2015 European Control Conference (ECC)
July 15-17, 2015. Linz, Austria
Automatic recovery from nonlinear oscillations in PID-controlled
anesthetic drug delivery
Zhanybai T. Zhusubaliyev1 , Margarida M. Silva,2 and Alexander Medvedev2
Abstract The problem of recovering from nonlinear oscil-
lations in a PID-controlled drug delivery system for the neuro-
muscular blockade (NMB) in closed-loop anesthesia is consid-
ered. The NMB system dynamics portrayed by a Wiener model
can exhibit sustained nonlinear oscillations for physiologically
feasible values of the model parameters and realistic PID gains.
Such oscillations, also repeatedly observed in clinical trials,
lead to under- and over-dosing of the administered drug and
undermine patient safety. This paper proposes an bifurcation
analysis-based tuning policy for the proportional PID gain that
ensures automatic recovery from those oscillations. It is shown
that with a time-varying proportional PID gain, the type of
equilibria of the closed-loop system remains the same as in the
case of constant controller gains and no additional types of
complex nonlinear behaviors are introduced by these auxiliary
dynamics. The recovery time is also evaluated in simulation
over a database of individualized patient models.
I. INTRODUCTION
Even though several attempts have been made to com-
pletely automatize the intravenous drug delivery to patients
under general anesthesia, see e.g. [1, Ch.4], no technique has
yet become widely accepted in the daily clinical practice.
The mismatch between research and practice is mainly due
to legal regulations. In fact, the chances of approval for
any closed-loop control strategy by the regulatory entities
are likely to increase with a demonstration of a clinically
significant safety benefit with respect to the manual mode
[2], such as a reduction of the incidence of underdose-related
awareness, or of overdose-related post-operative complica-
tions.
For the case of the neuromuscular blockade (NMB),
whenever a patient is underdosed, the patients muscles might
unexpectedly contract in response to the surgical stimulation.
This, in turn, might constrain the surgeons actions or even
cause severe bodily harm at the moment of the unexpected
contraction. Overdoses may, on the other hand, bring poten-
tial delays in the postoperative recovery and a risk of residual
blockade in the post-anesthetic period [3], that is highly
undesired both for physiological and economical reasons.
The effect of drugs in anesthesia is an intrinsically non-
linear dynamical process. The incorporation of a controller
in the loop adds further nonlinearities, e.g. due to actuator
saturation and sensor characteristics, as well as rises the
*This work was supported by the European Research Council, Advanced
Grant 247035 (SysTEAM).
1 Department of Computer Science, South West State University, 50 Years
of October Str., 94, 305040, Kursk, Russia zhanybai@hotmail.com
2 Department of Information Technology,
psala University, SE-751 05 Uppsala,
{margarida.silva,alexander.medvedev}@it.uu.se
978-3-9524269-3-7 2015 EUCA
question on whether typical nonlinear phenomena such as
sustained oscillations may appear. In fact, there is clinical
evidence of oscillatory behavior in the literature for cases
of closed-loop drug delivery in anesthesia, see e.g. [4]. The
results of [5] provide mathematical support to the clinical
findings. The bifurcation analysis in [5] shows that, for
the case of Proportional-Integral-Derivative (PID)-controlled
NMB, complex nonlinear behaviors such as sustained os-
cillations may indeed appear under certain conditions, as
a consequence of Andronov-Hopf bifurcation phenomena.
These oscillations result in under- and over-dosing of anes-
thetics, and should be avoided. An expression for distance to
bifurcation is also suggested in [5], giving rise to a way of
monitoring how far the closed-loop system is from sustained
nonlinear oscillations. Even though a PID controller design
based on an individualized Wiener model [5] can initially
ensure a safe distance to bifurcation, the model parameters
sometimes drift close to a critical zone as the surgery
proceeds. The latter has been demonstrated on clinical data
in [6] by estimating the distance to the Andronov-Hopf
bifurcation by means of a particle filter.
The main idea of the present paper is to ensure that the
closed-loop operating point of the drug delivery system is
moved away from the region of oscillatory dynamics. This
is guaranteed by systematically changing the controller gains.
The structure of the nonlinear plant is exploited to calculate
the point where oscillations arise. The bifurcation analysis of
the nonlinear closed-loop system is instrumental in ensuring
a bumpless transfer from the oscillatory unstable behavior to
stability.
The first contribution of this paper is hence the design of
a tuning procedure for a PID controller that ensures that the
closed-loop system recovers from sustained oscillations in an
autonomous way. This retuning guarantees that the system
recovers its reference tracking capabilities. Inspired by the
case of linear systems, where it is usually enough to lower the
loop gain to recover asymptotic stability [7], the proportional
gain in the PID controller is here chosen to be time-varying.
Considering that the nonlinear case is more complex than
the linear one, the second contribution of this paper is the
nonlinear analysis of the impact of the time-varying gain on
the type of equilibria of the system. This auxiliary dynamical
variable increases the order of the closed-loop system by
one during the recovery period. It is then expected that the
complexity of the system dynamics as well rises. The third
contribution is a study of the system dynamics in the time
Up-
Sweden domain during the transition from oscillation to stability over
a database of individualized patient models.
2725
 Regarding the novelty of the proposed approach, one has
to take into account the abundance of the literature on
adaptive (self-tuning, time-varying, etc.) PID control [8]. It
is really difficult to claim that something is new in this
area. The matter of bumpless PID control is also studied
extensively with wide industrial applications in e.g. process
control. Yet, the authors failed to find a single paper covering
oscillation recovery in closed-loop drug delivery, which topic
is in the focus of the present contribution. This application
area is quite different from traditional process control. For
instance, oscillation detection methods [9] based on signal
analysis are not applicable here. Indeed, when oscillations in
closed-loop drug delivery are evident, under- and over-dosing
of the patient has already occurred. Therefore, continuous
assessment of the risk for oscillation by e.g. the calculation
of distance to bifurcation from online data, as in [6], appears
to be a more suitable option.
II. CLOSED-LOOP MODEL
The results in [5] show that the minimally param-
eterized parsimonious (MPP) model for the NMB is
able to capture the same intrinsic nonlinear dynamics
of the system, e.g. limit cycles and sustained oscilla-
tions, as a standard physiologically-based pharmacokinetic-
pharmacodynamic (PK/PD) model. Also, it is suitable for
individualization under limited exogenous system excitation,
as it is usually present in a real-life clinical scenario. This
supports the use of the MPP models in the design of
controllers for drug delivery in anesthesia.
A state-space description of the linear dynamics of the
MPP Wiener model [10] is given by
x 1 = k3 (x1 u(t)), x 2 = k2 (x1 x2 ),
x 3 = k1 (x2 x3 ), (1)
where x1 and x2 are nonnegative auxiliary state variables,
and x3 , also nonnegative, is the output of the linear dynam-
ical block of the Wiener model.
The system input (atracurium administered rate) u(t) is
nonnegative and bounded 0 6 u(t) 6 umax , > 0 is the
patient-dependent parameter, while ki , i = 1, 2, 3 are positive
constants. In the following analysis, the values chosen in [10]
k1 = 1, k2 = 4 and k3 = 10 are assumed.
In the same way as in the PK/PD model, the effect of
the drug, as quantified by the measured NMB y(t) [%], is
modeled by the Hill function
100 C50
y(t) = . (2)
C50 + x3 (t)
Several sensors are available in the clinical practice to
quantify the NMB in patients. For a brief summary see e.g.
[1, Ch.2].
A. Time-varying PID controller
Following [5], the control signal in (1) is assumed to be
generated by a PID controller

