QUANTITATIVE EEG AND BRAINSTEM AUDITORY EVOKED POTENTIALS: COMPARISON OF ISOFLURANE WITH HALOTHANE USING THE CEREBRAL FUNCTION ANALYSING MONITORf

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1 British Journal of Anaesthesia 1990; 65: QUANTITATIVE EEG AND BRAINSTEM AUDITORY EVOKED POTENTIALS: COMPARISON OF ISOFLURANE WITH HALOTHANE USING THE CEREBRAL FUNCTION ANALYSING MONITORf A. R. LLOYD-THOMAS, P. V. COLE AND P. F. PRIOR SUMMARY We studied EEG and brainstem auditory evoked potentials (BAEP) during routine surgery at various concentrations of isoflurane (12 patients) or halothane (11 patients) or during prolonged (mean 2.5 h, range h) administration of 1% isoflurane (five patients). Recording and analysis was performed with the cerebral function analysing monitor (CFAM). At equivalent MAC, the two agents exhibited distinctive neurophysiological profiles. Increasing concentrations of isoflurane produced a clear sequence of EEG changes (decreasing fast and increasing slow components) then burst suppression activity suggesting cortical depression. With halothane, changes in EEG amplitude were less pronounced and those in frequency content less systematic, with no periods of suppression. Simultaneous BAEP showed greater latency increase with halothane than with isoflurane. Prolonged administration of 1 % isoflurane was associated with a stable EEG (no periods of suppression) and BAEP. KEY WORDS Anaesthetics, volatile: halothane, isoflurane. auditory evoked potentials. EEG. Monitoring: PATIENTS AND METHODS Following approval by the local Ethics Committee, we studied four male and 24 female (ASA I) patients (aged yr) during elective orthopaedic or gynaecological surgery. Premedication (90 min before operation) comprised papaveretum 0.2mgkg 1 and hyoscine 4 igkg~ 1 ; standardized anaesthesia comprised thiopentone 5 mg kg" 1, fentanyl 5 (ig kg" 1, tubocurarine 0.5 mg kg" 1 (chosen to minimize tachycardia) and 66% nitrous oxide in oxygen given by intermittent positive pressure ventilation. End-tidal carbon dioxide (FEco,) was maintained at 5%. The patients were allocated to three groups. Group I (n = 12) received isoflurane at end-tidal concentrations 0.5, 1.0, 1.5 and 2.0vol%; group II (n = 11) received halothane at end-tidal concentrations 0.5, 1.0 and 1.5vol%; group III {n = 5) received isoflurane at end-tidal concentration of 1 % for a mean of 2.5 (range ) h according to surgical need. Baseline measurements with nitrous oxide in oxygen were at a mean of ± 1.25 min after induction with thiopentone; the volatile agent was introduced and 20 min stabilization with continuous EEG and end-tidal gas monitoring at each concentration preceded neurophysiological measurements. If systolic arterial pressure decreased to less Although the neurophysiological effects of anaesthetic agents have been documented extensively, there are few quantitative data on EEG and evoked potential changes with standard anaesthetic procedures during surgery. We have studied the effects of nitrous oxide with increasing concentrations of isoflurane and halothane during routine operations. ADRIAN R. LXOYD-THOMAS*, M.B., B.S., F.F.A.R.C.S.; PETER V. COLE, M.B., B.S., F.F.A.R.CS. (Department of Anaesthesia); PAMELA F. PRIOR, M.D., F.R.C.P. (Department of Neurological Sciences); St Bartholomew's Hospital, West Smithfield, London EC1A 7BE. Accepted for Publication: March 1,1990. Present address: Department of Anaesthesia, Hospital for Sick Children, Great Ormond Street, London WC1N 3JH. A preliminary account of this work was presented to the Anaesthetic Research Society, London, November 1986.

