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Auditory evoked response during propofol anaesthesia after pre-induction with midazolam
British Journal of Anaesthesia 89 (2): 325±7 (2002)
SHORT COMMUNICATION Auditory evoked response during propofol anaesthesia after pre-induction with midazolam M. D. Brunner*, M. R. Nel, R. Fernandes, C. Thornton and D. E. F. Newton 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 Background. In clinical use, midazolam reduces the dose requirement for propofol. We studied the effect of midazolam given before anaesthesia on the amount of propofol needed and the time taken, to achieve loss of consciousness (LOC) in 20 patients. 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 de®ned by a loss of response to verbal command and eyelash re¯ex, occurred after 113 (95% CI, 99±131) s in the control group and 75 (56±101) s in the midazolam group (P<0.05). In the control group 2.3 (2.0±2.6) mg kg±1 propofol caused LOC compared with 1.3 (1.1±1.5) mg kg±1 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 signi®cant. Conclusions. We con®rmed that coinduction of anaesthesia with midazolam and propofol reduces the requirement of propofol. We also demonstrated that the AER re¯ects anaesthetic depth rather than plasma concentrations of anaesthetic drugs. Br J Anaesth 2002; 89: 325±7 Keywords: anaesthetics i.v., propofol; antagonists benzodiazepine, midazolam; brain, evoked potentials; monitoring, evoked potentials Accepted for publication: March 28, 2002
A propofol-sparing action of midazolam has been shown clinically.1 Propofol and midazolam seem to act at different sites in the g-aminobutyric acid type A (GABAA) receptor complex. They also have different effects on the waves of the early cortical auditory evoked response (AER) thought to re¯ect depth of anaesthesia. Propofol markedly reduces the amplitude of the waves Pa and increases the latency of Nb, as do other i.v. and inhalational general anaesthetic agents.2 In contrast, large doses of midazolam, which is not considered to be a general anaesthetic, are required to produce moderate reductions in Pa amplitude and increases in Nb latency.3 In view of these differences in the action of propofol and midazolam, there could be different effects on the AER if the same depth of anaesthesia is achieved using
propofol alone compared with a combination of propofol with midazolam. With propofol as the sole agent, a greater reduction in Pa amplitude and an increase in Nb latency might be expected. We have compared the AER at clinically similar depths of anaesthesia using either propofol alone or propofol with midazolam.
Methods and results The study was approved by the Harrow Research Ethics Committee and all the patients gave written informed consent. We studied 40 unpremedicated ASA I or II patients undergoing surgery requiring general anaesthesia. All the patients were aged 18±55 yr and were randomly assigned to
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2002
Brunner et al. Table 1 Means and 95% con®dence intervals for saline and midazolam groups. With the exception of age and weight, all variables in the table were log transformed for data analysis. The table shows the means and con®dence intervals for patients in the saline and midazolam groups. Note that the probability levels (S vs M) refer to the difference in the means of the saline and midazolam groups. The con®dence intervals of those differences are not shown in the table due to insuf®cient space. The means (which are the geometric means) and con®dence intervals were transformed back to the original units for display purposes. *Signi®cant difference (P<0.001) between post-LOC and awake values Saline Mean Age (yr) Weight (kg) Time to LOC (s) Total propofol to LOC (mg kg±1) AER variables Pa amplitude Awake (mv) Post-LOC (mv) Change (%) Nb latency Awake (ms) Post-LOC (ms) Change (%)
37 73 113 2.3
Midazolam 95% CI
Mean
Probability 95% CI
(S vs M)
32±41 66±79 99±131 2.0±2.6
39 76 75 1.3
35±44 69±84 56±101 1.1±1.5
0.71 0.28* ±60
0.62±0.8 0.23±0.37 ±69 to ±47
0.61 0.28* ±54
0.58±0.65 0.26±0.31 ±66 to ±35
ns ns ns
43.5 54.2* 24
41.7±45.4 50.3±58.2 13±37
43.8 58.1* 32
42.2±44.2 53.6±62.9 21±46
ns ns ns
one of two groups. Patients in group M (n=20), received i.v. midazolam 0.1 mg kg±1, while those in group S (n=20) received an equivalent volume of saline. The approximate time to peak midazolam effect is 4 min.4 Therefore, 3 min after saline or midazolam, a propofol infusion was started by target-controlled infusion (TCI) using a Diprifusor set to give a target plasma concentration of 8 mg ml±1. Loss of consciousness (LOC) was de®ned as a loss of both a response to verbal command and of eyelash re¯ex, and when this occurred the TCI concentration was recorded and the infusion was set to maintain this concentration. The EEG was recorded continuously throughout the study period from silver±silver chloride cup electrodes attached to the scalp at the vertex and inion using collodion glue. The auditory stimulus, a rarefaction click stimulus at 6 s±1, was delivered to each ear simultaneously through close ®tting ear pieces at 75 dB above the average hearing threshold. The EEG signal was analogue ®ltered with a bandwidth of 0.5±400 Hz and digitized at a 5 kHz sample rate. The signal was subsequently digitally ®ltered with a 400 Hz low pass ®lter 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 512±1024 sweeps (80±160 s of EEG data), were signal averaged to extract the AER. This was further ®ltered using a 25 Hz high pass ®lter 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 Student's t-test. For
ns ns P<0.05 P<0.001
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 signi®cantly sooner in the midazolam group, and signi®cantly 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 signi®cant differences between the groups.
