oulu 2015 d 1321 university of oulu p.o. box 8000 fi-90014...
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UNIVERSITY OF OULU P .O. Box 8000 F I -90014 UNIVERSITY OF OULU FINLAND
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 S
Professor Esa Hohtola
University Lecturer Santeri Palviainen
Postdoctoral research fellow Sanna Taskila
Professor Olli Vuolteenaho
University Lecturer Veli-Matti Ulvinen
Director Sinikka Eskelinen
Professor Jari Juga
University Lecturer Anu Soikkeli
Professor Olli Vuolteenaho
Publications Editor Kirsti Nurkkala
ISBN 978-952-62-0971-5 (Paperback)ISBN 978-952-62-0972-2 (PDF)ISSN 0355-3221 (Print)ISSN 1796-2234 (Online)
U N I V E R S I TAT I S O U L U E N S I S
MEDICA
ACTAD
D 1321
ACTA
Eila Sonkajärvi
OULU 2015
D 1321
Eila Sonkajärvi
THE BRAIN'S ELECTRICAL ACTIVITY IN DEEP ANAESTHESIAWITH SPECIAL REFERENCE TO EEGBURST-SUPPRESSION
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL
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 SD M e d i c a 1 3 2 1
EILA SONKAJÄRVI
THE BRAIN'S ELECTRICAL ACTIVITY IN DEEP ANAESTHESIAWith special reference to EEG burst-suppression
Academic Dissertation to be presented with the assent ofthe Doctora l Train ing Committee of Health andBiosciences of the University of Oulu for public defence inAuditorium 1 of Oulu University Hospital,on 13 November 2015, at 12 noon
UNIVERSITY OF OULU, OULU 2015
Copyright © 2015Acta Univ. Oul. D 1321, 2015
Supervised byProfessor Seppo AlahuhtaDocent Ville Jäntti
Reviewed byDocent Kaisa HartikainenProfessor Juhani V Partanen
ISBN 978-952-62-0971-5 (Paperback)ISBN 978-952-62-0972-2 (PDF)
ISSN 0355-3221 (Printed)ISSN 1796-2234 (Online)
Cover DesignRaimo Ahonen
JUVENES PRINTTAMPERE 2015
OpponentProfessor Leena Lindgren
Sonkajärvi, Eila, The brain's electrical activity in deep anaesthesia. With specialreference to EEG burst-suppressionUniversity of Oulu Graduate School; University of Oulu, Faculty of Medicine; MedicalResearch Center Oulu; Oulu University HospitalActa Univ. Oul. D 1321, 2015University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland
Abstract
Several anaesthetics are able to induce a burst-suppression (B-S) pattern in theelectroencephalogram (EEG) during deep levels of anaesthesia. A burst-suppression patternconsists of alternating high amplitude bursts and periods of suppressed background activity. Allmonitors measuring the adequacy of anaesthesia recognize the EEG B-S as one criterion. A betterunderstanding of EEG burst-suppression is important in understanding the mechanisms ofanaesthesia. The aim of the study was to acquire a more comprehensive understanding of thefunction of neural pathways during deep anaesthesia.
The thesis is comprised of four prospective clinical studies with EEG recordings from 64patients, and of one experimental study of a porcine model of epilepsy with EEG registrationstogether with BOLD fMRI during isoflurane anaesthesia (II). In study I, somatosensory corticalevoked responses to median nerve stimulation were studied under sevoflurane anaesthesia at EEGB-S levels. In study III, The EEGs of three Parkinson`s patients were observed to describe thecharacteristics of B-S during propofol anaesthesia using scalp electrodes and depth electrodes inthe subthalamic nucleus. In study IV, EEG topography was observed in 20 healthy children underanaesthesia mask induction with sevoflurane. Twenty male patients were randomized to eithercontrolled hyperventilation or spontaneous breathing groups for anaesthesia mask induction withsevoflurane in study V. EEG alterations in relation to haemodynamic responses were examined instudies IV and V.
Somatosensory information reached the cortex even during deep anaesthesia at EEG burst-suppression level. Further processing of these impulses in the cortex was suppressed. The EEGslow wave oscillations were synchronous over the entire cerebral cortex, while spindles and sharpwaves were produced by the sensorimotor cortex. The development of focal epileptic activitycould be detected as a BOLD signal increase, which preceded the EEG spike activity. Theepileptogenic property of sevoflurane used at high concentrations especially duringhyperventilation but also during spontaneous breathing together with heart rate increase, wasconfirmed in healthy children and male. Spike- and polyspike waveforms concentrated in amultifocal manner frontocentrally.
Keywords: anaesthesia, BOLD, burst suppression, electroencephalography, epilepsy,epileptogenic, functional magnetic resonance imaging, hyperventilation, propofol,sevoflurane, sleep spindle, somatosensory evoked potentials
Sonkajärvi, Eila, Aivojen sähköinen aktiivisuus syvässä anestesiassa. Erityisestiaivosähkökäyrän purskevaimentuman aikanaOulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical ResearchCenter Oulu; Oulun yliopistollinen sairaalaActa Univ. Oul. D 1321, 2015Oulun yliopisto, PL 8000, 90014 Oulun yliopisto
Tiivistelmä
Useat anestesia-aineet pystyvät aiheuttamaan aivosähkökäyrän (EEG) purskevaimentumansyvän anestesian aikana. Purskevaimentuma koostuu EEG:n suuriamplitudisten purskeiden sekävaimentuneen taustatoiminnan vaihtelusta. Kaikkien anestesian syvyyttä mittaavien valvontalait-teiden toiminta perustuu osaltaan EEG:n purskevaimentuman tunnistamiseen. Tämän ilmiönparempi tunteminen on tärkeää anestesiamekanismien ymmärtämiseksi. Tutkimuksen päämäärä-nä oli saada kattavampi käsitys hermoratojen toiminnasta syvässä anestesiassa.
Väitöskirjatyö koostuu neljästä prospektiivisesta yhteensä 64 potilaan EEG-rekisteröinnitsisältävästä tutkimuksesta sekä yhdestä kokeellisen epilepsiatutkimuksen koe-eläintyöstä, jossaporsailla käytettiin isofluraanianestesiassa sekä EEG-rekisteröintejä sekä magneettikuvantamis-ta (fMRI) samanaikaisesti (II). Ensimmäisessä osatyössä tutkittiin keskihermon stimulaationaiheuttamia somatosensorisia herätepotentiaaleja aivokuorella EEG:n purskevaimentumatasollasevofluraanianestesian aikana. Kolmannessa osatyössä selvitettiin propofolianestesian aiheutta-maa EEG:n purskevaimentumaa kolmelta Parkinsonin tautia sairastavalta potilaalta käyttäensekä pintaelektrodien että subtalamisen aivotumakkeen syväelektrodien rekisteröintejä. Neljän-nessä osatyössä tutkittiin EEG:n topografiaa 20:llä terveeellä lapsella indusoimalla anestesiasevofluraanilla. Kaksikymmentä miespotilasta nukutettiin sevofluraanilla ja heidät satunnaistet-tiin joko kontrolloidun hyperventilaation tai spontaanin hengityksen ryhmiin osatyössä V. EEG-muutoksia sekä niiden yhteyttä verenkiertovasteisiin selviteltiin molemmissa osatöissä IV ja V.
Omasta kehosta tuleviin tuntoärsykkeisiin liittyvä somatosensorinen informaatio saavuttiaivokuoren myös syvässä EEG:n purskevaimentumatasoisessa anestesiassa. Impulssien jatkokä-sittely aivokuorella oli kuitenkin estynyt. EEG:n hidasaaltotoiminta oli synkronista koko aivo-kuoren alueella, sen sijaan unisukkulat ja terävät aallot paikantuivat sensorimotoriselle aivokuo-relle. Paikallisen epileptisen toiminnan kehittyminen oli mahdollista havaita jo ennen piikikkäi-den EEG:n aaltomuotojen ilmaantumista edeltävänä BOLD-ilmiöön liittyvänä aivoverenkierronlisääntymisenä. Sevofluraanin epileptogeenisyys varmistui erityisesti hyperventilaation, muttamyös spontaanin hengityksen yhteydessä ja näihin liittyi sykkeen nousu sekä terveillä lapsillaettä miehillä. Piikkejä ja monipiikkejä käsittävien aaltomuotojen keskittymistä esiintyi otsaloh-kon keskialueilla.
Asiasanat: aivosähkökäyrä, anestesia, BOLD, epilepsia, epileptogeeninen,hyperventilaatio, magneettikuvaus, propofoli, purskevaimentuma, sevofluraani,somatosensoriset herätepotentiaalit, unisukkula
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Acknowledgements
The research for this thesis was carried out during the years 1996-2006 at the
Department of Anaesthesiology, in the Oulu University Hospital, in close
collaboration with the Department of Clinical Neurophysiology, Oulu University
Hospital. One of the studies was carried out at the Department of Diagnostic
Radiology, Oulu University Hospital.
I owe my deepest gratitude to my supervisors Professor Seppo Alahuhta,
M.D, Ph.D., and Docent Ville Jäntti, M.D, Ph.D. It has been a sincere delight and
privilege to have fruitful discussions and to share the moments of discovery
within their guidance. They have introduced me to the world of critical scientific
thinking. Seppo, you have given me the best possible support and encouridgement
in carrying out this project and you have patiently pushed me forward. Ville, you
have been the primus motor of this study and teached me the alphabet of clinical
neurophysiology, I am also grateful to the possibility you offered me to stay a few
months at the Department of Clinical Neurophysiology.
Docent Kaisa Hartikainen, M.D, Ph.D. and Professor Juhani Partanen, M.D,
Ph.D, who kindly agreed to be the official reviewers of this work, deserve my
sincere gratitude. Their valuable comments and constructive criticism have
improved the final outcome of this thesis.
I express my special thanks and respect to my co-author Minna Silfverhuth
nee Mäkiranta, Ph.D., for her encouraging example and scientific attitude. I also
want to thank all my other co-authors, especially Kalervo Suominen, Ph.Lic., Pasi
Puumala, M.D., Seppo Rytky, M.D., Docent Anne Vakkuri, M.D., Ph.D., Nita
Hakalax, specialised nurse in clinical neurophysiology, and Elina Karvonen,
M.D., for their professional assistance and contribution. The help by Professor
Heikki Löppönen, M.D, Ph.D, in making the fourth study in the
otorhinolaryngology unit possible is also acknowledged. I also want to owe my
warmest thanks to Raija Remes, specialised nurse in clinical neurophysiology, for
all her help and collaboration over this researh, it has meant a lot to me.
I am grateful to Professor Arvi Yli-Hankala, M.D., Ph.D., for his interest and
positive attitude for my project. He proposed the fourth study and also gave
valuable comments during the early stage of the writing process of the thesis.
I wish to thank Docent Kai Kiviluoma, M.D., Ph.D, and Docent Timo
Salomäki, M.D., Ph.D., for their valuable roles in the follow-up group.
My special thanks go to Pasi Ohtonen, for his excellent contribution on
biostatistics.
8
I am sincerely grateful to Michael Spalding, M.D., Ph.D., for his efficient and
thorough language revision.
I am greatly indebted to Professor Esa Heikkinen, M.D., Ph.D., the pioneer in
deep-brain stimulation treatment at the Department of Neurosurgery, for his
positive attitude and help with the study of Parkinson`s patients.
I express my sincere thanks to Docent Päivi Laurila, M.D, Ph.D., Head of the
Department of Anaesthesiology, and Professor Tero Ala-Kokko, M.D., Ph.D.,
head of the Division of the Intensive Care medicine, for their positive and helpful
attitude towards my scientific work.
I owe my deep appreciation of all help given by the skillful anaesthesia staff
participating in the care of the study patients, especially by Arto Seljänperä,
specialised nurse in anaesthesiology.
I want to thank all my collegues for friendly and stimulating working
athmophere. I wish to thank Salli Pätsi, M.D., for her kind practical help with the
child patients of the study, and Vesa Pakanen, M.D., for his supportive way of
listening and sharing the problems in everyday patient care. I owe my special
thanks to Pirjo Ranta, M.D., Ph.D, and Risto Ahola, M.D., for their help with all
arrangements related to the dissertation day, planning with them has been fun.
Merja Vakkala, M.D., Ph.D., Hanna Rautiainen, M.D., and Tanja Forchini, M.D.,
are adknowledghed for their support and flexibility in organizing the time-table of
my clinical and scientific working periods.
I owe my warmest thanks to all my dear friends, who have given me plenty of
positive energy. I especially want to thank my `soul sister` Riitta Vesikukka for
her great source of woman power and sense of humour during all those moments
we have spent together.
Finally, I want to thank my dear mother Elvi for her lifelong support and
never failing love. I also want to thank my brother Risto for unlimited practical
help during these years. I am grateful to my family, Timo and our belowed
daughter Sara, for all the joy and happiness you have brought to my life.
This work was supported by EVO grants from Oulu University Hospital,
Pharmacy grants of Oulu University Hospital, and Graduate School of Finnish
Academy, all of which are gratefully acknowledged.
Oulu October 2015 Eila Sonkajärvi
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Abbreviations
AEP Auditory evoked potentials
AVDO2 Arterio-venous oxygen content difference
BIS Bispectral index
BOLD Blood oxygen level-dependent
bpm Beats per minute
B-S Burst-suppression
CBF Cerebral blood flow
CBFV Cerebral blood flow velocity
CH Controlled hyperventilation
CMR Cerebral metabolic rate
CNS Central nervous system
CO2 Carbon dioxide
CV Controlled ventilation
D Delta, < 4 Hz activity in EEG
DC Direct current
DS Delta slow, < 2 Hz activity in EEG
ECG Electrocardiogram
ECoG Electrocorticogram
EEG Electroencephalogram
EMG Electromyogram
EP Evoked potential
EPSP Excitatory postsynaptic potential
ET End-tidal
ETCO2 End-tidal carbon dioxide
ETN2O End-tidal nitrous oxide
ETsevo End-tidal sevoflurane concentration
FFT Fast Fourier transformation
FiO2 Fraction of inspired oxygen
fMRI Functional magnetic resonance imaging
GABA Gamma-amino butyric acid
GM Grand mal, epileptic seizure with tonic-clonic convulsions
Hz Hertz
HR Heart rate
IPSP Inhibitory postsynaptic potential
kPa kiloPascal
10
MAC Minimal alveolar concentration
MAP Mean arterial pressure
MRI Magnetic resonance imaging
MV Minute ventilation
N20 Negative 20 ms wave in somatosensory evoked potentials
N2O Nitrous oxide
NMDA N-methyl-D-aspartic acid
NREM Non-REM or slow wave sleep
PaCO2 Arterial carbon dioxide concentration
PED Periodic epileptiform discharges
PS Polyspikes
PSP Postsynaptic potential
RCT Randomized controlled trial
RE Reticular nucleus of thalamus
REM Rapid eye movement sleep
S Suppression
SSEP Somatosensory evoked potentials
SB Spontaneous breathing
SAP Systolic arterial pressure
SSP Suppression with spikes
TR Thalamic reticular
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List of original publications
This thesis is based on the following publications, which are referred throughout
the text by their Roman numerals:
I Jäntti V, Sonkajärvi E, Mustola S, Rytky S, Kiiski P, Suominen K (1998) Single- sweep cortical somatosensory evoked potentials: N20 and evoked bursts in sevoflurane anaesthesia. Electroencephalogr clin Neurophysiol 108: 320–324.
II Mäkiranta M, Ruohonen J, Suominen K, Niinimäki J, Sonkajärvi E, Kiviniemi V, Seppänen T, Alahuhta S, Jäntti V, Tervonen O (2005) BOLD signal change precedes interictal spike activity in EEG – a dynamical model of experimental penicillin induced focal epilepsy in deep anesthesia. Neuroimage 27: 715–724.
III Sonkajärvi E, Puumala P, Erola T, Baer GA, Karvonen E, Suominen K, Jäntti V (2008) Burst-suppression during propofol anaesthesia recorded from scalp and subthalamic electrodes: report of three cases. Acta Anaesthesiol Scand 52: 274–279.
IV Sonkajärvi E, Alahuhta S, Suominen K, Hakalax N, Vakkuri A, Löppönen H, Ohtonen P, Jäntti V (2009) Topographic electroencephalogram in children during mask induction of anaesthesia with sevoflurane. Acta Anaesthesiol Scand 53; 77–84.
V Sonkajärvi E, Alahuhta S, Suominen K, Rytky S, Kumpulainen T, Ohtonen P, Karvonen E, Jäntti V. Epileptiform EEG activity induced by rapid sevoflurane anaesthesia induction. Manuscript.
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13
Contents
Abstract
Tiivistelmä
Acknowledgements 7 Abbreviations 9 List of original publications 11 Contents 13 1 Introduction 15 2 Review of the literature 19
2.1 General anaesthesia ................................................................................. 19 2.1.1 Mechanisms of anaesthesia .......................................................... 19
2.2 EEG ......................................................................................................... 21 2.2.1 Physiological basis of EEG .......................................................... 21 2.2.2 Registering EEG ........................................................................... 22 2.2.3 Epileptiform EEG discharges and signs of epilepsy ..................... 23 2.2.4 Burst-suppression ......................................................................... 25 2.2.5 Arousal in EEG ............................................................................ 31 2.2.6 Somatosensory evoked potentials (SSEP) .................................... 32 2.2.7 EEG based monitoring ................................................................. 33
2.3 Anaesthetics and the CNS ....................................................................... 34 2.3.1 Sevoflurane ................................................................................... 34 2.3.2 Isoflurane ...................................................................................... 45 2.3.3 Propofol ........................................................................................ 45 2.3.4 Nitrous oxide ................................................................................ 47 2.3.5 Summary of the neurophysiological effects of anaesthetics ......... 48
2.4 EEG during physiological sleep and general anaesthesia ....................... 50 2.5 Epileptiform EEG, anaesthesia and sleep ............................................... 53
3 Aims of the study 55 4 Subjects and Methods 57
4.1 Subjects ................................................................................................... 57 4.2 Variables and measurements ................................................................... 58 4.3 Anaesthesia ............................................................................................. 58 4.4 EEG Recordings and analyses ................................................................ 60 4.5 Stimulation .............................................................................................. 61 4.6 Statistical analysis ................................................................................... 61
5 Results 63
14
5.1 SSEP in sevoflurane anaesthesia (I) ........................................................ 63 5.2 Epileptiform EEG pattern in sevoflurane anaesthesia (IV, V) ................. 64 5.3 Focal seizure, fMRI and EEG (II) ........................................................... 68 5.4 Depth electrode recordings in propofol anaesthesia (III) ........................ 69
6 Discussion 71 6.1 Methodological aspects ........................................................................... 71 6.2 SSEP in sevoflurane anaesthesia (I) ........................................................ 71 6.3 Epileptiform EEG in sevoflurane anaesthesia (IV, V) ............................. 73 6.4 Focal seizure, fMRI and EEG (II) ........................................................... 76 6.5 Depth electrode recordings in propofol anaesthesia (III) ........................ 77
7 Conclusions 79 References 81 Original publications 97
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1 Introduction
General anaesthesia can be viewed as pharmacological actions administered to
prevent the adverse effects of surgical trauma and to create optimal conditions for
surgery. These pharmacological interventions include unconsciousness,
anxiolysis, amnesia, analgesia, autonomic stability and immobility (Kissin 1993).
