16 selected PPs. These
data are for a step change of 0.7068 vol % in the input C0, which
Table 1. Sixteen PPs and Their Associated PK and PD Parametersa
PK Parameters
patient
profile
1
2
3
4 (nominal)
5
6
7
8
9
10
11
12
13
14
15
16

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.

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

5721

Table 3. Tuning Rules and Their Associated PID Controller


Settings

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

Table 4. Cascade Controller Settings Using the Method of Chen and


Seborg21 for the Slave Controller and the IMC Method20 for the
Master Controllera
Slave Controller
setting

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 + ).

Table 2. Tuning Rules and the PI Controller Settings

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

controllers were tuned for minimal integral of absolute error


(IAE) and smaller undershoot in BIS response in the induction
period of t ) 0-100 min for the nominal patient. The
performance of all the controllers was then checked for the
maintenance period (i.e., for t ) 100-350 min) and was
determined to be satisfactory, before further testing and evaluation. Thus, controllers were designed not just for the induction
period but also for the maintenance period. PI(D) and cascade
controllers were designed with specific tuning rules and later
were fine-tuned, whereas MPC and RTDA controllers were
tuned via a direct search optimization algorithm. For the PI
controller, the nonlinear patient system was approximated by a
linear first-order (FO) model. Time delay was neglected due to
the large time constant of the open-loop response. Linear
approximation was performed near the operating point of the
system (i.e., when BIS is near its intraoperative range of 40-60),
to facilitate the design of a controller that can respond quickly
to changes in BIS set point and reject disturbances during the
surgical period. Model parameters (K ) -53.3 vol %-1, )
317.5 min) were determined by minimizing the sum of squared
error (SSE) between the actual BIS response and the FO model
response.
For FO systems with negligible time delay, three tuning rules
are applicable: internal model control (IMC) tuning, which was
proposed by Chien and Fruehauf;20 the tuning method of Chen
and Seborg;21 and that of Haeri.22 Of these, the PI controller
settings obtained by the method of Chen and Seborg21 were
determined to be better. These controller settings gave an
oscillatory response for safe application (because of the
nonlinear nature of the patient system), and therefore the
proportional gain was first lowered, to reduce both proportional
and integral actions. The integral action was then independently
increased, to hasten the response that had become too sluggish.
The initial and final settings of the PI controller are compared
in Table 2. Similar fine-tuning was applied to design other
controllers that are studied in this work.
For the PID controller, the tuning methods of Wojsznis et
al.23 and Friman and Waller,24 which are based on the ultimate
gain and frequency of the system, were used. Using P-only
control, the ultimate gain and period of the nominal PP were
determined to be -0.55 vol %-1 and 12.7 min, respectively.
The PID controller was such that the derivative (D) action acted
solely on the filtered BIS measurement, while proportional (P)

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Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

Figure 3. Setup of a feedback controller for hypnosis regulation.

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.

Figure 5. Disturbance profile (adopted from Struys et al.27).


Table 5. Series of Intra-Operative set point Changes
time, t (min)

BIS set point change

200
250
300

50 to 60
60 to 40
40 to 50

and integral (I) actions acted on the error in BIS. This is to


avoid sudden spikes in the controller output that are due to step
changes in the setpoint. Of the two methods attempted, the
settings obtained by Wojsznis et al.23 were determined to be
better. The tuning rules of Wojsznis et al.23 and the PID
controller settings obtained are reported in Table 3.
For the cascade controllers, the inner and outer controllers
were tuned sequentially. The inner process that related the
endtidal concentration (C1) to the isoflurane input was ap-

proximated by a FO model, and the model parameters (K )


