1Department of Anesthesiology, University Hospital of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands. 2Department of Anesthesiology, University Medical Centre Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands*Corresponding author
Accepted for publication: November 9, 2000
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Abstract |
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Br J Anaesth 2001; 86: 35460
Keywords: brain, electroencephalography; anaesthesia, depth; anaesthetics i.v., thiopental; anaesthetics i.v., propofol; anaesthetics i.v., etomidate; hypnotics benzodiazepine, midazolam; anaesthetics volatile, sevoflurane
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Introduction |
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We therefore studied the behaviour of four different EEG effect variables during slow induction of anaesthesia with thiopental, propofol, etomidate, midazolam, or sevoflurane with the aims of determining whether a biphasic EEG response was present, and to assess the time to the maximum EEG effect, the times of loss of consciousness, and the relationship between these variables for each study drug. The following variables were analysed: EEG amplitude in two frequency bands, spectral edge frequency 95%, and the bispectral index (BIS), a proprietary composite EEG effect variable designed to have no biphasic response pattern.
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Patients and methods |
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After arrival in the anaesthetic room, an i.v. cannula was inserted and 0.9% saline 500 ml was infused rapidly for fluid loading. Patients were monitored with a three-lead ECG, SpO2, and non-invasive arterial pressure measurements performed at 1-min intervals.
Each experiment took place before the start of surgery and lasted 15 min. The study period was divided into a 3 min baseline EEG recording, a 10 min duration EEG recording during study drug administration, and was followed by a 2 min EEG recording without drug administration. The calculation of the dose body weight, corrected for height, was: height (cm)100=kg body weight. The patients were randomly assigned to one of five groups to receive a 10 min constant rate infusion of thiopental 1 mg kg1 min1, propofol 0.5 mg kg1 min1, etomidate 0.06 mg kg1 min1, midazolam 0.03 mg kg1 min1, or sevoflurane in oxygen enriched air administered by a circle system with a fresh gas flow of 9 litre min1 and facemask. The sevoflurane concentration of the fresh gas was initially set at 2% and increased every minute by an additional 2% to a maximum of 8%. The last concentration was maintained for a further 7 min. With this dosing regimen we aimed to induce a steadily increasing blood and CNS concentration (Fig. 1).
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EEG was recorded from Cz-Fpz and the M2 (right mastoid)-Fpz2 with an electrode placed between Fpz and Fpz2 as reference. All signals were recorded with the patients in the supine position and eyes closed. The analogue EEG was recorded using the pre-amplifiers of the Lifescan EEG monitor and stored on tape for off-line analysis. For calculation of EEG amplitude in the 05 and 1120 Hz band we used aperiodic analysis7 (Lifescan, software version 4.3, Diatek, San Diego, CA, USA). For calculation of BIS8 and spectral edge frequency 95% (SEF95) values we used the Aspect A-1000 EEG monitor (BIS version 3.12: Aspect Medical Systems Inc., Natick, MA, USA). EEG amplitudes in the two frequency bands were calculated from 10-s epochs. Epochs containing an EEG amplitude greater than 30 µV in the 2530 Hz band were considered to contain too many artefacts and were rejected. The Aspect A1000 low pass filter was set at 30 Hz, the high pass filter was set to 2 Hz. Periods containing artefacts, as indicated by the Aspect A1000 were rejected. Spectral edge smoothing was set at 10 s and BIS smoothing at 15 s. No correction was made for the internal 60 s smoothing of the BIS 3.12. Thus, amplitude and SEF95 data represent EEG data of the preceding 10 s. BIS data represent data from the preceding 75 s.
Responsiveness was determined by testing the response of the patient to simple commands from a pre-recorded tape (raise your thumb, spread your fingers, and clench your fist), given by headphones every 30 s. The first time that the patient did not respond to a verbal command was registered as the time of loss of responsiveness (LR). The times of LR were related to the values of the EEG derived variables recorded at that moment.
