Chapter 11 Neurophysiology of anaesthesia

Clinical Neurophysiology at the Beginning of/he 21st Centur» (Supptemems to Clinical Neurophysiology Vol. 53) Editors: Z. Ambler, S. Nevsfmalova. Z. Kadanka. P.M. Rossini © 2000 Elsevier Science B.V. All rights reserved.

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Chapter 11

Neurophysiology of anaesthesia V. Jantti":" and A. Yli-Hankala b "Department of Clinical Neurophysiology. Oulu University Hospital. FlN-90221 Oulu (Finland) Research Group, Departments of OB-GYN, Helsinki University Hospital. Helsinki (Finland)

bAnaesthesia

Cellular mechanisms of sleep and anaesthesia

Depth of anaesthesia

Simultaneous recording of intracellular and extracellular activity from the brain has considerably increased our knowledge of the basic mechanisms of sleep and general anaesthesia during recent years. While recordings from brain slices or single cells can give us information about the effect of anaesthetics on receptors, cell membranes, and interactions of limited numbers of cells, they cannot resolve the problem of integration of the activity of different parts of brain. Rhythmic activity ofEEG is assumed to reflect these integrative processes, and they are different in the awake state, slow wave sleep and REM sleep. In particular, gamma rhythm of the awake state and REM sleep, alpha frequency rhythms of the awake state, and K-complexes of sleep (Amzica and Steriade 1998; Steriade and Amzica 1998) are assumed to serve these integrative purposes. Some of these rhythms are seen in general anaesthesia and reflect the transition from awake state to sleep-like state, and finally pathological activity resembling coma states, i.e. suppressed cortical activity.

Numerous attempts have been made to estimate the depth of anaesthesia from EEG during the past decades. The problem with EEG has been its sensitivity to drug combinations used: although 'drug effect' is clearly seen with all anaesthetics, all of them have their own unique impact on the EEG profile. Therefore, no simple time domain measures, nor simple univariates extracted from frequency domain EEG can tell us the exact depth of anaesthesia. During the last few years, a method based partly on the bispectrum of EEG (BIS) has been able to measure the hypnotic component of anaesthesia. This method is surprisingly insensitive to the anaesthetics used, at least as long as real hypnotics (like propofol or all fluranes) are used. It should be remembered, however, that BIS values do not correlate with the classical measure of anaesthesia, movement due to painful stimulus. Rampil (1994) has shown in an animal model that the MAC value, i.e. the minimum alveolar concentration of volatile anaesthetic causing inhibition of movement response to pain in 50% of cases, does not require the brain: the values are similar when the spinal cord is disconnected from the brain. Therefore, it is not a surprise that a cortical measure (EEG) does not monitor activity of the spinal cord (reflectory moving response).

* Correspondence to: Dr. Ville Jantti, Department of Clinical Neurophysiology, Oulu University Hospital. P.O. Box 22, FIN-90221 Oulu (Finland). Fax: +358-8-315-4544. E-mail: [email protected]

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EEG and cortical response is far from simple, as shown by the fact that SEPs and VEPs may be recorded during EEG suppression of deep anaesthesia (Porkkala et al. 1997; Sandell et al. 1998). Several other methods have been suggested: as mentioned, frontal muscle activity warns of inadequate anaesthesia (light hypnosis or perception of pain), and heart rate variability can be used to evaluate the depth of anaesthesia (Pomfrett et al. 1993; Yli-Hankala et al. 1994).

