N. R. WEBSTER, N. P. LUFF, C. D. FRITH AND C. J. DORE. SUMMARY. We have investigated the relationship between the auditory evoked response (AER) ...
British Journal of Anaesthesia 1992; 69: 122-129
AUDITORY EVOKED RESPONSE AND AWARENESS: A STUDY IN VOLUNTEERS AT SUB-MAC CONCENTRATIONS OF ISOFLURANE D. E. F. NEWTON, C. THORNTON, K. M. KONIECZKO, C. JORDAN, N. R. WEBSTER, N. P. LUFF, C. D. FRITH AND C. J. DORE
SUMMARY We have investigated the relationship between the auditory evoked response (AER) and simple tests of conscious awareness at four end-expiratory concentrations (0.0. 0.1. 0.2 and 0.4 MAC) of isoflurane in oxygen in each of eight anaesthetist volunteers, in random order, at least 1 week apart. The early cortical AER was recorded from electrodes at the vertex and inion. Amplitudes of the waves Pa, Nb and Pc and latencies of the waves Na, Pa, Nb, Pb and Nc were measured. All the AER variables were highly significantly related to end-expiratory anaesthetic concentration. Amplitudes decreased and latencies increased progressively with increasing anaesthetic concentration. The AER variables were also highly significantly related to the level of response. Amplitudes were greatest and the latencies shortest when there was full response to command. (Nb latency increased from 47.5 to 54.5 ms between partial and no response.) The close correlation between the effects of concentration and level of response, and between concentration and the AER implied that it was difficult to demonstrate those changes in the AER which specifically re/ate to changes in response. At 0.2 MAC, however, which was the concentration at which all subjects showed some deficit, the response to a shock word was distinguished clearly by Nb latency. In eight of 24 possible comparisons (eight AER variables and three types of psychological test) the AER fitted the response more closely than concentration.
KEY WORDS Anaesthetics, volatile: isoflurane. Measurement auditory evoked response.
techniques:
The auditory evoked response (AER) has been shown to change in response to increasing concentrations of anaesthetic agent [1,2]. In particular, the early cortical component has been shown, in previous studies, to change in a similar manner with increases in blood or end-expiratory concentration of a wide range of anaesthetic agents, both i.v. and volatile [1,3,4]. At low concentrations of anaesthetic, charac-
teristic changes in the early cortical AER also reflect the change between wakefulness (responding to command) and light anaesthesia (no response) [5]. These last experiments, performed on paralysed surgical patients, using the isolated arm technique before the start of surgery, demonstrated that a change in the latency of the early cortical AER wave Nb, characterized the transition from responsive to anaesthetized. However, there were several equivocal responses, and the ethical and practical problems associated with extending these studies in patients led to the conclusion that further studies should be conducted in volunteers. Preliminary studies, and previous experience, suggested that for isoflurane, the transition between wakefulness and light anaesthesia occurred at less than 0.4 MAC. A study was performed therefore on volunteers breathing stable end-expiratory concentrations of 0.1, 0.2 and 0.4 MAC and 100% oxygen (control) on separate occasions. The results of test studies, relating anaesthetic concentration to psychological tests of response to command, memory tasks and clinical signs of light anaesthesia, have been reported previously [6]. This paper reports the relationship of these findings to the AER. SUBJECTS AND METHODS
The study was approved by the hospital Ethics Committee. Eight anaesthetist volunteers breathed isoflurane vaporized in oxygen. Each was allocated randomly to receive either 100% oxygen, or 0.1, 0.2 or 0.4 MAC of isoflurane (end-expiratory) in oxygen at sessions separated by at least 1 week; 1 MAC = 1.15 % [7]. No correction was made for the age of the subjects. The end-expiratory concentrations were maintained by the technique of overpressure. The
D. E. F. NEWTON*, M.B., B.S., F.R.C.ANAES., C. THORNTON, A.SC, PH.D., K. M . KONIECZKO, M.B., B.S., F.R.C.ANAES., C. JORDAN, M.SC, B.TECH., N. R. WEBSTER, B.SC., M.B., CH.B., PH.D., F.R.C.ANAES., N. P. LUFF, B.SC. (Division of Anaesthesia); C. D. FRITH, M.A., PH.D, DIP.PSYCH. (Division of Psychiatry); C. J. DORE, B.SC.
(Section of Medical Statistics); Clinical Research Centre, Watford Road, Harrow, Middlesex HA1 3UJ. Accepted for Publication: November 25, 1991. *Address for correspondence: Anaesthetic Research Unit, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ.
