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Monitoring consciousness: the current status of EEG-based depth of anaesthesia monitors
Best Practice & Research Clinical Anaesthesiology Vol. 21, No. 3, pp. 313–325, 2007 doi:10.1016/j.bpa.2007.04.003 available online at http://www.sciencedirect.com
3 Monitoring consciousness: the current status of EEG-based depth of anaesthesia monitors Logan Voss *
PhD
Senior Research Scientist
Jamie Sleigh
MD, MBChB, FANZCA, FJFICM
Professor of Anaesthesia and Intensive Care Department of Anaesthesia, Waikato Clinical School, University of Auckland, Hamilton, New Zealand
Direct and indirect inhibitory effects of anaesthetic agents on cortical activity are reflected in the electroencephalogram (EEG) as: (i) a shift from low-amplitude, high-frequency EEG, to highamplitude, low-frequency activity (indicative of cortical depowering) and; (ii) the appearance of spindles and K-complexes (indicative of thalamocortical hyperpolarisation and sensory blockade). Existing EEG monitors use cortical activity as a proxy measure for consciousness. However the state of the cortex at any given moment does not accurately predict the state that it will enter in response to a noxious stimulus, and EEG monitors do not differentiate well between different levels of rousability. Also the literature reveals many instances where the EEG pattern is dissociated from conscious state (e.g. an awake-looking EEG, but an unresponsive patient; or a slow-wave EEG in an awake patient). Fortunately, a slow-wave EEG (even in the presence of a responsive patient) usually indicates profound amnesia for explicit memory. Key words: anaesthesia; electroencephalography; bispectral index; amnesia; artefact; spectral entropy.
INTRODUCTION A primary reason for the use of electroencephalography (EEG)-based monitoring in general anaesthesia is to detect and warn the anaesthetist that retrievable memories are being formed by the patient. Is it reasonable to expect that the EEG will provide insight into the state of consciousness of the patient? The aim of this chapter is to briefly review the basic science (neurobiological, neuropharmacological, and signal-processing) * Corresponding author. Department of Anaesthesia, Waikato Clinical School, University of Auckland, Hamilton, New Zealand. Tel.: þ64 7 8398899; Fax: þ64 7 8398761. E-mail address: [email protected] 1521-6896/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
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evidence that underpins the idea that EEG changes might be causally linked to loss of intra-operative recall. Consciousness is a word that describes the process by which objective reality becomes subjective. It is questionable whether consciousness is a subject that is even accessible to scientific enquiry. However since the daily business of anaesthetists is to reversibly disrupt the neural mechanisms that underlie this process, some understanding of the phenomenon of consciousness is necessary for safe clinical practice. At least two neurobiological processes are essential for consciousness to be present: the abilities to attend and to remember. Although it has been cogently argued that a definition of anaesthesia requires only amnesia and immobility; attention is usually a prerequisite of declarative memory, and anaesthetic drugs clearly act to impair the neurophysiological mechanisms required for attention. If we want to evaluate the effectiveness and usefulness of depth of anaesthesia monitors we need to ask four closely-linked questions. (1) What do we currently understand about the mechanism of anaesthetic drug effects on cortical neural function (particularly regarding attention and memory)? (2) Do these effects become manifest in changes in cortical dynamics, and hence in the EEG signal? (3) Can these EEG changes be captured by a single number? (4) Do these EEG changes reliably reflect conscious state and/or memory formation? To be clinically useful, the predictive error rate needs to be <0.01% (i.e. less than 1/10 000 patients who are predicted by the EEG to be amnesic, are actually able to recall intra-operative events). This is an extremely exacting level of certainty to require from a clinical monitor. If the answer is definitely ‘‘no’’ to either of the last two questions, then it is likely that the enterprise of using EEG information to modify anaesthetic drug dosage will fail. This review will describe the commonly accepted scientific explanation of how anaesthetic drugs could be expected to change the EEG, and how this might be reflected in changes in level of consciousness of the patients. It will conclude by reporting some interesting experiments that have been done, which call into question this ‘‘standard model’’. BACKGROUND How do anaesthetic drugs alter cortical neural function? The mechanisms of action of general anaesthetic drugs are complex and incompletely understood.1 The hypnotic effect of the most commonly-used volatile and intravenous general anaesthetics is generally ascribed to enhancement of ‘‘GABAergic’’ inhibition, although a role for reduction in excitatory neuronal activity may also be important.2,3 Either way, the end result is that anaesthesia causes cortical activity to decrease.4 This occurs: (i) by a direct action of general anaesthetic drugs on the cortex, and (ii) indirectly by inactivation of the endogenous brain stem and hypothalamic arousal systems — which then cause a secondary cortical shut down. The thalamus also drastically changes its mode of activity from that of a relatively depolarised state — in which accurate transmission of sensory information is maintained — to a hyperpolarized mode that facilitates stereotypical ‘‘burst firing’’ patterns of neuronal activity in corticothalamic networks.
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Corticothalamic burst activity effectively cuts the cortex off from external sensory input.5,6 With deepening anaesthesia, this burst activity becomes increasingly coherent across the cortex.4 These brain stem and corticothalamic changes overlap with the mechanisms that induce natural sleep.7 General anaesthesia obviously differs from natural sleep, in that anaesthetic drugs disable the ability of nociceptive input to activate cortico-thalamic arousal. All anaesthetic drugs have this action to some degree, but it is most important in the adjunctive action of opioids, nitrous oxide and ketamine. It is important to note that endogenous arousal control systems are intrinsically bistable.8 This means that these systems will tend to jump between the awake and asleep state, and do not naturally allow the brain to exist in an intermediate level of consciousness. Our current understanding of the action of anaesthetic drugs on global cortical function may be summarised as: (i) generalised cortical depowering via direct cortical actions and blockade of brain stem arousal systems, and/or (ii) thalamocortical sensory blockade. As we report later in this paper, EEG monitors measure cortical de-powering, but not thalamocortical blockade. What is the origin of the EEG signal and are the effects of general anaesthesia on cortical function visible to the EEG? The scalp EEG measures changes in voltage detected on the scalp. These voltage fluctuations are induced by currents that flow between the dendrites and the soma of the cortical pyramidal cells, that are some distance from the sensing electrodes on the scalp. The voltages are attenuated and smeared by passage through the skull and scalp. This has the effect of preferentially allowing large and slow voltages (generated by large collections of synchronously firing neurons) to be dominant in the EEG signal; as compared to electrocorticogram, which is recorded from electrodes positioned directly into the cortex. We may summarise the EEG signal as a frequency-distorted measure of the mean dendritic (post-synaptic potential) currents of hundreds of thousands (or millions — depending on the montage) of cortical pyramidal neurons that underlie the active electrode. The effects of GABAergic drugs to depower cortical activity are reflected in changes in the EEG, which are more-or-less consistent from one agent to another. At low doses of anaesthesia there is a paradoxical increase in amplitude, particularly in the beta frequency range (1–30 Hz). The appearance of this so-called ‘‘biphasic’’ effect has been related to the development of amnesia in the patient.9 As the brain concentration of the anaesthetic agent increases, the dominant frequency of the EEG slows to the theta (4–8 Hz) and then delta (1–4 Hz) wave bands and its amplitude increases. The transition from high frequency to low frequency activity in the EEG signal reflects thalamocortical hyperpolarisation and synchronised neuronal burst activity. Various episodic waveforms also appear in the EEG, such as spindles and K-complexes. These indicate: (i) thalamocortical sensory blockade and, (ii) that the cortical neurons are no longer able to generate transient high firing rates that are (usually) associated with cognitive activity. Quantification of this anaesthetic-induced shift of the dominant frequency of the EEG is so robust, that it is routinely used for very accurate doseresponse modelling of anaesthetic drug effect.10,11 At very high concentrations of anaesthetic drug, the burst suppression pattern appears, and eventually the EEG becomes isoelectric. The above EEG changes are not unique to anaesthesia. Many of the anaesthesiainduced changes in the EEG are also seen in natural sleep (implying the involvement
