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ISBN 978-951-42-9484-6 (Paperback)ISBN 978-951-42-9485-3 (PDF)ISSN 0355-3213 (Print)ISSN 1796-2226 (Online)

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OULU 2011

C 385

Jukka Kortelainen

EEG-BASED DEPTH OF ANESTHESIA MEASUREMENTSEPARATING THE EFFECTS OF PROPOFOL AND REMIFENTANIL

UNIVERSITY OF OULU,FACULTY OF TECHNOLOGY,DEPARTMENT OF COMPUTER SCIENCE AND ENGINEERING;INFOTECH OULU

C 385

ACTA

Jukka Kortelainen

C385etukansi.fm Page 1 Wednesday, July 6, 2011 9:47 AM

A C T A U N I V E R S I T A T I S O U L U E N S I SC Te c h n i c a 3 8 5

JUKKA KORTELAINEN

EEG-BASED DEPTH OF ANESTHESIA MEASUREMENTSeparating the effects of propofol and remifentanil

Academic dissertation to be presented with the assent ofthe Faculty of Technology of the University of Oulu forpublic defence in OP-sali (Auditorium L10), Linnanmaa, on26 August 2011, at 12 noon

UNIVERSITY OF OULU, OULU 2011

Copyright 2011Acta Univ. Oul. C 385, 2011

Supervised byProfessor Tapio Seppnen

Reviewed byProfessor Jamie SleighProfessor Tarmo Lipping

ISBN 978-951-42-9484-6 (Paperback)ISBN 978-951-42-9485-3 (PDF)http://herkules.oulu.fi/isbn9789514294853/ISSN 0355-3213 (Printed)ISSN 1796-2226 (Online)http://herkules.oulu.fi/issn03553213/

Cover DesignRaimo Ahonen

JUVENES PRINTTAMPERE 2011

Kortelainen, Jukka, EEG-based depth of anesthesia measurement. Separating theeffects of propofol and remifentanilUniversity of Oulu, Faculty of Technology, Department of Computer Science and Engineering;Infotech Oulu, P.O. Box 4500, FI-90014 University of Oulu, FinlandActa Univ. Oul. C 385, 2011Oulu, Finland

AbstractWithin the last few decades, electroencephalogram (EEG) has become a widely used tool for theautomatic assessment of depth of anesthesia. The EEG-based depth of anesthesia measurementhas been associated with several advantages, such as a decreased incidence of intraoperativeawareness and recall, faster recovery, and reduced consumption of anesthetics. However, themeasurement is challenged by simultaneous administration of different types of anesthetics, whichis the common practice in the operating rooms today. Especially, the assessment of depth ofanesthesia induced by supplementing the primary anesthetic drug, i.e. the hypnotic agent, with anopioid has been raised as one of the major problems in the field.

In this thesis, the EEG-based depth of anesthesia measurement during multidrug infusion withpropofol (hypnotic agent) and remifentanil (opioid) is addressed. The problem is approached byfirst giving a quantitative description for the EEG changes occurring during propofol infusion.Two different methods, both utilizing the spectral properties of EEG, for this are presented. Next,the effects of remifentanil on the clinical signs and EEG changes during propofol infusion areinvestigated by applying the first one of the presented methods. Coadministration of opioid isshown to significantly modify the mutual relations of the EEG changes and the clinical signs ofthe patient. Furthermore, remifentanil is found to significantly affect the EEG itself, morespecifically, the power spectrum and derived quantitative parameters during propofol infusion.This effect is strongly dependent on the level of anesthesia. Finally, by utilizing the results on theeffects of remifentanil, a technology is developed for the assessment of depth of propofol-remifentanil anesthesia. The technology is based on improving the determination of the anestheticstate of the patient by EEG-based separation of the effects of propofol and remifentanil.

The thesis provides a framework for the depth of anesthesia measurement during multidrugadministration with propofol and remifentanil. Due to the similar mechanisms of action, the resultsare likely to be generalizable to other hypnotic-opioid drug combinations. The study thus offerspotential for the development of more advanced systems for automatic monitoring of depth ofanesthesia.

Keywords: hypnotic, monitoring, opioid, pattern recognition, signal processing

Kortelainen, Jukka, EEG-pohjainen anestesian syvyyden mittaus. Propofolin jaremifentaniilin vaikutusten erotteluOulun yliopisto, Teknillinen tiedekunta, Tietotekniikan osasto; Infotech Oulu, PL 4500, 90014Oulun yliopistoActa Univ. Oul. C 385, 2011Oulu

TiivistelmViime vuosikymmenin elektroenkefalogrammista (EEG) on tullut suosittu apuvline anestesi-an syvyyden automaattisessa seurannassa. EEG-pohjaisella anestesian syvyyden mittauksella onsaavutettu useita hytyj: sill on pystytty esimerkiksi vhentmn leikkauksen aikaista hereilloloa, pienentmn anesteettien kulutusta sek nopeuttamaan anestesiasta palautumista. Mittauson kuitenkin haasteellista yhdistelmanestesiassa, jossa useampaa erityyppist anesteettia kyte-tn samanaikaisesti. Erityisesti nykyisin yleisesti kytss oleva tapa tydent pasiallistaanesteettia eli hypnoottia opioidilla on nostettu yhdeksi merkittvimmist haasteista automaatti-sessa anestesian syvyyden mittauksessa.