-1.06 vol %-1, ) 432.5 min) were determined by minimizing
the SSE value. The controller settings were determined using
the tuning method of Chen and Seborg,21 and their values are
as reported in Table 4. With the inner loop closed, the openloop response of BIS to set point changes in C1 was approximated by a FO-plus-time-delay model. Here, the action
of the inner loop resulted in faster dynamics of the outer loop,
and the time delay became significant when compared to the
small time constant. Using the model parameters that have been
determined (K ) -53.0 vol %-1, ) 5.0 min, ) 0.77 min),
the controller settings were calculated using the IMC tuning
method20 (see Table 4). Simulations showed that two sets of
settings (set 1, for PPs 1-14, and set 2, for PPs 15 and 16) are
required for PID-PI to guarantee satisfactory performance; only
one parameter of the master controller (I) was adjusted for
easier implementation. PID-P controller settings were obtained
by fine-tuning the PID-PI settings with the integral action
removed.
The basic objective of MPC is to determine the sequence of
M future control moves (i.e., manipulated input variable
changes) so that the sequence of P predicted responses (output
variables) has minimal set point tracking error. Although M
control moves are calculated at each sampling instant, only the
first manipulated variable move will be implemented, and the

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

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.

optimization procedure repeats for the next sampling instant


based on the latest measurements of the output variables.
The quadratic objective function for the proposed MPC
scheme is
k+P

min

uk,uk+1,...uk+M-1

J )

i)k+1

k+M-1

eTi Sei +

uTi Rui

(4)

i)k

subject to absolute and rate constraints on the manipulated


variable:
umin e ui e umax

(for

i ) k, k + 1, ...k + M)

ui-1 - umax e ui e ui-1 + umax


(for i ) k, k + 1, ...k + M)
where, at each sampling instant i, ui is the manipulated variable
deviation (ui ) ui+1 - ui), ei the predicted error (ei ) ri - yi),
ri the desired setpoint for BIS, and yi the future BIS value that
is predicted using the linear model. The weights S and R can
be used to tune the MPC controller to achieve the desired
tradeoff between output performance and manipulated variable
movement. The prediction horizon P is chosen based on the

open-loop settling time, whereas control horizon M is chosen


based on the tradeoff between faster response (large value of
M) and robustness (small value of M). Generally, the chosen
value for M is very small, compared to P. To reject constant
disturbances that are due to patient-model mismatch, the patient
model is augmented by the output disturbance model, which is
an integrator that is driven by white noise. The measurement
noise is modeled as Gaussian noise, having zero mean and unit
variance.
For the MPC controller, the patient system was taken to be
a SISO system. Although MPC allows control of multivariable
processes, the measured outputs (C1 and BIS) are related through
the pharmacodynamic model, and, hence, independent setpoints
cannot be prescribed for them. Therefore, the MPC is designed
as a SISO system, with BIS as a controlled variable, because
its setpoint is known (50 during the general surgery). In cases
where BIS must be estimated from C1 measurements (when the
BIS measurement fails, for example), theoretically, the pharmacodynamic parameters , EC50, and ke0 must be accurately
known. This could be impractical, because there will be
inevitable estimation errors in the pharmacodynamic parameters.
This issue is examined in section 6. For MPC design, the
nominal patient model was approximated to a linear SISO
system using Taylor series (with a reference point of BIS )
50). The MPC parameters that have been determined for
hypnosis regulation are output (BIS) weight (S ) 1), input
(isoflurane) weight (R ) 10), prediction (output) horizon (P )
50), control (input) horizon (M ) 2), and a sampling interval
of 5 s. Here, a finite horizon approach is used in the design of
MPC.
The RTDA controller involves a novel control scheme that
is sufficiently simple to implement and can achieve better
control.17,25,26 Each of its four tuning parameters (R, T, D,
A) is normalized between 0 and 1 (with 0 being aggressive
and 1 denoting conservative settings) and is related directly to
one performance attribute (namely, robustness, set point tracking, disturbance rejection, and aggressiveness). Hence, it is
possible to tune each parameter independently to obtain the
optimum for the corresponding performance attribute. Thus, the

5724

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

Figure 8. Performance of (a, b) PID, (c, d) MPC, and (e, f) RTDA controllers for PP 1, PP 4 (nominal), and PP 13.