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of similar neurophysiological mechanisms); and are accompanied by corresponding changes in the bispectral index (BIS) (Figure 1). One of the important differences between anaesthesia and natural sleep is the ability to be readily aroused from sleep by sensory stimulation — resulting in the re-appearance of a low-amplitude, highfrequency EEG — whereas a subject who is adequately anaesthetised will remain unresponsive to strong nociceptive input. In about 30% of lightly anaesthetised patients, a nociceptive stimulus will cause the appearance of large delta waves (termed ‘‘paradoxical cortical arousal’’).12 These examples highlight a very important principle that has implications for EEG monitoring; the state of your cortex at any given moment does not accurately predict the state you will enter in response to a noxious stimulus. EEG monitors do not differentiate well between different levels of rousability. A subject who is in natural slow wave sleep will have a BIS or entropy value that is indistinguishable from that of an anaesthetised subject. Similarly, the effect of opioids to reduce nociceptive stimulation usually does not necessarily decrease BIS or entropy values.12 How can we to turn the EEG signal into a number? Unlike most other forms of anaesthetic monitoring (which demand some skill in waveform pattern recognition from the anaesthetist for accurate diagnosis), the manufacturers of commercially available EEG monitors have concentrated on producing a single EEG index (usually scaled 0–100), that they hope reflects the patient’s ‘‘level of consciousness’’. Whilst the technical signal-processing issues of EEG artefact rejection and algorithm development are not trivial, they have been dealt with in detail in a previous book in this series. The most widely investigated proprietary algorithm is BIS. However a plethora of other indices have recently become commercially available (such as the M-Entropy, Narcotrend, Patient-State Analyser, SNAP, and various auditory evoked-potential methods). At the simplest level, all these quantitative EEG (qEEG) depth of anaesthesia monitors use the loss of high frequencies and shift to low frequencies, as a measure of anaesthetic drug action. The monitors differ considerably in the details of how this is achieved, speed of response, incorporation of burst
Figure 1. A plot of the bispectral index (BIS) during the course of a night’s natural sleep, which shows clear sleep architecture with pronounced 90 min cycles of slow-wave sleep early in the night (corresponding to low BIS periods); followed by more stage 2 and rapid eye movement (REM) sleep later in the night (seen as an increase in the BIS trend).
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suppression patterns for deep anaesthesia, and the handling of electromyogram (EMG) and various other artefacts. Our subsequent discussion will predominantly involve the BIS, because it has been the most widely investigated and used. However, no studies have demonstrated that any of the other monitors offer significant advantages over, or consistent clinical differences from, the BIS. The manufacturers of the BIS claim a point of difference from the other monitors in that the BIS quantifies the bispectrum as part of its algorithm. It is not clear whether this feature contributes significantly different information over and above simple spectral changes.13,14 It should be noted that there are a number of other anaesthetic-induced EEG phenomena that are not detected by the commercial algorithms (such as spindles, K-complexes, spatial correlations). Whether these phenomena are important to the accurate detection of unconsciousness has not yet been investigated thoroughly. How reliable is this number? This is the all-important question. We have established that most anaesthetic agents have well-defined and characteristic effects on cortical activity, which are reflected in EEG changes that can be quantified by EEG-processing algorithms in most patients. Does this change in cortical activity consistently relate to level of consciousness and/ or memory formation and consolidation? Do all patients who change from a state of conscious awareness to an anaesthetised state, consistently show increased lowfrequency waves and decreased high frequency waves? Is it possible to find counterexamples to disprove this statement? This would involve finding examples of: (i) patients with a predominance of high-amplitude low-frequency EEGs who are conscious, and/ or (ii) patients with low-amplitude high-frequency EEGs who are anaesthetised. If such examples can be found, then the presence of large slow waves in the EEG can be assumed to be a common epiphenomenon of the anaesthetised state — but not to be directly causally essential for the removal of consciousness. Dahaba has written an extensive review of over 30 published reports in which the BIS has been reported to be in error.15 In the following section we will discuss the documented discrepancies between the EEG, qEEG-based monitors and behavioural state, with a view to understanding the nature of these errors and how they effect interpretation of monitor output. CONSCIOUSNESS The problem of the ‘‘twilight zone’’ A thorough examination of the literature reveals many instances where the EEG pattern can be shown to dissociate from conscious state. For example, all the current qEEG monitors are effective in discriminating the extremes of alertness and deep anaesthesia, most of the time. However there exists a large intermediate area (that we term the ‘‘twilight zone’’) between these extremes, in which the discriminatory power of qEEG indices is much less impressive. Typically the prediction probability to differentiate awake from unresponsive states is only about 0.7.16 For example, in Figure 2, the EEG shows large delta waves, but also demonstrates a significant amount of high frequency power amongst the delta activity — hence the high response entropy. The standout feature is that there is no obvious change when comparing the EEG from the time zero (when the patient was responsive) to that
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Figure 2. Examples of variation in electroencephalography (EEG) around the point of loss-of-responsiveness (shown by vertical line at 10 s) in a patient undergoing slow inhalational induction of anaesthesia with sevoflurane. The response entropy at the point of loss of consciousness was 97.
at the end of the graph (when the patient wasn’t responsive) (i.e. loss of consciousness per se may not always be closely linked with any gross EEG change). The ‘‘twilight zone’’ effect is further illustrated in a study by Schneider et al., who induced anaesthesia with alfentanil and propofol in 20 patients. Anaesthesia was titrated to achieve a steady-state BIS value of 50–60 (so as to minimise the effects of lag in calculation and display of the BIS).17 They used muscle relaxation and communicated with the patients via the isolated forearm technique. Eight of the patients were wakeful after intubation (one at a BIS of 47), although none had any conscious recall. There are numerous other studies which show that, for individual patients receiving standard GABAergic anaesthetic drugs, the actual point at which the patients became unresponsive to verbal command can vary between BIS (or entropy) values of 40–90.16,18–27 In other words, many subjects become unconscious while the BIS or entropy remains at ‘awake’ levels, and a few become unconscious only at values well below the upper end of the recommended ‘anaesthesia’ target range of 60. This large range of uncertainty poses a major problem for the use of the BIS by the practicing anaesthetist. Aim for a BIS of 40, and most of the patients will be grossly overdosed. Aim for a BIS of 60, and occasional patients will be aware. One possible solution would be to individualise the BIS target. In this strategy the anaesthetist notes the BIS value at the point when the patient became unresponsive at induction; and then adjusts the anaesthetic dosage to keep the BIS value comfortably below that. This strategy is appealing, but has not been tested in a large series, and must take into account the lag in the BIS algorithm between EEG acquisition and display of the BIS index. In small series it has not been demonstrated that the BIS is able to consistently track multiple within-patient transitions between consciousness and unconsciousness.21,23 The relationships between the EEG, qEEG-index (e.g. BIS), and level of consciousness can be described diagrammatically, as shown in Figure 3. On the diagonal are the cells in which there is agreement between the BIS and the clinical state of consciousness (shown as ‘ticks’). On the off-diagonals are the problem areas (shown as ‘question marks’). The possible explanations for the problems areas are shown in the grey boxes. We will discuss each of the problem cells in turn.