2 EEG AND BAEP DURING ISOFLURANE OR HALOTHANE 307 than mm Hg, anaesthesia was lightened and data from that part of the study rejected. Monitoring The ECG (CM 6 ), oesophageal temperature, end-tidal carbon dioxide and end-tidal concentration of volatile agent (Datex Normac) were displayed continuously; arterial pressure was measured indirectly at 2.5-min intervals and intermittent arterialized venous blood samples were taken for confirmation of FEco,- The EEG from left and right parietal regions was processed continuously in 2-s epochs by the cerebral function analysing monitor [1] (fig. 1) (CFAM RDM Consultants); the raw EEG recorded on analog tape was replayed later onto a paper chart. The CFAM digital analysis was replayed subsequently into a mainframe computer; it comprised amplitude: maximum, 90th centile, mean, 10th centile, minimum; frequency: percent content of beta 2 (> 20 Hz), beta 1 ( Hz), alpha 2 ( Hz), alpha 1 ( Hz), theta 2 ( Hz), theta 1 ( Hz), delta 2 ( Hz), delta 1 (1-2 Hz), very low frequency (< 1 Hz) and suppressions (< 3 iv); and an indication of validity (electrode impedance, line interference and scalp muscle potentials) of each 2-s epoch. Careful inspection of the raw EEG and the CFAM chart with digital time log, enabled selection of artefact-free epochs, agreed by two observers, from each level of anaesthesia. The mean (SD) number of 2-s epochs analysed for each concentration of isoflurane was (291.7), for halothane (302.8) and for each sample period during prolonged isoflurane (287.3). After preoperative assessment of hearing, brainstem auditory evoked potentials (BAEP) were recorded between mastoid and vertex electrodes following 60-dB hearing level clicks to one ear. Because of time constraints, each BAEP was the average of only 0 responses and some were rejected as inadequate for unambiguous measurement. Two independent observers assessed amplitude, latency and inter-peak intervals of waves I, III and V. Statistical analysis All EEG variables at each depth of anaesthesia were normally distributed and changes from baseline were compared by both two-way analysis of variance and paired t tests. Both mean values and variance were analysed for each sample. RESULTS (Full numerical details of results may be obtained on application to the authors.) The patient groups did not differ significantly in respect of age, sex and weight. During anaesthesia there were no disturbances of cardiac rhythm or ischaemic changes. The maximum reduction in oesophageal temperature was 0.5 C, the lowest value being 36 C. There were no complications attributable to the anaesthetic or measurement techniques on postoperative examination at 1 and 24 h. During baseline light anaesthesia with nitrous oxide, the EEG showed predominantly fast activity; there were no significant EEG differences between any of the groups and the latencies of waves I, III and V of the BAEP were 1.76 (SD 0.07), 3.87 (0.06) and 5.46 (0.14) ms, respectively. After measurements at 0.5% isoflurane and 0.5% halothane, surgery commenced without producing any significant differences in EEG values or variability; no epileptiform activity appeared in the raw EEG of any patient. Isoflurane anaesthesia Significant EEG changes compared with nitrous oxide were as follows: 0.5% isoflurane increased EEG amplitude (fig. 2) and reduced percentage beta 2 content (fig. 3) (both P < 0.02); 1 % isoflurane reduced beta 1 +2 (P < 0.001) and increased theta 1 +2 (P < 0.01); 1.5% isoflurane further reduced beta 1 (P < 0.01), reduced alpha 2 (P < 0.05) and increased theta 1 (P < 0.01). Short ( s) periods of EEG suppression appeared in 2% of patients (1 % of the time). Isoflurane 2% further decreased beta 1, beta 2, alpha 1 and alpha 2, and minimum and 10th centile amplitudes and further increased theta 1+2 (all P < 0.001) and delta 2 (P < 0.02); suppressions of s duration appeared in nine patients, undue hypotension (systolic arterial pressure < mm Hg) having precluded administration of 2 % isoflurane in the other three patients. All EEG amplitude and frequency variables were altered significantly (P < 0.01, one-way analysis of variance) compared with baseline and other values as anaesthetic depth increased. Minimum and 10th centile amplitude, beta 1+2, theta 1+2, and delta 2 percentage frequency contents were most affected (highest F ratios). Ratios of fast to slow EEG activity (beta: delta and beta:theta) declined with increasing concentrations of isoflurane (fig. 4).