The BIS analyzer depends on time domain, frequency domain and 'bispectral domain' (phase relationship) subparameters of EEG (Rampil 1998). In the time domain, the monitor detects EEG suppressions as a measure of impractically deep anaesthesia. In the frequency domain, the monitor calculates the relative beta ratio (lOg(P3D-47 HzlP 11-20 Hz)) to characterize light sedation. Finally, in the 'bispectral domain', the algorithm computes log(Bo. 5-47 Hz1B4D-47 HZ)' As the BIS algorithm operates with relatively high frequency EEG, it is possible that the resulting index of 'anaesthetic depth' also partly depends on frontal EMG activity, which has been shown to monitor the adequacy of anaesthesia (Yli-Hankala et al. 1994). In addition to non-linearities, non-stationarities are likely to have a significant contribution, and several other mathematical approaches in addition to bispectrum analysis should be able to give reliable estimates based on the same physiological phenomena. Nevertheless, the BIS index has proved useful in practical work in avoiding unnecessarily deep anaesthesia. Another measure of the depth of anaesthesia derived from cortical electrical activity is the midlatency auditory response (Thornton and Sharpe 1998). Its quantification is dependent on the measurement of the latency of peaks. Recently, Nahm et al. (1999) showed that wavelet analysis can be used to extract the component of this evoked response, which best reflects the depth of anaesthesia. Steady state response has also been used. These methods can reasonably well predict the transition from consciousness to unconsciousness, but here, again, this does not mean a simple relationship of any component of anaesthesia and the evoked response. Interestingly, the correlation of I

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Deepening anaesthesia with most general anaesthetics causes an increase of slow activity which, finally, is abruptly suppressed, resulting in low amplitude mixed frequency activity. This abrupt change also involves a 'drop' to a positive DC level (Jantti et al. 1993), which is best seen in parietal leads. In most patients, this is reversed after an interval from a fraction of a second to several seconds, resulting in a burst of mixed frequency activity, starting with an abrupt change to a negative DC level (Fig. I). The shortest suppressions can only be distinguished from the DC level. The durations of bursts and suppressions are usually unpredictable unlike the periodic patterns like PED, where suppression can also be a very low amplitude. Interestingly, while burst suppression and PED are signs of severe brain damage or disease in an unanaesthesized patient, both are readily produced in a healthy brain with the volatile anaesthetics enflurane and sevoflurane (Rosen and Soderberg 1975; Jantti and Yli-Hankala 1990; Yli-Hankala et al. 1999).

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Fig. 1. After a long suppression in quiet conditions the patient is touched lightly, i.e. a sock is moved from one foot. This induces a burst of high amplitude EEG activity. The novelty of the stimulus is here the critical characteristic, while the subject has adapted to, for instance. mechanical ventilation by an intubation tube. which should be difficult to adapt to when awake.

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Different anaesthetics produce burst suppression of different patterns. In barbiturate anaesthesia the bursts can have very sharp spikes. In isoflurane and sevoflurane anaesthesia the bursts start with alphatheta range oscillations after the negative DC shift, then continue with irregular slower oscillations. In propofol anaesthesia the burst onset is typically a slower negative shift with only 10 Hz activity, and during suppression 15 Hz spindles are seen without the negative DC shift (Jantti et al. 1993). The cellular mechanisms of burst suppression have been studied by Steriade et al. (1994). They showed that 95% of cortical cells are silent during suppression. Thalamic cells are silent to a lesser degree. However, with the deepening of burst suppression, when silent EEG periods became longer than 30 s, thalamic cells also ceased firing. The assumption that full-blown burst suppression is achieved through virtually complete disconnection in brain circuits implicated in the genesis of the EEG is corroborated by the revival of normal cellular and EEG activities after volleys setting into action thalamic and cortical networks.

Reactivity of burst suppression The bursts in reaction to stimuli have been known since the initial description of Derbyshire et al. (1936) of burst suppression and the analysis of cortical responses to sensory stimulation under deep barbiturate narcosis by Forbes and Morison (1939). We have shown that minor sensory stimuli such as vibration (Yli-Hankala et al. 1993a), electrical, photic or auditory stimuli can produce bursts (Hartikainen et al. 1995) (Figs. 1 and 2). When trains of stimuli of 3 s duration were used, the bursts occurred after the beginning or end of stimulation, with a typical latency of 200-300 ms. The onset waveform of bursts was different with different stimuli, thus showing stimulus specificity.