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Figure 3. A diagram of the framework in which to examine the relationships between the electroencephalograph (EEG) signal, the bispectral index (BIS), and the conscious state of the patient.
BIS < 60 with awake patient and awake looking EEG If the BIS is low in an awake individual with an EEG showing lots of high frequency activity, it is clear that this is a problem of algorithm failure. The proprietary nature of the BIS algorithm precludes definitive explanation of where the algorithm fails, but in many cases it can be linked to the dominance of the burst-suppression component of the algorithm that drives the BIS value down. From the review by Dahaba, it would seem that most of the cases of low BIS in the awake but paralysed subject fall into this category; presumably the BIS erroneously interpreted the small amplitude EEG signal as burst suppression. Although the BIS may decrease to very low levels (e.g. 33 and 9) in awake, but paralysed, subjects; visual inspection of the raw EEG waveform shows a low-voltage awake-looking EEG waveform.28 A similar paradoxical decrease in BIS (although with no muscle relaxation present) has also been documented during recovery from remifentanil anaesthesia, resulting from a low-amplitude EEG being misinterpreted by the algorithm as burst suppression.29 Erroneous activation of the burst suppression component of the BIS algorithm also may be a problem in the 5–10% of the population who have a genetically-determined low amplitude EEG. BIS > 60 with an unconscious patient and awake looking EEG There are a number of examples of unconsciousness occurring in the presence of an activated cortex (i.e. a falsely high BIS) in the anaesthesia and sleep literature. In this case the BIS algorithm is accurately describing the frequencies present in the raw EEG, but the patient is unresponsive even though the cortex is in an apparently active state — indistinguishable from that found in the conscious state. These situations will tend to cause the anaesthetist to overdose the patient. For example it is possible to titrate an opioid-heavy balanced anaesthetic technique to a relatively higher BIS target, as compared to an anaesthetic technique in which there is only a small dose of opioid used. A clear dissociation between the EEG and conscious state is seen with the use of anaesthetic agents ketamine and nitrous oxide; and also in rapid eye
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movement (REM) sleep. In each case, awareness of external events is abolished while the EEG pattern closely resembles that of the awake state.19,30,31 The dreaming that occurs with ketamine and during REM sleep may be interpreted as a form of internal, introspective ‘‘consciousness’’, however its content bears no resemblance to reality and awareness of the objective world is absent. BIS < 60 with an awake patient but an asleep looking EEG There are also a few published instances of wakefulness with a ‘‘deactivated’’ cortex (i.e. a falsely low BIS). In these cases the BIS algorithm is accurately quantifying a raw EEG with predominant delta wave activity. These cases are more worrying because of the potential for BIS-guided under-dosing of anaesthesia. For example, post-ictal patients who are conscious (but amnesic - vide infra), commonly exhibit delta waves in the EEG and low BIS values (Figure 4).32,33 Enhanced delta wave activity may also be observed in the EEG of awake subjects with schizophrenia and in advanced dementia.34,35 Other examples of EEG monitor ‘‘errors’’ Artefacts Errors resulting from artefact in the EEG waveform may be classified as a form of EEG ‘‘failure’’. The review by Dahaba identified a number of cases where various devices (such as warming-blankets) have interfered with the EEG and resulted in an erroneous processed EEG output. Importantly, in these cases, the anaesthetist should be able to distinguish the true state of the patient by looking at the raw EEG. For example, in the case report of interference by the warming device the authors reported that the raw EEG showed ‘‘fast-moving waves of high amplitude’’. Typically the awake EEG does not exhibit high amplitude activity. Wada test In the Wada test, intravenous anaesthetic drugs (amylobarbitone, etomidate or methohexitone) are injected into the carotid arteries, enabling the effects of the drug to be
Figure 4. Raw electroencephalography (EEG) in a post-electoconvulsive therapy patient at the point of awakening to verbal command (at time ¼ 0 s). The EEG shows a predominance of large slow delta waves, more typical of deeply anaesthetised patients, than responsive patients. The bispectral index (BIS) was 42.
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relatively localised to the forebrain, relatively free from anaesthetic drug effects on the arousal system of the brainstem.36,37 The majority of patients show global frontal slowing (both contralateral and ipselateral effects)36,37 and might be expected to exhibit clinical signs of impaired frontal lobe function; such as drowsiness, amnesia, and disinhibition. However these patients maintain a good level of consciousness, and show insight into their neurological deficits36,37 — a clear dysjunction between EEG effects and neurological status. Heller et al. have measured the BIS during the Wada test, and showed bilateral decreases in the BIS value. Although slow waves were reported on inspection of the raw EEG signal in these patients, surprisingly the BIS decreased to only w95. This is not a level consistent with decreased consciousness. It is difficult to understand some of these phenomena. They may be explained by localised differences in drug concentration, however they do imply that the correlation between EEG and behaviour is often inconsistent across individuals. These data also highlight the fact that quite extensive EEG delta-wave activity can occur in the cerebral cortex without a decrease in consciousness; assuming that the mid- and hind-brain arousal centres are not affected by the anaesthetic drug delivery to the forebrain. The above cases highlight the main problem with EEG quantification — that there is often more than one brain process that generates ostensibly similar patterns on the EEG. This is made worse by the common practice of analysing the EEG in the frequency domain. The classical example is that of alpha (8–16 Hz) waveband power. A strong alpha frequency peak on the spectrogram, if observed in occipital EEG leads and continuous in pattern, indicates that the subject is conscious. An identical frequency peak, if observed frontally and waxing and waning over a period of seconds (sleep spindles), indicates the opposite, that the subject is unconscious. Frequency domain analysis will not easily differentiate between these cases. The differentiation can be made only by examining the EEG signal in the time domain (for example, by looking at the raw EEG waveform). MEMORY The neurobiological mechanisms of memory formation There is a clear discrepancy between the small-scale studies, which reported many patients were apparently conscious and responsive at BIS values 50-60, and large-scale studies that showed a very low incidence of perioperative conscious recall when the BIS was targeted to a similar range.38–40 Although the stress of surgery itself may contribute to the inhibition of memory consolidation, it is clear that anaesthetic agents are powerful amnesic drugs. Even at modest doses (e.g. BIS ¼ 70–85), very few patients will lay down explicit (episodic) memories. Is the use of the BIS in this way a proxy measure of anaesthetic dosage? Or is the EEG directly indicating an impairment of cortical function that is required for memory consolidation? There is a massive literature describing how neural activity changes synaptic weights, and hence memory formation. The framework for laying down memories includes formation of localised synaptic modifications (working memory) and incorporation of these constructs into distributed permanent synaptic modifications (long-term declarative memory). The specific processes involved are still poorly understood, but are believed to involve at least the following: (1) Working memory may be thought of as spontaneous prolonged synaptic activity (outlasting the stimulus-evoked response) occurring in a subset of neurons.
