British Journal of Anaesthesia 1990; 65: 313-318

ISOFLURANE PREVENTS EEG DEPRESSION DURING TRIMETAPH AN-INDUCED HYPOTENSION IN MANf A. R. LLOYD-THOMAS, P. V. COLE AND P. F. PRIOR

SUMMARY

We have studied the EEG analysed with the cerebral function analysing monitor (CFAM) during trimetaphan (TMP)-induced hypotension to a mean arterial pressure (MAP) of 40 mm Hg in 20 normocapnic patients anaesthetized with either 1 % end-tidalisoflurane or 0.5% halothane. During the acute reduction in MAP, the average reduction in mean EEG amplitude with halothane was 14%, two patients showing short periods of EEG suppression; the decline in EEG amplitude correlated with declining MAP in four patients. In contrast, the average reduction in mean EEG amplitude with isoflurane was only 0.3% and there were neither periods of suppression nor any correlation between EEG amplitude and MAP. No significant changes in EEG frequency PATIENTS AND METHODS occurred in either group. Isoflurane prevented EEG amplitude depression during TMP-induced Following approval by the hospital Ethics Committee, we studied six female and four male hypotension. KEY WORDS Anaesthetic techniques: hypotensive, trimetaphan. Anaesthetics, volatile: halothane, isoflurane. Monitoring: CFAM, electroencephalography.

patients aged 20-65 yr, during elective orthopaedic or plastic surgical operations for which we routinely use induced hypotension. The patients were healthy (ASA I or II), with no clinical or laboratory evidence of cardiovascular, cerebrovascular, renal or neurological disease. They were screened before and after operation by one investigator using a standard clinical neurological examination.

Induced hypotension may be required to facilitate certain surgical operations, but may cause a small risk of cerebral ischaemia in some patients. The Anaesthesia and hypotension type of hypotensive agent influences the extent of The anaesthetic technique was similar to that the reduction in cerebral blood flow (CBF) at used in our earlier study [3], except that 1 % equivalent mean arterial pressures (MAP) [1] and this difference is reflected in associated EEG R. LLOYD-THOMAS*, M.B., B.S., F.F.A.R.C.S., PETER V. changes [2]. We had previously studied patients ADRIAN COLE, M.B., B.S., F.F.A.R.C.S. (Department of Anaesthesia); during induced hypotension under halothane PAMELA F. PRIOR, M.D., F.R.C.P. (Department of Neurological anaesthesia and demonstrated that all patients Science); St Bartholomew's Hospital, West Smithfield, receiving trimetaphan (TMP) showed some de- London EC1A 7BE. Accepted for Publication: March 1, 1990. *Present address: Department of Anaesthesia, Hospital for gree of EEG deterioration during the acute Sick Children, Great Ormond Street, London WC1H 3JR. reduction in arterial pressure [3]. t A preliminary report of this work was presented at the Unlike other volatile anaesthetic agents, Anaesthetic Research Society, London, November 1986.

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isoflurane causes a dose-related reduction in cerebral metabolic requirement for oxygen (CMRo2) until there is suppression of cortical electrical activity reflected in an isoelectric EEG [4]. It may have cerebral protective properties during ischaemic hypotension in the dog [5] and probably also in man during the potential regional ischaemia of carotid surgery [6,7]. We investigated, therefore, the effect of substituting isoflurane for halothane during TMP-induced hypotension. We used light isoflurane anaesthesia with stable continuous EEG (no burst suppression) to permit neurophysiological detection of possible cerebral ischaemia and comparison with previous data obtained during TMP-induced hypotension with halothane [3].

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Monitoring, measurements and analysis