RTDA controller avoids the tuning problems that are associated


with PID and MPC controllers. Furthermore, the tuning of its
parameters requires the same process reaction curve information
used to tune the PID controller. The values found for RTDA
parameters for the present application are R ) 0.7675, T )
0.9884, D ) 0.5033, and A ) 0.6130.
4. Evaluation of Controllers
For realistic evaluation of the controllers, white noise with
zero mean and standard deviations (SD) of (3 and (0.045
vol %-1 was added to the BIS and C1, respectively, in all

simulations. The SD value of (3 in BIS was used in the study


of Struys et al.27 and is also employed here. This value is
consistent with our observations in the local hospital. The SD
value of C1 is not known, so we used 0.045%, which is 6% of
the nominal value (similar to the SD value of BIS). For PI,
PID, MPC, and RTDA controllers, the BIS measurement was
passed through a filter with a time constant of 5 min, whereas,
for cascade controllers, the BIS and C1 measurements were
passed through a filter with a time constant of 1 and 5 min,
respectively. For cascade control, the inner slave controller led
to faster dynamics of the outer BIS loop, requiring a smaller

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

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

PPs (PP 9-16) are more insensitive (mainly because of lower


fR, ke0 and higher EC50) compared to the first half (PP 1-8).
Furthermore, responses in the case of PP 9, 11, 13, and 16 are
oscillatory, because of the higher value that is associated with
these patient profiles. The settling time, for the case of the most
sensitive patient (PP 1), is 30 min, compared to 250 min for
the case of the most insensitive patient (PP 16).
The IAE was used as the main performance criterion, and
this value was calculated by integrating the absolute difference
(error, e) between the BIS setpoint and its measurement.
IAE )

|e(t)| dt
t

(5)

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Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

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.

wobble ) median{|PEi - MDPE|, i ) 1, 2, ...,N}

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 )

value - target value


( measuredtarget
) 100
value

(6)

The median performance error (MDPE) is a measure of bias


and indicates if the measured value is systematically above or
below the setpoint. MDPE can be calculated from the expression
MDPE ) median{PEi, i ) 1, 2, ...,N}

(7)

where N is the number of PE values obtained for that particular


subject. MDPE is a signed value and therefore represents the
direction of PE. It does not reveal either the oscillatory behavior
or the amplitude of possible oscillations in the output.27 On the
other hand, the median absolute performance error (MDAPE)
gives the magnitude of control inaccuracy, with larger MDAPE
values being indicative of poorer closed-loop performance.
MDAPE ) median{|PEi |, i ) 1, 2, ...,N}

(8)

Wobble is an index of time-related changes in performance;


it measures the degree of intrapatient variability in PEs. It also
gives an indication of the degree of oscillatory behavior.

(9)

Large wobble values indicate large variability in PE values and,


thus, signify a more oscillatory response.
In summary, conventional measures (such as IAE) indicates
the controller performance, in terms of sluggishness in response.
These measures do not indicate the oscillatory behavior in the
response. On the other hand, MDPE indicates whether the
measured values are systematically above or below the specified
setpoint. MDAPE reflects the magnitude of the control inaccuracy, similar to IAE. Finally, wobble is an index of oscillatory
behavior of the output response.
All the above criteria characterize only the output performance of the controller. Because controller design invariably
involves tradeoff between input and output performance,
another measure of controller performancesan input performance criterion (total variation, TV)is also used. The
required control effort is computed by calculating the TV of
the manipulated input, u:

|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

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

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.