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(2) Some of the working memory will become consolidated via a series of (parallel and redundant) calcium-dependent cellular processes, including activation of NMDA receptors and PKC IP3 pathways. These processes activate calcium-calmodulin protein kinase II; and hence modify synaptic connectivity by increasing the trafficking and insertion of AMPA receptors in synapses and new synapse formation. (3) The reinforcement and consolidation of very long term memory then involves a complex interplay between different brain regions, principally between the frontal cortex and the hippocampus/limbic system, and changes in neuronal gene expression. The effects of anaesthetic drugs on memory processes Even low doses of most commonly-used anaesthetic agents act to disrupt the sequence of events underlying memory formation, thus preventing conscious recall of intraoperative events. Both propofol and isoflurane have been shown to eliminate the phenomenon of long term potentiation.41,42 Various qEEG associations with memory performance have also been demonstrated. For example, an increase in beta power correlates with impaired memory performance in subjects sedated with low doses of propofol9; and increased alpha power is a common early sign of cognitive and memory decline in Alzheimer’s disease patients.34,35 However, a causal link between these changes in EEG pattern and memory formation has not been established, and it is unclear whether they represent specific indices of memory processing. It is difficult to imagine how a series of sub-cellular processes operating in shifting subsets of neurons could be reliably reflected in the EEG. Nevertheless there has been some recent theoretical work supporting the idea that the appearance of delta waves in the EEG indicates that the cortex is in a mode in which the consolidation of working memory is very unlikely.43 SUMMARY The fundamental neurophysiological basis of loss of consciousness is commonly (but not always) a depowering of cortical activity. This is reflected as low frequency, synchronous burst-firing activity of cortical neurons (and manifest in the EEG as low frequency oscillations). However, the counterexamples that we have presented in this chapter indicate that low-frequency EEG activity is: (i) neither necessary for loss of consciousness (unconsciousness may occur with an activated EEG [e.g. ketamine, nitrous oxide, REM sleep]); (ii) nor may it be sufficient for loss of consciousness (an individual may be awake with delta EEG activity, as shown in post-ictal states, schizophrenia and dementia). Current commercially available EEG-based anaesthetic monitors measure changes in cortical activity, not consciousness. Because the relationship between cortical activity and conscious state can be unpredictable, accurate behavioural/consciousness assessment cannot be made using monitor output alone. There is no short-cut. The information that these devices provide can only be properly interpreted in the full context of: (i) the raw EEG waveform, (ii) anaesthetic and anti-nociceptive drug dosing, (iii) level of nociception/stimulation, (iv) possible artfacts and, (v) patient pathology. The mechanisms by which anaesthetics modify the neurophysiological processes that underlie consciousness and memory formation are areas of intense study and speculation but remain poorly understood. In keeping with this, there is no known qEEG measure that can be shown to be causally related to either consciousness or
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memory 100% of the time. Existing EEG monitors use cortical activity as a proxy for consciousness.
Practice points The bispectral index measures cortical activity, not rousability. Many patients are unresponsive with an active cortex, and some patients are responsive with an inactive cortex. The recommended bispectral index range (45–60) is associated with significant incidence of responsiveness, although a very low incidence of conscious recall. Some, but not all, of the quantitative electroencephalographic (EEG) failures are algorithm failures. As with the use of any other anaesthetic monitor, these are usually detectable by inspection of the raw EEG signal.
Research agenda Future quantitative electroencephalographic (EEG) anaesthetic monitors should be able to demonstrate less overlap between awake and anaesthetised values (i.e. to narrow the ‘‘twilight zone’’), and to be able to reliably track sequential transitions between responsiveness and unresponsiveness. The use of other, perhaps occult, features of the EEG signal (such as sleep spindles, spatial coherence) that have been causally linked with cortical mechanisms of ‘‘failure of consciousness’’ should be investigated. Quantitative EEG measures of nociception, and thence opioid/hypnotic interactions should be developed and tested. There is a need for the determination and testing of reliable quantitative EEG measures of drug-induced amnesia.
ACKNOWLEDGEMENTS Dr Voss is supported in part by the Marsden Fund (University of Waikato #307). REFERENCES *1. Rudolph U & Antkowiak B. Molecular and neuronal substrates for general anaesthetics. Nature Reviews. Neuroscience 2004; 5: 709–720. 2. Scheller MS, Zornow MH, Fleischer JE et al. The noncompetitive N-methyl-D-aspartate receptor antagonist, MK-801 profoundly reduces volatile anesthetic requirements in rabbits. Neuropharmacology 1989; 28: 677–681. 3. Flohr H, Glade U & Motzko D. The role of the NMDA synapse in general anesthesia. Toxicology Letters 1998; 101: 23–29. *4. Erchova IA, Lebedev MA & Diamond ME. Somatosensory cortical neuronal population activity across states of anaesthesia. The European Journal of Neuroscience 2002; 15: 744–752.
324 L. Voss and J. Sleigh 5. Steriade M. Corticothalamic resonance, states of vigilance and mentation. Neuroscience 2000; 101: 243– 276. *6. Alkire MT & Miller J. General anesthesia and the neural correlates of consciousness. Progress in Brain Research 2005; 150: 229–244. 7. Nelson LE, Franks NP & Maze M. Rested and refreshed after anesthesia? Overlapping neuribiologic mechanisms of sleep and anesthesia. Anesthesiology 2004; 100: 1341–1342. 8. Lu J, Sherman D, Devor M & Saper CB. A putative flip-flop switch for the control of REM sleep. Nature 2006; 441: 589–594. 9. Veselis RA, Reinsel RA, Wronski M et al. EEG and memory effects of low-dose infusions of propofol. British Journal of Anaesthesia 1992; 69: 246–254. 10. Bruhn J, Bouillon TW, Radulescu L et al. Correlation of approximate entropy, bispectral index, and spectral edge frequency 95 (SEF95) with clinical signs of ‘‘anesthetic depth’’ during coadministration of propofol and remifentanil. Anesthesiology 2003; 98: 621–627. 11. Locher S, Stadler KS, Boehlen T et al. A new closed-loop control system for isoflurane using bispectral index outperforms manual control. Anesthesiology 2004; 101: 591–602. 12. Hagihira S, Takashina M, Mori T et al. Electroencephalographic bicoherence is sensitive to noxious stimuli during isoflurane or sevoflurane anesthesia. Anesthesiology 2004; 100: 818–825. *13. Hagihira S, Takashina M, Mori T et al. Practical issues in bispectral analysis of electroencephalographic signals. Anesthesia and Analgesia 2001; 93: 966–970. 14. Miller A, Sleigh JW, Barnard J & Steyn-Ross DA. Does bispectral index of the electroencephalogram add anything but complexity? British Journal of Anaesthesia 2004; 92: 8–13. *15. Dahaba AA. Different conditions that could result in the bispectral index indicating an incorrect hypnotic state. Anesthesia and Analgesia 2005; 101: 765–773. 16. Schneider G, Gelb AW, Schmeller B et al. Detection of awareness in surgical patients with EEG-based indices–bispectral index and patient state index. British Journal of Anaesthesia 2003; 91: 329–335. *17. Schneider G, Wagner K, Reeker W et al. Bispectral Index (BIS) may not predict awareness reaction to intubation in surgical patients. Journal of Neurosurgical Anesthesiology 2002; 14: 7–11. 18. McKay IDH, Voss LJ, Sleigh JW et al. Pharmacokinetic-pharmacodynamics modeling the hypnotic effect of sevoflurane using the spectral entropy of the electroencephalogram. Anesthesia and Analgesia 2006; 102: 91–97. 19. Anderson RE & Jakobsson JG. Entropy of EEG during anaesthetic induction: a comparative study with propofol or nitrous oxide as sole agent. British Journal of Anaesthesia 2004; 92: 167–170. 20. Baker GW, Sleigh JW & Smith P. Electroencephalographic indices related to hypnosis and amnesia during propofol anaesthesia for cardioversion. Anaesthesia and Intensive Care 2000; 28: 386–391. 21. Gajraj R, Doi M, Mantzaridis H & Kenny GN. Analysis of the EEG bispectrum, auditory evoked potentials and the EEG power spectrum during repeated transitions from consciousness to unconsciousness. British Journal of Anaesthesia 1998; 80: 46–52. 22. Iannuzzi M, Iannuzzi E, Rossi F et al. Relationship between bispectral index, electroencephalographic state entropy and effect-site EC50 for propofol at different clinical endpoints. British Journal of Anaesthesia 2005; 94: 613–616. 23. Kuizenga K, Proost JH, Wierda JM & Kalkman CJ. Predictability of processed electroencephalography effects on the basis of pharmacokinetic-pharmacodynamic modeling during repeated propofol infusions in patients with extradural analgesia. Anesthesiology 2001; 95: 607–615. 24. Schneider G, Kochs EF, Horn B et al. Narcotrend does not adequately detect the transition between awareness and unconsciousness in surgical patients. Anesthesiology 2004; 101: 1105–1111. *25. Schraag S, Bothner U, Gajraj R et al. The performance of electroencephalogram bispectral index and auditory evoked potential index to predict loss of consciousness during propofol infusion. Anesthesia and Analgesia 1999; 89: 1311–1315. 26. Sleigh JW & Donovan J. Comparison of bispectral index, 95% spectral edge frequency and approximate entropy of the EEG, with changes in heart rate variability during induction of general anaesthesia. British Journal of Anaesthesia 1999; 82: 666–671. 27. Kreuer S, Bruhn J, Larsen R et al. Comparison of Alaris AEP index and bispectral index during propofolremifentanil anaesthesia. British Journal of Anaesthesia 2003; 91: 336–340. *28. Messner M, Beese U, Romstoeck J et al. The bispectral index declines during neuromuscular block in fully awake persons. Anesthesia and Analgesia 2003; 97: 488–491.