Several studies suggest that different components of general anaesthesia result
from the actions of a single drug at separate molecular and anatomical sites in the
central nervous system (CNS), and it is now widely accepted that anaesthetic
agents produce immobility by acting primarily on the spinal cord (Rampil & King
1996), and amnesia and hypnosis by acting on neurons in the brain. Since the
introduction of inhaled anaesthetics in the 1840’s, anaesthetic practice has
changed significantly. Present-day anaesthetists employ a wide variety of drugs,
i.e. inhaled and intravenous anaesthetics, analgesics, muscle relaxants and
sedatives, to produce general anaesthesia (Rudolph & Antkowiak 2004,
Campagna et al. 2003). Consciousness is a complex entity comprising two major components: the
content of consciousness and the level of consciousness. The former means the
subject`s awareness of environment and of self and the latter wakefulness i.e. the
level of consciousness (Laureys 2005). Altered stages of consciousness are
produced via several different mechanisms such as physiological sleep, general
anaesthesia, intoxications, metabolic disorders, diffuse ischaemic brain damage
and epileptic seizures (Fig. 1). The electroencephalogram (EEG) pattern of burst-
suppression (B-S) may be observed in all of these states, but during sleep only the
discontinuous pattern of newborn babies resembles the B-S pattern (Jäntti 2012).
The safest way to produce unconsciousness is via the mechanisms of
physiological sleep. These include both sleep prompting mechanisms and arousal
mechanisms. This is obviously the reason why, with most anaesthetics, the EEG
closely resembles the patterns seen in physiological sleep. The most obvious
change is an increase in slow activity. This is an essentially local oscillation of the
cerebral cortex but in the healthy brain it is synchronized throughout the entire
cerebral cortex. During deep anaesthesia this is abruptly changed into a B-S
pattern which resembles the trace alternant, discontinuous pattern of neonatal
quiet sleep (Sainio 2006). In neonates, the postictal B-S pattern may sometimes
gradually transform into this physiological pattern after a focal seizure. Heart rate is mainly controlled by the autonomous nervous system. The
sympathetic system enhances, while the parasympathetic system inhibits the
16
cardiac pacemaker sinoatrial node. These pathways are under the control of the
higher brain regions, such as the hypothalamic, thalamic, and cortical brain
regions. EEG burst-suppression during some periods of anaesthesia, especially during
induction, is not an uncommon phenomenon. Pulse variation and moderate
alterations in systemic circulation, as well as blood flow in the circulation of the
cerebral cortex are related to B-S. All monitors which measure the adequacy of
anaesthesia recognize B-S as one criterion. At present, B-S is accepted as a
definition for deep anaesthesia. A better understanding of B-S is important in
understanding the mechanisms of anaesthesia, as well as when treating epileptic
patients in intensive care units. This study was carried out to acquire a more comprehensive understanding of
the function of sensory and neural pathways during deep anaesthesia. The effects
of sevoflurane and propofol on somatosensory evoked potentials (SSEP) and EEG
during deep anaesthesia in adults and children were studied. Most previous
studies have reported four channel EEG registrations, while in the present study
an extensive 32 channel array, according to the full 10–20 system, including
orbitofrontal and ear electrodes, and depth electrode were used. This enabled
more detailed analyses of the EEG. The relationship between EEG and the blood-
oxygen-level-dependent (BOLD) signal during isoflurane burst-suppression
anaesthesia was evaluated using an experimental model of epilepsy.
17
Fig. 1. An oversimplified illustration of the two major components of consciousness:
the level of consciousness (i.e. wakefulness or arousal) and the content of
consciousness (i.e. awareness or experience). In normal physiological states level
and content are positively correlated (with the exception of dream activity during
REM-sleep). Patients in pathological (e.g. intoxications, brain damage) or
pharmacological coma (that is, general anaesthesia) are unconscious and they cannot
be awakened. Dissociated states of consciousness (i.e. patients being seemingly
awake but lacking any behavioural evidence of voluntary or willed behaviour), such as
the vegetative state or much more transient equivalents such as absence and
complex partial seizures and sleepwalking, offer a unique opportunity to study the
neural correlates of awareness. (Modified from Laureys S. (2005) The neural correlate
of (un)awareness: lessons from vegetative state. TRENDS in Cognitive Sciences 9:
556-9.)
Sleepwalking Complex partial and
absence seizures Vegetative state
Cont
ent o
f con
scio
usne
ss(a
war
enes
s)
Level of consciousness (wakefulness)
General anaesthesia
Coma
REM sleep
ConsciousWakefulness
Drowsiness
Light sleep
Deep sleep
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19
2 Review of the literature
2.1 General anaesthesia
Since the introduction of surgical anaesthesia one hundred and seventy years ago
the definition of anaesthesia has evolved and is now defined as unconsciousness
(hypnotic effect) and blockade of somatic motor response to noxious stimulation
(analgesic effect). It is difficult to separate the anaesthetic actions taking part in
these two subcomponents. Very few anaesthetics act exclusively on either of these
components, as they are closely related to each other. Unconsciousness prevents
the (conscious) perception of pain, and nociception may serve as an arousal
stimulus and change the level of sedation and hypnosis. The type of interaction
(synergism, antagonism, summation) may vary from that of other components.
(Kissin 1993).
2.1.1 Mechanisms of anaesthesia
In past decades, research on anaesthetic mechanisms has mainly focused on ion
channels located in the membranes of nerve cells. The identification of specific
binding sites for volatile anaesthetics on certain proteins was a dramatic departure
from the classic view that all general anaesthetics act non-specifically. Gamma-
aminobutyric acid type A (GABAA) receptors are involved in the actions of many
general anaesthetics. GABAA receptors are found throughout the central nervous
system, both at synapses and extrasynaptically, and they are thought to be one of
the main sites for the actions of anaesthetic agents. Anaesthetic agents which have
an effect on GABAA receptors include volatile anaesthetics and most intravenous
anaesthetics, e.g. sodium thiopental, propofol and etomidate (MacIver et al. 1988,
Krasowski et al. 1998). These drugs can produce three kinds of effects on
GABAA receptors: potentiation, i.e. markedly increase the current elicited by low
concentrations of GABA (Wakamori et al. 1991), direct gating, i.e. activate
channels in the absence of GABA (Wittmer et al. 1996), and inhibition, i.e.
prevent current flow through channels (Hall et al. 1994). Another important
molecular target for anaesthetic agents is the NMDA-type (N-methyl-D-aspartic
acid) receptor, a major postsynaptic, ionotropic receptor for the excitatory
neurotransmitter glutamate. These receptors are also found both presynaptically
and extrasynaptically. NMDA receptors are sensitive to ketamine (Zeilhofer et al.
20
1992), nitrous oxide and xenon (Yamakura & Harris 2000), as well as to other
volatile anaesthetics to some extent - particularly with regards to their analgesic
effects (Aronstam et al. 1994). NMDA (glutamate) and GABA receptors together
constitute 90% of neurones in the mammalian brain. Potassium channels,
especially two-pore-domain potassium channels (2PK channels), have been
shown to be activated by volatile and gaseous anaesthetics, but not by clinically
relevant concentrations of intravenous anaesthetics. The anaesthesic activation of
2PK channels generally results in an inhibition of neuronal activity and a
reduction in excitatory currents (Patel et al. 1999). These channels are also found
presynaptically with either inhibitory or excitatory effects. There is growing
evidence that other receptors are also modulated by anaesthetics. These include
glycine receptors, where volatile anaesthetics and propofol increase the affinity of
the receptor for glycine, and neuronal nicotinic receptors, where channels are
inhibited by volatile anaesthetics. In addition, noradrenergic neurones and certain
Na+ channels modulate anaesthetic actions. The primary target for
dexmedetomidine is the alpha-2 receptors on neurons in the locus coeruleus
(Mizobe et al. 1996).
The fundamental mechanism which produces general anaesthesia is not fully
understood. Synaptic function is considered to be the major target of anaesthetic
drug action. It is widely considered that the deactivation of the thalamic nuclei
occurs during anaesthetic drug-induced unconsciousness. Current theories suggest
that disruption in information flow and integration within the corticothalamic and
corticocortical networks accounts for the mechanism of general anaesthesia. The
anaesthetic agents hyperpolarize neurons (create a more negative resting
membrane potential) by enhancing inhibitory or decreasing excitatory
transmission and alter neuronal activity depending on the site of action. Despite
different mechanisms and sites of action, the outcome produced by anaesthetic
agents is the same: i.e. unconsciousness. (Franks 2008, Alkire et al. 2008)
In the future, mathematical computational models advanced into more
sophisticated systems and replicating EEG patterns will enable the accurate
examination of anaesthesia mechanisms by offering directed simulations of
specific aspects of cortical function of neural responses to pharmacological
manipulation. A basic mean field method in which the mean activity of a small
region of the cortex is modelled, has already been used to study the mechanisms
of inhalation anaesthetics. The neural activity over roughly the extent of a cortical
macrocolumn of approximately one hundred inhibitory and excitatory neurons is
averaged in this model to produce a mean field description in space, while no
21
averaging with respect to time is necessary (Liley & Bojak 2005, Wilson et al. 2006, Sceniak 2006). In order to better understand the neurophysiological
mechanisms behind the different alterations in consciousness induced by
numerous anaesthesia agents, further studies linking methods of cognitive
neuroscience such as EEG, magnetoencephalography (MEG), isotope methods
such as positron emission tomography (PET) and functional magnetic resonance
imaging are necessary (Jäntti 2005).
2.2 EEG
2.2.1 Physiological basis of EEG
The macroscopic electrical potentials recorded at the scalp are a summation of the
microscopic potentials generated by individual cellular elements. These cells
include neurons, glial cells, and muscle cells in the scalp (hence the artefacts that
can be generated from scalp electromyography EMG). The EEG is mainly
generated from the superficial layer of pyramidal neurons by changes in
postsynaptic potentials (PSP) in the dendrites oriented perpendicular to the
cortical surface (Young 2003). The PSP occurs when the presynaptic neurons
release neurotransmitters which alter the permeability of the ion channels in cell
membranes of the postsynaptic neurons, while the transmembrane ionic
concentrations change inducing an alteration in the transmembrane voltage
(Rampil 1998). The neuronal contribution to the EEG comes as a summation of
excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials
(IPSPs), not from action potentials (Young 2003).
Anaesthesia as well as other mechanisms such as reduced vigilance, both in
normal sleep and in pathological states which depress consciousness, are
associated with increased cortical synchrony and high-voltage waves of low
frequency. Higher cortical function, such as cognitive activity, is usually
associated with desynchronization and low-voltage waves of high frequency, as
more neurons act independently in the creation of conscious human behaviour.
Synchrony is also reduced by arousal during anaesthesia or normal sleep (Young
2003, Binnie & Prior 1994). Desynchronization occurs with the activation of
ascending cholinergic projections of the basal forebrain and brainstem nuclei of
raphe (an important supplier of serotonin) and locus coeruleus (the main supplier
of noradrenalin). Each of the states of awareness, awake, slow sleep, and deep
22
sleep, has its characteristic rhythms of EEG oscillation. The rhythmicity is a result
of interactions between the thalamus and the cortex (John & Prichep 2005).
Most EEG signal activity manifests at below 30 Hz, at alpha, beta, theta and
delta frequencies. Alpha activity with a frequency of 8–13 Hz, mainly around
10 Hz, and an amplitude from 20 to 50 µV is distributed maximally in the
occipital regions bilaterally, while during the drowsy state this shifts anteriorly.
Alpha activity is blocked at eye opening when it becomes beta frequency (Berger
1929). By the age of three years, the alpha rhythm frequency is in the 8–9 Hz
range.
Beta rhythm is characteristic of an awake and alert person with a rapid
frequency of usually 13–30 Hz and an amplitude < 20 µV in most of adults. Beta
activity may exist during rapid eye movement (REM) and during light non-REM
(NREM) sleep (Steriade 2006), and at the beginning of anaesthesia.
Benzodiazepines are a group of sedatives known to potentiate beta activity.
Theta activity is rather slow in frequency, being between 4 and 7 Hz, with an
amplitude of 50–100 µV. This rhythm is observed in light sleep and may represent
the inhibitory action of GABAergic interneurons affecting the cortico-thalamic
network. It may be associated with limbic activity (John & Prichep 2005).
Delta rhythm has a slow frequency between 0.5 and 3–4 Hz, and a large
amplitude of 100–200 µV. This rhythm is observed in deep sleep, anaesthesia and
coma. It is generated in the cortical pyramidal cells with cortico-thalamic
dissociation in sensory input (Steriade 2006).
Gamma rhythm consists of rapid oscillations above 30 Hz. Reflecting the
interconnection of cortico-cortical and cortico-thalamo-cortical networks, this
rhythm may be involved in the processes of perception (John & Prichep 2005).
The EEG may contain special stereotypic waveforms, such as spikes or sharp
waves used in the diagnosis of epilepsy. They are sharply featured excursions in
the EEG and created by massive, but usually transient synchrony (Rampil 1998).
2.2.2 Registering EEG
The signal registered in an EEG is generated by the cerebral cortex. When a large
area of the cortex is active synchronously, it creates electrical currents which flow
through the skull to the scalp, then continue under the scalp to return to the inside
of the brain and close the current loop under the cortex (Fig. 2). Therefore the
EEG can be recorded both above the cortex as well as under the cortex. An EEG
is analyzed by measuring the frequency and amplitude of the electrical activity
23
and by recognition of the wave patterns. The analysis of the change over time in
the original raw EEG voltages change is called time domain analysis, where
amplitude is presented along the y-axis and time horizontally along the x-axis.
The most commonly used method to register EEG activity is the international
10–20 system based on meridians crossing the scalp based on key landmarks with
additional lines drawn over the mid-frontal and mid-parietal lobes (Rampil 1998).
The amplitude of the EEG signals is 10 to 100 µV, which is 100 times weaker
than that of the electrocardiogram. The basic types of EEG activity are continuous
and rhythmic activity, transients, background activity and asymmetries between
cerebral hemispheres (Rampil 1998).
Fig. 2. The EEG is produced by electrical currents in a volume conductor, also
intracerebrally. The voltmeter (V) of the EEG recording machine does not measure
potential directly; it measures the current in the measuring circuit. This current always
depends on the location of both electrodes. (Nunez PL & Srinivasan R (2006) Electrical
fields of the brain. The neurophysics of EEG. Reprinted with the permission of the
copyright holder).
2.2.3 Epileptiform EEG discharges and signs of epilepsy
Epileptiform EEG discharges consist of spikes, spike- and slow wave complexes
and sharp waves (Mervaala 2006). Single spikes are generally negative transients
24
clearly distinguished from the background EEG activity with variable amplitude
and duration, usually within a range of 20 to 70 ms (Chang et al. 2011). Sharp
waves have a longer duration of 70 to 200 ms with a prolonged descending phase
while the rising phase resembles that of single spikes (Chang et al. 2011). Sharp
waves are neurophysiologically closely related to spikes and both of these
paroxysmal discharges may take place during an interictal epilepsy period,
although they may also occur in persons without a history of seizure disorder
(Chang et al. 2011).
Rhythmic polyspikes consist of multiple spike complexes and occur more or
less rhythmically in bursts of variable duration. These paroxysmal waveforms
comprise more than two negative and positive deflections appearing at regular
intervals and are associated with a slow wave or mixed frequency EEG activity
between spike complexes. Polyspikes are usually bilateral. (Chang et al. 2011,
Nordli et al. 2011).
Periodic lateralized or focal epileptiform discharges (PLEDs) as described by
Chatrian et al. (1964), consist of simple and sharp waves or complex discharges
with mixed spiky and slower elements with amplitudes around 100 to 300 µV. It
is possible that PLED activity, however, is generated independently bilaterally
and synchronously over both hemispheres and the term generalized periodic
epileptiform discharges is often used to describe this activity (Chang et al. 2011).
PLEDs can be seen in the EEG in a variety of acute neurologic conditions such as
acute cerebral infarction, neoplastic or inflammatory central nervous diseases,
herpes simplex or infectious mononucleosis encephalitis (Mervaala 2006, Chang
et al. 2011).
Epileptogenesis refers to hypersynchrony involving either excitatory or
recurrent inhibitory neuronal networks (Binnie & Stefan 1999). Epileptogenesis is
a process which causes the brain to develop and extend the brain tissue capable to
generate spontaneous seizures resulting in the development of an epileptic
condition and, later, possible progression of established epilepsy (Pitkänen &
Engel 2014). Epileptogenic mechanismas are likely to be specific for many
different causes of epilepsy including genetic influences, malformations of
cortical development, autoimmune disorders, and cell loss and synaptic plasticity
e.g. hippocampal atrophy and sclerosis, the major cause of mesial temporal lobe
epilepsy (Pitkänen & Engel 2014). In epileptic current spontaneous seizures there
are paroxysmal hypersynchronous transient electrical discharges resulting from
too much activation or too little inhibition in the area of abnormal discharges
(Treiman 2001).
25
Goddard (Goddard 1967, Goddard et al. 1969) used repeated electrical
stimulations of low intensity to the brain limbic structures when studying learning
mechanisms and noticed that some laboratory animals developed epileptic
seizures. This model - called kindling - is one example of secondary
epileptogenesis which has been extensively studied in the laboratory over the last
50 years; nevertheless its relevance to human epilepsy remains controversial
(Cibula & Gilmore 1997).
Temporal lobe epilepsy and hippocampal sclerosis have been found to
develop after prolonged febrile seizures, especially after febrile status epilepticus
during early childhood (Scott et al. 2003). In the FEBSTAT (Consequences of
Prolonged Febrile Seizures) study, focal slowing or attenuation 72 h after
convulsion were seen maximally over the temporal areas in a substantial
proportion of children and these alterations were highly associated with acute
hippocampal injury illustrated with MRI (Nordli et al. 2012). Febrile seizures are
associated with a febrile illness without CNS infection, electrolyte imbalance or
prior afebrile seizures in children older than one month (Anonymous 1993). Some
investigators believe that genetic factors or malformations of cortical brain
development such as brain dysplasias may predispose to febrile status epilepticus
(Patteson et al. 2014).
The EEG pattern of the classical absence seizure (petit mal) of genetic origin
most characteristically consists of a generalized slow 3 Hz spike-wave complex, a
dicrotic negative spike followed by a negative slow wave (Mervaala 2006, Nordli
et al. 2011). Activity with a large amplitude and maximum activity on the
superior frontal area is symmetrical and synchronous in both hemispheres and
commences abruptly with the onset of the attack and ceases at its end (Nordli et al. 2011). In the primarily generalized spike-wave seizure, burst firing of cortical
neurons occurs during the spike while the slow wave is accompanied by
hyperpolarization due to recurrent inhibition (Binnie & Stefan 1999).