1
Z
de(t)
 x1
u(t) = K(t) e(t) + e(s) ds + Td , (3)
Ti dt
2726
with
K(t) = (K(t) K ) . (4)
Here e(t) = yr y(t) is the control error and yr is
the reference. The initial condition for the gain K(0) = 0
is assumed to correspond to weakly damped closed-loop
oscillations and the value Kref that is chosen from the interval
of variation for K is calculated to yield a safe distance to
bifurcation, for instance by using the PID design procedure
proposed in [5]. The constant adjusts the transition rate
and is chosen in the PID design procedure.
The automatic PID-tuning in the present paper is part of
the following scenario in the surgery room:
1) A Wiener individualized NMB model expressed by (1),
(2) is estimated from a bolus response to the drug in
the beginning of surgery. Based on the model, desired
controller convergence rate, distance to bifurcation,
and the gains of the PID controller K0 , Ti , Td are
calculated by e.g. the design method in [5].
2) The surgery proceeds under automatic muscle relaxant
delivery. The Wiener model parameters , and the
distance to bifurcation are estimated on-line by means
of a suitable identification algorithm, e.g. the particle
filter or the Extended Kalman Filter, see e.g. [6].
3) When the estimated distance to bifurcation goes under
a given threshold, a re-design of the PID controller
is undertaken for the current estimated values of the
Wiener model to yield the same distance to bifurcation
that the original design but for the current values of the
model parameters. This results in the PID controller
settings Kref , Ti , Td .
4) The recovery controller expressed by (3), (4) is ac-
tivated for transferring the closed-loop system to the
foreseen oscillation-free mode.
The mathematical model of the closed-loop NMB in (1)-
(4), can now be recast as a set of autonomous differential
equations [5]
dx
= f (x), (5)
dt
x = (x1 , x2 , x3 , x4 , x5 )T ,
f (x) = (f1 , f2 , f3 , f4 , f5 )T ,
with
f1 = k3 x1 2 k1 k3 Td x5 0 (x3 )(x2 x3 )
k3
+ k3 x5 (yr (x3 )) + x4 x5 ,
Ti
f2 = k2 (x1 x2 ), f3 = k1 (x2 x3 ),
f4 = yr (x3 ), f5 = (x5 K ),
0 (x3 ) = 3 2
(x3 ).
100 C50
B. Bifurcation analysis caught by the nonlinear constraints. This kind of oscillations
The system (5) has a single equilibrium state x = typically arises in continuous smooth systems with negative
[x1 , x2 , x3 , x4 , x5 ]T , where feedback regulation when the loop gain and/or the delay in
the feedback becomes sufficiently high [12].
Ti For the case of PID-controlled drug delivery, the normal
x1 = x2 = x3 , x4 = x ,
K 3 operational conditions are the regime of a stable equilibrium
 1
state. However, due to the subject uncertainty, the equilib-