3 1min pvp.p.a 10 1 (content, %) nt muscle beta alpha theta delta VLF suppr marks Is Z 1. Examples of CFAM recordings to show typical appearances at different concentrations of isoflurane. (Recordings not all from the same patient.) Top re ssed EEG (note that conventional frequency bands are not subdivided as for a digital output); lower records: intercurrent raw EEG samples (pas 0 Hz). A: Initially nitrous oxide in oxygen only note the variability, particularly in amplitude, and the increase in amplitude on introduction of 0.5 % iso rrow), B: Stable 0.5% isoflurane note the decrease in variability and the shift to slower frequencies, c: Isoflurane 1.0%, increased to 1.5% note su itude suppression up to 0.5 s. D: Isoflurane 1.5%, increasing to 2% note effect on 10th ccntilc and minimum amplitude and the appearance of suppressio min, which are notched by ECG pickup on the EEG sample, E: Isoflurane 2.0% note small ripple of residual EEG and ECG. F: Recovery note the increase in amplitude precedes shift to faster frequencies. VLF = very low frequency; Suppr. = suppression.

4 EEG AND BAEP DURING ISOFLURANE OR HALOTHANE 309 o o E (0 C3 LU Isof lurane 0.5X 1.0Z Halothane 0.5Z 1.0Z MAC equivalent of volatile agent 2.0Z R 15Z FIG. 2. Group average (1 SD) percentage change from nitrous oxide in oxygen only, in minimum (fine), mean (medium) and maximum (bold) EEG amplitude, measured by the CFAM in patients receiving isoflurane (continuous lines) or halothane (dotted lines). Concentrations of isoflurane and halothane are end-tidal (vol %). R = Recovery. The variance of frequency content increased with increasing concentrations of isoflurane whilst that of amplitude initially decreased, then increased markedly with onset of burst suppression pattern (fig. 1). Because the unprocessed EEG and the CFAM charts suggested that variability and absolute values in the EEG changed with anaesthetic depth, changes in amplitude variability were quantified by both variance of amplitude and a ratio (amplitude variance: minimum amplitude), the former diminishing considerably (average 60 %) with introduction of isoflurane and the latter decreasing in 10 patients and remaining static or increasing in the two other patients. This confirmed the visual impression of smoothing of EEG and CFAM traces by loss of moment to moment amplitude variations. With 1.5% isoflurane, high amplitude slow activity combined with short periods of suppression to increase amplitude variance and the ratio also increased in all but two patients. For group data, both R amplitude variance and ratio decreased with 0.5 % and 1%, but increased significantly with 1.5% and 2.0% isoflurane (P < 0.02 and < 0.05, respectively). Halothane anaesthesia Significant EEG changes were as follows: 0.5 % halothane increased beta 1 activity compared with nitrous oxide alone (P < 0.02) (fig. 3); 1.0% halothane was associated with a decrease in amplitude compared with 0.5 % (P < 0.05) (fig. 2); 1.5% halothane increased theta 1 and reduced beta 2 compared with nitrous oxide (both P < 0.001). One-way analysis of variance confirmed that only the proportions of beta 2 and theta 1 activity altered significantly with increasing depth of anaesthesia (P < 0.01), none of the amplitude measures being related to halothane concentration. After an initial increase with 0.5%, both fast:slow ratios declined as the concentration of halothane increased further (fig. 4). Individual variability assessed by the variance amplitude ratio increased in three patients, was unchanged in two and decreased in five patients with 0.5% halothane. With both 1.0% and 1.5% there were no changes in individual patients in EEG amplitude or frequency variability compared with nitrous oxide alone; inter-individual variation was not reduced by halothane, but both the group mean variance and variance amplitude ratio increased. Brainstem auditory evoked potentials Technically satisfactory complete series of BAEP were obtained in 12 patients (six from each group). No consistent amplitude changes were observed. With isoflurane, latencies of waves I and III remained unchanged at all concentrations, but that of wave V increased significantly from 5.46 (0.14) ms to 5.87 (0.13) ms (1% isoflurane, P<0.02) and 5.91 (0.09) ms (2% isoflurane, P < 0.01). With halothane, latency of wave III increased significantly from 3.72 (0.05) ms to 3.98 (0.82) ms (1.0% halothane, P < 0.02) and from 3.72 (0.05) ms to 4.1 (0.16) ms (1.5% halothane, P < 0.01) compared with nitrous oxide alone and wave V latency increased with increasing halothane concentrations but significantly only with 1.5% (P<0.01). Prolonged anaesthesia with 1 % isoflurane An end-tidal isoflurane concentration of 1 %