2.2.4 Burst-suppression
Burst-suppression (B-S) is an EEG pattern usually consisting of bilateral
intermittent quasiperiodical sequences of high-voltage slow and sharp waves, i.e.
bursts, which mainly have a less than 15 Hz frequency (Kroeger & Amzica 2007),
alternating with periods of depressed background activity with an amplitude
usually < less than 5–10 µV (Kuroiwa & Celesia 1980, Quasha et al. 1981)
26
lasting from a few seconds to minutes (suppression). B-S indicates a nonspecific
reduction in cerebral metabolic activity.
Derbyshire et al. (1936) initially reported on the B-S pattern and
demonstrated that it may appear under different anaesthetics and is reactive to
sensory stimulation. Because a large cortical response to mechanical nerve
stimulation was obtained even after the cortex had become completely quiescent
under pentobarbital or avertin anaesthesia, but under deep ether anaesthesia with
spontaneous waves still visible no response to stimulation appeared, they
concluded that the former two anaesthetics suppressed the cortex activity without
blocking the sensory paths, while ether blocked the sensory pathways before
cortical activity was wholly suspended. The name “burst suppression” was
introduced by Swank & Watson (1949) in deeply narcotized animals. They used
the term “suppression-burst”. Their discovery was that, during barbiturate
narcosis, spontaneous electrical activity periodically became decreased which was
then followed by bursts. According to their report, the phenomenon was found in
the frontal lobe cortex after isolation from the thalamus. Henry & Scoville (1952)
detected a B-S pattern by using subdural electrodes to register an EEG in the
surgically isolated cortex.
B-S is a phenomenon which can be induced by several inhalation anaesthetics
such as enflurane, isoflurane, desflurane and sevoflurane usually at concentrations
of 1.5–2 MAC. It is also induced with intravenous anaesthetics such as propofol,
thiopental and etomidate (Eger et al. 1971, Clark & Rosner 1973, Newberg et al. 1983, Jäntti & Yli-Hankala 1990, Yli-Hankala & Jäntti 1990, Rampil et al. 1991,
Hartikainen et al. 1995, Hartikainen et al. 1996, Arkawi et al. 1996). The B-S
pattern characteristic of deep anaesthesia varies with the anaesthetic used. During
enflurane anaesthesia, the spikes in the bursts are very sharp and during the
suppressions the EEG pattern is nearly isoelectric (Clark & Rosner 1973, Yli-
Hankala et al. 1990a). Hypocarbia lengthens the suppression time and decreases
the duration of bursts, but the amplitude and main frequency of the bursts increase
to resemble epileptoid spikes. Isoflurane bursts may have sharp waves but are not
as spiky as enflurane bursts and suppressions often have a low amplitude activity
of up to 10 µV (Clark & Rosner 1973). Hartikainen et al. (1996) used
somatosensory stimuli during isoflurane B-S anaesthesia. A local anaesthetic
nerve conduction block induced in a single finger in a double-blinded manner
caused a disappearance of the evoked EEG burst responses indicating a peripheral
conduction block in a somatosensory pathway. This test provided an example of
monitoring the integrity of the neural pathway during deep anaesthesia. Lipping et
27
al. (1995) compared isoflurane and enflurane B-S patterns and found that bursts
and suppressions were longer during isoflurane anaesthesia and that the B-S ratio
decreased as the anaesthesia deepened, while deepening enflurane anaesthesia did
not change the B-S ratio. Enflurane bursts were also spikier (Lipping et al. 1995).
Propofol bursts are slow negative waves with a smooth onset and a superimposed
alpha frequency of 12–13 Hz spindle waves which begin and end smoothly (Jäntti
& Yli-Hankala 1993, Huotari et al. 2004). In some cases, minor stimuli may
trigger bursts after prolonged suppression during isoflurane anaesthesia (Yli-
Hankala et al. 1993b), and auditory, photic, and somatosensory stimuli all readily
produce these (Derbyshire et al. 1936, Eger et al. 1971, Porkkala et al. 1994
Hartikainen et al. 1995, Hartikainen & Rorarius 1999). Yli-Hankala et al. (1993b)
used vibration stimuli with a duration of 3 seconds applied to the hand of patients
under isoflurane anaesthesia. The EEG bursts had a latency of approximately
0.5 seconds and differed from spontaneously evoked bursts. They were also
associated with increased heart rate, which may indicate an activation of the
autonomic nervous system brought on by the stimulus (Yli-Hankala et al. 1993b)
Heart rate and cerebral blood flow velocity (CBFV) changes are associated
with B-S anaesthesia. During enflurane anaesthesia at B-S level in the EEG, heart
rate increased at burst onset and decreased at suppression onset. Researchers have
theorized that both the B-S cortical activity and heart rate fluctuations may
possibly be controlled by the same subcortical mechanism (Yli-Hankala et al. 1990a, Jäntti & Yli-Hankala 1990, Yli-Hankala et al. 1993c). The onset of EEG
suppression was associated with an abrupt decrease of CBFV in normoventilated
patients at a physiological steady-state under anaesthesia with a high dose of
inhalants (isoflurane and desflurane) at 1.5–2 MAC (Lam et al. 1995). The
change in EEG always preceded a change in flow velocity by 5–7 seconds. The
parallel alterations in cerebral blood flow and electrical activity of the brain
suggested that the flow-metabolism coupling mechanism is at least partially
preserved during high-dose inhalant anaesthesia. The changes in CBF induced by
inhalation anaesthetics may be mediated by a dual mechanism representing a
balance between two opposing mechanisms, the direct cerebral vasodilative
action and the indirect flow-metabolism mediated cerebral vasoconstriction (Lam
et al. 1995).
B-S is also associated with coma (Young 2000, Kaplan & Bauer 2011),
hypoxia (Pressler et al. 2001, Thordstein et al. 2004), cardiac arrest (Zaret 1985,
Berkhoff et al. 2000, Thömke et al. 2002, Rundgren et al. 2006), drug-related
intoxications, different childhood encephalopathies (Lenard et al. 1976, Ohtahara
28
& Yamatogi 2003) and hypothermia (Quasha et al. 1981). Hofmeijer et al. (2014)
detected that identical bursts during B-S, with burst shapes highly similar and
bilaterally synchronous, were associated with a poor outcome in comatose
patients after cardiac arrest. Inter-burst intervals were variable in duration and
invariably flat. Widespread injury to the ascending neuronal systems normally
producing arousal and desynchronization of the EEG are observed in alpha coma
(Berkhoff et al. 2000). Postictal attenuation following epileptic seizure is in many
ways a phenomenon of the same type as B-S.
B-S usually occurs symmetrically, but in brain injury it may also appear
asynchronously or focally in brain hemispheres. In the Aicardi syndrome (Aicardi
et al. 1965), as well as in corpus callosum damage, asynchronic B-S is observed
with reference to B-S synchronization in hemispheres across this structure of the
brain. Lazar et al. (1999) demonstrated an interhemispheric asynchrony of
pentobarbital-induced B-S associated with a haemorrhage in the corpus callosum
in a child with status epilepticus.
The B-S level in the EEG can also be used as guided therapy level for epileptic
patients during status epilepticus treated with anaesthetics such as propofol or
barbiturates (Shorvon & Ferlisi 2012). Beydoun et al. (1991) used propofol for
treating status epilepticus patients by deepening anaesthesia until the suppression
time was approximately five seconds.
The neurophysiological mechanisms responsible for generating B-S patterns
are not fully understood. Burst may be developed in a small cortical area
synchronizing additional cortex or it may be generated via brainstem arousal
mechanisms. Focal or asymmetric bursts may represent the former description
while normal bursts during anaesthesia are examples of the latter. Using
intracellular recordings and extracellular calcium recordings in laboratory
animals, Kroeger & Amzica (2007) found that the brain becomes reactive to
subliminal stimuli (auditory, visual and somatosensory) during deep anaesthesia
at a B-S level in the EEG. The same stimuli did not provoke any overt responses
during varied depths of anaesthesia. They theorized that the increase in baseline
extracellular Ca2+ might constitute the main factor triggering cortical
hyperexcitability during B-S anaesthesia.
Figure 3 exemplifies bursts at a B-S anaesthesia level during
monoanaesthesia using the inhaled anaesthetic sevoflurane (Fig. 3) and the
intravenous anaesthetic propofol (Fig. 4).
29
Fig. 3. EEG during B-S in sevoflurane anaesthesia. Sevoflurane burst registered with
scalp- and deep brain electrodes of a patient with Parkinson`s disease. Surface
electrodes referred to depth electrode. The four upper traces are the EEG recorded
between frontal midline (Fz), left parietal (P3), neck (C7), chin and one contact in the
depth electrode in the subthalamic nucleus. Depth 1 – Depth 4 is recorded between
two contacts of the subthalamic electrode. Note that it records the cortically
generated activity of bursts.
30
Fig. 4. EEG during B-S in propofol anaesthesia. Propofol burst registered with scalp-
and deep brain electrodes of a patient with Parkinson`s disease (from study III). The
uppermost trace is the EEG from two scalp electrodes, the right parietal P4 and the
right frontal F4. The second trace is the EEG recorded between two contacts in the
depth electrode in the subthalamic nucleus. The lower traces are the EEG recorded
between scalp electrodes P4 and F4, and the electrode contact deepest in the
subthalamic nucleus (Jäntti et al. 2008. Reprinted with the permission of the copyright
holder).
31
2.2.5 Arousal in EEG
The concept of brainstem arousal systems was introduced by Moruzzi et al. in the
1940`s (Moruzzi & Magoun 1949). By stimulating the reticular formation of the
brain stem of anaesthetized animals they demonstrated a cessation of
synchronized discharge in the EEG and its replacement with low voltage fast
activity, while the intensity of the alteration varied with the degree of background
synchrony present. Actually, arousal was first demonstrated by Hans Berger in
1929, when he observed the alpha rhythm blockade and shift to beta dominance
during eye-opening in a subject under EEG monitoring.
Several nuclei located in the pons, midbrain, hypothalamus, and basal
forebrain regulate normal sleep-wake cycles. These wake-ON/sleep-OFF and
sleep-ON/wake-OFF nuclei are thought to inhibit each another reciprocally. Some
arousal centers are active primarily during wakefulness, with cholinergic nuclei
also active during rapid eye movement sleep. Other centers, such as the
GABAergic ventrolateral preoptic nucleus of the thalamus, are active during sleep
(Mashour et al. 2011).
The noradrenergic locus coeruleus in the pons and the histaminergic
tuberomamillary nucleus in the posterior hypothalamus are active during waking,
whereas the ventrolateral preoptic nucleus is inhibited. As the homeostatic
pressure for sleep builds, the ventrolateral preoptic nucleus becomes active in
association with sleep and then inhibits the activity of the arousal-promoting
locus coeruleus and tuberomamillary nuclei (Mashour et al. 2011).
While the EEG pattern during deepening anaesthesia resembles the patterns
of deepening sleep, the patterns induced by arousals also resemble the EEG
patterns of arousal during sleep. These arousal patterns are usually rapid
transitions to fast low activities (beta arousal), but occasionally they are high
amplitude rhythmic delta patterns, which resemble the arousal patterns
occasionally seen in children during awakening, delta arousal (Aho et al. 2011).
Both the burst-suppression and the delta arousal patterns therefore seem to reflect
a return to neonatal EEG mechanisms. Delta arousal, “paradoxical arousal”, is a
condition presenting with a marked decrease of EEG frequency and a decrease in
bispectral index (BIS) induced by a noxious stimulus. It is observed during
anaesthesia induced with volatile anaesthetics in combination with nitrous oxide.
In a topographical EEG study, Kochs et al. (1994) demonstrated that surgical
stimulus resulted in an increase in delta activity during 0.6 MAC isoflurane
anaesthesia with nitrous oxide while delta shift was attenuated by using larger
32
1.2 MAC concentrations of isoflurane. Pre-treatment with fentanyl suppressed the
paradoxical response of a decrease in BIS to intra-abdominal irrigation during
anaesthesia maintenance with sevoflurane and 50% N2O (Morimoto et al. 2005).
The study by Oda et al. (2006) confirmed these findings. BIS first increased after
intubation during isoflurane or sevoflurane anaesthesia. When 66% nitrous oxide
was added for intubation, BIS significantly decreased but pain medication with
fentanyl completely abolished the decrease in BIS.
Interestingly, a pattern similar to delta arousal has also been described in
deepening anaesthesia with sevoflurane and has been coined slow delta (Yli-
Hankala et al. 1999). The normal and pathological physiology of sleep and
arousal systems are essential keys for understanding unconsciousness during
anaesthesia, as is the level of EEG burst-suppression.
2.2.6 Somatosensory evoked potentials (SSEP)
Evoked potentials (EPs) are generated in the brain as electrophysiological
responses of the synchronized activation of the nervous system to external
sensory or motor stimulation. They are derived from the EEG in response to
auditory, somatosensory, nociceptive and visual stimuli. The evoked responses
reflect the functional integrity of specific peripheral and central nervous system
(CNS) regions (Thornton & Sharpe 1998). EPs are recorded at the scalp and
consist of precisely timed sequences of waves. The single cortical sensory evoked
response has a very low amplitude of 1–2 µV, compared with the much larger
EEG waves of 50–100 µV amplitude. Therefore, the EP wave has to be extracted
from concurrent spontaneous EEG activity and averaged by repetitive stimulation
and computer-signal techniques (Banoub & Tetzlaff 2003).
Intraoperative EP changes may result from surgical injury or ischaemia of the
specific neural pathway, or they may be due to nonspecific physiological or
pharmacological influences. Physiological factors influencing EPs include
temperature (Porkkala et al. 1997b), blood pressure, hematocrit, acid-base
balance, and oxygen and carbon dioxide tensions. Anaesthetic drugs and sedatives
are the most common pharmacologic causes of nonspecific EP changes (Porkkala
et al. 1997a). In addition to somatosensory EP, visual, auditory (brainstem) and
motor evoked potentials are also used to evaluate the integrity of the sensory
pathway. Sensory evoked potentials are classified as short-latency (< 30 ms),
intermediate-latency (30–75 ms), or long-latency (> 75 ms) waves (Banoub &
Tetzleff 2003).
33
Halogenated inhalation anaesthetics have been demonstrated to produce dose-
dependent attenuation on short-latency SEP amplitude as well as latency delay
especially in cortical components (Peterson et al. 1986, Samra et al. 1987, Sebel
et al. 1986, Sebel et al. 1987, Sloan 1998). Although nitrous oxide stimulates the
EEG, it also causes an amplitude reduction in the somatosensory median nerve
precentral negative cortical component (N20) without an effect on latency (Sebel
et al. 1984, Sloan & Koht 1985, Thornton et al. 1992). Vandesteene et al. (1993)
demonstrated via topographic brain mapping that nitrous oxide did not change the
distribution of the precentral positive cortical component (P22) of median nerve
SEP despite its clear amplitude increase. The generator of the cortical component
was the same as that recorded in a person awake.
2.2.7 EEG based monitoring
The EEG provides a good indicator as to whether the brain is active or inactive as
well as affording a window to the level of brain activity, such as the depth of
hypnosis during general anaesthesia (Crosby & Culley 2012). Various algorithms
for EEG signal processing have been developed in commercially available depth-
of-anaesthesia devices, such as the bispectral index (BISR, Aspect Medical
Systems) (Rampil 1998, Sigl & Chamoun 1994), Entropy (M-EntropyTM module,
GE Healthcare) (Viertiö-Oja et al. 2004), Narcotrend, and Cerebral State IndexTM
(CSITM, Danmeter, Odense, Denmark). BIS® is an index derived empirically from
the EEG to estimate the effect of anaesthetics and unconsciousness. It reflects the
spectral properties of the signal as well as the burst-suppression pattern
(Drummond 2000, Sebel et al. 1997, Bruhn et al. 2000). To date, spectral entropy
is the only method being applied in commercial use from the entropy measures.
Approximate entropy responds better, however, to the visual impression of the
signal regularity. It is more adept at taking into account the patterns and
waveforms, the phase information in the signal, and is consequently better at
describing the underlying physiology, for example, epileptic spikes (Anier et al. 2012).
Of the two parameters generated by entropy, State entropy (SE) is calculated
over the 0.8–32 Hz frequency range including the EEG-dominant part of the
spectrum. It therefore primarily reflects the cortical state and is a reflection of the
patient`s level of hypnosis. Response entropy (RE) is calculated over a frequency
rate from 0.8 Hz to 47 Hz including both the EEG-dominant and the EMG-
dominant part of the spectrum (Viertiö-Oja et al. 2004). RE at least partly reflects
34
the activation level of the upper facial EMG representing arousal and indirectly
provides a measurement of the adequacy of analgesia.
EEG-based depth-of-anaesthesia monitors reliably describe the hypnotic
effects of anaesthetics with a GABAergic (GABAA) mechanism of action such as
isoflurane, sevoflurane, desflurane, thiopental and propofol which cause a gradual
slowing of the EEG until burst suppression (Sebel et al. 1997, Ellerkmann et al. 2004, Vakkuri et al. 2004) whereas a correlation to discriminate unconsciousness
is poorer with anaesthetics acting mainly via NMDA receptors such as ketamine
(Hans et al. 2005, Maksimov et al. 2006) or nitrous oxide (Soto et al. 2006,
Ozcan et al. 2010). A correlation was found, however, with xenon anaesthesia
(Laitio et al. 2008, Fahlenkamp et al. 2010).
Using a BIS-monitor, Myles et al. (2004) reported a remarkable reduction in
risk of awareness during anaesthesia in high-risk patients. Depth-of-anaesthesia
monitoring also allows reduced anaesthetic consumption and faster emergence
(Vakkuri et al. 2005, Aime et al. 2006), postoperative nausea and vomiting
(Nelskylä et al. 2001) and cardiovascular stability during anaesthesia in elderly
patients (Riad et al. 2007).
Many authorities have highlighted the importance of interpreting the raw
EEG biosignal on the monitor while using a processed depth-of-anaesthesia
monitor to avoid under- or overdosing of anaesthetics (Jäntti 2005, Bennett et al. 2009, Mashour et al. 2011, Jäntti 2013).
2.3 Anaesthetics and the CNS
2.3.1 Sevoflurane
Sevoflurane (fluoromethyl 1, 1, 1, 3, 3, 3-heksafluoro-2-propyl-ether) is a methyl
isopropyl ether inhalational anaesthetic with a trifluorinated methyl group on the
alpha carbon atom. As a result of its chemical structure, sevoflurane is susceptible
to degradation by the hepatic microsomal enzymes P450 (specifically isoform
IIE1) with the release of an inorganic fluoride into the circulation. Sevoflurane
produces major potentiation in the GABAA and glycine receptors and major
inhibition in the NMDA and serotonin receptors.
Nonpungency and a rapid increase in alveolar anaesthetic concentration
makes sevoflurane the most popular agent for inhalation induction in paediatric
(Lerman et al. 1994, Goa et al. 1999) and adult patients (Yasuda et al. 1991, Eger
35
1994). The rapid increase in the inspiratory concentration of sevoflurane,
however, has been demonstrated to be associated with transient hyperdynamic
reactions in adult patients during controlled mild hypocapneic hyperventilation
(Vakkuri et al. 1999). The same research group later observed that the
hyperdynamic circulatory response was associated with epileptiform EEG in
adults (Yli-Hankala et al. 1999), as well as paediatric patients without
hyperventilation (Vakkuri et al. 2001). Hyperventilation per se at a high
sevoflurane concentration produces an epileptiform EEG regardless of its timing
and hypocapnia seems to have an additive effect on the incidence of epileptiform
EEG during sevoflurane inhaled anaesthetic induction (Vakkuri et al. 2000).