Definitions and statistical analysis
The EEG response to increasing blood concentrations was considered biphasic if after the start of the drug administration the EEG effect variable increased at least 2 SD above baseline value and, thereafter, decreased 20% below that maximum value.
The patient was supposed to have lost consciousness at the moment of the maximum change of the EEG variable if the moment of LR was less than 30 s different from it.
Data are presented as median and range. EEG data were compared using the Kruskal-Wallis test. P<0.05 was considered significant.
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Results |
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The EEG amplitude in both frequency bands and SEF95 showed biphasic effects for all drugs except midazolam. The BIS value decreased for all drugs (Table 2, Figs 2 and 3).
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Discussion |
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One explanation for the absence of a consistent correlation between the time to loss of consciousness and the value of the EEG effect variable or the time to peak EEG effect for the five drugs might be the biphasic response of the EEG variables to increasing blood concentrations. Such a biphasic response may be the result of simultaneous drug effects both on systems that cause EEG activation and on systems that cause EEG suppression. At lower concentrations, activation is more pronounced than suppression, which results in an increase of amplitude at higher frequencies. At higher concentrations the suppression becomes more evident which results in a decrease of amplitude at higher frequencies and eventually in a decrease of EEG amplitude at lower frequencies. All five drugs suppress consciousness in a dose dependent way. Midazolam does not induce a biphasic EEG response and consciousness was lost before maximal beta activity was reached. With the other drugs one might expect that consciousness would be lost when EEG activity was still increasing in a similar way to midazolam. However, EEG suppression at low concentrations might have counteracted the activation to such an extent that EEG activity had already started to decrease before consciousness was lost. As all drugs have different chemical structures it is likely that there will be differences in the balance of effects on activation and suppression. Therefore, such differences will result in differences in EEG effects at the moment of loss of consciousness.
BIS has been used successfully as an indicator of the level of sedation and hypnosis.17 18 In the present study we observed that consciousness in the sevoflurane group was lost at higher BIS values than in the other groups (Table 2). This might be caused by the steep decrease in BIS during induction. As a result of the long period over which BIS 3.12 calculates its value, for example, 60+15 s smoothing, the actual BIS value will be overestimated if BIS decreases rapidly. More recent software versions with a shorter calculation epoch may overcome this problem. Another explanation for the higher BIS values observed at the time of LR might be because of the non-specific mechanism of action of sevoflurane inducing loss of consciousness at lower levels of cortical suppression. In a study in which semi-steady state concentrations of sevoflurane were applied,4 a method that will effectively eliminate averaging effects, the average BIS for preventing response to verbal command was 73. This value is similar to the values found for midazolam, thiopental, propofol, and etomidate in our study. This finding makes the first explanation for the higher BIS values at loss of responsiveness for sevoflurane more likely.
A drawback of the present study is the lack of EEG data during return of consciousness. EEG values at return of consciousness might be different from the EEG values at loss of consciousness and variability might be less. More gradual concentration changes during emergence from anaesthesia will decrease inaccuracy in determination of EEG effect and the determination of the moment of return of consciousness will be less critical. However, other investigators19 have already indicated that during repeated transitions from unconsciousness to consciousness as the result of repeated interruptions of propofol administration to patients under spinal analgesia, neither SEF95 nor BIS are accurate indicators of imminent awareness.
We conclude that thiopental, propofol, etomidate, and sevoflurane, but not midazolam induce biphasic EEG effects during the transition from consciousness to unconsciousness. There is no consistent time relationship between the peak EEG effect and the moment of LR. In the BIS algorithm, the biphasic response has been linearized effectively, resulting in a progressive decrease of BIS during progressively increasing hypnotic drug concentrations. Both the large inter-subject variability in the values of EEG amplitude and spectral edge, and the relatively long averaging period of BIS, limit the applicability of these variables as markers for imminent consciousness.
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Acknowledgements |
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References |
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