induction. The surgical stimuli period in the present study spans


the time range of t ) 100-160 min, during which period the
disturbance profile (Figure 5) adopted from Struys et al.27 was
introduced into the patient system by adding an offset to the
BIS output from the PD model (see Figure 3). In Figure 5,
stimulus A mimics the response to intubation; B represents
surgical incision, followed by a period of no surgical stimulation
(e.g., waiting for pathology result); C represents an abrupt
stimulus after a period of low level stimulation; D shows onset
of a continuous normal surgical stimulation; E, F, and G simulate
short-lasting, larger stimulation within the surgical period; and
H simulates the withdrawal of stimulation during the closing
period.27
The maintenance period refers to the entire intra-operative
period during which the surgery proceeds and a desired level
of hypnosis must be guaranteed and maintained. In the simulations, the maintenance period spanned a time period of t )
100-350 min and, hence, included disturbances that were due
to both surgical stimuli (i.e., t ) 100-160 min) and intraoperative set point changes (i.e., t ) 200-350 min). The set point
changes and their time of introduction are given in Table 5.
These do not include the BIS set point change from 100 to 50
at t ) 10 min, for the induction.
5. Performance of Controllers
Figure 6 shows IAE values obtained during the maintenance
period for all six controllers when implemented on the 16 PPs.
Advanced controllers were determined to give better closedloop control, with reductions of up to 13%, 27%, and 33% in
the mean IAE value for cascade, MPC, and RTDA controllers,
respectively, compared to PI/PID controllers (see Table 6). The
additional integral action in the inner loop of the PID-PI

controller seems to have made the closed-loop system perform


poorly, with the IAE value for PP 16 and PP 15 deviating up
to 400% and 125% from that of the nominal patient, even when
different controller settings were used. PIDP gave better control
for PP 16, with an IAE value of 3375, compared to a value of
5087 for PID-PI. The performance of PID-PI is inferior to
that of PID-P for PP 13 to PP 16 (see Figure 6). This could be
due to the slow dynamics of the inner loop, which result from
the small value of fR (see Table 1) and because disturbances
are in the outer loop in hypnosis regulation. Both these are
uncommon in chemical process applications of cascade control.
Finally, MPC and RTDA gave the best robust performance with
coefficient of variance (SD/mean) values of 0.174 and 0.180,
compared to 0.385 and 0.349 for PID-P and PI (the best
performing cascade and single-loop controller), respectively.
This indicates that MPC and RTDA controllers have the least
dependence on the patients sensitivity to the drug.
Tables 6 and 7 summarize the performance, in terms of the
mean and standard deviation of each performance criterion, of
all six controllers during the maintenance and surgical stimuli
period, respectively. The MDPE values for all controllers were
negative, which indicated a consistent tendency for the measured
BIS to be less than the setpoint. This means that the controllers
had a tendency to slightly overdose, and this observation can
be explained by the asymmetric control operation that is
performed by the controllers. They govern only the infusion,
but not the elimination, of drugs from the body, which is a
slower process.27
Results in Tables 6 and 7 further confirm that cascade, MPC,
and RTDA controllers outperform PI and PID controllers for
hypnosis regulation, with reference to other performance criteria
besides IAE. In particular, for the maintenance period (see Table

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Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

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.

6), the use of MPC and RTDA resulted in reductions of 37%


and 44% in MDAPE and 30% and 33% in wobble,
respectively, compared to PI/PID controllers, indicating better
control and less oscillation. A significant improvement in the
percentage of time for which measured BIS value was within
(5 and (10 from the setpoint is also observed for the MPC
and RTDA controllers, which indicates tighter control over the
BIS output (see Figure 7). However, improvement in surgical
stimuli rejection alone is less with PIDP, MPC, and RTDA
controllers, giving a reduction of 9% to 19% in MDAPE and
14%-23% in wobble, respectively, compared to PI/PID controllers (see Table 7). The performance of PID-PI controller

is disappointing, despite the cascaded setup, giving <10%


improvement in the performance, compared to PI/PID controller
(see Tables 6 and 7).
The last row in Tables 6 and 7 compare the input performance
(i.e., control effort (TV)) for all the six controllers. These results
show that the better control performance of MPC and RTDA,
compared to other controllers, is accompanied by greater control
effort, which may still be acceptable. This clearly shows the
aggressive nature of these two controllers, compared to the
remaining four controllers.
It is worth mentioning that the performance of all six
controllers was determined to have a greater dependence on