100
x3 = C50 1 , x5 = K . rium point may lose stability. As a result, a stable limit cycle
yr
softly arises from the equilibrium state [5].
The local stability of the equilibrium x is determined by the The eigenvalues si , i = 1, 5 for the Jacobian matrix are
eigenvalues of the Jacobian matrix determined by
 
fi det (Df(x ) sI) =
Df(x ) = , (6)
xj 16i65; 16j65 = (s4 + b1 s3 + b2 s2 + b3 s + b4 )(s + ) = 0.
where Considering that one eigenvalue of (6) is equal to < 0, for
f1 the equilibrium state to be stable, the following inequalities
= k3 , have to be satisfied
x1
f1 bi > 0, i = 1, 4, b1 b2 b3 > 0, (7)
= 2 k1 k3 K Td 0 (x3 ),
x2 b1 b2 b3 b21 b4 b23 > 0. (8)
f1
= k3 K 0 (x3 ) + 2 k1 k3 K Td 0 (x3 ), Note that bi > 0, i = 1, 4 are positive. Numerical experi-
x3
f1 k 3 K f1 k3 x4 k3 x3 ments show that the Jacobian matrix has one or two pairs of
= , = = , complex conjugate eigenvalues for the considered range of
x4 Ti x5 Ti K
f2 f2 parameters. The factor (s+) in characteristic polynomial (6)
= k2 , = k2 , indicates a relative independence (in small) of the controller
x1 x2
gain rate from the plant parameters.
f2 f2 f2
= = = 0, An Andronov-Hopf bifurcation occurs when the second
x3 x4 x5 condition (8) is violated. The surface
f3 f3 f3 f3
= = = 0, = k1 , (Ti , Td , K , , ) = b23 b1 b2 b3 + b21 b4 = 0 (9)
x1 x4 x5 x2
f3 f4 defines the boundary of the stability region for the equilib-
= k1 , = 0, i = 1, 2, 4, 5,
x3 xi rium state, see [5].
f4 f5 Substituting b1 , b2 , b3 and b4 in into (9), an expression
= 0 (x3 ), = 0, i = 1, 4,
x3 xi for the bifurcation surface that depends explicitly on the
f5 parameters Ti , Td , K , , and is as follows
= ,
x5 (Ti , Td , K , , ) =
and k1 k2 k3 [Td (k1 + k2 + k3 ) 1] (0 (x3 ))2 K2
1 1
+ k1 k2 k3 (k1 + k2 + k3 )2 Td