5 310 BRITISH JOURNAL OF ANAESTHESIA Isoflurane Delta Theta Alpha Beta Halothane Delta Theta Alpha Beta T T I i 0.52 _L 1 i * i 1.52 FIG. 3. Group mean (1 SD) percentage change from nitrous oxide in oxygen only, in EEG frequency content measured by the CFAM in patients receiving isoflurane or halothane. T Isoflurane 3.0 Halothane 2.0 Beta Delta Beta Theta Beta-Delta Beta-Theta.2 I i End-tidal concn (vol Z ) End-tidal concn (vol X) FIG. 4. Behaviour of two fast: slow EEG ratios with increasing concentrations of isoflurane or halothane. With isoflurane a relatively steady state was reached at an end-tidal concentration of 1 %. was sustained for an average of 2.5 h during routine surgery, the ratio of end-tidal to inspired the whole period. EEG and BAEP remained stable throughout and were not significantly isoflurane increasing from an average of 0.65 after different from those in patients receiving 1 % the initial 20-min stabilization to only 0.7 during isoflurane for shorter periods described above.

6 EEG AND BAEP DURING ISOFLURANE OR HALOTHANE 311 DISCUSSION There were striking differences between the EEG effects of isoflurane and halothane (figs 2, 3), whilst the sequence of changes with each agent appeared consistent between subjects. Our study has established a database for these two volatile agents within a balanced anaesthetic technique during routine surgical operations. The EEG monitor (the CFAM) which we used in conjunction with conventional EEG, has the ability to quantify EEG even during the periods of burst suppression which characterize deeper levels of anaesthesia [2]. Because of its continuous display of analysed amplitude and frequency information (with visualization of the raw signal when required), it ajso permits detection of shortlived events and of moment to moment variability of the EEG. Methods based solely on Fast Fourier Transform or baseline crossing techniques use discrete periods (typically of the order of 4-60 s) of EEG and produce a mean analysis for each time sample, commonly displayed sequentially as a compressed spectral array. These techniques, and ajso related derived unitary measures such as spectral edge or median frequency, fail to reflect the full variability of the signal because of the smoothing introduced by the averaging process which may also mask short periods of suppression [3,4]. We found a consistent and stable high proportion of alpha and beta activity during anaesthesia with nitrous oxide alone, which seemed unlikely to be a residual effect of thiopentone, at an average interval of 10 min before starting EEG measurements [5]. These fast activities and their marked amplitude variability highlight the light level of anaesthesia afforded by nitrous oxide. This is underlined by the increase in EEG amplitude on introduction of either isoflurane or halothane which was similar to that reported on induction of anaesthesia from the awake state [6]. Unlike the inconsistent EEG changes with increasing concentrations of halothane, with isoflurane anaesthesia there was a pronounced frequency shift to slow wave activity with changes in amplitude distribution (reflecting onset of burst suppression activity) reflecting increasing depth of anaesthesia. Given the sequence of frequency changes, the ratio of fast to slow components might be considered a useful index of adequate anaesthesia and equate with the concept of an "anaesthetic pattern" propounded by Stullken and colleagues [7]. Our findings (fig. 4) suggest that there was a change in EEG state with 1 % isoflurane consistent with an anaesthetic pattern beyond which little further frequency change occurred with increasing concentration, although it is recognized that EEG frequency content and amplitude may behave independently during anaesthesia [1]. In our study, frequency ratios did not change significantly at concentrations of isoflurane