Comment In this study we did not wait for propofol to equilibrate at the effect site although the Diprifusor does predict what the effect site concentration is at any given time. The dose of propofol needed to cause LOC is reduced by 43% following pretreatment with midazolam 0.1 mg kg±1. This supports previous ®ndings1 where midazolam reduced the ED50 of propofol by 52%. Similarly, Tzabar and colleagues4 showed that midazolam reduced the dose of propofol needed to cause LOC. Our study differs from Tzabar and colleagues' in the following way. We showed that the amount of TCI propofol was reduced by a pre-induction dose of midazolam, whereas Tzabar and colleagues showed that the greater the dose of midazolam, the greater the proportion of people that were anaesthetized with a relatively low infusion rate of propofol. We also showed that the time to LOC was less following midazolam pretreatment. 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
326
Auditory evoked response during propofol anaesthesia
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 re¯ected the clinical signs of LOC and not the dose of propofol used. In the absence of midazolam, the AER re¯ects 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 re¯ects anaesthetic depth. Midazolam and propofol are both thought to act on GABAA receptors.5 Midazolam potentiates the actions of GABA at GABAA receptors with g 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 de®ned. As there was no difference in the Pa amplitude in the two groups we speculate that midazolam ampli®es the effect propofol has on the AER, perhaps by interaction at the GABAA receptor.
References
327
1 Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth 1992; 69: 162±7 2 Thornton C. Evoked potentials in anaesthesia. Eur J Anaesthesiol 1991; 8: 89±107 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: 633±4 4 Tzabar Y, Brydon C, Gillies GWA. Induction of anaesthesia with midazolam and a target-controlled propofol infusion. Anaesthesia 1996; 51: 536±8 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: 962±8
SHORT COMMUNICATION Auditory evoked response during propofol anaesthesia after pre-induction with midazolam M. D. Brunner*, M. R. Nel, R. Fernandes, C. Thornton and D. E. F. Newton 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 Background. In clinical use, midazolam reduces the dose requirement for propofol. We studied the effect of midazolam given before anaesthesia on the amount of propofol needed and the time taken, to achieve loss of consciousness (LOC) in 20 patients. 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 de®ned by a loss of response to verbal command and eyelash re¯ex, occurred after 113 (95% CI, 99±131) s in the control group and 75 (56±101) s in the midazolam group (P<0.05). In the control group 2.3 (2.0±2.6) mg kg±1 propofol caused LOC compared with 1.3 (1.1±1.5) mg kg±1 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 signi®cant. Conclusions. We con®rmed that coinduction of anaesthesia with midazolam and propofol reduces the requirement of propofol. We also demonstrated that the AER re¯ects anaesthetic depth rather than plasma concentrations of anaesthetic drugs. Br J Anaesth 2002; 89: 325±7 Keywords: anaesthetics i.v., propofol; antagonists benzodiazepine, midazolam; brain, evoked potentials; monitoring, evoked potentials Accepted for publication: March 28, 2002
A propofol-sparing action of midazolam has been shown clinically.1 Propofol and midazolam seem to act at different sites in the g-aminobutyric acid type A (GABAA) receptor complex. They also have different effects on the waves of the early cortical auditory evoked response (AER) thought to re¯ect depth of anaesthesia. Propofol markedly reduces the amplitude of the waves Pa and increases the latency of Nb, as do other i.v. and inhalational general anaesthetic agents.2 In contrast, large doses of midazolam, which is not considered to be a general anaesthetic, are required to produce moderate reductions in Pa amplitude and increases in Nb latency.3 In view of these differences in the action of propofol and midazolam, there could be different effects on the AER if the same depth of anaesthesia is achieved using
propofol alone compared with a combination of propofol with midazolam. With propofol as the sole agent, a greater reduction in Pa amplitude and an increase in Nb latency might be expected. We have compared the AER at clinically similar depths of anaesthesia using either propofol alone or propofol with midazolam.