yr2

100
0 (x3 ) = 1 .
100 C50 yr + (k12 k2 + k12 k3 + k1 k22 + k1 k2 k3 + k1 k32 + (10)
The eigenvalues of Df(x ) can either be real or complex + k22 k3
+ k2 k32 )
(k1 + k2 + k3 )2 /Ti 0 (x3 )K

and their total number is equal to the dimension of the
phase space. The real part of an eigenvalue determines the (k1 + k2 )(k1 + k3 )(k2 + k3 ) = 0.
rate of growth of the corresponding perturbation away from
the equilibrium point, and the imaginary part determines the III. NUMERICAL SIMULATIONS
angular frequency of an oscillatory component. In order to assess the performance of the proposed time-
An equilibrium point is stable if all eigenvalues have neg- varying PID controller, numerical simulations were designed
ative real part, corresponding to an exponentially decreasing as follows:
response to perturbations. However, if an eigenvalue or a pair Given nominal values of (0 , ), calculate the PID
of complex conjugated eigenvalues crosses the imaginary controller gains Ti , Td , K0 with e.g. the Ziegler-
axis into the positive complex half-plane, the equilibrium Nichols step-response tuning procedure [8];
point becomes unstable. The transition in which a pair of Simulate the closed-loop system for the time interval
complex conjugated eigenvalues simultaneously crosses the 0 t < t1 in order to assess the time-domain response
imaginary axis from the left to the right complex half-plane of the closed-loop system;
is known as an Andronov-Hopf bifurcation [11]. This is the Given (Ti , Td , K0 , ) calculate the bifurcation value
transition that leads to emergence of self-sustained oscilla- = bif as the real positive root of equation
tions provided that the expanding oscillatory dynamics are (Ti , Td , K0 , , ) = 0 (10) with respect to ;

