1 Department of Anaesthesiology, and 2 Department of Clinical Neurophysiology, Oulu University Hospital, Oulu, Finland. 3 Information Processing Laboratory, Department of Electrical Engineering, University of Oulu, Oulu, Finland. 4 Department of Psychology and Helen Wills Neuroscience Institute, University of California, Berkeley, California, USA. 5 Ragnar Granit Institute, Tampere University of Technology and Department of Clinical Neurophysiology, Tampere University Hospital, Tampere, Finland
*Corresponding author: Department of Anaesthesiology, Oulu University Hospital, Box 21, FIN-90029 OYS, Finland. E-mail: ari-matti.huotari@nic.fi
Accepted for publication: July 23, 2003
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Abstract |
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Methods. Eight patients were anaesthetized with propofol to allow burst suppression. Electrical stimulation of the median nerve was applied during general anaesthesia and the EEG was measured.
Results. The EEG response to a painful stimulus had four successive components: (i) N20 and P22 potentials, reflecting activation of fast somatosensory pathways; (ii) a high-amplitude negative wave, possibly reflecting activation of the somatosensory cortex SII bilaterally; (iii) a burst (i.e. a negative slow wave with superimposed 10 Hz activity, probably reflecting an arousal mechanism); and (iv) a 1315 Hz spindle, probably originating from the thalamus, similar to sleep spindles. These could be seen separately and in different combinations. Bursts and spindles during burst suppression were also seen without stimulation. In deepening propofol anaesthesia, spindles were seen in the continuous EEG before burst suppression was achieved. In deep anaesthesia, spindles were seen when bursts had ceased, and painful stimuli evoked sharp waves without subsequent bursts.
Conclusion. In addition to SSEP (somatosensory evoked potentials), three different evoked responses are noted that could be useful for clinical monitoring.
Br J Anaesth 2004; 92: 1824
Keywords: anaesthesia; anaesthetics i.v., propofol; brain, EEG; monitoring, somatosensory evoked potentials; pain
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Introduction |
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Methods based on the bispectrum and approximate entropy can measure the hypnotic component of anaesthesia. These methods are surprisingly insensitive to the agents used when obtunding agents such as propofol and volatile anaesthetics are used.3 4 These techniques use measurement of burst suppression during deep anaesthesia.
Somatosensory stimuli cause enhanced somatosensory evoked potentials (SSEPs) and trigger bursts during EEG suppression with isoflurane or sevoflurane.57 We could not cause bursts with painless stimuli during propofol anaesthesia. We wanted to see if somatosensory potentials, bursts or other EEG features could be caused by stimulation of the median nerve during EEG suppression with propofol, and if these features were potentially useful in assessing information processing during deep anaesthesia and in measuring depth of anaesthesia.
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Materials and methods |
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Anaesthesia
No premedication was used. After establishing EEG monitoring (see below), general anaesthesia was induced with propofol i.v., which was given until burst suppression was achieved. After induction of anaesthesia, the lungs were ventilated with oxygen 100% through a face mask. Rocuronium bromide 0.50.6 mg kg1 i.v. was given, the trachea was intubated, and controlled ventilation with air:oxygen 2:1 was begun. Additional doses of rocuronium were given as needed, indicated by measurements of neuromuscular transmission.
The propofol infusion was adjusted to maintain EEG burst suppression (1429 mg kg1 h1). Lidocaine was not added to the propofol. No patient complained of pain associated with propofol administration. Blood pressure was measured non-invasively at 5-min intervals, and ECG, end tidal carbon dioxide and oxygen saturation were monitored continuously. Ventilation was adjusted to keep FE'CO2 between 4.5 and 6 kPa, using a Datex Capnomac Ultima anaesthetic agent monitor (Datex, Helsinki, Finland). Mean arterial pressure was maintained above 70 mm Hg by rapid infusion of sodium chloride 0.9% if necessary.
EEG recordings and stimulation
EEG signals were recorded continuously using a NeuroScan Synamp amplifier (Neuroscan, El Paso, TX, USA). Silversilver chloride electrodes were applied on the nose and to the Fp1, Fp2, Fz, F3, F4, F7, F8, Cz, C3, C4, CPz, CP3, CP4, T3, T4, T5, T6, Pz, P3, P4, O1 and O2 points, the cervical spine of C7, the left and right zygoma, and over the mastoids (M1, M2). The reference electrode was attached to FCz. Bandpass was 0.051000 Hz with a sampling rate of 5000 Hz.
The patient was not touched or stimulated in any way during the experiment. The median nerve was electrically stimulated using surface electrodes at the wrist with a Medelec ST-10 stimulator (Medelec, Old Woking, UK) using 0.1 ms 100 mA pulses triggered manually during periods of EEG suppression.
