Changes in the electroencephalogram during anaesthesia and their physiological basis

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1 British Journal of Anaesthesia 215, i27 i31 doi: 1.193/bja/aev212 Review Article REVIEW ARTICLE Changes in the electroencephalogram during anaesthesia and their physiological basis S. Hagihira* Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka , Japan * Abstract The use of EEG monitors to assess the level of hypnosis during anaesthesia has become widespread. Anaesthetists, however, do not usually observe the raw EEG data: they generally pay attention only to the Bispectral Index (BIS ) and other indices calculated by EEG monitors. This abstracted information only partially characterizes EEG features. To properly appreciate the availability and reliability of EEG-derived indices, it is necessary to understand how raw EEG changes during anaesthesia. With hemi-frontal lead EEGs obtained under volatile anaesthesia or propofol anaesthesia, the dominant EEG frequency decreases and the amplitude increases with increasing concentrations of anaesthetic. Looking more closely, the EEG changes are more complicated. At surgical concentrations of anaesthesia, spindle waves (alpha range) become dominant. At deeper levels, this activity decreases, and theta and delta waves predominate. At even deeper levels, EEG waveform changes into a burst and suppression pattern, and finally becomes flat. EEG waveforms vary in the presence of noxious stimuli (surgical skin incision), which is not always reflected in BIS, or other processed EEG indices. Spindle waves are adequately sensitive, however, to noxious stimuli: under surgical anaesthesia they disappear when noxious stimuli are applied, and reappear when adequate analgesia is obtained. To prevent awareness during anaesthesia, I speculate that the most effective strategy is to administer anaesthetic agents in such a way as to maintain anaesthesia at a level where spindle waves predominate. Key words: electroencephalogram; reticulate nuclei of thalamus; spindle; thalamus Editor s key points Anaesthetists commonly use processed electroencephalographic data to guide anaesthesia, but the raw EEG can be more informative. The raw EEG changes in a characteristic dose-dependent manner for both volatile and i.v. anaesthetics, probably as a result of enhanced inhibitory effects. Processed EEG indices such as BIS are not as sensitive to noxious stimuli as the raw EEG; use of the raw EEG is a more sensitive way to monitor anaesthesia during surgery. During the past few decades, EEG monitors, such as the BIS monitor (Covidien, Boulder, CO USA), have become widely used. These devices calculate proprietary indices that purportedly show levels of hypnosis as numerical values. Most anaesthetists normally pay attention only to the indices and rarely take interest in the raw EEG. While it is true that EEG indices are convenient to use, they reveal only some aspects of raw EEG. Indeed, raw EEG, presenting richly complete data, initially seem more difficult to interpret. It is easy, however, to observe dramatic changes in the raw EEG as the administered concentration of anaesthetic increases. 1 While raw EEG patterns are anaesthetic-specific, concentration-related changes in EEG waveforms are quite similar This Article is accompanied by Editorial Aev223. Accepted: May 15, 215 The Author 215. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please journals.permissions@oup.com on 9 April 218 i27

2 i28 Hagihira among different agents that potentiate gamma-aminobutyric acid type-a (GABA A ) receptors. After just one or two weeks training, it seems likely that most anaesthetists should be able to reliably judge the effects of anaesthetic by observing raw EEG. In fact, Barnard and colleagues 1 have reported that most anaesthetists in their study were able to differentiate EEGs from anaesthetized and conscious states after only a short educational presentation. Furthermore, Bottros and colleagues 2 have reported that anaesthetists, after brief structured education and with access to data from a frontal EEG and relevant clinical data, can make accurate estimates of the processed bispectral index (BIS ). Many factors, such as noxious stimuli, hypercapnoea, hypocapnoea, and hypothermia, also affect changes in raw EEG waveforms. Among these, noxious stimuli are quite important during surgery, so the influence of noxious stimuli on the EEG waveform is discussed. If anaesthetists have knowledge of changes in the raw EEG during anaesthesia, it could help them judge the adequacy of EEG indices and enable them to respond more rapidly and confidently in circumstances where equipment algorithms provide misleading indications. EEG waveforms usually depend on electrode position. Here, I describe EEG changes and their neurophysiological background obtained using from hemi-frontal leadssuchasfp 1 A 1 or FP z At 1, which are commonly used in EEG-based anaesthesia monitors Iso=.3% Iso=.6% Iso=.9% Changes in the raw electroencephalogram during anaesthesia +5 Iso=1.2% Isoflurane, sevoflurane, thiopental, and propofol produce anaesthesia in part by potentiating inhibitory GABA A receptors. 