2727
 At t = t1 , choose = 1 as a 5% perturbation of bif ,
so that the operating point is in the region of instability;
Simulate the closed-loop system for the time interval
t1 t < t2 in order to assess the time-domain response
of the clsoed-loop system to this change;
Given nominal values of (Ti , Td , 1 , ) calculate Kbif
as a the real negative root of (Ti , Td , K, 1 , ) = 0
(10) with respect to K;
Choose
Kref = Kbif , (11)
with R+ , so that the system is in the region of
stability: (Ti , Td , Kref , 1 , ) = 0.
At t = t2 , apply K(t) from (4) in order to automatically
recover stability of the closed-loop system;
Simulate the closed-loop system for the time interval
t > t2 in order to assess the time-domain response of
the system to this change.
Note that, in a real scenario, the time instant t2 occurs as
soon as the calculated distance to the bifurcation phenomena
is smaller than a user-defined threshold, as mentioned in
Sec. II-A.
The previously described numerical simulations were run
for a database of patient models ((i) , (i) ), i = 1, 41,
obtained from clinical data [10]. The analysis presented here
is intended to demonstrate the feasibility of the proposed ap-
proach for the automatic recovery from nonlinear oscillations
in a real application. It is important to recall that oscillations
have been observed in real cases, see e.g. [13], and that
the current practice is to switch the system to manual mode
and to titrate the anesthetic dose manually afterwards. In an
automatic safety framework, it is recommended that the risk
for oscillation is assessed online by e.g. the calculation of
distance to bifurcation as in [6], and the re-tuning approach
proposed in this paper is applied before actual oscillations
arise.
The results of the numerical simulations for the database
of 41 models and different values of in (11) and in (4)
are shown in Table I.
TABLE I: Mean values of the recovery time tc > t2 : t >
tc , x3 (t) I, with I = [0.9x3 , 1.1x3 ] for all 41 cases (i =
1, 41) in the simulation database. The values in brackets are
[min, max].
tc [min]
((i) , (i) ) 0.1 0.01 6.321 [4.399, 7.980]
0.1 0.1 4.422 [3.185, 7.008]
0.5 0.1 9.353 [4.475, 14.437]
((i) , ) 0.1 0.1 4.075 [2.460, 5.674]
(, (i) ) 0.1 0.1 4.104 [ 2.379, 4.874]
As shown in Table I, the average recovery time tc >
t2 : t > tc , x3 (t) I, with I = [0.9x3 , 1.1x3 ] for all
41 cases (i = 1, 41) in the simulation database is best for
the combination x = 0.1 and = 0.1. Also, results indicate
that the behavior of the output during the recovery is more
affected by the value of Kref = Kbif than by the value of
, as expected from (6).
To exemplify the arising behaviors, a patient model from
the patients database in [10], [14] was randomly chosen.
The parameters of the patient model are 0 = 0.0364
and = 4.24358. The PID gains for the given model are
Ti = 11.72262, Td = 2.930656 and K0 = 1.30697.
Fig. 1a presents a bifurcation surface
(Ti , Td , K , , ) = 0, (9) in the PID-controller
parameter space (Ti , Td , K ) calculated for this patient
model. In the diagram, the domain of stability for the
equilibrium point is denoted by A. The space on the left
of surface (9), denoted by B, corresponds to the domain
of existence of the self-sustained oscillatory dynamics. As
mentioned above, this oscillatory mode appears through an
Andronov-Hopf bifurcation.
The point denoted as 1 corresponds to the parameter values
Ti = 11.72262, Td = 2.930656 and K0 = 1.30697.
K0 was chosen to be less than Kref = 0.07816 because,
for this combination of parameters, (Ti , Td , K, , ) <
0, K < Kref . As shown in this figure, Point 1 belongs
to the region A of stability for the equilibrium point. The
arrow represents the direction in the parameter space along
which the bifurcation surface is moved as the parameter
decreases from 0 = 0.0364 to 1 = 0.021435. Fig. 1b
shows a bifurcation surface for = 0.021435 after this
transition. As one can see from this figure, Point 1 moves
now to the region of instability B.
Fig. 2a and Fig. 2c illustrate in the time domain the effect
that this perturbation in the parameter has on the system.
The time interval t < t1 corresponds to the case when Point 1
is in the stability region A. For simulation purposes, the
variables x1 , x2 and x3 in (1) are initialized at zero, and
yr is made equal to 10. For t < t1 , the PID controller
stabilizes the system around the reference yr , as shown in
the time profile of x3 and y, in the middle and upper plots
of Fig 2a, respectively. The parameter is decreased to 1
at t1 , causing the bifurcation surface in Fig. 1a to slide to
the right (see Fig. 1b). Fig. 2d presents a magnification of
the bifurcation surface in Fig. 1b for 1 = 0.021435. As
seen from this figure, Point 1 now is in the region B of the
instability for the equilibrium state. As illustrated by the time
diagrams for x3 and y in Fig. 2a, this results in the oscillatory
dynamics and the trajectories of the dynamical system (5)
converge to a limit cycle in the time interval t1 t < t2 .
As the parameter K is increased from K0 = 1.30697
to Kref 0.07816 (as shown in the bottom plot of Fig. 2c),
while maintaining other parameters constant, Point 1 again
becomes in the region of stability A. The scanning direction
is indicated in Fig. 2d by the arrow. The observed sequence
of bifurcation transitions is shown in Fig. 2b. The upper
plot of Fig. 2b depicts the bifurcation diagram illustrating
the transition from a limit cycle to an equilibrium point as
the gain K increases from 1.30697 (Point 1 in Fig. 2d)
to 0.07816 (point 2 in Fig. 2d). The bottom plot shows
the variation of the real part of the complex-conjugated
eigenvalues s1,2 = i.
2728
 (a) (b)
Fig. 1: (a) Andronov-Hopf bifurcation boundary in the parameter space (Ti , Td , K ) for = 0.0364 and = 4.24358: A
is the domain of stability for an equilibrium state and B is the region where an equilibrium point is unstable. The point
1 corresponds to the parameter values: Ti = 11.72262, Td = 2.930656 and K0 = 1.30697 and it belongs to the region
of stability denoted as A. The arrow represents the direction in the parameter space along which the bifurcation surface is
moved as parameter decreases from 0.0364 to 0.021435. (b) Andronov-Hopf bifurcation boundary in the parameter space
(Ti , Td , K ) for = 0.021435 and = 4.24358. Now the point 1 becomes in the region of instability B.