Vitskirja ksittelee EEG-pohjaista anestesian syvyyden mittausta kytettess propofolin(hypnootti) ja remifentaniilin (opioidi) yhdistelm. Ongelmaa lhestytn antamalla aluksikvantitatiivinen kuvaus propofoli-induktion aikana ilmeneville EEG-muutoksille. Thn tarkoi-tukseen esitetn kaksi menetelm, joista molemmat hydyntvt EEG:n taajuussislt. Seu-raavaksi remifentaniilin vaikutusta potilaan kliinisiin merkkeihin sek EEG-muutoksiin propofo-li-infuusion aikana tutkitaan soveltamalla ensimmist esitetyist menetelmist. Opioidin osoite-taan vaikuttavan merkittvsti EEG-muutosten ja kliinisten merkkien vliseen yhteyteen. Lisksiremifentaniilin todetaan vaikuttavan merkittvsti mys propofoli-infuusion aikana ilmeneviinEEG-muutoksiin. Vaikutus heijastuu signaalin tehotiheysspektriin sek siit johdettuihin kvanti-tatiivisiin parametreihin ja on vahvasti riippuvainen anestesian syvyydest. Lopuksi, hydynt-mll tuloksia remifentaniilin vaikutuksista, esitetn teknologia propofoli-remifentanilli-yhdis-telmanestesian syvyyden mittaukseen. Teknologia perustuu propofolin ja remifentaniilin vaiku-tusten EEG-pohjaiseen erotteluun ja tt hydynten potilaan anestesian syvyyden tarkempaanmrittmiseen.

Vitskirja tarjoaa tarvittavan tutkimustiedon sek teknologian propofoli-remifentanilli-yhdistelmanestesian syvyyden mittaukseen. Samankaltaisten vaikutusmekanismien vuoksitulokset on mahdollista yleist mys muille hypnootti-opioidi-lkeyhdistelmille. Tutkimusavaa nin uusia mahdollisuuksia kehitt edistyneempi anestesian syvyytt automaattisesti seu-raavia jrjestelmi.

Asiasanat: hahmontunnistus, hypnootti, monitorointi, opioidi, signaalinksittely

Acknowledgements

This work was carried out during the years 20062011 at the Biosignal Processing

Team of the Department of Electrical and Information Engineering, University of Oulu,

Finland.

I would like to express my sincere gratitude to my supervisor Professor Tapio Sepp-

nen for his support and guidance throughout this project. I also wish to thank Professor

Jamie Sleigh and Professor Tarmo Lipping for prereviewing the thesis. The co-authors

Dr. Miika Koskinen, Dr. Seppo Mustola, and M.Sc. Eero Vyrynen are gratefully ac-

knowledged for providing essential contribution to the original publications. I would

also like to thank the whole Biosignal Processing Team for creating an inspiring and

warm working environment. For proofreading the manuscript, I wish to thank Dr. Pertti

Vyrynen. Furthermore, I am indebted to Professor Nitish Thakor for giving me the op-

portunity to visit his laboratory at Johns Hopkins University in summer 2009 and Dr.

Xiaofeng Jia for his help and guidance during this visit.

For the financial support, I am grateful to Graduate School in Electronics, Telecom-

munication, and Automation (GETA), Walter Ahlstrm Foundation, Tauno Tnning

Foundation, Instrumentarium Science Foundation, Finnish Foundation for Economic

and Technology Sciences KAUTE, The Finnish Medical Foundation, Orion-Farmos

Research Foundation, Oulu University Scholarship Foundation, and Ulla Tuominen

Foundation.

Finally, I would like to thank my family, especially my wife Terhi, for the continu-

ous support, patience, and encouragement during all these years.

Jukka Kortelainen

Oulu, 2011

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Abbreviations

AP Action potential

AEP Auditory evoked potential

AU Arbitrary units

BIS Bispectral Index

BSP Burst suppression pattern

BSR Burst suppression ratio

CNS Central nervous system

EEG Electroencephalogram

EMG Electromyogram

EP Evoked potential

EOG Electro-oculogram

FPP Frequency progression pattern

GABA Gamma-aminobutyric acid

GRNN Generalized regression neural network

IV Intravenous

LC Loss of counting

LRT Loss of reaction to tetanic stimulation

LVC Loss of obeying verbal command

MAC Minimum alveola