Department of Anaesthetics and Intensive Care, Division of Surgery, Anaesthetics and Intensive Care, Faculty of Medicine, Imperial College, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK*Corresponding author
Accepted for publication: March 28, 2002
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Abstract |
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Methods. We compared the auditory evoked responses (AER) in these patients with those in a group of 20 patients who were not given midazolam.
Results. LOC, as defined by a loss of response to verbal command and eyelash reflex, occurred after 113 (95% CI, 99131) s in the control group and 75 (56101) s in the midazolam group (P<0.05). In the control group 2.3 (2.02.6) mg kg1 propofol caused LOC compared with 1.3 (1.11.5) mg kg1 in the group pretreated with midazolam (P<0.001). Pa amplitude decreased by 60% in the control group and by 54% in the midazolam group while Nb latency increased by 24% in the control group and by 32% in the midazolam group following LOC. These differences were not significant.
Conclusions. We confirmed that coinduction of anaesthesia with midazolam and propofol reduces the requirement of propofol. We also demonstrated that the AER reflects anaesthetic depth rather than plasma concentrations of anaesthetic drugs.
Br J Anaesth 2002; 89: 3257
Keywords: anaesthetics i.v., propofol; antagonists benzodiazepine, midazolam; brain, evoked potentials; monitoring, evoked potentials
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Introduction |
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Methods and results |
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The EEG was recorded continuously throughout the study period from silversilver chloride cup electrodes attached to the scalp at the vertex and inion using collodion glue. The auditory stimulus, a rarefaction click stimulus at 6 s1, was delivered to each ear simultaneously through close fitting ear pieces at 75 dB above the average hearing threshold. The EEG signal was analogue filtered with a bandwidth of 0.5400 Hz and digitized at a 5 kHz sample rate. The signal was subsequently digitally filtered with a 400 Hz low pass filter and down sampled to 1 Hz before being saved onto the hard disk of a portable computer. After each study, blocks of AER data representing 5121024 sweeps (80160 s of EEG data), were signal averaged to extract the AER. This was further filtered using a 25 Hz high pass filter and three point smoothing.
For each patient, two AER waveforms were printed out and analysed, one corresponding to the awake period before starting the midazolam or saline and the other corresponding to the post-LOC period. The awake AER data were used as the baseline against which to compare the AER data after LOC because steady state conditions would be more likely to apply to the awake state. For each patient the Pa amplitudes and Nb latencies were measured. The data were log transformed and were tested using Students t-test. For changes in these variables from awake to post-LOC we used paired t-tests and for differences in these changes between the midazolam and saline control groups we used unpaired t-tests. When the results were transformed back, the differences from awake to anaesthesia were presented as percentage changes.
The groups appeared to be well matched. After starting the propofol TCI, LOC occurred significantly sooner in the midazolam group, and significantly less propofol was needed (Table 1). Pa amplitude decreased and Nb latency increased (P<0.001) from the awake to the post-LOC period in both groups, but there were no significant differences between the groups.
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Comment |
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We have shown that the AER can be used to measure anaesthetic depth, and that decreases in Pa amplitude and increases in Nb latency can be related to plasma or end tidal concentrations of various anaesthetic vapours and i.v. anaesthetic drugs.2 We have also shown that LOC after midazolam alone causes an increase in Nb latency with no effect on Pa amplitude.3 We have not studied the AER in patients anaesthetized with combinations of i.v. anaesthetic drugs. In this study, patients lost consciousness after different amounts of both propofol and midazolam. Despite this, the changes in the AER following LOC were similar in the two groups i.e. a decrease of 60% for Pa amplitude in the saline group compared with 54% in the midazolam group, and an increase of 24% for Nb latency in the saline group compared with 32% in the midazolam group. In other words the AER could not show which drugs a particular patient had received. (This study could have detected a difference of 84% between the saline and midazolam groups in Pa amplitude (not very sensitive for this variable) and 20% in Nb latency in the changes from awake to post-LOC, with a power of 80% and a probability of P<0.05.)
Because less propofol was used in the midazolam group, we expected to see a marked difference in the AER with less of a decrease in Pa amplitude. This is because the change in the AER, and in particular Pa amplitude, is relatively unaffected after midazolam. It is clear that the AER in this study reflected the clinical signs of LOC and not the dose of propofol used. In the absence of midazolam, the AER reflects not only clinical signs of LOC but can be related to the concentration of anaesthetic drugs as well.2 This study supports previous studies when we have demonstrated that the AER reflects anaesthetic depth.
Midazolam and propofol are both thought to act on GABAA receptors.5 Midazolam potentiates the actions of GABA at GABAA receptors with subunits. The general anaesthetics also potentiate the action of GABA but activate GABAA receptors directly as well, although their binding sites on the receptor are less well defined. As there was no difference in the Pa amplitude in the two groups we speculate that midazolam amplifies the effect propofol has on the AER, perhaps by interaction at the GABAA receptor.
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References |
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2 Thornton C. Evoked potentials in anaesthesia. Eur J Anaesthesiol 1991; 8: 89107[ISI][Medline]
3 Brunner MD, Umo-Etuk J, Sharpe RM, Thornton C. Effect of a bolus dose of midazolam on the auditory evoked response in humans. Br J Anaesth 1999; 82: 6334
4 Tzabar Y, Brydon C, Gillies GWA. Induction of anaesthesia with midazolam and a target-controlled propofol infusion. Anaesthesia 1996; 51: 5368[ISI][Medline]
5 Jones MV, Harrison NL, Pritchett DB, Hales TG. Modulation of the GABAA receptor by propofol is independent of the gamma subunit. J Pharmacol Exp Ther 1995; 274: 9628[Abstract]