17th Mediterranean Conference on Control & Automation Makedonia Palace, Thessaloniki, Greece June 24 - 26, 2009

Neuromuscular Blockade Nonlinear Model Identication

B. Andrade Costa, M. Silva, T. Mendonca and J. M. Lemos

Abstract This paper presents a methodology for parameter estimation of a nonlinear neuromuscular blockade dynamic model to be used as a predictive model for automated control, in general anesthesia. The neuromuscular blockade dynamic model comprises two blocks connected in series, a pharmacokinetic model and the pharmacodynamic model. The pharmacokinetic model is a second order linear dynamic model and describes the redistribution of the drug in the body. The pharmacodynamic model is a nonlinear function, named as the Hill equation, and it describes the interaction between the concentration of the drug in the effect site and the measured patients muscle paralysis state. The identication methodology uses four data points taken from the neuromuscular blockade response obtained with the administration of the rst bolus. The four data points are chosen to avoid the identication difculties caused by the presence of the nonlinear behavior of the Hill equation. This approach enables the identication of the pharmacokinetic dynamics, that is, the two poles of the second order linear dynamic model followed by the estimation of the normalized parameters of the Hill equation. Computer simulations show that the proposed identication methodology is able to provide good results even when the pharmacokinetic dynamics has an order higher that two. This suggests that the methodology may be employed in neuromuscular blockade automated control as a predictive model, to help the initial tuning of the controller parameters or in adaptive control to get a rst model that can be improved with online identication using some recursive minimization techniques to adjust the adaptive controller or as an advising mechanism to help the anesthesiologist during the anesthesia. Keywords: Biomedical engineering, Neuromuscular Blockade, Model Identication, Nonlinear Model

I. INTRODUCTION Computer controlled systems are being considered as a promising technology to improve the practice of anesthesia [1] [4]. In principle, it is possible to adjust the amount of drugs to the patients characteristics, that is, to keep the drug concentration in the patients body at a constant, safe and adequate level, and by that to have a quicker recovering time from anesthesia [3]. Another important eld is the utilization of automated systems to control anesthesia in animals to reduce the costs and work of the veterinary. At the core of any computer controlled system for anesthesia automation is a model describing the transport of the drug in the human body (pharmacokinetic model) and the
This work was developed in the project IDeA framework - Integrated Design for Automation of Anesthesia, contract PTDC/EEA-ACR/69288/2006 B. Andrade Costa, is with INESC-ID/DEEC/IST/TU Lisbon, R. Alves Redol 9, 1000-029 Lisboa Portugal, bac@comp.ist.utl.pt M. Silva, and T. Mendonca, are with Dep. Matem tica Apli a cada FCUP, Rua do Campo Alegre, 687 4169-007 Porto, Portugal

tmendo@fc.up.pt
J. M. Lemos, is with INESC-ID/DEEC/IST/TU Lisbon, R. Alves Redol 9, 1000-029 Lisboa Portugal, jlml@inesc-id.pt

effect of the drug in the patients state (pharmacodynamic model). These are the cases of TCI and TIVA systems [2]. These systems use compartmental models obtained by processing data, collected from a large sample to characterize the properties of a population. However the TCI and TIVA systems can be described as operating based on one mean model, there is one model able to describe the dynamics of all patients! But the current practice shows that for neuromuscular blockade control there is a huge variability between patients [5] [6]. This suggests that the administration of drugs during anesthesia must be based on methods able to estimate patients characteristics. With compartmental models, each compartment is assumed to have homogenous properties, that is, at each time instant the drug distribution inside a compartment is uniform. This approach is similar as modeling a lumped parameter system. Those models may have from 2 compartments to 12 compartments [7][8][9][10]. Other modeling techniques use more deep knowledge of physiology to build complex models [11], but this approach needs data and experimental procedures that are not available in a standard operating room. According to [7][8][9][12] a second order linear dynamic model is used to describe the pharmacokinetics of drugs belonging to the atracuriums family. This motivated the use of the second order linear dynamic model in the identication methodology presented in this paper, the model has a dened structure but the parameters must be estimated. An important issue comes from the constraint imposed by ethical and practical reasons that constrains the design of identication signals to be used in model identication, this makes low order dynamic models more suitable to describe local dynamics than higher order dynamic models where overparametrization cause identication problems. The problem is that low order models do not fully describe the all dynamics and may impose additional constrains in the control design. To tackle the problem online identication may be used to adjust the low order models. The aim of this work is to model the neuromuscular blockade dynamics using the information that a anesthetist/anesthesiologist has when performing her/his job in the operating room, by using the index evolution provided by the neuromuscular blockade monitor and using the information obtained from evolution of the infusion or from the sequence of bolus. This paper is structured as follows: Section II describes the neuromuscular blockade model based on a 3 compartmental model and gives a possible cue for the assumption of a pharmacokinetic second order linear model. Section III presents