Based on these results, the speed of induction of anaesthesia, high expired
concentration of sevoflurane, and hyperventilation have been proposed as risk
factors for the occurrence of sevoflurane-induced epileptiform EEG
abnormalities. Female gender has been shown to predispose to electrical seizure
during sevoflurane induction (Julliac et al. 2007).
The occurrence of sevoflurane-elicited epileptiform abnormalities seems to
be concentration dependent with a probable threshold around 3.2% in adults
(Jääskeläinen et al. 2003) and 4.3% in children (Gibert et al. 2012) expressed as
the expired fraction of sevoflurane. The risk of epileptiform EEG discharges can
be reduced, but not totally prevented, during the induction of anaesthesia with low
target concentrations of sevoflurane in normoventilated adult female patients
(Julliac et al. 2013). A non-randomized study found that epileptiform EEG
patterns were observed in 20% of normoventilated paediatric patients even though
the administration time of 8% sevoflurane was shortened by reducing the inspired
sevoflurane concentration to 4% immediately after loss of consciousness (Schultz
et al. 2012). The propensity for sevoflurane to produce epileptiform EEG activity
is greater in patients with epilepsy compared to normal controls (Iijima et al. 2000). The areas activated by sevoflurane in patients with epilepsy might not be
confined to the epileptogenic zones of spontaneous seizures (Hisada et al. 2001).
The combination of nitrous oxide with sevoflurane has been shown to decrease
the number of spikes in epileptic patients although it did not affect the extent of
areas with spikes (Kurita et al. 2005). Kaisti et al. (2002) detected in their PET
study that, at a surgical anaesthesia level of 1 MAC sevoflurane and an effective
concentration (EC50) of propofol, both anaesthetics caused a marked global
reduction of regional cerebral blood flow (rCBF), but propofol more than
sevoflurane. This effect was maintained with propofol even under deeper
anaesthesia, while at 2 MAC sevoflurane caused a noticeable redistribution.
36
The relationships of sevoflurane anaesthesia and epileptiform episodes have
been widely debated by anaesthesiologists, as sevoflurane is the most commonly
used inhalation anaesthetic. Several reports of seizure-like phenomena in patients
under sevoflurane anaesthesia are available, but only a few of these observations
have accompanying EEG recordings. Many of these documents are clinical notes
including one to some patients interpreted as epileptic phenomena because of
seizure-like movements during either the induction or maintenance of anaesthesia
with sevoflurane without EEG monitoring (Table 1). Alternatively, there are also
prospective studies with EEG registration (Table 2). Without EEG registration, it
is very difficult to determine whether seizure-like muscle movements are due to
epileptiform activity or to non-epileptic myoclonia (Modica et al. 1990a).
37
Ta
ble
1. S
ev
ofl
ura
ne
an
d e
pile
pti
form
EE
G,
ca
se
re
po
rts
(m
od
ifie
d f
rom
Co
ns
tan
t et
al.
200
5).
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Ada
chi e
t al.
1991
Cas
e re
port
(lette
r)
one
girl
9 ye
ars
Sev
o6 Fi1 4
% in
duct
ion
No
To
nic-
clon
ic m
ovem
ents
with
resp
alk
alos
is H
R, B
P o
k
Kom
atsu
et a
l.
1994
Cas
e re
port
two
epile
ptic
boy
s
aged
3 a
nd 8
yea
rs
Sev
o in
duct
ion
Fi 1
% to
7%
by in
crea
sing
0.5
-1.0
% d
urin
g
ever
y 1–
2 m
in
14-c
hann
el E
EG
(acc
ordi
ng to
10–
20)
Firs
t PS
2 , th
en R
PS
3 , B
-S5
with
incr
easi
ng s
evo
from
2 to
7%
in c
entra
l par
ieta
l,
occi
pita
l and
fron
tal a
reas
No
card
iova
sc s
ide-
effe
cts
No
mov
emen
t abn
orm
aliti
es
Tera
sako
& Is
hii
1996
Cas
e re
port
one
man
N
o E
EG
Sei
zure
-like
mov
emen
ts d
urin
g
emer
genc
y (la
sted
40
s)
Woo
dfor
th e
t al
1997
Cas
e re
port
one
girl
11 y
ears
Iv-in
duct
ion
(thio
pent
one)
mai
nten
ance
with
Fi s
evo
ad
7% in
O2/
air
No
prem
edic
atio
n
16-c
hann
el E
EG
(acc
ordi
ng to
10–
20)
PS
, RP
S, t
o lo
ng B
-S a
t
sevo
Fi 6
–7%
No
seiz
ure-
like
mov
emen
ts
Bös
enbe
rg e
t al.
1997
Cas
e re
port
(lette
r)
one
boy
12 y
ears
Sev
o in
duct
ion
(con
cent
ratio
n
not m
entio
ned)
No
S
eizu
re-li
ke m
ovem
ents
from
2 m
in o
f sta
rting
indu
ctio
n
Zach
aria
s et
al.
1997
Cas
e re
port
(lette
r)
two
child
ren
2 an
d
4 y
Sev
o Fi
7–8
% in
duct
ion
in
O2/a
ir
No
S
eizu
re-li
ke m
ovem
ents
Bai
nes
et a
l.
1998
Cas
e re
port
(lette
r)
child
ren
(num
ber n
ot
repo
rted)
Sev
o in
duct
ion
(% n
ot to
ld)
No
C
onvu
lsiv
e m
ovem
ents
inde
pend
ently
of w
heat
her o
r
not s
tepw
ise
incr
ease
of s
evo
Sch
ulz
& S
chul
z
1998
Cas
e re
port
(lette
r)
child
ren
and
adul
ts
(num
ber n
ot
repo
rted)
Sev
o in
duct
ion
Yes
E
pile
ptifo
rm c
hang
es w
ith
Fi s
evo
> 5%
(whe
n de
lta-
activ
ity c
hang
ed to
BS
)
38
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Kai
sti e
t al.
1999
Cas
e re
port
of tw
o
youn
g ad
ults
Sev
o m
aint
enan
ce w
ith s
low
ly
incr
easi
ng to
2 M
AC
in O
2/air
No
prem
edic
atio
n
Four
EE
G m
onta
ges
in
both
sid
es (a
ccor
ding
to
10–2
0)
BS
, asy
mm
etric
al P
ED
s4
in b
oth
at 2
MA
C
One
had
asy
mm
etric
clo
nic
mov
emen
ts (p
artia
l mot
or
seiz
ure)
PE
T sh
owed
dec
reas
e to
40–
80%
of r
CB
F8 in
2 M
AC
sev
o
Hilt
y &
Dru
mm
ond
2000
Cas
e re
port
one
mal
e pa
tient
Indu
ctio
n w
ith s
evo
Fi 8
% in
N2O
/O2 5
0% ->
mai
nten
ance
sevo
2%
, SB
Mid
azol
am p
rem
idec
atio
n
No
D
urin
g re
cove
ry c
linic
al e
pile
ptic
seiz
ure
(cer
ebra
l im
agin
g
show
ed b
rain
tum
or)
Sch
ultz
2000
Cas
e re
port
two
child
ren
Indu
ctio
n w
ith s
evo
Fi 7
–8%
Y
es
Epi
lept
iform
EE
G-
chan
ges
Sch
ultz
2001
Cas
e st
udy
one
adul
t
Y
es
Spi
kes
unde
r sev
o 5–
6%
Koy
ama
et a
l.
2002
Cas
e re
port
an e
pile
ptic
man
36 y
ears
Mai
nten
ance
sev
o E
T7 1.5
–
2.5%
in O
2/air
Yes
M
ore
spik
es w
ith E
t 2.5
%
sevo
than
1.5
%.
Fent
anyl
dec
reas
ed s
pike
frequ
ency
und
er E
T 1.
5%
sevo
.
Åke
son
&
Did
rikss
en
2004
Cas
e re
port
two
child
ren
N
o
Sei
zure
-like
mov
emen
ts d
urin
g
indu
ctio
n w
ith s
evo
ET
3%
Chi
nzei
2004
Cas
e re
port
one
epile
ptic
adu
lt
E
EG
, BIS
E
pile
ptifo
rm E
EG
with
mai
nten
ance
of s
evo
1%
asso
ciat
ed w
ith
fluct
uatio
ns o
f BIS
Hsi
eh
2004
Cas
e re
port
one
neon
ate
N
o
Sei
zure
-like
mov
emen
ts in
all
extre
miti
es d
urin
g em
erge
nce
39
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Lecl
erc
2006
Cas
e re
port
one
child
2 y
ears
Ana
esth
esia
indu
ctio
n w
ith
8% s
evo
Mid
azol
am p
rem
edic
atio
n
No
S
eizu
re-li
ke m
yocl
onic
mov
emen
ts
Yan
o
2008
Cas
e re
port
two
child
ren
with
hist
ory
of fe
brile
conv
ulsi
ons
Sev
o m
aint
enan
ce E
T 2–
3%
in 7
0% N
2O/O
2
No
D
urin
g m
aint
enan
ce o
ne h
ad
toni
c-cl
onic
sei
zure
and
the
othe
r one
dur
ing
reco
very
1 in
spira
tory
frac
tion,
2 po
lysp
ikes
and
–w
aves
, 3 rh
ythm
ic p
olys
pike
s, 4
perio
dic
epile
ptifo
rm d
isch
arge
s, 5
burs
t sup
pres
sion
, 6 se
voflu
rane
, 7 en
d-tid
al,
8 reg
iona
l cer
ebra
l blo
od fl
ow.
40
Ta
ble
2. S
ev
ofl
ura
ne
an
d e
pile
pti
form
EE
G,
pro
sp
ec
tiv
e s
tud
ies
(m
od
ifie
d f
rom
Co
ns
tan
t et
al.
200
5).
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Hag
a et
al.
1992
Pro
spec
tive
stud
y
180
child
ren
1–6
y
Sev
o9 Fi1 4
–6%
indu
ctio
n N
o
Sei
zure
-like
mov
emen
ts
in 6
% o
f chi
ldre
n
Artr
u et
al.
1997
Pro
spec
tive
rand
omiz
ed s
tudy
,
four
teen
adu
lts
Iv-in
duct
ion
(thio
pent
one
/
etom
idat
e) 0
.5–1
.0–1
.5 M
AC
mai
nten
ance
with
sev
o (n
= 8
)
or is
o10 (n
= 6
) in
O2/a
ir
EE
G 1
6 or
5 e
lect
rode
mon
tage
s (a
ccor
ding
to
10–2
0)
No
inst
ance
s of
epi
lept
iform
activ
ity in
EE
G
ICP
12 d
id n
ot c
hang
e
Vm
ca d
ecre
ased
Wat
ts e
t al.
1999
Pro
spec
tive
stud
y
(mea
n 27
yea
rs o
ld)
elev
en e
pile
ptic
adul
ts
Mai
nten
ance
sev
o 1.
5 M
AC
in
O2/a
ir w
ith
1) n
orm
oven
tilat
ion
and
2) h
yper
vent
ilatio
n
For E
CoG
14 w
ith h
yper
-
vent
ilatio
n in
O2/a
ir
1) is
o 0.
3–1.
5 an
d
2) s
evo
1.5
MA
C
Eig
ht c
hann
el E
EG
band
pas
s 0.
5–30
Hz
8 ch
anne
l EC
oG
Epi
lept
iform
EE
G-c
hang
es
unde
r 1.5
MA
C s
evo
(incr
ease
of i
nter
icta
l spi
kes
in a
ll) >
1.5
MA
C is
o un
der
1.5
MA
C n
o m
ore
epile
ptifo
rm E
EG
in
hype
r/nor
mov
entil
atio
n
Con
stan
t et a
l.
1999
Pro
spec
tive
rand
omiz
ed s
tudy
four
ty-fi
ve c
hild
ren
of
2–12
yea
rs
Indu
ctio
n w
ith
1) s
evo
Fi 7
% in
100
% 0
2
2) s
evo
Fi 2
to 4
to 6
%
3) h
alo11
Fi 1
to 2
to 3
to 3
.5%
in N
2O/O
2 50%
4) la
ter o
n se
vo F
i 7%
in
N2O
/O2 5
0%
Pre
med
icat
ion
mid
azol
am
16 c
hann
els
(10–
20)
band
pas
s 0.
5–30
Hz
spec
tral a
naly
sis
No
epile
ptifo
rm E
EG
chan
ges,
sha
rp s
low
wav
es
with
sev
o
typi
cal h
alo
traci
ng s
imila
r to
barb
itura
te s
pind
les
(slo
w
wav
es s
uper
impo
sed
with
fast
rhyt
hms
alph
a an
d be
ta)
with
hal
o
Clin
ical
agi
tatio
n w
ith
sevo
in te
n ou
t of 1
1, in
seve
n ou
t of 1
3 w
ith h
alo
With
sev
o 10
0% O
2 mor
e
agita
tion
than
with
N2O
.
41
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Yli-
Han
kala
et a
l.
1999
Pro
spec
tive,
rand
omiz
ed s
tudy
thirt
y he
alth
y w
omen
Indu
ctio
n w
ith s
evo
Fi 8
% in
N2O
/O2 5
0%
spon
tane
ous
vent
ilatio
n (S
V8 )
vs. c
ontro
lled
hype
rven
tilat
ion
(CH
V, E
TCO
213 2
6 m
mH
g)
Pre
med
icat
ion
diaz
epam
Four
bip
olar
ele
ctro
de
pairs
(10–
20)
(4 c
hann
els?
)
PS
2 13/
15 in
CH
V v
s 6/
15 in
SV
gro
up P
ED
4 in
13/1
5 C
HV
vs 1
/15
in S
V g
roup
B-S
6 with
spi
kes
3/15
in C
HV
grou
p
Ass
ocia
tion
betw
een
HR
rise
and
epile
ptifo
rm
EE
G (H
R ro
se >
30%
) in
CH
V p
atie
nts
Thre
e in
CH
V g
roup
had
jerk
ing
mov
emen
ts
Iijim
a et
al.
2000
Pro
spec
tive
cros
sove
r stu
dy s
evo
vs is
o (a
fter 3
mon
ths)
twel
ve e
pile
ptic
and
twel
ve n
on-e
pile
ptic
men
tally
hand
icap
ped
adul
ts
Indu
ctio
n se
vo/is
o 1.
0, 1
.5
and
2.0
MA
C
1) In
100
% O
2
norm
oven
tilat
ion
2) In
O2/
N2O
50%
norm
oven
tilat
ion
3) In
100
% O
2
hype
rven
tilat
ion
(HV
7 )
Pre
med
icat
ion
or a
nti-
conv
ulsa
nts
wer
e no
t giv
en
Hig
h ba
nd p
ass
120
Hz
In e
pile
ptic
pat
ient
s
epile
ptifo
rm E
EG
with
sev
o
1.5
MA
C >
iso
1.5
MA
C in
none
pile
ptic
pat
ient
s no
epile
ptifo
rm c
hang
es in
eith
er
grou
ps
Sup
plem
enta
tion
of N
2O o
r
HV
sup
pres
sed
occu
rren
ce
of s
pike
s
Vak
kuri
et a
l.
2000
Pro
spec
tive,
rand
omiz
ed s
tudy
thirt
y w
omen
Indu
ctio
n w
ith s
evo
Fi 8
% in
N2O
/O2 5
0%
1) im
med
iate
HV
ETC
O2
> 4%
2) d
elay
ed H
V (f
irst 2
min
SV
)
Four
bip
olar
ele
ctro
de
pairs
(acc
ordi
ng 1
0–20
)
band
pas
s 1–
50 H
z
sam
plin
g ra
te 1
28 H
z
Epi
lept
iform
EE
G in
13/
15
(gro
up 1
) vs
9/15
(gro
up 2
)
PE
D in
10/
15 in
gro
up 1
vs
5/15
in g
roup
2
Reg
ardl
ess
of ti
min
g, H
V
with
sev
o 8%
pro
duce
s
hype
rdyn
amic
circ
ulat
ory
resp
onse
Vak
kuri
et a
l.
2001
Pro
spec
tive,
rand
omiz
ed s
tudy
31 h
ealth
y ch
ildre
n of
1–12
yea
rs (m
ean
age
6 ye
ars)
Indu
ctio
n w
ith s
evo
Fi 8
% in
N2O
/O2 2
:1
1) c
ontro
lled
vent
ilatio
n
ETC
O2 4
.3–5
.3%
)
2) s
pont
aneo
us b
reat
hing
ETC
O2 a
d 6–
6.7%
Pre
med
icat
ion
mid
azol
am
Bip
olar
four
-cha
nnel
EE
G
Ban
d pa
ss 1
–50
Hz
Sam
plin
g ra
te 1
28 H
z
RP
S3 i
n 7/
16 in
CV
vs
3/15
in
SB
gro
up
PE
D in
7/1
6 in
CV
vs
none
in
SB
gro
up
SS
P5 i
n 4/
16 v
s no
ne in
SB
grou
p
No
mot
or m
anife
stat
ions
Epi
lept
iform
EE
G w
as
asso
ciat
ed w
ith
incr
ease
d H
R (m
ore
than
60%
from
bas
elin
e) a
nd
BP
42
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Con
reux
et a
l.
2001
Pro
spec
tive
stud
y
Twen
ty c
hild
ren
of 1
–
8 ye
ars
and
AS
A I-
II
Indu
ctio
n w
ith s
evo
Fi 8
% in
O2 1
00%
No
prem
edic
atio
n
Eig
ht b
ipol
ar m
onta
ges
Sam
plin
g ra
te 1
28 H
z
2/20
chi
ldre
n ha
d S
,PS
4/20
had
B-S
with
out s
pike
s
14/2
0 ha
d sh
arp
mon
opha
sic
slow
del
ta d
urin
g
lary
ngos
copy
2/20
chi
ldre
n ha
d
myo
clon
ic s
eizu
re-li
ke
mov
emen
ts
Sch
ultz
et a
l.
2001
Pro
spec
tive
stud
y
seve
n ad
ults
Indu
ctio
n w
ith s
evo
Yes
6/
7 ha
d sp
ikes
in E
EG
with
sevo
Fi 5
–6%
His
ada
et a
l.
2001
Pro
spec
tive
cros
s-
over
stu
dy
six
epile
ptic
adu
lts
Pro
pofo
l ind
uctio
n ->
mai
nten
ance
with
sev
o
1.5
MA
C (s
tepw
ise
incr
ease
)
in O
2/ N
2O 3
3% ->
cha
nged
to
iso
1.5
MA
C
No
prem
edic
atio
n or
antie
pile
ptic
s gi
ven
EC
oG s
ubdu
ral g
rid
elec
trode
s
Epi
lept
iform
cha
nges
far
mor
e th
an w
ith is
o, n
ot
conf
ined
to z
one
of
spon
tane
ous
seiz
ures
Sat
o et
al.