Monitoring consciousness 325 29. Muncaster ARG, Sleigh JW & Williams M. Changes in consciousness, conceptual memory and quantitative electroencephalographical measures during recovery from sevoflurane- and remifentanil-based anesthesia. Anesthesia and Analgesia 2003; 96: 720–725. 30. Yamamoto M & Nakahama H. Stochastic properties of spontaneous unit discharges in somatosensory cortex and mesencephalic reticular formation during sleep-waking states. Journal of Neurophysiology 1983; 49: 1182–1198. 31. Mirmiran M & Corner M. Neuronal discharge patterns in the occipital cortex of developing rats during active and quiet sleep. Brain Research 1982; 255: 37–48. 32. Gunawardane PO, Murphy PA & Sleigh JW. Bispectral index monitoring during electroconvulsive therapy under propofol anaesthesia. British Journal of Anaesthesia 2002; 88: 184–187. 33. White PF, Shivani R, Recart A et al. Can the bispectral index be used to predict seizure time and awakening after electroconvulsive therapy? Anesthesia and Analgesia 2003; 96: 1636–1639. 34. Hughes JR & John ER. Conventional and quantitative electroencephalography in psychiatry. The Journal of Neuropsychiatry and Clinical Neurosciences 1999; 11: 190–208. 35. Prichep LS, John ER, Ferris SH et al. Quantitative EEG correlates of cognitive deterioration in the elderly. Neurobiology of Aging 1994; 15: 85–90. *36. Heller H, Hatami R, Mullin P et al. Bilateral bispectral index monitoring during suppression of unilateral hemispheric function. Anesthesia and Analgesia 2005; 101: 235–241. 37. Jones-Gotman M. Etomidate speech and memory test. Neurology 2005; 65: 1728. 38. Deeprose C, Andrade J, Harrison D & Edwards N. Unconscious auditory priming during surgery with propofol and nitrous oxide anaesthesia: a replication. British Journal of Anaesthesia 2005; 94: 57–62. 39. Deeprose C, Andrade J, Varma S & Edwards N. Unconscious learning during surgery with propofol anaesthesia. British Journal of Anaesthesia 2004; 92: 171–177. *40. Myles PS, Leslie K, McNeil J et al. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004; 363: 1757–1763. 41. Nagashima K, Zorumski CF & Izumi Y. Propofol inhibits long-term potentiation but not long-term depression in rat hippocampal slices. Anesthesiology 2005; 103: 318–326. 42. Simon W, Hapfelmeier G, Kochs E et al. Isoflurane blocks synaptic plasticity in the mouse hippocampus. Anesthesiology 2001; 94: 1058–1065. 43. Steyn-Ross ML, Steyn-Ross DA, Sleigh JW et al. Proposed mechanism for learning and memory erasure in a white-noise-driven sleeping cortex. Physical Review. E, Statistical, Nonlinear, and Soft Matter Physics 2005; 72. 061910.
3 Monitoring consciousness: the current status of EEG-based depth of anaesthesia monitors Logan Voss *
PhD
Senior Research Scientist
Jamie Sleigh
MD, MBChB, FANZCA, FJFICM
Professor of Anaesthesia and Intensive Care Department of Anaesthesia, Waikato Clinical School, University of Auckland, Hamilton, New Zealand
Direct and indirect inhibitory effects of anaesthetic agents on cortical activity are reflected in the electroencephalogram (EEG) as: (i) a shift from low-amplitude, high-frequency EEG, to highamplitude, low-frequency activity (indicative of cortical depowering) and; (ii) the appearance of spindles and K-complexes (indicative of thalamocortical hyperpolarisation and sensory blockade). Existing EEG monitors use cortical activity as a proxy measure for consciousness. However the state of the cortex at any given moment does not accurately predict the state that it will enter in response to a noxious stimulus, and EEG monitors do not differentiate well between different levels of rousability. Also the literature reveals many instances where the EEG pattern is dissociated from conscious state (e.g. an awake-looking EEG, but an unresponsive patient; or a slow-wave EEG in an awake patient). Fortunately, a slow-wave EEG (even in the presence of a responsive patient) usually indicates profound amnesia for explicit memory. Key words: anaesthesia; electroencephalography; bispectral index; amnesia; artefact; spectral entropy.
INTRODUCTION A primary reason for the use of electroencephalography (EEG)-based monitoring in general anaesthesia is to detect and warn the anaesthetist that retrievable memories are being formed by the patient. Is it reasonable to expect that the EEG will provide insight into the state of consciousness of the patient? The aim of this chapter is to briefly review the basic science (neurobiological, neuropharmacological, and signal-processing) * Corresponding author. Department of Anaesthesia, Waikato Clinical School, University of Auckland, Hamilton, New Zealand. Tel.: þ64 7 8398899; Fax: þ64 7 8398761. E-mail address: [email protected] 1521-6896/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved.