ECG, oesophageal temperature, end-tidal concentrations of carbon dioxide and of volatile agent (Datex Normac) and intra-arterial pressure were monitored continuously. Systolic and diastolic arterial pressures were measured subsequently at 10-s intervals, by two independent observers, from the chart recording. MAP was calculated from the formula MAP = diastolic + (systolic/3). MAP was also remeasured directly from the original chart recordings of patients receiving halothane in our previous study [3]. The cerebral function analysing monitor (CFAM RDM Consultants) recorded raw and analysed EEG from left and right parietal electrodes and also provided a digital output of 15 EEG amplitude and frequency measures [9]. Amplitude is given in units, derived from the formula uV = 10((CFAM unit-10)/50), which convert the inherent asymmetric (Rayleigh) distribution of the amplitude fluctuations of the EEG to a normal (Gaussian) distribution. Frequency in any band is given as a percentage of the total frequency content. The raw EEG, recorded simultaneously on analog tape, was replayed on to a paper chart. Careful inspection of this, the CFAM chart and its digital time log enabled selection of artefact-free periods, agreed by two observers, for computer analysis. Two-second epochs were amalgamated into 10-s (during the acute reduction in arterial pressure, when the physical state was changing rapidly) and 1-min epochs (following the acute reduction and for the duration of hypotension), so deriving a mean and variance of each EEG measure for each period

analysed. The timing of the median epoch in each 10-s group corresponded with an arterial pressure measurement. Tape-recorded raw EEG from our previous study [3] was replayed through the CFAM and analysed, timing of EEG samples and correlation with the remeasured MAP values being made by reference to the original chart recordings. The statistical distribution of each variable was assessed before applying appropriate parametric or non-parametric tests. Changes in the 15 EEG parameters at end-tidal 1 % isoflurane after 20 min of stabilization were compared with the data obtained during the preceding 3 min of stable anaesthesia at normotension by analysis of variance, paired t tests and correlation with simultaneous MAP values. Statistical comparisons between isoflurane and the historical halothane group data were not undertaken. RESULTS

There was no significant difference in age, preoperative MAP, steady state MAP before induction of hypotension, or rate of reduction in MAP with TMP in the patients receiving isoflurane in the present study (isoflurane patients) and those receiving 0.5% halothane in our previous study [3] (halothane patients). Six of the halothane patients and all of the isoflurane patients required (3-block. The target MAP was reached in 5.4 (SD 4.5) min after starting TMP in the isoflurane patients, but at 9.1 (7.9) min in the halothane patients. Two isoflurane patients and six halothane patients did not reach 40 mm Hg MAP and two (isoflurane) momentarily overshot this value; MAP returned to 40 mm Hg within 5 min after stopping TMP and infusing colloid. Hypotension was maintained for an average of 83 (34.4) min in the isoflurane patients and for 70 (14) min in the halothane patients. There were no disturbances of cardiac rhythm and no ischaemic changes in the ECG of any patient. The maximum reduction in oesophageal temperature was 0.6 °(f; the lowest temperature recorded was 36.1 °C. Electroencephalogram

In the steady state, before induction of hypotension, there were significant differences in all the EEG amplitude measures between isoflurane and halothane patients, comparable to those seen

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isoflurane was substituted for 0.5% halothane. This concentration of isoflurane was chosen because it produced a stable continuous EEG pattern for long periods and was not associated with clinically significant cardiovascular depression [8]. A period of 20 min stabilization preceded neurophysiological measurements. Hypotension was,- induced with 0.2% trimetaphan camsylate (TMP) in 5 % glucose, to a target MAP of 40 mm Hg. Practolol was given in 5-mg increments if MAP failed to reach 40 mm Hg or if the heart rate exceeded 80 beat min"1. When clinically indicated, TMP was stopped and the arterial pressure allowed to increase.

BRITISH JOURNAL OF ANAESTHESIA

ISOFLURANE V. HALOTHANE DURING INDUCED HYPOTENSION

There was no significant correlation between acutely declining MAP and any EEG amplitude or frequency measure in the isoflurane patients, but a significant correlation in four halothane patients. In the former, the group mean amplitude did not change with the decline in MAP, whereas in the latter it decreased when MAP reached 60 mm Hg (fig. 1). Data from the two isoflurane patients who briefly overshot the target show that at MAP less than 40 mm Hg there was a decline in the amplitude of the EEG comparable to that seen at 60 mm Hg with halothane. In the 5 min following the acute hypotension, group mean EEG amplitude and frequency data in isoflurane patients showed no significant difference from the control data obtained before induction of hypotension. Comparable data were not available for analysis from the halothane patients. By the end of the period of hypotension (mean of 95.4 (27.6) min) all isoflurane patients showed a slight decline in mean amplitude of the EEG (group mean decrease 0.7 (0.66) uV—a 3.54% decrease from baseline values). This could not be correlated with age, lowest MAP, percentage acute reduction in MAP, dose of TMP, duration of hypotension or rate of decrease in MAP, although the two patients with the largest overall decrease in mean amplitude (6.3% and 4.7%) had the greatest rates of decrease in MAP. At the end of surgery, isoflurane patients awoke rapidly (mean time of anaesthesia 126.7

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FIG. 1. Group mean percentage change (1 SEM) in mean amplitude of CFAM trace at median points of 5-mm Hg MAP steps during TMP-induced hypotension in 10 patients (227 measurement points) receiving isoflurane ( 9 ) and 10 patients (189 measurement points) receiving halothane (O) [3]. C = Control.