2002
Pro
spec
tive
stud
y
seve
n no
nepi
lept
ic
adul
ts m
ean
age
59
year
s
Iv-in
duct
ion
Mai
nten
ance
1, 1
.5 a
nd
2 M
AC
sev
o in
= 2
/air
Pre
med
icat
ion
diaz
epam
EC
oG g
rid e
lect
rode
s
front
ally
and
tem
pora
lly
l.a b
and
pass
50
Hz
Spi
ke-a
ctiv
ity m
ax/m
in
anal
ysed
Epi
lept
iform
spi
ke a
ctiv
ity
and
B-S
in a
ll w
ith 1
.5–
2 M
AC
sev
o
End
o et
al.
2002
Pro
spec
tive
stud
y
ten
epile
ptic
adu
lts
Iv-in
duct
ion
(pro
pofo
l)
mai
nten
ance
with
0.5
–
1.5
MA
C s
evo
in O
2/air
EC
oG 1
6–64
ele
ctro
des
in g
rid th
roug
h se
izur
e
focu
s
Ban
d ba
ss 6
0 H
z
Spi
ke a
ctiv
ity m
ax/m
in
anal
ysed
Dur
ing
1.5
MA
C s
evo
spik
e
activ
ity d
ecre
ased
to 1
4/m
in
com
pare
d w
ith b
asel
ine
38/m
in
43
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Nie
min
en e
t al.
2002
Pro
spec
tive
stud
y
thirt
y he
alth
y ch
ildre
n
aged
3–8
yea
rs
Iv-in
duct
ion
thio
pent
al
Mai
nten
ance
with
sev
o Fi
2%
in O
2/ai
r
Pre
med
icat
ion
iv m
idaz
olam
5-ch
anne
l EE
G
(acc
ordi
ng to
10–
20)
Sam
plin
g 27
9 H
z
No
epile
ptifo
rm E
EG
-
chan
ges
Jääs
kelä
inen
et a
l.
2003
Pro
spec
tive
rand
omiz
ed s
tudy
sixt
een
heal
thy
men
Mai
nten
ance
with
1, 1
.5,
2.0
MA
C/E
C50
of e
ither
sev
o
or p
ropo
fol
4-ch
anne
l EE
G
SE
F 95
% a
nd p
eak
frequ
ency
Maj
or e
pile
ptifo
rm E
EG
-
chan
ges
and
B-S
in a
ll un
der
sevo
1.5
–2 M
AC
No
epile
ptifo
rm E
EG
chan
ges
but B
-S in
all
unde
r
prop
ofol
1–1
.5–2
EC
50.
Kur
ita e
t al.
2005
Pro
spec
tive
cros
sove
r stu
dy
11 e
pile
ptic
pat
ient
s
Mai
nten
ance
with
sev
o
1.5
MA
C w
ith 5
0% N
2O o
r
with
out N
2O
EC
oG
N2O
sig
nific
antly
dim
inis
hed
the
spik
e fre
quen
cy in
EC
oG
Vak
kuri
2005
P
rosp
ectiv
e
rand
omiz
ed s
tudy
31 a
dults
Ane
st in
d:pr
opo
Rap
id in
crea
se
1) s
evo
7% o
r
2) d
es 1
8%
Dia
zepa
m p
rem
edic
atio
n
BIS
E
pile
ptifo
rm E
EG
(S, P
S,
PE
D) w
ith 8
/15
in s
evo
grou
p
but n
one
in d
es g
roup
Sha
rp in
crea
se o
f HR
in
des
grou
p, g
radu
al
incr
ease
in s
evo
grou
p
San
din
et a
l.
2008
Pro
spec
tive
stud
y
ten
youn
g he
alth
y
adul
ts
Mai
nten
ance
with
1, 1
.5 a
nd
2 M
AC
sev
o in
oxy
gen-
air
BIS
A
t 2 M
AC
sev
o hi
gh B
IS
valu
es in
dica
ting
wak
eful
ness
due
to
epile
ptog
enic
act
ivity
At 2
MA
C s
evo
HR
chan
ged
sign
ifica
ntly
, but
not B
P, a
nd o
ne p
atie
nt
had
conv
ulsi
ons
Fuku
i et a
l.
2010
Pro
spec
tive
rand
omiz
ed s
tudy
twen
ty-tw
o ep
ilept
ic
brai
n tu
mor
pat
ient
s
aged
13
to 6
7 ye
ars
Mai
nten
ance
of s
evo
or
isof
lura
ne 1
.5–2
Mac
in O
2-ai
r
nitra
zepa
m p
rem
edic
atio
n
EC
oG g
rids
on fr
onta
l
corte
x
In is
oflu
rane
gro
up n
o
rem
arka
ble
findi
ngs
whi
le in
sevo
gro
up p
arox
ysm
al E
EG
activ
ity in
thre
e pa
tient
s
toge
ther
with
rCB
F15 in
crea
se
44
Stu
dy
Type
of s
tudy
S
tudy
pro
toco
l M
onito
ring
of E
EG
E
EG
find
ings
C
linic
al/o
ther
find
ings
Sch
ultz
et a
l.
2012
Pro
spec
tive
stud
y
seve
nty
AS
A I-
II
child
ren
aged
7 to
96
mon
ths
Indu
ctio
n w
ith 8
% s
evo
ad
LOC
(mea
n 1–
2 m
in)
mai
nten
ance
with
4%
insp
ired
conc
entra
tion
Mid
azol
am p
rem
edic
atio
n
EE
G m
onito
r Nar
cotre
nd
(two
elec
trode
s fro
ntal
ly,
from
whi
ch ra
w E
EG
)
Four
teen
chi
ldre
n ha
d
epile
ptifo
rm E
EG
pat
tern
s
(del
ta w
ith s
pike
s, rh
ythm
ic
PS
, PE
D) d
espi
te o
f sho
rt
indu
ctio
n tim
e
No
clin
ical
man
ifest
atio
ns
Gib
ert e
t al.
2012
Pro
spec
tive
rand
omiz
ed s
tudy
seve
nty-
nine
chi
ldre
n
aged
3 to
11
year
s
Mai
nten
ance
sev
o in
100
% O
2
or in
50%
N2O
-air
to
dete
rmin
e M
AC
of s
evo
asso
ciat
ed w
ith m
ajor
epile
ptifo
rm E
EG
sig
ns (M
ES
)
BIS
(with
fron
tal r
aw E
EG
cana
l, ba
nd p
ass
of 0
.5–
47.5
Hz,
sam
plin
g ra
te o
f
128
Hz)
ET-
sevo
for M
AC
(rhy
thm
ic
S/P
S e
tc.)
with
100
% O
2 w
as
4.3%
and
with
50%
N2O
-O2
was
4.6
%
One
chi
ld h
ad to
nic-
clon
ic c
onvu
lsio
n
Julli
ac e
t al.
2013
Pro
spec
tive
rand
omiz
ed s
tudy
thirt
y-th
ree
fem
ale
patie
nts
A: s
evo
indu
ctio
n w
ith 8
% fo
r
2 m
in, m
aint
enan
ce E
T se
vo
2.5%
B: t
arge
t con
trolle
d E
T se
vo
2.5%
no p
rem
edic
atio
n
EE
G o
f Fp1
, Fp2
, T3,
T4,
C3,
C4,
O1
and
O2
filte
red
0.1–
70 H
z,
sam
plin
g 25
6 H
z
Epi
lept
iform
dis
char
ges
durin
g in
duct
ion
in o
ne
patie
nt in
gro
up A
and
in fo
ur
patie
nts
in g
roup
B
Fifte
en p
atie
nts
had
abno
rmal
mov
emen
ts
with
out s
imul
tane
ous
EE
G a
bnor
mal
ity
Kre
uzer
et a
l.
2014
Pro
spec
tive
stud
y
100
child
ren
> 1y
AS
A I-
III
A: s
evo
indu
ctio
n w
ith 8
% in
100%
O2 fo
r 3 m
in, t
hen
4%
sevo
unt
il in
tub
B: s
evo
indu
ctio
n w
ith 6
% in
100%
O2 f
or 6
min
, the
n 4%
sevo
unt
il in
tub
Mid
azol
am p
rem
edic
atio
n
Nar
cotre
nd®
Epi
lept
iform
EE
G in
76%
(38)
with
sev
o 8%
and
in 5
2%(2
6)
with
6%
Epi
lept
iform
EE
G e
arlie
r with
8% s
evo
No
clin
ical
man
ifest
atio
ns
1 in
spira
tory
frac
tion,
2 po
lysp
ikes
and
–w
aves
, 3 rh
ythm
ic p
olys
pike
s, 4
perio
dic
epile
ptifo
rm d
isch
arge
s, 5
supp
ress
ion
with
spi
kes,
6 bu
rst s
uppr
essi
on,
7 hy
perv
entil
atio
n, 8
spon
tane
ous
vent
ilatio
n, 9
sevo
flura
ne, 10
isof
lura
ne, 11
hal
otha
ne, 12
intra
cran
ial p
ress
ure,
13 e
nd-ti
dal,
14 e
lect
roco
rtico
gram
, 15
regi
onal
cer
ebra
l blo
od fl
ow
45
2.3.2 Isoflurane
Isoflurane (1-chloro-2, 2, 2-trifuoroethyl difluoromethyl ether) is a chemical
isomer of enflurane with a pungent ethereal odour. The major targets for the effect
of isoflurane are GABAA, two-pore potassium channels, glycine and serotonin
receptors in which it potentiates currents. Unlike enflurane, isoflurane is
considered to not possess convulsive properties. It has no organ toxicity.
Experimental and human studies suggest that isoflurane has neuroprotective
effects (Berg-Johnsen et al. 1992, Larsen et al. 1998). Fraga et al. (2003)
compared 1 MAC isoflurane and desflurane in normocapnic patients undergoing
removal of supratentorial brain tumors without midline shift and did not detect
any variations in ICP. Case reports of tremor, clonus and clinical seizures during
isoflurane have been documented but no clinical study has reported EEG
abnormalities during isoflurane anaesthesia. In epileptic patients, isoflurane was
associated with spike activity in a small number of patients, while no epileptic
pattern was observed in the control group (Iijima et al. 2000). A study using an
animal model of temporal lobe epilepsy (kindling) suggested that isoflurane has
an intensifying effect on electrically evoked seizures (Veronesi et al. 2008). The
authors speculated that isoflurane has the potential to impact on the secondary
generalization of epilepsy during the anaesthesia recovery period. In a study of
epileptic patients with electrocorticogram (ECoG) monitoring, however,
isoflurane decreased the mean frequency of epileptiform spikes compared to N2O
in oxygen alone, while enflurane produced increasing paroxysms of high-voltage
spikes compared to N2O in oxygen alone (Ito el al. 1988).
2.3.3 Propofol
Propofol (2, 6-diisopropylphenol), which belongs to the alkylphenol group, is the
most frequently used intravenous anaesthetic agent with a rapid onset of action
and quick recovery. Alkylphenols are not water-soluble but highly liposoluble.
Clinically propofol is available in 1% and 2% formulations.
Unconsciousness following propofol administration results from a
potentiation of the gamma-aminobutyric acid (GABA)-induced chloride current
in the GABAergic interneurons of the cortex, the thalamic reticular nucleus, and
arousal centers in the midbrain and pons. Atonia associated with propofol
administration has been suggested to be attributed to actions on GABAergic
neural systems in the spinal cord and in the pontine and medullary reticular nuclei
46
(Kungys et al. 2009). In addition to the GABAA receptors, propofol potentiates
synaptic transmission in glycine receptors and has a minor inhibitive effect on
NMDA channels, voltage-gated potassium channels, and on nicotinic and
muscarinic channels (Kungys et al. 2009).
Alkire et al. (1995) reported in a positron emission tomography (PET) study
that propofol produced a global metabolic depression of the central nervous
system (CNS) by decreasing cortical metabolism more than subcortical
metabolism.
Auditory input is believed to be the final sensory modality to be blunted
during anaesthesia. Dueck et al. (2005) observed using propofol anaesthesia in a
fMRI study that propofol bilaterally attenuates the auditory-induced BOLD signal
of the auditory cortex in a dose-dependent manner. Complex analysis of the
auditory input was impaired even at low propofol concentrations, whereas basic
auditory information was still processed at high levels of sedation up to the
2.0 µg/ml plasma target concentrations (Dueck et al. 2005).
Propofol is considered to be an anticonvulsant, as modulation of neuronal
activity by propofol results from a depression of the excitatory mechanism, i.e. a
prolongation of GABAA-receptor function at GABAergic synapses, and an
enhancement of inhibitory transmission, i.e. the selective suppression of persistent
sodium channels and high-voltage-activated calcium channel conductance in
cortical neurons (Martella et al. 2005). Experimental studies in models of cerebral
ischaemia have provided evidence of the possible neuroprotective effects of
propofol through the prevention of an increase in neuronal mitochondrial swelling
(Adembri et al. 2006).
Propofol has been widely used for the treatment of patients with status
epilepticus. Spontaneous dystonic movements were found, however, during
propofol anaesthesia induction in children by Borgeat et al. (1991). They used
EEG registration but did not observe any cortical epileptiform activity, while the
movements occurred coincident with the appearance of slow delta waves in the
EEG. These movements may rather be related to subcortical structures. In their
systematic review of 512 case reports suggesting the use of propofol may be
associated with seizure-like phenomena, Walder et al. (2002) accepted 11 patients
with epilepsy and 70 patients without epilepsy to the final analysis and found
mainly seizure-like phenomena (SLP) such as tonic-clonic seizures, involuntary
movements, opisthotonus mainly on induction or emergence from anaesthesia. It
47
was noteworthy, however, that none of the patients underwent EEG registration
during SLP and EEG registration was only performed afterwards in 32% of cases.
The painful electrical stimulation of a peripheral nerve during deep propofol
anaesthesia induced a cortical response with four successive components, each
representing an at least partly independent cerebral mechanism. The B-S pattern
evoked by propofol was found to be different from that seen during isoflurane or
sevoflurane anaesthesia. Evoked potentials characteristic of propofol were also
recorded (Huotari et al. 2004). When propofol is administered in doses sufficient
to produce a B-S pattern in the EEG, there is a concern as to the haemodynamic
consequences. Doses of propofol sufficient to silence the EEG are associated with
venodilatation and myocardial depression, but the haemodynamic risk in healthy
patients is minimal if filling pressures are maintained with a crystalloid infusion
(Illevich et al. 1993).
2.3.4 Nitrous oxide
Nitrous oxide is frequently used as an adjunct to general anaesthesia. It
potentiates the depressant effects of both volatile and intravenous anaesthetics.
Nitrous oxide, similar to another NMDA receptor antagonist, ketamine, activates
the EEG (Maksimov et al. 2006), however, and increases cerebral blood flow
velocity (CBFV) by increasing the cerebral metabolic rate (CMR) (Matta & Lam
1995, Wilson-Smith et al. 2003). During isoflurane B-S steady-state anaesthesia,
supplementation with 65% nitrous oxide activated the EEG by decreasing
suppression periods and by increasing the duration of bursts (Yli-Hankala et al. 1993a). When nitrous oxide at 70% was added to propofol at steady-state EEG
suppression anaesthesia, the CBFV of the middle cerebral artery increased and
occasional burst activities of the EEG were also observed (Matta & Lam 1995).
Furthermore, in children aged 1.5 to 6 years anaesthetized with propofol in 35%
oxygen in air, the CBFV of the middle cerebral artery increased by 12% when air
was replaced with nitrous oxide (Wilson-Smith et al. 2003). Porkkala et al. (1997)
recognized activation of the EEG during stable anaesthesia maintenance with 1.9
ET isoflurane concentrations in a 60% air-oxygen mixture at B-S level when the
air was replaced with nitrous oxide. The proportion of EEG suppressions
decreased from 53% to 34%. At the same time, nitrous oxide induced a reduction
in the amplitude of cortical N20 component by 69% while the amplitude and the
latency of earlier components remained unchanged. Lam et al. (1994) observed
that the use of 0.5 MAC isoflurane together with 0.6 MAC (60%) nitrous oxide
48
was associated with a higher CBFV of the middle cerebral artery and an increased
cerebral arterio-venous oxygen content difference (AVDO2) reflecting an
increased cerebral metabolic rate compared to equipotent 1.1 MAC isoflurane
alone in healthy males.
Nitrous oxide has been shown to decrease epileptogenic patterns in the EEG
of epileptic patients (Kurita et al. 2005). An earlier study (Hosain et al. 1996) did
not demonstrate any difference in spike activity with or without nitrous oxide 60–
70% at low concentrations of isoflurane 0.25–0.5%.
2.3.5 Summary of the neurophysiological effects of anaesthetics
The effects of anaesthetics on neurophysiological information such as the
electroencephalogram, sensory evoked potentials, auditory evoked potentials and
motor evoked potentials are summarized and expressed in Table 3. The idea
behind neurophysiological monitoring is to improve the safety of the patient in
the demanding conditions of special operations.
49
Ta
ble
3. S
um
ma
ry o
f th
e n
eu
rop
hy
sio
log
ica
l eff
ects
of
an
aes
the
tics
. S
um
ma
ry o
f th
e n
eu
rop
hys
iolo
gic
al
eff
ec
ts o
f h
yp
no
tics
in
mo
no
an
ae
sth
es
ia a
t s
urg
ica
l le
ve
l (1
MA
C o
r h
igh
er
for
vo
lati
le a
nae
sth
eti
cs
). S
low
wa
ve
sle
ep
is
in
clu
de
d f
or
co
mp
ari
so
n,
as
th
e
EE
G p
att
ern
s a
nd
th
e e
ffe
ct
on
so
ma
tos
en
so
ry a
nd
mo
tor
res
po
ns
es o
f s
pec
ific
GA
BA
A a
go
nis
ts a
nd
alp
ha-2
ag
on
ists
are
pro
ba
bly
ca
use
d p
art
ly b
y t
he
sam
e m
ech
an
ism
s.
On
th
e o
the
r h
an
d,
aro
us
al
ch
an
ge
s a
ll t
he
se
neu
rop
hy
sio
log
ica
l m
eas
ure
s
tow
ard
s a
wa
ke p
att
ern
s,
alt
ho
ug
h w
e o
nly
wa
ke
up
fro
m p
hy
sio
log
ica
l s
lee
p.
SE
P r
efe
rs m
ain
ly t
o t
he
sh
ort
-la
ten
cy
co
rtic
all
y
ge
ne
rate
d w
ave
s a
nd
au
dit
ory
ev
ok
ed
po
ten
tia
l (A
EP
) m
ain
ly t
o c
ort
ica
l m
id-l
ate
nc
y A
EP
s.
B-S
, B
urs
t-s
up
pre
ss
ion
. (S
loa
n &
Jä
ntt
i (
20
08
) A
ne
sth
eti
c e
ffe
cts
on
evo
ke
d p
ote
nti
als
, in
Han
db
oo
k o
f C
lin
ica
l N
eu
rop
hy
sio
log
y.
Re
pri
nte
d w
ith
th
e p
erm
iss
ion
of
the
co
py
rig
ht
ho
lde
r).