Methods and results The study was approved by the Harrow Research Ethics Committee and all the patients gave written informed consent. We studied 40 unpremedicated ASA I or II patients undergoing surgery requiring general anaesthesia. All the patients were aged 18±55 yr and were randomly assigned to
Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2002
Brunner et al. Table 1 Means and 95% con®dence intervals for saline and midazolam groups. With the exception of age and weight, all variables in the table were log transformed for data analysis. The table shows the means and con®dence intervals for patients in the saline and midazolam groups. Note that the probability levels (S vs M) refer to the difference in the means of the saline and midazolam groups. The con®dence intervals of those differences are not shown in the table due to insuf®cient space. The means (which are the geometric means) and con®dence intervals were transformed back to the original units for display purposes. *Signi®cant difference (P<0.001) between post-LOC and awake values Saline Mean Age (yr) Weight (kg) Time to LOC (s) Total propofol to LOC (mg kg±1) AER variables Pa amplitude Awake (mv) Post-LOC (mv) Change (%) Nb latency Awake (ms) Post-LOC (ms) Change (%)
37 73 113 2.3
Midazolam 95% CI
Mean
Probability 95% CI
(S vs M)
32±41 66±79 99±131 2.0±2.6
39 76 75 1.3
35±44 69±84 56±101 1.1±1.5
0.71 0.28* ±60
0.62±0.8 0.23±0.37 ±69 to ±47
0.61 0.28* ±54
0.58±0.65 0.26±0.31 ±66 to ±35
ns ns ns
43.5 54.2* 24
41.7±45.4 50.3±58.2 13±37
43.8 58.1* 32
42.2±44.2 53.6±62.9 21±46
ns ns ns
one of two groups. Patients in group M (n=20), received i.v. midazolam 0.1 mg kg±1, while those in group S (n=20) received an equivalent volume of saline. The approximate time to peak midazolam effect is 4 min.4 Therefore, 3 min after saline or midazolam, a propofol infusion was started by target-controlled infusion (TCI) using a Diprifusor set to give a target plasma concentration of 8 mg ml±1. Loss of consciousness (LOC) was de®ned as a loss of both a response to verbal command and of eyelash re¯ex, and when this occurred the TCI concentration was recorded and the infusion was set to maintain this concentration. The EEG was recorded continuously throughout the study period from silver±silver chloride cup electrodes attached to the scalp at the vertex and inion using collodion glue. The auditory stimulus, a rarefaction click stimulus at 6 s±1, was delivered to each ear simultaneously through close ®tting ear pieces at 75 dB above the average hearing threshold. The EEG signal was analogue ®ltered with a bandwidth of 0.5±400 Hz and digitized at a 5 kHz sample rate. The signal was subsequently digitally ®ltered with a 400 Hz low pass ®lter 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 512±1024 sweeps (80±160 s of EEG data), were signal averaged to extract the AER. This was further ®ltered using a 25 Hz high pass ®lter 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 Student's t-test. For
ns ns P<0.05 P<0.001
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 signi®cantly sooner in the midazolam group, and signi®cantly 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 signi®cant differences between the groups.
Comment In this study we did not wait for propofol to equilibrate at the effect site although the Diprifusor does predict what the effect site concentration is at any given time. The dose of propofol needed to cause LOC is reduced by 43% following pretreatment with midazolam 0.1 mg kg±1. This supports previous ®ndings1 where midazolam reduced the ED50 of propofol by 52%. Similarly, Tzabar and colleagues4 showed that midazolam reduced the dose of propofol needed to cause LOC. Our study differs from Tzabar and colleagues' in the following way. We showed that the amount of TCI propofol was reduced by a pre-induction dose of midazolam, whereas Tzabar and colleagues showed that the greater the dose of midazolam, the greater the proportion of people that were anaesthetized with a relatively low infusion rate of propofol. We also showed that the time to LOC was less following midazolam pretreatment. 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
326
Auditory evoked response during propofol anaesthesia
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 re¯ected the clinical signs of LOC and not the dose of propofol used. In the absence of midazolam, the AER re¯ects 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 re¯ects anaesthetic depth. Midazolam and propofol are both thought to act on GABAA receptors.5 Midazolam potentiates the actions of GABA at GABAA receptors with g 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 de®ned. As there was no difference in the Pa amplitude in the two groups we speculate that midazolam ampli®es the effect propofol has on the AER, perhaps by interaction at the GABAA receptor.
References
327
1 Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth 1992; 69: 162±7 2 Thornton C. Evoked potentials in anaesthesia. Eur J Anaesthesiol 1991; 8: 89±107 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: 633±4 4 Tzabar Y, Brydon C, Gillies GWA. Induction of anaesthesia with midazolam and a target-controlled propofol infusion. Anaesthesia 1996; 51: 536±8 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: 962±8