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evidence that underpins the idea that EEG changes might be causally linked to loss of intra-operative recall. Consciousness is a word that describes the process by which objective reality becomes subjective. It is questionable whether consciousness is a subject that is even accessible to scientific enquiry. However since the daily business of anaesthetists is to reversibly disrupt the neural mechanisms that underlie this process, some understanding of the phenomenon of consciousness is necessary for safe clinical practice. At least two neurobiological processes are essential for consciousness to be present: the abilities to attend and to remember. Although it has been cogently argued that a definition of anaesthesia requires only amnesia and immobility; attention is usually a prerequisite of declarative memory, and anaesthetic drugs clearly act to impair the neurophysiological mechanisms required for attention. If we want to evaluate the effectiveness and usefulness of depth of anaesthesia monitors we need to ask four closely-linked questions. (1) What do we currently understand about the mechanism of anaesthetic drug effects on cortical neural function (particularly regarding attention and memory)? (2) Do these effects become manifest in changes in cortical dynamics, and hence in the EEG signal? (3) Can these EEG changes be captured by a single number? (4) Do these EEG changes reliably reflect conscious state and/or memory formation? To be clinically useful, the predictive error rate needs to be <0.01% (i.e. less than 1/10 000 patients who are predicted by the EEG to be amnesic, are actually able to recall intra-operative events). This is an extremely exacting level of certainty to require from a clinical monitor. If the answer is definitely ‘‘no’’ to either of the last two questions, then it is likely that the enterprise of using EEG information to modify anaesthetic drug dosage will fail. This review will describe the commonly accepted scientific explanation of how anaesthetic drugs could be expected to change the EEG, and how this might be reflected in changes in level of consciousness of the patients. It will conclude by reporting some interesting experiments that have been done, which call into question this ‘‘standard model’’. BACKGROUND How do anaesthetic drugs alter cortical neural function? The mechanisms of action of general anaesthetic drugs are complex and incompletely understood.1 The hypnotic effect of the most commonly-used volatile and intravenous general anaesthetics is generally ascribed to enhancement of ‘‘GABAergic’’ inhibition, although a role for reduction in excitatory neuronal activity may also be important.2,3 Either way, the end result is that anaesthesia causes cortical activity to decrease.4 This occurs: (i) by a direct action of general anaesthetic drugs on the cortex, and (ii) indirectly by inactivation of the endogenous brain stem and hypothalamic arousal systems — which then cause a secondary cortical shut down. The thalamus also drastically changes its mode of activity from that of a relatively depolarised state — in which accurate transmission of sensory information is maintained — to a hyperpolarized mode that facilitates stereotypical ‘‘burst firing’’ patterns of neuronal activity in corticothalamic networks.
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Corticothalamic burst activity effectively cuts the cortex off from external sensory input.5,6 With deepening anaesthesia, this burst activity becomes increasingly coherent across the cortex.4 These brain stem and corticothalamic changes overlap with the mechanisms that induce natural sleep.7 General anaesthesia obviously differs from natural sleep, in that anaesthetic drugs disable the ability of nociceptive input to activate cortico-thalamic arousal. All anaesthetic drugs have this action to some degree, but it is most important in the adjunctive action of opioids, nitrous oxide and ketamine. It is important to note that endogenous arousal control systems are intrinsically bistable.8 This means that these systems will tend to jump between the awake and asleep state, and do not naturally allow the brain to exist in an intermediate level of consciousness. Our current understanding of the action of anaesthetic drugs on global cortical function may be summarised as: (i) generalised cortical depowering via direct cortical actions and blockade of brain stem arousal systems, and/or (ii) thalamocortical sensory blockade. As we report later in this paper, EEG monitors measure cortical de-powering, but not thalamocortical blockade. What is the origin of the EEG signal and are the effects of general anaesthesia on cortical function visible to the EEG? The scalp EEG measures changes in voltage detected on the scalp. These voltage fluctuations are induced by currents that flow between the dendrites and the soma of the cortical pyramidal cells, that are some distance from the sensing electrodes on the scalp. The voltages are attenuated and smeared by passage through the skull and scalp. This has the effect of preferentially allowing large and slow voltages (generated by large collections of synchronously firing neurons) to be dominant in the EEG signal; as compared to electrocorticogram, which is recorded from electrodes positioned directly into the cortex. We may summarise the EEG signal as a frequency-distorted measure of the mean dendritic (post-synaptic potential) currents of hundreds of thousands (or millions — depending on the montage) of cortical pyramidal neurons that underlie the active electrode. The effects of GABAergic drugs to depower cortical activity are reflected in changes in the EEG, which are more-or-less consistent from one agent to another. At low doses of anaesthesia there is a paradoxical increase in amplitude, particularly in the beta frequency range (1–30 Hz). The appearance of this so-called ‘‘biphasic’’ effect has been related to the development of amnesia in the patient.9 As the brain concentration of the anaesthetic agent increases, the dominant frequency of the EEG slows to the theta (4–8 Hz) and then delta (1–4 Hz) wave bands and its amplitude increases. The transition from high frequency to low frequency activity in the EEG signal reflects thalamocortical hyperpolarisation and synchronised neuronal burst activity. Various episodic waveforms also appear in the EEG, such as spindles and K-complexes. These indicate: (i) thalamocortical sensory blockade and, (ii) that the cortical neurons are no longer able to generate transient high firing rates that are (usually) associated with cognitive activity. Quantification of this anaesthetic-induced shift of the dominant frequency of the EEG is so robust, that it is routinely used for very accurate doseresponse modelling of anaesthetic drug effect.10,11 At very high concentrations of anaesthetic drug, the burst suppression pattern appears, and eventually the EEG becomes isoelectric. The above EEG changes are not unique to anaesthesia. Many of the anaesthesiainduced changes in the EEG are also seen in natural sleep (implying the involvement
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of similar neurophysiological mechanisms); and are accompanied by corresponding changes in the bispectral index (BIS) (Figure 1). One of the important differences between anaesthesia and natural sleep is the ability to be readily aroused from sleep by sensory stimulation — resulting in the re-appearance of a low-amplitude, highfrequency EEG — whereas a subject who is adequately anaesthetised will remain unresponsive to strong nociceptive input. In about 30% of lightly anaesthetised patients, a nociceptive stimulus will cause the appearance of large delta waves (termed ‘‘paradoxical cortical arousal’’).12 These examples highlight a very important principle that has implications for EEG monitoring; the state of your cortex at any given moment does not accurately predict the state you will enter in response to a noxious stimulus. EEG monitors do not differentiate well between different levels of rousability. A subject who is in natural slow wave sleep will have a BIS or entropy value that is indistinguishable from that of an anaesthetised subject. Similarly, the effect of opioids to reduce nociceptive stimulation usually does not necessarily decrease BIS or entropy values.12 How can we to turn the EEG signal into a number? Unlike most other forms of anaesthetic monitoring (which demand some skill in waveform pattern recognition from the anaesthetist for accurate diagnosis), the manufacturers of commercially available EEG monitors have concentrated on producing a single EEG index (usually scaled 0–100), that they hope reflects the patient’s ‘‘level of consciousness’’. Whilst the technical signal-processing issues of EEG artefact rejection and algorithm development are not trivial, they have been dealt with in detail in a previous book in this series. The most widely investigated proprietary algorithm is BIS. However a plethora of other indices have recently become commercially available (such as the M-Entropy, Narcotrend, Patient-State Analyser, SNAP, and various auditory evoked-potential methods). At the simplest level, all these quantitative EEG (qEEG) depth of anaesthesia monitors use the loss of high frequencies and shift to low frequencies, as a measure of anaesthetic drug action. The monitors differ considerably in the details of how this is achieved, speed of response, incorporation of burst
Figure 1. A plot of the bispectral index (BIS) during the course of a night’s natural sleep, which shows clear sleep architecture with pronounced 90 min cycles of slow-wave sleep early in the night (corresponding to low BIS periods); followed by more stage 2 and rapid eye movement (REM) sleep later in the night (seen as an increase in the BIS trend).