Evoked potentials It is frequently claimed that primary cortical evoked potentials are suppressed by anaesthetics

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Fig. 2. Repeated stimuli, here a light touch of the hand, repeatedly cause bursts in sevoflurane anaesthesia. Note that the burst has a repeatable waveform up to 500 ms from the onset, resembling event related potentials when awake. Vertical lines preceding the burst represent the time of touch; the latency is more variable than with stronger stimuli.

like fluranes. We have shown that with long stimulus intervals, 2 s or longer, this is not true; on the contrary very high amplitude SEPs can be recorded during EEG suppression. These can be, in effect, seen without averaging (Jantti et al. 1998; Rytky et al. 1999). This was previously shown for P22 by Vandesteene et al. (1993). Only the primary cortical components, however, are enhanced, i.e. N201P20, P22, and ipsilateral N20. The later components are suppressed until the burst, which does not follow every stimulus. This should enable identification and localization of the primary excitatory activity in the cortex. Visual cortical evoked potentials are usually abolished during suppression, but in some patients we have been able to record flash evoked cortical evoked potentials even during isoflurane-induced suppression (Sandell et al. 1998). The primary response in the occipital region is followed by a slow negative slope until the abrupt negative DC shift of the burst at 200 ms after the flash. Minor somatosensory stimuli such as a light touch of the hand can produce bursts after long

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Fig. 3. Response to painful stimulation of the median nerve during propofol-induced suppression. Pz - nose. A vertical line indicates electrical stimulation of the median nerve at the wrist. Note the 3 components: (I) a high amplitude negative wave corresponding to ERP; (2) a burst, slow negative wave with 10 Hz ripples on it; and (3) a 15 Hz spindle occurring during suppression, as indicated by a lack of negative shift. All of these 3 components can occur independently.

suppressions despite the fact that the patient is ventilated by an intubation tube and may have an open wound (Yli-Hankala et a1. 1993a) (Fig. 1). Hence, the novelty of stimulus plays an important role. This, together with the repeatable waveform at the onset of a burst (Fig. 2), resembles the cognitive evoked potential MMN and P3a (Heinze et a1. 1999). It shows that even in deep anaesthesia, continuous EEG suppression, CNS monitors for novel stimuli and adapts even to continuous pain. Painful intermittent stimuli regularly evoke bursts (Hartikainen et a1. 1995). This is true also for propofol anaesthesia, where, in our experience, photic, auditory or minor somatosensory stimuli usually do not evoke bursts. A burst evoked by painful electrical stimulation of the median nerve during suppression in propofol anaesthesia is shown in Fig. 3. Note that here the two components of burst are clearly separate. The onset wave, corresponding to long latency evoked potentials, is a high amplitude negative wave. This is followed by a very slow negative wave with 10 Hz ripples on it. This, again, is followed by a 15 Hz spindle, which is on the negative side of the positive DC level of suppression, without the negative shift typical of burst.

Epileptic activity in EEG during general anaesthesia Previously, we have shown that an abrupt increase in isofturane concentration causes an increase in blood pressure and heart rate (YliHankala et a1. 1993b). In our recent experiment we showed that mask induction with sevofturane caused spikes, polyspikes, and PED in most adult patients (Yli-Hankala et a1. 1999). Heart rate and blood pressure increased strongly in those patients which showed these patterns. This, together with motor phenomena such as twitches of the arms and shoulders, suggests that these EEG patterns are not just harmless interictal patterns. A rapid increase of volatile anaesthetics may, therefore, cause imbalance of excitation and inhibition, which causes autonomic nervous reaction, and even epileptic activity with motor and cardiovascular manifestations.

Summary Methods of clinical neurophysiology are important in studying basic problems of anaesthesia such

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as the problem of the depth of anaesthesia. Some of the problems of clinical neurophysiology in awake subjects, such as the generators of somatosensory evoked potentials or cognitive evoked potentials, may be resolved by recordings during EEG suppression. Finally, the mechanisms by which some anaesthetics produce epileptic phenomena (others or even the same agents may suppress epileptic activity) can only be resolved by EEG and EP recordings in human subjects, and by simultaneous recordings of intracellular and extracellular potentials in animals.

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