REVIEW ArtICLE David S. Warner, M.D., Editor Clinical Electroencephalography for Anesthesiologists Part I: Background and Basic Signatures Patrick L. Purdon, Ph.D., Aaron Sampson, B.S., Kara J. Pavone, B.S., Emery N. Brown, M.D., Ph.D. Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/123/4/937/373943/20151000_0-00034.pdf by guest on 28 September 2021 ABSTRACT The widely used electroencephalogram-based indices for depth-of-anesthesia monitoring assume that the same index value defines the same level of unconsciousness for all anesthetics. In contrast, we show that different anesthetics act at different molecular targets and neural circuits to produce distinct brain states that are readily visible in the electroencephalogram. We present a two-part review to educate anesthesiologists on use of the unprocessed electroencephalogram and its spectro- gram to track the brain states of patients receiving anesthesia care. Here in part I, we review the biophysics of the electro- encephalogram and the neurophysiology of the electroencephalogram signatures of three intravenous anesthetics: propofol, dexmedetomidine, and ketamine, and four inhaled anesthetics: sevoflurane, isoflurane, desflurane, and nitrous oxide. Later in part II, we discuss patient management using these electroencephalogram signatures. Use of these electroencephalogram signatures suggests a neurophysiologically based paradigm for brain state monitoring of patients receiving anesthesia care. ( ANESTHESIOLOGY 2015; 123:937-60) The Electroencephalogram and Brain patients over time as a three-dimensional plot (power by fre- Monitoring under General Anesthesia quency vs. time).11 Fleming and Smith12 devised the density- modulated or density spectral array, the two-dimensional plot Almost 80 yr ago, Gibbs et al. demonstrated that system- of the spectrogram, for the same purpose.13 Levy14 later sug- atic changes occur in the electroencephalogram and patient gested using multiple electroencephalogram features to track arousal level with increasing doses of ether or pentobarbital. anesthetic effects. Despite further documentation of system- They stated that “a practical application of these observations atic relations among anesthetic doses, electroencephalogram might be the use of electroencephalogram as a measure of the 4,15–20 1 patterns, and patient arousal levels, use of the unpro- depth of anesthesia.” Several subsequent studies reported on cessed electroencephalogram and the spectrogram to monitor the relation between electroencephalogram activity and the the states of the brain under general anesthesia and sedation 2–6 7 behavioral states of general anesthesia. Faulconer showed never became a standard practice in anesthesiology. in 1949 that a regular progression of the electroencephalo- Instead, since the 1990s, depth of anesthesia has been gram patterns correlated with the concentration of ether in tracked using indices computed from the electroencephalo- arterial blood. Bart et al. and Findeiss et al. used the spec- gram and displayed on brain monitoring devices.21–25 The trum—the decomposition of the electroencephalogram signal indices have been developed by recording simultaneously into the power in its frequency components—to show that the the electroencephalogram and the behavioral responses to electroencephalogram was organized into distinct oscillations various anesthetic agents in patient cohorts.26 Some of the at particular frequencies under general anesthesia.8,9 Bickford indices have been derived by using regression methods to et al.10 introduced the compressed spectral array or spectrogram relate selected electroencephalogram features to the behav- to display the electroencephalogram activity of anesthetized ioral responses.26–29 One index has been constructed by This article is featured in “This Month in Anesthesiology,” page 1A. Drs. Purdon and Brown have summarized some of this work on the Web site www.anesthesiaEEG.com and have given several seminars on this topic in multiple venues during the last 2 yr. Submitted for publication April 8, 2013. Accepted for publication May 18, 2015. From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, and Department of Anesthesia, Harvard Medical School, Boston, Mas- sachusetts (P.L.P.); Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts (A.S., K.J.P.); and Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Anesthesia, Harvard Medical School, Boston, Massachusetts; Institute for Medical Engineering and Science and Harvard-Massachusetts Institute of Technology, Health Sciences and Technology Program; and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts (E.N.B.). Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2015; 123:937–60 Anesthesiology, V 123 • No 4 937 October 2015 Copyright © 2015, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Electroencephalography for Anesthesiologists using classifier methods to derive a continuum of arousal lev- signatures observable in the unprocessed electroencephalo- els ranging from awake to profound unconsciousness from gram and the spectrogram. The new concept of defining the visually categorized electroencephalogram recordings.30,31 anesthetic state by using drug-specific electroencephalogram Another index has been constructed by relating the entropy signatures that relate to molecular and neural circuit mecha- of the electroencephalogram signal—its degree of disorder— nisms of anesthetic action would allow anesthesiologists to to the behavioral responses of the patients.32,33 The indices make more detailed and accurate assessments than those are computed from the electroencephalogram in near real based on electroencephalogram-based indices. The potential time and displayed on the depth-of-anesthesia monitor benefits of using the unprocessed electroencephalogram to as values scaled from 0 to 100, with low values indicating monitor anesthetic states have been recently stated.48,49 Cur- greater depth of anesthesia. The algorithms used in many rent brain monitors display the unprocessed electroencepha- of the current depth-of-anesthesia monitors to compute the logram and the spectrogram.22,31,50 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/123/4/937/373943/20151000_0-00034.pdf by guest on 28 September 2021 indices are proprietary. To define anesthetic states in terms of drug-specific elec- Although the electroencephalogram-based indices have troencephalogram signatures that relate to molecular and been in use for approximately 20 yr, there are several reasons neural circuit mechanisms of anesthetic action, we synthesize why they are not part of standard anesthesiology practice. different sources and levels of information: (1) formal behav- First, use of electroencephalogram-based indices does not ioral testing along with either simultaneous human electro- ensure that awareness under general anesthesia can be pre- encephalogram recordings or human intracranial recordings vented.34,35 Second, these indices, which have been devel- during anesthetic administration; (2) clinical observations oped from adult patient cohorts, are less reliable in pediatric of behavior along with simultaneous electroencephalogram 36,37 populations. Third, because the indices do not relate recordings during anesthetic administration; (3) the neuro- directly to the neurophysiology of how a specific anesthetic physiology and the molecular pharmacology of how the anes- exerts its effects in the brain, they cannot give an accurate thetics act at specific molecular targets in specific circuits; picture of the brain’s responses to the drugs. Finally, the indi- (4) the neurophysiology of altered states of arousal such as ces assume that the same index value reflects the same level non-rapid eye movement sleep, coma (medically induced, of unconsciousness for all anesthetics. This assumption is pathologic, or hypothermia induced), hallucinations, and based on the observation that several anesthetics, both intra- paradoxical excitation; (5) time–frequency analyses of high- venous and inhaled agents, eventually induce slowing in the density electroencephalogram recordings; and (6) mathemat- 1,4,22 electroencephalogram oscillations at higher doses. The ical modeling of anesthetic actions in neural circuits. slower oscillations are assumed to indicate a more profound We present this new education paradigm in two parts. state of general anesthesia. Two anesthetics whose electroen- Here, in part I, we review the basic neurophysiology of the cephalogram responses frequently lead clinicians to doubt electroencephalogram and the neurophysiology and the elec- 38,39 40–42 index readings are ketamine and nitrous oxide. troencephalogram signatures of three intravenous anesthet- These agents are commonly associated with faster electro- ics: propofol, dexmedetomidine, and ketamine, and four encephalogram oscillations that tend to increase the value of inhaled anesthetics: sevoflurane, isoflurane, desflurane, and the indices at clinically accepted doses. Higher index values nitrous oxide. We explain, where possible, how the anesthet- cause concern as to whether the