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in our preliminary anaesthetic study [8], except for a slightly lower amplitude with halothane. In isoflurane patients, during the acute reduction in arterial pressure, the group average mean EEG amplitude decreased by 0.32 (0.05)%. Of the 10 patients, six had a reduction in mean amplitude of 0.3-3.8% and four had an increase of 0.71-2.92%. Thus, during the period in which the group MAP decreased by 28-52%, the greatest reduction in mean EEG amplitude in any individual isoflurane patient was 3.2% (from 82.3 to 79.7 CFAM units). Analysis of variance showed that there were no significant changes in any of the group average amplitude or frequency measures and at no time was burst suppression pattern observed. In the halothane patients, during the acute reduction in arterial pressure, the group average mean EEG amplitude decreased by 14%. There were significant changes in all group average amplitude measures, but none in frequency. Each of the 10 halothane patients exhibited a reduction in mean amplitude of 4.2-36%. During the period in which the group MAP decreased by 20-54 %, the greatest reduction in mean EEG amplitude in an individual patient was 36 % (from 45.4 to 29.0 CFAM units) and the smallest was 4.2% (from 57.5 to 55.1 CFAM units). In the two patients with the greatest decline in mean EEG amplitude, short periods of suppression (0.29-1.78% of time) were seen as MAP reached lowest values.

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These findings are supported by recent reports, in patients during carotid artery surgery, that EEG deterioration occurred at a lower regional CBF with light isoflurane anaesthesia compared with halothane or enflurane [6, 7]. Although we did not measure cardiac output, it probably decreased DISCUSSION after administration of TMP and (3-blocking Cerebral blood flow may diminish when induced drugs [10]. The difference in cardiac output hypotension reaches an individual threshold of between patients at 0.66 MAC halothane and arterial pressure; this reduction can be correlated those at 0.87 MAC isoflurane is unlikely to be with the mean amplitude of the EEG measured by large [11]. Moreover, neither isoflurane (up to the cerebral function monitor [2]. Cerebral 1.1 MAC) nor halothane (up to 0.6 MAC) ischaemia occurs if CBF decreases to less than a increases CBF in normocapnic, normotensive critical value and the earliest signs are short patients [11]. Therefore, the findings in patients periods of electrical silence on the EEG. One anaesthetized with isoflurane are unlikely to have advantage of isoflurane at a stable concentration of been caused by selective increase in CBF or 1 % and normotension is that it is not per se preservation of cardiac output. associated with periods of EEG suppression [8], Cerebral autoregulation maintains CBF over a thus allowing neurophysiological monitoring wide range of MAP. In all the halothane patients, when there is a potential risk of ischaemia. EEG changes commenced at a mean threshold of Previous experimental and clinical studies of 60 (5.7) mm Hg [3], which is close to the pressure TMP-induced hypotension during administration at which autoregulation normally fails in of halothane have shown that there may be a normotensive man. At normocapnia, 1 MAC of reduction in cerebral perfusion and deterioration halothane abolishes cerebral autoregulation, in the EEG [2,3]. Re-analysis of the tape- although it is restored partially by reduction to recorded EEG data from our earlier investigation less than 0.5 MAC [12]. Experimental studies [3] using the CFAM has confirmed that all have shown that isoflurane produces significantly patients showed some degree of deterioration less impairment of cerebral autoregulation than during the acute reduction in MAP, and in the MAC equivalents of halothane [13]. The two patients with the most severe amplitude threshold below which CBF becomes pressure decline, short periods of suppression of all EEG dependent is influenced by several factors: rate of activity appeared de novo. Periods of suppression and method used to induce hypotension [14]; preare not typical of uncomplicated halothane an- vious arterial pressure [15]; age of the patient and aesthesia [8]. In contrast, the present investigation rate of decrease in MAP. Whilst preservation of has shown that with 1 % isoflurane there was no autoregulation by isoflurane might account for the deterioration in the EEG and, specifically, no maintenance of the EEG at MAP 50-60 mm Hg, period of EEG suppression during a similar acute it would be surprising if CBF had not become pressure dependent in the range 40-50 mm Hg. reduction in arterial pressure. We are aware of the difficulties inherent in Experimental studies have suggested that nitrous comparisons with historical data. However, our oxide exaggerates the increase in CBF during previous assessment of the data from halothane both isoflurane and halothane anaesthesia [16], patients [3] had suggested that there was a but nitrous oxide was administered at equal MAC theoretical risk to patients from a combination of in both groups of patients and thus should not halothane and TMP in the presence of hypo- have biased the outcome. tension, and it was considered ethically unacCerebral protection from global ischaemia has ceptable to repeat the study. In the present study, been claimed using isoflurane in an experimental there was only a minimal, non-significant, decline model [5] and using thiopentone during cardiac in EEG amplitude in only six of 10 isoflurane surgery in man [17]. In both investigations, patients, in contrast with the major decline in all however, the presumed protective agents were halothane patients. This suggests that the balance given in doses sufficient to suppress partially the of cerebral oxygen supply and demand is spontaneous EEG, at which point the pharmamaintained during TMP-induced hypotension cological reduction in CMRo2 is maximal. Howwhen the background anaesthetic is isoflurane. ever, the dose-response curve of reduction in (54.6) min, mean time to recovery 10.7 (5.6) min). There was no neurological deficit in any patient after isoflurane or halothane anaesthesia.