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

PD parameters than PK parameters. Although not presented


here, all of them had been determined to give consistent and
acceptable performance in the presence of PK variation only
(i.e., with PD parameters kept at nominal values). PK parameters
affect the uptake and distribution of drugs, whereas PD
parameters describe the drug effect and degree of nonlinearity
in the patient system. Hence, variations in PD parameters are
expected to have greater influence on the closed-loop performance, especially because linear controllers were used.
The closed-loop performance of the PID controller for a few
patient models is compared to that of MPC and RTDA
controllers in Figures 8 and 9. Generally, regardless of the
controller, the closed-loop performance became more sluggish
with decreasing drug sensitivity (which can be observed for PP
15 and PP 16 in Figure 9). However, MPC and RTDA gave
tighter control of BIS for different PPs (i.e., from PP 1 to PP
16), as can be seen from Figures 6 and 7, which indicates a
weaker dependence of their performance on the drug sensitivity
of patients. Despite the sluggishness, these controllers tracked
the intra-operative set point changes and also rejected the
disturbances, for PP 13 (a considerably insensitive patient), PP
15, and PP 16 (highly insensitive patients).

5729

the electrodes attached to the patients head get disconnected,


BIS falls sharply to 0, and an estimated BIS value is automatically used as feedback. Furthermore, prolonged loss of BIS
signal (such as when the disconnection of electrodes goes
unnoticed) was assumed. For PP 3, using MPC and RTDA
controllers, Figures 11a and 11c show that BIS cannot be
maintained at its setpoint of 50 by simply using the last BIS
measurement recorded or BIS estimated from the nominal PD
model as feedback. On the other hand, using the patient-specific
EC50 value that was estimated from the measurements in the
induction period resulted in significantly improved closed-loop
performance.
The calculation of EC50 is patient-specific; therefore, this
method of BIS estimation during the loss of feedback signal
is expected to be robust for a wide range of patient
sensitivities. The results in Figure 12 confirm this for MPC
and RTDA. Similar trends were observed for all other
controllers studied in this work. Figure 12e shows the
comparison of performance, in terms of IAE for the 16
patients for MPC and RTDA controllers; RTDA shows
slightly better performance than MPC.
7. Conclusions

6. Controller Performance in the Absence of BIS Signal


The measured C1 and BIS are sometimes corrupted with
artifacts; C1 artifacts result from device calibration errors and
disconnection of sample lines, whereas BIS artifacts may come
from the high impedance of the electrodes, corruption of the
EEG with the electromyography (EMG) signal, and accidental
disconnection of electrodes from the patients head.7 The present
study focuses on evaluating controller performance during the
loss of BIS feedback signal, because of its higher likelihood of
occurrence and the higher risks involved.
When BIS signal is lost, the controllers are designed to
use an estimated BIS value as subsequent feedback until the
disconnection of electrodes is rectified. BIS may be estimated
using the last BIS measurement or using the measured C1
and the nominal PD model. We propose a modification of
the latter method using a patient-specific EC50 value, together
with nominal ke0 and values in the PD model for BIS
estimation. The problem with estimating the BIS value based
on a nominal PD model (which uses a nominal EC50 value
of 0.7478 vol %) arises when the patient has a different EC50
value. Simulations by varying each PD parameter independently were conducted, and the results (with noise removed
for clarity) are shown in Figure 10. In these simulations, each
patient PD parameter was varied individually, and the PID
controller performance using the nominal PD model for BIS
estimation during the loss of BIS signal was observed. The
results reflect that only EC50 has a drastic effect (as proven
by robustness analysis) on the accuracy of BIS prediction
(Figure 10); therefore, only this parameter must be known
accurately and the remaining PD parameters can be taken as
their nominal values for BIS estimation.
The patient-specific EC50 value can be estimated by averaging
all C1 concentrations (during the induction, t ) 0-100 min)
that correspond to the BIS value within (6 units (i.e., within
(2SD of BIS measurements) from BIS ) 50. Table 8
summarizes the estimated EC50 for all six controllers when
implemented on PP 1, PP 7, and PP 13. All estimates are very
good (within a deviation of 3% from the actual EC50 value).
The loss of BIS signal was simulated by breaking the BIS
loop at t ) 120 min during the occurrence of extreme surgical
stimuli to test the controllers in the most difficult scenario. When