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suppression patterns for deep anaesthesia, and the handling of electromyogram (EMG) and various other artefacts. Our subsequent discussion will predominantly involve the BIS, because it has been the most widely investigated and used. However, no studies have demonstrated that any of the other monitors offer significant advantages over, or consistent clinical differences from, the BIS. The manufacturers of the BIS claim a point of difference from the other monitors in that the BIS quantifies the bispectrum as part of its algorithm. It is not clear whether this feature contributes significantly different information over and above simple spectral changes.13,14 It should be noted that there are a number of other anaesthetic-induced EEG phenomena that are not detected by the commercial algorithms (such as spindles, K-complexes, spatial correlations). Whether these phenomena are important to the accurate detection of unconsciousness has not yet been investigated thoroughly. How reliable is this number? This is the all-important question. We have established that most anaesthetic agents have well-defined and characteristic effects on cortical activity, which are reflected in EEG changes that can be quantified by EEG-processing algorithms in most patients. Does this change in cortical activity consistently relate to level of consciousness and/ or memory formation and consolidation? Do all patients who change from a state of conscious awareness to an anaesthetised state, consistently show increased lowfrequency waves and decreased high frequency waves? Is it possible to find counterexamples to disprove this statement? This would involve finding examples of: (i) patients with a predominance of high-amplitude low-frequency EEGs who are conscious, and/ or (ii) patients with low-amplitude high-frequency EEGs who are anaesthetised. If such examples can be found, then the presence of large slow waves in the EEG can be assumed to be a common epiphenomenon of the anaesthetised state — but not to be directly causally essential for the removal of consciousness. Dahaba has written an extensive review of over 30 published reports in which the BIS has been reported to be in error.15 In the following section we will discuss the documented discrepancies between the EEG, qEEG-based monitors and behavioural state, with a view to understanding the nature of these errors and how they effect interpretation of monitor output. CONSCIOUSNESS The problem of the ‘‘twilight zone’’ A thorough examination of the literature reveals many instances where the EEG pattern can be shown to dissociate from conscious state. For example, all the current qEEG monitors are effective in discriminating the extremes of alertness and deep anaesthesia, most of the time. However there exists a large intermediate area (that we term the ‘‘twilight zone’’) between these extremes, in which the discriminatory power of qEEG indices is much less impressive. Typically the prediction probability to differentiate awake from unresponsive states is only about 0.7.16 For example, in Figure 2, the EEG shows large delta waves, but also demonstrates a significant amount of high frequency power amongst the delta activity — hence the high response entropy. The standout feature is that there is no obvious change when comparing the EEG from the time zero (when the patient was responsive) to that
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Figure 2. Examples of variation in electroencephalography (EEG) around the point of loss-of-responsiveness (shown by vertical line at 10 s) in a patient undergoing slow inhalational induction of anaesthesia with sevoflurane. The response entropy at the point of loss of consciousness was 97.
at the end of the graph (when the patient wasn’t responsive) (i.e. loss of consciousness per se may not always be closely linked with any gross EEG change). The ‘‘twilight zone’’ effect is further illustrated in a study by Schneider et al., who induced anaesthesia with alfentanil and propofol in 20 patients. Anaesthesia was titrated to achieve a steady-state BIS value of 50–60 (so as to minimise the effects of lag in calculation and display of the BIS).17 They used muscle relaxation and communicated with the patients via the isolated forearm technique. Eight of the patients were wakeful after intubation (one at a BIS of 47), although none had any conscious recall. There are numerous other studies which show that, for individual patients receiving standard GABAergic anaesthetic drugs, the actual point at which the patients became unresponsive to verbal command can vary between BIS (or entropy) values of 40–90.16,18–27 In other words, many subjects become unconscious while the BIS or entropy remains at ‘awake’ levels, and a few become unconscious only at values well below the upper end of the recommended ‘anaesthesia’ target range of 60. This large range of uncertainty poses a major problem for the use of the BIS by the practicing anaesthetist. Aim for a BIS of 40, and most of the patients will be grossly overdosed. Aim for a BIS of 60, and occasional patients will be aware. One possible solution would be to individualise the BIS target. In this strategy the anaesthetist notes the BIS value at the point when the patient became unresponsive at induction; and then adjusts the anaesthetic dosage to keep the BIS value comfortably below that. This strategy is appealing, but has not been tested in a large series, and must take into account the lag in the BIS algorithm between EEG acquisition and display of the BIS index. In small series it has not been demonstrated that the BIS is able to consistently track multiple within-patient transitions between consciousness and unconsciousness.21,23 The relationships between the EEG, qEEG-index (e.g. BIS), and level of consciousness can be described diagrammatically, as shown in Figure 3. On the diagonal are the cells in which there is agreement between the BIS and the clinical state of consciousness (shown as ‘ticks’). On the off-diagonals are the problem areas (shown as ‘question marks’). The possible explanations for the problems areas are shown in the grey boxes. We will discuss each of the problem cells in turn.
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Figure 3. A diagram of the framework in which to examine the relationships between the electroencephalograph (EEG) signal, the bispectral index (BIS), and the conscious state of the patient.
BIS < 60 with awake patient and awake looking EEG If the BIS is low in an awake individual with an EEG showing lots of high frequency activity, it is clear that this is a problem of algorithm failure. The proprietary nature of the BIS algorithm precludes definitive explanation of where the algorithm fails, but in many cases it can be linked to the dominance of the burst-suppression component of the algorithm that drives the BIS value down. From the review by Dahaba, it would seem that most of the cases of low BIS in the awake but paralysed subject fall into this category; presumably the BIS erroneously interpreted the small amplitude EEG signal as burst suppression. Although the BIS may decrease to very low levels (e.g. 33 and 9) in awake, but paralysed, subjects; visual inspection of the raw EEG waveform shows a low-voltage awake-looking EEG waveform.28 A similar paradoxical decrease in BIS (although with no muscle relaxation present) has also been documented during recovery from remifentanil anaesthesia, resulting from a low-amplitude EEG being misinterpreted by the algorithm as burst suppression.29 Erroneous activation of the burst suppression component of the BIS algorithm also may be a problem in the 5–10% of the population who have a genetically-determined low amplitude EEG. BIS > 60 with an unconscious patient and awake looking EEG There are a number of examples of unconsciousness occurring in the presence of an activated cortex (i.e. a falsely high BIS) in the anaesthesia and sleep literature. In this case the BIS algorithm is accurately describing the frequencies present in the raw EEG, but the patient is unresponsive even though the cortex is in an apparently active state — indistinguishable from that found in the conscious state. These situations will tend to cause the anaesthetist to overdose the patient. For example it is possible to titrate an opioid-heavy balanced anaesthetic technique to a relatively higher BIS target, as compared to an anaesthetic technique in which there is only a small dose of opioid used. A clear dissociation between the EEG and conscious state is seen with the use of anaesthetic agents ketamine and nitrous oxide; and also in rapid eye
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movement (REM) sleep. In each case, awareness of external events is abolished while the EEG pattern closely resembles that of the awake state.19,30,31 The dreaming that occurs with ketamine and during REM sleep may be interpreted as a form of internal, introspective ‘‘consciousness’’, however its content bears no resemblance to reality and awareness of the objective world is absent. BIS < 60 with an awake patient but an asleep looking EEG There are also a few published instances of wakefulness with a ‘‘deactivated’’ cortex (i.e. a falsely low BIS). In these cases the BIS algorithm is accurately quantifying a raw EEG with predominant delta wave activity. These cases are more worrying because of the potential for BIS-guided under-dosing of anaesthesia. For example, post-ictal patients who are conscious (but amnesic - vide infra), commonly exhibit delta waves in the EEG and low BIS values (Figure 4).32,33 Enhanced delta wave activity may also be observed in the EEG of awake subjects with schizophrenia and in advanced dementia.34,35 Other examples of EEG monitor ‘‘errors’’ Artefacts Errors resulting from artefact in the EEG waveform may be classified as a form of EEG ‘‘failure’’. The review by Dahaba identified a number of cases where various devices (such as warming-blankets) have interfered with the EEG and resulted in an erroneous processed EEG output. Importantly, in these cases, the anaesthetist should be able to distinguish the true state of the patient by looking at the raw EEG. For example, in the case report of interference by the warming device the authors reported that the raw EEG showed ‘‘fast-moving waves of high amplitude’’. Typically the awake EEG does not exhibit high amplitude activity. Wada test In the Wada test, intravenous anaesthetic drugs (amylobarbitone, etomidate or methohexitone) are injected into the carotid arteries, enabling the effects of the drug to be
Figure 4. Raw electroencephalography (EEG) in a post-electoconvulsive therapy patient at the point of awakening to verbal command (at time ¼ 0 s). The EEG shows a predominance of large slow delta waves, more typical of deeply anaesthetised patients, than responsive patients. The bispectral index (BIS) was 42.