For 1.30697 < K < Kbif , the system displays an
unstable equilibrium state surrounded by a stable oscillatory
state (limit cycle). For this parameter interval, the Jacobian
of system (5) has a pair of complex-conjugated eigenvalues
s1,2 = i with positive real parts > 0 (see Fig. 2b), and
three real and negative eigenvalues s3 < 0, s4 < 0, s5 < 0.
At K = Kbif , the equilibrium state undergoes a reverse
Andronov-Hopf bifurcation. When the parameter K passes
through the point Kbif , a pair of complex-conjugated eigen-
values s1,2 = i crosses the imaginary axis into the
negative real half-plane, and the equilibrium state becomes
stable.
This increase in the proportional gain K(t) of the PID
controller is simulated to occur at time t2 in Fig. 2c and
Fig. 2a. The bottom plot of Fig. 2c shows the time-profile
of the gain K(t), from K0 to Kref , following (4). The time-
behavior of the state variable x3 and the output y in Fig.
2c show that, for t t2 , the oscillations disappear and the
stable equilibrium behavior is recovered. The bottom plot of
Fig.2a is a zoom into the middle plot in the same figure for
t t2 . The amplitude of the oscillations decay, yielding a
recovery time of 4.37 min. This value is close to the mean
in the database for the same values of and , as shown in
Table I.
IV. CONCLUSIONS
This paper presented a PID-tuning policy to automatically
recover from undesired nonlinear oscillations in a drug deliv-
ery system for the neuromuscular blockade (NMB) in anes-
thesia. The proposed tuning allows the closed-loop system
to recover from oscillations that were previously observed in
clinical trials and that lead to under and overdosing of the
administered drug. By introducing a time-varying propor-
tional PID gain, as shown via a bifurcation analysis of the
closed-loop, the type of equilibria remains the same as in the
case of constant controller gains. This is desirable since no
additional complex nonlinear behavior types are introduced
by this tuning. The recovery time after applying the proposed
time-varying PID gain is evaluated in simulation to exemplify
the performance of the proposed strategy. For a realistic
database of cases, the average recovery time is 4.22 min,
which shows the feasibility of the PID re-tuning procedure.
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2729
 100
y 50
yr
0
0 t1 400 t2 800 1000
20
x3

10
0 t1 t2
0 400 800 1000
15
x3

10
5
590 t2 610 620
Time [min]
(a) Time-domain behavior of x3 and output y. The red dashed
line indicates 1.2 x3 , with x3 as the steady state value of the state (b) Bifurcation diagram and variation of the real part
variable x3 for t > t2 . of the complex-conjugated eigenvalues s1,2 = i
for 1.30697 K 0.07816 and = 0.021435.

0
0.03

1
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0
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K

0.8
K0
0 t1 400 t2 800 1000
0
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K0
590 t2 610 620
Time [min]
(c) Time-domain changes in and K, for = 0.1. (d) Zoom of the bifurcation boundary in Fig.2b for
The red square depicts the value of Kbif . 0 = 0.021435 and = 4.24358.

Fig. 2: Simulation results for K0 = 1.30697, Kref = 0.9Kbif = 0.07816, 0 = 0.0364, and 1 = 0.021435.

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