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ISOFLURANE V. HALOTHANE DURING INDUCED HYPOTENSION

We have shown that light isoflurane anaesthesia prevented EEG depression which occurred in all patients with halothane anaesthesia during TMPinduced hypotension. Light anaesthesia avoids profound circulatory depression and allows the use of more rapidly controllable hypotensive drugs. Furthermore, preservation of the spontaneous EEG, in particular avoidance of periods of EEG suppression, allows continuous neurophysiological monitoring.

ACKNOWLEDGEMENT We 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).

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CMRo2 with increasing concentrations of volatile agent is not linear [18]. In dogs, the greatest rate of decline in CMRo2 occurs when the EEG changes from an awake to an "anaesthetic" pattern, which occurred at 0.72 MAC for halothane and at 0.47 MAC for isoflurane [18]. End-tidal 1 % isoflurane (0.74 MAC) was associated with a 30% decline in CMRo2, whereas with end-tidal 0.61% halothane (0.7 MAC), the reduction was only 5-10% [18]. Up to 75% of the possible CMRo2 reduction from isoflurane is achieved by administering less than 1 MAC. Light isoflurane anaesthesia (insufficient to produce burst suppression activity and comparable to that in the present study) during carotid artery surgery has been reported as being associated with fewer ischaemic events in the EEG and considered to offer a degree of cerebral protection from transient incomplete regional cerebral ischaemia [6, 7]. Isoflurane, in both feline and rodent models, has been shown to be a more potent metabolic depressant than halothane at equal MAC concentrations [13, 19] and, in the rat, is associated with a relatively greater depression of neocortical CBF [20]. In our preliminary anaesthetic study [8], the EEG conformed to an anaesthetic pattern (decrease in faster and increase in slower activities) at much lower MAC equivalent concentrations of isoflurane than of halothane. In both animal and human studies of isoflurane-induced hypotension [21-23], CBF appeared to be maintained despite a reduction in MAP (except in one study when it decreased). Furthermore, using isoflurane to induce prolonged hypotension to either 40 or 50 mm Hg MAP did not result in any deterioration of cerebral energy stores in an animal model [21]. If these experimental studies are applicable to man, a more profound reduction in CMROj by light isoflurane anaesthesia (compared with other volatile agents) may be responsible for the maintenance of adequate cerebral oxygenation.

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Isoflurane prevents EEG depression during trimetaphan-induced hypotension in man.

We have studied the EEG analysed with the cerebral function analysing monitor (CFAM) during trimetaphan (TMP)-induced hypotension to a mean arterial p...
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