greater than 1 %, whilst maximum amplitude depression did not occur until 2 % was reached. However, these changes did not occur with halothane. With isoflurane there were inter-individual differences in the time of onset and degree of burst suppression pattern. They appeared unrelated to any physiological change, age, or undue susceptibility to central nervous system depressants, as judged by the patient's response to standardized premedication it was thought initially that those who were most sleepy with premedication were also those who most readily demonstrated burst suppression, but further analysis did not confirm this. Indeed, our detailed EEG analysis highlighted the different neurophysiological states induced by isoflurane and halothane at equivalent MAC concentrations used in clinical practice, and casts doubt upon the relevance of the MAC nomenclature. There were consistent EEG alterations with isoflurane, suggesting a progressive depression of cerebral cortical function leading to a burst suppression pattern which was not seen with halothane. In contrast, halothane rather than isoflurane elicited more consistently progressive alterations in brainstem function as measured by BAEP. The increases in latency in the brain stem auditory pathway were small but consistent and in keeping with those reported previously [8,9]. The limited number of recordings may explain our inability to demonstrate consistent changes in amplitude. However, we have confirmed previous reports of an increase in the latency of wave V during anaesthesia with up to 1 % isoflurane [10] and a similar prolongation in the latency of both waves III and V in patients receiving halothane [8]. We were not able to share the enthusiasm [11] for the use of BAEP. We found that processed EEG changes were of greater order and required much less skill to record during surgery. We accept that, ideally, measures of brainstem, subcortical and cortical effects of anaesthesia should

7 312 BRITISH JOURNAL OF ANAESTHESIA be made in parallel. This might have been more practical if evoked potentials in the somatosensory rather than the auditory pathway had been used. We consider that during isoflurane anaesthesia the EEG was a more effective monitor of anaesthetic depth. During halothane, however, EEG changes were much less consistent and the small but progressive BAEP changes which occurred might be more helpful. ACKNOWLEDGEMENTS We wish to thank C R. Green, R. C. Pottinger, J. Williams (data acquisition), D. S. L. Lloyd, D. E. Maynard, M. A. Tooley (data processing), P. Patel, J. Thomas and J. Loughnane (statistical analysis) for their help with, this project. REFERENCES 1. Maynard DE, Jenkinson JL. The cerebral function analysing monitor. Anaesthesia 1984; 39: Prior PF, Maynard DE, Brierley JB. EEG monitoring for the control of anaesthesia produced by the infusion of Althesin in primates. British Journal of Anaesthesia 1978; SO: Levy WJ. Intraoperative EEG patterns: implications for EEG monitoring. Anesthesiology 1984; 60: Levy WJ. Effect of epoch length on power spectrum analysis of the EEG. Anesthesiology 1987; 66: Frank M, Maynard DE, Tsanclis LM, Major E, Coutinho P. Changes in cerebral electrical activity measured by the cerebral function analysing monitor following bolus injections of thiopentone. British Journal of Anaesthesia 1984; 56; Dubois M, Savege TM, O'Carroll TM, Frank M. General anaesthesia and changes on the cerebral function monitor. Anaesthesia 1978; 33: Stullken EH, Milde JH, Michenfelder JD, Tinker JH. The non-linear responses of metabolism to low concentrations of halothane, enflurane, isoflurane and thiopental. Anesthesiology 1977; 46: Thornton C, Heneghan CPH, James MFM, Jones JG. Effects of halothane or enflurane with controlled ventilation on auditory evoked potentials. British Journal of Anaesthesia 1984; S6: Heneghan CPH, Thornton C, Navaratnarajah M, Jones JG. Effect of isoflurane on the auditory evoked response in man. British Journal of Anaesthesia 1987; 59: Manninen PH, Lam AM, Nicholas JF. The effects of isoflurane and isoflurane-nitrous oxide anetthesia on brainstem auditory evoked potentials in humans. Anesthesia and Analgesia 1985; 64: Jones JG, Konieczko K. Hearing and memory in anaesthetised patients. British Medical Journal 1986; 292: