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Nonlinear Modeling and Feedback Control of Drug Delivery in Anesthesia
Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

General anesthesia is a drug-induced reversible state where neuromuscular blockade (NMB), hypnosis, and analgesia (jointly denoted by depth of anesthesia - DoA) are guaranteed. This thesis concerns mathematical modeling and feedback control of the effect of the muscle relaxants atracurium and rocuronium, the hypnotic propofol, and the analgesic remifentanil. It is motivated by the need to reduce incidences of awareness and overdose-related post-operative complications that occur in standard clinical practice. A major challenge for identification in closed-loop is the poor excitation provided by the feedback signal. This applies to the case of drugs administered in closed-loop. As a result, the standard models for the effect of anesthetics appear to be over-parameterized. This deteriorates the result of system identification and prevents individualized control.

In the first part of the thesis, minimally parameterized models for the single-input single-output NMB and the multiple-input single-output DoA are developed, using real data. The models have a nonlinear Wiener structure: linear time-invariant dynamics cascaded with a static nonlinearity. The proposed models are shown to improve identifiability as compared to the standard ones.

The second part of the thesis presents system identification methods for Wiener systems: a batch prediction error method, and two recursive techniques, one based on the extended Kalman filter, and another based on the particle filter. Algorithms are given for both the NMB and the DoA using the minimally parameterized models.

Nonlinear adaptive controllers are proposed in the third part of the thesis. Using the model parameter estimates from the extended Kalman filter, the controller performs an online inversion of the Wiener nonlinearity. A pole-placement controller or a linear quadratic Gaussian controller is used for the linearized system. Results show good reference tracking performance both in simulation and in real trials.