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TABLE I PARAMETERS OF THE THREE COMPARTMENT MODEL 1.

q+k V1 f q+k V2 (1f )q+k V3 fq V2 fq V1 (1f )q+k V1 (1f )q V3

11 = 22 = 33 =

12 = 21 = 31 =

13 =

Fig. 1. The neuromuscular blockade model with a three compartmental model for the pharmacokinetics, where C1 represents the central compartment and C2 represents the effect compartment. The r(t) signal represents the neuromuscular blockade response.

atracurium is transformed by chemical reactions that depend on the bodys temperature and on the bloods acidity which is assumed identical in all compartments. Note that the model (1) may be considered a linear varying parameter model because the ji parameters depend on the hearts volumetric ow rate and on the bodys temperature and bloods acidity that may change over time. The pharmacodynamic model representing the effect of the drug is described by the Hill function, eq. (2), r(t) =
C50 C50 + (y(t))

the identication methodology. Section IV shows the results obtained with computer simulation using a database of 100 neuromuscular blockade models that have a pharmacokinetics of order 4 with a zero. Conclusions are presented in the last section. II. NEUROMUSCULAR BLOCKADE MODEL In this section a neuromuscular blockade model based on a three compartmental model is presented [13]. Fig. 1 shows the pharmacokinetics diagram with three compartments. The central compartment (C1 ) includes organs such as the cardiovascular and pulmonary system, brain and other organs that are highly irrigated. The second compartment (C2 ) represents the effect site in this case the muscle. The third compartment (C3 ) represents organs/tissues that have a low rate of drug absorption/diffusion. Considering a compartment i, Vi represents the total volume ([l]) of the uid (plasma/blood) in the compartment. The drugs mass is represented by mi ([mg]), and the volumetric ow rate of uid leaving the compartment i towards compartment j is denoted by qji ([ml.min1]), this quantity in directly correlated with the hearts volumetric ow rate, and ki represents the drugs elimination ow rate or the rate at which the drug loses its power. By performing a mass balance, the drugs concentrations in the three compartments are described by the following set of differential equations, where ci (t) = mi (t)/Vi . c. (t) = 1 c. (t) = 2 c. (t) 3 = y(t) = 11 c1 (t) + 12 c2 (t) + 13 c3 (t) + u(t) 22 c2 (t) + 21 c1 (t) (1) 33 c3 (t) + 31 c1 (t) c2 (t)

(2)

where C50 represents the drugs concentration to obtain half of the full effect, and is a non-dimensional parameter that characterizes the slope of the Hill function. A. Analysis of the three compartment model The three compartment model given by (1) is represented in the state-space form and it is necessary to estimate seven parameters, that may be difcult. In order to simplify the identication procedure, an input-output representation using y(s) a transfer function u(s) = P (s) will be obtained from (1). The transfer function P (s) has three poles and one zero and it can be written as shown in (3), with Q(s) = s+22 . s+33 P (s) = 21 (3) (s + 11 )(s + 22 ) 12 21 13 31 Q(s)

It is easy to conclude that P (s) can be simplied to a second order transfer function if Q(s) 1, that is, 22 33 . Now the issue is to demonstrate that there is some physical/physiological evidence to support that 22 33 . Taking the denition of both parameters from table I and assuming that (1f )q >> k and f q >> k, this is acceptable otherwise the drug is quickly removed and anesthesia is not possible, then (1f )q f q this implies that V3 V2 f V2 V2 + V3 (4)

The ji parameters are shown in table I, q represens the total ow rate leaving the central compartment and f represents the fraction of q entering/leaving compartment C2 , ki is assumed to be identical in all compartments, this is justied by [12], where the neuromuscular blockade drug such as

Dening now T2 = V2 /(f q) and T3 = V3 /((1 f )q) as the time needed to renew the uids inside compartment 2 and 3, and using eq. (4) then T2 = (V2 + V3 )/f q and T3 = (V2 + V3 )/q. That is, the renewal times for both compartments are identical. This can be justied if one considers that blood must be renewed in such a way that each cell must be supplied with a constant rate of oxygen, that is, the ow rate must be proportional to the number of cells (volume of the compartment). Assuming that the above

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Because the pharmacokinetic model response to the rst bolus is an approximation of the impulsive response of a dynamic system, the impulse response equation of a second order model hm (t), (10), is used ab (expat expbt ) (10) ba to estimate the parameters a and b from the measured values t1 < t2 < t3 < t4 . These time instants must be selected in such a way to avoid numeric problems. hm (t) = A. Estimating the dynamics of M (s)
Fig. 2. Description of the time instantes t1 < t2 < t3 < t4 to be used by the identication methodology.