3 Although each of these agents has its own characteristic EEG waveform, these waveforms undergo similar changes as the concentration of administered anaesthetic increases. Figure 1 shows raw EEG waveforms during isoflurane anaesthesia. During light anaesthesia, amplitude is shallow and frequency is high. When a higher concentration is administered, amplitude deepens and EEG frequency slows. During deep anaesthesia, a burst and suppression pattern becomes apparent, characterized by extreme activity, represented by high-frequency, large-amplitude waves (bursts), alternating with flat traces (suppression). This pattern, excluding brain ischaemia or other factors, indicates that anaesthesia is too deep. Beyond this, flat traces become dominant and, eventually waveforms are no longer apparent. During isoflurane, sevoflurane or propofol anaesthesia, this sequence of changes in pattern is almost identical. The major difference in EEG between the volatile agents (isoflurane or sevoflurane) and propofol is apparent in power in the theta range. During propofol anaesthesia, theta power remains low regardless of concentration, but during isofluraneorsevoflurane anaesthesia, it increases at surgical concentrations of anaesthesia. It is well known that alpha oscillation (around 1 Hz) are often observed when a person is awake with eyes closed. Such alpha oscillation is mostly observed in occipital regions. On the other hand, alpha rhythms observed during anaesthesia or natural sleep are mostly observed in the frontal region. This alpha rhythm shift is referred to as anteriorization of the alpha rhythm, and is common during isoflurane, sevoflurane or propofol anaesthesia. 5 Usually, anteriorization of the alpha rhythm predominates when anaesthesia is adequate for surgery, and is not clearly apparent just after loss of responsiveness. For example, Blain-Moraes and colleagues 6 have reported that sevoflurane did not result in consistent anteriorization of the alpha rhythm at around.8%, which was sufficient for loss of consciousness. 5 Iso=1.5% Changes of electroencephalogram-derived parameters during anaesthesia Fig 1 EEG waveform ( s duration) during.3,.6,.9, 1.2, and 1.5% isoflurane anaesthesia in a 55-year-old ovarian tumor patient undergoing resection. To clarify anaesthesia-related changes in EEG, it is necessary to consider how EEG data is analysed and presented by monitoring devices. Several analytic methods have been applied to construct EEG indices or EEG parameters. For example, time domain analysis is used for detection of suppression or calculation of amplitude and to provide burst suppression ratio (BSR) information. Power spectral analysis is the most commonly used tool, and is applied to calculate several parameters including spectral edge frequency (SEF), median frequency (MF), and relative β ratio (RBR). Spectral entropies are also calculated from power spectrum data. Bispectral analysis, the core technology of the BIS monitor, quantifies phase relations between the frequency components of EEG signals, and supplies SynchFastSlow (SFS) information. 7 Bispectral analysis will be discussed later in greater detail. It should be noted that BSR, RBR, and SFS results are used as sub-parameters for BIS calculation. 7 Generally speaking, as isoflurane is administered in greater concentrations, EEG amplitude increases and SEF95 decreases. In other words, the EEG waveform changes from fast wave, small amplitude to slow wave, large amplitude. But this is just a broad view: Figure 2 shows power spectrum changes during isoflurane anaesthesia. At isoflurane.3%, frequency is in the beta on 9 April 218

3 Changes in EEG during anaesthesia i29 (m V 2 ) %.5%.7%.9% 1.1% (Hz) Fig 2 Power spectrum changes during isoflurane anaesthesia in a 3- year-old female patient undergoing resection for colon cancer. Relative b ratio Awake Isoflurane (%) Fig 3 Relative β ratio (RBR) changes during isoflurane anaesthesia. RBR values were calculated from stored data used in a previous report. (Source: ref. 8 ). range and amplitude is comparatively low. When isoflurane is increased, peak frequency moves into the alpha range and amplitude increases. When concentration is further increased, amplitude decreases. In contrast, the power spectrum below Hz increases as isoflurane concentration increased. Thus, power spectrum changes are more complicated than they superficially appear. These more subtle changes might be conveyed by changes in the RBR. According to Rampil, 7 RBR is defined as the logarithm of the power ratios from the 3 7 Hz and 11 2 Hz ranges. RBR is mainly used to calculate BIS values from wakefulness to light anaesthesia, that is, BIS 6 to 1. Figure 3 shows the changes of RBR during isoflurane anaesthesia. Unlike SEF95 values, RBR shows bi-phasic changes, which would be caused by the transient increase of power spectrum in alpha range. Minimal RBR values correspond with maximal alpha activity. As alpha activity is most apparent at surgical concentrations of anaesthesia, I speculated that anaesthetic-concentrationrelated changes in alpha activity might hold the key to assessing anaesthetic effects during surgery. As suggested above, it is possible to estimate alpha activity from the RBR. Bispectral analysis is an advanced signal-processing technique. The concept is briefly outlined as follows. Assuming that a nucleus receives two waves with respective frequencies f 1 and f 2 and phase angles θ 1 and θ 2, a wave with frequency of f 1 +f 2 would be generated. If the phase angles of original waves (θ 1, θ 2 ) are inherited to the phaseangleoftheoutputsignalasθ 1 +θ 2, those signal components are regarded as phase coupled. Such a phenomenon is often observed in nonlinear systems. Bispectral analysis statistically quantifies the degree of phase coupling among the frequency components of a signal. Using a proper method for bispectral analysis of EEG data during anaesthesia, the direct indicator of the degree of phase coupling is bicoherence, the normalized bispectrum parameter. 9 While the bispectrum value is influenced by the magnitude of the original components and by the degree of phase-coupling, bicoherence values indicate only the phase relation. To investigate the relationship between EEG bicoherence and anaesthetic concentration, Bispectrum Analyzer (BSA) software was developed for real time bispectral analysis of EEG data. 9 As bispectrum or bicoherence is determined by two frequencies, plots of the values become three dimensional. The current version of BSA can gather raw EEG data and EEG-derived parameters such as BIS values from a BIS monitor. EEG bicoherence shows high values in rather restricted regions in the bi-frequency space. 9 When isoflurane concentration increases, two gradually growing peaks of EEG bicoherence emerge around the diagonal line representing f 1 =f 2, one at around Hz and another at around 1 Hz. Designating the Hz peak height as pbic low and the 1 Hz peak as pbic high. At.3% isoflurane, both pbics are low. As isoflurane concentration increases, pbic low increases until it reaches a plateau at.9% isoflurane. Meanwhile, pbic high also clearly increases to reach a somewhat lower plateau at isoflurane.9%, whereupon it slightly decreases at isoflurane concentrations of more than 1.1%. Furthermore, the frequency of pbic high gradually slows as isoflurane concentration increases. 8 Physiological basis of the electroencephalogram during anaesthesia Alpha activity observed during the stage II of slow wave sleep (SWS) is called spindle activity, a pattern characterized by waxing and waning of waveforms in the 7 1 Hz range. Alpha activity observed during anaesthesia appears to be generated by the same mechanism as sleep spindles. Spindles are usually observed, but only occasionally, in SWS. During surgical anaesthesia, however, they appear almost continuously. The usefulness of observing spindle activity can be understood if we consider why the two pbics changed as described in the previous section. At 7 1 Hz, the frequency of pbic high corresponds to the frequency of spindle patterns; the frequency of pbic low corresponds to delta waves. Using EEG combined with simultaneous intracellular recordings, Steriade and colleagues extensively investigated the drivers of these two EEG waves. They concluded that pacemaking for spindle patterns originated in reticulate nuclei (RE) of thalamus and thalamo-cortico-thalamic circuits, that the rhythm of delta waves was the intrinsic rhythm of thalamocortical neurons, and that these EEG rhythms were determined by the membrane potential of thalamocortical relay (TC) neurones. Nuñez and colleagues 12 reported that the EEG rhythm transits to a spindle pattern when the TC membrane potential was in the range of 55 mv to 65 mv, subsequently changing to delta waveforms when the membrane potential decreases below 65 mv. Figure schematically presents these neuronal circuits. RE of thalamus have GABAergic inhibitory input to TC neurones. Thus anaesthetic agents might concentration- on 9 April 218