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relatively localised to the forebrain, relatively free from anaesthetic drug effects on the arousal system of the brainstem.36,37 The majority of patients show global frontal slowing (both contralateral and ipselateral effects)36,37 and might be expected to exhibit clinical signs of impaired frontal lobe function; such as drowsiness, amnesia, and disinhibition. However these patients maintain a good level of consciousness, and show insight into their neurological deficits36,37 — a clear dysjunction between EEG effects and neurological status. Heller et al. have measured the BIS during the Wada test, and showed bilateral decreases in the BIS value. Although slow waves were reported on inspection of the raw EEG signal in these patients, surprisingly the BIS decreased to only w95. This is not a level consistent with decreased consciousness. It is difficult to understand some of these phenomena. They may be explained by localised differences in drug concentration, however they do imply that the correlation between EEG and behaviour is often inconsistent across individuals. These data also highlight the fact that quite extensive EEG delta-wave activity can occur in the cerebral cortex without a decrease in consciousness; assuming that the mid- and hind-brain arousal centres are not affected by the anaesthetic drug delivery to the forebrain. The above cases highlight the main problem with EEG quantification — that there is often more than one brain process that generates ostensibly similar patterns on the EEG. This is made worse by the common practice of analysing the EEG in the frequency domain. The classical example is that of alpha (8–16 Hz) waveband power. A strong alpha frequency peak on the spectrogram, if observed in occipital EEG leads and continuous in pattern, indicates that the subject is conscious. An identical frequency peak, if observed frontally and waxing and waning over a period of seconds (sleep spindles), indicates the opposite, that the subject is unconscious. Frequency domain analysis will not easily differentiate between these cases. The differentiation can be made only by examining the EEG signal in the time domain (for example, by looking at the raw EEG waveform). MEMORY The neurobiological mechanisms of memory formation There is a clear discrepancy between the small-scale studies, which reported many patients were apparently conscious and responsive at BIS values 50-60, and large-scale studies that showed a very low incidence of perioperative conscious recall when the BIS was targeted to a similar range.38–40 Although the stress of surgery itself may contribute to the inhibition of memory consolidation, it is clear that anaesthetic agents are powerful amnesic drugs. Even at modest doses (e.g. BIS ¼ 70–85), very few patients will lay down explicit (episodic) memories. Is the use of the BIS in this way a proxy measure of anaesthetic dosage? Or is the EEG directly indicating an impairment of cortical function that is required for memory consolidation? There is a massive literature describing how neural activity changes synaptic weights, and hence memory formation. The framework for laying down memories includes formation of localised synaptic modifications (working memory) and incorporation of these constructs into distributed permanent synaptic modifications (long-term declarative memory). The specific processes involved are still poorly understood, but are believed to involve at least the following: (1) Working memory may be thought of as spontaneous prolonged synaptic activity (outlasting the stimulus-evoked response) occurring in a subset of neurons.
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(2) Some of the working memory will become consolidated via a series of (parallel and redundant) calcium-dependent cellular processes, including activation of NMDA receptors and PKC IP3 pathways. These processes activate calcium-calmodulin protein kinase II; and hence modify synaptic connectivity by increasing the trafficking and insertion of AMPA receptors in synapses and new synapse formation. (3) The reinforcement and consolidation of very long term memory then involves a complex interplay between different brain regions, principally between the frontal cortex and the hippocampus/limbic system, and changes in neuronal gene expression. The effects of anaesthetic drugs on memory processes Even low doses of most commonly-used anaesthetic agents act to disrupt the sequence of events underlying memory formation, thus preventing conscious recall of intraoperative events. Both propofol and isoflurane have been shown to eliminate the phenomenon of long term potentiation.41,42 Various qEEG associations with memory performance have also been demonstrated. For example, an increase in beta power correlates with impaired memory performance in subjects sedated with low doses of propofol9; and increased alpha power is a common early sign of cognitive and memory decline in Alzheimer’s disease patients.34,35 However, a causal link between these changes in EEG pattern and memory formation has not been established, and it is unclear whether they represent specific indices of memory processing. It is difficult to imagine how a series of sub-cellular processes operating in shifting subsets of neurons could be reliably reflected in the EEG. Nevertheless there has been some recent theoretical work supporting the idea that the appearance of delta waves in the EEG indicates that the cortex is in a mode in which the consolidation of working memory is very unlikely.43 SUMMARY The fundamental neurophysiological basis of loss of consciousness is commonly (but not always) a depowering of cortical activity. This is reflected as low frequency, synchronous burst-firing activity of cortical neurons (and manifest in the EEG as low frequency oscillations). However, the counterexamples that we have presented in this chapter indicate that low-frequency EEG activity is: (i) neither necessary for loss of consciousness (unconsciousness may occur with an activated EEG [e.g. ketamine, nitrous oxide, REM sleep]); (ii) nor may it be sufficient for loss of consciousness (an individual may be awake with delta EEG activity, as shown in post-ictal states, schizophrenia and dementia). Current commercially available EEG-based anaesthetic monitors measure changes in cortical activity, not consciousness. Because the relationship between cortical activity and conscious state can be unpredictable, accurate behavioural/consciousness assessment cannot be made using monitor output alone. There is no short-cut. The information that these devices provide can only be properly interpreted in the full context of: (i) the raw EEG waveform, (ii) anaesthetic and anti-nociceptive drug dosing, (iii) level of nociception/stimulation, (iv) possible artfacts and, (v) patient pathology. The mechanisms by which anaesthetics modify the neurophysiological processes that underlie consciousness and memory formation are areas of intense study and speculation but remain poorly understood. In keeping with this, there is no known qEEG measure that can be shown to be causally related to either consciousness or
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memory 100% of the time. Existing EEG monitors use cortical activity as a proxy for consciousness.
Practice points The bispectral index measures cortical activity, not rousability. Many patients are unresponsive with an active cortex, and some patients are responsive with an inactive cortex. The recommended bispectral index range (45–60) is associated with significant incidence of responsiveness, although a very low incidence of conscious recall. Some, but not all, of the quantitative electroencephalographic (EEG) failures are algorithm failures. As with the use of any other anaesthetic monitor, these are usually detectable by inspection of the raw EEG signal.
Research agenda Future quantitative electroencephalographic (EEG) anaesthetic monitors should be able to demonstrate less overlap between awake and anaesthetised values (i.e. to narrow the ‘‘twilight zone’’), and to be able to reliably track sequential transitions between responsiveness and unresponsiveness. The use of other, perhaps occult, features of the EEG signal (such as sleep spindles, spatial coherence) that have been causally linked with cortical mechanisms of ‘‘failure of consciousness’’ should be investigated. Quantitative EEG measures of nociception, and thence opioid/hypnotic interactions should be developed and tested. There is a need for the determination and testing of reliable quantitative EEG measures of drug-induced amnesia.
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