Mec
hani
sm o
f act
ion
Hyp
notic
E
EG
S
EP
A
EP
M
EP
Spe
cific
GA
BA
ago
nist
P
ropo
fol
Spi
ndle
s, v
erte
x-w
ave,
B-S
↓
↓↓
↓
E
tom
idat
e S
pind
les,
ver
tex-
wav
e, B
-S
↑ ↓↓
↓
GA
BA
and
oth
ers
Hal
otha
ne
B-S
var
iabl
e ↓↓
↓↓
↓↓
Is
oflu
rane
B
-S
↓↓
↓↓
↓↓
E
nflu
rane
B
-S, s
eizu
res
↓↓
↓↓
↓↓
S
evof
lura
ne
B-S
, sei
zure
s ↓↓
↓↓
↓↓
D
esflu
rane
B
-S
↓↓
↓↓
↓↓
B
arbi
tura
tes
B-S
, epi
lept
iform
pat
tern
s ↓↓
↓↓
↓↓
Alp
ha 2
ago
nist
C
loni
dine
S
low
↓
? ↓
D
exm
edet
omid
ine
Slo
w
↓ ?
↓
NM
DA
ant
agon
ist
Nitr
ous
oxid
e Fr
onta
l bet
a ↓↓
-
↓↓
K
etam
ine
Thet
a ↑
- ↓
X
enon
C
entra
l slo
w
↓ ↓
↓
Slo
w w
ave
slee
p
Spi
ndle
s, v
erte
x-w
ave
↓ ↓
↓
50
2.4 EEG during physiological sleep and general anaesthesia
Loomis et al. (1935a, 1935b) first described the EEG patterns during sleep states
and during disturbance of sleep including the K-complex (Loomis et al. 1938), a
large potential change as a result of tone stimulation. Furthermore, Davis et al. (1939) precisely described the single components of the K-complex.
Sleep and anaesthesia may have many common mechanisms, but distinct
behavioural and physiological differences clearly distinguish these two states.
Sleep is a state associated with loss of reactivity to surroundings or
unconsciousness regulated both homeostatically and via circadian rhythm and
may be disturbed by environmental factors, but the depth and duration of general
anaesthesia is influenced by anaesthesia agent dosage and duration of
administration (Tung & Mendelson 2004). In general anaesthesia, arousal
mechanisms become weaker, whereas physiological sleep allows arousal and is
broken by external stimuli (Tung & Mendelson 2004).
GABAergic anaesthetics have many EEG effects similar to that of
physiological non-rapid eye movement (NREM) or slow wave sleep. EEG
oscillations mimicking NREM physiological sleep such as sleep spindles, delta-
waves and slow waves have been observed during propofol anaesthesia (Huotari
et al. 2004). Nelson et al. (2002) emphasized the role of the tuberomamillary
nucleus in the sedative response to GABAergic anaesthetics. Dexmedetomidine, a
selective alpha2-adrenoceptor agonist, caused slow wave sleep-like EEG patterns
mimicking physiological sleep-promoting factors (Nelson et al. 2003). The
researchers observed that the sedative properties of dexmedetomidine involve an
inhibition of the locus ceruleus, which inhibits ventrolateral preoptic nucleus
firing, thus increasing GABA release and inhibiting tuberomamillary nucleus
firing (Nelson et al. 2003). Huupponen et al. (2007) also used dexmedetomidine
and found that at a sedation dose it produced a state closely resembling
physiological light sleep in humans. Sleep and anaesthesia share common
regulatory mechanisms, and interactions between them produce the possibility
that certain anaesthetics may facilitate sleep in environments where sleep
deprivation is common (Tung et al. 2004b, Drouot et al. 2008).
At subanaesthetic doses, both intravenous and inhaled hypnotics induce
rapid, mainly beta frequency EEG oscillations: initially mainly in the frontal
regions, but then spreading to the more posterior regions. As anaesthesia is
deepened, an increase in the amplitude and a decrease in the frequency of the
51
EEG occur as slow theta and delta waves proliferate. Under deep anaesthesia with
supra-anaesthetic doses, most hypnotics suppress cortical activity and induce B-S
in the EEG and when anaesthesia is further deepened, suppression alone. (Clark
& Rosner 1973, John & Prichep 2005).
Non-rapid eye movement (NREM) sleep is associated with synchronized
activity across large areas of the brain, including well-defined EEG oscillations
such as sleep spindles, delta-waves, and slow cortical oscillations. The transition
from wakefulness to NREM sleep is associated with typical signs of brain
electrical activity, characterised by prolonged periods of hyperpolarization and
increased membrane conductance in thalamocortical (TC) neurons (Sinha 2011).
The early stage of quiescent sleep is associated with sleep spindles in the
EEG, waxing and waning spindle waves occurring at a frequency of 7 to 14 Hz
typically lasting for 2–3 seconds and repeated once every 3 to 10 seconds during
NREM sleep, especially in stages 2 and 3. In adults, sleep spindles are most
commonly seen over the central regions, near electrodes C3 and C4 of the
international 10–20 system. In children, slower 10–12 Hz spindles with a more
anterior prominence are observed. The reticular nucleus (RE) of the thalamus and
its connection to the dorsal thalamus appears to be responsible for generating
sleep spindles. The spindle oscillation generated in the RE cells is transferred to
thalamocortical relay cells and drives the cortical cells which produce the EEG
spindles (Steriade et al. 1994, Contreras et al. 1996, Sinha 2011).
As sleep deepens, waves with slower frequencies of 1 to 4 Hz appear on the
EEG. These delta waves were shown to arise between cortical layers 2 to 3 and 5
(Steriade et al. 1993b). The thalamus is also involved in the generation of this
rhythm. The hyperpolarization of thalamocortical cells is a critical factor in the
generation of delta oscillations. Delta oscillations occur when the thalamocortical
cells are more hyperpolarized than they are during the spindle oscillations
(Steriade et al. 1993c).
The low-frequency sleep oscillations of 0.5–1 Hz of NREM sleep originate in
the cortex and were first described by Steriade and co-workers (1993b, 1993c) in
anaesthetized cats. The slow oscillations consist of rhythmic alternating
membrane potentials between depolarizing components of 0.4–0.8 seconds
duration separated by prolonged hyperpolarization levels lasting 0.2–0.8 seconds.
Prolonged hyperpolarizations are seen in the surface EEG as high amplitude
negative field potentials. Acherman & Borbely (1997) and Amzica & Steriade
(1997) investigated the slow oscillation in human sleep. Using high-density EEG
recordings in humans Massimini et al. (2004) showed that sleep slow oscillations
52
are travelling waves which sweep the human cerebral cortex up to once per
second as sleep deepens. Each slow oscillation has a definite site of origin and
direction of propagation, which vary from one cycle to the next. Slow oscillations
originate more frequently at anterior cortical regions and propagate in an
anteroposterior direction (Massimini et al. 2004). The electrodes with the highest
probability of detecting a slow oscillation were concentrated in a scalp region
anterior to the central midline electrode, and posterior to the anteriofrontal
midline electrode, projecting onto cortical areas 8 and 9. Slow oscillations can
occur during any stage of NREM sleep (Massimini et al. 2004). The increase in
slow wave activity after sleep deprivation is highest in the anterior prefrontal
regions (Finelli et al. 2000).
The K-complex, which is unique to NREM sleep, consists of an ample
surface-positive transient followed by a slow surface-negative component, which
may be followed by a spindle wave (Davis et al. 1939, Amzica & Steriade 1997).
The K-complex emerges from a cortically generated slow oscillation, occurs
spontaneously, but can also be evoked by sensory stimuli (Amzica & Steriade
1997, Sinha 2011). The same circuit that generates sleep spindles is also thought
to play a role in the 1–4 Hz delta oscillation which has both a cortical and a
thalamic component. The slow oscillation is thought to form the basis for the K
complex, which occurs at periodic intervals in all stages of NREM sleep. K
complexes are thought to represent fluctuating arousals and can be provoked by
external sensory stimuli and intrinsic sleep oscillations (Sinha 2011).
REM sleep, associated with rapid eye movements and dreaming episodes, is
characterised by an abolition of low-frequency oscillations with a relatively
desynchronized EEG resembling the waking state and an increase in cellular
excitability, although motor output is markedly inhibited. Activation of the
thalamo-cortical system by ascending brainstem cholinergic arousal systems
during the steady depolarisation of cortical cells in waking and REM sleep
suppresses the autonomous slow oscillations and increases activities within both
beta and gamma frequencies (Steriade et al. 1993a, Steriade 2006). These fast
oscillations may also appear during light anaesthesia and, sometimes, during
NREM sleep (Steriade 2006).
Decreased blood flow in the thalamus and in the prefrontal and multimodal
parietal association cortices accompanies the onset and deepening of NREM
sleep.
53
REM sleep is associated with an increase in blood flow in the pons, midbrain
and thalamus, amygdala, hypothalamus and basal ganglia. Activated thalamic
nuclei, which occupy key sites in sensory-relay and other brain circuits, transmit
endogenous stimuli, which results in the sensory phenomena of dreaming
(Hobson & Pace-Schott 2002).
The EEG oscillations which occur during sleep and arousal states are
generated in the thalamus and cerebral cortex, two regions intimately linked by
means of reciprocal projections (Steriade 2006). The thalamus is the major
gateway for the flow of information toward the cerebral cortex and is the first
station at which incoming signals can be blocked by synaptic inhibition during
sleep (Steriade 2006). This mechanism contributes to the shift that the brain
undergoes as it changes from an aroused state, open to signals from the outside
world, to the closed state of sleep (Hobson & Pace-Schott 2002).
2.5 Epileptiform EEG, anaesthesia and sleep
While decreasing activity in the central nervous system (CNS), some general
anaesthetics can also paradoxically provoke cortical seizures in the EEG in deeply
anaesthetized patients (Modica 1990a, 1990b, Faizo et al. 2014). It has been
proposed that proconvulsant drugs may act by decreasing the amplitude of
miniature inhibitory postsynaptic currents (IPSCs) or by eliciting a greater
calcium-induced presynaptic mobilization of excitatory neurotransmitters (Wilson
et al. 2006). Epileptiform EEGs have been detected, for instance, during
enflurane (Neigh et al. 1971, Rosen & Söderberg 1975, Burchiel et al. 1977,
Jäntti & Yli-Hankala 1990) and sevoflurane anaesthesia (Yli-Hankala et al. 1999,
Kaisti et al. 1999, Vakkuri et al. 2000, Vakkuri et al. 2001, Jääskeläinen et al. 2003). Vakkuri et al. (2005) also found epileptiform EEGs and tachycardia during
deep sevoflurane anaesthesia, but tachycardia was not associated with
epileptiform EEG during desflurane anaesthesia. Compared with isoflurane, the
proconvulsant properties of enflurane may be due to its potency to reduce the
peak magnitude of synaptically induced IPSCs to a greater extent than isoflurane
(Banks & Pearce 1999).
Epileptic seizures mainly develop during slow wave sleep. During sleep
initiation, thalamic activity changes are a response to the characteristic cortical
synchronization observed in sleep. Such thalamic neuronal activity changes are
related to the action of GABA systems from the thalamic reticular nucleus
inducing a bursting pattern, which might account for the cortical
54
hypersynchronization observed during sleep initiation. The experiments of
Steriade et al. (2003) using multi-site, extra- and intracellular recordings, showed
a transformation without discontinuity from sleep patterns to seizures. The
spindle oscillations of physiological sleep were related to the development of the
spike-and-wave EEG complexes, which were associated with absence (petit mal)
epileptic seizures. Steriade et al. (1993a) stated that while the reticular thalamic
nucleus is central to the genesis of spindle oscillations, decreasing or abolishing
the inhibitory efficacy of the RE upon thalamocortical cells would decrease the
incidence of epileptic spike-and-wave discharges. In their prospective study using
continuous EEG monitoring with automated seizure detection in patients with
partial-onset seizures, Herman et al. (2001) found that frontal lobe seizures were
most likely to occur during sleep while seizures arising from the parietal or
occipital area rarely occurred during sleep. Temporal lobe complex partial
seizures were more likely to secondarily generalize during sleep than during
wakefulness. The researchers concluded that hypersynchrony - particularly during
light stage 2 NREM sleep - facilitated both the initiation and propagation of
partial seizures, but the synchronizing and activating effects of sleep on various
brain regions could differ. No seizures occurred during REM sleep and they were
also rare during the deeper NREM sleep stages.
Arousal state transitions are also known to promote the occurrence of
epileptiform phenomena or seizures in patients with epilepsy (Contreras &
Steriade 1995). The transitional state occurs during drowsiness, especially
between waking and NREM sleep. It is of remarkable interest that spike- and
wave seizure patterns are totally absent or significantly decreased during REM
sleep (Steriade 2006).
55
3 Aims of the study
1. To examine whether median nerve SSEP cortical short latency waveforms
can be detected without averaging at EEG burst-suppression level during
sevoflurane anaesthesia and to compare those with SSEPs recorded awake.
2. To analyse temporal and spatial relationships between EEG and BOLD
signals during the dynamic induction of focal epileptic seizures at EEG burst-
suppression level of deep isoflurane anaesthesia in an experimental epilepsy
model in pigs.
3. To obtain a better understanding of electric fields during EEG burst-
suppression of propofol anaesthesia in humans by using both scalp and depth
electrode recordings.
4. To describe the topography of EEG features during sevoflurane mask
induction anaesthesia in children and to evaluate, whether BIS can recognize
these waveforms.
5. To describe the electric fields of burst-suppression and epileptiform patterns
in sevoflurane anaesthesia during spontaneous breathing and controlled
hyperventilation in male patients and to compare these patterns to
cardiovascular parameters.
56
57
4 Subjects and Methods
Study I was a prospective monoanaesthesia study with sevoflurane in adult
patients. Cortical evoked responses to median nerve stimulation were recorded
under EEG B-S anaesthesia levels.
Study II was an experimental epilepsy model with EEG registration together
with fMRI under EEG B-S level of isoflurane anaesthesia in piglets.
Study III was a prospective study where EEG was registered under
anaesthesia maintenance with an intravenous anaesthetic propofol during EEG B-
S levels. Both scalp electrodes and deep brain electrodes in the subthalamic
nucleus were used in patients with Parkinson`s disease.
Study IV was a prospective anaesthesia induction study with EEG
registration under sevoflurane anaesthesia using normoventilation in children.
Study V was a prospective randomized study in adult males with EEG
registration under induction of sevoflurane anaesthesia. The patients were
randomized either to normoventilation or hyperventilation groups. The closed
envelopes used for randomization were opened immediately prior to the induction
of anaesthesia in the operation room. The neurophysiologist (V.J.) who examined
the EEG was blinded to the study groups.
The summary of subjects and methods are summarised in Table 4.
4.1 Subjects
Study I was based on 21 ASA I-II risk classification patients, aged 22 to 52 years,
scheduled for routine surgery. In study III, three Parkinson’s patients underwent
stimulator implantation for electrical stimulation of the subthalamic nucleus for
treatment of Parkinson`s disease. Study IV involved 20 children aged 4–10 years
undergoing otolaryngological or orthopaedic surgery. The children were of the
ASA I risk classification group with no previous history of febrile convulsions or
other neurological disorders. Twenty ASA I risk group men aged 23–52 years
undergoing cervical or lumbar disc operation participated in study V. Study II was
performed on seven 2–3 month-old female pigs.
The clinical studies I, III, IV and V were approved by the Oulu University
Ethics Committee and written informed consent was obtained from all patients (I,
III, V) or from the parents of the children (IV). In study II, all experiments were
performed in compliance with the guidelines of the European Convention for the
Protection of Vertebrate Animals used for Experimental and Other Scientific
58
Purposes (1986) and in compliance with the European Union Directive
86/609/EEC (1997). Study II was approved by the Animal Care and Use
Committee of the University of Oulu.
Table 4. Summary of the subjects and methods.
Study Subjects N Age EEG monitoring Other measurements
I 5 females
16 males
21 22–52 years,
mean 35
8-channel HR, blood pressure, SaO2, ETsevo,
ETCO2, inspiratory O2
II piglets 7 2 – 3 months 4-channel,
fMRI
HR, blood pressure, SaO2,
ETisoflurane, MV, ETCO2,
III Parkinso
n’s
patients
3 40, 44, 67
years
18-channel, 1–2
depth electrodes
with 4 contacts
each
HR, blood pressure, SaO2, ETCO2,
inspiratory O2, MV
IV children 20 4–10 years,
mean 6.9
32-channel
HR, blood pressure, SaO2, ETsevo,
ETCO2, inspiratory O2
V males 20 23–52 years,
mean 42
32-channel HR, blood pressure, SaO2, ETsevo,
ETCO2, inspiratory O2 and N2O,
blood-gas analysis
4.2 Variables and measurements
Haemodynamic and ventilatory monitoring was performed using the Datex-
Ohmeda AS/3 Anaesthesia Monitor (Datex-Ohmeda division, Instrumentarium,
Helsinki, Finland), and consisted of heart rate, electrocardiography, non-invasive
blood pressure, oxygen saturation with pulse oximetry, end-tidal carbon dioxide
pressure, end-tidal sevoflurane concentration, end-tidal isoflurane concentration,
inspiratory oxygen and nitrous oxide concentrations. Ventilatory and anaesthesia
gas measurements were performed from the ventilatory circuit, with the
connecting piece close to the face mask. Haemodynamic and gas measurements
were performed once a minute during anaesthesia.
4.3 Anaesthesia
In study I, anaesthesia of the adult patients was induced by mask with sevoflurane
in 100% oxygen and they were intubated after induction under deep sevoflurane
anaesthesia at a level of steady-state burst-suppression achieved at 1.5–2.5 MAC.
Anaesthesia was maintained with sevoflurane in 40% oxygen in air. Four patients
59
required muscle relaxation with succinyl choline due to spontaneous ventilation
after a precurarisation dose of vecuronium.
In study II, after a fasting period of 12 hours and premedication using
1.5 mg/kg midazolam and 15 mg/kg ketamine, the animals were anaesthetised
with thiopental 25 mg/kg. After intubation, anaesthesia was maintained using
isoflurane at an end-tidal concentration of 1.4–1.8% in 40% oxygen/air, with the
EEG burst-suppression pattern used as an end-point. Normocapnia was
maintained during mechanical ventilation.
Patients in study III were pre-loaded with 500 ml of hydroxyethyl starch and
NaCl 0.9% 1 000 ml in order to prevent vasodilation-induced hypotension.
Muscle relaxation was induced and maintained with rocuronium bromide.
Anaesthesia was maintained and adjusted with a propofol infusion at a rate of 12–
20 mg/kg/h to maintain the EEG at the burst-suppression level. Ventilation was
controlled with air/oxygen 60% /40%. Normocapnia (end-tidal CO2 between 4.8
and 5.5 kPa) was maintained during mechanical ventilation. Phenylephrine was
administered either as boluses or as an infusion if mean arterial pressure dropped
under 60 mmHg.