Using the constraint z(t1 ) = z(t4 ) and eq. (10) then a is given by 1 exp0 t4 1 ln[ ] (11) a= t4 t1 1 exp0 t1 with 0 = b a. A similar equation can now be written with parameters t2 and t3 a= 1 1 exp0 t3 ln[ ] t3 t2 1 exp0 t2 (12)

argument is true then Q(s) 1 and the transfer function (3) is written as 21 P (s) = (5) (s + a)(s + b) with a and b being the transfer function poles computed from the parameters 11 , 22 , 12 , 21 , 13 and 31 . III. IDENTIFICATION METHODOLOGY In order to present the identication methodology, the second order linear model is normalized such that its static gain is set to one, and the Hill function parameters are modied in such a way that the input-output properties of {r(t), u(t)} are maintained. The new model is represented by z(s) u(s) = M (s), with M (s) = and r(t) =

The eq.s (12) and (11) are now used to dene a function, f (), such that f () = 1 1 expt3 ln[ ] t3 t2 1 expt2 1 1 expt4 ln[ ] t4 t1 1 expt1

(13)

ab (s + a)(s + b)

The 0 = b a is obtained by solving the nonlinear equation f () = 0. Knowing the estimate 0 then a and can be computed from b a
1 exp0 t4 1 ln[ ] 0 t1 t4 t1 1 exp = 0 + a b

(6)

(C50 ) (C50 ) + (z(t))

(7)

(14)

where C50 = (a.b.C50 )/21 . This enables the separation of the parameters in two classes, {a, b} are estimated rst, and {, C50 } are estimated later using a, and b. The development of the identication methodology is based on the fact that the rst neuromuscular blockade bolus usually forces the patient to a state of total paralysis, the index monitor r(.) goes from the value 1.0 to 0.0 or to a value near 0.0, as in g. (2). After some time and depending on the pharmacokinetics, r(.) starts to increase. As a standard practice the anesthesiologist manipulates the drug infusion rate or the bolus sequence to maintain r(.) near the value of 0.1 (10%). This means that there is a time window dened by {t0 < t < tf : r(t) < 0.1} where it is possible to select 4 data points with time instantes such that

B. Estimating the parameters of the Hill function Knowing the estimates a and and using eq.(10) it is pos b sible to compute z (t1 ) and z (t2 ) corresponding respectively to the measured values r(t1 ) and r(t2 ). Rearranging the Hill function it can be written as z = (C50 ) (1/r 1). This yields ((t1 )/(t2 )) = (1/r(t1 ) 1)/(1/r(t2 ) 1). By z z further algebraic manipulation then and C50 are obtained from z(t1 ) 1 1 1 = [ln( )] [ln( 1) ln( 1)] (15) z(t2 ) r(t1 ) r(t2 ) r(t1 ) C50 = z(t1 ) r(t1 ) 1 C. Evaluating the parameter estimation error In practice the measurements of the time instants t1 < t2 < t3 < t4 have always a measurement error, not only because there is noise but also due to the fact that the neuromuscular blockade monitor signal provides values at discrete time instants, usually at a sampling time of 20s. To improve the measurements, a linear interpolation is used to nd t1 , t2 , t3 , t4 . (16)

r(t1 ) = r(t4 ) r(t2 ) = r(t3 ) with t1 < t2 < t3 < t4 , g.(2). The constraints imposed by (8) imply that z(t1 ) = z(t4 ) z(t2 ) = z(t3 )

(8)

(9)

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Fig. 3. Mean square error of each estimated model for the 100 model database, using the impulsive responses.

Fig. 4. Neuromuscular blockade response for the rst atracurium bolus of 500g/kg, using model n.2 (symbol - o). Response of the estimated model, symbol +.