4 i3 Hagihira dependently hyperpolarize the membrane potential of TC neurones, decreasing the frequency of pbic-high. The changing power spectrum pattern in Figure 2 also seems to reflect a transient increase in spindle activity and concentration-related changes in delta activity. Influence of noxious stimuli on the EEG So far, only the effects on the EEG of varying anaesthetic concentrations have been discussed. EEG is also influenced, however, by noxious stimuli. Changes in EEG bicoherence and BIS or other EEG-derived parameters have been reported in 12 subjects at incision and at 5 min after administration of 3 µg kg 1 of fentanyl during administration of 1.% isoflurane. 13 After initial skin incision (noxious stimulus), the EEG frequency increased and the amplitude decreased. In other words, the EEG pattern was desynchronized. This pattern was different, however, to those obtained with isoflurane at lower concentrations. Furthermore, in some patients (%) Pyramidal neuron Basal ganglia RE neuron GABA PPT/LDT TC neuron GABA Excitatory synapse Inhibitory synapse Fig Scheme of neuronal circuits related to spindle generation GABA, gamma-amino butyric acid;, acetylcholine;, glutamate; PPT/LDT, pedunculopontine tegmental/laterodorsal tegmental nuclei. (Source: compiled from refs ). 1.% isoflurane the EEG pattern changed to show a predominance of large delta waves, so called paradoxical arousal 1 marked by dips in BIS or SEF or other EEG index values. Kochs and colleagues 15 have reported that noxious stimuli promptly decreased alpha activity in 53% and increased delta activity in % of instances during 1.2% isoflurane with 66% nitrous oxide. Such EEG power spectrum changes seem to caused BIS or SEF values to decrease. The situation is further complicated in that the EEG involved a mixed pattern of these two patterns in some patients. Currently, there is little information about what situations give rise to paradoxical arousal. Using an anaesthetized cat model, Kaada and colleagues 16 have reported on the effect on EEG of highfrequency electrical stimulation to the midbrain reticular formation. Their results suggest that EEG changes depend on both on the concentration of anaesthetic and the intensity of stimulus, even when stimulation was intensified at the same neurone. When noxious stimulation is applied, BIS shows variable changes: in some patients, the BIS value increases after incision; in others, it decreases; and in others, BIS remains unchanged. Interestingly, when BIS changed, administration of fentanyl restored BIS values to those before incision in a sample of 12 subjects. 13 SEF95 values show a tendency to change in the same way as BIS values. These results indicate that it is imprudent to assess analgesia using BIS or SEF95 values. Going further, it is first necessary to ensure adequate analgesia before assessing the level of hypnosis using BIS or SEF95 values. Changes in EEG after noxious stimuli during sevoflurane anaesthesia have also been investigated and the results were quite similar to those obtained during isoflurane anaesthesia. 13 Furthermore, similarities are also apparent during propofol anaesthesia (data not published). On the other hand, pbic-high decreased after incision and, in all patients, rose to previous values after administration of fentanyl (Fig. 5). Meanwhile, spindle activity disappeared after incision and, in all patients, re-appeared after fentanyl administration. This correspondence indicates that pbic-high is likely to be a good indicator of adequate analgesia. As pbic-high seems to indicate spindle activity, spindle patterns observed in raw EEG or in the power spectrum might also provide a basis for assessing adequacy of analgesia. This hypothesis warrants further study. During more than 15 years of clinical practice, I have observed the raw EEG during anaesthesia in more than 1 surgeries, and I have managed many patients using pbic-high as an indicator of adequacy of analgesia. A limitation of my strategy is interindividual variation in the raw EEG