The children in study IV were premedicated with oral midazolam 0.4 mg/kg,
up to a maximum dose of 10 mg, and 0.005 mg/kg glycopyrrolate was
administered i.v. after peripheral vein cannulation. Anaesthesia was induced with
sevoflurane inhalation using a semi-open anaesthesia system primed with a fresh
gas flow of at least 6 L/min (nitrous oxide 3 L/min and oxygen 3 L/min) and the
sevoflurane vaporizer (Sevorane Abbott Vapor 19,3; Draegerwerk AG, Lubeck,
Germany) set at a maximum of 8%. The induction phase lasted for 8 min at
maximum. Ventilation was manually assisted after spontaneous ventilation had
ceased. End-tidal CO2 was kept above 4.5 kPa in order to maintain
normoventilation. Mivacuronium was given to facilitate intubation. Thereafter the
sevoflurane vaporizer was adjusted to 2% with an oxygen-nitrous oxide ratio at
1:2 and EEG registration continued for a further three minutes.
The patients in study V were randomly allocated to receive either controlled
hyperventilation (CH) or spontaneous ventilation (SP) during induction.
Anaesthesia was induced via a face mask with sevoflurane (8% in nitrous oxide
50% in oxygen) using a semi-open system primed with a fresh gas flow of
10 L/min. Ventilation of the patients in the hyperventilation group was manually
assisted to maintain an end-tidal CO2 concentration below 4 kPa while in the
normoventilation group spontaneous ventilation was allowed but assisted if
needed to keep end-tidal CO2 below 6.5 kPa. At the end of the 5 min induction
60
phase, a blood gas sample was obtained from a radial artery using a single-
puncture method. Thereafter the trachea was intubated without muscle relaxation.
4.4 EEG Recordings and analyses
In study I, the EEG data was collected with a Nicolet Viking IV P
electromyography, using the IOM programme, electrodes at Fp1, F3, FC3, C3,
CP3, P3, O1, F4, C4, P4, O2, ear electrode A2 and extracerebral electrodes at
neck C7 or the shoulder contralateral to the stimulus. Due to the limited number
of channels, different recording montages were used for different patients. Eight
channels were recorded: one was used to monitor EEG on screen to detect burst-
suppression pattern, one recorded the electrical stimulation at the wrist, and 6
were used to continuously record the EEG on to a hard disk at a sampling
frequency of 1 000 Hz. The amplifier bandwidths were 0.2–100 Hz. A custom-
made analysis program was used to mark bursts and suppressions onsets and
classify responses. This program also configurated montages and averaged
selected sweeps.
EEG registration using two electrodes and a ground electrode was employed
in study II. The fMRI terminology and methods visualizing function, i.e.
perfusion, diffusion and BOLD imaging were covered in detail by Mäkiranta in
her dissertation in 2004. The EEG data was collected on the hard disk of the
NeuroScan™ recorder with the following amplifier set-up parameters: DC-
recording, 0–200 Hz bandwidth, gain 150, sampling frequency 1 000 Hz, range
37 mV, accuracy of 0.559 μV. The EEG electrodes were attached with tissue glue
on the following positions: the surface of the pig skull, the right (contralateral to
the lesion) and left (ipsilateral to the lesion) side posteriorly to the coronal suture.
The equipment, cables and electrodes were compatible with the MRI
environment. The EEG was recorded continuously during the MRI session.
In study III, a Nervus™ digital EEG recorder (Taugagreining, Reykjavik,
Iceland) was used to record the EEG together with the ECG. EEG data was
registered from electrodes Fp1, Fp2, F3, Fz, F4, T3, Cz, P3, Pz, P4, O1, O2, A1,
A2, the four depth electrodes, and an electrode on the spinous process of C7.
Bandpass was 0.016–100 Hz with a sampling rate of 256 Hz (patient 1) and
512 Hz (patient 2). The EEG for patient 3 was recorded with the NeuroScan
Synamp amplifier™ using a sampling frequency of 8 000 Hz, down-sampled to
200 Hz and filtered 0–30 Hz for illustration.
61
In study IV the EEG was registered together with an ECG using a digital
EEG device Nervus™ (Taugagreining, Reykjavik, Iceland) from the surface
electrodes of the international 10–20 system, with added orbitofrontal and ear
electrodes. The sampling frequencies were 256 Hz in eleven patients and 512 Hz
in nine patients. A bandpass of 5.0 Hz–70 Hz was used for spike evaluation with
an ear reference and 0.016 Hz–70 Hz was used for evaluation of slow activity,
also with an ear reference. Placing the EEG surface electrodes in the paediatric
patients took time (approximately 20–30 minutes) and was done in the operation
room. A baseline EEG was recorded with the patient awake for at least two
minutes before the onset of induction, and then continued for approximately three
minutes after the induction period. The topographies of the waveforms were
analysed with different band-pass filters and montages of the EEG. The beat-to-
beat heart rate was analysed offline.
In study V, the EEG data was collected together with an ECG using the
NeuroscanTM digital EEG device with surface electrodes according to the 10–20
system, including orbitofrontal and ear electrodes at a frequency of 2 000 Hz. A
bandpass was 0.016–134 Hz. The EEG data was stored on a computer for later
analyses. The location and topography of the waveforms were analysed by
adjusting the EEG filtrations and couplings.
4.5 Stimulation
In study I, somatosensory evoked potential (SSEP) registration was used.
Electrical stimulation during burst-suppression level was applied to the right
median nerve in 20 patients and to the left in one patient. The intensity was
adjusted to three times the sensory threshold, which was enough to produce
movement of the thumb with a duration of 0.2 ms. Trains of stimuli at frequencies
of 20, 10, 5, 4, 3, 2 and 1 Hz were applied in addition to single stimuli, and
different stimulation trains were studied in different patients due to the limited
recording time prior to the start of the operation.
4.6 Statistical analysis
In the statistical analysis of study IV, summaries of the variables were expressed
as means and standard deviation (SD) and range, or median with range. A Linear
Mixed Model (LMM) was utilized for repeatedly measured data (MAP and heart
rate) with SAS procedure mixed; the Toeplitz covariance structure was defined in
62
repeated statements, and independence between subjects (children) was assumed
by random statement. In the analysis of repeatedly measured data, heart rate and
MAP were compared with children who displayed a suppression (short and/or
long suppression), and those who did not display this suppression. The p-values
were reported as follows: p-group, indicates a level of difference between groups,
p-time*group, indicates interaction between group and time. The T-test was used
to compare demographic data and values before anaesthesia induction. Statistical
analysis was performed using SPSS (SPSS, version 12.0.1, SPSS Inc, Chicago,
IL) and SAS (version 8.02, SAS Institute Inc., Cary, NC) statistical programs.
Two-tailed p-values are reported.
In the statistical analysis of study V, summaries of the variables were
presented as mean standard deviation (SD) unless otherwise stated. Repeatedly
measured data was analysed using LMM using a combination of random effects
model and covariance pattern model. If time x group interaction was significant
(p<0.05) the differences in separate time points were estimated by LMM: Simple
between group comparisons were performed using Student`s t-test or Mann-
Whitney U-test (continuous data) and Fisher`s exact test (categorical data). Two
tailed p-values were presented. Analyses were performed using SPSS (IBM Corp.
Released 2011. IBM SPSS Statistics for Windows. Version 20.0. Armonk, NY:
IBM Corp. and SAS for Windows version 9.3. SAS Institute Inc., Cary, NC,
USA).
63
5 Results
5.1 SSEP in sevoflurane anaesthesia (I)
Two types of responses to median nerve stimulation could be recorded without
averaging during sevoflurane-induced EEG burst-suppression: the short-latency
response N20/P20 and partly overlapping-P22, and the long-latency burst (Fig. 5).
The percentage of stimuli evoking bursts in individual patients changed from 0 to
54%, mean 17%. The short latency N20/P20 and partly-overlapping P22 could be
recorded particularly with short derivations across the central sulcus after every
stimulus in all our patients. They could often be reliably evaluated from two or
three single sweeps with a stimulation interval exceeding one second, with
amplitudes in the higher frequencies decreasing rapidly. Even with a stimulus rate
of one per second, there was a 30% decrease in amplitude from the first to the
second stimulus (Fig. 6). The other response was a burst, which involved the
entire cortex, but did not follow every stimulus. No cortical activity was visible
between the two responses, after averaging several responses.
Fig. 5. Two types of responses without averaging to right median nerve stimulation:
the short-latency response N20 and the long-latency burst.
64
Fig. 6. Adaptation of the cortical component of median nerve SSEP in sevoflurane B-S
level anaesthesia during different stimulation frequencies. This recording is from P3
to C3, presented as an average over six patients.
5.2 Epileptiform EEG pattern in sevoflurane anaesthesia (IV, V)
The rapid induction of anaesthesia using high 8% concentrations of sevoflurane in
children (study IV) produced an initial increase in beta activity, followed by a
dominancy of alpha activity and thereafter slow delta wave activity with a very
high amplitude (ad 2 050 µV, mean 1 447), which sometimes developed into
sharper waveforms. Thereafter, polyspike and -wave activity appeared in the
EEG, in which the spikes were mainly located frontally and were multifocal with
frontocentral maxima. The increase in heart rate appeared before epileptogenic
spikes. Four patients had long suppressions. The examples of EEG patterns are
expressed in Fig. 7. No symptoms of epilepsy were detected clinically. The time
interval to appearance and duration and also location of the main EEG events in
children during anaesthesia induction with sevoflurane are presented in Table 5
and Table 6.
Adult male patients with controlled hyperventilation (study V) under rapid
induction of anaesthesia with high sevoflurane concentration had epileptiform
EEG patterns (EEG gr. 2–4) in 90% of cases, such as polyspikes (PS), periodic
epileptiform discharges occurring bilaterally, or PEDs during EEG suppression
(S). Furthermore, 40% of spontaneously breathing (SB) patients also displayed
65
epileptiform EEGs. No focal or generalized epileptic activity was seen in the
EEG.
Fig. 7. Examples of EEG patterns during anaesthesia induction with sevoflurane in
children.
A. Onset of suppression after polyspike and wave activity,
B. High-amplitude spike during suppression,
C. Onset of activity after long suppression,
D. Multifocal spikes frontally,
E. Short suppression during high amplitude slow wave activity,
F. High-amplitude delta activity.
66
Ta
ble
5. T
ime
in
terv
al
(ap
pe
ara
nc
e)
in s
ec
on
ds (
s)
an
d l
oc
ati
on
of
ma
in e
lec
tro
en
ce
ph
alo
gra
m (
EE
G)
ev
en
ts a
nd
ag
ita
tio
n i
n
ch
ild
ren
du
rin
g i
nd
uc
tio
n o
f an
ae
sth
es
ia w
ith
se
vo
flu
ran
e. P
ati
en
ts 1
–1
0.
Pat
ient
N:o
1
2 3
4 5
6 7
8 9
10
Age
(yea
rs)
7.1
6.5
8.4
6.3
6.3
6.3
10.7
5.
7 6.
5 6.
3
Agi
tatio
n
JM1
M
2 M
M
M
M
Slo
w d
elta
appe
aran
ce
24
122
96
98
73
86
11
2 11
4 46
max
am
plitu
de (n
V)
704
1525
2048
16
02
1570
13
53
1760
15
40
1543
frequ
ency
(Hz)
2.
3 1
1.
3 1.
3 1.
3 1.
3 1.
3 1.
5 1.
5
Firs
t irr
itatio
n S
S3
SS
S
S
MS
4 S
S
MS
M
S
MS
M
S
MS
appe
aran
ce
60
180
120
60
120
60
240
180
120
60
Max
irrit
atio
n S
S
SS
S
S
S
S
M
S
S
S
PE
D
appe
aran
ce
65
212
318
184
155
300
452
473
420
120
loca
tion
F3, F
4 F3
, F4
Fp2
front
. F3
, F4
Fp1,
Fp2
Fp
i, Fp
2 fro
nt.
F3, F
4 fro
nt.
Fz
F7
F3
, F4
Fp
1, F
p2
F3, F
4, F
8 F3
, F7
Fp
1, F
p2
O1,
O2
Fz
, Cz,
C3
Sho
rt su
ppre
ssio
ns
appe
aran
ce
12
0
300
18
0
60
num
ber
2
2
10
6
dura
tion
(ms)
Long
sup
pres
sion
appe
aran
ce
42
0
480
17
7
dura
tion
29
8
299
16
1
PE
D5
P
ED
Spi
kes
durin
g lo
ng s
uppr
.
Yes
1 je
rkin
g m
ovem
ent,
2 m
ovem
ent,
3 si
ngle
spi
kes,
4 m
ultis
pike
s an
d –w
aves
, 5 pe
riodi
c ep
ilept
iform
dis
char
ges.
67
Ta
ble
6. T
ime
in
terv
al
(ap
pe
ara
nc
e)
in s
ec
on
ds (
s)
an
d l
oc
ati
on
of
ma
in e
lec
tro
en
ce
ph
alo
gra
m (
EE
G)
ev
en
ts a
nd
ag
ita
tio
n i
n
ch
ild
ren
du
rin
g i
nd
uc
tio
n o
f an
an
esth
esia
wit
h s
evo
flu
ran
e. P
ati
en
ts 1
1–
20
.
Pat
ient
N:o
11
12
13
14
15
16
17
18
19
20
Age
(yea
rs)
8 9.
7 4.
6 4.
8 7.
7 8.
1 5.
5 6.
4 7
5.6
Agi
tatio
n H
1 H
, M2
H
M
M
M
Slo
w d
elta
appe
aran
ce
88
86
51
53
71
176
133
11
5 22
2
max
am
plitu
de (n
V)
1386
18
63
1663
12
54
781
1679
16
48
1032
16
17
1719
frequ
ency
(Hz)
1
1.3
1.3
1.8
2 1
1.3
1.5
1.3
1
Firs
t irr
itatio
n M
S3
MS
M
S
SS
4 S
S
MS
M
S
SS
M
S
MS
appe
aran
ce
60
90
120
60
120
240
120
120
180
150
Max
irrit
atio
n
P
ED
S
S
SS
P
ED
M
S
SS
M
S
MS
appe
aran
ce
240
30
0
420
300
16
2
180
loca
tion
F3
, F4
F3, F
4 F3
, F4
F3, F
4 Fp
1, F
p2
front
. F3
, F4
Fp1,
F3
F3, F
4 fro
nt.
Fp
1, F
p2
Fp1,
Fp2
Fz
sp
read
s
F4, F
7 Fp
1, F
7
Sho
rt su
ppre
ssio
ns
appe
aran
ce
60
120
60
300
num
ber
7 13
3
1
dura
tion
(ms)
840
Long
sup
pres
sion
appe
aran
ce
292
dura
tion
159
PE
D5
PE
D
PE
D
Spi
kes
durin
g lo
ng s
uppr
.
1 sp
onta
neou
s hy
perv
entil
atio
n te
nden
cy, 2
mov
emen
t, 3 m
ultis
pike
s an
d –w
aves
, 4 si
ngle
spi
kes,
5 pe
riodi
c ep
ilept
iform
dis
char
ges
68
5.3 Focal seizure, fMRI and EEG (II)
Penicillin, administered in the cortex while the EEG was in continuous
suppression during isoflurane anaesthesia with ETisoflurane 1.4–1.7%, induced focal
epileptic activity. This was associated with focal EEG discharge and a fMRI
signal increase in the swine brain. The most important result was that the initial
continuous blood-oxygen-level-dependent (BOLD) signal increased from 9.4% to
21.3%, which was clear prior to the appearance of spike activity in the scalp EEG.
This appeared 49 s–2 min 40 s after the penicillin injection (Fig. 8).
Fig. 8. Comparison of fMRI and EEG signals. A. Average signal changes of BOLD
activation map and background gray matter (GM) region of interest (ROI). B. Ipsilateral
EEG signal, 1 500 ms window plotted and the respective EEG total power C.
Dotted line represents the interrupted continuity (approximately 20 s pause
between two scans). Arrowheads point to the time points of ipsilateral spikes (at
1 min), biphasic spikes (at 3 min), double spikes (at 8 min) to high amplitude
monophasic spikes at 13 min).
69
5.4 Depth electrode recordings in propofol anaesthesia (III)
Propofol burst suppression characteristics were studied by describing electrical
fields of three EEG patterns, the sharp wave, the burst and the spindle (Fig. 9 and
Fig. 10) Simultaneous recording of the EEG from both depth and scalp electrodes
showed that bursts and their slow wave oscillations were synchronous throughout
the entire cortex, as well as in the basal regions of the brain, while spindles and
sharp waves were produced by the sensorimotor cortex.
Sharp waves maximal up to 170 μV with the depth electrode reference at
vertex were negative. Bursts were positive, resembling the delta waves of non-
REM sleep. Burst-suppression could also be recorded between two contacts in the
depth electrode, although with a much lower amplitude than between two widely
spaced scalp electrodes, while the highest amplitude was recorded between the
scalp and depth electrode.
Fig. 9. The burst consists of slow waves with mixed-frequency fast activity and a
rhythmic β spindle on it. The spindle is enlarged on the right. Cz = central,
Fp1 = frontopolar, C7 = skin electrode on the spine of the cervical vertebra C7,
D1 = depth electrode of the subthalamic nucleus.
70
Fig. 10. Sharp wave and bursts. The sharp wave is enlarged on the right. Cz = central,
Fp2 = frontopolar, A2 = ear electrode, C7 = skin electrode on spine of cervical vertebra
C7. D1 = depth electrode reference. D1-D2 is recorded between the electrode at tip and
the most proximal of the four electrode points of the deep electrode.
71
6 Discussion
6.1 Methodological aspects
The EEG in studies IV and V were recorded using extensive 32 channel
recordings according to the full 10–20 system used in the EEG laboratory,
including orbitofrontal and ear electrodes and the topography of the EEG could
therefore be examined more extensively than in earlier published examinations.
For example, Yli-Hankala et al. (1999) used four channels (four bipolar electrode
pairs: Fp1-left mastoid, Fp2-right mastoid, Fpz-F7, and Fpz-F8) with adult
patients randomly allocated to spontaneous breathing or controlled
hyperventilation groups in their sevoflurane anaesthesia induction study. When
studying EEG phenomena in sevoflurane anaesthesia induction with
normoventilated children, Vakkuri et al. (2001) also used a four-channel EEG
registration (four bipolar electrode pairs (Fp1-left mastoid, Fp2-right mastoid,
Fpz-left temporal, Fpz-right temporal). Constant (1999) used a 16-channel EEG
registration in sevoflurane and halothane anaesthesia induction study with
children. The EEG was analysed in the frequency domain. Spectral analysis of the
EEG signals was performed using fast Fourier transformation (FFT). Julliac et al. (2007) studied EEG alterations during sevoflurane anaesthesia induction with
adults using four channels (positions Fp1, Fp2, T3, T4, C3, C4, O1 and O2).
6.2 SSEP in sevoflurane anaesthesia (I)
As anaesthesia deepens and activation of the thalamic nuclei decreases,
information is still relayed forward as the cortex remains active for an extended
period. This was demonstrated in study I, in which somatosensory information
was received in the cerebral cortex while under deep sevoflurane anaesthesia with
burst-suppression patterns observed in the EEG, similar to the manner in which it
is in subjects who are awake. Our observation is in agreement with findings
presented in the study by Hartikainen et al. (1995), who reported that all auditory,
visual and somatosensory (median nerve) stimulation modalities readily evoked
bursts, decreased the duration of suppression and increased the total duration of
bursts during steady-state B-S anaesthesia at a 1.5% end-tidal isoflurane
concentration (ETiso). Under deeper anaesthesia (at 1.8 ETiso concentrations) the
72
stimuli created less of a reaction and there was a predominance of stimulus offset-
evoked bursts over onset bursts (Hartikainen et al. 1995).