To quantify the level of error in the estimates of a, b, and C50 due to t1 , t2 , t3 , t4 , a rst order analysis using a Taylor expansion of f (0 , t1 , t2 , t3 , t4 ) can be used. Noting that f (0 , t1 , t2 , t3 , t4 ) = 0 and f (0 , t1 , t2 , t3 , t4 ) = 0, then |0 0 |
4 f i=1 | ti | |ti | f |

ti |

(17)

with the partial derivatives being evaluated at the nominal point dened by (0 , t1 , t2 , t3 , t4 ). Knowing the error level |0 0 | and using a similar approach it is possible to evaluate the error level on a, b, z (t1), z (t2), and C50 . However this analysis is lengthy and will not be presented here, instead computer simulations are used to evaluate the identication methodology. IV. SIMULATION RESULTS Computer simulations were performed to evaluate the identication methodology. A database with 100 neuromuscular blockade models [6] was used. These models have a pharmacokinetics that is characterized by a 4th order linear continuous-time dynamics with a zero. A 20s period was used to sample the neuromuscular blockade response, this simulates the operation of the neuromuscular blockade monitor. The sampled data was used to nd the time instants t1 , t2 , t3 , t4 . The time values were determined for r(t1 ) = r(t4 ) = 0.09 (9%) and r(t2 ) = r(t3 ) = 0.055 (5.5%). Fig. (3) shows the mean square error for the estimated model using the impulsive responses, it is dened as M Serror = N (1/N ) k=1 (r(Ts .k) r(Ts .k))2 , where Ts is the sampling period and N.Ts is 100 min. The estimated model corresponding to the database model number 18 presents the higher mean square error. Three simulation results are shown corresponding to database models 2, 18, and 69. A. Simulation results from the model n.2 The model number 2 is characterized by the following parameters: Static gain Sg = 0.1822, z1 = 0.0889, p1 = 0.0362 , p2 = 0.0909, p3 = 0.2156, p4 = 0.2643, C50 = 0.6370, = 4.1103. Note that z1 is near p2 , so it can be considered a zero-pole cancelation but the transfer function is of order 3 with pole p3 being near pole p4 . The

normalized C50 is C50 = C50 /Sg = 3.4962. The measured time instants (in [min]) are obtained from the bolus sampled data response, t1 = 5.3031, t2 = 5.9576, t3 = 35.1212, t4 = 38.7325. Using the estimation methodology, the estimated nonlinear second order model has p1 = 0.0179, p2 = 0.1676, C50 = 3.8026, = 8.4879. The C50 and C50 parameters are very similar but is two times the value of . However the impulsive response of the estimated neuromuscular blockade model is very similar to the impulsive response of neuromuscular blockade model with the 4 order pharmacokinetics, this is shown in g.(4).

B. Simulation results from the model n.18 The model number 18 is characterized by the following parameters: Static gain Sg = 0.1722, z1 = 0.1521, p1 = 0.0356 , p2 = 0.0814, p3 = 0.3672, p4 = 2.3261, C50 = 0.6535, = 3.6135. Note that with this model there is no zero-pole cancelation. The normalized C50 is C50 = C50 /Sg = 3.4962. The measured time instants (in [min]) obtained by linear interpolation the bolus sampled data response are t1 = 3.8994, t2 = 5.0908, t3 = 26.5349, t4 = 32.3945. Using the estimation methodology, the estimated nonlinear second order model has p1 = 0.0278, p2 = 0.1809, C50 = 3.4046, = 3.4733. In this case the C50 and C50 are similar and the same is true for and , however the time response of the estimated model has a relative high error for r(t) > 0.2 and a small error for r(t) 0.2, as shown in g.(5). This estimation result is the worst case obtained with the 100 model database. C. Simulation results from the model n.69 The model number 69 is characterized by the following parameters: Static gain Sg = 0.2108, z1 = 0.1230, p1 = 0.0360 , p2 = 0.0723, p3 = 0.0996, p4 = 0.2999, C50 = 0.6163, = 4.2189. Note that in this model z1 is near p3 and it can be considered a zero-pole cancelation. The normalized C50 is C50 = C50 /Sg = 2.9236. The measured time instants (in [min]) obtained by linear interpolation the

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1 + Model of order 2 0.9 o Output of the true model 0.8

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Fig. 5. Neuromuscular blockade response for the rst atracurium bolus of 500g/kg, using model n.18 (symbol - o). Response of the estimated model, symbol +.
1 + Model of order 2 0.9 o Output of the true model 0.8

computer simulation using a neuromuscular blockade model database with 100 models. The computer simulation results show that the proposed identication methodology has a good performance when tested with the models of the database. The worst case was obtained with models that cannot be approximated by a second order system, that is, they do not have a near zero-pole cancelation. Despite this fact, the estimated models were able to provide a good approximation of the neuromuscular blockade response for r(.) < 0.2 (20%). The main conclusion from the above results is that, to obtain a good modeling of the bolus response it is necessary to obtain a good estimation of the pharmacokinetics model, and this raises the problem of selecting the best structure to model the real cases. At the present stage there are several unanswered questions, that is:

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What is the noise effect in the estimation? There is a signicant number of real cases with a at response at r(t) = 0.05. How to handle it? What is the closed-loop performance of a controller that is designed using above identication methodology?