AUDITORY EVOKED RESPONSE AND AWARENESS TABLE I. Experimental procedure
Period 1 2 3 4 5 6
Activity Breathing 100% oxygen Test gas: resting then clinical assessment of depth Test gas: given commands Test gas: hears words Test gas: resting Breathing 100% oxygen
Duration (min) 10 10
2.75 2.75 5.5
Until awake
inspired concentration of isoflurane was adjusted manually to hold the end-expiratory concentration at the target level. The test sessions were divided into six periods, the first breathing 100% oxygen, and subsequent periods breathing the test mixture with the subjects resting, given commands, given word lists, again resting, and finally breathing 100% oxygen, respectively (table I). Subjects and observers were blinded to the target composition of the endexpiratory gas, and the controls were given a trace smell of isoflurane to blind them [6]. Psychological tests were of three types. The level of consciousness was assessed at the end of the second period when the end-tidal isoflurane concentration had been stable for at least 10 min (table I). The subject was asked loudly to open his eyes and close them. If there was no response the eyelash reflex was tested. In the third period, commands to raise a finger were presented. During the fourth period the subject heard 30 words. He was again asked to signal by raising a finger that he had heard each word. Included in each word list was a " shock " word (usually amusing) and any additional response of the subject was noted. The subjects were tested for memory of words and events 1 h after the anaesthetic. AER recording In all subjects the EEG was recorded unfUtered on an FM tape recorder using a purpose built, optically isolated, low noise amplifier, from silver-silver chloride electrodes on the vertex and inion, with an indifferent electrode placed over the right sternoclavicular joint. The contact of the electrodes was checked to ensure that inter-electrode resistances were less than 5 kQ. Rarefaction clicks were presented at a rate of 6 s'1 to both ears using Cadwell insert headphones which had been found by experiment to be more acceptable to awake subjects than the Telephonies TDH 39P headphones used in previous patient studies. Commands and words were fed from a cassette player into the same headphones using an audio mixing system, such that the intensity of the stimulation clicks was unaffected. The clicks were recorded separately on the same tape. At each recording, a calibration signal was put onto the tape recorder and the resulting signal used to set the gain on playback. AER analysis The FM tapes were played back at 16 times real time. The EEG signal was analogue filtered with an
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effective real-time band width of 25-500 Hz. The filtered EEG signal and the trigger stimulus signal were fed into a Loughborough Sound Images digital signal processing (DSP) card, resident within an IBM AT PC. To reduce noise levels further, digital filtering was performed on the final averages with a high-pass filter of greater than 30 Hz and a low-pass filter of 125 Hz. The high-pass filter was of the linear phase finite impulse response type and the low-pass filter was a Butterworth infinite impulse response filter which was applied to the data once in each direction to nullify any phase changes. The evoked response was extracted from the background noise (mainly EEG and EMG) by signal averaging. To reduce the influence of artefacts a weighted averaging technique was used in which each sweep was weighted by a factor that was inversely proportional to the noise power in that sweep, before being added to the accumulating sum. Thus noisy sweeps contributed less to the averages than "quieter" sweeps. A total of 1024 sweeps were averaged for statistical analysis. This represents the last 2.8 min of periods 1, 2 and 5 and the whole of periods 3 and 4. On occasions, in order to differentiate between short consecutive periods when the subjects were responding intermittently, a smaller number of sweeps was averaged. Amplitudes and latencies were measured by handon printed plots. The amplitude of a peak is defined as the height of a vertical dropped onto a line drawn between adjacent troughs. Statistical analysis The order of presentation of the four treatments and four word lists for each of the subjects was randomized using a Greco-Latin square. The desired anaesthetic concentration was communicated only to the operator of the vaporizer/gas analyser. The AER data were log10 transformed and analysed using ANOVA in the Genstat V, release 1.3 program installed on a Sun computer. The analyses were: AER variables vs concentration; and AER variables vs responses to command which were either full (all words and commands responded to), partial (some words and commands responded to) or absent in each of the three periods 2-4 (table I). Results are expressed as the geometric mean and 95 % confidence intervals. To differentiate between the relationship of the AER variables to concentration, and response to command, the residual mean squares from each of the analyses were compared for the eight variables and the three test periods (2-4). RESULTS
The responses to commands and words at the various MAC are summarized in table II and have also been discussed previously [6]. At 0 MAC (100% oxygen) there was full response to commands and words. At 0.1 MAC small deficits in the response were seen in subjects 1, 2, 4 and 8. Differences in the AER between 0 and 0.1 MAC were small and not restricted to the subjects showing deficits. The relationship between the AER variables and MAC is shown in table III.
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TABLE II. Response to the command "open your eyes" (OYE) and the raising of a finger on hearing each of 40 commands (COM) to do so, or each of 30 words (WD) read from a list for each subject at four values of MAC isofiurane. ^Subject 8 developed "second stage excitation" and although not responding to commands was tuithdrawn from the scoring
MAC isoflurane 0
0.2
0.1
0.4
Subject
OYE
COM
WD
OYE
COM
WD
OYE
COM
WD
OYE
COM
WD
1 2 3 4 5 6 7 8
+ + + + + + + +
40 40 40 40 40 40 40 40
30 30 30 30 30 30 30 30
+
39 39 40 39 40 40 40 40
24 30 30
+ + +
0 38 0 37 28 32 24 23
0 25 0 30 0 24 18 30
— — — — — — *
0 0 0 0 0 0 0 *
0 0 0 0 0 0 0 *
+ + + + + +
30
30 30 30 29
+ + + +
TABLE I I I . Changes in the AER variables with increasing concentration of MAC of isofiurane. Means (95% confidence intervals) during periods 2-5 at each concentration (n = 32). P value from comparison of all four concentrations (analysis of variance)
MAC isoflurane AER
0
0.1
0.2
0.4
P
18.2 (17.3-19.1) 29.6 (28.2-31.1) 44.9 (42.9-46.9) 59.7 (56.7-63.0) 73.8 (69.4-78.5)
18.9 (18.0-19.8) 30.1 (28.7-31.6) 46.3 (44.3-^8.5) 61.0 (57.9-64.3) 75.1 (70.6-79.9)
18.3 (17.4-19.2) 31.1 (29.7-32.7) 46.7 (44.7^18.9) 63.2 (60.0-66.6) 79.6 (74.8-84.7)
21.8 (20.8-22.9) 36.3 (34.6-38.1) 53.9 (51.5-56.3) 71.9 (68.2-75.7) 87.4 (82.2-93.0)