during anaesthesia. Some patients do not manifest high spindle activity at any level of anaesthesia. Generally speaking, this absence is more frequent in elderly patients but, even so, some patients aged more than 8 or 85 still show predominant spindle activity. At the same time, some younger patients, even in the 3 to year range, do not show predominant spindle activity. The variation cannot be solely attributed to aging. What we can conclude is that absence of spindle activity does not necessarily indicate insufficient analgesia. On the other hand, after assessing spindle activity after induction of anaesthesia and immediately before the start of surgery, a shift to predominant spindle activity is likely to be a good indicator that analgesia is adequate during surgery. Control After incision After fentanyl Fig 5 Effect of surgical incision (noxious stimuli) on pbic-high in 12 patients during isoflurane anaesthesia (Source: Plotter data from ref. 13 ). Conclusion Although the raw EEG varies widely from individual to individual, the way the EEG patterns change when differing concentrations of anaesthetic are administered is quite similar among patients. While it is easier to refer to EEG indices, they might not adequately on 9 April 218

5 Changes in EEG during anaesthesia i31 convey the information necessary to control anaesthesia. In particular, adequate analgesia is required before the indices can be used as indicators of level of hypnosis. As it is relatively easy to interpret raw EEG changes during anaesthesia, all anaesthetists should acquire the ability to interpret raw EEG. Author s contribution S.H. is the sole author of this paper, accountable for accuracy and integrity of the paper. Declaration of interest None declared. Funding This study was funded by the Department of Anesthesiology and Intensive Care Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. References 1. Barnard JP, Bennett C, Voss LJ, Sleigh JW. Can anaesthetists be taught to interpret the effects of general anaesthesia on the electroencephalogram? Comparison of performance with the BIS and spectral entropy. Br J Anaesth 27; 99: Bottros MM, Palanca BJA, Mashour GA, et al. Estimation of the Bispectral Index by anesthesiologists. An inverse turing test. Anesthesiology 211; 11: Hemmings HC Jr, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci 25; 26: Hall JE, Guyton AC. Textbook of Medical Physiology, 12th Edn. Philadelphia: Saunders Elsevier, Akeju O, Westover B, Pavone KJ, et al. Effects of sevoflurane and propofol on frontal electroencephalogram power and coherence. Anesthesiology 21; 121: Blain-Moares S, Tarnal V, Vanini G, et al. Neurophysiological correlates of sevoflurane-induced unconsciousness. Anesthesiology 215; 122: Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: Hagihira S, Takashina M, Mori T, Mashimo T, Yoshiya I. Changes of electroencephalographic bicoherence during isoflurane anesthesia combined with epidural anesthesia. Anesthesiology 22; 97: Hagihira S, Takashina M, Mori T, Mashimo T, Yoshiya I. Practical issues in bispectral analysis of electroencephalographic signals. Anesth Analg 21; 93: Steriade M, Nuñez A, Amzica F. Intracellular analysis of relations between the slow (<1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. J Neurosci 1993; 13: Steriade M, Contreras D, Dossi RC, Nuñez A. The slow (<1 Hz) oscillation in reticular thalamic and thalamocortical neurons: Scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J Neurosci 1993; 13: Nuñez A, Dossi CC, Contreras D, Steriade M. Intracellular evidence for incompatibility between spindle and delta oscillations in thalamocortical neurons of cat. Neuroscience 1992; 8: Hagihira S, Takashina M, Mori T, Ueyama H, Mashimo T. Electroencephalographic bicoherence is sensitive to noxious stimuli during isoflurane or sevoflurane anesthesia. Anesthesiology 2; 1: Bischoff P, Kochs E, Droese D, Meyer-Moldenhauer WH, Schulte am Esch J. Topographic-quantitative EEG-analysis of the paradoxical arousal reaction. EEG changes during urologic surgery using isoflurane/n2o anesthesia. Anaesthesist 1993; 2: Kochs E, Bischoff P, Pichlmeier U, Schulte am Esch J. Surgical stimulation induces changes in brain electrical activity during isoflurane/nitrous oxide anesthesia. a topographic electroencephalographic analysis. Anesthesiology 199; 8: Kaada BR, Thomas F, Alnaes E, Wester K. EEG synchronization induced by high frequency midbrain reticular stimulation in anesthetized cats. Electroenceph Clin Neurophysiol 1967; 22: 22 3 Handling editor: H. C. Hemmings on 9 April 218