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As a future work the identication methodology will be evaluated with realistic data taken from real cases and if possible the methodology will be extended to higher order models. R EFERENCES
[1] S. Schraag , Theoretical basis of target controlled anaesthesia: history, concept and clinical perspectives, Best Practice & Research Clinical Anaesthesiology, Vol. 15, No. 1, pp. 1-17, 2001 [2] DK. Sreevastava, KK. Upadhyaya, Automated Target Controlled Infusion Systems: The Future of Total Intravenous Anaesthesia, MJAFI, Vol. 64, No. 3; 2008 [3] P. Gorce, Economical aspects of concentration-oriented anaesthesia: intravenous agents, Best Practice & Research Clinical Anaesthesiology, Vol. 15, No. 1, pp. 137-142, 2001 [4] JM. Bailey, WM. Hadda Drug Dosing Control in Clinical Pharmacology, IEEE Control Systems Magazine, Vol. April, No. April, pp. 35-51, 2005 [5] T. Mendonca, P. Lago PID control strategies for the automation control of neuromuscular blockade, Control Engineering Pratice, Vol. 6, pp. 1225-1231, 1998 [6] H. Alonso, J.M. Lemos, T. Mendonca A Target Control Infusion method for neuromuscular blockade based hybrid parameter estimation, 30th Annual International IEEE EMBS Conference Proceedings, August 20-24, pp. 707-1231, 2008 [7] ST. Young, KN. Hsiao, A Pharmacokinetic Model To Study Administration of Intravenous Anaesthetic Agents, IEEE Engineering in Medice and Biology, Vol. April/May, pp. 263-268, 1994 [8] Dorene A. OHara, John G. Hexem, et al., The Use of a PID Controller to Model Vecuronium Pharmacokinetics and Pharmacodynamics During Liver Transplantation, IEEE Transactions On Biomedical Engineering, Vol. 44: No. 7, pp. 610619, July 1997 [9] R. R. Jaklitsch, D. R. Westenskow, A Model-Based Self-Adjusting Two-Phase Controller for Vecuronium-Induced Muscle Relaxation During Anesthesia, IEEE Transactions On Biomedical Engineering, Vol. BME-34, No. 8, pp. 583-594, August 1987 [10] P. M. Schumacher, K. S. Stadler, et al., Model-based control of neuromuscular block using mivacurium: design and clinical verication, European Journal of Anaesthesiology, Vol. 23: pp. 691699, 2006 [11] K.S. Pang, M. Weiss, P. Macheras, Advanced Pharmacokinetic Models Based on Organ Clearance, Circulatory and Fractal Concepts, The AAPS Journal, Vol 9, No. 2, pp-E268-E283, 2007

Fig. 6. Neuromuscular blockade response for the rst atracurium bolus of 500g/kg, using model n.69 (symbol - o). Response of the estimated model, symbol +.

bolus sampled data response are t1 = 9.9364, t2 = 11.3413, t3 = 49.7039, t4 = 54.4795. Using the estimation methodology, the estimated nonlinear second order model has p1 = 0.0185, p2 = 0.0725, C50 = 3.1387, = 7.3714. In this case, the C50 and C50 are similar, and are very different. But if one compares the neuromuscular blockade responses of both models they are very similar as shown in g.(6). The main conclusion from the above results is that, to obtain a good modeling of the bolus response it is necessary to obtain a good estimation of the pharmacokinetic model. The estimate C50 is near the true value, but has a huge error, however this huge error causes a degradation in the bolus response estimation. V. CONCLUSIONS This paper presents an identication methodology to obtain a second order non-linear model to describe the patient/drug interaction for the neuromuscular blockade in general anesthesia. The model is identied using four data points taken from the rst bolus response. The method estimates in rst place the pharmacokinetics followed by the pharmacodynamics which is described by the Hill equation with normalized parameters. The method was evaluated by

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[12] D. M. Fisher, P. C. Canfell, et al, Elimination of Atracurium in Humans: Contribution of Hofmann Elimination and Ester Hydrolysis versus Organ-based Elimination, Anesthesiology, Vol. 65, pp. 6-12, 1986 [13] Colins A. Shanks Pharmacokinetics of the Nondepolarizing Neuromuscular Relaxants Applied to Calculation of Bolus and Infusion Dosage Regimens, Anesthesiology, Vol. 64, pp. 72-86, 1986

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