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Results |
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Negative sharp wave
A large-amplitude negative wave was recorded with an onset latency between 100 and 450 ms, peak from 180 to 1000 ms, duration 6502000 ms and amplitude 40330 µV. This negative sharp wave occurred in all scalp electrodes, with the greatest amplitude in central and occipital areas using a nose or ear reference (Fig. 3). The negative sharp-wave response was seen after most stimuli. This negative sharp wave was also seen when stimuli were applied during continuous EEG and during bursts, but the amplitude was less than during suppression.
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Spindle
The fourth distinct component was a spindle with a frequency of 1315 Hz and a typical latency of 1 s, but latencies up to 67 s were recorded. The duration was between 2.2 and 5.7 s and the amplitude was 35100 µV. It sometimes started on the slow-burst wave but often distinctly after it (Fig. 1). It was clearly different from the slow-burst wave or the rhythmic component of this burst (Fig. 1). It was asymmetrical, with negative excursions from the DC level.
We also observed spontaneous spindles of this form, with amplitudes of 4060 µV and durations of 10001150 ms. They started to appear on slow waves even before burst suppression was achieved and were also seen even when complete suppression was present and bursts had ceased.
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Discussion |
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Propofol has been suggested as the anaesthetic of choice for monitoring SSEPs, because somatosensory potentials are better preserved during propofol anaesthesia than during anaesthesia with nitrous oxide or isoflurane.9 10
Pain-evoked potentials provide an objective way to measure the sensation of pain.11 12 The stimulus is usually an electrical or laser stimulus, which is often to hand, but chemical, mechanical, cold and heat stimuli have also been used.11 12 Electrical stimuli to a peripheral nerve have been widely used, although they also stimulate other than purely nociceptive fibres.11 12
In awake subjects, a painful electrical skin stimulus evokes a positive wave of the vertex 80 ms after the application of the stimulus (P80), followed by a negative wave at 150 ms (N150), a further positive wave at 250 ms or later (P250), and occasionally a negative wave at
330 ms.11 12 In magnetoencephalography (MEG) recordings with a painful stimulus from a laser, a bilateral response from the secondary somatosensory cortex (SII) has been identified with a latency of 200 ms.13 From the apparent relationship between the intensity of stimulation and the response amplitude, these potentials should indicate the sensory-discriminative aspects of pain. Another EEG wave, P300, could reflect the emotional and motivational features of the pain response.14 The amplitude of pain-related SSEP decreases with sleep stage15 and general anaesthesia.16
Most studies of pain with evoked potentials have analysed traces <500 ms in duration.11 17 These changes in cerebral potentials can only reflect the first pain, mediated by thin myelinated A fibres. Pain elicited by cutaneous C-nociceptors should only reach the brain after
1 s.11 17 18
Possible origins of the components of the response to painful stimuli during EEG burst suppression with propofol
Short-latency SSEP
The waveforms appearing contralateral to stimulation correspond to the primary cortical somatosensory responses N20 and P22. They are probably not caused by specific pain fibres but are more likely to arise from other modalities of somatosensory perception and fast-conducting fibres.11 12 During anaesthesia with sevoflurane, stimulation of the median nerve produces somatosensory evoked responses after every stimulus, corresponding to N20 and P22, of greater amplitude than in awake conditions. The later cortical waves are abolished.6 7 These adapt more rapidly than SSEPs in awake conditions. Single N20 responses were occasionally seen during burst suppression in the present study, but they were not so large as in sevoflurane anaesthesia, where N20 values up to 10 µV have been reported.6 However, they are large enough to be sometimes seen without averaging during burst suppression with propofol.
The N20 wave and, at least to some extent, also the later potentials evoked by median nerve stimulation could be generated by the posterior surface of the central sulcus, area 3b.19 The sources of P22 are less well known.20 Recently, a biphasic effect of anaesthesia on N20 amplitude was reported by Vaughan and colleagues,21 but their method of recording may measure the sum of N20 and P22.
Negative wave: vertex wave of sleep wave or N100
This coincides temporally with the response that laser stimuli and MEG have shown to produce bilaterally in the SII area. These sources could elicit a response with the distribution of this wave.13 The distribution and latency of the large negative wave are like the vertex wave of physiological sleep, and are also like N100 and some components of cognitive potentials, such as P300.22
During physiological sleep, a K-complex, i.e. a negative sharp vertex wave, followed by a spindle can be seen after a stimulus.22 23 In latency and topography, the sharp wave we observed during burst suppression resembles the K-complex,2225 while in appearance it is similar to the spindle that follows it.22 24 25 K-complexes appear in Stage 2 sleep in response to arousing stimuli. They are maximal over the vertex.2225 K-complexes may be elicited by sensory stimulation or may occur spontaneously in a stimulus-free environment.23 25
Amzica and Steriade24 25 found a relationship between the slow (<1 Hz) oscillation and sleep K-complexes. They suggest that K-complexes are generated by a synchronized cortical network that periodically excites or inhibits cortical neurons, and that spontaneous K-complexes indicate slow oscillation. Their presence through the stages of sleep is related to the increasing synchrony within cortical networks with the deepening of sleep and sensory deafferentation. Hence, either responses from the secondary cortex or a more extensive activation of the cortex, such as a K-complex, might cause this pain-induced negative sharp wave.