It has been widely debated whether the thalamus blocks the flow of
information during anaesthesia. It would appear, however, that it does not block
that flow, but rather that the subsequent processing of information is prevented.
Hudetz & Imas (2007) compared the spatiotemporal properties and frequency
spectra of discrete flash stimuli-induced cortical field potential responses with
spontaneous bursts during isoflurane 1.4–1.8% B-S anaesthesia in laboratory
animals. Each flash produced a visual evoked potential in the primary visual
cortex followed by secondary bursting activity in the more anterior regions while
spontaneous and flash-induced bursts did not differ in frequency, duration or
spatial distribution, with maximal power in the frontal (primary motor) cortex.
Electrocortical suppression of the cortex during anaesthesia did not prevent a
response to visual stimuli. Anaesthetic unconsciousness may not be due to
cortical deafferentation, but may arise from an inability of the brain to integrate or
perceive, rather than receive, sensory information (Hudetz & Imas 2007).
Vandesteen et al. (1991) evaluated the effects of isoflurane, enflurane and
halothane anaesthesia on SSEP by stimulation of the median nerve. Of the median
nerve SSEP components, the pre-central P22 was enhanced while the parietal N20
potential did not increase. In the present study I, however, N20 increased.
Halothane does not induce B-S, nor does it increase P22 (Vandesteene et al. 1991). One reason for the enhancement of the early components of the median
nerve-evoked potential P22 and N20/P20 during B-S anaesthesia under
sevoflurane, isoflurane and enflurane may be that by reflecting an increased
tendency to suppression of the inhibitory activity these anaesthetics permit
thalamocortical excitatory activity.
The stimulation frequency is of significance in the registration of SSEP under
deep inhalation anaesthesia. We could regularly record a high amplitude N20/P22
wave by stimulating the median nerve under sevoflurane anaesthesia at B-S level
and a reduction in stimulus frequency from 5 Hz to 1 Hz resulted in a marked
increase in the N20 amplitude without averaging in single sweeps. Porkkala
(1994) used a stimulation frequency from 4 to 5 Hz on the median nerve during
isoflurane anaesthesia and found a reduction in N20 amplitude and an increase in
latency at isoflurane concentrations over 1 MAC. In some cases the N20 response
was almost entirely abolished during suppression of the EEG.
Cortical tibial nerve SSEP with a high amplitude (up to 7.2 µV) was
registered under deep sevoflurane suppression anaesthesia and was usually visible
73
without averaging when the stimulation frequency was less than one per second
(Rytky et al. 1999). Stimulation frequencies higher than 1 Hz produced a
significant decrease in amplitude, which is in agreement with study I.
Westeren-Punnonen et al. (2008) used a sevoflurane end-tidal concentration
of 2% (corresponds to 1 MAC) for the maintenance of anaesthsia after induction
with thiopental while studying median nerve SSEP responses in children aged
three to eight years. The study group used a stimulation frequency of 5 Hz and
found that the somatosensory cortical N20 component latency was prolonged by
25% as a result of central conduction time (interpeak latency N13-N20)
prolongation, while no or minimal changes were recorded in the peripheral or
cervical SEP latencies. The mean cortical N20-P22 amplitude was decreased by
32%.
6.3 Epileptiform EEG in sevoflurane anaesthesia (IV, V)
High concentrations of sevoflurane (8%) in 50% nitrous oxide and oxygen were
used for anaesthesia induction in healthy children with spontaneous and
subsequently controlled normoventilation during the deepening of anaesthesia
(study IV). The study confirmed epileptiform EEG patterns, which began as early
as one to four minutes after the start of anaesthesia induction, with multifocal
single spikes and polyspikes with frontal maxima. Later on, PEDs developing
from polyspikes and waves in some subjects were recorded synchronously over
the entire cortex. Gibert et al. (2012) found major epileptiform signs in the EEG
in 50% of healthy normoventilated children receiving 1.7 MAC sevoflurane in
100% oxygen at steady-state maintenance anaesthesia. Nitrous oxide 50% in
oxygen or alfentanil raised the threshold for epileptiform EEG transients.
No focal epileptiform EEG seizures were observed in studies IV and V. Focal
epileptiform EEG seizures have not been detected in other anaesthesia induction
studies with high concentrations of sevoflurane, using either hyper- or
normoventilation (Yli-Hankala et al. 1999, Vakkuri 2000 et al, Vakkuri 2001 et al., Constant et al. 1999). In an earlier study with enflurane, EEG bursts gradually
transformed into an epileptic discharge in children (Rosen & Söderberg 1975) and
in adults (Neigh et al. 1971, Lebowitz et al. 1972, Yli-Hankala & Jäntti 1990a)
being hyperventilated. Enflurane and sevoflurane seem to share, at least, some
common mechanisms in producing epileptiform discharges in the EEG during
deep anaesthesia.
74
In contrast to the above, focal epileptiform EEG transitions with motoric
seizures were reported at high concentrations of sevoflurane maintenance
anaesthesia in healthy young adults (Kaisti et al. 1999, Jääskeläinen et al. 2003).
Seizure-like activity was observed in all patients under steady-state anaesthesia
with a maintenance sevoflurane concentration over 1.5 MAC (Sato et al. 2002,
Jääskeläinen et al. 2003). Nieminen et al. (2002) used intravenous anaesthesia
induction and sevoflurane maintenance with an end-tidal concentration of 2% in
40% oxygen in air for healthy children aged three to eight years and EEG
registration was carried out with a five-channel measure according to the 10–20
system. They did not detect any epileptiform EEG alterations with this
sevoflurane maintenance concentration.
Epileptiform EEG patterns related to the use of sevoflurane are observed
during the rapid increase in sevoflurane concentrations at anaesthesia induction
(Yli-Hankala et al. 1999, Vakkuri et al. 2000, Vakkuri et al. 2001, Julliac et al. 2007, Schultz et al. 2012, Julliac et al. 2013, Kreuzer et al. 2014), during long-
lasting maintenance of anaesthesia with high sevoflurane concentrations (Kaisti et al. 1999, Jääskeläinen et al. 2003), and when sevoflurane is used in mentally
disabled patients with lowered seizure thresholds, as well as in epileptic patients
(Iijima et al. 2000).
The heart rate rise observed in study IV appeared before epileptogenic spikes
were seen anywhere in the cortex, suggesting a complex relationship with
epileptiform EEG. The polyspike and -wave activity yields erroneous BIS values,
as the depth-of-anaesthesia cannot be defined during seizure activity.
Risk factors for epileptiform discharges among healthy adult patients during
anaesthesia induction with sevoflurane have been found to be the speed of
anaesthesia induction, a high alveolar sevoflurane concentration, and female sex
(Julliac et al. 2007). Rapid sevoflurane induction may induce a too rapid sleep
initiation and thus trigger epileptiform discharges, as epileptiform phenomena
corresponding to pathologic cortical EEG hypersynchronization and EEG
abnormalities can be more frequent during sleep initiation (Julliac et al. 2007).
Even after decreasing the speed of the increase in the sevoflurane CNS
concentration by delaying the onset of hyperventilation for two minutes at high
sevoflurane concentrations during anaesthesia induction in healthy women, severe
epileptiform EEGs with a hyperdynamic response were still observed (Vakkuri et al. 2000). PED, however, tended to occur more often with an immediate onset of
hyperventilation (Vakkuri et al. 2000). In addition, anaesthesia induction with a
75
low target for sevoflurane end-tidal concentration of 2.5% failed to totally prevent
epileptiform EEGs in young healthy female patients (Julliac et al. 2013)
In study V, the controlled hyperventilated (CH) male adults had more
epileptiform EEG alterations (90%) than did spontaneously breathing (SB) ones
(40%). The deviations of heart rate values in CH patients were significant in study
V, but the mean HR was higher than in the SB group. Mean HR increased during
the first two minutes in both groups and thereafter decreased in SB patients. Heart
rate rose abruptly at burst onset and dropped at suppression onset during deep
enflurane or isoflurane anaesthesia (Yli-Hankala et al. 1990a, Yli-Hankala &
Jäntti 1990b, Jäntti & Yli-Hankala 1990). An increase in heart rate up to 54% as
well as a smaller increase in blood pressure was detected by Yli-Hankala et al. (1999) in hyperventilated patients, but not in spontaneously breathing patients
during high concentration sevoflurane anaesthesia induction, and a 30% increase
in heart rate was associated with epileptiform EEGs, while no such connection
was seen between EEG and mean arterial pressure (MAP). The higher level of
mean HR in study V resembles the observation by Yli-Hankala et al. (1999), but
the lack of statistical significance may be due to the smaller number of patients
(n = 10 compared to n = 15). In study V, spontaneous breathing, allowing relative
carbon dioxide retention, maintained both EEG and HR alterations to a lesser
degree than by using controlled normoventilation (Vakkuri et al. 2001).
Premedication with a benzodiazepine - midazolam in study IV and diazepam
in study V - was used, both of which increase the threshold for convulsion (Rivera
et al. 1993, Scott et al. 1998). Nitrous oxide was used in 50% oxygen during
anaesthesia induction for both children and adults (studies IV and V). Nitrous
oxide reduces the epileptogenic effects in the EEG. Kurita et al. (2005) used an
electrocorticogram (ECoG) in epileptic patients below 1.5 MAC of sevoflurane
anaesthesia concentration with or without 50% nitrous oxide and found that the
numbers of spikes with nitrous oxide were significantly lower than those without
nitrous oxide, although the areas displaying spike activity did not differ.
Regardless of the use of both midazolam premedication and nitrous oxide,
however, the first spikes in the EEG were observed as early as from one to four
minutes from the beginning of anaesthesia induction in normoventilated children
in study IV.
In study IV, the location of spikes and polyspikes were concentrated mainly
frontally and were sometimes limited entirely to the frontocentral region. They
might therefore not be recognized in the fronto-temporal recordings used by
depth-of-anaesthesia monitors (Vakkuri et al. 2004).
76
The BIS calculated offline from the EEG recordings of patients in study IV
increased due to epileptogenic EEG activity (Jäntti et al. 2013). The BIS first
dropped under 10 in 11 children during high amplitude monophasic delta activity,
the average being 13.7, which ordinarily suggests a B-S pattern. After a slow delta
pattern, the EEG changed to epileptiform activity in all patients and the BIS
jumped to 95 in two patients and over 60 in two others. Sandin et al. (2008) also
demonstrated a similar pattern of BIS increase at a 2 MAC sevoflurane
concentration in healthy young adults and regarded it as being associated with the
epileptogenic activity of sevoflurane. One of their patients suffered a concomitant
short convulsive episode.
6.4 Focal seizure, fMRI and EEG (II)
The basic principle of the BOLD signal depends on the association of neuronal
activation with an increase in regional cerebral blood flow and a proportional
reduction in oxygen extraction resulting in a regional decrease of
deoxyhemoglobin. This change of regional deoxyhemoglobin concentration can
be detected by fMRI, thus representing an indirect, secondary measure of
neuronal activation (Dueck et al. 2005).
A remarkable BOLD increase prior to spike activity in the EEG was found in
the experimental penicillin-induced epileptic focus study in pigs anaesthetized
with isoflurane to a deep burst-suppression level of anaesthesia (study II). Thus,
this remarkable cerebral blood flow elevation was related to epileptiform activity
at an EEG burst suppression level (study II). Burst-suppression did not protect
from focal discharge. Hawko et al. (2007) examined epileptic patients in their
EEG-fMRI study and also detected a BOLD response occurring several seconds
prior to interictal scalp EEG discharges. This finding may imply that some
epileptic discharges are preceded by an energy-consuming phenomenon which
lasts several seconds and may not consist of a synchronized neuronal discharge
(Hawko et al. 2007). A study by Jacobs et al. (2009) also confirmed the
occurrence of BOLD changes prior to spikes in patients with idiopathic or
symptomatic focal epilepsy. Early BOLD changes were strongly related to the
spike field and were more local in comparison with later spike-related BOLD
changes, thus resulting in a better localizing value. Pittau et al. (2011) came to the
same conclusion in their study of focal epilepsy patients in which they also used
depth electrodes. They speculated that, in some cases, the early BOLD activity
was explained by a synchronized neural discharge which was detectable with
77
stereo-EEG but not visible in the scalp EEG, while in other cases the early BOLD
response possibly reflected a metabolic phenomenon not resulting from a
synchronized neuronal discharge, but rather from non-neuronal mechanisms
including the glia. In another study (Moeller et al. 2008), patients with
generalized epilepsy displayed a BOLD increase several seconds prior to
generalized spike wave discharges, with the earliest haemodynamic changes in
the medial thalamus. Faizo et al. (2014) studied functional connectivity changes
in a neural network prior to interictal spikes with simultaneous EEG and fMRI in
patients with mesial temporal lobe focal epilepsy. They found a significant loss of
connectivity between the hippocampi several seconds before the appearance of
spikes on EEG signifying a decoupling of hippocampal inhibition which may
predispose to spike generation.
Isoflurane exerts a more potent anticonvulsant effect as compared to
sevoflurane and halothane (Murao et al. 2000), so the focal penicillin-induced
findings were not manipulated by anaesthetic agent-induced epileptogenic
findings. Alternatively, isoflurane at an anaesthesia level close to a B-S pattern
did not suppress epileptic spikes in humans (Fiol et al. 1993). Isoflurane
anaesthesia also enabled the localization of the primary epileptogenic focus by
limiting the spread of epileptic activity.
6.5 Depth electrode recordings in propofol anaesthesia (III)
Study III elucidated the biophysics of the EEG. In that study, it was demonstrated
that EEG bursts are positive waves like the delta waves of deep, non-REM sleep.
The vertex-wave was negative. The slow waves of bursts were synchronous over
the entire cortex, even in the basal regions.
The reticular nucleus of the thalamus is a small structure and unlikely to
produce an EEG field visible at the scalp. It has been deduced through
thalamocortical projections that it probably drives cortical neurons, which then
produce the EEG spindles recorded off the scalp (Sinha 2011). The results of
study III show that spindles recorded from the depth electrodes are very low in
amplitude but high in the transcortical recording, i.e. between the scalp and the
depth electrode. This means that the scalp-recorded signal must be generated by
the cerebral cortex and that the reticular nucleus is only a pacemaker, contrary to
what has been claimed by Velly et al. (2007).
78
Touching, skin pinching or sound stimuli did not evoke bursts in propofol
burst-suppression anaesthesia. This was in agreement with the results presented in
the study by Huotari et al. (2004).
Due to synchronous slow activity over the entire cortex (including the basal
areas) resulting in a partly closed field, the EEG patterns and their generators
cannot be described precisely with scalp-recordings alone. The amplitude of EEG
patterns can only be measured using both surface and depth electrodes. In study
III, the recordings were made from scalp and neck electrodes referred to the depth
electrode at the subthalamic nucleus.
Wennberg & Lozano (2003) showed that the slow waves in the K-complex
during physiological NREM sleep were in the same phase in all surface electrodes
when referred to the depth electrode in a protocol similar to that used in the
present study III during propofol anaesthesia at burst-suppression level. The slow
waves of the K-complex were also more than twice the amplitude in any of the
scalp-depth recordings compared with the maximal amplitude of scalp-recording,
as with the burst slow waves in study III.
79
7 Conclusions
1. The amplitude of the short latency N20 wave of the median nerve SSEP
enhanced and was detected without averaging during sevoflurane-induced
EEG suppression. The latter components adapted and disappeared. This
showed that the somatosensory information reached the cortex and was not
totally blocked by the thalamus. Further processing of these impulses in the
cortex was suppressed.
2. Locally administered penicillin induced typical focal seizures during EEG
suppression in an experimental focal epilepsy model in pigs and provided
additional insight into the localization of epileptic foci with fMRI. The
development of focal epileptic activity could be detected as a BOLD signal
increase, which preceded the scalp EEG spike activity in deep isoflurane
anaesthesia at continuous EEG suppression.
3. Bursts and their slow wave oscillations were observed synchronously over
the entire cortex during propofol anaesthesia at EEG burst-suppression level
in Parkinson`s patients, while spindles and sharp waves were produced by the
sensorimotor cortex. The slow waves were surface positive and the vertex
wave was negative. Cortically generated burst-suppression could also be
recorded using depth electrodes.
4. Spike- and polyspike waveforms during 8% sevoflurane anaesthesia mask
induction in children were concentrated in a multifocal manner fronto-
centrally. These epileptiform waveforms may be underestimated when using
the typical processed depth-of-anaesthesia monitoring devices.
5. High sevoflurane concentrations during anaesthesia mask induction caused
epileptiform EEG activity concomitant with dynamic cardiovascular
phenomena in controlled hyperventilated adult male patients. Both
spontaneously breathing and controlled normoventilated subjects displayed
these alterations.
80
81
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Original publications
I Jäntti V, Sonkajärvi E, Mustola S, Rytky S, Kiiski P & Suominen K (1998) Single-sweep cortical somatosensory evoked potentials: N20 and evoked bursts in sevoflurane anaesthesia. Electroencephalogr clin Neurophysiol 108: 320–324.
II Mäkiranta M, Ruohonen J, Suominen K, Niinimäki J, Sonkajärvi E, Kiviniemi V, Seppänen T, Alahuhta S, Jäntti V & Tervonen O (2005) BOLD signal change preceeds interictal spike activity in EEG – a dynamical model of experimental penicillin induced focal epilepsy in deep anesthesia. Neuroimage 27: 715–724.
III Sonkajärvi E, Puumala P, Erola T, Baer GA, Karvonen E, Suominen K & Jäntti V (2008) Burst-suppression during propofol anaesthesia recorded from scalp and subthalamic electrodes: report of three cases. Acta Anaesthesiol Scand 52: 274–279.
IV Sonkajärvi E, Alahuhta S, Suominen K, Hakalax N, Vakkuri A, Löppönen H, Ohtonen P & Jäntti V (2009) Topographic electroencephalogram in children during mask induction of anaesthesia with sevoflurane. Acta Anaesthesiol Scand 53: 77–84.
V Sonkajärvi E, Alahuhta S, Suominen K, Rytky S, Kumpulainen T, Ohtonen P, Karvonen E, & Jäntti V (2015) Epileptiform EEG activity induced by rapid sevoflurane anaesthesia induction. Manuscript.
Reprinted with permission from John Wiley & Sons Ltd (III, IV) and Elsevier
(I, II)
Original publications are not included in the electronic version of the dissertation.
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Eila Sonkajärvi
THE BRAIN'S ELECTRICAL ACTIVITY IN DEEP ANAESTHESIAWITH SPECIAL REFERENCE TO EEGBURST-SUPPRESSION
UNIVERSITY OF OULU GRADUATE SCHOOL;UNIVERSITY OF OULU,FACULTY OF MEDICINE;MEDICAL RESEARCH CENTER OULU;OULU UNIVERSITY HOSPITAL