The efficacy of PI, PID, PID-PI, PID-P, MPC, and RTDA


controllers was evaluated and compared for a range of patient
drug sensitivities and extreme surgical scenarios. For this
purpose, after analyzing the effect of PK and PD model
parameters, a set of 16 patient profiles was constructed to
represent patients with different drug sensitivities; these patient
profiles will be useful in future works on hypnosis regulation
by closed-loop isoflurane administration. MPC and RTDA
controllers are capable of improving hypnosis regulation by up
to 40%, compared to PI/PID controllers, and also display better
robustness when implemented on different patient profiles.
Cascade controllers provide an improvement of up to 20% in
performance, compared to PI/PID, but they exhibit less robustness than MPC and RTDA. To cope with the possible loss of
BIS signal during surgery, estimation of a patient-specific EC50
value (based on BIS and endtidal concentration measurements
in the induction period) and its use for estimating BIS for
subsequent feedback was proposed, and its effectiveness was
shown via simulation.
Acknowledgment
The authors would like to thank Dr. F. G. Chen, Head,
Department of Anesthesia, National University of Singapore for
fruitful discussions on anesthesia and other medical issues.
Literature Cited
(1) Doyle, F.; Jovanovic, L.; Seborg, D.; Parker, R. S.; Bequette, B. W.;
Jeffrey, A. M.; Xia, X.; Craig, I. K.; McAvoy, T. A tutorial on biomedical
process control. J. Process Control 2007, 17, 571594.
(2) Bibian, S.; Ries, C. R.; Huzmezan, M.; Dumont, G. Introduction to
automated drug delivery in clinical anesthesia. Eur. J. Control 2005, 11,
535557.
(3) Sigl, J. C.; Chamoun, N. G. An introduction to bispectral analysis
for the electroencephalogram. J. Clin. Monit. 1994, 10, 392404.
(4) Glass, P. S.; Bloom, M.; Kearse, L.; Rosow, C.; Sebel, P.; Manberg,
P. Bispectral analysis measures sedation and memory effects of propofol,
midazolam, isoflurane, and alfentanil in healthy volunteers. Anesthesiology
1997, 86, 836847.
(5) Vernon, J. M.; Lang, E.; Sebel, P. S.; Manberg, P. Prediction of
movement using bispectral electroencephalographic analysis during propofol/
alfentanil or isoflurane/alfentanil anesthesia. Anesth. Analg. 1995, 80, 780
785.

5730

Ind. Eng. Chem. Res., Vol. 48, No. 12, 2009

(6) Morley, A.; Derrick, J.; Mainland, P.; Lee, B. B.; Short, T. G. Closed
loop control of anaesthesia: an assessment of the bispectral index as the
target of control. Anaesthesia 2000, 55, 953959.
(7) Gentilini, A.; Rossoni-Gerosa, M.; Frei, C.; Wymann, R.; Morari,
M.; Zbinden, A.; Schnider, T. Modeling and closed-loop control of hypnosis
by means of bispectral index (BIS) with isoflurane. IEEE Trans. Biomed.
Eng. 2001, 48, 874889.
(8) Locher, S.; Stadler, K. S.; Boehlen, T.; Bouillon, T.; Leibundgut,
D.; Schumacher, P. M.; Wymann, R.; Zbinden, A. M. A new closed-loop
control system for isoflurane using bispectral index outperforms manual
control. Anesthesiology 2004, 101, 591602.
(9) Puebla, H.; Alvarez-Ramirez, J. A cascade feedback control approach
for hypnosis. Ann. Biomed. Eng. 2005, 33, 14491463.
(10) Dua, P.; Pistikopoulos, E. N. Modelling and control of drug delivery
systems. Comput. Chem. Eng. 2005, 29, 22902296.
(11) Sreenivas, Y.; Lakshminarayanan, S.; Rangaiah, G. P. A model
predictive control strategy for the regulation of hypnosis. In IFMBE
Proceedings WC 2006: World Congress on Medical Physics and Biomedical
Engineering; IFMBE Proceedings Series, Vol. 14; Springer: Berlin,
Heidelberg, 2007; pp 77-81.
(12) Struys, M. M. R. F.; Mortier, E. P.; Smet, T. D. Closed loops in
anaesthesia. Best Pract. Res. Clin. Anaesthesiol. 2006, 20, 211220.
(13) Beck, C.; Lin, H.-H.; Bloom, M. Modeling and control of anesthetic
pharmacodynamics. In Biology and Control Theory: Current Challenges;
Queinnec, I., Tarbouriech, S., Garcia, G., Eds.; Lecture Notes in Control
Information Science, Vol. 357; Niculescu, S. I., Ed.; SpringersVerlag:
Berlin, Heidelberg, 2007; pp 263-289.
(14) Ogunnaike, B. A.; Ray, W. H. Process Dynamics, Modeling, and
Control; Oxford University Press: New York, 1994; pp 991-1032.
(15) Qin, S.; Badgwell, T. A survey of industrial model predictive control
technology. Control Eng. Pract. 2003, 11, 733764.
(16) Araki, M.; Furutani, E. Computer control of physiological states
of patients under and after surgical operation. Annu. ReV. Control 2005,
29, 229236.
(17) Ogunnaike, B. A.; Mukati, K. An alternative structure for next
generation regulatory controllers: Part I: Basic theory for design, development and implementation. J. Process Control 2006, 16, 499509.