Burst similarity with isoflurane-induced burst activity
A burst can be described as event-related synchronization, although it probably also reflects activation of cortical cells, which are silent during EEG suppression.26
The evoked potential is followed by a burst with a latency of 200 ms, but this does not occur after every stimulus. During anaesthesia with isoflurane, spontaneous bursts and bursts induced by vibration have distinctly different waveforms.27 Photic, auditory and somatosensory stimuli cause bursts with clearly different onset waveforms and with mean latencies of 290440 ms, sometimes up to 510 ms, from stimuli specific to the modality of stimulation.5
The burst suppression pattern seen in propofol anaesthesia is not the same as that seen during isoflurane or sevoflurane anaesthesia. The bursts are very slow negative waves with smooth onset and superimposed alpha-frequency waves. In isoflurane and sevoflurane anaesthesia, the bursts start and end with an abrupt DC shift,5 6 whereas with propofol the burst onset and end are smooth. Bursts during anaesthesia with volatile agents start with a stimulus-specific onset waveform,57 which may correspond to the negative sharp wave we noted before burst onset. In isoflurane and sevoflurane anaesthesia, the negative wave preceding the burst seems to merge with the burst and to occur synchronously with the burst onset,57 while in propofol anaesthesia they are temporally separate events. In isoflurane anaesthesia, a burst can be evoked by very minor novel stimuli.5 We hypothesize that this could reflect the arousal mechanism.
In our preliminary experiments with propofol anaesthesia, we could not induce bursts with minor somatosensory, photic or auditory stimuli. We now report that electrical stimuli during propofol-induced burst suppression can cause bursts and SSEP.
Spindle
The spindle is similar to the sleep spindles often seen during stage 2 sleep in response to an external stimulus, preceded by a vertex negative sharp wave. Spindles are defined as a group of rhythmic waves characterized by progressively increasing, then gradually decreasing amplitude.22 In propofol anaesthesia, they appear before the onset of burst suppression, then continue to occur, sometimes during bursts, but most typically after bursts. Spindles are seen both during bursts and separately during suppression. They resemble focal epileptic discharges, which may start during a burst and continue during suppression.28 In deeper anaesthesia, they persist during continuous suppression. They are probably generated by the thalamus, and during physiological sleep they are related to the blocking of sensory information flow from the thalamus to the cortex. We have not seen spindles in isoflurane or sevoflurane burst suppression.2 58 The pain-evoked responses during propofol burst suppression resemble K-complexes and spindles during physiological sleep. Some features of physiological sleep seem to be better preserved during propofol anaesthesia than in anaesthesia with other agents.
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Conclusions |
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Acknowledgement |
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References |
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2 Hartikainen K, Rorarius M, Mäkelä K, Yli-Hankala A, Jäntti V. Propofol and isoflurane induced EEG burst suppression patterns in rabbits. Acta Anaesthesiol Scand 1995; 39: 8148[ISI][Medline]
3 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. Br J Anaesth 1999; 82: 66671
4 Bruhn J, Bouillon TW, Shafer SL. Onset of propofol-induced burst suppression may be correctly detected as deepening of anaesthesia by approximate entropy but not by bispectral index. Br J Anaesth 2001; 87: 5057
5 Hartikainen KM, Rorarius M, Peräkylä JJ, Laippala PJ, Jäntti V. Cortical reactivity during isoflurane burst-suppression anesthesia. Anesth Analg 1995; 81: 12238[Abstract]
6 Jäntti V, Sonkajärvi E, Mustola S, Rytky S, Kiiski P, Suominen K. Single-sweep cortical somatosensory evoked potentials: N20 and evoked bursts in sevoflurane anaesthesia. Electroencephalogr Clin Neurophysiol 1998; 108: 3204[CrossRef][Medline]