Relating to patient safety, the existence of undesirable sustained oscillations as consequence of Andronov-Hopf bifurcations for a NMB PID-controlled system is analyzed. Essentially the same bifurcations are observed in the standard and the minimally parameterized models, confirming the ability of the latter to predict the nonlinear behavior of the closed-loop system. Methods to design oscillation-free controllers are outlined.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 75 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1187
Keyword [en]
anesthesia, drug delivery, feedback control, nonlinear modeling, pharmacokinetics/pharmacodynamics, PID control, system identification, Wiener model
National Category
Control Engineering
Research subject
Electrical Engineering with specialization in Automatic Control
Identifiers
URN: urn:nbn:se:uu:diva-233290ISBN: 978-91-554-9054-6 (print)OAI: oai:DiVA.org:uu-233290DiVA: diva2:751821
Public defence
2014-11-21, Room 2347, Polacksbacken, Lägerhyddsvägen 2, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
EU, European Research Council, 247035
Available from: 2014-10-30 Created: 2014-10-01 Last updated: 2015-01-23
List of papers
1. Nonlinear identification of a minimal neuromuscular blockade model in anesthesia
Open this publication in new window or tab >>Nonlinear identification of a minimal neuromuscular blockade model in anesthesia
2012 (English)In: IEEE Transactions on Control Systems Technology, ISSN 1063-6536, E-ISSN 1558-0865, Vol. 20, no 1, 181-188 p.Article in journal (Refereed) Published
National Category
Control Engineering
Identifiers
urn:nbn:se:uu:diva-150539 (URN)10.1109/TCST.2011.2107742 (DOI)000302693700015 ()
Available from: 2011-12-12 Created: 2011-03-31 Last updated: 2017-12-11Bibliographically approved
2. Online nonlinear identification of the effect of drugs in anæsthesia using a minimal parameterization and BIS measurements
Open this publication in new window or tab >>Online nonlinear identification of the effect of drugs in anæsthesia using a minimal parameterization and BIS measurements
2010 (English)In: Proc. American Control Conference: ACC 2010, American Automatic Control Council , 2010, 4379-4384 p.Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
American Automatic Control Council, 2010
National Category
Control Engineering Information Science
Identifiers
urn:nbn:se:uu:diva-138747 (URN)978-1-4244-7426-4 (ISBN)
Available from: 2010-07-29 Created: 2010-12-19 Last updated: 2014-10-30Bibliographically approved
3. Nonlinear estimation of a parsimonious Wiener model for the neuromuscular blockade in closed-loop anesthesia
Open this publication in new window or tab >>Nonlinear estimation of a parsimonious Wiener model for the neuromuscular blockade in closed-loop anesthesia
2014 (English)In: Proc. 19th IFAC World Congress, International Federation of Automatic Control , 2014, 9258-9264 p.Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
International Federation of Automatic Control, 2014
National Category
Control Engineering
Identifiers
urn:nbn:se:uu:diva-233194 (URN)10.3182/20140824-6-ZA-1003.01876 (DOI)978-3-902823-62-5 (ISBN)
Available from: 2014-08-24 Created: 2014-09-30 Last updated: 2014-10-30Bibliographically approved
4. Local identifiability and sensitivity analysis of neuromuscular blockade and depth of hypnosis models
Open this publication in new window or tab >>Local identifiability and sensitivity analysis of neuromuscular blockade and depth of hypnosis models
Show others...
2014 (English)In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 113, no 1, 23-36 p.Article in journal (Refereed) Published
National Category
Control Engineering
Identifiers
urn:nbn:se:uu:diva-207830 (URN)10.1016/j.cmpb.2013.07.020 (DOI)000327180900003 ()
Available from: 2013-08-28 Created: 2013-09-19 Last updated: 2017-12-06Bibliographically approved
5. Nonlinear adaptive control of the neuromuscular blockade in anesthesia
Open this publication in new window or tab >>Nonlinear adaptive control of the neuromuscular blockade in anesthesia
2011 (English)In: Proc. 50th Conference on Decision and Control, Piscataway, NJ: IEEE , 2011, 41-46 p.Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
Piscataway, NJ: IEEE, 2011
National Category
Control Engineering
Identifiers
urn:nbn:se:uu:diva-165454 (URN)10.1109/CDC.2011.6160227 (DOI)978-1-61284-800-6 (ISBN)
Available from: 2012-03-01 Created: 2012-01-08 Last updated: 2014-10-30Bibliographically approved
6. Exactly linearizing adaptive control of propofol and remifentanil using a reduced Wiener model for the depth of anesthesia
Open this publication in new window or tab >>Exactly linearizing adaptive control of propofol and remifentanil using a reduced Wiener model for the depth of anesthesia
2012 (English)In: Proc. 51st Conference on Decision and Control, Piscataway, NJ: IEEE, 2012, 368-373 p.Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
Piscataway, NJ: IEEE, 2012
National Category
Control Engineering
Identifiers
urn:nbn:se:uu:diva-185426 (URN)10.1109/CDC.2012.6425924 (DOI)000327200400061 ()978-1-4673-2065-8 (ISBN)
Conference
CDC 2012, December 10–13, Maui, HI
Available from: 2013-02-04 Created: 2012-11-23 Last updated: 2017-08-10Bibliographically approved
7. Performance of an adaptive controller for the neuromuscular blockade based on inversion of a Wiener model
Open this publication in new window or tab >>Performance of an adaptive controller for the neuromuscular blockade based on inversion of a Wiener model
2015 (English)In: Asian journal of control, ISSN 1561-8625, E-ISSN 1561-8625, Vol. 17, no 4, 1136-1147 p.Article in journal (Refereed) Published
National Category
Control Engineering
Identifiers
urn:nbn:se:uu:diva-233197 (URN)10.1002/asjc.981 (DOI)000357974700003 ()
Funder
EU, European Research Council, 247035
Available from: 2014-09-10 Created: 2014-09-30 Last updated: 2017-12-05Bibliographically approved
8. Bifurcation analysis of PID-controlled neuromuscular blockade in closed-loop anesthesia
Open this publication in new window or tab >>Bifurcation analysis of PID-controlled neuromuscular blockade in closed-loop anesthesia
2015 (English)In: Journal of Process Control, ISSN 0959-1524, E-ISSN 1873-2771, Vol. 25, 152-163 p.Article in journal (Refereed) Published
National Category
Control Engineering
Identifiers
urn:nbn:se:uu:diva-233201 (URN)10.1016/j.jprocont.2014.10.006 (DOI)000348962000015 ()
Funder
EU, European Research Council, 247035
Available from: 2014-11-13 Created: 2014-09-30 Last updated: 2017-12-05Bibliographically approved

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