(18) Yasuda, N.; Lockhart, S. H.; Eger, E. I.; Weiskopf, R. B.; Liu, J.;
Laster, M.; Taheri, S.; Peterson, N. A. Comparison of kinetics of sevoflurane
and isoflurane in humans. Anesth. Analg. 1991, 72, 316324.
(19) Tian, W. Y.; Sreenivas, Y.; Rangaiah, G. P.; Lakshminarayanan,
S. A comprehensiVe eValuation of PID, cascade and model predictiVe
controllers for isoflurane administration using BIS as the controlled
Variable. Presented at International Symposium on Advanced Control of
Industrial Processes (ADCONIP), Jasper, Canada, 2008.
(20) Chien, I.-L.; Fruehauf, P. Consider IMC tuning to improve controller
performance. Chem. Eng. Progress 1990, 86, 3341.
(21) Chen, D.; Seborg, D. E. PI/PID controller design based on direct
synthesis and disturbance rejection. Ind. Eng. Chem. Res. 2002, 41, 4807
4822.
(22) Haeri, M. PI design based on DMC strategy. Trans. Inst. Meas.
Control 2005, 27, 2136.
(23) Wojsznis, W.; Blevins, T.; Thiele, D. Neural network assisted
control loop tuner. Proc. IEEE Int. Conf. Control Appl. 1999, 1, 427431.
(24) Friman, M.; Waller, K. V. A two-channel relay for autotuning. Ind.
Eng. Chem. Res. 1997, 36, 26622671.
(25) Mukati, K.; Ogunnaike, B. Stability analysis and tuning strategies
for a novel next generation regulatory controller. Proc. Am. Control Conf.
2004, 5, 40344039.
(26) Chng, K. L.; Lakshminarayanan, S. Performance assessment and
sensitivity test of novel regulatory RTD-A controller. Proc. Asian Control
Conf. 2006, 273282.
(27) Struys, M. M. R. F.; Smet, T. D.; Greenwald, S.; Absalom, A. R.;
Bing, S.; Mortier, E. P. Performance evaluation of two published closedloop control systems using bispectral index monitoring: A simulation study.
Anesthesiology 2004, 100, 640647.
(28) Struys, M. M.; Smet, T. D.; Versichelen, L. F.; Velde, S. V. D.;
den Broecke, R. V.; Mortier, E. P. Comparison of closed-loop controlled
administration of propofol using bispectral index as the controlled variable
versus standard practice controlled administration. Anesthesiology 2001,
95, 617.

ReceiVed for reView June 12, 2008


ReVised manuscript receiVed March 22, 2009
Accepted April 27, 2009
IE800927U

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