7 Rytky S, Huotari AM, Alahuhta S, Remes R, Suominen K, Jäntti V. Tibial nerve somatosensory evoked potentials during EEG suppression in sevoflurane anaesthesia. Clin Neurophysiol 1999; 110: 16558[CrossRef][ISI][Medline]
8 Jäntti V, Yli-Hankala A, Baer GA, Porkkala T. Slow potentials of EEG burst suppression pattern during anaesthesia. Acta Anaesthesiol Scand 1993; 37: 1213[ISI][Medline]
9 Kalkman CJ, ten Brink SA, Been HD, Bovill JG. Variability of somatosensory cortical evoked potentials during spinal surgery. Effects of anesthetic technique and high-pass digital filtering. Spine 1991; 16: 9249[ISI][Medline]
10 Kalkman CJ, Traast H, Zuurmond WW, Bovill JG. Differential effects of propofol and nitrous oxide on posterior tibial nerve somatosensory cortical evoked potentials during alfentanil anaesthesia. Br J Anaesth 1991; 66: 4839[Abstract]
11 Bromm B. Pain related components in the cerebral potential. Experimental and multivariate statistical approach. In: Bromm B, ed. Pain Measurement in Man. Neurophysiological Correlates of Pain. New York: Elsevier Science Publishers, 1984; 25790
12 Bromm B, Lorenz J. Neurophysiological evaluation of pain. Electroencephalogr Clin Neurophysiol 1998; 107: 22753[CrossRef][ISI][Medline]
13 Schnitzler A, Ploner M. Neurophysiology and functional neuroanatomy of pain perception. J Clin Neurophysiol 2000; 17: 592603[ISI][Medline]
14 Zaslansky R, Sprecher E, Katz Y, Rozenberg B, Hemli JA, Yarnitsky D. Pain-evoked potentials: what do they really measure? Electroencephalogr Clin Neurophysiol 1996; 100: 38491[Medline]
15 Naka D, Kakigi R. Simple and novel method for measuring conduction velocity of A delta fibers in humans. J Clin Neurophysiol 1998; 15: 1503[ISI][Medline]
16 Kochs E, Treede RD, Schulte am Esch J, Bromm B. Modulation of pain-related somatosensory evoked potentials by general anesthesia. Anesth Analg 1990; 71: 22530[Abstract]
17 Becker DE, Noss RS, Fein G, Yingling CD. Very late pain-related activity identified with topographically mapped frequency domain analysis of evoked potentials. Electroencephalogr Clin Neurophysiol 1998; 108: 398405[CrossRef][Medline]
18 Bromm B, Treede RD. Pain related cerebral potentials: late and ultralate components. Int J Neurosci 1987; 33: 1523[ISI][Medline]
19 Wikström H, Huttunen J, Korvenoja A, et al. Effects of interstimulus interval on somatosensory evoked magnetic fields (SEFs): a hypothesis concerning SEF generation at the primary sensorimotor cortex. Electroencephalogr Clin Neurophysiol 1996; 100: 47987[CrossRef][Medline]
20 Vandesteen A, Nogueira MC, Mavroudakis N, Defevrimont M, Brunko E, Zegers de Beyl D. Synaptic effects of halogenated anesthetics on short-latency SEP. Neurology 1991; 41: 9138[Abstract]
21 Vaughan DJA, Thornton C, Wright DR, et al. Effects of different concentrations of sevoflurane and desflurane on subcortical somatosensory evoked responses in anaesthetized, non-stimulated patients. Br J Anaesth 2001; 86: 5962
22 Niedermeyer, E, da Silva, L, eds. Electroencephalography: Basic Principles, Clinical Applications, and Related Fields, 2nd edn. Baltimore: Urban & Schwarzenberg, 1987
23 Niiyama Y, Satoh N, Kutsuzawa O, Hishikawa Y. Electrophysiological evidence suggesting that sensory stimuli of unknown origin induce spontaneous K-complexes Electroencephalogr Clin Neurophysiol 1996; 98: 394400[CrossRef][ISI][Medline]
24 Amzica F, Steriade M. The K-complex: its slow (<1-Hz) rhythmicity and relation to delta waves. Neurology 1997; 49: 9529[Abstract]
25 Amzica F, Steriade M. Cellular substrates and laminar profile of sleep K-complex. Neuroscience 1998; 82: 67186[CrossRef][ISI][Medline]
26 Steriade M, Amzica F, Contreras D. Cortical and thalamic correlates of electroencephalographic burst-suppression. Electroencephalogr Clin Neurophysiol 1994; 90: 116[ISI][Medline]
27 Yli-Hankala A, Jäntti V, Pyykkö I, Lindgren L. Vibration stimulus induced EEG bursts in isoflurane anaesthesia. Electroencephalogr Clin Neurophysiol 1993; 87: 21520[CrossRef][ISI][Medline]
28 Jäntti V, Eriksson K, Hartikainen K, Baer GA. Epileptic EEG discharges during burst suppression. Neuropediatrics 1994; 25: 2713[ISI][Medline]